Tuberculosis [2 ed.] 9788184485141, 818448514X

Table of contents :
Cover
Prelims_2
Chapter-01_Introduction
Chapter-02_History
Chapter-03_Epidemiology
Chapter-04_Epidemiology Global Perspective
Chapter-05_Pathology
Chapter-06_The Mycobacteria
Chapter-07_Immunology of Tuberculosis
Chapter-08_Genetic Susceptibility Parameters in Tuberculosis
Chapter-09_Genetics of Susceptibility to Tuberculosis
Chapter-10_Laboratory Diagnosis
Chapter-11_The Tuberculin Skin Test
Chapter-12_Diagnosis of Latent Tuberculosis Infection Recent Advances and Future Directions
Chapter-13_Roentgenographic Manifestations of Pulmonary Tuberculosis
Chapter-14_Pulmonary Tuberculosis
Chapter-15_Lower Lung Field Tuberculosis
Chapter-16_Endobronchial Tuberculosis
Chapter-17_Tuberculosis Pleural Effusion
Chapter-18_Silicotuberculosis
Chapter-19_Abdominal Tuberculosis
Chapter-20_Granulomatous Hepatitis
Chapter-21_Neurological Tuberculosis
Chapter-22_Tuberculosis and the Heart
Chapter-23_Skeletal Tuberculosis
Chapter-24_Musculoskeletal Manifestations of Tuberculosis
Chapter-25_Cutaneous Tuberculosis
Chapter-26_Lymph Node Tuberculosis
Chapter-27_Tuberculosis in Otorhinolaryngology
Chapter-28_Ocular Tuberculosis
Chapter-29_Breast Tuberculosis
Chapter-30_Tuberculosis in Pregnancy
Chapter-31_Female Genital Tuberculosis
Chapter-32_Genitourinary Tuberculosis
Chapter-33_Tuberculosis in Chronic Renal Failure
Chapter-34_Disseminated and Miliary Tuberculosis
Chapter-35_Complications of Pulmonary Tuberculosis
Chapter-36_Tuberculosis and Acute Lung Injury
Chapter-37_Haematological Manifestations of Tuberculosis
Chapter-38_Adrenocortical Reserve in Tuberculosis
Chapter-39_Endocrine Implications of Tuberculosis
Chapter-40_Tuberculosis and Human Immunodeficiency Virus Infection
Chapter-41_Tuberculosis in Children
Chapter-42_Diagnosis of Childhood Tuberculosis Recent Advances and Applicability of New Tools
Chapter-43_Surgical Aspects of Childhood Tuberculosis
Chapter-44_Tuberculosis in Elderly
Chapter-45_Tuberculosis in Health Care Workers
Chapter-46_Nutrition and Tuberculosis
Chapter-47_Reactivation and Reinfection Tuberculosis
Chapter-48_Nontuberculous Mycobacterial Infections
Chapter-49_Drug-Resistant Tuberculosis
Chapter-50_Antituberculosis Drug Resistance Surveillance
Chapter-51_Evolution of Chemotherapeutic Regimens in the Treatment of Tuberculosis and their Scientific Rationale
Chapter-52_Treatment of Tuberculosis
Chapter-53_Treatment of Latent Tuberculosis Infection
Chapter-54_Antituberculosis Treatment Induced Hepatotoxicity
Chapter-55_Surgery for Pleuropulmonary Tuberculosis
Chapter-56_DOTS The Strategy that Ensures Cure of Tuberculosis
Chapter-57_Directly Observed Therapy
Chapter-58_The Role of Medical Colleges in Tuberculosis Control
Chapter-59_Public-Private Mix for Tuberculosis Control
Chapter-60_Building Partnerships for Tuberculosis Control
Chapter-61_Non-Governmental Organizations and Tuberculosis Control
Chapter-62_Global Tuberculosis Control The Future Prospects
Chapter-63_The Revised National Tuberculosis Control Programmme [RNTCP]
Chapter-64_Tuberculosis Vaccine Development Current Status and Future Expectations
Chapter-65_Ethical and Legal Issues in Tuberculosis Control
Chapter-66_Tuberculosis Some Web-based Resources on the Internet
Chapter-67_International Standards for Tuberculosis Care [ISTC]
Index_2

Citation preview

Contributors i

TUBERCULOSIS

TUBERCULOSIS Second Edition

Editor SURENDRA K. SHARMA Chief, Division of Pulmonary, Critical Care and Sleep Medicine Professor and Head, Department of Medicine All India Institute of Medical Sciences New Delhi 110 029, India Assistant Editor ALLADI MOHAN Chief, Division of Pulmonary and Critical Care Medicine Professor and Head, Department of Medicine Sri Venkateswara Institute of Medical Sciences Tirupati 517 507, India

Foreword by MARIO C. RAVIGLIONE Director Stop TB Department World Health Organization Geneva, Switzerland

®

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi • Ahmedabad • Bengaluru • Chennai • Hyderabad • Kochi • Kolkata • Lucknow • Mumbai • Nagpur • St Louis (USA)

Published by Jitendar P Vij Jaypee Brothers Medical Publishers (P) Ltd Corporate Office 4838/24 Ansari Road, Daryaganj, New Delhi - 110002, India, +91-11-43574357 Registered Office B-3 EMCA House, 23/23B Ansari Road, Daryaganj, New Delhi 110 002, India Phones: +91-11-23272143, +91-11-23272703, +91-11-23282021, +91-11-23245672, Rel: +91-11-32558559 Fax: +91-11-23276490, +91-11-23245683 e-mail: [email protected], Visit our website: www.jaypeebrothers.com Branches  2/B, Akruti Society, Jodhpur Gam Road Satellite Ahmedabad 380 015 Phones: +91-79-26926233, Rel: +91-79-32988717 Fax: +91-79-26927094 e-mail: [email protected]  202 Batavia Chambers, 8 Kumara Krupa Road, Kumara Park East Bengaluru 560 001 Phones: +91-80-22285971, +91-80-22382956 +91-80-22372664, Rel: +91-80-32714073 Fax: +91-80-22281761 e-mail: [email protected]  282 IIIrd Floor, Khaleel Shirazi Estate, Fountain Plaza, Pantheon Road Chennai 600 008 Phones: +91-44-28193265, +91-44-28194897 Rel: +91-44-32972089 Fax: +91-44-28193231 e-mail: [email protected]  4-2-1067/1-3, 1st Floor, Balaji Building, Ramkote Cross Road Hyderabad 500 095 Phones: +91-40-66610020 +91-40-24758498, Rel:+91-40-32940929 Fax:+91-40-24758499 e-mail: [email protected]  No. 41/3098, B & B1, Kuruvi Building, St. Vincent Road Kochi 682 018, Kerala Phones: +91-484-4036109, +91-484-2395739 +91-484-2395740 e-mail: [email protected]  1-A Indian Mirror Street, Wellington Square Kolkata 700 013 Phones: +91-33-22651926, +91-33-22276404 +91-33-22276415 Rel: +91-33-32901926 Fax: +91-33-22656075 e-mail: [email protected]  Lekhraj Market III, B-2, Sector-4, Faizabad Road, Indira Nagar Lucknow 226 016 Phones: +91-522-3040553, +91-522-3040554 e-mail: [email protected]  106 Amit Industrial Estate, 61 Dr SS Rao Road, Near MGM Hospital, Parel Mumbai 400012 Phones: +91-22-24124863, +91-22-24104532 Rel: +91-22-32926896 Fax: +91-22-24160828 e-mail: [email protected]  “KAMALPUSHPA” 38, Reshimbag, Opp. Mohota Science College, Umred Road Nagpur 440 009 (MS) Phone: Rel: +91-712-3245220 Fax: +91-712-2704275 e-mail: [email protected] USA Office 1745, Pheasant Run Drive, Maryland Heights (Missouri), MO 63043, USA, Ph: 001-636-6279734 e-mail: [email protected], [email protected]

Tuberculosis © 2009, Editors All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the editors and the publisher. This book has been published in good faith that the material provided by contributors is original. Every effort is made to ensure accuracy of material, but the publisher, printer and editors will not be held responsible for any inadvertent error(s). In case of any dispute, all legal matters are to be settled under Delhi jurisdiction only. First Edition: 2001 Second Edition: 2009 ISBN 978-81-8448-514-1 Typeset at JPBMP typesetting unit Printed at Ajanta Press

This book is dedicated to Our Parents for their encouragement Our Teachers and Students for their inspiration Anju and Himabala for their moral support Abhishek, Animesh and Vikram Chandra for their cheerful enthusiasm

Contributors S.K. Acharya Professor and Head Department of Gastroenterology and Human Nutrition All India Institute of Medical Sciences New Delhi 110 029, India

M. Bajpai Professor Department of Paediatric Surgery All India Institute of Medical Sciences New Delhi 110 029, India

S.K. Agarwal Additional Professor Department of Nephrology All India Institute of Medical Sciences New Delhi 110 029, India

V.H. Balasangameshwara Former Chief Medical Officer National Tuberculosis Institute ‘AVALON’, No. 8, Bellary Road Bengaluru 560 003, India

A.N. Aggarwal Associate Professor Department of Pulmonary Medicine Postgraduate Institute of Medical Education and Research Chandigarh 160 012, India

Rani Balasubramanian Former Deputy Director [Senior Grade] Tuberculosis Research Center [Indian Council of Medical Research] Mayor Ramanathan Road, Chetpet Chennai 600 031, India

Praveen Aggarwal Professor Department of Emergency Medicine All India Institute of Medical Sciences New Delhi 110 029, India

Sharmistha Banerjee Lecturer Department of Biochemistry School of Life Sciences University of Hyderabad Hyderabad 500 046, India

G. Ahluwalia Professor Department of Medicine Dayanand Medical College and Hospital Ludhiana 141 001, India

S. Basu Yale University School of Medicine 367 Cedar St., New Haven Connecticut, USA

Vineet Ahuja Associate Professor Department of Gastroenterology and Human Nutrition All India Institute of Medical Sciences New Delhi 110 029, India

D. Behera Director LRS Institute of Tuberculosis and Respiratory Diseases Sri Aurobindo Marg, Mehrauli New Delhi 110 030, India

Jason Andrews Resident Physician Department of Medicine University of California San Francisco, USA

Surya Bhan Former Professor and Head Department of Orthopaedics All India Institute of Medical Sciences New Delhi 110 029, India

viii Tuberculosis Rajesh Bhatia Regional Adviser WHO Regional Office for South-East Asia WHO House IP Estate, Ring Road New Delhi 110 002, India

S. Datta Gupta Professor Department of Pathology All India Institute of Medical Sciences New Delhi 110 029, India

V.K. Chaddha Senior Epidemiologist National Tuberculosis Institute ‘AVALON’, No. 8, Bellary Road Bengaluru 560 003, India

Sajal De Vallabhbhai Patel Chest Institute University of Delhi, P.O. Box No. 2101 Delhi 110 007, India

Major A.K. Chakraborty Epidemiology Analyst “BIKALPA” # 557, 4th Block, 8th Main Koramangala, Bengaluru 560 034, India V.K. Challu National Tuberculosis Institute ‘AVALON’, No. 8, Bellary Road Bengaluru 560 003, India Abha Chandra Professor Department of Cardiovascular and Thoracic Surgery Sri Venkateswara Institute of Medical Sciences Tirupati 517 507, India L.S. Chauhan Deputy Director General TB Central TB Division Directorate General of Health Services Ministry of Health and Family Welfare Government of India New Delhi 110 011, India Rohan Chawla Dr Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of Medical Sciences New Delhi 110 029, India E. Cooreman Regional Advisor WHO Regional Office for South-East Asia Dhaka, Bangladesh

Bappaditya Dey Department of Biochemistry University of Delhi South Campus Benito Juarez Road New Delhi 110 021, India S.S. Dhillon Department of Pulmonary, Critical Care and Sleep Medicine 85 Spring Street, 3rd Floor Lakes Region General Hospital Laconia, New Hampshire 03246, USA Tania Di Pietrantonio Department of Human Genetics The Centre for the Study of Host Resistance McGill University Montreal, QC, Canada D. Dilip Professor Department of Cardiovascular and Thoracic Surgery Sri Venkateswara Institute of Medical Sciences Tirupati 517 507, India Thomas R. Frieden Commissioner, New York City Department of Health and Mental Hygiene 125 Worth Street, Room 331 New York, NY 10013, USA Caroline J. Gallant Department of Human Genetics The Centre for the Study of Host Resistance McGill University Montreal, QC, Canada

Contributors ix P.K. Garg Associate Professor Department of Gastroenterology All India Institute of Medical Sciences New Delhi 110 029, India S.P. Garg Professor Dr Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of Medical Sciences New Delhi 110 029, India Col. S.S. Gill Associate Professor Department of Pathology Armed Forces Medical College Pune 411 040, India P.C.F.M. Gondrie KNCV Tuberculosis Foundation Post Box 146, 2501CC The Hague, Holland R. Goswami Associate Professor Department of Endocrinology and Metabolism All India Institute of Medical Sciences New Delhi 110 029, India Reuben Granich Medical Officer [HIV/TB] Antiretroviral Treatment and HIV Care Department of HIV/AIDS Building D, 1st Floor, Room No. 1005 World Health Organization Geneva 27, Switzerland J.S. Guleria Former Dean, Professor and Head Department of Medicine All India Institute of Medical Sciences New Delhi 110 029, India K.K. Guntupalli Professor of Medicine Chief, Pulmonary, Critical Care and Sleep Medicine Section Baylor College of Medicine Houston TX 77030, USA

Arun K. Gupta Professor and Head Department of Radiodiagnosis All India Institute of Medical Sciences New Delhi 110 029, India Puneet Gupta Lecturer Department of Surgical Oncology Institute of Medical Sciences Banaras Hindu University Varanasi 221 005, India Nicola A. Hanania Associate Professor Department of Pulmonary and Critical Care Medicine Director, Asthma Clinical Research Baylor College of Medicine 1504 Taub Loop, Houston, Texas 77030, USA Seyed E. Hasnain Vice Chancellor University of Hyderabad Hyderabad 500 046, India A.K. Hemal Professor Department of Urology All India Institute of Medical Sciences New Delhi 110 029, India N.C. Jain Scientist F Division of Publication and Information Indian Council of Medical Research V. Ramalingaswami Bhawan, Ansari Nagar New Delhi 110 029, India Ruchi Jain Department of Biochemistry University of Delhi, South Campus Benito Juarez Road New Delhi 110 021, India V. Jain Department of Paediatric Surgery All India Institute of Medical Sciences New Delhi 110 029, India

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S.K. Jindal Professor and Head Department of Pulmonary Medicine Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India

Arvind Kumar Professor Department of Surgical Disciplines All India Institute of Medical Sciences New Delhi 110 029, India

Rajnish Joshi Department of Medicine Mahatma Gandhi Institute of Medical Sciences Sevagram, Wardha 442 102, India

Ashok Kumar Professor Department of Medicine All India Institute of Medical Sciences New Delhi 110 029, India

S.K. Kabra Additional Professor Department of Paediatrics All India Institute of Medical Sciences New Delhi 110 029, India S.P. Kalantri Professor Department of Medicine Mahatma Gandhi Institute of Medical Sciences Sevagram, Wardha 442 102, India D.R. Karnad Professor and Chief Medical - Neuro Intensive Care Unit Department of Medicine Seth G.S. Medical College and K.E.M. Hospital Parel, Mumbai 400 012, India V.M. Katoch Secretary, Department of Health Research Ministry of Health and Family Welfare Government of India, and Director General Indian Council of Medical Research New Delhi 110 029, India N. Kochupillai Former Professor and Head Department of Endocrinology and Metabolism All India Institute of Medical Sciences New Delhi 110 029, India S.S. Kothari Professor Department of Cardiology All India Institute of Medical Sciences New Delhi 110 029, India

Shaji Kumar Associate Professor Division of Hematology, Mayo Clinic 200 First Street SW Rochester, MN 55906, USA Subirendra Kumar Former Associate Professor Department of Otorhinolaryngology and Head and Neck Surgery All India Institute of Medical Sciences New Delhi 110 029, India Sunesh Kumar Professor Department of Obstetrics and Gynecology All India Institute of Medical Sciences New Delhi 110 029, India J. Kumaresan Executive Secretary Stop TB Secretariat, World Health Organization Geneva 27, Switzerland Rakesh Lodha Assistant Professor Department of Paediatrics All India Institute of Medical Sciences New Delhi 110 029, India Knut Lonnroth Medical Officer, TB Strategy and Health Systems Stop TB Department World Health Organization Geneva 27, Switzerland

Contributors xi A.N. Malaviya Consultant Rheumatologist A&R Clinic and Visiting Senior Consultant Rheumatologist Indian Spinal Injuries Centre [ISIC] Superspeciality Hospital New Delhi 110 070, India Ben J. Marais Professor Department of Pediatrics and Child Health Faculty of Health Sciences Stellenbosch University, South Africa D.S. Maru Yale University School of Medicine 367 Cedar St. New Haven Connecticut, USA P.S. Mathuranath Department of Neurology Sree Chitra Tirunal Institute for Medical Sciences and Technology Trivandrum 695 011, India N.K. Mehra Professor and Head Department of Transplant Immunology and Immunogenetics All India Institute of Medical Sciences New Delhi 110 029, India S. Mishra Department of Endocrinology All India Institute of Medical Sciences New Delhi 110 029, India D.K. Mitra Associate Professor Department of Transplant Immunology and Immunogenetics All India Institute of Medical Sciences New Delhi 110 029, India Alladi Mohan Chief, Division of Pulmonary and Critical Care Medicine Professor and Head, Department of Medicine Sri Venkateswara Institute of Medical Sciences Tirupati 517 507, India

T. Mohan Kumar Senior Consultant Pulmonologist Sri Ramakrishnan Hospital, Sarojini Naidu Street Avarampalayam, Coimbatore 641 044, India Sima Mukhopadhyay Former Professor and Head Department of Radiodiagnosis All India Institute of Medical Sciences New Delhi 110 029, India H.L. Nag Additional Professor Department of Orthopaedics All India Institute of Medical Sciences New Delhi 110 029, India Nani Nair Regional Adviser – Tuberculosis WHO Regional Office for South-East Asia World Health House, IP Estate Mahatma Gandhi Marg New Delhi 110 002, India J.P. Narain Director, Department of Communicable Diseases WHO Regional Office for South-East Asia World Health House, IP Estate Mahatma Gandhi Marg New Delhi 110 002, India Sujatha Narayanan Deputy Director, Department of Immunology Tuberculosis Research Centre Mayor V.R. Ramanathan Road, Chetpet Chennai 600 031, India L.M. Nath Former Professor and Head Centre for Community Medicine All India Institute of Medical Sciences New Delhi 110 029, India C.B. Ogbunugafor Yale University School of Medicine 367 Cedar St., New Haven Connecticut, USA

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Madhukar Pai Assistant Professor Department of Epidemiology, Biostatistics and Occupational Health McGill University 1020 Pine Avenue West Montreal Canada H3A1A2 Myo Paing National Programme Officer WHO Country Office Myanmar C.N. Paramasivan Project Manager Tuberculosis – Laboratory Aspects Foundation For Innovative New Diagnostics [FIND] 71, av. Lovis Casaï, P.O. Box 93 CH-1216 Cointrin/Geneva Switzerland John Porter Professor of International Health and Public Health and Policy Department of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine Keppel Street London WC1E7HT, UK G.A. Prasad Assistant Professor Division of Gastroenterolgy and Hepatology Mayo Clinic, College of Medicine Rochester, MN 55906, USA K. Radhakrishnan Senior Professor and Head Department of Neurology Sree Chitra Tirunal Institute for Medical Sciences and Technology Trivandrum 695 011, India A.K. Rai Department of Transplant Immunology and Immunogenetics All India Institute of Medical Sciences New Delhi 110 029, India

Rajeswari Ramachandran Former Deputy Director Tuberculosis Research Centre [Indian Council of Medical Research] Mayor V.R. Ramanathan Road, Chetpet Chennai 600 031, India M. Ramam Additional Professor Department of Dermatology and Venereology All India Institute of Medical Sciences New Delhi 110 029, India Ruma Ray Professor Department of Pathology All India Institute of Medical Sciences New Delhi 110 029, India A. Roy Department of Cardiology All India Institute of Medical Sciences New Delhi 110 029, India B.C. Roy Department of Otorhinolaryngology and Head and Neck Surgery All India Institute of Medical Sciences New Delhi 110 029, India S.P. Sahoo Department of Surgical Oncology Institute of Medical Sciences Banaras Hindu University Varanasi 221 005, India Erwin Schurr McGill Centre for the Study of Host Resistance Department of Human Genetics McGill University, Montreal, QC, Canada Ashu Seith Associate Professor Department of Radiodiagnosis All India Institute of Medical Sciences New Delhi 110 029, India

Contributors xiii Anju Sharma Scientist E Division of Publication and Information Indian Council of Medical Research V. Ramalingaswami Bhawan, Ansari Nagar New Delhi 110 029, India S.C. Sharma Professor Department of Otorhinolaryngology and Head and Neck Surgery All India Institute of Medical Sciences New Delhi 110 029, India Surendra K. Sharma Chief, Division of Pulmonary, Critical Care and Sleep Medicine Professor and Head, Department of Medicine All India Institute of Medical Sciences New Delhi 110 029, India H.S. Shukla Former Professor and Head Department of Surgical Oncology Institute of Medical Sciences Banaras Hindu University Varanasi 221 005, India Noman Siddiqi Director, ABSL3 Department of Immunology and Infectious Diseases SPH1, Room No. 906 Harvard School of Public Health 665 Huntington Avenue Boston MA 02445, USA

Ramnath Subbaraman Resident Physician Department of Medicine, University of California San Francisco, USA R.K. Tandon Senior Consultant Gastroenterologist Pushpawati Singhania Research Institute New Delhi 110 017, India M. Tewari Lecturer Department of Surgical Oncology Institute of Medical Sciences Banaras Hindu University Varanasi 221 005, India Srikanth Tripathy Scientist F National AIDS Research Institute [Indian Council of Medical Research] Plot No. 73, Block G, MIDC Complex Bhosari, Pune 411 026, India Anil K. Tyagi Professor Department of Biochemistry University of Delhi, South Campus Benito Juarez Road New Delhi 110 021, India Mukund Uplekar Medical Officer TB Strategy and Health Systems Stop TB Department, World Health Organization Geneva 27, Switzerland

Meenakshi Singh Department of Transplant Immunology and Immunogenetics All India Institute of Medical Sciences New Delhi 110 029, India

M. van Cleeff KNCV Tuberculosis Foundation Post Box 146, 2501CC The Hague, Holland

Ian Smith Adviser to the Director-General WHO World Health Organization Geneva 27, Switzerland

J. Veen KNCV Tuberculosis Foundation Post box 146, 2501CC, The Hague Holland

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Pradeep Venkatesh Associate Professor Dr Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of Medical Sciences New Delhi 110 029, India V.K. Vijayan Director Vallabhbhai Patel Chest Institute University of Delhi P.O. Box No. 2101 Delhi 110 007, India

D. Fraser Wares Medical Officer – Tuberculosis WHO Country Office for India Shri Ram Bharatiya Kala Kendra 1, Copernicus Marg, 5th Floor Near Mandi House New Delhi 110 001, India W.W. Yew Chief, Tuberculosis and Chest Unit Grantham Hospital Hong Kong, China

Foreword Rarely has any epidemic tormented the humankind with the tenacity and destructive impact of tuberculosis [TB]. While TB never disappeared from the developing world, it re-emerged globally from the oblivion and has resurged with a vengeance with the advent of the global pandemic of human immunodeficiency virus [HIV] infection in the 1980s. Additionally, in the new millennium, TB, especially in the multidrug-resistant [MDR] and extensively drug resistant [XDR] forms, continues to haunt us as a dark reminder from the past. Indeed, TB still constitutes a social, economic and political threat set to impede development of entire populations. The war between human race and Mycobacterium tuberculosis is far from over and the relentless fight against this ancient scourge is still going on globally. During the last decade, the realization that mere availability of drugs, which became available starting in the 1940s, was not enough to cure, control and eliminate TB has led to the establishment of the DOTS strategy. The DOTS is a five-element approach including: governmental commitment; bacteriological diagnosis; standardized treatment with supervision; an effective drug supply system; and monitoring and evaluation of programme performance. DOTS, which has been promoted by the World Health Organization [WHO] starting in 1995 as the most cost-effective strategy currently available to conquer this scourge, has taken firm roots in the national TB control programmes world over with virtually all countries implementing it. The Millennium Development Goals set by the United Nations for 2015 include, under Goal 6, target 8 which calls for halting and beginning to reverse the incidence of TB. The Stop TB Partnership, additionally, set the ambitious targets to halve TB prevalence and deaths by 2015, compared to 1990. To achieve these targets, WHO has defined a new Stop TB strategy endorsed by the World Health Assembly in 2007, that addresses current challenges preventing progress towards TB elimination and emphasizes the importance of individual care besides confirming a sound public health approach to TB control. Such strategy begins with reiteration that quality DOTS and proper implementation of its essential elements are the sine-qua-non for TB control. The strategy also explicitly recognizes that HIV-associated TB, multidrug- resistant TB, and other special challenges must be addressed with additional interventions. It defines that contributing to health system strengthening is a concern of TB control implementers. It clearly acknowledges that the non-state, private sector has to be engaged fully if TB control is to be achieved in any community, and it promotes The International Standards for TB Care [ISTC], developed to facilitate the effective engagement of all care providers, public as well as private in delivering high-quality care to patients with TB. It also provides the basis for empowerment of communities as a key step to effective delivery of care and broad, grassroots mobilization. It finally emphasizes the urgent need for research, both basic, to develop new more effective tools, and operational, to optimize use of current ones. In this scenario, the publication of the second edition of “Tuberculosis” by Professor S.K. Sharma is indeed a welcome and extremely useful addition to the literature on TB. Keeping with the spirit of providing a comprehensive first-hand account regarding all aspects of TB from that part of the world where it is a crisis, with which the first edition was conceived eight years ago, the thoroughly and extensively revised, rewritten and updated second edition has contributions from leading experts on TB from India and all over the world. This comprehensive, well-referenced textbook which contains a wealth of information and is richly illustrated with clinical and gross pathology specimen photographs and photomicrographs, provides a perfect blend between the remarkable advances in the molecular pathogenesis, laboratory diagnosis, the latest innovations in terms of medical and surgical management and global efforts for TB control. The book also contains useful internet links for obtaining the latest updated information regarding various guidelines that are published periodically by international bodies such as the WHO, American Thoracic Society [ATS], U.S. Centers for Disease Control and Prevention [CDC], Infectious Diseases Society of America

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[IDSA], National Institute for Health and Clinical Excellence [NICE], European Respiratory Society [ERS], and the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India, among others. Undergraduate and postgraduate medical students, clinicians, practitioners, nurses, paramedical personnel and health authorities caring for patients with TB should find this book to be a valuable asset and source of information. The book deserves a place in the shelves of every medical college library. It is my fond hope that Professor Sharma’s “Tuberculosis” will be a useful companion for all those involved in the fight against TB. Mario C. Raviglione M.D. Director Stop TB Department World Health Organization Geneva, Switzerland

Preface to the Second Edition Welcome to the second edition of “Tuberculosis”! In 2001, we had brought out the first edition of “Tuberculosis”, with an aim to provide a well referenced standard textbook on tuberculosis [TB], that will chronicle the rich and vast experience of clinicians and researchers from India. The first edition was widely received by the faculty, graduate and postgraduate students, researchers and practitioners not only in India and South-East Asia, but also in several other parts of the world and the book established itself as a standard textbook on tuberculosis. The recent years have witnessed an enormous change in various aspects related to our understanding of TB. Furthermore, there were overwhelming requests for an updated version of the textbook. This prompted us to bring out the second edition. In the preface to the first edition we mentioned that we “attempted to present tuberculosis as it is seen in India”. With the second edition, we have gone one step further and have strived to bring out a textbook that provides a “global perspective” of TB. The second edition has several new contributors, all of them leading authorities, from various parts of the world. All the chapters have been thoroughly re-written and updated, many of them are by new contributors. With this edition, we have introduced a full-colour format that is easy to the readers’ eye and facilitates inclusion of several high quality clinical and gross pathology specimen photographs, radiographic images and photomicrographs for the readers’ convenience. The recent years have witnessed several spectacular advances in TB research. Our understanding of the hostpathogen interaction at the molecular level, especially, immunology and immunopathogenesis of TB has improved enormously and this has led to the development of several new drug and vaccine candidates. We have also witnessed exciting developments, such as the interferon-gamma release assays [IGRAs] for latent TB infection, use of liquid culture and molecular method of diagnosis ushering in a new era in TB diagnostics. Furthermore, issues concerning quality assurance in antituberculosis drug susceptibility testing are getting established. We have accumulated over a decade of experience with DOTS strategy. The global efforts to contain and eventually eliminate TB are still ongoing. The recent guidelines issued by the World Health Organization [WHO] for the treatment of TB under national programmes, drug-resistant tuberculosis, management of human immunodeficiency virus- [HIV-] TB coinfection; new Stop-TB strategy; and International Standards for Tuberculosis Care have all been brought out. Data are rapidly accumulating from all over the world regarding the efficacy of standardized treatment regimens for drug-sensitive, drug-resistant TB and latent TB infection. Several innovative strategies such as ‘public-private mix’, involvement of medical colleges in TB control, have entrenched themselves as useful measures to contain TB. While we were coming to terms to tackle the menace of multidrug-resistant TB [MDR-TB], extensively drug-resistant tuberculosis [XDRTB] has emerged threatening to undermine global efforts at TB control. Further refinements in the imaging modalities such as ultrasonography, computed tomography and magnetic resonance imaging have not only enhanced the localization, and diagnosis of TB of various organ systems, but also have facilitated objective follow-up. The second edition of “Tuberculosis” covers all these developments in great detail; several new chapters that were not present in the first edition have been introduced covering immunology, immunogenetics, vaccine development, public-private mix, building partnerships, the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India, and global efforts at TB control. The second edition has also been enriched by many new tables, figures and high quality images. The first decade in the new millennium has also witnessed the widespread availability of broadband internet connectivity globally. In order to facilitate the interested readers to update themselves, we have introduced a chapter that provides details on various web resources available on the internet that may be useful to persons interested in TB. We sincerely believe that the second edition will help undergraduate and postgraduate students to update their knowledge. We hope that it will be a valuable source of reference to researchers and better the understanding of

xviii Tuberculosis practising physicians and contribute to patient management. We also hope that the second edition will serve as a practical guide for health care workers, nurses, and other paramedical staff. This effort would not have been possible but for the kind cooperation and magnanimity of our contributors who patiently went through endless series of revisions and constant updating. We thank them for their valuable time. We would like to thank Shri Jitendar P. Vij (Chairman and Managing Director) and Mr Tarun Duneja (DirectorPublishing) M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi for their encouragement and support and excellent technical assistance. Our march towards the second edition saw the sad demise of mother of Surendra K. Sharma, and both parents of Alladi Mohan. Our families have stood by us through these turbulent times and without their unstinting support, constant encouragement, this second edition would not have seen the light of the day. Surendra K. Sharma Alladi Mohan

Preface to the First Edition Tuberculosis is an ancient disease which continues to haunt us even as we step into the next millennium. Tuberculosis is the most common cause of death world over due to a single infectious agent in adults and accounts for over a quarter of all avoidable deaths globally. One third of India’s population is infected with Mycobacterium tuberculosis, there are 12 million active tuberculosis cases in India. One person dies of tuberculosis every minute in India. The deadly synergy between Mycobacterium tuberculosis and the human immunodeficiency virus [HIV] has resulted in a resurgence of tuberculosis world over. The impact of this “cursed duet” on human suffering has been enormous. With HIV making rapid inroads in India, the spectre of dual infection with HIV and tuberculosis is going to be a daunting prospect. Inspite of this gloomy scenario, the treatment of tuberculosis is one of the most cost-effective methods of cure. Research work carried out in India has had a tremendous impact on tuberculosis control. The observations from the well-known, randomized controlled trial “The Madras Study” carried out at the Tuberculosis Research Centre [TRC], Chennai, established efficacy of the domiciliary treatment and has paved way for the National Tuberculosis Programme in India and several other countries. Pioneering contributions from eminent clinicians, bacteriologists and epidemiologists from the TRC, Chennai; National Tuberculosis Institute, Bangalore; Sanatoria at Madanapalle, Kasauli, Dharampur, Bhowali, have greatly enhanced our understanding of tuberculosis. The changing clinical presentation of tuberculosis, advances in laboratory and imaging diagnostic modalities and therapeutic measures such as directly observed treatment, short-course [DOTS] all suggest a pressing need to have a recent textbook of tuberculosis. Furthermore, while every doctor working in India encounters the disease in one or other form, very little has been documented regarding the Indian perspective of tuberculosis. Often, the medical students, postgraduates and researchers returning empty handed from libraries expressed their desire for a book which documents the Indian experience. Paucity of a well referenced, standard textbook of tuberculosis which chronicles the rich and vast clinical experience of clinicians from India prompted us to undertake this venture. We have attempted to present a picture of tuberculosis as it is seen in India with contributions from experts who have vast experience in managing tuberculosis in the Indian setting. Our book contains chapters on History, Pathology, Epidemiology, Clinical Presentation, Diagnosis, Treatment, Prevention and Control of tuberculosis highlighting the Indian perspective of tuberculosis. We have also provided guidelines published by authorities concerned with tuberculosis control, and other statements as useful appendices. Though we have made an effort to maintain a uniform style and format, we have been careful to preserve the views expressed by the contributors in their original form. As we step into the new millennium, it is obvious that the crusade against this ancient foe of mankind is still going on. Contrary to the wishful thinking in the 1980s, tuberculosis still remains to be a research priority of paramount importance and is an important component of curricula of medical schools. Keeping in mind the need of the hour, we have attempted to highlight the rationale behind DOTS and its importance in tuberculosis control. We believe that our book will help undergraduate and postgraduate medical students to update their knowledge. It will also be a source of reference to researchers and better the understanding of practising physicians and help in patient management. We also hope that the book can serve as a practical guide on the management of tuberculosis to health care workers, nurses and other paramedical staff. A book of this magnitude would not have been possible but for the magnanimity and kindness of our contributors who took time off their busy schedule to prepare their manuscripts. We would like to thank Mr. Jitendar P Vij, Chairman and Managing Director and Mr RK Yadav, Publishing Director, M/s Jaypee Brothers Medical Publishers Pvt Ltd., for their support, co-operation and technical excellence. Without the unstinting support, constant encouragement and help from our families this endeavour would not have been possible. S.K. Sharma A. Mohan

Acknowledgements We would like to specially thank the Editors and Authors to permit us to reproduce their work. We have acknowledged their help in the respective chapters. The kind help of the World Health Organization [WHO], Geneva for liberally granting permission to reproduce figures and tables from several of their publications is thankfully acknowledged. We are indebted to Dr L.S. Chauhan, Deputy Director General [Tuberculosis], Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, for his constant support and encouragement. We express our gratitude to the following from the WHO, Geneva, Drs Mario Raviglione, Ian Smith, Mukund Uplekar, Reuben Granich, Knut Lonnroth and J. Kumaresan for their excellent contributions. We specially thank Dr Jai P. Narain, Director, Department of Communicable Diseases, WHO Regional Office for South-East Asia, New Delhi, for his contribution, critical comments, and stimulating discussions. We will also like to thank Drs Nani Nair, New Delhi, E. Cooreman, Dhaka, WHO Regional Office for South-East Asia, and Dr Myo Paing, WHO Country Office, Myanmar, for their useful suggestions and contributions. We are greatly indebted to WHO India Staff Drs D. Fraser Wares, Rajesh Bhatia, for their valuable contributions. We express our heartfelt thanks to Drs Thomas Frieden, New York, USA, Madhukar Pai, Montreal, Canada, Dr S.E. Hasnain, Hyderabad, India for their creative inputs and contributions. We wish to thank Drs M van Cleeff, PCFM Gondrie, J Veen, KNCV Tuberculosis Foundation and Dr John Porter, UK for their contributions. We will also like to thank Dr D.S. Maru, USA for his valuable suggestions. Special thanks are also due to Dr P.C. Hopewell, University of California, San Francisco, USA for his suggestions on the International Standards for Tuberculosis Care [ISTC]. We would like to thank Dr N.K. Ganguly, former Director General, Indian Council of Medical Research [ICMR], Dr V.M. Katoch, Secretary, Department of Health Research, Ministry of Health and Family Welfare, Government of India, and Director General, ICMR, New Delhi, India, and Dr C.N. Paramasivan, FIND, Geneva, for their constant encouragement. We are deeply grateful to Departments of Pathology, All India Institute of Medical Sciences [AIIMS], New Delhi; Sri Venkateswara Institute of Medical Sciences [SVIMS], Tirupati; and Postgraduate Institute of Medical Education and Research [PGIMER], Chandigarh for providing gross pathology specimen figures and histopathology photomicrographs. We wish to thank the Departments of Radiodiagnosis, AIIMS, New Delhi and SVIMS, Tirupati for providing classic radiological imaging figures. We also wish to thank Directors of Tuberculosis Research Centre [ICMR], Chennai and National Tuberculosis Institute, Bengaluru, The Administration of Arogyavaram Medical Centre, Madanapalle and TB Sanatorium at Bhowali [now, Kamla Nehru Chest Institute] for permitting us to reproduce the images of these well known institutions. We also wish to thank faculty members of AIIMS, New Delhi; SVIMS, Tirupati; and other medical colleges across India and several other parts of the world, several generations of undergraduate and postgraduate students, for their constructive criticism and useful suggestions during our discussions. These inputs proved to be crucial in shaping the second edition of the book. Our special thanks are also due to the technical staff of the K.L. Wig Centre for Medical Education and Technology [CMET], AIIMS, New Delhi, and Mr Vaka Sudarsan, Photo Artist, SVIMS, Tirupati for their help in organizing clinical and radiographic photographs. Invaluable help rendered by Krishna Srihasam, Boston, USA, and Srinivas Bollineni, Houston, USA, in obtaining full text references is also thankfully acknowledged. We also wish to thank Alladi V. Srikumar’s timely help with broadband connectivity. We wish to specially thank Mr Shree Prakash Kandpal for his constant encouragement and for facilitating visit to Bhowali sanatorium.

xxii Tuberculosis We wish to thank Mr Mukesh Juyal, Mrs Rekha Sharma, Ms Deepa Dhawan and Mrs Veena Dawar Department of Medicine, AIIMS, New Delhi, and Mrs Radha, Department of Medicine, SVIMS, Tirupati, for their excellent help in typing the early drafts of the book and ushering the later drafts with their cheerful enthusiasm and competence. Special thanks are also due to Mrs Samina Khan and Mrs Yashu Kapoor of Jaypee Brothers Medical Publishers (P) Ltd for their untiring help and assistance.

Contents 1. Introduction S.K. Sharma

1

2. History Alladi Mohan, S.K. Sharma

7

3. Epidemiology A.K. Chakraborty

16

4. Epidemiology: Global Perspective D.S. Maru, Jason Andrews

55

5. Pathology S. Datta Gupta, Ruma Ray, S.S. Gill

66

6. The Mycobacteria Rajesh Bhatia

102

7. Immunology of Tuberculosis D.K. Mitra, A.K. Rai

108

8. Genetic Susceptibility Parameters in Tuberculosis N.K. Mehra, Meenakshi Singh

124

9. Genetics of Susceptibility to Tuberculosis Caroline J. Gallant, Tania Di Pietrantonio, Erwin Schurr

143

10. Laboratory Diagnosis Rajesh Bhatia

160

11. The Tuberculin Skin Test V.K. Chadha, V.K. Challu

173

12. Diagnosis of Latent Tuberculosis Infection: Recent Advances and Future Directions Madhukar Pai, Rajnish Joshi, Shriprakash Kalantri

186

13. Roentgenographic Manifestations of Pulmonary Tuberculosis Sima Mukhopadhyay, Ashu Seith

200

14. Pulmonary Tuberculosis V.K. Vijayan, Sajal De

217

15. Lower Lung Field Tuberculosis G. Ahluwalia, S.K. Sharma

227

16. Endobronchial Tuberculosis S.S. Dhillon, N.A. Hanania

232

17. Tuberculosis Pleural Effusion A.N. Aggarwal

245

18. Silicotuberculosis Praveen Aggarwal

268

19. Abdominal Tuberculosis M. Tewari, S.P. Sahoo, H.S. Shukla

275

xxiv Tuberculosis 20. Granulomatous Hepatitis Vineet Ahuja, S.K. Acharya

294

21. Neurological Tuberculosis P.S. Mathuranath, K. Radhakrishnan

304

22. Tuberculosis and the Heart S.S. Kothari, A. Roy

330

23. Skeletal Tuberculosis S. Bhan, H.L. Nag

342

24. Musculoskeletal Manifestations of Tuberculosis Ashok Kumar, A.N. Malaviya

373

25. Cutaneous Tuberculosis M. Ramam

384

26. Lymph Node Tuberculosis Arvind Kumar

397

27. Tuberculosis in Otorhinolaryngology Subirendra Kumar, B.C. Roy, S.C. Sharma

410

28. Ocular Tuberculosis S.P. Garg, Rohan Chawla, Pradeep Venkatesh

420

29. Breast Tuberculosis Puneet Gupta, M. Tewari, H.S. Shukla

434

30. Tuberculosis in Pregnancy Sunesh Kumar

441

31. Female Genital Tuberculosis Sunesh Kumar

449

32. Genitourinary Tuberculosis A.K. Hemal

463

33. Tuberculosis in Chronic Renal Failure S.K. Agarwal

479

34. Disseminated and Miliary Tuberculosis S.K. Sharma, Alladi Mohan

493

35. Complications of Pulmonary Tuberculosis D. Behera

519

36. Tuberculosis and Acute Lung Injury D.R. Karnad, K.K. Guntupalli

532

37. Haematological Manifestations of Tuberculosis Shaji Kumar

542

38. Adrenocortical Reserve in Tuberculosis G.A. Prasad, S.K. Sharma, N. Kochupillai

553

39. Endocrine Implications of Tuberculosis R. Goswami, S. Mishra, N. Kochupillai

561

40. Tuberculosis and Human Immunodeficiency Virus Infection Srikanth Tripathy, Myo Paing, Jai P. Narain

574

Contributors xxv 41. Tuberculosis in Children S.K. Kabra, Rakesh Lodha

591

42. Diagnosis of Childhood Tuberculosis: Recent Advances and Applicability of New Tools Ben J. Marais, Madhukar Pai

602

43. Surgical Aspects of Childhood Tuberculosis M. Bajpai, V. Jain, Arun K. Gupta

615

44. Tuberculosis in Elderly M. van Cleeff, P.C.F.M. Gondrie, J. Veen

625

45. Tuberculosis in Health Care Workers S.K. Jindal

634

46. Nutrition and Tuberculosis Jason Andrews, Ramnath Subbaraman

646

47. Reactivation and Reinfection Tuberculosis Sujatha Narayanan, J.S. Guleria

656

48. Nontuberculous Mycobacterial Infections V.M. Katoch, T. Mohan Kumar

665

49. Drug-Resistant Tuberculosis Sharmistha Banerjee, N. Siddiqi, Seyed E. Hasnain

682

50. Antituberculosis Drug Resistance Surveillance C.N. Paramasivan, V.H. Balasangameshwara

714

51. Evolution of Chemotherapeutic Regimens in the Treatment of Tuberculosis and their Scientific Rationale Rani Balasubramanian, Rajeswari Ramachandran

734

52. Treatment of Tuberculosis W.W. Yew

751

53. Treatment of Latent Tuberculosis Infection D.S. Maru, C.B. Ogbunugafor, S. Basu

776

54. Antituberculosis Treatment Induced Hepatotoxicity P.K. Garg, R.K. Tandon

783

55. Surgery for Pleuropulmonary Tuberculosis Arvind Kumar, D. Dilip, Abha Chandra

796

56. DOTS: The Strategy that Ensures Cure of Tuberculosis Thomas R. Frieden

814

57. Directly Observed Therapy Ian Smith

827

58. The Role of Medical Colleges in Tuberculosis Control Jai P. Narain, E. Cooreman, L.M. Nath

839

59. Public-Private Mix for Tuberculosis Control Mukund Uplekar, Knut Lonnroth

846

60. Building Partnerships for Tuberculosis Control Nani Nair, J. Kumaresan

854

61. Non-Governmental Organizations and Tuberculosis Control Ian Smith

866

xxvi Tuberculosis 62. Global Tuberculosis Control: The Future Prospects D. Fraser Wares

874

63. The Revised National Tuberculosis Control Programmme [RNTCP] Reuben Granich, L.S. Chauhan

894

64. Tuberculosis Vaccine Development: Current Status and Future Expectations Anil K. Tyagi, Bappaditya Dey, Ruchi Jain

918

65. Ethical and Legal Issues in Tuberculosis Control John Porter

947

66. Tuberculosis: Some Web-based Resources on the Internet Anju Sharma, N.C. Jain

963

67. International Standards for Tuberculosis Care [ISTC]

980

Index

1041

Introduction

Introduction

1

1 SK Sharma

INTRODUCTION Tuberculosis [TB] continues to intimidate the human race since time immemorial not only due to its effects as a medical malady, but also by its impact as a social and economic tragedy. At the dawn of the new millennium, we are still mute witnesses to the silent yet efficient march of this sagacious disease, its myriad manifestations and above all its unequalled, vicious killing power. Through the millennia, TB never ever disappeared from the developing world. In the developed world, it only went into hibernation for a while in the mid and late 1970s, to explode once again with the advent of human immunodeficiency virus [HIV] infection and acquired immunodeficiency syndrome [AIDS] pandemic in the 1980s. In 1991, the World Health Assembly [WHA] resolution recognized TB as a major global public health problem (1) and suggested two targets for National Tuberculosis Programmes, of detecting 70 per cent of new smear-positive patients and curing 85 per cent of such cases by the year 2000 in an attempt to rejuvenate global TB control. Thereafter, in 1993, the World Health Organization [WHO] recognized the lethal impact of this disease and declared it a “Global Emergency” (2). The DOTS strategy was launched in 1994, and became the globally recommended strategy for TB control since then (3). The DOTS strategy was rapidly adopted all over the world and has become the standard of TB care (4-6). TUBERCULOSIS EPIDEMIC During the last decade, DOTS not only facilitated control of TB, but was also instrumental in establishing a system of documentation and generation of reliable epidemio-

logical data on TB that were lacking in the pre-1990 period (7-13). Table 1.1 and Figure 1.1 (13) provide a glimpse of the current global TB scenario. The year 2005 data cited in the WHO Report 2007 (7) suggest, for the first time since 1993 that, the TB incidence rates have stabilized or are in decline in all six WHO regions. A similar trend has also been observed in the year 2006 data cited in the WHO Report 2008 [Figure 1.2] (8). Table 1.1: Current global tuberculosis scenario (2006) New TB cases HIV co-infected cases New sputum smear-positive cases Prevalence of TB Total TB deaths Deaths due to HIV-TB

9.2 millions [139/100 000] 0.7 millions [7.7%] 4.1 millions [62/100 000] 14.4 millions [219/100 000] 1.7 millions [25/100 000] 0.23 millions

TB = tuberculosis; HIV = human immunodeficiency virus Source: reference 8

Towards the end of 1990s it was apparent that the WHA 1991 targets for TB were not likely to be achieved by the year 2000 as planned. The WHA had postponed the target date to 2005 (9) or as soon as possible thereafter. Global TB case detection rate significantly increased from 11 per cent in 1995 to 60 per cent by 2005 (10). Similarly, the global TB treatment success rate had reached 84 per cent by 2003 (10). Thus, even though the deferred deadline had already passed, these goals are yet to be achieved (10-12). While results have been exceedingly good in the WHO Western Pacific region, the cure rates have been disappointing in the African region, the established market economies, and eastern Europe (4,11). This patchy performance can be attributed to several

2 Tuberculosis

Figure 1.1: Trajectories of tuberculosis epidemic for nine epidemiologically different regions of the world. Points mark trends in estimated incidence rates, derived from case notifications for 1990–2003. Groupings of countries based on WHO regions. High HIV = incidence > 4% in adults aged 15–49 years in 2003; low HIV = incidence < 4%. Established market economies = all 30 Organization for Economic Co-operation and Development [OECD] countries, except Mexico, Slovakia, and Turkey, plus Singapore Reproduced with permission from “Dye C. Global epidemiology of tuberculosis. Lancet 2006;367:938-49 (reference 13)” Copyright [2006] Elsevier

Figure 1.2: Estimated global prevalence, mortality and incidence rates 1990-2006. Note the different scales on the y-axes Adapted and reproduced with permission from “World health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008 (reference 8)”

reasons including expanding HIV/AIDS epidemic and poor health systems. Looking back at the last decade, several factors have threatened to thwart the TB control (11,13,14). These include HIV-TB co-infection (15), the global presence of multidrug-resistant tuberculosis [MDR-TB] (16-18), the emergence of extensively drug-resistant tuberculosis

[XDR-TB] (19,20), widespread use of immunosuppressive drugs following organ transplantation (21,22), and increasing use of anti-tumour necrosis factor-α [TNF-α] agents [e.g., infliximab and etanercept] (23,24). Further, recently, several systematic reviews and meta-analyses have provided evidence that tobacco smoking is associated with an increased risk of TB (25-27). The HIV/AIDS

Introduction pandemic fuels the TB epidemic and has a catastrophic effect on TB control. Reduced numbers in revised global as well as Indian estimates of HIV epidemic is a good news (28) and should be welcomed as it provides a good opportunity for HIV care but there is no room for complacency and all efforts must continue towards its prevention as well as control. TUBERCULOSIS DIAGNOSTICS Widespread use of newer imaging facilities such as ultrasonography [US], computed tomography [CT] and magnetic resonance imaging [MRI] has revolutionized the diagnosis of extra-pulmonary TB. These imaging modalities can also be used to follow the disease course in an individual patient. Nevertheless, these tests cannot provide mycobacteriological diagnosis of TB (29). As the conventional mycobaterial culture and sensitivity testing is time consuming, impetus has been on evolving rapid methods of reliable diagnosis. Thus, laboratories are a key component of TB control, providing inputs on the diagnosis, surveillance and treatment monitoring (30). There is a need to strengthen laboratory capacity as the implementation of new and rapid diagnostic methods for TB not only requires provision of supplies and equipment, but also ensuring quality standards, appropriate human resource, and attention to safety. A network of laboratories with quality management systems needs to be established for ensuring internal and external quality assurance and periodic accreditation of laboratories to ensure high standards and quality of mycobacterial culture and sensitivity testing. At the same time, the cost involved in these new and rapid diagnostic methods needs to be kept under wraps, through innovations in technology and/or funding. Deciphering the biology of Mycobacterium tuberculosis, from the complete genome sequence, in 1998 (31) evoked immense interest as it marked a paradigm shift in the understanding of the molecular genetics of TB and signalled a hope for evolving tools to address the needs of TB control. Efforts are underway to sequence several Mycobacterium tuberculosis clinical isolates to identify specific genes that have potential for development of new diagnostic tools or targets for drug discovery. Recent introduction of microscopic-observation drug-susceptibility [MODS] assay (32) for the bacteriologic diagnosis of TB and detection of drug resistance in such an example.

3

This technology is considered to be inexpensive and suitable for use in resource limited settings. The initial results have been promising (33,34). Accurate and speedy diagnosis is required especially in paucibacillary smear-negative pulmonary TB, extrapulmonary TB and HIV associated TB. A number of exciting technologies are being developed to facilitate an early diagnosis, especially in HIV associated TB. Revised diagnostic algorithms, improved microscopy and rapid mycobacterial culture may become available in near future (35). Several TB diagnostic tests using newer technologies are in various phases of development. These aim at case detection [growth-based detection, direct visualization, volatile organic compound {VOC} detection, antigen, antibody detection, and molecular diagnosis], species identification [luminescent probe of culture isolate, fluorescent probe of smear-positive sputum, reverse hybridization line probe from culture isolates, dipstick detection of TB antigens in positive cultures, speciesspecific amplification or sequencing] and detection of latent TB infection [LTBI] using MPB-64 skin patch, whole-blood interferon-γ [IFN-γ] release assay, enzyme linked immunospot [ELISPOT] IFN-γ release assay, skin testing with TB-specific antigens, among others. The advent of the interferon-γ [IFN-γ] release assays [IGRAs] heralds a new era in the diagnosis of LTBI as these assays have shown potential to overcome the problems that hamper the interpretation of tuberculin skin test [TST] in situations, such as prior bacille CalmetteGuerin [BCG] vaccination, infection with HIV and infection with nontuberculous mycobacteria [NTM] (36,37). The IGRAs are considered to be more specific for TB infection than the TST. However, high cost has been a problem for their wide spread use in resource limited settings (38). Reliable method of detecting LTBI opens up new avenues for halting the progression of LTBI to active TB disease by administering effective treatment and has been an area of intense research. Several agencies have evinced interest in TB diagnostics in recent times. One such non-profit product development partnership based in Geneva, Switzerland, Foundation for Innovative New Diagnostics [FIND] (39) has been involved in innovative research. In partnership with Eiken Chemical Co. of Japan, FIND has been developing LAMP [loop-mediated isothermal amplification] technology for use in TB diagnosis. Field studies are underway in several countries including India, Vietnam,

4 Tuberculosis South Africa and Brazil. Several such inputs are required to strengthen the laboratory set-up in resource limited countries. NEWER ANTITUBERCULOSIS DRUG DISCOVERY The fact that no exciting antituberculosis drug as good and effective as rifampicin has become available has been a stumbling block in the further refinement of the treatment of TB, be it shortening the duration of treatment or treating LTBI, MDR-TB, or XDR-TB (13). The quest for the ideal antituberculosis drug is still on and the advances in mycobacterial genetics and related bioinformatics are expected to turn the tide to realize this goal in the years to come (40). Currently, several TB drug candidates including fluoroquinolones [gatifloxacin, moxifloxacin], diarylquinoline [TMC207], nitroimidazoles [OPC-67683 and PA-824], pyrrole [LL-3858] and diamine [SQ-109] are in various phases of clinical development (41). These compounds may further shorten the duration of antituberculosis treatment and some of them may be useful for the treatment of MDR-TB. VACCINE The BCG, one of the world’s most widely used vaccines, has shown consistently high efficacy against miliary TB and childhood TB meningitis, however, its efficacy against adult pulmonary TB and other forms of TB is variable. A recent meta-analysis of the effect of worldwide BCG vaccination on miliary TB and childhood TB meningitis found it to be a highly cost-effective intervention against severe childhood TB and recommended that it should be retained in high-incidence countries as a strategy to supplement the chemotherapy of active TB (42). It has been possible to construct the recombinant BCG [rBCG] strains with the assistance of DNA technology. These improved candidates have superior immunogenicity (43). Several vaccine candidates are being tried in various phases of clinical trials, and they must show superior efficacy as well as safety as compared with the currently available BCG vaccine (44,45). CORRELATES OF IMMUNOPROTECTION FROM TUBERCULOSIS There is an urgent need to identify new correlates of immune protection to facilitate the design and testing of new drugs and vaccines for TB. Surrogate markers to

predict relapse risk may act as tools for individual patient treatment and thus assist National TB control programmes. The last few years have increased our understanding of immunity to TB. We now recognize that in addition to Th1 and Th2 cell mediated immune response, innate and regulatory immune responses play an important role in the disease process. Animal and human studies also indicate that although IFN-γ is essential for protective immunity but other cytokines may also be involved in immunoprotection. Several clinical studies have shown that the cytokine IFN-γ is secreted in response to TB antigens in patients with TB; however, in some patients the secretion of IFN-γ is reduced. This apparent reduction in secretion of IFN-γ may be due to suppressive effects of regulatory T-cells [Treg, CD4 + CD25 + FoxP3 +], a class of T-cells, that may mediate this effect through secretion of cytokines, such as interleukin-10 [IL-10] and transforming growth factor-β [TGF-β]. Further, persistent signalling through toll-like receptor-2 [TLR-2] as a result of chronic exposure to Mycobacterium tuberculosis antigens can downregulate major histocompatibility complex [MHC] class II mediated immune responses (46,47). Further advances in technologies such as DNA microarray analysis and flow cytometry may unravel surrogate novel markers of immunoprotection (48). Response to the Challenge of Multidrug-resistant and Extensively Drug-resistant Tuberculosis Availability of quality assured, periodically accredited mycobacteriology laboratory services and good quality second-line antituberculosis drugs with proven bioavailability are essential elements in the battle against drug-resistant TB. Since it has become evident that DOTS alone may be inadequate to contain TB in areas where MDR-TB is highly prevalent, as a first step in moving beyond DOTS, the DOTS-Plus strategy, has been evolved as the WHO’s supplemental strategy. The Working Group on DOTS-Plus for MDR-TB was established in 1999 (18). In 2000, the “Green Light Committee” [GLC] was launched as a sub-group of the working group in order to increase access to low-price, quality-assured second-line drugs and ensure their proper use (49). In 2001, this has been integrated into the Stop TB Partnership and has now been termed as the Stop TB Working Group on MDR-TB. The earliest beneficiaries of this scheme were Estonia, Lativia, Peru, the Phillippines, and the Russian Federation [Tomsk Oblast]. As of December 2006, there were 53 GLC approved projects underway in 42 countries globally (18).

Introduction In India, provision of standardized DOTS-Plus regimen is underway in Gujarat and Maharashtra and is likely to cover the entire country in a phased manner (50). The DOTS strategy, by ensuring standard treatment of TB, prevents the emergence of MDR-TB. The DOTS-Plus strategy, by ensuring the correct treatment of MDR-TB, is likely to prevent the emergence of XDR-TB. This seems to be the most logical approach to control the menace of these lethal forms of drug-resistant TB. Other Innovations The observation that TB is still plaguing us even after 50 years of availability of effective antituberculosis drugs is an ample testimony to the fact that mere availability of drugs is not adequate for ensuring control and elimination of this scourge. Direct observation of treatment [DOT] to ensure treatment compliance has been found to yield promising results (51). Similarly, the efforts to involve nongovernmental organizations [NGOs], and private sector [public-private mix DOTS], use of paramedical persons such as Anganwadi workers to promote treatment adherence has proved to be effective in the field setting in India (16). The International Standards for Tuberculosis Care [ISTC] (52) also provides insights into what is expected as the best possible care to patients with TB who get treated outside the National Tuberculosis Control Programmes. Another effort worth mentioning is the involvement of Medical Schools in TB control that has been tried in India. For the first time in the annals of history of any disease has an association between the academicians and the public health experts been so fruitful (53-55). This venture has been tremendously successful in bridging the gap between what is practiced and what is preached. Though the achievements in the field of TB control are gratifying, the march ahead is long and the end [TB elimination] is nowhere in sight. It is time to sustain the all pronged onslaught against this ancient foe. Any let down in the guard and slackening of the commitment in this battle is likely to have disastrous consequences and the dreadful prospect of return to the era of untreatable TB. REFERENCES 1. World Health Organization. Forty-fourth World Health Assembly, Resolutions and Decisions. WHA44/1991/REC/1. Geneva: World Health Organization; 1991. 2. Anonymous. Tuberculosis: a global emergency. World Health Forum 1993;14:438.

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3. World Health Organization. WHO Tuberculosis Programme: framework for effective tuberculosis control. WHO/TB/ 94.179. Geneva: World Health Organization; 1994. 4. Sharma SK, Liu JJ. Progress of DOTS in global tuberculosis control. Lancet 2006;367:951-2. 5. Frieden TR, Munsiff SS. The DOTS strategy for controlling the global tuberculosis epidemic. Clin Chest Med 2005;26:197205. 6. Sharma SK, Mohan A. Scientific basis of directly observed treatment, short-course [DOTS]. J Indian Med Assoc 2003; 101:157-8, 166. 7. World Health Organization. WHO report 2007. Global tuberculosis control: surveillance, planning, financing. WHO/ HTM/TB/2007.376. Geneva: World Health Organization; 2007. 8. World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing. WHO/ HTM/ TB/2008.393. Geneva: World Health Organization; 2008. 9. World Health Organization. Fifty-third World Health Assembly, Resolutions and Decisions. Resolution WHA 53.1. Geneva: World Health Organization; 2000. 10. Dye C, Hosseini M, Watt C. Did we reach the 2005 targets for tuberculosis control? Bull World Health Organ 2007;85:364-9. 11. Dye C, Watt CJ, Bleed DM, Hosseini SM, Raviglione MC. Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence, and deaths globally. JAMA 2005;293:2767-75. 12. Dye C, Maher D, Weil D, Espinal M, Raviglione M. Targets for global tuberculosis control. Int J Tuberc Lung Dis 2006;10:460-2. 13. Dye C. Global epidemiology of tuberculosis. Lancet 2006;367: 938-40. 14. Dye C, Williams BG. Eliminating human tuberculosis in the twenty-first century. J R Soc Interface 2007 Aug 9; [Epub ahead of print]. 15. Sharma SK, Mohan A, Kadhiravan T. HIV-TB co-infection: epidemiology, diagnosis and management. Indian J Med Res 2005;121:550-67. 16. Sharma SK, Mohan A. Multidrug-resistant tuberculosis: a menace that threatens to destabilize tuberculosis control. Chest 2006;130:261-72. 17. Zignol M, Hosseini MS, Wright A, Weezenbeek CL, Nunn P, Watt CJ, et al. Global incidence of multidrug-resistant tuberculosis. J Infect Dis 2006;194:479-85. Epub 2006 Jul 12. 18. Blöndal K. Barriers to reaching the targets for tuberculosis control: multidrug-resistant tuberculosis. Bull World Health Organ 2007;85:387-90; discussion 391-4. 19. Iseman MD. Extensively drug-resistant Mycobacterium tuberculosis: Charles Darwin would understand. Clin Infect Dis 2007;45:1415-6. Epub 2007 Oct 22. 20. Goldman RC, Plumley KV, Laughon BE. The evolution of extensively drug resistant tuberculosis [XDR-TB]: history, status and issues for global control. Infect Disord Drug Targets 2007;7:73-91. 21. Rose G. The risk of tuberculosis transmission in solid organ transplantation: is it more than a theoretical concern? Can J Infect Dis Med Microbiol 2005;16:304-8.

6 Tuberculosis 22. Hsu MS, Wang JL, Ko WJ, Lee PH, Chou NK, Wang SS, et al. Clinical features and outcome of tuberculosis in solid organ transplant recipients. Am J Med Sci 2007;334:106-10. 23. British Thoracic Society Standards of Care Committee. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment. Thorax 2005;60:8005. Epub 2005 Jul 29. 24. Theis VS, Rhodes JM. Minimizing tuberculosis during antitumour necrosis factor-alpha treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2008;27:19-30. Epub 2007 Oct 16. 25. Pai M, Mohan A, Dheda K, Leung CC, Yew WW, Christopher DJ, et al. Lethal interaction: the colliding epidemics of tobacco and tuberculosis. Expert Rev Anti Infect Ther 2007;5:385-91. 26. Lin HH, Ezzati M, Murray M. Tobacco smoke, indoor air pollution and tuberculosis: a systematic review and metaanalysis. PLoS Med 2007;4:e20. 27. Bates MN, Khalakdina A, Pai M, Chang L, Lessa F, Smith KR. Risk of tuberculosis from exposure to tobacco smoke: a systematic review and meta-analysis. Arch Intern Med 2007;167:335-42. 28. Steinbrook R. HIV in India – a downsized epidemic. N Engl J Med 2008;358:107-9. 29. Sharma SK, Kadhiravan T. Sarcoidosis. N Engl J Med 2008; 358:1402. 30. Ridderhof JC, van Deun A, Kam KM, Narayanan PR, Aziz MA. Roles of laboratories and laboratory systems in effective tuberculosis programmes. Bull World Health Organ 2007;85:354-9. 31. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998;393:537-44. 32. Moore DA, Evans CA, Gilman RH, Caviedes L, Coronel J, Vivar A, et al. Microscopic-observation drug-susceptibility assay for the diagnosis of TB. N Engl J Med 2006;355:1539-50. 33. Caws M, Ha DT, Torok E, Campbell J, Thu do DA, Chau TT, et al. Evaluation of the MODS culture technique for the diagnosis of tuberculous meningitis. PLoS ONE 2007;2:e1173. 34. Moore DA. Future prospects for the MODS assay in multidrugresistant tuberculosis diagnosis. Future Microbiol 2007;2:97-101. 35. Perkins MD, Cunningham J. Facing the crisis: improving the diagnosis of tuberculosis in the HIV era. J Infect Dis 2007;196[Suppl1]:S15-27. 36. Pai M, Menzies D. The new IGRA and the old TST: making good use of disagreement. Am J Respir Crit Care Med 2007;175: 529-31. 37. Menzies D, Pai M, Comstock G. Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 2007;146:340-54. 38. Mohan A, Sharma SK. In search of a diagnostic test for tuberculosis infection: where do we stand? Indian J Chest Dis Allied Sci 2006;48:5-6. 39. Foundation for Innovative New Diagnostics. When molecular diagnostics meet microscopy. Available at URL: http:// www.finddiagnostics.org/news/ docs/lamp_india_nov07. shtml. Accessed on September 30, 2008.

40. Brosch R, Vincent V. Cutting-edge science and the future of tuberculosis control. Bull World Health Organ 2007;85:410-2. 41. Ginsberg AM, Spigelman M. Challenges in tuberculosis drug research and development. Nat Med 2007;13:290-4. 42. Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet 2006;367:1173-80. 43. Kaufmann SH, Baumann S, Nasser Eddine A. Exploiting immunology and molecular genetics for rational vaccine design against tuberculosis. Int J Tuberc Lung Dis 2006;10:1068-79. 44. Doherty TM, Rook G. Progress and hindrances in tuberculosis vaccine development. Lancet 2006;367:947-9. 45. Rook GA, Dheda K, Zumla A. Immune responses to tuberculosis in developing countries: implications for new vaccines. Nat Rev Immunol 2005;5:661-7. 46. Pai RK, Pennini ME, Tobian AA, Canaday DH, Boom WH, Harding CV. Prolonged toll-like receptor signaling by Mycobacterium tuberculosis and its 19-kilodalton lipoprotein inhibits gamma interferon-induced regulation of selected genes in macrophages. Infect Immun 2004;72:6603-14. 47. Tobian AA, Potter NS, Ramachandra L, Pai RK, Convery M, Boom WH, et al. Alternate class I MHC antigen processing is inhibited by Toll-like receptor signaling pathogen-associated molecular patterns: Mycobacterium tuberculosis 19-kDa lipoprotein, CpG DNA, and lipopolysaccharide. J Immunol 2003;171:1413-22. 48. Cox RA. A scheme for the analysis of microarray measurements based on a quantitative theoretical framework for bacterial cell growth: application to studies of Mycobacterium tuberculosis. Microbiology 2007;153:3337-49. 49. Pablos-Mendez A, Gowda DK, Frieden TR. Controlling multidrug-resistant tuberculosis and access to expensive drugs: a rational framework. Bull World Health Organ 2002;80:489-95. 50. Central TB Division, Ministry of Health and Family Welfare, Government of India. RNTCP launches Category IV treatment [DOTS-Plus treatment] for multi-drug resistant tuberculosis patients in Gujarat on the 29th of August 2007. Available at URL: http://www.tbcindia.org/Pdfs/RNTCP%20Launches % 20DOTS%20Plus%20 treatment.pdf. Accessed on September 30, 2008. 51. Frieden TR, Sbarbaro JA. Promoting adherence to treatment for tuberculosis: the importance of direct observation. Bull World Health Organ 2007;85:407-9. 52. Hopewell PC, Pai M, Maher D, Uplekar M, Raviglione MC. International standards for tuberculosis care. Lancet Infect Dis 2006;6:710-25. 53. Tahir M, Sharma SK, Rohrberg DS, Gupta D, Singh UB, Sinha PK. DOTS at a tertiary care center in northern India: successes, challenges and the next steps in tuberculosis control. Indian J Med Res 2006;123:702-6. 54. Sharma SK, Lawaniya S, Lal H, Singh UB, Sinha PK. DOTS centre at a tertiary care teaching hospital: lessons learned and future directions. Indian J Chest Dis Allied Sci 2004;46:251-6. 55. Mohan A, Sharma SK. Medical schools and tuberculosis control: bridging the discordance between what is preached and what is practiced. Indian J Chest Dis Allied Sci 2004;46:5-7.

History

History

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2 Alladi Mohan, SK Sharma

INTRODUCTION As a destroyer of mankind, tuberculosis has no equal... VA Moore (1) Tuberculosis [TB] has been a major cause of suffering and death since times immemorial. Thought to be one of the oldest human diseases, the history of TB is at least as old as the mankind. Over the years, not only the medical implications but also the social and economic impact of TB has been enormous. There have been references to this ancient scourge in the Vedas [vide infra] and it was called “rajayakshma” [meaning “wasting disease”]. Hippocrates [460-377 B.C.] called the disease “pthisis”, a Greek word which meant “to consume”, “to spit” and “to waste away“ (2,3). The word “consumption” [derived from the Latin word “consumere”] has also been used to describe TB in English literature. The Hebrew word “schachepheth” [meaning “waste away”] has been used in the Bible. J.L. Schonlein, Professor of Medicine at Zurich, is credited to have named the disease “tuberculosis” (1). The word “tuberculosis” is a derivative of the Latin word “tubercula” which means “a small lump” (2,4,5). Several names have been used to refer to TB in the years gone by. Acute progressive TB has been referred to as “galloping consumption”. Pulmonary TB has been referred to as “tabes pulmonali”. Tuberculosis cervical lymphadenitis has been called as “scrofula”, “King’s Evil”, “stroma”. Abdominal TB has been called as “tabes mesenterica”. Cutaneous TB has been called “lupus vulgaris”. Vertebral TB has been called as “Pott’s disease”. Oliver Wendell

Holmes referred to the disease as “white plague” (6). While scores of other diseases like smallpox and plague killed millions of people, their reign has been relatively short-lived. Tuberculosis has been ever present and is resurging with a vengeance. TUBERCULOSIS IN ANCIENT TIMES It is thought that TB probably existed in cattle before its advent in man. There have been references to TB in the Vedas and it was called “rajayakshma”. muncami tva havisa jivanayakam agnatayaksmad uta rajayakshma... [I deliver you by means of oblation so that you may live from the unknown disease and from the “rajayakshma”] [RV, X,161,1] In the Krishna Yajurveda Samhita, there is reference to how, Soma [Moon] had been affected by “yakshma”. Since “Soma”, who was the “King and Ruler” was affected by “yakshma”, it came to be known as “rajayakshma” [Figure 2.1]. In Sanskrit, the disease has been called “rajayakshma”, “ksayah”, and “sosa”. Rajayakshma ksayah soso rogarad iti cha smritah naksatranam, dvijanam cha rajno bhud yad aym pura yach cha raja cha yakshma cha rajayakshma tato matah [Vagabhata, Ast-s and Ast-hrd, Nidana V, 1-2] Krodho yakshma jvaro roga eko ‘rtho dukhasamjnitah yasmat sa rajnah prag asid rajayakshma tatomatah [Charaka Samhita, Chikitsasthanam VIII, 11]

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Figure 2.1: Krishna Yajurveda Samhita, II Kanda, III prasna, V anuvaka, 25th stanza, where the legend of “Soma” being afflicted with “rajayakshma” is described

Changes resembling those caused by TB have been described in the skeletal remains of neolithic man (7). Terms such as “lung cough” and “lung fever” have been used in ancient Chinese literature to describe a disease which may have been TB (8). There have been references to what could have been TB in the Code of Hammurabi of the Babylonian era (6). Evidence of TB lesions of bone have also been found in Egyptian mummies dating back to 3400 B.C. (7). Mycobacterium tuberculosis has been demonstrated microscopically in the mummy of a child about five years of age (8). There are several references to conditions resembling TB in Greek literature by Homer [800 B.C.], Hippocrates, Aristotle [384-322 B.C.] and Plato [430-347 B.C.], Galen [129-199], Vegetius [420] were also familiar with consumption. Arabic physicians Al Razi [850-953], Ibn Sina [980-1037] correlated lung cavities with skin ulceration. During the middle ages, there are records of healing touch of monarchs was being used to treat “scrofula” [King’s Evil]. King Charles II bestowed the royal touch on an astounding 92 102 patients with “scrofula” (9). By around 1629, death certificates in London specified the disease as “consumption” which was a leading cause of death. By this time the contagious nature of TB was strongly believed though there were people who contested this opinion. The Republic of Lucca is credited to have passed the first legislative action aimed at controlling TB in the world (4,9). This was followed by similar measures in several Italian cities and Spain.

DIAGNOSIS Why, when one comes near consumptives... does one contract their disease, while one does not contract dropsy, apoplexy, fever, or many other ills?.... Aristotle In the early days, diagnosis of TB was based on symptoms and signs. In Charaka Samhita [Nidanasthana, VI, 14], heaviness in the head, coughing, dyspnoea, hoarseness of voice, vomiting of phlegm, spitting of blood, pain in the sides of the chest, grinding pain in the shoulder, fever, diarrhoea and anorexia have been described as the eleven symptoms of TB. Furthermore, a physician who is well versed in the aetiology, clinical presentation and premonitory symptoms of “consumption” was considered to be a “Royal Physician” [Charaka Samhita, Nidanasthana, VI, 17]. The earliest classical descriptions of TB in Greek literature date back to the writings by Hippocrates. Aretaeus the Cappodocian [50 B.C.], in his book The causes and symptoms of chronic diseases gave a very accurate description of TB and mentioned that fever, sweating, fatigue and lassitude were symptoms of TB. He suggested testing the sputum with fire or water was of diagnostic value (7). Galen described that patients with “consumption” manifest cough, sputum, wasting, chest pain and fever and considered haemoptysis to be pathognomonic of the disease (6). Following the pioneering efforts by Andreas Vesalius [1514-1564] post-mortem examination was performed frequently. This method of study facilitated under-

History standing of pathological findings such as lung cavities, empyema among others. Franciscus de Boe [1614-1672] [also known as Sylvius] for the first time associated small hard nodules discovered in various tissues at autopsy with symptoms of “consumption” which the patients suffered during their life-time though his explanation for the same was not correct (7). John Jacob Manget in 1700 gave the description of classical miliary TB (10). The clinical presentation of consumption was described in detail by Thomas Willis [1621-1675]. Richard Morton [1637-1698] had described several pathological appearances of “pthisis” in his treatise Pthisiologica (4,6,7). Meaningful clinical examination became possible with the description of the technique of percussion by Leopold Auenbrugger [1722-1809]. However, Auenbrugger’s work was virtually ignored until the time of Jean Nicolas Covisart [1775-1821] who rediscovered and propagated the technique. Gaspard Bayle [17741816] accurately described many of the pathological changes of TB, but unfortunately succumbed to the disease which he probably contracted while performing autopsy studies (11). The technique of physical examination of the lung was further refined by the invention of stethoscope by Rene Theophile Hyacinthe Laennec [1781-1826] who was a student of Corvisart and a friend of Bayle. Sadly, Laennec, his younger brother, mother and two uncles all succumbed to TB (6). Fracastorius [1443-1553] is credited to have originated the “germ theory” and believed that TB was contagious. He also mentioned about antiseptics in his chapter on the treatment of TB. In 1720, the English physician Benjamin Marten conjectured, in his publication A new theory of consumption, that TB could be caused by “certain species of animalcula or wonderfully minute living creatures”, which, once they had gained a foothold in the body, could generate the lesions and symptoms of the disease. He also stated that “it may be therefore very likely that by an habitual lying in the same bed with a consumptive patient, constantly eating and drinking with him, or by very frequently conversing so nearly as to draw in part of the breath he emits from the lungs, consumption may be caught by a sound person...I imagine that slightly conversing with consumptive patients is seldom or never sufficient to catch the disease” (12)

9

For unknown reason the work of Marten went into oblivion for a long time. The likely reason could be that he was thinking very much ahead of his time. Jean Antoine Villemin [1827-1892] in a series of experiments provided conclusive evidence that TB was indeed a contagious disease though some workers of that era did not accept these results. He presented his results to the Academie de Medcine on December 5, 1865 and stated that TB was a specific infection caused by an inoculable agent (3,6). ”During my wandering through medicine, I encountered sites where gold was lying around. It needs a lot of serendipity to distinguish gold from ignobility; this, however, is not a particular achievement.” Robert Koch (13) Robert Koch [Figure 2.2], the son of a mining engineer, was born on December 11, 1843 in Clausthal village in the Harz mountains (3,6,14). Koch pursued medical studies at the Gottingen University in 1862 and qualified maxima cum laude in 1866 with his M.D. thesis on

Figure 2.2: Robert Koch: the discoverer of Mycobacterium tuberculosis Reproduced with permission from: “Rubin SA. Tuberculosis. The captain of all these men of death. Radiol Clin North Am 1995;33:61939 (reference 6)”

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succinic acid. On 24th March 1882 Koch announced the discovery of the tubercle bacillus during the monthly evening meeting of the Berlin Physiological Society. In 1884, he published a more comprehensive paper Die aetiologic der tuberculose in the second volume of the Reports of the Imperial Health Office. In 1905, he was awarded the Nobel Prize for his contributions in the field of TB research (3,5,6). It was Robert Koch who finally demystified the secret of the cause of TB and after thousands of years, the organism finally revealed itself to humans. Though, Robert Koch was wrong in his belief that tuberculin would cure TB, tuberculin became an invaluable tool for the diagnosis of latent TB infection (15). With the advent of Wilhelm Conrad Roentgen [18451923], the technique of radiological imaging became available. Francis Williams in Boston, L. Bouchard and A. Beclere in France, John MacIntyre and David Lawson in Britain were pioneers in the use of radiography in the study of TB (3,6). By this time, the deep mystery that was TB, became demystified to some extent in that basic concepts of the agent, the pathology as a result of it and its detection became established ushering in the era of definitive diagnosis of TB. TREATMENT In the Yajurveda there are references to Soma performing a “yagna” [sacred offering] seeking cure form TB. Since ancient times amulets, invocations, charms, Royal touch and prayers have been used to treat TB. Chemicals such as arsenic, sulphur, calcium, several vegetable, plant and animal products including excreta of humans and animals, blood letting have been used over the centuries in the fond hope of curing TB. Robert Koch, soon after his discovery of the tubercle bacillus, ambitiously introduced treatment with “Koch’s lymph” with disastrous results. It would later be known that the substance was a glycerin extract of the tubercle bacillus and would be named as “tuberculin” (3,6). During the 19th century, bed rest and change in environment emerged as important forms of treatment of TB. Hermann Brehmer, Peter Dettweiler, George Bodington, Edward Livingstone Trudeau were all pioneers of the sanatorium movement. Hermann Brehmer, a Botany student suffering from TB, was instructed by his physician to seek out a healthier climate.

He travelled to the Himalayan mountains where he could pursue his botanical studies while trying to rid himself of the disease. He returned home cured and began to study medicine. In 1854, he presented his doctoral dissertation bearing the title, “Tuberculosis is a curable disease”. In the same year, he built an institution in Gorbersdorf where, in the midst of fir trees, and with good nutrition, patients were exposed on their balconies to continuous fresh air. This set up became the blueprint for the subsequent development of sanatoria (12). During this period, surgery was extensively used for the treatment of TB. The reader is referred to the chapter “Surgery for pleuropulmonary tuberculosis” [Chapter 55] for the details. Efforts by Albert Calmette and his assistant Camille Guérin resulted in the introduction of bacille CalmetteGuérin [BCG] vaccine (16). Pioneering work of Selman Waksman led to the introduction of streptomycin as an effective antituberculosis agent. Jorgen Lehman was instrumental in the discovery of para-amino salicylic acid [PAS]. With the availability of these drugs and isoniazid, the era of modern predictably effective treatment ushered in. With the availability of rifampicin, the treatment duration could be further shortened to the present day six-month short-course chemotherapy. TUBERCULOSIS IN ARTS AND LITERATURE Youth grows pale, and spectre thin, and dies John Keats Ode to a Nightingale There have been references to TB in several works of fiction. There are references to TB in William Shakespeare’s plays such as the “consumptive lover” of Much Ado About Nothing and “scrofula” in Macbeth. Charles Dickens describes the sufferings of Little Blossom in David Copperfield. Thomas Mann’s The Magic Mountain contains one of the most well-known descriptions of TB sanatorium. Little Eva of Harriet Beecher Stowe’s Uncle Tom’s Cabin, Milly Theale in Henry James’ The Wings of the Dove, Marguerite Gautier in Alexander Dumas’ La Dame aux Cameilas also suffered from TB. Tuberculosis does not respect anybody. Several important personalities, statesmen, writers, poets, performing artists have been consumed by TB [Table 2.1]. John Keats and Percy Bysshe Shelley symbolized the era of the “romantic consumptive youths of the 19th century” (3). The image of John Keats conveyed by the writings of

History 11 Table 2.1: Well known victims of tuberculosis Mathematician Srinivasa Ramanujan Doctors Rene Theophile Hyacinthe Laennec Edward Livingston Trudeau Writers and Poets Alexander Pope Samuel Johnson Jean-Jacques Rosseau Johann Wolfgang von Goethe Sir Walter Scott Percy Bysshe Shelley John Keats Leigh Hunt Elizabeth Barret Browning Charlotte Bronte Emily Bronte Anne Bronte Fyodor Dostoyevsky Robert Louis Stevenson Anton Chekov Franz Kafka Katherine Mansfield George Orwell Munshi Prem Chand Statesmen/Stateswomen Kamala Nehru Eleanor Roosevelt Mohammed Ali Jinnah Nelson Mandela Musicians Frederic Francois Chopin Niccolo Paganini Carl Maria Von Weber Performing Artists Vivian Leigh Elisa Rachel Felix

contemporaries of his era is that of a fragile poet who fell victim to TB because his sensitive nature had been unable to withstand contact with a crude world (3). In a well known anecdote, when his friend John Brown discovers a drop of blood on the sheet while examining him, Keats says: “I know the colour of that blood. It’s ‘arterial blood’... That blood is my death warrant, I must die ... (3) Shelley, a fellow poet also suffered from TB pleurisy but did not succumb to the disease. On hearing the passing of Keats, Shelley wrote:

From the contagion of the world’s slow stain He is secure, and now can never mourn A heart grown cold, a head grown gray in vain; Nor, when spirit’s self has ceased to burn, With sparkless ashes load an unlamented urn... The Bronte family included six children all of whom succumbed to TB. Maria and Elizabeth died at a very young age. The son died of consumption, alcohol and opium. Emily [Wuthering Heights] and Charlotte [Jane Eyre] died aged 29 and 39 respectively. It was thought that, their father Rev. Patrick Bronte was the source of infection. The families of Ralph Waldo Emerson and Henry David Thoreau were also wiped out by consumption (3,6). Several famous Indians had also succumbed to TB. The list includes the famous mathematician Srinivasa Ramanujan, writer Munshi Prem Chand, Kamala Nehru, among others. HUMAN IMMUNODEFICIENCY VIRUS INFECTION No account of the history of TB would be complete without a reference to this modern foe. The impact of the twin disaster of human immunodeficiency virus [HIV] infection and TB on human suffering has been covered in the chapter “Tuberculosis and human immunodeficiency virus infection” [Chapter 40]. INDIA AND TUBERCULOSIS CONTROL Research carried out in India has had a tremendous impact on TB and this experience has been of immense value in the control of TB worldwide. The first sanatorium in India was started in 1906 in Tilaunia, Rajasthan. Subsequently, other sanatoria were setup in Almora in 1908 and Pendra Road, Central Provinces in Madhya Pradesh, at about the same time. The first sanatorium outside the patronage of Christian missionary organizations, called Hardinge Sanatorium was established at Dharampur, near Shimla in 1909 with the help of donations from some Mumbaibased philanthropists, mainly Parsis, under the banner of the Consumptives’ Homes Society. The first Government run sanatorium [King Edward Sanatorium] was started at Bhowali in Uttaranchal [Figure 2.3]. The Union Mission Tuberculosis Sanatorium [UMTS] was established in Arogyavaram, Madanapalle, Chittoor district,

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Figure 2.3: Sanatorium at Bhowali, Nainital, Uttaranchal state [A,B]. Late Dr Tarachand, originally a physician, who became a famous thoracic surgeon and his wife Dr Shanti Tarachand [expert in anaesthesiology] are well-known names at this King Edward Sanatorium. The museum in the sanatorium houses many of the surgically resected gross pathology specimens [C,D,E and F]

Andhra Pradesh in 1915. With the advent of the National Tuberculosis Programme [NTP] in 1962, the UMTS sanatorium was converted to a general hospital called the Aroyavaram Medical Centre [Figure 2.4] which is continuing to function even today. Till the mid-1950s, important TB research activity in India was pioneered by the UMTS (17,18). India became a member of the International Union Against Tuberculosis in 1929. From the funds generated in response to the appeal made on behalf of the government by the then Vicereine Lady Linithgow, . and the King George V Thanksgiving [Anti-TB] Fund, The Tuberculosis Association of India [TAI] was formed in February, 1939. In 1940 the Tuberculosis Association of India and Government of India decided to set up jointly the New Delhi Tuberculosis Centre as a model clinic. In 1951, the clinic was upgraded as first TB Training and Demonstration Centre in the country. In 1941, the Lady Linlithgow sanatorium, was setup at Kasauli (17-20). The subsequent years saw the establishment of the Tuberculosis Chemotherapy Centre at Chennai [then called Madras] and the National Tuberculosis Institute [NTI] at Bengaluru [then called Bangalore]. The work

Figure 2.4: The Union Mission Tuberculosis Sanatorium [UMTS], at Arogyavaram, Madanapalle, Chittoor district, Andhra Pradesh, that later became the Arogyavaram Medical Centre

done in these institutions has contributed significantly to the understanding of the epidemiology and treatment of TB in India. Tuberculosis Research Centre, Chennai In the early days, TB being a chronic disease required hospitalization of patients for a prolonged period. As the

History 13 TB burden was enormous it was not possible to accommodate all needy patients for the treatment. In October 1955, at the request of the Government of India, the World Health Organization [WHO] sponsored the visit to India of three representatives of the British Medical Research Council [BMRC] to advise on studies designed to provide information on the mass domiciliary application of chemotherapy in the treatment of pulmonary TB. This was particularly relevant as the number of patients with TB far outnumbered the number of beds available for their admission at that time. It was feared that out-patient treatment might prove inadequate for the treatment of the disease, and that a high proportion of patients so treated might become chronic excretors of drug-resistant organisms and might pose a serious public health risk if use of domiciliary chemotherapy was widespread. With the knowledge then available, it was agreed that it would be premature to begin mass domiciliary application of chemotherapy, even in a limited area. It was finally decided, to undertake a controlled comparative study of the treatment of patients at home and in a sanatorium initially, and to follow up the family contacts. Patients were to be admitted to study from among those routinely diagnosed by the chest clinic service of a large city. In order to implement these decisions, the Tuberculosis Chemotherapy Centre was established at Madras [Chennai] in 1956 as a five-year project, under the joint auspices of the Indian Council of Medical Research [ICMR], the Government of Tamil Nadu, the WHO and the BMRC. The Centre is housed in two main blocks, in a one-and-a-quarter hectare campus on Spur Tank Road, Chetput, in the heart of Chennai city. The Centre, which had an initial lease of life of only five years and had faced the threat of closure in 1961, has moved from strength to strength and has now firmly established itself as one of the foremost internationally recognized institutions in TB research. In keeping with the wide sphere of activities of the Centre, the ICMR in 1978 renamed the Tuberculosis Chemotherapy Centre as the “Tuberculosis Research Centre”. The Tuberculosis Research Centre [TRC] is now housed in a new building [Figure 2.5] (21). The Madras Experiment The findings of the “Home-Sanatorium study” conducted by the TRC, Madras [Chennai], have found their way into several journals and textbooks on TB. The

Figure 2.5: Tuberculosis Research Centre, Chennai

finding that TB patients can be effectively treated as outpatients and continue to live in their homes without added risk to their family contacts has revolutionized the whole concept of the management of TB (21). These pioneering studies also form the conceptual basis for the modern day “DOTS”. National Tuberculosis Institute In order to formulate an effective strategy to control TB in India, the NTI was established under Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, at Bengaluru [then, called Bangalore] in 1959, and was formally inaugurated on 16th September 1960 by Pandit Jawaharlal Nehru, the first Prime Minister of India (22). The NTI is located in the northern part of the Bengaluru near Rajamahal Guttahally on a sprawling field of 23 acres of land [Figure 2.6A]. The main central old building of oriental architecture called “Avalon”, was a palace belonging the erstwhile Maharaja of Mysore [Figure 2.6B]. The NTI has grown rapidly and has been designated as the WHO Collaborating Centre for TB research and training since June 1985. The NTI plays an important role in organising training activities in TB control for medical and paramedical personnel, in policies and procedures consistent with the WHOrecommended DOTS strategy. Other functions of the NTI include monitoring and supervising TB control programme in the country, to plan, co-ordinate and execute research in TB epidemiology in India. The NTI has to its credit several outstanding contributions in the

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Figures 2.6: National Tuberculosis Institute, Bengaluru: A. Entrance. B. Avalon building

Figure 2.7: A brief history of TB HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome; TB = tuberculosis; MDR-TB = multidrug-resistant tuberculosis; XDR-TB = extensively drug-resistant tuberculosis

History 15 field of TB research, the most recent one being the annual risk of infection [ARI] study (23). Revised National Tuberculosis Control Programme Considered to be one of the most spectacular cost-effective health interventions ever conceived, the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India, which began in 1997, now covers the whole country. The RNTCP, has been the fastest expanding programme, and the largest in the world in terms of patients initiated on treatment. The reader is referred to the chapter “Revised National Tuberculosis Control Programme” [Chapter 63] for details on this topic. EPILOGUE A look at the history of TB [Figure 2.7] reveals that it took several thousands of years for humans to identify the causative organism, another 60 years to arrive at effective treatment. Towards the end of the twentieth century, the twin disaster of HIV and TB and multidrug-resistant tuberculosis [MDR-TB] seem to be on the verge of threatening to ruin the mankind. While it is heatedly debated that TB is “resurging”, this may hold true for the industrialized countries. But in the third world countries like India, TB never seems to have “disappeared” to “resurge” later. Tuberculosis has always been with us, only revealing itself every now and then and making us wiser. ACKNOWLEDGEMENTS The authors wish to acknowledge the help rendered by Vedic scholars K. Gopala Ghanapatigal, Vedaparayandar, Tirumala Tirupati Devasthanams, Tirupati and V. Swaminatha Iyer, Retired Principal, Kendriya Vidyapeetha, Guruvayoor, Kerala for their invaluable help in tracing the references to TB in the Vedas.

REFERENCES 1. Rosenblatt MB. Pulmonary tuberculosis: evolution of modern therapy. Bull NY Acad Med 1973;49:163-96. 2. Flick LF. Development of our knowledge of tuberculosis. Philadelphia: Wickersham; 1925.

3. Webb GB. Tuberculosis. New York: Hoeber; 1936. 4. Dubos R, Dubos J. The white plague. Tuberculosis, man and society. Boston: Little, Brown and Company; 1952. 5. Waksman SA. The conquest of tuberculosis. Berkeley and Los Angeles: University of California Press; 1964. 6. Rubin SA. Tuberculosis. The captain of all these men of death. Radiol Clin North Am 1995;33:619-39. 7. Keers RY. Pulmonary tuberculosis. A journey down the centuries. London: Bailliere-Tindall; 1978. 8. Zimmerman MR. Pulmonary and osseus tuberculosis in an Egyptian mummy. Bull NY Acad Med 1979;55:604-8. 9. Evans CC. Historical background. In: Davies PDO, editor. Clinical tuberculosis. London: Chapman and Hall Medical; 1994. 10. Mangett JJ. Sepulchretum sive anatomica practice, vol 1. Observatio XLVII [3 vols]. London: Cramer and Perachon; 1700. 11. Duffin JM. Sick doctors: Bayle and Laennec on their own pthisis. J Hist Med Allied Sci 1988;43:165-82. 12. Brief history of tuberculosis. Available from URL: http:// www.umdnj.edu/~ntbcweb/history.htm. Accessed on September 24, 2008. 13. Kaufmann SHE. Robert Koch, the Nobel Prize, and the ongoing threat of tuberculosis. N Engl J Med 2005;353:24236. 14. Sakula A. Robert Koch: centenary of the discovery of the tubercle bacillus, 1882. Thorax 1982;37:246-51. 15. Daniel TM. Robert Koch and the pathogenesis of tuberculosis. Int J Tuberc Lung Dis 2005;9:1181-2. 16. Calmette A. Tubercle bacillus infection and tuberculosis in man and animals [translated by Soper WB, Smith GB]. Baltimore: Williams and Wilkins; 1923. 17. Leaves from history-12. Anti-tuberculosis movement in India. Indian J Tuberc 2002;49:132. 18. Leaves from history-15. The Union Mission Tuberculosis Sanatorium, Arogyavaram, Madanapalle. Indian J Tuberc 2003;50:70. 19. Mahadev B, Kumar P. History of tuberculosis control in India. J Indian Med Assoc 2003;101:142-3. 20. The early days. Available from URL: http:// www.tbcindia.org/history.asp. Accessed on October 5, 2008. 21. Tuberculosis Research Centre. Available from URL: http:// www.icmr.nic.in/pinstitute/trc.htm. Accessed on October 5, 2008. 22. National Tuberculosis Institute. Available from URL: http:/ /ntiindia.kar.nic.in. Accessed on October 5, 2008. 23. Chadha VK, Kumar P, Jagannatha PS, Vaidyanathan PS, Unnikrishnan KP. Average annual risk of tuberculous infection in India. Int J Tuberc Lung Dis 2005;9:116-8.

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Epidemiology

3 AK Chakraborty

INTRODUCTION For the planning and subsequent review of the strategy for control of any communicable disease, information on its epidemiological situation and the trend is a virtual prerequisite. In a chronic infectious disease like tuberculosis [TB], the precise estimate on mortality as well as the prevalence or incidence over long-term needs to be obtained in order to study its time trend. Health information systems in developing countries are as yet inadequate to provide meaningful information on the above. Surveys therefore, need to be conducted, if possible repeatedly, in order to study the situation, especially in time dimension (1). At the same time, it should be realized that a TB survey is an expensive proposition. It is difficult to set up an organization with the required expertise and discipline and to ensure the availability of funds to carry out the surveys. The problems could be compounded many times over in the case of repeat surveys, necessary for studying the long-term time trend, as in TB, to be organized in a country of India’s proportion, and socioeconomic diversity. Until the early 1950s, the TB problem in India was estimated on the basis of some isolated surveys conducted at different times in several areas (2,3). The main conclusion that could be drawn from these studies was that TB was one of the major health problems in the country. The limited size of the population studied, and that too among special groups examined in these surveys, coupled with the differences in methodology, had made it difficult to compare the results obtained from these and make precise observations. Though, a series of surveys in the same community for the first time any-

where in India was carried out by Frimodt-Moller (4) to study the time dynamics of TB with or without an intervention, these were restricted to a small population group in south India. It was open to doubt at the time, to what extent the findings could be extrapolated to the country as a whole. In the mid 1950s, large-scale TB control measures were being contemplated as part of the five years plans. In the wake of it, it was thought essential to secure additional data, in order to provide the baseline information for assessing the effectiveness of the contemplated antituberculosis measures in course of time. A nationwide TB prevalence survey was accordingly conducted in India in 1955-58 (5). The nationwide sample survey conducted by the Indian Council of Medical Research [ICMR] 1955-58 (5) had succeeded in providing the basis for planned action in India, as was intended. Data generated from the study were profitably used by the programme-planners to decide upon the form and scale of the National Tuberculosis Programme [NTP], which was formulated a few years later both for diagnosis and treatment of TB (6). For example, the relative stress on the planned efforts towards making the TB services available in the rural areas was based on the observed distribution of both the population and the disease. Further, the overwhelmingly large distribution of the sputum smear-positive cases among the adults had a considerable bearing on the development of a simplified symptom-based programme of detecting cases on a national scale. Guided by the epidemiological dimensions and as a part of operational research activities, many other studies were carried out in the following years to pave the way for the

Epidemiology 17 development of a feasible programme. In the decades following the launching of the NTP in India, it has rather been an intriguing experience to observe the gradually ebbing levels of efficiency of the activities under it. It became clear that opportunities for meaningful intervention were being insidiously lost in India, principally due to a low level of programme management coupled with a grossly inadequate success rate of standard regimens, given under the programme conditions. The shortfall in expectations was attributed to the fact that the health care system could not afford the resources, both for the technology [diagnostic and treatment services] as well as for the running of a sensitive and effective management system required to ensure an adequate logistics support for the countrywide NTP. There was an all round realization on this as articulated by Pio (7), perhaps the most serious source of uncertainty is the possibility that there has been an overestimate of what can be achieved by the basic TB programme. In fact, there was no detailed information on how great a reduction in the problem can be obtained through the basic control programme in developing countries (7). As a result of this continued shortfall in cure-rate over the years, the TB situation in India was interpreted to be showing signs of an ‘epidemic of left-overs’, i.e., partially treated cases with extended life-span increasing the problem in terms of prevalence of disease, even though a reduction in incidence of cases or in transmission of infection was the expectation (1,8). This situation had developed over the last few decades prior to the nineties in India, notwithstanding the World Health Organization [WHO] observing in a 1974 document, ‘An effective national TB programme can be delivered under any situation, provided planning and application are guided by a clear understanding of the epidemiological, technical, operational, economic and social aspects’ (9). The dynamics as outlined by Grzybowski (1) need to be viewed in the light of relative uncertainty and lack of unanimity among the intervention planners (8,9), regarding the possible role of intervention dynamics in altering the course of epidemiology of TB in these countries. The dominant issue with the epidemiologists has for long been the challenge of observing a change following intervention in such situations. The foregoing has in fact been the essence of epidemiological situation and the human efforts to come to terms with it in the developing countries, especially in those with large population sizes, as in India and China.

During the last four decades or so, when the developing countries like India were trying to solve the nittygritties of running the TB programme, global research did make considerable headway towards reducing the morbidity and mortality from TB, to be achieved through effective management of cases. The key to success was identified to be the ability to obtain a massive cure-rate of the positive cases. Epidemiologists contend today, that through the achievement of an effective cure-rate [more than 85 per cent for sputum smear-positive cases], the problem could be drastically reduced in a foreseeable future (10). For an example, it is stated that an annual decline in the newly occurring TB infection to the extent of 14 per cent could halve the problem in five years. In contrast, an annual decrease of one to two per cent could achieve the same in about a century. Indian government with assistance from the World Bank and the WHO (11), in early nineties evaluated performance of the NTP and decided to start a Revised National Tuberculosis Control Programme [RNTCP]. The programme was introduced in a phased manner and now covers the entire country (12,13). In this chapter, the data on TB in India are reviewed keeping in view the special areas requiring to be addressed while planning, as also to suit needs of evaluation processes. It needs to be recalled that the load of infection and disease in the community, in its various forms and presentations, happens to be the result of some complex epidemiological processes at play. A short review of this background is followed by analysis of the Indian situation. Related information from the western epidemiological scenario are also presented in appropriate context, wherever necessary, in order to help appreciate the underlying principles and the concept. The following aspects of the Indian situation are discussed: [i] the course of progress from infection to disease in individuals as well as the community – the background behind the epidemiological concept of disease accumulation in the community; [ii] prevalence and incidence of TB infection as well as sputum smearpositive and -negative pulmonary TB, by age and sex in India; [iii] prevalence of TB infection and disease by socioeconomic status of population; [iv] time-trend and epidemiology of intervention in India, including prediction through modelling; and [v] risk factors impinging on the trend.

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In a susceptible host, following infection, the tubercle bacilli grow unhindered and exponentially at the site of entry [the lung], till three weeks or so [Figure 3.1] (14). The growth then ceases and this event is near synchronous with the development of tuberculin positivity in the animal. Simultaneously with this, the phase of bacillaemia ensues and the bacilli can be recovered from the other lobes of the lung and extra-pulmonary sites such as spleen also. In the immediate post-primary phase, bacillaemia results in bacillary implantation in the apical and sub-apical regions of the lungs. It is presumed that the dissemination takes place approximately at the time cell mediated immunity [CMI] supervenes and bacterio-

stasis has already set in at the site of entry [primary site], leading to stoppage of bacillary growth at that site. Even as their growth stops at the site of the primary infection, the bacilli, however, still continue to multiply in the primary free lobe of the lungs, and at other sites [Figure 3.2] probably because of local macrophage activation. Approximately, a period of 70 days or so is needed for the bacilli to get reduced to significant numbers at the primary site, followed by a similar phenomenon at the other sites. Through the CMI-activation, the site of entry is sterilized. However, the bacilli are still capable of surviving in low numbers at the apical and sub-apical regions. Thus, it could be observed during the course of these events that the host factor has a decisive role in limiting the effect of infection, on its own. It is postulated that subsequent development of the pulmonary TB [postprimary TB] could be the result of suppression of the CMI and consequent reactivation of the dormant bacilli harboured in the apical and sub-apical regions [endogenous reactivation pathway]. Alternatively, it could also be conceived to be due to infection by the bacilli afresh, and in an overwhelming dose, enough to override the CMI-barrier [exogenous reinfection pathway]. The latter is considered to be a strong possibility, especially in areas with a high risk of infection transmission. However, what strikes one as remarkable in the entire process of primary

Figure 3.1: Number of Mycobacterium tuberculosis recovered from the lungs in guinea pigs killed between 3 and 35 days after infection via the respiratory route Reproduced with permission from “Smith DW, Weigeshaus EH. What animal models can teach us about the pathogenesis of tuberculosis in humans. Rev Infect Dis 1989;11[Suppl2]:S385-93 (reference 14)”

Figure 3.2: Change with time in the number [log10] of Mycobacterium tuberculosis recovered from excised primary lung lesions and from lung lobes without primary lesions in guinea pigs killed 16, 22, 30, 41 or 56 days after challenge via the respiratory route Reproduced with permission from “Smith DW, Weigeshaus EH. What animal models can teach us about the pathogenesis of tuberculosis in humans. Rev Infect Dis 1989;11[Suppl2]:S385-93 (reference 14)”

INFECTION AND ITS PROGRESS IN INDIVIDUALS AND COMMUNITY: THE BACKGROUND BEHIND EPIDEMIOLOGICAL LOAD The epidemiology of TB in a community is the resultant of the interplay between the environmental conditions, socioeconomic state of the population, the host factors and the agent characteristics. The course of the events following infection as observed in a susceptible animal host is recalled here, before studying the course in human beings, followed by that in the community at large. Experience from Animal Models of Pulmonary Tuberculosis

Epidemiology 19 and post-primary phases of host-agent interaction appears to be the dominant host reaction in the large majority of cases, so as to prevent TB infection manifesting as a clinical form of TB disease in the susceptible host. Progress of Infection into Clinical Tuberculosis The course of development of clinical TB in an infected human being, during the entire period following infection is shown in Figure 3.3 (15). Primary infection is mostly a silent event and so could be many of the events taking place in the immediate post-primary phase. These go unrecognized. Only when symptoms develop, that a person is subjected to diagnostic testing. Most of the clinical forms tend to be cured in a natural course of events, and the affected individuals may become asymptomatic without treatment. The hypothetical dividing line, drawn in Figure 3.3, separates the recognizable clinical forms of TB from the silent ones, and could be called as the ‘Clinical Horizon’ (15). It could be observed that most of the infected persons remain below the

clinical horizon, never manifesting disease. Even when clinical forms develop and the line showing the course of clinical events is traced to be crossing the ‘Clinical Horizon’, the dominant host factor supervenes and there is at all times, an overriding possibility of self-cure. This has been observed even in pulmonary TB, as its natural dynamics, both during the pre-chemothera-peutic days, as also during the longitudinal surveys carried out by the National Tuberculosis Institute [NTI], Bengaluru, [earlier called Bangalore] (15). The self-limiting predilection for the curve of disease development in the course of its natural dynamics, as observed both in animal models as also in human hosts, finds an almost synonymous replay in the epidemic curve of TB in the community as well. The Course of Tuberculosis Epidemic A hypothetical epidemic curve of TB (15), adapted from Grigg (16) is depicted in Figure 3.4. The epidemic curve is essentially, the same as for any other infectious disease, with an ascending limb, the peak or transitional phase, a

Figure 3.3: Natural history of tuberculosis Reproduced with permission from “Gothi GD. Natural history of tuberculosis. Indian J Tuberc 1977;25[suppl]:1-12 (reference 15)”

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Figure 3.4: Secular curve of epidemics Adapted from references 15,16

descending limb and a steady endemic phase. The whole epidemic would last several centuries, instead of a few weeks or days, as in the case of other epidemics. The ascending limb is characterized by proximity between the rates of infection, disease and deaths, the gap between them widening as the epidemic would progress. The ascending limb is steeper than the descending one. The former is characterized by higher rate of disease and death in the underprivileged and in those who are relatively more susceptible, e.g., the females and young ones. The epidemic curve in the urban areas could be faster to develop, with higher rates than in the rural, because of higher transmission of infection taking place due to factors related to relatively more intercourse of population and destabilization of population groups. As the epidemic would develop in time, the urban rate would start declining, even when the rural rate is going up, causing a crossover. As the epidemic curve would be ageing, the relative peaks in respect of the mortality rates, disease and infection rates would be attained one by one, followed by decline; starting with the mortality rate—the earliest to reach the peak and start declining [Figure 3.5]. Based on the above relative behaviour pattern of indices within the hypothesis of the epidemic curve, epidemiologists would conveniently draw conclusions on the age of the epidemic in a given community (2,16,17). It is, however, argued that the benefit of progress in the socio-economic sector, which has often been ascribed to be the factor principally guiding the course of the epidemic, even without active intervention, has been very unequally distributed both between and within nations (18). As a result, the epidemic curve may not be

Figure 3.5: Development of the wave of tuberculosis epidemic through time as described by Grigg (reference 16). The tuberculosis epidemic curve develops through centuries. The essential proximity of infection, disease and mortality curves characterises the phase of spread [shown with arrow ‘a”]. Wide gaps between one and the other rate develop at the peak and descending limb [shown with arrow ‘b’]. In India, gaps similar to the latter, exist now Reproduced with permission from “Chakraborty AK. Tuberculosis situation in India: measuring it through time. Indian J Tuberc 1993;40:215-25 (reference 17)”

uniform, even within a given nation or a community. This factor of course finds an expression in Grigg’s model (16) for urban and rural curves following different courses. Because of this disparity and variable attributes of socio-economic nature within nations, it may not be possible to develop an epidemic curve for the whole nation, especially with those with large population sizes, as the disease behaviour in groups within it may not after all be uniform. It is argued that whilst it may be appropriate to conceive of TB epidemic curves for the industrialized nations, it may not be so for the others. In the latter, the transition from one to the other limb of the curve may not, after all, be uni-directional, as envisaged. Progress could also be followed by “counter-transition” in the epidemic, in case there is a lack of sustained direction of socio-economic transition over a long period of time, say over centuries. In the case of a long sustained phase of economic reversal, as happening in some of the sub-Saharan countries, there could even be several epidemic curves superimposed on one another. Moreover, superimposition by other variables such as HIV infection which is operational in these parts of the world is sure to influence the course of the curve.

Epidemiology 21 Grigg’s model (16) of course provides for small reversals of trends following the situations of deprivations triggered by war and pestilences, as seen in Europe during the world war years. Past these temporary aberrations, the course of the natural trend is resumed. Grigg (16) terms the former as “cyclic” and the long-term one, as secure from temporary fluctuations, as the “secular curve”. Of course it is possible to envisage rapid socio-economic changes as in Japan, hastening the epidemic transitions in time rather drastically. In such an instance, the progress of the epidemic curve could also be squeezed in time, one phase dovetailing into the other in rather rapid succession [accelerated model] (18). However, in such a contingency, the decline could no longer be as steep, after a time, as seen in the classical European model. It is pertinent to emphasize here the fact that even within the group of industrialized countries, the epidemic curves could be of different ages, for example the decline in England and Wales appeared to have accelerated 10 years later [1950 onwards] than in the Netherlands (19). Even within an industrialized country, the trend among the outside born group was different than in those indigenously born. For the purpose of the following the epidemiological trend in a community over a long time dimension, the hypothesis put forward by Grigg (16) is generally found convenient. However, it is conceded that for countries like India, China, etc., because of the large masses of people with socio-economic disparity within them, a single epidemic curve of TB for the country as a whole may be too much of simplification for a hypothesis. INDICES USED AND DEFINITIONS Tuberculosis situation in an area is conveniently measured in terms of death, prevalence and incidence of infection and disease. Definitions Used Death Death among the known cases of TB, has been described as case fatality; or that attributable to TB, among total population in the community, mortality. The term ‘mortality’ could be considered in terms of deaths among total cases of TB in a given community as indicated by Frimodt-Moller (4) in India. It is, however, more appro-

priate to consider only the excess mortality among the cases of TB for the purpose as per analysis carried out by Chakraborty et al (20). The latter excludes the possible occurrence of deaths due to natural causes in TB patients and gives figures of only the deaths attributable to TB disease in the community. In the RNTCP of the Government of India, deaths reported among registered TB cases are considered to be due to TB unless specified otherwise. Prevalence and Incidence of Infection Prevalence of infection refers to the number of persons infected with tubercle bacilli at a given point in time, based on information obtained on tuberculin testing of the population. Incidence of infection refers to the number of persons infected between two successive points in time among those not infected or, bacille Calmette-Guérin [BCG] vaccinated initially. The figures on incidence are obtained exclusively through community surveys, covering the same population repeatedly. Prevalence of Disease Prevalence of disease refers to number of persons diseased at a given point in time in the community and is usually arrived at through a survey. Incidence of Disease Incidence of disease refers to the occurrence of disease between two successive points in time in the community among those not initially affected. The information is derived through repeat surveys examining the same persons in the community. Prevalence and incidence of disease are considered in terms of culture-positive cases with or without smear positivity [C+], smear-positive cases [SS+] or, X-ray positive, culture/smear-negative cases [X+]. Sputum smear-positive TB patients diagnosed under the RNTCP in India are registered as ‘newly diagnosed’ SS+ cases. These are reported every year along with the new sputum smear-negative cases with pulmonary TB. It is inappropriate to consider the new SS+ cases diagnosed in the programme, to be equivalent to incident cases as synonymous with the incidence observed in epidemiological surveys. Under the programme set up, these cases could be a mix of newly arising SS+ cases during the course of the preceding year, along with the part of the

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prevalence of the past year[s]. Clarity in understanding the above is required to construct the picture of epidemiology of intervention. Concepts Regarding the Use of the Indices Death Death from TB is the most severe ‘fate’. Occurrence of death is the first of the indices to decline in the secular curve of a TB epidemic, followed by morbidity and infection in that order (16). Subsequently, however, it is not much informative to trace the course of the epidemic and to classify countries on the basis of their progress in the epidemiological situation. For example, TB death toll in several European metropolitan areas was nearly one per cent annually, at the height of the epidemic. It had reduced in course of the centuries long epidemic process, to be one to two per 100 000 population by the end of 1980s, that is a 500 to 1000 fold reduction (21). Presently, most TB deaths among the indigenous Europeans would occur in persons above the age of 65 years. To record significant change at that level among the indigenous general population group may not be practical. Thus, even though death ceases to be significant epidemiological information for the advanced countries, it could still possibly be a measure of the extent of success of the antituberculosis programme delivery and its management, in case of the developing countries. For example, it is reported that nearly 70 per cent of possible deaths between 1991 and 2000 in Peru (22), and nearly 46 per cent in China between 1991 and 1997 (23), were averted among sputum smear-positive cases of TB, through a heightened programme delivery. As an immediate and the most visible effect of antituberculosis intervention, prevention of death appears without doubt, to be an attractive index to the programme planners. For the purpose of this chapter, however, death is not included as an index to classify the countries in their progress towards “elimination” goal, in pursuance of the hypothesis of Styblo (24). Prevalence and Incidence Infection Prevalence of infection in the Indian context cannot be estimated accurately in those aged 14 years and above. Failure to demarcate the infected from the non-infected due to high prevalence of intermediate reactors in India in higher ages, does not allow prevalence

of infection to be a sensitive indicator (2). In fact, incidence of infection as studied among the unvaccinated subjects in younger age groups representing the “force of infection”, is the appropriate index to measure the TB situation in a community. However, estimating incidence would call for repeat testing of the same children. To avoid repeat tuberculin testing of the same children, as necessary to observe the incidence of infection, a mathematical estimation is carried out, using the figures on the prevalence of infection, in younger ages [say, in the 0 to 14 years old children] to obtain the incidence of infection. The latter is termed the annual risk of infection [ARI] (25). The ARI, which in the present times is increasingly being referred to as annual risk of TB infection, designed through the work of Styblo (26) and others in the Netherlands, is an innovative index. It is defined by them as “the proportion of the population which will be primarily infected or reinfected [in those who have been previously infected] with tubercle bacilli in the course of one year, and usually expressed as a “percentage” or as a “rate” (26). The ARI is calculated through the simple formula derived on the basis of the above work (27): R Where R A P

= = = =

1 – (1 – P)1/A ARI; average age studied; prevalence of infection.

The estimated ARI is actually demonstrated to be the same as the incidence of infection, worked out by repeat testing of the same population under Indian conditions (28), being the only experimental evidence in this regard anywhere in the world. It is understood that ARI is studied among the unvaccinated subjects only (25). However, in situations where mass BCG vaccination at birth or soon after is the national policy, it is not a convenient study subject to have, as most of the children will already be vaccinated. The alternative could be to study the incidence of infection in the vaccinated, on the lines as carried out originally by Raj Narain, for identifying the newly infected subjects by the differences of reactions method (29). Chadha et al (30) in a recent study have shown the infection estimates in the vaccinated and unvaccinated as not materially different. The same does not stand corroborated from other sources in India [Regional Medical Research Centre, Port Blair 2002, personal communication].

Epidemiology 23 While on the topic, it should be noted that for developing the information base on infection, both for prevalence and incidence, periodic community surveys have necessarily to be carried out and these serve as the only data source. This is so even for the industrially developed countries. Disease Whereas in most of the western European countries and others in the industrially advanced world, the data on disease and death are obtained mainly from national statistical reports, provided by the Ministry of Health and National TB Organization (16,21,22,31-34), no such data are available for vast population groups elsewhere, e.g., in India and China. Tuberculosis, for example, is not considered to be a notifiable disease in India and hence routine health data have not served as the source of information for estimating the disease state in the community. Periodic community surveys, sporadic and in different areas, dependent solely on an investigator’s convenience, are therefore relied upon, and extrapolated to observe and assess the TB disease situation in India (2,17). In the present chapter, estimates of the burden of infectious TB in India, were computed depending largely on the information obtained from community surveys carried out from time to time, beginning with the first ICMR survey (5). Additionally, the WHO global reports on programme monitoring, and some recent Indian monitoring reports (12,13) have also been used. It should be understood in this context that a nationally representative statement on the magnitude of the TB situation in India and its direct measurement of change in time, with or without intervention, are beyond the scope of observational studies. Several essential variables, identifiable or otherwise, seem to be affecting the trend, differently, from area to area. Only very complicated stratification procedures could probably satisfy the sampling needs of a representative national sample survey, which could be highly impossible (17). However, average rates could be worked out for the country; with best and the worst possible case scenario as attempted in this chapter. Data Source and Indices Used for Observing Trend Information on disease trend is available from repeat TB surveys carried out 1961 onwards, in various areas namely, Delhi [urban], Madanapalle, Bengaluru, Car

Nicobar and Tamil Nadu (2). The Tuberculosis Research Centre in Chennai [TRC] has recently brought out a comprehensive report on the disease situation in the area 1968 to 1986, along with that from a subset for the area till 1996 (35), as a follow up to their original report (36). The isolated tribal community in Car Nicobar is also further followed up in 2002 (37), following the first two surveys in 1986 and 1988. Of the repeat surveys, mentioned above, Delhi and Madanapalle had efficient treatment services for TB, provided in the study areas. The last two, namely Car Nicobar and Chingleput areas in Tamil Nadu, also had provision for treatment for every identified case, through the NTP operating with its given efficiency. The Bengaluru area survey, on the other hand, was planned to study the natural dynamics, without a programme in the area for the initial period of five years. It was intended to study the baseline problem making it possible to assess intervention effects with the programme introduced at a later date. At the time these surveys were originally planned, it had appeared logical to expect TB case prevalence rate to be reduced over a period of time, following intervention. However, it is now understood, both as a consequence of the above quoted Indian studies, as also from the earlier and path breaking study from Kolin, Czechoslovakia, that prevalence and incidence of cases are not affected over relatively short periods of time, unless of course very intensive and effective treatment of sputum smear-positive cases is carried out (26). This is especially true for the countries with a high infection transmission. Moreover, small rates of change neither in the case prevalence rates, nor in incidence, which are already small, could be appreciated in sample sizes, not specifically decided upon to be sensitive to register very small changes in them (17). Prevalence of real sputum smear-positive cases is likely to be a good epidemiological index, when the intervention measure is either very effective [close to 100%] or when there is no treatment at all (26). It is understood that inefficient treatment services would only multiply the prevalence of smear-positive cases, due to pooling of inadequately converted cases [vide infra, under Car Nicobar experience] (37). The incident cases, on the other hand, occur as a result of breakdown from among those previously infected decades back, as could be seen in Figure 3.3. The incidence rates are therefore constant year to year,

24

Tuberculosis

representing the ageing and progress of the infected cohort of previous decades, with time. In any case, the incident cases would represent the transmission taking place in the community decades ago and would represent the risk over a long period of time among cohorts of those infected in the past years, at varying yearly infection rates. The subsequent breakdown into cases may not, thus, necessarily represent the instant TB risk to the community. Also, incidence rates of cases are not expected to undergo any change following the best of interventions, in a comparatively short period of three to four years, given the long span of the TB epidemic. As against incidence of disease, prevalence represents a pool of “leftovers”, carried over time, reflecting a failure of the TB control measures. It should be noted that both the indices are observed in older age groups in the population. As it is to be presently discussed, the incidence prevalence ratio in India is about 1:3. In case an efficient TB control programme, targeting a sufficient number of sputum smear-positive prevalent cases in the community is run for a sufficiently long period of time, it could bring down the case prevalence, till probably the point when incidence and prevalence come to be in the same proportions in the community [1:1]. From studies by Styblo and his group (25) in the Netherlands, it is now understood that incidence of infection in the younger age group can really be the index representing the current transmission situation. A series of TB infection surveys, carried out at intervals of seven to ten years, depending on and related to the inter-

vention-efficiency in a given area, could give a trend, following intervention. In the Netherlands, Styblo (24) estimated that of the 14 per cent annual decline that was observed, nine per cent was due to the intervention measures that were instituted while the remaining five per cent represented the process of natural decline. On the same lines, in developing countries, the zero to two per cent natural decline should be augmented by another five to ten per cent decline achieved by the TB control measures for these measures to be cost-effective. As distinct from the prevalence and incidence of cases, ARI represents the direct and a near immediate consequence of the presence of bacteriological case load in the community [force of infection]. It has presently been recognized to reflect the current epidemiological situation in an area, in preference to the disease rates (25). It is also possible to calculate the TB trend in an area from the current ARI, with hypothetical rates of exponential decline. Table 3.1, gives an estimate of the ARI for an area five years ago, based on currently observed ARI [between prevalence of infection ranging from seven and ten, i.e., rates likely for Indian areas], calculated for three possible levels of exponential decline as calculated by Styblo et al (25). It is possible to work out appropriate sample size of population with the hypothesis of decline given above, to measure likely change in India or elsewhere in the developing world, making allowance for the Design Factor [say between 2 and 3], confidence intervals [CI] of the proportions in the population studied [95%], years

Table 3.1: Annual percentage decline in ARI among children aged 5.5 years by some selected initial prevalence rates of infection in them Initial prevalence rates of infection [%] * Risk this year 7.0 7.5 8.0 9.0 10.0

1.206 1.295 1.385 1.565 1.747

Approximate percentage decrease in ARI each year† Risk 5 years ago 1.400 1.503 1.607 1.816 2.026

Risk this Year 1.140 1.224 1.308 1.479 1.651

Risk 5 years ago 1.461 1.569 1.677 1.895 2.114

Risk this year

Risk 5 years ago

1.076 1.155 1.235 1.396 1.558

1.523 1.636 1.748 1.975 2.204

ARI = annual risk of infection * Only some selected prevalence rates as are likely to be encountered for Indian areas at the given age are shown † Percentage decline hypothetically selected to be at 3%, 5% or 7% only, to be close to Indian reality The reader is referred to reference 25 for other alternative selections of prevalence and change in ARI Source: reference 25

Epidemiology 25 intervening the surveys [say 7 to 10 years], relative proportions of annual change designed to be appreciated [say, upwards of 50% in 7 years] and relative precision of the estimates (2,17). Given the proportion of the BCG vaccinated children in India, this is also a variable to be considered in deciding the sample size. A word of caution on following epidemiological trend through repeat surveys including infection surveys may not be out of the place here. In order to follow the intervention-effects over a long time, large-scale ARI surveys need to be organized in a valid sample of unvaccinated children, from time to time. In view of the widespread use of BCG vaccination in India, and the usual complexities in carrying out community surveys, gathering of such exclusive data and their appropriate interpretation at repeated intervals, for a country of India’s proportion could be a difficult proposition. Moreover, estimating the disease incidence and prevalence from ARI is an exercise in modelling (38). The recommended rule of the thumb is not an universally corroborated observation (2,36,39). Whereas the figures on incidence of cases obtained on conversion from ARI data could be of use in planning for resources, its reliability in measurement of changes could be open to question. Notification data on disease were considered reliable when provided by programmes with an established surveillance system (21,34). In most developing nations it is unreliable to interpret it as community prevalence. Huge costs involved in obtaining incidence rates by conducting population surveys could be avoided if the routine data could be interpreted after necessary adjustments. However, for information derived from monitoring data to transcend itself from mere indicators of programme efficiency at their best, as at the present times, into indices of trend measurement, would require considerable efforts in this direction. SETTING THE GOAL OF INTERVENTION IN INDIA: THE EPIDEMIOLOGICAL CONTEXT The concept involved in setting the final “goal” of antituberculosis activity requires to be understood in the context of the tasks to be set and performed under it. Whereas, it is theoretically possible to “eliminate” a disease in humans, while the microorganisms remain at large, as could be envisaged in the case of some of the infectious diseases, e.g., neonatal tetanus, the terms “eradication” and “elimination” need not be used

synonymously (40). True “eradication” is ideally taken to represent a situation for the mankind, where the microorganisms are totally eliminated from the nature, e.g., smallpox. To call a disease state to be “eliminated”, on the other hand, there has to be a defined situation of the disease, falling short of total eradication of the microbes in nature. However, these need to be universally and globally available situations to qualify for the status of “elimination”. In other words, “elimination”, in the manner the term “eradication” is used, represents a global state of the disease. Intermediate states could on the other hand, be visualized [“close to elimination” or “virtual elimination”] under which, the existing situations could be expressed. Tuberculosis could in this context be defined as “eliminated” either in parts of the world, or, in terms of [i] cut in transmission, e.g., in yaws; or, [ii] manifestation of disease to prevent it from becoming one of public health importance, when judged against arbitrary levels of disease control and prevention, e.g., leprosy, TB, etc. In the case of TB, depending on the current epidemiological situation and trends in countries of the world, they could be seen to be on their respective paths and levels towards TB control and elimination. Whereas the required specifications for qualification for intermediate levels of elimination have been respectively defined for a few of the developed countries, as in the USA (41), these remain undefined in the case of most countries. In line with the hypothesis made by Frost (42) way back in 1940, the countries of the world seem to conveniently align themselves in two broad groups, namely, those in whom the “tubercle bacillus is losing ground”, so that a given number of sputum smearpositive transmitters “do not succeed in establishing an equivalent number to carry on the succession”, and the others, in whom “no such prospect is in sight” in the conceivable future. It is not a mere coincidence that the above alignment happens to be across the socio-economic divide, between the highly industrialized nations of the world and the so-called developing nations. It is also relevant to take into account an additional dimension of the problem; i.e., the huge population size in the latter, in absolute numbers, as well as in its escalation with time. Apart form the above two groups, there are of course others, in whom the TB situation may not be at either extremes of the divide. Following this broad posturing, countries of the world could be grouped in four major categories, as shown in

26

Tuberculosis

Table 3.2 (2,24,43). In arriving at the pragmatic definition of “goal” to be pursued by countries of the world (2), data on incidence of sputum smear-positive cases on “goal” to be pursued by the countries of the world, and prevalence of TB infection, likely to be attained by 2050, among the countries with the most favourable TB situation are used [Table 3.3]. While the term “control” is used by policy makers and programme managers in designating the long- term objective of the programme [RNTCP] in India, it should be understood that the parameters of “control” remain yet to be defined. This is for understandable reasons, in the context of the developing countries, where the specific ‘goals’ of TB control programme, as shown in Table 3.3 are rather distant and remote, say in the case of India, as compared to a Group I country, say the Netherlands [highlighted in Table 3.4]. Even then, it should be understood that the ‘goals’ of human endeavour, in its fight against TB , are for the first time defined in concrete terms [Table 3.3]. These are based on epidemiological situations, attained through the best possible of human efforts, anywhere in the world. Table 3.3 defines the stages that the countries could possibly pass through in their journey towards attainment of the final ‘goal’, i.e., “virtual elimination”. Table 3.5 provides the likely timetable for the journey. It is necessary to understand the terms “eradication” and “elimination” in their proper perspective. The term Table 3.2: Global tuberculosis situation [grouping of countries] ARI [%]

Annual decline [%]

0.1 to 0.01

> 10

0.5 to 1.5

5 to 10

1 to 2.5

3 to 5

1 to 2.5

0 to 3

ARI = Annual risk of infection Source: references 2,24

Group Group I Industrialized Countries [e.g., Netherlands, Norway] Group II Middle income countries [e.g., Latin America, West and North Africa] Group III Middle income countries [e.g., East and South-East Asia] Group IV [e.g., sub-Saharan Africa and Indian sub-continent]

Table 3.3: Suggested definition of goal Eradication

Elimination

Virtually identical with elimination Incidence of smear-positive cases: below 1 per 10 million population [Prevalence of infection in general population 0.1%]

Close to elimination Incidence of smear-positive cases: 1 per million population [Prevalence of infection below 1%] Source: references 2,24 Adapted and reproduced with permission from “Chakraborty AK. Epidemiology of tuberculosis: Current Status in India. Indian J Med Res 2004;120:248-75 (reference 3)”

eradication means “extinction of all bacillary sources of TB transmission, in all the countries of the world, in an irreversible manner”. In comparison, elimination is defined as a situation under which “virtual elimination” is attained in all countries of the world. Though Frost (42) had talked of an eventual “eradication”, the “goal” of antituberculosis efforts could obviously be less optimistic as seen from the preceding. Instead of “eradication” and “elimination”, as used interchangeably, even by Styblo, inspite of reservations expressed by himself on this score (24), the present chapter considers “eradication” and “elimination” to be outside the purview of human endeavour. Long-term epidemiological trend in TB, unaffected by and secured against short-term spikes or dips through transitory influences, is termed as “secular trend”. In respect of the ARI (9), there is an exponential decline in the case of countries with the best possible case scenario, say the Netherlands [decline up to about 14 per cent annually: some five per cent of it natural and the rest attributed to antituberculosis measures in specific]. For the worst case scenario, on the other hand, there could be situations varying between a rise [Afghanistan] to a position of minimal decline of between 1 and 1.4 per cent annually [Lesotho] (9,27,32). The problem is likely to be halved in five years in countries with the best possible

Epidemiology 27 Table 3.4: Task in front of Group IV countries set against Group I, for pursuing close to elimination status Country Present Incidence of smearpositive cases per million/year Most Advanced* India China

Epidemiological situation Qualification for ‘close to elimination’ status

Prevalence of infection all ages [%]

12-15 500† [850‡] 515‡

15 40

Incidence of smear Prevalence of positive cases infection all ages per million/year [%] 1.0

1.0

* Annual risk of infection 0.1% to 0.01%, annual decline 10%, ‘close to elimination’ status projected to be achieved by the year 2025 [e.g., Norway, The Netherlands] (Source: references 17,43) † Source: reference 39 ‡ Source: reference 32 Adapted and reproduced with permission from “Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248-75 (reference 3)”

Table 3.5: Global situation-time frame of achievement [best possible] Group I [e.g., The Netherlands] Prevalence of infection

Time

15%

Present

[Incidence of smear-positive cases: 12-15 per million]

9%

[2000]

1%

[2025]

[Incidence of smear-positive cases: < 1 per million]

0.1%

[2050]

Source: references 2,17,24 Adapted and reproduced with permission from “Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248-75 (reference 3)”

case scenario, without any such prospect in the others (9). Disease rates, expressed as incidence of smear positive cases in Group IV vs Group I countries in point, as at present, set against those required to be achieved in case the goal of elimination is addressed, are given in Table 3.4. It could be observed that for the Group I countries [The Netherlands] the annual incidence of 12 to 15 per million per year observed at present, needs to be reduced to less than one per million population per year, to achieve the ‘close to elimination’ status by 2025

(24). For the Group IV countries on the other hand, this could mean requiring the present incidence of sputum smear-positive cases of about 510 per million, as say in China (23), or 840 per million for India (32), to be brought down to one to two per million by that date (24) [Table 3.4]. Against this epidemiological scenario with respect to the Group IV countries, Canetti’s statement on priority as quoted by Styblo (10), merits recalling, “on the global level, and among the efforts required to make headway towards TB ‘eradication’, an absolute priority stands out imperatively: to develop chemotherapeutic methods, adapted to the conditions prevailing in “underdeveloped countries” (10). Following up, Styblo (10) had highlighted the challenge before the policy makers, “unless a massive increase in the cure rate for sputum smear-positive pulmonary TB was achieved, there would be no marked improvement in the TB problem in many developing countries for the fore seeable future”. One might consider here that the intervention effects need to be continuously evaluated in a regular ongoing manner [“monitoring”]. Without an effective monitoring, the improvements or otherwise in disease trend would not be documented. For such ongoing evaluation to take place, the development indicators need to be suitably designed, requiring these to be sensitive and easily obtainable. On sustained monitoring and agglomeration of such indicators, one could derive the course of the disease with time. Surveillance systems are, therefore, critical to build and sustain if one has to follow disease trend. Periodic surveys in some selected areas, do give

28

Tuberculosis

some information, but may not replace a disease surveillance system in the long run. TUBERCULOSIS PROBLEM: STUDIES ON INDIAN SITUATION Epidemiological Methods: Some Prominent Indian Studies Some of the more prominent Indian studies on this subject are described below. A Community-wide Tuberculosis Study in Madanapalle, South India [Madanapalle Study] It happens to be the mother of all the community surveys conducted in India, especially of the longitudinal epidemiological surveys (3,4). The field work was carried out in the period between 1950 to 1955, in a rural area of 336 km2 radius, covering a population of nearly 60 000 residing around Madanapalle town, with support from the WHO. The programme had centred around the Union Mission Tuberculosis Sanatorium, Arogyavaram and the Tuberculosis Field Research Centre at Madanapalle. The objective was to study the incidence and prevalence of infection and disease. Another of its aims was to see if it would be possible, within a foreseeable future, to reduce significantly the problem of TB in the community. The fieldwork consisted of mass mobile miniature X-ray [MMR] examination of the population aged fiveyears and more and tuberculin testing of the entire population on a house-to-house basis. This was followed by bacteriological investigation [sputum culture] of the persons found to have an abnormal X-ray. The BCG vaccination was also used for prevention and its efficacy studied. All patients detected in the study were offered treatment with provision for hospitalization of the infectious cases[C+]. It was an eye opener to conclude from results of the surveys that the intervention methods were inadequate to bring changes in disease prevalence [C+ cases] for the period of observation between 1950-55, as reported (3,4). However, the finding that has been severally corroborated in India and elsewhere in the world in recent times, appears remarkable in that, a well delivered intervention measure could succeed in visibly and dramatically bringing down the TB-related deaths in the community from 200 per 100 000 to 21 per 100 000 in a span of less than four years for the study under reference.

Tuberculosis Sample Survey in India A Sample Survey, eponymously the ‘National Sample Survey’ [NSS] was carried out between 1955-58, under the auspices of the ICMR (5). Six zones were selected, rather on practical considerations than otherwise; namely, Madanapalle, Hyderabad [both from Andhra Pradesh], Patna [Bihar], Trivandrum [Kerala], Delhi and Calcutta [West Bengal]. Though the survey was not expected, by design, to provide average estimates of morbidity on a national basis, it still did provide information from some selected areas covering wide geographical expanse of the country. The six zones included in the survey had covered 40 per cent of the Indian population. The three cross-sections included in each zone [i.e., the largest city, medium sized towns and accessible villages] had indeed covered 80 to 90 per cent of the population within the zones selected, with the exception of Trivandrum where 62 per cent and of the Calcutta zone, where only Calcutta city could be covered. The blocks within the cities, towns and the villages to be surveyed were decided upon, following random sampling devices. Total eligible population added up to 131 319 for cities; 59 548 for towns and 137 271 for villages. A co-efficient for variation of 15 per cent for the estimates of morbidity was arbitrarily considered adequate. As there was paucity of data on sampling variations, the sampling size for achieving the desired level of accuracy of the estimates was only approximate. The sampling ratio was about 0.2 per cent of the eligible population. The actual operations in the field were limited to: [i] population census and collection of information on economic status by recording the nature of dwelling unit i.e., ‘kutcha’ house [thatched hut], ‘pucca’ house [builtin unit]; [ii] one miniature 70 mm X-ray of persons aged five years and more [eligibles]; [iii] collection of sputum [2 samples] and two laryngeal swab specimens for bacteriological examinations from persons with suspicious X-rays, by paying a single visit. The sputum samples were examined by direct smear for acid-fast bacilli [AFB] and the laryngeal swabs were subjected to culture for Mycobacterium tuberculosis. No tuberculin testing was carried out; hence no estimate of infection was available from this cross-sectional survey. Information was available for X-ray active and bacteriological disease status for the areas studied.

Epidemiology 29 Tuberculosis Studies in Bengaluru Area: National Tuberculosis Institute Longitudinal Epidemiological Studies The objective of these longitudinal studies was to observe the natural history of pulmonary TB under the existing socio-economic conditions in an area, i.e., the epidemiological dynamics which could occur, without the influence of any control measures, such as BCG vaccination or chemotherapy. It is probably the first time ever anywhere in the world, that the natural dynamics of TB was studied. A rural population residing in 119 randomly selected villages of three of the administrative sub-divisions [Taluks] of Bengaluru district were surveyed four times between 1961 to 1968 (39). Three surveys were carried out at intervals of one-and-a-half, one-and-a-half, and two years. At each of the surveys, each person was identified by carrying out house-to-house visits and given a tuberculin test following identification of the BCG scar, if any. All persons aged five years and more were X-rayed with a 70 mm X-ray in the villages and those with radiological abnormality were bacteriologically investigated [two samples collected in the villages, both examined by smear test for AFB and culture for Mycobacterium tuberculosis]. No intervention of any kind, either by offering BCG vaccination or treatment of cases detected during the survey, was carried out. The NTP was not operating in the area at the time the four surveys were carried out. Following the fourth survey, the NTP was implemented in the three taluks constituting the longitudinal survery area. Eleven years after the fourth survey, i.e., in 1977, a fifth survey was carried out in a sub-sample of 22 of the earlier 119 villages (44). The same methodology, as in the earlier surveys was followed with the objectives to study changes in TB situation for the area over a period of 16 years [1961-1977]. Even though the study population was only a meagre 14 382, useful observations were made on the trend. A follow-up to these studies was undertaken 23 years after the first survey between 1984 and 1986 (28). Two of the three taluks, which had formed the area under the original longitudinal survey, were selected on grounds of logistics. In these two taluks 40 villages were earmarked for the study on the basis of simple random sampling. These villages were different from the 119, where longitudinal studies were earlier conducted. A total of nearly 30 000 persons were surveyed on a house-

to-house basis. Tuberculosis testing of persons aged 0 to 44 years was carried out. Persons with test induration size of 10 mm or more were eligible for sputum examination, besides all those aged 45 years or more without discrimination. The tuberculin test results from this survey were converted into ARI and were compared with ARI worked out for the area derived from earlier surveys (28). This was the first time that TB trend in the form of ARI was available for any area in India over a fairly long period of 23 years. The results from the above series of surveys could be taken to represent the natural dynamics of TB in a rural community for the first five years, followed by a TB situation for the remaining 16 years or so, after implementation of the District Tuberculosis Programme [DTP]. Even though it was not the stated objective of the study to observe the trend of bacteriologically positive disease in the area, there was nevertheless an opportunity to obtain the prevalence rate of smear-positive cases in the community in 1984 to 1986 and its trend over a period of 23 years (45). Tuberculosis Prevention Trial, Madras [Variously known as Feasibility Study, Chingleput Trial or BCG-Trial] This long-term study in a large population in rural south India was started in 1968 and the population was comprehensively followed up for a period of seven-anda-half years to start with (36). The elaborate follow-up procedures adopted in the BCG-Trial were designed with the objective to study the efficacy of BCG vaccination in preventing incidence of TB in the non-infected, by different strains of BCG and their dosages. For this a factorial design was employed, the factors being the vaccine strain and placebo and the dosages. It was also designed to have a common control group for all the vaccinated groups, who were administered a placebo. Thus, epidemiological data on TB in the community in the form of prevalence of infection, radiological and bacteriological disease as well as incidence of infection and disease were available from the study, both for the control as well as the treated group. Adequate size of the population was selected so as to give accepted CIs for incident cases etc., so necessary for the efficacy trial. This was possible as the study had prior knowledge on likely incidence in the community from the Madanapalle study and NTI longitudinal epidemiological studies to arrive at a proper sample size. A very credible set of data

30

Tuberculosis

are, thus, available from the study on the epidemiological situation in India (36). A total population of 360 000 persons residing in 209 contiguous panchyats [sampling units] and one town [sampling unit-blocks] in Chingleput district of Tamil Nadu was selected. Whole of one Taluk [Tiruvallur] and part of another [Tiruttani] formed the study area. All individuals aged one year and above were X-rayed, using 70 mm miniature mass radiography [MMR] unit, visiting the villages. From such persons, whose X-rays were interpreted as abnormals, two specimens of sputum were collected and examined by direct smear for AFB and cultured for Mycobacterium tuberculosis. Total number of persons actually undergoing the tests had numbered 263 842 for tuberculin test, and 213 000 for X-ray. Immediately following the tuberculin test in an individual BCG vaccine and placebo were allocated randomly. Intensive efforts were made, to re-survey the population every two-and-half years and more frequently. The same techniques of tuberculin testing and X-ray were followed at re-surveys, as during the initial survey. Selective active case finding was conducted in persons found to be suspects during the initial survey. Simultaneous efforts were made through passive case finding at the identified general health service clinics to diagnose all new patients of TB occurring in the community. Cases diagnosed were treated on domiciliary basis in an appropriate manner. Mutually exclusive random samples of the population were re-tested with tuberculin at intervals. After the initial survey in 1968 to 1969 [Survey I] tuberculin testing was repeated twice in two of the Panchayat Unions, following the same methods, twice-at an interval of 10 years [Survey II], and then at 15 years [Survey III] (46). Owing to high prevalence of non-specific infection in the area, the testing was carried out only in a population aged one to nine years at each survey. Data on incidence of infection from 8703 and 9709 children at Surveys I and II respectively were used for computing the 10-year trend; and from 4808, 4965 and 4889 children at Surveys I, II, and III respectively, for observing the trend for the 15-year period. Results over a period of 15 years, both for the protective effect of BCG as well as prevalence of disease are also available from this study (47). The epidemiological situation obtained in the area pertaining to the period 1991 to 1996 has been made available in a recent report (35). This makes it the longest

ever that a given community in India has been repeatedly surveyed for the purpose of studying disease trend [vide infra]. Tuberculosis Trends in New Delhi [New Delhi Study] Apart from the information that is available from the NSS, the New Delhi Study (48) is the only other source, from which the TB situation for an urban metropolitan area in India could be observed. The area is thickly populated, inhabited by low-income families. The New Delhi Tuberculosis Centre [NDTBC] runs a TB clinic of great repute for the area. A population of nearly 30 000 persons was repeatedly surveyed for 30 years [1962 to 1991] by the NDTBC. Following the baseline survey in 1962, seven more surveys were carried out. An interval of two-and-half years was maintained up to the fifth survey. The interval between last four surveys [between the survey numbers V and VI, VI and VII, VII and VIII] were four, six and nine years respectively. The survey procedures, which had remained unchanged throughout, consisted of [i] accurate census on house-to-house visits; [ii] about 90 per cent of all eligible persons were X-rayed and [iii] ‘X-ray abnormals’ were further investigated and followed up at the Centre. Investigations amounted to at least two to three radiographic examinations, two cultures of sputum or laryngeal swab for Mycobacterium tuberculosis and clinical observation extending sometimes up to six months. Between 86 to 97 per cent of X-ray abnormal were further investigated. All diagnosed patients were treated appropriately at the NDTBC. A report on all eight surveys gives data on prevalence and incidence on TB for the urban area with a running TB control facility over a fairly long time frame. However, it could now be said that through deficient appreciation of the relevant indices, sensitive to changes in the TB situation for an area, only culture-positive TB disease was sought to be measured in the study, leaving out SS+ case and the ARI. To that extent the findings are less appropriate in reflecting the trend following intervention, for a relatively short period. India: Distribution of the Problem Annual Risk of Infection Annual risk of infection from different parts of India till the middle of the last decade [1991 to 1996] was reported

Epidemiology 31 to be between one and two per cent [Table 3.6] (2,3,35,37, 49-55). There have been fresh estimates available from a few areas in the country since then, the best possible situation being reports from Kerala [ARI, 0.75%] (49). The high rates of ARI observed in Thane in the outskirts of Mumbai [3.3%] (55) and in the Care Nicobar district [3.8%] (37) merit mention, being among the worst case scenario on record. The rate in Thane urban area is interpreted to be due to HIV seroprevalence and to the increasing component of slum dwellers in the fast expanding population group inhabiting the area (55,56). The ARI from Car Nicobar, on the other hand, is the only documented instance of ARI in India, escalating with time. It is discussed in detail later, in the section on

epidemiological trend, along with the data from Chingleput area. The recent data on ARI, as shown in Table 3.6 confirm the author’s earlier suggestions of differences in TB situation between areas in India (17). It could be recalled that in the Bengaluru area the urban-rural difference in ARI was also evident with rural ARI declining from 1.1 per cent to 0.61 per cent in 23 years up to 1985 (28), urban ARI being 1.67 per cent (50). Prevalence of Pulmonary Tuberculosis The data presented in Table 3.7 are the outcome of several surveys, conducted from time to time in different areas of the country. An average rate of infection and disease

Table 3.6: Annual risk of infection in various areas in India Study (reference)

State/District/Region

Kerala TB Association (49) NTI, Bengaluru (2) NTI, Bengaluru (2) NTI, Bengaluru (2) NTI, Bengaluru (50) NTI, Bengaluru (51)

Kerala, Trivandrum Karnataka, Tumkur Dist Karnataka, Bengaluru rural Karnataka, Bengaluru rural Bengaluru, urban North India Rural Urban Uttar Pradesh, Rae Bareilly Uttar Pradesh, Hardoi Uttar Pradesh, Jaunpur Gujarat, Junagadh Western India Rural Urban Rajasthan Chingleput, rural Chingleput, rural Orissa Rural Urban Car Nicobar Car Nicobar Maharashtra Nagpur, rural Nagpur, urban Thane, rural Thane, urban

NTI, Bengaluru (51)

NTI, Bengaluru (52) NTI, Bengaluru (53)

Urmul Trust (2) TRC, Chennai (35) DANIDA (54)

Andaman and Nicobar Government (2) RMRC, Port Blair (37) MGIMS, Sevagram, NTI, Bengaluru (55)

Period of study 1991-92 1960-72 1962 1985 1996-99 2000-01 2000-01 2000-01 2000-01 2000-01 2000-01 2000-02 2000-02 2000-02 2000-02 1995 1969-84 1991-1996 2000-02 2000-02 2000-02 1986 2002 2000-02 2000-02 2000-02 2000-02 2000-02

ARI [%] 0.75 1.66-1.08 1.1 0.61 1.67 1.9 1.62 2.6 2.3 1.9 1.5 0.73 1.8 1.5 [5.9-9.7]* 2.4 [8.3-17]* 1.44 1.8-1.9 2.9-3.2 1.72 [7.5-11.3]* 1.62 [7.2-10.3]* 2.48 [7.7-19.8]* 1.53 3.8 1.2 [6.34-6.38]* 1.6 [8.44-8.50]* 1.6 [8.07-8.10]* 3.3 [15.75-15.80]*

*numbers in square brackets indicate 95 per cent confidence intervals ARI = annual risk of infection; DANIDA = Danish International Development Agency; RMRC = Regional Medical Research Centre; MGIMS = Mahatma Gandhi Institute of Medical Sciences; NTI = National Tuberculosis Institute Adapted and reproduced with permission from “Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248-75 (reference 3)”

32

Tuberculosis

categories for the country as a whole are presented in this table, along with the range, to represent the best and the worst possible case scenario. Necessary corrections and refinement to the existing rates of disease are also suggested (2). For the latter, specific survey results devised to study and correct the observed inaccuracies and inconsistencies in the previous estimates are relied upon (2). Appendix Table 3.1 presents the necessary database for corrections given in Table 3.7. This method for computation of average rate with the range is adopted, since a representative sample for the country as a whole, has so far eluded the researchers, as also the sample, sensitive enough to discriminate prevalence or incidence rates between one area and the other (17). As already explained, notification of sputum positive or other diagnosed cases of TB is not yet the source of data on incidence and prevalence in India.

A more detailed and extensive exercise was conducted by Dye et al (32) directed towards providing an average estimate for the country. This was a part of the global task, in order to make a consensus statement of the problem, [burden] by regions of the world. The average rates of disease and infection [both prevalence and incidence], as well as death were computed. Data from: [i] survey results, as in previous para for India; [ii] incidence of cases, calculated out of the ARI based on an empirical model suggested by Styblo (38); and [iii] the likely disease rates computed from “notification” of cases made to the WHO (13), were mutually compared and assessed for reliability and internal consistency in this work. These data are shown in Table 3.7. The problem is expressed in terms of rates and absolute numbers, based on a population of 1000 million, both for prevalence as well as for incidence [Table 3.7].

Table 3.7: Problem of tuberculosis in India [average for the country] [estimated for 1000 million population] 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

11.

Population: 1000 million [850 million in 5+ years age, 85%] Prevalence of infection* Rate: [a] 38% all ages [a1] 44% all ages Prevalence of radiologically active abacillary pulmonary TB [X+ cases] Rate: [a] 16 per thousand [3.0, 2.6-4.7] Prevalence of all forms of TB disease Rate: [a1] 5.05 per thousand Prevalence of culture-positive cases [C+ cases] Rate: [a] 4.0 per thousand [9.6, 3.0-11.0] Prevalence of smear-positive cases [SS+ cases] Rate: [a1] 2.27 per thousand Prevalence of total pulmonary TB cases Rate: [a] 20.0 per thousand [9.0, 5.6-15.7] New culture positive [C+ cases] arising annually Rate: [a] 1.3 per thousand New smear positive [SS+ cases] arising annually Rate: [a1] 0.84 per thousand Mortality rate [annual] Rate: [a] 50-80/100 000 [a1] 46, 28-71/100 000 Case fatality rate [annual] Rate: [a] 14% of untreated C+ cases [a1] 24% of all TB

Number [b] 380 Million [b1] 440 million Number: [b] 13.6 million [2.6 million] Number: [b1] 5.05 million Number: [b] 3.4 million [8.2 million] Number: [b1] 1.93 million Number: [b] 17.0 million [7.7 million] Number: [b] 1.1 million Number: [b1] 0.71 million Number: [b] 0.43-0.68 million Number: [b1] 0.39, 0.24-0.60 million Number: [a1] 0.48 million [b1] 1.21 million

Data given under a and b = worked out by Chakraborty (2) from Indian survey data; data given under a1 and b1 = worked out by Dye et al (32) by aligning several hypotheses and sets of data from India *Infected: more than 50% in age group 40 years and more; disease rates applicable to population in 5+ years age for rows 3,5 and 6-9; for rows 4 and 10 = calculated for persons in all ages; rates, their ranges and numbers in millions shown in bracket = as per revision suggested by the author on the basis of correctional surveys, vide Appendix Table 3.2. For average absolute numbers on revised rates in bracket = range not presented; only minimum number in the range shown. Current estimates allowing for time dynamics after Corbett et al (57) TB = tuberculosis Adapted and reproduced with permission from “Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248-75 (reference 3)”

Epidemiology 33 Appendix Table 3.1: Suggested revision of average tuberculosis rates [per 1000] [India] Variable X+ C+ Total C+:X+

Currently used*

Suggested rate†

Correction factor‡

16.0 [10.0-19.0] 4.0 [2.0-8.0] 20.0 [13.5-25.0] 1:4

3.0 [2.6-4.7] 6.0 [3.0-11.0] 9.0

0.2 1.4

2:1

-

-

Suggested rate = currently used rate × correction factor Numbers in square brackets indicate 95% confidence intervals X+ = radiologically active, bacteriologically negative; C+ = culture positive Source: Chakraborty AK. Prevalence and incidence of tuberculosis infection and disease in India: a comprehensive review. Geneva: World Health Organization; 1997.p.1-26. WHO/TB/97.231. Available at URL: http://whqlibdoc.who.int/hq/1997/WHO_TB_ 97.231.pdf. Accessed on October 5, 2008 (reference 2)

standardization in calculating the burden from time to time, by applying age-wise prevalence rates of earlier surveys to later populations, has been appreciated in recent times and needs to be addressed for computing the absolute numbers (56). Being an elaborate task in modelling in itself, the same has not been attempted here. The global data on TB burden as presented in Dye’s (32) estimate are updated for 2000 and 2001 by Corbett et al (57), based on the current results of intervention measures and population escalation. The rates pertaining to the Indian scenario for 2001 are presented in Appendix Table 3.2. The hypothesis used for the parameter estimates in arriving at the current rates and burden are also shown there. For the reason that the population for India has since changed, the estimated absolute numbers are not quoted in Appendix Table 3.2. However, the rates could be applied to the current population size in India to get the likely Indian TB burden for the year. Area-wise Distribution

The hypothesis in computing the numbers diseased for the present population, is that the disease rates in India remain static, but absolute numbers increase owing to demographic reasons. It also needs to be pointed out in this connection, that the prevalence and incidence rates are applied to 1000 million population, across the board, in the manner it was applied to 8.5 million in the previous estimate (2), without making allowances for changes in age sex-wise composition of the population between the two, taking place during the decade. The issue of lack of

From the results of the country-wide sample survey conducted by the ICMR (5), it was observed that the prevalence rates for this country as a whole were by and large similar in six zones studied and across the urbanrural divide (5). On a careful review of the above data, it could, however, be observed that the prevalence rates throughout the country were really not similar (17). In the first place, the sampling framework did not allow testing of the hypothesis of difference between the areas and zones, if any. Further, the prevalence rates, on further

Appendix Table 3.2: Tuberculosis prevalence and incidence: some average current estimates [per 100 000] Prevalence of infection [%]

46

Tuberculosis cases Prevalence*

Incidence* All forms

SS+

All forms

SS+

178

79

444

199

Mortality All forms* Due to HIV [%] 44

4.8

*Allowing for the time dynamics following intervention, as in 2001 Hypothesis on parameters used: [i] ARI falling at 2.5% annually [ii] Ratio of ARI to incidence of SS+ cases [cases per 100 000 population for 1% of ARI] = 60 [range 40-80] [iii] Trend in incidence of all forms of TB [% per year] = Best [-] 1.3 [iv] Proportion of tuberculosis cases [SS– / SS+] on treatment [%] = on DOTS 0.1, on non-DOTS 0.7 [v] HIV prevalence in new adult TB cases = 4% [vi] Population of India in 2003 = 1 025 096 104 ARI = annual risk of infection; SS+ = sputum smear-positive; SS– = sputum smear-negative; HIV = human immunodeficiency virus Data source: reference 57

34

Tuberculosis

assessment with the help of 95 per cent Cls do not support the hypothesis of lack of difference between the geographical areas [Table 3.8]. For example, for the city areas under the Madanapalle zone, the C+ case prevalence rates [2.40/1000; 95% CI 1.64 to 3.16 were significantly lower than those in towns [8.13/1000, 95% CI, 6.58 to 9.68], or in the villages [6.11/1000; 95% CI, 5.02 to 7.20]. It will not be out of place to mention here, that from the data shown in Table 3.8, as also from information available from surveys elsewhere in India over the years, Bengaluru area falling within the Madanapalle zone in the country-wide ICMR survey, appears to have the best possible TB case scenario anywhere in India [vide infra]. Further, the bacteriological case prevalence rates [C+] for Trivandrum city [2.96/ 1000; 95% CI 2.14 to 3.78] were different from Patna city [6.38/1000; 95% CI 5.10 to 7.66]. Citing the case of metropolitan cities also, it could be seen that the prevalence rate for Calcutta city [6.39/1000; 95% CI 5.16 to 7.62] differed from Delhi city [4.06/1000; 95% CI 3.23 to 4.89]. Tuberculosis disease prevalence rates are not similar between areas in India. This is understandably so, given Table 3.8: Culture-positive case [C+] prevalence of tuberculosis by geographical areas Zone

Area

Calcutta Delhi

City City Towns Villages City Towns Villages City Towns Villages City Towns Villages City Towns Villages

Hyderabad

Madanapalle

Patna

Trivandrum

95% Confidence Average C+ case prevalence intervals* [per 1000] Lower Upper 6.39 4.06 2.45 2.49 4.18 3.44 2.29 2.40 8.13 6.11 6.38 5.25 5.85 2.96 3.20 2.59

5.16 3.23 1.54 1.87 3.44 2.32 1.70 1.64 6.58 5.02 5.10 3.83 4.58 2.14 1.93 2.08

7.62 4.89 3.36 3.11 4.92 4.56 2.88 3.16 9.68 7.20 7.66 6.67 7.12 3.78 4.47 3.10

* Calculated from reference 4 Adapted and reproduced with permission from “Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248-75 (reference 3)”

the regional diversities in terms of ethnic, economic, cultural complexities and variables, pervading the vast land masses and the population size of near continental dimensions. With this background information, one could now argue that the average prevalence rate [and incidence rate also] as worked out by Dye et al (32) [Table 3.7], may not be used indiscriminately for all areas of the country, as a sort of target, with the ostensible purpose of evaluating supposedly epidemiological gains, through a set of programme activities, as currently being practiced under the RNTCP. This could of course be used for resource mobilization and advocacy purposes. Measurement of change on a time series or of geographical differences would require statistically sensitive indices of disease [and infection] in order to test a given hypothesis of change or difference [or, otherwise] by examining an appropriate population sample, calculated for the purpose (17). The grossly average and well-rounded rates may not lend themselves to a measurement of change in them with the required degree of precision. Prevalence and Incidence by Age Both prevalence and incidence were observed to rise with age, in both sexes, in surveys conducted so far in the country. The rise is seen in all categories of cases, namely X+, C+, and SS+ in the community [Figure 3.6] (36). The information on the proportional distribution of smearpositive prevalence cases in the community by age [1984 to 1986] in the Chennai area, is given in Table 3.9 (35). It could be observed that, of the prevalent cases in the community, the age-wise proportion of cases were substantially higher 35 to 44 years onwards, to be at the peak for the age group 55 to 64 years [28.4%]. Moreover, it remained as high as 22.67 per cent in age-group 65 years and above, being similar to that in 45 to 54 years. This could be contrasted to the distribution proportions of 0.7 per cent, 1.54 per cent and 7.25 per cent in age groups, 10 to 14, 15 to 24 and 25 to 34 years, respectively. In contrast to the epidemiological distribution given above, the age-wise proportional distribution of smearpositive cases for India, diagnosed both under the NTP and RNTCP, combined for the year 2000 (13) is presented in Table 3.10. The peak concentration is seen to be at 25 to 34 year age group, declining thereafter. In 55 to 64 and 65 years and above age groups, only 10.47 per cent and 5.91 per cent of all the cases are respectively

Epidemiology 35

Figure 3.6: Prevalence of disease by age, sex and method of diagnosis Categories of cases: A = culture-positive on sputum specimens B = culture-positive on one sputum specimen only C = culture-negative, smear-positive [3+ or more acid-fast bacilli] D = abacillary, rated as active on miniature mass radiography by two readers Source: references 2,36 Adapted and reproduced with permission from “Chakraborty AK, Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248-75 (reference 3)”

distributed. The relative concentration of diagnosed SS+ cases to be in the younger age group, peak in 25 to

34 years, is a phenomenon also seen in some of the African countries, who are similarly placed with India with respect to TB situation as Group IV countries, e.g., Tanzania [1985-87], Mozambique [1989], Malawai [1989] and Nicaragua [1989] (58). The situation of less than expected detection of cases in older age groups, as observed under the NTP and RNTCP in India, could be attributed to deficient attendance of the symptomatics in older age groups at the general health service facilities, i.e., not commensurate with the likely prevalence of TB among them (59). The situation in India appears not to have altered, since, be it under NTP, or RNTCP. It appears to be a problem of access owing possibly to a degree of discrimination by the society. The latter seems, in a way, to decide on the attendance pattern of the sick persons to the health delivery outlets, younger people being possibly encouraged and preferred to take action and seek relief. The programme, thus, seems to benefit the younger and socio-economically the more important group within the population, i.e., the younger age group, as against the older population group. The above discriminatory situation seems to have an epidemiologic significance of no mean consequence. The large majority of the persons transmitting infection and most of the uninfected and susceptible population at risk of being infected, seem to distribute themselves at the two extremes of the age groups, the former being in the older age groups and the latter in the younger age groups and children. The former remain comparatively unattended to, under the programme, and keep on increasing in number and proportion in comparison to the middle age groups. Thus, a relative concentration of cases seems to be occurring by age. Due to their position in the society and restricted movement, the persons in the older age groups seem to be in close proximity to the susceptible young children within the family, increasing chances of transmission. The situation in the western countries, on the other hand, [i.e., Group I countries] appears to be quite different in this regard. In 1970, for example, 70 per cent of the cases in Sweden, diagnosed among the Swedish born, were in the age group 65 years and above. In England and Wales also similar was the case (21). The difference in this regard may not only be among the countries, depending on their grouping, I through IV. Even within the most developed countries of the world, the age

36

Tuberculosis Table 3.9: Age distribution of smear-positive prevalent cases [for 100 000 population] in a survey area 1984 to 1986* Age [years] 10-14 15-24 25-34 35-44 45-54 55-64 65+ All*

1968-70

1973-75

1979-81

1984-86

35 [0.88] 108 [2.73] 425 [10.74] 729 [18.42] 899 [22.71] 994 [25.11] 768 [19.40] 3958 [457]

14 [0.3] 111 [2.40] 461 [9.96] 691 [14.93] 1127 [24.36] 1218 [26.32] 1005 [21.72] 4627 [511]

8 [0.20] 105 [2.61] 404 [10.06] 570 [14.19] 1050 [26.14] 966 [24.05] 914 [22.75] 4017 [444]

3 [0.07] 62 [1.54] 292 [7.25] 693 [17.20] 921 [22.86] 1144 [28.40] 913 [22.67] 4028 [428]

* Figures in square brackets indicate % of total cases † Standardized prevalence rates Source: reference 35

Table 3.10: Age distribution of smear-positive cases in India [year 2000] Age [years] 0-14 15-24 25-34 35-44 45-54 55-64 65+ All

Total

Non- DOTS

DOTS

3838 [2.02] 35458 [18.65] 45377 [23.86] 42597 [22.40] 31746 [16.69] 19902 [10.47] 11231 [5.91] 190149

2041 [2.08] 14055 [14.32] 23911 [24.36] 22750 [23.18] 17450 [17.78] 11205 [11.42] 6735 [6.86] 98147

1797 [1.95] 21403 [23.26] 21466 [23.33] 19847 [21.57] 14296 [15.54] 8697 [9.457] 4496 [4.89] 92002

Figures in square brackets indicate % of total cases Source: reference 13

distribution of TB cases has a direct relationship with the socio-economic and ethnic variables. For example, the relatively unfavourable epidemiological scenario, occurring among the American minorities is distinctly different from that among the non-Hispanic whites, as also the proportional age distribution of cases occurring in them (11,60). It is possible that apart from the social and programme driven discrimination, the concentration of cases in older age could take place as a secular trend of disease (16), as also due to demographic situation, related to higher population size in the elderly, with time. The situation prevalent in India is a symptom of its socioeconomic milieu, interacting with the disease situation. It also remains a moot point fit for investigation, whether the intervention programme, as it is in India, could result in further concentration of cases among the elderly,

through a system of a preferential intervention dynamics, related both to social as well as service delivery factors. Distribution of Prevalence and Incidence by Gender In Figure 3.6, the prevalence by sex and age in the BCG trial area in Chingleput [TRC] is depicted (2,36). Prevalence and incidence [not shown] in all categories of diagnosis had increased with age in males. For females, up to 45 to 49 years of, the rates had increased, to be at a plateau thereafter. At all ages the prevalence was considerably higher in males than in females. Of all culture positive cases, 79 per cent were found to be in males. In the later TRC follow-up study 1968 to 1986, the average male:female ratio was 3.7 for C+ cases and 4.5 for SS+ cases (35). Of all pulmonary TB cases in males, 70 per cent were in the age group 20 to 54 years [39% of male population]. Among females on the other hand, 56 per cent of these cases were in age group 20 to 44 years, i.e., in the reproductive age [constituting 40% of female population]. In the longitudinal epidemiological study in Bengaluru rural area carried out between 1961 to 1968, the annual incidence rate of C+ cases in males increased during the five-year observation period from 200 to 300 per 100 000 (2,39). It, however, remained stable among females at 100 per 100 000. Whereas, the incidence among males aged 55 years and above in successive surveys for the five years period, ranged from 400 to 700 per 100 000, in females it had increased only from 150 to 200 per 100 000. However, an unexplained observation in these surveys was the annual incidence of about 100 per

Epidemiology 37 100 000 in both genders in the 15 to 34 year age group. Aside from the above exceptional parity in incidence between the genders in this age group, the observations are similar in most Indian epidemiological studies. In general, the disease occurrence rates are similar in both genders, till the onset of puberty in females. Thereafter, a female preponderance has been observed with the gender difference acutely accentuating beyond the 35 year age mark. In the European countries during the earlier part of the last century, the case rates among females between the ages 15 to 35 years were generally 10 to 35 per cent higher than in males. Prompted by this, the postulate of a higher case rate in females in India as well, has been the recurrent theme of many investigations carried out in India in recent times, especially with foreign funding. It appears that, in so far as general distribution of prevalence and incidence of TB cases in India is concerned, the epidemiological observations from industrialized countries of the West is a poor guide (Klaus J. Sex and age distribution of TB cases, registered in Medak and Hyderabad Districts under the RNTCP, 1999. Nuffield Institute for Health, Consultancy Report under DFIDI Project, unpublished data). Instead of investigating the anticipated but unsubstantiated gender bias against women reflected in the occurrence of disease in the community, the reasons for apparent protection enjoyed by the women across the age groups, could rather

be a theme of immunobiological and sociological investigations in the Indian context. Tuberculosis by Socio-Economic Criteria The survey carried out in Wardha District [Maharashtra] is the only source of data linking TB in the community to socio-economic criteria [unpublished observations, cited in reference 2]. In this survey, variations in the prevalence rate of TB was observed in terms of literacy [lowest in the graduates and highest among the illiterates], employment held [highest among the professionals, followed by cultivators and agricultural labourers], income, living standard [those living in “kutcha” houses had a higher prevalence than “pucca” house dwellers] [Table 3.11]. Of the total cases among females, 48 per cent were among those unemployed [including housewives]. For all demographic variables, rates in females were less than those in males. As per Dholakia (61), evidence is lacking suggesting a difference in the prevalence of TB among workers than among non-workers. Of the ‘workers’ group, estimated to be suffering from TB in India, about 52 per cent were in the age group 15 to 44 years. In this age group, about 40 per cent of the workers with TB, were women in the urban areas. The proportion was only 17.9 per cent in rural areas. There was much lower proportion of women among workers with TB in higher ages, especially in the urban areas. In the Wardha survey, the urban profes-

Table 3.11: Prevalence of culture-positive pulmonary tuberculosis by occupation in Wardha [per 100 000 population] Urban and rural

Sex ratio [M:F]

Occupation

Population [%]

Sex ratio [M:F]

Proportion of total cases [%]

Urban

Rural

Non-worker Student Service Professional Cultivator Agricultural labourers Non-agricultural labourers Others Total

26.8 29.0 5.3 2.0 15.0 16.4 3.9 1.5 100.0

0.34 1.25 12.19 2.45 0.85 1.08

24.9 6.6 4.4 24.8 21.4 100.0

2.30 1.17 1.40 0.40 0.48 2.25 4.22 1.53 1.77

1.41 1.56 0.53 1.73 1.94 2.05 2.87 1.84

M = male; F = female Source: reference 2 Adapted and reproduced with permission from “Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248-75 (reference 3)”

38

Tuberculosis

sionals and rural service workers, who had a higher prevalence, had a low proportion of the female population in them, and had consequently accounted for a small proportion of the total cases among females. The extent of TB morbidity in the males in the economically active age and in females in the reproductive age, marks it out as a priority among the public health problems in India. Epidemiological Classes of Tuberculosis States in the Community and Relative Risks Development of various epidemiological classes in the community as linked to their respective TB states, ranging from infection to bacteriologically positive pulmonary disease, would depend largely on the inherent processes of pathogenesis, and would by and large follow an average time line [Figure 3.3]. The consequences to these processes keep creating groups or classes in the population, either “infected” or “uninfected” with tubercle bacilli, to start with. In their life time, individuals belonging to each of these two classes go through the risk of progression into active disease, with or without reversal to a non-disease state with time [Figure 3.3]. Thus, members of these two initial classes could further be grouped in accordance with their TB disease status, as revealed from their chest radiograph and bacteriological examination results as follows: normal, and those with inactive TB state, with non-TB disease, with probably/possibly active TB disease state but bacteriologi-

cally negative and lastly bacteriologically positive disease. Table 3.12 shows the size of each of these classes/ groups, by the results of tuberculin test, chest X-ray interpretation and bacteriological examination results in each individual followed up in a given community, repeatedly for a period of five years (2,62). Information is available from the study on the attendant risk of breakdown into active bacillary cases [C+] and of death, by person years of observation. It is important to appreciate that the size of each of these classes and the risk of developing bacillary cases associated with each of them would jointly influence the incidence of C+ [and/ or, say, SS+] cases in the community and thus the size of the problem of TB. For example, the two groups with the highest risk of developing bacillary TB as shown in the Table 3.12 [namely, tuberculin positive persons with chest radiograph classified as having active TB lesions, or other than active TB shadows] had together constituted only 5.6 per cent of the total population. Yet these classes between themselves had contributed close to 46 per cent to the total new C+ cases arising in the community in a year. Surveillance of these two could be rewarding under the TB programme delivery system. The attendant element of risk for each of the classes would surely have escalated in the era of HIV-TB, including that among the group of “infected only” [i.e., without TB disease]. These need to be investigated in the present scenario, and more comprehensively at that, for the purpose of priority setting under programme formulation exercises.

Table 3.12: Annual incidence of sputum culture-positive tuberculosis cases in the community by epidemiological class Epidemiological class Infection status

Radiological activity status

Tuberculin-negative

Tuberculin-positive

N AB CD N AB CD

Annual Incidence of C+ cases [per 1000/year] Size [%] 63.1 5.2 0.5 25.6 4.6 1.0

0.41 1.03 6.76 1.73 6.83 35.15

Proportional contribution to annual incidence of C+ cases By each By tuberculin class [%] status [%] 17.8 3.7 2.2 30.4 21.5 24.4

23.7

76.3

N = radiologically normal; AB = Persons with chest X-ray abnormality considered non-TB or TB without active disease; CD = persons with chest X-ray lesion considered to have active TB; TB = tuberculosis; C+ = culture-positive Source: references 2,62

Epidemiology 39

From the natural dynamics of TB as studied in the rural area around Bengaluru, the TB situation is supposed to be presenting a steady state [Figure 3.7] (2). Without active intervention, a third of the existing pool of bacillary cases in a year would get eliminated through death and natural cure. But during the interval, the same proportion gets added to it. The results of the observations from the Bengaluru study (39) presenting a trend that could be summarized as below. It is apt to describe the same as natural trend up to the first five years (39). Thereafter an element of NTP-triggered intervention effect could cloud the interpretations, as it was introduced in the area after the fourth survey [5 years]. Prevalence and incidence rates of C+ cases and X+ cases revealed no change in the period of 12 years [19611968 to 1977-1978], for which information was available

(44). The mean age of cases was higher at later surveys, up to 12 year period studied (44). The ARI had declined [Figure 3.8] from 1.1 to 0.65 per cent in 23 years [1961 to 1984], at around 2.35 per year (28). Incidence of smearpositive cases had declined for the area from about 65 to 23 per 100 000 in the same period (45). It was observed to the declining in consonance with the fall in the ARI. The observations from the above time series study were extrapolated to the population, taking care of demographic changes in it with time, over a 50-year period (63). The observed dynamics of deaths and those due to transfers between the non-infected, infected, and several epidemiological classes formed on the basis of the actual study findings over a period of five years, were fed into the mathematical construct for a period of over 50 years. The natural dynamics were compared with likely disease situations, under various programme effectivity modes, hypothesized for the purpose and fed into the model. The above model showed that even in 50 years, TB case rates would come down only minimally. Very large population sizes would be required to be surveyed repeatedly to appreciate a change, if any (2). Various case finding and treatment levels were included into the model, as per the data available from a study on programme dynamics (64). The model demonstrated that high levels of intervention, could, however, result in

Figure 3.7: Pool of tuberculosis cases in the community [natural dynamics] Source: reference 2 Adapted and reproduced with permission from “Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248-75 (reference 3)”

Figure 3.8: Annual risk of infection [1962 to 1985] and observed annual incidence of infection [1962 to 1967] Source: reference 2 Adapted and reproduced with permission from “Chakraborty AK, Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248-75 (reference 3)”

EPIDEMIOLOGICAL TREND OF TUBERCULOSIS IN INDIA Tuberculosis Trend in the Bengaluru Rural Area

40

Tuberculosis

substantial change in the prevalence rates [Figure 3.9] (63). The projections could serve as a decision-making one, guiding policy planners to look at various efficiency modes necessary to be in place for the likely road maps to be pursued. Tuberculosis Trend in a Rural Area of Tamil Nadu Annual Risk of Infection In the study carried out in a rural population of Chingleput in Tamil Nadu by TRC Chennai (35) [1968 to 1984, and in a subset of population, again in 1991 to 1992 and 1994 to 1996], the ARI had remained unchanged for the entire period. It was between 1.8 and 1.9 per cent in the earlier period [1969 to 1984] and 2.9 to 3.2 per cent [1991 to 1992, 1994 to 1996] [Table 3.6] (35). Prevalence of Cases The study has shown no change in C+ case prevalence during the period 1968 to 1975. However, as the resurveys were extended further up to 1984 to 1986, a decline of 2.3 per cent per year was recorded for the later period [overall being 1.4% per annum]. Such a decline

was not seen in Bengaluru rural area [surveyed for 12 years] (2,35). There was a declining trend in C+ cases in all ages, especially in 10 to 14 years. This was in line with the age-wise trend seen in the 12 years follow up in the Bengaluru rural area (2,35). There was no change in SS+ case prevalence, for all ages [Table 3.9]. However, a declining trend was visible in the younger population, i.e., among those aged up to 35 years. It was statistically significant for 10 to 14 years old children (35). There was a strong evidence of decline in both C+, as well as SS+ case prevalence in females: [3.8% and 2.8% annually, respectively]. The C+ cases had shown decline at a later period of the follow up in males [i.e., between 1975 to 1978 and 1979 to 1981], without any significant change in the trend of SS+ cases. Because of the above gender related difference, the male: female ratio in C+ cases had increased from 3.5 in 1968 to 1970 to 5.2 in 1984 to 1986 survey [average 4.7]. The average for SS+ cases for the entire period stood at 1.7 only. Incidence of Cases There was a steady decline in the incidence of C+ cases [at 4.3% per annum] from 352/100 000 between the first two surveys [1968, 1971] to 189 between the last two [1981, 1984]. The decline was seen in both genders and in all age groups. There was only a tendency for decline in incidence of SS+ cases. Ratio of prevalence and incidence of SS+ cases remained 3.6, at the surveys, probably indicating that new SS+ patients would probably continue as SS+ cases, after occurrence, cumulating themselves for 3.6 years in the community, to constitute prevalence. Findings are more or less similar for both rural Bengaluru and urban Delhi [between 3.33 and 3.7]. X+ Cases

Figure 3.9: Model depicting hypothetical time-trend of tuberculosis in Bengaluru rural area DTP = district tuberculosis programme; CF = case-finding; SR = standard regimen Source: references 2,63 Adapted and reproduced with permission from “Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248-75 (reference 3)”

There was significant and substantial decline in X+ case prevalence rate from 1289/100 000 to 827/100 000 between 1968 and 1986 [average decline 3.2% per year]. The pattern was not gender specific. Comments on Findings It was heartening to observe that incidence of SS+ cases, arising at a later survey, from the radiographic class of TB shadows on X-ray in an earlier survey, was coming down significantly with time for the area. This was likely

Epidemiology 41 to be due to the treatment programme in place for the area, as pursued under NTP, no doubt accentuated due to the presence and interaction with the research field staff of TRC Chennai. They could act either by motivating patients and probably ensuring drug supply at treatment centres also. Being the long-term study area for the TRC, evidently had influenced intervention situations and brought long-term benefit to the area. The decline in C+ cases, not initially seen, could also be observed on a long-term follow up, as different from the NTI rural area. There was substantial reduction in C+ case prevalence in later surveys [1991/1996 surveys]. Whether it had anything to do with reduction of incidence from X+ case class, is a point to consider. A hypothesis could be considered that when the ARI and SS+ case prevalence and incidence are relatively high in an area, as it appears to be so in Tamil Nadu rural area, active and intense intervention for a long enough and sustained span of time, are necessary to record change in them. The situation in the subset for example in Chingleput area, could record a change in C+/SS+ case situation, only in later surveys. For example, in the subset studied for a longer period [1991, 1994] a significant decline [2.7% per year] had occurred in the prevalence of SS+ cases [398 to 262 per 100 000]. However, for reducing breakdown from among the X+ cases into C+ cases, a relatively low-key treatment, as followed in the programme could suffice to achieve the objective early enough. It is of consequence to programme managers, in their bid to estimate SS+ case load from ARI, to observe that the rate of incidence of SS+ to one per cent of ARI had decreased from 74 to 42 per 100 000 in about 7.5 years of observation [a decrease by over 40%]. The decline in the relationship between SS+ incidence and ARI with time in the Indian context is reported earlier from the Bengaluru rural areas under long-term repeat surveys (45). The findings of the Chingleput area appear to be in line with the overall projections of change made in the 50-year construct of epidemiological situation with a 2.3 per cent reduction annually, in response to a relatively low key programme dispensation (63). One of the most significant findings from this study concerned the incidence of C+ and SS+ cases, from out of those diagnosed as having radiographic abnormality at an earlier survey. There was no decline in incidence from

out of those with a normal chest X-ray or in those with chest X-ray abnormalities not due to TB. However, in those with a TB abnormality initially, the incidence of C+ cases had declined substantially [4.7% annually] and also in SS+ cases. Of the total C+ S+ cases, arising in 1971 to 1973, about a third had originated from those with an X-ray abnormality interpreted as TB. This proportion declined consistently from year-to-year and was only eight per cent at the 1984 to 1986 survey. . It could be interpreted that the treatment given to the specific epidemiological class of X-ray shadows consistent with TB disease [X+ cases] had caused a substantially reduced incidence of SS+/C+ cases from out of this class. The selective decline in incidence by radiological classes moreover indicates a good standard of interpretation and classification of various radiographic abnormalities, through the survey period. An alternative hypothesis of likely socio-economic change in the area reducing breakdown may not be tenable, as the same was not reflected in ARI and incidence of SS+ cases. The socio-economic improvement, if responsible, could have caused reduction in incidence in all radiographic classes, not confined to X+ cases alone. It is generally recognized that for appreciation of change with time, C+ case prevalence rate of TB is not the appropriate index to rely on. In the Kolin study (26), for example, the C+ prevalence rate had been observed to register a high only during the survey years. However, it was also a crucial observation in the above study that the SS+ cases, detected in a survey, and not confirmed on culture, were mostly found not to be the real cases. It, thus, stands to reason that in considering trend in the Chingleput studies, SS+ cases were considered as cases, only when they were C+. The same was the case in NTI longitudinal surveys also. Thus prevalence of smear positivity in a survey, unless supported by culture, is not taken as representative. At the same time, prevalence of real smear-positive cases, in situations where there is considerable pooling of untreated or inadequately treated cases, is the index which is influenced in an effective control programme. For example, in a situation like India, where prevalence is about thrice the annual incidence, an effective control programme could possibly work by reducing the smear-positive case prevalence. It is in this context that the reduction in C+ prevalence cases over time, even earlier to that in SS+ incidence cases, needs to be understood. It appears to be due to reduced

42

Tuberculosis

breakdown, and the consequent incidence, specifically from among the X+ cases, through their treatment [a sort of “secondary chemoprophylaxis”], as postulated in the foregoing paragraph. It appears possible that transmission in the present time did not come down sufficiently largely to be reflected in ARI. It needs to be kept in mind that the treatment of SS+ cases was not energetic enough under the routine NTP treatment regimens, as pursued in the study area. Even though it had a salutory effect with regard to the breakdown from X+ class, in the manner of a secondary chemoprophylaxis, it could not reduce SS+ case incidence/prevalence as a whole, and consequently the ARI for the area. Tuberculosis Trend in an Urban Area Findings from a study carried out in the New Delhi Tuberculosis Centre area are unique in the sense that it gives the only trend for an urban area in the country. The study was conducted for a sufficiently long span of 30 years, following up the same community seven times after the first survey (48). The diagnosis in the survey was based only on culture and X-ray results. All the X+ and C+ cases were efficiently treated through the survey period [90% cure rate achieved during 1995 to 1996]. The findings and comments on the trend are summarized as follows. About a tenth [8%] of the bacillary cases had continued as such for about a decade [i.e., between the last two follow-ups , 1982 to 1991]. This was despite a good service programme in the area. Of the C+ cases 30 per cent were dead in the period. The proportions remaining as C+, or, as X+ cases during the above period were significantly lower than observed between earlier two periods of follow up. The standardized prevalence rate of C+ cases had not changed over the period, being around four per thousand [95% CI 2.54 to 4.84]. However, as in Bengaluru and Chingleput study areas, there was a higher C+ prevalence at Survey VIII among population aged 55 years and above, compared to earlier surveys. The peak of C+ cases at Survey VIII in females had shifted to around 45 to 54 years from around 25 to 34 years, as seen between Survey I through VI. However, a proportional concentration in the number of cases in higher ages with time, as seen in Bengaluru rural area (2,44), did not occur in the New Delhi area. This was interpreted to be due to a significant reduction in population size in the area, in the age group of 45 years and above, compared to that in Survey I, 30 years back.

Influx of wage earners in younger group and exodus of those in higher age [possibly considered to be without ostensible economic worth] from out of city area, was the essential demographic feature in the New Delhi city area. This was not observed to be so in the rural areas of Bengaluru, possibly causing the difference in the nature of epidemiological pooling of cases by age with time, between the areas There was considerable decline in prevalence of X+ cases at later compared to the earlier surveys [Survey I: 13.2 and Survey VII, VIII: 6.5 and 5.4 per 1000]. The X+ cases of earlier surveys had the highest rate of breakdown into C+ cases subsequently, this being the highest risk group. The reduction in rate of incidence from among X+ cases with time, as observed in Chingleput study was not observed in New Delhi. Data on SS+ cases as well as ARI were not studied in these surveys. Tuberculosis Trend in a Tribal Area The Car Nicobar is an island in the Bay of Bengal, with a total population of 15 575 residing in 15 villages. An intensified TB control project was launched there by the Island Administration in 1986 (65,66). All SS+ as well as C+ prevalence cases were detected on house-to-house survey and treated adequately. Children aged five years and above were given chemoprophylaxis for six months after tuberculin testing and those under four years in age given BCG vaccination. Infection prevalence was 10 per cent among those under 14 years of age [Table 3.12]. The prevalence rate of SS+ cases was 4.1 per 1000 and X+ case, 7.9 per 1000. At the end of nine-month short-course chemotherapy 94 per cent of SS+ cases were sputumnegative. At a re-survey after a 16-month period, no freshly infected children were detected by the differences of reactions method (29,66). Number of new SS+ cases arising in the area in the period of 16 months was only a third of the previous prevalence, similar to the observations from the NTI surveys (39). The intensive programme was then discontinued, at a time when there was no observed cumulative prevalence and no fresh infection taking place in 16 months. At this point, the NTP was implemented, leaving the routine DTP to operate in the area. The survey in the area has been repeated between 2001 and 2002 (37). The findings are shown in Tables 3.13 and 3.14. It appears from treatment records available with the local health authorities that, over the years, the

Epidemiology 43 Table 3.13: Comparison of notified new sputum smearpositive cases in India [1993-2000] with expected incident sputum smear-positive cases Year

Diagnosed new SS+ cases*

Rate [per 100 000]

1993 1994 1995 1996 1997 1998 1999 2000 Total

225 256 226 543 264 515 290 953 274 877 278 275 345 150 349 374 2 254 943

25 25 29 31 29 29 35 35 25 to 35

*Numbers expressed in thousands SS+ = sputum smear-positive Source: reference 13

Table 3.14: Tuberculosis situation in Car Nicobar [1986-2002] Period

1986 2001-2002

Prevalence of infection [%] among 0-14 year children without BCG

ARI [%/year]

10.0 25.1

1.53 3.80 [3.50]

Prevalence of SS+ cases/ 1000

4.10 7.30 [7.10]*

ARI = annual risk of infection; BCG = bacille Calmette-Guerin; SS+ = sputum smear-positive Numbers in square brackets indicate ARI calculated from a standardized prevalence rate of infection * Prevalence of disease significantly higher in 2001-2002 Source: reference 37

programme was not maintained in the island. Investigation and follow-up of cases, diagnosed from year-to-year since 1988 in the area, showed only 66 per cent of the SS+ cases on register completed treatment and their sputum results were not available. Incomplete treatment, if taking place in these cases year-to-year, could have prevented death, not ensuring sputum negativity though. Annual case fatality 3.7 per cent among the cases on record since 1988, as against the likely rate of over 20 per cent among the cases in an area without an organized programme (39), the latter taken to represent the natural dynamics of TB. In all likelihood this accumulation of cases over the years had returned

the tribal community, back to where their epidemiological trend originally was, in fact much worse than it was, before 1986. The force of infection of the relatively fresh cases diagnosed after 1986, must have caused an escalation of ARI as well, the incident cases being more prone to cause higher transmission of infection in the community. Similar reversal of the trend from a tribal community in Greenland (67) may be recalled in this connection. Obviously, programmes need to be continued with an accepted level of efficiency for a long enough time. Lack of advocacy and priority could be important causes of attenuation of epidemiological trend in a community. Trends of reduction in a community, achieved through care and effort, as in Car Nicobar, could be rudely halted or reversed, through lack of prioritization at a later stage. This could be seen even in the most developed countries, as in Japan, for example (68). Tuberculosis in India: Current Status The estimated TB burden in India in the year 2006, published in the WHO Report 2008 (69) are listed in Table 1.1. The current ARI data in India have also been recently published (70). In this nation wide study [20002003] (70), children one to nine years of age in selected clusters of 26 districts in four defined zones of India were subjected to tuberculin testing with 1 TU PPD RT23 with Tween 80. For the country as a whole, the average ARI computed from estimated prevalence was 1.5%. The ARI showed regional variations and was higher in the northern [1.9%] and western [1.8%] zones compared with the eastern [1.3%] and southern [1%] zones. The proportion of infected children was found to be significantly higher in urban than in rural areas in all zones. REVIEW OF RECENT FACTORS THREATENING ESCALATION Tuberculosis and HIV/AIDS The reader is referred to the chapter “Tuberculosis human immunodeficiency virus infection” [Chapter 40] for more details.

44

Tuberculosis

Tuberculosis and Multidrug-resistant and Extensively Drug-resistant Tuberculosis The reader is referred to the chapter “Drug-resistant tuberculosis” [Chapter 49] for more details. ASSESSING TUBERCULOSIS SITUATION THROUGH MATHEMATICAL MODELLING Tuberculosis Across the Globe In the global context, the process of mathematically estimating the impact of the strategy of DOTS is possible now (71-73). Murray (72) has evaluated a range of extensions to global control strategies in terms of their potential effects on TB incidence and mortality, by regions of the world, from 1998 to 2030. The impact of each of the likely items of the DOTS strategy are evaluated separately and incrementally. They have concluded, that globally, 171 million new cases and 60 million deaths are expected in the best possible DOTS scenario and 249 million new cases and 90 million deaths in the worst case scenario, by 2028. Uncertainty prevails on outcome estimates for Asia. In the model by Dye et al (73), it is shown that the potential effect of chemotherapy delivered as DOTS, on TB, is greater in many developing countries now, than it was in developed countries years ago. The potential needs to be realized fully. It is forecast that without greater effort to control TB, the annual incidence of TB disease is expected to increase by 41 per cent, between 1998 and 2020 [from 7.4 to 10.6 million cases per year] in view of the HIV/AIDS-TB epidemic. It is envisaged that DOTS would save a greater proportion of deaths than lower the incidence of cases. The proportion of difference is bigger in the presence of HIV- infection. Tuberculosis Modelling in the Indian Context The first mathematical model to study the natural trend of TB in India and on some hypothetical situational outcomes created through various efficiency variables of programme delivery was developed at the NTI in 1992 (63). However, the model was meant for decision making on alternatives rather than on forecasting the disease situation. Further, it also did not make the equations available, in a manner that other set of variables could be used in forecasting. Clearly, with the change in the nature of the programme and in the hypotheses

oscillating around it, there is a felt need today for forecasting the situation with the help of model constructs. One needs to construct situational variables owing to introduction of DOTS, the attendant HIV problem, a fastpaced programme expansion along with a changed face of programme delivery with higher private participation, among others. Efforts are underway to construct a model to address the Indian TB situation (74). The mathematical model depicted in Appendix Figure 3.3 and Appendix Table 3.4 prepares the initial disease state as caused due to programme delivery process and the respective efficiency levels of various components under it, with time. The itinerant size of the classes and the fractional changes in them, caused through processes of transfers between classes together with the directional forces responsible for these, are expressed in mathematical denominations, called “Symbols” and “Vectors”, respectively. Persuaded by an unavoidably large number of variables, 47 model vector states and 26 mathematical equations are conceived. These are intended to measure the effect of intervention, causing changes in the size of the respective classes, including that of “Cure”. The equations await simulation and validation in due course. It could pave the way for an epidemiological statement of the disease state in India, in an ongoing manner, disaggregated to state levels. EPIDEMIOLOGICAL EVALUATION: FUTURE DIRECTIONS As estimate on the TB burden and the distribution of the problem are the basic and important information for the planners to have, on which intervention strategies are devised and necessary resources deployed. These are given here based both on Indian survey results, as well as on the basis of global consensus statements. These are expressed both in terms of average rates [with range for 95% CI] and the absolute numbers. Disease rates are also presented, after adjusting for under and over diagnosis made in the surveys, from which the rates are derived, depending on the survey method used. It could be of considerable significance in this context to note that the adjusted rates for culture positive cases could be as high as six per thousand and that for radiologically positive cases, about three per thousand on an average (2). These disease categories, along with

Epidemiology 45

Appendix Figure 3.3: Schematic representation of the proposed model for TB in India Index r takes three values, namely 1 for RNTCP, 2 for NTP/SCC, and 3 for NTP/CR. Pathways from f4 and f6 to c4 and from f′4 and f′6 to c′4 not shown [See Appendix Table 3.4 for notations] Source : Yajnik K, Chakraborty AK, Jochem K. A mathematical model for determining the effect of tuberculosis control programmes on its prevalence in India. A report submitted to the World Bank, New Delhi Office: 2002.p.1-131 (Unpublished)

46

Tuberculosis Appendix Table 3.4: Model states Symbol*

Definition of classes

u n v cp, c’p

Uninfected individuals. Infected individuals. Vaccinated individuals. TB cases [8 cases, indexed by p, for each of sputum smear-positive type and of other types, that is, sputum smearnegative and extra-pulmonary type]. 1 = under no allopathic antituberculosis treatment**, 2 = under allopathic antituberculosis treatment in private sector, 3 = under RNTCP, new case, 4 = under RNTCP, retreatment case, 5 = under NTP/SCC, new case, 6 = under NTP/SCC, retreatment case, 7 = under NTP/CR, new case, 8 = under NTP/ CR retreatment case Treatment failure cases/lost cases [6 cases, indexed by r, each of sputum smear-positive and of other types, that is, sputum smear-negative and extra-pulmonary]. 1 = RNTCP for new cases, 2 = RNTCP for retreatment cases, 3 = NTP/SCC for new cases, 4 = NTP/SCC for retreatment cases, 5 = NTP/CR for new cases, 6 = NTP/CR for retreatment cases Recovered TB cases [cured/treatment completed] [8 cases, indexed by p, for each of sputum smear-positive type and of other types, that is, sputum smear-negative and extra-pulmonary type]. 1 = recovered without allopathic antituberculosis treatment, 2 = recovered with allopathic antituberculosis treatment in private sector, 3 = recovered from RNTCP, new case, 4 = recovered from RNTCP, retreatment case, 5 = recovered from NTP/SCC, new case, 6 = recovered from NTP/SCC, retreatment case, 7 = recovered from NTP/CR, new case, 8 = recovered from NTP/ CR, retreatment case

fr, f ’r

rp, r’p

*A letter in bold lower case indicates a vector of 2K components, 2K being the number of gender-cum-age groups spanning the age spectrum. For example, ui is the ith component of u. The components of a vector represent the number of members of each class in the selected gender-cum-age groups at a given time. If the index i has an odd value, the state is for the male gender and if i has an even value, the state is for the female gender. For example, u[2k – 1] and u2k refer to uninfected males in the [2k–1]th group and uninfected females in the 2kth group. There is no restriction on the number of gender-cum-age groups or on the age interval of any group A lower case letter in italics with two indices q and i corresponding to a bold letter with an index q refers to the ith component of the vector with index q. The first suffix refers to the vector suffix and the second suffix refers to the number of the gender-cum-age group. For instance, c32 is the second component of the vector c3 and it refers to the number of new female TB cases in the first age group in RNTCP The suffixes i, j, and k are reserved for denoting components of vectors, and suffixes p, q and r are reserved for vectors. In the case of the last three symbols, an unprimed symbol indicates sputum smear-positive case [current or recovered] and a primed symbol indicates sputum smear negative or extra-pulmonary cases [current or recovered] ** It is to be noted that all TB cases that are taking any non-allopathic or alternative medical treatment [including ayurvedic, unani and tribal] are in this group. The members of this group are assumed not to have taken allopathic antituberculosis treatment for one month or more in public health programme TB = tuberculosis; RNTCP = Revised National Tuberculosis Control Programme; NTP = National Tuberculosis Programme; SCC = short-course chemotherapy; CR = conventional regimen Source : Yajnik K, Chakraborty AK, Jochem K. A mathematical model for determining the effect of tuberculosis control programmes on its prevalence in India. A report submitted to the World Bank, New Delhi Office: 2002 .p.1-131 (Unpublished)

the estimates of infection reflect the total TB problem created through mycobacterial infection. It is the SS+ case who has the obvious priority in the RNTCP because of its infection transmission potential, as well as for causing higher mortality and suffering. Even then changes in all the above disease variables are customarily observed in studies on epidemiology of TB. Besides, these epidemiological classes assume added relevance in the HIV-era. The treatment policy of these categories with or without HIV-infection is of concern, given the size of the classes

and higher risks due to dual infection. The average rates for the above categories given in Table 3.7, especially that of SS+ cases and mortality, are conveniently used for the estimation of the TB burden in the country for the purpose of resources mobilization and advocacy. However, these have obvious limitations, for the purpose of evaluation exercises, as discussed here. Currently, single target rates, one each for the total incidence of TB cases and the other for incidence of SS+ cases, are in use for the country as a whole under the

Epidemiology 47 RNTCP in India, based on Dye’s work [Table 3.7]. These are based on an estimated relationship between the average ARI for the country and the incidence of SS+ cases. This does not appear to be an appropriate approach at target setting of individual district performance in India, given the wide variation in ARI [Table 3.6], the urban rural variations of significance [Table 3.8], the variable socio-economic conditions and the likely attendant variations in the epidemiological trend. Hence, it is suggested that for ongoing evaluation of programme efficiency, instead of average rates as in use for the vast country under RNTCP, alternative rates for the given areas, corresponding to their identification as having the best and worst possible disease scenario could be more desirable to use. The hypothetical disease situations for the best and worst possible case scenarios, as per information available for some areas, are depicted in Appendix Table 3.5 (75). It is true that the type of disease categories used in Appendix Table 3.5 to formulate the hypothesis of the best and the worst possible case scenarios in India, make it almost impossible to work out their extent, given the complicated nature of their identification, in various areas in India, in actual clinical practice or in survey situations. The information in Appendix Table 3.5 is in

fact presented only in support of the hypothesis of variability in the epidemiological situation within India. The international experience in evaluating the TB control efforts with either the culture or SS+ results through repeat surveys during a comparatively short time frame, is not encouraging. Similar has been the Indian experience too. Of the indices presented, it is, however, possible to visualize ARI as a potent index for the purpose of intermediate and long-term evaluation of programme effect on the epidemiological dynamics. For the ARI to be thus used, it needs to enjoy the freedom from some confounding influences of socio-economic variables, the possible levels of malnutrition in the country affecting tuberculin hypersensitivity measurement, and possibly varying levels of exclusion of the BCG vaccinated subjects from tuberculin tests employed to measure ARI. Significant work in the past has paved the way for the use of ARI for the intended purpose, as follows: Nutrition states of children ranging from malnutrition grades I to III in the proportions as are generally prevalent in the Indian areas, may not effect the TST reaction sizes and their interpretation for TB infection prevalence (76,77). Prevalence of grade IV malnutrition does affect the appreciation of the skin hypersensitivity (78).

Appendix Table 3.5: Varying epidemiological observations by areas in India

Areas

Urban-rural distribution ARI [%] Infection prevalence [%] Age group 0-4 years Age group 5-9 years Disease incidence [per 1000/year] Type of disease

TB mortality in children [< 4 years age]

Worst case-scenario

Best case-scenario

Chennai slum, Wardha district Nicobar tribal High in urban pockets Around 3.0

Bengaluru area [Urban slum and rural] No difference 1.0

> 7 [U], 2-3 [R] 22.0 [U], 15.0 [R] 3.0 [U] [i] Disseminated forms [Lymphadenopathy predominant, 4-6/1000] [ii] Pulmonary TB [iii] Spinal TB

2-4 8-12 1.0

Very high > 230/100 000

About 50/100 000

Pulmonary fibrosis [remnant of primary TB]

U = urban; R = rural; ARI = annual risk of infection; TB = tuberculosis Source: reference 75 Adapted and reproduced with permission from “Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248-75 (reference 3)”

48

Tuberculosis Appendix Table 3.6: Uses of epidemiology as applicable to tuberculosis situation in India

Summary of epidemiological observations 1. [a]

Comments and inference on likely trend of epidemiological situation in India

Tuberculosis is a long-term epidemic spanning several centuries Transient changes in the epidemic curve may occur, e.g., through war, famine etc., but the trend resumes its natural course after their effects disappear [secular trend]

1. Two points of observations separated by 10-25 years or more are so close to each other in the context of the epidemic curve spanning several centuries, that quantitative changes in disease rates cannot be measured, unless massive [which is unlikely]

2. Tuberculosis problem is more or less spread all over the country. Proper sampling required to measure statistically significant areawise differences. Barring a few exceptions, ARI is different from area to area. There are significant urban-rural differences in ARI

2. Wide spread tuberculin use has taken place, with the inference that TB curve is in endemic phase in the country. However, there could be differences in the age of epidemic from area to area

3. Prevalence rate of cases was same for the rural and urban areas as per the NSS. It has later on been shown to be higher in the urban areas

3. Disease not likely to be in the spreading phase: probably on the descending limb

4. About 38% of persons of all ages and both sexes and almost 70% of males above 40 years of age are infected. Prevalence of bacillary cases: 0.4%, mortality rate: 0.05% to 0.09%

4. The wide gap between the rates may mean that the disease is on the descending phase

[b]

Epidemiological rationale of NTP in India 1. [a]

Tuberculosis programme should be a long-term programme. Vertical programmes not suitable. Case finding/ treatment activities to be carried out as service component of an integrated health care delivery system [b] No quick change in situation to be expected [c] No all India repeat sample survey at small intervals of 10-25 years called for 2. Almost a similar and uniform kind of programme is required all over the country. No special programme was formulated for urban slums, etc. However, the indices for measurement of programme activity [expectation] need to be varied, depending on epidemiological situation in the area, as revealed by ARI studies 3. In absolute numbers, 80% of the total problem is distributed in rural areas [since 80% of the population live in villages]. Hence, TB services should cover rural areas adequately. Emphasis needs to be on equitable spread of programme maintaining the quality of care. The NTP had an initial bias in favour of rural areas, since corrected under the RNTCP, in view of the concentration of cases in urban areas 4. [a] Presence of 38% of total persons infected in the community may mean that eradication cannot be conceived as a goal [b] Also, the large pool of the infected is of great significance because of HIV-risk [c] High infection prevalence and incidence represents a high transmission of infection, related to smear positive case prevalence. The HIV prevalence would augment the case incidence. High quality programme with a fast spread throughout the country is advocated -Contd-

Epidemiology 49 Appendix Table 3.6 -ContdSummary of epidemiological observations

Comments and inference on likely trend of epidemiological situation in India

5. Prevalence rate of infection and disease as well as mortality are more in males than females 6. There is a decreasing trend in the infection rate of about 2% per year, over a long-term observation for a period of ranging from 5-25 years or more among children [from longitudinal surveys of NTI]. But the same is not seen in the adjoining areas of Tumkur, Doddaballapur and in the neighbouring state of Tamil Nadu [the last one for nearly over 15 years]

5. The disease is beyond the peak, probably in the descending limb of the curve or endemic phase 6. Probably represents a secular trend of infection rate. Tuberculosis situation may be on slow downward trend in some areas and not changing in some other areas. It is logical to postulate different epidemiological age from area in India, given its vast expanse

7. [a]

7. Proportional concentration of disease in adults may mean that disease is beyond the peak. It is most likely that the epidemic curve is not on ascending limb. Even as the population aged 40+ years would contain 50% of the cases, the public health significance of young adults between 20-39 years age containing 43% of cases cannot be over-emphasized, as it happens to be the most productive segment in population. Similar is the situation in females, where the disease burden is borne by those in the reproductive age, nearly half of the cases in women being in this age group. May mean that TB is in declining phase 8. [a] This is commensurate with fall in the ARI from 1% to 0.6%. May mean that TB is in declining phase [b] The high ARI with no or small extent of decline below 3% per year, marks out India to be one of the high prevalence areas, together with the sub- Saharan African countries 9. This is probably related to lowering of priority

[b]

8. [a]

Pulmonary TB is an adult disease. Population in 0-19 years [comprising 50% of total population] contain only 7% of total prevalence cases. Remaining 93% of the cases are distributed in population aged 20+ years Relatively higher and higher concentration of cases in higher age groups has occurred in later surveys as compared to earlier surveys. In later surveys in Bengaluru rural areas, about 80% of cases were detected among those in 40+ age group.

The incidence of smear-positive cases in the community is observed to have dwindled in 23 years in Bengaluru rural area from around 65 to 23 per 100 000. This could be the best possible case-scenario in India 8. [b] Other areas in India have a ARI without change in time e.g., Tamil Nadu. 9. There is an evidence of reversal of a disease trend in Car Nicobar with increase in ARI 10. [a] Nearly 10% of all cases of crude mortality in the community is contributed by tuberculosis deaths

10. Disease is on downward trend or in the endemic phase

Epidemiological rationale of NTP in India

—

6. [a]

Programme interference-efficiencies be augmented to hasten the decline [b] Surveillance system should be developed to study infection rate in different parts continually, with provision for stratification even within districts. This could serve as effectevaluation of the programme if performed over 7-10 years, area wise. 7. Since cases in adults can be easily [a and b] diagnosed by simple tools [microscopy] from among symptomatics, disease among relatively articulate adults is possible to be tackled under a public health programme. [Note: 80% of cases are aware of symptoms and 50% have taken action]

8. The effect evaluation indices following intervention need to be areaspecific within India, to suit the variable epidemiological situations

9. The antituberculosis measures need to be sustained at a high level of efficiency over a long time 10. [a] Tuberculosis is a major public health problem and deserves appropriate priority -Contd-

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Appendix Table 3.6 -ContdSummary of epidemiological observations

[b]

11. [a]

[b]

Dramatic reduction in case facility is possible in a short time with adequate intervention as shown in Madanapalle and Bengaluru surveys Mortality rate decreasing with time from survey to survey, but is still high. Survival rate of cases diagnosed in later surveys were better as compared to in earlier rounds of longitudinal surveys

12. Paediatricians generally report seeing less of military, meningeal or fulminant forms of TB. Same is the experience of TB specialists, working in clinics

Comments and inference on likely trend of epidemiological situation in India

Epidemiological rationale of NTP in India

[b] Programme effectivity in preventing deaths needs to be recorded and highlighted for advocacy purposes 11. Disease is on downward trend or in the endemic phase

12. Policy of BCG vaccination to younger children might have been effective in revising the extent as well as incidence characteristics in children, by arresting haematogenous dissemination

11. Better case-holding should be attempted to save life. Treatment services to be widely distributed through integrated delivery approach. Programme effectivity in preventing deaths needs to be recorded and highlighted for advocacy purposes 12. BCG vaccination programme to be continued in younger population [0-1 year or 0-4 years]

ARI = annual risk of infection; BCG = bacille Calmette-Guerin; TB = tuberculosis; NTP = National Tuberculosis Programme; RNTCP = Revised National Tuberculosis Control Programme; NTI = National Tuberculosis Institute, Bengaluru; HIV = human immunodeficiency virus Source: reference 2

However, such prevalence is minimal enough in the Indian context to have a bearing on the observation of infection rates through tuberculin test reactions. Thus protein energy malnutrition [PEM] levels as prevalent in India may not affect the infection rates calculations and comparison in area and time dimension, unless high levels of grade IV malnutrition is present in some specific instances. The varying proportions of the BCG vaccinated children excluded from the test does not affect the estimation of infection, as arrived at by testing the unvaccinated (79). Moreover, high proportion of the BCG vaccinated children excluded from the test, could still allow enough unvaccinated children in the community to be tested, and to draw inferences on infection rate and the trend in a community (80). Even the question of appropriate dosage of tuberculin antigen to be used in the epidemiological setting as in India has been selected carefully. The dose of 1 TU has been found suitable, as different from the international practice of using 2 TU (81). Previous research in India has, thus, prepared the ground for ARI to be used in this country as an index of measurement of

epidemiological situation and surveillance. The baseline ARI studies have been completed throughout the country (71). These would have to be repeated in due time to obtain a trend in the TB situation, subject to various levels of the intervention-efficiencies. Small population sizes, as required for infection surveys, make such studies possible to conduct and they could yield valuable information. Some economic indices in the nature of physical quality of life indices [literacy rate, life expectancy at birth, maternal mortality rate and infant mortality rate], as developed from census data, could also be used along with ARI to classify areas for the purpose of applying average indices [virtual “targets”] for monitoring. Over comparatively shorter periods of observation of the natural dynamics in the NTI longitudinal survey (39) or the TRC study in rural Tamil Nadu (35,36), TB appears to be having a near steady state in India (2). Evidence is available to permit one to draw the hypothesis that the epidemic situation in India is probably on a slow downward curve of the epidemic. Such evidences could be as follows: declining mortality and case fatality rates

Epidemiology 51 due to TB, decline in meningeal and miliary forms of the disease, a relatively high prevalence of cases in higher ages with a low rate of positive cases in children, and a higher prevalence of cases especially in adult males [Appendix Table 3.6]. However, even if on a downward limb of the epidemic curve, the decline at present could only be minimal, as seen from the direct measurement of ARI in some areas in India [Table 3.6], and the nature and extent of the recorded decline in Bengaluru and Chennai areas, under long-term surveys. It is apparent that India has the epidemiological trend in common with the countries of sub-Saharan region, with an ARI between one and three per cent, and an annual decline of around 0 to 3 per cent. Only when high efficiency intervention, both in case finding and treatment is carried out, would a decline of between seven and ten per cent result. In the early 1960s the NTP was launched in India following a study of the countrywide TB epidemiological situation. A fairly large number of observational studies were since carried out in India, even with the meagre resources available for pursuing the scientific studies. The information from these was used in getting the NTP in place and reviewing its evaluation needs. These are summarized in Table 3.6. India is classified along with the sub-Saharan African countries to be among those with a high load and the least prospects of a favourable time trend of the disease as of now [“Group IV countries”]. The average prevalence of all forms in India is estimated to be 5.05 per thousand, prevalence of smear-positive cases 2.27 per thousand and average annual incidence of smear positive cases at 84 per 100 000 annually, as estimated through global consensus statement published in 1999. These estimates were updated in 2001 [Appendix Table 3.2]. The governmental efforts at intervention through RNTCP, and at monitoring the epidemiology of intervention through organising routine reporting, need to be understood in perspective. Data on these are reviewed here. It appears that the intervention dynamics are too nascent at this stage. The RNTCP needs to be used as an effective instrument to bring a change in epidemiological situation, and achievement of “global target” (82,83). ACKNOWLEDGEMENTS The author wishes to thank Dr Jochem Klaus and M.S. Krishnamurthy for their valuable suggestions. The secretarial

assistance of Mr V. Pandu and Ms Savitha Kumar is also thankfully acknowledged.

REFERENCES 1. Grzybowski S. Natural history of tuberculosis epidemiology. Bull Int Union Tuberc Lung Dis 1991;66:193-4. 2. Chakraborty AK. Prevalence and incidence of tuberculosis infection and disease in India: a comprehensive review. WHO/TB/97.231. Geneva: World Health Organization; 1997.p.1-26. Available at URL: http://whqlibdoc.who.int/ hq/1997/WHO_TB_97.231.pdf. Accessed on October 5, 2008. 3. Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248-75. 4. Frimodt-Moller J. A community wide tuberculosis study in a South Indian rural population, 1950-55. Bull World Health Organ 1960;22:61-70. 5. Indian Council of Medical Research. Tuberculosis in India [Special report series No. 34]. A sample survey 1955-58. New Delhi: Indian Council of Medical Research; 1959.p.1-121. 6. Nagpaul DR. District tuberculosis control programme in concept and outline. Indian J Tuberc 1967;14:186-98. 7. Pio A. Impact of present control methods on the problem of tuberculosis. Rev Infect Dis 1989;11[Suppl 2]:S360 -5. 8. Grzybowski S. Drugs are not enough. Failure of short-course chemotherapy in a district in India. Tuber Lung Dis 1993;74:145-6. 9. World Health Organization. WHO Expert Committee on Tuberculosis. Ninth Report. WHO Tech Rep Ser 1974;552:1-40. 10. Styblo K. Overview and epidemiological assessment of the current global tuberculosis situation with an emphasis on control in developing countries. Rev Infect Dis 1989; 11[Suppl 2]:S339-46. 11. Sarin R, Dey LBS. Indian National Tuberculosis Programme: revised strategy. Indian J Tuberc 1995;42:95-100. 12. Central TB Division, Ministry of Health and Family Welfare, Government of India. TB India 2002. RNTCP status report. New Delhi: Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare; Geneva: World Health Organization; 2002. 13. World Health Organization. WHO Report 2002. Global TB control, surveillance, planning, financing. Country Profile India, 2002. WHO/CDS/TB/2002.295. Geneva: World Health Organization; 2002. 14. Smith DW, Weigeshaus EH. What animal models can teach us about the pathogenesis of tuberculosis in humans. Rev Infect Dis 1989;11[Suppl 2]:S385-93. 15. Gothi GD. Natural history of tuberculosis. Indian J Tuberc 1977; 25[suppl]:1-12. 16. Grigg ER. The arcana of tuberculosis with a brief epidemiologic history of the disease in USA. Am Rev Tuberc 1958;78:583-603. 17. Chakraborty AK. Tuberculosis situation in India: measuring it through time. Indian J Tuberc 1993;40:215-25.

52

Tuberculosis

18. Bobadilla JL, Frenk J, Lozano R, Frejka T, Stern C. The epidemiologic transition and health priorities. In: Jamison DT, Mosley WH, Mesham AR, Bobadilla JL, editors. Disease control and priorities in developed countries. New York: Oxford University Press; 1993.p.51-66. 19. Vynnycky E, Fine PE. The annual risk of infection with Mycobacterium tuberculosis in England and Wales since 1901. Int J Tuberc Lung Dis 1997;1:389-96. 20. Chakraborty AK, Gothi GD, Dwarkanath S, Singh H. Tuberculosis mortality rate in a south Indian rural population. Indian J Tuberc 1978;25:181-6. 21. Raviglione MC, Sudre P, Rieder HL, Spinaci S, Kochi A. Secular trends of tuberculosis in Western Europe: epidemiological situation in 14 countries. WHO/TB/92.170. Geneva: World Health Organization, Tuberculosis Program, Division of Communicable Diseases; 1992. 22. Suarez PG, Watt CJ, Alarcon E, Portocarrero J, Zavala D, Canales R, et al. The dynamics of tuberculosis in response to 10 years of intensive control effort in Peru. J Infect Dis 2001;184:473-8. 23. Dye C, Fengzeng Z, Scheele S, Williams B. Evaluating the impact of tuberculosis control: number of deaths prevented by short-course chemotherapy in China. Int J Epidemiol 2000;29:558-64. 24. Styblo K. The elimination of tuberculosis in the Netherlands. Bull Int Union Tuber Lung Dis 1990;65:49-55. 25. Styblo K, Meijer J, Sutherland I. The transmission of tubercle bacilli. Its trend in human population. Bull Int Union Tuberc 1969;41:137-78. 26. Sytblo K. Recent advances in epidemiological research in tuberculosis. Adv Tuberc Res 1980;20:1-63. 27. Cauthen GM, Pio A, ten Dam HG. Annual risk of tuberculous infection. WHO/TB/88.154. Geneva: World Health Organization; 1988. 28. Chakraborty AK, Chaudhury K, Sreenivas TR, Krishnamurthy MS, Shashidhara AN, Channabasavaiah R. Tuberculosis infection in a rural population of south India: 23-year trend. Tuber Lung Dis 1992;73:213-8. 29. Narain R, Nair SS, Chandrasekhar P, Rao RG. Problems connected with estimating the incidence of tuberculosis infection. Bull World Health Organ 1966;34:605-22. 30. Chadha VK, Krishnamurthy MS, Shashidhara AN, Jagannath PS, Magesh V. Estimation of annual risk of infection among BCG vaccinated children. Indian J Tuberc 1999;46:105-12. 31. Dolin PJ, Raviglione MC, Kochi A. A review of current epidemiological data and estimation of future tuberculosis incidence and mortality. WHO/TB/93.173. Geneva: World Health Organization;1993. 32. Dye C, Scheele S, Dolin, PJ, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 1999;282:677-86. 33. Zaki MH. On the epidemiology of tuberculosis in some selected countries. Highlights and prospects for control and

eradication. II. Am J Public Health 1971; 61:843-54. 34. Sudre P, ten Dam G, Chan C, Kochi A. Tuberculosis in the present time: a global overview of the tuberculosis situation. WHO/TUB/91.158. Geneva: World Health Organization; 1991. 35. Tuberculosis Research Centre, Chennai. Trends in the prevalence and incidence of tuberculosis in South India. Int J Tuberc Lung Dis 2001;5:142-57. 36. Tuberculosis Prevention Trial. Trial of BCG vaccine in South India for tuberculosis prevention. Indian J Med Res 1980;72[suppl]:1-74. 37. Murhekar MV, Kolappan C, Gopi PG, Chakraborty AK, Sehgal SC. Tuberculosis situation among tribal population of Car Nicobar India, 15 years after intensive tuberculosis control programme. Bull World Health Organ 2004;82:83643. 38. Styblo K. The relationship between the risk of tuberculosis infection and the risk of developing infectious tuberculosis. Bull Int Union Tuberc 1985;60:117-9. 39. National Tuberculosis Institute, Bangalore. Tuberculosis in a rural population of south India: a five year epidemiological study. Bull World Health Organ 1974;51:473-88. 40. Centres for Disease Control and Prevention. Recommendation of the International Task Force for Disease Eradication. Morb Mortal Wkly Rep MMWR 1993;42:1-38. 41. Centres for Disease Control and Prevention. Advisory Council for the Elimination of Tuberculosis [ACET]. Tuberculosis elimination revisited: obstacles, opportunities and a renewed commitment. MMWR Morb Mortal Wkly Rep 1999;48:1-13. 42. Frost WH. How much control of tuberculosis? Am J Public Health 1937;27:759-66. 43. Styblo K. Tuberculosis control and surveillance. In: Flenley DC, Petty TL, editors. Recent advances in respiratory medicine. Volume 4. Edinburgh: Churchill Livingstone; 1986.p.77-107. 44. Chakraborty AK, Singh H, Srikantan K, Rangaswamy KR, Krishnamurthy MS, Stephen JA. Tuberculosis in a rural population of south India: report on five surveys. Indian J Tuberc 1982;29:153-67. 45. Chakraborty AK, Suryanarayana HV, Krishnamurthy VV, Krishnamurthy MS, Shashidhara AN. Prevalence of tuberculosis in a rural area by an alternative survey method without prior radiographic screening of the population. Tubercle Lung Dis 1995;76:20-4. 46. Mayurnath S, Vallishayee RS, Radhamani MP, Prabhakar R. Prevalence study of tuberculosis infection over fifteen years in a rural population in Chingleput district [south India]. Indian J Med Res 1991;93:74-80. 47. Tuberculosis Research Centre, Chennai. Fifteen year follow up of trial of BCG vaccines in south India for tuberculosis prevention. Indian J Med Res 1999;110:56-59. 48. New Delhi Tuberculosis Centre. Study of epidemiology of tuberculosis in an urban population of Delhi: Report on 30 year follow up. Indian J Tuberc 1999;46:113-24.

Epidemiology 53 49. Indira KS, Sivaraman S, Joshi M, Pillai NS. Annual risk of tuberculosis infection: an estimate from ten year old children in Trivandrum district. Indian J Tuberc 2000; 47:211-7. 50. Chadha VK, Jagannatha PS, Savanur SJ. Annual risk of infection in Bangalore city. Indian J Tuberc 2001;48:63-71. 51. Chadha VK, Jagannatha PS, Vaidyanathan PS, Singh S, Laxminarayana. Annual risk of tuberculosis infection in rural areas of Uttar Pradesh, India. Int J Tuberc Lung Dis 2003;7:52835. 52. Chadha VK, Vaidyanathan PS, Jagannatha PS. Annual risk of tuberculosis infection in rural areas of Junagadh district. J Commun Dis 2001; 33:231-40. 53. Chadha VK, Vaidyanathan PS, Jagannatha PS, Unnikrishnan KP, Savanur SJ, Mini PA. Annual risk of tuberculosis infection in the Western zone of India. Int J Tuberc Lung Dis 2003; 7:536-42. 54. Shashidhara AN, Chadha VK, Jagannath PS, Ray TK, Mania RN. The Annual risk of tuberculosis infection in Orissa state, India. Int J Tuberc Lung Dis 2004;8:545-51. 55. Chadha VK, Jagannatha PS, Narang P, Savanur SJ, Mendiratta DK, Lakshminarayana. Annual risk of tuberculosis infection in three districts of Maharashtra. Indian J Tuberc 2003;50:25-32. 56. Krishnamurthy MS. Problems in estimating the burden of pulmonary tuberculosis in India: a review. Indian J Tuberc 2001;48:193-6. 57. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, et al. The growing burden of tuberculosis: global trends and interaction with the HIV epidemic. Arch Intern Med 2003;163:1009-21. 58. Murray C, Styblo K, Rouillon A. Tuberculosis. In: Jamison DT, Mosley WH, Mesham AR, Bobadilla JL, editors. Disease control and priorities in developing countries. New York: Oxford University Press; 1993.p.233-59. 59. Chakraborty AK. Tuberculosis case finding among symptomatics in the community: a reappraisal. Indian J Tuberc 1981; 28;12–7. 60. Rieder HL, Cauthen GM, Comstock GW, Snider DE. Epidemiology of tuberculosis in the United States. Epidemiol Rev 1989;11:79–98. 61. Dholakia R. The potential economic benefits of the DOTS strategy against TB in India. WHO/TB/96.218. Geneva: World Health Organization;1996. 62. Gothi GD, Chakraborty AK, Jayalakshmi MJ. Incidence of sputum positive tuberculosis in different epidemiological groups during five year follow up of a rural population in south India. Indian J Tuberc 1978; 25:83-92. 63. Balasangameshwara VH, Chakraborty AK, Chaudhury K. A mathematical construct of epidemiological time trend in tuberculosis – fifty year study. Indian J Tuberc 1992;39:8798. 64. Chakraborty AK, Balasangameshwara VH, Jagota P, Sreenivas TR, Chaudhury K. Short course chemotherapy and efficiency variables in NTP: a model. Indian J Tuberc 1992;39:9-20.

65. Directorate of Health Services, A & N Administration. Intensified TB Control Programme in the isolated tribal population of Car Nicobar. WHO-HSR GOI Project No. IND/ HSR/001/D. 1989. p 1- 64. [Unpublished]. 66. Chakraborty AK, Channabasavaiah R, Krishnamurthy MS, Shashidhara AN, Motiram G. Tuberculin skin sensitivity following chemoprophylaxis in an island community. Indian J Tuberc 1991;38:201-11. 67. Soborg C, Soborg B, Pouelsen S, Pallisgaard G, Thybo S, Bauer J. Doubling of the tuberculosis incidence in Greenland over an 8-year period [1990-1997]. Int J Tuberc Lung Dis 2001;5:25765. 68. Inoue K, Matoba S. Counterattack of re-emerging tuberculosis after 38 years. Int J Tuberc Lung Dis 2001;5:873-5. 69. World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008. 70. Chadha VK, Kumar P, Jagannatha PS, Vaidyanathan PS, Unnikrishnan KP. Average annual risk of tuberculous infection in India. Int J Tuberc Lung Dis 2005;9:116-8. 71. Murray CJ, Salomon JA. Modeling the impact of global tuberculosis control strategies. Proc Natl Acad Sci USA 1998;95:13881-6. 72. Murray C, Salamon JA. Using mathematical models to evaluate global tuberculosis control strategies. Cambridge MA: Harvard Center for population development studies;1998. 73. Dye C, Garnett GP, Sleeman K, Williams Brian G. Prospects for worldwide tuberculosis control under the WHO DOTS strategy. Directly observed therapy short-course. Lancet 1998;352:1886-91. 74. Yajnik K, Chakraborty AK, Jochem K. A mathematical model for determining the effect of tuberculosis control programmes on its prevalence in India. A report submitted to the World Bank, New Delhi Office: 2002.p.1-131. [Unpublished]. 75. Chakraborty AK. Problem of tuberculosis among children in the community: Situation analysis in the perspective of TB in India. Indian J Tuberc 1999;46:91–104. 76. Chakraborty AK, Ganapathy KT, Rajalakshmi R. Effect of nutritional status on delayed hypersensitivity due to tuberculin test in children of an urban slum community. Indian J Tuberc 1980;27,:115-9. 77. Chadha VK, Suryanarayana HV, Krishnamurthy MK, Jagannath PS, Shashidhara AN. Prevalence of undernutrition among periurban children and its influence on the estimation of annual risk of infection. Indian J Tuberc 1997; 44:67-71. 78. Ganapathy KT, Chakraborty AK. Does malnutrition affect tuberculin hypersensitivity reaction in the community? Indian J Pediatr 1982;49:377-82. 79. Chakraborty AK, Ganapathy KT, Gothi GD. Prevalence of infection among unvaccinated children for tuberculosis surveillance. Indian J Med Res 1980;72:7-12.

54

Tuberculosis

80. Salelkar A, Edo N, Porobo J, Dessai HP, Aranjo. BCG scar prevalence among rural children in Goa. NTI Bulletin 1993;29:17-2 0. 81. Chadha VK, Jagannath PS, Vaidyanathan P, Jagota PS. PPD RT 23 for tuberculin surveys in India. Int J Tuberc Lung Dis 2003;7:172-9. 82. Chakraborty AK. Expansion of the tuberculosis programme

in India: the policy evolution towards decentralization and integration. The Centre for Health Research and Development [CHRD] – A unit of The Maharashtra Association of Anthropological Sciences [MASS]. 2003;25:194-5. 83. Dye C, Bassili A, Bierrenbach AL, Broekmans JF, Chadha VK, Glaziou P, et al. Measuring tuberculosis burden, trends, and the impact of control programmes. Lancet Infect Dis 2008;8:233-43. Epub 2008 Jan 16.

Epidemiology: Global Perspective 55

Epidemiology: Global Perspective

4 DS Maru, Jason Andrews

INTRODUCTION Tuberculosis [TB] remains the number one cause of adult deaths by a curable infectious disease worldwide despite the availability of effective diagnostic, preventive, and curative strategies against Mycobacterium tuberculosis (1). Indeed, the failure of global public health in controlling this epidemic has as much to do with the host and its environment as it does with the microbe. Persistent or rising rates of human immunodeficiency virus infection [HIV], poverty, illiteracy, smoking, and malnutrition, together with wars, political uncertainty and an increasing migratory population patterns, provide an ideal host and environment for the survival and spread of TB. This chapter reviews the historical and present epidemiology of this devastating epidemic and discusses the factors that have been responsible for the divergent pattern of prevalence and mortality trends. ISSUES IN MEASUREMENT Evidence-based public health practice requires both the political will to develop data-driven health policy and the technical capacity to collect sound data. Unfortunately, these two prerequisites often are lacking in the countries most hard-hit with TB. First, some of the key parameters that constitute the bedrock of TB control policy are defined and some of the challenges in collecting good data to estimate these parameters are discussed.

Case Notification and Passive Case Detection The most widely available statistics on TB come from reports of active cases from clinics and hospitals. The advantage of these statistics is that they come directly from providers treating patients, which can be coordinated with central surveillance agencies to provide reasonably reliable estimates over time. Their accuracy, on the other hand, may be compromised in settings where treatment is primarily through unregulated private practitioners, where access to care is low, and where diagnostic facilities are wanting. Indeed, in the very places where TB may be highest, reporting standards may be poorest. The World Health Organization [WHO] endorses DOTS as the key strategy for controlling and eventually eradicating TB in the guidelines for National Programmes (2). Accurate recording and reporting are virtues of this system which has gained acceptance world over. As DOTS expands, it is hoped that TB detection and treatment will become more standardized and, consequently, these rates will become more accurate. Active Case Detection Active case detection requires a much greater investment of resources, and most developing countries do not view this as a priority strategy. This method has been proposed through the following broad measures: [i] active case finding through mass miniature radiography and sputum examination; and [ii] contact tracing of close contacts of active TB cases (3). Active case finding could

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be undertaken in a periodic fashion, for example, once in every seven years, or as a single cycle. While the primary aim of such programmes is in improving treatment and detection, they also can serve as strategies to improve surveillance. Active case detection could provide a more accurate estimate of TB epidemiology, as well as engage TB control programmes and communities in broader primary care. However, the experience of active case finding in various contexts and populations over the past 80 years has been variable, with some programmes finding great success and having a population-level impact on TB incidence and others suffering from high costs, inefficiencies, and the limited sensitivity of chest radiograph and sputum examination (4). Nevertheless, in recognition that additional strategies are needed in areas where TB control is failing, such as settings of HIV prevalence, large scale evaluations of this tool are currently underway. Distinct but related approaches include enhanced case finding and contact investigation. Enhanced case finding is a term used to denote a programme that informs a population about TB symptoms and treatment availability, encouraging self-presentation to medical services rather than individually engaging the patient outside the context of care. Contact investigations can be considered forms of active case finding, whereby the close contacts or household contacts of patients diagnosed with TB are screened for the disease. The yield of this approach—and, correspondingly, the costeffectiveness—has been highly variable and is very much context- and population-dependent (5). For example, the tracing of paediatric TB patients has generally found a low yield, despite the fact that TB in children represents a recent infection. Secondary case detection rates through routine contact investigation have ranged from two per cent in the USA, to 12 per cent in India and 61 per cent in Malawi (6-8). While the utility of this approach continues to be evaluated, more recent evidence has suggested that contact investigations can be useful in patients with multidrug-resistant TB [MDR-TB] as a means of timely identification and treatment of individuals with drugresistant infection (9). Aggregating Data and Geographical Heterogeneity Aggregating these data from local epidemics and estimating the size of a more conceptual “global epidemic” is central global public health planning. It is also

important in fostering the political will necessary to procure the massive funding for the Millennium Development Goals [MDGs] (10). Unfortunately, analysis of aggregated data may be misleading given the considerable heterogeneity in the levels and trajectories of the innumerable local epidemics. So, while disease transmission is increasingly a global phenomenon, the fact remains that, even within countries and indeed towns, the burden of disease tends to operate in very specific, complex patterns. For example, when there is a major outbreak of TB among the most marginalized homeless segments of New York City, most citizens of the city are not placed at appreciably greater risk. Determining incidence rates on city-wide scale may be much less fruitful in assessment, strategy development, and monitoring than determining risk among high-risk populations. Especially when assessing global epidemiology, these locally-specific data are either not available or are overly cumbersome to interpret. Tuberculosis may be spiralling out of count in some countries, but, because their population size is small, they have little impact on the numbers of the global epidemic. So, while 199 countries reported to the WHO in 2006, 80 per cent of all incident cases of TB were from 22 high-burden countries [HBCs] (11). On the other hand, many of the African countries with the highest incidence rates per capita are not on the list of HBCs, owing to their small size. As such, setting global TB priorities needs to account for both national and highly local epidemiological dynamics. Mathematical Models and Epidemic Prediction Data generated from the above measurement strategies are important not only for enhancing our understanding of present TB epidemiology, but also in predicting future epidemics. Mathematical models can provide rigorous prediction of future TB epidemiology, crucial to public health planning. While an in-depth treatment of mathematical models is beyond the scope of this text, the basic foundation for even the most complex models is a modified Susceptible-Infected-Recovered [SIR] model that allows for both latent infection and active disease. A simple model for illustrative purposes [Figure 4.1A] is modified from Blower (12,13). This is modelled by a series of differential equations as shown in Figure 4.1B. Essentially, the model allows for individuals in each compartment to flow between each other at constant

Epidemiology: Global Perspective 57

Figure 4.1A: A mathematical model for tuberculosis epidemiology. The letters X, L, T, and R indicate separate compartments between which an individual in the population flows Source: references 12,13 Figure 4.2: Changes in tuberculosis mortality rate in Western Europe, 1750-1980 Reproduced with permission from reference “Murray JF. A thousand years of pulmonary medicine: good news and bad. Eur Respir J 2001;17:558-65 (reference 19)”

ment from a different path. For interesting applications of mathematical models to TB epidemiology and prediction, see references (14-16). The reader is also referred to the chapter “Epidemiology” [Chapter 3] for details regarding mathematical modelling as applied to the Indian scenario. Figure 4.1B: Mathematical equations underlying the model described in Figure 4.1A. The parameters are defined as:  is the birth rate; μ is the mortality rate [this can differ between compartments; for simplicity not shown]; λ is the “force of infection” which depends upon the contact rate and the transmissibility of infectious active TB in the population; p is the probability that an infection will rapidly progress to TB [primary progressive TB]; f is the fraction of primary progressive active TB cases that are smear-positive; q is the fraction of endogenous reactivation active TB cases that are smear-positive; w is the rate at which recovered cases relapse; and c is the treatment rate Source: references 12,13

rates; by varying various parameters, for example, the treatment rate, one can assess the long-term behaviour of the system. A few key assumptions of this kind of model are: homogenous mixing; homogenous dynamic behaviour of individuals within each of the compartments; constant flow rates between compartments that are independent of the size of individual compartments; additive mortality rates. Additionally, note that there is no age structure and that the system is memory-less in the sense that an individual that reached one compartment from a particular other compartment behaves in the same way as an individual that reached the compart-

THE GLOBAL SCENARIO Historical Trajectory Prior to the development of effective antituberculosis therapy in the late 1940s, TB was a major public health threat in both developing and developed countries; mortality due to pulmonary TB was 50 per cent and TB meningitis and miliary TB were almost 100 per cent fatal. While there was already a decline in prevalence of TB in the developed world prior to the advent of antituberculosis treatment [the reasons for which are still being debated] (17,18), the introduction of specific treatment with antituberculosis drugs resulted in a precipitous reduction in mortality due to TB in the developed world [Figure 4.2] (19) and may have further accelerated the decline in prevalence. However, progress has been much slower in developing countries; although there is a paucity of data on TB prevalence and mortality in developing countries prior to the 1990s, when the disease was declared a “global emergency” and surveillance and control efforts became systematized, a snapshot of the global prevalence of TB in 1990 is suggestive; while the prevalence of TB in Europe and the USA was 55 and

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8 per 100 000, respectively, in Africa and South-East Asia the corresponding figures were 317 and 536 (20). Where historical data are available, a steady-state in disease, during the period of TB decline in the West, is revealed; in India, for example, prevalence of sputum smear-positive pulmonary TB decreased modestly from 400 per 100 000 in the 1950s to 330 per 100 000 in 1991, and incidence between 1990 and 2004 was essentially constant (20,21). Furthermore, global progress in TB control has not been uniformly smooth. The decline in TB prevalence in developed countries began to reverse in the 1980s; in the United States, for example, TB incidence rose steadily between 1985 and 1992, following 30 consecutive years of decline (22). This trend has been attributed to immigration from high-prevalence countries, urban poverty, HIV, and a response weakened by the perception that TB was a disease of the past. While TB rates among the US-born population declined 63 per cent between 1993 and 2005, it fell by a little over half that rate in foreign-born residents of the US over this time (23). Many Western European countries have seen similar trends, while countries in the former Soviet Union are seeing high and rising rates due to poverty, malnutrition, poor living conditions, breakdown in the law and order situation and an inadequate health care infrastructure. GLOBAL TUBERCULOSIS EPIDEMIC: CURRENT STATUS The WHO’s 2008 report (11) presents an overview regarding the year 2006 data and estimates, basing on the reports from 202 countries representing 99.9 per cent of the world’s population. This report (11) provides a comprehensive insight into the current status and trends of the global TB epidemic. In 2006, globally there were an estimated 9.2 million new TB cases [139 per 100 000] globally [Figures 4.3A, 4.3B, and 4.3C; Tables 4.1A and 4.1B] (11,24). Of these, 4.1 million [62 per 100 000] were new sputum smear-positive cases. Tuberculosis prevalence rates appear to be falling globally for several years. The TB incidence rate in 2006 was stable or in decline in all six WHO regions, and appears to have levelled off for the first time since 1993 (11). The total number of new TB cases registered slow increase because of the continuing increase in the caseload in the African, Eastern Mediterranean and SouthEast Asia regions. Majority of the cases [55%] were in Asia [South-East Asia and Western Pacific regions] and

Figure 4.3A: Relative contribution to the global tuberculosis incidence Source: reference 11 Reproduced with permission from “Central TB Division. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. TB India 2008. RNTCP status report. New Delhi: Central TB Division. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India; 2008 (reference 24)”

sub-Saharan Africa [31%]. As per the estimated number of incident cases, 22 countries have been given special attention. This large excess has partly been ascribed to the effect of HIV infection. In 2006, 1.7 million people died of TB, including 231 000 patients co-infected with HIV (11). Expansion of DOTS In 1993, the WHO declared TB to be a global health emergency; subsequent to this, momentum for DOTS built up, and the 1990s showed a remarkable expansion of DOTS coverage throughout the globe. By 2006, DOTS has been implemented in 184 countries [93% of the world’s population] (11) [Figure 4.4]. Case detection rates followed; from 11 per cent in 1995 to over 50 per cent by 2006 (25-27). Data from India show the great speed with which this programme has been enacted; from its start in 1997 as national expansion of the Revised National Tuberculosis Control Programme [RNTCP] to 2006, over a billion Indian citizens came to live in areas covered by DOTS (24). The Figure 4.5 (11) shows this remarkable

Epidemiology: Global Perspective 59

Figure 4.3B: Estimated numbers of new tuberculosis cases [all forms], 2006 TB = tuberculosis Reproduced with permission from “World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008 (reference 11)” The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current year available at the URL: http://www.who.int/topics/tuberculosis/en/

Figure 4.3C: Estimated numbers of new tuberculosis cases [all forms] per 100 000 population, 2006 TB = tuberculosis Reproduced with permission from “World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008” (reference 11)” The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current year available at the URL: http://www.who.int/topics/tuberculosis/en/

60

Tuberculosis Table 4.1A: Estimated tuberculosis burden 2006 in 22 high prevalence countries Incidence*

All forms per 100 000 population per year 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

India China Indonesia South Africa Nigeria Bangladesh Ethiopia Pakistan Philippines DR Congo Russian Federation Vietnam Kenya UR Tanzania Uganda Brazil Mozambique Thailand Myanmar Zimbabwe Cambodia Afghanistan High-burden countries

168 99 234 940 311 225 181 378 287 392 107 173 384 312 355 50 443 142 171 557 500 161 177

Prevalence, all Mortality, all HIV prevalence, in incident forms per 100 000 forms per 100 000 population per year population per year cases %†

Smear-positive per 100 000 population per year 75 45 105 382 137 101 82 168 129 173 48 77 153 135 154 31 186 62 76 227 220 73 79

299 201 253 998 615 391 263 641 432 645 125 225 334 459 561 55 624 197 169 597 665 231 286

28 15 38 218 81 45 34 83 45 84 17 23 72 66 84 4 117 20 13 131 92 32 32

1.2 0.3 0.4 44.0 9.6 0.0 0.3 6.3 0.1 9.2 3.8 5.0 52.0 18.0 16.0 12.0 30.0 11.0 2.6 43.0 9.6 0.0 11.0

* All estimates include TB in people with HIV † Prevalence of HIV in incident TB cases in adults aged 15-49 years HIV = human immunodeficiency virus; TB = tuberculosis Adapted and reproduced with permission from “World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2008.393 Geneva: World Health Organization; 2008 (reference 11)” The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current year available at the URL: http://www.who.int/topics/tuberculosis/en/

trend. China, the most populous country in the world and one of the highest burdens of TB, had similarly reached nearly 100 per cent coverage by 2005 (26). Assessing the impact of DOTS on global epidemiology is difficult owing to its patchy and sporadic distribution with high variability between DOTS programmes, and the lack of hard data as to its real-world effectiveness. Mathematical modelling, however, does suggest that the epidemiologic potential is quite high, with annual decreases in tuberculosis incidence and deaths on the order of 10 per cent; the impact is dampened, however, by the HIV epidemic (25). The reader is referred to the chapter “DOTS: the strategy that ensures cure of tuberculosis” [Chapter 56] for further details.

Human Immunodeficiency Virus Co-infection The HIV/AIDS epidemic is the major reason for increasing host susceptibility patterns in the 1980s and 90s and continues to fuel the tuberculosis epidemic [Figure 4.6]. The HIV is responsible for nearly 10 per cent of new cases of TB worldwide and more than 30 per cent of new cases in Africa (27). Widespread HIV/AIDS is a central reason why the WHO African region remains the one region that has failed to decrease incidence during the DOTS era; indeed, several African countries have seen rising incidence rates. A recent study of a high HIV-prevalence community in South Africa found a 2.5fold increase in TB notification [to more than 1400 per 100 000, a staggering and unparalleled figure]

Epidemiology: Global Perspective 61 Table 4.1B Estimated global tuberculosis burden 2006 Incidence* WHO region

AFR AMR EMR EUR SEAR WPR Global

All forms per 100 000 population

Smear-positive per 100 000 population per year

346 37 105 49 180 109 139

155 18 47 22 81 49 62

Prevalence, all forms per 100 000 population per year

547 44 152 54 289 199 219

Mortality, all forms per 100 000 population per year

83.0 5.4 20.0 7.0 30.0 17.0 25.0

HIV prevalence, in incident cases %†

22.0 6.4 1.1 3.0 1.3 1.2 7.7

* All estimates include TB in people with HIV † Prevalence of HIV in incident TB cases in adults aged 15-49 years HIV = human immunodeficiency virus; TB = tuberculosis; WHO = World Health Organization; AFR = African region; AMR = American region; EMR = Eastern Mediterranean region; EUR = European region; WPR = Western Pacific region; SEAR = South-east Asian region Adapted and reproduced with permission from “World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008 (reference 11)” The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current year available at the URL: http://www.who.int/topics/tuberculosis/en/

“Tuberculosis and human immunodeficiency virus infection” [Chapter 40] for more details. Drug-resistant Tuberculosis

Figure 4.4: Number of countries implementing DOTS [out of a total of 212 countries], 1991-2006 Reproduced with permission from “World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008 (reference 11)” The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current year available at the URL: http://www.who.int/ topics/tuberculosis/en/

concomitant with a 3.5-fold rise in HIV infection in the adult population (28). Alarmingly, this trend unfolded in a community with excellent DOTS coverage, confirming the claim that DOTS alone will be an insufficient strategy for containing TB in areas with high rates of HIV infection. The reader is referred to the chapter

The spectre of MDR-TB has provoked considerable fear in the public health community in recent years. The concerns are not without justification: MDR-TB can be difficult to treat, requires long durations of therapy with regimens that are orders of magnitude more expensive than first-line short-course chemotherapy, and carry higher rates of mortality. Data presented in the third round of surveys (29,30) coordinated by WHO and the International Union Against Tuberculosis and Lung Disease [IUATLD] between 1996 and 2002 from 77 settings or countries that were collected between 1999 and 2002 indicate that MDR-TB was found in all regions of the world (29). The problem of drug-resistant TB has been compounded by the recent documentation of extensively drug-resistant tuberculosis [XDR-TB] as a global phenomenon (31). The epidemiological aspects related to MDR-TB and XDR-TB are exhaustively covered in the chapter “Antituberculosis drug resistance surveillance” [Chapter 50] and the reader is referred to this chapter for more details.

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Figure 4.5: Contributions to the global increase in the number of new smear-positive cases notified under DOTS made by highburden countries, 2005-2006 Reproduced with permission from “World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008 (reference 11)”

Figure 4.6: Estimated HIV prevalence in new adult tuberculosis cases, 2006 HIV = Human immunodeficiency virus; TB = tuberculosis Reproduced with permission from “World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008 (reference 11)” The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current year available at the URL: http://www.who.int/topics/tuberculosis/en/

Epidemiology: Global Perspective 63

Figure 4.7: The new Stop TB strategy at a glance TB = tuberculosis; HIV = human immunodeficiency virus infection; MDR-TB = multidrug-resistant tuberculosis Reproduced with permission from “World Health Organization. Stop TB Partnership. The Stop TB Strategy. Building on and enhancing DOTS to meet the TB-related Millennium Development Goals. WHO/HTM/TB/2006.368. Geneva: World Health Organization; 2006 (reference 36)”

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GLOBAL TARGETS In light of the early forays and global expansion of DOTS, the first Global Plan to Stop TB charted the actions that were needed in TB control over the period 2001-2005 (32). The United Nations MDGs frame work (33) included TB control as one of the priorities. The “Goal 6” addresses “Combat HIV/AIDS, malaria and other diseases”; “Target 8” aims at “To have halted by 2015 and begun to reverse the incidence of malaria and other major diseases”. The MDG framework includes additional indicators: prevalence and deaths [indicator 23], and the World Health Assembly [WHA] targets for case detection rate and treatment success rate [indicator 24]. Even though these goals facilitate the measurement of the epidemiological impact, clear-cut targets for reducing the global TB prevalence and death rates were not evident in them. The new Stop TB strategy (34-36), and the Global Plan to Stop TB, 2006-2015 (37) have been evolved to meet the challenge of TB control [Figure 4.7]. The new Stop TB strategy (34-36) aims at reducing the disease prevalence and deaths by 50 per cent relative to 1990 levels. This translates to reducing prevalence to 155 per 100 000 or lower and deaths to 14 per 100 000 per year or lower by the year 2015 and includes TB cases co-infected with HIV. It is also aimed that the number of people dying from TB in 2015 should be less than about one million, including those co-infected with HIV. By 2050, it is aimed that the global incidence of TB disease will be less than one case per million population per year. Global epidemiology of TB remains plagued by social and biological complexities that challenge efforts at standardized methods of diagnosis, detection, and reporting. While the expansion of DOTS and the refinement of mathematical models represent significant steps in better understanding the history, present, and future of the global TB epidemic, even now great uncertainties remain in basic estimates of incidence, prevalence, and annual risk of infection [ARI]. Still, the purpose of epidemiology is to provide a basis for sound control strategies, and indeed available data and projections provide a basic course to follow: further improving economic and social development; distributing and improving upon chemotherapy; expansion of DOTS and DOTS-Plus; decrease HIV transmission and impact; and improving population-wide nutritional status.

REFERENCES 1. World Health Organization. World health report 2004: Changing history. Geneva: World Health Organization; 2004. 2. World Health Organization, Stop TB Department. Treatment of tuberculosis: guidelines for national programmes. 3rd edition. Geneva: World Health Organization; 2003. 3. Murray CJ, Salomon JA. Expanding the WHO tuberculosis control strategy: rethinking the role of active case-finding. Int J Tuberc Lung Dis 1998;2[9 Suppl 1]:S9-15. 4. Golub JE, Mohan CI, Comstock GW, Chaisson RE. Active case finding of tuberculosis: historical perspective and future prospects. Int J Tuberc Lung Dis 2005;9:1183-203. 5. Reichler MR, Etkind S, Taylor Z, Castro KG. Tuberculosis contact investigations. Int J Tuberc Lung Dis 2003;7[12 Suppl 3]:S325-7. 6. Topley JM, Maher D, Mbewe LN. Transmission of tuberculosis to contacts of sputum positive adults in Malawi. Arch Dis Childhood 1996;74:140-3. 7. Kamat SR, Dawson JJ, Devadatta S, Fox W, Janardhanam B, Radhakrishna S, et al. A controlled study of the influence of segregation of tuberculous patients for one year on the attack rate of tuberculosis in a 5-year period in close family contacts in South India. Bull World Health Organ 1966;34:517-32. 8. Reichler MR, Reves R, Bur S, Thompson V, Mangura BT, Ford J, et al; Contact Investigation Study Group. Evaluation of investigations conducted to detect and prevent transmission of tuberculosis. JAMA 2002;287:991-5. 9. Bayona J, Chavez-Pachas AM, Palacios E, Llaro K, Sapag R, Becerra MC. Contact investigations as a means of detection and timely treatment of persons with infectious multidrugresistant tuberculosis. Int J Tuberc Lung Dis 2003;7[12 Suppl3]:S501-9. 10. UN Statistics Division. Millennium indicators database. Available at URL: http://unstats.un.org/unsd/mdg/ default.aspx. Accessed on October 7, 2008. 11. World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization;2008. 12. Blower SM, Small PM, Hopewell PC. Control strategies for tuberculosis epidemics: new models for old problems. Science 1996;273:497-500. 13. Blower SM, McLean AR, Porco TC, Small PM, Hopewell PC, Sanchez MA, et al. The intrinsic transmission dynamics of tuberculosis epidemics. Nat Med 1995;1:815-21. 14. Murray CJ, Salomon JA. Modeling the impact of global tuberculosis control strategies. Proc Natl Acad Sci USA 1998;95:13881-6. 15. Dye C, Garnett GP, Sleeman K, Williams BG. Prospects for worldwide tuberculosis control under the WHO DOTS strategy. Directly observed short-course therapy. Lancet 1998;352:1886-91. 16. Vynnycky E, Fine PE. The natural history of tuberculosis: the implications of age-dependent risks of disease and the role of reinfection. Epidemiol Infect 1997;119:183-201.

Epidemiology: Global Perspective 65 17. Davies RP, Tocque K, Bellis MA, Rimmington T, Davies PD. Historical declines in tuberculosis in England and Wales: improving social conditions or natural selection? Int J Tuberc Lung Dis 1999;3:1051-4. 18. Grange JM, Gandy M, Farmer P, Zumla A. Historical declines in tuberculosis: nature, nurture and the biosocial model. Int J Tuberc Lung Dis 2001;5:208-12. 19. Murray JF. A thousand years of pulmonary medicine: good news and bad. Eur Respir J 2001;17:558-65. 20. World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO Report 2006. WHO/ HTM/TB/2006.362. Geneva: World Health Organization; 2006. 21. Chadha VK. Tuberculosis epidemiology in India: a review. Int J Tuberc Lung Dis 2005;9:1072-82. 22. Layton MC, Cantwell MF, Dorsinville GJ, Valway SE, Onorato IM, Frieden TR. Tuberculosis screening among homeless persons with AIDS living in single-room-occupancy hotels. Am J Public Health 1995;85:1556-9. 23. Centers for Disease Control and Prevention. Trends in tuberculosis-United States, 2005. MMWR Morb Mortal Wkly Rep 2006;55:305-8. 24. Central TB Division. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. TB India 2008. RNTCP status report. New Delhi: Central TB Division. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India; 2008. 25. Dye C, Watt CJ, Bleed DM, Hosseini SM, Raviglione MC. Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence, and deaths globally. JAMA 2005;293:2767-75. 26. Sharma SK, Liu JJ. Progress of DOTS in global tuberculosis control. Lancet 2006;367:951-2. 27. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009-21.

28. Lawn SD, Bekker LG, Middelkoop K, Myer L, Wood R. Impact of HIV infection on the epidemiology of tuberculosis in a peri-urban community in South Africa: the need for agespecific interventions. Clin Infect Dis 2006;42:1040-7. 29. World Health Organization. Anti-tuberculosis drug resistance in the world. Report No. 4. WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. WHO/HTM/TB/2008.394. Geneva: World Health Organization; 2008. 30. Aziz MA, Wright A, Laszlo A, De Muynck A, Portaels F, Van Deun A, et al; WHO/International Union Against Tuberculosis and Lung Disease Global Project on Antituberculosis Drug Resistance Surveillance. Epidemiology of antituberculosis drug resistance [the Global Project on Antituberculosis Drug Resistance Surveillance]: an updated analysis. Lancet 2006;368:2142-54. 31. World Health Organization. Countries with XDR-TB Confirmed cases to date. Available at URL: http:// www.who.int/tb/challenges/xdr/xdrmap_oct07_en.pdf. Accessed on October 7, 2008. 32. World Health Organization. The Global Plan to Stop Tuberculosis. WHO/CDS/STB/2001.16. Geneva: World Health Organization;2001. Accessed on October 7, 2008. 33. United Nations Statistics Division. Millennium Indicators Database. New York: United Nations Statistics Division, 2004. 34. Raviglione MC, Uplekar MW. WHO’s new Stop TB Strategy. Lancet 2006;367:952-5. 35. Raviglione MC. The new Stop TB Strategy and the Global Plan to Stop TB, 2006-2015. Bull World Health Organ 2007;85:327. 36. Stop TB Partnership. World Health Organization. The Stop TB Strategy Building on and enhancing DOTS to meet the TB-related Millennium Development Goals. WHO/HTM/ TB/2006.368. Geneva: World Health Organization; 2006. 37. The Global Plan to Stop TB 2006-2015. Available at URL: http://www.stoptb.org/globalplan. Accessed on October 7, 2008.

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Pathology

5 S Datta Gupta, Ruma Ray, SS Gill

He becomes the true discoverer who establishes the truth; and the sign of truth is the general acceptance. In science, credit goes to the man who convinces the world, not to the man to whom the idea first comes Dubos RJ, Dubos J (1) INTRODUCTION Tuberculosis [TB] has been known to mankind since many years. The aetiology, pathogenesis, clinical features and the treatment of TB have been the subject of controversy and myths for centuries. However, there was agreement on one score and that was the observation that the disease was associated with a poor prognosis. It was hoped that the discovery of the cause of TB marked the end of the scourge, phthisis, struma, phyma, hectic fever, consumption, ‘white death’, the ‘white plague’, or the ‘Captain of all these men of death’ as remarked by the evangelist John Bunyon. Unfortunately, this did not happen. The human immunodeficiency virus [HIV], acquired immunodeficiency syndrome [AIDS] pandemic has had a devastating effect on this scenario. Despite the emergence of drug-resistant cases, the treatment of TB is the most cost-effective of all cures (2,3). It must be realized that a significant number of TB cases go unreported until death. This underlines the danger of open cases spreading infection to others. Tuberculosis also constitutes a grave danger to health care professionals (4). The pathology of TB is essentially similar to most other infectious diseases. It is the process and the consequence of interplay between the bacillus and host immunity. The relationship between the two can be varied, complex and can last life long. The host can win

over the bacillus or the bacillus can overwhelm the host. At times the battle may stop for years, only to resume later on. All this is reflected in the gross and microscopic appearances of the different organs. Tuberculosis infection is spread by aerosol. Therefore, pulmonary TB is the predominant form of disease. The lung is indeed the primary site of infection in most instances. Extra-pulmonary TB is commonly a consequence or accompaniment of pulmonary TB. However, TB affects almost every organ in the body. It would be beyond the scope of this chapter to deal with the pathology of TB with reference to each and every organ in detail. Readers are, therefore, referred to the respective chapters concerned with different organ systems that supplement this chapter. CLASSIFICATION Tuberculosis is classified into different clinicopathological types depending on various factors [Table 5.1]. Though there may be some link in the relationship of age to the exposure and type of TB, terminology related to age such as “childhood TB” and “adulthood TB” should not be used. Primary TB occurs in persons who have been exposed to Mycobacterium tuberculosis for the first time. In areas of the world where TB is highly endemic, primary TB usually occurs in children. In countries where substantial control of TB has been achieved, increasing number of adults lack acquired immunity. When these adults are infected for the first time, they can manifest the primary form of the disease. Primary TB can also occur when acquired immunity to TB is lost due to senescence or

Pathology 67 Table 5.1: Classification of tuberculosis Based on sequence of events following the first exposure Primary TB Disease caused by Mycobacterium tuberculosis in a person with no previous exposure Progressive primary TB Primary disease which is generally self-limiting may progress to give rise to larger lesions Post-primary TB Disease which is the result of endogenous reactivation [in a person previously exposed to Mycobacterium tuberculosis] or exogenous reinfection Based on location Localized disease Pulmonary TB Extra-pulmonary TB Disseminated TB Tuberculosis disease process involving more than 2 non-contiguous sites. Disseminated TB can occur in primary [early generalized TB] and post-primary [late generalized TB] forms of the disease. When the lesions are uniform and are of the size of a millet seed [< 2 mm], the term miliary TB is used TB = tuberculosis

occurrence of some specific immune defect. As pointed out by Rich (5) “resistance is a notoriously fluctuating condition and even though resistance may have been previously acquired, it may be overcome by new invasion of tubercle bacillus”. Progressive primary TB arises when there is inadequate immunity. It is most commonly seen in infants, adolescents and elderly. Post-primary TB, is generally a disease of the adults due to endogenous reactivation or exogenous reinfection in a patient who has been infected in the past and has retained a degree of acquired immunity. Haematogenous spread of the disease throughout the lungs and to multiple organs [miliary TB] may occur in both the primary and post-primary forms of the disease. HISTOPATHOLOGICAL APPEARANCE The histopathological hallmark of TB is a granuloma. Infact, TB is cited as the classical example of a granulomatous inflammation. It is, therefore, necessary to briefly discuss the features of a granuloma here. Granuloma The term granuloma [derived from the diminutive of the Latin term for a grain, granulum] was used by Rudolph

Virchow [1818] to describe tumours that may ulcerate and give rise to granulation tissue (6,7). However, the present connotation is different. Granuloma can be defined as a focal, compact collection of inflammatory cells in which mononuclear cells predominate. Granulomas are the result of a persistent non-degradable product or organism, or the result of hypersensitivity or both. Therefore, granulomas may form as a consequence of an immunological mechanism or otherwise. Granulomas which are due to a non-immunological mechanism generally do not reveal a lymphocyte response [e.g., some of the foreign body granulomas] whereas those due to an immunological mechanism have a prominent lymphocyte component. There is an almost sequential change due to interplay amongst the causative agent [identifiable or non identifiable], macrophage activity, T-cell responses, B-cell overactivity and circulating immune complexes of biological mediators resulting in a granulomatous inflammation. Granuloma is not a mere collection of inflammatory cells but an active site of numerous enzymes and cytokines involved in the very serious business of removing the causative agent (8). Morphologically, granulomas invariably show some degree of organization. Centrally, macrophages predominate and are essential constituents of most granulomas because these are sites where an attempt is being made to remove the causative agent through phagocytosis. When macrophages become activated, the cytoplasm assumes a large, pale, eosinophilic or even foamy appearance. The margins become indistinct so that adjacent macrophages seem to form a continuous sheet, akin to the surface epithelium. Such cells are called epithelioid cells and the granuloma is known as an epithelioid cell granuloma. Not all granulomas are of the epithelioid cell type. Epithelioid cells may fuse to form multinucleated giant cells. Generally, two types of giant cells are identifiable in TB. In one type, the nuclei are arranged along the periphery, almost forming a rosette around the central cytoplasmic area. This is called the Langhans’ type of giant cell after Theodore Langhans [1868] who critically evaluated granulomas in TB (5). In the foreign-body type of giant cells, the nuclei do not show such a regular arrangement. The offending foreign-body may or may not be identified within this giant cell. In some lesions associated with multiple discrete granulomas, it appears as though each granuloma has a single giant cell.

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Sometimes such independent granulomas [if such a term can be used] appear to coalesce to form confluent granulomas. Surrounding the macrophages is a variable cuff of lymphocytes which may be relatively more prominent in immunologically induced granulomas. Other types of inflammatory cells such as eosinophils may also form a part of the granuloma. Older granulomas that are healing show fibrosis. Ultimately, the entire granuloma may undergo fibrosis, hyalinization, calcification and even ossification. The presence of a central area of necrosis distinguishes a necrotising granuloma from a nonnecrotising granuloma. The histopathological lesion of TB is the prototype of a necrotising epithelioid cell granuloma [Figure 5.1] while that of sarcoidosis is a classical example of a non-necrotising epithelioid cell granuloma. Therefore, it is not uncommon to refer to tuberculoid type and sarcoid type of granulomas. The causes of granulomatous infection are numerous and are provided in Table 5.2 (9). The diagnosis of the aetiology of granulomas, on histopathological grounds, can vary from “accurate” to “presumptive” to “impossible”. If the cause is apparent, as in the case of a foreign body or a parasite or fungus or acid-fast bacilli [AFB], then the diagnosis can be made with a reasonable certainty. Newer, sensitive molecular biological techniques such as the polymerase chain reaction [PCR] often resolve the issue. In other instances, the diagnosis is at the best presumptive or compatible with a clinical suspicion. In many cases, the cause of granulomatous inflammation may not be evident on histopathological examination.

Table 5.2: Aetiology of some granulomatous infections Well recognized agents Tuberculosis, leprosy, Buruli ulcer, Mycobacteria swimming pool [fish tank] granuloma Bacteria Brucellosis, melioidosis, actinomycosis, nocardiosis, granuloma inguinale, listeriosis, tularemia Chlamydiae Lymphogranuloma venereum, trachoma Rickettsiae Qfever [Coxiella burnetii infection] Spirochetes [syphilis], pinta, yaws Fungi Cryptococcosis, candidiasis, sporotrichosis, histoplasma, aspergillosis, blastomycosis, coccidiodomycosis, chromoblastomycosis, mycetoma Protozoa Leishmaniasis, toxoplasmosis Nematodes Visceral larva migrans [toxocariasis] Trematodes Schistosomiasis, paragonimiasis, fascioliasis, clonorchiasis Viruses Infectious mononucleosis, cytomegalovirus, measles, mumps Foreign body Talc, silica, zirconium Recently recognized Bacterium Actinomyces

Cat-scratch disease [Bartonella henselae] Whipples disease [Tropheryma whippeli]

Idiopathic or suspected but not established Measles virus Crohn’s Disease Mycobacterium Primary biliary cirrhosis Viral Kikuchi’s disease ? Sarcoidosis ? Chronic granulomatous disease of childhood, orofacial granulomatosis [Melkerson-Rosenthal syndrome]

Granulomatous Inflammation in Tuberculosis

Figure 5.1: Photomicrograph showing necrotising [caseating] granulomatous tuberculosis lymphadenitis [Haematoxylin and eosin x 100]

The characteristic, but not necessarily diagnostic, lesion in TB is a confluent necrotising epithelioid cell granuloma (10). Broadly, the microanatomical lesions in TB are classified into exudative and proliferative lesions. Exudative lesions are less well-demarcated, comprise of neutrophils, lymphocytes, macrophages and epithelioid histiocytes arranged in a loose collection with little fibroblastic proliferation. These lesions are also described as soft granulomas and are likely to contain AFB. Proliferative lesions are well circumscribed with a lymphocyte cuff surrounding well-aggregated epithelioid histiocytes. Plasma cells may be found but neutrophils are scant. Surrounding fibroblastic proliferation is more marked [hard granulomas]. Acid-fast

Pathology 69 bacilli are less readily demonstrated. Langhans’ giant cells are seen in both types but are more common in the proliferative type. These two types of granuloma are not specific to a particular type of TB and both lesions are frequently seen to coexist. The number, size and extent of these granulomas depend upon the number of infecting bacilli, mode of spread and amount of tuberculoprotein discharged into the developing lesion. It may be mentioned that exudative lesions, sometime with a predominance of neutrophils, are seen more often in TB of serous surfaces, such as the meninges and peritoneum. Sometimes, neutrophils may predominate in TB lesions in organs with a loose texture [e.g., TB bronchopneumonia], giving the appearance of a nonmycobacterial infection. It is in such instances that TB may be mistaken for an acute inflammation and the diagnosis can be missed, if Ziehl-Neelsen staining is not performed. Eosinophils are conspicuous by their absence in TB except in the gastrointestinal tract lesions. Mathew Ballie in 1709 and subsequently, Alois Rudolph Vetter in 1803, compared some of the lesions in phthisis to cheese (11). This “cheese-like” necrosis on gross examination of TB lesions is called caseous necrosis. This term has been extended to microscopy also. Caseating granulomas are characteristically but not exclusively found in TB. Caseation necrosis is a structureless necrosis. It not only implies permanent tissue destruction, but is also a mechanism for destruction of Mycobacterium tuberculosis. Within the caseum low oxygen tension, low pH and local accumulation of fatty acids inhibit bacillary replication. The caseum can become inspissated and encapsulated by fibrous tissue [fibrocaseous granuloma]. The caseous focus can become completely organized and converted to fibrous scar that is often calcified or ossified. It may undergo liquefaction and cavitation. Liquefaction probably involves proteolytic enzymes derived from neutrophils and macrophages which are present within or around the caseous focus. Unlike caseous debris, liquefied material is usually teeming with bacilli. Cavitation occurs when the liquefied area ruptures into an airway and is evacuated. Dissemination of bacilli in this manner contributes to the development of TB pneumonia. The caseous areas can become completely organized and converted to fibrous scar over a period of weeks [Figure 5.2]. These areas may become calcified over several months [Figure 5.3]. After several years, the foci may even be ossified [Figure 5.4].

Figure 5.2: Photomicrograph showing extensive hyalinization of granulomas in tuberculosis [Haematoxylin and eosin x 40]

Figure 5.3: Nodular tuberculosis of the lung. Photomicrograph showing caseation with calcification [blue] and circumferential fibrosis [Haematoxylin and eosin x 30]

The presence of caseation necrosis generally implies that the lesion is active. However, it may be mentioned that tubercle bacilli may lie dormant for many years even in calcified lesions. Of interest is the recent observation that instead of the usual reaction referred to, mycobacterium can give rise to a spindle cell-lesion. These pseudotumours are often loaded with bacilli (12). The typical lesions described above are responsible for the tiny tubercles that may be visible to the unaided eye. Galen noted tubercles in various animals [tubercle, Latin tuberculum = a diminutive of tuber, small swelling, e.g., tuberosity] in the condition called Hydrops Thoracis. Sylvius noted that

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Tuberculosis Table 5.3: Comparison between tuberculosis and sarcoidosis granulomas Feature

Tuberculosis

Epithelioid cells Necrosis Confluent granulomas Giant cells in granulomas Reticulin within granulomas

Present Usual Usual Multiple Usually lost

Acid-fast bacilli

Sarcoidosis

Present Not common Discrete Few Usually preserved May be present Absent

Figure 5.4: Photomicrograph showing bone and marrow in healed tuberculosis granuloma [Haematoxylin and eosin x 30]

phthisis was accompanied by tubercles. Francisus Delaboe Sylvius in his Opera Medica in 1679 (11) also made a description of tubercles. The name TB was derived for this disease because in 1839, JN Schonlein, Professor of Medicine at Zurich, suggested that TB be used as a generic term for all the manifestations of phthisis (11). In 1869, Richard Morton in his book [Phthisiologica] named these lesions tubercles (1) and thus this term has been in use ever since.

Figure 5.5: Photomicrograph showing necrosis in a granuloma due to sarcoidosis [Haematoxylin and eosin x 200]

DIFFERENTIAL DIAGNOSIS The histopathological diagnosis of TB lies essentially in the demonstration of the characteristic granulomatous inflammation and the causative organism. A presumptive diagnosis of TB can be made if a necrotising, confluent epithelioid cell granuloma is demonstrated. Unfortunately, not all TB granulomas are necrotising. Similarly in the list of granulomatous diseases [Table 5.2], there are conditions that reveal granulomas identical to TB. Comparison between TB and sarcoidosis granulomas is provided in Table 5.3. It must be emphasized that there is no single appearance or combination of features that can distinguish TB and sarcoidosis histopathologically. Schaumann and Asteroid bodies within giant cells may be found in TB. Necrotising sarcoid granulomas [Figure 5.5] are found especially in cutaneous sarcoidosis and are reported even in pulmonary lesions (13). The preservation of reticulin in sarcoidosis can be attributed to the lack of necrosis and early fibrosis and is a useful distinguishing feature.

Table 5.4: Methods of demonstration of mycobacteria in tissues Culture Modified Ziehl-Neelsen staining Dieterle staining Auramine-Rhodamine staining Immunohistochemistry Polymerase chain reaction

Both reticulin-rich and reticulin-poor granulomas may be found in TB, there is nothing more rewarding than the demonstration of Mycobacterium tuberculosis. Table 5.4 lists some of the possible methods of demonstrating Mycobacterium tuberculosis in tissue samples. Appropriate precautions are to be taken and protocols are to be followed for the collection and transport of tissue samples. It is always necessary to contact the laboratory for this purpose. Often invaluable information is lost because of improper collection and transport of samples.

Pathology 71 It is not possible to go into the details of all these techniques here. The reader is referred to the chapter “Laboratory diagnosis” [Chapter 10] for more details. The most frequently employed method is the modified ZiehlNeelsen staining. In May 1882, Paul Ehrlich published a paper indicating that tubercle bacilli are not decolourized by nitric acid following staining by a mixture of gentian violet and aniline oil. Hence, the expression “acid-fast” bacilli. Koch accepted this method. Franz Ziehl recommended that carbolic acid be used instead of aniline. Freidrich Neelsen recommended fuchsin and sulphuric acid instead of gentian violet and nitric acid. This is the Ziehl-Neelsen stain [1892] which is widely employed worldwide. Ironically, Paul Ehrlich diagnosed that he had TB by staining his own sputum sample. He spent a year resting in Egypt and returned to Germany in good health (1). The Ziehl-Neelsen staining is relatively simple, is applicable to paraffin sections and has been in use for many years throughout the world. However, with Ziehl-Neelsen stain, AFB are not always demonstrable and the species of the bacillus cannot be identified. False-positive staining due to Nocardia, Legionella and Mycobacterium leprae may pose problems. These disadvantages do not in any way undermine the importance of this staining and all attempts should be made to demonstrate AFB [Figure 5.6], whenever necessary. Less frequently used methods include fluorescence with Auramine-Rhodamine staining, Dieterle stain (14), and immunohistochemistry (15). All these methods are more sensitive than the conventional Ziehl-Neelsen

Figure 5.6: Photomicrograph showing acid-fast bacilli in a lymph node [Ziehl-Neelsen staining x 1000]. Note the beaded appearance of the acid-fast bacilli

staining and are applicable to paraffin sections and archival blocks. The former requires a fluorescence microscope for visualization. The Dieterle stain is less specific due to morphologic similarities of organisms with Nocardia and those of cat-scratch disease (14). Immunohistochemical staining lacks the simplicity of routine stains and is more expensive. Perhaps it would take some more time before this method gains as much popularity and acceptance for the demonstration of organisms as in diagnosis of tumours. Direct detection of Mycobacterium tuberculosis, rapidly, is perhaps one of the most significant landmarks in medicine. Nucleic acid amplification [NAA] based technology (16) is being utilized to detect the AFB. However, things are not so simple in real practice. Nevertheless, these techniques are definitely a vast improvement over some of the routinely available methods. The details of the pros and cons are beyond the scope of this chapter. In the authors’ institution, due to high prevalence of cases of TB [and belief in the dictum: diagnose a rare disease and you will be rarely right!], in suspected cases, the demonstration of caseating epithelioid cell granulomas is considered sufficient to strongly suggest TB even if AFB are not demonstrated. Therefore, it is not unusual to start appropriate therapy following a biopsy report of “granulomatous lymphadenitis compatible with TB”. PATHOGENESIS OF TUBERCULOSIS The lung is the predominant primary site of TB infection in postnatal life. Mycobacterium tuberculosis is the most frequent pathogen. In the past Mycobacterium bovis was a significant pathogen but with the pasteurization of milk and relative control over bovine TB, infection by Mycobacterium bovis is now rare. A variety of conditions are reported to render individuals susceptible or are associated with an increased risk of TB. Many of these result in decreased immunity. Some of these include silicosis, pulmonary alveolar proteinosis, malignant neoplasm (17) and immunodeficiency disorders among others [Table 5.5]. The key aspects related to the pathogenesis of TB are covered in the chapters “Pulmonary tuberculosis” [Chapter 14], “Tuberculosis in children” [Chapter 41], “Immunology of tuberculosis” [Chapter 7], “Genetic susceptibility parameters in tuberculosis” [Chapter 8], and “Genetics of susceptibility to tuberculosis” [Chapter 9].

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Tuberculosis Table 5.5: Conditions predisposing to the development of tuberculosis

Immunodeficiency disorders affecting CMI including HIV infection and AIDS Immunosuppressive therapy Immunomodulator drugs [e.g. infliximab, etanercept] Malignant neoplasm [carcinomas of the head and neck, stomach, intestines and lungs; Hodgkin’s disease, non-Hodgkin’s lymphoma, acute lymphocytic and myelogenous leukaemia] Silicosis High dose, long-term corticosteroid treatment Poorly controlled diabetes mellitus Chronic renal failure, haemodialysis Connective tissue disorders Organ transplantation Intravenous drug abuse, heroin addiction Tobacco smoking CMI = cell-mediated immunity; HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome

PRIMARY TUBERCULOSIS The following discussion focusses on the pathogenesis and pathology of primary TB in general. Primary pulmonary TB will be discussed a little later under “pulmonary TB”. The earliest foundation of primary TB was actually laid by Marie-Jules Parrot [1829-1883] in 1876. At a time when the understanding of TB was based on several conjectures, primary TB in children was explained on the basis of what is known as the Parrot’s Law which stated that: “pulmonary TB does not exist in the child without involvement of the tracheobronchial gland”. In other words, this observation implies that primary TB includes a prominent lymph nodal involvement. The significance of this was not clear even after the discovery of the tubercle bacillus. In 1896, George Kuss [1867-1936] brought out a monograph on the pathology of TB due to aerogenous infections which included what is understood as primary TB. Once again his ideas did not receive much attention. Eugene Albrecht [1872-1908] in 1907 extended the concept of primary TB in childhood to adult TB and Hans Albrecht in 1909 confirmed the observations of Kuss and elaborated on Parrot’s law (18). These studies formed the basis of the observations of Anton Ghon [1866-1936](19). The infection is carried along the lymphatics to the draining tracheobronchial lymph nodes that enlarge. The regional nodes are invariably involved and may be more prominent than the parenchymal lesion especially so in

children. Spread of infection to the draining lymph nodes as well as vascular involvement, mentioned earlier, may lead to dissemination of bacilli from primary complex to almost all tissues through blood and lymphatics. A bacillaemia is, therefore, common at this stage (20,21). The initial infection is typically unrecognized though the tubercle bacilli disseminate throughout the body. Most primary TB infections heal spontaneously with calcification in some of the cases. Repair begins with the resorption of caseous material, followed by fibrosis and dystrophic calcification. A typical primary parenchymal focus of TB in the lung is characterized by a nodular, often subpleural, area of necrosis surrounded by fibrosis. Hyalinization and eventual calcification of this nodule is the routine. Microscopic calcification can occur as early as two months but radiologically visible calcification takes a year or longer. Calcification does not imply a sterile lesion. The most important aspect of primary TB is that the organisms remain dormant for a variable length of time. Resorption of calcium from the lung and lymph node lesions occurs subsequently in about one-third of children with primary complex [see below] over a period of years (22). Although the above account of the sequence of events briefly describes primary TB in the lungs, the description in other organs is essentially similar. Primary Complex It can be appreciated that in primary TB there is usually a unit comprising of the focus of primary TB and the infected draining lymph nodes. This is known as the primary complex of Ranke. Invariably the intervening lymphatics between the lesion and the lymph nodes are included as a constituent of the primary complex. The term primary complex as such is used with reference to TB and has the advantage that it can be used as a general term implying primary TB without any reference to a particular organ. A similar primary complex has been described in the case of cryptococcosis (23). Over the years, the terms primary complex in the lung and Ghon’s complex [named after Anton Ghon] are used synonymously. The focus of primary infection in the lung is usually subpleural, in the middle portion [upper region of the lower lobe or the lower portion of the middle lobe when on the right side] and is known as the Ghon’s focus. Therefore, the unit of Ghon’s focus and the draining tracheobronchial lymph nodes [with the intervening lymphatics, included by some] is the Ghon’s complex [Figure 5.7]. The term Ghon’s complex should not be used

Pathology 73

Figure 5.8: Photomicrograph showing lymph node with anthracotic pigment and granuloma [Haematoxylin and eosin x 200]

Figure 5.7: Primary complex in the lungs. Arrow heads indicate Ghon’s focus in the parenchyma and enlarged tracheobronchial lymph nodes

to denote primary complex in organs other than the lung. More details regarding Ghon’s complex will be discussed in the section on “pulmonary TB”. In keeping with Koch’s observations in guinea pigs, the lesion in primary TB is small, often not discernible; whereas the draining lymph nodes are appreciably enlarged. This is reflected in Parrot’s Law mentioned earlier. This is opposite to what is seen in post-primary TB. Therefore, the presence of an enlarged lymph node [Figures 5.8 and 5.9] with a correspondingly smaller parenchymal lesion is suggestive of primary TB and serves as a general guideline to distinguish primary and post-primary TB. In post-primary TB the parenchymal lesion usually overshadows the lesion in the draining lymph nodes. The importance of the lung being a common site of primary TB has already been mentioned. The mucosa of the gastrointestinal tract is another site of entry of tubercle bacilli. However, there are other routes of infection that are less common and less easily recognized (24).

Figure 5.9: Enlarged pancreatico-duodenal lymph nodes due to tuberculosis. Areas of caseation are seen

Congenital and Perinatal Tuberculosis The youngest possible contact of TB is the foetus of a mother with active TB. Fortunately, the foetus is less susceptible to TB in utero in contrast to the vulnerability of the newborn infant. Although the cause for this is not apparent, a relative anoxia of foetal tissues may be a reason. Rarely, infection may occur in utero or at birth. There are over three hundred cases of congenital TB reported in the literature (25). The route of infection could be aspiration of the amniotic fluid [due to TB of the endometrium, genital tract or placenta] or haematogenous spread. When the route of infection is haematogenous, the bacilli reach the foetus through the placenta

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along the umbilical vein so that a primary complex forms in the liver and accompanying portal lymph nodes. The bacilli may bypass the liver and may be conveyed via the ductus venosus to the lungs. Widespread involvement of the lungs, hilar and mediastinal lymph nodes without an associated hepatic lesion indicates aspiration of the infected amniotic fluid (26), inhalation of tubercle bacilli from the genital tract or from the room air (27). Congenital TB is characterized by a non-immune, non-reactive response. Multiple primary foci or miliary distribution are common (28,29), and regional lymph node involvement occurs with emphasis on caseation and a large number of bacilli. Microscopically, polymorphonuclear leucocytes predominate but lymphocytes, epithelioid cells and Langhans’ giant cells are rare. Similarly, oral and gastrointestinal infection may occur before or at birth from swallowing infected material. The clinical picture has been well described with symptoms occurring around two to three weeks of life (30). Sudden cyanotic attacks have been described following few days of the birth. Diagnosis is difficult and an investigation such as the tuberculin test is unreliable in the first six weeks of life (31). Diagnosis is often delayed and the illness is often fatal. When the lesions are in the liver, the term congenital TB is appropriate, but for all other cases perinatal TB seems to be a more appropriate term. Skin The skin when intact is the best form of protection from infections. Unfortunately, even a small breach in this seemingly impenetrable barrier exposes the individual to infections. Thus, the skin may provide a site of entry for tubercle bacilli. Usually there is a history of trauma at the site of infection ranging from a dog’s scratch to a major road accident. Common sites include exposed areas such as the face, scalp, knees, legs, feet, hands and forearm. Persons with occupations which involve contact with potentially infective material such as pathologists, microbiologists, laboratory workers, necropsy attendants, butchers, slaughter house workers, cattle handlers and milkers are all at special risk. Due to its similarity to primary syphilis, cutaneous TB is also known as “tuberculosis chancre”. Regional lymph node enlargement occurs as in the case of primary complex at other body sites (32). Primary cutaneous TB has been described in a doctor eight weeks after he administered mouth to mouth

respiration to a comatose TB patient (33). Tuberculosis has also been described following subcutaneous or intramuscular injection. Either the syringe, needle or fluid to be injected has been contaminated or the medical attendant has exhaled tubercle bacilli into the patients’ skin, which are then introduced by the injection. A primary syringe-transmitted infection of a muscle should be distinguished from secondary infection of a muscular haematoma from a patient with TB elsewhere in the body. There is a report of 102 children developing primary TB at the site of typhoid and paratyphoid A and B [TAB] vaccination, transmitted by a school vaccinator who was found to have active TB (34). Primary cutaneous TB has followed venepuncture (35). As in other situations, it may be difficult to differentiate primary TB of the skin from a secondary one (36). It would not be out of place to mention that bacille Calmette-Guérin [BCG] inoculation is in essence an iatrogenic primary infection (3). Primary inoculation TB has been reported following BCG vaccination as a form of immunotherapy for malignant melanoma (37). Therefore, it appears that in many countries where BCG vaccination is given to the newborn, the commonest primary TB is cutaneous, and with the draining lymph nodes [axillary in most instances] accounts for a frequent primary complex in such cases (38). Perhaps in years to come this form of cutaneous primary complex may be commoner than pulmonary primary complex [provided the current controversies are sorted out and BCG vaccination is widely accepted]. Gastrointestinal Tract and Liver The gastrointestinal tract is one of the sites of primary contact between the tubercle bacilli and the host. With a significant reduction in the number of cases due to contaminated milk, it is unlikely that the gastrointestinal tract would be a relatively frequent site for primary TB. It should be noted that the lack of evidence or inability to demonstrate another site of infection often results in a mistaken labelling a site of TB as “primary”. Almost every organ in the gastrointestinal tract is reported to as a likely site of primary TB. An associated enlargement of regional lymph nodes may or may not have been observed. Primary TB has also been described in the oral cavity (39). The buccal mucosa is reported to be one of the sites of primary TB. It may follow dental extraction and result in infection of the tooth socket (40). The primary focus is usually small or not easily recognizable whereas the

Pathology 75 lymph node enlargement, mainly submandibular, is prominent. The tongue is rarely the site of primary infection (41-43). Secondary TB of the tongue is more frequent and invariably follows TB of the respiratory tract. Isolated reports of primary TB of the oesophagus (44,45), stomach (46-48), duodenum (49), ileum (50) and the colon (51) are available. Primary TB of the vermiform appendix is rare. Most of the cases of TB of the appendix are secondary to TB of the ileocaecal region (24). Nevertheless, there are cases of apparently primary infection of the vermiform appendix (24,52,53). An interesting report describes multiple sites of primary TB of the gastrointestinal tract (54). It may be mentioned that earlier observations indicate that primary TB of the gastrointestinal tract due to bovine TB infrequently involves the lungs. The classical evidence of primary infection of the gastrointestinal tract by TB is provided by observations following the tragedy at Lubeck, in Germany. During the period of this disaster, avirulent TB bacillus of the bovine strain [BCG] was employed for immunization by mouth. Unfortunately, a contamination of the cultures led to the accidental administration of virulent human strain of TB bacillus to 251 newborn infants. The bacilli were administered orally on three separate occasions during the first 10 days of life. A total of 72 infants died of primary and fatal TB while 175 were reported to be alive with arrested lesions at the end of four years. An autopsy study revealed that the alimentary tract was involved in all the cases. The small intestine was most frequently affected [98.3%], while the upper alimentary tract and the cervical lymph nodes were affected in 78.3 per cent of the cases. Interestingly, pulmonary lesions were found in 15 per cent of the autopsies. In all probability, these lesions were secondary to aspiration because simultaneous lesions were demonstrated in the mouth, pharynx or the intestine (5). Primary TB of the liver is invariably congenital. This has already been discussed in the description of congenital and perinatal primary TB. Cases of primary hepatic TB are reported from time to time (55,56). It must be emphasized that in adults, the lack of evidence for a focus of TB elsewhere does not necessarily indicate that the lesion in the liver is primary TB. Head and Neck Cervical lymph nodes are not infrequently affected by TB. A proportion of these may reflect a constituent of a

primary complex. The likely route of infection in the case of cervical lymph node is considered to be the tonsil (57). However, in most cases, the focus in the tonsil is microscopic and difficult to identify. Exceptionally, the tonsillar lesion may be readily apparent and ulcerated. The mucosa over the lymphoid tissue at the pharyngeal entrance may be the site of primary infection (58). Similarly, the uvula (59), the pharynx (60) and the larynx (61,62) have been reported to be the sites of primary TB. In these instances the infection may follow the common mode of entry that is through inhalation. It is, therefore, not surprising that the nose (63,64) and the nasopharynx have been infected primarily (65,66). This forms the basis of the Calmette test wherein tuberculin is dropped into the conjunctiva (5). Primary TB can involve the middle ear (67-69). The bacilli are thought to enter the Eustachian tube by swallowing and regurgitation of the infected amniotic fluid by the foetus. In the Lubeck disaster, some of the victims developed middle ear infection probably by aspiration of vomited vaccine into the Eustachian tube (8). Primary TB of the parotid gland (70,71) is thought to occur due to infection of the buccal mucosa at the site of the third molar tooth. Primary TB involving adenolymphoma [Warthin’s tumour] of the parotid (5,24) has been described. Genitourinary Tract The skin of the penis is another rare site of primary TB (72-74). In some cases the infection is transmitted following circumcision (73) by operators suffering from TB. An interesting report (24) records penile TB in 72 Jewish infants following ritual circumcision. As apart of haemostasis, the circumcised organ was sucked and in this manner the infection was supposedly transmitted from an infected rabbi to the infants. Some cases may occur following sexual transmission. Similarly an infected male may transmit the disease to the female partner (24). In general, it appears that the vagina is less often the site of primary TB than the penile skin. Infection of the vulva has also been reported. Eye Primary TB of the conjunctiva (75-77) and the lachrymal sac without the involvement of the conjunctiva have been described. Lesions probably occur after some minor injury or abrasion. Enlarged regional lymph nodes [preauricular or submandibular] complete the primary

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complex (24). It may be mentioned that phlyctenular keratoconjunctivitis may appear as a consequence of hypersensitivity to proteins to which the individual has been previously exposed. Thus, phlyctenules may appear if droplets of coughed sputum containing bacilli or tuberculoprotein are deposited on the conjunctiva of such individuals. A rare instance of primary TB of the retina has been reported (78). Whether it is necessary to catalogue and compile a list of sites of primary TB [Table 5.6] is open to debate. However, this gives an insight into the variety of possible locations through which the Mycobacterium tuberculosis can enter the human body. It must be emphasized that the lung is perhaps the most frequent site of primary TB. The course of primary TB is generally benign especially with the advent of effective chemotherapy. In a majority no ill effect is felt and infection is recognized by delayed type hypersensitivity reaction [DTH] reaction to tuberculin skin testing. There are two more aspects that need to be mentioned. Primary TB is invariably associated with haematogenous dissemination or generalization. Subsequently, either disseminated/ miliary TB may result or seeding of various organs may not be associated with concurrent disease. Later, depending on the relationship between the host immunity and the mycobacteria that may lie dormant for years, TB may manifest in one or more of these organs. In a small proportion of cases the primary infection may not heal but progress. GENERALIZED [DISSEMINATED] TUBERCULOSIS Generalized TB is the occurrence of wide spread visceral tubercles due to haematogenous dissemination Table 5.6: List of some reported sites of primary tuberculosis Common Lung BCG vaccination [when vaccination is successful in infancy] Less common Tonsil Adenoids Probably uncommon Ileum [common in era when bovine type of infection was frequent] Rare Colon, pharynx, duodenum, stomach, uvula, skin, liver [in congenital infection], buccal mucosa, oesophagus, larynx, parotid gland, nasopharynx, tongue, nose, penile skin, conjunctiva, vulva, middle ear, injection site, lacrimal gland, retina

Figure 5.10: Photomicrograph showing epithelioid cell granulomas adjacent to the wall of a vein in the lung. Invasion of the vein may result in disseminated disease [Haematoxylin and eosin x 30]

[Figure 5.10] of virulent TB bacilli from an active caseous source of infection (79,80). The reader is referred to the chapter “Disseminated and miliary tuberculosis” [Chapter 34] for further details. The characteristic findings of miliary TB include small, discrete nodules, grey to reddish on cut surface, 1 to 2 mm in diameter, distributed evenly throughout the affected organ. Older lesions, that may be caseous, tend to be yellowish in colour. The lung, liver, spleen [Figures 5.11 and 34.1] and bone marrow are most frequently affected. Even in these organs, tubercles tend to be larger in the lung and spleen than in the liver and marrow. Miliary tubercles at the apical lobes of the lungs may be larger and more numerous, especially in adults. Pleural and pericardial involvement is common with bilateral pleural effusions frequently associated with miliary TB. Miliary tubercles may be found studding other organs such as the kidney, intestine, fallopian tube, epididymis, prostate, adrenals, bone, meninges, brain, skin, eye and lymph nodes. Mediastinal lymph node enlargement occurs in a high percentage of infants. Patients may present with features that point to the involvement of only one organ, such as, meningitis despite disseminated disease. All tubercles resulting from acute generalized dissemination are approximately of the same size and in the same stage of histological spectrum. However, repeated showers of bacillaemia may yield tubercles of different sizes. Histologically, miliary tubercles typically consist of a Langhans’ giant cell with surrounding

Pathology 77

Figure 5.11: Photomicrograph showing tuberculosis granuloma in the spleen [Haematoxylin and eosin x 200]

logy of pulmonary TB may include certain features that have been described earlier. Although the intention is not to repeat, some aspects of primary TB are included with special reference to the lung as an organ and also to provide a basis for understanding further course of pulmonary TB. The pathology of pulmonary TB has been elucidated by a number of studies that included a careful and detailed examination of lungs obtained at autopsies. In addition to the elegant studies of Rich (5), Medlar (81) based his observations on 1332 unexpected deaths in New York and further evaluated 17000 necropsy records with reference to pulmonary TB. The Indian perspective is available from the study based on 1680 autopsies by Nayak and co-workers at New Delhi (82,83). Primary Pulmonary Tuberculosis

epithelioid cells. Depending on the compactness of the arrangement of epithelioid cells and necrosis, miliary tubercles are of two types: cellular and caseating. The cellular form consists of compact epithelioid and giant cells with very little or no caseation and are known as “hard” tubercles [ordinary miliary tubercles]. The caseating type consists of loosely formed tubercles with caseation necrosis. These are known as “soft” tubercles [acute caseating miliary tubercles]. Acid-fast bacilli are more likely to be found in soft tubercles. It is not clear whether one type of granuloma is the precursor of the other. Patients who survive for weeks may show a central area of caseation surrounded by satellite granulomas. Eventually healing takes place and the granulomas undergo progressive hyalinization and calcification. This may give a fine mottling on chest radiographs. Some immunosuppressed patients with generalized [disseminated] TB may show granulomas that are softer than the soft tubercles. Giant cells are not found. The epithelioid cells are not well developed and are dispersed. On the other hand, there is prominent necrosis with numerous bacilli. This is also referred to as non-reactive TB. PULMONARY TUBERCULOSIS Pulmonary TB is the most frequent organ TB worldwide. Lungs account for a majority of both primary and postprimary forms of TB. Miliary TB invariably affects both lungs symmetrically. Further, pulmonary TB is a major source of infection. The following account of the patho-

Primary TB has already been dealt with in detail earlier. Only certain relevant aspects shall be highlighted here. Classical features of a primary complex in the lung [Ghon complex] are a small [usually less than one centimeter] often inapparent parenchymal lesion [Ghon lesion or Ghon focus] coupled with enlarged, ipsilateral hilar and less commonly paratracheal nodes [Figure 5.7]. The lymph nodes are generally much larger than the parenchymal focus. As has been repeatedly indicated, the location of the parenchymal lesion is usually towards the middle of the lung [upper part of the lower lobe or the lower region of the middle or upper lobe depending on the side]. Certain sites such as the apical and posterior segments of the upper lobe, apical segment of the lower lobe or upper portion of right middle lobe are described as likely sites of primary infection, however, no part of the lung is exempt (81). A single Ghon’s complex was identified in 58 per cent and multiple in 16 per cent of the cases studied by Medlar (81). In one case, five foci were identified, one in each different lobe. In 26 per cent cases, the complex was incomplete because either a parenchymal or lymph nodal component was not demonstrated. A typical primary or Ghon’s focus is single, two millimeters or more in size and located within one centimeter of the pleura of the collapsed lung. Lesions within the lung are relatively uncommon. A majority of the primary foci calcify and a minority show caseous necrosis [85% and 15% respectively]. Lymph node enlargement is easily identified in a large majority [87%]. In order to demonstrate the tubercle, it may be necessary

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to make serial slices in about three-fourths of the cases whereas in the remaining the lesions are readily apparent. Bilateral adenopathy is uncommon except with left-sided primary foci (84). Massive lymphadenopathy is reported (85), especially in the poorly nourished. Progression of Tuberculosis The natural history of TB in the human host is influenced by age, sex, mycobacterial virulence, infecting dose, natural and acquired resistance, certain host factors resulting in a tendency of the disease to follow a pattern of progression according to Wallgren’s timetable (86). Interplay of these factors and the likely mode of spread of the bacillus result in different manifestations. Early in the course of, disease, tuberculin conversion after primary infection may result in mild illness. In the first few years there is increased susceptibility to miliary spread and meningitis. Miliary disease and meningitis follow within two to nine months in 10 per cent of children under two years of age, although these forms can be seen at any age. Segmental lesion [epituberculosis] is an early sequel in infants and in a minority of adolescents and young adults generally within two to nine months of primary infection. Pleural effusion, which follows primary TB, is also seen as a sequel of the postprimary pulmonary disease. Progression to post-primary TB is more likely if primary infection is acquired in the later years of young adulthood than in childhood. In childhood infection the post-primary disease is delayed until adolescence. Extra-pulmonary organ TB is variable. Cervical lymphadenitis may be early but, skeletal and renal TB, usually present very late. This progression is only a broad direction and not absolute. Further Changes of the Primary Complex The primary complex may heal or progress further. Progression occurs in a small proportion of cases. Early dissemination is common but may not necessarily result in concurrent illness. The spread of infection from the primary lesion is by a variety of ways, such as, direct extension into adjacent tissue or by endobronchial, lymphatic or vascular pathways for a disseminated spread. Endobronchial spread of liquefied caseous material is a cause of ipsilateral or contralateral acinar pneumonia. Implantation of mycobacterium in the mucosa of the upper

airway can result in laryngotracheal, oral or middle ear TB. Swallowing infective sputum can also lead to TB and ulceration of the intestinal mucosa. Ipsilateral hilar lymph node spread is especially prominent in primary infections. Perforation of a bronchus by an enlarged caseous lymph node followed by endobronchial spread can result in massive segmental or lobular pneumonia. From regional lymph nodes bacilli can disseminate through lymphatics to the pleura, spine and other viscera. Haematogenous dissemination can occur through the thoracic duct after lymph node involvement or by direct extension of the lesion into branches of the pulmonary vein. Healing Healing of the primary lesions is the rule. The caseous focus is gradually replaced by reticulin and collagen deposition. Eventually, hyalinization, and calcification are common [up to 85%]. Subsequent demonstration of these lesions may be difficult. However, a minority of patients may demonstrate radiologically a residual hyalinized scar or calcification at the site of the primary [Ghon] lesion, in the lung parenchyma and in the hilar or paratracheal lymph nodes—a combination referred to as the healed primary [Ghon] complex. Early Generalization Early generalization or dissemination is an invariable accompaniment of primary pulmonary TB [detailed above]. The primary infection is accompanied by early lymphohaematogenous spread within hours or days from the site of initial implantation (87). It is felt that occult mycobacteraemia is probably common before acquired immunity and thus may seed many sites in the body especially where the bacillus is favoured to remain viable (20). While the sites of these seedings have already been mentioned, one aspect needs to be highlighted here. Huebschmann [1928] (5) observed a group of nodular lesions in one or both apices of the lung that occasionally follow primary TB in children. These foci are so small that special techniques may be necessary to demonstrate them. These Huebschmann foci heal and cause no further disease. It is likely that Simon foci which are larger, single or multiple apical caseous nodules with a tendency to calcification are exaggerated form of these smaller foci. The importance of Simon foci lies in the pathogenesis of

Pathology 79 post-primary TB (5). In a minority of the cases haematogenous dissemination results in miliary TB. Liquefaction and Progressive Primary Tuberculosis Liquefaction of solid caseous foci is thought to be related to the onset of DTH with the release of hydrolytic enzymes by macrophages (88). Liquefaction may result in a caseous mass that may include the enlarged lymph nodes. Within the liquefied area there are multiplying tubercle bacilli and, therefore, there is a risk of transmission of disease. Due to the liquefactive necrosis there is extensive parenchymal destruction and cavitation, which is generally a little less than the size of the original caseous mass. The cavity may communicate with an airway and thus promote bronchial spread to other parts of the lung, larynx and the alimentary tract. An acute fatal bronchopneumonia may result. In some of these cases the inflammatory reaction is neutrophilic, like in the case of bacterial pneumonia, but AFB are demonstrable. Due to such a reaction, the diagnosis may be missed. Discharge of the liquefied material through the adjacent pleura results in pleural effusion, pneumothorax or empyema. Caseous lymph nodes may similarly discharge liquefied contents into the bronchus. Progressive primary TB directly follows the primary lesion. There occurs an extended primary focus or TB bronchopneumonia. Cavitation may ensue. Cavitation and progressive primary disease are more likely in infancy, at puberty and in the elderly. There is a tendency for progressive primary TB to involve lesions that are apical. This location is similar to that of post-primary TB. Lobar and Segmental Lesions As a consequence of spread along the submucosal lymphatics of bronchi, tubercle formation with ulceration of bronchial mucosa at times is followed by complete necrosis of the bronchus. Within the bronchus a cold abscess may develop and can be seen on the radiograph as a rounded or elongated shadow. Bronchial lesions are rare but may result in narrowing of the lumen. Extrinsic compression from enlarged lymph nodes is a relatively more likely cause of bronchial obstruction. The lobe or segment subtended by the obstruction may be the seat of obstructive hyperinflation, atelectasis, secondary [nonTB] pneumonia, TB pneumonia, and disseminated intraalveolar epithelioid cell granulomas. Atelectasis most

commonly affects the anterior segments of the upper lobes and the right middle lobe. Endobronchial TB is a complication of primary TB in children (89). Residual bronchostenosis and bronchiectasis may occur as late complications. Hilar and mediastinal lymph nodes may very rarely cause impaired venous return severe enough to cause superior mediastinal syndrome. Such lymph nodes may result in tracheal obstruction at the thoracic inlet, rupture into the mediastinum and pointing abscess into the supraclavicular fossa, erosion of blood vessel, invasion of pericardium, compression of or erosion into the oesophagus and the formation of various fistulae. Epituberculosis Epituberculosis is a rare but more frequent in infants and children than in adults. It is a benign lesion appearing as a dense homogenous shadow on chest radiographs, typically wedge-shaped, extending from the hilum to the pleura. The lesion is frequently large rather sharply defined and has the appearance of an area of consolidation. Clinical symptoms are few and the shadow generally clears after several months. Residual changes are infrequent and radiographs may show slight abnormal marking or calcifications. The radiographic appearance is relatively dramatic and sinister, in contradiction to clinical symptoms and the outcome. It has been suggested that this is a non-specific pneumonic consolidation that occurs in TB. Hence, Eliasberg and Newland suggested the term “epituberculosis” which implied a non-tuberculosis consolidation in a TB lung (5). The current view is that it is either resolving TB pneumonia or an atelectasis produced by obstruction of a bronchus by a TB lymph node or by a primary pulmonary lesion. A combination of the two is possible. Since the shape of the shadow is highly suggestive of involvement of a portion of lung tissue supplied by a bronchus, Rich studied several cases and found that a caseous lymph node had perforated the bronchial wall, discharged its contents and resulted in aspiration of the material. It is understandable that the caseous material is poor in bacilli, otherwise the lesion would be a progressive bronchopneumonia. The resulting consolidation could be partly due to a “hypersensitive” reaction to contents of the lymph node [a positive “pulmonary tuberculin test”, if such a term is acceptable]. The alveoli in such cases would

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resemble pneumonia with epithelioid cells and few or no AFB. There is also sufficient evidence to suggest the atelectasis theory and relief of atelectasis by interventional bronchoscopy. A combination of aspiration and obstruction by lymph nodal compression may occur. Since encroachment by an enlarged lymph node is a common accompaniment, therefore, these lesions are common in children (5). Primary Tuberculosis in Adults The radiological and other features of adult primary TB are essentially similar to childhood primary disease (90). Primary TB poses diagnostic problems in adults (91). Prominent hilar and mediastinal glands and caseation are less frequent in adults except in patients with AIDS. Also, bronchial obstruction and dissemination are less common. As in children, endobronchial TB can complicate post-primary TB in adults. With increasing primary adult TB, endobronchial TB may occur as a sequelae of adjacent parenchymal disease from which submucosal lymphatic spread leads to mucosal ulceration, hyperplastic polyp formation or fibrostenosis with atelectasis of the subtended lobe (92).

The great majority of these cases represent recrudescence of dormant tubercle bacilli occurring several years after the primary infection or even decades after primary infection. As has been mentioned earlier, there is a haematogenous seeding of the apical and sub-apical regions of the lungs, following primary infection. This is the endogenous pathway resulting in reactivation TB (95). However, there is evidence to suggest that a bronchial spread from an index case may be the route of infection. This is the exogenous pathway resulting in reinfection TB. The organisms may reach by either pathways (5). Infection with other related species of mycobacteria may also have the same result. The pathological lesions seen in post-primary pulmonary TB are enumerated in Table 5.7, based on the findings of Medlar (81), and Nayak et al (82). Early Lesions The earliest lesion is probably an apical or subapical lobular pneumonia (82). These lesions are not well documented because it is believed that the pneumonia gives way to a granuloma rapidly. An outline of the alveolar reticulin framework in the centre of some of these granulomas may suggest such a transition (82).

Post-Primary Pulmonary Tuberculosis

Table 5.7: Lesions in post-primary pulmonary tuberculosis

In contrast to primary TB, the localization of postprimary pulmonary TB is apical or sub-apical. This area has been referred to as the ‘vulnerable region’ by Medlar (81). This site probably relates to the relatively higher oxygen tension in the region resulting from the effect of gravity on the ventilation-perfusion ratio in the upright lung. Presently, evidence suggests that this is possibly because of better survival of the bacillus at this region as the higher oxygen tension has an unfavourable effect on the macrophage and thereby permits intracellular growth (93). This may also influence progressive primary disease that is more frequent in the apical and posterior segments of the upper lobe. Higher vascularity and consequently increased oxygen tension may determine the preferential multiplication of bacilli at other sites also, such as ends of long bones, vertebrae and the renal cortex. Similarly, mitral stenosis, which results in higher pulmonary arterial pressure and increased apical blood flow, confers a protective effect. The reverse is true for pulmonary stenosis (94). Lowered blood flow may also be associated with decreased lymph flow and thus lesser antigen clearance.

Pulmonary lesions Lobular pneumonia Nodular TB Small nodule Large nodule Healed nodules Fibrocaseous TB With cavity Without cavity Tuberculosis bronchopneumonia Bronchial lesions Bronchial inflammation Endobronchial TB Bronchiectasis Whole lung TB Miliary TB Complications Haemoptysis Aspergilloma Amyloidosis Carcinoma Oral cavity and upper respiratory tract TB Pleural lesions TB = tuberculosis Source: references 81,82

Pathology 81 It may be mentioned that in 1925, Assmann drew attention to the fact that the earliest lesions clearly visible in clinical TB consist of infiltrates not at the apex, but at the sub-apical and infraclavicular region. These infiltrates [Fruhinfiltrat] are known as Assmann infiltrates or foci (5). The histological counterpart of these lesions is not known.

nodules are not related to Ghon’s focus. The location and the absence of accompanying enlarged lymph nodes should provide a clue. Acid-fast bacilli could be demonstrated in seven per cent of small nodules and 29 per cent of large nodules (82). Fibrocaseous Tuberculosis

Nodular Lesions Nodular lesions [coin lesions, tuberculomas] are localized, well-defined areas of TB wherein the adjacent pulmonary parenchyma is usually normal or may show some scarring [Figure 5.3]. A small nodule is less than a centimeter in diameter whereas the large nodule is larger than a centimeter in diameter. Grossly, nodules are white to yellow in colour and may vary in consistency from soft lesions that are largely necrotic to firm or hard lesions that are fibrosed [Figure 5.12] or calcified [Figure 5.13]. Small nodules have a central area of caseation, are surrounded by epithelioid cells and giant cells and are encapsulated by a fibrous wall. Large nodules are similar but show more caseation and less encapsulation. Healed nodules are of the size of small nodules and are fibrosed or hyalinized or calcified. Anthracotic pigment may be identified in any nodule (82). Active nodules especially of the small size are predominantly located in the apical and sub-apical regions and may be single or multiple. The reverse is true for healed nodules. It appears that small nodules give rise to larger ones and nodular TB may expand to form fibrocaseous lesions. It may be mentioned that these

Fibrocaseous TB includes lesions that reveal wellknown features of TB such as caseation, consolidation, liquefaction and fibrosis. Grossly, various patterns are seen. The apical and posterior segments of the upper lobes are predominantly involved (96-98). Lymph node involvement is slight in comparison to primary TB. Retraction of lung parenchyma is associated often with pleural thickening. In some cases the lung may have an appearance of bronchopneumonia due to consolidation [Figure 5.14]. At times the caseous areas stand out amidst the black background of anthracotic pigmentation. The most striking feature is the presence of one or more cavities [Figures 5.15 and 5.16]. Cavities may assume varying sizes and may be so large as to result in a severe loss of lung parenchyma. The wall of the cavity may be lined by TB granulation tissue or show varying fibrosis. Often the thick walls of cavities seen on radiographs are found to be accounted for by a rim of consolidation of the adjacent lung. Communication may or may not have been established with a bronchus [Figure 5.17]. These findings have implications on auscultation of the chest. Traversing the wall or the lumen along fibrous bands, are bronchi and branches

Figure 5.12: Photomicrograph showing healed tuberculosis of the lung with hyalinization and fibrosis [Haematoxylin and eosin x 30]

Figure 5.13: Photomicrograph showing healed calcific nodule in tuberculosis of the lung [Haematoxylin and eosin x 30]

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Figure 5.14: Tuberculosis bronchopneumonia with a cavity in the left upper lobe

Figure 5.15: Specimen of lungs showing fibrocaseous and cavitary lesions [arrow]

Figure 5.17: Specimen showing tuberculosis cavity in the upper lobe of the right lung communicating with the bronchus [arrow]

Figure 5.16: Close up of cavities in the upper lobe. The lining of the wall is relatively smooth. Note the thickened pleura at the apex

of pulmonary artery. Fortunately in most instances the chronic process allows the arteries to obliterate. The caseous material may soften the wall of the arteries

Pathology 83 giving rise to Rasmussen’s aneurysms. These may give rise to haemoptysis that may be fatal Microscopically variable caseous necrosis, extensive fibrosis, numerous palisades of epithelioid cells and fibroblasts together with Langhans’ giant cells are seen [Figures 5.18, 5.19, 5.20 and 5.21]. Areas of consolidation may show caseous pneumonia or even a neutrophilic response. Microscopic cavities may be identified in such pneumonic foci. Cavities are lined by necrotic TB granulation tissue and show fibrosis. Occasional cavities may be lined in part by columnar or squamous epithelium. Acid-fast bacilli can be demonstrated more frequently

in fibrocaseous lesions than in nodular TB. Acid-fast bacilli were found more frequently in cavitary lesions [88%] in comparison to non-cavitary lesions [77%] (5). Smaller cavities may heal. Healing in general results in fibrosis and cicatrisation extending between the upper pole of the hilum and the apex, thus elevating the hilum on that side. This causes volume loss on the ipsilateral side. Simultaneously the upper mediastinum would be pulled towards the side of the lesion distorting the trachea and giving a characteristic radiological appearance. Modern treatment, however, allows rapid closure of cavities, which leaves little evidence of disease on chest

Figure 5.18: Tuberculosis of lung. Portions of a bronchus with the bronchial cartilage and submucosal mucous glands are seen with the epithelioid cell granuloma [Haematoxylin and eosin x 200]

Figure 5.19: Pulmonary tuberculosis. Photomicrograph showing necrosis and destruction of parenchyma [Haematoxylin and eosin x 30]

Figure 5.20: Fibrocaseous tuberculosis of the lung. There is a large area of caseation with surrounding fibrosis and destruction of pulmonary parenchyma [Haematoxylin and eosin x 30]

Figure 5.21: Photomicrograph showing caseation in tuberculosis of the lung with poor encapsulation and spread [Haematoxylin and eosin x 30]

84

Tuberculosis Bronchiectasis directly attributable to pulmonary TB is rare (81). In those instances when this is found it usually occurs in the upper lobe and is relatively asymptomatic. Along with bronchostenosis it predisposes to secondary infection, haemoptysis and atelectasis. Extension of TB to the pleura is common. Pericardial TB may follow pleuritis or by lymphatic spread from a pulmonary focus. Whole Lung Tuberculosis Rarely, TB can affect the whole lung. This condition has a high mortality and results from diffuse bronchogenic spread or haematogenous dissemination (100).

Figure 5.22: Photomicrograph showing tuberculosis involving a bronchiole and adjacent alveoli. Rupture into the bronchus may result in endobronchial spread of the disease [Haematoxylin and eosin x 30]

radiographs. Serious complications resulting from pulmonary TB are uncommon now except when the disease has been neglected and becomes chronic and progressive. Other Lesions Tuberculosis bronchopneumonia and miliary TB are a consequence of a large dose of virulent organisms disseminating through the bronchus [Figure 5.22] or the blood stream [Figure 5.10], respectively. It is obvious that the host immunity may be compromised. The lesions have been described earlier. Bronchial Lesions Despite being closely associated with the lung parenchyma, bronchi do not appear to be frequently affected in pulmonary TB (81). In a majority of cases, the inflammation is non-specific and typical granulomas may not be seen. In some cases endobronchial TB, as discussed under primary pulmonary TB, may follow post-primary lesions (99) and this is characterized by bronchial inflammation, ulceration, granuloma, small pseudopolyps and eventual healing by fibrosis. Bronchostenosis may give rise to post-stenotic dilatation of the bronchus. This should not be confused with bronchiectasis. The reader is referred to the chapter “Endobronchial tuberculosis” [Chapter 16] for further details.

Complications The reader is referred to the chapter “Complications of tuberculosis” [Chapter 35] for more details. Pleural Tuberculosis Pleural effusion is a frequent sequel to primary TB in adolescents and adults. It is uncommon in younger children. It can occur many years after primary infection as an extension of post-primary TB or as an isolated effusion. Pleural effusion may complicate any TB pathology of lung or rib cage where the pleura is an involved bystander. Primary effusion usually occurs on the same side as the primary complex and hence is a result of contiguous affliction. Bilateral pleural effusions or those on the side opposite to the primary complex should suggest miliary or disseminated TB. Pleural and subpleural granulomas, usually seen on both visceral and parietal surfaces [Figure 5.23], tend to follow the lymphatics on the visceral surface and may be discrete. Diffuse or focal fibrosis may follow. Large caseous or cavitary lesions rupture into the pleural space more commonly in post-primary TB and cause bronchopleural fistula with empyema. Empyema may heal with a fibrothorax and sometimes as a calcified pleural plaque resulting in a trapped lung [Figure 5.24]. These patients may present with functional disability. Histological diagnosis is based on the identification of granulomas [Figure 5.25]. The volume and cellular nature of the exudate are dictated by the cell-mediated immunity. The fluid is exudative, serofibrinous and occasionally purulent. Predominant cell type is lymphocyte with few meso-

Pathology 85

Figure 5.25: Tuberculosis of pleura. Photomicrograph showing epithelioid cell granuloma [Haematoxylin and eosin x 200]

Figure 5.23: Tubercles [arrows] in the lower lobe of right lung. Thickened pleura can also be seen

Therefore, treatment of pleural effusion with antituberculosis drugs is fully justified. ABDOMINAL TUBERCULOSIS The term abdominal TB generally includes TB of the gastrointestinal tract and the peritoneum. It is customary to exclude TB of organs like the kidneys and adrenals from this list. Isolated TB of organs, such as, the liver is uncommon. The TB of the intestines accounts for a majority of such cases [65% to 78%]. Disseminated abdominal TB has also been observed (101,102). Intestinal Tuberculosis

Figure 5.24: Thickened fibrous pleura due to chronic tuberculosis encasing the lungs

thelial cells. Rarely, histiocyte clusters may be seen which strongly suggest TB pleural effusion. A neutrophilic response does not rule out TB, though it is necessary to demonstrate the organism unequivocally in such cases. Direct microscopy and culture studies often do not reveal tubercle bacilli. Primary pleural TB usually resolves without antimicrobial therapy but when it develops in adolescence and young adulthood it may carry the risk of postprimary TB, usually pulmonary within five to ten years.

The primary form of gastrointestinal TB is extremely rare and has been discussed earlier. Intestinal TB usually involves the ileum, ileocaecal region and the adjacent caecum. Although this disease is chronic and invariably presents with symptoms suggestive of an abdominal disorder. Recurrent intestinal obstruction is an important presentation. Around one-third to a quarter of the patients present with acute abdomen (102,103). Most cases of intestinal TB are due to post-primary TB. Gross and Microscopic Pathology The credit to the description of intestinal TB goes to F. Koenig whose masterly description in 1892 resulted in the disease being called “Koenig’s syndrome” (104). Grossly, intestinal TB is classified into three types: ulcerative [60%], hypertrophic [10%] and ulcerohyper-

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trophic [30%]. Ulcerative lesions indicate a highly virulent process (105-107). The intestine is indurated with an increase in mesenteric fat. Ulcers are generally transverse to the long axis [Figure 5.26]. Circumferential or annular ulcers are usually less than 3 cm in length (108,109). The ulcers are superficial and may have undermined edges. Apparently the disposition of the ulcers is a reflection of the direction of lymphatics around the intestine. However, these may be a consequence of vascular changes (110-112). The base of the ulcer is covered by necrotic sloughs. On the serosa small tubercles may be present. Authors feel that it is necessary to document these lesions in the serosa since in essence these are lesions of TB peritonitis. However, these are localized lesions and do not result in the usual manifestations of peritonitis that are discussed below. Perforation of the intestine when present is usually proximal to a stricture [Figure 5.27]. The hypertrophic type is characterized by scarring and often mimics a carcinoma. The ulcerohypertrophic type has features of the two types described earlier [Figure 5.28]. There is a thickening of the wall of the intestine. The mucosa may show very superficial fissures giving rise to a cobblestone appearance of the mucosa. Small pseudopolyps may be identified. The ileocaecal region is distorted and the normal angle as seen on barium films becomes obtuse. It is important to note that in TB both sides of the ileocaecal valve are involved leading to its incompetence. This is unlike the features seen in Crohn’s disease (108,109). Lymph nodes may be enlarged, but as in other cases of post-primary TB these may not be prominent. Rarely,

Figure 5.27: Multiple strictures of the ileum due to tuberculosis with perforation

Figure 5.28: Ileocaecal tuberculosis. There is a prominent thickening of the ileocaecal valve

Figure 5.26: Ileocaecal tuberculosis showing multiple strictures and transverse ulceration

lymph nodes may assume a large size [Figure 5.29], giving rise to the condition called tabes mesenterica. It must be emphasized that the gross appearance of TB can mimic a variety of conditions. Authors have seen cases that have very little resemblance to the description provided above. Surely, if the abdomen is a magic box to the surgeon, intestinal TB has all the ingredients for a very successful show. Endoscopic diagnosis of colonic TB is possible. In the colon, TB may resemble an

Pathology 87 inflammatory bowel disease [Figure 5.30] with a prominent mucosal granularity. Microscopic appearance of intestinal TB is similar to that of TB elsewhere. Necrotising and non-caseating granulomas [Figure 5.31] are the hallmark of intestinal TB. While early lesions show granulomas in the mucosa and Peyer’s patches, in later lesions any portion of the intestine may be affected. Pyloric gland metaplasia is not uncommon. The base of ulcers is lined by inflammatory granulation tissue. Fibrosis and scaring are variable. In cases that have undergone chemotherapy, hyalinization is common. Sometimes the granulomas may be elusive and certain specimens may not reveal any granuloma. In fact in some studies granulomas have been demonstrated in only 40 per cent of the resected intestinal

Figure 5.31: Ileocaecal tuberculosis showing granulomatous inflammation in the submucosa [Haematoxylin and eosin x100]

specimens. The clue to the diagnosis is provided by the identification of granulomas in the lymph node. In such cases the diagnosis is either not made or at best presumptive. Acid-fast bacilli can be demonstrated in six to eight per cent of cases (109). Cultures may increase the yield ten-fold. In the case of the colon, histological and bacteriological examinations can provide diagnosis in 60 per cent of the cases (113). Tuberculosis in other regions of the gastrointestinal tract reveals the characteristic granulomas [Figure 5.32].

Figure 5.29: Specimen showing mesenteric lymph node tuberculosis

Figure 5.30: Tuberculosis of the colon showing granularity and ulceration of the mucosa

Figure 5.32: Tuberculosis of anus. Photomicrograph showing lining squamous epithelium and caseating granuloma [Haematoxylin and eosin x 200]

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Tuberculosis Table 5.8: Differentiating features between intestinal tuberculosis and Crohn’s disease Feature

Tuberculosis

Crohn’s Disease

Macroscopic Anal involvement Serosal tubercles Length of strictures Internal fistulae Perforation Ulcers

Rare Usually present Short [< 3 cm] Rare Uncommon Circumferential/transverse

Relatively common Not seen Long Common Rare Along mesenteric border/ longitudinal serpiginous

Microscopic Granuloma in intestine/lymph node Lymph node granulomas Type of granuloma Caseation Cuff of inflammatory cells Fibrosis and hyalinization Fissures beyond submucosa Transmural lymphoid aggregates Submucosal widening Fibrosis of muscularis propria Pyloric gland metaplasia

Present in majority May be only site Large, confluent Present Common Can be seen Absent Not seen Absent May be present May be seen

Absent in a quarter Absent Small, discrete Absent Usually absent Rare Present Present Present Not seen Absent

Adapted from reference 109

Complications Haemorrhage, perforation, obstruction, fistula formation and malabsorption due to obstruction and blind-loop syndrome and massive enlargement of mesenteric lymph nodes [tabes mesenterica] can occur in intestinal TB. Differential Diagnosis Intestinal TB can mimic a variety of diseases. The common differential diagnosis includes Crohn’s disease [Table 5.8] (109) and ischaemic enteritis. Iscaemic enteritis closely resembles TB on gross examination. The presence of a boggy mucosa due to mucosal and submucosal oedema and the absence of granulomas strongly favour the diagnosis of ischaemic enteritis. Other diseases include Yersinia enterocolitica, amoebiasis and carcinoma caecum (111). Syphilis and lymphogranuloma venereum are curiosities of historical interest. Peritoneal Tuberculosis Peritoneal TB is post-primary and is the result of either haematogenous spread from a focus elsewhere or due to a spread from an abdominal organ, usually a ruptured TB lymph node. The lesions in peritoneal TB can be

classified into two types: exudative or moist type, clinically characterized by ascites and the plastic or dry type that is responsible for the typical doughy abdomen. Cirrhosis may be associated in a small proportion [6%] of patients with peritoneal TB (114). On gross examination, multiple, white tubercles are generally seen. With ascites such lesions may resemble a metastatic carcinoma. In some cases numerous peritoneal adhesions are identified. Microscopic examination reveals typical granulomas [Figure 5.33]. Ascitic fluid cytology shows a predominance of lymphocytes. It must be pointed out that on some occasions the reaction may be neutrophilic mimicking an acute bacterial peritonitis. Tuberculosis of the Liver Hepatic involvement by TB is not a rare entity. The frequency of hepatic changes in lethal cases remains higher than in cases of localized forms of TB. Actual involvement of the liver by granulomatous process is common in fatal cases [Figures 5.34 and 5.35] as opposed to the localized form where non-specific histological changes predominate.

Pathology 89

Figure 5.33: Tuberculosis of omentum. Photomicrograph showing lobules of adipose tissue, epithelioid granulomas with lymphocytic infiltration [upper panel, left; Haematoxylin and eosin x 60], epithelioid granulomas lymphocytic infiltration, Langhans’ giant cell, foreign body giant cell and fibrosis [upper panel, right; Haematoxylin and eosin x 100], epithelioid granulomas [lower panel, left; Haematoxylin and eosin, x 400], multiple epithelioid granulomas with lymphocytic infiltration [lower panel, right: Haemotoxylin and eosin x 200]

Figure 5.35: Granulomatous hepatitis. Photomicrograph showing epithelioid cell granuloma in the liver parenchyma [Haematoxylin and eosin x 200]

may yield better results with the presence of hepatic granulomas in 30 per cent of cases with TB (116). The liver in TB can have specific and non-specific histopathological changes [Table 5.9]. Korn et al (117) have emphasized the occurrence of focal hyperplasia of Kupffer cells in TB. This refers to localized areas of Kupffer cell proliferation with dilated sinusoids and radiation into adjacent sinusoids. Although such lesions may be the fore runners of microgranulomas, they differ from microgranulomas in that they are composed of typical Kupffer cells, have a stellate rather than rounded configuration and lack characteristic epithelioid cells. On the other hand, microgranulomas are small aggregates of epithelioid cells, usually centrilobular in location and lack giant cells and caseation (117). In fatal cases of TB, actual involvement by granulomatous process is common, whereas in localized form the non-specific changes predominate. The rarer forms of hepatic TB Table 5.9: Histopathological changes seen in the liver

Figure 5.34: Slice of liver from a patient with miliary tuberculosis showing a large area of necrosis

The highest incidence of hepatic TB has been reported in the miliary form of the disease. In a study of pediatric TB, only 12 per cent of cases showed granulomas in the liver (115). This low incidence can be attributed to the inherent drawback of needle biopsy as it samples a very small portion of the liver. Examination of serial sections

Specific changes Granulomatous hepatitis Miliary pattern Tuberculoma Non-specific changes Fatty change Spotty necrosis Portal fibrosis Portal triaditis Focal sinusoidal dilation Kupffer cell proliferation

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lesions include TB cholangitis, tuberculoma and TB of the lymph nodes at the porta hepatis. GENITOURINARY TUBERCULOSIS Genitourinary TB usually occurs in the reproductive age group with a considerable lag period following the occurrence of primary TB. The disease involves the urinary tract and the genital tract either singly or in combination. Due to anatomical considerations, infection of the urinary tract and the male genital tract in combination is common. Urinary Tract Initially, renal TB granulomas are located in the cortex, which has a high perfusion rate. Cortical granulomas may remain dormant and if the host resistance is favourable, then fibrosis ensues. Highly virulent organisms or low resistance can cause progression of the lesion and the necrosis debris may lodge in the loop of Henle. These produce medullary lesions which can enlarge, coalesce and produce papillary necrosis. The larger medullary lesions can persist as localized tuberculomas or discharge into the draining calyx. Sloughing of the necrotic contents into the calyx leads to cavity formation. Such cavities have shaggy necrotic walls with fibrosis of the adjacent renal parenchyma (118). Tuberculosis may result in changes of pyonephrosis with dilatation of calyces [Figure 5.36]. Severe lesions may destroy the parenchyma fairly extensively [Figures 5.37 and 5.38]. Some observers believe that kidneys can be involved by ascending infection from the bladder through the ureteral route. While such ascending infection is not very common, communication of the caseating granuloma with the collecting system is usually responsible for the spread of infection into the distal urinary system, like pelvis, ureter and urinary bladder. Additionally, lymphatic spread can occur to contiguous structures. Tuberculosis ureteritis can lead to stricture formation as a result of fibrosis. This can lead to obstruction, which in advanced cases may result in TB pyonephrosis [Figure 5.36]. There may be focal or diffuse calcification of the renal parenchyma. Renal amyloidosis can occur in patients with pulmonary TB of long duration. Apart from specific TB process, kidney can show several non-specific changes in pulmonary TB. Shah et al (119) examined renal needle

Figure 5.36: Tuberculosis of the kidney resulting in dilated calyces and ureter. Caseation can be identified along some of the calyces

Figure 5.37: Tuberculosis of kidney in a child showing distortion and caseation necrosis of the upper pole

biopsy specimens from 30 patients with pulmonary TB. Seventy per cent of them had abnormal renal histology in the form of cloudy swelling of the tubular epithelial cells, focal lymphocytic aggregates, membranous glomerulonephritis, interstitial fibrosis and amyloidosis (119).

Pathology 91

Figure 5.38: Tuberculosis of the kidney. Photomicrograph showing granulomas including Langhans’ giant cell and renal parenchyma [Haematoxylin and eosin x 200]

Figure 5.40A: Tuberculosis epididymo-orchitis in a child showing distortion of the testis and epididymis. Distortion and caseation of the upper pole of the testis can be seen

Figure 5.39: Tuberculosis cystitis. Metaplastic squamous epithelium and multiple epithelioid granulomas in submucosa are seen [Haematoxylin and eosin x 200]

The initial lesions of vesical [urinary bladder] TB are seen around the urethral orifices. Progressively in advanced lesion, the whole bladder wall may be involved. There is granulomatous inflammation and ulceration of the mucosa [Figure 5.39]. Later on, fibrosis may lead to urethral stricture formation and reduction in the bladder capacity. It may be mentioned that treatment of transitional cell carcinoma of the urinary bladder often involves instillation of BCG into the bladder. This may give rise to BCG granulomas, indistinguishable from TB.

Figure 5.40B: Cut-section of testis and spermatic cord from a patient with tuberculosis epididymo-orchitis

Male Genital Tract If the infection proceeds from the urinary bladder, involvement of seminal vesicle, vas deferens and epididymis can occur. Isolated testicular TB is rare. All such cases are accompanied by epididymal infection, TB epididymo-orchitis [Figures 5.40A, 5.40B and 5.41].

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Figure 5.41: Tuberculosis of the testis. Photomicrograph showing semeniferous tubules, granulomas and caseous necrosis [Haematoxylin and eosin x 100]

Tuberculosis epididymitis can lead to thickening of vas by the granulomatous process. Rarely, cold abscess can also form near the epididymis. Tuberculosis of the prostate can mimic a nodular or benign hyperplasia clinically [Figure 5.42]. Involvement of multiple sites in the male genital tract is not uncommon, as reported in an autopsy series (118). As concurrent or previous renal TB is seen in many cases (120), genital TB is usually sequelae to a descending infection from the kidney. Penile TB is very rare. As a form of skin TB, it can be acquired from sexual contact. It can also be a manifestation of either local or haematogenous spread.

Figure 5.42: Tuberculosis of the prostate. Characteristic granulomatous inflammation and a prostatic mucosal gland can be identified [Haematoxylin and eosin x 100]

Female genital TB is usually secondary to a pulmonary focus. It may be a component of generalized miliary TB. Transmission by sputum, used as a lubricant by an infected partner, has been reported (121). Pathologically, the fallopian tube is the most common site of involvement (122,123). The tubes are usually involved bilaterally. These get seeded during the primary infection. The lesions get reactivated or clinically manifested usually after a long latent period. Endometrial TB is related to spread from the fallopian tubes (124). Less commonly, cervix and vagina are involved, as an extension from the endometrial lesion. Ovarian infection can also occur from the tubal source. Rarely, sexual transmission can cause vulvar ulcers and inguinal lymphadenopathy in females (125). Frequently, more than one organ may be involved [Figure 5.43]. Gross lesions can be miliary, ulcerative, proliferative or a combination of these. Fistula formation has also been reported. Granulomas are identified usually in the mucosa of the affected organ [Figures 5.44, 5.45 and 5.46]. Histopathological confirmation by endometrial curettage with staining for AFB and culture are necessary for diagnosis. Curettage should ideally be done in the late menstrual cycle. However, it is not necessary to believe that granulomas are identified only in secretory endometrium. Granulomas can be found in any phase of the menstrual cycle and also in hyperplasia of the endometrium. Cervical biopsy is also useful. Identification of necrotising epithelioid cell granulomas with or

Figure 5.43: Bilateral tuberculosis salpingitis with fibroids

Pathology 93

Figure 5.44: Tuberculosis salpingitis. Note the lining epithelium and a granuloma [Haematoxylin and eosin x 200]

Figure 5.45: Tuberculosis of the endometrium. Photomicrograph showing portions of endometrial glands and granulomas [Haematoxylin and eosin x 200]

without demonstration of AFB establishes the diagnosis in a considerable number of cases. Caseation has been reported to be more frequent in the elderly. Unfortunately, AFB are hardly identifiable in most instances. NEUROTUBERCULOSIS Neurotuberculosis includes TB of the meninges, the brain, spinal cord and the nerves. Tuberculosis meningitis [TBM] is the commonest form of neurotuberculosis and generally develops from the breakdown of a small initial focus in the superficial cortex or leptomeninges. This focus discharges caseous material into the cerebrospinal fluid [CSF] (126). Such a focus can destabilize

Figure 5.46: Tuberculosis of the uterine cervix. Granuloma and endocervical glands are seen [Haematoxylin and eosin x 200]

following years of quiescence due to advanced age, trauma, malnutrition, chronic debilitation and immune suppression. Tuberculosis meningitis can also result from miliary spread of the disease. The miliary tubercles in the leptomeninges are most frequently seen on the lateral aspect of parietal and temporal lobes on either side of the Sylvian fissure and along the blood vessels at these sites. There are six main parenchymal changes in neurotuberculosis. These are: ventriculitis, border zone encephalitis, infarction, internal hydrocephalus, diffuse oedema, and tuberculoma. Ventriculitis is less frequently encountered than meningitis. In this condition, the ependymal lining of the ventricles and choroid plexus show tubercles. Border zone encephalitis is caused by impingement of the meningeal exudate on the underlying brain parenchyma. Frequently, there is only a glial reaction. Occasionally, the changes may be of inflammatory nature. Infarction is caused by vasculitis due to inflammation of the vessels in the meningeal exudate. The vessels commonly involved are branches of the middle cerebral artery, especially the perforating vessels to the basal ganglia (127). The vascular changes occur in the form of periarteritis, endarteritis, panarteritis, necrosis and thrombosis. Narrowing or total occlusion of the vessels results in infarction of the zone supplied by the artery. In TBM, hydrocephalus evolves due to the following reasons: [i] blockage of the basal cisterns and medullocerebellar angles and obstruction to the flow of

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the CSF by the basal exudate; and [ii] interference in the absorption of CSF by arachnoid granulations. Macroscopic Features In TBM, the brain is heavier in weight due to cerebral oedema. The leptomeninges in the basilar area appear opaque as the underlying thick exudate fills up the cisterns. Sometimes, the exudate is found on the surface of the brain mimicking pyogenic meningitis [Figure 5.47]. The gyri appear flattened with obliteration of sulci. Superficial blood vessels look congested. Serial slicing reveals ventriculitis with matted appearance of the choroid plexus. There may be ventricular dilatation and areas of infarction in the middle cerebral artery territory. Finding the parenchymal tubercles giving rise to TBM is difficult task because: [i] the tubercles are frequently of small size [commonly 3 mm to 5 mm in diameter]. Thus if the slices are thicker than 3 mm, the lesions may be missed; [ii] the site of origin is frequently a caseous meningeal plaque which is often masked macroscopically by the surrounding meningitis; and [iii] macroscopic visualization of caseous nodules is often difficult. Parenchymal tuberculoma is less frequently seen than TBM. This may be due to the difference in their pathogenesis. Usually small tubercles are found in association with TBM. While TBM is a typical leptomeningeal reaction to tubercle bacilli, tuberculoma is the manifestation of hypersensitivity to tuberculoproteins in the susceptible individual (128). Generally, tuberculomas [Figure 5.48] favour infratentorial location, the most

Figure 5.47: Tuberculosis meningitis with loss of normal transparency and granularity

Figure 5.48: Small tuberculomas of the brain [red arrow heads]

frequent site being the cerebellum. The physical continuity between a tuberculoma and meningeal exudate is usually not evident, although this has been occasionally observed (129). Microscopic Features Large areas of caseous necrosis feature the leptomeningeal reaction with a cellular infiltrate consisting predominantly of lymphocytes and plasma cells. There may be focal epithelioid granulomas with giant cell reaction [Figure 5.49]. The ependymal lining of the ventricles reveals ependymitis which resembles the inflammatory reaction of meningitis (129). Choroid plexitis may also be evident. In some cases the

Figure 5.49: Photomicrograph of tuberculosis of meninges [Haematoxylin and eosin x 100]

Pathology 95 inflammatory reaction may be polymorphic giving the appearance of a pyogenic meningitis. However, in these cases, numerous AFB are demonstrable. Immediately beneath the meningeal exudate, the brain shows oedema, perivascular inflammatory infiltrate and microglial reaction. In long-standing cases gliosis ensues. If the inflammation is caused by fewer bacilli, complete resolution of the exudate is possible with treatment. Residual well-circumscribed, small caseous foci may remain following treatment if the bacilli are abundant. Histopathologically, tuberculomas show epithelioid granulomatous response with chronic inflammatory cells and Langhans’ giant cells [Figure 5.50]. There are areas of caseous necrosis. An occasional case shows focal calcification. The TB abscess consists of pus filled cavities containing tubercle bacilli. The wall of TB abscess shows granulation tissue with inflammatory cells. There is usually a paucity of epithelioid cells or giant cells and the lesion may be misdiagnosed clinically as pyogenic abscess. The content of the cavity usually shows numerous AFB. Intracranial TBM often extends into the spinal meninges. Only in a few cases the inflammation starts in the subarachnoid space from a small subpial tubercle [Rich focus] or TB vertebral osteomyelitis. Rarely, there can be spinal intramedullary tuberculomas similar to intracranial lesions.

Figure 5.50: Tuberculosis of the brain [tuberculoma]. Photomicrograph showing epithelioid cell granuloma and Langhans’ giant cells [Haematoxylin and eosin x 200]

SKELETAL TUBERCULOSIS Bone and joint TB usually follows a primary pulmonary infection. Less commonly, there can be contiguous spread from pleura and periaortic lymph nodes. The most frequently involved site is the vertebral body and this form of spinal TB is known as “Pott’s” disease. In this disease, the classical involvement is of two consecutive vertebrae with destruction of the intervertebral discs. The lower thoracic and upper lumbar areas are common sites of disease. Any other bone or joint can be involved by TB, but weight bearing ones like knee and hip joints are more prone to be affected. Histopathologically, the presence of a granulomatous inflammation with necrosis is compatible with the diagnosis of TB [Figures 5.51 and 5.52]. In the case of the bone, identification of necrotic or dead bone is useful. Special stains can demonstrate AFB in some cases (130,131). TUBERCULOSIS IN THE IMMUNOCOMPROMISED Tuberculosis is often the sentinel disease warning of HIV infection and the development of AIDS. When active TB occurs in patients with AIDS, pulmonary TB is almost always present and, in up to 70 per cent of the cases extrapulmonary disease is associated. The source of infection could be recrudescence of latent infection [the commonest source], or accelerated progression of newly acquired disease or superinfection of those previously infected.

Figure 5.51: Tuberculosis osteomyelitis with necrotic lamellar bone and granuloma [Haematoxylin and eosin x 200]

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Figure 5.52: Tuberculosis of the synovium. Photomicrograph showing necrotising granulomatous inflammation [Haematoxylin and eosin x 200]

Impaired cell-mediated immunity [CMI] due to the reduced number of T-cells, specifically, the CD4+ subset is considered to be the reason for the higher incidence of TB in AIDS. Macrophage and peripheral monocyte function is reduced and consequently there is reduced activation of lymphokines. The cellular arm of immunity is, thus, seriously impaired and the body’s defences against intracellular pathogens such as mycobacteria and other organisms such as Pneumocystis jiroveci become defective. Tuberculosis itself may cause immunosuppression (132). Until a late stage has been reached in the immune impairment, TB presents the usual clinical and pathologic patterns observed in immunocompetent persons. Postprimary TB is most often encountered. Only when the immune defect has become severe the presentation becomes atypical and resembles more the pattern of primary disease (133-135). Hilar and mediastinal lymphadenopathy [often bilateral] can occur in up to 60 per cent of adult TB cases co-infected with AIDS, while this is observed only in three per cent patients without AIDS. Middle and lower zone involvement is more often observed than the usual upper lobe involvement. Diffuse infiltrates or a miliary pattern is apparent in 15 per cent cases and distant haematogenous dissemination to unusual sites is common. Pleurisy commonly occurs. The disease, thus, resembles primary or progressive primary TB. Cavitation is less frequent. Therefore, sputum is less frequently positive for AFB. Surprisingly, even in the late stages of immunosuppression, typical compact or ‘hard’ tuber-

culoid granulomas with minimal necrosis and few bacilli, epithelioid cells and Langhans’ giant cells can be seen. There is, however, the eventual tendency for the cell aggregates to become smaller. They are more loosely formed and the lymphocyte collar may not be evident. Acid-fast bacilli are often found, giant cells are rare and karyorrhexis [nuclear fragmentation] is often seen (133-135). Chest radiograph may be confusing. In a few cases, the chest radiograph may be normal even in patients with bacteriologically proven parenchymal TB. This is especially so in infections caused by Mycobacterium avium intracellulare complex [MAIC]. Diffuse interstitial pattern on chest radiographs can be caused by Pneumocystis jiroveci infection in patients with AIDS and is easily confused with other diseases. A positive blood culture for Mycobacterium tuberculosis has been observed in up to about 26 to 40 per cent cases. Immune anergy with loss of tuberculin reactivity is common. The progressive loss of tuberculin reactivity appears to coincide with a CD4+ T-lymphocyte count below 300 to 400 per cubic millimeter, although very low counts may be associated with a significant tuberculin reaction at a level of 5 mm or greater particularly after boosting by a second test (133-135). In the terminal stages, when the immune defect is severe, there may be aggregates of macrophages but no granuloma formation with numerous intracellular organisms. Disseminated, non-reactive TB with necrosis, much nuclear debris, many extracellular stainable AFB and minimal cellular reaction are also seen. Surrounded by a few histiocytes and lymphocytes areas of naked necrosis can be seen. The mechanism of necrosis in the absence of significant numbers of inflammatory cells is unclear. NONTUBERCULOUS MYCOBACTERIAL INFECTIONS OF LUNG The focus of this section is on the pathogenesis and pathology of the infections caused by nontuberculous mycobacteria [NTM]. Microbiological classification, characterization and other details regarding NTM are dealt with elsewhere. The reader is referred to the chapters titled “The mycobacteria” [Chapter 6] and “Nontuberculous mycobacterial infections” [Chapter 48] for more details.

Pathology 97 Pathology The gross and microanatomical knowledge regarding NTM disease is incomplete as the number of cases studied that have not been modified by previous treatment are rare. Also many cases have not been studied, as they have been passed of as resistant TB or a nodular infiltrative disease. Disease caused by NTM differs from TB in not causing a defined sequence of primary and post-primary disease (136,137). Haematological dissemination occurs only in the immunosuppressed. Radiological patterns of MAIC, Mycobacterium kansasii disease and Mycobacterium xenopi resemble post-primary TB. In Mycobacterium kansasii, the cavities are thin walled. In NTM disease, the anterior segments of the upper lobes are more frequently affected. Spread to contiguous pleura and pericardium is rare and spread to the lymph nodes is uncommon. Study of a HIV-negative elderly female without other lung disease showed a wide distribution of the lesions, frequent bronchiectasis, patchy air-space disease, nodules and relative infrequency of cavities (138). The histopathology of the lung in NTM infections can be summed up as a spectrum ranging from a collection of lymphocytes through aggregations of epithelioid cells and typical sarcoid-like tubercles to characteristic caseating granulomas (139). The nodular pattern seen on computerized tomography [CT] scan consists of discrete peribronchial granulomas, some caseating or multiple granulomas in a group. Mycobacterium kansasii has been reported to have spread transplacentally. Histopathologically, the features are dimorphic displaying both loose granulomas with giant cells containing a central aggregation of polymorphs and areas of acute inflammation often with microabscesses within which clusters of AFB may sometimes be identified. Wellformed epithelioid granulomas are uncommon and caseous necrosis is not a feature. Disseminated disease from rapid growers is uncommon. With more effective treatment of Pneumocystis jiroveci there is an increasing evidence that the occurrence of NTM is growing. As NTM infection in AIDS is a late feature, these infections occur at a point when other opportunistic infections are present and this may complicate the histopathology of MAIC and other mycobacterial infections (140,141). Radiological findings are frequently negative even when tissue evidence of pulmonary infection by MAIC

is present (142,143). Macroscopically the organs are often enlarged and may be yellow because of the pigment. Recognizable granulomas may not be present or when present may be poorly formed. Acid-fast bacilli may be plentiful with minimal or absent inflammatory reaction. A particular feature of MAIC infection is the occurrence of aggregates of macrophages filled with many AFB, so called multibacillary histiocytosis, a feature not seen in TB and AIDS. The use of antiviral therapy has permitted the repair of CMI which restores a more typical granulomatous response and an improved clinical response to antimycobacterial drug therapy. Diagnosis is achieved by blood culture, biopsy examination and culture of tissue from liver, bone marrow and other organs (140-143). In the present era, mere identification of AFB in tissue sections would not suffice. It has become a goal of paramount importance to identify, whenever possible, the species of the mycobacterium and its drug susceptibility patterns for diagnostic, prognostic, therapeutic and public health reasons. REFERENCES 1. Dubos RJ, Dubos J. The white plague: tuberculosis, man and society. Boston: Little Brown and Company; 1952. 2. Zumla A, Mwaba P, Squire SB, Grange JM. The tuberculosis pandemic: which way now? J Infect 1999;38: 74-9. 3. Maes RF. Tuberculosis II: the failure of the BCG vaccine. Med Hypotheses 1999;53:32-9. 4. Menzies D, Joshi R, Pai M. Risk of tuberculosis infection and disease associated with work in health care settings. Int J Tuberc Lung Dis 2007;11:593-605. 5. Rich AR. The pathogenesis of tuberculosis. 2nd edition. Illinois: Charles C. Thomas; 1951. 6. Skinner HA. The origin of medical terms. 2nd edition. Baltimore: The Williams and Wilkins Company;1961. 7. Wain H. The story behind the word. Illinois: Charles C. Thomas; 1958. 8. Russell DG. Who puts the tubercle in tuberculosis? Nat Rev Microbiol 2007;5:39-47. Epub 2006 Dec 11. 9. Zumla A, James GD. Granulomatous infections: etiology and classification. Clin Infect Dis 1996;23:146-58. 10. Rook GAW, al Attiyah R. Cytokines and Koch phenomenon. Tubercle 1991;72:13-20. 11. Walksman SA. The conquest of tuberculosis. Berkley: University of California Press; 1964. 12. Morrison A, Gyure KA, Stone J, Wong K, Mc Evoty, Koeller K, et al. Mycobacterial spindle cell pseudotumor of the brain: a case report and review of the literature. Am J Surg Pathol 1999;23:1294-9. 13. Le Gall , Loeiullet L, Delaval P, Thoreux PH, Desrues B, Ramee MP. Necrotising sarcoid granulomatosis with and

98

14.

15.

16.

17.

18. 19. 20. 21. 22. 23.

24. 25. 26.

27. 28.

29.

30. 31.

32. 33.

Tuberculosis without extrapulmonary involvement. Pathol Res Pract 1996;192:306-13. Brady JG, Schutze GE, Seibert R, Horn HV, Marks B, Parham DM. Detection of mycobacterial infections using the Dieterle stain. Pediatr Dev Pathol 1998;1:309-13. Gutierrez-Cancela MM, Garcia Marin JF. Comparison of Ziehl-Neelsen staining and immunohistochemistry for detection of Mycobacterium bovis in bovine and caprine tuberculous lesions. J Comp Pathol 1993;109:361-70. Dinnes J, Deeks J, Kunst H, Gibson A, Cummins E, Waugh N, et al. A systematic review of rapid diagnostic tests for the detection of tuberculosis infection. Health Technol Assess 2007;11:1-196. Kaplan MH, Armstrong D, Rosen P. Tuberculosis complicating neoplastic disease: a review of 201 cases. Cancer 1974;33:850-8. Mettler CC. History of Medicine. Philadelphia: The Blakiston Company; 1947. Ghon A. The primary lung focus of tuberculosis in children [Translation by King DB]. London: Churchill; 1916. Smith DW. Bacillemia in primary tuberculosis. Ann Intern Med 1971;75:479-80. Stead WW, Bates JH. Evidence of a “silent” bacillemia in primary tuberculosis. Ann Intern Med 1971;74:559-61. Morrison JB. Resorption of calcification in primary pulmonary tuberculosis. Thorax 1990;25:643-6. Salyer WR, Salyer DC, Baker RD. Primary complex of cryptococcus and pulmonary lymph nodes. J Infect Dis 1974;130:74-7. Anonymous. Unusual tuberculosis [leading article]. Tubercle 1965;46:420-6. Snider DE, Bloch AB. Congenital tuberculosis. Tubercle 1984;65:81-2. Lee LH, Le Vea CM, Graman PS. Congenital tuberculosis in a neonatal intensive care unit. Case report, epidemiological investigation and management of exposures. Clin Infect Dis 1998;27:474-7. Kang GH, Chi JG. Congenital tuberculosis-report of an autopsy case. J Korean Med Sci 1990;5:59-64. Hageman J, Shulman S, Schreiber M, Luck S, Yogev R. Congenital tuberculosis: critical reappraisal of clinical findings and diagnostic procedures. Pediatrics 1980;66:980-4. Machin GA, Homore LH, Fanning EA, Molesky M. Perinatally acquired neonatal tuberculosis: report of two cases. Pediatr Pathol 1992;12:707-16. Miller FJW, Seal RME, Taylor MD. Tuberculosis in children. London: J and A Churchill;1963. Smith MHD, Teele DW. Tuberculosis. In: Remington JS, Klein JO, editors. Infectious diseases of the fetus and newborn. 3rd edition. Philadelphia:W.B. Saunders Company; 1990.p.1079. Fisher I, Orkin M. Primary tuberculosis of the skin. Primary complex. JAMA 1966;195:314-6. Hellman KM, Muschenhe C. Primary cutaneous tuberculosis resulting from mouth to mouth resuscitation. New Engl J Med 1965;273:1035-6.

34. Tamura M, Ogawa G, Sagawa I, Amano S. Observations on an epidemic of cutaneous and lymphatic tuberculosis which followed the use of anti-typhoid vaccine. Am Rev Tuberc 1955;71:465-72. 35. Irani A, Colaco P, Desai MP. Cutaneous primary complex following venepuncture. Indian Pediatr 1978;15:181-3. 36. Strikas R, Venezio FR, O’Keefe JP. A case of cutaneous tuberculosis: primary or secondary? Am Rev Respir Dis 1983;128:316-8. 37. Caplan SE, Kauflman CL. Primary inoculation tuberculosis after immunotherapy for malignant melanoma with BCG vaccine. J Am Acad Dermatol 1996;35:783-5. 38. Jakubikova J, Trupl J, Nevicka E, Drdos M, Zitnan D, Hrusovska F. Child’s tuberculous lymphadenitis with fistula evoked by the BCG. Int J Pediatr Otolaryngol 1996;37:85-90. 39. Dimitrakopoulos I, Zoiloumis L, Lazarrdis N, Karkasis D, Trigonidis, Sichetidis L. Primary tuberculosis of the oral cavity. Oral Surg Oral Med Oral Pathol 1991;72:712-5. 40. Miller FJW. In: Health and Tuberculosis Conference. London: Chest and Heart Association, London; 1962.p.76. 41. Verma A, Mann SB, Radotra B. Primary tuberculosis of the tongue. Ear Nose Throat J 1989;68:718-20. 42. Hashimoto Y, Tanioka H.Primary tuberculosis of the tongue: report of a case. J Oral Maxillofac Surg 1989;47:744-6. 43. Gupta A, Shinde KJ, Bharadwaj I. Primary lingual tuberculosis: a case report. J Laryngol Otol 1998;112:86-7. 44. Eng J, Sabanathan S. Tuberculosis of the esophagus. Dig Dis Sci 1991;361:536-40. 45. Sood A, Sood N, Kumar R, Midda V. Primary tuberculosis of esophagus. Indian J Gastroenterol 1996;15:75. 46. Talib SH, Chawhan RN, Zaheer A, Talib VA. Primary tuberculosis of the stomach [a case report]. J Assoc Physicians India 1975;23:291-3. 47. Sengupta P, Ghosh P, Mukherjee SD. Primary tuberculosis of the stomach. J Indian Med Assoc 1978;71:209-10. 48. Singh B, Moodley J, Ramdial P, Haffejee AA, Royeppen E, Maharaj J. Primary gastric tuberculosis. A report of 3 cases. S Afr J Surg 1996;34:29-32. 49. Ray JD, Sriram PV, Kumar S, Kochhar R, Vaiphei K, Singh K. Primary duodenal tuberculosis diagnosed by endoscopic biopsy. Trop Gastroenterol 1997;18:74-5. 50. Lanzieri CF, Keller RJ. Primary tuberculosis of the ileum: roentgen features. Mt.Sinai J Med 1980;47:596-9. 51. Deodhar SD, Patel VC, Bharucha MA, Vora IM. Primary tuberculosis of the large bowel [a case report]. J Postgrad Med 1986;32:161-2. 52. Beibanaste M. Apparently primary tuberculosis of the vermiform appendix. Rass Clin Ther 1965;64:273-5. 53. Murali VP, Divakar D, Thachil MV, Raghu CG, Jacob MC. Primary tuberculosis of the appendix. J Indian Med Assoc 1989;87:162-3. 54. Stirk DI. Primary tuberculosis of the stomach, caecum, and appendix treated with antituberculous drugs. Br J Surg 1968;55:230-5.

Pathology 99 55. Desai HG, Raman G, Lele RD. “Primary” tuberculosis of the liver. Indian J Gastroenterol 1983;2:14-6. 56. Essop AR, Moosa MR, Segal I, Posen J. Primary tuberculosis of the liver - a case report. Tubercle 1983;64:291-3. 57. Selimoglu E, Sutbeyaz Y, Ciftcioglu MA, Parlak M, Esrefoglu M, Ozturk A. Primary tonsillar tuberculosis: a case report. J Laryngol Otol 1995;109:880-2. 58. Mahindra S, Bazaz-Malik G, Sohail MA. Primary tuberculosis of the adenoids. Acta Otolaryngol Stockh 1981;92:173-80. 59. Murray A, Gardiner DS, McGuiness RJ. Primary mycobacterial infection of the uvula. J Laryngol Otol 1998;112:1183-5. 60. Sharma HS, Kurl DN, Kamal MZ. Tuberculoid granulomatous lesion of the pharynx-review of literature. Auris Nasus Larynx 1998;25:187-91. 61. Sinha SN, Dewan VK. Primary tuberculosis of the larynx. Ear Nose Throat J 1978;57:158. 62. Ali F. Primary tuberculosis of the larynx in children. Ear Nose Throat J 1985;64:139-40. 63. Sharan R. Primary tuberculosis of the nose. Practitioner 1981;225:1506-7. 64. Purohit SD, Gupta RC. Primary tuberculosis of nose. Indian J Chest Dis Allied Sci 1997;39:63-4. 65. Sim J, Ong BH. Primary tuberculosis of the nasopharynx. Singapore Med J 1972;13:39-43. 66. Gnanapragasam A. Primary tuberculosis of the nasopharynx. Med J Malaysia 1972;26:3194-7. 67. Midholm A, Brahe-Pedersen C. Primary tuberculosis otitis media. J Laryngol Otol 1971;85:1195-200. 68. Sharan R, Isser DK. Primary tuberculosis of the middle ear cleft. Practitioner 1979;222:93-5. 69. Ozcelik, Ataman M, Gedikoglu G. An unusual presentation: primary tuberculosis of middle ear cleft. Tuber Lung Dis 1995;76:178-9. 70. Ustuner TE, Sensoz O, Kocer U. Primary tuberculosis of the parotid gland. Plast Reconst Surg 1991;88:884-5. 71. Kant R, Sahi RP, Mahendra NN, Agarwal PK, Shankhdhar R. Primary tuberculosis of the parotid gland. J Indian Med Assoc 1977;68:212. 72. Annobil SH, al-Hilfi A, Kazi T. Primary tuberculosis of the penis in an infant. Tubercle 1990;71:229-30. 73. Konohana A, Noda J, Shoji K, Hanyaku H. Primary tuberculosis of the glans penis. J Am Acad Dermatol 1992;26:10023. 74. Rossi R, Urbam F, Tortoli E, Trolta M, Zuccati G, Cappugi P. Primary tuberculosis of the penis. J Eur Acad Dermatol 1999;12:174-6. 75. Archer D, Bird A. Primary tuberculosis of the conjunctiva. Br J Ophthalmol 1967;51:679-84. 76. Whitford J, Hansman D. Primary tuberculosis of the conjunctiva. Med J Aust 1977;1:486-7. 77. Charles V, Charles SZ. Primary tuberculosis of conjunctiva. J Indian Med Assoc 1980;74:74-5. 78. Saini JS, Mukherjee AK, Nadkarni N. Primary tuberculosis of the retina. Br J Opthalmol 1986;70:533-5.

79. Slavin RE, Walsh TJ, Pokkack AD. Late generalised tuberculosis: a clinical, pathologic analysis and comparison of 100 cases in the pre-antibiotic and antibiotic eras. Medicine 1980;59:352-66. 80. Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis 2005;5:415-30. 81. Medlar EM. The behaviour of pulmonary tuberculous lesion: a pathological study. Am Rev Tuberc 1955;71[Suppl]:1-244. 82. Nayak NC, Sabharwal BD, Bhathena D, Mital GS, Ramalingaswami V. The pulmonary tuberculous lesion in north India: a study in medico-legal autopsies. I. Incidence, nature and evolution. Am Rev Respir Dis 1970;101:1-17. 83. Bhathena D, Mohapatra LN, Mital GS, Ramalingaswami V, Nayak NC. The pulmonary tuberculous lesion in north India: A study in medico-legal autopsies. II. Bacteriologic aspects. Am Rev Respir Dis 1970;101:18-26. 84. Lincoln EM, Sewell BH. Tuberculosis in children. New York: McGraw-Hill; 1963.p.19-83. 85. Giammona ST, Poole CA, Zelkowitz P, Skrovan C. Massive lymphadenopathy in primary pulmonary tuberculosis in children. Am Rev Respir Dis 1969;100:480-9. 86. Wallgren A. The timetable of tuberculosis. Tubercle 1948;29:245-51. 87. Bates JH. Transmission and pathogenesis of tuberculosis. Clin Chest Med 1980;1:167-74. 88. Dannenberg AM Jr, Sugimoto M. Liquefaction of caseous foci in tuberculosis. Am Rev Respir Dis 1976;113:257-9. 89. Altin S, Cikrikaogln S, Morgul M, Rosar T, Ozyurt H. Fifty endobronchial tuberculosis cases based on bronchoscopic diagnosis. Respiration 1997;64:162-4. 90. Choyke PL, Sostman HD, Curtis AM, Ravin CE, Chen JT, Godwin JD, et al. Adult onset pulmonary tuberculosis. Radiology 1983;148:357-62. 91. Tead WW, Kerby GR, Schleuter DP, Jordahl CW. The clinical spectrum of primary tuberculosis in adults. Confusion with reinfection in the pathogenesis of chronic tuberculosis. Ann Intern Med 1968;68:731-45. 92. Smith LS, Schillaci RF, Sarlin RF. Endobronchial tuberculosis: serial fiberoptic bronchoscopy and natural history. Chest 1987;91:644-7. 93. Meylan PRA, Richman DD, Kornbluth RS. Reduced intracellular growth of mycobacteria in human macrophages cultivated at physiologic oxygen pressure. Am Rev Respir Dis 1992;145:947-53. 94. Goodwin RA, Des Prez RM. Apical localisation of pulmonary tuberculosis, chronic pulmonary histoplasmosis and progressive massive fibrosis of the lung. Chest 1983;83:801-5. 95. Weigeshaus E, Balasubramanian V, Smith DW. Immunity to tuberculosis from the perspective of pathogenesis. Infect Immun 1989;57:3571-6. 96. Woodring JH, Vandiviere HM, Lee C. Intrathoracic lymphadenopathy in post-primary tuberculosis. South Med J 1988;81:992-7.

100

Tuberculosis

97. Lung AN, Muller NL, Pineda PR, Fitgerbld JM. Primary tuberculosis in childhood: radiographic manifestations. Radiology 1992;182:87-91. 98. Sweany HC, Cook CE, Kegeggereis R. A study of the position of primary cavities in pulmonary tuberculosis. Am Rev Tuberc 1931;24:558-82. 99. Van den Brande PM, Van de Mierop F, Verbeken EK, Demedts M. Clinical spectrum of endobronchial tuberculosis in elderly patients. Arch Intern Med 1990;150:2105-8. 100. Tsao TC, Juang YC, Tsai YH, Lan RS, Lee CH. Whole lung tuberculosis. A disease with high mortality which is frequently misdiagnosed. Chest 1992;101:1309-11. 101. Kapoor VK. Abdominal tuberculosis. Postgrad Med J 1998;74:459-67. 102. Rasheed S, Zinicola R, Watson D, Bajwa A, McDonald PJ. Intra-abdominal and gastrointestinal tuberculosis. Colorectal Dis 2007 Sep 14; [Epub ahead of print]. 103. Agarwal S, Gera N. Tuberculosis–an underestimated cause of ileal perforation. J Indian Med Assoc 1996;94:341,352. 104. Haddad FS, Ghossain A, Sawaya E, Netson AR. Abdominal tuberculosis. Dis Col Rectum 1987;30:724-35. 105. Benttey G, Webstar JHH. Gastrointestinal tuberculosis: A 10year review. Br J Surg 1967;54:90. 106. McGee GS, Williams LF, Potts J, Barnwell S, Sawyers JL. Gastrointestinal tuberculosis: resurgence of an old pathogen. Am Surg 1989;55:16-20. 107. Marshall JB. Tuberculosis of the gastrointestinal tract and peritoneum. Am J Gastroenterol 1993;88:989-99. 108. Tandon HD, Prakash A, Rao VB, Prakash O, Nair SK. Ulceroconstrictive disorders of the intestine in northern India: a pathologic study. Indian J Med Res 1966;54:129-41. 109. Tandon HD, Prakash A. Pathology of intestinal tuberculosis and its distinction from Crohn’s disease. Gut 1972;13:260-9. 110. Shah P, Ramakantan R. Role of vasculitis in the natural history of abdominal tuberculosis - evaluation by mesenteric angiography. Indian J Gastroenterol 1991;10:127-30. 111. Kuwajerwala NK, Bapat RD, Joshi AS. Mesenteric vasculopathy in intestinal tuberculosis. Indian J Gastroenterol 1997;16:124-6. 112. Sarode R, Bhasin D, Marwah N, Roy P, Singh K, Panigrahi D. Hyperaggregation of platelets in intestinal tuberculosis. Am J Hematol 1995;48:52-4. 113. Bhargava DK, Kushawaha AK, Dasarathy S. Endoscopic diagnosis of segmental colonic tuberculosis. Gastrointest Endosc 1992;82:511-4. 114. Manohar A, Simjee AA, Pettengill KE. Symptoms and investigative findings in 145 patients with tuberculous peritonitis diagnosed by peritoneoscopy and biopsy over a five-year period. Gut 1990;31:1130-2. 115. Shakil AO, Korula J, Kanel GC, Murray NGB, Reynolds TB. Diagnostic features of tuberculous peritonitis and presence of chronic liver disease. A case-control study. Am J Med 1996;100:179-85. 116. Sundervalli N, Karpagam CP, Raju B. Hepatomegaly in childhood tuberculosis. Indian Pediatr 1979;16:143-6.

117. Korn RJ, William FK, Paul H, Bernhard C, Hyman J, Zimmerman. Hepatic involvement in extra-pulmonary tuberculosis–histologic and functional characteristics. Am J Med 1959;27:60 118. Rosenberg S. Has chemotherapy reduced the incidence of genitourinary tuberculosis? J Urol 1963;90:317-23. 119. Shah PKD, Jain HK, Mangel HN, Singhi NM. Kidney changes in pulmonary tuberculosis–a study by kidney biopsy. Indian J Tuberc 1975;22:23. 120. Caorse CA, Belshe RB. Male genital tuberculosis - a review of the literature with instructive case reports. Rev Infect Dis 1985;7:511-24. 121. Roychowdhury NN. Overview of tuberculosis of the female genital tract. J Indian Med Assoc 1996;94:345-61. 122. Brown AB, Gilbent CRA, Te Linde RW. Pelvic tuberculosis. Obstet Gynecol 1953;2:476-83. 123. Sutherland AM. Tuberculosis of the female genital tract. Tubercle 1985;66:79-83. 124. Aliyu MH, Aliyu SH, Salihu HM. Female genital tuberculosis: a global review. Int J Fertil Womens Med 2004;49:123-36. 125. Lattimer JK, Colmore HP, Sanger CA, Robertson DB, McLellan FC. Transmission of genital tuberculosis from husband to wife via the semen. Am Rev Tuberc 1954;69:618-24. 126. Rich AR, Mc Cordock HA. Pathogenesis of tuberculous meningitis. Bull Johns Hopkins Hosp 1933;52:5-37. 127. Leonard JM, Des Prez RN. Tuberculous meningitis. Infect Dis Clin North Am 1990;4:769-87. 128. Dinakar I, Seetharam W, Ravilochan K. Tuberculoma of the brain with tuberculous meningitis. Indian J Tuberc 1983; 30:101. 129. Barucha PE, Iyer CGS, Barucha EP, Deshpande DM. Tuberculous meningitis in children–a clinicopathological evaluation of 24 cases. Indian Pediatr 1969;6:282-90. 130. Gorse GJ, Pais MJ, Kusske JA, Cesario TC. Tuberculous spondylitis: a report of six cases and a review of literature. Medicine 1983;62:178-93. 131. Tuli SM. Tuberculosis of the spine: An historical review. Clin Orthop Relat Res 2007 May 3;[Epub ahead of print]. 132. Ellner JJ, Wallis RS. Immunologic aspects of mycobacterial infections. Rev Infect Dis 1989;[Suppl]2:5455-9. 133. Chaisson RE, Schecter GF, Theuer CP, Rutherford GW, Echenberg DF, Hopewell PC. Tuberculosis in patients with acquired immunodeficiency syndrome. Clinical features, response to therapy and survival. Am Rev Respir Dis 1987;136:570-4. 134. Hill AR, Premkumar S, Brustein S, Vaidya K, Powell S, Li PW, et al. Disseminated tuberculosis in the acquired immunodeficiency syndrome era. Am Rev Respir Dis 1991;144:1164-70. 135. Sharma SK, Mohan A, Kadhiravan T. HIV-TB co-infection: epidemiology, diagnosis and management. Indian J Med Res 2005;121:550-67. 136. Khan K, Wang J, Marras TK. Nontuberculous mycobacterial sensitization in the United States: national trends over three

Pathology 101 decades. Am J Respir Crit Care Med 2007;176:306-13. Epub 2007 May 16. 137. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367-416. 138. Moore EH. Atypical mycobacterial infection in the lung: CT appearance. Radiology 1993;187:777-82. 139. Chapman JS. The atypical mycobacteria. Am Rev Respir Dis 1982;15:119-24.

140. El-Solh AA, Nopper J, Abdul-Khoudoud MR, Sherif SM, Aquilina AT, Grant BJ. Clinical and radiographic manifestations of uncommon pulmonary nontuberculous mycobacterial disease in AIDS patients. Chest 1998;114:138-45. 141. Andrejak C, Lescure FX, Douadi Y, Laurans G, Smail A, Duhaut P, et al. Non-tuberculous mycobacteria pulmonary infection: management and follow-up of 31 infected patients. J Infect 2007;55:34-40. Epub 2007 Mar 13. 142. Turenne CY, Wallace R Jr, Behr MA. Mycobacterium avium in the postgenomic era. Clin Microbiol Rev 2007;20:205-29. 143. Appelberg R. Pathogenesis of Mycobacterium avium infection: typical responses to an atypical mycobacterium? Immunol Res 2006;35:179-90.

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The Mycobacteria

6 Rajesh Bhatia

INTRODUCTION The generic name Mycobacterium was introduced by Lehmann and Neumann in 1896. The organisms were named so because of the mold like [myco: fungus; bacterium: bacteria] pellicular growth of these organisms in liquid medium (1). The true bacterial nature of these organisms was, however, soon established. The genus Mycobacterium is the only genus in the family Mycobacteriaceae and order Actinomycetales. The guanine + cytosine [G+C] ratio in the deoxyribonucleic acid [DNA] of mycobacteria is 62 to 70 mol per cent and similar to that observed in Nocardia (2). An important character of the mycobacteria is their ability to resist decolourization by a weak mineral acid after staining with one of the aryl-methane dyes. This property of acid fastness is, however, not unique to mycobacteria because Nocardia species and bacterial spores are also acid-fast. The genus is better defined on the chemical structure of the mycolic acids and its antigenic structure. CLASSIFICATION The genus Mycobacterium comprises of more than 50 species, of which several are non-pathogenic environmental bacteria. It has been classified in a variety of ways. A clinical classification is more practical and is described in Table 6.1. Mycobacteria other than human or bovine tubercle bacilli that cause human disease resembling tuberculosis [TB] are called atypical mycobacteria. These are also known as anonymous, unclassified, tuberculoid, paratubercle, or nontuberculous mycobacteria [NTM], mycobacteria

Table 6.1: Classification of mycobacteria Group 1 Obligate pathogens Mycobacterium tuberculosis Mycobacterium leprae Mycobacterium bovis Group 2 Skin pathogens Mycobacterium marinum Mycobacterium ulcerans Group 3 Opportunistic pathogens Mycobacterium kansasii Mycobacterium avium intracellulare [MAIC] Group 4 Non- or rarely pathogenic Mycobacterium gordonae Mycobacterium smegmatis Group 5 Animal pathogens Mycobacterium paratuberculosis Mycobacterium lepraemurium

other than tuberculosis [MOTT]. These have been classified by Runyon (3) into several groups [Table 6.2]. MYCOBACTERIUM TUBERCULOSIS Morphology The tubercle bacilli are slender, straight or slightly curved rod shaped organisms measuring two to four μm in length and 0.2 to 0.8 μ in breadth occurring singly, in pairs or in small groups. The size depends on conditions of growth and long, filamentous, club shaped and

The Mycobacteria 103 Table 6.2: Runyon classification of nontuberculous mycobacteria Runyon group I Photochromogens

II Scotochromogens

III Nonphotochromogens IV Rapid growers

Species

Disease in humans

Mycobacterium kansasii Mycobacterium marinum Mycobacterium simiae Mycobacterium scrofulaceum Mycobacterium gordonae Mycobacterium szulgai Mycobacterium avium

Pulmonary disease Swimming pool granuloma

Mycobacterium intracellulare Mycobacterium xenopi Mycobacterium chelonae Mycobacterium fortuitum

Lymphadenitis in children

Pulmonary disease in immunocompromised

Superficial and systemic diseases

Source: reference 3

branching forms may sometimes be seen. Mycobacterium bovis is usually straighter, stouter and shorter. However, no distinction between Mycobacterium bovis and Mycobacterium tuberculosis can be made based on morphology. The bacilli are non-sporing, non-motile and noncapsulated. In suitable liquid culture media, virulent human and bovine tubercle bacilli form characteristic long, tight, serpentine cords in which organisms are aligned in parallel. The bacilli are Gram positive though they do not take the stain readily. These organisms resist decolourization by 25 per cent sulphuric acid and absolute alcohol for 10 minutes and hence these are called acid and alcohol fast. Acid fastness is based on the integrity of the cell wall. Beaded or barred forms are frequently seen in Mycobacterium tuberculosis while Mycobacterium bovis stains more uniformly. In younger cultures non-acid-fast rods and granules have been reported. Mycobacterial Cell Wall The mycobacterial cell wall is complex in nature. It essentially distinguishes mycobacteria from other prokaryotes. Mycobacteria in general give a weakly positive response to Gram stain but are phylogenetically more closely related to Gram positive bacteria (4). It has high lipid content which accounts for about 60 per cent of the cell wall weight. The cell wall has several distinct layers. The inner layer, overlying the cell membrane is composed of peptidoglycan [murein]. External to the murein is a layer of arabinogalactan, which is covalently

linked to a group of long chain fatty acids termed mycolic acid. Cultural Characters Growth Requirements Mycobacteria are obligate aerobes and derive energy from oxidation of many simple carbon compounds. Biochemical activities are not characteristic and growth rate is much slower than that of most bacteria. The generation time in vitro is about 18 hours. At the earliest, the growth appears in about two weeks but may be delayed up to six to eight weeks. Optimum temperature for growth is 37 °C and growth does not occur below 25 °C and above 40 °C. Optimum pH for growth is 6.4 to 7.0. Increased CO 2 tension [5% to 10%] enhances growth. Human strains grow more luxuriantly in culture [eugonic] than do bovine strains [dysgonic]. The addition of a low percentage of glycerol to the medium encourages the growth of human strains but not that of bovine strains, which may infact be inhibited. Culture Media The reader is referred to the chapter “Laboratory diagnosis” [Chapter 10] for details on various types of media (5) that are commonly used for cultivation of mycobacteria. Colony Characteristics On solid media human type of tubercle bacilli give rise to discrete, raised, irregular, dry, wrinkled colonies which

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are creamy white to begin with and then develop buff colour. By contrast, the bovine type grows as flat, white, smooth, moist colonies which “break up” more readily when touched. Tubercle bacilli will grow on top of liquid medium as a wrinkled pellicle if the inoculum is carefully floated on the surface and the flask left undisturbed otherwise they will grow as floccules throughout the medium. However, a diffuse growth can be obtained by adding a wetting agent such as Tween 80. Virulent strains tend to form long serpentine cords in the liquid media while avirulent strains grow in a more dispersed fashion. Virulence in Animals Under natural conditions Mycobacterium tuberculosis infects humans, monkeys, cows, buffaloes, pigs, dogs and occasionally parrots. Under experimental conditions, it is virulent to guinea pigs and mice and less virulent in rabbits and avirulent in chicken. Mice are most commonly used for reasons of cost, convenience, their amenability to genetic manipulations (6). Guinea pigs exhibit many pathological features similar to those seen in humans, but unlike humans they are exquisitely sensitive to a progressive pulmonary infection (7). Rabbits display pathogenicity more characteristic of human disease, ranging from spontaneous healing to caseous and cavitary pulmonary lesions (8). Susceptibility to Physical and Chemical Agents The best method to inactivate tubercle bacilli is by heat and the efficacy of chemical methods are all relative to heat inactivation. The thermal death time at 60 oC is 15 to 20 minutes. They are more resistant to chemical agents than other bacteria because of the hydrophobic nature of the cell surface and their clumped growth. Dyes such as malachite green or antibiotics such as penicillins can be incorporated into media without inhibiting the growth of tubercle bacilli. Acids and alkalies permit the survival of some exposed tubercle bacilli and are used for concentration of clinical samples and partial elimination of contaminating organisms. These organisms can survive exposure to five per cent phenol, 15 per cent sulphuric acid, three per cent nitric acid, five per cent oxalic acid and four per cent sodium hydroxide. Tincture iodine destroys it in five minutes while 80 per cent ethanol does so in two to ten minutes. Thus, 80 per cent ethanol is recommended as a disinfectant for skin, rubber

gloves, and other such material. The cultures of tubercle bacilli can be killed by exposure to direct sunlight for three hours while in sputum they can survive for 20 to 30 hours. In droplets these may survive for 8 to 10 days. Cultures can be stored for two years in a deep freezer at –20 °C. The organisms are resistant to drying and can survive for long periods in dried sputum. Ordinary daylight even passing through glass has a lethal effect on mycobacteria. Antigenic Structure Mycobacteria being complex unicellular organisms, contain many antigenic proteins, lipids and polysaccharides. The exact number of antigenic determinants is unknown. The mycobacterial antigens have been broadly classified as: [i] soluble [cytoplasmic] and insoluble [cell wall lipid bound]; and [ii] carbohydrates or proteins. Antigens have been extensively used to classify, identify and type the mycobacteria. Soluble Antigens Up to 90 soluble antigens are demonstrated by sensitive techniques. Soluble antigens are divisible into four major groups designated as group i to iv [Table 6.3]. Polysaccharide Antigens Polysaccharide antigens are responsible for the group specificity while type specificity is due to protein antigen. Following infection by tubercle bacilli, delayed hypersensitivity develops to the protein [tuberculin]. The tuberculins from Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium microti appear to be indistinguishable. Biochemical Properties Mycobacterium tuberculosis has distinctive biochemical properties, some of which are utilized for identification of various species. The reader is referred to the chapter “Laboratory diagnosis” [Chapter 10] for further details. Table 6.3: Soluble antigen sharing in mycobacteria Group

Present in

Shared with

Group i

All mycobacteria

Group ii Group iii Group iv

Slow growing mycobacteria Rapid growing mycobacteria Individual species

Nocardia Corynebacterium Listeria Nocardia None, unique

The Mycobacteria 105 Pathogenesis The first event in the pathogenesis of TB, whether inapparent or overt, is the implantation of bacilli in tissues. The most frequent portal of entry is lungs, resulting from the inhalation of airborne droplets containing a few bacilli that are expectorated by an open case of TB. Less frequently, the bacilli may be ingested and lodged in the tonsil or in the wall of the intestine, which may follow consumption of raw contaminated milk. Finally, third but a rare mode of infection is direct implantation of bacilli into the skin, such as in workers while handling material containing tubercle bacilli. The reader is referred to the chapters “Pathology” [Chapter 5], “Reactivation and reinfection tuberculosis” [Chapter 47] for more details. Mycobacteria produce no recognized toxins. Various components of the bacillus have been shown to possess different biological activities which may influence pathogenesis, allergy and immunity of the disease [Table 6.4]. The production and development of lesions and their healing or progression are determined chiefly by the number of mycobacteria in the inoculum and their subsequent multiplication and resistance and hypersensitivity of the host. The essential pathology of TB in infected tissues consists of production, of a characteristic lesion, the tubercle. Mycobacteriophages Mycobacteriophages have been used for subdivision of some species of mycobacteria. Mycobacterium tuberculosis Table 6.4: Mycobacterial components as determinants of pathogenicity Cell component Cell wall

Pathogenic effect

Induces resistance to infection Causes delayed hypersensitivity Can replace whole cell in Freund’s adjuvant Tuberculoprotein Elicits tuberculin reaction Induces delayed hypersensitivity Induces formation of epithelioid and giant cells Polysaccharides Induce immediate hypersensitivity Causes exudation of neutrophils from blood vessels Lipids Cause accumulation of macrophages and neutrophils Phosphatides Induce formation of tubercles

has been divided into four phage types—A, B, C and I [I stands for intermediate between A and B]. Bacteriocins There is a limited evidence that some strains of mycobacteria liberate substances that inhibit the growth of other species. Mycobacterium tuberculosis is divisible into 11 types by means of bacteriocins produced by rapidly growing mycobacteria. Immunity and Hypersensitivity Infection with Mycobacterium tuberculosis induces delayed hypersensitivity [allergy] and resistance to infection [immunity]. Unless a host dies during the first infection with tubercle bacilli, there is an increased capacity to localize tubercle bacilli, retard their multiplication, limit their contiguous spread and reduce haematogenous and lymphatic dissemination. This can be attributed to the development of cellular immunity during the initial infection. In the course of primary infection the host also acquires hypersensitivity to the tubercle bacilli. This is made evident by the development of a positive tuberculin reaction. The reader is referred to the chapter “Immunology of tuberculosis” [Chapter 7] for further details on this subject. Koch’s Phenomenon The contrast between primary infection and reinfection is shown experimentally in Koch’s phenomenon. When a guinea pig is injected subcutaneously with virulent tubercle bacilli, the puncture wound heals quickly, but a nodule forms at the site of injection in two weeks. This nodule ulcerates and the ulcer does not heal. The regional lymph nodes develop tubercles and extensive caseation. When the same animal is later injected with tubercle bacilli in another part of the body, the sequence of events is quite different. There is a rapid necrosis of the skin and tissue at the site of injection, but the ulcer heals rapidly. Regional lymph nodes either do not become infected at all or do so only after a delay. These differences are attributed to immunity and hypersensitivity induced by the primary infection. The Koch’s phenomenon has three components: [i] a local reaction, [ii] a focal response consisting of an acute congestion around the TB foci in tissues and [iii] a “systemic” response of fever which at times may be fatal.

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This effect is not caused exclusively by living tubercle bacilli, but also by killed ones, no matter whether they are killed by low temperatures or prolonged periods, or by boiling or by certain chemicals.

based on production of pigment and rate of growth. The reader is referred to the chapter “Nontuberculous mycobacterial infections” [Chapter 48] for further details. MYCOBACTERIA PRODUCING SKIN ULCERS

Laboratory Diagnosis The laboratory diagnosis is based on demonstration and isolation of tubercle bacilli and no other test is of much use. The essential steps for diagnosis are: [i] collection of specimens; [ii] demonstration of organism; [iii] culture on suitable media; [iv] species identification by various tests; [v] use of molecular methods; and [vi] antituberculosis drug susceptibility testing [wherever possible]. Microscopy and culture are done in peripheral and intermediate laboratories, whereas identification of Mycobacterium tuberculosis and antituberculosis drug susceptibility testing are done in selected referral places. The reader is referred to the chapter “Laboratory diagnosis” [Chapter 10] for further details. Drug Susceptibility Testing With the emergence of multidrug-resistance in mycobacteria it is essential to perform drug susceptibility testing on the tubercle bacilli isolates as an aid and guide to treatment. Drug-resistant mutants continuously arise at a low rate in any mycobacterial population. The purpose of sensitivity testing is to determine whether the great majority of the bacilli in the culture are susceptible to the antituberculosis drugs currently in use. Drug susceptibility testing may be performed directly on the original specimen or indirectly on a subculture. Four methods of drug susceptibility testing have been standardized. These are: [i] absolute concentration method; [ii] resistance ratio method, [iii] proportion method and [iv] BACTEC-460 radiometric method. The reader is referred to the chapter “Drug-resistant tuberculosis” [Chapter 49] for more details. NONTUBERCULOUS MYCOBACTERIA The NTM were initially grouped according to speed of growth at various temperatures and production of pigments (9). More recently, individual species or complexes are defined by additional laboratory characteristics, e.g., nitrate reduction, production of urease, catalase and certain antigenic features. The NTM have been classified into four groups by Runyon (3)

Two conditions that are associated with skin ulceration include Mycobacterium ulcerans infection also known as Buruli ulcer and infection with Mycobacterium marinum which causes swimming-pool granuloma. In addition to these two, there are some other inoculation-associated infections. Mycobacterium ulcerans This organism was first described in Australia and was given the name Mycobacterium ulcerans in the year 1948. Later, a similar disease was seen in the Buruli county of Uganda and hence the name Buruli ulcer was given. Epidemiological investigations suggest that the organism is inoculated into the skin by thorny vegetation. The disease has an enormous socio-economic impact and is an important public health issue (10). The earliest sign is a discrete firm nodule fixed to the skin but mobile over deep tissues. It is painless, but may present with severe itching. If it does not resolve at this stage it progresses to the ulcerative stage which is full of bacilli. As the disease progresses, the overlying skin becomes anoxic and necrotic. Subsequently, skin ulceration occurs with the escape of liquefied necrotic tissue and a deep ulcer with undermined edges is formed. The lesions which may be single or multiple, are more common on exposed parts of the body, especially limbs. The disease is progressive for about three years but then an effective immune response develops. Eventually, the lesion heals but often with extensive fibrosis and contractures leading to crippling deformities. In general, chemotherapy has not proved very successful in its treatment. Simple excision of the lesion early in the disease is curative. Physiotherapy is required to prevent deformities. Mycobacterium marinum Mycobacterium marinum is a natural pathogen of coldblooded animals. The skin disease produced is known as “swimming-pool granuloma” or “fish tank granuloma” or “fish fancier’s finger”. The organism was initially named as Mycobacterium balnei but it was later

The Mycobacteria 107 found to be identical to the fish tubercle bacillus and was re-named as Mycobacterium marinum. Lesions occur at sites of injury, which are usually the knees and elbows of swimming pool users and the hands of the fish fanciers. The lesion commences as a solitary raised watery lesion, but secondary lesions develop along the draining lymphatics. Occasionally, tenosynovitis may develop at back. Human infection may occur in epidemic form. Infection with Mycobacterium marinum causes a low-grade tuberculin reaction. The reader is also referred to the chapter “Cutaneous tuberculosis” [Chapter 25] for further details. SAPROPHYTIC MYCOBACTERIA Saprophytic mycobacteria are non-pathogenic acid-fast bacilli found in milk, butter, water, manure, grass and smegma of human beings and animals. Important features of these mycobacteria are: [i] inability to set up a progressive infection in mammals or birds; [ii] profuse growth at room temperature, giving rise to growth in two to three days; [iii] optimum temperature is in the vicinity of 37 °C but growth at room temperature is also very good; and [iv] extracts and purified protein derivative [PPD] prepared from many of these mycobacteria may cross-react with PPD-S from Mycobacterium tuberculosis, resulting in positive skin tests in persons who are tuberculin negative. A higher proportion of the population becomes hypersensitive to mycobacteria acquired from the environment. Mycobacterium smegmatis is present in the smegma and contaminates urine samples. It needs to be differentiated from Mycobacterium tuberculosis. It is acid-fast but not alcohol-fast. Mycoabcterium w is a saprophytic, cultivable, nonpathogenic, rapidly growing atypical mycobacterium listed in Runyon Group IV. Heat-killed suspension of Mycoabcterium w has been tried as an immunomodulator in the treatment of leprosy (11). Its efficacy in pulmonary TB is under evaluation (12). Mycobacterium avium sub-species paratuberculosis [often abbreviated as M.ap], is an obligate pathogenic bacterium. It is a slow-growing, fastidious, heat-resistant organism. It can be characterized rapidly with the help of molecular techniques. It causes Johne’s disease in cattle (13). It has long been suspected as an aetiological

agent in Crohn’s disease in humans (14); however, this hypothesis has never been conclusively proven. REFERENCES 1. Grange JM. Mycobacterium. In: Greenwod D, Slack S, Peutherer J, editors. Medical Microbiology. New York: Churchill Livingstone; 1997.p.200-14. 2. Runyon EH. Anonymous mycobacterial in pulmonary disease. Med Clin North Am 1959;43:273-90. 3. Wayne LG, Kubica GP. The Mycobacteria. In: Sneath PHA, Mair NS, Sharpe ME, Holt JG, editors. Bergey’s manual of systematic bacteriology. Baltimore: Williams and Wilkinsons; 1989.p.1435-57. 4. Brennan PJ, Draper P. Ultrastructure of Mycobacterium tuberculosis. In: Bloom BR, editor. Tuberculosis: pathogenesis, protection and control. Washington: ASM Press; 1994.p.271-84. 5. Petran EI, Vera HD. Media for selective isolation of mycobacteria. Health Lab Sci 1971;8:225-30. 6. Orme IM, Collins FM. Mouse model of tuberculosis. In: Bloom BR, editor. Tuberculosis: pathogenesis, protection and control. Washington: ASM Press; 1994.p.113-34. 7. McMurray DN. Guinea pig model of tuberculosis. In: Bloom BR, editor. Tuberculosis: pathogenesis, protection and control. Washington: ASM Press; 1994.p.135-47. 8. Cosma CL, Sherman DR, Ramakrishnan L. The secret lives of the pathogenic mycobacteria. Annu Rev Microbiol 2003;57:641-76. 9. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367-416. 10. Sizaire V, Nackers F, Comte E, Portaels F. Mycobacterium ulcerans infection: control, diagnosis and treatment. Lancet Infect Dis 2006; 6:288-96. 11. De Sarkar A, Kaur I, Radotra BD, Kumar B. Impact of combined Mycobacterium w vaccine and 1 year of MDT on multibacillary leprosy patients. Int J Lepr Other Mycobact Dis 2001;69:187-94. 12. Katoch K, Singh P, Adhikari T, Benara SK, Singh HB, Chauhan DS, et al. Potential of Mw as a prophylactic vaccine against pulmonary tuberculosis. Vaccine 2008;26:1228-34. 13. Wells SJ, Whitlock RH, Wagner BA, Collins J, Garry F, Hirst H, et al. Sensitivity of test strategies used in the Voluntary Johne’s Disease Herd Status Program for detection of Mycobacterium paratuberculosis infection in dairy cattle herds. J Am Vet Med Assoc 2002;220:1053-7. 14. Shafran I, Burgunder P. Potential pathogenic role of Mycobacterium avium subspecies paratuberculosis in Crohn’s disease. Inflamm Bowel Dis 2008 May 28 [Epub ahead of print].

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Immunology of Tuberculosis

7 DK Mitra, AK Rai

INTRODUCTION Protective immunity and varied clinical manifestations of infection with Mycobacterium tuberculosis represent a delicate balance between the bacillus and the type as well as magnitude of the immune response elicited by the host. Host immune response is a broad term reflecting complex interactions among various arms of the immunity involving numerous cell types and molecules. This confers a homeostatic balance either in favour of the host, leading to containment of the infection, disease or in parasite’s favour resulting in failure of containment of infection. Immunity against tuberculosis [TB] needs to be understood not only in terms of sterilising immunity that eliminates Mycobacterium tuberculosis infection at the initial exposure, but also with respect to immunity of granuloma formation that maintains the steady state control over the bacillary spread and prevents the occurrence of clinical disease. Antituberculosis immunity involves innate as well as adaptive immunity at various levels following Mycobacterium tuberculosis infection. Both of these will be discussed separately here: first the innate and then the adaptive one. It should be understood that separating these immune mechanisms is only for the sake of better understanding of the complex cross-talk among diverse cell subsets and bio-molecules and obtaining reductionist insights into the antituberculosis immunity in totality. However, in vivo, the innate and the various components of adaptive immunity are complementary and work synergistically in concert. CHRONOLOGY OF IMMUNOPATHOGENESIS OF TUBERCULOSIS Pulmonary TB can be marked with four distinct phases following Mycobacterium tuberculosis infection

[Figure 7.1]. Each of these phases is determined by the homeostasis between the bacillary factors and host immune status including both innate and adaptive immunity [cellular as well as humoral]. First, following inhalation of Mycobacterium tuberculosis, depending on their intrinsic microbicidal capability alveolar macrophages ingest the pathogen and destroy them. However, bacilli often evade initial destruction by phagocytes and continue to multiply inside them ending in their disruption to cause fresh infection of the bystander macrophages. This heralds the second phase, characterized by recruitment of blood monocytes and other inflammatory cells to the primary disease site, the lungs in most instances. Monocytes ingest the bacilli and differentiate into macrophages, but fail to eliminate them completely. This stage is marked by logarithmic growth of the pathogens with little tissue destruction. Following this, antigen specific T-cells are recruited to the pathologic site[s] that activate the monocytoid cells leading to their differentiation into either of these two types of giant cells, epithelioid and multi-nucleated Langhans’ type giant cells. This is the third stage of granuloma formation, which aims at walling off the infection from the rest of the body and prevents dissemination of bacilli, thus contains the infection. This stage of latency, which disrupts under conditions of failing immune surveillance and gives rise to endogenous reactivation of dormant foci culminating in post-primary TB which is characterized by cessation necrosis [fourth phase]. In summary, after entry into the body, Mycobacterium tuberculosis encounters a series of host defense mechanisms with final outcome depending on the balance between bacillary growth and extent of host immunity. Essentially, all these phases of TB infection involve various arms of innate and acquired immunity sequentially in an orchestrated manner.

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Figure 7.1: Events during TB infection. Broadly, TB infection is divided into four phases: First phase includes an initial establishment of Mycobacterium tuberculosis infection in the resident macrophages [alveolar]. This is followed by influx of PMNs, which prevents Mycobacterium tuberculosis to escape from the innate immune factors. Subsequently, monocytes are recruited to the site of infection/ pathological site [second phase]. Third phase includes granuloma formation. Core of granuloma is made up of multinucleated giant cells and elongated epithelioid cells. These are surrounded by T-cells. This is aimed at restricting the bacilli from spreading. The fourth and terminal phase includes dissemination of bacilli. Defective granuloma formation promotes release of bacilli from control of immune system. Organs/loci targeted by bacilli after dissemination are listed here DC = dendritic cells; Mφ = macrophages; PMNs = polymorphonuclear leucocytes; TB = tuberculosis

INITIAL ENCOUNTER AND INNATE IMMUNITY Mononuclear cells including alveolar macrophages and dendritic cells [DCs] play a crucial role during their initial encounter with Mycobacterium tuberculosis by their intrinsic or innate defense mechanism[s]. This has been demonstrated by Lurie in animal model where early infection and bacillary multiplication occur in susceptible rabbits (1). A probable role of DC specific intercellular adhesion molecule 3 [ICAM-3] grabbing nonintegrin [DC-SIGN], a recently discovered type II transmembrane protein has been implicated in DC mediated dissemination of Mycobacterium tuberculosis. Subsequently, DCs in the lymph nodes present some of the early secretory antigens such as early secreted antigenic target 6 [ESAT6] and antigen 85 with major histocompatibility complex

[MHC] class II. These antigens presumably serve as the dominant antigens for CD4+ cells, which start accumulating in large numbers in lesions during the early stages of Mycobacterium tuberculosis infection. Recent data suggest that probably T-cell dependent acquired immunity is also critical for protection against dissemination and disruption of latency of TB. However, they may not be so critical for eliminating the initial infection with Mycobacterium tuberculosis (2,3). This dynamics of effector immune mechanisms fits well with the basic fact that the acquired immunity requires time to develop and until then innate mechanisms attempt to either eliminate or control multiplication of the bacilli so that effective T-cell response eventually may contain the infection through stable granuloma formation (4). A plethora of clinical and experimental evidence suggests

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an essential role of innate immune responses during an early phase of infection with Mycobacterium tuberculosis. Alveolar macrophages are the first line of cellular elements of initial uptake of aerosolized Mycobacterium tuberculosis, although subsequently DCs and monocytes are also involved in the process. Various receptors expressed on the phagocytes mediate endocytosis of the bacilli. Uptake of opsonized bacilli [coated with preformed humoral elements like antibodies or complement split products] is greatly facilitated by complement receptors expressed on macrophages such as complement receptors [CRs] CR1, CR3 and CR4. Bacillary uptake by human macrophages deficient in CRs is found to be reduced up to 80 per cent indicating their role in engulfing Mycobacterium tuberculosis (5). Non-opsonized bacilli are engulfed by macrophages through mannose receptors [MRs] that recognize the terminal mannose moieties of mycobacteria (6). Additionally, nonopsonized Mycobacterium tuberculosis can be taken up by the macrophages through binding to the scavenger receptor type A, as blocking CRs and MRs could not completely abrogate the bacillary uptake. Several other groups of molecules of the innate immune system may also facilitate binding and uptake of Mycobacterium tuberculosis. Collectins, a structurally related group of proteins are important in this regard. Surfactant protein A enhances the uptake while surfactant D blocks it. Another member of collectins, the plasma factor mannose binding lectins is also involved in macrophage uptake of the bacilli. Fibronectins also facilitate uptake of Mycobacterium tuberculosis by alveolar epithelial cells through binding to antigenic proteins (7). Thus, multiple mechanisms are operational in the uptake of Mycobacterium tuberculosis by mononuclear phagocytes giving them a chance to kill the bacilli. However, all these mechanisms only facilitate in their uptake but fail to elicit any immune recognition leading to macrophage activation. Up-regulation of a battery of surface expressed and soluble molecules determine the shape of the eventual acquired immunity on the surface of macrophages. Toll-like receptors [TLRs] are such family of molecules on the surface of macrophages that play a critical role in immune recognition of Mycobacterium tuberculosis and elicitation of an effective innate immune response. The TLRs are phylogenetically conserved molecules mediating the innate immunity and dictating the development of eventual T-cell responses. They are

transmembrane proteins with leucine rich repeat motifs in extracellular domain. Cytoplasmic domains of TLRs are homologous to the signalling domain of IL-1 receptor [IL-1R] and are linked to signalling molecule IL-1R associated protein kinase [IRAK-1], a serine kinase that activates transcription factors of several key immunoregulatory cytokines, such as nuclear factorkappa beta [NF-kB]. Of the several TLRs discovered till date TLR2, TLR4, TLR3 and TLR9 appear to elicit cellular response to mycobacterial antigens including the 19-kDa lipoprotein and lipoarabinomannan [LAM]. In context of CD14, TLR2 binds to LAM, a heterodimer of TLR2 and TLR6 binds to CD19 kDa lipoprotein. The TLR4 binds to yet undefined heat labile cell associated factor and TLR9 binds to mycobacterial DNA motifs. Engagement of TLRs by mycobacterial antigens leads to coupling of myeloid differentiation primary response gene [88] [MyD88] and IRAK signalling molecules resulting in multiple signalling events that ultimately translocate transcription factor NF-kB from cytosol to nucleus and stimulate the production of various cytokine required for innate as well as adaptive immune events. Production of cytokines following TLRs induced activation of macrophages is important for immunity to Mycobacterium tuberculosis. Several cytokines are released, some of which take part in non-specific inflammation, and others regulate the functional bias of the relevant Tcells. A brief account of the important cytokines produced by Mycobacterium tuberculosis infected macrophages is provided in Figure 7.2. These cytokines eventually induce further activation of immune cells and lead to a complex process of immune regulation. Among the pro-inflammatory cytokines tumour necrosis factor-α [TNF-α], interleukin-1β [IL-1β], interleukin-6 [IL-6], interleukin12 [IL-12], interleukin-15 [IL-15] and interleukin-18 [IL-18] are important. Each of them plays a distinct role in the immune response against TB. α Tumour Necrosis Factor-α This prototype pro-inflammatory cytokine is produced by macrophages, DCs and Th1 like cells upon infection and stimulation with Mycobacterium tuberculosis. It plays key roles in macrophage activation, immune regulation and particularly granuloma formation by induction of appropriate chemokine receptors on the effector T-cells and thus recruiting them to the disease site (8). In mice it has been shown to be involved in maintaining the latency

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Figure 7.2: Summary of the immune response in tuberculosis pathogenesis. After infection, innate immune responses try to put check on increasing infection. Meanwhile, immature DCs after taking up the antigens, move towards the draining lymph nodes and antigen recognition and presentation to T-cells occur inside the regional/draining lymph nodes. Recruitment of antigen specific T-cells at the pathological sites and production of pro-inflammatory cytokines such as tumour necrosis factor-α [TNF-α], interferon-γ [IFN-γ] etc., lead to granuloma formation to localize the pathogen. Later on, depending on presence/absence of Th1/Th2 skewed response, dissemination or containment of bacilli occurs DC = dendritic cell; TLRs = toll-like receptors; ROI = reactive oxygen intermediates; RNI = reactive nitrogen intermediates; IL = interleukins; Tc cell = T-cytotoxic cell; FAS-FASL = tumour necrosis factor receptor superfamily, member 6 - tumour necrosis factor receptor superfamily, member 6 ligand; ICAM-1 = intracellular adhesion molecule-1

of TB infection and has been found at the disease site[s]. Its role in humans is best evidenced by occurrence of high incidence of TB among rheumatoid arthritis patients when treated with anti-TNF-α antibodies. However, it is thought to be a “double edged sword” causing bystander damage of the host tissue and cavity formation, particularly when present in relative excess in the milieu. Interleukin-1β β and Interleukin-6 Interleukin-1β is another proinflammatory cytokine secreted by the Mycobacterium tuberculosis infected

macrophages and DCs and is found in excess at the pathologic site[s] of TB. An increased mycobacterial growth and a defective granuloma formation are observed in IL-1β knock out mice (9). Interleukin-6 on the other hand, may serve as both pro- and antiinflammatory cytokines and is found to be present in TB patients (10). Various reports suggest that it may antagonise either TNF-α or interferon-γ [IFN-γ], both of which are widely believed to be critical for protective immune response against TB.

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Interleukin-12 and Interleukin-18 Interleukin-12 is the most potent Th1 driving regulatory cytokine produced by infected or stimulated macrophages and DCs and thus, plays a crucial role in the development of protective Th1 type immunity in TB. In TB, IL-12 has been detected in disease sites such as lung infiltrates, pleurisy and granulomas (9,11). Its receptor is also over-expressed in these sites. Children with deleterious mutation of genes encoding IL-12p40 subunit and IL-12 receptor are highly susceptible to recurrent nontuberculous mycobacterial infections (12). Interleukin-18, another pro-inflammatory cytokine is important for IFN-γ axis of the T-cell response. High susceptibility of IL-18 knock out mice to Mycobacterium tuberculosis, bacille Calmette-Guérin [BCG] and Mycobacterium leprae strongly suggests a protective role of this cytokine in TB (13). A close parallelism has been noted between the concentration of IL-18 and IFN-γ among patients suffering from TB pleural effusion (14). Protective effect of IL-18 may be mediated by enhanced production of IFN-γ, another potent effector cytokine for macrophage activation leading to killing of the intracellular mycobacteria. Interferon-γγ A protective role of IFN-γ in TB is beyond doubt. But it must be remembered that it is not the only terminal effector cytokine to confer protection in TB. Mycobacterial antigen specific in vitro production of IFN-γ by T-cells from patients represents a surrogate marker of immunity against TB. However, there exists a great deal of divergence of opinion in this respect among the researchers and clinicians. In TB, physiologically relevant sources of IFN-γ are natural killer cells [NK-cells], antigen specific T-cells [helper and cytotoxic], macrophages themselves, and other relatively rare fine T-cell subsets such as γδ T-cells and CD1d restricted NKT-cells (15). The IFN-γ is a potent activator of infected macrophages resulting in potentiation of lytic mechanism[s] responsible for killing of intracellular Mycobacterium tuberculosis and enhancement of human leucocyte antigen [HLA] and co-stimulatory molecules which result in efficient presentation of macrophage processed mycobacterial antigens and elicitation of strong T-cells responses (16). In addition to the production of the above proinflammatory cytokines, certain anti-inflammatory

cytokines are produced as well in TB. Some of these, such as interleukin-4 [IL-4], interleukin-10 [IL-10] and transforming growth factor-β [TGF-β], are Th2 like cytokines and their role in the immunopathogenesis of TB has provided the concept of Th1/Th2 paradigm in various forms of TB. These cytokines are believed to antagonise the protective and/or containing immunity, thus suppressing the required immunity. Therefore, they have been implicated in enhanced susceptibility as well as disease severity in terms of clinical manifestation and the extent of the disease. Interleukin-10 Interleukin-10 is produced by the macrophages after phagocytosis of Mycobacterium tuberculosis and also by the Th2 cells following recognition of duly processed mycobacterial antigens. Mononuclear cells from TB patients, particularly those with disseminated disease, produce copious amounts of IL-10 in vitro in response to mycobacterial antigens (17). Interleukin-10 transgenic mice supports better bacillary growth. Also in humans, IL-10 production is significantly higher in patients with purified protein derivative [PPD] anergy and severe forms of TB. Interleukin-10 is well known for its ability to suppress IFN-γ, TNF-α and IL-12, all of which are critical for eliciting a desired Th1 type immune response in host’s favour. Interleukin-4 The deleterious influence of IL-4 in TB is well known and is attributed to its suppressive effect on IFN-γ production. Mycobacterium tuberculosis infected mice with progressive form of disease shows a significantly higher production of IL-4 (18). Disseminated form of TB, such as miliary TB, is associated with a very high production of IL-4 by T cells derived from peripheral blood and bronchoalveolar lavage [BAL] fluid following in vitro stimulation (19,20). However, several studies failed to reproduce similar observation, which may be due to variation in the study subjects and methods used for the detection of IL-4. It is widely believed that IL-4 production is responsible for suppression of Th1 type immune responses against TB. Thus, the host fails to contain the disease, leading to the development of severe and disseminated forms of TB. In some recent elegant studies, a splice variant of IL-4 gene has been detected. This truncated splice variant called IL-4δ gives rise to protein isoform, which inhibits

Immunology of Tuberculosis 113 the immunosuppressive Th2 like function of native IL-4. Expression of IL-4δ messenger ribonucleic acid [mRNA] was very minimal in the peripheral blood mononuclear cells [PBMCs] of the healthy subjects. On the other hand, it was found to be expressed in significantly higher amount in the thymocytes and BAL fluid cells from patients with TB. Tissue specific expression of this splice variant and tight correlation with the disease severity suggests a potential immunoregulatory role in pathogenesis of TB. Plausibly, IL-4δ functionally inhibits Th2 skewing of the host immune response by antagonising the effect of native IL-4 and facilitates the desired Th1 response. Ratio of IL-4/IL-4δ may be useful in monitoring the cytokine polarized immune response among TB patients. β Transforming Growth Factor-β Transforming growth factor-β also appears to inhibit the protective immunity against Mycobacterium tuberculosis and aggravates the pathology. The TGF-β is also produced in abundance by TB patients and its expression is observed at the pathologic site[s] (21). The TGF-β is a well known inhibitor of T-cell proliferation, IFN-γ production, macrophage activation and antigen presentation. Moreover, it is also known for its potent host tissue damaging effect and fibrosis (22). The TGF-β along with IL-10 potently suppresses the Th1 function during TB infection and is thought to contribute to the pathogenesis of TB. IMMUNE EFFECTOR MECHANISMS AGAINST MYCOBACTERIUM TUBERCULOSIS Activated macrophages are the terminal effector cells responsible for killing of intracellular bacilli in TB. Multiple factors are responsible for this activation finally resulting in triggering the major lytic mechanisms. Among several factors, the most well documented and definitive mediators are IFN-γ and TNF-α. These cytokines are primarily derived from the Th1 cells and activate the macrophages to induce the intracellular messenger molecules, reactive oxygen intermediates [ROIs] and reactive nitrogen intermediates [RNIs] that are thought to be involved in killing of the intracellular mycobacteria. Also important for macrophage activation synergistically with IFN-γ and TNF-α is the active metabolite of vitamin D [1,25-dihydroxy vitamin D] (23).

Several studies have reported reduced levels of vitamin D among TB patients. Recent clinical trials suggest a distinct role for vitamin D in potentiating the immunity against TB. An interesting element involved in macrophage activation as well as killing of intracellular mycobacteria is the solute carrier family 11 [protoncoupled divalent metal ion transporters], member 1 [Slc11a1], and its human orthologue, SLC11A1, formerly known as natural resistance associated macropahge protein [Nramp1]. It is an integral membrane protein belonging to a family of metal ion transporter, particularly the iron [Fe++]. Following phagocytosis Slc11a1 becomes integrated to the phagosomes and activates macrophages with generation of toxic anti-microbial radicals, particularly ROIs (24). The Slc11a1 mutant mice show reduced phagosomal maturation and acidification. In humans, polymorphism of this gene associated with reduced expression of SLC11A1 is associated with susceptibility to TB in West African population (25). Therefore, genetic variation of this gene may in part determine the outcome of Mycobacterium tuberculosis infection. Generation of ROIs appears to be important for killing of intracellular bacilli. However, the conclusive proof is still awaited due to variation among experimental systems, particularly among mice and human studies. In vitro mycobacteria are resistant to killing by superoxides and hydrogen peroxides, this may be due to presence of LAM on Mycobacterium tuberculosis that can scavenge the ROIs. In mice lacking functional P47 unit of nicotinamide adenine dinucleotide phosphate [NADPH], which is required for the generation of superoxide ions, early and excessive growth of Mycobacterium tuberculosis has been demonstrated (26). This points towards an important role of ROIs in mycobacterial killing. On the contrary, patients suffering from chronic granulomatous disease [CGD] with a defect in production of superoxide radicals have not been demonstrated to be susceptible to TB (27). Therefore, a precise role of ROIs in killing Mycobacterium tuberculosis is still not conclusively demonstrated, even though it is strongly suggested. Similarly, the role of RNIs still remains inconclusive as well. In vitro infection of macrophages with Mycobacterium tuberculosis leads to up-regulation and excessive production of inducible nitric oxide synthase [iNOS2], which is required for the production of nitric oxide. Alveolar macrophages obtained from the BAL fluid of

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patients with TB have shown an increased expression of iNOS gene (28). But the precise role of over-expression of iNOS in patients with TB remains uncertain, as posttranslational modification of iNOS is required for functional activity. ACQUIRED T-CELL MEDIATED IMMUNE MECHANISM T-cell mediated immune response is at the hub of immunity against Mycobacterium tuberculosis as antibodies fail to contain the infection due to its intracellular habitat. Upon initial exposure and recognition of immuno-dominant epitopes, naive T-cells are primed and converted into effector and memory T-cells. Effector T-cells contain the initial infectious load. However, dormant foci of Mycobacterium tuberculosis within macrophages persist and reactivation of the bacillary foci occurs in the event[s] of perturbation of a delicate balance of T-cell immunity that contained the foci so far (29). Additionally, a fresh exogenous infection may also take place. Whatever is the case, on these subsequent exposures, the memory T-cells generated during the primary infection elicit a strong Th1 response and migrate to the site of the pathogen. These migrated T-cells are further activated by the processed antigens presented by the local infected macrophages and secrete key effector cytokines, such as IFN-γ and TNF-α, which help in activation as well as terminal differentiation of the macrophages into the giant cells. A well-defined architectural aggregation of T-cells and the giant cells [both multinucleated and epithelioid types] results in granuloma formation, the immunopathologic hallmark of TB. An evolution of granuloma occurs through a sequential influx of various types of cells of the immune system (30). Neutrophils migrate quite early in this process followed by the monocytes which differentiate into macrophages within two to three days. Chemokines induced in the granuloma begin to recruit T-cells which are activated to secrete cytokines. Among the T-lymphocyte layer surrounding the granuloma are predominantly of CD4+ type, although CD8+ T-cells are also present. The T-cell derived cytokines locally trigger the macrophages to terminally differentiate into highly active giant cells. Apoptosis of cells, prominently in epithelioid cells has been demonstrated by terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling [TUNEL] immunostaining (31). Appropriate positioning of various cell types within the granuloma

is mediated by the expression of adhesion molecules and chemokines. Many of these cell homing molecules are known to be induced by Mycobacterium tuberculosis. The intracellular adhesion molecule-1 [ICAM-1], a major adhesion molecule involved in granuloma formation, is induced by TNF-α, IL-6 and IFN-γ. Chemokines, such as macrophage inflammatory protein [MIP1-α], regulated on activation, normal T-expressed and secreted [RANTES], monokine induced by interferon γ [Mig], and IFN-γ-inducible protein-10 [IP-10] etc., all associated with inflammation are also induced by the bacilli (32,33). The Th1 cells preferentially recruited by these homing molecules, through the release of cytokines promote terminal differentiation of macrophages into giant cells like multinucleated and epithelioid types. These activated cells of monocyte/macrophage lineage ultimately kill the intracellular Mycobacterium tuberculosis through ROIs and RNIs. Mycobacteria are also capable of inducing caseation necrosis in the centre of the granuloma. Conventionally, TNF-α has been thought to be the prime mediator of caseation necrosis. However, recent findings of caseation necrosis among mice lacking functional component of TNF receptor [55 kDa TNF-R] suggest the existence of other mechanism[s] for this phenomenon. Mycobacterial components such as, LAM have been demonstrated to activate interstitial collagenase gene and matrix metalloproteinase-9 [MMP9]. These extracellular matrix enzymes probably play a major role in caseation necrosis. Interestingly, upregulation of MMP-9 has been observed in BAL cells recovered from cavitary TB patients (34). Granuloma may be regarded as a localized immune reaction that attempts to wall off the pathogen and prevents its further spread. The dormant foci of infection may remain as such for years or even life-long. However, perturbation of a delicate balance of immunity with suppression of critical mechanism[s] may lead to activation of endogenous foci containing dormant mycobacteria. Alternatively, fresh exogenous infection can also occur. Both of these develop into a clinical disorder such as pulmonary TB. Immune response to Mycobacterium tuberculosis continues to play a critical role and dictates the clinical outcome of the disease as well. The extent and severity of the disease appear to be determined by the type and magnitude of the T-cell response elicited eventually. As Th1 like response is critical for containment of Mycobacterium tuberculosis infection, its robustness and balance between

Immunology of Tuberculosis 115 Th1 and Th2 type of response play an important role to dictate whether the disease will be of limited extent with localized form such as pulmonary TB or will disseminate to give rise to severe forms of disease such as miliary TB, multidrug-resistant TB [MDR-TB] [Figure 7.2] (20,35). CD4+ AND CD8+ T-CELLS IN TUBERCULOSIS Importance of CD4+ helper T-cells is best demonstrated by significantly higher incidence and occurrence of severe and disseminated forms of TB among patients coinfected with human immunodeficiency virus [HIV] and Mycobacterium tuberculosis (36). It is also suggested by the predominant presence of CD4+ helper T-cells in the granuloma outnumbering the CD8+ T-cells. Functionally, mature or memory helper T-cells are of two distinct types, namely, Th1 and Th2 cells. The Th1 cells preferentially produce IL-2, IFN-γ and TNF-α to stimulate the cell mediated immunity which is crucial for containment of Mycobacterium tuberculosis. On the other hand, Th2 cells are biased to produce more of IL-4, interleukin-13 [IL13], and IL-10, etc., and boost the antibody production, particularly of IgE isotype and suppress the Th1 like immunity. The importance of Th1/Th2 paradigm has been studied in various diseases; the most notable is that among polar leprosy patients. Tuberculoid leprosy, which is characterized by high degree of T-cell reactivity against Mycobacterium leprae is associated with Th1 like polarized cytokine response while lepromatous leprosy, hallmarked by T-cell anergy towards Mycobacterium leprae strongly correlates with dominant Th2 like cytokine profile (37). Similar association in TB has been proposed and subsequently demonstrated by several groups of investigators. However, conclusive picture is yet awaited. In vitro studies of T-cell proliferation and their cytokine production profile upon antigen stimulation of PBMCs obtained from TB patients and control subjects support the role of cytokine polarized immunity in TB. Cytokine profile skewed towards dominant production of the IL-4 along with lower IFN-γ level was found among TB patients compared to that of the controls and healthy contacts. At the same time several other groups failed to observe the same. The reasons for this apparent discrepancy may be the variations of the experimental systems, use of different antigens, different populations with diverse host genetic factors and importantly, a great deal of variation among the study subjects and the extent as

well as severity of their disease. Another major limitation of these studies is that all of them looked either at the soluble and accumulated cytokine level in the peripheral blood or long term in vitro stimulation which might have imposed functional bias on the responding T-cell in terms of cytokine production. To address the issue of Th1/Th2 paradigm in TB, investigators focussed attention to the cells producing the cytokines particularly the T-cells derived from the disease site. Data emanating from these recent studies indicate a possible compartmentalization of T-cell mediated immune response among TB patients and a predominant role of IL-12. Cytokine profile of the pleural fluid revealed excess levels of IFN-γ and IL-12 relative to their levels in the peripheral blood compartment (37). Several investigators have demonstrated a Th1 biased response in the pleural compartment representing the site of a strong T-cell response of local TB pathology. To understand the Th1/Th2 phenomenon in TB researchers have studied patients suffering from disseminated and severe forms of TB. The T-cells from TB patients in the setting of HIV infection showed predominant IL-4 production with excess of IL-10 that is known to drive the effector T-cell responses towards Th2 and antagonize the Th1 driving cytokine IL-12. Study of T-cells from patients with miliary TB provided strong indication that extent and dissemination of TB tightly correlate with a strong Th2 bias demonstrated by the T-cells derived from BAL fluid representing the pathologic site of disseminated TB (19). Interestingly, IFN-γ production by the T-cells from the BAL fluid could be restored by supplementation with IL-12. Using flow cytometry based assay of intracellular cytokines, Mitra et al (20) have demonstrated that the T-cells from TB pleural effusion predominantly produce IFN-γ, the Th1 designate cytokine, while the T-cells from BAL fluid of miliary TB patients predominantly produce IL-4, the designate cytokine for Th2 response. These elegant recent studies with the patients diagnosed on stringent criteria and specimens from both peripheral as well as the local compartments representing the immune response at the local pathologic site[s] provided important insights in understanding the dynamics of Th1/Th2 paradigm in human TB. The emerging picture of the immune response in TB indicates the importance of polarized cytokine response and T-cells in a similar way as has been observed in leprosy. Plausibly, a strong Th1 response

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dictates either disease containment or development of localized form of disease, such as solitary lesion in pulmonary TB and the pleural effusion. On the other hand, a dominant Th2 like response fails to contain the disease and, thus leads to the development of severe and disseminated forms of TB such as miliary TB and extensive cavitary disease. Further investigations with larger and diverse patient populations are required to conclusively address these issues. The role of CD8+ T-cells in immunity against TB has drawn a relatively less attention from the investigators in the felid. However, with recent studies demonstrating susceptibility of the mice lacking MHC class I expression to mycobacterial infection (38), alteration of CD4+/CD8+ cells ratio among TB patients, antigen specific in vitro proliferation indicate a definitive role of CD8+ T-cells in TB pathogenesis. Production of IFN-γ and TNF-α by CD8+ T-cells in response to mycobacterial antigens such as, ESAT-6 by CD8+ T-cells derived from pleural fluid of patients suffering from TB pleural effusion have substantiated the role of CD8+ T-cells in the immunity of TB (39). The CD8+ T-cells most probably play an important role in killing the Mycobacterium tuberculosis infected target cells initially by [i] TNF receptor superfamily, member 6 [FAS] independent granule exocytosis pathway releasing lytic molecules such as granulysin (40) and subsequently by [ii] FAS-FAS ligand dependent apoptosis of the infected target cells (41). Interestingly, CD8+ T-cells from household contact of TB patients demonstrated significantly better control of bacillary growth within autologous alveolar macrophages, whereas CD8+ T-cells from the contacts of unexposed subjects failed to do so. Probably, circulating antigen specific CD8+ effector T-cells expand after exposure to Mycobacterium tuberculosis and are recruited to the local site[s] of inflammation in the lungs to play an important role during initial infection (42). This observation may have implications for vaccine development. In addition to the activation of macrophages by secreted cytokines, particularly IFN-γ, recent evidences indicate that CD8+ T-cells can kill mycobacteria directly through the cytotoxic T-lymphocyte [CTL] activity (43). Therefore, a direct role of CTL in host immunity against TB, in addition to their macrophage activating property is well established. However, their precise function still remains to be elucidated.

CYTOKINES, CHEMOKINES AND GRANULOMA FORMATION As discussed previously, granuloma formation is the most important immunopathologic hallmark representing immune response containing the infection with Mycobacterium tuberculosis. Generation of effector T-cells capable of producing pro-inflammatory cytokines that can activate macrophages is one critical element in the process of granuloma formation. These cells are generated through priming of resting memory T-cells by captured antigens presented on the surface of antigen presenting cells [APCs] in the draining lymphoid tissues and then released into the peripheral compartment. Following this, what is critically required is their selective recruitment at the site[s] of bacillary invasion. Homing of effector and various other T-cell subsets is mediated by active process of well orchestrated trafficking of T-cells mediated by the groups of molecules, such as selectins, adhesion molecules and chemokines. Chemokines [chemotactic cytokines] are largely responsible for such well organized recruitment of T-cells involved in the granuloma formation (44). A number of chemokines have been found to be involved in TB. The IL-8 was found to be produced by macrophages infected with Mycobacterium tuberculosis (45) and this could be blocked by neutralising antibodies against TNF-α and IL-1β, suggesting that IL-8 production was under the control of these cytokines and is produced early in TB (46). Patients with TB showed higher IL-8 levels in their peripheral blood and BAL fluid (47). Another critical chemokine in TB and granuloma formation is monocyte chemoattractant protein 1 [MCP-1] which is produced by monocyte/macrophage and attracts the same (48). In murine models, deficiency of MIP1-α inhibited the granuloma formation (49). Moreover, MIP1-α level was noted to be significantly elevated in the serum, BAL and pleural fluids in patients with TB. All these observations indicate an important role of this chemokine in human TB (50). Expression of RANTES, an important chemokine responsible for recruitment of T-cells particularly the Th1 like cells, is also increased in serum and pleural fluid of TB patients. Apart from these several other chemokines such as MIP1α and MIP1-β, Mig, IP-10 and interferon-inducible T-cell alpha chemoattractant [ITAC] are all found to be elevated in TB patients, particularly at the local disease site[s] such

Immunology of Tuberculosis 117 as pleural effusion (35). All these chemokines are known to facilitate recruitment of Th1 like effector T-cells via their binding to the chemokine receptors such as CCR5 and CXCR3 preferentially expressed on them. These Th1 cell recruiting chemokines are induced on endothelial cells and macrophages, by the initial pathologic onslaught and help trapping the Th1 cell preferentially expressing their respective receptors, following which T-cells permeate through vascular barrier and migrate toward the site of pathology under the influence of chemokine gradient formed at the site of bacillary invasion. Inhibition of these chemokines may impair the granuloma formation. However, due to redundancy of chemokine system, the function of a given chemokine can be replaced by another member of the chemokine family, thus making it difficult to define the precise role of an individual chemokine in TB. Recent investigations in TB pleural effusion patients demonstrated that some of the chemokine receptor and/or chemokines can play a definitive hierarchical role in selective recruitment of Th1 cells at the disease site[s] and delineating such interaction is critical in designing molecular immunotherapeutic strategies. It was found that CXCR3 - ITAC interaction was dominant in selective recruitment of IFN-γ producing Th1 cells in addition to RANTES –CCR5 and CD11a – ICAM interactions. Interestingly, expression of many of these chemokine receptors on the T-cells and adhesion molecules on the endothelium is influenced by TNF-α-the importance of which in TB immunity is well established. FINE T-CELL SUBSETS WITH AN IMMUNOREGULATORY ROLE These are regarded as non-classical T-cells in the sense that they either bear non-conventional T-cell receptors [TCRs] or do not recognize the antigens in context of classical MHC gene products [MHC non-restricted] and exert an immunoregulatory influence on rest of the T-cells including the effector T-cells. Important among them include γδ T-cells [Tγδ-cells], NK-cells and the regulatory T-cells [Treg-cells]. γδ T-cells In contrast to the T-cells expressing TCRs comprising of α-β heterodimer, these cells bear functional TCRs on their surface made of heterodimer of γ-δ chains. They are

usually represented in the peripheral blood in a relatively low frequency, less than 10 per cent of total circulating T-cell population. Recent data support their role in the host response to human TB. Although mice with severe combined immunodeficiency fail to form granuloma in response to challenge with BCG and succumb to death, they can survive such challenge when engrafted with syngenic lymph node cells depleted of αβ T-cells, suggesting an important role for Tγδ-cells (51). Recent data in patients also substantiate a possible role of γδ T-cells in TB. Mycobacterium tuberculosis reactive Tγδ-cells are increased in the peripheral blood of tuberculin positive healthy contacts (52,53). Increase in the Tγδ-cells [20% to 30%] was noted in the peripheral blood of patients with a strong immune reactivity compared to the patients with disseminated forms of TB, such as extensive pulmonary or miliary TB. Depletion of Tγδ-cells results in less wellformed granulomas and increased infiltration of neutrophils. This indicates that Tγδ-cells are recruited quite early in the infection with Mycobacterium tuberculosis and direct the granuloma formation. Disappearance of Tγδ-cells from the peripheral blood of TB patients may be explained by their early recruitment at the disease site[s] and FAS-FAS ligand mediated apoptosis. Natural Killer T-cells Natural killer T-cells are non-conventional in the sense that they bear cell surface markers distinctive of NK-cells in addition to functional TCR. They represent a subset of T-cells with a distinct lineage and not restricted by MHC. They recognize lipid antigens in context of MHC like but relatively less polymorphic CD1 molecules (54). The CD1 molecules are sub-grouped into group I consisting of CD1a, b and c whereas CD1d is the only member of group II so far known. The CD1d restricted NKT-cells are heterogeneous in terms of their expression of CD4+/ CD8+ markers and an important subset of NKT-cells uses restricted set of TCR chain pairs, namely Vα.24/Vβ.11. These are called invariant chain NKT-cells [iNKT-cells]. The NKT-cells are one of the earliest T-cells to be triggered in an immune response and are known to produce several immunoregulatory cytokines [IFN-γ, IL4, IL-10, and TGF-β etc.,] in abundance (55). Through these released cytokines, NKT-cells are believed to exert a strong regulatory effect on the effector T-cell response. The first reported non-protein mycobacterial antigen was

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mycolic acid. Several other lipid antigens of mycobacteria such as LAM, phosphatidyl inositol manoside [PIM], glucose monomycolate and isoprenoid glycolipids have been found to be recognized by NKT-cells when presented by CD1d molecules. Heterogeneity of NKTcells in terms of release of either Th1 driving IFN-γ or Th2 driving IL-4 or immunosuppressive IL-10 and TGFβ determines the influence that NKT-cell subsets may impose on the bulk T-cell responses. Selective expansion and/or activation of NKT-subset[s] may dictate their immunoregulatory role. Expansion and preferential homing of iNKT-cells have been documented in granuloma formation. In addition to their prompt cytokine releasse, NKT-cells exhibit a potent cytolytic activity both by perforin/granzyme and FAS-FAS ligand dependent mechanisms. Cytotoxic NKT-cells may be relevant in immunity against intracellular microorganism including Mycobacterium tuberculosis [Figure 7.3] (54,55). Treg-Cells Recent experimental evidences strongly suggest the existence and role of a unique subset of T-cells with

capability of suppressing the other T-cells through contact dependent as well as contact independent cytokine mediated pathways. These cells with immunosuppressive characteristics are known as Treg-cells [Figure 7.3]. The Treg activity, which is defined by their functional suppressive properties, has been found to be enriched within CD4+ T-cells constitutively expressing CD25 [IL-2 receptor α chain]. However, not all the CD4+ CD25+ T-cells function as Treg indicating that a precise phenotype of Treg is still awaited. Recent reports strongly indicate that forkhead/winged helix transcription factor of scurfin family, Foxp3 behaves like a master transcription factor essential for development of Treg cells and has been proposed and remains till date as the most reliable marker for Treg-cells (56). The CD4+ CD25+ Foxp3+ cells are maximally [but not completely] enriched for Treg activity. The Treg-cells express CTLA4, which can induce negative signalling through CD80/CD86 costimulatory molecules expressed on the effector T-cells, via contact dependent mechanism. In addition, Treg can secrete a battery of suppressive cytokines such as IL-10, TGF-β which may be responsible for their suppressive

Figure 7.3: Orchestration of effector immune component in building up response against Mycobacterium tuberculosis. Priming of T-cells for effector functions requires recognition by activated macrophages with stimulation by a battery of potentiating cytokines [IL-12, IL-6, IL-1β etc.,] released by the infected macrophages. The response of effector T-cells will decide the extreme/polarity of upcoming disease pathogenesis. Regulatory T-cells [CD4+CD25+FoxP3+ T-cells, natural killer T-cells etc.,] can also modulate the protective effector T cell responses either in a contact dependent/independent way IFN-γ = interferon-γ; TNF-α = tumour necrosis factor-α; IL = interleukin; TGF-β = transforming growth factor-β; TCR = T-cell receptor; NKT = natural killer T-cells; RNI = reactive nitrogen intermediates; ROI = reactive oxygen intermediates; MΦ = macrophage; DC = dendritic cell

Immunology of Tuberculosis 119 effect on activated T-cells. Immunosuppression by Tregcells essentially requires [i] their expansion and [ii] a preferential recruitment at the pathologic sites where they are supposed to suppress the T-cells. The Treg-cells have been shown to express on their surface a battery of chemokine receptors such as CCR1 and CCR4 that help their recruitment. The Treg-cells also express TLR2 (57,58) and TLR4 (59) which can bind to diverse mycobacterial pattern recognition molecules like lipids. Recent reports suggest that TLR2 engagement with mycobacterial component[s] may eliminate Treg-cells thereby stimulating a Th1 response, while TLR4 engagement results in persistent expansion and activation of Treg cells thus, causing immunosuppression (59). The role of Treg in human TB has been elegantly demonstrated. Frequency of Treg is increased in the peripheral blood of patients with disseminated form of TB, such as miliary TB. Their frequency was found to be even more in BAL fluid when compared to that of the peripheral blood of the same patients. This is strongly suggestive of selective homing or enrichment of Treg-cells at the pathologic site. Recently, it has been demonstrated that a greater number of Treg-cells were recruited into the lung in patients with miliary TB compared with effector T-cells (60). These Treg-cells suppressed the autologous T-cell response to Mycobacterium tuberculosis through release of IL-10. These findings strongly indicate the role of Treg-cells in modulating the local immune response at the pathological site of TB (60). Further studies are required to substantiate their immunoregulatory role in human TB which shows a remarkable variation in its clinical manifestation. Also critical is to understand the phenomenon of their preferential trafficking to the disease site and capability to modulate the local pathology of TB and the extent of the disease. Delineation of the finer details of Treg-cell biology among TB patients may offer unique molecular therapeutic modalities. IMMUNE EVASION BY MYCOBACTERIUM TUBERCULOSIS Mycobacterium tuberculosis can evade and subvert various immune mechanisms adopted by the host to either eradicate or eliminate the infection. Even during the phase of latency the bacilli use various immune evasion strategies to circumvent the effective host immune response that generally contains the infection but fails to eradicate them [Figure 7.4]. Clearly, such containing

immune mechanisms are effective as any disruption in these results in reactivation of the persistent dormant infection, for example, in HIV infection. The ability of Mycobacterium tuberculosis to survive the immune response clearly indicates existence of series of immune evasion mechanism[s]. Mycobacteria are capable of producing ammonia and sulphatides which inhibit the fusion between phagosomes with lysosomes. In addition, ammonia prevents alkalization of intralysosomal contents thus, diminishing the lytic potency of the fused phagolysosomes. Inefficient phagolysosomes fail to process the mycobacterial antigens and their presentation to the cognate T-cells. This in turn fails to stimulate repertoire of T-cells optimally leading to weak or no immunity against the pathogen. Interestingly, cholesterol mediates the phagosomal association of tryptophan aspartate-containing coat protein [TACO] and prevents their fusion with lysosomes. Also by retaining TACO and intercepting the phagolysosomal fusion mycobacteria trigger their evasion mechanisms. Lack of TACO expression on the Kupffer cells of the liver may be responsible to the well-known resistance of liver to infection by Mycobacterium tuberculosis (61). Mycobacterium tuberculosis infected macrophages are relatively ineffective at optimally triggering the T-cell proliferation and cytokine production. Down-regulation of HLA class II expression has been noted among the infected macrophages (62). Infected macrophages are also known to secrete immunosuppressive cytokines such as IL-10 and TGF-β (63). Experimental evidences suggest that Mycobacterium tuberculosis infected macrophages are relatively refractory to the effects of IFN-γ, which is a key mediator in macrophage activation. Recent studies suggest that recognition of mycobacterial antigens by TLR2 and TLR4 differentially regulates either pro- or antiinflammatory cytokine production by macrophages and through these cytokines can suppress the immune recognition. Moreover, mycobacterial interaction with TLR2 and TLR4 can differentially expand or eliminate the Treg-cells which suppress the effector T-cells (64). All these mechanism[s] help the ingested bacilli either to silence or to evade the immune effector function of the host and help the pathogen survival. IMMUNOMODULATORS IN TUBERCULOSIS An extensive role of host immunity in protection, containment and pathogenesis of TB and its molecular understanding has generated a great interest in immunomodu-

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Figure 7.4: Comparative chart showing different components of immune system involved in various stages of infection with Mycobacterium tuberculosis; primary infection, latency and active disease/pathology. In first exposure, weak host immune status facilitates the survival and expansion of bacilli and helps in establishment of infection due to delayed immune recognition [primary infection]. The delayed immune recognition caused by several immune-escape mechanisms adapted by bacilli, develops low level of immunity helping in establishment of infection. Later on, ensuing effector immune response dictates the disease course. Firstly, protective and eradicative immune response helps in containment of bacilli leading to persistence of bacilli without any sign of pathology [latent infection]. The tight balance of pro- and anti-inflammatory factors in restricting the bacilli below a threshold number are the major characteristics of latent infection. Secondly, a non-optimal [excessive and sub-optimal] immune response developed by host against bacilli may lead to the two extremes/poles of the disease: [i] contained disease; and [ii] disseminated disease. Excessive or strong immune response facilitates clearance of bacilli and disease is contained or localized. In this form, the pathology is mostly associated with Th1 like response. On the other hand, disseminated disease is characterized by Th2 associated weak immune response resulting in bacillary spread TNF-α = tumour necrosis factor-α; IFN-γ = interferon-γ; IL = interleukin; Treg = regulatory T-cells; Teff = effector T-cells; ↑ = increased; ↓ = decreased

latory approaches for the disease intervention. This is more true in the face of development of MDR-TB and challenges imposed by dual infection with HIV and Mycobacterium tuberculosis. Several newer approaches to block certain key molecules responsible for tissue destruction are gaining attentions for molecular therapy. Proinflammatory cytokines like TNF-α may be a target for healing of cavitary TB, while TGF-β is thought to be a good candidate for prevention of fibrosis, as it helps development of fibrotic lesions (63). Role of various other cytokines in the pathogenesis of TB makes them potential targets for intervention. Recent data support the role of aerosolized IFN-γ in disease resolution among patients with MDR-TB. Granulocyte, monocyte- colony stimulat-

ing factor [GM-CSF] has also been used simultaneously with IFN-γ (65). Daily low dose administration of recombinant IL-2 has been found to activate the immune system and may enhance the effect of the drugs in patients suffering from MDR-TB (66). Recent data on the role of chemokines and their receptors in selective homing of inflammatory Th1 like cells in TB has opened a new avenue to modulate the immune response by controlling selective recruitment of specific subset[s] of T-cells including the regulatory T-cells [NKT- and Tregcells] to the pathologic site[s]. Molecular strategies to modulate the immune response by means of changing the balance of cytokines and chemokines involved in TB are new fields and require further investigations.

Immunology of Tuberculosis 121 Several agents have provoked interest as candidate adjuvant therapeutic elements. Heat killed preparation of other mycobacteria such as Mycobacterium vaccae (67) and Mycobacterium w have been co-administered with standard chemotherapy to enhance the immune response. It has been proposed that immunopotentiation by such adjuvant therapeutic vaccination may promote Th1 immunity while acting simultaneously with the drugs. Thalidomide and pentoxyfylline have been found to rescue the patients from excessive effect of TNF-α (68). Other agents like levamisole, inhibitors of IL-12, IFN-α have also been used in TB. However, further studies are required to confirm their definite therapeutic role. So far immunity in TB is concerned, a major emphasis has been placed on the T-cell mediated cellular responses. Role of B-cells and antibodies in TB failed to draw much serious emphasis except for immunodiagnostic purposes. The B-cells and their effector molecules like antibodies have so far been ignored in terms of immunopathogenesis of TB. However, recent studies of the role of B-cell subsets and various classes of antibodies produced by them in dictating the early events such as T-cell recruitment at the site of delayed type hypersensitivity reaction clearly points to their critical role in the early phase of T-cell mediated immune response. Emerging evidences support a definitive role of B-cells in immunity against TB and requires further attention of the investigators in the field. REFERENCES 1. Lurie MB. Resistance to tuberculosis: experimental studies in native and acquired defense mechanism. Cambridge: Harvard University Press; 1964. 2. Cooper AM, Callahan JE, Keen M, Belisle, JT, Orme IM. Expression of memory immunity in lung following reexposure to M.tuberculosis. Tubercle Lung Dis 1997;78:6773. 3. North RJ, LaCourse R, Ryan L. Vaccinated mice remain more susceptible to M.tuberculosis infection initiated via the respiratory route than via intravenous route. Infect Immun 1999;76:2010-2. 4. van Crevel R, Ottenhoff TH, van der Meer JW. Innate immunity to Mycobacterium tuberculosis. Clin Microbiol Rev 2002;15:294-309. 5. Schlesinger LS, Bellinger-Kawahara CG, Payne NR, Horwitz MA. Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement component C3. J Immunol 1990;144:277-80. 6. Schlesinger LS. Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated

7.

8. 9.

10.

11.

12.

13.

14.

15.

16. 17.

18.

19.

20.

21.

by mannose receptors in addition to complement receptors. J Immunol 1993;150:2920-30. Bermudez LE, Goodman J. Mycobacterium tuberculosis invades and replicates within type II alveolar cells. Infect Immun 1996;64:1400-6. Orme IM, Cooper AM. Cytokine/chemokine cascade in immunity to tuberculosis. Immunol Today 1999; 20:307-12. Bergeron A, Bonay M, Kambouchner M, Lecossier D, Riquet M, Soler P, et al. Cytokine patterns in tuberculosis and sarcoid granulomas: correlation with histopathologic features of the granulomatous response. J Immunol 1997;159:3034-43. Hoheisel G, Izbicki G, Roth M, Chan CH, Leung JC, Reichenberger F, et al. Compartmentalisation of proinflammatory cytokines in tuberculous pleurisy. Respir Med 1998;92:14-7. Casarini M, Ameglio F, Alemanno L, Zangrilli P, Mattia P, Paone G, et al. Cytokine levels correlate with a radiologic score in active pulmonary tuberculosis. Am J Respir Crit Care Med 1999;159:143-8. de Jong R, Altare F, Haagen IA, Elferink DG, Boer T, van Breda Vriesman P, et al. Severe mycobacterial and Salmonella infection in interleukin-12 receptor deficient patients. Science 1998; 280:1435-8. Sugawara I, Yamada H, Kaneko H, Mizuno S, Takeda K, Akira S. Role of IL-18 in mycobacterial infection in IL-18 gene disrupted mice. Infect Immun 1999;67:2585-89. Vankayalapati R, Wizel B, Weis SE, Samten B, Girard WM, Barnes PF. Production of interleukin-18 in human tuberculosis. J Infect Dis 2000;182:234-9. van Crevel R, Ottenhoff TH, van der Meer JW. Innate immunity to Mycobacterium tuberculosis. Adv Exp Med Biol 2003;531:241-7. Flynn JL, Chan J. Tuberculosis: latency and reactivation. Infect Immun 2001;69:4195-201. Boussiotis VA, Tsai EY, Yunis EJ, Thim S, Delgado JC, Dascher CC, et al. IL-10 producing T cells suppress immune responses in anergic tuberculosis patients. J Clin Invest 2000;105:131725. Hernandez-Pando R, Orozco H, Sampieri A, Pavon L, Velasquillo C, Larriva Sahd J, et al. Correlation between the kinetics of Th1/Th2 cells and pathology in a murine model of experimental pulmonary tuberculosis. Immunology 1996;89:26-33. Sánchez FO, Rodríguez JI, Agudelo G, García LF. Immune responsiveness and lymphokine production in patients with tuberculosis and healthy controls. Infect Immun 1994;62:56738. Sharma SK, Mitra DK, Balamurugan A, Pandey RM, Mehra NK. Cytokine polarisation in miliary and pleural tuberculosis. J Clin Immunol 2002;22:345-52. Toossi Z, Gogate P, Shiratsuchi H, Young T, Ellner JJ. Enhanced production of TGF-beta by blood monocytes from patients with active tuberculosis and presence of TGF-beta in tuberculous granulomatous lung lesions. J Immunol 1995;154:465-73.

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22. Toossi Z, Ellner JJ. The role of TGF beta in the pathogenesis of human tuberculosis. Clin Immunol Immunopathol 1998;87:107-14. 23. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O’Riordan J, Stanford J. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 1986;57:159-63. 24. Zwilling BS, Kuhn DE, Wikoff L, Brown D, Lafuse W. Role of iron in Nramp1-mediated inhibition of mycobacterial growth. Infect Immun 1999;67:1386-92. 25. Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med 1998;338:6404. 26. Cooper AM, Segal BH, Frank AA, Holland SM, Orme IM. Transient loss of resistance to pulmonary tuberculosis in p47phax mice. Infect Immun 2000;68:1231-4. 27. Winkelstein JA, Marino MC, Johnston RB, Boyle J, Curnutte J, Gallin JI, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine [Baltimore] 2000;79:155-69. 28. Nozaki Y, Hasegawa Y, Ichiyama S, Nakashima I, Shimokata K. Mechanism of nitric oxide-dependent killing of Mycobacterium bovis BCG in human alveolar macrophages. Infect Immun 1997;65:3644-7. 29. Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis 2005;5:415-30. 30. Adams D. The structure of mononuclear phagocytes differentiating in vivo: I. Sequential fine and histologic studies of the effect of bacillus Calmette-Guerin [BCG]. Am J Pathol 1974;76:17-48. 31. Keane J, Balcewicz-Sablinska MK, Remold HG, Chupp GL, Meek BB, Fenton MJ, et al. Infection by Mycobacterium tuberculosis promotes human alveolar macrophage apoptosis. Infect Immun 1997;65:298-304. 32. Lopez Ramirez GM, Rom WN, Ciotoli C, Talbot A, Martiniuk F, Cronstein B, et al. Mycobacterium tuberculosis alters expression of adhesion molecules on monocytic cells. Infect Immun 1994;62:2515-20. 33. Bean AG, Roach DR, Briscoe H, France MP, Korner H, Sedgwick JD, et al. Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J Immunol 1999;162:3504-11. 34. Chang JC, Wysocki A, Tchou-Wong KM, Moskowitz N, Zhang Y, Rom WN. Effect of Mycobacterium tuberculosis and its components on macrophages and the release of matrix metalloproteinases. Thorax 1996;51:306-11. 35. Mitra DK, Sharma SK, Dinda AK, Bindra MS, Madan B, Ghosh B. Polarised helper T cells in tubercular pleural effusion: phenotypic identity and selective recruitment. Eur J Immunol 2005;35:2367-75. 36. Law KF, Jagirdar J, Weiden MD, Bodkin M, Rom WN. Tuberculosis in HIV-positive patients: cellular response and

37.

38.

39.

40.

41.

42. 43.

44.

45.

46.

47.

48.

49.

immune activation in the lung. Am J Respir Crit Care Med 1996;153:1377-84. Zhang M, Gately MK, Wang E, Gong J, Wolf SF, Lu S, et al. Interleukin 12 at the site of disease in tuberculosis. J Clin Invest 1994;93:1733-9. Flynn JL, Goldstein MM, Triebold KJ, Bloom BR. Major histocompatibility complex class I-restricted T cells are necessary for protection against M. tuberculosis in mice. Infect Agents Dis 1993;2:259-62. Carranza C, Juarez E, Torres M, Ellner JJ, Sada E, Schwander SK. Mycobacterium tuberculosis growth control by lung macrophages and CD8 cells from patient contacts. Am J Respir Crit Care Med 2006;173:238-45. Canaday DH, Ziebold C, Noss EH, Chervenak KA, Harding CV, Boom WH. Activation of human CD8+ alpha beta TCR+ cells by Mycobacterium tuberculosis via an alternate class I MHC antigen-processing pathway. J Immunol 1999;162:3729. Canaday DH, Wilkinson RJ, Li Q, Harding CV, Silver RF, Boom WH. CD4+ and CD8+ T cells kill intracellular M. tuberculosis by a perforin and Fas/Fas ligand-independent mechanism. J Immunol 2001;167:2734-42. Lazarevic V, Flynn J. CD8+ T cells in tuberculosis. Am J Respir Crit Care Med 2002;166: 1116-21. Stenger S, Mazzaccaro RJ, Uyemura K, Cho S, Barnes PF, Rosat JP, et al. Differential effects of cytolytic T cell subsets on intracellular infection. Science 1997;276:1684-7. Nau GJ, Guilfoile P, Chupp GL, Berman JS, Kim SJ, Kornfeld H, et al. A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis. Proc Natl Acad Sci USA 1997;94:6414-9. Juffermans NP, Verbon A, van Deventer SJ, van Deutekom H, Belisle JT, Ellis ME, et al. Elevated chemokine concentrations in sera of human immunodeficiency virus [HIV]seropositive and HIV-seronegative patients with tuberculosis: a possible role for mycobacterial lipoarabinomannan. Infect Immun 1999;67:4295-7. Zhang Y, Broser M, Cohen H, Bodkin M, Law K, Reibman J, et al. Enhanced interleukin-8 release and gene expression in macrophanges after exposure to Mycobacterium tuberculosis and its components. J Clin Invest 1995;95:586-92. Sadek MI, Sada E, Toossi Z, Schwander SK, Rich EA. Chemokines induced by infection of mononuclear phagocytes with mycobacteria and present in lung alveoli during active pulmonary tuberculosis. Am J Respir Cell Mol Biol 1998;19:513-21. Kasahara K, Tobe T, Tomita M, Mukaida N, Shao Bo S, Matsushima K, et al. Selective expression of monocyte chemotactic and activating factor/monocyte chemoattractant protein1 in human blood monocytes by Mycobacterium tuberculosis. J Infect Dis 1994;170:1238-47. Lu B, Rutledge BJ, Gu L, Fiorillo J, Lukacs NW, Kunkel SL, et al. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med 1998;187:601-8.

Immunology of Tuberculosis 123 50. Kurashima K, Mukaida N, Fujimura M, Yasui M, Nakazumi Y, Matsuda T, et al. Elevated chemokine levels in bronchoalveolar lavage fluid of tuberculosis patients. Am J Respir Crit Care Med 1997;155:1474-7. 51. Munk ME, Gatrill AJ, Kaufmann SH. Target cell lysis and IL2 secretion by gamma/delta T lymphocytes after activation with bacteria. J Immunol 1990;145:2434-9. 52. North RJ, Izzo AA. Granuloma formation in severe combined immunodeficient [SCID] mice in response to progressive BCG infection: tendency not to form granulomas in the lung is associated with faster bacterial growth in this organ. Am J Pathol 1993;142:1959-66. 53. Barnes PF, Grisso CL, Abrams JS, Band H, Rea TH, Modlin RL. Gamma delta T lymphocytes in human tuberculosis. J Infect Dis 1992;165:506-12. 54. Schaible UE, Kaufmann SH. CD1 and CD1-restricted T cells in infections with intracellular bacteria. Trends Microbiol 2000;8:419-25. 55. Ulrichs T, Porcelli SA. CD1 proteins: targets of T cell recognition in innate and adaptive immunity. Rev Immunogenet 2000;2:416-32. 56. Mendez S, Reckling SK, Piccirillo CA, Sacks D, Belkaid Y. Role for CD4[+] CD25[+] regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity. J Exp Med 2004;200:201-10. 57. Sutmuller RP, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ, et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 2006;116:48594. 58. Liu H, Komai-Koma M, Xu D, Liew FY. Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci USA 2006;103:7048-53. 59. Caramalho I, Lopes-Carvalho T, Ostler D, Zelenay S, Haury M, Demengeot J. Regulatory T cells selectively express tolllike receptors and are activated by lipopolysaccharide. J Exp Med 2003;197:403-11.

60. Sharma PK, Saha PK, Singh A, Sharma SK, Ghosh B, Mitra DK. FoxP3+ regulatory T cells suppress effector T cell function at pathologic site in miliary tuberculosis. Am J Respir Crit care Med 2008 [in press]. 61. Collins HL, Kaufmann SH. The many faces of host responses to tuberculosis. Immunology 2001;103:1-9. 62. Hmama Z, Gabathuler R, Jefferies WA, Dejong G, Reiner NE. Altenuation of HLA-DR expression by mononuclear phagocytes infected with Mycobacterium tuberculosis is related to intracellular sequestration of immature class II heterodimers. J Immunol 1998;161:4882-93. 63. Hirsch CS, Hussain R, Toossi Z, Dawood G, Shahid F, Ellner JJ. Cross-modulation by transforming growth factor beta in human tuberculosis: suppression of antigen-driven blastogenesis and interferon gamma production. Proc Natl Acad Sci USA 1996;93:3193-8. 64. Chang J, Huggett JF, Dheda K, Kim LU, Zumla A, Rook GA. Mycobacterium tuberculosis induces selective up-regulation of TLRs in the mononuclear leukocytes of patients with active pulmonary tuberculosis. J Immunol 2006;176:3010-8. 65. Etemadi A, Farid R, Stanford JL. Immunotherapy for drugresistant tuberculosis. Lancet 1992;340:1360-1. 66. Raad I, Hachem R, Leeds N, Sawaya R, Salem Z, Atweh S. Use of adjunctive treatment with interferon-gamma in an immunocompromised patient who had refractory multidrugresistant tuberculosis of the brain. Clin Infect Dis 1996;22:5724. 67. Johnson JL, Nunn AJ, Fourie PB, Ormerod LP, Mugerwa RD, Mwinga A, et al. Effect of Mycobacterium vaccae [SRL172] immunotherapy on radiographic healing in tuberculosis. Int J Tuberc Lung Dis 2004;8:1348-54. 68. Strieter RM, Remick DG, Ward PA, Spengler RN, Lynch JP, Larrick J. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem Biophys Res Commun 1988;155:1230-6.

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Genetic Susceptibility Parameters in Tuberculosis

8

NK Mehra, Meenakshi Singh

INTRODUCTION Tuberculosis [TB] is no longer restricted to developing nations, since it has now returned to industrialized countries due to the acquired immunodeficiency syndrome [AIDS] epidemic and the emergence of multidrugresistant strains of Mycobacterium tuberculosis (1). Most people exposed to TB develop effective immunity against the invading bacillus and do not develop disease. A strong host genetic influence has been proposed to be an important factor for the development of disease in a limited percentage of the population in a hyperendemic area. Evidence supporting the role of genetic factors influencing susceptibility or resistance to TB includes differences in the development of infection and disease among various human racial groups (2,3) and animal strains (4,5) concordance of the disease in monozygotic twins (6,7) and familial occurrence of the disease. Clinical manifestations of pulmonary TB are due to delayed type hypersensitivity [DTH] reaction against the Mycobacterium tuberculosis rather than direct damage caused by the bacillus. Thus, the final outcome of the disease is the result of interaction between the bacillus and host genes that govern immune response. Susceptibility to TB is multifactorial. Host genetic factors explain partly why some people are resistant and others susceptible to infection. Rare gene disruptions cause fatal vulnerability to certain pathogens, but more subtle differences are common and arise from minor variations in many genes. To predict how much our genetic make up determines the different ways in which we respond to some infectious agents is a difficult task. This is especially because of the many contributory

factors, such as previous health status, acquired immunity and variability in the pathogen. Analysis of the genetic basis of susceptibility to major infectious diseases is potentially a most complex area. Many immunogenetic loci influence susceptibility to several infectious agents. A genetic basis for inter-individual variation in susceptibility to human infectious disease is also explained through candidate gene studies (8). The goal of identification of host genetic factors that underlie susceptibility to TB can be approached by two ways: [i] candidate gene studies can be carried out on genes of known function that have a possible biological role in the control of infection or disease; and [ii] a second approach utilizes a non-targetted genome-wide linkage analysis, in which increased sharing of chromosomal regions by affected individuals leads to identification of positional candidates. Recently, development of high throughput genotyping technologies and identification of thousands of polymorphic microsatellite markers has led to the identification of genes [candidate] not previously associated with the disease. A better understanding of the disease mechanisms and of host-pathogen interplay could help to identify people at high or low risk of infection and provide a basis for early diagnosis and pre-emptive treatment of susceptible individuals [Table 8.1]. In this chapter, the role of genetic as well as non-genetic factors in influencing the incidence of TB in a population is discussed. HOST IMMUNE RESPONSE AGAINST MYCOBACTERIUM TUBERCULOSIS Mycobacterium tuberculosis is a classic example of a pathogen for which the protective response relies on cell-

Genetic Susceptibility Parameters in Tuberculosis 125 Table 8.1: Genetic susceptibility to infectious diseases Certain individuals appear to be predisposed to infections; others are protected By studying the immune response and the genetic make-up of these individuals one can get a better understanding of disease mechanism and of host-pathogen interplay in various diseases Detecting genetic susceptibility facilitates identification of those at high/low risk of certain deadly infections Genetic susceptibility data may form a basis for early diagnosis and institution of pre-emptive treatment for susceptible individuals Ideas for rational, genetically targeted approaches to disease prevention or effective intervention can be derived

mediated immunity. This is because the pathogen resides primarily in a vacuole within the macrophage and thus, the major histocompatibility complex [MHC] class II presentation of mycobacterial antigens to CD4+ T-cells is an obvious outcome of infection. It is well documented that people with defective T-cell responses are at higher risk for developing primary or reactivation TB. The interaction of T-cells and infected macrophages is central to development of protective immunity to Mycobacterium tuberculosis. The CD4+ T-cells have an essential role but are supported by other T-cell subsets such as CD8+, γδ T-cell receptor [TCR] positive T-cells [γδ T-cells], and CD1 restricted T-cells. Tuberculosis granuloma contains both CD4+ and CD8+ T-cells that predominantly participate in the antipathogenic response to contain the infection within the granuloma and inhibit reactivation (9,10). Mycobacteria-specific CD4+ T-cells are typically of the Th1 type, in that they are potent interferon-γ [IFN-γ] producers. The IFN-γ plays a central role in the activation of anti-mycobacterial activities of macrophages, which makes it crucial for protection against TB. The Th2 cytokines, such as interleukin-4 [IL-4] and interleukin-10 [IL-10] are scarce, though not fully absent (11). Apoptosis or lysis of infected cells by CD4+ T-cells may also play a role in controlling infection. In recent years, CD8+ T-cells specific for mycobacterial antigens have been isolated from the infected hosts, which point towards their emerging role in anti-Mycobacterium tuberculosis response. The CD8+ T-cells, like CD4+ T-cells, can produce IFN-γ, but their main function is target cell killing via perforin and granzyme or tumour necrosis factor receptor superfamily, member 6 - tumour necrosis factor receptor superfamily, member 6 ligand [FAS-FASL] pathway.

The CD8+ T-cells are non-classically restricted by CD1 molecules. These are non-polymorphic antigen presenting molecules having structural similarities to MHC Class I molecules. However, the antigen-binding groove of CD1 is much deeper and more hydrophobic than that of MHC class I or II molecules. In contrast to the peptide epitopes presented by MHC class I molecules, CD1 present lipids or glycolipids to T-cells (12). A recent study provided the first evidence of a recall T-cell response to a CD-restricted antigen in Mycobacterium tuberculosis exposed purified protein derivative [PPD] positive subjects. Peripheral blood mononuclear cells [PBMCs] from these subjects proliferated in response to an isoprenoid glycolipid in contrast to those from PPDnegative subjects, and this proliferation was inhibited by anti-CD1c antibody (13). Effector functions of CD1 restricted CD8+ T-cells include IFN-γ production and cytotoxic activity, but the target of these cells may not be the macrophages. The differentiation of T-lymphocytes during immune priming over the course of disease progression is promoted by the cytokine milieu of the host, which includes IL-4, interleukin-6 [IL-6], IL-10, interleukin-12 [IL-12], and interleukin-18 [IL-18], among others. Although the central role of IFN-γ in the control of Mycobacterium tuberculosis is beyond doubt, other cytokines, in particular tumour necrosis factor-α [TNF-α], transforming growth factor-β [TGF-β] participate by regulating the formation and maintenance of the structural integrity of granulomas, (14-21), thus influencing the pathology and disease course. Mycobacterium tuberculosis infected macrophages appear to be diminished in their ability to present antigens to CD4+ T-cells, which would contribute to the inability of the host to eliminate a persistent infection. One mechanism by which Mycobacterium tuberculosis might inhibit recognition of macrophages by CD4+ Tcells is by down-regulation of the cell surface expression of MHC class II molecules. Another mechanism by which antigen presenting cells [APCs] contribute to defective T-cell stimulation may be through production of cytokines, including TGF-β (20,22), IL-6 (21), or IL-10 (22,23). Production of these cytokines by infected macrophages can directly and indirectly affect T-cell proliferation and function. It is now recognized that CD4+, CD25+ regulatory T- cells [Tregs] play a central role in the prevention of autoimmunity and in the control of immune responses

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by down-regulating the function of effector CD4+ or CD8+ T-cells. The role of Tregs in the context of TB infection and persistence is, however, inadequately documented. A recent report indicates that the number of Treg cells increase in the blood or at the site of infection in patients with active TB (24). This suggests that the presence of Treg cells may limit the immunopathology and suppress cellular immune responses in patients with TB. Emerging evidence suggests that the human Toll-like receptors [TLRs] also play an important role in the activation of innate immunity by Mycobacterium tuberculosis. Human TLRs are transmembrane proteins with a leucine rich repeat in the extracellular domain. Their cytoplasmic constituents are homologous to those of the human interleukin-1 [IL-1] receptor. It appears that distinct mycobacterial components may interact with different members of the TLRs family (25) and that Mycobacterium tuberculosis can signal via both human TLR2 and TLR4 in a ligand-specific manner. The reader is referred to the chapter “Immunology of tuberculosis” [Chapter 7] for further details. NON-GENETIC FACTORS INFLUENCING THE INCIDENCE OF TUBERCULOSIS Demographic Factors The risk of acquiring infections is particularly high between the period of infancy and the early adult age (26), probably because of the compromised or incompetent immunity during the early periods and exposure to newer antigens. In the developing countries, vast majority of cases occur between the ages of 15 and 59 years, economically the most productive individuals in the society. In industrialized countries, on the other hand, TB has been reported mainly in older men (27). The other risk factors including individual lifestyle such as alcoholism and cigarette smoking cause severe morbidity and mortality among TB patients. Due to the inhibitory action of smoke on lung functions, particularly on macrophages and altered immune response in chronic alcoholics, the incidence and severity of pulmonary TB have shown a steady increase in several populations (28). The occupation of an individual is yet another important factor that may predispose to TB. Socio-economic Factors The association between underprivileged sections of the society and TB is well known (29). Poor housing condi-

tions and overcrowding have been reported to foster the development of TB by enhancing the airborne transmission of Mycobacterium tuberculosis from infectious patients to susceptible hosts (30). The disease has been well documented in restricted environments such as nursing homes, prisons and hospices (31). Malnutrition World Health Organization [WHO] estimates have indicated that poor nutritional status might predispose an individual to TB, but, exactly how malnutrition favours the development of the disease is not clear. Presumably, various components of the immune system including T-lymphocyte function and cell-mediated immunity are impaired. It is also not known which dietary elements [proteins, vitamins, micronutrients] are necessary to protect against the occurrence of TB. Recently, experimental studies have provided credence to an important contributory role of protein calorie malnutrition (32). Occupation Workers with silicosis have a greatly increased risk of developing TB, which reflects the fact that respirable silica particles directly impair the function of macrophages, thereby inhibiting their ability to deal with organisms such as mycobacteria (33,34). There is an increased risk of TB development among health care workers due to the concentration of infectious patients in their environment and only prompt diagnosis and initiation of treatment may minimize the risk (35). A recent survey indicates that low socio-economic status and lack of resources are important risk factors for non-adherence to TB treatment in a poor country such as Nepal (36). Alcoholism and Cigarette Smoking Tuberculosis is common in alcoholics, which may be due to the direct effect of alcohol on the host defenses. Mortality and frequency of adverse effects of antituberculosis drugs are higher in patients with cirrhosis of liver who develop active TB. Recent evidence suggests that multidrug regimen used to treat TB could be well tolerated in the situation of pre-existing liver dysfunction, if patients are carefully monitored for side effects (37). Studies have also shown that tobacco smokers are more prone to develop TB than non-smokers (38). The smoke may have inhibitory action on lung defenses, particularly

Genetic Susceptibility Parameters in Tuberculosis 127 on macrophages (27). Smoking thereby affects the clinical manifestations of TB. It has been shown that smokers are more likely to have cough, dyspnoea, chest radiograph appearance of upper zone involvement, cavity and miliary appearance and positive sputum culture but are less likely to have isolated extra-pulmonary involvement than non-smokers (39). Smoking has been found to be associated with both relapse of TB and its mortality. Corticosteroids and Other Immunosuppressive Agents Patients with chronic renal failure or lymphoproliferative disorders receiving steroids or immunosuppressive drug therapy often have suppression of their immune system. Such individuals have an increased likelihood of developing clinical TB (40). Human Immunodeficiency Virus Infection The reader is referred to the chapter “Tuberculosis and human immunodeficiency virus infection” [Chapter 38] for details on this topic. Other Diseases Diseases associated with impaired cellular immunity, such as leukaemia, lymphoma, disseminated malignancy have all been found to predispose to the development of pulmonary TB. In addition, patients with diabetes mellitus, hypothyroidism and those undergoing gastrectomy also have an increased risk of developing TB, although the mechanisms underlying their susceptibility are not well characterized (40,41). GENETIC SUSCEPTIBILITY TO TUBERCULOSIS The natural history of TB is covered in the chapter “Reinfection and reactivation tuberculosis” [Chapter 47] Extensive exposure to Mycobacterium tuberculosis in a hyperendemic area does not always result in disease in all individuals. Though environmental and socioeconomic factors are primarily related, numerous studies have emphasized the importance of host resistance and hereditary susceptibility. Although about one-third of the world’s population is infected with Mycobacterium tuberculosis, only around 10 per cent of those who get infected will ever develop clinical disease (40). Even in families with similar socio-economic and nutritional conditions, the disease develops only in a few children indicating the existence of host genetic factors regulating disease expression or resistance.

Racial differences in susceptibility (42), family segregation analyses, association studies, candidate gene studies (43,44) and genome scan studies (45,46) have all implicated host genetics as a factor in determining the susceptibility or resistance to infectious diseases. Racial Differences Racial differences influence the degree of resistance to mycobacterial diseases. For example, the African Americans (45,47) and certain African tribes (48) have been reported to be particularly more susceptible to pulmonary TB as compared to Jews, who are relatively immune. Reports from Brailey (49) suggest that the nonwhite patients in the age group of one to twenty years had higher deaths rates from pulmonary TB as compared to white children of the same age group. Similarly, the disease prevalence in Gurkhas of Nepal has been found to be higher than other ethnic groups in the same geographical area (50). Twin Studies Pulmonary TB has been reported to occur more commonly in twins even when they are living separately (6). It has been suggested that the disease expression rate of TB is significantly higher in monozygotic twins [33.3%] than dizygotic twins [15.7%] (51). Among household contacts, the disease is more likely to occur in siblings than in the spouse despite closer physical contact in the latter. ABO and Rh Blood Groups There are reports indicating that Rh-negative persons are more susceptible to TB than their Rh-positive counterparts (52). Others have, however, failed to confirm this observation (53). Incidentally, Chinese with blood group ‘O’ have been found to be more resistant to develop pulmonary TB than those with other blood groups (54). A significant increase of pulmonary TB in persons with blood groups ‘O’ and ‘AB’ has also been reported in sputum positive Danish patients as compared to those with group ‘A’ or ‘B’ (55). IMMUNE RESPONSE GENES Genes within and associated with the MHC have been shown to play a crucial role in governing susceptibility

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to intracellular mycobacterial infections (56). It is now recognised that MHC gene products play a crucial role in the immune response by not only providing a context for the recognition of foreign antigens by T-lymphocytes but also by controlling the immunoregulatory processes and final elimination of the cell bound antigen (57). Some MHC gene products promote efficient T-cell function, whereas others elicit a poor T-cell response or no response at all. These MHC products include immune response [Ir] genes and/or immune suppressive [Is] genes. In pulmonary TB, the host immune response to Mycobacterium tuberculosis is responsible for clinical expression of the disease rather than damage by the mycobacteria. Therefore, an in-depth study of MHC linked genes is essential for understanding mechanisms underlying disease susceptibility. MOLECULAR GENETICS AND ORGANIZATION OF HUMAN MAJOR HISTOCOMPATIBILITY COMPLEX GENES Human MHC gene cluster spans a region of about 4000 kb length [4 x 10 6 nucleotides] on the short arm of chromosome 6 in the distal portion of the 6p21.3 band. Studies on the structural organization of MHC molecules have helped in understanding the functional role of MHC gene products in the host immune response. In the MHC region, a total of 224 genes have been identified, of which 128 are assumed to be functional genes and 96 are pseudogenes. More than 40 per cent of the genes have one or more assigned immune functions (58). These genes are arranged in three distinct sets of molecules, each comprising of a cluster of Ir genes [Figure 8.1A] (59). The most centromeric segment is the class II region that spans around 1100 kb and contains the human leucocyte antigen [HLA]-DP, DQ and DR loci, which are found as pairs, encoding the α and β chains. These chains encode the heterodimeric class II protein molecules expressed at the cell surface of antigen presenting cells [macrophages, dendritic cells, Kupffer cells, Langerhans’ cells, B-cells, and activated T-cells]. The class I region, on the other hand, lies at the telomeric end and contains the classical HLA-A, B and C and related loci, spread over a region of approximately 2Mb. The HLA class I molecules are expressed ubiquitously on almost all nucleated cells. The HLA genes that are involved in immune regulation are mainly in the class I and class II region, which are structurally and functionally different.

Figure 8.1A: Human major histocompatibility complex [MHC]. Chromosomal location and gene map showing multiple genes on the short arm of chromosome 6 [6p21.3]. The two-way arrow shows the genetic distance covered by the respective regions on the chromosome. The circled loci are known to be highly polymorphic Adapted from reference 59

Class III genes [central genes] placed between class I and class II regions consist of genes involved in the complement system, tumour necrosis factor [TNF], heat shock proteins [HSP] and others with non-immune functions, not directly related to antigen presentation. Major Histocompatibility Complex Class I Genes The class I region is the most telomeric part of the MHC complex. Although 36 genes have been defined so far in this region, HLA-A, B and C are the most important since their products have been well defined as ‘classical transplantation antigens’. They are characterized by the high degree of polymorphism in most vertebrate species. Other human class I genes that show sequence homology to classical loci include HLA-E, F, G, H, and a set of five MHC Class I related [MIC] genes [MIC A–E]. These have reduced expression, restricted to certain tissues such as thymus, liver, intestine or placenta, and have low polymorphism. Of the five MIC genes, only MIC-A and MIC-B, situated between the TNF and HLA-B locus are expressed. Closely related to these genes lies the haemochromatosis disease candidate gene designated, that regulates iron absorption designated HFE. The HLA-A, B and C molecules are heterodimeric glycoproteins consisting of a MHC-encoded α or heavy chain of about 45 kDa and a non-MHC-encoded light chain [β2- microglobulin] of 12 kDa molecular weight [Figure 8.1B]. The α chain is some 350 amino acid residues long and can be divided into three functional regions:

Genetic Susceptibility Parameters in Tuberculosis 129

Figure 8.1B: Pictorial view of HLA class II and class I molecular structures showing peptide binding cleft formed between α1 and β1 domains in case of class II, and α1 and α2 domains in case of class I molecules Adapted from reference 59

Figure 8.1C: Location of known ‘pockets’ within the peptide binding region of class II and class I molecules Adapted from reference 59

external, transmembrane and intracytoplasmic. The extracellular portion of the heavy chain is folded into three globular domains, α1, α2 and α3, each of which contains stretches of about 90 amino acids encoded by separate exons. While the α1 and α2 domain take part in antigen binding [antigen-binding domains], the α3 domain is essentially conserved. It contains binding sites for the α chain of the CD8 glycoprotein, which is important for recognition of antigens by cytotoxic T-cells. The outermost domains [α1 and α2] comprise two long α

helices separated by a cleft with a floor composed of a plane of eight antiparallel β-pleated sheets. Dimensions of this cleft [2.5 x 1.0 x 1.1 nm] are suited to accommodate nonamers, but peptides ranging from 10-15 amino acids in length, can also bind, depending on how they fold (60,61). The amino acid side chains of the peptide are accommodated in a series of pockets named A-F [Figure 8.1C] (62,63). These peptide positions are critical for binding to specific pockets of a particular HLA class I

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molecule, hence termed anchors. Pockets A and F lie at the two ends of the peptide – binding groove, are highly conserved among the various HLA class I molecules and accommodate the amino and carboxyl terminal residues, respectively. The interactions of the peptide with conserved residues in A and F pockets, therefore, fix the peptide in the binding groove and play a major role in stabilising the MHC-peptide complex. Although the peptide residues P2 and P9 serve as primary anchors, the residues P1, 3, 6 and 7 act as secondary anchors, and the P4, 5 and 8 interact with the TCRs. Major Histocompatibility Complex Class II Genes The MHC class II region extends over 1000 to 1200 kb with at least six subregions, termed DR, DQ, DP, DO, DN and DM. Structurally, the class II molecules are similar to class I molecules and are expressed as heterodimers on the cell surface with one heavy α chain [molecular weight 34 kDa] and one β chain [molecular weight 29 kDa] of integral membrane glycoproteins [Figure 8.1B]. Three-dimensional structural differences between the two include an altered position of the immunoglobulin-like β2 domain relative to that of the α3 domain of class I HLA, and considerable changes in the peptide-binding site. The α and β chains assemble non-covalently to create an antigen-binding cleft located above a conserved membrane proximal structure, which can interact with the CD4 molecules on T-cells. Found mainly on cells of the immune system, including B-cells, macrophages, DCs and thymic epithelium, class II molecules display a more limited distribution. The DR region contains multiple, highly polymorphic β genes and only one invariant α gene. The conventional serologically defined DR molecules [DR1 to DR18] are coded for by the DRB1 gene, whereas the DR52 and DR53 specificities are encoded by the DRB3 and DRB4 genes, respectively. The DRB2, DRB6, DRB7, DRB8 and DRB9 are pseudogenes without a first domain exon. The DQ subregion contains five genes, DQA1, DQA2, DQB1, DQB2 and DQB3, of which DQA2, DQB2 and DQB3 are not known to be expressed. In contrast, both DQA1 and DQB1 are functional and polymorphic, expressing four different types of DQ molecules by different ‘cis’ and ‘trans’ combinatorial events. The DP sub-region contains two α and two β genes, with DPA2 and DPB2 being pseudogenes. The DPB1 shows extensive polymorphism, while DPA1 displays limited polymorphism. The DO,

DM and DN lie between the DQ and DP loci, and have very limited polymorphism, if any. Three-dimensional structural analysis has demonstrated that peptides bind to HLA class II molecules in an extended conformation. By contrast to class I bound peptides, the N- and C-termini of class II bound peptides often extend beyond the binding groove. Three asparagine residues [α62Asn, α69Asn and β82Asn], β81His and β61Trp are conserved in all class II molecules and positioned to make hydrogen bonds with the peptide main chain. The α1 and β1 helical regions of most class II molecules are joined by a salt bridge formed between [α76Arg, β57Asp] that stabilizes the αβ dimer. The peptide bound by the class II groove twists along the length, progressing approximately three residues for each turn. Successive side chains project from the class II bound peptide at regular intervals, many of which are directed towards the class II molecule. The groove is lined by series of pockets [P1 to P9] that align the peptide to be read as a single unique determinant by the TCR [Figure 8.1C]. The size of the hydrophobic P1 pocket is controlled by the Gly/Val dimorphism at position 86 on the β chain. The deepest and the most commonly used binding pockets are P1 and P9 followed by P4 and P6. In addition to the above, two groups of non-HLA genes have been identified in the MHC class II region. The first group is ABC transporter genes called transporter associated with antigen processing or transporter of antigen peptides 1 and 2 [TAP1 and TAP2] genes (64). The TAP1 and TAP2 gene products associate as a heterodimer that is involved in the transport of antigen fragments produced in the cytoplasm, into the lumen of the endoplasmic reticulum. The second group is proteasome related genes that includes low molecular mass polypeptide or large multifunctional protease 2 and 7 [LMP2 and LMP7] genes. The products of LMP2 and LMP7 genes are large cytoplasmic proteolytic complex molecules that contain multiple catalytic sites. The LMP complex is involved in the production of multiple peptides simultaneously from the same substrate to produce peptides better suited for MHC class I binding. Major Histocompatibility Complex Class III Genes [Central Genes] The central region of MHC has no structural or functional correlation with the class I or class II region. Presently, at least 39 genes have been located in a 680 kb stretch of

Genetic Susceptibility Parameters in Tuberculosis 131 deoxyribonucleic acid [DNA] within this region. This includes genes encoding proteins involved in the immune system: the complement genes C4, C2 and factor B [Bf], the TNF-α and TNF-β [lymphotoxin] genes and the heat-shock protein [HSP70] genes. Genes with no obvious association with the immune system have also been identified in this region. These include valyl transfer ribonucleic acid synthetase [G7a]. Further, two B-cell associated transcript genes, BAT2 [G2] and BAT3 [G3] are novel genes in the class III region that encode large proline rich proteins with molecular masses of 228 and 110 kDa, respectively, while the RD gene encodes a 42 kDa intracellular protein. Apart from the complement components, this region also contains two genes coding for synthesis of the steroid hormone, 21-hydroxylase [CYP21] genes. The genes associate very closely with the C4A and C4B genes. Of these, the 21B gene [CYP21B gene] is more functional, and deficiency of this leads to congenital adrenal hyperplasia or salt-wasting disease. The CYP21A gene on the other hand, is most often deleted in certain specific HLA haplotypes, particularly the extended haplotype HLA-A1, B8, DR3, SCO1 in Western Caucasians. Such a haplotype is known to be associated with several autoimmune diseases including type 1 diabetes mellitus. BIOLOGICAL FUNCTIONS OF HUMAN LEUCOCYTE ANTIGEN The determination of the crystal structure of the human MHC class I and class II molecules and the identification of the putative peptide binding cleft established that MHC molecules are the principal antigen binding and presenting molecules to the T-cells. Thus, peptide antigens alter the HLA molecule by occupying the cleft to be scrutinized by the T-cell. This concept was first put forward by Zinkernagel and Doherty (65) who were awarded the Nobel Prize for Medicine in 1996 for their studies of anti-viral T-cell recognition. The fundamental difference in the above process is that whereas class I MHC molecules bind ‘endogenous’ peptides and eliminate them through the process of cytotoxic T-cell killing [inside out mechanisms], the class II molecules, on the other hand, bind peptides derived from ‘external’ sources [exogenous] and present them to CD4+ helper T-cells [outside in mechanism].

The processing pathway in both situations utilizes highly specialized cell machinery that works most effectively. The endogenous proteins in the cytoplasm of the cells are digested into nine to ten amino acid peptides by the LMP complex, a distinct subset of the cellular pool of proteasome. Peptides in the cytoplasm may gain access to the TAP transporter on the membrane of the endoplasmic reticulum [ER] via a specific transporter. Peptides transported into the ER lumen bind to class I molecules, inducing a conformational change that may facilitate their export to the cell surface. The CD8+ cytotoxic T-lymphocytes see this MHC-peptide complex through the TCR and other co-receptors, subsequently causing killing of the target cell. In the class II pathway, antigens taken from outside the cell by endocytosis are digested by the proteolytic enzymes in the endosomal compartment into small peptide fragments. The MHC class II molecule with its α and β chains assembles in the ER with the invariant chain to form a stable trimolecular complex which inhibits the binding of endogenous or self-peptides in the ER. The trimolecular complex is efficiently transported out of the ER and is targeted to a post-Golgi compartment in the peripheral cytoplasm. The invariant chain is subsequently cleaved in endosomes, opening up the cleft for peptide occupancy. The development of accurate and reproducible highresolution DNA-based HLA typing methods have significantly improved our capabilities to define HLA alleles at a single nucleotide difference. Further advanced technologies based on sequencing, mass spectroscopy and DNA chips have now opened up a whole new dimension of studying single nucleotide polymorphisms [SNPs]. Using these procedures, an appreciable number of ‘novel alleles’ and unique HLA haplotypes have been discovered in the Indian population (66,67). HUMAN LEUCOCYTE ANTIGEN AND DISEASE ASSOCIATIONS The MHC is considered to be associated if one or more alleles are increased or decreased significantly in patients when compared with ethnically matched healthy controls. However, the underlying mechanisms for most disease associations are still poorly understood. Accumulating evidence suggests a direct disease related role for polymorphic HLA proteins, whereby they

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recognize peptide motif signatures and allow/prohibit their binding to antigen-binding groove. An increasing number of HLA-binding motifs are being discovered for several autoimmune and infectious agents. One main limitation in identifying primary determinants within the MHC, however, is the linkage disequilibrium that keeps several genes linked together on a haplotype. Generally, it is more difficult to demonstrate a negative association of MHC with a disease. These associations vary greatly among populations and defined ethnic groups. IMMUNOGENETICS OF TUBERCULOSIS The demonstration of MHC as T-cell restriction element and its linked Ir and/or Is genes has resulted in a series of HLA and disease association studies at the population level (68,69). Several workers have demonstrated an association of HLA antigens [or haplotypes] with diseases caused by known infectious agents. These include hepatitis B virus infection, infectious mononucleosis, viral capsid antigen in Epstein-Barr virus infection, human T-cell lymphotropic virus III [HTLV III] infection and the development of Kaposi’s sarcoma in patients with AIDS, poliomyelitis, typhoid fever, congenital rubella, etc. In most cases, however, a clear relationship between HLA antigens and susceptibility to infectious diseases has not been established. Several explanations can be put forward to explain this lack of association. One of these relates to the complexity of Ir gene effects due to heterozygosity of the MHC gene products. Another contributing factor could be ‘disease heterogeneity’ because of the multiplicity of epitope specific antigenic determinants on the infectious agents, which preclude the detection of the effects of HLA encoded factors as risk factors for infection. This antigenic complexity of the invading pathogen leads to an almost incomplete recognition of the relevant products of the HLA system, particularly those in the HLA-D region, which harbours majority of the genes relevant to antigen recognition and T-cell interaction. Population Studies Among the major infectious diseases, leprosy and TB have emerged as good examples of the role of HLA on susceptibility to infection. Like in leprosy, TB too follows a disease spectrum with the localized disease having limited lung involvement at one end of the spectrum and

a more diffuse, disseminated infection at the other. The pathogenesis of pulmonary TB appears to be due to a detrimental cell mediated immune response to Mycobacterium tuberculosis. Several investigators have searched for an association of the disease with either HLA class I [HLA-A, -B, -C] or class II [HLA-DR, -DQ] antigens. Human Leucocyte Antigen Class I Association Studies Table 8.2 summarizes the reported HLA class I antigen associations with pulmonary TB in different populations (70-86). Studies conducted by our group in the population living in the region of Delhi revealed a significantly increased frequency of HLA-A2 in pulmonary TB patients as compared to healthy controls (84). Similar association of HLA-A2 with pulmonary TB has earlier been reported in Egyptian patients. Other studies have suggested an association between pulmonary TB and HLA-B15 in North American Blacks and South Chinese, HLA-B35 in Northern Chinese, HLA-B5 in Egyptians, HLA-B8 in Canadians and multiple HLA-A and -B specificities in Russian populations. However, no association of HLA class I antigens with pulmonary TB was reported in Mexican Americans, European Caucasians and Japanese subjects [Table 8.2]. Studies carried out in Asian Indians have demonstrated an association of pulmonary TB with B44 in north Indians. Such a heterogeneity in HLA class I association in different populations may be due to the ethnic variability of the population groups tested. Small number of study groups, poor documentation of diagnosis, batch variation in HLA antisera used in these studies may also account for such heterogeneity. It is also possible that the putative disease susceptibility gene lies in the HLA-class II region [DR/DQ locus] rather than the class I. The study reported by Balamurugan et al (86) is an attempt to delineate HLA class I association in TB on the basis of a shared ‘sequence motif’ in peptide-binding pockets of HLA molecules. Although, HLA alleles are highly polymorphic, small degree of genetic polymorphism may or may not affect peptide presentation and molecular function. Among genetically related MHC alleles, each HLA molecule preferentially binds peptides with certain anchor residues and then presents it to the CD8+ T-cells. However, within these allelic groups, there are shared peptide epitopes and a considerable overlap in peptides binding capacity. Therefore, the need arises

Genetic Susceptibility Parameters in Tuberculosis 133 Table 8.2: Association between HLA class I antigens and pulmonary tuberculosis Study (reference) [Year]

Population

HLA [RR]*

Rosenthal et al (70) [1973] Lee (71) [1976] Selby et al (72) [1978] Takata et al (73) [1978] Al-Arif et al (74) [1979] Cox et al (75) [1982] Jiang et al (76) [1983] Hafez et al (77) [1985] Hwang et al (78) [1985] Mehra et al (79) [1986] Xu et al (80) [1986] Mehra et al (79) [1986]

European caucasoids Korean Japanese New Foundland North American Blacks Mexican Americans North Chinese Egyptians North American Blacks North Chinese South Chinese North Indians South Indians South Indians Armenians

NA ↑B12 NA ↑B8 [0.44] ↑B15 NA ↓A19 [0.3], ↑B5 [7.4], ↑B27 [3.7] ↑A2 ↓B5 [0.26] ↑A29, ↑B47 ↑B44, ↑A11[2.1], ↑B15 [ 2.4], ↓Cw3 [0.3] ↑B12, ↑B44 ↑B49 NA ↑A19 [3.64], ↑B12 [2.82], ↑B35 [2.77], ↑Cw4 [19.37] ↓A2 [1.92], ↓A3 [0.29], ↓Cw1 [0.44], ↑B14 [3.20], ↑B35 [2.55] ↓A10 [0.43], ↓Cw9 [0.35], ↑B5 [2.75] ↑B5 [2.06], ↑B7 [4.84] ↓A3 [0.44], ↓B79 [1.90] ↑B12 [3.99 ↓A19 [0.6] ↓A24[0.4], ↓B17[0.6], ↓B52 [0.4] ↓B57 [0.1], ↓B61 [0.2] ↑A10 [2.8], ↑B8 [3.2], ↑B14 [9.9] ↑A2 [1.76] ↑B38 ↑A3 like supertype, ↓A1 like supertype

Papiha et al (81) [1987] Khomenko et al (82) [1990]

Kazhaks

Brahmajothi et al (83) [1991]

Moldavians Russians Turkmans Uzbeks South Indians

Rajalingam et al (84) [1997] Goldfield et al (85) [1998] Balamurugan et al (86)† [2004]

North Indians Cambodians North Indians

* Most of these studies have been conducted on pulmonary tuberculosis patients in different populations. All these studies did not show consistent and strong association of a particular HLA Class I allele with pulmonary tuberculosis † disseminated and miliary tuberculosis HLA = human leucocyte antigen; RR = relative risk; NA = not available

to analyse the functional differences of the ‘peptide presenting MHC class I molecules’. Based on the similarities of peptide binding pockets [B and F] and the preference of identical peptide motifs, Sette and Sidney (87) reported nine different supertypes covering most if not all HLA class I alleles. The specificities of the anchor residues are determined by the amino acid sequences that constitute the peptide binding pockets as described by the crystallographic studies (60,61). In the Indian study (86), the class I supertypes were evaluated for their possible association with TB by comparing the data with a set of healthy controls belonging to the same ethnic background and socio-economic status. The data revealed a strong positive association of ‘A3- like’ and a negative association of ‘A1-like’ supertypes particularly

in patients with more severe forms of the disease such as miliary, disseminated TB and MDR-TB. Human Leucocyte Antigen Class II Association Studies Since 1983 several workers have tried to search for an association of HLA class II antigens and alleles with pulmonary TB. The data have been summarized in Table 8.3 (88-96). The first such report came from north India (94) where a moderate increase of HLA-DR2 was demonstrated in sporadic patients with pulmonary TB. This finding was also confirmed in multiplex family studies suggesting a DR2 linked control of susceptibility to the disease (90). This association was later confirmed in several other populations, including south Indians and Chinese (79,83,95), Indonesians (93) and Russians (82).

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SEAR

DQB1*0601

DQB1*0503

DQB1*0501

DQB1*0402

DQA1*0101

DQ1

DR10

DR8

–

DPB1*08

WPR

+

DPB1*02

EUR

DR6

North American Blacks (78) Mexican Americans (75)

DR5

AMR

DR4

Populations

DR2

WHO region

DR3

Table 8.3: Association between HLA class II antigens/alleles and pulmonary tuberculosis

+

–

–

Kazakhs (82) Russians (82) Turkman (82) Uzbeks (82) Armenian (82) North Poland (88)

+ + + + + +

North Chinese (79) South Chinese (79) Hong Kong Chinese (89)

+ +

North Indians (79,90,91) South Indians (92) Indonesians (93)

+ + +

– – – – – – + –

+ +

–

+ +

–

WHO = World Health Organization; AMR = American region; EUR = European region; WPR = Western Pacific region; SEAR = SouthEast Asian region

However, others could not confirm this association in studies on Hong Kong Chinese (89), Egyptians (77), North American Blacks (78), Mexican Americans (75), as well as in a study on south Indian patients using the technique of restriction fragment length polymorphisms [RFLP] (96). Except for the study by Sanjeevi et al (96), all other studies were based on serological testing of expressed HLA antigens on the surface of lymphocytes. In 1991, Opelz and co-workers (97) reported that up to 25 per cent discrepancy has been found in DR typing results by serology when compared with the more sensitive techniques of polymerase chain reaction based sequence specific oligonucleotide probe [PCR-SSOP] hybridization. Besides being sensitive, these techniques have allowed definition of molecular subtypes of several serologically defined HLA-DR specificities, differing even at a single nucleotide level. This has significantly enhanced our capabilities to identify critical amino acids in the MHC binding groove that are relevant in disease causation. Subsequent studies on the possible association of HLA class II alleles with pulmonary TB have utilized the PCR based techniques. Almost all published studies on HLA association with TB have been performed in patients with pulmonary TB

and no data are available regarding other clinical forms of the disease including extra-pulmonary disease. Therefore, we investigated HLA association with various clinical subgroups including pulmonary TB, MDR-TB, miliary, disseminated TB and lymph node TB. Further, molecular subtyping of polymorphic DRB1 alleles has revealed that in addition to the increased occurrence of DR2 subtypes, a positive association of specific DR6 subtypes was noticed in different clinical forms of TB, particularly DRB1*1301 in patients with pulmonary TB and MDR-TB and DRB1*1302 in extra-pulmonary TB [miliary, disseminated TB and lymph node TB]. Although the DR2 associated haplotype association has been reported earlier also in pulmonary TB (98), the existence of additional DR6 associated haplotypes [both DRB1*13 and DRB1*14] in other clinical forms of TB indicates that alleles with similar ‘sequence motif’ in the peptide binding groove may influence susceptibility to Mycobacterium tuberculosis infection and subsequent development of severe clinical disease. Data on the clinical and immunogenetic association for the development of MDR-TB suggest that, in addition to poor past compliance to treatment and presence of higher number of cavities in the chest radiographs,

Genetic Susceptibility Parameters in Tuberculosis 135 presence of HLA-DRB1*14 allele in patients with pulmonary TB acts as an independent predictor for the development of MDR-TB (99). Also, the development of hepatotoxicity during antituberculosis treatment was found to be associated with alleles in this DQ locus, namely DQA1*0102 and DQB1*0201 (100). Family Studies The variability of the associated HLA antigens observed in different ethnic groups indicates that genes controlling host response to mycobacteria may be ‘linked’ but not situated at the HLA class I and class II determinants, and, therefore, reveal different linkage disequilibria in different populations. In order to understand the mode of inheritance or HLA linked control of disease susceptibility, family studies particularly those with at least two affected sibs are most informative. Such studies conducted by us provided the first conclusive evidence for an important role of HLA-linked genes in governing susceptibility to pulmonary TB (90,94,101). Further, the data collected at the Third Asia-Oceania Histocompatibility Workshop involving families from north India, south India, Hong Kong and China corroborated these findings, suggesting an increased sharing of HLA haplotypes by the affected sibs as compared to the unaffected healthy sibs (79). Combined data from these studies suggested that DR2-positive haplotypes from the affected parents showed a non-random segregation among pulmonary TB affected children indicating that

HLA- linked susceptibility to pulmonary TB follows a dominant rather than a recessive mode of inheritance. This is in contrast to the situation in TT leprosy, where the data favour a recessive mode of inheritance (102-104). In a recently published meta-analysis (105) [1988 patients and 2897 controls], a lower risk of thoracic TB was found in carriers of B13, DR3, and DR7 antigens. Carriers of DR8 were at higher risk for thoracic TB. Though the risk of thoracic TB tended to be higher in carriers of DR2 the results were not consistent between studies. High Resolution Analysis of Molecular Subtypes of HLA-DR2 in Mycobacterial Diseases The population frequency of HLA alleles in the north Indian population has revealed that two alleles, namely DRB1*1501 and DRB1*1502 constitute greater than 90 per cent of the DR2 alleles in this population. Other alleles such as DRB1*1506 and DRB1*1602 are represented at much decreased frequencies. The DRB1*1601 occurred in only four per cent of DR2 positive healthy controls (106). Studies carried out both in north as well as south India have indicated a population association of DRB1*1501 [rather than other subtypes of DR2] in patients with TB (107). Sequence analysis of the DRB1 first domain residues has disclosed that only one amino acid variation can discriminate the products of DRB1*1501 from DRB1*1502 and DRB1*1601 from DRB1*1602 [Table 8.4]. Particularly

Table 8.4: Amino acid sequences of molecular subtypes of HLA-DR2* Serological specificity DR15

DR16

DR2 Subtypes

HVR I 30 31

*1501 *1502 *1503 *1504

Y

*1601 *1602 *1603 *1604 *1605 *1606

Y

F

Amino acid variation in DRβ1-domain HVR II 47 67 70 71 72 74 F

I

Q

A

R

D

R

R

86

A

V G V V

H F F

Y

F L

A

G

A L I I

A

* Note residue differences in the first and second hyper variable regions [HVRs] in the first domain of the DRB1 gene. DRB1*1501 differs from *1502 by a single amino acid substitution at position 86

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Tuberculosis

Figure 8.2: Frequency distribution of major DR2 subtypes in pulmonary tuberculosis patients with varying degree of lung lesions UL = unilateral limited disease; UE = unilateral extensive disease; BL = bilateral limited disease; BE = bilateral extensive disease

DRB1*1501 carries valine at amino acid position 86 while it is substituted with glycine in DRB1*1502. Similarly, DRB1*1601 subtype has the aromatic amino acid phenylalanine at position 67 which is substituted by aliphatic leucine in DRB1*1602. Studies on pulmonary TB did not favour a preferential involvement of any of these common subtypes of DR2 suggesting that the whole DR2 molecule or its closely linked gene[s] may be involved in governing susceptibility to pulmonary TB and the expression of its various clinical forms. However, analysis of DR2 subtypes and the differences in radiographic severity based on the extent of lung lesions unilateral limited [UL], unilateral extensive [UE], bilateral limited [BL] and bilateral extensive [BE] revealed an increased trend in the frequency of DRB1*1501 as the pulmonary severity increased [49% in UL vs 55% in controls 82% in BE vs 55% in controls] [Figure 8.2]. Similar trends have been observed in leprosy patients. A comparison of the distribution of DRB1*1501 in the two clinical subgroups of patient revealed increased occurrence of this allele in lepromatous [BL/LL] leprosy as compared to tuberculoid [BT/TT] patients [81% vs 64%]. This is in contrast to the distribution of DRB1*1502 in these patients. This suggest that a single amino acid difference between the DRB1*1501 [valine] and DRB1*1502 [glycine] at codon 86 of the DRβ chain may play an important role in disease manifestation.

The report by Singh et al (108) further evaluated all five different DR2 subtypes based on the V/G dimorphism at codon β86 and observed an inverse association of DR2. The results revealed an inverse association of DR2 alleles with V86 and G86 as the pulmonary severity increased from unilateral limited [UL] to bilateral extensive [BE] lung lesions. Similar inverse relationship of V86/G86 has also been observed in leprosy as the disease severity progressed from paucibacillary to the BL/LL multibacillary leprosy (108). Knowledge on the three-dimensional crystallography structure of the human class II HLA molecule has revealed that residues at position 67 and 86 of the α-helix of the β-chain are actively involved in the binding of a foreign peptide [Figure 8.1C]. Accordingly, the peptide binding and subsequent immune triggering capability of the host depends critically on these single amino acid variants. It is possible that DRB1*1501 and 1502 alleles may be selectively implicated in the presentation of pathogenic mycobacterial peptides leading to the development of pulmonary TB. Recently, the amino acid sequence analysis of the associated HLA-DRB1 genes in tuberculoid leprosy has yielded crucial information on critical sites in the peptidebinding groove of the DR molecule that affects peptide binding and/or T-cell interaction in immune response against mycobacteria (109). A large majority of patients [87%] carry specific alleles of DRB1 characterized by positive charged residues Arg13 or Arg70 or Arg71 as compared to 43 per cent controls conferring a relative risk of 8.8. Thus, susceptibility to tuberculoid leprosy involves three critical amino acid positions of the β-chain, the side chains of which when modelled on the DR1 crystal structure, line a pocket [pocket 4] accommodating the side chain of a bound peptide. Characteristically, pocket 4 is formed by the side chains of amino acids α9, β13, β70, β71, β74 and β78. Substitutions of any of these can affect the local charge. For example, presence of positively charged Arg at position 13 or Arg at position 70 or 71 will probably accommodate the binding of a negatively charged residue of the same foreign peptide. According to the leprosy model, it is likely that peptides originating from Mycobacterium leprae bind preferentially to HLA allelic forms characterized by arginine at positions 13 or 70 and 71 and stimulate particular T-cell clones that result in detrimental immune response as seen in tuberculoid leprosy. Identification

Genetic Susceptibility Parameters in Tuberculosis 137 of peptide motifs that bind different allelic forms associated with disease would contribute significantly to the search for mycobacterial antigenic determinants that initiate this response. Similarly, sequence analysis of class II alleles [both DR2 and non DR2] in TB patients can help in the identification of critical amino acid residues for the binding of Mycobacterium tuberculosis derived pathogenic peptide[s] responsible for the detrimental or protective immune response. This has potential implications in immune interventions therapies in pulmonary TB. NON-HUMAN LEUCOCYTE ANTIGEN GENES IN MYCOBACTERIAL INFECTIONS From the above, it follows that HLA associations and relative risk of the concerned HLA antigens and alleles differ in various populations and this can be attributed to the assumption that in polygenic diseases, there can be more than one pathway and involvement of other genes. The combination of such genes and their polymorphic forms may differ from population to population. This favours looking at a possible role of non-HLA polymorphic gene variants such as TAP, TNF-α and TNF-β, mannose binding lectin [MBL], vitamin D receptor [VDR], solute carrier family 11 [proton-coupled divalent metal ion transporters], member 1 [SLC11A1], formerly known as natural resistance associated macrophage protein [Nramp1] genes and interleukin-1 receptor antagonist [IL-1RA]. Further, a genome-wide scan of various genes in mycobacterial diseases could provide crucial information on the involvement of nonHLA genes in governing susceptibility to these diseases. Amongst the non-HLA genes, combined occurrence of TAP2 along with HLA-DR2 and their association with susceptibility to pulmonary TB has been reported (110). Similarly, an association with haptoglobin 2-2 phenotype has been shown in Russian patients (111), although, this could not be corroborated in Indonesians (112) and Indian patients (81). Genome-wide linkage studies on sibling pairs of families affected with the TB has led to the identification of several candidate genes, some of which show association with the susceptibility to TB (45).

polymorphic microsatellite markers have made genomewide linkage studies possible. This approach has the advantage that no disease model or prior knowledge of the structure-function or location of the disease gene is required. The chromosomal regions identified by this approach are initially much larger than that of an association study. Also, the genome-wide scan has the advantage that gene[s] of unknown function and those not previously suspected as possible candidates can be identified. Bellamy (45) has performed genome-wide screening for TB susceptibility loci [genes] among 136 African families containing 173 independently affected sib pairs. Suggestive evidence of linkage was observed on two regions of chromosome Xq27 and 15q11. Though the evidence of linkage did not reach the criteria for genome-wide statistical significance, further support for the presence of the loci was obtained using the method of common ancestory mapping. Interesting candidate genes in this region are P protein and the HERC2 genes on chromosome 15 and CD 40 ligand on the X chromosome. Similarly, in the mouse model of TB, a new locus with a major effect on TB susceptibility, designated as susceptibility to TB [sst1] has been mapped to a 9 centiMorgan [cM] region on chromosome 1 (113). It is located 10 to 19 cM distal to a previously identified gene, Slc11a1 that controls the innate resistance of mice to the attenuated bacille Calmette-Guerin [BCG] vaccine strain. The phenotypic expression of the newly identified locus is distinct from that of Slc11a1 in that sst1 controls progression of TB infection in a lung specific manner. Similar genome-wide scans have been conducted in Brazilian patients with TB and leprosy. Non-parametric multipoint analysis detected 8 and 9 chromosomal regions respectively with provisional evidence for linkage. Three regions [10q26.13, 11q12.3 and 20p12.1] are suggestive of linkage to TB (114). CANDIDATE GENES IN TUBERCULOSIS Several candidate genes have been implicated in TB. These include Slc11a1 , MBL, and vitamin D receptor [VDR] genes. The reader is referred to the chapter “Genetics of susceptibility to tuberculosis” [Chapter 9] for more details.

Genome-wide Linkage Analysis

Cytokine Genes and Receptors

The development of high throughput genotyping technologies and the identification of thousands of

Experiences on the gene-knock out mice have provided clues on the potential relevance of genetic polymor-

138

Tuberculosis Table 8.5: Candidate gene variants associated with susceptibility or resistance to tuberculosis

Candidate genes HLA HLA-DR2 DRB1*1501, *1502 DQB1 *1601 Haplotype DRB1*1501-DQB1*0601 Non-classical HLA TAP2 and DR2 Non-HLA MBL VDR SLC11A1 [{CA}n,823 C/T TGTG+/del and D543N G/A] Cytokine genes TNF-α -238, -308 Genome-wide scans

Innate immunity TLR2 TLR4

Chromosome location

Main function of protein encoded

Effect

6p21.3 6p21.3

Immune response gene Immune response gene

Susceptibility Susceptibility

6p21.3

Immune response gene

Susceptibility

6p21.3

Peptide translocation

Susceptibility

10q21.1 12q12-14

Innate immunity Suppression of inflammation

2q13

Macrophage activation

Susceptibility/resistance Differential susceptibility/resistance in males and females No association with susceptibility/ resistance

6p21.3

Pleiotropic, both innate/ acquired immunity Suggestive of linkage to tuberculosis

No association

Role in pathogen recognition and innate immunity

Susceptibility

Xq27 15q11 10q26.13 11q12.3 20p12.1 4q32 4q32

Severity of disease

HLA= human leucocyte antigen; TAP = transporter of antigen peptides; MBL = mannose binding lectin; SLC11A1 = solute carrier family 11 [proton-coupled divalent metal ion transporters], member 1, formerly known as natural resistance associated macrophage protein [Nramp1]; TNF-α = tumour necrosis factor-α; TLR = Toll-like receptor

phisms in cytokine and cytokine receptor genes to infectious disease susceptibility in humans. The reader is referred to the chapter “Genetics of susceptibility to tuberculosis” [Chapter 9] for more details. INNATE IMMUNITY TO TUBERCULOSIS: ROLE OF TOLL–LIKE RECEPTORS The reader is referred to the chapter “Immunology of tuberculosis” [Chapter 7] for more details. THE FUTURE The development of TB is the result of a complex interaction between the host and pathogen influenced by environmental factors. Numerous host genes are likely to be involved in this process [Table 8.5]. Recently,

developments in modern genetics and genomics have contributed to our understanding of the pathogenic processes that underlie major infectious diseases by allowing a more systematic study of the genetic influences. Identifying HLA and non-HLA genes and products which are associated with susceptibility or resistance to TB could provide important genetic makers to predict the development or predisposition to TB. An understanding of the presence of risk conferring and/or protection genes in the human MHC will be useful for the development of new epitope based vaccines. The number of candidate susceptibility genes is expanding rapidly. Moreover, genome-wide linkage analysis is also beginning to provide insights into complex disease. Advances in SNP typing, microarray technology and bioinformatics will be helpful in the study of infectious

Genetic Susceptibility Parameters in Tuberculosis 139 diseases. Hence, these studies may be useful for better management and control of the disease. Thus far, genes suggested to have a role in governing susceptibility to TB either act directly and modulate development of the adaptive response [HLA, TAP, VDR], or may bridge the innate and adaptive responses [SLC11A1, TLR 2, TLR 4, various cytokine genes and their receptors]. This is consistent with the idea that an appropriate cell-mediated immune response is critical in the control of mycobacterial infections. Many of the associations have only been found in a small series of patients, or in a single population, and should be repeated in larger studies. Lack of correlation in results between populations should not necessarily be regarded as negation of initial associations but may instead reflect heterogeneity in the genetic susceptibility to this disease. REFERENCES 1. Maartens G, Wilkinson RJ. Tuberculosis. Lancet 2007;370: 2030-43. 2. Opie EL. The epidemiology of TB in Negroes. Am Rev Tuberc 1930;22:603-28. 3. Large SE. Tuberculosis in the Gurkhas of Nepal. Tubercle 1964;45:320-35. 4. Lurie MB. Hereditary constitution and TB, an experimental study. Am Rev Tuberc 1941;44:1-125. 5. Nakamura RM, Tokunaga T. Strain difference of delayedtype hypersensitivity to BCG and its genetic control in mice. Infect Immun 1978;11:657-64. 6. Kallmann FJ, Reisner D. Twin studies on the significance of genetic factors in tuberculosis. Am Rev Tuberc 1942;47:54974. 7. Comstock GW. Tuberculosis in twins: a re-analysis of the Prophit survey. Am Rev Respir Dis 1978;117:621-4. 8. Hill AV. The genomics and genetics of human infectious disease susceptibility. Annu Rev Genomics Hum Genet 2001;2:373-400. 9. Caruso AM, Serbina N, Klein E, Triebold K, Bloom BR, Flynn JL. Mice deficient in CD4 T cells have only transiently, diminished levels of gamma interferon. J Immunol 1999;62:5407-16. 10. Tascon RE, Lukacs KV, Colston MJ. Protection against M.tuberculosis infection by CD8+ T cells requires production of gamma interferon. Infect Immun 1998;66:830-4. 11. Kafmann SH. How can immunology contribute to the control of tuberculosis? Nat Rev Immunol 2001;1:20-30. 12. Moody DB, Besra GS, Wilson IA, Porcelli SA. The molecular basis of CD1-mediated presentation of lipid antigens. Immunol Rev 1999;172:285-96. 13. Moody DB, Ulrichs T, Muhlecker W, Young DC, Gurcha SS, Grant E, et al. CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection. Nature 2000;404:884-8.

14. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med 1993; 178:2249-54. 15. Toossi Z, Gogate P, Shiratsuchi H, Young T, Ellner JJ. Enhanced production of TGF-beta by blood monocytes from patients with active tuberculosis and presence of TGF-beta in tuberculous granulomatous lung lesions. J Immunol 1995;154:465-73. 16. Ladel CH, Szalay G, Riedel D, Kaufmann SH. Interleukin-12 secretion by Mycobacterium tuberculosis-infected macrophages. Infect Immun 1997;65:1936-8. 17. Fenton MJ, Vermeulen MW, Kim S, Burdick M, Strieter RM, Kornfeld H. Induction of gamma interferon production in human alveolar macrophages by Mycobacterium tuberculosis. Infect Immun 1997;65:5149-56. 18. Keane J, Balcewicz-Sablinska MK, Remold HG, Chupp GL, Meek BB, Fenton MJ, et al. Infection by Mycobacterium tuberculosis promotes human alveolar macrophage apoptosis. Infect Immun 1997;65:298-304. 19. VanHeyningen TK, Collins HL, Russell DG. IL 6 produced by macrophages infected with Mycobacterium species suppresses T cell responses. J Immunol 1997;158:330-7. 20. Hirsch CS, Ellner JJ, Blinkhorn R, Toossi Z. In vitro restoration of T cell responses in tuberculosis and augmentation of monocyte effector function against Mycobacterium tuberculosis by natural inhibitors of transforming growth factor beta. Proc Natl Acad Sci USA 1997;94:3926-31. 21. Wang J, Wakeham J, Harkness R, Xing Z. Macrophages are a significant source of type 1 cytokines during mycobacterial infection. J Clin Invest 1999;103:1023-9. 22. Rojas RE, Balaji KN, Subramanian A, Boom WH. Regulation of human CD4[+] alphabeta T-cell-receptor-positive [TCR(+)] and gammadelta TCR[+] T-cell responses to Mycobacterium tuberculosis by interleukin-10 and transforming growth factor beta. Infect Immun 1999;67:6461-72. 23. Gong JH, Zhang M, Modlin RL, Linsley PS, Iyer D, Lin Y, et al. Interleukin-10 downregulates Mycobacterium tuberculosis-induced Th1 responses and CTLA-4 expression. Infect Immun 1996;64:913-8. 24. Chen X, Zhou B, Li M, Deng Q, Wu X, Le X, et al. CD4[+] CD25[+] FoxP3[+] regulatory T cells suppress Mycobacterium tuberculosis immunity in patients with active disease. Clin Immunol 2007;123:50-9. 25. Tjarnlund A, Guirado E, Julian E, Cardona PJ, Fernandez C. Determinant role for Toll-like receptor signalling in acute mycobacterial infection in the respiratory tract. Microbes Infect 2006;8:1790-800. 26. Sutherland I, Fayers PM. The association of the risk of tuberculous infection with age. Bull Int Union Tuberc 1975;50:70-81. 27. Horne N. Tuberculosis and other mycobacterial diseases. In: Cook G, editor. Mansons tropical diseases. London: WB Saunders; 1996.p.971-1015. 28. Tocque K, Bellis MA, Beeching NJ, Syed Q, Remmington T, Davies PD. A case-control study of lifestyle risk factors

140

29. 30.

31.

32.

33. 34. 35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

Tuberculosis associated with tuberculosis in Liverpool, North-West England. Eur Respir J 2001;18:959-64. Spence DP, Hotchkiss J, Williams CS, Davies PD. Tuberculosis and poverty. BMJ 1993;307:759-61. Munch Z, Van Lill SW, Booysen CN, Zietsman HL, Enarson DA, Beyers N. Tuberculosis transmission patterns in a highincidence area: a spatial analysis. Int J Tuberc Lung Dis 2003;7:271-7. Stead WW, Lofgren JP, Warren E, Thomas C. Tuberculosis as an endemic and nosocomial infection among the elderly in nursing homes. N Engl J Med 1985; 312:1483-7. McMurray DN, Bartow RA. Immunosuppression and alteration of resistance to pulmonary tuberculosis in guinea pigs by protein undernutrition. J Nutr 1992;122:738-43. Snider DE Jr. The relationship between tuberculosis and silicosis. Am Rev Respir Dis 1978;118:455-60. Rees D, Murray J. Silica, silicosis and tuberculosis. Int J Tuberc Lung Dis 2007;11: 474-84. Tam CM, Leung CC. Occupational tuberculosis: a review of the literature and the local situation. Hong Kong Med J 2006; 12:448-55. Mishra P, Hansen EH, Sabroe S, Kafle KK. Socio-economic status and adherence to tuberculosis treatment: a case-control study in a district of Nepal. Int J Tuberc Lung Dis 2005;9:11349. Saito A, Nagayama N, Yagi O, Ohshima N, Tamura A, Nagai H, et al. Tuberculosis complicated with liver cirrhosis. Kekkaku 2006; 81:457-65. Pai M, Mohan A, Dheda K, Leung CC, Yew WW, Christopher DJ, et al. Lethal interaction: the colliding epidemics of tobacco and tuberculosis. Expert Rev Anti Infect Ther 2007;5:385-91. Leung CC, Yew WW, Law WS, Tam CM, Leung M, Chung YW, et al. Smoking and tuberculosis among silicotic patients. Eur Respir J 2007;29:745-50. Sharma SK, Aggarwal G, Seth P, Saha PK. Increasing HIV seropositivity among adult tuberculosis patients in Delhi. Indian J Med Res 2003;117:239-42. Bacakoglu F, Basoglu OK, Cok G, Sayiner A, Ates M. Pulmonary tuberculosis in patients with diabetes mellitus. Respiration 2001;68:595-600. Stead WW, Senner JW, Reddick WT, Lofgren JP. Racial differences in susceptibility to infection by Mycobacterium tuberculosis. N Engl J Med 1990;322:422-7. Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV. Assessment of the interleukin 1 gene cluster and other candidate gene polymorphisms in host susceptibility to tuberculosis. Tuber Lung Dis 1998;79:83-9. Bellamy R. The natural resistance-associated macrophage protein and susceptibility to intracellular pathogens. Microbes Infect 1999;1:23-7. Bellamy R. Identifying genetic susceptibility factors for tuberculosis in Africans: a combined approach using a candidate gene study and a genome-wide screen. Clin Sci [Lond] 2000;98:245-50. Siddiqui MR, Meisner S, Tosh K, Balakrishnan K, Ghei S, Fisher SE, et al. A major susceptibility locus for leprosy in

47. 48. 49.

50. 51. 52. 53. 54.

55. 56. 57. 58.

59.

60.

61.

62.

63.

64.

65.

66.

India maps to chromosome 10p13. Nat Genet 2001;27:43941. Mc Caine PP. Tuberculosis among Negroes in the United States. Am Rev Tuberc 1937;35:25-35. Cummins SL. Primitive tuberculosis. London: John Bale Publications; 1939.p.14-35. Brailey M. A study of tuberculosis infection and mortality in the children of tuberculosis households. Am J Hyg 1940;31:143. Large SE. Tuberculosis in the Gurkhas of Nepal. Tubercle 1964;45:320-35. Comstock GW. Frost revisited: the modern epidemiology of tuberculosis. Am J Epidemiol 1975;101:363-82. Trobridge GF. Blood groups in tuberculosis. PhD Thesis. Birmingham: University of Birmingham; 1956. Lewis JG, Woods AC. The ABO and Rhesus blood groups in patients with respiratory disease. Tubercle 1961;42:362-5. Saha N, Banerjee B. Incidence of ABO and RH blood groups in pulmonary tuberculosis in different ethnic groups. J Med Genet 1968;5:306-7. Viskum K. The ABO and rhesus blood groups in patients with pulmonary tuberculosis. Tubercle 1975;56:329-34. Skamene E. Genetic control of resistance to mycobacterial infection. Curr Top Microbiol Immunol 1986;124:49-66. Brodsky FM, Lem L, Bresnahan PA. Antigen processing and presentation. Tissue Antigens 1996;47:464-71. Shiina T, Tamiya G, Oka A, Takishima N, Yamagata T, Kikkawa E, et al. Molecular dynamics of MHC genesis unraveled by sequence analysis of the 1,796,938-bp HLA class I region. Proc Natl Acad Sci USA 1999;96:13282-7. Mehra NK, Kaur G. HLA genetics and disease with particular reference to Type 1 diabetes and HIV infection in Asian Indians. Expert Rev Clin Immunol 2006;2:901-13. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. Structure of the human class I histocompatibility antigen, HLA-A2. Nature 1987;329:506-12. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 1987;329:512-8. Garrett T, Saper M, Bjorkman P, Strominger J, Wiley D. Specificity pockets for the side chains of peptide antigens in HLA-Aw68. Nature 1989;342:692-6. Saper MA, Bjorkman PJ, Wiley DC. Refined structure of the human histocompatibility antigen HLA-A2 at 2.6A resolution. J Mol Biol 1991;219:277-319. Spies T, Bresnahan M, Strominger JL. Human major histocompatibility complex contains a minimum of 19 genes between the complement cluster and HLA-B. Proc Natl Acad Sci USA 1989;86:8955-8. Zinkernagel RM, Doherty PC. Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis. Nature 1974; 251:547-8. Mehra NK, Jaini R, Rajalingam R, Balamurugan A, Kaur G. Molecular diversity of HLA-A*02 in Asian Indians: predominance of A*0211. Tissue Antigens 2001;57:502-7.

Genetic Susceptibility Parameters in Tuberculosis 141 67. Jaini R, Kaur G, Mehra NK. Heterogeneity of HLA-DRB1*04 and its associated haplotypes in the North Indian population. Hum Immunol 2002;63:24-9. 68. Tiwari JL, Terasaki PI. HLA antigens associated with diseases. In: Anonymous HLA and Disease Associations. New York: Springer; 1985.p.42-8. 69. Becker KG, Barnes KC, Bright TJ, Wang SA. The genetic association database. Nat Genet 2004;36:431-2. 70. Rosenthal AS, Shevach EM. Function of macrophages in antigen recognition by guinea pig T lymphocytes. I. Requirement for histocompatible macrophages and lymphocytes. J Exp Med 1973;138:1194-212. 71. Lee SY, Ko KW. A study on the frequency of HLA antigens in various diseases. Seoul Med J 1976;17:159-70. 72. Selby R, Barnard JM, Buehler SK, Crumley J, Larsen B, Marshall WH. Tuberculosis associated with HLA-B8, BfS in a Newfoundland community study. Tissue Antigens 1978;11:403-8. 73. Takata H, Sada M, Ozawa S, Sekiguchi S. HLA and mycobacterial infection: increased frequency of B8 in Japanese leprosy. Tissue Antigens 1978;11:61-4. 74. Al-Arif LI, Goldstein RA, Affronti LF, Janicki BW. HLA-Bw15 and tuberculosis in a North American black population. Am Rev Respir Dis 1979;120:1275-8. 75. Cox RA, Downs M, Neimes RE, Ognibene AJ, Yamashita TS, Ellner JJ. Immunogenetic analysis of human tuberculosis. J Infect Dis 1988;158:1302-28. 76. Jiang ZF, An JB, Sun YP, Mittal KK, Lee TD. Association of HLA-Bw35 with tuberculosis in the Chinese. Tissue Antigens 1983;22:86-8. 77. Hafez M, el-Salab S, el-Shennawy F, Bassiony MR. HLAantigens and tuberculosis in the Egyptian population. Tubercle 1985;66:35-40. 78. Hwang CH, Khan S, Ende N, Mangura BT, Reichman LB, Chou J. The HLA-A, -B, and -DR phenotypes and tuberculosis. Am Rev Respir Dis 1985;132:382-5. 79. Mehra NK, Taneja V, Chaudhri Kailash S, Bin AJ, Chang SX, Hawkins BR, et al. Pulmonary tuberculosis In: Aizawa M, editor. HLA in Asia- Oceania 1986. Sappro Japan: Hokkaido University Press;1986.p.374-9. 80. Xu XP, Li SB, Wang CY, Li QH. Study on the association of HLA with pulmonary tuberculosis. Immunol Invest 1986;15:327-32. 81. Papiha SS, Singh BN, Lanchbury JS, Roberts DF, Parsad CE, Wentzel J, et al. Association of HLA and other genetic markers in South Indian patients with pulmonary tuberculosis. Tubercle 1987;68:159-67. 82. Khomenko AG, Litvinov VI, Chukanova VP, Pospelov LE. Tuberculosis in patients with various HLA phenotypes. Tubercle 1990;71:187-92. 83. Brahmajothi V, Pitchappan RM, Kakkanaiah VN, Sashidhar M, Rajaram K, Ramu S, et al. Association of pulmonary tuberculosis and HLA in south India. Tubercle 1991;72:123-32. 84. Rajalingam R, Mehra NK, Mehra RD, Neolia S, Jain RC, Pande JN. HLA class I profile in Asian Indian patients with pulmonary tuberculosis. Indian J Exp Biol 1997;35:1055-9.

85. Goldfeld AE, Delgado JC, Thim S, Bozon MV, Uglialoro AM, Turbay D, et al. Association of an HLA-DQ allele with clinical tuberculosis. JAMA 1998;279:26-8. 86. Balamurugan A, Sharma SK, Mehra NK. Human leukocyte antigen class I supertypes influence susceptibility and severity of tuberculosis. J Infect Dis 2004;189:805-11. 87. Sette A, Sidney J. Nine major HLA class I supertypes account for the vast preponderance of HLA-A and -B polymorphism. Immunogenetics 1999;50:201-2. 88. Dubaniewicz A. HLA-DR antigens in patients with pulmonary tuberculosis in northern Poland. Preliminary report. Arch Immunol Ther Exp [Warsz] 2000;48:47-50. 89. Hawkins BR, Higgins DA, Chan SL, Lowrie DB, Mitchison DA, Girling DJ. HLA typing in the Hong Kong Chest Service/ British Medical Research Council study of factors associated with the breakdown to active tuberculosis of inactive pulmonary lesions. Am Rev Respir Dis 1988;138:1616-21. 90. Singh SP, Mehra NK, Dingley HB, Pande JN, Vaidya MC. Human leukocyte antigen [HLA]-linked control of susceptibility to pulmonary tuberculosis and association with HLA-DR types. J Infect Dis 1983;148:676-81. 91. Rajalingam R, Mehra NK, Jain RC, Myneedu VP, Pande JN. Polymerase chain reaction-based sequence-specific oligonucleotide hybridization analysis of HLA class II antigens in pulmonary tuberculosis: relevance to chemotherapy and disease severity. J Infect Dis 1996;173:669-76. 92. Selvaraj P, Uma H, Reetha AM, Kurian SM, Xavier T, Prabhakar R, et al. HLA antigen profile in pulmonary tuberculosis patients and their spouses. Indian J Med Res 1998;107:155-8. 93. Bothamley GH, Beck JS, Schreuder GM, D’Amaro J, de Vries RR, Kardjito T, et al. Association of tuberculosis and M. tuberculosis-specific antibody levels with HLA. J Infect Dis 1989;159:549-55. 94. Singh SP, Mehra NK, Dingley HB, Pande JN, Vaidya MC. HLA-DR associated genetic control of pulmonary tuberculosis in north India. Indian J Chest Dis Allied Sci 1983;25:252-8. 95. Mehra NK, Bovornkitti S. HLA and tuberculosis - a reappraisal. Asian Pac J Allergy Immunol 1986;4:149-56. 96. Sanjeevi CB, Olerup O. Restriction fragment length polymorphism analysis of HLA-DRB, -DQA, and -DQB genes in south Indians and Swedish Caucasians. Transplant Proc 1992;24:1687-8. 97. Opelz G, Mytilineos J, Scherer S, Dunckley H, Trejaut J, Chapman J, et al. Survival of DNA HLA-DR typed and matched cadaver kidney transplants. The collaborative transplant study. Lancet 1991;338:461-3. 98. Mehra NK, Rajalingam R, Mitra DK, Taneja V, Giphart MJ. Variants of HLA-DR2/DR51 group haplotypes and susceptibility to tuberculoid leprosy and pulmonary tuberculosis in Asian Indians. Int J Lepr Other Mycobact Dis 1995;63:241-8. 99. Sharma SK, Turaga KK, Balamurugan A, Saha PK, Pandey RM, Jain NK, et al. Clinical and genetic risk factors for the development of multidrug-resistant tuberculosis in non-HIV

142

100.

101.

102.

103.

104.

105.

106.

Tuberculosis infected patients at a tertiary care center in India: a casecontrol study. Infect Genet Evol 2003;3:183-8. Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 2002;166:916-9. Singh SPN, Mehra NK, Dingley HB, Pande JN, Vaidya MC. HLA haplotype segregation study in multiple case families of pulmonary tuberculosis. Tissue Antigens 1984;23:84-6. de Vries RR, Mehra NK, Vaidya MC, Gupte MD, Meera Khan P, Van Rood JJ. HLA-linked control of susceptibility to tuberculoid leprosy and association with HLA-DR types. Tissue Antigens 1980;16:294-304. van Eden W, de Vries RR, Mehra NK, Vaidya MC, D’Amaro J, van Rood JJ. HLA segregation of tuberculoid leprosy: confirmation of the DR2 marker. J Infect Dis 1980;141:693701. Mehra NK. Role of HLA linked factors in governing susceptibility to leprosy and tuberculosis. Trop Med Parasitol 1990;41:352-4. Kettaneh A, Seng L, Tiev KP, Tolédano C, Fabre B, Cabane J. Human leukocyte antigens and susceptibility to tuberculosis: a meta-analysis of case-control studies. Int J Tuberc Lung Dis 2006;10:717-25. Mehra NK, Verduijn W, Taneja V, Drabbels J, Singh SP, Giphart MJ. Analysis of HLA-DR2-associated polymorphisms by oligonucleotide hybridization in an Asian Indian population. Hum Immunol 1991;32:246-53.

107. Pitchappan RM. Castes, migration, immunogenetics and infectious diseases in south India. Community Genet 2002;5:157-61. 108. Singh M, Balamurugan A, Katoch K, Sharma SK, Mehra NK. Immunogenetics of mycobacterial infections in the North Indian population. Tissue Antigens 2007; 69[Suppl1]:228-30. 109. Zerva L, Cizman B, Mehra NK, Alahari SK, Murali R, Zmijewski CM, et al. Arginine at positions 13 or 70-71 in pocket 4 of HLA-DRB1 alleles is associated with susceptibility to tuberculoid leprosy. J Exp Med 1996;183:829-36. 110. Rajalingam R, Singal DP, Mehra NK. Transporter associated with antigen-processing [TAP] genes and susceptibility to tuberculoid leprosy and pulmonary tuberculosis. Tissue Antigens 1997;49:168-72. 111. Kharakter ZH, Mazhak KD, Pavlenko AV, Kapral’AIa. Genetic variants of haptoglobin in patients with destructive pulmonary tuberculosis. Vrach Delo 1990;8:54-5. 112. Grange JM, Davies PD, Brown RC, Woodhead JS, Kardjito T. A study of vitamin D levels in Indonesian patients with untreated pulmonary tuberculosis. Tubercle 1985;66:187-91. 113. Kramnik I, Dietrich WF, Demant P, Bloom BR. Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2000;97:8560-5. 114. Miller EN, Jamieson SE, Joberty C, Fakiola M, Hudson D, Peacock CS, et al. Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians. Genes Immun 2004;5:63-7.

Genetics of Susceptibility to Tuberculosis

9

Caroline J Gallant, Tania Di Pietrantonio, Erwin Schurr

INTRODUCTION There is a significant historical evidence demonstrating the importance of host genetic factors in susceptibility to tuberculosis [TB]. It is thought that the variable pattern of TB incidence reflects in part a population’s history of exposure to Mycobacterium tuberculosis, the causative agent of TB. Infectious diseases, such as TB, that entail a high morbidity and mortality in early life are expected to select genetic variants that confer resistance. Consequently, populations with a long history of exposure to Mycobacterium tuberculosis, such as Europeans, compared with populations only recently exposed, such as North American natives and sub-Saharan Africans, show greater resistance to TB (1,2). Population Variability in Susceptibility to Tuberculosis Two historical events illustrate both population differences and inter-individual variability in TB susceptibility. The accidental inoculation of infants with a virulent strain of Mycobacterium tuberculosis instead of the live attenuated vaccine strain Mycobacterium bovis bacille Calmette-Guérin [BCG] in Lübeck, Germany, in 1929 (3) provided inadvertent verification that, following uniform infectious exposure, individual variations exist in humans regarding susceptibility to TB. Of the 251 immunologically naive infants administered virulent Mycobacterium tuberculosis, four showed no signs of infection, 72 died of TB within one year of infection, and 175 overcame the infection (3). In comparison to the high survival rate of the German infants, North American

natives were devastated by TB upon initial exposure and TB death rates among American natives during the late 19th century were the highest ever recorded (2). Abel and Casanova (4,5) describe the genetic control of TB as a continuous spectrum, with simple Mendelian disease at one end [rare mutations with a strong effect], complex polygenic disease predisposition at the other [polymorphisms with a modest effect], and intermediate major susceptibility genes providing the link. High-risk alleles are rare in a population and explain very little of the overall disease prevalence. There is an evidence for major gene control of susceptibility in certain populations or epidemiologic contents where gene-environment interactions can be modelled (6). It is unknown if major gene effects are rare occurrences limited to specific epidemiological situations or go undetected due to the inherent difficulties in capturing important geneenvironment interactions in common diseases, such as TB. The relative importance of a locus in a public health context has been described using the population attributable fraction [PAF] which is defined as the fraction of the disease that would be eliminated if the risk factors were removed. It is hypothesized that common modestrisk variants may account for a greater PAF in complex diseases than rare high-risk alleles (7). For TB, numerous common genetic variants contributing moderately to susceptibility have been identified but their functional relevance and impact at the population level remain elusive (8-10). It seems likely that the genetic dissection of TB susceptibility will depend on studying all aspects of disease pathogenesis and the continuous study in both animal and human models (11).

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Pathogenesis and Genetic Studies The natural history of TB is described in the chapters “Pulmonary tuberculosis” [Chapter 14], and “Reactivation/ reinfection tuberculosis” [Chapter 47]. Understanding the natural history of TB and distinguishing between infection and disease progression are essential to dissect the genetic basis of TB (11). Exposure to mycobacteria usually does not result in clinical disease [Figure 47.1]. The outcome of exposure depends on a complex interaction between environmental factors, including the virulence, genetic make-up and mode of exposure to the infectious agent, and both host genetic and non-genetic factors (4,12). For example, host genetic susceptibility could involve a variant affecting the function of a gene involved in immunity to infection. Non-genetic factors might include human immunodeficiency virus [HIV] infection and acquired immunodeficiency syndrome [AIDS], advanced age, alcohol abuse, corticosteroids use, diabetes mellitus, nutritional status or co-infection with other pathogens (5). Ultimately, the outcome of exposure depends on the ability of the host’s innate and adaptive immunity to control and clear the infection, which, in turn, depends on the genetic background of both the host and the tubercle bacilli. Host-pathogen Interplay Several recent studies have shown important interactions between the host and genetically heterogeneous Mycobacterium tuberculosis strains (12-14). A study investigating the influence of strain genetic diversity on the course of disease in a mouse model of infection showed a marked difference in immunopathological events ranging from limited disease and 100 per cent survival with Canetti strains to extensive disease and significant earlier mortality with Beijing strains (14). Another study showed that the overexpression of a lipid species produced by strains belonging to the W-Beijing family inhibited the release of the pro-inflammatory cytokines tumour necrosis factor-α [TNF-α], interleukin-6, [IL-6], and interleukin-12 [IL-12] in murine monocyte-derived macrophages. The authors propose that Mycobacterium tuberculosis strain related differences are important in disease pathogenesis by modifying the host cellular immune response and thereby contributing to the diversity of clinical outcomes (12).

A study (13) of TB patients from the cosmopolitan urban centre of San Francisco, California, showed stable associations between genetically distinct strains of Mycobacterium tuberculosis and human host populations stratified according to place of birth. The association was shown for both reactivation disease and recent transmissions occurring in San Francisco. The authors (13) extend that the most important factors maintaining the association are epidemiological and social. However, they also suggest that given the stability and longevity of the association, it is possible that Mycobacterium tuberculosis would be allowed to adapt to the genetic, cultural and environmental characteristics of specific host populations (13). METHODS IN THE GENETIC DISSECTION OF COMPLEX INFECTIOUS DISEASES Numerous methods have been developed to identify genetic control elements of infectious diseases. Taking a forward genetics approach [phenotype-to-genotype], mendelian or complex inheritance in humans is dissected using hypothesis-driven or -generating methods both leading to candidate genes. Complementary studies in animals provide an experimental model of infection, which has been successful in identifying novel mycobacterial susceptibility genes. Candidate genes are validated by association studies, mutation detection, and finally, functional studies to determine the impact of the polymorphism on gene function and on the phenotype of interest (5). A key consideration in studying the genetics of complex disease is to take into account that a clinical outcome, i.e., active TB disease, is the synthesis of many intermediate phenotypes. For example, an intermediate phenotype could be the extent of an acquired immune response to specific Mycobacterium tuberculosis antigens, such as Ag85 (15). Studying intermediate and welldefined phenotypes increases the chance of identifying the genetic factors contributing to the risk of disease, although to date, few studies have taken this into account (7). Therefore, when designing a study to understand the genetic susceptibility to TB, it is important to distinguish between infection and disease progression, primary and reactivation disease, or pulmonary and disseminated TB. Inadequate definition, selection or

Genetics of Susceptibility to Tuberculosis 145 knowledge of the disease phenotype likely explains part of the poor reproducibility of genetic studies in TB and other common diseases. Whole-genome scans using linkage analysis are most successful in identifying genes with strong effects on disease susceptibility. Linkage analyses search within families for regions of the genome that segregate nonrandomly with the phenotype of interest (7). Wholegenome scans have been used to identify susceptibility loci in several human infectious diseases, including schistosomiasis (16), visceral leishmaniasis and leprosy (9,17,18) but results in TB have been less clear (19,20). Whole-genome association studies have long been suggested to be a more powerful approach than linkage analysis to identify common modest-risk genes (7,21). However, until recently, the lack of high-density single nucleotide polymorphism [SNP] maps and limited technological capabilities have inhibited its use (7). To date, whole-genome association studies have not been used to identify any genes important in infectious disease susceptibility but may be a powerful tool in future studies. Candidate genes can be identified from linkage hits in whole-genome scans (22), based on studies of animal models in vivo (23) or human cells in vitro, or by comparison with human inherited disorders with a related clinical phenotype (5). Candidate genes are tested by association using population or family-based case-control designs. The estimated relative risk of variants for TB in many of these candidate genes is often small [1.5 to 4] and many results have been proven difficult to replicate in independent studies. A widely used and powerful approach for the study of infectious disease genetics are experiments in mouse models. Mouse models have helped uncover numerous genes involved in the control of TB infection. Gene-disrupted mice are useful in that they provide a controlled approach for the genetic dissection of Mycobacterium tuberculosis infection. Furthermore, new experimental and analytical tools have facilitated genome-wide scanning, promoting the identification of new TB genes. These advances in TB research have made important contributions to our knowledge of TB susceptibility that will lead to increased prevention and maintenance of the human disease. Selected data will be shortly reviewed in the following sections.

MOUSE MODELS Studies involving mouse models have provided important insight into the mechanisms of susceptibility and resistance to TB. Although Mycobacterium tuberculosis is not a natural mouse pathogen, inbred strains of mice vary extensively in their susceptibility to TB (24-26). Moreover, experimental crosses between susceptible and resistant mouse strains have shown that, as in humans, murine disease is under multigenic control (27). Specifically, mouse susceptibility loci identified through wholegenome scanning have expanded our knowledge of the host genetic contribution to Mycobacterium tuberculosis infection outcome. In addition, mice with targeted gene deletions have led to the identification of critical mediators involved in antituberculosis immunity. Novel susceptibility genes identified through these genetic studies have subsequently been exploited as human candidate TB susceptibility genes. A well-documented example is the discovery of the murine solute carrier family 11 [proton-coupled divalent metal ion transporters], member 1 [Slc11a1], formerly known as natural resistance associated macrophage protein [Nramp1] gene whose human orthologue, SLC11A1, was later determined to be a susceptibility gene in TB, leprosy and HIV (28-30). Solute Carrier Family 11 [Proton-Coupled Divalent Metal Ion Transporters] Member 1 [SLC11A1] Studies Mendelian segregation analysis in populations of informative crosses between inbred mouse strains revealed that natural resistance to BCG was under the control of a single autosomal dominant gene designated ‘Bcg’. The Bcg gene exists in two phenotypic allelic forms in inbred mouse strains: susceptible Bcg s mice are permissive to mycobacterial replication in their reticuloendothelial organs at the initial phase of infection whereas Bcgr strains restrict growth of the bacilli (31). Chromosomal mapping localized the Bcg gene to the proximal portion of mouse chromosome 1 (32), a region overlapping the previously identified Lsh and Ity loci which controlled infection with the taxonomically unrelated intracellular pathogens Leishmania donovani (33) and Salmonella typhimurium (34). The candidate for the Bcg/ Ity/Lsh locus, Slc11a1, was isolated by positional cloning and found to encode a 12-transmembrane divalent cation

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transporter expressed by professional phagocytes (23). Susceptibility to infection was later determined to be the result of a single, non-conservative, glycine-to-aspartate substitution at position 169 of the SLC11A1 protein (35). Although the Slc11a1 gene confers protection against the mycobacterial species BCG, Mycobacterium intracellulare (36) and Mycobacterium lepraemurium (37,38), its role in modulating infection with virulent Mycobacterium tuberculosis remains elusive. For example, a number of groups examining the effects of Slc11a1 on the growth kinetics of Mycobacterium tuberculosis following low dose infection observed higher bacillary loads in the lungs and spleens of Slc11a1s (39,40) animals while others failed to detect any differences (26). In a strain susceptibility survey, Slc11a1r strains had consistently shorter survival times than Slc11a1s mice (25). Concomitant with the polygenic control of TB, F1 hybrids from resistant and susceptible strains were all resistant to infection whereas the F2 progeny had random survival times. However, the length of survival was independent of the Slc11a1 genotype (41). Additional evidence against a role for Slc11a1 in murine TB arose from studies involving congenic Slc11a1r strains (40,42) and Slc11a1 gene deletion strains (43). In both instances, the Slc11a1-modified mice displayed a similar resistance to Mycobacterium tuberculosis as their wild-type counterparts. Mouse Knock-out Studies Since macrophages are the primary host cells in which Mycobacterium tuberculosis bacilli persist and replicate, a deficiency in macrophage genes involved in pathogen recognition as well as in macrophage activation and recruitment render the host incapable of containing infection with Mycobacterium tuberculosis. Consequently, infection of targeted gene disrupted mice with Mycobacterium tuberculosis can help to delineate the role of different cell populations as well as cytokines, chemokines, signalling molecules, receptors and adhesion molecules involved in host-Mycobacterium tuberculosis interaction. Cellular Immunity Control of Mycobacterium tuberculosis infection necessitates cell-mediated rather than humoral immunity and involves a direct interaction between effector T-cells and infected macrophages. To assess the role of T- and B-cells in Mycobacterium tuberculosis eradication, mice

devoid of either cell type have been generated. Despite the conflicting results observed in mice lacking B-cells (44-46), protection against TB is clearly mediated by T-cells of the α/β lineage with the possible help of γδ T-cells. Specifically, mutant mice lacking αβ T-cells succumb quickly to Mycobacterium tuberculosis infection (47,48) while those deficient in γδ T-cells survive a low dose but die when a high inoculum is administered (47,49). To further dissect the importance of αβ T-cells subsets, CD4- and CD8- disrupted mice infected with Mycobacterium tuberculosis were tested for increased susceptibility. Both knockout mouse strains were shown to have increased bacterial burdens (50-52) and earlier mean time to death (50) compared to control animals. To date, the contribution of CD4+ T-cells in antituberculosis immunity has clearly been shown to reside in its involvement in Th1 cytokine production. However, the function of CD8+ T-cells has not been fully established. Although a lytic role had initially been ascribed to CD8 T-cells, studies involving perforin- and granzymedeficient mice (53,54) suggest that CD8+ protective effects may be mediated by other mechanisms including the synthesis of the cytokine interferon-gamma [IFN-γ] (55). Cytokines The development of Th1 cell-mediated immunity involving the central cytokine IFN-γ, as well as TNF-α, and IL-12 has been postulated to be a critical mechanism of genetic resistance to Mycobacterium tuberculosis. Mice with a targeted IFN-γ gene deletion exhibit extreme susceptibility to TB, succumbing to a fulminant and disseminated form of the disease (56-59). Importantly, the genetic disruption of the IFN-γ receptor 1 [IFN-γr1] (60) or IFN-γ-responsive genes including the signal transducer and activator of transcription 1 [Stat1] (60,61), the nuclear factor-kappa beta p50 [Nfkb1] (62), the interferon regulatory factor-1 [Irf1] (63,64), and the interferon inducible protein LRG-47 [Ifi1] (60,65) also produce a severe pathological condition characterized by early death following Mycobacterium tuberculosis infection. Since an important effector mechanism of IFN-γ is the production of reactive nitrogen intermediates (66), ablation of the nitric oxide synthase [Nos2] gene also elicits a highly susceptible phenotype (67,68). Similarly, genetic deletion of TNF-α (69-71) abolishes the hosts’ ability to form functional

Genetics of Susceptibility to Tuberculosis 147 granulomas causing rapid mortality following infection while a deficiency in its receptor [TNFrsf1a and TNFrsf1b] (72,73) results in widespread tissue necrosis. Interestingly, mice with disruptions in other members of the TNF superfamily such as lymphotoxin a [Lta] also display a heightened susceptibility to infection with Mycobacterium tuberculosis (74,75). However, the deletion of a novel TNF superfamily member, LIGHT [Tnfsf14], did not affect TB susceptibility (75) whereas lymphotoxin β [Ltb] or Ltb receptor [Ltbr] deficient animals were observed by some (74), but not by others (75) to successfully contain the infection. Lastly, since IL-12 is a potent stimulator of IFN-γ production (76), it also plays a critical role in anti-mycobacterial immunity. Direct evidence for its mycobacteriostatic effects arose from studies in mice with a genetic disruption in either the p40 [Il12b] or p35 [Il12a] subunit of the IL-12 molecule (77,78). Strains deficient in IL-12p35 survived longer than those lacking p40 possibly due to an alternative activation by interleukin-23 [IL-23]. Since IL-12 signals mainly through the STAT4 protein, a knock-out of the STAT4 gene obliterated both IL-12 responsiveness and IFN-γ production, resulting in early death following Mycobacterium tuberculosis infection (79). Unlike Th1 cell-mediated immunity, the role of the Th2 response in the host defense against Mycobacterium tuberculosis has not been defined. The Th2 cell activation, characterised by IL-4 and interleukin-10 [IL-10] production, promotes principally humoral immunity and antagonizes the Th1 proliferation pathway. With the exception of one study (80), the absence of the Il-4 gene was not shown to alter mycobacterial growth (59,81) while the functional deletion of the genes encoding the IL-4 responsive molecules STAT6 and the alpha chain of the IL-4 receptor [Il4ra] slightly increased susceptibility to Mycobacterium tuberculosis-triggered disease (82). Furthermore, a double knock-out of Il4 and Il13, whose gene products both signal through IL-4Rα, did not affect mycobacterial replication. Finally, depletion of the Th2polarising cytokine IL-10 was shown to be associated with a decreased pulmonary bacterial load in one study (83) while another group failed to observe any difference (59,84). Although the interleukin-18 [IL-18], IL-6 and interleukin-1 [IL-1] cytokines regulate both Th1 and Th2

immune responses (85-89), their significance in Mycobacterium tuberculosis immunity lies primarily in the generation of protective Th1 responses. In IL-18-deficient mice for example, a reduced production of IFN-γ caused enhanced susceptibility to mycobacterial infection (90,91). Recently, mice lacking Il-12, Il-18 and Il-23 due to the double knock-out of Il12b and Il18 were still shown to synthesize IFN-γ in response to Mycobacterium tuberculosis, suggesting an IL-12, IL-18 and IL-23-independent IFN-γ production (92). In fact, the proinflammatory cytokine IL-6 has been shown to induce IFN-γ synthesis and, in its absence, mice develop high bacillary loads early in response to an aerosol infection with Mycobacterium tuberculosis (81) and succumb rapidly to a large intravenous infection (93). Similarly, studies involving mice with a targeted disruption of the Il1a and Il1b genes (94) or the Il1r gene encoding its receptor (95,96) also demonstrated that IL-1 signalling participates in the response to Mycobacterium tuberculosis. However, reduced IFN-γ production was observed in IL-1R depleted mice only. Chemokines Chemokines and their receptors mediate cellular trafficking to and from inflammatory sites, outlining a plausible role for these cytokines in granuloma formation. Functional redundancy among chemokines may explain the observation that the genetic deletion of chemokine ligand 2 [CCL2], which is also referred to as monocyte chemoattractant protein 1 [MCP-1], did not drastically diminish resistance to Mycobacterium tuberculosis (97,98). In contrast, an exacerbation of Mycobacterium tuberculosis growth and rapid mortality was observed in mice deficient in the receptor for CCL2, the C-C chemokine receptor 2 [CCR2], only after a high dose infection with Mycobacterium tuberculosis (99,100), likely the result of the promiscuity of CCR2 for multiple chemokines. Interestingly, mutant mice with a disruption in the gene encoding the chemokine receptor CCR5 had increased levels of dendritic cells and Mycobacterium tuberculosis bacilli in their lymph nodes, alluding to the role of CCR5 in dendritic cellular migration to and from the lymph nodes (101). Furthermore, genetic deletion of CXCR3 resulted in impaired and delayed granuloma formation, suggesting that CXCR3-signalling is involved in granuloma regulation (102).

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Adhesion Molecules Adhesion molecules are logical TB candidate genes due to their involvement in cellular migration. Truncation of the intracellular adhesion molecule 1 [ICAM-1] by genetic disruption of the Icam gene did not alter the initial course of infection (103), although it was shown to be essential for granuloma formation and long-term mycobacterial containment (104). Infection of mice deficient in the complement receptor type 3 [CR3] was indiscernible from wild type controls (105) whereas the deletion of the CD44 antigen promoted bacterial growth and rapid mortality (106). Pattern Recognition Receptors To investigate the role of so-called pattern recognition receptors [PRRs] in Mycobacterium tuberculosis immunity, mice defective in a number of Toll-like receptors [TLR] as well as in the TLR intracellular adaptor molecule myeloid differentiation factor 88 [MyD88] have been generated. Studies in mice without functional TLR4 (107) or TLR6 (108) have indicated that these PRRs are not involved in mycobacterial clearance. Although one study suggested that the protective effect of TLR2 is doserelated (107), conflicting data exist regarding the relevance of TLR2 deficiency in host survival following Mycobacterium tuberculosis infection (108,109). Furthermore, disruption of CD14, encoding a molecule that interacts with both TLR2 and TLR4 (110), did not influence susceptibility to TB (107). Deletion of MyD88, whose gene product is shared among the TLRs, was shown to profoundly affect mycobacterial proliferation by one group (111) but these results were not corroborated by another study in which differences were undetectable (112). Major Histocompatibility Complex The CD4 and CD8 T-cells interact with the class II and class I major histocompatibility complex [MHC], respectively. Disruption of the latter molecules provided direct evidence for their importance in mycobacterial control. Interestingly, mice lacking MHC class II molecules manifest greater susceptibility than either CD4 (50) or MHC class I deficient animals (48). In fact, some studies reported that the genetic deletion of the β2-microglobulin component of MHC class I causes only a slight difference in resistance (47) while discordant results showed a highly susceptible phenotype (51,52,113).

Although the H-2 genes have been implicated in the antibody response to mycobacterial antigen (114,115), the generation of a granulomatous inflammatory response to Mycobacterium tuberculosis does not appear to be under H-2 control (116). Nonetheless, carriers of the H-2k haplotype have been shown to display greater susceptibility to Mycobacterium tuberculosis than H-2b and H-2d carriers as evidenced by biological phenotypes such as bacterial burden in the lung (117) and median survival times (25). Paradoxically, infection with a large inoculum of Mycobacterium tuberculosis caused the H-2k haplotypes to be associated with a longer duration of survival while H-2b and H-2d appear to confer an increase in susceptibility (118). Quantitative Trait Locus Analysis Due to the multigenic nature of host resistance to TB, quantitative trait locus analysis has been adopted to identify genes involved in disease control. Essentially, genome-wide scans are performed on populations of informative backcross or intercross animals generated between strains representing polar ends of a resistance/ susceptibility spectrum. The quantitative trait locii that impact on TB susceptibility are then assigned to specific chromosomal regions through the use of sophisticated algorithms (119,120) and high-density genome-wide maps. The first of the genome-wide scans investigated Mycobacterium tuberculosis triggered weight loss in a panel of backcross animals derived from resistant A/Sn and susceptible I/St mice (121). The quantitative trait locii were identified in female mice only on a region of chromosome 3 containing the peroxisomal membrane protein 1 [Pxmp1] gene as well as on an area of proximal chromosome 9 overlapping the macrophage metalloelastase [Mme1] gene and the IL-10 receptor α-chain [Il10ra] gene. In addition, suggestive linkages were observed on chromosomes 8 and 17 in females and 5 and 10 in males. Recently, each of these loci was tested for linkage to cachexia and survival time in Mycobacterium tuberculosis-infected F2 hybrid mice from A/Sn and I/St parental strains (122). The quantitative trait locii on chromosomes 3 and 9, designated TB severity 1 [tbs1] and tbs2 respectively, were only suggestively linked to post-infection body weight loss in F2 mice of both sexes. Another important susceptibility locus was mapped to a region located only 10 centiMorgan [cM] from the

Genetics of Susceptibility to Tuberculosis 149 Sic11a1 gene on mouse chromosome 1. This locus, designated sst1 for susceptibility to TB, controlled the progression of lung disease caused by virulent Mycobacterium tuberculosis in an F2 population derived from resistant C57BL/6J and susceptible C3HeB/FeJ progenitor strains (123). Interestingly, C57BL/6J mice, which are resistant to infection with Mycobacterium tuberculosis, carry both the resistant allele of sst1 and the susceptibility allele of Sic11a1. Recently, it has been shown that the sst1 locus influences susceptibility to another intracellular pathogen, Listeria monocytogenes (124). Positional cloning isolated the candidate for sst1, the intracellular pathogen resistance 1 [Ipr1] gene, which is thought to encode a putative transcription factor. Another TB resistance locus, Trl-1, localized on mouse chromosome 1, was shown to be mutually exclusive of both Sic11a1 and Ipr1 (125). This locus, which impacted on the mean survival time in response to Mycobacterium tuberculosis injected intravenously, was identified using a panel of F2 mice derived from susceptible DBA/2J and resistant C57BL/6J mouse strains. Importantly, the Trl1 region encompassed several interesting genes including the chemokine receptor Cxcr4, l10, the Fas ligand [Fasl], the selectin and the neutrophil cytosolic factor 2 [Ncf2] gene encoding the p67 phox subunit of the NADPHdependent oxidase. The Trl-2 locus, which was suggestively linked to the proximal portion of chromosome 7, included Il2, Il12a, and I16 interleukin genes and interleukin receptor chain genes, while the interval for Trl-3 on the proximal portion of chromosome 3 did not contain any obvious candidate genes. Recently, a Trl-4 locus on chromosome 19 was shown to regulate the pulmonary replication of Mycobacterium tuberculosis in response to a low dose aerosol infection (126). Among the genes contained in this region are those encoding nuclear factor-kappa beta [NF-kB], NF-kB inducing kinase α [Ikkα], and the α chain of the cell surface receptor for granulocyte/macrophage colony stimulating factor [GM-CSFRα]. GENETIC STUDIES IN HUMAN POPULATIONS Mendelian Susceptibility to Mycobacterial Disease [OMIM 209950] The lack or partial deficiency of proteins in the IL-12/ IL-23-IFN-γ axis can lead to a rare syndrome called mendelian susceptibility to mycobacterial disease [MSMD]. Individuals with the syndrome are highly

susceptible to poorly virulent mycobacteria such as environmental nontuberculosis mycobacteria [NTM] and BCG vaccine. With the exception of salmonellosis occurring in fewer than half the MSMD cases, disease caused by other microorganisms is very rare (127). Several patients with the syndrome have been diagnosed with clinical TB but it is unclear to what extent the mutations are important in Mycobacterium tuberculosis infection or disease progression (127-130). Five genes have been found to be mutated in patients with the syndrome. Mutations in the IFN-γ receptor 1 [IFNGR1, OMIM 107470] and IFN-γ receptor 2 [IFNGR2, OMIM 147569], which encode the two IFN-γ receptor chains, and signal transducer and activator of transcription 1 [STAT1, OMIM 600555], an essential signalling component, result in impaired cellular responses to IFN-γ. Mutations in the interleukin-12 subunit p40 [IL-12B, OMIM 161561] and interleukin-12 receptor β-1 subunit [IL-12Rβ1, OMIM 601604] result in impaired IFN-γ production. The mutations can be classified into three classes of alleles: recessive nonfunctional; recessive, partially-functional; and dominantnegative partially-functional (127). The classes of alleles correspond to distinct clinical, immunological and histopathological outcomes. Individuals with mutations resulting in complete IFNGR1 and IFNGR2 deficiency lack cellular response to IFN-γ. Patients invariably develop BCG and/or NTM disease which is early onset, disseminated and often lethal. All BCG-vaccinated IFNGR1 and IFNGR2 deficient patients develop BCG-disseminated disease (5,127). Mutations leading to partially-recessive IFNGR1 and IFNGR2 deficiency result in impaired but not abolished response to IFN-γ. The resulting clinical phenotype is milder and the prognosis better than for children with complete IFNGR deficiency (127,131). There is a clear correlation between IFNGR1 and IFNGR2 genotype [loss-of-function or hypomorphic mutation], the cellular phenotype [complete or partial defect of response to IFN-γ] and clinical phenotype [favourable or poor outcome]. From this observation, IFN-γ-mediated immunity can be viewed as a quantitative trait that is critical for the outcome of mycobacterial infection (127,131). Mutations in STAT1, a critical transducer of interferon-mediated signals, cause a partially-dominant deficiency (132). Clinical and cellular phenotypes are similar to patients with partially-recessive IFN-GR

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deficiency (127,133). Complete deficiency of IL-12p40, encoded by IL-12β, results in impaired production of IFN-γ. Monocytes or dendritic cells from these patients are unable to secrete IL-12 upon stimulation and consequently their lymphocytes secrete less IFN-γ than those of normal individuals. Patients with complete IL12Rβ1 deficiency show no cellular response to both IL12 and IL-23. The clinical outcome of IL-12 deficient patients varies from case to case suggesting that alternate pathways are compensating for the loss of IL-12 signalling. In addition, strictly asymptomatic individuals with a loss-of-function mutation have been identified. A greater proportion of patients with IL-12/IL-23 deficiency have a history of severe salmonella disease than those with IFN-γ deficiency. These findings suggest a greater importance of IL-12/IL-23 mediated through IFN-γ independent pathways than IFN-γ in immunity against salmonella (134). Interleukin-23, a recently identified IL-12 like heterodimer, is composed of IL-12p40 and p19 and binds to a heterodimeric receptor composed of IL-12Rβ1 and a novel chain (135). Individuals that are completely or partially IL-12p40 or IL-12Rβ1 deficient are also IL-23 or IL-23R deficient. It is possible that the phenotypes seen in these individuals result from the disruption of both cytokines (136). A recent study has provided evidence that IL-23 is important for infection and possibly the primary type 1 cytokine. The study showed that mycobacterium-activated type-1 macrophages secrete IL23 [p40/p19] but not IL-12 [p40/p35]. The macrophages required IFN-γ as a secondary signal to induce IL-12p35 gene transcription and IL-12 secretion (137). Although the phenotype-genotype relationship for IFN-γ-mediated immunity against mycobacterial disease is relatively clear, the importance of genetic variation in the IL-12/IL-23-IFN-γ pathway at the population level is less well understood. The extent of cases of rare Mendelian mutations responsible for cases of TB in areas of endemicity is unknown, as well as the contribution of more common genetic variants within the IL-12/IL-23IFN-γ pathway exerting a more modest effect on the genetic control of TB (138,139). CANDIDATE GENES Interleukin-12/Interleukin-23/Interferon-γγ [IL-12/IL-23-IFN-γγ] Pathway The observation that some IL-12Rβ1-deficient patients present with TB as the only clinical phenotype led to a

family-based association study in Moroccan pulmonary TB patients. None of the genetic variants identified in IL-12Rβ1 were loss-of-function or hypomorphic, however, two promoter variants were associated with TB (138). A case-control study in Hong Kong Chinese TB patients (140) found a strong association between a IL-12B intron 2 genetic variant and TB susceptibility. Individuals homozygous for the associated variant had an estimated 2.14-fold increased risk of developing TB. In addition, specific IL-12B haplotypes were found to be over-represented in TB patients. No correlation was found between IL-12p70 expression and associated genetic polymorphisms (140). No associations were found in a Gambian population between IFNGR1 polymorphisms, including one variant previously found associated in a Croatian (141) population, and adult pulmonary TB (142). A study looking at polymorphisms in the IFNGR1 promoter region and either pulmonary or disseminated NTM infection, or pulmonary NTM infection also failed to show an association. Two SNPs were reported to influence expression but were not associated with increased susceptibility (139). Overall, it appears that genes of the IL-12/IL-23-IFN-γ pathway are risk factors for TB but that the genetic effect is weak. It is possible that the pathway is more important for primary infection during childhood or the development of disseminated TB rather than pulmonary TB (142), a suggestion that deserves further experimental study. Interferon-γγ Given the importance of IFN-γ-mediated immunity in MSMD and in animal models of infection, IFNG is a prime TB susceptibility candidate gene. A T to A polymorphism was identified in the first intron of IFNG where the T-allele is associated with increased in vitro IFN-γ production. This polymorphism coincides with a putative NF-kb binding site where NF-kb was shown to preferentially bind to the T-allele (143). Two studies in a South African population further investigated the role of the T to A polymorphism in TB [both pulmonary and meningitis] susceptibility. In a case-control study, the polymorphism showed a significant association with TB. The T-allele was over-represented in the controls and, therefore, suggested to confer protection. This result was replicated in a family-based association study of individuals from the same community (10). These findings were also reproduced in a Sicilian population. The

Genetics of Susceptibility to Tuberculosis 151 TT genotype was significantly decreased in TB patients compared with the controls (144). In contrast, no association between IFNG and TB was found in TB patients from the Karonga district of northern Malawi (145). The importance of IFN-γ in Mycobacterium tuberculosis infection has been questioned as the pathogen interferes with IFN-γ signalling and downregulates the transcription of IFN-γ inducible genes (146,147). However, the combined results from human and animal genetic studies make a strong case for the importance of IFN-γ levels in variation of susceptibility to TB. Solute Carrier Family 11 [Proton-coupled Divalent Metal Ion Transporters] Member 1 [SLC11A1] The human orthologue of murine Slc11a1, which confers susceptibility to specific Salmonella, Leishmania and Mycobacterium species (148), has been tested in numerous association studies. Initially, SLC11A1 variants were found to be associated with TB susceptibility in a West African population (149). Individuals with TB were fourtimes more likely to have a disease-associated SLC11A1 genotype combination than healthy controls (149). These observations have been replicated in several studies of patients from China, Japan, Korea, Malawi, GuineaConakry and Cambodia (145,150-154). The independent replication of SLC11A1 association with TB across different populations makes SLC11A1 the most solidly established TB susceptibility gene. Nevertheless, several studies failed to detect an SLC11A1/TB association (155,156) providing strong evidence for genetic heterogeneity in TB susceptibility. The modest genetic impact of the gene on susceptibility has been interpreted to suggest that the gene accounts for only a small proportion of the total genetic contribution to susceptibility (9,157). However, an alternative explanation is provided by a genetic study of TB susceptibility in a native Canadian community. In this study, it was possible to detect a very strong genetic effect [relative risk of 10] of the SLC11A1 region on TB (6). Of importance, this strong genetic effect was only detected when gene-environment interactions were included into the analysis. Despite substantial genetic evidence implicating SLC11A1 in TB susceptibility, a causal relationship between specific SLC11A1 variants and increased TB susceptibility remains to be established.

Vitamin D Receptor Before the development of antimycobacterial drugs, vitamin D was administered with some success to treat TB (158). It has since been discovered that the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25[OH]2D3], interacting with the vitamin D receptor [VDR], acts as an important immunomodulatory molecule (159). Vitamin D plays a role in activating monocytes and cell-mediated immunity, modulates the Th1-Th2 host immune response, phagocytosis, and suppresses lymphocyte proliferation, immunoglobulin production and cytokine synthesis (160-162). In vitro, 1,25[OH] 2D 3 restricts the growth of Mycobacterium tuberculosis in human macrophages (163,164). In addition, results from epidemiologic studies point to a link between vitamin D deficiency and a higher risk of TB (19,165). This is demonstrated by seasonal variation of TB incidence, lower vitamin D serum levels in untreated TB patients, and higher incidence of TB in individuals with relatively low serum vitamin D levels (166,167). Given that vitamin D exerts its effects via the VDR, and that the receptor is present on monocytes and on Tand B-lymphocytes (168), several studies have investigated the role of VDR genetic variants in TB susceptibility. Two case-control association studies done in a Gambian population found conflicting results. The earlier study reported that the TaqI tt genotype was found to be over-represented in healthy controls (169). However, in a subsequent study, the association was not reproduced (170) and no individual VDR polymorphism was found associated with TB susceptibility. The authors explain the discrepancy by stating that the previous study might have been flawed because of ill-diagnosed TB patients and poorly chosen controls (170). A family-based design in the same population but different individuals showed a significant “global” association of TB and the polymorphisms FokI-BsmI-ApaI-TaqI and FokI-ApaI. Only the FokI polymorphism has been shown to have functional significance. It is correlated with increased vitamin Dinduced receptor function (171). The authors concluded that their study supports a role for VDR haplotypes, rather than individual genotypes, in susceptibility to TB (170). Studies that took into account vitamin D serum levels or treatment outcome were more successful in detecting

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a significant genetic effect. A small case-control study in a Peruvian population found specific VDR polymorphisms [TaqI Tt and FokI FF] associated with the time to sputum culture and auramine stain conversion during treatment. No VDR polymorphisms were associated with susceptibility to progression of pulmonary TB, although the TaqI t allele was over-represented in the healthy controls compared with the TB patients. It should be noted that the homozygous tt genotype was virtually absent in the population sample. A larger sample size would be needed to demonstrate the effect of the TaqI polymorphism (172). A case-control association study (167) of Gujarati Asians/Indians living in west London, England, investigated the interaction between VDR genotype and serum vitamin D concentrations. The study failed to show a significant association between VDR genotype and increased risk of TB. However, a strong association was observed between vitamin D deficiency and TB. In addition, the study was able to detect evidence for an interaction between genotype [either TaqI TT/Tt or FokI ff], deficient or undetectable vitamin D serum levels and susceptibility to TB (167). Several other studies have investigated the role of the VDR polymorphisms and TB susceptibility, however, the reports vary considerably in their findings (145,154, 173,174). The findings from the case-control association studies indicate a potential role of VDR polymorphisms in TB susceptibility; however, most of the studies suffer from a lack of power due to small sample sizes. These findings need to be replicated in larger samples and the functional relevance of the associated polymorphisms needs to be further studied. Major Histocompatibility Complex Reports of association between highly polymorphic class II human leucocyte alleles and TB susceptibility are conflicting and vary among populations. Different studies have found associations with human leucocyte antigen- [HLA-] DR2 alleles (175-177) and with HLADQB1*0501 (177) and DQB1*0503 alleles (178). Some studies failed to detect the HLA-DR2 or DQB1 associations (179,180). One study reported HLA-DR3 to be enriched in healthy controls suggesting a protective effect of the antigen. The functional significance of the positive associations are not known. Further studies are required to fully understand the importance of the MHC in TB

susceptibility, whether in infection, disease progression or chemotherapy, before any conclusions can be made. The reader is also referred to the chapter “Genetic susceptibility parameters in tuberculosis” [Chapter 8] for more details on this topic. Mannose Binding Lectin Mannose binding lectin [MBL2] is an important part of innate immunity, which acts in concert with the classical complement system to opsonize and facilitate phagocytosis of a variety of microorganisms. For mycobacteria, it binds to the mannose residues in the lipoarabinomannan membrane [LAM] covering the bacteria (181,182). Several high frequency mutations in the MBL gene, MBL2 result in complete MBL deficiency in the homozygote state. Heterozygous individuals show low MBL serum concentrations. The high frequency of these loss-of-function mutations in several populations suggests that they may confer an advantage against certain infections. Intracellular pathogens, such as Mycobacterium tuberculosis, partly exploit the complement system to invade and replicate within host cells. Several studies have investigated whether mutations leading to partial or complete MBL deficiency provide a protective effect against TB. Studies in South African, Gabonese, Danish and African-American populations showed significant associations between MBL2 genetic variants encoding low serum MBL levels and protection against active TB (23,183-185). In addition, one study found significantly lower levels of serum MBP concentrations in TB-negative controls compared with fully recovered TB patients (186). One study in a population from the Karonga district of northern Malawi showed no association between MBL2 genotype and TB susceptibility or protection (145). Functional studies on the interaction between MBL and Mycobaterium tuberculosis need to be done to confirm the importance of the MBL in TB susceptibility. Linkage Studies Complementary to candidate gene studies are genomewide scans, a powerful approach to identify major susceptibility loci. A study was performed in 92 sib-pairs with TB from Gambia and South Africa. Weak evidence for linkage was detected on chromosome regions 15q and Xq (19). Expectations that major novel loci had been identified were not borne out in a follow-up association

Genetics of Susceptibility to Tuberculosis 153 study of the 15q region (8). More recently, a genome scan for TB in a Brazilian population found three regions with suggestive evidence for linkage: 6q21.32, 17q22, 20p13 (20). No subsequent studies on these regions have been reported. Dissection of the genetic susceptibility to TB using both murine and human models has led to the identification of specific genes and immunological pathways important in antituberculosis immunity. To confirm current findings, further genetic studies are required that involve larger study populations and well-defined disease phenotypes. In addition, functional studies are necessary to understand the importance of critical murine antituberculosis mechanisms at the human level and to determine the effect of associated genetic variants on gene function specifically and on TB susceptibility generally. The knowledge gained from studying host genetic susceptibility will ultimately contribute to designing an effective TB vaccine and novel therapeutic strategies, both being urgent needs given the impact of TB on global health.

10.

11. 12.

13.

14.

15.

16.

REFERENCES 1. Motulsky AG. Metabolic polymorphisms and the role of infectious diseases in human evolution 1960. Hum Biol 1989;61:835-69. 2. Daniel TM, Bates JH, Downes KA. History of tuberculosis. In: Bloom BR, editor. Tuberculosis pathogenesis, protection and control. Washington: ASM; 1994.p.13-24. 3. Schurmann P. Beobachtungen bei den Lubecker sauglingstuberkulosen. Beit Klin Tuberk 1932;81:294. 4. Abel L, Casanova JL. Genetic predisposition to clinical tuberculosis: bridging the gap between simple and complex inheritance. Am J Hum Genet 2000;67:274-7. 5. Casanova JL, Abel L. The human model: a genetic dissection of immunity to infection in natural conditions. Nat Rev Immunol 2004;4:55-66. 6. Greenwood CM, Fujiwara TM, Boothroyd LJ, Miller MA, Frappier D, Fanning EA, et al. Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family. Am J Hum Genet 2000;67:405-16. 7. Carlson CS, Eberle MA, Kruglyak L, Nickerson DA. Mapping complex disease loci in whole-genome association studies. Nature 2004;429:446-52. 8. Cervino AC, Lakiss S, Sow O, Bellamy R, Beyers N, Hoalvan Helden E, et al. Fine mapping of a putative tuberculosissusceptibility locus on chromosome 15q11-13 in African families. Hum Mol Genet 2002;11:1599-603. 9. Shaw MA, Collins A, Peacock CS, Miller EN, Black GF, Sibthorpe D, et al. Evidence that genetic susceptibility to Mycobacterium tuberculosis in a Brazilian population is

17.

18.

19.

20.

21. 22.

23.

24.

25.

under oligogenic control: linkage study of the candidate genes NRAMP1 and TNFA. Tuber Lung Dis 1997;78:35-45. Rossouw M, Nel HJ, Cooke GS, van Helden PD, Hoal EG. Association between tuberculosis and a polymorphic NFkappaB binding site in the interferon gamma gene. Lancet 2003;361:1871-2. Kaufmann SH. How can immunology contribute to the control of tuberculosis? Nat Rev Immunol 2001;1:20-30. Reed MB, Domenech P, Manca C, Su H, Barczak AK, Kreiswirth BN, et al. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 2004;431:84-7. Hirsh AE, Tsolaki AG, DeRiemer K, Feldman MW, Small PM. Stable association between strains of Mycobacterium tuberculosis and their human host populations. Proc Natl Acad Sci USA 2004;101:4871-6. Lopez B, Aguilar D, Orozco H, Burger M, Espitia C, Ritacco V, et al. A marked difference in pathogenesis and immune response induced by different Mycobacterium tuberculosis genotypes. Clin Exp Immunol 2003;133:30-7. Russo DM, Kozlova N, Lakey DL, Kernodle D. Naive human T cells develop into Th1 effectors after stimulation with Mycobacterium tuberculosis-infected macrophages or recombinant Ag85 proteins. Infect Immun 2000;68:6826-32. Marquet S, Abel L, Hillaire D, Dessein H, Kalil J, Feingold J, et al. Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31q33. Nat Genet 1996;14:181-4. Siddiqui MR, Meisner S, Tosh K, Balakrishnan K, Ghei S, Fisher SE, et al. A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nat Genet 2001;27:439-41. Mira MT, Alcais A, Van Thuc N, Thai VH, Huong NT, Ba NN, et al. Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nat Genet 2003;33:412-5. Bellamy R, Beyers N, McAdam KP, Ruwende C, Gie R, Samaai P, et al. Genetic susceptibility to tuberculosis in Africans: a genome-wide scan. Proc Natl Acad Sci USA 2000;97:8005-9. Miller EN, Jamieson SE, Joberty C, Fakiola M, Hudson D, Peacock CS, et al. Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians. Genes Immun 2004;5:63-7. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science 1996;273:1516-7. Mira MT, Alcais A, Nguyen VT, Moraes MO, Di Flumeri C, Vu HT, et al. Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 2004;427:636-40. Vidal SM, Malo D, Vogan K, Skamene E, Gros P. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell 1993;73:469-85. Pierce C, Dubos RJ, Middlebrook G. Infection of mice with mammalian tubercle bacilli grown in tween-albumin liquid medium. J Exp Med 1947;86:159-74. Medina E, North RJ. Resistance ranking of some common inbred mouse strains to Mycobacterium tuberculosis and

154

26.

27.

28.

29.

30.

31.

32.

33.

34. 35.

36.

37.

38.

39.

40.

41.

Tuberculosis relationship to major histocompatibility complex haplotype and nramp1 genotype. Immunology 1998;93:270-4. Musa SA, Kim Y, Hashim R, Wang GZ, Dimmer C, Smith DW. Response of inbred mice to aerosol challenge with Mycobacterium tuberculosis. Infect Immun 1987;55:1862-6. Lynch CJ, Pierce-Chase CH, Dubos R. A genetic study of susceptibility to experimental tuberculosis in mice infected with mammalian tubercle bacilli. J Exp Med 1965;121:105170. Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med 1998;338: 6404. Abel L, Sanchez FO, Oberti J, Thuc NV, Hoa LV, Lap VD, et al. Susceptibility to leprosy is linked to the human NRAMP1 gene. J Infect Dis 1998;177:133-45. Marquet S, Sanchez FO, Arias M, Rodriguez J, Paris SC, Skamene E, et al. Variants of the human NRAMP1 gene and altered human immunodeficiency virus infection susceptibility. J Infect Dis 1999;180:1521-5. Gros P, Skamene E, Forget A. Genetic control of natural resistance to Mycobacterium bovis [BCG] in mice. J Immunol 1981;127:2417-21. Skamene E, Gros P, Forget A, Kongshavn PA, St Charles C, Taylor BA. Genetic regulation of resistance to intracellular pathogens. Nature 1982;297:506-9. Bradley DJ, Taylor BA, Blackwell J, Evans EP, Freeman J. Regulation of Leishmania populations within the host. III. Mapping of the locus controlling susceptibility to visceral leishmaniasis in the mouse. Clin Exp Immunol 1979;37:7-14. Plant J, Glynn AA. Locating salmonella resistance gene on mouse chromosome 1. Clin Exp Immunol 1979;37:1-6. Malo D, Vogan K, Vidal S, Hu J, Cellier M, Schurr E, et al. Haplotype mapping and sequence analysis of the mouse Nramp gene predict susceptibility to infection with intracellular parasites. Genomics 1994;23:51-61. Goto Y, Buschman E, Skamene E. Regulation of host resistance to Mycobacterium intracellulare in vivo and in vitro by the Bcg gene. Immunogenetics 1989;30:218-21. Brown IN, Glynn AA, Plant J. Inbred mouse strain resistance to Mycobacterium lepraemurium follows the Ity/Lsh pattern. Immunology 1982;47:149-56. Skamene E, Gros P, Forget A, Patel PJ, Nesbitt MN. Regulation of resistance to leprosy by chromosome 1 locus in the mouse. Immunogenetics 1984;19:117-24. Brown DH, Miles BA, Zwilling BS. Growth of Mycobacterium tuberculosis in BCG-resistant and -susceptible mice: establishment of latency and reactivation. Infect Immun 1995;63:2243-7. Nikonenko BV, Apt AS, Mezhlumova MB, Avdienko VG, Yeremeev VV, Moroz AM. Influence of the mouse Bcg, Tbc1 and xid genes on resistance and immune responses to tuberculosis infection and efficacy of bacille Calmette-Guerin [BCG] vaccination. Clin Exp Immunol 1996;104:37-43. Medina E, Rogerson BJ, North RJ. The Nramp1 antimicrobial resistance gene segregates independently of resistance to

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

virulent Mycobacterium tuberculosis. Immunology 1996;88:479-81. Medina E, North RJ. Evidence inconsistent with a role for the Bcg gene [Nramp1] in resistance of mice to infection with virulent Mycobacterium tuberculosis. J Exp Med 1996;183:1045-51. North RJ, LaCourse R, Ryan L, Gros P. Consequence of Nramp1 deletion to Mycobacterium tuberculosis infection in mice. Infect Immun 1999;67:5811- 4. Vordermeier HM, Venkataprasad N, Harris DP, Ivanyi J. Increase of tuberculous infection in the organs of B celldeficient mice. Clin Exp Immunol 1996;106:312-6. Johnson CM, Cooper AM, Frank AA, Bonorino CB, Wysoki LJ, Orme IM. Mycobacterium tuberculosis aerogenic rechallenge infections in B cell-deficient mice. Tuber Lung Dis 1997;78:257-61. Bosio CM, Gardner D, Elkins KL. Infection of B cell-deficient mice with CDC 1551, a clinical isolate of Mycobacterium tuberculosis: delay in dissemination and development of lung pathology. J Immunol 2000;164:6417-25. Ladel CH, Blum C, Dreher A, Reifenberg K, Kaufmann SH. Protective role of gamma/delta T cells and alpha/beta T cells in tuberculosis. Eur J Immunol 1995;25:2877-81. Mogues T, Goodrich ME, Ryan L, LaCourse R, North RJ. The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice. J Exp Med 2001;193:271-80. D’Souza CD, Cooper AM, Frank AA, Mazzaccaro RJ, Bloom BR, Orme IM. An anti-inflammatory role for gamma delta T lymphocytes in acquired immunity to Mycobacterium tuberculosis. J Immunol 1997;158:1217-21. Caruso AM, Serbina N, Klein E, Triebold K, Bloom BR, Flynn JL. Mice deficient in CD4 T cells have only transiently diminished levels of IFN-gamma, yet succumb to tuberculosis. J Immunol 1999;162:5407-16. Sousa AO, Mazzaccaro RJ, Russell RG, Lee FK, Turner OC, Hong S, et al. Relative contributions of distinct MHC class Idependent cell populations in protection to tuberculosis infection in mice. Proc Natl Acad Sci USA 2000;97:4204-8. D’Souza CD, Cooper AM, Frank AA, Ehlers S, Turner OC, Hong S, et al. A novel nonclassic beta2-microglobulinrestricted mechanism influencing early lymphocyte accumulation and subsequent resistance to tuberculosis in the lung. Am J Respir Cell Mol Biol 2000;23:188-93. Cooper AM, D’Souza C, Frank AA, Orme IM. The course of Mycobacterium tuberculosis infection in the lungs of mice lacking expression of either perforin- or granzyme-mediated cytolytic mechanisms. Infect Immun 1997;65:1317-20. Laochumroonvorapong P, Wang J, Liu CC, Ye W, Moreira AL, Elkon KB, et al. Perforin, a cytotoxic molecule which mediates cell necrosis, is not required for the early control of mycobacterial infection in mice. Infect Immun 1997;65:127-32. Tascon RE, Stavropoulos E, Lukacs KV, Colston MJ. Protection against Mycobacterium tuberculosis infection by CD8+ T cells requires the production of gamma interferon. Infect Immun 1998;66:830-4.

Genetics of Susceptibility to Tuberculosis 155 56. Cooper AM, Dalton DK, Stewart TA, Griffin JP, Russell DG, Orme IM. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med 1993;178:2243-7. 57. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med 1993;178: 2249-54. 58. Pearl JE, Saunders B, Ehlers S, Orme IM, Cooper AM. Inflammation and lymphocyte activation during mycobacterial infection in the interferon-gamma-deficient mouse. Cell Immunol 2001;211:43-50. 59. North RJ. Mice incapable of making IL-4 or IL-10 display normal resistance to infection with Mycobacterium tuberculosis. Clin Exp Immunol 1998;113:55-8. 60. MacMicking JD, Taylor GA, McKinney JD. Immune control of tuberculosis by IFN-gamma-inducible LRG-47. Science 2003;302:654-9. 61. Sugawara I, Yamada H, Mizuno S. STAT1 knockout mice are highly susceptible to pulmonary mycobacterial infection. Tohoku J Exp Med 2004;202:41-50. 62. Yamada H, Mizuno S, Reza-Gholizadeh M, Sugawara I. Relative importance of NF-kappaB p50 in mycobacterial infection. Infect Immun 2001;69:7100-5. 63. Yamada H, Mizuno S, Sugawara I. Interferon regulatory factor 1 in mycobacterial infection. Microbiol Immunol 2002;46:751-60. 64. Cooper AM, Pearl JE, Brooks JV, Ehlers S, Orme IM. Expression of the nitric oxide synthase 2 gene is not essential for early control of Mycobacterium tuberculosis in the murine lung. Infect Immun 2000;68:6879-82. 65. Feng CG, Collazo-Custodio CM, Eckhaus M, Eckhaus M, Hieny S, Belkaid Y, et al. Mice deficient in LRG-47 display increased susceptibility to mycobacterial infection associated with the induction of lymphopenia. J Immunol 2004;172:11638. 66. Ding AH, Nathan CF, Stuehr DJ. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J Immunol 1988;141:2407-12. 67. Scanga CA, Mohan VP, Tanaka K, Alland D, Flynn JL, Chan J. The inducible nitric oxide synthase locus confers protection against aerogenic challenge of both clinical and laboratory strains of mycobacterium tuberculosis in mice. Infect Immun 2001;69:7711-7. 68. MacMicking JD, North RJ, LaCourse R, Mudgett JS, Shah SK, Nathan CF. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acad Sci USA 1997; 94:5243-8. 69. Kaneko H, Yamada H, Mizuno S, Udagawa T, Kazumi Y, Sekikawa K, et al. Role of tumor necrosis factor-alpha in Mycobacterium-induced granuloma formation in tumor necrosis factor-alpha-deficient mice. Lab Invest 1999;79:379-86. 70. Bean AG, Roach DR, Briscoe H, France MP, Korner H, Sedgwick JD, et al. Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J Immunol 1999;162:3504-11. Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ. TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol 2002;168:4620-7. Flynn JL, Goldstein MM, Chan J, Tan X, Skerrett SJ, Wilson CB, et al. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995;2:561-72. Smith S, Liggitt D, Jeromsky E, Tan X, Skerrett SJ, Wilson CB. Local role for tumor necrosis factor alpha in the pulmonary inflammatory response to Mycobacterium tuberculosis infection. Infect Immun 2002;70:2082-9. Roach DR, Briscoe H, Saunders B, France MP, Riminton S, Britton WJ. Secreted lymphotoxin-alpha is essential for the control of an intracellular bacterial infection. J Exp Med 2001;193:239-46. Ehlers S, Holscher C, Scheu S, Tertilt C, Hehlgans T, Suwinski J, et al. The lymphotoxin beta receptor is critically involved in controlling infections with the intracellular pathogens Mycobacterium tuberculosis and Listeria monocytogenes. J Immunol 2003;170:5210-8. Murphy EE, Terres G, Macatonia SE, Hsieh CS, Mattson J, Lanier L, et al. B7 and interleukin 12 cooperate for proliferation and interferon gamma production by mouse T helper clones that are unresponsive to B7 costimulation. J Exp Med 1994;180:223-31. Cooper AM, Magram J, Ferrante J, Orme IM. Interleukin 12 [IL-12] is crucial to the development of protective immunity in mice intravenously infected with mycobacterium tuberculosis. J Exp Med 1997;186:39-45. Cooper AM, Kipnis A, Turner J, Magram J, Ferrante J, Orme IM. Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J Immunol 2002;168:1322-7. Sugawara I, Yamada H, Mizuno S. Relative importance of STAT4 in murine tuberculosis. J Med Microbiol 2003;52:2934. Sugawara I, Yamada H, Mizuno S, Iwakura Y. IL-4 is required for defense against mycobacterial infection. Microbiol Immunol 2000;44:971-9. Saunders BM, Frank AA, Orme IM, Cooper AM. Interleukin6 induces early gamma interferon production in the infected lung but is not required for generation of specific immunity to Mycobacterium tuberculosis infection. Infect Immun 2000;68:3322-6. Jung YJ, LaCourse R, Ryan L, North RJ. Evidence inconsistent with a negative influence of T helper 2 cells on protection afforded by a dominant T helper 1 response against Mycobacterium tuberculosis lung infection in mice. Infect Immun 2002;70:6436-43. Roach DR, Martin E, Bean AG, Rennick DM, Briscoe H, Britton WJ. Endogenous inhibition of antimycobacterial

156

84.

85.

86.

87. 88.

89. 90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

Tuberculosis immunity by IL-10 varies between mycobacterial species. Scand J Immunol 2001;54:163-70. Jung YJ, Ryan L, LaCourse R, North RJ. Increased interleukin10 expression is not responsible for failure of T helper 1 immunity to resolve airborne Mycobacterium tuberculosis infection in mice. Immunology 2003;109:295-9. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev 2001;12:53-72. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol 2001;19:423-74. Daugelat S, Kaufmann SH. Role of Th1 and Th2 cells in bacterial infections. Chem Immunol 1996;63:66-97. Satoskar AR, Okano M, Connaughton S, Raisanen-Sokolwski A, David JR, Labow M. Enhanced Th2-like responses in IL-1 type 1 receptor-deficient mice. Eur J Immunol 1998;28:206674. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood 1996;87:2095-147. Kinjo Y, Kawakami K, Uezu K, Yara S, Miyagi K, Koguchi Y, et al. Contribution of IL-18 to Th1 response and host defense against infection by Mycobacterium tuberculosis: a comparative study with IL-12p40. J Immunol 2002;169:323-9. Sugawara I, Yamada H, Kaneko H, Mizuno S, Takeda K, Akira S. Role of interleukin-18 [IL-18] in mycobacterial infection in IL-18-gene-disrupted mice. Infect Immun 1999;67:2585-9. Kawakami K, Kinjo Y, Uezu K, Miyagi K, Kinjo T, Yara S, et al. Interferon-gamma production and host protective response against Mycobacterium tuberculosis in mice lacking both IL-12p40 and IL-18. Microbes Infect 2004;6:339-49. Ladel CH, Blum C, Dreher A, Reifenberg K, Kopf M, Kaufmann SH. Lethal tuberculosis in interleukin-6-deficient mutant mice. Infect Immun 1997;65:4843-9. Yamada H, Mizumo S, Horai R, Iwakura Y, Sugawara I. Protective role of interleukin-1 in mycobacterial infection in IL-1 alpha/beta double-knockout mice. Lab Invest 2000;80:759-67. Sugawara I, Yamada H, Hua S, Mizuno S. Role of interleukin [IL]-1 type 1 receptor in mycobacterial infection. Microbiol Immunol 2001;45:743-50. Juffermans NP, Florquin S, Camoglio L, Verbon A, Kolk AH, Speelman, et al. Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. J Infect Dis 2000; 182:902-8. Lu B, Rutledge BJ, Gu L, Fiorillo J, Lukacs NW, Kunkel SL, et al. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med 1998;187:601-8. Kipnis A, Basaraba RJ, Orme IM, Cooper AM. Role of chemokine ligand 2 in the protective response to early murine pulmonary tuberculosis. Immunology 2003;109:547-51. Peters W, Scott HM, Chambers HF, Flynn JL, Charo IF, Ernst JD. Chemokine receptor 2 serves an early and essential role

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

in resistance to Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2001;98:7958-63. Scott HM, Flynn JL. Mycobacterium tuberculosis in chemokine receptor 2-deficient mice: influence of dose on disease progression. Infect Immun 2002;70:5946-54. Algood HM, Flynn JL. CCR5-deficient mice control Mycobacterium tuberculosis infection despite increased pulmonary lymphocytic infiltration. J Immunol 2004;173:3287-96. Seiler P, Aichele P, Bandermann S, Hauser AE, Lu B, Gerard NP, et al. Early granuloma formation after aerosol Mycobacterium tuberculosis infection is regulated by neutrophils via CXCR3-signaling chemokines. Eur J Immunol 2003;33:2676-86. Johnson CM, Cooper AM, Frank AA, Orme IM. Adequate expression of protective immunity in the absence of granuloma formation in Mycobacterium tuberculosisinfected mice with a disruption in the intracellular adhesion molecule 1 gene. Infect Immun 1998;66:1666-70. Saunders BM, Frank AA, Orme IM. Granuloma formation is required to contain bacillus growth and delay mortality in mice chronically infected with Mycobacterium tuberculosis. Immunology 1999;98:324-8. Hu C, Mayadas-Norton T, Tanaka K, Chan J, Salgame P. Mycobacterium tuberculosis infection in complement receptor 3-deficient mice. J Immunol 2000;165:2596-602. Leemans JC, Florquin S, Heikens M, Pals ST, van der Neut R, Van Der Poll T. CD44 is a macrophage binding site for Mycobacterium tuberculosis that mediates macrophage recruitment and protective immunity against tuberculosis. J Clin Invest 2003;111:681-9. Reiling N, Holscher C, Fehrenbach A, Kroger S, Kirschning CJ, Goyert S, et al. Cutting edge: Toll-like receptor [TLR]2and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. J Immunol 2002;169:3480-4. Sugawara I, Yamada H, Li C, Mizuno S, Takeuchi O, Akira S. Mycobacterial infection in TLR2 and TLR6 knockout mice. Microbiol Immunol 2003;47:327-36. Drennan MB, Nicolle D, Quesniaux VJ, Jacobs M, Allie N, Mpagi J, et al. Toll-like receptor 2-deficient mice succumb to Mycobacterium tuberculosis infection. Am J Pathol 2004;164:49-57. Muta T, Takeshige K. Essential roles of CD14 and lipopolysaccharide-binding protein for activation of toll-like receptor [TLR]2 as well as TLR4 Reconstitution of TLR2- and TLR4activation by distinguishable ligands in LPS preparations. Eur J Biochem 2001;268:4580-9. Scanga CA, Bafica A, Feng CG, Cheever AW, Hieny S, Sher A. MyD88-deficient mice display a profound loss in resistance to Mycobacterium tuberculosis associated with partially impaired Th1 cytokine and nitric oxide synthase 2 expression. Infect Immun 2004;72:2400-4. Sugawara I, Yamada H, Mizuno S, Takeda K, Akira S. Mycobacterial infection in MyD88-deficient mice. Microbiol Immunol 2003;47:841-7. Flynn JL, Goldstein MM, Triebold KJ, Bloom BR. Major histocompatibility complex class I-restricted T cells are

Genetics of Susceptibility to Tuberculosis 157

114.

115.

116.

117.

118.

119.

120. 121.

122.

123.

124.

125.

126.

127.

128.

necessary for protection against M. tuberculosis in mice. Infect Agents Dis 1993;2:259-62. Brett SJ, Ivanyi J. Genetic influences on the immune repertoire following tuberculous infection in mice. Immunology 1990;71:113-9. Ivanyi J, Sharp K. Control by H-2 genes of murine antibody responses to protein antigens of Mycobacterium tuberculosis. Immunology 1986;59:329-32. Orrell JM, Brett SJ, Ivanyi J, Coghill G, Grant A, Beck JS. Morphometric analysis of Mycobacterium tuberculosis infection in mice suggests a genetic influence on the generation of the granulomatous inflammatory response. J Pathol 1992;166:77-82. Brett S, Orrell JM, Swanson Beck J, Ivanyi J. Influence of H-2 genes on growth of Mycobacterium tuberculosis in the lungs of chronically infected mice. Immunology 1992;76: 129-32. Apt AS, Avdienko VG, Nikonenko BV, Kramnik IB, Moroz AM, Skamene E. Distinct H-2 complex control of mortality, and immune responses to tuberculosis infection in virgin and BCG-vaccinated mice. Clin Exp Immunol 1993;94:322-9. Darvasi A, Weinreb A, Minke V, Weller JI, Soller M. Detecting marker-QTL linkage and estimating QTL gene effect and map location using a saturated genetic map. Genetics 1993; 134:94351. Jansen RC. Interval mapping of multiple quantitative trait loci. Genetics 1993;135:205-11. Lavebratt C, Apt AS, Nikonenko BV, Schalling M, Schurr E. Severity of tuberculosis in mice is linked to distal chromosome 3 and proximal chromosome 9. J Infect Dis 1999;180:150-5. Sanchez F, Radaeva TV, Nikonenko BV, Persson AS, Sengul S, Schalling M, et al. Multigenic control of disease severity after virulent Mycobacterium tuberculosis infection in mice. Infect Immun 2003;71:126-31. Kramnik I, Dietrich WF, Demant P, Bloom BR. Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2000;97:8560-5. Boyartchuk V, Rojas M, Yan BS, Jobe O, Hurt N, Dorfman DM, et al. The host resistance locus sst1 controls innate immunity to Listeria monocytogenes infection in immunodeficient mice. J Immunol 2004;173:5112-20. Mitsos LM, Cardon LR, Fortin A, Ryan L, LaCourse R, North RJ, et al. Genetic control of susceptibility to infection with Mycobacterium tuberculosis in mice. Genes Immun 2000;1:467-77. Mitsos LM, Cardon LR, Ryan L, LaCourse R, North RJ, Gros P. Susceptibility to tuberculosis: a locus on mouse chromosome 19 [Trl-4] regulates Mycobacterium tuberculosis replication in the lungs. Proc Natl Acad Sci USA 2003;100: 6610-5. Casanova JL, Abel L. Genetic dissection of immunity to mycobacteria: the human model. Annu Rev Immunol 2002;20:581620. Jouanguy E, Lamhamedi-Cherradi S, Altare F, Fondaneche MC, Tuerlinckx D, Blanche S, et al. Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guerin infection and a sibling with clinical tuberculosis. J Clin Invest 1997;100:2658-64.

129. Picard C, Fieschi C, Altare F, Al-Jumaah S, Al-Hajjar S, Feinberg J, et al. Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. Am J Hum Genet 2002;70:336-48. 130. Caragol I, Raspall M, Fieschi C, Feinberg J, Larrosa MN, Hernandez M, et al. Clinical tuberculosis in 2 of 3 siblings with interleukin-12 receptor beta1 deficiency. Clin Infect Dis 2003;37:302-6. 131. Dupuis S, Doffinger R, Picard C, Fieschi C, Altare F, Jouanguy E, et al. Human interferon-gamma-mediated immunity is a genetically controlled continuous trait that determines the outcome of mycobacterial invasion. Immunol Rev 2000;178:129-37. 132. Dupuis S, Dargemont C, Fieschi C, Thomassin N, Rosenzweig S, Harris J, et al. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 2001;293: 300-3. 133. Gollob JA, Veenstra KG, Jyonouchi H, Kelly AM, Ferrieri P, Panka DJ, et al. Impairment of STAT activation by IL-12 in a patient with atypical mycobacterial and staphylococcal infections. J Immunol 2000;165:4120-6. 134. MacLennan C, Fieschi C, Lammas DA, Picard C, Dorman SE, Sanal O, et al. Interleukin [IL]-12 and IL-23 are key cytokines for immunity against Salmonella in humans. J Infect Dis 2004;190:1755-7. 135. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol 2002;168:5699-708. 136. Hoeve MA, de Boer T, Langenberg DM, Sanal O, Verreck FA, Ottenhoff TH. IL-12 receptor deficiency revisited: IL-23mediated signaling is also impaired in human genetic IL-12 receptor beta1 deficiency. Eur J Immunol 2003;33:3393-7. 137. Verreck FA, de Boer T, Langenberg DM, Hoeve MA, Kramer M, Vaisberg E, et al. Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to mycobacteria. Proc Natl Acad Sci USA 2004;101:4560-5. 138. Remus N, El Baghdadi J, Fieschi C, Feinberg J, Quintin T, Chentoufi M, et al. Association of IL12RB1 polymorphisms with pulmonary tuberculosis in adults in Morocco. J Infect Dis 2004;190:580-7. 139. Rosenzweig SD, Schaffer AA, Ding L, Sullivan R, Enyedi B, Yim JJ, et al. Interferon-gamma receptor 1 promoter polymorphisms: population distribution and functional implications. Clin Immunol 2004;112:113-9. 140. Tso HW, Lau YL, Tam CM, Wong HS, Chiang AK. Associations between IL12B polymorphisms and tuberculosis in the Hong Kong Chinese population. J Infect Dis 2004;190:913-9. 141. Fraser DA, Bulat-Kardum L, Knezevic J, Babarovic P, Matakovic-Mileusnic N, et al. Interferon-gamma receptor-1 gene polymorphism in tuberculosis patients from Croatia. Scand J Immunol 2003;57:480-4. 142. Awomoyi AA, Nejentsev S, Richardson A, Hull J, Koch O, Podinovskaia M, et al. No association between interferongamma receptor-1 gene polymorphism and pulmonary

158

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

156.

Tuberculosis tuberculosis in a Gambian population sample. Thorax 2004;59:291-4. Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV. A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol 2000;61:863-6. Lio D, Marino V, Serauto A, Gioia V, Scola L, Crivello A, et al. Genotype frequencies of the +874T→A single nucleotide polymorphism in the first intron of the interferon-gamma gene in a sample of Sicilian patients affected by tuberculosis. Eur J Immunogenet 2002;29:371-4. Fitness J, Floyd S, Warndorff DK, Sichali L, Malema S, Crampin AC, et al. Large-scale candidate gene study of tuberculosis susceptibility in the Karonga district of northern Malawi. Am J Trop Med Hyg 2004;71:341-9. Ting LM, Kim AC, Cattamanchi A, Ernst JD. Mycobacterium tuberculosis inhibits IFN-gamma transcriptional responses without inhibiting activation of STAT1. J Immunol 1999;163:3898-906. Fortune SM, Solache A, Jaeger A, Hill PJ, Belisle JT, Bloom BR, et al. Mycobacterium tuberculosis inhibits macrophage responses to IFN-gamma through myeloid differentiation factor 88-dependent and -independent mechanisms. J Immunol 2004;172:6272-80. Skamene E, Schurr E, Gros P. Infection genomics: Nramp1 as a major determinant of natural resistance to intracellular infections. Annu Rev Med 1998;49:275-87. Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med 1998;338:640-4. Delgado JC, Baena A, Thim S, Goldfeld AE. Ethnic-specific genetic associations with pulmonary tuberculosis. J Infect Dis 2002;186:1463-8. Gao PS, Fujishima S, Mao XQ, Remus N, Kanda M, Enomoto T, et al. Genetic variants of NRAMP1 and active tuberculosis in Japanese populations. International Tuberculosis Genetics Team. Clin Genet 2000;58:74-6. Cervino AC, Lakiss S, Sow O, Hill AV. Allelic association between the NRAMP1 gene and susceptibility to tuberculosis in Guinea-Conakry. Ann Hum Genet 2000;64:507-12. Ryu S, Park YK, Bai GH, Kim SJ, Park SN, Kang S. 3’UTR polymorphisms in the NRAMP1 gene are associated with susceptibility to tuberculosis in Koreans. Int J Tuberc Lung Dis 2000; 4:577-80. Liu W, Cao WC, Zhang CY, Tian L, Wu XM, Habbema JD, et al. VDR and NRAMP1 gene polymorphisms in susceptibility to pulmonary tuberculosis among the Chinese Han population: a case-control study. Int J Tuberc Lung Dis 2004;8:428-34. Liaw YS, Tsai-Wu JJ, Wu CH, Hung CC, Lee CN, Yang PC, et al. Variations in the NRAMP1 gene and susceptibility of tuberculosis in Taiwanese. Int J Tuberc Lung Dis 2002;6:454-60. El Baghdadi J, Remus N, Benslimane A, El Annaz H, Chentoufi M, Abel L, et al. Variants of the human NRAMP1 gene and susceptibility to tuberculosis in Morocco. Int J Tuberc Lung Dis 2003;7:599-602.

157. Bellamy R. Susceptibility to mycobacterial infections: the importance of host genetics. Genes Immun 2003;4:4-11. 158. Bell B. Calciferol for tuberculous adenitis. Lancet 1946;248:808. 159. Tsoukas CD, Provvedini DM, Manolagas SC. 1,25-dihydroxyvitamin D3: a novel immunoregulatory hormone. Science 1984;224:1438-40. 160. Reichel H, Koeffler HP, Tobler A, Norman AW. 1 alpha, 25Dihydroxyvitamin D3 inhibits gamma-interferon synthesis by normal human peripheral blood lymphocytes. Proc Natl Acad Sci USA 1987;84:3385-9. 161. D’Ambrosio D, Cippitelli M, Cocciolo MG, Mazzeo D, Di Lucia P, Lang R, et al. Inhibition of IL-12 production by 1,25dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest 1998;101:252-62. 162. Christakos S, Dhawan P, Liu Y, Peng X, Porta A. New insights into the mechanisms of vitamin D action. J Cell Biochem 2003;88:695-705. 163. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O’Riordan J, et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 1986;57:159-63. 164. Rockett KA, Brookes R, Udalova I, Vidal V, Hill AV, Kwiatkowski D. 1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun 1998;66:5314-21. 165. Davies PD. A possible link between vitamin D deficiency and impaired host defence to Mycobacterium tuberculosis. Tubercle 1985;66:301-6. 166. Davies PD, Brown RC, Woodhead JS. Serum concentrations of vitamin D metabolites in untreated tuberculosis. Thorax 1985;40:187-90. 167. Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 2000;355:618-21. 168. Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25dihydroxyvitamin D3 receptors in human leukocytes. Science 1983;221:1181-3. 169. Bellamy R, Ruwende C, Corrah T, McAdam KP, Thursz M, Whittle HC, et al. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis 1999;179:721-4. 170. Bornman L, Campbell SJ, Fielding K, Bah B, Sillah J, Gustafson P, et al. Vitamin D receptor polymorphisms and susceptibility to tuberculosis in West Africa: a case-control and family study. J Infect Dis 2004;190:1631-41. 171. Whitfield GK, Remus LS, Jurutka PW, Zitzer H, Oza AK, Dang HT, et al. Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene. Mol Cell Endocrinol 2001;177:145-59. 172. Roth DE, Soto G, Arenas F, Bautista CT, Ortiz J, Rodriguez R, et al. Association between vitamin D receptor gene polymorphisms and response to treatment of pulmonary tuberculosis. J Infect Dis 2004;190:920-7.

Genetics of Susceptibility to Tuberculosis 159 173. Selvaraj P, Narayanan PR, Reetha AM. Association of vitamin D receptor genotypes with the susceptibility to pulmonary tuberculosis in female patients and resistance in female contacts. Indian J Med Res 2000;111:172-9. 174. Selvaraj P, Chandra G, Jawahar MS, Rani MV, Rajeshwari DN, Narayanan PR. Regulatory role of vitamin D receptor gene variants of Bsm I, Apa I, Taq I, and Fok I polymorphisms on macrophage phagocytosis and lymphoproliferative response to mycobacterium tuberculosis antigen in pulmonary tuberculosis. J Clin Immunol 2004;24:523-32. 175. Singh SP, Mehra NK, Dingley HB, Pande JN, Vaidya MC. Human leukocyte antigen [HLA]-linked control of susceptibility to pulmonary tuberculosis and association with HLADR types. J Infect Dis 1983;148: 676-81. 176. Bothamley GH, Beck JS, Schreuder GM, D’Amaro J, de Vries RR, Kardjito T, et al. Association of tuberculosis and M. tuberculosis-specific antibody levels with HLA. J Infect Dis 1989;159:549-55. 177. Teran-Escandon D, Teran-Ortiz L, Camarena-Olvera A, Gonzalez-Avila G, Vaca-Marin MA, Granados J, et al. Human leukocyte antigen-associated susceptibility to pulmonary tuberculosis: molecular analysis of class II alleles by DNA amplification and oligonucleotide hybridization in Mexican patients. Chest 1999;115:428-33. 178. Goldfeld AE, Delgado JC, Thim S, Bozon MV, Uglialoro AM, Turbay D, et al. Association of an HLA-DQ allele with clinical tuberculosis. JAMA 1998;279:226-8. 179. Sanjeevi CB, Narayanan PR, Prabakar R, Charles N, Thomas

180.

181.

182. 183.

184.

185.

186.

BE, Balasubramaniam R, et al. No association or linkage with HLA-DR or -DQ genes in south Indians with pulmonary tuberculosis. Tuber Lung Dis 1992;73:280-4. Amirzargar AA, Yalda A, Hajabolbaghi M, Khosravi F, Jabbari H, Rezaei N, et al. The association of HLA-DRB, DQA1, DQB1 alleles and haplotype frequency in Iranian patients with pulmonary tuberculosis. Int J Tuberc Lung Dis 2004;8:1017-21. Turner MW. Mannose-binding lectin: the pluripotent molecule of the innate immune system. Immunol Today 1996;17: 532-40. Casanova JL, Abel L. Human mannose-binding lectin in immunity: friend, foe, or both? J Exp Med 2004;199:1295-9. Soborg C, Madsen HO, Andersen AB, Lillebaek T, Kok-Jensen A, Garred P. Mannose-binding lectin polymorphisms in clinical tuberculosis. J Infect Dis 2003;188:777-82. Mombo LE, Lu CY, Ossari S, Bedjabaga I, Sica L, Krishnamoorthy R, et al. Mannose-binding lectin alleles in sub-Saharan Africans and relation with susceptibility to infections. Genes Immun 2003;4:362-7. El Sahly HM, Reich RA, Dou SJ, Musser JM, Graviss EA. The effect of mannose binding lectin gene polymorphisms on susceptibility to tuberculosis in different ethnic groups. Scand J Infect Dis 2004;36:106-8. Hoal-Van Helden EG, Epstein J, Victor TC, Hon D, Lewis LA, Beyers N, et al. Mannose-binding protein B allele confers protection against tuberculous meningitis. Pediatr Res 1999; 45:459-64.

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Laboratory Diagnosis

10 Rajesh Bhatia

INTRODUCTION Since Robert Koch’s discovery of Mycobacterium tuberculosis in 1882, microscopic detection of the bacilli in clinical specimens has remained the mainstay of tuberculosis [TB] diagnosis in developing nations. However, in human immunodeficiency virus [HIV] era microscopic diagnosis has certain drawbacks: [i] a low clinical sensitivity of the technique in HIV-associated TB; and [ii] lack of access to quality microscopy services in HIV endemic areas. Recently, a number of exciting technologies are being developed for rapid and improved diagnosis of TB including HIV-associated TB. These include improvements in microscopy, growth-based detection and subsequent strain characterization including drug susceptibility testing [DST], antigen detection, molecular detection and recently described interferon-γ release assays [IGRAs]. CLINICAL SPECIMENS: COLLECTION AND TRANSPORTATION In pulmonary TB, sputum is the specimen of choice. If TB of any other organ of the body is suspected, specimen should be from specific organ or system such as urine for renal TB and cerebrospinal fluid [CSF] for TB meningitis. Mycobacterium tuberculosis is in abundance in lesions showing rapid caseation. Sputum The specimen is collected in a sterile container. It is a common misassumption that as mycobacterial specimens are decontaminated before culture, cleanliness of the container is not important. Unsterilized containers

may be contaminated with environmental mycobacteria. To facilitate the choice of container, following specifications are recommended for a container: [i] widemouthed so that the patient can expectorate easily inside the container without contaminating it from outside; [ii] volume capacity of approximately 25 ml; [iii] made of transparent material in order to observe specimen volume and quality without opening the container; [iv] screw-capped to obtain a water-tight seal, to reduce the risk of leakage during transport; [v] easily-labelled to allow permanent identification; and [vi] rigid, to avoid breakage during transit. An ideal container is the 28 ml universal container, which is a heavy glass, screw-capped bottle. This container is reusable after thorough cleaning and sterilization. The identification number can be permanently engraved on the bottle cap. In TB diagnosis, care must be taken to obtain adequate and satisfactory specimens. Correct collection and transportation of specimens to the laboratory are important to ensure that the results are accurate and reliable. Collection Procedure It is best to obtain a sputum specimen early in the morning before the patient has eaten, since food particles in smears make them difficult to examine (1). For collecting a good sputum specimen, the patient must be given clear instructions (2). Aerosols containing mycobacteria may be formed when the patient coughs to produce a sputum specimen. Patients should, therefore, produce specimens either outside in the open air or away from other people and not in confined spaces such as toilets. Because of the intermittent excretion of tubercle bacilli,

Laboratory Diagnosis 161 three specimens should be collected for diagnosis as follows: [i] one spot specimen when the patient first attends the health service; [ii] one early morning specimen [preferably the next day]; [iii] one spot specimen when the early morning specimen is being submitted for examination. These should not be pooled but should be sent to the laboratory as separate specimens. If a patient has a productive cough, obtaining a sputum specimen is a fairly straightforward procedure. The patient is given a container on his first attendance. He should be instructed with demonstration by actual actions such as: [i] to inhale deeply two to three times; [ii] to cough out deep from the chest; [iii] to open the container and spit the sputum into the bottle; [iv] to avoid saliva or nasal secretions; and [v] to close the container. A good sputum specimen should be thick, purulent and of sufficient quantity [at least 5 ml]. The details of the patient’s name, address, age, sex and bottle number are to be recorded in a form/card and sent to the laboratory with the specimen. Specimens should be transported to the laboratory as soon as possible after collection. If the delay is unavoidable, the specimens should be refrigerated or kept in as cool a place as possible to inhibit the growth of unwanted micro-organisms. If refrigerator is not available and specimen is to be transported in hot climate then it should be preserved by adding equal volume of one per cent cetyl pyridinium chloride in two per cent saline. Collection of Specimens Other Than Sputum Fibreoptic Bronchoscopy Fibreoptic bronchoscopy has been extensively used to ascertain the diagnosis in patients who produce inadequate sputum or do not produce sputum at all, and in those with smear-negative pulmonary TB. Various bronchoscopic specimens such as bronchial washings, brushings, bronchoalveolar lavage [BAL] fluid and transbronchial lung biopsy have been evaluated and found to be useful (3,4).

of the cases and the yield may be greater in infants with extensive disease (5). Gastric lavage should be performed early in the morning, when the patient has been fasting for the preceding eight hours. Securing the specimen at this time would minimize the dilution of the bronchial secretions swallowed during the night by saliva or tears. Inhalation of superheated nebulized saline prior to gastric lavage has been reported to increase the bacteriologic yield (6). Following insertion of nasogastric tube, the stomach contents are aspirated. Then a small amount of sterile distilled water, [not more than 50 to 70 ml], is instilled through the nasogastric tube and the aspirate is added to the first collection. As gastric acidity is poorly tolerated by Mycobacterium tuberculosis, the gastric aspirate should be immediately neutralized either with 10 per cent sodium carbonate [added by dropper] to just pink [pH 7] indicated by phenol red, or with 40 per cent anhydrous sodium phosphate to green with bromothymol blue as an indicator. Urine The first few millilitres of urine should be allowed to flush the external urethra. Thereafter, clean-voided total volume of the first early morning urine specimen on three consecutive days is collected in a sterile container and transported to the laboratory as early as possible. Cerebrospinal Fluid About 5 to 10 ml of CSF should be collected for culture in a sterile vial. Serous Fluids The largest possible volume of pleural, pericardial, synovial and ascitic fluid is procured for culture and 1 ml of 3.8 per cent sodium citrate solution per 4 ml of specimen or 1 ml of 1:1000 heparin per 50 ml of fluid is added to prevent clotting of the serous fluid. Tissue

Gastric Lavage Gastric lavage has often been used for the diagnosis of pulmonary TB in young children instead of sputum. Young children seldom produce adequate sputum and secretions from the respiratory tract are often swallowed. Gastric lavage reveals the organism in 30 to 40 per cent

Tissue biopsy specimens of lymph nodes, liver etc., are aseptically collected in a vial containing normal saline and transported to the laboratory immediately. Tissue in formalin should never be sent for culture. Pus and bronchial secretions should be collected in sufficient quantities when possible to enable the

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concentration of mycobacteria. Bone marrow aspirates, which are generally free of rapid growing non-acid fast bacteria, can be directly inoculated onto the LowensteinJensen [L-J] medium. Urine, CSF, synovial or other fluids which are collected aseptically need no decontamination. For other specimens, sodium hydroxide in the final concentration of two per cent in the diluted specimen is the most commonly used liquefying agent and digestant. The decontaminated specimen is concentrated by sedimentation in a refrigerated centrifuge at 3000 g for 30 minutes. The sediment is used for inoculating media and preparation of smears while the supernatant can be used for biochemical and/or immunological investigations. DIRECT DEMONSTRATION OF MYCOBACTERIA BY STAINING TECHNIQUES Use of microscopy in diagnosis of TB is of paramount importance, as culture takes a long time before the results are ready. Microscopy is also helpful in the detection of open or infectious cases. Stained smears are examined directly from the sputum and after concentration (7). The tubercle bacilli are Gram positive though they do not take the stain readily. Mycobacteria retain the primary stain even after decolourization with acidalcohol; hence the term “acid-fast”. A counter-stain is employed to highlight the stained organisms for easier recognition. There are several methods of determining the acid-fast nature of mycobacteria. In the carbol-fuchsin [Ziehl-Neelsen] procedure, acid-fast organisms appear red against a blue background. Acid fastness is based on the integrity of the cell wall. Beaded or barred forms are frequently seen in Mycobacterium tuberculosis while Mycobacterium bovis stains more uniformly. In younger cultures, non acid-fast rods and granules have been reported. The mycobacterial cell wall is complex in nature. It has high lipid content, which accounts for about 60 per cent of the cell wall weight. The cell wall has several distinct layers. The inner layer, overlying the cell membrane is composed of peptidoglycan [murein]. External to the murein is a layer of arabinogalactan, which is covalently linked to a group of long chain fatty acids termed mycolic acid. These form a dense pallisade, arranged in rope-like structure, which gives the cell wall its thickness and is largely responsible for acid fastness.

It has been shown that at least 10 000 bacilli per ml of sputum are required for direct microscopy to be positive. The sensitivity can be further improved by examining more than one specimen from a patient. Examination of two specimens will, on an average, detect more than 90 per cent of cases and the addition of a third specimen increases the percentage to approximately 95 to 98 per cent. A negative smear, however, does not exclude the diagnosis of TB as some patients harbour fewer numbers of bacilli which cannot be detected by direct microscopy. A poor quality specimen or smear may also produce negative results. New glass slides should be used for making smears as acid-fast bacilli [AFB] are not always removed from the old slides. Only those reagents and diluents should be used which have been shown to be free of environmental mycobacteria to avoid false positive smears. Direct examination is performed by selecting a purulentlooking portion of sputum and spreading it thinly on a glass slide with a bacteriological loop or a wooden stick. The watery part of sputum is less likely to contain bacilli. The AFB are seen as bright red rods against the blue, green or yellow background [depending upon the counterstain used in staining]. A negative result does not exclude TB. As recommended by World Health Organization [WHO], before declaring a slide negative it is essential that at least 100 fields are examined taking over at least 10 minutes. Smears can be graded according to the number of bacilli seen [Table 10.1]. Other Staining Methods Using Carbol Fuchsin Other staining methods using carbol fuchsin for light microscopy include the cold staining methods [such as, Kinyoun’s or with Gabett’s solution]. The performance of these techniques might have been overestimated. Carefully planned studies have shown that the quantity of bacilli seen with a cold stain method is generally less than that with the conventional Ziehl-Neelsen [Z-N] staining method, which might pose a problem in paucibacillary specimens. The Gabett’s solution has advantages only for experienced technicians who have to stain large numbers of smears, since it consists of only two steps [acid and methylene blue combined]. However, the background colour with this method is often not satisfactory.

Laboratory Diagnosis 163 Table 10.1: Grades according to the number of bacilli seen with Ziehl-Neelsen staining

Table 10.2: Grades according to the number of bacilli per high power field seen with fluorescent staining

No. of AFB

Fields

Report

No. of bacilli per high power field

None 1-9

per 100 oil immersion fields per 100 oil immersion fields

Less than 6 per field 6 to 100 bacilli per field More than 100 per field or large clumps

10-99 1-10

per 100 oil immersion fields per oil immersion field [examine 50 fields] per oil immersion field [examine 20 fields]

Negative Scanty [report exact number] 1+ 2+

> 10

3+

AFB = acid-fast bacilli

Grade 1+ 2+ 3+

To increase the sensitivity of microscopic examination, various methods for concentrating the bacillary content of sputum and other clinical specimens are used. The most widely used method which concentrates the bacilli without inactivating them is Petroff’s method.

Fluorescent Staining

Petroff’s Method

Ziehl-Neelsen staining is a time consuming process for staining as well as examination. The WHO has recommended that the maximum number of Z-N smears examined by a microscopist in a day should not exceed 20. If more than this number of examinations is attempted, visual fatigue will lead to a deterioration of reading quality. On the other hand, proficiency in reading the Z-N smears can only be maintained by examining at least 10 to 15 Z-N smears per week, i.e., an average of two to three smears per day. Establishment of fluorescence microscopy is recommended where more than 50 smears are examined per day, and if electricity is continuously available. Under such circumstances fluorescence microscopy might be cost-effective. Additional requirements in training and economic considerations [capital investment and maintenance] need to be taken into account before introducing fluorescence microscopy. Fluorescence staining utilizes basically the same approach as Z-N staining, but carbol fuchsin is replaced by a fluorescent dye [auramine-O, rhodamine, auraminerhodamine, acridine orange etc.,], the acid for decolourisation is milder and the counterstain, though not essential, is useful to quench background fluorescence (8). Both sensitivity and specificity of fluorescence microscopy are comparable to the characteristics of the Z-N technique. The most important advantage of the fluorescence technique is that the slides can be examined at a lower magnification, thus allowing the examination of a much larger area per unit of time. In fluorescence microscopy, the same area that needs examination for 10 minutes with a light microscope can be examined in two minutes [Table 10.2].

In this method, the sputum is incubated with an equal volume of four per cent sodium hydroxide at 37 °C with frequent shaking till it becomes clear. This takes an average of 15 to 20 minutes. It is centrifuged at 3000 rpm for 30 minutes. The deposit is neutralized with dilute hydrochloric acid using neutral red as an indicator. This deposit can be used for making microscopy, culture and other diagnostic tests. Value of Smear Examination in Extra-pulmonary Specimens Specimens from extra-pulmonary sources, such as urine, CSF and other body fluids are centrifuged and the deposit is stained and examined. The benefit of microscopy in these specimens is limited because of their paucibacillary nature and it is, therefore, recommended that the extra-pulmonary specimens be referred for culture and other molecular techniques. Gastric Washings Examination of direct smears of gastric lavage should be avoided, as the results could be misleading. The AFB are frequently present in food and water and hence in the stomach. There is no way of distinguishing such organisms from tubercle bacilli on microscopy and positive results must be regarded with suspicion. Laryngeal Swabs Direct smear examination of laryngeal swabs is not much useful. A negative result cannot rule out TB and whenever possible, the material obtained should be subjected to mycobacterial culture.

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Pus and Thick Aspirates Direct smears of pus and other body fluids, should be made thin. Thick smears tend to float off the slide and even if they are retained, the AFB may be difficult to see after staining. Problems may arise if a large amount of blood is present in the specimen since blood may sometimes produce acid-fast artifacts. Pleural and Pericardial Fluid The pleural and pericardial fluids should be centrifuged and smears should be prepared from the sediment. Again, these should be thin otherwise they may float off the slide. Cerebrospinal Fluid Smears from CSF are rarely positive and sediment from the CSF should rather be cultured. If a smear is desired, two parallel marks about 10 mm long and 2 mm apart should be made on a clean glass slide. A loopful of the sediment is spread between these marks and the smear is allowed to dry. Another loopful of the sediment is then spread over the first. When this is dry, the process may be repeated depending on how much sediment is available. This procedure clearly marks the area to be searched for AFB. It is desirable that two independent readers examine the smears. The clots should be saved for culture.

proliferates extremely slowly [generation time 18 to 24 hours]. Further, growth requirements of mycobacteria are such that they will not grow on primary isolation in simple chemically defined media. Hence, culture methods for mycobacteria are expensive and require considerable infrastructure and technical expertise. Cultures are very sensitive for the detection of tubercle bacilli and may detect as few as 10 to 100 bacilli per ml of sputum. The culture is considered as gold standard (9). Most commonly used medium is L-J medium. It contains eggs, asparagine, glycerol and some mineral acids. Cultural Characters The growth appears in about two weeks but may be delayed up to six to eight weeks. Optimum temperature for growth is 37 °C; growth does not occur below 25 °C and above 40 °C. Optimum pH for growth is 6.4 to 7.0. Increased carbon dioxide [CO2] tension [5% to 10%] enhances growth. Human strains grow more luxuriantly in culture [eugonic] than do bovine strains [dysgonic]. The addition of a low percentage of glycerol to the medium encourages the growth of human strains but not that of bovine strains, which may in fact be inhibited. Culture Media Various types of media that are commonly used have been summarized in Table 10.3.

Urine

Colony Characteristics

Smears of centrifuged urine deposits are most unreliable and should be avoided. Nontuberculous mycobacteria [NTM] are sometimes present in the urine, either when it is voided or as a result of poor collection techniques. The presence of AFB in urine should be viewed with suspicion.

On solid media human type of tubercle bacilli give rise to discrete, raised, irregular, dry and wrinkled colonies which are creamy white to begin with and then develop Table 10.3: Media used for the growth of Mycobacterium tuberculosis Solid media

ISOLATION OF MYCOBACTERIA BY CULTURE Culture examination, on the other hand, detects fewer bacilli and increases the number of TB cases found, often by 30 to 50 per cent. Culture methods provide definitive diagnosis by establishing the viability and identity of the organisms. Further, in order to distinguish between different mycobacterial species as well as to perform drug susceptibility tests, culture examination becomes a necessity. Compared to other bacteria, which typically reproduce within minutes, Mycobacterium tuberculosis

Functions Isolation of organism Antigen preparation Chemical tests Examples L-J medium* Loeffler serum slope Pawlowsky’s medium [potato medium] Tarshis medium [blood medium] * most widely used L-J = Lowenstein-Jensen

Liquid media Sensitivity testing

Dubos’ medium Middlebrook’s medium Sula’s medium Sauton’s medium

Laboratory Diagnosis 165 buff colour. By contrast, the bovine type grows as flat, white, smooth, moist colonies which “break up” more readily when touched. Tubercle bacilli will grow on top of liquid medium as a wrinkled pellicle if the inoculum is carefully floated on the surface and flask left undisturbed otherwise they will grow as floccules throughout the medium. However, a diffuse growth can be obtained by adding a wetting agent such as Tween 80. Virulent strains tend to form long serpentine cords in the liquid media while avirulent strains grow in a more dispersed fashion. The clinical specimen as such, or after concentration, is inoculated onto two bottles of L-J medium and incubated at 37 °C. Cultures are examined initially after three to four days to rule out the presence of rapid growing mycobacteria and contaminant fungi and bacteria. Thereafter, cultures are examined twice weekly. A negative result is given, if no growth appears after eight to twelve weeks. If growth is obtained, then a Z-N stained smear made from the same is examined and routine biochemical tests put up. All cultures should be examined 48 to 72 hours after inoculation to detect gross contaminants. Thereafter cultures are examined weekly, up to eight weeks on a specified day of the week. With doubtful cultures, the acid-fastness should be confirmed by Z-N staining. A very small amount of growth is removed from the culture using a loop and gently rubbed into one drop of sterile saline on a slide. At this point the ease with which the organisms emulsify in the liquid should be noted; as tubercle bacilli do not form smooth suspensions, unlike some other mycobacteria. The smear is allowed to dry, fixed by heat and stained by the Z-N method. Rapid Culture Methods A constraint faced with the conventional methods using egg-based or agar-based media is that they require two to eight weeks for detection of mycobacteria. In case of extra-pulmonary specimens, the time taken may be even longer. A technique for automated detection of bacterial metabolism by measuring radioactive CO2 liberated during decarboxylation of 14C labelled substrates was developed in 1969. This principle was further developed by several workers, which led to the development of the BACTEC radiometric system for mycobacteria (10). This system is now commercially available.

When the BACTEC 12B vial is inoculated, mycobacteria, if present, utilize the 14C labelled substrate [palmitic acid] and release 14CO2. The BACTEC instrument measures quantitatively the radioactivity in terms of numbers on a scale ranging from 0 to 999, designated as the growth index [GI]. The daily increase in GI is directly proportional to the rate and amount of growth in the medium. When an inhibitory agent is introduced in the medium, inhibition of metabolism is indicated by reduced production of 14CO2, which in turn is indicated by decrease in GI. This basic principle is utilized in isolation of mycobacteria and drug susceptibility testing in this method. This system is, at present, standard practice among laboratories in the developed nations as a routine method. Several investigators have successfully used BACTEC 12B medium for isolation of mycobacteria from blood specimens. However, a large quantity of blood cannot be inoculated into 12B medium because it produces turbidity and high background reading. Another approach is to process the specimen by lysing the blood cells and concentrating the specimen by centrifugation. The introduction of BACTEC 13A medium has eliminated the time consuming and potentially hazardous processing step by allowing a larger volume [up to 5 ml] of blood to be inoculated directly into 30 ml of 13A medium (11). The 13A medium can also be used for aseptic collection of extra-pulmonary specimens such as bone marrow and CSF, which can be directly inoculated [up to 5 ml]. Septi Chek Acid-fast Bacilli Method Recently, a novel biphasic-culture approach for detection and isolation of mycobacteria from clinical specimens has been described. It showed higher mycobacterial recovery when this biphasic system was compared with conventional mycobacterial isolation culture techniques as well as the BACTEC system (11). Rapid Liquid Tuberculosis Culture Rapid liquid tuberculosis culture is also known as Mycobacteria Growth Indicator Tube [MGIT]. The culture is done using manual or automated systems in which tubes contain enriched Middlebrook 7H9 broth and an oxygen sensitive fluorescent sensor embedded in silicone on the bottom of the tube. The presence of oxygen dissolved in the broth quenches emissions from the compound. As the actively growing and respiring

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mycobacteria consume the dissolved oxygen, the sensor glows indicating mycobacterial growth. This can be observed by using an ultraviolet lamp with a wave length of 365 nm. The fully automated version can incubate up to 960 samples for Mycobacterium tuberculosis. Diagnosis for sputum positive material is obtained within a week while for negative results incubation has to continue for six weeks. The culture system has also been used for drug susceptibility testing for the first-line drugs. These cultures have shown higher rates of mycobacterial isolation and a shorter time-to-detection compared to cultures on solid media. Mycobacteriophage-based Detection Tests Phage-based tests require limited culture facilities and promise rapid results [within 2 days]. Phage tests are based on the ability of viable Mycobacterium tuberculosis to support the replication of an infecting mycobacteriophage. Plaques of lysed cells in a lawn culture of mycobacteria are counted (12). Phage-based tests are technically complex to perform requiring a well-functioning bacteriology laboratory, a strict incubation protocol and well-trained technicians. They are very labour intensive and some studies also report a high rate of contamination, making the test and its results both difficult to perform and to interpret. TESTS FOR CONFIRMATION OF IDENTITY Biochemical Properties Mycobacterium tuberculosis has distinctive biochemical properties, some of which are utilized for identification of various species. Their brief description follows: Niacin Test All mycobacteria produce nicotinic acid or niacin during growth. However, only Mycobacterium tuberculosis produces niacin in sufficient quantities to give a positive niacin test. The niacin production test is today the most extensively used in diagnostic mycobacteriology. Nitrate Reduction Mycobacterium tuberculosis suspended in a buffer solution containing nitrate and incubated at 37 oC for

two hours reduces nitrate to nitrite which gives a pink or red colour when treated with sulphanilamide and N-naphthyl-ethylene diamine dihydrochloride. This test differentiates Mycobacterium tuberculosis from Mycobacterium bovis which does not reduce nitrate. Tween 80 Degradation [Tween Hydrolysis] The test is carried out by suspending the growth from a slope in a mixture of Tween 80-buffer-neutral red at 37 oC. The reaction is read at four hours, five days and 10 days. A pink colour indicates hydrolysis of Tween 80. Mycobacterium tuberculosis does not produce hydrolysis of Tween 80. This test is particularly useful in differentiating Mycobacterium scrofulaceum [negative] from Mycobacterium gordonae and Mycobacterium flavescens [positive]. Neutral Red Test This test detects the ability of a strain to bind neutral red in an alkaline buffer solution. Positive tests are obtained with Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium avium and Mycobacterium ulcerans. Arylsulphatase Test The organism is grown for two weeks in a medium containing 0.0001 M tripotassium phenolphthalein disulphate. The liberation of free phenolphthalein is detected by the red colour produced on addition of an alkali. Mycobacterium tuberculosis gives a negative test. Catalase at Room Temperature The test is usually performed by suspending growth in a mixture of Tween 80-hydrogen peroxide; the appearance of bubbles is interpreted as a positive reaction. The NTM usually have catalase activity. Catalase at 68 oC The growth is incubated in phosphate buffer [pH 7] at 68 °C in a water bath for 20 minutes and cooled to room temperature. Tween peroxide mixture is then added. The appearance of bubbles indicates a positive reaction. Mycobacterium tuberculosis and Mycobacterium bovis give negative reaction, while positive reactions are usually obatined with several other NTM.

Laboratory Diagnosis 167 Peroxidase Test

Table 10.4: Biochemical tests to differentiate mycobacteria

Isoniazid-sensitive Mycobacterium tuberculosis is peroxidase positive, while unclassified mycobacteria and isoniazid-resistant strains of Mycobacterium tuberculosis are peroxidase negative.

Test

Nicotinamidase and Pyrazinamidase Activity Mycobacterium tuberculosis has the ability to deaminate nicotinamide to nicotinic acid and pyrazinamide to pyrazinoic acid; these properties differentiate Mycobacterium tuberculosis and Mycobacterium bovis. Susceptibility to Pyrazinamide Mycobacterium tuberculosis is sensitive to 50 μg/ml pyrazinamide, while Mycobacterium bovis and other mycobacteria are resistant.

Mycobac- Mycobac- Nontuberculous terium mycobacteria terium tuberculosis bovis

Production of niacin + Binding of neutral red + Hydrolysis of Tween 80 – Production of enzymes Nitrate reduction + Arylsulphatase – Catalase at room temp – at 68 °C – Catalase-Peroxidase Weak + Nicotinamidase + Pyrazinamidase + Susceptibility to: Pyrazinamide + Uptake of iron –

– + –

– +/– +

– –

+/– –/+

– – Weak + – –

+ + Strong + – +/–

– –

– –/+

+ = positive; – = negative

Susceptibility to P-Nitrobenzoate Mycobacterium tuberculosis and Mycobacterium bovis are inhibited by 500 μg/ml of sodium p-nitrobenzoate in L-J medium, while the saprophytes and the unclassified mycobacteria are resistant. Susceptibility to Thiophen-2-Carboxylic Acid Hydrazide [TCH] Mycobacterium tuberculosis is usually not inhibited by 10 μg/ml of thiophen carboxylic hydrazide; however, many Indian strains of Mycobacterium tuberculosis with low virulence to guinea-pigs are susceptible to TCH. Mycobacterium bovis strains are usually susceptible. The results obtained with these tests have been summarized in Table 10.4.

Identification of Nontuberculous Mycobacteria The reader is referred to the chapter “Nontuberculous mycobacterial infections” [Chapter 48] for the salient features of NTM and their diagnostic criteria. ANIMAL INOCULATION Guinea pig inoculation was once a popular way of diagnosing TB but should now be regarded as obsolete. It has been clearly demonstrated that the use of this animal offers no practical advantage over in vitro culture. In addition to humane considerations, animal inoculation is costly and generates many biohazards. However, in some laboratories it is still used. IMMUNODIAGNOSIS

Identification of Mycobacterium tuberculosis

Antibody Detection Tests

There is no single reliable test that will differentiate Mycobacterium tuberculosis from other mycobacteria. Nevertheless, the following tests, when used along with the morphological characteristics, will enable a precise identification of more than 95 per cent of the Mycobacterium tuberculosis strains: [i] susceptibility to p-nitrobenzoic acid; [ii] niacin production test; [iii] catalase activity at 68 oC/pH 7; and [iv] nitrate reduction test [optional].

Various antigens have been evaluated for detection of antibody to Mycobacterium tuberculosis. The A60 is the most extensively used antigen for both pulmonary and extrapulmonary, adult and childhood TB. Immunoglobulin [Ig] G [IgG] and IgM detection has been evaluated. In various studies the sensitivity of these test has ranged between 30 to 100 per cent (13-15). A variety of commercial kits are available primarily in developing countries. However, all them lack adequate sensitivity and specificity.

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Tests are also available which use purified antigens mainly 38kDa and 30kDa. The former is very specific and the latter is highly immunogenic and more sensitive (16-18). Antibody detection by enzyme linked immunosorbent assay [ELISA] or other serological tests are of limited use since less than 70 per cent of patients produce specific antibodies in high levels. Moreover, presence of antibody does not indicate current disease or past infection. Accordingly, presence of antigen may be a better indicator of the disease than the antibody. However, antigen quantity in circulation is usually very limited and masked by the antibody and hence difficult to detect. Though various tests have been attempted (19-21), there is none that can be recommended and is widely used. A recent WHO study found that TB rapid diagnostic tests currently available in the market vary widely in performance, with some products showing a high lotto-lot and reader-to-reader variability. At less than 80 per cent, the specificity was poor in the majority of products when tested in TB suspected cases from endemic settings. Those tests with a better specificity [over 90%] had poor sensitivity, detecting fewer than 40 per cent of TB patients. The tests performed even worse in HIV coinfected samples. The conclusion of a review of several studies showed that none of the assays perform well enough even to replace microscopy (22). Antigen Detection Test Lipoarabinomannan Urine Test The test detects lipoarabinomannan [LAM] in urine as a surrogate marker for Mycobacterium tuberculosis infection. Lipoarabinomannan is a component of the TB bacterial cell wall. The test exists in ELISA and simplified “tube” format. Clinical trials to develop a dipstick format are ongoing. The simplified tube format is apparently robust and does not require cold chain. Flow-through Filter Tests These tests rely on detection of Mycobacterium tuberculosis in sputum or body fluids with a polyclonal antibody, using a flow-through device. Nucleic Acid Amplification Tests Nucleic Acid Probes Deoxyribonucleic acid [DNA] hybridization technique detects small numbers of Mycobacterium tuberculosis with

no cross hybridization with non-mycobacterial respiratory pathogens (23) with sensitivity equivalent to smear examination by Z-N staining. Polymerase Chain Reaction Polymerase chain reaction [PCR] is extremely sensitive and specific technique (24). A protocol for detection of insertion element IS6110 was described and it gave a positive result in nine out of the fifteen TB pleural effusions, while a PCR for conserved region was positive in only three of these patients. However, it was also reported that when different specimens from the same patient were tested, positive results were obtained intermittently (25). Initially developed PCR could detect as low as 10 bacilli in the specimen. Recent modifications have enabled DNA extracted from a fraction of a bacilli to be detected after suitable amplification (26). The DNA ligase functions to link two strands of DNA together to continue a double strand segment. The seal can reliably take place only if the ends are complementary and are an exact match. In ligase chain reaction [LCR], the fragmented primers are four in number and are added in excess. Results from PCR and LCR tests are available in three days as compared to culture which takes six weeks. Its power can, however, be its greatest weakness as even the smallest amount of contaminating DNA can be amplified, resulting in misleading results. Amplified Mycobacterium tuberculosis Direct Test The amplified Mycobacterium tuberculosis direct test is specific for Mycobacterium tuberculosis complex. It is an isothermal transcription mediated amplification [TMA] test in which the target is the mycobacterial 16SrRNA. The entire process is performed at 42 ºC. The test is highly specific, and gives result within three hours. This is the first test to be approved by the FDA for smear-positive respiratory specimens. Similarly, other PCR test systems that target 16SrRNA including the real time assays have been developed. Efforts are being made to simplify the nucleic acid testing systems. In loop mediated isothermal amplification [LAMP], Mycobacterium tuberculosis DNA is amplified directly from clinical samples. A positive result is signalled by a colour reaction visible to the naked eye.

Laboratory Diagnosis 169 Overall, sensitivity of nucleic acid amplification tests [NAAT] is higher when test is applied to the respiratory samples as opposed to other body fluids (27). GenoType Assays Two GenoType assays are commercially available. The first is for TB diagnosis [GenoType Mycobacteria Assay], the second for detection of rifampicin and isoniazid resistance [GenoType MTBDR Assay]. Isolation is commonly done by PCR amplification of the 16S-23S ribosomal DNA spacer region followed by hybridization of the biotinylated amplified DNA products with 16 specific oligonucleotide probes. The specific probes are immobilized as parallel lines on a membrane strip. Polymerase Chain Reaction Sequencing Specific Mycobacterium tuberculosis genetic material is amplified and sequenced, allowing the DNA to be “read”. This is the gold standard and the most widely used method for defining genetic resistance for drug sensitivity testing. It has been commonly used for characterising mutations in the rpoB gene in rifampicinresistant strains and to detect mutations responsible for other antituberculosis drugs. Most protocols include the repeat insertion sequence IS6110 as a target for amplification. This sequence is specific of Mycobacterium tuberculosis complex and is present in many copies in the Mycobacterium tuberculosis genome. Identification of Mycobacteria by High Performance Liquid Chromatography Identification of mycobacteria to the species level by using biochemical and microbiological methods is a time consuming process. However, in the recent past, several newer rapid methods have become available to achieve reliable results. One such rapid method, developed at the Centers for Disease Control [CDC], Atlanta, USA, is the use of high performance liquid chromatography [HPLC] for the analysis of species-specific mycolic acids present in the cell walls of mycobacteria. Extensive work with this technique has resulted in a dramatic increase in the usage of this technique by several laboratories. This popularity is due to the simplicity and reliability of the method and its ability to accurately identify the mycobacteria from a single test.

DRUG SUSCEPTIBILITY TESTING With the emergence of multidrug-resistance in mycobacteria it is essential to perform DST on the tubercle bacilli isolates as an aid and guide to the treatment. Drugresistant mutants continuously arise at a low rate in any mycobacterial population. The purpose of DST is to determine whether the great majority of the bacilli in the culture are sensitive to the antituberculosis drugs currently in use. The DST tests should be performed in the following instances: [i] for relapse or retreatment cases; [iii] to change the drug regimen when drug resistance is suspected; and [iii] undertaking drug-resistance surveillance studies in a region/country. The DST may be direct [performed on the original specimen] or indirect [performed on a subculture]. Direct Method For the direct method, the inoculum is a digested and decontaminated sputum [or other clinical specimen] in which AFB have been demonstrated in stained smears. In this method, the inoculum is truly representative of the bacillary population present in the specimen. The advantage of this method is that the drug susceptibility test results are available along with the culture results [by 3 to 4 weeks]. Indirect Test The indirect test is used for specimens that are smearnegative but culture-positive or when the growth in the control slope of the direct test is inadequate. Further, in the indirect test, the inoculum is standardized but at the same time is not truly representative and hence there is a chance of selecting a proportion of susceptible or resistant bacilli from the slope. For this reason, the inoculum is prepared by using a representative sweep of the entire surface of the growth on the slope. There are three general methods used for determining drug susceptibility of mycobacteria by the indirect method. These include the absolute concentration method also called [MIC method], the resistance ratio [RR] method, and the proportion method. When properly standardized and performed, all three methods have been shown to be equally satisfactory.

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Absolute Concentration Method The absolute concentration method uses a standardized inoculum grown on drug-free media and media containing graded concentrations of the drug[s] to be tested. Several concentrations of each drug are tested, and resistance is expressed in terms of the lowest concentration of the drug that inhibits growth, i.e., MIC. This method is greatly affected by inoculum size and by the viability of the organisms. Resistance Ratio Method The resistance ratio method compares the growth of unknown strains of tubercle bacilli with that of a standard laboratory strain [H 37 Rv]. Parallel sets of media, containing two-fold dilutions of the drug, are inoculated with a standard inoculum prepared from both the unknown and standard strains of tubercle bacilli. Resistance is expressed as the ratio of the MIC of the test strain to the MIC for the standard strain in the same set. This test is also greatly affected by the inoculum size as well as the viability of the strains. In addition, any variation in the susceptibility of the standard strain also affects the RR of the test strain. Proportion Method The proportion method enables a precise estimation of the proportion of mutants resistant to a given drug. Several 10-fold dilutions of inoculum are planted on to both control [drug-free] and drug-containing media; at least one dilution should yield isolated countable [50 to 100] colonies. When these numbers are adjusted by multiplying by the dilution of inoculum used, the total number of viable colonies on the control medium, and the number of mutant colonies resistant to the drug concentrations tested may be estimated. The proportion of bacilli resistant to a given drug is then determined by expressing the resistant proportion as a percentage of the total population tested. The proportion method is currently the method of choice. E Test The technique is based on determination of drug susceptibility testing using strips containing gradients of impregnated antibiotics. The E test strip is placed on the surface of the solid culture medium and MICs a measure of the susceptibility of a strain to an antibiotic

are determined by interpreting the point at which the ellipse of inhibition crosses the strip. This is a simple method which does not require sophisticated infrastructure or highly skilled personnel. It has been shown to be accurate and reproducible and results become available within five to ten days after primary culture. It, however, requires a higher bacterial concentration in the inoculum. Microscopic-Observation Drug-Susceptibility Assay The microscopic-observation drug-susceptibility [MODS] assay (28-30) facilitates the detection of Mycobacterium tuberculosis, directly from the sputum. This innovative technique utilizes a liquid medium which facilitates faster growth of the TB bacillus and thereby aids in the early microscopic visualization of characteristic cord formation. Furthermore, incorporation of drugs allows rapid and direct drug-susceptibility testing concomitantly with the detection of bacterial growth. In this method, the sputum specimen is subjected to the digestion–decontamination procedure using a mixture of two reagents, N-acetyl-L-cysteine and sodium hydroxide and is directly inoculated into the selective 7H9 liquid culture medium in 24-well plates. Following concentration by centrifugation, the characteristic cord [microcolonies] formation is detected by light microscopy. Comparison of growth in drug-containing and drug-free wells, susceptible or resistant strains facilitates identification of antituberculosis drug sensitivity. The inverted light microscope that is required for MODS assay is expensive and may preclude its wide-spread application in resource limited settings. In the study reported by Moore et al (31), of 3760 sputum samples evaluated, 401 [10.7%] yielded positive cultures for Mycobacterium tuberculosis. The sensitivity of MODS assay was 97.8 per cent compared with 89 per cent for automated mycobacterial culture, and 84 per cent for L-J culture. The MODS assay yielded the culture results much faster [median time 7 days] compared with MBBacT system [bioMérieux] and LJ method which required a median time of 13 and 26 days, respectively. Similarly, drug susceptibility results were also available earlier with MODS assay [median time 7 days] as compared with the median time required for MBBacT system [22 days] and L-J method [68 days].

Laboratory Diagnosis 171 BIOCHEMICAL AND IMMUNOLOGICAL MARKERS Adenosine deaminase and Interferon-γγ Measurement of adenosine deaminase [ADA] is a relatively sensitive and specific test for the diagnosis of TB pleurisy. A recent meta-analysis (32) indicated sensitivity of 0.92, specificity 0.90, positive likelihood ratio 9.03, negative likelihood ratio 0.10, and diagnostic odds ratio 110.08. The measurement of IFN-γ levels in pleural effusions is also likely to be a useful tool for diagnosis of TB pleurisy. A recent meta-analysis (33) demonstrated the results as follows: sensitivity 0.89, specificity 0.97, positive likelihood ratio 23.45, negative likelihood ratio 0.11 and diagnostic odds ratio 272.7. Another meta-analysis (34) of ADA and IFN-γ measurements for the diagnosis of tuberculous pleurisy found both tests to be accurate. In peritoneal TB (35), IFN-γ and ADA assays showed equal sensitivity of 0.97 and differed marginally in specificity of 0.97 and 0.94 respectively. For differentiating TB from non-TB ascites, optimal cut-off points were 112 pg/ml for IFN-γ and 37 IU/l for ADA. The accuracy of the ADA assay was similar to that of IFN-γ assay in differentiating TB from non-TB ascites. As ADA assay is cost-effective, it appears to be the most appropriate diagnostic test for analysis of peritoneal fluid in resourcelimited settings. TUBERCULOSIS LABORATORY RELATED SAFETY ISSUES Laboratory work is associated with several specific hazards. Risk of TB infection is much higher for laboratory workers when compared to administrative staff or the general community, depending on the type of laboratory work. Mycobacterium tuberculosis is included in Risk Group III in the WHO classification of risk to infect laboratory workers by the airborne route. The number of tubercle bacilli required to initiate infection is low, the infective dose being less than 10 bacilli. Infective particles in the laboratory are usually derived from moist droplets discharged into the air by procedures liberating aerosols. When aerosolized material dry out, droplet nuclei are formed creating infective particles, which may remain in the air for long periods of time.

Safety precautions in TB laboratories must involve: [i] provision of safe building and equipment and their proper maintenance; [ii] education of all staff about safety precautions; and [iii] continuous supervision to ensure that these precautions are strictly observed. The focus on biosafety in the TB laboratory should be on primary containment measures, which are aimed at protecting laboratory staff and the immediate environment. These include: [i] proper training in safe laboratory procedures; [ii] adequate information of essentially hazardous techniques and procedures that require special care; [iii] availability of adequate safety equipment and clothing; [iv] preparedness for prompt corrective action following a laboratory accident; [v] education about their risk of acquiring TB; and [vi] periodic monitoring by the medical personnel. The most expensive and sophisticated equipment is no substitute for safe techniques and meticulous care. Good hygiene practices and adherence to safety procedures are the responsibility of every laboratory worker. REFERENCES 1. American Thoracic Society and Center for Disease Control. Diagnostic standards and classification of tuberculosis. Am Rev Respir Dis 1990;149:264-7 2. Strumpf IJ, Tsang AY, Sayre JW. Re-evaluation of sputum staining for diagnosis of pulmonary tuberculosis. Am Rev Respir Dis 1979;119:599-602. 3. Mohan A, Pande JN, Sharma SK, Rattan A, Guleria R, Khilnani GC. Bronchoalveolar lavage in pulmonary tuberculosis: a decision analysis approach. QJM 1995;88:269-76. 4. Mohan A, Sharma SK. Fibreoptic bronchoscopy in the diagnosis of sputum smear-negative pulmonary tuberculosis: current status. Indian J Chest Dis Allied Sci 2008;50:67-78. 5. Lincoln EM, Harris LC, Bovornkilli S, Carretero RW. Endobronchial tuberculosis in children, a study of 156 patients. Am Rev Tuberc 1958;77:39-61. 6. Giammona ST, Zelkowitz PS. Superheated nebulized saline and gastric lavage to obtain bacterial cultures in primary pulmonary tuberculosis in children. Am J Dis Child 1969;117:198-200. 7. American Thoracic Society. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 2000;161:1376-95. 8. Kent PT, Kubica GP. Public health mycobacteriology as a guide for the level III laboratory. Atlanta, GA: Centres for Disease Control; 1985.p.31-46. 9. Fregnan GB, Smith DW. Description of various colony forms of mycobacteria. J Bacteriol 1962;83:819-27.

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10. Siddiqi SH, Libonati JP, Middlebrook G. Evaluation of a rapid radiometric method of drug susceptibility testing of Mycobacterium tuberculosis. J Clin Microbiol 1981;13:908-12. 11. Isenberg HD, D’Amato RF, Heifets L, Murray PR, Scardamaglia M, Jacobs MC, et al. Collaborative feasibility study of a biphasic system [Roche Septi-Chek AFB] for rapid detection and isolation of mycobacteria. J Clin Microbiol 1991;29:171922. 12. Park DJ, Drobniewski FA, Meyer A, Wilson SM. Use of a phage-based assay for phenotypic detection of mycobacteria directly from sputum. J Clin Microbiol 2003;41:680-8. 13. Rosen EU. The diagnostic value of an enzyme-linked immunosorbent assay using absorbed mycobacterial sonicates in children. Tubercle 1990;71:127-30. 14. Delacort C, Gobin J, Gaillard JL, De Blic J, Veron M, Scheinmann P. Value of ELISA using antigen 60 for the diagnosis of tuberculous children. Chest 1993;104:393-8. 15. Munshi MM, Chiddarwar S, Patel A, Grover S. Serodiagnosis of extrapulmonary tuberculosis by ELISA. Indian J Pathol Microbiol 1993;36:356-60. 16. Gupta S, Kumari S, Banwalikar JN, Gupta SK. Diagnostic utility of the estimation of mycobacterial antigen A60 specific immunoglobulins IgM, IgA and IgG in the sera of cases of adult human tuberculosis. Tuber Lung Dis 1995;76:418-24. 17. Cole RA, Lu HM, Shi YZ, Wang J, De-Hua T, Zhou AT. Clinical evaluation of a rapid immunochromatographic assay based on the 38kDa antigen of Mycobacterium tuberculosis on patients with pulmonary tuberculosis in China. Tuber Lung Dis 1996;77:363-8. 18. Chiang Hl, Suo J, Bai KJ, Lin TP, Luh KT, Yu CJ, et al. Serodiagnosis of tuberculosis. A study comparing three specific mycobacterial antigens. Am J Respir Crit Care Med 1997;156:906-11. 19. Rosales-Borjas DM, Zambrano-villa S, Elinos M, Kasem H, Osuna A, Mancilla R, et al. Rapid screening test for tuberculosis using a 38kDa antigen from Mycobacterium tuberculosis. J Clin Lab Anal 1998;12:126-9. 20. Mahajan M, Singh NP, Gadre DJ, Talwar V, Gupta HC, Agarwal DS. Detection of IgM antibodies in pulmonary tuberculosis by ELISA using A60 antigen. J Commun Dis 1996;28:176-80. 21. Gupta S, Bhatia R, Datta KK. Serological diagnosis of childhood tuberculosis by estimation of mycobacterial antigen 60-specific immunoglobulins in the serum. Tuber Lung Dis 1997;78:21-7. 22. Steingart KR, Henry M, Laal S, Hopewell PC, Ramsay A, Menzies D, et al. Commercial serological antibody detection tests for diagnosis of pulmonary tuberculosis: a systematic review. PLoS Med 2007;4:e202.

23. Shoemaker SA, Fisher JH, Scoggin CH. Techniques of DNA hybridisation detect small numbers of mycobacteria with no cross hybridisation with non-mycobacterial respiratory organisms. Am Rev Respir Dis 1985;131:760-3. 24. Shankar P, Manjunath N, Lakshmi R, Aditi B, Seth P, Shriniwas. Identification of Mycobacterium tuberculosis by polymerase chain reaction. Lancet 1990;335:423. 25. Clarridge JE, Shawar RM, Shinnick TM, Plikaytis BB. Largescale use of polymerase chain reaction for detection of Mycobacterium tuberculosis in a routine mycobacteriology laboratory. J Clin Microbiol 1993;31:2049-56. 26. Wilson SM, McNerney R, Nye PM, Godfrey-Faussett PD, Stoker NG, Voller A. Progress towards a simplified polymerase chain reaction and its application to diagnosis of tuberculosis. J Clin Microbiol 1993;31:776-82. 27. Dinnes J, Deeks J, Kunst H, Gibson A, Cummins E, Waugh N, et al. A systematic review of rapid diagnostic tests for detection of tuberculosis infection. Health Technol Assess 2007;11:1-196. 28. Caviedes L, Lee TS, Gilman RH, Sheen P, Spellman E, Lee EH, et al. Rapid, efficient detection and drug susceptibility testing of Mycobacterium tuberculosis in sputum by microscopic observation of broth cultures. The Tuberculosis Working Group in Peru. J Clin Microbiol 2000;38:1203-8. 29. Moore DA, Mendoza D, Gilman RH, Evans CA, Hollm Delgado MG, Guerra J, et al. Tuberculosis Working Group in Peru. Microscopic observation drug susceptibility assay, a rapid, reliable diagnostic test for multidrug-resistant tuberculosis suitable for use in resource-poor settings. J Clin Microbiol 2004;42:4432-7. 30. Iseman MD, Heifets LB. Rapid detection of tuberculosis and drug-resistant tuberculosis. N Engl J Med 2006;355:1606-8. 31. Moore DA, Evans CA, Gilman RH, Caviedes L, Coronel J, Vivar A, et al. Microscopic-observation drug-susceptibility assay for the diagnosis of TB. N Engl J Med 2006;355:1539-50. 32. Liang QL, Shi HZ, Wanq K, Qin SM, Qin XJ. Diagnostic accuracy of adenosine deaminase in tuberculous pleurisy: a meta-analysis. Respir Med 2008;102:744-54. 33. Jiang J, Shi HZ, Liang QL, Qin SM, Qin XJ. Diagnositic value of interferon-gamma in tuberculous pleurisy: a metaanalysis. Chest 2007;131:1133-41. 34. Greco S, Girardi E, Masciangelo R, Capoccetta GB, Saltini C. Adenosine deaminase and interferon gamma measurements for the diagnosis of tuberculous pleurisy: a meta-analysis. Int J Tuberc Lung Dis 2003;7:777-86. 35. Sharma SK, Tahir M, Mohan A, Smith-Rohrberg D, Mishra HK, Pandey RM. Diagnostic accuracy of ascitic fluid IFNgamma and adenosine deaminase assays in the diagnosis of tuberculous ascites. J Interferon Cytokine Res 2006;26:484-8.

The Tuberculin Skin Test

The Tuberculin Skin Test

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11 VK Chadha, VK Challu

INTRODUCTION The tuberculin skin test [TST] is mainly used to detect infection with tubercle bacilli. The test is based on the fact that infection with Mycobacterium tuberculosis produces sensitivity to certain components [sensitins], which are contained in culture extracts called tuberculins. The TST finds its best use among children for detection of tuberculosis [TB] infection and as a supportive tool for the diagnosis of TB disease. The TST, however, has a limited value for the diagnosis of TB disease among adults living in areas where TB is highly endemic. The TST has also been used extensively by the epidemiologists for assessment of TB situation in the community. The usefulness of the test lies not only on proper technique of administering a specified dose of a standard tuberculin and reading of the reactions by trained personnel but also in its careful interpretation. The interpretation of TST is complicated by cross-sensitivity to tuberculin induced by infection with environmental mycobacteria or by bacille Calmette-Guerin [BCG] vaccination. HISTORICAL BACKGROUND It was Sir Robert Koch who first produced a filtrate prepared from heat sterilized concentrated broth cultures of human tubercle bacilli, in the late nineteenth century (1). This was initially prepared for treatment of TB but soon proved ineffective for this purpose. However, the observations of Sir Robert Koch that a subcutaneous inoculation in a patient suffering from TB resulted in a local reaction at the inoculation site laid the foundation

of its use as a diagnostic aid. Experimental confirmation of this fact came very quickly from animal testing. This product was later named as old tuberculin [OT]. Sir Robert Koch injected the OT subcutaneously in large doses, which produced systemic reactions including fever. The OT was gradually replaced by a low dose, intradermal test using a purified protein derivative [PPD] that was well tolerated. Clement Von Pirquet (2) observed in 1907 that a tiny scratch with a little quantity of tuberculin resulted in a local reaction at the test site. Subsequently, several modifications were made to improve the tuberculin, its mode of administration, reading and interpretation of the test. Moro (3) in 1908 announced his patch test, where tuberculin was incorporated into an ointment that was smeared onto the skin, with a piece of gauze over it. Around the same time, Charles Mantoux (4) developed the intradermal test to be administered by injection as a measured volume [Mantoux test]. Subsequently, other test techniques were developed such as Heaf test (5) which used a simple instrument, that caused six springloaded needles to pierce the skin with a drop of undiluted OT. Similarly, the Tine test (6) was developed as a disposable multiple puncture test where the tuberculin was introduced into the skin by puncture with four tines coated with dried tuberculin. However, the dose of tuberculin administered through these techniques was subjected to a lot of variation. Therefore, most of these tests have become obsolete and only the Mantoux technique which allowed quantitative measurement has stood the test of time and is now the standard method of administration of the TST.

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THE TUBERCULINS The OT was a crude product that contained a number of extraneous agents including impurities of the culture media and was observed to cause many false reactions. This prompted many to develop a more suitable preparation in terms of better specificity of the test and consistency of results. Siebert (7) in 1934 showed that the active principle in the tuberculin reaction was the protein fraction. She made a preparation from heat concentrated synthetic medium OT by precipitation with trichloroacetic acid. It still contained lipopolysaccharides and nucleic acids. Later, precipitation was accomplished with ammonium sulphate to obtain a preparation with less nucleic acid and polysaccharide content. It was termed as purified protein derivative [PPD] of tuberculin. A large batch of PPD was later produced by Siebert in 1941, which was termed as PPD-S. It was also called as mammalian tuberculin and was adopted as the international standard of tuberculin by the World Health Organization [WHO] in 1951 (8). All other tuberculins are standardized for biological activity against this preparation. One tuberculin unit [TU] of PPD was defined as the activity contained in 0.02 microgram of PPD (9); ‘5TU’ was defined as the standard dose of PPDS. The standard dose of any other tuberculin preparation is defined as the dose of that product which elicits reactions of size equivalent to 5TU of PPD-S [± 20%]. The products labelled, as ‘10TU’, ‘50TU’, etc., do not necessarily contain that many times the activity. In the following years, two batches of tuberculin were prepared by Statens Serum Institute [SSI], Copenhagen and labelled as RT-19-20-21 and RT-22 respectively (9). It was later observed that the strength of PPD varied from batch to batch even when different batches were prepared using similar technique. This necessitated the production of a large batch, which would also eliminate the need for repeated and cumbersome process of standardization. Such a large batch of PPD [dry weight 670 g] was prepared in the year 1952, by SSI at the behest of United Nations Children’s Fund [UNICEF] and WHO (10). This batch would meet the requirements of tuberculin for next several years. It was designated as PPD RT23. It was supplied in freeze-dried form to laboratories of the individual countries. The dried powder is stored in the country laboratories and dilutions are prepared as per requirements using isotonic phosphate buffer

saline, to which a detergent called Tween 80 is added. It had been observed earlier that the tuberculoprotein, when diluted in the buffered diluent was adsorbed in varying amounts to glass and plastic of the vials containing it. This resulted in variation in the potency of different samples of the same batch (11). Therefore, a small amount of Tween 80 was added to the diluent as a stabilising agent to prevent the absorption of tuberculin to glass surface. As a result, RT23 with Tween 80 was found to increase the potency of the tuberculin dilution in terms of reaction size and was observed to be three times more potent compared to RT23 without Tween 80 (12). The seed-lot of PPD RT23 was maintained in India by BCG Vaccine Laboratory, Guindy, Chennai. It is reconstituted and supplied as ready to use preparation in isotonic buffer solution as 5 ml vials, 0.1 ml corresponding to ‘1 TU’. Most countries use PPD RT23 with Tween 80, while few others like USA continue to use PPD-S. Some pharmaceutical companies have also produced PPD from different strains of Mycobacterium tuberculosis while employing varying techniques. In India, many such products are available in the market. These products are not standardized and their sensitivity and specificity vary substantially. The sensitins prepared from species other than Mycobacterium tuberculosis and Mycobacterium bovis [e.g., PPD-B derived from Mycobacterium intracellulare, PPDG from Mycobacterium scrofulaceum and PPD-A from Mycobacterium avium] are used only in epidemiological surveys for studying the prevalence of infection with environmental mycobacteria, which are usually nonpathogenic. These sensitins are not used in clinical practice in India. IMMUNOLOGICAL BASIS OF TUBERCULIN TEST Individuals infected with Mycobacterium tuberculosis respond with delayed type hypersensitivity [DTH] to the TST. In general, the sensitization is induced by natural mycobacterial infection or by vaccination with BCG, a live attenuated mycobacterial strain derived from Mycobacterium bovis. Clinically, it is a manifestation of previous infection with tubercle bacilli or a variety of nontuberculous mycobacteria [NTM] (13). The sequence of events following exposure to Mycobacterium tuberculosis are discussed in detail in the chapters “Pulmonary

The Tuberculin Skin Test tuberculosis” [Chapter 14], “Immunology of tuberculosis” [Chapter 7], and “Tuberculosis vaccine development: current status and future expectations” [Chapter 64]. The tuberculin sensitivity tends to persist once acquired. The injection of the tuberculin antigen leads to migration and proliferation of the sensitized T-cell lymphocytes to the test site. These T-cells release cytokines and chemokines, which further attract other lymphocytes and monocytes. These reactions along with increased permeability of the local blood capillaries lead to an induration at the test site (14). SKIN CHANGES IN TUBERCULIN SKIN TEST The characteristic features of the reaction include a delayed course reaching a peak more than 24 hours after injection and an induration with occasional vesiculation and necrosis (14). Some subjects with heavy exposure to mycobacterial antigens show an immediate erythematous reaction, maximal at six to eight hours (15). However, most subjects show little, if any, immediate reaction to the intradermal injection of PPD (14). Such immediate reactions that begin shortly after injection of tuberculin and disappear by 24 hours are not to be confused with DTH. In fact, more emphasis was placed on measurement of erythema in the early period of the use of TST. This was found impracticable in subjects with dark skin and reliance began to be placed more on the size of induration for interpretation of the TST. The DTH reaction peaks at 48 to 96 hours with an area of erythmatous induration, which resolves in a week’s time. The size of this induration is, thus, maximal between 48 to 96 hours after the test (16). Rarely, a giant reaction may occur in extremely sensitive subjects and there may be local vesicle formation or ulceration in a minority of subjects. In some, the skin test site may undergo necrosis. Lymphangitis may also be observed in few subjects. THE STANDARD TUBERCULIN SKIN TEST The low dose intradermal TST to be administered as Mantoux test has been adopted as the standard tuberculin test, after extensive studies on various aspects of tuberculin testing and vast experience gained in all parts of the world. The standard test employs a single batch tuberculin, i.e., PPD RT-23.

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Product and Dosage The dose of the standard TST was established as 0.02 microgram [1 TU] of PPD RT-23 in 0.1 ml of the diluent with Tween 80 (8). However, 2 TU of PPD RT-23 is now recommended as the standard dose. A series of studies conducted in India demonstrated equal sensitivity for 1 TU and 2 TU in detecting true infection with Mycobacterium tuberculosis and no change in the potency of 1 TU PPD RT-23 with Tween 80 has been observed in India in about four decades of its use (17). Storage Tuberculin vials should always be stored at 2 to 8 °C and used before the expiry period. Exposure to sunlight and heat must be avoided (18). The tuberculin should never be allowed to freeze or kept at temperatures exceeding 20 °C, except for short periods. The vials once used may be re-used within a maximum of 48 hours. Administration of Test A special glass syringe was developed for the purpose of the test. The 1 ml syringe was graduated to hundredth of a milliliter to facilitate exact measurement of 0.1 ml and it was fitted with a 26-gauge platinum needle of half an inch length and 20 degree bevel. A rubber ring was provided at the lower end of the piston to make it absolutely air-tight so as to avoid leakage which may occur due to pressure that is required to be exerted on the plunger for intradermal injection. If the syringe is not air tight, the amount of tuberculin injected will not be precise. The platinum needles were preferred to steel needles, which are subject to corrosion and hinder painless injection. Therefore, other syringes which may lead to leakage should not be used for the purpose. The disposable plastic tuberculin syringes that are now available are preferred these days, since it is cumbersome to use glass syringe which required not only proper sterilization but also frequent heating of the needle to red hot. Many brands of disposable syringes are available in the market, though not all conform to the requirements especially with respect to leakage. Therefore, the brand of disposable tuberculin syringe must be selected with caution. Conventionally, the test is given on the mid-volar aspect of the forearm [Figures 12.1 and 12.2] since this

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area is usually hair free. It is given on the left arm by convention, to avoid errors in reading. However, right arm may be used in case of any contraindication to use the left arm. The skin area chosen should be free of scars, veins and areas of inflammation. The test site need not be sterilized before injection (6). It can be simply cleaned with soap and water and should be dried before injection. The skin is lightly stretched and the needlepoint is inserted with its bevel facing upward into the superficial layers of the skin and 0.1 ml of tuberculin is injected slowly. Care should be taken to hold the syringe only by the barrel and not to touch the plunger before the needlepoint has been satisfactorily inserted into the skin. A satisfactory test should raise a flat pale pea-sized wheal with clear pits of hair follicles and a well demarcated border and without leakage of tuberculin. If the test is unsatisfactory, i.e., the correct amount has not been injected or the injection has been made into the subcutaneous tissue, then another injection can be given either at a sufficient distance from the first injection or on the other forearm. The site chosen for the second test should be appropriately recorded. The subcutaneous injection is dome shaped, less pale and is also difficult to read. Adverse Effects In some atopic individuals, an urticarial wheal may appear within minutes of injection. It usually disappears within a few hours. However, occurrence of such an allergic reaction does not signify the presence of TB infection. Systemic allergic reactions seldom occur. The formation of vesicles, bullae, lymphangitis, ulceration or necrosis at the test site, which may occur in a proportion of children, indicates a high degree of tuberculin sensitivity (14). Reading of the Test The TST result is read between 48 to 96 hours after the test in good day light, keeping the forearm flexed, by carefully palpating the site of injection using one finger. The induration may be easily recognized as a firm well circumscribed density. Sometimes, it may present as a soft ill-defined swelling as the addition of Tween 80 has been found to result in softer reactions. Thus, small indurations may be missed if not sought carefully with a light touch. The transverse margins of the induration are

marked with the ballpoint pen and the maximum transverse diameter is measured in ‘millimetres’ [mm] with a transparent ruler. For marking with the pen, the ball-point is drawn towards the induration from a point 5 to 10 mm away from the margin of the induration until a resistance is felt. The procedure is repeated on the opposite side. The erythema at the test site due to increased vascular permeability extends beyond the induration and is not considered for interpretation of the test results. The test result should never be recorded as ‘positive’ or ‘negative’ and must always be recorded in ‘mm of size’. Induration up to 40 mm in diameter has been observed in practice. Record should also be made of vesicles, bullae, lymphangitis, ulceration and necrosis at the test site. Besides, the date of testing, date of reading, details of previous BCG vaccination should also be recorded. A very high degree of inter-reader variation has been observed in measurement of induration sizes and more commonly, there is a tendency towards under-reading (19). Therefore, the health workers need to be appropriately trained for performing and reading the TST. Each trainee performs about 1500 TSTs and readings over a period of six weeks in the assessment phase. The measurements of indurations by the trainee reader are compared against those of standard reader (20,21). Only those workers who give less than two per cent unsatisfactory tests qualify as ‘testers’. Similarly, those who achieve a high correlation [of more than 90%] with the standard reader and a minimal intra-reader variation are considered eligible for reading of the tests. SKIN SENSITIVITY TO TUBERCULIN The TST gives rise to a DTH reaction in the form of induration at the test site in a sensitized host. The persons with sensitivity to tuberculin are called as reactors. However, not all reactors are infected with tubercle bacilli. The sensitivity to tuberculin may occur due to one or more of the following factors. Infection with Environmental Mycobacteria Infection with environmental mycobacteria also leads to sensitization of the host. The sensitivity induced by these generally non-pathogenic mycobacteria cross-reacts with tuberculin and is known as ‘non-specific sensitivity’ [NSS]. This NSS is highly prevalent in most parts of India

The Tuberculin Skin Test as in other tropical countries. In a survey conducted by National Tuberculosis Institute [NTI], Bengaluru [then called Bangalore], about half and two-thirds of the children were found to be infected with environmental mycobacteria by the ages of 10 and 14 years respectively (22,23). During the Tuberculosis Prevention Trial (24) at Chingleput, 61 per cent of children were found to be infected with environmental mycobacteria by the age of nine years and almost all were infected by the age of 19 years (24). Therefore, much of tuberculin sensitivity in the community is due to frequent contact with ubiquitous environmental mycobacteria. The distinction between reactions that represent infection with environmental mycobacteria and TB infection is not always very clear. However, in general the sensitivity induced by environmental mycobacteria results in smaller reactions to tuberculin than from true infection with Mycobacterium tuberculosis (25). Bacille Calmette-Guerin Vaccination It was observed in European countries, during the early 1950s, that the tuberculin sensitivity among school children, when vaccinated with BCG resembled that induced by natural TB infection (26). It was also observed to remain stable for a number of years. This led to the general belief that tuberculin test is of no value among vaccinated populations, to detect natural infection with tubercle bacilli. However, during the Mass BCG Vaccination Programme in India, tuberculin reactions due to BCG induced sensitivity were found to be smaller than those due to true infection with Mycobacterium tuberculosis (27). During the Tuberculosis Prevention Trial at Chingleput (24), post-vaccination tuberculin sensitivity was found highly satisfactory when full dose [0.1 ml] of BCG was administered under controlled conditions. It was observed to peak at 2.5 months after which it began to wane with time. Similar waning between three months and six years after vaccination was observed in other countries (28-30). Thus, BCG induced sensitivity may vary in intensity from very weak to about the same level as natural infection, in different population groups. It depends not only on the strength of vaccine but also the way it is handled and administered as well as on the age of vaccination and time interval between vaccination and tuberculin testing (24,27,29-32). Under Universal Immunization Programme [UIP] in India, multipurpose health workers administer a reduced

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dose of 0.05 ml of the reconstituted freeze-dried BCGvaccine [Danish 1331 strain] during early infancy. In a study conducted by NTI, about 70 per cent of the children with BCG scar in the age group up to nine years elicited either no reaction or reaction below 10 mm in size, to 1 TU of PPD RT 23 with Tween 80 (33). Even in the immediate post-vaccination period, i.e., during infancy and second year of age, same proportion of children elicited reactions below 10 mm. Similar observations have also been made by other investigators in India and Sri Lanka (34-36). Many factors including administration of a reduced dose of the vaccine, administration during early infancy and difficulty in maintaining the standards in the vaccination technique might have been responsible for results obtained in the NTI study under programme conditions. In another study, comparing the tuberculin reaction sizes among children with BCG scar compared to those without BCG scar, a higher proportion of reactions in the range of 4 to 13 mm was observed among the former (37). However, the proportion of children with larger reactions that signify natural infection with tubercle bacilli was similar in the two groups. That the BCG vaccination does not influence the tuberculin sensitivity due to natural infection with tubercle bacilli has also been observed in other places where BCG is given in infancy (38-40). Therefore, it may be inferred that the BCG induced sensitivity to tuberculin is generally weaker than the sensitivity induced by infection with tubercle bacilli. It has also been confirmed experimentally that the sensitivity to heterologous sensitins is weaker than to homologous sensitins. Nevertheless, it must be remembered that the absence or presence of weak sensitivity does not imply that vaccination is ineffective. The degree of protection conferred by BCG has been found unrelated to the extent of tuberculin sensitivity induced by it (31). Infection with Mycobacterium tuberculosis The specific tuberculin sensitivity induced by infection with Mycobacterium tuberculosis is more pronounced compared to the NSS induced by infection with environmental mycobacteria or BCG vaccination, as explained above. Therefore, most of the individuals harbouring TB infection usually elicit a larger reaction to tuberculin. However, in general, the probability that a skin reaction to tuberculin is due to infection with tubercle bacilli rather than due to infection with environmental mycobacteria or BCG vaccination increases as the size

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of reaction increases. This probability is also increased in the presence of history of contact with a sputum smearpositive case of TB. Similar is the case as the time since BCG vaccination elapses. Nevertheless, it is difficult to distinguish the sensitivity induced by Mycobacterium tuberculosis and Mycobacterium bovis. In India, infection due to Mycobacterium bovis is rare because of the practice of boiling milk before consumption. SEPARATION OF REACTIONS DUE TO INFECTION WITH TUBERCLE BACILLI FROM REACTIONS DUE TO OTHER CAUSES The tuberculin reaction sizes recorded among apparently healthy individuals during population based surveys when plotted as frequency histograms have shown that there are two main sub groups of individuals in any community, one consisting of those ‘infected with Mycobacterium tuberculosis’ and the rest having no tuberculin sensitivity or sensitivity due to other causes. The frequency distribution of reaction sizes usually shows two peaks (24,37,41-55). An example is illustrated in Figure 11.1. In this figure, the peak on the left with the reactions spread around it, i.e., from 0 to 14 mm represents generally the group of uninfected individuals or individuals with tuberculin sensitivity due to cross-

reactions. Some of the small reactions may also be due to needle trauma. The peak on the right with the reactions spread around it, i.e., from 15 to 28 mm represents the reactions due to infection with Mycobacterium tuberculosis. Such a distribution with two modes is called ‘bimodal distribution’. The peak on the left is called as first mode and the peak on the right is called as second mode. The point at which the two subgroups meet is called antimode. The majority of the reactions above the antimode signify infection with Mycobacterium tuberculosis and majority of reactions below this are considered due to other causes (43). This has been consistently reported from the results of tuberculin reactions among confirmed cases with sputum smear-positive TB. The distribution of reactions in such patients has been found symmetrical and lies on the same size scale as the subgroup on the right side of the distribution among apparently healthy individuals. The antimodes as obtained during epidemiological surveys have been found to vary between 10 to 15 mm in different parts of India. Many a times, it is difficult to find a definite cut-off even from tuberculin surveys due to some degree of overlapping around the antimode, between the infected group and the rest. The overlap around the antimode increases in areas with high

Figure 11.1: Frequency distribution of tuberculin reaction size among Indian children one to nine years of age [n = 5370] Data source: National Tuberculosis Institute, Bengaluru, India

The Tuberculin Skin Test prevalence of non-specific tuberculin sensitivity and the subgroups cannot be clearly discerned. In fact, for any cut-off point, some true infections will be missed and some others falsely included. In general, as the cut-off point moves to the left, there is an increase in sensitivity of the test at the expense of specificity and vice versa. Practically, it is not feasible to conduct tuberculin surveys all over the country to find suitable cut-off points in respective areas. In clinical practice, it is best to consider other circumstances also to decide on the significance of the reactions, such as history of contact, presence of symptoms, among others. FALSE-POSITIVE AND FALSE-NEGATIVE REACTIONS The false-positive reactions may be observed as seen above due to tuberculin sensitivity induced by infection with environmental mycobacteria or BCG vaccination. However, the errors can be minimized with careful interpretation. False-positive reactions may also occur due to testing with high dose of tuberculin and repeat testing, and due to reading errors by untrained and inexperienced readers. It is also important to recognize that a non-significant reaction does not always exclude the presence of TB infection or disease. The most common reason of a falsenegative result is the poor technique of administering or reading the test, besides improper storage of tuberculin. The tuberculin reaction may be suppressed in the presence of immunosuppresion. The size of induration has been observed to be diminished among children who are suffering from TB disease, especially those suffering from disseminated TB (56,57). The sensitivity of the test among bacteriologically confirmed cases of pulmonary TB has been found to be around 80 per cent and the remaining about 20 per cent of the cases do not manifest a significant reaction (52,53,55,58). This is because a few sensitized circulating T-cells are available to participate in the reaction, since most of these may be collected in the TB lesions. The mean reaction size of TST has also been found to decrease with increasing grade of undernutrition (48). Tuberculin induration size may similarly be diminished in the presence of a co-existing immunosuppressive disorder, such as malignancy, Hodgkin’s disease and sarcoidosis. During human immunodeficiency virus [HIV] infection, though tuberculin sensitivity is not affected at the initial stages,

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a greater proportion of individuals show suppression of test reactions as the CD4+ counts decline (59). A transient supression of sensitivity has also been observed in acute viral infections as well as after vaccination with live virus vaccines. The DTH may be impaired among persons receiving corticosteroids and other immunosuppressive agents (60). The false-negative reactions may also be observed among infants below three months of age, due to immature immune system (58). Similarly, false-negative reaction may be observed during the window period, since the sensitivity to tuberculin is evident only after four to eight weeks of infection with Mycobacterium tuberculosis. The tuberculin reactivity also tends to wane with time in some individuals (61). However, the reactivity may be recalled by repeat infection or even by repeat tuberculin testing. The tuberculin sensitivity is also suppressed in old age, due to generalized suppression of cellular immunity (62). Sometimes, a non-significant reaction may be due to a general inability to respond [anergy]. If such a possibility is suspected, then it may be desirable to test for DTH to some other antigens to which the individual is likely to have been exposed, e.g., candida, tetanus toxoid. A failure to respond to any of such antigens suggests a non-functioning immune system which may be responsible for a false non-significant reaction to tuberculin. INTERPRETATION OF TUBERCULIN TEST The interpretation of the test is influenced not only by the size of induration but also by the purpose of the test as well as the consequences of false classification. Based on the descriptions given in the previous sections and the experience gained during various tuberculin studies in India, the following general guidelines [Table 11.1] may be followed while interpreting tuberculin test results. Not all reactions to tuberculin are attributable to infection with Mycobacterium tuberculosis. Larger the size of induration at the test site, higher is the probability of presence of infection with Mycobacterium tuberculosis. This is supported by the observation that TB morbidity increased with the size of induration (63). Almost all reactions with induration of 15 mm or more in size may be considered attributable to infection with tubercle bacilli, irrespective of the presence or absence of BCG scar. The formation of vesicles, bullae or necrosis at the test site indicates high degree of tuberculin sensitivity,

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Tuberculosis Table 11.1: Interpretation of the tuberculin test

Size of induration 15 mm and above Signifies infection with tubercle bacilli, irrespective of BCG vaccination status Size of induration 10 to 14 mm Could be attributable to one or more of the following: Cross-sensitivity induced by environmental mycobacteria BCG induced sensitivity Infection with Mycobacterium tuberculosis Size of induration 5 to 9 mm Majority of such reactions are attributable to cross-sensitivity induced by environmental mycobacteria and/or BCG vaccination Could be attributable to infection with tubercle bacilli in the presence of immunosuppresive conditions Size of induration less than 5 mm Indicates absence of any type of mycobacterial infection except in individuals with severe degree of immunosuppression BCG = bacille Calmette-Guerin

and thus, presence of infection with Mycobacterium tuberculosis (13). The reactions with induration of less than 5 mm size usually indicate lack of tuberculin sensitivity, and thus, absence of infection. Simple trauma of the needle has been observed to give rise to induration usually in the range of 1 to 4 mm NTI, Bengaluru, unpublished data]. However, some individuals infected with Mycobacterium tuberculosis but suffering from severe degree of immunosuppression may show induration in this range. Among children without a BCG scar, the majority of reactions with indurations in the range of 5 to 9 mm are attributable to cross-sensitivity to environmental mycobacteria. Some of these children might actually have been vaccinated with BCG but do not show the BCG scar (64,65). Thus, in a proportion of children without BCG scar, the indurations in this range may be attributable to BCG vaccination. Among children with BCG scar, the reactions with indurations in this range may be attributable to BCG vaccination and/or infection with environmental mycobacteria. The reactions in 10 to 14 mm range require most careful interpretation as these could be attributable to infection with tubercle bacilli or due to cross sensitivity to environmental mycobacteria and/or BCG-induced sensitivity. An induration in this size range is more likely to be attributable to infection with tubercle bacilli among high-risk contacts e.g., infants of mothers suffering from TB, individuals with history of contact with smear-

positive case of pulmonary TB or presence of symptoms or clinical findings suggestive of TB. The probability of a reaction in this range attributable to infection with tubercle bacilli is relatively higher among children without BCG scar compared to those with scar. However, higher the age of the child, lesser the probability of the reaction attributable to BCG. As noted above, the tuberculin reaction may be suppressed in the presence of certain conditions. This does not mean that the test should not be carried out in the presence of those conditions. The size of induration depends upon the degree of immunosuppression and the level of immunodeficiency should be considered while interpreting tuberculin reactions. Also, there should be a minimum time gap of eight weeks between exposure and performing TST, since infection with tubercle bacilli may be missed if the test is carried out during the ‘window period’. The interpretation of TST also depends on the purpose of the test. In case the test is used for screening apparently healthy children for subjecting to further investigations for diagnosis of TB, it is more desirable to have a higher sensitivity by deciding on a lower cut-off point at 10 mm, so that most of those excluded are not infected. For a decision on preventive chemotherapy, it is desirable to have a higher cut-off point of 15 mm, to be more specific so that most of those put on chemoprophylaxis are definitely infected. Though chemoprophylaxis is not routinely recommended in India, it may be considered in special situations, e.g., HIV positive contact of a case with TB. Under the Revised National Tuberculosis Control Programme [RNTCP], of the Government of India, every asymptomatic child under the age of six years in contact with smear-positive case is started on preventive chemotherapy (66). This is because the tuberculin test may not be available at every place and there is high risk of such children acquiring TB infection. It is also well known that the risk of developing active TB disease is maximum in the period immediately following acquisition of infection especially among children (67). Interpretation of Tuberculin Skin Test Among Human Immunodeficiency Virus Infected Persons All HIV-seropositive individuals should be assessed for the presence of active TB. Once active TB is excluded, TST should be performed as soon as possible since the reliability of the test can diminish as the CD4+ T-

The Tuberculin Skin Test lymphocyte count declines, especially to less than 200/mm3 (59). A good proportion of the HIV-infected persons may even be anergic. Studies indicate that the probability of a significant induration to the tuberculin test indicative of TB infection is significantly lower among HIV-infected persons compared to HIVuninfected (68). Therefore, some countries advise a lower cut-off point for diagnosing latent TB infection (69,70). However, it remains to be proved that a lower cut-off point will increase the sensitivity of the test. Nevertheless, irrespective of the test results, patients with evidence of old healed TB on chest radiograph or with a past history of active TB and also those with a previously documented history of a positive TST result may be considered as infected for all practical purposes. Similarly, those with a history of recent exposure to a sputum positive case may be considered as infected. The TST only detects the presence or absence of TB infection. The presence of infection is not synonymous with disease. Thus, TST should never be the sole criteria for diagnosing TB. REVERSION, BOOSTER PHENOMENON AND CONVERSION In elderly subjects and many adults, the percentage of significant reactors to tuberculin declines with age. Loss of tuberculin reactivity over time has been termed skin test reversion and is estimated to occur at a rate of five per cent per year in a healthy population (61,71). This is attributed to a specific waning of cell-mediated immunity for tuberculin antigen rather than to a generalized anergy or a diminished cutaneous reactivity of the elderly patients (72,73). Loss of lymphocyte blastogenic capacity has been shown to be responsible for skin test reversion (74). It is usually unnecessary to repeat the TST unless the test injection or reading was performed unsatisfactorily. The repeat test should be given at a different site within one week of the first test (75). This is because the small amount of tuberculin injected for the first test can boost the size of the second test though it per-se does not sensitize the individual. This boosting results from ‘recall’ of sensitivity induced by infection with environmental mycobacteria or BCG vaccination, that had waned by the time of first test. In a study conducted by NTI (76), the boosting effect was observed when the test was repeated after two months. The boosting phenomenon

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was not observed when the test was repeated after 18 months (77). However, the time of disappearance of boosting effect could not be ascertained. In another study, boosting was observed within three weeks of the first test (78). Therefore, previous history of the individual taking the test should always be ascertained while interpreting the test result. Repeating the test with a higher dosage may result in larger reactions which are actually attributable to nonspecific sensitivity or BCG induced sensitivity (22,23). Therefore, a repeat test with a higher dose is of no value for detection of infection with tubercle bacilli. DETECTION OF NEWLY INFECTED PERSONS The TST does not distinguish between past and new infection. As stated above, the incidence of disease among recently infected is much higher compared to the incidence among previously infected, especially in the paediatric age group (49). Therefore, detection of newly infected individuals may be important in some situations, e.g., among children who showed a reaction of less than 10 mm at an earlier test but have been exposed to a smearpositive case thereafter. For detection of such new infection occurring in the intervening period between the two tests, there should be a significant increase in reaction size. Studies conducted by the NTI (79,80) have shown an increase of 14 mm and above among those infected during the intervening period when two tests were conducted one-and-half to three years apart. In clinical practice, it would be more useful to consider an increase of 10 mm between the two tests as indicative of new infection. There should be a minimum period of eight weeks between exposure and the second test. This applies to BCG vaccinated as well as unvaccinated children. It needs to be emphasized that a simple ‘tuberculin conversion’ from a non-significant reaction at first test to a significant reaction at a subsequent test does not necessarily signify new infection. Such ‘conversion’ may be attributable to a number of factors besides true fresh infection, e.g., boosting of tuberculin sensitivity on account of previous test and infection with environmental mycobacteria in the intervening period. The risk of developing TB has been found to be highest among those who have a larger increase in reaction size between tests conducted at a reasonable time interval (81).

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HEALTH CARE WORKERS AND TUBERCULIN TEST

Tuberculin Skin Test, Tuberculosis and Sarcoidosis

The reader is referred to the chapter “Tuberculosis in health care workers” [Chapter 45] for more details.

Patients with sarcoidosis frequently manifest tuberculin anergy (89). In areas where TB is highly endemic this may not always be true. In a study from India (90), it was reported that the TST in patients with sarcoidosis has a high specificity but a poor sensitivity for TB. The authors also suggest that while a negative TST in the general population is a sensitive test for sarcoidosis, a positive TST among sarcoidosis patients is a specific test for indicating TB. A positive TST in a patient suspected to suffer from sarcoidosis should, therefore, be an absolute indication for a thorough work-up for TB.

BACILLE CALMETTE GUERIN TEST Some medical practitioners use BCG vaccination for detection of TB infection by assessment of local reactions. However, the interpretation of BCG test has not been standardized since the number of injected viable and dead organisms is highly variable. Moreover, the vaccine has not been prepared for eliciting tuberculin sensitivity. Therefore, BCG test is not recommended to be used for detecting TB infection. EPIDEMIOLOGICAL USES OF TUBERCULIN TEST The TST has been put to maximum use by epidemiologists to study the epidemiological situation of TB in the community. The tuberculin surveys are often conducted in a representative sample of children without BCG scar and based on the frequency distribution of tuberculin reaction size, the prevalence of infection in the study group is estimated. Prevalence represents a cumulative effect of the infection acquired by the study group in all their years of exposure. The average annual risk of infection [ARI] is mathematically derived from the estimated prevalence using appropriate statistical formula (82,83). The ARI is defined as the average probability of acquiring new TB infection over the course of one year. It expresses the overall impact of the prevalence of infectious cases in the community as well as the efficiency of TB control activities. Any change in the epidemiological situation of TB is first reflected in a change in ARI rates. The tuberculin surveys to estimate ARI are also relatively simpler to conduct compared to disease surveys. These are generally carried out among young children since the results obtained reflect relatively recent situation. The trends in ARI obtained by repeating tuberculin surveys at an interval are also used to study the impact of TB control activities (84-88). The epidemiological studies conducted with antigens derived from environmental mycobacteria [e.g., PPD-B, PPD-G] are also used to study the geographic distribution of non-specific tuberculin sensitivity. The reader is also referred to the chapter “Epidemiology” [Chapter 3] for more details.

NEWER TUBERCULINS Though more specific than old tuberculin, PPD is not a fully species-specific antigen and results in wide crossreactivity to sensitivity induced by environmental mycobacteria and BCG vaccination. Further attempts are thus being made by various scientists to develop newer tuberculins, which are more species-specific. One of the improvizations that has been made is to avoid heating since heat can denature protein content of the PPD. Recent developments in the manufacture of purer tuberculins include use of methods, such as electrophoresis and chromatography. The experimental assays with some of these products designated by different codes, e.g., T-1327 and T-1456 are under progress and none has yet been produced on a large scale (81-83). THE FUTURE For nearly a century, the TST was the only method of detecting TB infection. The new millennium has witnessed introduction of the newer diagnostic methods for TB such as interferon-γ release assays [IGRAs]. The initial experience with the IGRAs indicates that they are proving to be more reliable than the TST in detecting TB infection (91,92). The reader is referred to the chapter “Diagnosis of latent tuberculosis infection: recent advances and future directions” [Chapter 12] for more details. REFERENCES 1. Koch R. Weitere Mitteilungen uber ein heilmittel gegen tuberculose. Disch Med Wschr 1891;17:101-2. 2. Von Pirquet C. Demonstration Zur Tuberculin diagnose durch Hautimpfung. Berl Med Wschr 1907;48:699.

The Tuberculin Skin Test 3. Moro E. Uber line diagnosetisch verwerybare reaktion der haut auf eireibung mit tuberkulinsalbe. Munch Med 1908;55:216-8. 4. Mantoux CL. Intradermo-reaction a la tuberculin et son interpretation clinique. Presse med 1910;18:10-3. 5. Heaf F. The multiple puncture tuberculin test. Lancet 1951;2:151-3. 6. Caplin M. The tuberculin test in clinical practice. An illustrated guide. London: Bailliere Tindall; 1980. 7. Siebert FB. The isolation and properties of the purified protein derivative of tuberculin. Am Rev Respir Dis 1934;30:713. 8. World Health Organization. The WHO standard tuberculin test. WHO/TB/Technical Guide/3. Geneva: World Health Organization; 1963. 9. Guld J, Weis Bentzon M, Bleiker MA, Griep WA, Magnusson M, Waaler H. Standardization of a new batch of purified tuberculin [PPD] intended for international use. Bull World Health Organ 1958;19:845-951. 10. Magnusson M, Weis Bentzon M. Preparation of purified tuberculin RT 23. Bull World Health Organ 1958;19:829-44. 11. Waaler H, Guld J, Magnus K, Magnusson M. Adsorbtion of tuberculin to glass. Bull World Health Organ 1958;19:783-98. 12. Landi S, Held HR, Tseng MC. Disparity of potency between stabilized and nonstabilized dilute tuberculin solutions. Am Rev Respir Dis 1971;104:385-93. 13. American Thoracic Society. The tuberculin skin test. Statement of American Thoracic Society, Medical Section of the American Lung Association. Am Rev Respir Dis 1981;124:356-63. 14. Beck JS. Skin changes in the tuberculin test. Tubercle 1991;72:81-7. 15. Kardjito T, Grange JM. Immunological and clinical features of pulmonary tuberculosis in East Java. Bull Int Union Tuberc Lung Dis 1980;61:231-8. 16. World Health Organization. Tuberculosis Research Office. Tuberculin reaction size on five consecutive days. Bull World Health Organ 1955;12:189-96. 17. Chadha VK, Jagannatha PS, Vaidyanathan P, Jagota P. PPD RT23 for tuberculin surveys in India. Int J Tuberc Lung Dis 2003;2:172-9. 18. World Health Organization. Tuberculosis Research Office. Effect of exposure of tuberculin to light. Bull World Health Organ 1955;12:179-88. 19. Kendig EL Jr, Kirkpatrick BV, Carter WH, Hill FA, Caldwell K, Entwistle M. Underreading of the tuberculin skin test reaction. Chest 1998;113:1175-7. 20. Shashidhara AN. An introduction to tuberculin testing and BCG vaccination. Bangalore: National Tuberculosis Institute; 1980. 21. Chadha VK, Jagannatha PS, Nagaraj AV, Narayana Prasad D, Anantha N. A comparative study of tuberculin reactions to 1TU and 2TU of PPD-RT 23. Indian J Tuberc 2000;47:15-20. 22. Chakraborty AK, Ganapathy KT, Nair SS, Kul Bhushan. Prevalence of non-specific sensitivity to tuberculin in a south Indian rural population. Indian J Med Res 1976;64:639-51.

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23. World Health Organization. Tuberculosis Research Office. Sensitivity of human populations to human and avian tuberculins. Bull World Health Organ 1955;12:85-99. 24. Baily GV. Tuberculosis Prevention Trial, Madras. Indian J Med Res 1980;72[Suppl]:1-74. 25. Edwards LB, Acqiavina FA, Livesay VT. Identification of tuberculosis infected. Am Rev Res Dis 1973;108:1334-9. 26. Palmer CE, Edwards LB. Identifying the tuberculous infected. The dual-test technique. JAMA 1968;205:167-9. 27. World Health Organization Tuberculosis Research Office. Certain characteristics of BCG an induced tuberculin sensitivity. Bull World Health Organ 1955;12:123-41. 28. Shaw LW. Field studies on immunization against tuberculosis. Tuberculin allergy following BCG vaccination of school children in Muscogee County, Georgia. Publ Health Rep [Wash] 1951;66:1415-26. 29. Toman K. Sensibilite, specificite et valeur predicuve des tests diagnostiques. Bull Int Union Tuberc Lung Dis 1979;54:289. 30. Lifschitz M. The value of the tuberculin skin test as a screening test for tuberculosis among BCG vaccinated children. Pediatrics 1965;36:624-7. 31. Hart DD, Sutherland I, Thomas J. The immunity conferred by effective BCG and variations in induced tuberculin sensitivity and the technical variations in the vaccines. Bull Int Union Tuberc Lung Dis 1967;48:201. 32. Ashley MJ, Siebenmann CO. Tuberculin skin sensitivity following BCG vaccination with vaccines of high and low viable counts. Can Med Assoc J 1967;97:1335-8. 33. Chadha VK, Jagannatha PS, Suryanarayana HV. Tuberculin sensitivity in BCG vaccinated children and its implications for ARI estimation. Indian J Tuberc 2000;47:139-46. 34. Kulkarni ML, Rao NS. Tuberculin conversion after neonatal BCG. Indian Pediatr 1990;27:765-6. 35. Vijayalakshmi V, Devi PS, Murthy KJR, Rao DV, Jain SN. Cell mediated immune responses in BCG vaccinated children. Indian Pediatr 1993;30:899-903. 36. Karalliede S, Katugha LP, Uragoda CG. The tuberculin response of Sri Lankan children after BCG vaccination at birth. Tuber Lung Dis 1987;68:33-8. 37. Chadha VK, Jagannatha PS, Vaidhyanathan PS, Singh S, Lakshminarayana. Annual risk of tuberculous infection in rural areas of Uttar Pradesh, India. Int J Tuberc Lung Dis 2003;7:528-35. 38. Comstock GW. Tuberculin conversions. True or False? Am Rev Respir Dis 1978;118:215-7. 39. Menzies R, Vissandjee B. Effect of bacille Calmette-Guerin vaccination on tuberculin reactivity. Am Rev Respir Dis 1992;145:621-5. 40. Johnson H, Lee B, Doherty E, Kelly E, McDonell T. Tuberculin sensitivity and BCG scar in tuberculosis contacts. Tuber Lung Dis 1995;76:122-5. 41. Raj Narain, Geser A, Jambunathan MV, Subramanian M. Tuberculosis prevalence survey in Tumkur district. Indian J Tuberc 1963;10:85-116.

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Tuberculosis

42. Gothi GD, Chakraborty AK, Nair SS, Ganapathy KT, Banerjee GC. Prevalence of tuberculosis in a south Indian district twelve years after initial survey. Indian J Tuberc 1979;26:12135. 43. Bleiker MA, Sutherland I, Styblo K, Ten Dam HG, Misljenovic. Guidelines for estimating the risk of tuberculous infection from tuberculin test results in a representative sample of children. Bull Int Union Tuberc Lung Dis 1989;64: 7-12. 44. Mayurnath S, Vallishayee RS, Radhamani MP, Prabhakar R. Prevalence study of tuberculosis infection over 15 years in a rural population in Chingleput district [South India]. Indian J Med Res 1991;93:74-80. 45. Chakraborty AK, Chaudhuri K, Sreenivas TR, Krishnamurthy MS, Shashidhara AN, Channabasavaiah R. Tuberculosis infection in a rural population of south India: 23-year trend. Tubercle Lung Dis 1992;73:213-8. 46. Chakma T, Rao VP, Pall S, Kaushal LS, Datta M, Tiwary PS. Survey of pulmonary TB in a primitive tribe of Madhya Pradesh. Indian J Tuberc 1996;43:85-9. 47. Siddiqi D, Ghose S, Krishnamurhy MS, Shashidhara AN. TB infection in a rural population of Bikaner District. Indian J Tuberc 1996;43:91-7. 48. Chadha VK, Krishnamurthy MS, Shahsidhara AN, Jagannatha PS, Magesh V. Prevalence of under-nutrition in a south Indian community and its influence on estimates of annual risk of tuberculous infection. Indian J Tuberc 1997;44:67-71. 49. Rieder HL. Epidemiological basis of tuberculosis control. Paris: International Union Against Tuberculosis and Lung Diseases; 1999. 50. Chadha VK, Jagannatha PS, Shashidhara AN, Savanur J. Annual risk of tuberculosis infection in Bangalore city. Indian J Tuberc 2001;48:63-71. 51. Kumari Indira KS, Sivaraman S, Joshi M, Pillai SN. Annual risk of tuberculosis infection: an estimate from ten-year-old children in Trivandrum district. Indian J Tuberc 2000;47:2118. 52. Chadha VK, Vaidyanathan PS, Jagannatha PS, Unnikrishnan KP, Mini PA. Annual risk of tuberculous infection in north Zone of India. Bull World Health Organ 2003;81:573-81. 53. Chadha VK, Vaidyanathan PS, Jagannatha PS, Unnikrishnan KP, Savanur SJ, Mini PA. Annual risk of tuberculous infection in the Western Zone of India. Int J Tuberc Lung Dis 2003;7:53642. 54. Kolappan C, Gopi PG, Subramani R, Chadha VK, Kumar P, Prasad VV, et al. Estimation of annual risk of tuberculosis infection [ARTI] among children aged 1-9 years in the south zone of India. Int J Tuberc Lung Dis 2004;8:418-23. 55. Chadha VK, Kumar P, Gupta J, Jagannatha PS, Lakshminarayana, Magesh V, et al. The annual risk of tuberculous infection in the eastern zone of India. Int J Tuberc Lung Dis 2004;8:537-44. 56. Suryanarayana L, Suryanarayana HV, Jagannatha PS. Prevalence of pulmonary tuberculosis among children in a south Indian community. Indian J Tuberc 1999;46:171-8.

57. Hopewell PC. Overview of clinical tuberculosis. In: Bloom BR, editor. TB – pathogenesis, protection and control. Washington: ASM Press; 1994.p.25-46. 58. Aziz S, Haq G. The Mantoux reaction in pulmonary tuberculosis. Tuber Lung Dis 1985;66:133-6. 59. Klien RS, Flanigan T, Schuman P, Smith D, Vlahov D. The effect of immunodeficiency on cutaneous delayed-type hypersensitivity testing in HIV-infected women without anergy: implications for tuberculin testing. Int J Tuberc Lung Dis 1999;3:681–8. 60. Schaaf HS, Gie RP, Beyers N, Smuts N, Donald PR. Tuberculosis in infants less than 3 months of age. Arch Dis Child 1993;69:371-4. 61. Menzies D. Interpretation of repeated tuberculin tests. Boosting, conversion and reversion. Am J Respir Crit Care Med 1999;159:15-21. 62. Korzeniewska-Kosela M, Krysl J, Muller N, Black W, Allen E, Fitzgerald JM. Tuberculosis in young adults and the elderly. Chest 1994;106:28-32. 63. Gothi GD, Nair SS, Pyare Lal. Some epidemiological aspects of tuberculous disease and infection in pediatric age group in a rural community. Indian Pediatrics 1971;8:186-94. 64. Chanabasavaiah R, Murali Mohan, Suryanarayana HV, Krishnamurthy MS, Shashidhara AN. Waning of BCG scar. Indian J Tuberc 1993;40:137-44. 65. National Tuberculosis Institute, Bangalore. Tuberculin testing in a partly BCG vaccinated population. Indian J Tuberc 1992;39:149-58. 66. Technical Guidelines on Revised Strategy of National Tuberculosis Programme. New Delhi: Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India; 1997. 67. Krishnamurthy VV, Nair SS, Gothi GD, Chakraborty AK. Incidence of tuberculosis among newly infected population and its relation to the duration of infected status. Indian J Tuberc 1976;23:3-7. 68. Janis EM, Allen DW, Glesby MJ, Carey LA, Mundy LM, Gopalan R, et al. Tuberculin skin test reactivity, anergy and HIV infection in hospitalized patients. Am J Med 1996;100:186-92. 69. Long R, Houstan S, Hershfield E. Recommendations for screening and prevention of tuberculosis in patients with HIV and for screening for HIV in patients with tuberculosis and their contacts. Canadian Med Ass J 2003;169:789-91. 70. American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Care Med 2000;161:S221-S47. 71. Grzybowski S, Allen EA. The challenge of tuberculosis in decline: a study based on the epidemiology of tuberculosis in Ontario, Canada. Am Rev Respir Dis 1964;90:707-20. 72. Creditor M, Smith E, Gallai J, Baumann M, Nelson K. Tuberculosis, tuberculin reactivity and delayed cutaneous hypersensitivity in nursing home residents. J Gerontol Med Sci 1988;43:M97-M100. 73. Van den Brande P, Demedts M. Four-stage tuberculin in elderly subjects induces age-dependent progressive boosting. Chest 1992;101:447-50.

The Tuberculin Skin Test 74. Havlir DV, van der Kuyp F, Duffy E, Marshall R, Hom D, Ellner JJ. A 19-year follow-up of tuberculin reactors. Assessof skin test reactivity and in vitro lymphocyte responses. Chest 1991;99:1172-6. 75. Comstock GW. Tuberculosis conversions. True or False? Am Rev Respir Dis 1978;118:215-7. 76. Raj Narain, Nair SS, Ramanatha Rao G, Chandrasekhar P, Pyare Lal. Enhancing of tuberculin allergy by previous tuberculin testing; Bull World Health Organ 1966;34:623-38. 77. Raj Narain, Gothi GD, Ganapathy KT, Shyamasunder CV. Effect on tuberculin allergy of tuberculin tests given 18 months earlier. Indian J Med Res 1979;69:886-92. 78. Thompson NJ, Glassroth JN, Snider DE Jr, Farer LS. The booster phenomenon in serial tuberculin testing. Am Rev Respir Dis 1979;119:587–97. 79. Chadha VK, Krishnamurthy MS, Shashidhara AN, Jagannatha PS, Magesh V. Estimation of annual risk of tuberculosis infection among BCG vaccinated children. Indian J Tuberc 1999;46:105-12. 80. Raj Narain, Nair SS, Chandrasekhar P, Ramanatha Rao G. Problems connected with estimating the incidence of tuberculosis infection. Bull World Health Organ 1966;34:605-22. 81. Mande R. BCG vaccination. London: Dawsons of Pall Mall; 1968. 82. Cauthen GM, Pio A, ten Dam HG. Annual risk of tuberculous infection. WHO/TB/88.154. Geneva: World Health Organization;1988. 83. Stanford JL, Ganapati R, Revankar CR, Lockwood D, Price J, Ashton P, et al. Sensitization by mycobacteria and the effects of BCG on children attending schools in the slums of Bombay. Tubercle 1988;69:293-8.

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84. Stanford JL, Sheikh N, Bogle G, Baker C, Series H, Mayo P. Protective effect of BCG in Ahmednagar, India. Tubercle 1987;68:169-76. 85. Chadha VK, Jagannatha PS, Kumar P. Can BCG-vaccinated children be included in tuberculin surveys to estimate the annual risk of tuberculous infection in India? Int J Tuberc Lung Dis 2004;8:1437-42. 86. Chadha VK, Kumar P, Jagannatha PS, Vaidyanathan PS, Unnikrishnan KP. Average annual risk of tuberculous infection in India. Int J Tuberc Lung Dis 2005;9:116-8. 87. Chadha VK, Agarwal SP, Kumar P, Chauhan LS, Kollapan C, Jaganath PS, et al. Annual risk of tuberculous infection in four defined zones of India: a comparative picture. Int J Tuberc Lung Dis 2005;9:569-75. 88. Chadha VK. Tuberculosis epidemiology in India: a review. Int J Tuberc Lung Dis 2005;9:1072-82. 89. Sharma SK, Mohan A. Sarcoidosis: global scenario and Indian perspective. Indian J Med Res 2002;116:221-47. 90. Smith-Rohrberg D, Sharma SK. Tuberculin skin test among pulmonary sarcoidosis patients with and without tuberculosis: its utility for the screening of the two conditions in tuberculosis-endemic regions. Sarcoidosis Vasc Diffuse Lung Dis 2006;23:130-4. 91. Ozekinci T, Ozbek E, Celik Y. Comparison of tuberculin skin test and a specific T-cell-based test, T-Spot. TB, for the diagnosis of latent tuberculosis infection. J Int Med Res 2007;35:696-703. 92. Kim SH, Choi SJ, Kim HB, Kim NJ, Oh MD, Choe KW. Diagnostic usefulness of a T-cell based assay for extrapulmonary tuberculosis. Arch Intern Med 2007;167:2255-9.

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Diagnosis of Latent Tuberculosis Infection: Recent Advances and Future Directions

12

Madhukar Pai, Rajnish Joshi, Shriprakash Kalantri

INTRODUCTION Approximately one-third of the world’s population is estimated to be infected with Mycobacterium tuberculosis (1,2). This enormous pool of individuals with latent tuberculosis infection [LTBI] poses a hurdle for global tuberculosis [TB] control, because it is from this vast reservoir that new TB cases will emerge in future. Between eight and nine million people develop TB disease each year, and about two million die from TB every year (1,2). Despite this tremendous global burden, case detection rates continue to be low (2). Conventional TB diagnostic approaches utilize tests such as sputum smear microscopy, sputum culture, chest radiographs, and tuberculin skin test [TST] also known as Mantoux test. These tools have been in use, almost unchanged, for almost a century. Because of the limitations of these tests, particularly in areas affected by the human immunodeficiency virus [HIV] epidemic, there is an urgent need for more rapid, accurate and convenient diagnostic tests (3-5). After a prolonged period of neglect, there has been a recent resurgence of interest in developing new tools for TB control. The active involvement of agencies such as the Stop TB Working Group on New Diagnostics [one of the Working Groups of the International Stop TB Partnership], the Foundation for Innovative New Diagnostics [FIND], a non-profit agency dedicated to developing new diagnostics for neglected diseases, and the TB Diagnostics Initiative of the Special Programme for Research and Training in Tropical Diseases [TDR], World Health Organization [WHO], have led to renewed interest in the development of new tools for TB diagnosis (6). Similar efforts are ongoing to develop new TB vaccines (7) and

drugs (8), mainly through non-profit agencies and publicprivate partnerships. The new Global Plan to Stop TB, 2006-2015 (9), released in early 2006 places a great deal of emphasis on the development of new tools for TB control. In this chapter the advances and emerging technologies in the diagnosis of LTBI are described (4,1015). The focus is primarily on a novel group of T-cell based cytokine assays that have shown promise in several clinical studies. CURRENT APPROACH TO DIAGNOSIS OF TUBERCULOSIS INFECTION: THE TUBERCULIN SKIN TEST Infection with Mycobacterium tuberculosis, in most individuals, is contained by the host immune defenses, and the infection remains latent. This state is called “LTBI”. In LTBI, the Mycobacterium tuberculosis bacilli that persist in asymptomatic individuals can reactivate and cause active disease in about five to ten per cent of those infected over a lifetime (16). Because of the risk of progression from latent infection to active disease, targeted testing and treatment for LTBI is a key component of TB control in many low incidence, high-income countries (17). For example, countries such as the United States actively screen and treat selected high risk groups [e.g., close contacts] for LTBI (18). In contrast, LTBI testing and treatment is not routinely done in high incidence, resource limited countries, such as India. Until recently, the only diagnostic test available to detect LTBI was the TST. First introduced in 1890, the TST is probably the oldest diagnostic test in clinical use (19). Figures 12.1 and 12.2 show the Mantoux technique

Diagnosis of Latent Tuberculosis Infection: Recent Advances and Future Directions 187

Figure 12.1: Administration of the tuberculin skin test TU = tuberculin units Source: US Centers for Disease Control and Prevention, Atlanta, GA (www.cdc.gov)

Figure 12.2: Reading of the tuberculin skin test TU = tuberculin units Source: US Centers for Disease Control and Prevention, Atlanta, GA (www.cdc.gov)

used to administer and read TST. The TST detects cellmediated immunity [CMI] in the form of a delayed-type hypersensitivity [DTH] response to the purified protein derivative [PPD]. The PPD is a crude cocktail of several antigens, many of which are shared among Mycobacterium tuberculosis, Mycobacterium bovis bacille CalmetteGuérin [BCG], and several nontuberculous mycobacteria [NTM]. As a result, the TST has lower specificity in populations with high BCG coverage and NTM exposure (20-22). The sensitivity of TST may be low due to anergy

in individuals with depressed immunity, e.g., HIV infection and other immunosuppressive conditions, e.g., due to medications such as corticosteroids and tumour necrosis factor-α [TNF-α] blockers, advanced TB, cancer and malnutrition (20-22). Table 12.1 shows the common causes of false-positive and false-negative TST results. In addition to known limitations with accuracy, the administration and reading of TST also poses problems— inter- and intra-reader variability [i.e., reproducibility]

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Tuberculosis Table 12.1: False-positive and false-negative tuberculin skin test results

TST result

Possible reasons for such a result

Individuals who are likely to have such a result

False-positive

BCG vaccination

Individuals who received BCG vaccination in the past, especially if they were vaccinated after infancy, or if they received repeated BCG vaccinations Individuals who were exposed to NTM or had infection or disease with NTM species [e.g., Mycobacterium avium] HIV infection, certain viral infections [e.g., measles], live virus vaccinations, immunosuppressive medications, such as steroids, patients on cancer chemotherapy, malnutrition, elderly, renal failure, severe TB disease, lymphoma or leukaemia Individuals who were recently infected [within the past 10-12 weeks] Children younger than 6 months Inadequate dose of PPD or poor quality PPD, poor Mantoux technique, early or late reading

NTM False-negative

Anergy

Recent TB infection Very young age Technical reasons

BCG = bacille Calmette-Guérin; NTM = nontuberculous mycobacteria; TB = tuberculosis; PPD = purified protein derivative; HIV = human immunodeficiency virus

is a concern, trained personnel are required for administration and reading, and patients have to be seen a second time for the purpose of reading the results (22). In some settings [e.g., homeless individuals and intravenous drug users], patients often do not come back for the reading of the skin test. Also, when TST is repeated [e.g., annual testing of health care workers], boosting, conversions, and reversions can occur, and, these can complicate the interpretation of serial skin testing (20). Despite these limitations, the TST is still widely used because of its ability to predict active disease in latently infected individuals, and the fact that trials have shown that treatment of LTBI with isoniazid for six to nine months, diagnosed on the basis of TST results, reduces the risk of active disease by about 60 per cent (17,23,24). This strong experimental evidence has resulted in targeted skin testing and LTBI treatment programmes in developed countries (17). A major advantage of the TST is its low material cost, and the fact that it does not require any laboratory infrastructure. This is a key consideration for developing countries such as India. INTERFERON-GAMMA RELEASE ASSAYS: BIOLOGY AND DEVELOPMENT The successful sequencing of Mycobacterium tuberculosis and Mycobacterium bovis genomes, and the development of genomic tools such as deoxyribonucleic acid [DNA] microarrays and genome-wide scans, has led to the

emergence of the field of comparative genomics. In addition, the advent of proteomics has greatly enhanced our ability to identify and clone highly specific proteins. Because of such advances in molecular biology and genomics, for the first time, an alternative to the TST has emerged in the form of a new class of in vitro assays that measure interferon-γ [IFN-γ] released by sensitized Tlymphocytes after stimulation with Mycobacterium tuberculosis antigens (25-29). These assays are now called IFN-γ release assays [IGRAs]. Interferon-γ is a cytokine, and a classic marker of Th-1 type cellular immune response. The biological rationale for T-cell based IGRAs is shown in Figure 12.3 (30). T-cell based IGRAs for LTBI actually belong to a larger family of cytokine-based assays that can be used to detect cellular immune response to a variety of antigens [Figure 12.4]. As shown in Figure 12.4, several factors including host, microbial exposure and disease, can impact the results of these cytokine assays. In contrast to the TST, cytokine-based assays probably detect only some components of the cellular immune response. For example, IGRAs detect only one cytokine [IFN-γ], while the TST probably detects a more complex immune response involving more than one type of cytokine. Early versions of IGRAs used PPD as the stimulating antigen, but these tests have been replaced by newer versions that use antigens that are more specific to Mycobacterium tuberculosis than PPD. These antigens include early secreted antigenic target 6 [ESAT-6], culture

Diagnosis of Latent Tuberculosis Infection: Recent Advances and Future Directions 189

Figure 12.3: Biological rationale for T-cell based assays for tuberculosis infection TNF-α = tumour necrosis-α; IFN-γ = interferon-γ; IL = interleukin Reproduced with permission from “Andersen P, Munk ME, Pollock JM, Doherty TM. Specific immune-based diagnosis of tuberculosis. Lancet 2000;356:1099-104 (reference 30)”

Figure 12.4: Factors that can affect T-cell based assays of cellular immunity TNF-α = tumour necrosis factor-α; IFN-γ = interferon-γ; IL = interleukin; TB = tuberculosis; PBMC = peripheral blood mononuclear cells; PPD = purified protein derivative; ELISA = enzyme linked immunosorbent assay; ELISPOT = enzyme linked immunospot; PCR = polymerase chain reaction; RD = region of difference; ESAT = early secreted antigenic target; CFP = culture filtrate protein; BCG = bacille CalmetteGuerin

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Figure 12.5: Overview of the QuantiFERON-TB Gold® In Tube assay technology IFN-γ = interferon-γ Reproduced with permission from Cellestis Limited, Carnegie, Australia (www.cellestis.com)

filtrate protein 10 [CFP-10], and TB7.7 [Rv2654]. The ESAT-6 and CFP-10 are encoded by genes located within the region of difference 1 [RD1] segment of the Mycobacterium tuberculosis genome; they are more specific than PPD because they are not shared with any of the BCG vaccine strains or certain species of NTM, e.g., Mycobacterium avium (30,31). This is because the RD1 region is deleted in all BCG vaccine sub-strains and in several species of NTM (31). Thus, the use of such specific antigens in an ex vivo assay format is a key feature of IGRAs. COMMERCIALLY AVAILABLE INTERFERONGAMMA RELEASE ASSAYS TESTS AND THEIR LABORATORY CHARACTERISTICS Within a short span of less than 10 years, two IGRAs have been developed into commercial kits: the QuantiFERON®TB Gold® [QFT-G] [Cellestis Ltd, Carnegie, Victoria, Australia] assay, and the T-SPOT.TB® test [Oxford

Immunotec, Oxford, UK]. The QFT-G assay is available in two formats, a 24-well culture plate format [approved by the US Food and Drug Administration [FDA] (32)], and a newer, simplified In Tube format also FDA approved and now the most widely used format (29). Figure 12.5 shows the QFT-G In Tube assay format. The T-SPOT.TB test [Figure 12.6] is currently CE marked for use in Europe, and is likely to receive FDA approval in future. In India, the QFT-G In Tube assay kit is available, although mostly used in research settings (33-35). As seen in Figure 12.7 (29), the two commercially available IGRA kits differ in many aspects. The T-SPOT. TB assay requires purified peripheral blood mononuclear cells [PBMC], and uses a sensitive enzymelinked immunospot [ELISPOT] technology to detect IFN-γ producing T-cells [as “spot-forming cells”]. In contrast, the QFT-G assay requires whole blood, and uses the enzyme-linked immunosorbent assay [ELISA] technology to detect the amount of IFN-γ released into

Diagnosis of Latent Tuberculosis Infection: Recent Advances and Future Directions 191

Figure 12.6: Overview of the T SPOT-TB® assay technology TB = tuberculosis Reproduced with permission from Oxford Immunotec, Oxon, UK (www.oxfordimmunotec.com)

the supernatant [measured as international units per mL]. In general, the ELISPOT technology is more complicated and involves more steps, including separation and counting of PBMCs. The ELISPOT-based test also costs more than the ELISA-based test. However, there is some evidence that the ELISPOT-based test is less prone to indeterminate results [due to lack of response to mitogen control] than the ELISA-based whole blood assay (36). Indeterminate QFT-G results have been reported in groups such as HIV-infected individuals (37), individuals with other immunocompromising conditions (38), and in children (39). It is possible that the wholeblood assay is more affected by conditions that result in decreased T-cell counts. WHAT IS KNOWN ABOUT INTERFERON-GAMMA RELEASE ASSAYS TEST PERFORMANCE? Several studies have been published on IGRAs, including some from India. The available research evidence on IGRAs [Table 12.2], reviewed extensively elsewhere (10,14,25-29,32,40), suggests that IGRAs have higher specificity than TST, better correlation with surrogate

measures of exposure to Mycobacterium tuberculosis in low incidence settings, and less cross-reactivity due to BCG vaccination than the TST. The IGRAs that use at least two RD1 antigens [e.g., ESAT-6 and CFP-10] appear to be at least as sensitive as the PPD-based TST for active TB. In the absence of a gold standard for LTBI, active TB is used as a surrogate for LTBI. Figure 12.8 (14) shows forest plots of sensitivity and specificity [for active disease] from studies that used the research or commercial versions of the QFT-G and T-SPOT.TB assays (41-53). Overall, the plot shows high specificity [> 95%] in most of the studies. Sensitivity, on the other hand, is lower and variable [70%-97%]. Figure 12.8 also suggests that the QFT-G assay may be slightly more specific but less sensitive than the ELISPOT assay. Recently published head to head comparisons of these two commercial assays lend support to this observation (36,52). Given the lack of a gold standard for latent infection, the sensitivity and specificity of IGRAs for LTBI cannot be directly estimated, and there is some concern that sensitivity for LTBI might be less than that of the TST, especially in high-risk populations (32). Besides high

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Tuberculosis to be useful in low-endemic, high income settings [i.e., countries that usually implement targeted LTBI screening and treatment programmes] where cross-reactivity due to BCG adversely impacts the utility of TST. CURRENT INTERNATIONAL RECOMMENDATIONS AND GUIDELINES

Figure 12.7: Comparison of the two commercially available interferon-gamma assays ELISA = enzyme linked immunosorbent assay; ELISPOT = enzyme linked immunospot; PBMC = peripheral blood mononuclear cells; ESAT = early secreted antigen; CFP = culture filtrate protein Reproduced with permission from “Rothel JS, Andersen P. Diagnosis of latent Mycobacterium tuberculosis infection: is the demise of the Mantoux test imminent? Expert Rev Anti Infect Ther 2005;3:981-93 (reference 29)”

specificity, other potential advantages of IGRAs include logistical convenience, avoidance of poorly reproducible measurements such as skin induration, need for fewer patient visits, and the ability to perform repeated [serial] testing without inducing the boosting phenomenon. Overall, because of its high specificity, IGRAs are proving

The US Centers for Disease Control and Prevention [CDC] published its guidelines on the QFT-G assay in December 2005 (32). The CDC recommended that QFT-G may be used in all circumstances in which the TST is currently used, including contact investigations, evaluation of immigrants, and serial testing of health care workers (32). The guidelines suggest that QFT-G can be used in place of [and not in addition to] the TST (32). In 2005, the CDC also published its updated guidelines for preventing the nosocomial transmission of TB in health care settings (54). These guidelines suggest that QFT-G can be used in place of the TST for infection control surveillance, and conversion [i.e., new infection] has been defined as change from a negative to a positive result (54). The UK National Institute for Health and Clinical Excellence [NICE] TB guidelines were published in 2006 (55). These guidelines recommend a two-step [hybrid] strategy for LTBI diagnosis: initial screen with TST, and those who are positive [or in whom TST may be unreliable] should then be considered for IGRA testing, if available, to confirm positive TST results (55). Overall, these currently available recommendations should be viewed as interim guidelines that will require updates as new evidence rapidly accumulates on the accuracy and role of IGRAs. For example, there are no published studies that have used the hybrid strategy recommended by NICE (55). This approach, although reasonable, is yet to be validated in clinical practice. Also, there is limited evidence on the use IGRAs in serial testing of health care workers. The current CDC recommendation (54) on the use of the diagnostic threshold for conversion does not take into account the possibility of misclassifying non-specific IFN-γ changes as true conversions (35). AREAS OF CONTROVERSY AND DIRECTIONS FOR FUTURE RESEARCH The body of literature supporting the use of IGRAs has exploded (25-29,32,40). However, several unresolved and controversial issues still remain. Several ongoing and

Diagnosis of Latent Tuberculosis Infection: Recent Advances and Future Directions 193 Table 12.2: Comparison of tuberculin skin test and interferon-gamma release assays Performance and operational characteristics

TST

IGRA

Estimated sensitivity in patients with active TB

75%-90% lower in immunocompromised populations

75%-95% [inadequate data in immunocompromised populations; but appears promising]

Estimated specificity in healthy individuals with no known TB disease or exposure

70%-95% lower in BCG-vaccinated, especially if BCG is given after infancy

90%-100% [maintained in BCG vaccinated]

Cross-reactivity with BCG

Yes

Less likely

Cross-reactivity with NTM

Yes

Less likely, but limited evidence

Association between test-positivity and subsequent risk of active TB during follow-up

Moderate to strong positive association

Insufficient evidence

Correlation with Mycobacterium tuberculosis exposure

Yes

Yes [correlated better with exposure than TST in some, but not all, headto-head comparisons]

Benefits of treating test-positives based on randomized controlled trials

Yes

No evidence

Reliability and reproducibility

Moderate and variable

Limited evidence but appears high; no evidence on within subject variability during serial testing

Boosting phenomenon

Yes

No

Potential for conversions and reversions

Yes

Insufficient evidence

Adverse reactions

Rare

Rare

Material costs

Low

Moderate to high

Patient visits

Two

One

Laboratory infrastructure required

No

Yes

Time to obtain a result

2 to 3 days

1 to 2 days, but longer if run as batches

Trained personnel required

Yes

Yes

TST = tuberculin skin test; IGRA = interferon-gamma release assay; TB = tuberculosis; BCG = bacille Calmette-Guérin; NTM = nontuberculous mycobacteria Adapted with permission from “Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: Part 1. Latent tuberculosis. Expert Rev Mol Diagn 2006;6:413-22 (reference 14)”

new studies should help to clarify the role of these assays in various settings, and resolve some of the controversies. One area of considerable confusion is discordance between TST and IGRA and their interpretation. Several studies have shown discordance between TST and IGRA results; discordance estimates have ranged between 10 to 40 per cent in most studies. While some discordance, especially the type where TST is positive but IGRA is negative, was probably due to prior BCG vaccination in certain studies (43,56,57), other studies found no clear explanations for discordance (34,58). Research is needed to determine the biological basis for discordance, especially when discordance is extreme. For example, a recent study from South Africa found that among those

with large TST reactions [> 15 mm, and, therefore, high likelihood of infection], about one-third were negative by the QFT-G In Tube assay (58). In a study (34) from Sevagram, India, 11 per cent of individuals with TST >15 mm were negative by the QFT-G In Tube assay. While such discordance could be due to false-positive TST, it plausible that IGRAs are less sensitive than TST in detecting LTBI, or IGRAs may detect only a subset of all those with LTBI [i.e., those with recent, persistent infection versus remote infection which has been cleared spontaneously or after treatment]. Discordance of the reverse type [i.e., TST negative but IGRA positive] has also been documented (34,59-61); they are largely unexplained. Future studies, therefore,

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Figure 12.8: Forest plots of sensitivity and specificity from studies that used research or commercial versions of the QuantiFERON-TB Gold and T-SPOT.TB assays with RD1 antigens *Not all studies reported data on specificity Point estimates of sensitivity and specificity from each study are shown as solid circles. Error bars are 95% confidence intervals [CI] QFT-G = QuantiFERON-TB Gold; ELISPOT = enzyme linked immunospot [T-SPOT.TB] Adapted with permission from “Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: Part 1. Latent tuberculosis. Expert Rev Mol Diagn 2006;6:413-22 (reference 14)”

should perform thorough analyses of correlates of discordance, including a description of discordance due to variability of TST and IFN-γ values around their thresholds [cut-points]. It is important to acknowledge that both TST and IGRAs results are continuous measures, and, therefore, thresholds are needed to interpret them as dichotomous [positive or negative] outcomes. At least some of the observed discordance could be due to minor variations around the TST and IFN-γ thresholds, as shown in a large study from India (62). The association between surrogate markers for TB exposure and IGRA results appears to be stronger and better defined in low TB incidence (56,57,60,61,63,64) than

high incidence settings (34,59,65). The basis for this phenomenon is unclear. Variations in BCG vaccination practices might be a relevant factor. Also, in high incidence settings, it is possible that IGRAs detect recent [effector] as well as remote [memory] T-cell responses. Further, in such settings, there are several factors that might modulate immune responses, such as malnutrition, BCG vaccination, NTM exposure, leprosy, helminthic, and tropical infections that impact the Th1/Th2 immune balance. These issues underscore the importance of studies from high incidence countries (34,46,48,49,59). There are few studies on the performance of IGRAs in vulnerable subgroups including immunocompro-

Diagnosis of Latent Tuberculosis Infection: Recent Advances and Future Directions 195 mized individuals [e.g., HIV/AIDS, and those on immunosuppressive medications such as TNF-α blockers], patients with extra-pulmonary TB, contacts, children, and health care workers. At present, it is difficult to make strong clinical recommendations in these high risk groups. In immunocompromized individuals, IGRAs might have a higher proportion of indeterminate results [mostly due to lack of T-cell response to mitogen, a potent stimulant of T-cell response] and this may indicate underlying anergy (37,38,66). Recent studies suggest that IGRAs may be promising in individuals with HIV infection (37,48,67), contacts (56,57,60,61,63), children (33,39,49,68), and health care workers (34,35,69), but this requires confirmation in larger studies. For periodic testing of health care workers, IGRAs may have important advantages: they might eliminate the need for two-step testing protocol at baseline, avoid sensitization and boosting, and may minimize interpretational difficulties that often hamper serial TST screening. However, there are virtually no data on the longterm reproducibility of IGRAs, particularly withinsubject variability in serial testing, where conversions and reversions can occur (35). Without data on longitudinal changes and biological variability, the results of serial IGRA testing are hard to interpret. Currently, there is no consensus as to what an IGRA “conversion” is. Preliminary data from a recent cohort study in India suggests that IGRAs conversions are strongly correlated with TST conversions when stringent thresholds were used for both tests; however, it is still not clear how much IFN-γ levels must increase in order to be considered a true “conversion” (35). This study showed that conversions, reversions, and non-specific variations occur with serial IGRA testing, as they do with TST (35). Although IGRAs are often thought of as tests that produce simple yes/no results, the data suggest that these tests are threshold dependent. Analogous to the TST, different thresholds may be appropriate for different populations, or clinical settings [e.g., threshold for diagnosis vs conversion]. To meaningfully interpret repeat IGRA results, the optimal thresholds to distinguish new infections from nonspecific variations must be determined. Therefore, longitudinal studies of serial testing will be of great interest. Such studies should concurrently perform serial TSTs, in order to provide a baseline for comparison with changes in IFN-γ responses over time.

Another area of controversy is the kinetics of T-cell responses during and after treatment for latent and active TB. As reviewed elsewhere (25,26), some studies have shown declining responses after treatment, whereas others have shown unchanging, fluctuating, or increasing responses during treatment. Therefore, it is not clear if these tests have a clear correlation with bacterial [antigen] burden, and therefore can be used for monitoring response to LTBI and active TB treatment. Variations in incubation periods, antigens [proteins vs peptides], and assay formats might explain some of the discrepancies (25,26). A recent study from India (70) showed that IGRAs may offer interesting insights into T-cell kinetics after LTBI treatment. In an environment with ongoing, intensive nosocomial exposure, Indian health care workers had strong IFN-γ responses [measured using QFT-G] when LTBI was diagnosed, and continued to have persistently elevated responses, even after six months of isoniazid treatment for LTBI. It is possible, although unproven as yet, that persistence of infection and/or reinfection [or repeated exposure] might account for this, and raises concerns about efficacy of conventional preventive therapy in high incidence settings with recurrent exposure (70). Further research is needed to study T- cell kinetics during LTBI treatment, and determine the effect of repeated exposures on host cellular immune responses, particularly in high incidence settings. The availability of standardized, commercial T cell-based IGRAs such as QFT-G and T-SPOT.TB might greatly facilitate such novel investigations. Can IGRAs be used to diagnose active TB disease? The CDC guidelines recommend the use of the QFT-G assay for diagnosing infection with Mycobacterium tuberculosis, including both LTBI and active disease (32). According to these guidelines, persons who have positive IGRA results, regardless of symptoms or signs, should be evaluated for TB disease before LTBI is diagnosed (32). It is important to note that currently available IGRAs assays cannot distinguish between active disease and LTBI, and this may pose problems for diagnosing active disease in countries with high burden of LTBI. It is, therefore, important to interpret the results in a specific clinical context. In an individual being investigated for suspected TB disease, a positive result may be due to active TB or irrelevant concurrent LTBI. However, a negative IGRA result may represent a useful ‘rule out’

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test, particularly in low incidence settings (26). However, a negative test, particularly if there is underlying immunosuppression, should not preclude further investigation or treatment if the clinical suspicion is high. The negative predictive value of IGRAs for active TB requires further evaluation. Another important unresolved issue is whether IGRAs have the ability to identify latently infected individuals who are most likely to progress to active disease, and, therefore, most likely to benefit from preventive therapy. Although there are limited data, based on one small African study (71), of an association between IFN-γ response to ESAT-6 and subsequent progression to active TB among contacts of TB patients, the association between IGRA positivity and progression to active disease is largely unknown. Long-term cohort studies are needed to address this critical issue. Lastly, a limitation of IGRAs, particularly for high burden, resource limited countries, is their higher material and equipment costs and the need for laboratory infrastructure and trained personnel (27). The IGRAs require equipment such as ELISA or ELISPOT readers, and also technicians skilled in running such immunological assays. Such resources are not easily accessible in developing countries where even quality sputum smear microscopy services are often lacking. Economic evaluations are needed to better delineate the role of IGRAs in public health and routine clinical settings (40,72). It is possible that, at least in some settings [i.e., high income countries], the advantages of a more convenient and specific blood test might outweigh the higher costs. It is also possible that hybrid strategies that combine TST and IGRA might be more cost-effective (55,73,74). Cost and requirement for laboratory support are obviously very important issues in developing countries such as India. IMPLICATIONS FOR RESOURCE-LIMITED HIGH BURDEN COUNTRIES Tuberculosis continues to be a major public health problem worldwide. Despite the enormous global burden of TB, case detection rates continue to be low, compromising TB control, particularly in areas with high HIV prevalence. The portfolio of currently used TB diagnostic tools relies on century old tests with several known limitations. The long felt need for new tools, including

new diagnostics, vaccines, and drugs, is currently being addressed by several global health agencies, non-profit groups, industry, funding agencies, public-private partnerships, and academic institutions. In this context, the emergence of IGRAs is a much anticipated, welcome development that has, for the first time, increased the range of diagnostic tools available for LTBI. Detection and treatment of LTBI is an important component of TB control efforts in low incidence [high income] settings. Until recently, the TST was the only tool available to detect LTBI. The most important breakthrough in recent years has been the development of IGRAs. Because of their high specificity and logistical convenience, IGRAs might replace the century-old TST in selected low incidence, high-income settings in the next decade. Research during the next few years will help settle unresolved issues, and define the exact role for these assays in clinical and public health settings. Further refinement [e.g., inclusion of additional antigens to increase sensitivity] and standardization of these commercial assays will also occur, and that will enhance their utility and applicability. At this time, the role for IGRAs in low income, high burden settings [e.g., India] is rather limited. Simplification of the test format and reduction of costs might enhance applicability in such settings, particularly in selected subgroups such as HIV-infected individuals, children, and other high-risk groups [e.g., household contacts]. In addition, IGRAs may serve as useful tools to investigate the transmission dynamics and epidemiology of TB in various settings (35,70,75). Until IGRAs become widely accessible, the TST will continue to be a useful, simple, low-cost tool in developing countries where BCG vaccination is given in infancy [and, therefore, has limited impact on TST results (21,22)] (27). However, if IGRAs are shown to be more predictive of active TB than the TST in large cohort studies, then the use of IGRAs can be expected to be expand exponentially, with the potential to revolutionize our approach to LTBI diagnosis and treatment. Recent studies from India have shown that the TST and QFT-G produce fairly comparable results (33-35). Also, several Indian studies, including large nation-wide tuberculin surveys, have shown that prior BCG vaccination does not significantly affect the TST results (76-79). Also, a 15-year follow-up of 280 000 subjects in the South Indian BCG vaccine trial showed that TST

Diagnosis of Latent Tuberculosis Infection: Recent Advances and Future Directions 197 response is significantly associated with long-term development of active TB (80). Thus, all these studies suggest that the TST is a useful test for LTBI in the Indian milieu, particularly because of the low cost, relatively easy accessibility, and because BCG does not significantly affect TST specificity. Future Indian studies should help to settle the debate on whether IGRAs should replace the TST. For now, it is probably a good strategy to keep both TST and IGRAs on the LTBI diagnostic menu, and select the appropriate test based on the population, the purpose of testing, and the resources available.

16.

17.

18.

19. 20.

REFERENCES 1. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009-21. 2. World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO Report 2005. Geneva: World Health Organization; 2005. 3. Foulds J, O’Brien R. New tools for the diagnosis of tuberculosis: the perspective of developing countries. Int J Tuberc Lung Dis 1998;2:778-83. 4. Perkins MD. New diagnostic tools for tuberculosis. Int J Tuberc Lung Dis 2000;4[Suppl2]:S182-8. 5. Perkins MD, Small PM. Admitting defeat. Int J Tuberc Lung Dis 2006;10:1. 6. Perkins MD, Roscigno G, Zumla A. Progress towards improved tuberculosis diagnostics for developing countries. Lancet 2006;367:942-3. 7. Doherty TM, Rook G. Progress and hindrances in tuberculosis vaccine development. Lancet 2006;367:947-9. 8. Spigelman M, Gillespie S. Tuberculosis drug development pipeline: progress and hope. Lancet 2006;367:945-7. 9. Stop TB Partnership and World Health Organization. The Global Plan to Stop TB 2006 - 2015. Geneva: World Health Organization; 2006. 10. Brodie D, Schluger NW. The diagnosis of tuberculosis. Clin Chest Med 2005;26:247-71. 11. Palomino JC. Nonconventional and new methods in the diagnosis of tuberculosis: feasibility and applicability in the field. Eur Respir J 2005;26:339-50. 12. Hazbon MH. Recent advances in molecular methods for early diagnosis of tuberculosis and drug-resistant tuberculosis. Biomedica 2004;24[Supp1]:149-62. 13. Nahid P, Pai M, Hopewell PC. Advances in the diagnosis and treatment of tuberculosis. Proc Am Thorac Soc 2006;3:10310. 14. Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: Part 1. Latent tuberculosis. Expert Rev Mol Diagn 2006;6:413-22. 15. Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: Part 2. Active

21.

22.

23.

24. 25.

26.

27.

28.

29.

30.

31.

32.

tuberculosis and drug resistance. Expert Rev Mol Diagn 2006;6:423-32. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974;99:131-8. American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221-47. Horsburgh CR Jr. Priorities for the treatment of latent tuberculosis infection in the United States. N Engl J Med 2004;350:2060-7. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect Dis 1993;17:968-75. Menzies D. Interpretation of repeated tuberculin tests. Boosting, conversion, and reversion. Am J Respir Crit Care Med 1999;159:15-21. Menzies D. What does tuberculin reactivity after bacille Calmette-Guerin vaccination tell us? Clin Infect Dis 2000; 31[Suppl3]:S71-4. Menzies RI. Tuberculin skin testing. In: Reichman LB, Hershfield ES, editors. Tuberculosis: a comprehensive international approach. New York: Marcel Dekker; 2000.p.279-322. Comstock GW. How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults? Int J Tuberc Lung Dis 1999;3:847-50. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Bibl Tuberc 1970;26:28-106. Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4:761-76. Dheda K, Udwadia ZF, Huggett JF, Johnson MA, Rook GA. Utility of the antigen-specific interferon-gamma assay for the management of tuberculosis. Curr Opin Pulm Med 2005;11:195-202. Pai M. Alternatives to the tuberculin skin test: interferongamma assays in the diagnosis of mycobacterium tuberculosis infection. Indian J Med Microbiol 2005;23:151-8. Menzies D, Pai M, Comstock G. New tests for diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Annals Int Med 2007;146:340-54. Rothel JS, Andersen P. Diagnosis of latent Mycobacterium tuberculosis infection: is the demise of the Mantoux test imminent? Expert Rev Anti Infect Ther 2005;3:981-93. Andersen P, Munk ME, Pollock JM, Doherty TM. Specific immune-based diagnosis of tuberculosis. Lancet 2000;356:1099-104. Mahairas GG, Sabo PJ, Hickey MJ, Singh DC, Stover CK. Molecular analysis of genetic differences between Mycobacterium bovis, BCG and virulent M. bovis. J Bacteriol 1996;178:1274-82. Mazurek GH, Jereb J, Lobue P, Iademarco MF, Metchock B, Vernon A. Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR Recomm Rep 2005;54:49-55.

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33. Dogra S, Narang P, Mendiratta DK, Chaturvedi P, Reingold AL, Colford JM Jr, et al. Comparison of a whole blood interferon-gamma assay with tuberculin skin testing for the detection of tuberculosis infection in hospitalized children in rural India. J Infect 2007;54:267-76. 34. Pai M, Gokhale K, Joshi R, Dogra S, Kalantri SP, Mendiratta DK, et al. Mycobacterium tuberculosis infection in health care workers in rural India: comparison of a whole-blood, interferon-gamma assay with tuberculin skin testing. JAMA 2005;293:2746-55. 35. Pai M, Joshi R, Dogra S, Mendiratta DK, Narang P, Kalantri SP, et al. Serial testing of health care workers for tuberculosis using interferon-gamma assay. Am J Respir Crit Care Med 2006;174:349-55. 36. Ferrara G, Losi M, D’Amico R, Roversi P, Piro R, Meacci M, et al. Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study. Lancet 2006;367:1328-34. 37. Brock I, Ruhwald M, Lundgren B, Westh H, Mathiesen LR, Ravn P. Latent tuberculosis in HIV positive, diagnosed by the M.tuberculosis specific interferon gamma test. Respir Res 2006;7:56. 38. Ferrara G, Losi M, Meacci M, Meccugni B, Piro R, Roversi P, et al. Routine hospital use of a new commercial whole blood interferon-gamma assay for the diagnosis of tuberculosis infection. Am J Respir Crit Care Med 2005;172:631-5. 39. Connell TG, Curtis N, Ranganathan SC, Buttery JP. Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children. Thorax 2006;61:616-20. 40. Whalen CC. Diagnosis of latent tuberculosis infection: measure for measure. JAMA 2005;293:2785-7. 41. Mori T, Sakatani M, Yamagishi F, Takashima T, Kawabe Y, Nagao K, et al. Specific detection of tuberculosis infection: an interferon-gamma-based assay using new antigens. Am J Respir Crit Care Med 2004;170:59-64. 42. Ravn P, Munk ME, Andersen AB, Lundgren B, Lundgren JD, Nielsen LN, et al. Prospective evaluation of a whole-blood test using Mycobacterium tuberculosis-specific antigens ESAT-6 and CFP-10 for diagnosis of active tuberculosis. Clin Diagn Lab Immunol 2005;12:491-6. 43. Kang YA, Lee HW, Yoon HI, Cho B, Han SK, Shim YS, et al. Discrepancy between the tuberculin skin test and the wholeblood interferon gamma assay for the diagnosis of latent tuberculosis infection in an intermediate tuberculosis-burden country. JAMA 2005;293:2756-61. 44. Pai M, Joshi R, Dogra S, Bandopadhaya M, Mendiratta DK, Narang P, et al. Preliminary results from an evaluation of a whole-blood, interferon-gamma assay in individuals with tuberculosis infection and disease in a rural Indian hospital. Poster presented at 36th IUATLD, Paris 2005. 45. Lalvani A, Pathan AA, McShane H, Wilkinson RJ, Latif M, Conlon CP, et al. Rapid detection of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Am J Respir Crit Care Med 2001;163:824-8.

46. Lalvani A, Nagvenkar P, Udwadia Z, Pathan AA, Wilkinson KA, Shastri JS, et al. Enumeration of T cells specific for RD1encoded antigens suggests a high prevalence of latent Mycobacterium tuberculosis infection in healthy urban Indians. J Infect Dis 2001;183:469-77. 47. Pathan AA, Wilkinson KA, Klenerman P, McShane H, Davidson RN, Pasvol G, et al. Direct ex vivo analysis of antigen-specific IFN-gamma-secreting CD4 T cells in Mycobacterium tuberculosis-infected individuals: associations with clinical disease state and effect of treatment. J Immunol 2001;167:5217-25. 48. Chapman AL, Munkanta M, Wilkinson KA, Pathan AA, Ewer K, Ayles H, et al. Rapid detection of active and latent tuberculosis infection in HIV-positive individuals by enumeration of Mycobacterium tuberculosis-specific T cells. AIDS 2002;16:2285-93. 49. Liebeschuetz S, Bamber S, Ewer K, Deeks J, Pathan AA, Lalvani A. Diagnosis of tuberculosis in South African children with a T-cell-based assay: a prospective cohort study. Lancet 2004;364:2196-203. 50. Meier T, Eulenbruch HP, Wrighton-Smith P, Enders G, Regnath T. Sensitivity of a new commercial enzyme-linked immunospot assay [T SPOT-TB] for diagnosis of tuberculosis in clinical practice. Eur J Clin Microbiol Infect Dis 2005;24:529-36. 51. Goletti D, Vincenti D, Carrara S, Butera O, Bizzoni F, Bernardini G, et al. Selected RD1 peptides for active tuberculosis diagnosis: comparison of a gamma interferon whole-blood enzyme-linked immunosorbent assay and an enzyme-linked immunospot assay. Clin Diagn Lab Immunol 2005;12:1311-6. 52. Lee JY, Choi HJ, Park IN, Hong SB, Oh YM, Lim CM, et al. Comparison of two commercial interferon gamma assays for diagnosing Mycobacterium tuberculosis infection. Eur Respir J 2006;28:24-30. 53. Taggart EW, Hill HR, Ruegner RG, Litwin CM. Evaluation of an in vitro assay for interferon gamma production in response to the Mycobacterium tuberculosis-synthesized peptide antigens ESAT-6 and CFP-10 and the PPD skin test. Am J Clin Pathol 2006;125:467-73. 54. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR 2005;54:1-141. 55. National Institute for Health and Clinical Excellence. Clinical Guideline 33. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London: National Institute for Health and Clinical Excellence. 56. Ewer K, Deeks J, Alvarez L, Bryant G, Waller S, Andersen P, et al. Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet 2003;361:1168-73. 57. Lalvani A, Pathan AA, Durkan H, Wilkinson KA, Whelan A, Deeks JJ, et al. Enhanced contact tracing and spatial tracking of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Lancet 2001;357:2017-21.

Diagnosis of Latent Tuberculosis Infection: Recent Advances and Future Directions 199 58. Mahomed H, Hughes EJ, Hawkridge T, Minnies D, Simon E, Little F, et al. Comparison of Mantoux skin test with three generations of a whole blood IFN-gamma assay for tuberculosis infection. Int J Tuberc Lung Dis 2006;10:310-6. 59. Hill PC, Brookes RH, Fox A, Fielding K, Jeffries DJ, JacksonSillah D, et al. Large-scale evaluation of enzyme-linked immunospot assay and skin test for diagnosis of Mycobacterium tuberculosis infection against a gradient of exposure in The Gambia. Clin Infect Dis 2004;38:966-73. 60. Richeldi L, Ewer K, Losi M, Bergamini BM, Roversi P, Deeks J, et al. T cell-based tracking of multidrug resistant tuberculosis infection after brief exposure. Am J Respir Crit Care Med 2004;170:288-95. 61. Shams H, Weis SE, Klucar P, Lalvani A, Moonan PK, Pogoda JM, et al. Enzyme-linked immunospot and tuberculin skin testing to detect latent tuberculosis infection. Am J Respir Crit Care Med 2005;172:1161-8. 62. Pai M, Kalantri S, Menzies D. Discordance between tuberculin skin test and interferon-gamma assays. Int J Tuberc Lung Dis 2006;10:942-3. 63. Brock I, Weldingh K, Lillebaek T, Follmann F, Andersen P. Comparison of tuberculin skin test and new specific blood test in tuberculosis contacts. Am J Respir Crit Care Med 2004;170:65-9. 64. Zellweger JP, Zellweger A, Ansermet S, de Senarclens B, Wrighton-Smith P. Contact tracing using a new T-cell-based test: better correlation with tuberculosis exposure than the tuberculin skin test. Int J Tuberc Lung Dis 2005;9:1242-7. 65. Hill PC, Brookes RH, Adetifa IM, Fox A, Jackson-Sillah D, Lugos MD, et al. Comparison of enzyme-linked immunospot assay and tuberculin skin test in healthy children exposed to Mycobacterium tuberculosis. Pediatrics 2006;117:1542-8. 66. Pai M, Lewinsohn DM. Interferon-gamma assays for tuberculosis: is anergy the Achilles’ heel? Am J Respir Crit Care Med 2005;172:519-21. 67. Dheda K, Lalvani A, Miller RF, Scott G, Booth H, Johnson MA, et al. Performance of a T-cell-based diagnostic test for tuberculosis infection in HIV-infected individuals is independent of CD4 cell count. AIDS 2005;19:2038-41. 68. Connell T, Bar-Zeev N, Curtis N. Early detection of perinatal tuberculosis using a whole blood interferon-gamma release assay. Clin Infect Dis 2006;42:e82-5. 69. Harada N, Nakajima Y, Higuchi K, Sekiya Y, Rothel J, Mori T. Screening for tuberculosis infection using whole-blood interferon-gamma and Mantoux testing among Japanese

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

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healthcare workers. Infect Control Hosp Epidemiol 2006;27:442-8. Pai M, Joshi R, Dogra S, Mendiratta DK, Narang P, Dheda K, et al. Persistently elevated T cell interferon-gamma responses after treatment for latent tuberculosis infection among health care workers in India: a preliminary report. J Occup Med Toxicol 2006;1:7. Doherty TM, Demissie A, Olobo J, Wolday D, Britton S, Eguale T, et al. Immune responses to the Mycobacterium tuberculosis-specific antigen ESAT-6 signal subclinical infection among contacts of tuberculosis patients. J Clin Microbiol 2002;40:704-6. Dewan PK, Grinsdale J, Liska S, Wong EH, Fallstad R, Kawamura LM. Feasibility, acceptability, and cost of tuberculosis testing by whole-blood interferon-gamma assay. BMC Infect Dis 2006;6:47. Diel R, Nienhaus A, Lange C, Schaberg T. Cost optimization of screening for latent tuberculosis in close contacts. Eur Respir J 2006;28:35-44. Wrighton-Smith P, Zellweger JP. Direct costs of three models for the screening of latent tuberculosis infection. Eur Respir J 2006;28:45-50. Soysal A, Millington KA, Bakir M, Dosanjh D, Aslan Y, Deeks JJ, et al. Effect of BCG vaccination on risk of Mycobacterium tuberculosis infection in children with household tuberculosis contact: a prospective community-based study. Lancet 2005;366:1443-51. Chadha VK, Jagannatha PS, Kumar P. Tuberculin sensitivity among children vaccinated with BCG under universal immunization programme. Indian J Pediatr 2004;71:1063-8. Chadha VK, Jagannatha PS, Kumar P. Can BCG-vaccinated children be included in tuberculin surveys to estimate the annual risk of tuberculous infection in India? Int J Tuberc Lung Dis 2004;8:1437-42. Chadha VK, Jagannatha PS, Suryanarayana HV. Tuberculin sensitivity in BCG vaccinated children and its implications for ARI estimation. Indian J Tuberc 2000;47:139-46. Chadha VK, Krishna Murthy MS, Shashidhar AN, Jagannatha PS, Magesh V. Estimation of annual risk of tuberculosis infection among BCG vaccinated children. Indian J Tuberc 1999;46:105-12. Radhakrishna S, Frieden TR, Subramani R. Association of initial tuberculin sensitivity, age and sex with the incidence of tuberculosis in south India: a 15-year follow-up. Int J Tuberc Lung Dis 2003;7:1083-91.

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Roentgenographic Manifestations of Pulmonary Tuberculosis

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Sima Mukhopadhyay, Ashu Seith

INTRODUCTION Tuberculosis [TB] is a major public health problem in the developing countries (1). With the advent of the human immunodeficiency virus [HIV] infection and the acquired immunodeficiency syndrome [AIDS], the clinical presentation of TB is changing. Lungs are the most common and often the first site of involvement in TB. Early diagnosis and treatment of pulmonary TB is extremely important for ensuring cure. Imaging plays a very important role in the diagnosis and follow-up of patients with pulmonary TB. IMAGING MODALITIES Chest Radiograph In a patient suspected to have pulmonary TB, posteroanterior [PA] view of the chest is the first imaging modality and is mostly adequate for diagnosis and subsequent follow-up of such patients. Lateral view of the chest is necessary to confirm findings of the PA view or to evaluate inadequately visualized areas in a selected group of patients. Apicogram of the chest is needed if the lesion is partially obscured by the medial end of the clavicle and the nearby ribs in a PA view of the chest. Computed Tomography Computed tomography [CT] can give important information in patients with pulmonary TB and may identify foci in the lungs undetected on a plain film. Occult cavitation may be detected particularly when obscured by pleural effusion, bones or diaphragm. Bronchial stenosis or occlusion and nature and extent of bron-

chiectasis can be detected by CT. The newer multidetector CT scanners [MDCT] are useful in delineating length of the stenotic segments. Lymphadenopathy which is a common feature in pulmonary TB can be detected and nature of the lymph nodes can be characterized by CT. Pleural pathology [i.e., effusion, empyema, thickening, calcification, etc.,] and underlying bony changes in empyema are well evaluated by CT. Miliary lesions in the lungs are well shown by CT, especially high resolution CT [HRCT], even when the plain film is normal. The CT has a definite role in symptomatic Mantoux positive patients with a normal plain chest radiograph. In a study from Korea (2), chest CT findings in 41 children with confirmed pulmonary TB were reviewed retrospectively. In 37 per cent patients, CT gave additional information which altered clinical management (2). The HRCT is also useful in predicting the activity of TB by demonstrating evidence of bronchogenic spread and characterising the pulmonary lesions seen on plain radiographs. Ultrasonography Ultrasonography can be used to evaluate pleural pathology. Pleural aspiration and biopsy can be safely performed under ultrasonography guidance. Ultrasonography can also be used to evaluate hepatosplenomegaly and abdominal lymphadenopathy in patients with TB. Additionally, lesions of the pelvic organ scan be diagnosed in female patients using ultrasonography. Magnetic Resonance Imaging Magnetic resonance imaging [MRI] can be used to evaluate mediastinal and hilar lymphadenopathy. It is equally accurate as CT in this regard.

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IMAGING IN PULMONARY TUBERCULOSIS Pulmonary TB can be considered under two broad headings as follows: [i] primary TB, and [ii] post-primary TB. The reader is referred to the chapter “Reactivation and reinfection tuberculosis” [Chapter 47] for more details. Though radiographically primary and post-primary TB are different in the nature of the lesion, site of involvement, lymphadenopathy and pleural involvement, often, there is a considerable overlap in the findings observed in both the forms. PRIMARY TUBERCULOSIS Primary disease now accounts for 23 to 34 per cent of all adult cases of TB (3). A large number of paediatric patients are asymptomatic at presentation and even in symptomatic patients, early diagnosis by bacteriology is hampered by the difficulty in obtaining suitable sputum samples (4). A positive tuberculin skin test [TST] and an abnormal chest radiograph are the only clues to the diagnosis in this group. Primary TB may involve one or more of the following structures, i.e., lung parenchyma, lymph nodes, tracheobronchial tree and pleura. However, chest radiograph may be normal in up to 15 per cent. Radiographic features in primary pulmonary TB are shown in Table 13.1. Table 13.1: Radiographic features in primary pulmonary tuberculosis Parenchymal consolidation Tuberculoma Miliary tuberculosis Lymphadenopathy Airway involvement Pleural effusion

Parenchymal Involvement Consolidation The primary parenchymal lesion is typically seen as an area of consolidation. The lesion is usually single, of variable size, often less than 2 cm in diameter, homogeneous with ill-defined margins [Figure 13.1]. The lesion may involve the entire lobe due to endobronchial obstruction (5). Consolidation abutting a fissure may show sharp margins. Consolidation of pulmonary TB is often indistinguishable from bacterial pneumonia. But

Figure 13.1: Chest radiograph [postero-anterior view] showing an ill-defined area of consolidation [arrow] in the right lower lobe in a child with primary tuberculosis

lack of systemic toxicity, associated lymphadenopathy and/or failure to respond to conventional antibacterial therapy may help in predicting TB aetiology (5). There is no predilection for a particular form of regional involvement within the lungs. While different workers have documented predilection for the upper lobe or lower lobe, no regional preference has been reported by others. Right sided predominance has been noted in many series. For practical purposes, primary TB can cause consolidation in any lobe (5). In adults with primary TB, the lesion is often seen in the lower lobe. Cavitation of the parenchymal lesion is rare in children but can be seen in seven to twenty-nine per cent adults with primary TB (6,7). Endobronchial spread is rare since cavitation is uncommon. Computed tomography is superior to plain chest radiographs in demonstrating the parenchymal changes. Consolidation is seen as a homogeneous soft tissue attenuation lesion with air bronchogram or areas of breakdown within. Parenchymal changes are better appreciated on HRCT (8). Computed tomography is superior to MRI in the demonstration of pulmonary parenchymal changes. In a series of 2677 patients with pulmonary TB seen at the Paediatric Tuberculosis Clinic at the All India Institute of Medical Sciences [AIIMS] hospital, New Delhi, over a period of 29 years, 50 per cent had primary pulmonary complex. Of these, 39 per cent had only parenchymal lesion without lymphadenopathy (9).

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Figures 13.2: Chest radiograph [postero-anterior view] [A] and CECT of the chest [B], showing well-defined, single, oval lesion in the left upper lobe [arrow] with cavitation within the mass, suggestive of a tuberculoma

Tuberculoma A tuberculoma is a persistent mass-like opacity which may be seen either in primary or post-primary TB. It is seen in seven to nine per cent of patients with tuberculosis. It is a round or oval lesion, most commonly seen in the upper lobes, more often on the right side. Small discrete lesions in the immediate vicinity of the main lesion [satellite lesions] may be seen in as many as 80 per cent of the cases (10). Tuberculomas range from 0.5 to 4 cm or more in diameter, though majority are less than 3 cm in size. Cavitation is seen in 10 to 50 per cent of cases. Majority remains stable over a long time (5) [Figures 13.2A and 13.2B]. On CT, usually tuberculoma appears as a nodule with a regular and smooth outline. Calcification within the nodule or satellite nodules around the periphery of the dominant nodule is found in 20 to 30 per cent of the lesions. Cavitation may also be seen [Figure 13.2B]. Tuberculomas show ring-like or central curvilinear enhancement (11-13). Miliary Tuberculosis Dissemination of organisms via the haematogenous route leads to miliary TB in the lungs and other organs (14). Miliary TB is mostly a feature of primary TB, although it may be seen in post-primary disease also. Radiographically detectable miliary TB occurs in one to seven per cent of patients of all forms of TB (3,6,15). In the initial period following haematogenous dissemination, the chest radiograph is usually normal. During this period, the foci are too small to be identified radiographically. There is

probably an interval of about six weeks or more between dissemination of bacilli and positive findings on a chest radiograph. When the lesions increase in size, they appear as tiny, discrete, pinpoint opacities, evenly distributed throughout both the lungs with some basal predominance. This is thought to be due to gravity dependent increase in the blood flow to the lung bases (10) [Figure 13.3A]. Even distribution of nodules is seen in 85 per cent of cases while 15 per cent show asymmetric dissemination (16). Initially, the foci are about 1 mm in diameter. If not treated, the foci may reach 3 to 5 mm in size and become confluent, presenting a “snow-storm” appearance (10). Associated lymphadenopathy is seen more commonly in children [95%] than in adults [11%]. Affected lymph nodes are mostly seen on the right side, in paratracheal location. Associated parenchymal consolidation is also more common in children (15). In a series from a teaching hospital at New Delhi (9), of 2677 paediatric patients with pulmonary TB, miliary and bronchopneumonic forms were seen in three per cent patients. In a case of miliary TB, CT, especially HRCT, plays an important role in establishing the diagnosis (17). Often in the appropriate clinical setting, a patient with miliary TB may have a normal chest radiograph. The HRCT can detect miliary nodules with or without lymphadenopathy even when a chest radiograph is normal [Figure 13.3B]. With treatment radiographic clearance is seen in two to six months. Some of the patients with miliary TB may develop acute respiratory distress syndrome [ARDS](18). The reader is referred to the chapter “Tuberculosis and acute lung injury” [Chapter 36] for more details.

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Figure 13.3: Chest radiograph [postero-anterior view] [A] and HRCT ot the chest [B], showing bilateral, diffuse, tiny, discrete, pinpoint opacities, suggestive of miliary tuberculosis

Lymph Node Involvement Radiographically visible lymphadenopathy is a common feature of primary TB, especially in children. Lymphadenopathy is seen in up to 96 per cent children (11,13)

Figure 13.4: Chest radiograph [postero-anterior view] showing right parahilar consolidation [black arrow] with enlarged ipsilateral hilar and paratracheal lymph nodes [white arrows]

and 10 to 43 per cent adults (6,7) with primary TB. This is usually associated with a parenchymal component. When associated with parenchymal lesion, lymph nodes draining that area are enlarged [Figure 13.4]. Typically, the involvement is unilateral. Right hilum and right paratracheal areas are the most commonly involved areas. Less commonly, subcarinal, azgyo-oesophageal and aortopulmonary window regions are involved [Figure 13.5]. A recent study has reported the subcarinal region as the most frequently involved site seen in 90 of the 92 patients (19). Bilateral adenopathy occurs in up to 31 per cent of cases (4,11). Right sided predominance of lymphadenopathy is postulated to be due to the predominance or right sided parenchymal lesions and due to the fact that right sided nodes drain the entire right lung along with left lower lobe. Lymphadenopathy may be the sole finding in primary TB. Occurrence of isolated lymphadenopathy decreases with increasing age (4), being seen in up to 49 per cent of children aged under three years, in nine per cent of children aged four to fifteen years and only

Figure 13.5: CECT of the chest of three different patients showing necrotic right paratracheal nodes [arrow] [A], necrotic right hilar and subcarinal nodes with rim enhancement [arrow] [B] and homogeneously enhancing right paratracheal nodes [arrow] [C]

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rarely in adults (20-22). In the study reported by Mukhopadhyay and Gupta (9), 50 per cent of the 2677 subjects with paediatric pulmonary TB had primary complex. Of these 32 per cent had only lymphadenopathy, 29 per cent had parenchymal and lymph node involvement while 39 per cent had only parenchymal lesions (9). Computed tomography is more sensitive than a chest radiograph for detection and characterization of intrathoracic lymphadenopathy (23,24). Variable postcontrast CT appearances of TB lymph node involvement have been described [Table 13.2]. Peripheral rim enhancement with or without central low attenuation is the commonest pattern. Such nodes are 0.5 to 5 cm in diameter. Rim enhancement may be: [i] uniform, thin, complete enhancing rim; [ii] thick, irregular, complete or incomplete, peripheral rim; or [iii] conglomerated group of nodes showing peripheral and central areas of rim enhancement [Figures 13.5A and 13.5B]. With CThistologic correlation, excised nodes exhibiting this pattern of enhancement have been found to contain complete central necrosis in association with a highly vascular, inflammatory, capsular and perinodal reaction (13,23). There may be diffuse perinodal fat plane obliteration. Non-homogeneous enhancement of the lymph nodes has also been described. These nodes are 1.5 to 3.5 cm in diameter. This is also a relatively frequent manifestation of TB. Andronikou et al (19) described ‘ghost-like’ ring enhancement in a group of matted nodes as the most common pattern of enhancement rather than discreet rim-enhancement of a single large node. Homogeneous enhancement in nodes of a size less than 2 cm in diameter is not frequently seen [Figure 13.5C]. Sometimes, lymph nodes may not show any enhancement. Though peripheral rim enhancement pattern can suggest a diagnosis of TB in the appropriate clinical setting, it is, however, not pathognomonic of TB. Similar pattern can be seen in malignant adenopathy, especially Table 13.2: Contrast-enhanced computed tomography findings in tuberculosis intrathoracic lymphadenopathy Peripheral rim enhancement with or without central low attenuation Non-homogeneous enhancement Homogeneous enhancement No enhancement

metastases from testicular tumours, head and neck squamous cell carcinoma and Crohn’s disease (23). Calcification is uncommon, seen in 10 to 21 per cent children with TB and is never present in children less than six months of age (13,19) [Figure 13.6]. Disease activity in mediastinal TB lymphadenopathy was assessed by CT and correlated with biopsy findings in a study of 49 Korean patients (25). Findings of central low attenuation and peripheral enhancement on CT suggested active disease while homogeneous and calcified nodes suggested inactive disease. Since low attenuation areas within the nodes pathologically correspond to areas of caseation necrosis and may be a reliable indicator of disease activity (25). Mediastinal and hilar nodes are equally well demonstrated on MRI. Focal areas of necrosis are seen as areas of increased signal intensity on T2-weighted images (16). Three patterns of MRI appearances of TB nodes have been described: [i] relatively homogeneous nodes, hyperintense on both T1- and T2-weighted images; [ii] inhomogeneous nodes with peripheral hypointense and central hyperintense areas with strong peripheral enhancement; and [iii] homogeneously hypointense nodes on both T1- and T2-weighted images [Figure 13.7]. Type 2 lymph nodes were the most common and were seen in symptomatic patients suggesting active disease (26). Airways Involvement Airways involvement is caused either by extrinsic compression by the enlarged lymph nodes or due to endobronchial TB. The resultant narrowing leads to segmental or lobar atelectasis. This is frequently seen in primary TB in children below two years of age and is less common in older children [9%] (20) and adults [18%] (6,9). Atelectasis in primary TB characteristically affects the anterior segment of an upper lobe or the medial segment of the middle lobe. In adults such atelectasis is less commonly seen than in children; the usual site of involvement is anterior segment of the upper lobes and may simulate bronchogenic carcinoma (27). On HRCT bronchial compression by enlarged nodes as well as endobronchial involvement is well detailed. Acute tracheo-bronchial TB manifests on HRCT as irregular or smooth bronchial wall thickening associated with luminal narrowing (28).

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Figure 13.6: NCCT [A] and CECT of the chest [B] of two different patients showing calcification in paratracheal nodes [arrow]

The airway abnormality can be better delineated with the recent multislice scanners which provide excellent reconstructions obtained in multiple planes as well as the endoscopic view. Pleural Involvement Pleural effusion as a manifestation of TB is particularly common in adolescents and young adults [6% to 38%] and usually reflects primary TB. Pleural effusion is uncommon in young children with primary TB and if present, is very small in quantity. Pleural effusion is most commonly unilateral, nonloculated and moderate to large in quantity. Contralateral shift of the mediastinum is seen in patients with large effusions [Figure 13.8]. At times the effusion may be subpulmonary in location and produces apparent elevation of the ipsilateral dome of the diaphragm. A lateral decubitus radiograph will show the fluid shift along the lateral chest wall [Figure 13.9].

Complications may rarely be seen in the form of empyema, bronchopleural fistula, empyema necessitates or bone erosion. With healing, residual pleural thickening or calcification may remain [Figure 13.10]. Ultrasonography is a useful investigation in the evaluation of pleural effusion [Figure 13.11], pleural thickening and empyema. In a patient with small pleural effusion, chest radiograph may be normal, but ultrasonography can demonstrate small amount of effusion. Effusion or empyema can be repeatedly evaluated by ultrasonography without radiation to the patient. Computed tomography plays an important role in complicated pleural involvement in TB by demonstrating extent of disease, site and amount of loculations in empyema, effusion, status of the underlying rib and lung pathology and helps in planning the management. On contrast enhanced CT, loculated empyema is seen as an encysted pleural collection of fluid with smooth, enhancing surrounding pleura [Figure 13.12].

Figure 13.7: T1 [A] and T2 [B] weighted magnetic resonance images showing pre and paratracheal nodes [arrows] that appear mildly hyperintense compared to muscle

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Figure 13.8: Chest radiograph [postero-anterior view] of two different patients showing massive left sided free pleural effusion [arrows] with contralateral mediastinal shift [A]; right sided free as well as loculated pleural effusion [arrows] [B]

Figure 13.9: Chest radiograph [postero-anterior view] showing an opacity in the left lower zone [asterisk] with apparent elevation of the left dome of the diaphragm [arrow] suggestive of subpulmonary effusion. Left lateral decubitus view of the same patient [B] showing the diaphragm [asterisk] to be in normal place. The subpulmonary fluid has now settled along lateral chest wall [arrows]

Figure 13.10: Chest radiograph [postero-anterior view] [A] showing ill-defined opacity all along the lateral chest wall [arrows] with loss of volume of left hemithorax. CECT of the chest of the same patient [B] showing loss of volume, dense and thick peripheral pleural thickening with calcification [arrows]

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usually complete within two to six months. Clearance is slower in older than in younger patients. Atelectasis secondary to nodal compression may disappear with the regression of enlarged lymph nodes or perforation of the node into the bronchus provided the bronchial occlusion did not persist too long (10). However, with bronchostenosis, the collapse is often persistent. With appropriate treatment, most often there is a complete resolution of pleural effusion. However, residual pleural thickening or calcification may persist [Figure 13.10]. Figure 13.11: Ultrasonography of the chest showing significant right sided pleural effusion [asterisk]

POST- PRIMARY TUBERCULOSIS Majority of post-primary TB occurs as a result of reactivation of a focus of infection acquired in earlier life. Occasionally, the disease results from initial infection by virulent organisms in individuals who have been vaccinated with bacille Calmette-Guerin [BCG]. A minority of cases represent exogenous reinfection. Several radiographic patterns can be identified in postprimary TB and one or more of the patterns can be seen [Table 13.3]. There is considerable overlap between primary and post-primary TB on a chest radiograph. But the following points favour post-primary TB: [i] predilection for upper lobe involvement; [ii] propensity for cavitation; and [iii] rarity of lymphadenopathy (5).

Figure 13.12: CECT of the chest showing loculated empyema [asterisk] surrounded by thick enhancing pleura [arrows]

Follow-up of Primary Tuberculosis On follow-up evaluation, two-thirds of patients show complete clearance of parenchymal lesions. Resolution may require six months to two years time. Associated lymphadenopathy takes more time to resolve as compared to the parenchymal lesion. It is important to recognize that a paradoxical worsening of radiographic findings is common in both parenchymal and extraparenchymal TB in the first three months of follow-up despite adequate therapy (29). In a series of 252 paediatric patients with TB, consolidation resolved completely within two years in all cases, 18 per cent had parenchymal scarring, 11 per cent had parenchymal calcification and nodal calcification was seen in six per cent cases (20). On treatment, radiographic clearance of miliary TB is

Parenchymal Disease Exudative Lesion Consolidation which is patchy or confluent in nature can occur in specific anatomic regions, i.e., the apical and posterior segment of an upper lobe or the superior Table 13.3: Radiographic features in post-primary pulmonary tuberculosis Local exudative lesion Local fibroproductive lesion Tuberculoma Cavitation Bronchogenic spread Miliary tuberculosis Bronchostenosis Pleural disease Other complications

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segment of a lower lobe. The consolidation is heterogeneous and ill-defined. Often, more than one segment is involved [88%] [Figures 13.13 and 13.14]. Bilateral upper lobe involvement is seen in 32 to 64 per cent cases. Cavitation occurs in about 45 per cent cases (6). The lesion resolve completely with appropriate treatment. At times, the disease worsens initially but subsequently clears. Exudative lesion if not treated properly may lead to lobar or total lung consolidation with rapid destruction. But even with inadequate therapy, exudative lesion may regress and become fibroproductive. Lymphadenopathy is very uncommon and is seen in five per cent cases (6).

Figure 13.13: Chest radiograph [postero-anterior view] showing massive right upper lobe consolidation [asterisk] in a patient with post-primary tuberculosis

Figure 13.14: HRCT of the chest of another patient showing consolidation involving apical segment of right lower lobe [asterisk]

Fibroproductive or Fibroproliferative Lesion The ill-defined exudative lesion is replaced by more sharply defined medium to coarse reticular and nodular opacities [Figure 13.15]. Healing occurs by replacement of TB granulation tissue by fibrous tissue resulting in a considerable loss of volume [Figure 13.16]. In patients with a significant volume loss of the affected area of the lung, elevated diaphragm, tracheal and hilar retraction may be seen. In 41 per cent cases an apical opacity or apical cap results from pleural thickening, subpleural

Figure 13.15: Chest radiograph [postero-anterior view] showing coarse, sharply defined opacities mainly in left upper lobe suggestive of parenchymal fibroproliferative lesion [asterisk]

Figure 13.16: Chest radiograph [postero-anterior view] showing volume loss of right upper lobe, extensive fibrosis both upper lobes, elevated right hilum, residual cavities [arrow] and bronchiectatic changes in the left lung [asterisk]

Roentgenographic Manifestations of Pulmonary Tuberculosis atelectasis and extrapleural fat deposition. Mixed exudative and fibroproductive lesion is the commonest finding and is seen in 79 per cent cases. Pure exudative or fibroproductive lesions are uncommon (6). Cavitation With lysis of semisolid caseous material, the liquefied caseous material may be expelled from the centre of the lesion into the bronchial tree with a resultant cavity formation. Cavitation in an area of consolidation is a distinct feature of post-primary TB and indicates likely active disease [Figures 13.17 and 13.18]. Cavitation may be seen on chest radiographs in 40 to 87 per cent patients sometime during the course of their disease. Size of the cavity is variable [few mm to several cm] depending on the extent of caseation and extrusion. Multiple cavities are more common [54% to 76%] than a single cavity (6). The wall of an untreated TB cavity may be variably thin

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or thick, and smooth or internally nodular [Figures 13.17 and 13.18]. A thick-walled cavity with healing may progressively become thin walled and ultimately balloon into a large emphysematous space (30), although they usually resolve with or without scarring. This progression is well demonstrated on HRCT (13). The cavitary disease usually involves the apical and/or posterior segments of the upper lobes in 83 to 85 per cent and the superior segments of the lower lobes in 11 to 14 per cent patients (31). Air-fluid level is not very common in a TB cavity and is seen in 9 to 22 per cent of uncomplicated cases (5). As a rule, there is a fairly wide opening of the bronchus into a TB cavity. The cavities are mostly situated in the upper lobe, posterior segment and are peripherally located. The draining bronchus is usually basal in position and has a downward course. The basal position of the entering bronchus, its downward course and its free communi-

Figure 13.17: Chest radiograph [postero-anterior view ] [A] and HRCT of the chest [B] showing a thick walled cavity [arrow] in the left upper lobe with surrounding fibroproliferative lesions. Miliary lesions are seen in rest of the lungs

Figure 13.18: Chest radiograph [A] and HRCT of the chest [B] showing a large thick walled cavity [asterisk] with surrounding consolidation [black arrow] and contralateral nodules [white arrows] in another patient with post-primary tuberculosis

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cation with the cavity tend to keep the TB cavity empty (32). Tuberculosis cavity may be complicated by intracavitary fungal ball [“mycetoma” or commonly “aspergilloma”]. In patients with dense fibrosis, consolidation, or architectural distortion, cavity may not be visible on a chest radiograph. The CT is extremely helpful in detecting a cavity and intracavitary fungal ball through the dense lung. Tuberculosis Bronchopneumonia Tuberculosis cavity may communicate with the bronchial tree resulting in endobronchial spread of the liquefied caseous material. Similar spread may occur occasionally from intrabronchial rupture of caseous material of a lymph node. Bronchial dissemination causes multiple poorly defined parenchymal acinar nodules in the same lobe or in other lobes of either lung, predominantly in the dependent areas [Figure 13.19]. Extension of the disease through surrounding air spaces may result in acute confluent pneumonia, indistinguishable from causes other than TB. The presence of an open cavity or fairly discrete nodules in other parts of the lung suggests TB as the probable aetiological cause (10). Endobronchial spread is seen in a chest radiograph in 19 to 58 per cent (22) and by HRCT in up to 98 per cent (27) cases. The nodules are distributed in the

Figure 13.19: Chest radiograph [postero-anterior view] showing extensive bilateral bronchopneumonic tuberculosis

peribronchial and centrilobular regions and the pattern is known as “tree-in-bud” appearance as seen in HRCT. “Tree- in- bud” lesion which was first described by Im et al (33) is a combination of centrilobular nodules and branching linear structures [Figures 13.20 and 13.21]. These lesions are a result of bronchogenic spread of infection causing impaction of caseous material in the terminal or respiratory bronchioles and are considered an important sign of activity (33). The appearance, however, is non-specific and can result from any condition that causes plugging of small airway with fluid or exudates (11). While 70 per cent of such lesions

Figure 13.20: HRCT of the chest of two different patients, illustrating the typical “tree-in-bud” nodules [arrow], in a bronchovascular distribution [arrow]

Roentgenographic Manifestations of Pulmonary Tuberculosis

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Figure 13.21: HRCT of the chest [A] showing middle lobe consolidation with cavitation [asterisk] and bronchogenic spread to the right lower lobe. There is also bronchostenosis of the middle lobe bronchus [black arrow]. Coronal multiplanar reconstruction [B] shows middle lobe consolidation with volume loss [white arrow]

clear completely, 30 per cent may have parenchymal scarring, residual nodules and calcification (10). Airway Involvement [Bronchostenosis] Bronchostenosis occurs in 10 to 40 per cent of patients with active TB by direct extension from adjacent lymphadenitis, endobronchial spread of infection or lymphatic dissemination to airways. The CT can depict the bronchial abnormality in 93 to 100 per cent of cases (34) [Figure 13.21]. Pleural Effusion Pleural effusion is mostly seen in primary TB but may occur in six to eighteen per cent patients with postprimary disease (6). Pleural effusion in post-primary TB is usually small and typically seen as a loculated effusion associated with parenchymal disease. Frank TB empyema is less common. Residual pleural thickening and calcification may also occur (5). Pneumothorax may occur due to rupture of a cavity into the pleural space. Evaluation of Activity of Tuberculosis on Imaging One should never be dogmatic about the activity of a TB lesion on a single radiograph. Typical exudative lesion on a chest radiograph may remain unchanged even on adequate therapy and the patient may still be sputum culture negative. On the other hand, a typical fibrocavitary lesion may look inactive but show active granulomatous inflammation and contain viable tubercle bacilli (10). Radiographic stability of a lesion for a period of at

least six months and repeated negative sputum cultures are the best indicators of an inactive lesion (6). It is also suggested that the cases should be reported as “radiographically stable” rather than “inactive” (6). The HRCT has a definite role in prediction of activity of parenchymal lesions. The presence of thick-walled cavities, consolidation and centrilobular nodules indicate active disease. Ground glass opacities may also be seen around active lesions. Amongst these, centrilobular lesions without evidence of surrounding bronchovascular distortion or fibrosis were the most common and reliable CT findings in active TB. On HRCT, characteristic findings of bronchogenic spread are reported in more than 94 per cent of cases (34,35) [Figures 13.20 and 13.21]. Whereas, thin-walled cavities, fibrotic bands and well-defined nodules are seen in inactive disease [Figure 13.22]. Some workers suggest that these findings should be described as ‘stable’ rather than ‘inactive’, because of the possibility of future recrudescence of latent bacilli in such residual cavities. The CT picture can, however, be equivocal and clinical correlation in this regard is imperative. The CT cannot always accurately predict the disease activity. Well-defined nodules can also be seen in patients with inactive TB and in such cases ascertaining activity on HRCT may be difficult (11,36,37). Evaluation of activity in nodes is difficult, though presence of low attenuation areas has been suggested as a sign of activity. However, this sign is of limited reliability as enhancement patterns of the nodes can be quite variable as discussed previously (25).

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Figure 13.22: Chest radiograph [postero-anterior view] [A] and HRCT of the chest [B] showing extensive destruction of right lung with volume loss and fibro-bullous changes [asterisk]

In pleural TB, fibrothorax with diffuse pleural thickening and calcification, but without pleural effusion on CT, suggests inactivity (28). SEQUELAE AND COMPLICATIONS OF TUBERCULOSIS A variety of sequelae and complications can occur in pulmonary TB. Parenchymal Complications Parenchymal complications include thin-walled cavities, fibrotic bands, cicatrization, end-stage lung destruction and aspergilloma. Residual thin-walled cavities may be seen in both active and inactive disease. After antituberculosis chemotherapy, the TB cavity may disappear; occasionally, the wall becomes paper-thin and an airfilled cystic space remains [Figure 13.22]. Serial imaging helps determine the stability or activity of pulmonary disease (38). The characteristics of residual fibrosis include grooving, calcification and retraction of the adjoining parenchyma. These changes can be extensive and result in considerable destruction of the lung parenchyma. Cavities and bronchiectasis may be colonized by Aspergillus species forming an aspergilloma [Figure 13.23], or other organisms. Haemoptysis is clinically most important consequence of these sequelae. Airway Complications Airway complications include bronchiectasis, tracheobronchial stenosis, and broncholithiasis (38).

Figure 13.23: Mycetoma in a tuberculosis cavity. CT of the chest showing loss of volume of right upper lobe with a cavity. Soft tissue mass seen inside the cavity is caused by fungus ball [arrrow]

Bronchciectasis in post-primary TB can develop most commonly due to destruction and fibrosis of lung parenchyma, resulting in retraction and irreversible bronchial dilatation or due to cicatricial bronchostenosis secondary to localized endobronchial tuberculosis, resulting in obstructive pneumonitis and distal bronchiectasis [Figure 13.24]. Most of the post-primary TB lesions are in the apical and posterior segment of upper lobes, hence these are common sites for bronchiectasis. Since bronchial drainage is adequate from these sites, usually symptoms are minimal [bronchiectasis sicca] (10). Bronchostenosis may result in persistent segmental or lobar collapse [Figures 13.25, 13.26, and 13.27], lobar hyperinflation or obstructive

Roentgenographic Manifestations of Pulmonary Tuberculosis

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Figure 13.24: Chest radiograph [postero-anterior view] [A] and CT of the chest [B] of the same patient showing collapse of left lower lobe with cystic bronchiectasis, loss of volume of left hemithorax [arrow] and herniation of right lung to the left [asterisk]

pneumonitis. Broncholithiasis is an uncommon complication of pulmonary TB and is defined as the presence of calcified or ossified material within the lumen of the tracheobronchial tree.

Vascular Complications

Pleural complications include chronic empyema, fibrothorax, bronchopleural fistula, and pneumothorax. Fibrothorax with pleural thickening and calcification results in a significant loss of thoracic volume (38) [Figure 13.10].

Vascular lesions include pulmonary or bronchial arteritis and thrombosis, bronchial artery dilatation, and Rasmussen aneurysm (38). Vascular complications in pulmonary TB can result in massive haemoptysis which may be life-threatening and often needs emergency embolotherapy. At times in post-primary TB, pulmonary arteries and veins in an area of active TB infection may show vasculitis and thrombosis. Arteries near chronic TB cavities frequently show endarteritis obliterans. There is an increase in the number and

Figure 13.25: Chest radiograph [postero-anterior view] showing a triangular opacity through the heart suggestive of left lower lobe collapse [arrow]

Figure 13.26: Chest radiograph [postero-anterior view] showing dense opacities in right upper lobe with elevated horizontal fissure and right hilar adenopathy, suggestive of collapse consolidation of the right upper lobe [arrow]

Pleural Complications

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size of bronchial artery branches [Figure 13.28]. Occasionally, an artery lies contiguous with the fibrous capsule of a cavity and undergoes localized dilatation, known as Rasmussen’s aneurysm [Figure 35.3]. It is seen as an enlarging mass or rapidly enlarging consolidation due to haemorrhage. This is seen in four to five per cent of autopsy cases in patients with chronic TB (10). TUBERCULOSIS AND HUMAN IMMUNODEFICIENCY VIRUS INFECTION Patients with HIV infection are more prone to develop an overwhelming disease process of primary TB. In

patients who had previous primary TB, HIV infection significantly impairs cellular immunity and leads to reactivation TB (39). The radiographic manifestations of tuberculosis in patient with AIDS depend upon the degree of immunosuppression. Early in HIV disease, clinical presentation of TB is similar to that observed in immunocompetent individuals and upper lobe infiltrates, cavities and bronchogenic spread may be evident. At this stage infection is confined to the lungs in more than 75 per cent of cases. In more advanced AIDS, radiographic findings are often atypical including diffuse infiltrates, multiple pulmonary nodules or masses and significant mediastinal lymphadenopathy (40). The infiltrates may

Figure 13.27 Chest radiograph [postero-anterior view] [A] showing volume loss of left upper lobe [asterisk]. HRCT of the chest of the same patient [B], in addition, reveals narrowing of the left main bronchus [arrow]

Figure 13.28: HRCT of the chest [A] showing extensive fibrocavitary lesions in the right upper lobe [white arrow]. Selective bronchial artery angiogram [B] reveals a hypertrophied intercosto-bronchial artery supplying the region [black arrow]

Roentgenographic Manifestations of Pulmonary Tuberculosis be quite extensive, fairly rapidly progressive and randomly distributed in upper and lower lobes. Cavitation is rare in the advanced stage of AIDS. The reader is also referred to the chapter “Tuberculosis and human immunodeficiency virus infection” [Chapter 40] for more details. FAMILY SURVEY It is essential to survey the family members who stay in close contact with a patient of pulmonary TB (41). All contacts should have a chest radiograph taken and all those below 12 years of age should undergo tuberculin testing to detect asymptomatic contacts with latent TB infection. In our experience with 2677 children with pulmonary TB, there was a positive family history of TB in 30 per cent patients. Radiographic screening of 300 adult contacts of children with primary pulmonary complex showed active pulmonary lesions in four to five per cent of those screened (9). The reader is referred to the chapter “Tuberculosis in children” [Chapter 41] for more details. RADIOGRAPHIC FOLLOW-UP SCHEDULE The American Thoracic Society and Centres for Disease Control (41) recommend the following radiographic schedule. In patients with a negative sputum mycobacterial culture, a repeat chest radiograph is indicated at two months of treatment; another chest radiograph is considered as desirable at the end of treatment. In patients with a positive sputum mycobacterial culture, repeat chest radiographs at two months and at the end of treatment are considered desirable [but not essential] (42). REFERENCES 1. Mohan A, Sharma SK. Tuberculosis: current concepts. In: Sharma SK, Behera D, Mohan A, editors. Recent advances in respiratory medicine. New Delhi: Jaypee Brothers Medical Publishers; 1998.p.159-93. 2. Kim WS, Moon WK, Kim IO, Lee HJ, Im JG, Yeon KM, et al. Pulmonary tuberculosis in children: evaluation with CT. AJR Am J Roentgenol 1997;168:1005-9. 3. Miller WT, Miller WT Jr. Tuberculosis in the normal host: radiological findings. Semin Roentgenol 1993;28:109-18. 4. Lamont AC, Cremin BJ, Pelteret RM. Radiological patterns of pulmonary tuberculosis in the paediatric age group. Paediatr Radiol 1986;16:2-7.

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5. McAdams HP, Erasmus J, Winter JA. Radiologic manifestations of pulmonary tuberculosis. Radiol Clin North Am 1995;3:655-78. 6. Woodring JH, Vandiviere HM, Fried AM, Dillon ML, Williams TD, Melvin IG. Update: the radiographic features of pulmonary tuberculosis. AJR Am J Roentgenol 1986;146:497-506. 7. Choyke PL, Sostman HD, Curtis AM, Ravin CE, Chen JT, Godwin JD, et al. Adult-onset pulmonary tuberculosis. Radiology 1983;148:357-62. 8. Buxi TB, Sud S, Vohra R. CT and MRI in the diagnosis of tuberculosis. Indian J Paediatr 2002;69:965-72. 9. Mukhopadhyay S, Gupta AK. Imaging in childhood tuberculosis. In: Seth V, editor. Essentials of tuberculosis in children. New Delhi: Jaypee Brothers Medical Publishers; 1997.p.240-63. 10. Fraser RG, Pare JA, Fraser RS, Genereux GP. In: Diagnosis of diseases of the chest. Vol.II. 3rd ed. Philadelphia: W.B. Saunders and Company; 1989.p.882-933. 11. Lee JY, Lee KS, Jung KJ, Han J, Kwon OJ, Kim J, et al. Pulmonary tuberculosis: CT and pathologic correlation. J Comput Assist Tomogr 2000;24:691-8. 12. Lee KS, Song KS, Lim TH, Kim PN, Kim IY, Lee BH. Adultonset pulmonary tuberculosis: findings on chest radiographs and CT scans. AJR Am J Roentgenol 1993;160:753-8. 13. Leung AN. Pulmonary tuberculosis: the essentials. Radiology 1999;210:307-22. 14. Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis 2005; 5:415-30. 15. Weber AL, Bird KT, Janower ML. Primary tuberculosis in childhood with particular emphasis on changes affecting the tracheobronchial tree. AJR Am J Roentgenol 1968; 103:12332. 16. Reed MH, Pagtakhan RD, Zylak CJ, Berg TJ. Radiologic features of miliary tuberculosis in children and adults. J Can Assoc Radiol 1977;28:175-81. 17. Pipavath SN, Sharma SK, Sinha S, Mukhopadhyay S, Gulati MS. High resolution CT [HRCT] in miliary tuberculosis [MTB] of the lung: correlation with pulmonary function tests and gas exchange parameters in north Indian patients. Indian J Med Res 2007;126:193-8. 18. Sharma SK, Mohan A, Banga A, Saha PK, Guntupalli KK. Predictors of development and outcome in patients with acute respiratory distress syndrome due to tuberculosis. Int J Tuberc Lung Dis 2006;10:429-35. 19. Andronikou S, Joseph E, Lucas S, Brachmeyer S, Du Toit G, Zar H, et al. CT scanning for the detection of tuberculous mediastinal and hilar adenopathy. Pediatr Radiol 2004;33:2326. 20. Leung AN, Muller NL, Pineda PR, FitzGerald JM. Primary tuberculosis in childhood: radiographic manifestations. Radiology 1992;182:87-91. 21. Amorosa JK, Smith PR, Cohen JR, Ramsey C, Lyons HA. Tuberculous mediastinal lymphadenitis in the adult. Radiology 1978;126:365-8.

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22. Hadlock FP, Park SK, Awe RJ, Rivera M. Unusual radiographic findings in adult pulmonary tuberculosis. AJR Am J Roentgenol 1980;134:1015-8. 23. Pombo F, Rodriguez E, Mato J, Perez-Fontan J, Rivera E, Valvuena L. Patterns of contrast enhancement of tuberculous lymph nodes demonstrated by computed tomography. Clin Radiol 1992;46:13-7. 24. Im JG, Song KS, Kang HS, Park JH, Yeon KM, Han MC. Mediastinal tuberculous lymphadenitis: CT manifestations. Radiology 1987;164:115-9. 25. Moon WK, Im JG, Yeon KM, Han MC. Mediastinal tuberculous lymphadenitis: CT findings of active and inactive disease. AJR Am J Roentgenol 1998;170:715-8. 26. Moon WK, Im JG, Yu IK, Lee SK, Yeon KM, Han MC. Mediastinal tuberculous lymphadenitis: MR imaging appearance with clinicopathologic correlation. AJR Am J Roentgenol 1996;166:21-5. 27. Matthews JI, Matarese SL, Carpenter JL. Endobronchial tuberculous simulating lung cancer. Chest 1984;86:642-4. 28. Van Dyck P, Vanhoenacker FM, Van den Brande P, De Schepper AM. Imaging of pulmonary tuberculosis. Eur Radiol 2003;13:1771-85. 29. Agrons GA, Markowitz RI, Kramer SS. Pulmonary tuberculosis in children. Semin Roentgenol 1993;28:158-72. 30. Im JG, Itoh H, Shim YS, Lee JH, Ahn J, Han MC, et al. Pulmonary tuberculosis: CT findings – early active disease and sequential change with antituberculous therapy. Radiology 1993;186:653-60. 31. Poppius H, Thomander K. Segmentary distribution of cavities; a radiologic study of 500 consecutive cases of cavernous pulmonary tuberculosis. Ann Med Interne Fenn 1957;46:113-9.

32. Burrill J, Williams CJ, Bain G, Conder G, Hine AL, Misra RR. Tuberculosis: a radiologic review. Radiographics 2007; 27:1255-73. 33. Im JG, Itoh H, Lee KS, Han MC. CT-pathology correlation of pulmonary tuberculosis. Crit Rev Diagn Imaging 1995;36:22785. 34. Lee KS, Kim YH, Kim WS, Hwang SH, Kim PN, Lee BH. Endobronchial tuberculosis: CT features. J Comput Assist Tomogr 1991;15:424-8. 35. Hatipoglu ON, Osma E, Manisali M, Ucan ES, Balci P, Akkoclu A, et al. High resolution computed tomographic findings in pulmonary tuberculosis. Thorax 1996;51:397-402. 36. Bombarda S, Figueiredo CM, Seiscento M, Terra Filho M. Pulmonary tuberculosis: tomographic evaluation in the active and post-treatment phases. Sao Paulo Med J 2003;121:198202. 37. Lee KS, Hwang JW, Chung MP, Kim H, Kwon OJ. Utility of CT in the evaluation of pulmonary tuberculosis in patients without AIDS. Chest 1996;110:977-84. 38. Kim HY, Song KS, Goo JM, Lee JS, Lee KS, Lim TH. Thoracic sequelae and complications of tuberculosis. Radiographics 2001;21:839-58. 39. Miller WT. Tuberculosis in the 1990s. Radiol Clin North Am 1994;32:649-61. 40. Kuhlman JE. Pulmonary manifestations of acquired immunodeficiency syndrome. Semin Roentgenol 1994;29:242-74. 41. Abernathy RS. Tuberculosis in children and its management. Semin Respir Infect 1989;4:232-42. 42. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al; American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603-62.

Pulmonary Tuberculosis

14 VK Vijayan, Sajal De

INTRODUCTION Pulmonary tuberculosis [TB] is a chronic infectious disease caused by Mycobacterium tuberculosis (1). Other mycobacteria can also produce pulmonary TB and these include Mycobacterium africanum and Mycobacterium bovis. Usually, patients with pulmonary TB who have cavitary lesions are an important source of infection. These patients are usually sputum smear-positive. Coughing produces tiny infectious droplets. Usually, one bout of cough produces 3000 droplet nuclei and these can stay in the air for a long period of time. Ventilation removes these infectious nuclei. Mycobacterium tuberculosis can survive in the dark for several hours. Direct exposure to sunlight quickly kills these bacilli. Of the several factors, determining an individual’s risk of exposure, two factors are important. These include the concentration of droplet nuclei in contaminated air and the length of time that air is breathed. The risk of transmission of infection from a person with sputum smear-negative pulmonary TB and miliary TB is low and with extra-pulmonary TB is even lower. However, infection with Mycobacterium bovis is rare in India because milk is often boiled before use. Even though nontuberculous mycobacteria [NTM] are harmless, some can cause human disease especially in immunocompromised individuals (2). NATURAL HISTORY OF TUBERCULOSIS The cardinal event in the pathogenesis of TB, whether inapparent or overt is the implantation of Mycobacterium tuberculosis in the tissues. Lung is the most frequent portal of entry [Figures 14.1A and 14.1B]. The organism enters the lung from the inhalation of air borne droplets which

have been coughed out by ‘open’ [sputum-positive] pulmonary TB patients who have received no treatment, or have not been treated fully. The initial contact with the organism results in few or no clinical symptoms or signs. The tubercle bacillus sets up a localized infection in the periphery of the lung. Four to six weeks later, tuberculin hypersensitivity along with mild fever and malaise develops. In the majority of patients, the process is contained by local and systemic defenses. Rupture of the sub-pleural primary pulmonary focus into the pleural cavity may result in the development of TB pleurisy with effusion. Less commonly, tubercle bacilli may be ingested and lodge in the tonsil or in the wall of the intestine. This form of TB occurs following the ingestion of contaminated milk or milk products. Rarely, TB can occur as a result of direct implantation of the organisms into the skin through cuts and abrasions. This form of TB is a health hazard faced by health care workers and laboratory staff who handle materials infected with Mycobacterium tuberculosis. These lesions were termed “prosector’s warts” (2). Interestingly, Laennec, the inventor of the stethoscope, acquired TB in this fashion which eventually led to his death (2). Primary Tuberculosis From the implantation site, the organisms disseminate via the lymphatics to the regional lymph nodes. The lesion at the primary site of involvement, draining lymphatics and the inflamed regional lymph node constitute the primary complex. When the primary site of implantation is in the lung, it is called Ghon’s focus. The draining lymphatics and the involved lymph nodes

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Figure 14.1A: Chest radiograph [postero-anterior view] showing a cavity in left upper zone [arrow]. Sputum culture was positive for Mycobacterium tuberculosis

Figure 14.1B: Chest radiograph [postero-anterior view] of the same patient at 24 months of follow-up. The patient had received six months short-course chemotherapy. The left upper zone cavity has disappeared

together with Ghon’s focus constitute the primary complex [Ghon complex]. In children, the lymph node component may be much larger than the Ghon’s focus. Having secured entry, the tubercle bacilli then disseminate via the haematogenous route to other parts of the lung and many organs of the body. Thus, primary TB is a widely disseminated infection. This fact is often not realized by clinicians. Most of these metastatic foci heal. However, some of these metastatic foci may remain dormant and may reactivate at a later date when the host resistance decreases. The subsequent course of the events varies considerably. In most of the patients, the primary complex resolves without becoming clinically apparent. This occurs when the immune status of the host is good, and healing occurs by fibrosis and calcification. In a minority of patients, progressive primary TB due to the extension of the inflammatory process at the site of the primary focus can occur. In the lung, this can present as an area of consolidation [TB pneumonia]. This form of the disease was often encountered in the prechemotherapeutic era and was termed “galloping consumption” or “pneumonia alba” [white pneumonia]. This form is encountered in the

present era in patients with human immunodeficiency virus [HIV] infection. Caseation necrosis at the Ghon’s focus may lead to liquefaction. Expectoration of the liquefied material can leave a cavity with shaggy margins in the pulmonary parenchyma which may be apparent on the chest radiograph. Mediastinal and tracheobronchial lymph nodes may produce compression of the adjacent bronchus. If this obstruction is complete, the lung distal to the site of bronchial obstruction becomes atelectatic [epituberculosis] (3). If the obstruction is incomplete, it may act as a “ball-valve” and results in obstructive emphysema. The inflamed caseous lymph nodes may erode through the walls of the bronchus and result in bronchogenic dissemination. Bronchial mucosal involvement may result in TB bronchitis. In a patient with overwhelming infection, large number of Mycobacterium tuberculosis may gain access to the circulation and result in miliary and meningeal TB. In majority of the patients, the initial focus of infection subsides. Cicatrization, scar formation and often calcification develop. Repeated episodes of extension of infection followed by healing and fibrosis may result in the formation of “onion skin” or “coin lesion” (2).

Pulmonary Tuberculosis 219 Post-primary Tuberculosis Rarely, the primary lesion may progress directly to the post-primary form, characterized by extensive caseation necrosis and cavitation. More commonly, the primary lesion remains quiescent, and may remain so for decades or for the remainder of the individual’s lifetime. The precise mechanism[s] underlying this phenomenon have not yet been clarified as yet. However, reactivation or reinfection TB may occur due to old age, malnutrition, malignant disease, HIV infection and acquired immunodeficiency syndrome [AIDS], use of immunosuppressive drugs and intercurrent infections. While reactivation can occur at any site, postprimary TB classically involves the apical and posterior segments of the upper lobes, or, the superior segment of the lower lobes in more than 95 per cent of the cases. Balasubramanian et al (4) have critically reviewed the pathway to the apical localisation in TB and proposed the integrated model for the pathogenesis of TB. Post-primary lesions are different from primary lesions in that, local progression and central caseation necrosis are much more marked in post-primary TB as compared to primary TB. Tuberculosis cavities are abundant sites for the growth of Mycobacterium tuberculosis as the temperature in them is optimal, there is abundance of oxygen and various nutrients derived from the cell wall are readily available. The bacilli in the wall of the cavity gain free access into the sputum and are expectorated. Such patients are said to have “open tuberculosis” and are infectious to the community. If these bacilli are aspirated from the cavity to other parts of the lung via the bronchi, many secondary pulmonary lesions develop. Early in the illness, TB cavities are moderately thick walled, usually have a smooth inner surface, lack an air-fluid level and are surrounded by an area of consolidation. Later, in the chronic phase of the disease, the wall may become thin, and the cavities may appear spherical. SYMPTOMS Pulmonary TB is a disease of protean manifestations and can mimic many diseases. Previous accounts referred to the development of erythema nodosum, phlyctenular conjunctivitis and fever at the time of

tuberculin conversion (2). However, this presentation is not commonly seen these days. The patient may develop symptoms insidiously and some may remain asymptomatic. Usually patients with pulmonary TB present with constitutional and respiratory symptoms (3). Constitutional symptoms include tiredness, headache, weight loss, fever, night sweats and loss of appetite. The classic symptoms and signs of TB were noted in a significantly higher proportion of the younger group than elderly: fever [62% versus 31%], weight loss [76% versus 34%], night sweats [48% versus 6%], sputum production [76% versus 48%], and haemoptysis [40% versus 17%] (5). Clinical manifestations of TB in HIV infected patients vary and generally depend upon the severity of immunosuppression. In early stages of HIV disease, clinical presentation of TB tends to simulate that observed in persons without immunodeficiency. Fever is often present in the late afternoon or evening, and is low-grade at the onset and becomes high-grade with the progression of disease. Weight loss may precede the symptoms. Some patients may remain afebrile. Associated laryngeal TB can result in hoarseness of the voice. Amenorrhoea can occur in severe diseases. The most common respiratory symptom of pulmonary TB is cough which lasts for three or more weeks. Cough may be dry or productive. It is nearly impossible to differentiate cough due to pulmonary TB from cough due to other respiratory diseases including smoking, and it is often passed off as a smoker’s cough. Sputum may be mucoid, mucopurulent, purulent or blood-tinged and is usually scanty. Haemoptysis, although observed in many diseases, is an important and often the presenting symptom of pulmonary TB. Furthermore, TB is the most common cause of haemoptysis in India. Severity of haemoptysis in pulmonary TB varies from blood-stained sputum to massive haemoptysis. Massive haemoptysis usually results from rupture of a bronchial artery (1). Chest pain may be dull aching in character. Acute chest pain can occur in TB pleurisy or in pneumothorax; with severe pain occurring at the height of inspiration. In diaphragmatic pleurisy, pain is referred to the ipsilateral shoulder when central part of the diaphragm is involved. Occasionally chest pain can occur from fracture of ribs due to violent coughing. Breathlessness results from extensive disease or if complications such as bronchial obstruction, pneumothorax or pleural effusion occur. Localized wheeze can occur due to endobronchial TB or

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because of the pressure of enlarged lymph nodes on the bronchus. PHYSICAL SIGNS A thorough general physical examination should be done in all patients with pulmonary TB. Anaemia and cachexia may be observed in severe cases. Tachycardia can occur and is usually proportional to the fever. Digital clubbing occurs rarely in advanced cases and with superadded suppuration. There can be an increase in the respiratory rate. Extra-pulmonary TB foci such as cold abscess, enlarged cervical and mesenteric lymph nodes, deformity or localized immobility of the spine, epididymitis, etc., can be discovered on general physical examination. In addition, general physical examination may also reveal phlyctenular conjunctivitis or keratitis. Further, signs of meningeal irritation and focal neurological signs may be apparent in patients with extra-pulmonary focus in the nervous system. Associated signs of protein energy malnutrition such as anasarca, change in hair colour and leuconychia may occur. Adult patients with chronic disease can present with lower body-mass index [BMI]. Respiratory system examination may reveal displacement of the trachea and the heart depending on the underlying pathology. Asymmetrical abnormalities of the chest wall such as retraction, fibrosis or collapse and prominence in pleural effusion, emphysema or pneumothorax may be observed. Undue prominence of the clavicular head of the sternocleidomastoid muscle [Trail’s sign] on one side may be indicative of apical fibrosis due to TB. Mobility of any part of the chest wall may be restricted on the affected side. A dull percussion note can occur as a result of consolidation, collapse of the lung, or thickened pleura or extensive infiltration of the lung due to TB. A stony dull note can be elicited over a pleural effusion or empyema. Hyperresonance on percussion is encountered in pneumothorax. Cracked-pot sound may be elicited in cases where percussion is practiced over a cavity which communicates with bronchus of moderate size and is most distinct when the mouth is open. It results due to a sudden expulsion of air through a constricted orifice. It has a hissing character, combined with a clinking sound like that produced by shaking coins together. It is a rare finding. Cracked-pot sound is often produced in healthy children when percussion is performed during crying. Myotactic irritability or myoidema can occur due to hyperirritability of malnourished

muscles in front of the thorax. A light tap over the sternum produces fibrillary contractions, at some distance off, in the pectoral muscles. High-pitched [tubular] bronchial breathing can be heard in patients with TB pneumonia. Bronchial breathing can be low-pitched [cavernous] if there is an underlying cavity in the lung or an open pneumothorax. A special type of high-pitched bronchial breathing with an “echo-like” quality [amphoric breathing] is indicative of a large cavity with smooth walls or a pneumothorax communicating with a bronchus. It resembles the sound produced by blowing across the mouth of a bottle and consists of one or more low-pitched fundamental tones and a number of high-pitched overtones. Vocal fremitus is increased when lung is consolidated or contains a large cavity near the surface. Vocal fremitus is diminished when the corresponding bronchus is obstructed and is absent when there is pleural effusion or thickening. The presence of fine crepitations, especially post-tussive crepitations, is an important sign of TB infiltration. A pleural rub is characteristic of pleurisy. Hippocratic succussion is the splashing sound which can be heard when a patient who has both air and fluid in the pleural cavity is shaken or moved suddenly. Posttussive suction, a sucking noise resembling that produced by an India-rubber ball that is springing open again, can be heard after a coughing, over a cavity in the lung when its walls are not too rigid. It occurs due to re-entry of air. DIAGNOSIS The diagnosis of primary and post-primary forms of pulmonary TB involves detection and isolation of Mycobacterium tuberculosis (6-12). In addition, identification of the mycobacterial species and determination of their susceptibility to antimycobacterial drugs are required for management. Tuberculin Skin Test Tuberculin skin test [TST] is useful for the detection of infection with Mycobacterium tuberculosis which leads to the development of sensitivity to certain antigenic components of the organisms called “tuberculins”. Intracutaneous injection of tuberculin results in a classic delayed [cellular] hypersensitivity reaction. A delayed hypersensitivity reaction to tuberculin may indicate previous natural infection with NTM or vaccination with bacille Calmette-Guérin.

Pulmonary Tuberculosis 221 Haematology Haematological abnormalities in pulmonary TB include anaemia, leucocytosis, leucopenia, purpura, leukaemoid reaction and polycythaemia vera.

frequently atypical, particularly in the late stage of HIV infection, and include non-cavitary disease, lower lobe infiltrates, hilar lymphadenopathy and pleural effusion.

Radiology Standard posterior-anterior and lateral radiographs of the chest should be obtained in patients who have signs and symptoms suggestive of pulmonary TB. The initial radiological manifestations include parenchymal infiltration with ipsilateral lymph node enlargement. Hilar or mediastinal lymph node enlargement in TB is usually unilateral and this lymph nodal enlargement persists longer than the parenchymal lesions. Calcification of the lymph nodes and the lung lesions could occur several years after infection. In adults, the lesions may be patchy or nodular infiltrates and may occur in any segment. Dense and homogeneous lesions with lobar, segmental or subsegmental distributions are also encountered frequently [Figures 14.1A, 14.1B, 14.2, 14.3A, 14.3B and 14.4]. Cavitation, often multiple, occurs in immunocompetent individuals, but is rare in immunocompromised individuals. The X-ray features of pulmonary TB in HIV-seropositive patients are

Figure 14.2: Chest radiograph [postero-anterior view] showing extensive parenchymal lesions in the left lung. Few scattered lesions are also seen in the right lung. The sputum smear and culture were positive for Mycobacterium tuberculosis

Figure 14.3A: Chest radiograph [postero-anterior view] showing extensive parenchymal infiltrates in the right lung. Few scattered infiltrates are also seen in the left lung. The patient had multidrugresistant pulmonary tuberculosis

Figure 14.3B: Chest radiograph [postero-anterior view] of the same patient taken a year later showing pneumothorax on the right side and a large cavity in the left lung. The patient did not respond to treatment and died

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Figure 14.4: Chest radiograph [postero-anterior view] of a patient with sputum smear-negative and culture-positive pulmonary tuberculosis

More typical post-primary TB with upper lobe infiltrates and cavitations is seen in the earlier stages of HIV infection. Computed tomography [CT] is more sensitive than chest radiograph in detecting subtle parenchymal changes and mediastinal involvement. Primary TB typically appears as air-space consolidation with hilar or mediastinal lymphadenitis. Post-primary TB most commonly appears as nodular and linear opacities at the lung apex. The CT findings of early bronchogenic spread of post-primary TB include centrilobular nodules [2 to 4 mm] or branching linear structures. These findings correspond to caseous material filling the bronchioles (13), and this is referred as “tree-in-bud” appearance. Cavitations usually occur at the centrilobular area and may progress to a larger coalescent cavity. The CT can document miliary disease even when chest radiograph is normal. The CT findings of early miliary dissemination commonly include ground-glass opacification with barely discernible nodules. On high-resolution computed tomography [HRCT], miliary TB typically shows fine, nodular or reticulonodular pattern with nodules involving both intralobular interstitium, interlobular septa and subpleural, and perivascular regions. Nodules

are evenly distributed throughout the lung. Computed tomography more accurately defines the group of lymph nodes involved, their extent and size. The lymph nodes with central low attenuation and peripheral rim enhancement, especially with contrast, strongly suggest a diagnosis of mycobacterial infection. Complications of TB, such as post-TB bronchiectasis, aspergilloma etc., are better diagnosed with the help of a CT. Other radiographic findings in pulmonary TB include atelectasis and fibrotic scarring with retraction of the hila and deviation of the trachea. Unilateral pleural effusion may be the only radiographic abnormality in pleural TB. Rarely, chest radiographs may be normal especially in patients with endobronchial TB and HIV infection. It is important to compare the current chest radiographs with previous radiographs done months or years earlier, so that subtle changes can be detected. Progression of lesions on serial chest radiographs indicates active disease. Apical-lordotic or oblique view of, chest may aid in visualization of lesions obscured by bony structures or the heart. Contrast-enhanced CT [CECT] and magnetic resonance imaging [MRI] of the chest may be useful in defining intrathoracic lymph nodes, nodules, cavities, cysts, calcification and vascular details in the lung parenchyma. Bronchial stenosis or bronchiectasis can be defined by bronchography and CT of the chest. Fluoroscopy may be useful in the detection of the mobility of thoracic structures. Fibreoptic Bronchoscopy Patients with positive skin tests and abnormal chest radiographs compatible with TB pose diagnostic problems and therapeutic dilemma [to treat or not to treat for TB] to chest physicians. Microbiologic confirmation of TB among sputum smear-negative is increasingly important because of an increasing incidence of smear negativity, especially among immunocompromised hosts. Fibreoptic bronchoscopic studies provide various types of specimens [aspirate, brush, lavage fluid and biopsy] for early diagnosis of sputum smear-negative pulmonary TB. An early diagnosis of TB is possible in nearly one-third of sputum smear-negative pulmonary TB, if different bronchoscopic procedures are employed instead of a single procedure alone during bronchoscopy (14-17). The overall yield of bronchoscopy is greater than 90 per cent, especially when culture were included in analysis (18). Examination and culture of post-broncho-

Pulmonary Tuberculosis 223 scopy sputum also had high diagnostic yield [93%] (19). The topical anaesthetic agents that are used during bronchoscopic procedure had inhibitory effect on mycobacteria. Therefore, these agents should be carefully used. Bronchoscopic examination may show normal bronchial mucosa to ulcerative lesions, granulomatous lesions, and ulcerative-granulomatous tumour-like lesions and residual fibrotic stenosis. Because of high mortality in miliary TB, it is imperative that the diagnosis is confirmed as quickly as possible. In miliary TB, bronchoscopy is diagnostic in 73 to 83 per cent of cases (20). The yield of bronchoscopy for diagnosis of pulmonary TB in HIV infected patients is similar to that in patients without HIV infection and transbronchial biopsy provides incremental diagnostic information (14). In paediatric patients the gastric lavage is superior to bronchoalveolar lavage [BAL] for bacteriologic confirmation of pulmonary TB. The overall bacteriologic yield was 34 per cent while gastric lavage alone was positive in 32 per cent of the cases (21). Indications for bronchoscopy as a diagnostic tool for pulmonary TB may include: [i] patients suspected of having pulmonary TB with negative smears and in whom treatment must be started due to clinical status; [ii] suspicion of associated neoplasia; [iii] selected patients with negative cultures; and [iv] lack of material being obtained by simpler methods. However, it has been demonstrated that sputum induction is a safe procedure with a high diagnostic yield and high agreement with the results of fiberoptic bronchoscopy for the diagnosis of pulmonary TB in both HIV-seronegative and HIVseropositive patients. Sputum induction was well tolerated, involved low-cost, and provided the same, if not better, diagnostic yield compared with bronchoscopy in the diagnosis of smear-negative pulmonary TB (22,23). In a decision analysis model to assess the overall utility of BAL in clinically suspected sputum smear-negative pulmonary TB, it has been suggested that, in a region of high TB prevalence, empirical treatment is the best course of action (17). Diagnostic Mycobacteriology The definitive diagnosis of pulmonary TB is made by the isolation and identification of the infecting organism. All patients presenting with cough and sputum for more than three weeks must have their sputum examined for Mycobacterium tuberculosis. In addition, Mycobacterium

tuberculosis can be isolated from blood, gastric aspirate, bronchial washings, BAL fluid, pleural fluid, pus, cerebrospinal fluid, urine, bone marrow biopsy and other tissue biopsy specimens. All diagnostic specimens should be collected before the patient is given antituberculosis treatment. Sputum microscopy is the earliest and quickest procedure for the preliminary diagnosis of pulmonary TB. Patients should be instructed that the material brought out from the lungs after a productive cough. Patients should be instructed not to submit the nasopharyngeal discharge and saliva. The patient should rinse his/her mouth with water before specimen collection to remove materials that interfere with the culture results. Sputum collection should be done in an isolated, well-ventilated area. Sputum specimen should be collected in a wide-mouth, rigid container with tightfitting screw tops. If the patient cannot produce sputum, deep coughing may be induced by inhalation of an aerosol of warm hypertonic [3% to 15%] saline. Sputum containers should be examined in each patient. The bacilli can be stained with basic fuchsin dyes [Ziehl-Neelsen or Kinyoun method] or with a fluorochrome [auraminerhodamine] staining. The positive predictive value of a properly performed smear is more than 90 per cent for pulmonary TB. DIFFERENTIAL DIAGNOSIS Tuberculosis can practically involve all organs of the body and can simulate most of the diseases. Diseases which are to be differentiated from pulmonary TB are listed in Table 14.1. However, by no means this list is exhaustive. Bacterial Pneumonia Bacterial pneumonia, especially occurring in the upper part of the lung, may mimic TB. In acute pneumonia, symptoms occur suddenly and a raised white blood cell count may point to the diagnosis. If sputum is negative for Mycobacterium tuberculosis, antibiotics which have no effect on Mycobacterium tuberculosis can be given for seven to ten days. A rapid fall in temperature may occur following treatment with antibiotics if the lesion is due to acute pneumonia. The patient may be re-evaluated after a course of antibiotics with a chest radiograph which may show clearance of the lesions in acute pneumonia. However, it should be noted that shadows may look

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Tuberculosis Table 14.1: Differential diagnosis of pulmonary tuberculosis

Infections Bacterial pneumonia Lung abscess Fungal and miscellaneous bacterial infections Bronchogenic carcinoma Bronchiectasis Bronchial asthma Sarcoidosis Pneumoconiosis Cardiovascular disease Congenital abnormalities Other diseases Hyperthyroidism Diabetes mellitus

smaller after the antibiotic course if there is collapse of the part of the lung or pneumonia due to obstruction of a bronchus. Pneumonia due to Pneumocystis jiroveci is common in patients with AIDS. If the sputum examination is non-contributory, BAL fluid examination for Mycobacterium tuberculosis and Pneumocystis jiroveci cysts is indicated (17,24). Lung Abscess Patients with lung abscess often produce foul-smelling purulent sputum. Clubbing of fingers is a prominent feature in these patients. Peripheral blood examination reveals neutrophilic leucocytosis. Ziehl-Neelsen staining is negative for Mycobacterium tuberculosis. Fungal and Miscellaneous Bacterial Infections The important fungal diseases of the lung that may mimic pulmonary TB include aspergillosis, blastomycosis, coccidioidomycosis, cryptococcosis, and histoplasmosis. Other miscellaneous bacterial infections can also simulate pulmonary TB and these include nocardiosis and actinomycosis. Nocardia micro-organisms are common bacterial inhabitants of soil. Examination of sputum or pus reveals crooked, branching, beaded, Gram-positive filaments. Most Nocardia microorganisms are acid-fast in direct smears if a weak acid is used for decolourisation. The organisms often take up silver stains. Actinomycosis is an indolent, slowly progressive bacterial infection caused by a variety of Gram-positive, non-spore forming anaerobic or microaerophilic rods. The most characteri-

stic feature of actinomycosis is the demonstration of “sulphur granules” in sputum, pus or tissue specimens. These are usually yellow and consist of aggregated microorganisms. Aspergillus is responsible for four types of pulmonary manifestations, viz: allergic bronchopulmonary aspergillosis [ABPA], aspergilloma, chronic necrotizing pulmonary aspergillosis and invasive aspergillosis. Allergic bronchopulmonary aspergillosis is characterized by asthma-like symptoms, eosinophilia, fleeting pulmonary infiltrates, a positive immediate skin test response to aspergillin, elevated serum IgE and antiAspergillus IgG antibodies. Aspergilloma occurs in patients with pre-existing TB or other cavities and these patients can have high serum IgG antibody titres of Aspergillus. Invasive aspergillosis usually occurs in immunocompromised patients. Blastomycosis can be diagnosed by demonstration of yeast-like organisms with a highly refractile cell wall and multiple nuclei in sputum samples. Patients with coccidioidomycosis can be diagnosed by showing spherules in the sputum stained with Gomori’s or Papanicolaou’s stains. Cryptococcosis can be identified by staining the biological specimens with India ink and demonstration of doubly refractile cell wall, the presence of budding and the clean capsule. Viable organisms in macrophages can be seen in histoplasmosis. Candidiasis can occur in pulmonary TB patients with immunodeficiency. Bronchogenic Carcinoma A solid round tumour in the chest radiograph may be difficult to distinguish from a well-circumscribed TB lesion. Both bronchogenic carcinoma and pulmonary TB cause weight loss, cough, blood-streaked sputum and fever. Bronchogenic carcinoma may also cavitate. Bronchogenic carcinoma can produce post-obstructive pneumonitis and lung abscess. The patient with bronchogenic carcinoma is usually a chronic smoker and sputum will be negative for Mycobacterium tuberculosis. Confirmation of diagnosis requires bronchoscopic biopsy in these patients. Bronchiectasis Patients with bronchiectasis have a long history of respiratory symptoms, especially since childhood. They produce purulent sputum. Clubbing of fingers is a

Pulmonary Tuberculosis 225 prominent sign and coarse bubbling crepitations can be heard on auscultation. Sputum examination is negative for Mycobacterium tuberculosis. The middle and lower lobes [or lingula on the left side] are commonly involved in bronchiectasis. The CT of the chest and bronchography will aid in the diagnosis. Bronchial Asthma Patients with bronchial asthma often manifest wheezing. They often give history of allergy to inhalants or ingestants. However, a localized wheeze can occur in TB if a bronchus is obstructed by an enlarged lymph node or if there is TB bronchitis. Bronchial asthma can be diagnosed by demonstrating reversibility in pulmonary function after inhalation of bronchodilator aerosols. Sarcoidosis Sarcoidosis usually presents with bilateral hilar lymphadenopathy and pulmonary infiltration. It can also present with pulmonary infiltrates or nodular lesions without mediastinal lymphadenopathy. In these situations it is difficult to differentiate these lesions from pulmonary TB, especially miliary TB. These patients often have negative tuberculin test and the sputum is negative for Mycobacterium tuberculosis (25). Almost every organ of the body can be involved in sarcoidosis and the tissue biopsy reveals non-caseating epithelioid cell granulomas. Pneumoconiosis

when enlarged left atrium compresses the left recurrent laryngeal nerve [Ortner’s syndrome] and this may be mistaken for hoarseness due to TB. Radiographic abnormalities seen in haemosiderosis due to long-standing mitral stenosis can be confused with miliary TB. Haemoptysis can also occur in patients with primary or secondary pulmonary arterial hypertension and in severe pulmonic stenosis. Careful examination of the heart and appropriate investigations [electrocardiogram and echocardiogram] will help in the differential diagnosis. Congenital Abnormalities Dermoid cysts, arteriovenous fistulae and hamartomas may require differentiation from pulmonary TB. Sequestration of the lung may produce difficulty in diagnosis, if associated with bronchiectasis or purulent sputum and fever. Bronchoscopy, aortography, CT and sputum examination can facilitate the diagnosis. Other Diseases Hyperthyroidism and diabetes mellitus can have symptoms such as loss of weight, easy fatigability and malaise which can be mistaken for the constitutional symptoms associated with TB. Appropriate investigations will facilitate the diagnosis. PRACTICAL APPROACH TO THE DIAGNOSIS OF ACTIVE PULMONARY TUBERCULOSIS

Occupational exposure to silicon dioxide, asbestos, coal dust, beryllium, ferrous oxide, etc., and hypersensitivity reactions to organic inhalants can cause pulmonary infiltration that may mimic pulmonary TB. Conglomerate masses and even cavitation can occur in silicosis. Sometimes TB develops in a patient with silicosis [silicotuberculosis]. Coal miners suffering from rheumatoid arthritis can develop round shadows in the lung resembling TB. Some patients with pneumoconiosis develop progressive massive fibrosis. A carefully elicited occupational history and absence of Mycobacterium tuberculosis in the sputum help in the diagnosis.

Even in a country like India where TB is highly endemic, diagnosis of active pulmonary TB can be a diagnostic dilemma. The following criteria would indicate active pulmonary TB. These include: [i] clinical signs of infection and features of TB toxaemia [fever with evening rise, night sweats, malaise, weight loss, etc.]; [ii] progressive radiographic changes; [iii] microbiological or histopathological evidence of TB infection; and [iv] response to therapeutic trial with antituberculosis treatment. Of these, microbiological or histopathological evidence [Figure 14.5] is conclusive and the remaining are suggestive.

Cardiovascular Diseases

TREATMENT

Haemoptysis can occur in patients with mitral stenosis. In addition, hoarseness of voice occurs in mitral stenosis

The reader is referred to the chapter “Treatment of tuberculosis” [Chapter 52], for more details.

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Figure 14.5: Pulmonary tuberculosis. Photomicrograph showing bronchial cartilage with ossification [thin arrow], marrow development [asterisk] and bronchial mucosal glands [upper panel, left; Haematoxylin and eosin x 60], bronchial tissue exhibiting epithelioid granulomas [arrow heads], lymphocytic infiltration, acini of bronchial mucosa [upper panel right; Haematoxylin and eosin x 60; lower panel right; Haematoxylin and eosin x 200] and alveoli with anthracotic pigment [thick arrow] [lower panel, left; Haematoxylin and eosin x 60]

REFERENCES 1. Ducati RG, Ruffino-Netto A, Basso LA, Santos DS. The resumption of consumption-a review on tuberculosis. Mem Inst Oswaldo Cruz 2006;101:697-714. 2. Grange JM. Mycobacteria and human disease. London: Arnold; 1996. 3. Miller FJW. Tuberculosis in children. Edinburgh: Churchill Livingstone; 1982. 4. Balasubramanian V, Wiegeshaus EH, Taylor BT, Smith DW. Pathogenesis of tuberculosis: pathway to apical localisation. Tuber Lung Dis 1994;75:168-78. 5. Alvarez S, Shell C, Berk SL. Pulmonary tuberculosis in elderly men. Am J Med 1987;82:602-6. 6. Enarson DA, Grosset J, Mwinga A, Hershfield ES, O’Brien R, Cole S, et al. The challenge of tuberculosis: statements on global control and prevention. Lancet 1995;346:809-19. 7. Crofton J, Horne N, Miller F. Clinical tuberculosis. New Delhi: CBS Publishers and Distributors; 1996.p.1-194.

8. American Thoracic Society. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 2000;161:1376-95. 9. Schluger, Rom WN. Current approaches to the diagnosis of active pulmonary tuberculosis. Am J Respir Crit Care Med 1994;149:264-7. 10. Shinnick TM, Good RC. Diagnostic mycobacteriology laboratory practices. Clin Infect Dis 1995;21:291-9. 11. Steingart KR, Ramsay A, Pai M. Optimizing sputum smear microscopy for the diagnosis of pulmonary tuberculosis. Expert Rev Anti Infect Ther 2007;5:327-31. 12. Manjunath N, Shankar P, Rajan L, Bhargava A, Saluja S, Shriniwas. Evaluation of polymerase chain reaction for the diagnosis of tuberculosis. Tubercle 1991;72:21-7. 13. Im JG, Itoh H, Lee KS, Han MC. CT- pathology correlation of pulmonary tuberculosis. Crit Rev Diagn Imaging 1995;36:22785. 14. Kennedy DJ, Lewis WP, Barnes PF. Yield of bronchoscopy for the diagnosis of tuberculosis in patients with human immunodeficiency virus infection. Chest 1992;102:1040-4. 15. Vijayan VK, Paramasivan CN, Sankaran K. Comparison of bronchoalveolar lavage fluid with sputum culture in the diagnosis of sputum smear negative pulmonary tuberculosis. Indian J Tuberc 1996;43:179-82. 16. Chawla R, Pant K, Jaggi OP, Chandrashekhar S, Thukral SS. Fibreoptic bronchoscopy in smear negative pulmonary tuberculosis. Eur Respir J 1988;1:804-6. 17. Mohan A, Pande JN, Sharma SK, Rattan A, Guleria R, Khilnani GC. Bronchoalveolar lavage in pulmonary tuberculosis: a decision analysis approach. QJM 1995;88:269-76. 18. Mohan A, Sharma SK. Fibreoptic bronchoscopy in the diagnosis of sputum smear-negative pulmonary tuberculosis: current status. Indian J Chest Dis Allied Sci 2008;50:67-78. 19. de Gracia J, Curull V, Vidal R, Riba A, Orriols R, Martin N, et al. Diagnostic value of bronchoalveolar lavage in suspected pulmonary tuberculosis. Chest 1988;93:329-32. 20. Pant K, Chawla R, Mann PS, Jaggi OP. Fibrebronchoscopy in smear-negative miliary tuberculosis. Chest 1989;95:1151-2. 21. Somu N, Swaminathan S, Paramasivan CN, Vijayasekaran D, Chandrabhooshanam A, Vijayan VK, et al. Value of bronchoalveolar lavage and gastric lavage in the diagnosis of pulmonary tuberculosis in children. Tuber Lung Dis 1995;76:295-9. 22. Conde MB, Soares SL, Mello FC, Rezende VM, Almeida LL, Reingold AL, et al. Comparison of sputum induction with fiberoptic bronchoscopy in the diagnosis of tuberculosis: experience at an acquired immune deficiency syndrome reference center in Rio de Janeiro, Brazil. Am J Respir Crit Care Med 2000;162:2238-40. 23. Anderson C, Inhaber N, Menzies D. Comparison of sputum induction with fiberoptic bronchoscopy in the diagnosis of tuberculosis. Am J Respir Crit Care Med 1995;152:1570-4. 24. Sharma SK, Pande JN. Fiberoptic bronchoscopy. Indian J Chest Dis Allied Sci 1988;30:163-5. 25. Sharma SK, Mohan A, Guleria R, Padhy AK. Diagnostic dilemma: tuberculosis? or, sarcoidosis? Indian J Chest Dis Allied Sci 1997;39:119-23.

Lower Lung Field Tuberculosis

15

G Ahluwalia, SK Sharma

INTRODUCTION Classically, the post-primary pulmonary tuberculosis [TB] is a disease located predominantly in the upper lobes. Since Laennec’s era, lower lung field TB was considered a rarity. In fact, Laennec himself opined that TB hardly ever developed in the middle or lower lobes of the lungs (1). Throughout the 19th century, most of the authors were of the view that involvement of the lower lung field from TB was an irrelevant issue (2,3). However, there was a school of thought holding a divergent view. In 1886, Kidd stated that “the apex of lower lobe is very prone to TB disease and may be attacked before the apex of the upper lobe” (4). Subsequently, two years later, Fowler stated that “the upper and posterior part of the lower lobe is a spot only second in point of vulnerability to the apex itself’” (5). Except these two early documentations, the literature is silent over the occurrence of lower lung field TB till the first quarter of the 20th century. Subsequently, many authors (6-11) concluded that lower lung field may be the site of pulmonary TB in specific situations which one encounters rather frequently. Therefore, a high index of suspicion is the key to the diagnosis of lower lung field TB. TERMINOLOGY OF LOWER LUNG FIELD TUBERCULOSIS It is important to understand the meaning of the term ‘lower lung field TB’. In the earlier reports (4-11), the term ‘basal TB’ was frequently used. However, with the advent of lateral radiographs of the chest, the term ‘lower lobe TB’ had been used by various authors (12-16). In

view of the proximity of the lesion to hilum, the term ‘hilar and perihilar TB’ was also used by a few authors (17,18). However, Ostrum and Saber (16) suggested that various terms used by different authors were infact referring to the same entity. The lower lung field is defined as the area on the postero-anterior [PA] chest radiograph, which extends below an imaginary horizontal line traced across the hilum and includes the parahilar regions. A standard PA chest radiograph is ordinarily sufficient for the diagnosis of pulmonary TB. Since lateral films of the chest are available very infrequently, it is difficult to identify the exact topographic location of the lesion, i.e., whether the disease is confined to the lower lobe only or is present in the middle lobe and lingula as well. Therefore, the term ‘lower lung field TB’ has come into vogue. In a PA radiograph of the chest, lower lung field includes the middle lobe and lingula in addition to the lower lobe. PREVALENCE The prevalence of lower lung field TB has ranged from 0.003 to 17 per cent. In fact, Ross (19) reported a high prevalence of 18.3 per cent in their series. The reason for the wide variation in the prevalence is probably due to confusion in the terminology used [basal, parahilar, lower lobe, lower lung field] and selection bias [hospitalized or ambulatory patients]. The prevalence of lower lung field TB in studies reported from India has been observed to be higher than that reported in western studies [Table 15.1]. This may be due to the fact that a majority of Indians tie their clothes [women their sari and men their loin cloth] tightly

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Table 15.1: Prevalence of lower lung field tuberculosis Study (reference)

Year

No. of Prevalence pulmonary of lower lung TB field TB cases [%]

Colton (7)

1928

2335

Ross (19)

1930

60

Du Fault (8)

1932

365

0.27

Reisner (20)

1935

4494

0.68

Hamilton and Fredd (12)

1935

349

2.9

Viswanathan (21)

1936

638

6.4

Romendick et al (22)

1944

2354

2.7

0.003 18.3

Segarra et al (23)

1963

10962

0.85

Parmar (24)

1967

1455

3.4

Tripathy and Nanda (25)

1970

707

5.1

Mathur et al (26)

1974

5072

0.63

Berger and Granada (27)

1974

386

7.0

Chang et al (28)

1987

1276

5.1

Wang et al (29)

2006

520

15.8

TB = tuberculosis

around the upper abdomen and this results in impaired movement of diaphragm. This theory has been substantiated by Viswanathan (21), who studied the diaphragmatic movements on the radiographic screen in subjects accustomed to tight lacing around their waists. It has been suggested that the resultant impaired movement of diaphragm leads to costal type of breathing [as in females], which leads to decreased ventilation, retarded blood circulation and lymphatic flow in lower lung fields, thus making them more vulnerable to TB. PATHOGENESIS Besides the above cited palusible mechanisms (20,21), the most common pathogenetic mechanism of lower lung field TB is the ulceration of a bronchus by a lymph node affected by TB with spillage of TB material into the bronchus. Most authors have proposed that lower lung field TB occurs as a continuum of primary TB or soon after in the post-primary phase (23,24). CLINICAL FEATURES In most studies (9,19,23,30), female preponderance and predilection for patients under the age of 40 years has been reported. Segarra et al (23) reported that 89 per cent

of patients with lower lung field TB were less than 40 to years old while Parmar (24) reported that 46 per cent of the patients were less than 20 years of age. However, Tripathy and Nanda (25) did not find a similar distribution in their study. Unlike previous reports, Chang et al (28) have observed that lower lung field TB is no longer a disease of the young. Associated Conditions Lower lung field TB appears to be more common in patients receiving corticosteroid treatment, patients with hepatic or renal disease, diabetes mellitus, pregnancy, silicosis and kyphoscoliosis (23,28,30-32). Symptoms The duration of symptoms may be less than two weeks, although the mean duration is twelve weeks (28). Most series report symptoms for less than six months (23,27,28). Tripathy and Nanda (25) have observed that about 20 per cent of patients reported within two weeks and 70 per cent of patients within six months in their series of 36 cases. Cough with variable amounts of expectoration is the most frequent symptom (21,23,25). Mathur et al (26) reported cough in 100 per cent cases. Many workers have noted haemoptysis as an important symptom (8,11,12,2024). Tripathy and Nanda (25) noted haemoptysis in nearly two-thirds of the cases, while Romendick et al (22) noted it in 75 per cent of cases. The general toxic manifestations of TB infection such as fever, chills, malaise, weakness and anorexia are also frequently present. Segarra et al (23) reported these symptoms in about 40 per cent of their cases whereas Tripathy and Nanda (25) reported them in 86 per cent of their cases. Signs The physical signs vary with the extent and character of the lesions. Patients with extensive involvement of the lungs have pronounced signs of the underlying lesion. However, patients who have involvement of a relatively small area, especially those in whom the lesion is limited to the apical segment of lower lobe, physical signs may be scanty or even absent. However, physical signs are encountered more often in patients with lower lung field TB than in those with the classical form of upper lobe pulmonary TB (27).

Lower Lung Field Tuberculosis 229 INVESTIGATIONS Sputum Examination Although sputum examination is the simplest way to diagnose lower lung field TB, isolation of Mycobacterium tuberculosis is difficult on smear or culture examination (27,28). However, the diagnostic yield of sputum examination is better in patients with cavitary lesions (33). Chest Radiograph More than half of the cases of lower lung field TB have right lung involvement, whereas one-third have left lung involvement. Bilateral lesions are reported in 10 per cent of the cases (24,25,30). The radiographic findings in lower lung field TB differ significantly from those found in upper lobe disease (20). The most frequent radiographic finding is consolidation, which is more confluent and extensive than that found in upper lobe TB (33) [Figure 15.1]. Cavitary lesions are also frequently seen, which may be single or multiple and may lie within an area of consolidation (27,28) [Figure 15.2]. Cavities may be large [3 to 4 cm in diameter]. The presence of tension cavities [thinwalled with fluid] is also a radiological feature of lower

Figure 15.2: Chest radiograph [postero-anterior view] showing cavitary lesion in the right lower zone

lung field TB (23,25,34,35). Other radiological features include evidence of atelectasis or solitary mass with intrathoracic lymphadenopathy. The radiological features also have a prognostic value. The outcome is unfavourable in patients with lower lung field TB who have lung collapse or pulmonary consolidation in the chest radiograph (33,35). Bronchoscopy

Figure 15.1: Chest radiograph [postero-anterior view] showing consolidation in the right lower zone

The early diagnosis of lower lung field TB is important for prevention of severe sequelae. Fibreoptic bronchoscopy is the preferred diagnostic modality for the diagnosis of lower lung field TB. Abnormal bronchoscopic findings in lower lung field TB include ulcerative granuloma, mucosal erythema, submucosal infiltration and fibrostenosis [Figure 15.3]. Fibreoptic bronchoscopy provides a higher diagnostic yield than sputum examination, especially in patients who present with radiographic findings of pulmonary consolidation, lung collapse or solitary mass (22,33). Fibreoptic bronchoscopy is also important in assessing the severity of endobronchial lesions in lower lung field TB. The outcome is unfavourable in patients with lower lung field TB when fibreoptic bronchoscopy reveals fibrostenosis or ulcerative granuloma. If severe fibrostenosis is present, early surgical intervention should be considered to prevent damage of the lung distal to the obstruction (27,33).

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Figure 15.3: Mucosal erythema and submucosal infiltration observed during fibreoptic bronchoscopy in a patient with right lower lung field tuberculosis. Bronchoalveolar lavage revealed Mycobacterium tuberculosis

MANAGEMENT Lower lung field TB presents a definite problem in diagnosis because of its location and radiographic findings. Moreover, when TB is confined to lower lung field, it often masquerades as pneumonia, lung cancer, bronchiectasis or lung abscess, thereby, delaying the correct diagnosis. The shift in age-distribution from the young to the aged and non-specific clinical features adds another challenge in the diagnosis of lower lung field TB (33,35). Therefore, TB should be considered a diagnostic possibility in patients with lower lung field lesions who have the following conditions: diabetes mellitus, advanced age, steroid treatment, renal or hepatic illness, malignancy or lesions with poor response to adequate antibiotic therapy (35,36). Fibreoptic bronchoscopy should be performed early to ascertain the diagnosis of TB and assess the severity of the endobronchial lesions. The patients with lower lung field TB show a favourable response to conventional antituberculosis therapy. Delayed diagnosis affects the outcome in these patients (35,36). Significant resolution of chest radiograph findings and/or sputum negativity was observed with antituberculosis therapy, if the diagnosis to treatment time was less than three months (33). Treatment of lower lung field TB is similar to the treatment elsewhere in the body. The reader is referred to the chapter “Treatment of tuberculosis” [Chapter 52] for

details. Long-term follow-up is recommended to diagnose possible relapse after the completion of treatment. In India, patients with lower lung field TB receive DOTS under the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India. The reader is referred to the chapter “Revised National Tuberculosis Control Programme” [Chapter 63] for more details. Tracheobronchial stenosis is an important complication of lower lung field TB leading to permanent damage of lung distal to the obstruction. Since the outcome is poor in patients with lower lung field TB, when fibreoptic bronchoscopy findings show fibrostenosis or ulcerative granuloma, these patients should be followed-up closely. The non-invasive methods such as chest radiograph and flow-volume loops on pulmonary function testing are insensitive for detecting or monitoring tracheobronchial stenosis. In these patients, close follow-up with fibreoptic bronchoscopy is necessary if chest radiograph shows no significant improvement or clinical features that suggest progression of endobronchial lesions after antituberculosis therapy for a few months. Surgical intervention is indicated if re-examination with fibreoptic bronchoscopy shows no significant improvement or worsening of endobronchial involvement. However, if severe fibrostenosis is present, early surgical intervention in the form of sleeve operation is indicated before permanent sequelae such as damage of lung distal to the obstruction and respiratory failure occur (27,33). REFERENCES 1. Laennec RH. Treatise on the diagnosis and treatment of the diseases of the chest. New York: Hafner Publishing; 1962. 2. Landis HRM, Norris GW. Diseases of the chest. Second edition. Philadelphia: W.B. Saunders Company; 1921. 3. Fishberg M. Pulmonary tuberculosis. Third edition. Philadelphia: Lea and Febiger; 1922. 4. Kidd P. Basic tuberculous phthisis. Lancet 1886;2:616. 5. Fowler JK. The localization of lesions of phthisis. London: J and A Churchill; 1888. 6. Busby JF. Basal tuberculosis. Am Rev Tuberc 1939;40:692-703. 7. Colton WA. Basal lesions in pulmonary tuberculosis with report of seven cases. US Vet Bureau Med Bull 1928;4:503. 8. Du Fault P. Basal pulmonary lesions. Am Rev Tuberc 1932;25:17-23. 9. Dunham K, Norton W. Basal tuberculosis. JAMA 1927;89:1573-5. 10. Lander F. Selective thoracoplasty for persistent basal tuberculosis cavities. J Thorac Surg 1938;7:455.

Lower Lung Field Tuberculosis 231 11. Gordon BL, Charr R, Sokoloff MJ. Basal pulmonary tuberculosis. Am Rev Tuberc 1944;49:432-6. 12. Hamilton CE, Fredd H. Lower lobe tuberculosis. JAMA 1935;105:427-30. 13. Jacob M. Lower lobe pulmonary tuberculosis. Med J Record 1929;129:32. 14. Middleton WS. Lower lobe pulmonary tuberculosis. Am Rev Tuberc 1923;7:307. 15. Ossen EZ. Tuberculosis of the lower lobe. N Engl J Med 1944;230:693-8. 16. Ostrum HW, Saber W. Early recognition of lower lobe tuberculosis. Radiology 1949;53:42-8. 17. Bernard M, Lelong M, Renard G. La localisation perihilare de la tuberculose pulmonaire chronique de la adultae. Ann de Med 1927;21:366. 18. Faber K. Perihilar pulmonary tuberculosis in adults. Acta Med Scand 1931;75:403. 19. Ross EL. Tuberculosis in nurses–a study of the disease in 60 nurses admitted to Manitoba sanatorium. Can Med Assoc J 1930;22:347-54. 20. Reisner D. Pulmonary tuberculosis of the lower lobe. Arch Intern Med 1935;56:258-80. 21. Viswanathan R. Tuberculosis of the lower lobe. Br Med J 1936;2:1300-2. 22. Romendick SS, Friedman B, Schwartz HF. Lower lung field tuberculosis. Dis Chest 1944;10:481-8. 23. Segarra F, Sherman DS, Rodriguez-Aguero J. Lower lung field tuberculosis. Am Rev Respir Dis 1963;87:37-40. 24. Parmar MS. Lower lung field tuberculosis. Am Rev Respir Dis 1967;96:310-3.

25. Tripathy SN, Nanda CN. Lower lung field tuberculosis in adults. J Assoc Physicians India 1970;18:999-1008. 26. Mathur KC, Tanwar KL, Razdan IN. Lower lung field tuberculosis. Indian J Chest Dis 1974;16:31-41. 27. Berger HW, Granada MG. Lower lung field tuberculosis. Chest 1974;65:522-6. 28. Chang SC, Lee PY, Perng RP. Lower lung field tuberculosis. Chest 1987;91:230-2. 29. Wang JY, Hsueh PR, Lee CH, Chang HC, Lee LN, Liaw YS, et al. Recognizing tuberculosis in the lower lung field: an age- and sex-matched controlled study. Int J Tuberc Lung Dis 2006;10:578-84. 30. Sokoloff MJ. Lower lobe tuberculosis. Radiology 1940;34:58994. 31. Fernandez MZ, Nedwicki EG. Lower lung field tuberculosis. Mich Med 1969;68:31-5. 32. Morris JT, Seaworth BJ, McAllister CK. Pulmonary tuberculosis in diabetics. Chest 1992;102:539-41. 33. Chang SC, Lee PY, Perng RP. The value of roentgenographic and fiberbronchoscopic findings in predicting outcome of adults with lower lung field tuberculosis. Arch Intern Med 1991;151:1581-3. 34. Perez-Guzman C, Torres-Cruz A, Villarreal-Velarde H, Salazar-Lezama MA, Vargas MH. Atypical radiological images of pulmonary tuberculosis in 192 diabetic patients: a comparative study. Int J Tuberc Lung Dis 2001;5:455-61. 35. Kobashi Y, Matsushima T. Clinical analysis of recent lower lung field tuberculosis. J Infect Chemother 2003;9:272-5. 36. Bacakoglu F, Basoglu OK, Cok G, Sayiner A, Ates M. Pulmonary tuberculosis in patients with diabetes mellitus. Respiration 2001;68:595-600.

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Endobronchial Tuberculosis

16

SS Dhillon, NA Hanania

INTRODUCTION Endobronchial tuberculosis [TB], which refers to the involvement of trachea and bronchi, was first described in 1689 by an English physician, Richard Morton (1). However, it remained mainly a post-mortem diagnosis and was infrequently reported until the advent of bronchoscopy in the late 1920s (2-4). Subsequently, the natural history of endobronchial TB was described in large clinical and pathological series (2-4). Following the introduction of effective chemotherapy for TB, reports on endobronchial TB decreased dramatically to the extent that no cases were reported in several large studies on the bronchoscopic evaluation of patients with TB (5-9). More recently, several case series of patients with endobronchial TB have been published (10-20) and the interest in this topic has re-emerged. EPIDEMIOLOGY The exact prevalence of endobronchial TB is not known. In autopsy studies on patients with TB, the reported prevalence has ranged from three per cent (21) to 72 per cent (22) although most series report a rate of about 40 per cent (23,24). This variation in prevalence rate may be due to the difference in severity of cases of TB studied and/or the extent of tracheobronchial tree evaluation (23). For example, in a study published in the pre-chemotherapy era, more than 30 per cent of the patients with endobronchial TB had concomitant pulmonary TB for a duration of more than two years, a fact that may explain the high prevalence of endobronchial TB noted (23). Based on previously published bronchoscopic studies, endobronchial TB was reported in 10 to 20 per

cent of patients with active TB (24-28). However, in recent studies, a lower prevalence rate has been reported, which is most likely due to the timely and more effective chemotherapy received by patients with TB (5-9). In fact, the current prevalence rate may be as low as 0.18 per cent in areas where TB is not endemic (29). The difference in prevalence between autopsy and bronchoscopy studies is likely due to the inclusion of microscopic involvement of airways in autopsy data that is not detected by bronchoscopy (23). Endobronchial TB is mostly seen in patients between 21 to 40 years of age and rarely in those 60 years or older (12,19,23). The majority of studies report a female preponderance (4,12,14,19,23,30). This may be due to the fact that the implantation of organisms from infected sputum occurs easily in women who tend to voluntarily suppress their cough because of socio-cultural and cosmetic reasons (19,31,32). Small airways in women may also contribute to the observed difference in prevalence. PATHOPHYSIOLOGY Mechanisms of Endobronchial Infection Five potential mechanisms for the spread of endobronchial infection with TB have been suggested (3). Extension from the Lungs by Direct Infiltration Direct spread probably occurs when bronchi in the immediate neighbourhood of an infected lung are involved. In general, tracheobronchial ulceration is more commonly seen adjacent to areas of extensive and progressive parenchymal TB (23).

Endobronchial Tuberculosis 233 Implantation of Organisms from Infected Sputum The finding of endobronchial disease on the wall of bronchi opposite the opening of a diseased lobe is likely due to the implantation from infected material passing over the mucous membrane. Auerbach (23) observed the presence of gross airways ulcerations on the same side where cavities in the lung were present. These cavities are a potential source of bacilli causing the endobronchial involvement. However, in some cases, cavity formation may follow the diagnosis of endobronchial TB, pointing to the possibility of other mechanisms (15). In addition, the absence of endobronchial involvement in cases where large cavities are present argues against this mechanism (33). Haematogenous Dissemination Haematogenous spread is possible but very rare, as endobronchial TB is not commonly described in miliary TB (23). Lymphatic Spread This mechanism involves retrograde passage of the tubercle bacilli through lymphatics from bronchioles and sub-segmental bronchi to the main-stem bronchus. Peribronchial infection of the lymphatics may be seen histologically in some cases. However, the data by Auerbach (23) suggests that in most cases the infection starts in the submucosal region and progresses towards the adventitia. Only in few cases, infection is limited to or starts from the adventitia, where lymphatics are located. This fact argues against the lymphatic spread as a common mechanism. As a Part of the Primary Infection In certain cases of primary TB a lymph node erodes into a bronchus. The lymph node becomes attached to the bronchial wall because of the ongoing inflammatory changes and, thus, the infection spreads through the walls of the bronchus to the mucosal lining. This mechanism is predominantly seen in children (34,35). Chang et al (36) reported endobronchial involvement in 12 of the 16 patients with intrathoracic TB lymphadenopathy. Baran et al (37) found endobronchial abnormalities in 15 of the 17 patients with intrathoracic TB lymphadenopathy in the absence of parenchymal lesions.

Four of these patients had ulcerating endobronchial granulomas. Direct perforation of TB lymph nodes into the bronchi is relatively uncommon in adults, especially now in the post-chemotherapy era (38,39). In summary, although different mechanisms for the endobronchial spread of TB have been described, implantation of the organisms from infected sputum is likely the most frequent mechanism in adults. Macroscopic Appearance The earliest bronchoscopic sign of endobronchial TB is the finding of erythematous mucous membranes. Discrete tubercles may have a rough granulated appearance to the naked eye or may lead to shallow ulcers of the mucous membrane that progress to deep ulcers involving the bronchial wall. Formation of extensive granulation tissue may occasionally result in a tumourlike growth into the lumen of the bronchus mimicking a neoplasm. In most cases where ulcers are deep, healing will be complicated by stenosis secondary to extensive fibrosis. Bronchial stenosis may also result from oedema or from extrinsic compression by a lymph node (23). On rare occasions, post-obstructive pneumonia, lung abscess, obstructive emphysema and subsequent bronchiectasis may develop distal to this stenosis (23). Autopsy studies suggest that ulcers are more common in region of the carina and posterior surface of the tracheobronchial tree (23). The size of these ulcers varies from 1 to 5 mm and their long axes are usually parallel to the cartilaginous rings (23). Ulcers may progressively coalesce leaving the cartilage partially exposed at the base of the ulcer (23). Endobronchial TB may be an integral part of the parenchymal lung involvement with TB but this involvement is overlooked, as smaller airways cannot be accessed by bronchoscopy. Diffuse stenosis of small bronchi distal to the fourth generation mimicking bronchiolitis obliterans has been described (40). Microscopic Appearance Small, oval and round foci of epithelioid giant cell tubercles, with or without a central zone of caseation within the wall especially in the subepithelial region and in the region of mucous glands, are the early microscopic findings with endobronchial TB. In advanced cases, these foci are also present in the adventitia and in rare occasions

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they may only be seen in the adventitia (23). Involvement of the cartilage is usually limited to very extensive cases. Rupture of one of these submucosal foci results in ulceration and gradual destruction of the wall of bronchus. The zone of caseation is usually surrounded by vascular granulation tissue and is occasionally covered by a pseudomembrane formed by fibrin exuded from capillaries in this granulation tissue. During the process of healing, granulation tissue replaces the inner zone of caseation and regenerating epithelium from all sides will eventually cover the ulcer. Connective tissue ultimately replaces the cells and capillaries within the granulation tissue. If this process is extensive and involves most of the circumference of the airway, stenosis will eventually occur. CLINICAL COURSE The clinical presentation of endobronchial TB is variable. In adults, it may occur as primary or reactivation TB. However, in children, it is usually a complication of primary TB. The onset of endobronchial TB may be acute mimicking asthma, pneumonia and foreign body aspiration (3,29,41,42) or insidious, simulating lung cancer (10,43-47). Symptoms may start years after the diagnosis and treatment of pulmonary TB (48). A barking cough has been reported in the majority of patients. Dyspnoea, chest pain, fever, generalized weakness, weight loss and haemoptysis may also be present (10,12). Sputum production is variable; bronchorrhoea [> 500 ml/ day] has been reported in rare cases (49). Physical examination may reveal diminished breath sounds or a localized wheeze (3,30). Wheezing is classically lowpitched, constantly present, and heard over the same area of the chest wall (2), but may disappear as the airways become progressively narrowed. Partial airway obstruction may on rare occasions act as a one-way valve leading to distal air-trapping (3). Expectoration of bronchial cartilages (50,51) and fistula formation between the right and left main bronchi have also been described (52). Bronchial stenosis is the most important complication of endobronchial TB. It may present with slowly progressive shortness of breath years after the diagnosis and treatment of pulmonary TB. Respiratory failure, difficult endotracheal intubation, need for tracheostomy and death by suffocation may occur as a consequence of tracheal stenosis (15).

Simultaneous involvement of other organs has been reported. Auerbach, hypothesized that endobronchial TB represents a tendency towards the development of “tract tuberculosis”. Concomitant intestinal and laryngeal involvement with TB was noted in 82 and 60 per cent of autopsy cases respectively (23). However, these findings have not been reported in more recent studies and were limited to older studies which included patients with progressive TB of a long duration. LABORATORY AND RADIOLOGIC INVESTIGATIONS Sputum Examination Sputum smear for Mycobacterium tuberculosis has a low yield [15% to 20%] (10,12) for the diagnosis of endobronchial TB. This may be because expectoration of sputum is difficult due to mucus entrapment by proximal bronchial granulation tissue (10). Furthermore, ulceration of the involved mucosa may be necessary for obtaining a positive sputum smear (12). Thus, a negative sputum smear does not exclude the diagnosis. Chest Radiograph Endobronchial TB usually co-exists with extensive pulmonary parenchymal or intrathoracic lymph node involvement. However, 10 per cent to 20 per cent of the patients have a normal chest radiograph (10,12,25,30,5358). Chest radiograph may show patchy infiltrates (15), evidence of collapse [25% to 35%] or consolidation [35% to 60%] (10,12). Other radiological features include hyperinflation, cavity formation, pleural effusion, miliary infiltrates and mediastinal lymphadenopathy (10,15). Computed Tomography Computed tomography [CT] of the chest is an important tool for evaluation of endobronchial TB. While the findings are non-specific, it may show endobronchial involvement of both large and small airways. In fact, in some studies the endobronchial involvement is more pronounced in small airways than large airway (59-62). These CT findings have been well correlated with corresponding pathological findings by Im et al (61). Findings on CT of endobronchial disease in small airways may include: poorly-defined nodules, centrilobular nodules, bronchial wall thickening and “tree-in-bud”

Endobronchial Tuberculosis 235 appearance [Figure 16.1] (59-61). All these findings are best visualized on high resolution CT [HRCT ] (60). Centrilobular lesions reflect solid caseation material within or around the terminal or respiratory bronchioles. Terminal tufts of the “tree-in-bud” may represent the lesions within the bronchioles and alveolar ducts, while the stalk may represent a lesion that affects the last order bronchus within the secondary lobule [Figure 16.1] (61). The CT may also show stenosis or obstruction of the major airways. A peribronchial cuff of soft tissue may be seen (62,63). During the active TB stage, irregular and circumferential luminal narrowing may be visualized. However, during the fibrotic stage, wall thickening is much less prominent and an equal distribution of smooth and irregular narrowing occurs (64,65). The CT may on occasion show enlarged lymph nodes in the mediastinum and other parenchymal lesions, such as segmental collapse, collapse with multiple low density areas, cavities and round low density lesions which most likely represent mucoid impaction distal to obstruction (62,63). An intra-luminal lower density polypoid mass with narrowing may sometimes be seen in a bronchus (62). While the CT is extremely accurate in detecting focal bronchial lesions, it is inaccurate in predicting whether the lesion is endobronchial, submucosal or outside the airway (62,63). In addition, it may not be possible to accurately assess the thickness of the bronchial wall in many cases because of the loss of silhouette of the outer

wall of the involved bronchus by the adjacent consolidation or of the inner wall by the absence of intraluminal air. It is extremely difficult to differentiate endobronchial TB from bronchogenic carcinoma by CT, and therefore, bronchoscopy is ultimately needed. However, CT has the advantage of revealing areas of the airway beyond the stenosis as well as the length of stenosis and the extent of peribronchial soft tissue, lymph nodes involvement (20,66). Thus, CT complements bronchoscopy in evaluating these patients and can also be used to monitor response to treatment (66). While it is very helpful, radiologic findings of endobronchial TB are non-specific and can be seen in other diseases. Conditions that may show bronchial wall thickening and luminal narrowing on CT, like sarcoidosis, amyloidosis, relapsing polychondritis and tracheopathia osteoplastica, should always be kept in mind (64). Evolving radiologic techniques such as multiplanar and 3D helical CT images with reconstruction [virtual bronchoscopy] may play a better role in evaluating the tracheobronchial tree in endobronchial TB (64,65,67,68). Spirometry The most common abnormality seen on spirometry in endobronchial TB is restriction. Lee and Chung (20) evaluated spirometry findings in 68 patients and

Figure 16.1: CT scan of the chest showing “tree-in-bud” pattern seen [arrows] in endobronchial tuberculosis [A]. This pattern refers to peripheral, small centrilobular, and well-defined nodules that are connected to linear, branching opacities that have more than one contiguous branching site, thus, resembling a “tree-in-bud” [arrows] [B]. In histopathologic studies, the “tree-in-bud” appearance correlates well with the presence of plugging of the small airways with mucus, pus, or fluid; dilated bronchioles; bronchiolar wall thickening; and peribronchiolar inflammation

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demonstrated a restrictive abnormality in 47 per cent, obstructive abnormality in 5.9 per cent, mixed in 23.5 per cent, and normal spirometry in 23.5 per cent of the patients. The flow-volume loop abnormalities classically seen in patients with upper airway obstruction are rarely seen in endobronchial TB. Unlike patients with bronchial asthma, patients with endobronchial TB do not have increased bronchial hyper-reactivity to inhaled histamine (69). Bronchoscopy Bronchoscopy is the gold standard for diagnosis of endobronchial TB. The diagnosis can be missed in some cases with normal chest radiograph if bronchoscopy is not considered (70,71). Unlike pre-chemotherapy era where tracheal ulcerations were commonly seen, most of the recent bronchoscopy series report more common involvement of the main-stem and upper lobe bronchi (12,16). Endobronchial biopsies usually reveal the classic histological features of TB. These range from non-necrotic epithelioid cell granulomas with no acid-fast bacilli [AFB] to necrotic granulomas with abundant AFB. Bronchial brushings obtained along with biopsy increase the diagnostic yield (72). Bronchoscopy has been useful in learning about the natural history and progression of endobronchial TB.

Salkin and colleagues (24) presented one of the earliest serial follow-up data and documented the progression of bronchial ulceration to polyp formation and stenosis in three to six months. Bronchostenosis develops in 50 to 90 per cent of patients despite effective therapy (10,19). This complication which can present years after diagnosis and therapy may involve the trachea or main-stem bronchi. Ip and colleagues (10) showed that stenosis developed in all but one of the 12 patients who had a follow-up bronchoscopy within eight to forty-nine months of completing antituberculosis therapy. Eight of these patients were asymptomatic including one who had severe stenosis of the left main-stem bronchus. Several bronchoscopic classifications of endobronchial TB have been proposed (14,19,20,73). The most recent classification by Chung and Lee (19) describes seven forms of bronchoscopic findings [Figure 16.2] (19). Chung and Lee (19) studied 81 patients with endobronchial TB who underwent serial bronchoscopy to examine the predictive value of this classification. Bronchoscopic examination was initially performed every month until there was no subsequent change in the endobronchial lesions followed by an examination every three months until the completion of antituberculosis chemotherapy. Seven forms of bronchoscopic findings are described below.

Figure 16.2: Classification of endobronchial tuberculosis by bronchoscopic findings. Top: A, actively caseating type; B, oedematoushyperaemic type; C, fibrostenotic type; and D, tumorous type. Bottom: E, granular type; F, ulcerative type; and G, non-specific bronchitic type Reproduced with permission from “Chung HS, Lee JH. Bronchoscopic assessment of the evolution of endobronchial tuberculosis. Chest 2000;117:385-92 (reference 19)”

Endobronchial Tuberculosis 237 Non-specific Bronchitic Endobronchial Tuberculosis Only mild mucosal swelling and/or hyperaemia are seen on bronchoscopy in this form. The prognosis is overall good and all cases resolve within two months of treatment. Granular Endobronchial Tuberculosis In this form, the bronchoscopic appearance mimics scattered grains of boiled rice, and the underlying bronchial mucosa shows severe inflammatory changes. Only 20 per cent of the cases develop fibrostenosis. Oedematous-hyperaemic Endobronchial Tuberculosis In the oedematous-hyperaemic form, severe mucosal swelling with surrounding hyperaemia causing narrowing of the bronchial lumen is seen. Patients with these findings have poor prognosis as 60 per cent of cases develop fibrostenosis within two to three months after treatment, and 30 per cent progress to complete obstruction of the bronchial lumen. Actively Caseating Endobronchial Tuberculosis Caseating endobronchial TB is the most commonly seen form and bronchoscopy shows swollen and hyperaemic mucosa that is diffusely covered with whitish cheeselike material. Luminal narrowing at diagnosis is usually seen whether granulation tissue is present or not. A significant improvement of bronchial stenosis is seen with treatment, although 65 per cent of patients progress to fibrostenosis. Ulcerative Endobronchial Tuberculosis This form is characterized by the presence of ulcers in the tracheobronchial tree. The prognosis is generally good as most of the cases will completely resolve within three months of treatment. Fibrostenotic Endobronchial Tuberculosis In the fibrostenotic form, a marked narrowing of the bronchial lumen due to fibrosis is seen and patients show no response to treatment. Progression of fibrosis despite treatment may result in complete obstruction of the bronchial lumen two or three months after treatment. Tumorous Endobronchial Tuberculosis Tumorous endobronchial TB class is characterized by the presence of an endobronchial mass whose surface is often

covered with caseous material. This endobronchial mass may occlude the bronchial lumen and is frequently mistaken for lung cancer. The prognosis of tumorous endobronchial TB is grave and the most unpredictable. Seventy per cent of patients in this report (19) had fibrostenosis at the end of treatment. More tumorous lesions can appear subsequently at different segmental bronchi. The above classification closely correlates to the microscopic changes seen in endobronchial TB. Nonspecific bronchitic endobronchial TB corresponds to the initial lesion, which presents as simple erythema and oedema of the mucosa with lymphocytic infiltration of the submucosa. This is followed by submucosal tubercle formation which produces erythema, granularity and partial bronchial stenosis, seen at bronchoscopy, caused by considerable congestion and oedema of the mucosa. These represent the granular and oedematoushyperaemic type, respectively. With more progressive disease, caseous necrosis with formation of TB granulomas at the mucosal surface is seen and constitutes the actively caseating endobronchial TB. When the inflammation progresses through the mucosa, an ulcer, which may be covered by caseous material, is formed and this represents the ulcerative class. Finally, the bronchial mucosal ulcer may evolve into hyperplastic inflammatory polyps, and the endobronchial tuberculous lesion heals by fibrostenosis, explaining the next two stages seen on bronchoscopy. On rare occasions, TB lymph nodes may rupture into a bronchus (74). In the early stage, the lymph node may be seen as a greyish-yellow mass protruding through the mucosa sometimes obstructing the lumen. The bronchial wall may show haemorrhage and granulation tissue formation. A fistula may subsequently develop in the bronchial wall with caseous material protrusion. The mucous membrane then becomes less inflammed and evacuation of the node occurs. The opening then gradually closes and fibrosis with scarring of the bronchial wall followed by bronchial stenosis may subsequently develop. Perforation of a lymph node into the lumen of a bronchus may present as a pigmented mass or stenotic bronchus with black pigmentation overlying the mucosa (11,39,44,47,75,76). This pigmentation is likely from the anthracotic material in lymph nodes and has been termed “anthracofibrosis” (76). Chung and colleagues (76) demonstrated that 60 per cent of patients whose bronchoscopy showed bronchial

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narrowing and black pigmentation had active TB. Endobronchial TB should be strongly considered when such findings are encountered on bronchoscopy. All forms of endobronchial TB lie between the two ends of the spectrum of healing and fibrostenosis. The extent of disease progression (14) and formation of granulation tissue (11) are important determinants of the different forms and outcome. Bronchial stenosis is inevitable in the presence of progressive disease. Therefore, prompt diagnosis including timely bronchoscopy and efficacious treatment are of paramount importance in order to minimize the progression to bronchial stenosis. The concern of worsening of TB and asphyxiation as a result of aspiration of caseous particles to opposite lung as a result of bronchoscopy should not be a limiting factor to perform a bronchoscopy. These complications have not been described recently, despite the large number of bronchoscopies performed on such individuals (10,16,23). Bronchography Bronchography was once used for the definitive diagnosis and preoperative evaluation of bronchial stenosis (27,77). However, with widespread availability and imporvements in the CT scan this procedure is rarely performed now.

occurs in one to seven per cent of patients with pulmonary TB. It is more commonly seen in patients with diabetes mellitus, pregnancy, chronic renal disease and malignancy. Endobronchial involvement has been reported in up to 75 per cent of these patients (89-95). Therefore, there should be a low threshold to perform a bronchoscopic examination in such patients. The reader is referred to the chapter “Lower lung field tuberculosis” [Chapter 15] for further details. Elderly About 15 per cent of elderly patients with pulmonary TB have concomitant endobronchial TB (45). Many of these cases are diagnosed during a work-up for lung cancer, or non-resolving pneumonia (44,45). The pathogenesis of endobronchial TB in the elderly is believed to be similar as in other age groups. Cough is the most commonly observed symptom. Other symptoms, such as dyspnoea, haemoptysis, chest pain and hoarseness of voice may be present. Constitutional symptoms, such as anorexia, weight loss and fatigue are usually present in most of the patients. Endobronchial appearances are similar to those described in younger subjects. Bronchial stenosis occurs in about 60 per cent of elderly patients with endobronchial TB (45). Human Immunodeficiency Virus Infection

DIFFERENTIAL DIAGNOSIS Presence of an endobronchial mass should always raise the suspicion of malignancy or TB co-existing with malignancy (78), infection with nontuberculous mycobacteria [NTM] (79-85), sarcoidosis (86), actinomycosis (87) and papillomatosis (88). Presence of airway stenosis may be seen in other conditions. Focal stenosis may be a result of previous endotracheal intubation, or various systemic diseases that may involve the airways, such as Crohn’s disease and Behcet’s syndrome (88). Diffuse stenosis of the central airways may be seen in Wegener’s granulomatosis, relapsing polychondritis, tracheobronchopathia osteochondroplastica, amyloidosis, papillomatosis, and rhinoscleroma (88). SPECIAL SITUATIONS Lower Lung Field Tuberculosis Tuberculosis involving the right middle lobe, lingular division of left upper lobe and both lower lobes (89,90)

Endobronchial TB is not uncommon in patients with human immunodeficiency virus [HIV] infection. In one study, six out of 25 HIV-positive patients with TB who underwent bronchoscopy had endobronchial TB (96). Endobronchial TB may be a part of primary infection in patients with HIV, and hilar and mediastinal lymphadenopathy is commonly seen on chest radiograph (9699). Other radiological findings described in these patients include a normal chest radiograph, a miliary pattern and a small pleural effusion. Pulmonary infiltrates are rare (96). The findings on bronchoscopy are similar to those observed in HIV-negative patients, although the tumorous form has been more commonly reported (96-98). Because the tumorous form is likely to be caused by the erosion of a lymph node into a bronchus (19), the higher prevalence of mediastinal and hilar lymphadenopathy in patients with HIV-associated TB may explain why this finding is not uncommon in such patients. Lymph node perforation into the airway in HIV-associated TB has also been described by

Endobronchial Tuberculosis 239 bronchoscopy (96,99). Bronchial stenosis has not been reported in HIV-associated endobronchial TB. Indian Experience Few case reports have been published describing endobronchial TB in Indian adults (100-102). A large study (103) reporting the bronchoscopic findings in 85 Indian children with active TB has been published. In that study, the prevalence of endobronchial TB was 9.4 per cent (103). In a series published by Parmar (93), 42 per cent of the 50 patients with lower lobe TB from a sanatorium in Amritsar were thought to have endobronchial TB based on clinical and radiographic findings, although it was confirmed in five of the 13 patients who underwent a bronchoscopic examination. In a study assessing the usefulness of bronchoalveolar lavage in the diagnosis of sputum smear-negative pulmonary TB from New Delhi, endobronchial TB was not described in any of the 50 adult HIV-negative patients (104). Endobronchial Involvement by Nontuberculous Mycobacteria Endobronchial involvement with NTM is rare and mostly seen in patients with HIV (79-85). Most cases respond to therapy without any residual stenosis. TREATMENT Before the introduction of streptomycin and paraaminosalicylic acid [PAS] for clinical use, the treatment of endobronchial TB lesions involved painting the small ulcers directly with caustic soda or silver nitrate to enhance fibrosis (3,105). These methods, however, caused more fibrosis due to their effect on the surrounding normal tissue (3,105). Salkin et al (24) demonstrated that many of the endobronchial TB ulcers heal when the parenchymal disease is adequately treated. Effective drug therapy and preventive measures have altered the natural history of endobronchial TB (106,107). A high clinical index of suspicion and prompt bronchoscopy are essential for the early diagnosis of this condition, as it can present several years after the actual treatment of pulmonary TB (48,108). Treatment options currently available for patients with endobronchial TB are listed below.

Antituberculosis Treatment Treatment of endobronchial TB is similar to the treatment of pulmonary TB. The reader is referred to the chapter “Treatment of tuberculosis” [Chapter 52]. The addition of inhaled streptomycin (107,109,110) and inhaled isoniazid (111) to the standard therapy has improved outcomes in some studies but their efficacy in large randomized, controlled trials has not yet been evaluated. Corticosteroids Corticosteroids have been used empirically with antituberculosis medications in some cases to prevent bronchial stenosis (10,12,19). Lee and colleagues (12) felt that corticosteroids may suppress the barking cough but may not alter the course of the disease or prevent bronchostenosis. Hypersensitivity reaction associated with antituberculosis medications is another situation where corticosteroid therapy may be beneficial (41,112,113). Local endoscopic injection of corticosteroids in endobronchial tuberculous lesions has been described in one case report (114). Some studies have suggested a positive role for corticosteroid therapy in children with lymph node TB causing bronchial obstruction (115-117). However, the benefit of corticosteroids in this situation remains speculative (10,15) and a recent randomised trial in adults with endobronchial TB failed to show any beneficial effect (118). Bronchoscopy Bronchoscopic procedures are helpful in relieving stenosis if used alone or in combination with chemotherapy depending on the clinical situation in symptomatic patients. Lee and colleagues (12) advocated curettage with forceps during bronchoscopy for the removal of the pseudomembrane. Dilatation of the narrowed airway can be achieved with the use of dilators, balloons or using the bronchoscope itself. Balloon dilatation is usually successful when the stenotic segment is short (14, 119,120). Repeated dilatation of the stenotic segment may be required (23,100). Removal of tissue by forceps and carbon dioxide [CO2] laser, or neodymiumyttrium aluminium garnet [Nd-YAG] laser is useful in some situations (121-123). Following tissue removal and

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dilatation, patency of the stenotic area can be maintained by the placement of self-expanding metallic stent (124-127). Potential complications of such procedures include perforation, injury, stent migration and re-stenosis due to granulation tissue formation (127,128). Endoluminal dilatation and stenting is currently recommended as first-line intervention for managing tracheobronchial stenosis due to TB (126). Surgery In the early part of last century, collapse therapy by inducing a pneumothorax, phrenic nerve paralysis or thoracoplasty [surgical removal of several rib bones from the chest wall in order to collapse a lung] for pulmonary TB was commonly performed. Endobronchial TB was noted to be an exception for the above procedures due to the high incidence of subsequent atelectasis, failure/ delayed lung expansion, empyema and anaerobic infections (129). Pneumonectomy and lobectomy were commonly performed for endobronchial TB in the past, but became unpopular because of high operative mortality of about 27 per cent (129). Recently, new surgical techniques have evolved and several series report a very low mortality when resection along with surgical bronchoplasty [sleeve resection with end-to-end anastomosis] is done (130-135). Surgery should be performed when the patient is no longer considered to have active disease (134). Resection of lung parenchyma should be minimal, as the objective of the surgery is to restore pulmonary function of the hypoventilated lung. The mode of operation is determined by the location, extent and degree of stenosis (134). For lesions involving lobar or segmental bronchi, lobectomy may need to be performed. For lesion involving the trachea or mainstem bronchus, bronchoplastic surgery along with lobectomy [if needed] is performed. Pneumonectomy should be left as the last resort when the involved lung has extensive bronchiectasis/damage from recurrent infections or when the main-stem bronchus is completely obliterated (135). Re-stenosis at the site of anastomosis may occur and repeated bronchoscopic dilatation may be needed (134). The reader is also referred to the chapter “Surgery for pleuropulmonary tuberculosis” [Chapter 55] for more details.

In conclusion, endobronchial TB is a frequently undiagnosed complication of pulmonary TB. It is often overlooked as bronchoscopy, which is the key for diagnosis, is not always performed in these patients (136138). The presentation of endobronchial TB may precede, occur concomitantly or occur up to 17 years after the diagnosis and treatment of pulmonary TB (121). Bronchoscopy should be considered in any patient with a history of pulmonary TB and symptoms suggestive of endobronchial involvement. Treatment involves antituberculosis treatment along with bronchoscopic procedures or surgery as indicated. The role of adjuvant corticosteroids is unclear at this time. REFERENCES 1. Morton R. Phthisiologica, seu exercitationes de phthisi. London: S. Smith; 1689. 2. Cohen AG, Wessler H. Clinical recognition of tuberculosis of major bronchi. Arch Intern Med 1939;63:1132-57. 3. Smart J. Endobronchial tuberculosis. Br J Tuberc Dis Chest 1951;45:61-8. 4. Wilson NJ. Bronchoscopic observations in tuberculosis tracheobronchitis: clinical and pathological correlations. Dis Chest 1945;11:36-59. 5. Danek SJ, Bower JS. Diagnosis of pulmonary tuberculosis by flexible fiberoptic bronchoscopy. Am Rev Respir Dis 1979;119:677-9. 6. Jett JR, Cortese DA, Dines DE. The value of bronchoscopy in the diagnosis of mycobacterial disease: a five year experience. Chest 1981;80:575-8. 7. Wallace JM, Deutsch AL, Harrell JH, Moser KM. Bronchoscopy and transbronchial biopsy in patients with suspected active tuberculosis. Am J Med 1981;70:1189-94. 8. Willcox PA, Benatar SR, Potgieter PD. Use of flexible fiberoptic bronchoscope in diagnosis of sputum-negative pulmonary tuberculosis. Thorax 1982;37:598-601. 9. Stenson W, Aranda C, Bevelaqua FA. Transbronchial biopsy culture in pulmonary tuberculosis. Chest 1983;83:883-4. 10. Ip MS, So SY, Lam WK, Mok CK. Endobronchial tuberculosis revisited. Chest 1986;89:727-30. 11. Smith LS, Schillaci RF, Sarlin RF. Endobronchial tuberculosis. Serial fiberoptic bronchoscopy and natural history. Chest 1987;91:644-7. 12. Lee JH, Park SS, Lee DH, Shin DH, Yang SC, Yoo BM. Endobronchial tuberculosis: clinical and bronchoscopic features in 121 cases. Chest 1992;102:990-4. 13. Kurasawa T, Kuze F, Kawai M, Amitani R, Murayama T, Tanaka E, et al. Diagnosis and management of endobronchial tuberculosis. Intern Med 1992;31:593-8. 14. Kim YH, Kim HT, Lee KS, Uh ST, Cung YT, Park CS. Serial fiberoptic bronchoscopic observations of endobronchial

Endobronchial Tuberculosis 241

15.

16. 17.

18.

19. 20.

21. 22. 23. 24. 25.

26.

27.

28.

29.

30. 31.

32.

33. 34.

tuberculosis before and early after antituberculosis chemotherapy. Chest 1993;103:673-7. Hoheisel G, Chan BK, Chan CH, Chan KS, Teschler H, Costabel U. Endobronchial tuberculosis: diagnostic features and therapeutic outcome. Respir Med 1994;88:593-7. Wang SY, Zhang XS. Endobronchial tuberculosis: report of 102 cases. Chest 1994;105:1910-1. Singla R, Kumar A, Chauhan D, Juneja D, Tyagi VN, Arora VK. Endobronchial tuberculosis presenting as tumorous mass. Indian J Chest Dis Allied Sci 2007;49:45-7. Altin S, Cikrikcioglu S, Morgul M, Kosar F, Ozyurt H. Fifty endobronchial tuberculosis cases based on bronchoscopic diagnosis. Respiration 1997; 64:162-4. Chung HS, Lee JH. Bronchoscopic assessment of the evolution of endobronchial tuberculosis. Chest 2000;117:385-92. Lee JH, Chung HS. Bronchoscopic, radiologic and pulmonary function evaluation of endobronchial tuberculosis. Respirology 2000;5:411-7. Flance IJ, Wheeler PA. Postmortem incidence of tuberculous tracheobronchitis. Am Rev Tuberc 1939;39:633-6. Sweany HC, Behm H. Tuberculosis of the trachea and major bronchi. Dis Chest 1948;14:1. Auerbach O. Tuberculosis of trachea and major bronchi. Am Rev Tuberc 1949;60:604-20. Salkin D, Cadden AV, Edson RC. The natural history of tuberculosis tracheobronchitis. Am Rev Tuberc 1943;47: 351-69. McIndoe RB, Steele JD, Samson PC, Anderson RS, Leslie GL. Routine bronchoscopy in patients with active pulmonary tuberculosis. Am Rev Tuberc 1939;39:617-28. Wilson NJ. Bronchoscopic observations in tuberculous tracheobronchitis: Clinical and pathological correlations. Dis Chest 1945;11:36-59. Jokinen K, Palva T, Nuutinen J. Bronchial findings in pulmonary tuberculosis. Clin Otolaryngol Allied Sci 1977; 2:139-48. So SY, Lam WK, Yu DY. Rapid diagnosis of suspected pulmonary tuberculosis by fiberoptic bronchoscopy. Tubercle 1982;63:195-200. Soni R, Barnes D, Torzillo P. Post obstructive pneumonia secondary to endobronchial tuberculosis: an institutional review. Aust NZ J Med 1999;29:841-2. Stone MJ. Clinical aspects of endobronchial tuberculosis. Dis Chest 1945;11:60-71. Dhillon SS, Watanakunakorn C. Lady Windermere syndrome: middle lobe bronchiectasis and Mycobacterium avium complex infection due to voluntary cough suppression. Clin Infect Dis 2000;30:572-5. Reich JH, Johnson RE. Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern. The Lady Windermere syndrome. Chest 1992;101:1605-9. Reichle HS, Frost TT. Tuberculosis of the major bronchi. Am J Path 1934;10:651-6. Jones EM, Rafferty TN, Willis HS. Primary tuberculosis complicated by bronchial tuberculosis with atelectasis. Am Rev Tuberc Dis 1942;46:392-406.

35. Frostad S. Lymph node perforation through the bronchial tree in children with primary tuberculosis. Acta Tuberc Scan 1959:47[Suppl]:104-24. 36. Chang SC, Lee PY, Perng RP. Clinical role of bronchoscopy in adults with intrathoracic tuberculous lymphadenopathy. Chest 1988;93:314-7. 37. Baran R, Tor M, Tahaoglu K, Ozvaran K, Kir A, Kizkin O, et al. Intrathoracic tuberculous lymphadenopathy: clinical and bronchoscopic features in 17 adults without parenchymal lesions. Thorax 1996;51:87-9. 38. Schwartz P. The role of lymphatics in the development of bronchogenic tuberculosis. Am Rev Tuberc 1953;67:440-52. 39. Arnstein A. Non-industrial pneumoconiosis, pneumoconiotuberculosis and tuberculosis of the mediastinal and bronchial lymph glands in old people. Tubercle 1941;22:281-95. 40. Eloesser L. Bronchial stenosis in pulmonary tuberculosis. Am Rev Tuberc 1934;30:123-80. 41. Williams DJ, York EL, Nobert EJ, Sproule BJ. Endobronchial tuberculosis presenting as asthma. Chest 1988;93:836-8. 42. Caglayan S, Coteli I, Acar U, Erkin S. Endobronchial tuberculosis simulating foreign body aspiration. Chest 1989; 95:1164. 43. Matthews JI, Matarese SL, Carpenter JL. Endobronchial tuberculosis simulating lung cancer. Chest 1984;86:642-4. 44. van den Brande P, Lambrechts M, Tack J, Demedts M. Endobronchial tuberculosis mimicking lung cancer in elderly patients. Respir Med 1991;85:107-9. 45. van den Brande PM, Van De Mierop F, Verben EK, Demedts M. Clinical spectrum of endobronchial tuberculosis in elderly patients. Arch Intern Med 1990;150:2105-8. 46. Lynch JP, Ravikrishnan KP. Endobronchial mass caused by tuberculosis. Arch Intern Med 1980;140:1090-1. 47. Yee A, Hardwick JA, Wasef E, Sharma OP. Pigmented polypoid obstructive endobronchial tuberculosis. Chest 1985; 87:702-3. 48. Albert RK, Petty TL. Endobronchial tuberculosis progressing to bronchial stenosis. Fiberoptic bronchoscopic manifestations. Chest 1976;70:537-9. 49. So SY, Lam WK, Sham MK. Bronchorrhea. A presenting feature of active endobronchial tuberculosis. Chest 1983;84:6356. 50. Park MJ, Woo IS, Son JW, Lee SJ, Kim DG, Mo EK, et al. Endobronchial tuberculosis with expectoration of tracheal cartilages. Eur Respir J 2000;15:800-2. 51. Memon AM, Shafi A, Thawerani H. Endobronchial tuberculosis-manifesting by coughing up of bronchial cartilage. J Pak Med Assoc 1996;46:86-8. 52. Yilmaz E, Akkoclu A, Sevinc C. CT and MRI appearance of a fistula between the right and left main bronchus caused by tracheobronchial tuberculosis. Br J Radiol 2001;74:1056-8. 53. Seiden HS, Thomas P. Endobronchial tuberculosis and its sequelae. Can Med Assoc J 1981;124:165-9. 54. Pierson DJ, Lakshminarayan S, Petty TL. Endobronchial tuberculosis. Chest 1973;64:537-9. 55. Volckaert A, Roels P, Van Der Niepen P, Schandevyl W. Endobronchial tuberculosis: report of three cases. Eur J Respir Dis 1987;70:99-101.

242

Tuberculosis

56. Watson JM, Ayres JG. Tuberculous stenosis of the trachea. Tubercle 1988; 69:223-6. 57. Shipman SJ. Diagnostic bronchoscopy in occult tuberculosis. Am Rev Tuberc 1939;39:629-32. 58. Golshan M. Tuberculous bronchitis with normal chest-X ray among a large bronchoscoic population. Ann Saudi Med 2002;22:98-101. 59. Long R, Maycher B, Dhar A, Manfreda J, Hershfield E, Anthonisen N. Pulmonary tuberculosis treated with directly observed therapy: serial changes in lung structure and function. Chest 1998;113:933-43. 60. Gruden JF, Webb WR, Warnock M. Centrilobular opacities in the lung on high-resolution CT: diagnostic considerations and pathologic correlation. AJR Am J Roentgenol 1994;162:569-74. 61. Im JG, Itoh H, Shim YS, Lee JH, Ahn J, Han MC, et al. Pulmonary tuberculosis: CT findings–early active disease and sequential change with antituberculous therapy. Radiology 1993;186:653-60. 62. Lee KS, Kim WS, Hwang SH, Kim PN, Lee BH. Endobronchial tuberculosis: CT features. J Comput Assist Tomogr 1991;15:424-8. 63. Naidich DP, Lee JJ, Garay SM, McCauley DI, Aranda CP, Boyd AD. Comparison of CT and fiberoptic bronchoscopy in the evaluation of bronchial disease. AJR Am J Roentgenol 1987;148: 1-7. 64. Kim Y, Lee KS, Yoon JH, Chung MP, Kim H, Kwon OJ, et al. Tuberculosis of the trachea and main bronchi: CT findings in 17 patients. AJR Am J Roentgenol 1997;168:1051-6. 65. Moon WK, Im JG, Yeon KM, Han MC. Tuberculosis of the central airways: CT findings of active and fibrotic disease. AJR Am J Roentgenol 1997;169:649-53. 66. Choe KO, Jeong HJ, Sohn HY. Tuberculous bronchial stenosis: CT findings in 28 cases. AJR Am J Roentgenol 1990;155:9716. 67. Finkelstein SE, Summers RM, Nguyen DM, Stewart JH 4th, Tretler JA, Schrump DS. Virtual bronchoscopy for evaluation of malignant tumors of the thorax. J Thorac Cardiovasc Surg 2002;123:967-72. 68. Lee KS, Yoon JH, Kim TK, Kim JS, Chung MP, Kwon OJ. Evaluation of tracheobronchial disease with helical CT with multiplanar and three-dimensional reconstruction: correlation with bronchoscopy. Radiographics 1997;17:555-70. 69. Park CS, Kim Ku, Lee SM, Jeong SW, Uh S, Kim HT, et al. Bronchial hyperreactivity in patients with endobronchial tuberculosis. Respir Med 1995;89:419-22. 70. Schmidek HH, Hardy MA. Pulmonary tuberculosis with normal chest radiographs: report of eight cases. Can Med Assoc J 1967;67:178-80. 71. Husen L, Fulkerson LL, Del Vecchio E, Zack MB, Stein E. Pulmonary tuberculosis with negative findings on chest-X ray films: a study of 40 cases. Chest 1971;60:540-2. 72. Fang X, Ma B, Yang X. Bronchial tuberculosis. Cytologic diagnosis of fiberoptic bronchoscopic brushings. Acta Cytol 1997;41:1463-7.

73. Rikimaru T, Kinosita M, Yano H, Ichiki M, Watanabe H, Shirasi T, et al. Diagnostic features and therapeutic outcome of erosive and ulcerous endobronchial tuberculosis. Int J Tuber Lung Dis 1998; 2:558-62. 74. Kraan JK, Muller S. Perforation of tuberculosis gland into a bronchus. Acta Tuber Scand 1950;24:88-102. 75. Abrahams GC. Atelectasis of right middle lobe resulting from perforation of tuberculous lymph node into bronchi in adults. Ann Intern Med 1951;35:820-35. 76. Chung MP, Lee KS, Han J, Kim H, Rhee CH, Han YC, Kwon OJ. Bronchial stenosis due to anthracofibrosis. Chest 1998;113:344-50. 77. Rose RM, Cardona J, Daly JF. Bronchographic sequelae of endobronchial tuberculosis. Ann Otol Rhinol Laryngol 1965;74:1133-43. 78. Gopalakrishnan P, Miller JE, McLaughlin JS. Pulmonary tuberculosis and coexisting carcinoma: a 10-year experience and review of the literature. Am Surg 1975;41:405-8. 79. Connolly MG Jr, Baughman RP, Dohn MN. Mycobacterium kansasii presenting as an endobronchial lesion. Am Rev Respir Dis 1993;148:1405-7. 80. Quieffin J, Poubeau P, Laaban JP, Brechot JM, Capron F, Rochemaure J. Mycobacterium kansasii infection presenting as an endobronchial tumor in a patient with the acquired immune deficiency syndrome. Tuber Lung Dis 1994;75:3135. 81. Asano T, Itoh G, Itoh M. Disseminated Mycobacterium intracellulare infection in an HIV-negative, nonimmunosuppressed patient with multiple endobronchial polyps. Respiration 2002;69:175-7. 82. Shih JY, Wang HC, Chiang IP, Yang PC, Luh KT. Endobronchial lesions in a non-AIDS patient with disseminated Mycobacterium avium-intracellulare infection. Eur Respir J 1997;10:497-9. 83. Cordasco EM Jr, Keys T, Mehta AC, Mehle ME, Longworth DL. Spontaneous resolution of endobronchial Mycobacterium avium-intracellulare infection in a patient with AIDS. Chest 1990;98:1540-2. 84. Mehle ME, Adamo JP, Mehta AC, Wiedemann HP, Keys T, Longworth DL. Endobronchial Mycobacterium avium-intracellulare infection in a patient with AIDS. Chest 1989;96:199201. 85. Lambert GW, Baddour LM. Right middle lobe syndrome caused by Mycobacterium fortuitum in a patient with human immunodeficiency virus infection. South Med J 1992;85:7679. 86. Hsu JT, Cottrell TS. Pulmonary sarcoidosis: unilateral hilar adenopathy presenting as an endobronchial tumor. Case report. Radiology 1971;98:385-6. 87. Lee SH, Shim JJ, Kang EY, Lee SY, Jo JY, In KH, et al. Endobronchial actinomycosis simulating endobronchial tuberculosis: a case report. J Korean Med Sci 1999;14:315-8. 88. Prince JS, Duhamel DR, Levin DL, Harrell JH, Friedman PJ. Nonneoplastic lesions of the tracheobronchial wall: radiologic findings with bronchoscopic correlation. Radiographics 2002;22:S215-30.

Endobronchial Tuberculosis 243 89. Chang SC, Lee PY, Perng RP. Lower lung field tuberculosis. Chest 1987;91:230-2. 90. Chang SC, Lee PY, Perng RP. The value of roentgenographic and fiberbronchoscopic findings in predicting outcome of adults with lower lung field tuberculosis. Arch Intern Med 1991;151:1581-3. 91. Rothstein E. Pulmonary tuberculosis involving the lower lobes. Am Rev Tuberc 1949;59:39-49. 92. Segarra F, Sherman DS, Rodriguez-Aguero J. Lower lung field tuberculosis. Am Rev Respir Dis 1963;87:37-40. 93. Parmar MS. Lower lung field tuberculosis. Am Rev Respir Dis 1967;96:310-3. 94. Pratt Johnson JH. Observations on lower lobe tuberculosis. Br J Dis Chest 1959;53:385-9. 95. Khan MA, Kovnat DM, Bachus B, Whitcomb ME, Brody JS, Snider GL. Clinical and roentgenographic spectrum of pulmonary tuberculosis in the adult. Am J Med 1977;62:318. 96. Calpe JL, Chiner E, Larramendi CH. Endobronchial tuberculosis in HIV-infected patients. AIDS 1995;9:1159-64. 97. Maguire GP, Delorenzo LJ, Brown RB, Davidian MM. Endobronchial tuberculosis simulating bronchogenic carcinoma in a patient with the acquired immunodeficiency syndrome. Am J Med Sci 1987;294:42-4. 98. Wasser LS, Shaw GW, Talavera W. Endobronchial tuberculosis in the acquired immunodeficiency syndrome. Chest 1988;94:1240-4. 99. Alame T, Dierckx P, Carlier S, Sergysels R. Lymph node perforation into the airway in AIDS-associated tuberculosis. Eur Respir J 1995;8:658-60. 100. Guleria R, Behera D, Dhaliwal RS, Jindal SK. Tracheobronchial stenosis–report of 3 cases. Indian J Chest Dis Allied Sci 1991;33:165-70. 101. Guleria R, Gupta R, Pande JN. Endobronchial tuberculosis simulating lung cancer. Indian J Chest Dis Allied Sci 1997;39:251-4. 102. Gupta A, Narasimhan KL. Endobronchial tuberculosis and the surgeon [Letter]. Indian Pediatr 2002;39:977. 103. Joshi S, Malik S, Kandoth PW. Diagnostic and therapeutic evaluation of bronchoscopy. Indian J Pediatr 1995;62:83-7. 104. Mohan A, Pande JN, Sharma SK, Rattan A, Guleria R, Khilnani GC. Bronchoalveolar lavage in pulmonary tuberculosis: a decision analysis approach. QJM 1995;88:269-76. 105. Judd AR. Tuberculous tracheobronchitis. J Thoracic Surg 1947;16:512-23. 106. Medical Research Council. Streptomycin treatment of tuberculous lesions of the trachea and bronchi. Lancet 1951;1:2537. 107. Brewer LA, Bogen E. Streptomycin in tuberculous tracheobronchitis. Am Rev Tuberc 1947;56:408-14. 108. Tse CY, Natkunam R. Serious sequelae of delayed diagnosis of endobronchial tuberculosis. Tubercle 1988;69:213-6. 109. Rikimaru T, Tanaka Y, Ichikawa Y, Oizumi K. Endoscopic classification of tracheobronchial tuberculosis with healing processes. Chest 1994;105:318-9.

110. Rikimaru T, Koga T, Sueyasu Y, Ide S, Kinosita M, Sugihara E, et al. Treatment of ulcerative endobronchial tuberculosis and bronchial stenosis with aerosolized streptomycin and steroids. Int J Tuberc Lung Dis 2001;5:769-74. 111. Yokota S, Miki K. Effects of INH [Isoniazid] inhalation in patients with endobronchial tuberculosis [EBTB]. Kekkaku 1999;74:873-7. 112. Chan HS, Pang JA. Effect of corticosteroids on deterioration of endobronchial tuberculosis during chemotherapy. Chest 1989;96:1195-6. 113. Chan HS, Sun A, Hoheisel GB. Endobronchial tuberculosis is corticosteroid treatment useful? A report of 8 cases and review of literature. Postgrad Med J 1990;66:822-6. 114. Verhaeghe W, Noppen M, Meysman M, Monsieur I, Vincken W. Rapid healing of endobronchial tuberculosis by local endoscopic injection of corticosteroids. Monaldi Arch Chest Dis 1996;51:391-3. 115. Toppet M, Malfroot A, Derde MP, Toppet V, Spehl M, Dab I. Corticosteroids in primary tuberculosis with bronchial obstruction. Arch Dis Child 1990;65:1222-6. 116. Nemir RL, Cardona J, Lacoius A, David M. Prednisone therapy as an adjunct in the treatment of lymph node bronchial tuberculosis in childhood. Am Rev Tuberc 1963;88:18998. 117. Nemir RL, Cardona J, Vaziri F, Toledo R. Prednisone as an adjunct in the chemotherapy of lymph node–bronchial tuberculosis in childhood: a double-blind study. II. Further term observation. Am Rev Respir Dis 1967;95:402-10. 118. Park IW, Choi BW, Hue SH. Prospective study of corticosteroid as an adjunct in the treatment of endobronchial tuberculosis in adults. Respirology 1997;2:275-81. 119. Ball JB, Delaney JC, Evans CC, Donnelly RJ, Hind CR. Endoscopic bougie and balloon dilatation of multiple bronchial stenoses: 10-year follow up. Thorax 1991;46:933-5. 120. Chhajed PN, Malouf MA, Glanville AR. Bronchoscopic dilatation in the management of benign [non-transplant] tracheobronchial stenosis. Intern Med J 2001;31:512-6. 121. Tong MC, van Hasselt CA. Tuberculous tracheobronchial strictures: clinicopathological features and management with the bronchoscopic carbon dioxide laser. Eur Arch Otorhinolaryngol 1993;250:110-4. 122. Mariotta S, Guidi L, Aquilini M, Tonnarini R, Bisetti A. Airway stenosis after tracheo-bronchial tuberculosis. Respir Med 1997;91:107-10. 123. Lur AC, Mehta AC, Golish JA. Upper airway obstruction due to tuberculosis. Treatment by photocoagulation. Postgrad Med 1985;78:275-8. 124. Han JK, Im JG, Park JH, Han MC, Kim YW, Shim YS. Bronchial stenosis due to endobronchial tuberculosis: successful treatment with self-expanding metallic stent. AJR Am J Roentgenol 1992;159:971-2. 125. Nomori H, Horio H, Suemasu K. Bougienage and balloon dilation using a conventional tracheal tube for tracheobronchial stenosis before stent placement. Surg Endosc 2000;14:587-91.

244

Tuberculosis

126. Wan IY, Lee TW, Lam HC, Abdullah V, Yim AP. Tracheobronchial stenting for tuberculous airway stenosis. Chest 2002;122:370-4. 127. Yim AP, Abdullah V, Izzat MB, van Hasselt CA. Videoassisted interventional bronchoscopy. The Hong Kong experience. Surg Endosc 1998;12:444-7. 128. Nomori H, Horio H, Suemasu K. Granulation stenosis caused by a Dumon stent placed for endobronchial tuberculous stenosis. Surg Laparosc Endosc Percutan Tech 2000;10:41-3. 129. Overholt RH, Wilson NJ. Pulmonary resection for tuberculosis complicated by tuberculous bronchitis [Preliminary report]. Dis Chest 1945;11:72-91. 130. Caligiuri PA, Banner AS, Jensik RJ. Tuberculous main stem bronchial stenosis treated with sleeve resection. Arch Intern Med 1984;144:1302-3. 131. Natkunam R, Ong BH, Tse CY, Sriragavan P. Carinal resection for stenotic tuberculous tracheitis. Thorax 1988;43: 491-3. 132. Mellem H, Boye NP, Arnkvaern R, Fjeld NB. Stenotic tuberculous tracheitis treated with resection and anastomosis. Eur J Respir Dis 1986;68:224-5.

133. Watanabe Y, Murakami S, Iwa T. Bronchial stricture due to endobronchial tuberculosis. Thorac Cardiovasc Surg 1988;36:27-32. 134. Kato R, Kakizaki T, Hangai N, Sawafuji M, Yamamoto T, Kobayashi T, et al. Bronchoplastic procedures for tuberculous bronchial stenosis. J Thorac Cardiovasc Surg 1993;106:111821. 135. Watanabe Y, Murakami S, Oda M, Hayashi Y, Ohta Y, Shimizu J, et al. Treatment of bronchial stricture due to endobronchial tuberculosis. World J Surg 1997;21:480-7. 136. Agerton T, Valway S, Gore B, Pozsik C, Plikaytis B, Woodley C, et al. Transmission of a highly drug-resistant strain [strain w1] of Mycobacterium tuberculosis: community outbreak and nosocomial transmission via a contaminated bronchoscope. JAMA 1997; 278:1073-7. 137. World Health Organization. Guidelines for the prevention of tuberculosis in health care facilities in resource-limiting settings. Geneva: World Health Organization; 1999.p.1-51. 138. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 1994. MMWR 1994;43:1-132.

Tuberculosis Pleural Effusion

17 AN Aggarwal

INTRODUCTION The frequency of tuberculosis [TB] as a cause of pleural effusion depends on the prevalence of TB in a particular population. In many regions of the world where TB is more common, TB pleural effusion maintains its position as the leading inflammatory pleural disease (1-8). In fact, pleural disease is one of the most common extra-pulmonary involvement in TB in developing countries (9,10). The increasing prevalence of human immunodeficiency virus [HIV] infection in some of these geographical locations may be an additional factor explaining the higher frequency of TB pleural effusion (4,7). The entity is relatively uncommon in the developed world where prevalence of TB is low (11-14). For example, in the USA the incidence of TB pleural effusion has been estimated to be only about one in 1000 cases. Furthermore, in the USA, TB pleural effusion accounts for approximately one in every 30 cases of TB and this ratio has remained constant even after the advent of the acquired immunodeficiency syndrome [AIDS] epidemic (12). However, there is some evidence that these low figures may be an underestimation of the true disease burden in the general population (15). PATHOGENESIS AND IMMUNOLOGY Tuberculosis may affect the pleura at different stages of pulmonary or systemic disease by various mechanisms. Tuberculosis pleural effusion may represent a manifestation of either primary infection or reactivation of latent disease, the latter being more common (16). Pleural effusion is believed to occur secondary to the rupture of a subpleural caseous focus in the lung [or less commonly

a lymph node] into the pleural space. Supportive evidence comes from the operative findings of Stead and co-workers (17), who could demonstrate such a focus in lung contiguous to the pleura in 12 of 15 patients with TB pleuritis; the remaining patients had parenchymal TB, although this focus was not adjacent to the pleura. More recently, such foci have been demonstrated on thoracic computed tomography [CT] in patients with TB pleural effusion (18). Possibly, rupture of such a focus allows the tubercular protein to enter the pleural space and generate hypersensitivity responsible for most clinical manifestations. Pleural effusions may also be seen with direct contiguous spread of the disease to the pleura or by haematogenous spread (11). Occasionally, it can also occur as a complication of thoracic vertebral tuberculosis with paravertebral cold abscess. Tuberculosis osteitis of the rib may also be associated with pleural effusion. One might speculate that the intense pleural inflammation and consequently increased vascular permeability would provide an obvious and satisfying explanation for fluid retention. However, at least in animal models, no significant alterations in vascular permeability have been demonstrated (19). It is now believed that the intense inflammatory reaction obstructs the lymphatic pores in the parietal pleura, causing proteins to accumulate in pleural space with subsequent retention of fluid (19,20). Delayed hypersensitivity, rather than a TB infection per se, plays an important role in the development of TB pleural effusion. This explains the poor rate of isolation of mycobacteria from pleural fluid samples from these patients [vide infra]. Pleural effusion has been shown to

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develop in non-sensitized animals that have received cells from immunized animals. Similarly, on administration of anti-lymphocyte serum, pleural effusion does not develop in sensitized animals (19,21). Tuberculosis pleural fluid is also rich in several potentially immunoreactive cells and substances that contribute to the vigorous local cell mediated immune response (22,23). Mycobacterial antigens enter the pleural space and interact with Tlymphocytes previously sensitized to mycobacteria, resulting in delayed hypersensitivity reaction and accumulation of fluid. Several investigators have demonstrated T-lymphocytes specifically sensitized to protein[s] of Mycobacterium tuberculosis in TB pleural fluid (24-27). The concentration of such lymphocytes in pleural fluid is nearly eight-fold than that found in the peripheral blood (26). It is not clear whether this represents sequestration of these cells from peripheral blood into pleural space, or local expansion in the pleural cavity. In addition, these lymphocytes show greater responsiveness to purified protein derivative [PPD], and when cocultured with PPD, produce far greater levels of cytokines than do peripheral blood lymphocytes (25,28). The ratio of CD4+ [helper-inducer] to CD8+ [suppressor/ cytotoxic] lymphocytes is also much higher in TB pleural fluid as compared to peripheral blood [3:4 vs 1:7] (22,29). Patients with TB pleural effusion have significantly higher interferon-γ [IFN-γ] levels in their pleural fluid than in peripheral blood, thus exhibiting localization of predominantly T-helper cell type 1 [Th1] type immunity in the pleural space (29,30). Based on experimental evidence, the sequence of immunological processes involved in TB pleuritis has recently been described in terms of a three-stage pattern of cellular and granulomatous tissue reactions. Experimental data suggest that neutrophils are the first cells responding to mycobacterial protein in the pleural space. When intrapleural bacille Calmette-Guerin [BCG] is administered to previously BCG-sensitized animals, the resultant pleural fluid is rich in neutrophils in the first 24 hours (31). The accumulation of pleural fluid and inflammatory cells is markedly decreased in neutropenic animals, and appears to be restored by intrapleural injection of neutrophils. Any trigger mechanism that allows access of mycobacterial protein to the pleura will set off a rapid mesothelial-cell initiated and interleukin8 [IL-8] mediated polymorphonuclear neutrophil cell influx, within a few hours. In addition, macrophages and

blood-recruited monocytes determine this early stage with the predominant expression of pro-inflammatory chemokines interleukin-1 [IL-1], interleukin-6 [IL-6] and tumour necrosis factor [TNF]. In animal models, after the initial neutrophil-rich phase, macrophages predominate in the pleural fluid from second to fifth day (31). Neutrophils in pleural space appear to secrete a monocyte chemotaxin that recruits monocytes to the pleural space and helps in granuloma formation (31). In addition, mesothelial cells may also play an important role. Animal models have shown that mesothelial cells stimulated with BCG or IFN-γ produce macrophage inflammatory protein and monocyte chemotactic peptides, and that these two proteins account for more than 75 per cent of the mononuclear chemotactic factor in the TB pleural fluid (32,33). After three to four days, in the following intermediary stage, lymphocytes are the prominent cell in the pleural fluid (34). They are mostly T-cells comprising CD4+ helper cells as well as CD8+ cytotoxic cells with a CD4+/CD8+ ratio of about 4.3, and so-called unconventional cells including T-cell receptor double-negative [DN] αβ T-cells and γδ T-cells [Figure 17.1] (35,36). A strong promoter of macrophage activation and granuloma formation, IFN-γ, together with TNF-α are the predominant cytokines at this stage. Initially these lymphocytes do not respond to PPD. However, reactivity is restored over the next few days, and parallels the reactivity of lymphocytes in the peripheral blood (37). Lymphocyte activation can occur in the pleura of some patients who fail to react to cutaneous PPD, a fact that is explained by the presence in the circulation of suppressor cells that inhibit response in the skin; these suppressor cells are apparently lacking in the pleural fluid (24). Helper T-cells in pleural fluid express a battery of homing receptors such as CD11a, CCR5 and CXCR3, which are important in modulating cell trafficking and recruitment to pleural space and tissue (36). The late phase of TB pleural effusion is characterized by an equilibrated and sustained CD4+/CD8+ cell-based response with persistent IFN-γ release and consequent granuloma formation that is modulated by the release of Th1-cells [Figure 17.1] supporting interleukin-12 [IL-12] and counter-regulatory anti-inflammatory cytokines such as interleukin-10 [IL-10] and transforming growth factor-β [TGF-β]. Recent data also suggest a hierarchial role of CXCR3+ T-cells and crucial role of chemokines in the selective recruitment of Th1 like cells in TB pleural effusion (38).

Tuberculosis Pleural Effusion 247

Figure 17.1: Enrichment of Th1-like antigen-specific memory cells in tuberculosis pleural effusion and DTH sites [a] Frequency of naive [CD45RA+] and memory [CD45RA–] helper [CD4 gated] T-cells in peripheral and pleural compartments of 19 tuberculosis patients. Inset shows one representative FACS histogram of naive and memory T-cells in peripheral blood lymphocytes [solid line] and pleural fluid [dotted line], respectively; [b] lymphoproliferative response of peripheral and pleural fluid-derived T-cells from nine tuberculosis patients to Mycobacterium tuberculosis [EA = Erdman’s antigen]. Error bar depicts mean ± SEM; [c] profile of intracellular designate polarized cytokines [gamma interferon and interleukin-4] in peripheral and pleural helper T-cells following in vitro stimulation; and [d] statistical representation of frequencies of Th1 like and Th2 like T-cells in peripheral and pleural compartment of 19 patients with tuberculosis pleural effusion. Cells were gated on CD45RA– helper subset Reproduced with permission from “Mitra DK, Sharma SK, Dinda AK, Bindra MS, Madan B, Ghosh B. Polarized helper T cells in tubercular pleural effusion: phenotypic identity and selective recruitment. Eur J Immunol 2005;35:2367-75 (reference 36)”

Recent studies have improved our understanding of the immunological pathways involved in TB pleuritis. After phagocytosing mycobacteria, macrophages act as antigen presenting cells and present TB antigen to T-lymphocytes. This results in activation of T-lymphocytes and subsequent promotion of macrophage differentiation and granuloma formation. Some components of the mycobacterial cell wall, such as protein/

proteoglycan complex and lipoarabinomannan, can stimulate macrophages to produce TNF-α, which regulates granuloma formation (39). Activated pleural macrophages can also produce IL-1 which along with TNF-α is involved in lymphocyte activation (40). On exposure to mycobacterial antigens, pleural T-lymphocytes produce IFN-γ, which is an important activator of macrophage killing capacity, as well as interleukin-2

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[IL-2] which is a regulator of T-cell proliferation (40,41). Cytotoxic cell activity could be an additional defense mechanism. The CD4+ and natural killer cells present in pleural fluid of these patients demonstrate cytotoxic activity when stimulated with PPD (42,43). On the other hand, there is also a strong evidence that infectious invasion of the pleural space actually occurs at a substantial, albeit variable degree. At thoracoscopy, even with negative fluid studies, extensive inflammatory granuloma formation and fibrin deposits with unexpected abundant recovery of mycobacteria are a common finding (44). Also, the increasingly emerging evidence of a preferred association of TB pleurisy with reactivated TB in Western populations may be interpreted in favour of true infectious mechanisms (16). Thus, the concept of exudative pleurisy representing exclusively delayed hypersensitivity may not hold true. Infectious as well as immunological mechanisms are obviously closely interrelated and operative in complex patterns. CLINICAL MANIFESTATIONS Tuberculosis pleural effusion is typically a disease of young men (45,46). Patients with post-primary pleural effusion secondary to reactivation tend to be older than those with progressive primary pleural effusion (16). The clinical presentation of TB pleural effusion may vary from an acute illness simulating bacterial pneumonia to an indolent disease first suspected on a chest radiograph in a patient with minor constitutional symptoms. Tuberculosis pleuritis occurs as an acute illness in about twothirds of cases, with symptoms often of less than a month’s duration (47-49). In fact, the illness often mimics bacterial pneumonia with parapneumonic effusion (49). As a general rule an acute illness is more likely to occur in younger and the more immune-competent patients. Older patients more frequently present with an insidious onset of symptoms (48). Tuberculosis pleuritis is a more chronic process in patients with reactivation disease than in those with classic pleuritis. Non-productive cough [70%] and chest pain [75%] are the two most common symptoms at presentation (49). If both cough and pleuritic chest pain are present, the pain usually precedes the cough (48). Despite the frequency of pleuritic chest pain, a pleural friction rub is unusual. The patient is usually febrile, but absence of fever does not rule out the disease (49). Other systemic manifestations include night sweats,

weakness, weight loss, anorexia and fatigue. Physical examination usually provides only non-specific signs of pleural effusion, including dullness to percussion and the occasional demonstration of a pleural rub at auscultation. Untreated, this effusion will usually resolve spontaneously. RADIOLOGY Tuberculosis pleural effusion is unilateral in more than 90 per cent instances, and usually small to moderate in size, although it may occupy the entire hemithorax (46,49,50). Although conventionally regarded as a rare cause of massive pleural effusion, recent data suggest that TB may represent more than 10 per cent of all cases of large pleural effusion in high prevalence areas (51,52). In up to half of these patients, co-existing parenchymal disease can be demonstrated by conventional chest radiographs (46,49). In such patients, the pleural effusion is almost always on the side of the parenchymal infiltrate and invariably indicates active parenchymal disease [Figure 17.2]. In three-fourths of such cases, the parenchymal disease is located in the upper lobe, suggestive of reactivation TB (53). In the remaining patients, the parenchymal disease involves the lower lobe and resembles primary disease. It is likely that even in cases with no radiographic evidence of parenchymal involvement, the effusion is associated with a subpleural focus of infection. If carefully searched for, thoracic CT can demonstrate this subpleural focus in many such patients (18,54). Computed tomography is more sensitive than chest radiography, showing parenchymal disease in over 80 per cent of cases. Almost half of these patients have smooth pleural thickening exceeding 1 cm on a thoracic CT; involvement of mediastinal pleura is uncommon (54). Classically, TB pleural effusion associated with acute symptoms and the absence of radiographically evident parenchymal lung disease has been felt to represent primary infection. By contrast, TB effusion that is associated with an indolent course and with parenchymal lung disease on the chest radiograph has been seen more frequently in older patients and has been considered to be a manifestation of post-primary [reactivation] disease (55) [Figure 17.2]. However, such a clear-cut distinction between primary and reactivation disease cannot always be made with confidence based solely on chest radiography (55).

Tuberculosis Pleural Effusion 249

Figure 17.2: Chest radiograph [postero-anterior view] of a woman being investigated for pulmonary tuberculosis showing a right sided mid zone lesion [A]. Sputum examination was non-contributory, but bronchoalveolar lavage showed presence of acid-fast bacilli. During the course of her evaluation, she developed ipsilateral exudative pleural effusion [B]. Both pulmonary and pleural lesions responded to antituberculosis therapy

Conventional chest radiography requires fluid amounts of at least 200 ml to become detectable as blunting of the costophrenic angle in standard projections. Thoracic ultrasonography may detect much smaller effusions. Specific advantages of ultrasonography include more precise volumetry than by chest radiography, localization of septae, membranes and pleural thickening, along with its clinical versatility for bedside diagnosis and in addition intervention guidance on demand. DIAGNOSIS The step-wise diagnosis of TB pleural effusion is essentially the same as for any other exudative pleural effusion. An initial diagnostic thoracocentesis is always indicated. The diagnosis of TB pleural effusion can be difficult because of the low sensitivity of various diagnostic tools. No single laboratory test has 100 per cent sensitivity and specificity for diagnosis of TB pleural effusion. Most patients undergo a battery of investigations, and the diagnosis is often established after careful consideration of clinical features and results of several laboratory parameters (55-58). Despite a comprehensive

evaluation, almost 20 per cent of TB pleural effusions will defy a definitive diagnosis. A brief diagnostic approach is outlined in Figure 17.3. Sputum Examination Only a minority of patients with TB pleural effusion are sputum smear-positive for acid-fast bacilli [AFB]. Sometimes, AFB can be demonstrated even in patients with no radiographic evidence of pulmonary involvement (59). Sputum cultures grow mycobacteria in 30 to 50 per cent of patients having both pulmonary and pleural TB (49,60). However, cultures are positive in less than five per cent of patients with isolated TB pleural effusion (61). The yield of sputum cultures obtained after sputum induction may be much higher even in patients with no apparent radiological parenchymal lesions (62). Tuberculin Skin Test In populations with a low prevalence of TB infection, a positive tuberculin skin test [TST] in a patient with exudative pleural effusion strongly suggests the diagnosis of TB, whereas the diagnostic value of a positive test in countries with a high prevalence of TB is lower.

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Figure 17.3: Algorithm for diagnosis of tuberculosis pleural effusion TB = tuberculosis; ADA = adenosine deaminase; AFB = acid-fast bacilli; ATT = antituberculosis treatment; PCR = polymerase chain reaction; +ve = positive; – = negative

The TST is positive in majority of patients, but a negative test does not rule out the diagnosis. About 30 to 50 per cent patients can demonstrate a negative skin test at initial evaluation (46,49,63). Such negative tests may be

even more common in HIV-infected patients (64). This anergy to PPD appears to be due to an antigen-specific extrapleural immunosuppression. Although pleuritis is considered to be related to a delayed hypersensitivity,

Tuberculosis Pleural Effusion 251 circulating adherent cells in the acute phase of the disease may suppress the specifically sensitized T-lymphocytes in the peripheral blood and in the skin [but not in the pleural fluid], accounting for the negative results in these patients (24). Anergy may occasionally result from pleural compartmentalization of PPD-sensitized lymphocytes occurring in the early phase of infection, resulting in a relative depletion of these cells in the circulation. If the patient is not anergic or immunosuppressed, the skin test will almost always become positive within eight weeks of the development of the symptoms. Pleural Fluid Analysis The pleural fluid in TB pleuritis is invariably a serous [serosanguinous in less than 10%] exudate. Frequently, the pleural fluid protein level exceeds 5 g/dl (63,65). Chemical analysis of the fluid is otherwise of a limited value. Although in the past it was observed that the pleural fluid glucose was reduced in most patients with TB pleural effusion (66), more recent studies show that majority of patients have a pleural fluid glucose of more than 60 mg/dl (49,61). A low pleural fluid pH was once thought to be suggestive of TB pleural effusion, but subsequent reports have not confirmed this (67-69). Glucose and pH values are in general not substantially different from exudates due to other aetiologies, and their diagnostic significance has probably been over-estimated in the past. In most patients, the pleural fluid differential cell count reveals more than 50 per cent lymphocytes. In a series of 49 patients, only five had fewer than 50 per cent lymphocytes in the pleural fluid (49). In fact, the overwhelming predominance of lymphocytes on preparations examined cytologically can sometimes result in a misdiagnosis of lymphoma (70). The percentage and absolute numbers of CD4+ T-lymphocytes in pleural fluid are higher than in the blood (71-74); by contrast, the percentage and number of B-lymphocytes are significantly lower (25,26,75). However, the separation of lymphocytes into T and B subsets is not useful diagnostically. In patients with symptoms of less than twoweek duration, the fluid may reveal predominantly polymorphonuclear leucocytes (48). If serial thoracenteses are performed, the differential count will reveal a shift to predominantly small lymphocytes (49). The fluid rarely contains more than five per cent mesothelial cells, although the finding is not diagnostic (76,77). Several

other disorders associated with pleural inflammation and infiltration are associated with decreased shedding of mesothelial cells in the pleural cavity, and numerous mesothelial cells can sometimes be found in some patients with pleural TB (78). Presence of eosinophils in a significant number in the fluid makes the diagnosis of TB unlikely, except in patients having a hydropneumothorax due to a previous thoracocentesis (79,80). It is reasonable to assume that effusions containing more than 50 per cent of these cells are of a non-TB aetiology. Pleural fluid smear for AFB is positive in less than 10 per cent instances in most reports, while mycobacteria can be cultured from pleural fluid in 10 to 70 per cent cases (47,50,60,61,63,81-84). In one study, steroid use, concurrent TB involving another site, increased neutrophils and decreased glucose levels in pleural fluid were predictive factors for culture positivity (85). Sensitivity of mycobacterial cultures is improved if pleural fluid is transported in heparinized containers, bedside inoculation of pleural fluid is substituted for laboratory inoculation, or if liquid culture media and/or a radiometric [e.g., BACTEC] system are used (86-88). Pleural Biopsy A closed parietal pleural biopsy can be performed using a Cope or Abram needle. The demonstration of parietal pleural granulomata on histopathological examination is suggestive of TB pleuritis; caseation necrosis and AFB are not always present (65). Although other disorders such as fungal diseases, sarcoidosis and rheumatoid arthritis may produce granulomatous pleuritis, more than 95 per cent of patients with this histopathological picture have TB. The initial biopsy reveals granulomas in 50 to 97 per cent patients with TB pleural effusion (50,60,61,63,81,83,89). The yield increases if multiple biopsies are performed (90-92). However, if properly obtained, even a single high quality sample should be enough to obtain a diagnosis (92,93). Mycobacteria can be cultured from pleural biopsy specimens in 33 to 80 per cent cases (50,60,61,63,83,89,94). When culture of biopsy specimen is combined with microscopic examination, the diagnosis can be established in up to 95 per cent instances (95). Even when granulomata are not demonstrated, the biopsy specimen should be examined for AFB. In less than 10 per cent of cases, organisms may still be demonstrated when no granulomas are present in the biopsy (49,60). A visceral pleural biopsy obtained

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through video-assisted thoracoscopic surgery [VATS] can sometimes yield diagnosis in patients with a negative parietal pleural biopsy (96). Adenosine Deaminase Adenosine deaminase [ADA] is an enzyme involved in the purine catabolism. It catalyses the deamination of adenosine to inosine and of deoxyadenosine to deoxyinosine. Adenosine deaminase is found in most cells, but its chief role concerns the proliferation and differentiation of lymphocytes, especially T-lymphocytes. For this reason ADA has been looked on as a marker of cell-mediated immunity, which encompasses the delayed hypersensitivity reaction. The ADA activity correlates to CD4+ T-lymphocyte cell infiltration in the pleura and the fluid (97). Determination of pleural fluid ADA level appears to be a promising marker in the diagnosis of TB pleural effusion because of the ease, rapidity, and costeffectiveness of the assay. Estimation of ADA is performed using a simple colorimetric method that is quite suitable for use in the field setting (98). Recently, meta-analyses have shown that ADA estimation is reasonably accurate in diagnosing TB pleural effusion (99,100). However, the results of ADA assays should be interpreted in conjunction with clinical findings and the results of conventional investigations. It appears that pleural fluid ADA in excess of 70 IU/l is highly suggestive of TB pleuritis, whereas a level below 40 IU/l virtually rules out the diagnosis (101,102). In addition,

higher the pleural fluid ADA, the more likely the diagnosis of TB. Essentially, all reports from the West have been very positive in finding that pleural fluid ADA level is useful diagnostically (103). Early reports from Asia were much less positive, though more recent reports have been more favourable (104). It is not clear whether these differences represent methodologic differences or true ethnic variation. Some of the differences could also be explained by differences in methodology used for ADA estimation, as well as delays in transportation and processing of pleural fluid samples. It is well known that ADA levels in pleural fluids maintained at ambient temperatures, and without the use of specific additives, decrease with passage of time (105). Several investigators from India have reported the use of pleural fluid ADA in the diagnosis of TB effusions (106-121). Overall, the sensitivity and specificity of the test in diagnosis of TB are not as good as in Western studies [Table 17.1]. However, based on epidemiological and Bayesian considerations, positive predictive value of pleural fluid ADA in the diagnosis of TB pleural effusion should be far better in geographical regions with a higher prevalence of TB as a cause of pleural effusion [Figure 17.4] (99). Hence, elevated ADA can provide a reliable basis of diagnosing TB pleural effusion in such areas (122). It also appears that ADA is a poor discriminator when used as a single investigation, but may be more useful when results are interpreted in conjunction with clinico-radiological data and results of other investigations (100,123).

Table 17.1: Performance of adenosine deaminase estimation in the evaluation of tuberculosis pleural effusion in Indian patients

Raj et al (106) Sinha et al (107) Sinha et al (108) Chopra et al (109) Gilhotra et al (110) Gupta et al (111) Subhakar et al (112) Kaur et al (113) Prasad et al (114) Nagaraja et al (115) Maldhure et al (116) Singh et al (117) Ghelani et al (118) Parandaman et al (119) Nagesh et al (120) Sharma et al (121)

Cases/controls

Cut-off [IU/l]

Sensitivity

Specificity

30/25 22/14 37/16 37/27 30/43 36/57 62/18 21/52 21/26 30/18 83/42 41/43 54/27 25/9 20/40 48/27

40 30 30 – 40 50.8 38 30 30 50 40 – 40 47.3 50 35

1.000 1.000 1.000 0.892 1.000 1.000 0.984 0.667 1.000 1.000 1.000 0.902 0.722 0.760 0.550 0.833

– 1.000 1.000 0.852 0.907 0.941 1.000 0.923 1.000 1.000 0.348 0.870 0.593 0.714 0.550 0.666

Tuberculosis Pleural Effusion 253 Interferon-gamma

Figure 17.4: Effect of prevalence on the operating characteristics of pleural fluid adenosine deaminase [ADA] and interferon-γ [IFN] for diagnosis of tuberculosis pleural effusion. The curves depict post-test probability of pleural tuberculosis after knowing positive [top] or negative [bottom] results of ADA [inner curves] or of IFN [outer curves] for different pre-test probabilities of disease Adapted with permission from reference 99

There are several isoforms of ADA, but the prominent ones are ADA1 and ADA2, which are coded by different gene loci (124). The ADA1 isoenzyme is found in all cells, with the highest concentration found in lymphocytes and monocytes, whereas ADA2 isoenzyme is found only in monocytes (125). The ADA2 is the predominant isoform in the TB pleural fluid, accounting for approximately 90 per cent of total ADA activity, whereas ADA1 is elevated in empyema (126). This would suggest that ADA2 is a more efficient marker of TB pleural effusion and has been shown to be increased in TB pleural effusions (126-128). In pleural fluids with a high ADA level, a ADA1:ADA2 ratio less than 0.45 is highly suggestive of TB, whereas a ratio greater than 0.45 may be seen in malignancy, empyema, and other conditions (117,129). The measurement of ADA2 is almost 10 times more expensive than estimation of total ADA. Although determination of this ratio may increase the diagnostic accuracy of ADA estimation in TB pleural fluids, in clinical practice the difference in the use of total ADA and isoform ADA2 may not be significant (130). In fact, there may be an advantage in the measurement of total ADA because of its low cost and rapid turnover. Activity of ADA1 is determined by subtracting ADA2 measurement from total ADA activity.

Interferon-γ is produced by the CD4+ T-lymphocytes in patients with TB pleural effusion in response to mycobacterial antigens (131,132). In fact, the concentration of Mycobacterium tuberculosis in pleural liquid correlates with the amount of IFN-γ (133). Patients with pleural effusion may have up to 25-fold higher IFN-γ levels in the pleural fluid as compared to their peripheral blood, suggesting homing of Th1 cells in the pleural fluid from the peripheral blood and enrichment of pleural space with Th1 cytokines (30). The IFN-γ can be estimated either by enzyme-linked immunosorbent assay [ELISA] or radioimmunoassay [RIA]. Estimation of pleural fluid IFN-γ levels is reported to be useful in differentiating TB from other pleural fluids [Figure 17.4] (99). A number of reports have demonstrated that IFN-γ levels in patients with TB pleurisy are high, with sensitivity and specificity ranging from 90 to 100 per cent (102,132-145). However, proper comparison of results from different studies is not possible due to differences in methods of estimation and units used for quantification. Although the test is promising, it is expensive and still not widely available. The cost of performing a single IFN-γ test in India is, in fact, equivalent to the cost of a complete course of antituberculosis treatment for such patients, and therefore, does not appear to be a cost-effective investigation for differentiating TB from non-TB pleural effusions (146). Recently, meta-analyses (99,147) have demonstrated the utility of estimation of pleural fluid IFN-γ in the diagnosis of TB pleurisy. Serodiagnosis Till date only a few studies are available on the immunodiagnosis of TB pleural effusion (118,148-159). Both mycobacterial antigens and their antibodies have been estimated in pleural fluid and/or serum using ELISA based techniques to assess their utility in the diagnosis [Table 17.2]. The sensitivity reported in most studies is much less than desirable. The problem of false-positive results has also been troublesome in other studies (149,157,158,160). The kaolin agglutination test, which detects antituberculophospholipid antibodies, may also provide equivalent sensitivity and specificity, while being much simpler (161). The origin of antibodies to mycobacterial antigens in pleural fluid of these patients is not clear. Levy and co-workers (162) found close

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Table 17.2: Evaluation of tuberculosis antigens and antibodies in the diagnosis of tuberculosis pleural effusion Study (reference) Antibody in pleural fluid

Antibody in serum

Antigen in pleural fluid

Antigen in serum

Sensitivity

Samuel et al (148) 0.683 Murate et al (149) 0.226 Caminero et al 0.500 (150,151) Ghelani et al (118) 0.907 Chierakul et al (152) 0.254 Kunter et al (153) 0.841 Yokoyama et al (154) 0.500 Kaisermann et al (155) 0.764 Caminero et al (150) 0.550 Caminero et al (151) 0.533 Arora et al (156) 0.900 Chierakul et al (152) 0.463 Kunter et al (153) 0.591 Samuel et al (148) 0.488 Baig et al (157) 0.600 Ramkisson et al (158) 1.000 Dhand et al (160) 0.800 Banchuin et al (159) 0.115 Banchuin et al (159) 0.000

Specificity 1.000 0.949 1.000 0.333 0.904 0.730 0.938 0.963 1.000 1.000 0.950 0.596 0.811 1.000 0.800 0.983 0.381 1.000 1.000

correlation between pleural fluid and serum levels, reflecting passive diffusion. Other investigators have demonstrated higher titers of antibodies in pleural fluid, indicating local accumulation (163). Assays based on detection of tuberculostearic acid [TSA] in pleural aspirates have not yielded encouraging results (164). Further work needs to be done before immunodiagnostic techniques can be recommended for routine use in the diagnosis of TB pleural effusions. Lysozyme Lysozyme is a low molecular weight bacteriolytic protein distributed extensively in organic fluids. Its estimation in pleural fluid has been proposed as a useful test in the diagnosis of TB pleural effusion. Mean lysozyme levels in TB pleural fluid have been reported to be higher than in other exudative effusions (101,165-167). However, there is so much overlap that the levels themselves are not diagnostic. Pleural fluid to serum lysozyme ratio of more than 1 or 1.2 can differentiate better between TB and non-TB pleural fluids (164,166,167). A more recent report (102) has, however, not reproduced these good results.

Thoracoscopy Thoracoscopy, often considered the ‘gold standard procedure’ for the diagnosis of TB pleuritis, may have a role in evaluation of pleural effusions undiagnosed by less invasive investigations. The diagnostic accuracy of this procedure is greater because multiple selected biopsies can be obtained, which have a higher yield both on microbiologic as well as histopathological examinations (168-170). The endoscopic appearance of pleural TB is well described. It is characterized by greyish-white granulomata covering the entire parietal and diaphragmatic pleura, and in particular, the costovertebral gutter (171,172). However, lesions have often lost their specific appearance by the time of thoracoscopy and may mimic a simple inflammatory process. In addition, the examination itself may be difficult because of numerous bands and adhesions. Complication rates for thoracoscopically guided pleural biopsy are minimal, and similar to closed pleural biopsy (170-172). Apart from cost concerns, the performance of thoracoscopy is limited by availability of equipment, and of personnel with expertise to perform this procedure. Nucleic Acid Amplification Techniques Various nucleic acid amplification methods that have been used in the diagnosis of mycobacterial infection include target amplification techniques such as polymerase chain reaction [PCR], strand displacement amplification, and transcription mediated amplification, as well as probe, primer amplification techniques such as ligand chain reaction and Q-Beta replicase amplification. Polymerase chain reaction, the most widely used of these techniques, is based on the amplification of mycobacterial deoxyribonucleic acid [DNA]. In respiratory specimens, the PCR can be performed rapidly and has a diagnostic yield comparable to that of culture (173). Polymerase chain reaction offers the option of referring the sample, rather than the patient, to a specialized centre or laboratory. This procedure has also been used to detect mycobacterial DNA in pleural fluid (119,120,174-187). Its sensitivity in the diagnosis of TB pleural effusion ranges from as low as 17 per cent to as high as 100 per cent, depending on the patients selected, genomic sequence amplified, and the procedure used in the extraction of DNA [Table 17.3]. Specificity ranges from

Tuberculosis Pleural Effusion 255 Table 17.3: Pleural fluid polymerase chain reaction in the diagnosis of tuberculosis pleural effusion Study (reference)

Cases/Controls

Sequence amplified

Sensitivity

Specificity

de Wit et al (174) de Lassence et al (175)

53/31 15/10

Verma et al 176) Querol et al (177) Tan et al (178)

38/29 21/86 10/13

Villena et al (179) Seethalakshmi et al (180) Mitarai et al (181) Martins et al (182) Parandaman et al (119) Villegas et al (183) Reechaipichitkul et al (184) Nagesh et al (120) Lima et al (185) Kim et al (186) Moon et al (187)

33/98 22/– 36/39 19/11 30/20 42/98 36/62 20/40 16/29 9/92 57/54

336 bp repetitive sequence IS6110 sequence Gene coding 65 kD antigen 150 bp sequence IS6110 sequence IS6110 sequence MPB64 fragment IS6110 sequence IS6110 sequence Amplicor kit MPB64 fragment IS6110 sequence and TRC4 IS6110 sequence 16S-23S rRNA gene spacer sequence 150 bp sequence IS6110 sequence Amplicor kit Amplicor kit

0.811 0.600 0.200 0.632 0.809 0.700 0.700 0.424 0.409 0.273 0.684 1.000 0.738 0.500 0.700 0.313 0.333 0.175

0.774 1.000 1.000 0.931 0.977 1.000 1.000 0.990 -– 0.976 0.909 0.850 0.898 0.613 1.000 0.966 1.000 0.981

TRC = insertion element like repetitive sequence

61 to 100 per cent. The parameter that determines the sensitivity of PCR is probably the number of bacilli in the sample of pleural fluid analysed. Series with a pleural fluid culture positivity of as high as 69 per cent report more than 80 per cent sensitivity of PCR (177). The PCR may be positive in 100 per cent of culture-positive TB pleural fluids and only in 30 to 60 per cent of culturenegative pleural fluids (174-176,179-181,184,187). The lower sensitivity is most likely attributable to the inefficient recovery of genomic DNA from the characteristically low number of mycobacteria in patients with pleural TB. Genomic sequences present in multiple copies in mycobacteria give better results than sequences present in only a single copy (174-176). Contamination of samples by mycobacterial DNA in the laboratory environment is partly responsible for the low specificity. Few investigators have also evaluated the value of various nucleic acid extraction and amplification techniques in formalin-fixed and paraffin-embedded pleural tissue samples (188-194). Although specificity of these techniques is high, approaching 100 per cent in several instances, sensitivity was seen to be low [47% to 90%]. However, in these studies, nucleic acid amplification techniques resulted in a similar or higher positivity as compared to histological examination or culture of pleural biopsy specimens. Thus, PCR of pleural

biopsy specimens can be useful when employed in combination with microbiological and histological examinations (194). Although these techniques are promising, the high cost and the technology involved in the procedure do not permit the routine diagnostic use of PCR at present (195). NATURAL HISTORY In the short-term, TB pleural effusion seems to be a selflimited inflammatory process in most instances. The natural history of untreated TB pleuritis and effusion is usually complete absorption of fluid and apparently complete restoration of the patient’s health to normal [although some degree of pleural fibrosis may be evident pathologically or radiologically]. However, the likelihood of subsequent development of pulmonary TB is high; for example, in one study (196) from the pre-chemotherapy era on 2816 members of the Finnish army with pleural effusion followed up for seven years, 43 per cent developed active TB during the follow-up period. Confirmatory evidence was provided in another study on 141 American military personnel who had presented with pleural effusion and a positive tuberculin skin test; nearly twothird subsequently developed some form of TB (197). In

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this study, isolation of mycobacteria from pleural fluid or size of pleural effusion were not correlated with subsequent appearance of active TB. Thus, the long-term prognosis in patients who have TB pleurisy is determined by its prompt recognition and the early initiation of effective therapy, which lowers the risk of subsequent disease (198). TREATMENT AND ITS RESPONSE The goals of therapy in patients with TB pleural effusion are: [i] prevention of subsequent development of active TB; [ii] relief of symptoms; and [iii] limitation of pleural fibrosis. Antituberculosis Treatment Patients with TB pleural effusion respond well to treatment with standard short-course antituberculosis therapy (199,200) and DOTS is preferred. Under the Revised National Tuberculosis Control Programme [RNTCP], of the Government of India, patients with massive or moderately severe pleural effusion receive Category I treatment, while patients with small and unilateral pleural effusion receive Category III treatment. The reader is referred to the chapters “Treatment of tuberculosis” [Chapter 52], and, “Revised National Tuberculosis Control Programme” [Chapter 63] for more details. This form of treatment is well accepted by patients, and has a relapse rate of less than three per cent (201). Because patients with TB pleural effusion have low mycobacterial burden, less intensive regimens may also prove effective (202,203). With treatment, patients generally become afebrile within about two weeks, and the pleural effusion resolves within two months (204). Lung functions continue to improve even after completion of therapy (205). There appears no medical reason to confine these patients to bed, and patients need to be isolated only if their sputum smear examination demonstrates AFB. In some patients, the pleural effusion may worsen after antituberculosis treatment is initiated. In this situation, the possibility of a wrong diagnosis must be considered, but paradoxical worsening can also occur with a correct diagnosis and appropriate antituberculosis medications (206). One hypothesis is that these paradoxical responses are related to isoniazid-induced lupus pleuritis (207). New pleural effusion may occasionally arise on the contralateral side as well (208-210). Similarly, new parenchymal lesions may also be noticed within

three months of start of medications, which eventually resolve on the same treatment (211). Even after successful completion of treatment, nearly 10 per cent patients may have a residual restrictive ventilatory defect on pulmonary function testing (212). Mild degree of pleural fibrosis may be present on chest radiographs a year after therapy is begun in up to 50 per cent of patients (63). With the strict definition of fibrothorax as a pleural membrane of at least 5 mm thickness extending across major portions of the hemithorax, a figure of around five per cent is perhaps the more realistic and widely accepted rate of this complication. The presence of fibrosis is not related to the initial pleural fluid findings and is of limited clinical significance, although a higher pleural fluid glucose may be associated with increased residual pleural thickening (213,214). A faster resolution of pleural effusion during the initial phase of treatment may decrease the occurrence of significant pleural thickening (215). The correlation between radiographic and functional sequelae [as assessed by pulmonary function testing] is poor (212). Corticosteroids Evidence regarding efficacy of systemic corticosteroids in the treatment of TB pleuritis remains insufficient (216,217). Three randomized, double-blind, placebocontrolled trials have been completed, but all had important methodological differences. There was no benefit with the use of systemic corticosteroids in two controlled studies in which therapeutic thoracocentesis was also performed (218,219). However, the duration of fever and the time required for fluid resorption were decreased in a third study in which no therapeutic thoracocentesis was performed (220). Administration of corticosteroids did not influence residual pleural thickening in any of these studies. Based on these data, routine use of corticosteroids cannot be recommended and should only be used if acute symptoms, such as fever, chest pain, or dyspnoea, are disturbing to the patient. If needed, corticosteroids should be prescribed only after the institution of appropriate antituberculosis treatment. Patients can start therapy with 0.5 to 0.75 mg/kg body weight of prednisolone [or equivalent] daily until acute symptoms have subsided, with rapid tapering thereafter. Surgery In general, surgical procedures have no place in the routine management. Therapeutic thoracocentesis is only

Tuberculosis Pleural Effusion 257 indicated if the patient has a moderate-sized or larger pleural effusion producing significant breathlessness. In fact, routine serial therapeutic thoracenteses, or continuous pigtail catheter drainage, does not alter the course of illness or the development of residual pleural fibrosis (221,222). Early surgery for pleural thickening is also not recommended, as the thickening decreases with treatment. A recent study also suggests that instillation of a fibrinolytic agent into a loculated collection may help in subsequent reduction of pleural thickening (223). Although medical thoracoscopy can open intrapleural loculations, completely evacuate the pleural fluid, and to some extent produce effective debridement, no controlled study has so far proven the value of these efforts. HUMAN IMMUNODEFICIENCY VIRUS CO-INFECTION It appears that co-infection with HIV is the main factor responsible for the increase in TB pleurisy in the West and in Africa (224,225). Pleural effusion is seen in six to twenty-eight per cent of HIV-infected patients with TB (226-228). These patients tend to develop pleural effusion in early stages of immunosuppression and the frequency of pleural effusion is higher in patients with CD4+ Tlymphocyte counts exceeding 200 cells/mm3 (229). Pooled estimates from several reports reveal that TB is responsible for almost a quarter of all pleural effusions seen in patients with HIV infection, and that the condition is second only to bacterial parapneumonic effusions in terms of frequency (226). In addition to the delayed hypersensitivity phenomenon, persistence of mycobacteria in the pleural space as result of failure of immune system has been proposed as an alternative explanation for the higher incidence of pleural disease in these patients (230). It is not clear if the higher rate of pleural disease reflects a greater burden of pleural mycobacteria or dysregulation of immune function in the pleural space. Affected patients usually are symptomatic for longer periods, have additional symptoms [fever, dyspnoea, night sweats, fatigue, diarrhoea, etc.,] and more commonly have hepatomegaly, splenomegaly and lymphadenopathy than patients who are HIV-seronegative (231,232). The diagnostic approach in patients with HIV infection is largely similar to other patients with TB pleural effusion, although the performance of some individual diagnostic tests is different. Patients are more

likely to be anergic on (231,233). The AFB can be demonstrated on pleural fluid smears in six to fifteen per cent and on pleural biopsy specimens in 44 to 69 per cent cases (230,232,234). The AFB smears are more likely to be positive when CD4+ T-lymphocyte counts fall below 200 cells/mm3 (232). Pleural fluid and/or biopsy cultures grow mycobacteria in 30 to 50 per cent cases (230,233235). Despite the impaired T-lymphocyte function, pleural biopsy specimens show granulomatous inflammation in 44 to 88 per cent cases (230,234,235). The role of PCR, and measurements of ADA, lysozymes, or IFN-γ in the diagnosis of TB pleural effusion in these patients is still not clear. Management guidelines for these patients are similar to those for other patients, and standard four-drug antituberculosis treatment is the treatment of choice (236). The clinical and microbiologic response to treatment in these patients appears to be similar to that in patients not infected with HIV. Most HIV-infected patients with TB pleural effusion respond favourably to standard treatment, with mortality rates less than 10 per cent after an average follow-up of more than two years (230,237). Patients with poor or absent tissue reaction on pleural biopsy histology appear to have a less favourable response to therapy and higher mortality (233). Paradoxical reactions or immune reconstitution inflammatory syndrome [IRIS] are much more common in patients with HIV-TB co-infection (238). PLEURAL EFFUSION DUE TO NONTUBERCULOUS MYCOBACTERIA As with pulmonary disease, the vast majority of cases of pleural mycobacterial infection are caused by Mycobacterium tuberculosis; only occasional cases are related to nontuberculous mycobacteria [NTM] (239,240). Pleural effusions without parenchymal disease analogous to the post-primary pleural effusion with Mycobacterium tuberculosis do not occur. Approximately five per cent of patients with parenchymal disease due to either Mycobacterium avium-intracellulare complex [MAIC] or Mycobacterium kansasii have an associated small pleural effusion (240). About 15 per cent patients with parenchymal disease due to Mycobacterium intracellulare have marked pleural thickening as well (240). In patients with AIDS and disseminated disease due to MAIC, pleural fluid cultures are sometimes positive for MAIC (241). However, it is not clear whether these NTM are actually

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responsible for the pleural effusion. Even in immunocompetent patients one must be cautious regarding the interpretation of isolation of NTM from pleural fluid. It has been suggested that NTM cultured from pleural fluid should not be considered aetiologic, unless there is evidence of the same organism infecting other tissues (242). TUBERCULOSIS EMPYEMA Tuberculosis empyema is an entity distinct from, and much less common than, TB pleural effusion. In contrast to delayed hypersensitivity leading to pleural fluid accumulation in a TB pleural effusion, TB empyema is characterized by chronic, active mycobacterial infection of the pleural space. It usually represents the failure of a primary TB effusion to resolve and subsequent progression to a chronic suppurative form, and may develop in fibrous scar tissue resulting from pleurisy, artificial pneumothorax, or thoracoplasty (243). In addition, TB empyema can also occur due to extension of infection from intrathoracic lymph nodes or a subdiaphragmatic focus, or haematogenous spread (244). In TB empyema the pleural contamination is massive, the pleural fluid is purulent, and it is common to find mycobacteria on direct smear examination or culture of pleural fluid (245). Tuberculosis empyema represents nearly 20 per cent of all cases of empyema seen in high prevalence countries like India (246). In many patients with chronic TB empyema, the inflammatory process may be present for years with a paucity of clinical symptoms (243,247). This prolonged asymptomatic course is largely related to the marked pleural thickening that isolates the tubercle bacilli to the empyema cavity. Patients are often diagnosed only after a routine chest radiograph or after development of complications, such as bronchopleural fistula or empyema necessitans. Other patients may present with low-grade fever, night sweats and constitutional symptoms, such as fatigue and weight loss. Patients often have respiratory symptoms for several months prior to diagnosis (248). The typical radiological findings of chronic TB empyema include a moderate to large loculated pleural effusion with pleural calcification and thickening of the overlying ribs (18). Diagnosis is confirmed after thoracocentesis by finding grossly purulent fluid that is smear- positive for AFB and subsequently grows

mycobacteria on culture. Pleural fluid cell counts usually exceed 100 000/mm3, with virtually all cells being neutrophils (245). The pleural fluid has low glucose [usually below 20 mg/dl] and high protein concentration [usually more than 5 g/dl], and is acidic [with pH usually below 7.20]. Anaerobic and aerobic cultures should also be performed to exclude concomitant bacterial and mycobacterial infection. The principles of treatment, pleural space drainage, and antimicrobial chemotherapy are similar for bacterial and TB empyema. Difficulties specific to management of TB empyema include the inability of the trapped lung to re-expand adequately and failure to achieve therapeutic drug levels in pleural fluid, which can lead to drug resistance (245,249). It is, therefore, important to use multiple drugs at their maximum tolerated dosages. Pleural drainage is indicated for large empyemas and mixed empyemas, especially if there is a bronchopleural fistula. Because intensive chemotherapy coupled with serial thoracocentesis can be curative at times, this approach should be attempted initially (250). In addition to standard antituberculosis treatment, patients usually require surgery (251). Surgical procedures include standard decortication, decortication limited to the parietal sides of the empyema collection, thoracoplasty, muscle flap, plombage, parietal wall collapse, open drainage, or resection of the entire lung along with the empyema (244). Most patients have associated significant pulmonary parenchymal involvement (245). The status of the underlying lung should be determined before planning any surgery, because presence of massive fibrotic lesions, cavities, or bronchiectasis can make surgery difficult or inadvisable. Ideally, antituberculosis medications are given for two to four months preoperatively and the sputum should be negative for AFB for two months prior to surgery. Morbidity and mortality related to surgery continue to be high (245,252,253). It must be stressed that such surgery is extremely complex and challenging, and should only be undertaken by experienced thoracic surgeons. As with other forms of chronic empyema, surgery can help in postoperative improvement of lung function (254). Presence of bronchopleural fistula, chronicity of the lesion and presence of disease in the underlying and/or contralateral lung contribute to a poorer outcome with treatment (251). The relative lung volume of the affected side, as well as the volume of empyema, can help predict the quantum of improvement in lung function after

Tuberculosis Pleural Effusion 259 surgery (255). The reader is referred to the chapter “Surgery for pleuropulmonary tuberculosis” [Chapter 55] for more details. PSEUDOCHYLOTHORAX AND CHYLOTHORAX The anatomic substratum of pseudochylothorax is a thickened [and often calcified] pleura that contains cholesterol rich fluid. Pleural fluid cholesterol levels exceeding 200 mg/dl sustain the diagnosis, which is confirmed if cholesterol crystals are demonstrated (256). The precise mechanism of cholesterol accumulation has not been elucidated, though it probably results from accumulation of cellular inflammatory debris secondary to local degeneration of red and white blood cells. Tuberculosis is the main aetiology of pseudochylothorax, accounting for more than half of all reported cases (257). There is a remarkable correlation with previous collapse therapy and long standing pleural effusions [typically five or more years]. Pseudochylothorax can develop even after, and despite, successful antituberculosis treatment (258). Pleural fluid is usually sterile (256,257). However, antituberculosis treatment should be administered to patients in whom mycobacteria are demonstrated on pleural fluid analysis or pleural biopsy histology, and those with enlarging effusions of suspected TB origin (257). Drainage is recommended only in symptomatic patients. Pulmonary decortication should be reserved for recurrent and symptomatic patients not responding to medical measures. In contrast to pseudochylothorax, chylothorax is an acute effusion formed by accumulation of chyle in pleural space secondary to damage of thoracic duct. Triglyceride levels in pleural fluid are always above 50 mg/dl and usually higher than 110 mg/dl, but the main diagnostic criterion is the presence of chylomicrons in pleural fluid (256). Tuberculosis is a rare cause of chylothorax (259-263). The genesis of chylothorax in TB is not clear, but may be related either to lymph nodes obstructing and eroding into the cisterna chyli or thoracic duct, or to direct involvement of lymphatic channels by tubercle bacilli. REFERENCES 1. Gopi A, Madhavan SM, Sharma SK, Sahn SA. Diagnosis and treatment of tuberculous pleural effusion in 2006. Chest 2007;131:880-9.

2. Sinzobahamvya N, Bhakta HP. Pleural exudate in a tropical hospital. Eur Respir J 1989;2:145-8. 3. Shah A. Tuberculous pleural effusion: a diagnostic problem. Indian J Chest Dis Allied Sci 1992;34:115-6. 4. Batungwanayo J, Taelman H, Allen S, Bogaerts J, Kagame A, Van de Perre P. Pleural effusion, tuberculosis and HIV-1 infection in Kigali, Rwanda. AIDS 1993;7:73-9. 5. Elliott AM, Halwiindi B, Hayes RJ, Luo N, Tembo G, Machiels L, et al. The impact of human immunodeficiency virus on presentation and diagnosis of tuberculosis in a cohort study in Zambia. J Trop Med Hyg 1993;96:1-11. 6. al-Quorain A, Larbi EB, Satti MB, al-Muhanna F, Baloush A. Tuberculous pleural effusion in the eastern province of Saudi Arabia. Trop Geogr Med 1994;46:298-301. 7. Richter C, Perenboom R, Swai AB, Kitinya J, Mtoni I, Chande H, et al. Diagnosis of tuberculosis in patients with pleural effusion in an area of HIV infection and limited diagnostic facilities. Trop Geogr Med 1994;46:293-7. 8. Valdes L, Alvarez D, Valle JM, Pose A, San Jose E. The etiology of pleural effusions in an area with high incidence of tuberculosis. Chest 1996;109:158-62. 9. Yoon HJ, Song YG, Park WI, Choi JP, Chang KH, Kim JM. Clinical manifestations and diagnosis of extrapulmonary tuberculosis. Yonsei Med J 2004;45:453-61. 10. Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316-53. 11. Sahn SA. State of the art. The pleura. Am Rev Respir Dis 1988;138:184-234. 12. Mehta JB, Dutt A, Harvill L, Mathews KM. Epidemiology of extrapulmonary tuberculosis. A comparative analysis with pre-AIDS era. Chest 1991;99:1134-8. 13. Menzies R, Charbonneau M. Thoracoscopy for the diagnosis of pleural disease. Ann Intern Med 1991;114:271-6. 14. Marel M, Stastny B, Melinova L, Svandova E, Light RW. Diagnosis of pleural effusions. Experience with clinical studies, 1986 to 1990. Chest 1995;107:1598-603. 15. Bouros D, Demoiliopoulos J, Panagou P, Yiatromanolakis N, Moschos M, Paraskevopoulos A, et al. Incidence of tuberculosis in Greek armed forces from 1965-1993. Respiration 1995;62:336-40. 16. Moudgil H, Sridhar G, Leitch AG. Reactivation disease: the commonest form of tuberculous pleural effusion in Edinburgh, 1980-1991. Respir Med 1994;88:301-4. 17. Stead WW, Eichenholz A, Stauss H. Operative and pathological findings in 24 patients with syndrome of idiopathic pleurisy with effusion, presumably tuberculous. Am Rev Tuberc 1955;71:473-502. 18. Hulnick DH, Naidich DP, McCauley DI. Pleural tuberculosis evaluated by computed tomography. Radiology 1983;149:75965. 19. Allen JC, Apicella MA. Experimental pleural effusion as a manifestation of delayed hypersensitivity to tuberculin PPD. J Immunol 1968;101:481-7. 20. Leckie WJ, Tothill P. Albumin turnover in pleural effusion. Clin Sci 1965;29:339-52.

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21. Leibowitz S, Kennedy L, Lessof MH. The tuberculin reaction in the pleural cavity and its suppression by anti-lymphocyte serum. Br J Exp Pathol 1973;54:152-62. 22. Ellner JJ, Barnes PF, Wallis RS, Modlin RL. The immunology of tuberculous pleurisy. Semin Respir Infect 1988;3: 335-42. 23. Kroegel C, Antony VB. Immunobiology of pleural inflammation: potential implications for pathogenesis, diagnosis and therapy. Eur Respir J 1997;10:2411-8. 24. Ellner JJ. Pleural fluid and peripheral blood lymphocyte function in tuberculosis. Ann Intern Med 1978;89:932-3. 25. Shimokata K, Kawachi H, Kishimoto H, Maeda F, Ito Y. Local cellular immunity in tuberculous pleurisy. Am Rev Respir Dis 1982;128:822-4. 26. Fujiwara H, Tsuyuguchi I. Frequency of tuberculin-reactive T-lymphocytes in pleural fluid and blood from patients with tuberculous pleurisy. Chest 1986;89:530-2. 27. Lorgat F, Keraan MM, Ress SR. Cellular immunity in tuberculous pleural effusions: evidence of spontaneous lymphocyte proliferation and antigen-specific accelerated responses to purified protein derivative [PPD]. Clin Exp Immunol 1992;90:215-8. 28. Mehra V, Gong JH, Iyer D, Lin Y, Boylen CT, Bloom BR, et al. Immune response to recombinant mycobacterial proteins in patients with tuberculosis infection and disease. J Infect Dis 1996;174:431-4. 29. Jalapathy KV, Prabha C, Das SD. Correlates of protective immune response in tuberculous pleuritis. FEMS Immunol Med Microbiol 2004;40:139-45. 30. Sharma SK, Mitra DK, Balamurugan A, Pandey RM, Mehra NK. Cytokine polarization in miliary and pleural tuberculosis. J Clin Immunol 2002;22:345-52. 31. Antony VB, Sahn SA, Antony AC, Repine JE. Bacillus Calmette-Guerin-stimulated neutrophils release chemotaxins for monocytes in rabbit pleural spaces and in vitro. J Clin Invest 1985;76:1514-21. 32. Antony VB, Hott JW, Kunkel SL, Godbey SW, Burdick MD, Strieter RM. Pleural mesothelial cell expression of C-C [monocyte chemotactic peptide] and C-X-C [interleukin 8] chemokines. Am J Respir Cell Mol Biol 1995;12:581-8. 33. Mohammed KA, Nasreen N, Ward MJ, Mubarak KK, Rodriguez-Panadero F, Antony VB. Mycobacteriummediated chemokine expression in pleural mesothelial cells: role of C-C chemokines in tuberculous pleurisy. J Infect Dis 1998;178:1450-6. 34. Widstrom O, Nilsson BS. Pleurisy induced by intrapleural BCG in immunized guinea pigs. Eur J Respir Dis 1982;63:42534. 35. Baganha MF, Pego A, Lima MA, Gaspar EV, Cordeiro AR. Serum and pleural adenosine deaminase: correlation with lymphocytic populations. Chest 1990;97:605-10. 36. Mitra DK, Sharma SK, Dinda AK, Bindra MS, Madan B, Ghosh B. Polarized helper T cells in tubercular pleural effusion: phenotypic identity and selective recruitment. Eur J Immunol 2005;35:2367-75.

37. Widstrom O, Nilsson BS. Low in vitro response to PPD and PHA in lymphocytes from BCG-induced pleurisy in guinea pigs. Eur J Respir Dis 1982;63:435-41. 38. Saha PK, Sharma PK, Saxena A, Sharma SK, Mitra DK. Coexpression of CXCR3 on both CCR5+ and CD11a bright Th1 cells in tuberculosis pleural effusion. Chest 2007;132:640S. 39. Barnes PF, Fong SJ, Brennan PJ, Twomey PE, Mazumder A, Modlin RL Local production of tumor necrosis factor and IFN-gamma in tuberculous pleuritis. J Immunol 1990;145:14954. 40. Kurasawa T, Shimokata K. Cooperation between accessory cells and T lymphocytes in patients with tuberculous pleurisy. Chest 1991;100:1046-52. 41. Ribera E, Espanol T, Martinez-Vazquez JM, Ocana I, Encabo G. Lymphocyte proliferation and gamma-interferon production after “in vitro” stimulation with PPD. Differences between tuberculous and nontuberculous pleurisy in patients with positive tuberculin skin test. Chest 1990;97:1381-5. 42. Lorgat F, Keraan MM, Lukey PT, Ress SR. Evidence for in vivo generation of cytotoxic T cells. PPD-stimulated lymphocytes from tuberculous pleural effusions demonstrate enhanced cytotoxicity with accelerated kinetics of induction. Am Rev Respir Dis 1992;145:418-23. 43. Ota T, Okubo Y, Sekiguchi M. Analysis of immunologic mechanisms of high natural killer cells activity in tuberculous pleural effusions. Am Rev Respir Dis 1990;142:29-33. 44. Loddenkemper R, Boutin C. Thoracoscopy: present diagnostic and therapeutic indications. Eur Respir J 1993;6:1544-55. 45. Aktogu S, Yorgancioglu A, Cirak K, Kose T, Dereli SM. Clinical spectrum of pulmonary and pleural tuberculosis: a report of 5,480 cases. Eur Respir J 1996;9:2031-5. 46. Valdes L, Alvarez D, San Jose E, Penela P, Valle JM, GarciaPazos JM, et al. Tuberculous pleurisy: a study of 254 patients. Arch Intern Med 1998;158:2017-21. 47. Sibley JC. A study of 200 cases of tuberculous pleurisy with effusion. Am Rev Tuberc 1950;62:314-23. 48. Levine H, Szanto PB, Cugell DW. Tuberculous pleurisy: an acute illness. Arch Intern Med 1968;122:329-32. 49. Berger HW, Mejia E. Tuberculous pleurisy. Chest 1973;63:8892. 50. Seibert AF, Haynes J Jr, Middleton R, Bass JB Jr. Tuberculous pleural effusion: twenty year experience. Chest 1991;99:8836. 51. Maher GG, Berger HW. Massive pleural effusions: malignant and nonmalignant causes in 46 patients. Am Rev Respir Dis 1972;105:458-60. 52. Porcel JM, Vives M. Etiology and pleural fluid characteristics of large and massive effusions. Chest 2003;124:978-83. 53. Arriero JM, Romero S, Hernandez L, Candela A, Martin C, Gil J, et al. Tuberculous pleurisy with or without radiographic evidence of pulmonary disease. Is there any difference? Int J Tuberc Lung Dis 1998;2:513-7. 54. Yilmaz MU, Kumcuoglu Z, Utkaner G, Yalniz O, Erkmen G. Computed tomography findings of tuberculous pleurisy. Int J Tuberc Lung Dis 1998;2:164-7.

Tuberculosis Pleural Effusion 261 55. Kim HJ, Lee HJ, Kwon S-Y, Yoon HI, Chung HS, Lee C-T, et al. The prevalence of pulmonary parenchymal tuberculosis in patients with tuberculous pleuritis. Chest 2006;129:1253-8. 56. Aggarwal AN, Gupta D, Jindal SK. Diagnosis of tuberculous pleural effusion. Indian J Chest Dis Allied Sci 1999;41:89-100. 57. Ghanei M, Aslani J, Bahrami H, Adhami H. Simple method for rapid diagnosis of tuberculosis pleuritis: a statistical approach. Asian Cardiovasc Thorac Ann 2004;12:23-9. 58. Neves DD, Dias RM, da Cunha AJ, Preza PC. What is the probability of a patient presenting a pleural effusion due to tuberculosis? Braz J Infect Dis 2004;8:311-8. 59. Ghosal AG, Ghosh S, Guhathakurta R, Sinha A, Banerjee AK, Chakrabarti AK. Sputum AFB positivity in tuberculous pleural effusion with no radiologically apparent parenchymal lung lesion. Indian J Tuberc 1997;44:13-5. 60. Escudero Bueno C, Garcia Clemente M, Cuesta Castro B, Molinos Martin L, Rodriguez Ramos S, Gonzalez Panizo A, et al. Cytologic and bacteriologic analysis of fluid and pleural biopsy specimens with Cope’s needle. Study of 414 patients. Arch Intern Med 1990;150:1190-4. 61. Epstein DM, Kline LR, Albelda SM, Miller WT. Tuberculous pleural effusion. Chest 1987;91:106-9. 62. Conde MB, Loivos AC, Rezende VM, Soares SL, Mello FC, Reingold AL, et al. Yield of sputum induction in the diagnosis of pleural tuberculosis. Am J Respir Crit Care Med 2003;167:723-5. 63. Chan CH, Arnold M, Chan CY, Mak TW, Hoheisel GB. Clinical and pathological features of tuberculous pleural effusion and its long term consequences. Respiration 1991;58:171-5. 64. Relkin F, Aranda CP, Garay SM, Smith R, Berkowitz KA, Rom WN. Pleural tuberculosis and HIV infection. Chest 1994;105:1338-41. 65. Light RW. Tuberculous pleural effusions. In: Light RW, editor. Pleural diseases. Fourth Edition. Philadelphia: Lippincott Williams and Wilkins;2001.p.182-95. 66. Barber LM, Mazzadi L, Deakins DD. Glucose level in pleural fluid as a diagnostic aid. Dis Chest 1957;31:680-1. 67. Light RW, MacGregor MI, Ball WC Jr, Luchsinger PC. Diagnostic significance of pleural fluid pH and PCO2. Chest 1973;64:591-6. 68. Chavalittamrong B, Angsusingha K, Tuchinda M, Habanananda S, Pidatcha P, Tuchinda C. Diagnostic significance of pH, lactic acid dehydrogenase, lactate and glucose in pleural fluid. Respiration 1979;38:112-20. 69. Good JT Jr, Taryle DA, Maulitz RM, Kaplan RL, Sahn SA. The diagnostic value of pleural fluid pH. Chest 1980;78:55-9. 70. Spieler P. The cytologic diagnosis of tuberculosis in pleural effusions. Acta Cytol 1979;23:374-9. 71. Kapila K, Pande JN, Garg A, Verma K. T lymphocyte subsets and B lymphocytes in tubercular pleural effusion. Indian J Chest Dis Allied Sci 1987;29:90-3. 72. Lucivero G, Pierucci G, Bonomo L. Lymphocyte subsets in peripheral blood and pleural fluid. Eur Respir J 1988;1:33740.

73. Albera C, Mabritto I, Ghio P, Scagliotti GV, Pozzi E. Lymphocyte subpopulations analysis in pleural fluid and peripheral blood in patients with lymphocytic pleural effusions. Respiration 1991;58:65-71. 74. Gambon-Deza F, Pacheco Carracedo M, Cerda Mota T, Montes Santiago J. Lymphocyte populations during tuberculosis infection: V beta repertoires. Infect Immun 1995;63: 1235-40. 75. Pettersson T, Klockars M, Hellstrom PE, Riska H, Wangel A. T and B lymphocytes in pleural effusions. Chest 1978;73:4951. 76. Light RW, Erozan YS, Ball WC. Cells in pleural fluid. Their value in differential diagnosis. Arch Intern Med 1973;132:85460. 77. Hurwitz S, Leiman G, Shapiro C. Mesothelial cells in pleural fluid: TB or not TB. S Afr Med J 1980;57:937-9. 78. Lau KY. Numerous mesothelial cells in tuberculous pleural effusions. Chest 1989;96:438-9. 79. Adelman M, Albelda SM, Gottlieb J, Haponik EF. Diagnostic utility of pleural fluid eosinophilia. Am J Med 1984;77:91520. 80. Lakhotia M, Mehta SR, Mathur D, Baid CS, Varma AR, Lakhotia M. Diagnostic significance of pleural fluid eosinophilia during initial thoracocentesis. Indian J Chest Dis Allied Sci 1989;31:259-64. 81. Onandeko BO. Tuberculous pleural effusion: Clinical patterns and management in Nigerians. Tubercle 1978;59:269-75. 82. Spieler P. The cytologic diagnosis of tuberculosis in pleural effusion. Acta Cytol 1979;23:374-9. 83. Kumar S, Seshadri MS, Koshi G, John TJ. Diagnosing tuberculous pleural effusion: comparative sensitivity of mycobacterial culture and histopathology. Br Med J [Clin Res Ed] 1981;283:20. 84. Enarson DA, Dorken E, Grzybowski S. Tuberculous pleurisy. Can Med Assoc J 1982;126:493-5. 85. Liu SF, Liu JW, Lin MC. Characteristics of patients suffering from tuberculous pleuritis with pleural effusion culture positive and negative for Mycobacterium tuberculosis, and risk factors for fatality. Int J Tuberc Lung Dis 2005;9:111-5. 86. Maartens G, Bateman ED. Tuberculous pleural effusions: increased yield with bedside inoculation of pleural fluid and poor diagnostic value of adenosine deaminase. Thorax 1991;46:96-9. 87. Cheng AF, Li MS, Chan CY, Chan CH, Lyon D, Wise R, et al. Evaluation of three culture media and their combinations for the isolation of Mycobacterium tuberculosis from pleural aspirates of patients with tuberculous pleurisy. J Trop Med Hyg 1994;97:249-53. 88. Cheng AF, Tai VH, Li MS, Chan CH, Wong CF, Yew WW, et al. Improved recovery of Mycobacterium tuberculosis from pleural aspirates: bedside inoculation, heparinized containers and liquid culture media. Scand J Infect Dis 1999;31:485-7. 89. Scharer L, McClement JH. Isolation of tubercle bacilli from needle biopsy specimens of parietal pleura. Am Rev Respir Dis 1968;97:466-8.

262

Tuberculosis

90. Levine H, Metzger W, Lacera D, Kay L. Diagnosis of tuberculous pleurisy by culture of pleural biopsy specimen. Arch Intern Med 1970;126:269-71. 91. Suri JC, Goel A, Gupta DK, Bhatia A. Role of serial pleural biopsies in the diagnosis of pleural effusions. Indian J Chest Dis Allied Sci 1991;33:63-7. 92. Kirsch CM, Kroe DM, Azzi RL, Jensen WA, Kagawa FT, Wehner JH. The optimal number of pleural biopsy specimens for a diagnosis of tuberculous pleurisy. Chest 1997;112:7026. 93. Jimenez D, Perez-Rodriguez E, Diaz G, Fogue L, Light RW. Determining the optimal number of specimens to obtain with needle biopsy of the pleura. Respir Med 2002;96:14-7. 94. Katiyar SK, Singh RP, Singh KP, Upadhyay GC, Sharma A, Tripathi LK. Cultivation of Mycobacterium tuberculosis from pleural tissue and its histopathology in suspected cases of tuberculous pleural effusion. Indian J Pathol Microbiol 1997;40:51-4. 95. Prakash UB, Reiman HM. Comparison of needle biopsy with cytologic analysis for the evaluation of pleural effusion: analysis of 414 cases. Mayo Clin Proc 1985;60:158-64. 96. Jain NK, Guhan AR, Joshi N, Dixit R, Singh V, Meena RP. Comparative study of visceral and parietal pleural biopsy in the etiological diagnosis of pleural diseases. J Assoc Physicians India 2000;48:776-80. 97. Gaga M, Papamichalis G, Bakakos P, Latsi P, Samara I, Koulouris NG, et al. Tuberculous effusion: ADA activity correlates with CD4+ cell numbers in the fluid and the pleura. Respiration 2005;72:160-5. 98. Sharma SK, Mohan A. Adenosine deaminase in the diagnosis of tuberculosis pleural effusion. Indian J Chest Dis Allied Sci 1996;38:69-71. 99. Greco S, Girardi E, Masciangelo R, Capoccetta GB, Saltini C. Adenosine deaminase and interferon gamma measurements for the diagnosis of tuberculous pleurisy: a meta-analysis. Int J Tuberc Lung Dis 2003;7:777-86. 100. Liang QL, Shi HZ, Wang K, Qin SM, Qin XJ.Diagnostic accuracy of adenosine deaminase in tuberculous pleurisy: a meta-analysis. Respir Med 2008;102:744-54. Epub 2008 Jan 28. 101. Fontan Bueso J, Verea Hernando H, Garcia-Buela JP, Dominguez Juncal L, Martin Egana MT, Montero Martinez MT. Diagnostic value of simultaneous determination of pleural adenosine deaminase and pleural lysozyme/serum lysozyme ratio in pleural effusion. Chest 1988;93:303-7. 102. Valdes L, San Jose E, Alvarez D, Sarandeses A, Pose A, Chomon B, et al. Diagnosis of tuberculous pleurisy using the biologic parameters adenosine deaminase, lysozyme, and interferon gamma. Chest 1993;103:458-65. 103. Perez-Rodriguez E, Jimenez Castro D. The use of adenosine deaminase and adenosine deaminase isoenzymes in the diagnosis of tuberculous pleuritis. Curr Opin Pulm Med 2000;6:259-66. 104. Light RW. Clinical manifestations and useful tests. In: Light RW, editor. Pleural diseases. Fourth Edition. Philadelphia: Lippincott Williams and Wilkins;2001.p.42-86.

105. Miller KD, Barnette R, Light RW. Stability of adenosine deaminase during transportation. Chest 2004;126:1933-7. 106. Raj B, Chopra RK, Lal H, Saini AS, Singh V, Kumar P, et al. Adenosine deaminase activity in pleural fluids - a diagnostic aid in tuberculous pleural effusion. Indian J Chest Dis Allied Sci 1985;27:76-80. 107. Sinha PK, Sinha BB, Sinha AR. Diagnosing tuberculous pleural effusion: comparative sensitivity of mycobacterial culture, histopathology and adenosine deaminase activity. J Assoc Physicians India 1985;33:644-5. 108. Sinha PK, Sinha BB, Sinha AR. Adenosine deaminase activity as a diagnostic index of pleural effusion. J Indian Med Assoc 1987;85:11-3. 109. Chopra RK, Singh V, Lal H, Saini AS, Chawla RK, Raj B. Adenosine deaminase and T-lymphocyte levels in patients with pleural effusions. Indian J Tuberc 1988;35:22-4. 110. Gilhotra R, Sehgal S, Jindal SK. Pleural biopsy and adenosine deaminase enzyme activity in effusions of different aetiologies. Lung India 1989;7:122-4. 111. Gupta DK, Suri JC, Goel A. Efficacy of adenosine deaminase in the diagnosis of pleural effusions. Indian J Chest Dis Allied Sci 1990;32:205-8. 112. Subhakar K, Kotilingam K, Satyasri S. Adenosine deaminase activity in pleural effusions. Lung India 1991;9:57-60. 113. Kaur A, Basha A, Ranjan M, Oommen A. Poor diagnostic value of adenosine deaminase in pleural, peritoneal and cerebrospinal fluids in tuberculosis. Indian J Med Res 1992;95:270-7. 114. Prasad R, Tripathi RP, Mukerji PK, Singh M, Srivastava VM. Adenosine deaminase activity in pleural fluid. Indian J Chest Dis Allied Sci 1992;34:123-6. 115. Nagaraja MV, Ashokan PK, Hande HM. Adenosine deaminase in pleural effusions. J Assoc Physicians India 1992;40:1579. 116. Maldhure BR, Bedarkar SP, Kulkarni HR, Papinwar SP. Pleural biopsy and adenosine deaminase in pleural fluid for the diagnosis of tubercular pleural effusion. Indian J Tuberc 1994;41:161-5. 117. Singh V, Kharb S, Ghalaut PS, Janmeja A. Serum adenosine deaminase activity in pleural effusion. Thorax 1998;53:814. 118. Ghelani DR, Parikh FS, Hakim AS, Pai-Dhungat JV. Diagnostic significance of immunoglobulins and adenosine deaminase in pleural effusion. J Assoc Physicians India 1999;47:787-90. 119. Parandaman V, Narayanan S, Narayanan PR. Utility of polymerase chain reaction using two probes for rapid diagnosis of tubercular pleuritis in comparison to conventional methods. Indian J Med Res 2000;112:47-51. 120. Nagesh BS, Sehgal S, Jindal SK, Arora SK. Evaluation of polymerase chain reaction for detection of Mycobacterium tuberculosis in pleural fluid. Chest 2001;119:1737-41. 121. Sharma SK, Suresh V, Mohan A, Kaur P, Saha P, Kumar A, et al. A prospective study of sensitivity and specificity of adenosine deaminase estimation in the diagnosis of tuberculosis pleural effusion. Indian J Chest Dis Allied Sci 2001;43:149-55.

Tuberculosis Pleural Effusion 263 122. Valdes L, Alvarez D, San Jose E, Juanatey JR, Pose A, Valle JM, et al. Value of adenosine deaminase in the diagnosis of tuberculous pleural effusion in young patients in a region of high prevalence of tuberculosis. Thorax 1995;50:600-3. 123. Kataria YP, Khurshid I. Adenosine deaminase in the diagnosis of tuberculous pleural effusion. Chest 2001;120:334-6. 124. Hirschhorn R, Ratech H. Isozymes of adenosine deaminase. In: Rattazzi MC, Scandalios JG, Whitt GS, editors. Isozymes: current topics in biological and medical research. Volume 4. New York, NY: Liss; 1980.p.131-57. 125. Ungerer JP, Oosthuizen HM, Bissbort SH, Vermaak WJ. Serum adenosine deaminase: isoenzymes and diagnostic application. Clin Chem 1992;38:1322-6. 126. Ungerer JP, Oosthuizen HM, Retief JH, Bissbort SH. Significance of adenosine, deaminase and its isoenzymes in tuberculous effusions. Chest 1994;106:33-7. 127. Gakis C, Calia G, Naitana A, Ortu AR, Contu A. Serum and pleural adenosine deaminase activity. Correct interpretation of the findings. Chest 1991;99:1555-6. 128. Valdes L, San Jose E, Alvarez D, Valle JM. Adenosine deaminase [ADA] isoenzyme analysis in pleural effusions: diagnostic role, and relevance to the origin of increased ADA in tuberculosis. Eur Respir J 1996;9:747-51. 129. Gakis C. Adenosine deaminase [ADA] isoenzymes ADA1 and ADA2: diagnostic and biological role. Eur Respir J 1996;9:632-3. 130. Carsten ME, Burges LJ, Maritz FJ, Taljaard JJ. Isoenzymes of adenosine deaminase in pleural effusion: a diagnostic tool? Int J Tuberc Lung Dis 1998;2:831-5. 131. Barnes PF, Mistry SD, Cooper Cl, Pirmez C, Rea TH, Modlin RL. Compartmentalisation of a CD4+ T lymphocyte subpopulation in tuberculous pleuritis. J Immunol 1989;142:1114-9. 132. Esteban R, Teresa E, Jose MM, Immaculada O, Gloria E. Lymphocyte proliferation and gamma-interferon production after ‘in-vitro’ stimulation with PPD. Chest 1990;37:1381-5. 133. Soderblom T, Nyberg P, Teppo AM, Klockars M, Riska H, Pettersson T. Pleural fluid interferon-gamma and tumour necrosis factor-alpha in tuberculous and rheumatoid pleurisy. Eur Respir J 1996;9:1652-5. 134. Kim YC, Park KO, Bom HS, Lim SC, Park HK, Na HJ, et al. Combining ADA, protein and IFN-gamma best allows discrimination between tuberculous and malignant pleural effusion. Korean J Intern Med 1997;12:225-31. 135. Ribera ER, Ocana I, Martinez-Vazquez JM, Rossell M, Espanol T, Ruibal A. High level of interferon gamma in tuberculous pleural effusion. Chest 1988;93:308-11. 136. Shimokata K, Saka H, Murate T, Hasegawa Y, Hasegawa T. Cytokine content in pleural effusion. Chest 1991;99:1103-7. 137. Villena V, Lopez-Encuentra A, Echave-Sustaeta J, MartinEscribano P, Ortuno-de-Solo B, Estenoz-Alfaro J. Interferongamma in 388 immunocompromised and immunocompetent patients for diagnosing pleural tuberculosis. Eur Respir J 1996;9:2635-9. 138. Ogawa K, Koga H, Hirakata Y, Tomono K, Tashiro T, Kohno S. Differential diagnosis of tuberculous pleurisy by

139.

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

measurement of cytokine concentrations in pleural effusions. Tubercle Lung Dis 1997;78:29-34. Yamada Y, Nakamura A, Hosoda M, Kato T, Asano T, Tonegawa K, et al. Cytokines in pleural liquid for diagnosis of tuberculous pleurisy. Respir Med 2001;95:577-81. Aoe K, Hiraki A, Murakami T, Eda R, Maeda T, Sugi K, et al. Diagnostic significance of interferon-gamma in tuberculous pleural effusions. Chest 2003;123:740-4. Wong CF, Yew WW, Leung SK, Chan CY, Hui M, Au-Yeang C, et al. Assay of pleural fluid interleukin-6, tumour necrosis factor-alpha and interferon-gamma in the diagnosis and outcome correlation of tuberculous effusion. Respir Med 2003;97:1289-95. Hiraki A, Aoe K, Matsuo K, Murakami K, Murakami T, Onoda T, et al. Simultaneous measurement of T-helper 1 cytokines in tuberculous pleural effusion. Int J Tuberc Lung Dis 2003;7:1172-7. Prabha C, Jalapathy K, Matsa RM, Das SD. Role of TNF-alpha in host immune response in tuberculous pleuritis. Curr Sci 2003;85:639-42. Hiraki A, Aoe K, Eda R, Maeda T, Murakami T, Sugi K, et al. Comparison of six biological markers for the diagnosis of tuberculous pleuritis. Chest 2004;125:987-9. Sharma SK, Banga A. Diagnostic utility of pleural fluid interferon-gamma in tuberculosis pleural effusion. J Interferon Cytokine Res 2004;24:213-7. Sharma SK, Banga A. Pleural fluid interferon-gamma and adenosine deaminase levels in tuberculosis pleural effusion: a cost-effectiveness analysis. J Clin Lab Anal 2005;19:40-6. Jiang J, Shi HZ, Liang QL, Qin SM, Qin XJ. Diagnostic value of interferon-gamma in tuberculous pleurisy: a metaanalysis. Chest 2007;131:1133-41. Samuel AM, Kadival GV, Ashtekar MD, Ganatra RD. Evaluation of tubercular antigen and antitubercular antibodies in pleural and ascitic effusions. Indian J Med Res 1984;80:563-5. Murate T, Mizoguchi K, Amano H, Shimokata K, Matsuda T. Antipurified-protein-derivative antibody in tuberculous pleural effusions. Chest 1990;97:670-3. Caminero JA, deCastro FR, Carillo T, Cabrera P. Antimycobacterial antibody in tuberculous pleural effusions: reliability of antigen 60. Chest 1991;99:1315-6. Caminero JA, deCastro FP, Carrila T, Diaz F, Bermijo JCR, Cabrera P. Diagnosis of pleural tuberculosis by detection of specific IgG anti-antigen 60 in serum and pleural fluid. Respiration 1993;60:58-61. Chierakul N, Damrongchokpipat P, Chaiprasert A, Arjratanakul W. Antibody detection for the diagnosis of tuberculous pleuritis. Int J Tuberc Lung Dis 2001;5:968-72. Kunter E, Cerrahoglu K, Ilvan A, Isitmangil T, Turken O, Okutan O, et al. The value of pleural fluid anti-A60 IgM in BCG-vaccinated tuberculous pleurisy patients. Clin Microbiol Infect 2003;9:212-20. Yokoyama T, Rikimaru T, Kinoshita T, Kamimura T, Oshita Y, Aizawa H. Clinical utility of lipoarabinomannan antibody

264

155.

156.

157.

158.

159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169.

170.

Tuberculosis in pleural fluid for the diagnosis of tuberculous pleurisy. J Infect Chemother 2005;11:81-3. Kaisermann MC, Sardella IG, Trajman A, Coelho LV, Kampfer S, Jonas F, et al. IgA antibody responses to Mycobacterium tuberculosis recombinant MPT-64 and MT10.3 [Rv3019c] antigens in pleural fluid of patients with tuberculous pleurisy. Int J Tuberc Lung Dis 2005;9:461-6. Arora BR, Saini V, Prasad R, Kaur J, Arora K, Lal H. ELISA technique for the serodiagnosis of tuberculous pleural effusion. Lung India 1993;11:87-90. Baig MM, Pettengell KE, Simjee AE, Safhar MA, Vorster BJ. Diagnosis of tuberculosis by detection of mycobacterial antigen in pleural effusion and ascites. S Afr Med J 1986;69:101-2. Ramkisson A, Coovadia YM, Coovadia HM. A competition ELISA for the detection of mycobacterial antigen in tuberculous exudates. Tubercle 1988;69:209-12. Banchuin N, Wongurajana S, Pumprueg U, Jearanaisilavong J. Value of an ELISA for mycobacterial antigen detection as a routine diagnostic test of pulmonary tuberculosis. Asian Pac J Allergy Immunol 1990;8:5-11. Dhand R, Ganguly NK, Vaisnavi C, Gilhotra R, Malik SK. False positive reactions with enzyme-linked immunosorbent assay of Mycobacterium tuberculosis antigens in pleural fluid. J Med Microbiol 1988;26:241-3. Sarnaik RM, Sharma M, Kate SK, Jindal SK. Serodiagnosis of tuberculosis: assessment of kaolin agglutination test. Tuberc Lung Dis 1993;74:405-6. Levy H, Wayne LG, Anderson BE, Barnes PF, Light RW. Antimycobacterial antibody level in pleural fluid as a reflection of passive diffusion from serum. Chest 1990;97:1144-7. van Vooren J, Farber C, deBruyn J, Yernault JC. Antimycobacterial antibodies in pleural effusions. Chest 1990;97:8890. Yew WW, Chen CY, Kwan SY, Cheung SW, French GL. Diagnosis of tuberculous pleural effusion by the detection of tuberculostearic acid in pleural aspirates. Chest 1991;100:1261-3. Piras MA, Gakis C, Budroni M, Andreoni G. Adenosine deaminase activity in pleural effusions: an aid to differential diagnosis. Br Med J 1978;4:1751-2. Asseo PP, Tracopoulos GD, Kostovoulou-Fouskak V. Lysozyme [muramidase] in pleural effusions and serum. Am J Clin Pathol 1982;78:763-7. Verea Hernando HR, Masa Jimenez JF, Dominguez Juncal L, Perez Garcia-Buela J, Martin Egana MT, Fontan Bueso J. Meaning and diagnostic value of determining the lysozyme level of pleural fluid. Chest 1987;91:342-5. Mathur PN, Boutin C, Loddenkemper R. “Medical” thoracoscopy: techniques and indications in pulmonary medicine. J Bronchol 1994;1:1153-6. Harris RJ, Kavuru MS, Mehta AC. The impact of thoracoscopy on the management of pleural disease. Chest 1996;107:84552. Loddenkemper R. Thoracoscopy – state of the art. Eur Respir J 1998;11:213-21.

171. Mathur PN, Loddenkemper R. Medical thoracoscopy. Role in pleural and lung diseases. Clin Chest Med 1995;16:487-96. 172. Boutin C, Astoul P. Diagnostic thoracoscopy. Clin Chest Med 1998;19:295-309. 173. Chin DP, Yajko DM, Hadley WK, Sanders CA, Nassos PS, Madej JJ, et al. Clinical utility of a commercial test based on the polymerase chain reaction for detecting Mycobacterium tuberculosis in respiratory specimens. Am J Respir Crit Care Med 1995;151:1872-7. 174. de Wit D, Maartens G, Steyn L. A comparative study of the polymerase chain reaction and conventional procedures for the diagnosis of tuberculous pleural effusion. Tuber Lung Dis 1992;73:262-7. 175. de Lassence A, Lecossier D, Pierre C, Cadranel J, Stern M, Hance AJ. Detection of mycobacterial DNA in pleural fluid from patients with tuberculous pleurisy by means of the polymerase chain reaction: comparison of two protocols. Thorax 1992;47:265-9. 176. Verma A, Dasgupta N, Aggrawal AN, Pande JN, Tyagi JS. Utility of a Mycobacterium tuberculosis GC-rich repetitive sequence in the diagnosis of tuberculous pleural effusion by PCR. Indian J Biochem Biophys 1995;32:429-36. 177. Querol JM, Minguez J, Garcia-Sanchez E, Farga MA, Gimeno C, Garcia-de-Lomas J. Rapid diagnosis of pleural tuberculosis by polymerase chain reaction. Am J Respir Crit Care Med 1995;152:1977-81. 178. Tan J, Lee BW, Lim TK, Chin NK, Tan CB, Xia JR, et al. Detection of Mycobacterium tuberculosis in sputum, pleural and bronchoalveolar lavage fluid using DNA amplification of the MPB 64 protein coding gene and IS6110 insertion element. Southeast Asian J Trop Med Public Health 1995;26:247-52. 179. Villena V, Rebollo MJ, Aguado JM, Galan A, Lopez Encuentra A, Palenque E. Polymerase chain reaction for the diagnosis of pleural tuberculosis in immunocompromised and immunocompetent patients. Clin Infect Dis 1998;26:212-4. 180. Seethalakshmi S, Korath MP, Kareem F, Jagadeesan K. Detection of Mycobacterium tuberculosis by polymerase chain reaction in 301 biological samples–a comparative study. J Assoc Physicians India 1998;46:763-6. 181. Mitarai S, Shishido H, Kurashima A, Tamura A, Nagai H. Comparative study of amplicor Mycobacterium PCR and conventional methods for the diagnosis of pleuritis caused by mycobacterial infection. Int J Tuberc Lung Dis 2000;4:871-6. 182. Martins LC, Paschoal IA, Von Nowakonski A, Silva SA, Costa FF, Ward LS. Nested-PCR using MPB64 fragment improves the diagnosis of pleural and meningeal tuberculosis. Rev Soc Bras Med Trop 2000;33:253-7. 183. Villegas MV, Labrada LA, Saravia NG. Evaluation of polymerase chain reaction, adenosine deaminase, and interferon-gamma in pleural fluid for the differential diagnosis of pleural tuberculosis. Chest 2000;118:1355-64. 184. Reechaipichitkul W, Lulitanond V, Sungkeeree S, Patjanasoontorn B. Rapid diagnosis of tuberculous pleural effusion using polymerase chain reaction. Southeast Asian J Trop Med Public Health 2000;31:509-14.

Tuberculosis Pleural Effusion 265 185. Lima DM, Colares JK, da Fonseca BA. Combined use of the polymerase chain reaction and detection of adenosine deaminase activity on pleural fluid improves the rate of diagnosis of pleural tuberculosis. Chest 2003;124:909-14. 186. Kim SY, Park YJ, Kang SJ, Kim BK, Kang CS. Comparison of the BDProbeTec ET system with the Roche COBAS AMPLICOR System for detection of Mycobacterium tuberculosis complex in the respiratory and pleural fluid specimens. Diagn Microbiol Infect Dis 2004;49:13-8. 187. Moon JW, Chang YS, Kim SK, Kim YS, Lee HM, Kim SK, et al. The clinical utility of polymerase chain reaction for the diagnosis of pleural tuberculosis. Clin Infect Dis 2005;41:6606. 188. Takagi N, Hasegawa Y, Ichiyama S, Shibagaki T, Shimokata K. Polymerase chain reaction of pleural biopsy specimens for rapid diagnosis of tuberculous pleuritis. Int J Tuberc Lung Dis 1998;2:338-41. 189. Salian NV, Rish JA, Eisenach KD, Cave MD, Bates JH. Polymerase chain reaction to detect mycobacterium tuberculosis in histologic specimen. Am J Respir Crit Care Med 1998;158:1150-5. 190. Marchetti G, Gori A, Catozzi L. Evaluation of PCR in detection of Mycobacterium tuberculosis from formalin-fixed paraffinembedded tissues: comparison of four amplification assays. J Clin Microbiol 1998;36:1512–7. 191. Gamboa F, Fernandez G, Padilla E. Comparative evaluation of initial and new versions of the Gen-Probe Amplified Mycobacterium tuberculosis in respiratory and nonrespiratory specimens. J Clin Microbiol 1998;36:684-9. 192. Palacios JJ, Ferro J, Ruiz-Palma N. Comparison of the ligase chain reaction with solid and liquid culture media for routine detection of Mycobacterium tuberculosis in nonrespiratory specimens. Eur J Clin Microbiol Infect Dis 1998;17:767–72. 193. Ruiz-Manzano J, Manterola JM, Gamboa F, Calatrava A, Monso E, Martinez C, et al. Detection of Mycobacterium tuberculosis in paraffin-embedded pleural biopsy specimen by commercial ribosomal RNA and DNA amplification kits. Chest 2000;118:648–55. 194. Hasaneen NA, Zaki ME, Shalaby HM, El-Morsi AS. Polymerase chain reaction of pleural biopsy is a rapid and sensitive method for the diagnosis of tuberculous pleural effusion. Chest 2003;124:2105-11. 195. Aggarwal AN. Polymerase chain reaction for the diagnosis of tuberculous pleural effusion. Natl Med J India 2004;17:3213. 196. Patiala J. Initial tuberculous pleuritis in the Finnish Armed Forces in 1939-1945 with special reference to eventual post pleuritic tuberculosis. Acta Tuberc Scand 1954;36[Suppl]:157. 197. Roper WH, Warring JJ. Primary serofibrinous pleural effusion in military personnel. Am Rev Tuberc 1955;71:61634. 198. Patiala J, Mattila M. Effect of chemotherapy of exudative tuberculous pleurisy on the incidence of post pleuritic tuberculosis. Acta Tuberc Scand 1964;44:290-6.

199. Bass JB Jr, Farer LS, Hopewell PC, O’Brien R, Jacobs RF, Ruben F, et al. Treatment of tuberculosis and tuberculous infection in adults and children. Am J Respir Crit Care Med 1994;149:1359-74. 200. Ormerod LP, McCarthy OR, Rudd RM, Horsfield N. Shortcourse chemotherapy for tuberculous pleural effusion and culture-negative pulmonary tuberculosis. Tuber Lung Dis 1995;76:25-7. 201. Dhingra VK, Rajpal S, Aggarwal N, Aggarwal JK. Treatment of tuberculous pleural effusion patients and their satisfaction with DOTS: one and half year follow-up. Indian J Tuberc 2004;51:209-12. 202. Dutt AK, Moers D, Stead WW. Tuberculous pleural effusion: 6-month therapy with isoniazid and rifampin. Am Rev Respir Dis 1992;145:1429-32. 203. Canete C, Galarza I, Granados A, Farrero E, Estopa R, Manresa F. Tuberculous pleural effusion: experience with six months of treatment with isoniazid and rifampicin. Thorax 1994;49:1160-1. 204. Cohen M, Sahn SA. Resolution of pleural effusions. Chest 2001;119:1547-62. 205. Singla R. Pulmonary function tests in patients of tuberculous pleural effusion before, during and after chemotherapy. Indian J Tuberc 1995;42:33-41. 206. Al-Majed SA. Study of paradoxical response to chemotherapy in tuberculous pleural effusion. Respir Med 1996;90:211-4. 207. Hiraoka K, Nagata N, Kawajiri T, Suzuki K, Kurokawa S, Kido M, et al. Paradoxical pleural response to antituberculous chemotherapy and isoniazid-induced lupus. Review and report of two cases. Respiration 1998;65:152-5. 208. Vilaseca J, Lopez-Vivancos J, Arnau J, Guardia J. Contralateral pleural effusion during chemotherapy for tuberculous pleurisy. Tubercle 1984;65:209-10. 209. Raj B, Chawla RK, Chopra RK, Gupta KB, Kumar P. Development of contralateral pleural effusion during tuberculosis chemotherapy. Indian J Tuberc 1987;34:164-5. 210. Al-Ali MA, Almasri NM. Development of contralateral pleural effusion during chemotherapy for tuberculous pleurisy. Saudi Med J 2000;21:574-6. 211. Choi YW, Jeon SC, Seo HS, Park CK, Park SS, Hahm CK, et al. Tuberculous pleural effusion: new pulmonary lesions during treatment. Radiology 2002;224:493-502. 212. Candela A, Andujar J, Hernandez L, Martin C, Barroso E, Arriero JM, et al. Functional sequelae of tuberculous pleurisy in patients correctly treated. Chest 2003;123:1996-2000. 213. Barbas CS, Cukier A, de Varvalho CR, Barbas Filho JV, Light RW. The relationship between pleural fluid findings and the development of pleural thickening in patients with pleural tuberculosis. Chest 1991;100:1264-7. 214. Kunter E, Ilvan A, Kilic E, Cerrahoglu K, Isitmangil T, Capraz F, et al. The effect of pleural fluid content on the development of pleural thickness. Int J Tuberc Lung Dis 2002;6:516-22. 215. Wong CF, Leung SK, Yew WW. Percentage reduction of pleural effusion as a simple predictor of pleural scarring in tuberculous pleuritis. Respirology 2005;10:515-9.

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Tuberculosis

216. Dooley DP, Carpenter JL, Rademacher S. Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 1997;25:872-87. 217. Engel M, Matchaba PT, Volmink J. Corticosteroids for tuberculous pleurisy. Cochrane Database Syst Rev 2007;4:CD001876. 218. Galarza I, Canete C, Granados A, Estopa R, Manresa F. Randomised trial of corticosteroids in the treatment of tuberculous pleurisy. Thorax 1995;50:1305-7. 219. Wyser C, Walzl G, Smedema JP, Swart F, van Schalkwyk EM, van de Wal BW. Corticosteroids in the treatment of tuberculous pleurisy: A double-blind, placebo-controlled, randomized study. Chest 1996;110:333-8. 220. Lee CH, Wang WJ, Lan RS, Tsai YH, Chiang YC. Corticosteroids in the treatment of tuberculous pleurisy. A double-blind, placebo-controlled, randomized study. Chest 1988;94:1256-9. 221. Large SE, Levick RK. Aspiration in the treatment of primary tuberculous pleural effusion. Br Med J 1958;1:1512-4. 222. Lai YF, Chao TY, Wang YH, Lin AS. Pigtail drainage in the treatment of tuberculous pleural effusions: a randomised study. Thorax 2003;58:149-51. 223. Kwak SM, Park CS, Cho JH, Ryu JS, Kim SK, Chang J, et al. The effects of urokinase instillation therapy via percutaneous transthoracic catheter in loculated tuberculous pleural effusion: a randomized prospective study. Yonsei Med J 2004;45:822-8. 224. Mlika-Cabanne N, Brauner M, Mugusi F, Grenier P, Daley C, Mbaga I, et al. Radiographic abnormalities in tuberculosis and risk of coexisting human immunodeficiency virus infection. Results from Dar-es-Salaam, Tanzania, and scoring system. Am J Respir Crit Care Med 1995;152:786-93. 225. Mlika-Cabanne N, Brauner M, Kamanfu G, Grenier P, Nikoyagize E, Aubry P, et al. Radiographic abnormalities in tuberculosis and risk of coexisting human immunodeficiency virus infection. Methods and preliminary results from Bujumbura, Burundi. Am J Respir Crit Care Med 1995;152:794-9. 226. Afessa B. Pleural effusions and pneumothoraces in AIDS. Curr Opin Pulm Med 2001;7:202-9. 227. Deivanayagam CN, Rajasekaran S, Senthilnathan V, Krishnarajasekhar OR, Raja K, Chandrasekar C, et al. Clinicoradiological spectrum of tuberculosis among HIV seropositives: a Tambaram study. Indian J Tuberc 2001;48:123-7. 228. Debnath J, Sreeram MN, Sangameswaran KV, Panda BN, Tiwari SC, Mohan R, et al. Comparative study of chest radiographic features between HIV seropositive and HIV seronegative patients of pulmonary tuberculosis. Med J Armed Forces India 2002;58:5-8. 229. Jones BE, Young SM, Antoniskis D, Davidson PT, Kramer F, Barnes PF. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993;148:1292-7. 230. Frye MD, Pozsik CJ, Sahn SA. Tuberculous pleurisy is more common in AIDS than in non-AIDS patients with tuberculosis. Chest 1997;112:393-7.

231. Richter C, Perenboom R, Mtoni I, Kitinya J, Chande H, Swai AB, et al. Clinical features of HIV-seropositive and HIVseronegative patients with tuberculous pleural effusion in Dar-es-Salaam, Tanzania. Chest 1994;106:1471-5. 232. Heyderman RS, Makunike R, Muza T, Odwee M, Kadzirange G, Manyemba J, et al. Pleural tuberculosis in Harare, Zimbabwe: the relationship between human immunodeficiency virus, CD4 lymphocyte count, granuloma formation and disseminated disease. Trop Med Int Health 1998;3:1420. 233. Kitinya JN, Richter C, Perenboom R, Chande H, Mtoni IM. Influence of HIV status on pathological changes in tuberculous pleuritis. Tuber Lung Dis 1994;75:195-8. 234. Relkin F, Aranda CP, Garay SM, Smith R, Berkowitz KA, Rom WN. Pleural tuberculosis and HIV infection. Chest 1994;105:1338-41. 235. Gil V, Cordero PJ, Greses JV, Soler JJ. Pleural tuberculosis in HIV-infected patients. Chest 1995;107:1775-6. 236. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus. Principles of therapy and revised recommendations. MMWR Morb Mortal Wkly Rep 1998;47:1-51. 237. Arora VK, Gowrinath K, Rao RS. Extrapulmonary involvement in HIV with special reference to tuberculous cases. Indian J Tuberc 1995;42:27-32. 238. Sharma SK, Mohan A, Kadhiravan T. HIV-TB co-infection: epidemiology, diagnosis and management. Indian J Med Res 2005;121:550-67. 239. Repo UK, Nieminen P. Tuberculosis pleurisy due to Mycobacterium fortuitum in a patient with chronic granulocytic leukemia. Scand J Respir Dis 1975;56:329-36. 240. Christensen EE, Dietz GW, Ahn CH, Chapman JS, Murry RC, Anderson J, et al. Initial roentgenographic manifestations of pulmonary Mycobacterium tuberculosis, M. kansasii, and M. intracellularis infections. Chest 1981;80:132-6. 241. Aronchick JM, Miller WT. Disseminated nontuberculous mycobacterial infections in immunosuppressed patients. Semin Roentgenol 1993;8:150-7. 242. Gribetz AR, Damsker B, Marchevsky A, Bottone EJ. Nontuberculous mycobacteria in pleural fluid. Assessment of clinical significance. Chest 1985;87:495-8. 243. Mancini P, Mazzei L, Zarzana A, Biagioli D, Sposato B, Croce GF. Post-tuberculosis chronic empyema of the “forty years after”. Eur Rev Med Pharmacol Sci 1998;2:25-9. 244. Sahn SA, Iseman MD. Tuberculous empyema. Semin Respir Infect 1999;14:82-7. 245. Bai KJ, Wu IH, Yu MC, Chiang IH, Chiang CY, Lin TP, et al. Tuberculous empyema. Respirology 1998;3:261-6. 246. Gupta SK, Kishan J, Singh SP. Review of one hundred cases of empyema thoracis. Indian J Chest Dis Allied Sci 1989;31:1520. 247. Reeve PA, Seaton D. Tuberculous empyema - a case history extending over 30 years. Tubercle 1986;67:147-50. 248. Al-Kattan KM. Management of tuberculous empyema. Eur J Cardiothorac Surg 2000;17:251-4.

Tuberculosis Pleural Effusion 267 249. Elliott AM, Berning SE, Iseman MD, Peloquin CA. Failure of drug penetration and acquisition of drug resistance in chronic tuberculous empyema. Tuber Lung Dis 1995;76:463-7. 250. Neihart RE, Hof DG. Successful nonsurgical treatment of tuberculous empyema in an irreducible pleural space. Chest 1985;88:792-4. 251. Khanna BK. Management of tuberculous empyema. Indian J Tuberc 1987;34:147-9. 252. Mouroux J, Maalouf J, Padovani B, Rotomondo C, Richelme H. Surgical management of pleuropulmonary tuberculosis. J Thorac Cardiovasc Surg 1996;111:662-70. 253. Lahiri TK, Agrawal D, Gupta R, Kumar S. Analysis of status of surgery in thoracic tuberculosis. Indian J Chest Dis Allied Sci 1998;40:99-108. 254. Choi SS, Kim DJ, Kim KD, Chung KY. Change in pulmonary function following empyemectomy and decortication in tuberculous and non-tuberculous chronic empyema thoracis. Yonsei Med J 2004;45:643-8. 255. Kim DJ, Im JG, Goo JM, Lee HJ, You SY, Song JW. Chronic tuberculous empyema: relationships between preoperative CT findings and postoperative improvement measured by pulmonary function testing. Clin Radiol 2005;60:503-7.

256. Light RW. Chylothorax and pseudochylothorax. In: Light RW, editor. Pleural diseases. Fourth Edition. Philadelphia: Lippincott Williams and Wilkins; 2001.p.327-43. 257. Garcia-Zamalloa A, Ruiz-Irastorza G, Aguayo FJ, Gurrutxaga N. Pseudochylothorax. Report of 2 cases and review of the literature. Medicine [Baltimore] 1999;78:200-7. 258. Hamm H, Pfalzer B, Fabel H. Lipoprotein analysis in a chyliform pleural effusion: implications for pathogenesis and diagnosis. Respiration 1991;58:294-300. 259. Vennera MC, Moreno R, Cot J, Marin A, Sanchez-Lloret J, Picado C, et al. Chylothorax and tuberculosis. Thorax 1983;38:694-5. 260. Menzies R, Hidvegi R. Chylothorax associated with tuberculous spondylitis. Can Assoc Radiol J 1988;39:238-41. 261. Anton PA, Rubio J, Casan P, Franquet T. Chylothorax due to Mycobacterium tuberculosis. Thorax 1995;50:1019. 262. Singh S, Girod JP, Ghobrial MW. Chylothorax as a complication of tuberculosis in the setting of the human immunodeficiency virus infection. Arch Intern Med 2001;161:2621. 263. Gupta D, Maheswari U, Aggarwal AN. Tuberculous chylothorax. Lung India 2004;21:54-5.

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Silicotuberculosis

18 Praveen Aggarwal

INTRODUCTION Silicosis is a major occupational lung disease which remains a problem in both industrialized and developing countries. Tuberculosis [TB] contributes significantly to the morbidity and mortality of patients with silicosis (1-3). In order to have a proper understanding of silicotuberculosis, it is important to discuss briefly about silicosis. SILICOSIS Silicosis, one of the most common forms of pneumoconiosis, is an ancient disease which probably dates from the Stone Age. Pneumoconiosis is defined as a condition characterized by an accumulation of dust in the lung parenchyma and the tissue reaction to it (4). Silicosis develops from the inhalation of silica particles. The industries involved in silicosis include quarrying and rockbreaking, sandblasting, construction and the founding of ferrous and non-ferrous metals. The exact prevalence of silicosis in India is not known. Several studies have been carried out in persons working in highrisk industries. Most of these studies have utilized radiographic findings to make a diagnosis of silicosis. Gupta et al (5) from Rohtak reported radiologic evidence of silicosis in 28.3 per cent of stone-cutters. When the study was extended, silicosis was evident radiologically in as many as 35.2 per cent of 227 stone-cutters (6). In slate pencil workers of Madhya Pradesh, silicosis was reported in 57 per cent workers (7). The main determinants of silicosis are exposure to silica dust, its duration and the level, the size, distribution and respirability of airborne particles, and their

fibrogenic potential. Factors which can modify the exposure response to airborne silica include the presence of other dust particles. For instance, the mixed dust pneumoconiosis in foundry workers probably represents the modification of the response to silica in the presence of other dusts which contaminate many foundries (8). Host factors probably also contribute to the clinical picture of silicosis. There may be an association between exposure to silica dust [and/or silicosis] and the presence of progressive systemic sclerosis (9,10). Genetic factors may also influence the body’s response to silica exposure though there are inconsistent reports regarding this (11,12). The clinical presentation of silicosis is usually grouped into three types (13) as described below. Chronic Silicosis Chronic silicosis is the commonest form of silicosis which occurs after many decades of exposure to relatively low levels of silica. It is usually seen in industries with rigorous environmental control procedures. This form of silicosis is characterized by gradually progressive dyspnoea, dry cough and evidence of progressive fibrosis of both lungs on a chest radiograph. The course of this form of silicosis is often compatible with a normal life span (14). Acute Silicosis Acute silicosis occurs after exposure to a very high concentration of dust over a few months and is usually rapidly fatal within years (14). Currently, sandblasters and silica flour mill workers are the two groups considered at high risk of developing acute silicosis.

Silicotuberculosis Accelerated Silicosis Accelerated silicosis occurs after a few years of exposure to silica and is associated with rapidly progressive features of dyspnoea and pulmonary fibrosis. Radiographic Findings The radiological features of silicosis [Table 18.1] are variable and range from diffuse fine rounded regular nodularity resembling miliary TB to coarser irregular nodules or extensive fibrosis resembling progressive massive fibrosis. In early stages, upper zones of the lungs are more commonly involved as compared to the lower zones. The involvement of lymph nodes by chronic silicosis is fairly characteristic, with a tendency towards peripheral calcification, which produces the so-called eggshell appearance [Figure 18.1]. The hilar and mediastinal groups are most often affected, but other thoracic and extrathoracic nodes may also be affected. The visceral pleura is often diffusely thickened by fibrosis with occasional focal calcification. Involvement of the middle Table 18.1: Radiographic findings in patients with silicosis Multiple nodular shadows Reticular pattern Conglomerate nodular shadows and large opacities Cavitation Egg-shell calcification involving hilar and mediastinal lymph nodes Extensive fibrosis

Figure 18.1: Chest radiograph [postero-anterior view] showing egg-shell calcification in the hilar lymph nodes

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and lower zones of the lungs is more frequent in accelerated silicosis. Bronchoalveolar Lavage Bronchoalveolar lavage shows increased number of total cells in patients with silicosis as compared to normal subjects. This increase is due to an increase in both lymphocytes and alveolar macrophages. However, the proportion of alveolar macrophages is significantly lower, whereas lymphocytes are significantly higher in patients with silicosis than in control subjects (15,16). Complications Tuberculosis is the most frequent complication of silicosis. Other complications include oesophageal compression, left recurrent laryngeal nerve palsy, atelectasis, pulmonary artery hypertension, chronic respiratory failure, recurrent chest infections, lung abscess, chronic cor-pulmonale, pneumothorax, hydropneumothorax, perforation of the bronchial tree by the calcified lymph nodes and lung cancer (14,17). SILICOTUBERCULOSIS Epidemiology Much of the information about the association between silicosis and TB was documented by clinical observations and autopsy reports in the early part of the 20th century, and later by epidemiological surveys conducted in different parts of the world. In a study from Spain, the incidence of TB was found to be 150.1 [±30.9] cases per 100 000 miners per year between 1971 and 1985 (18). This incidence was three times that in the general population in that area. Studies from Hong Kong revealed a 27 per cent incidence of TB over five years among a group of 679 patients with silicosis (3). In a study from China, TB was diagnosed in as many as 43 per cent patients with silicosis when followed over a period of 18 years (19). Of these, 55.1 per cent cases of TB were identified when silicosis was first diagnosed. Tuberculosis was the major cause [62.1%] of deaths in these patients. However, over the years, the mortality from TB has reduced possibly because of better surveillance and treatment. In another study, TB accounted for 11.8 per cent deaths in patients with silicosis (20). It has also been shown that in small industries where the environmental conditions are poor, the prevalence of silicosis and silicotuberculosis is high (21).

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In a recent study (22), the mortality data over 40 years was analysed in 200 silica-exposed persons. Of 200 persons, 99 died during this period. Pulmonary TB was responsible for 10 deaths of which nine had silicosis. The standardized mortality ratio for pulmonary TB in the studied population was much higher compared to that in the general population, indicating that silicotuberculosis has a greater mortality compared to TB without underlying silicosis (22). The prevalence of pulmonary TB is closely associated with age and service duration of the workers (23), as well as the severity of underlying silicosis (24). From India, a few studies are available which have shown a higher incidence of TB in patients with silicosis. In 1949, Sikand and Pamra (25) reported TB in 28.6 per cent of patients with silicosis. Other workers have reported three to seven times higher incidence of TB in persons with silicosis compared to those without silicosis among persons working at the same place (5,6). Overall, it appears that TB occurs in as many as 20 to 25 per cent of all silicosis patients in their lifetime. Tuberculosis is one of the important predictors of mortality in patients with silicosis. For the same radiological extent of silicosis, the mortality risk is higher than expected if TB develops (26,27). It appears that the relative risk of death from TB is three- to six-fold greater in patients with silicosis than in the general population. Epidemiological and experimental studies also suggest that the exposure to silica dust, even in the absence of radiological silicosis, may be responsible for the increased rate of pulmonary TB (2,28). It is generally agreed that the prevalence rate of TB in the general population at a given point in time determines the incidence of infection in patients with silicosis. Better control of TB in a population has an important influence on decreasing the risk of TB in patients with silicosis (29). The distribution and prevalence of different species of mycobacteria in the general population also determine the incidence of mycobacterial diseases in patients with silicosis. In a study by Bailey et al (13), Mycobacterium kansasii and Mycobacterium avium-intracellulare were reported in 12 of the 22 cases of silicosis with mycobacterial infection. Cowie et al (30) reported atypical mycobacteria in 14 per cent of 234 gold miners. On the other hand, no case of atypical mycobacterial infection was reported in the study from Hong Kong (3). This is

because atypical mycobacteria are encountered infrequently in the general population (3). Influence of Tuberculosis on the Progression of Silicosis Animal experiments suggest that concomitant exposure to silica has an unfavourable influence on the course of induced TB (31,32) and that more fibrosis is produced by silicosis and TB combined than by either of these acting alone. Although clinical evidence is limited, such a synergistic effect of silicosis and TB in producing more proliferative fibrous reaction appears to be substantiated by general clinical impression (13). Moreover, TB may complicate simple silicosis as well as advanced disease (28). It has been postulated that TB infection might contribute to the development of massive fibrosis in patients with silicosis (33-35). Pathogenesis Several pathogenetic processes are common to TB and silicosis which may be synergistic in producing more fibrosis and in enhancing susceptibility to mycobacterial infection or reactivation of a latent focus of infection. The silica particles are phagocytosed by the alveolar macrophages. Inside these cells, silica particles are engulfed in phagolysosomes. Silica has the capacity to cause damage to the cell membranes which leads to the death of the macrophages with re-exposure of the other macrophages to the same particles. Prior to their death, the macrophages become activated and secrete interleukin 1β [IL-1β] and tumour necrosis factor-α [TNF-α] (36). These cytokines are responsible for fibroblast activation and fibrosis. The TNF-α also stimulates neutrophils to release oxidants which produce local damage. It has been postulated that both humoral and cellmediated immune responses are inhibited in silicosis. Cell-mediated immunity is important to contain the mycobacteria, and its alteration could facilitate infection with mycobacteria. Lung fibrosis occurs in both diseases and may interfere with the clearance of dust-laden alveolar macrophages or mycobacteria-laden material from the lung. Lymphatic obstruction causes macrophages to accumulate in the interstitial tissues resulting in local fibrosis (34). Another hypothesis for the unexplained incidence of pulmonary TB in patients with silicosis is through the

Silicotuberculosis surface coordination of iron by dust particles (37). By this process, the body iron is adsorbed by the silica crystals in the lung. Indeed, low serum iron has been observed among people exposed to silicates (38). Evidence that iron is complexed on the silicate dust can be found by the use of specific stains for iron or by measurement of the iron content of lungs in which silicate content is increased (39). This iron can be mobilized from the silicate surface by a strong iron chelator. Mycobacteria are dependent on iron for growth and produce the iron chelators, namely, mycobactin and exochelin to mobilize the metal from body stores; indeed iron is considered a virulence factor for mycobacteria. It has been hypothesized that silicate particles act as a reservoir of iron which can be used by the mycobacteria thereby, explaning the increased incidence of TB among those who inhale silica dust (37). The iron made available from silicato-iron complexes may activate dormant tubercle bacilli by a mechanism similar to the effect of iron repletion (40). Clinical Features The manifestations of TB in patients with silicosis are similar to those in general population. However, since malaise, fatiguability, dyspnoea and night sweats occur in silicosis also, at times, it may be difficult to detect superimposed TB clinically. Diagnosis The diagnosis of active TB in patients with silicosis demands a high degree of suspicion [Table 18.2]. From the point of view of radiology, it is usually quite challenging to differentiate abnormalities in the chest radiograph of a patient with silicosis who has superimposed TB. Tuberculosis can be suspected in patients with silicosis when the radiographic abnormalities are seen in the apical area of either of the lungs. These abnormalities include poorly demarcated infiltrates of variable size that do not cross the lung fissures (41). These opacities may Table 18.2: Features suggestive of tuberculosis in patients with silicosis Apical location Cavitation Rapidly changing opacities Pleural effusion Pericardial effusion

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Figure 18.2: Chest radiograph [postero-anterior view] showing tuberculosis cavity in a patient with silicosis

surround pre-existing silicotic nodules. Presence of a cavity in a nodule is usually indicative of TB [Figure 18.2] (41,42) though large fluid-filled cavities have been reported in silicosis also (43). Tuberculosis cavities in patients with silicosis are usually not traversed by large vessels possibly due to vascular obstruction frequently seen in these patients (44). Additional suggestive findings include rapid changes in the radiographic picture, development of pericardial or pleural effusion, or onset of bronchial stenosis, especially of the right middle lobe (41). Computed tomography [CT] of the chest may be useful in some patients (44). Establishing the diagnosis of pulmonary TB in a patient with silicosis by bacteriological methods is often difficult (41,45). Therefore, more frequent sputum examination for acid-fast bacilli is recommended (45). The need for mycobacterial culture is more important in areas where there is a high prevalence of nontuberculous mycobacterial infection. Distinguishing this disease from miliary TB is particularly important as some patients have both conditions. Previous recommendation was to treat all patients with any possibility of miliary TB with antituberculosis treatment (46). It is suggested that sputum examination, fibreoptic bronchscopy, bronchoalveolar lavage and transbronchial lung biopsy should be performed in all patients to facilitate accurate and early

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diagnosis and, thus, obviating the need for a therapeutic trial of antituberculosis treatment (47). Treatment Presently, empirical treatment with antituberculosis drugs is often necessary because of the serious consequences of not treating miliary TB, if the diagnosis is not obvious despite a bronchoscopic examination and bronchoalveolar lavage. Previously, the success rate of the treatment of TB in patients with silicosis was reported to be lower than that in patients without silicosis (45,48,49). It has been postulated that the intense fibrotic reaction and vascular obstruction seen in patients with silicosis makes it difficult for the drugs to reach their target. However, most of these studies were conducted at time when new effective antituberculosis agents were not available. Based on the results of these studies, those miners working in the South African gold mines who were diagnosed to have pulmonary TB were excluded by law from further underground work. This regulation was based on experimental evidence from animal studies that the pulmonary resistance to infection by mycobacteria is impaired in direct proportion to its total silica dust load, and the belief that TB can never be cured in patients with silicosis (30,50,51). However, it was shown later that once the febrile phase of the disease subsides on treatment with antituberculosis drugs, the return to underground work did not adversely affect the treatment outcome as reflected by the relapse rate which may be same (30,52,53), or a little higher in patients with silicosis than in those without silicosis (54). As in pulmonary TB, most of the relapses in patients with silicotuberculosis occur within first two years after stopping the drugs but the risk of relapse may continue indefinitely after completion of treatment (30). In several recent trials, the efficacy of a short-course chemotherapy has been established in patients with silicotuberculosis (30,52-54). However, a few studies have suggested the need for a longer duration of antituberculosis treatment (55). Treatment of silicotuberculosis is similar to the treatment of TB elsewhere in the body. The reader is referred to the chapter “Treatment of tuberculosis” [Chapter 52] for more details. Long-term follow-up is recommended to diagnose possible relapse after the completion of treatment. In India, patients with TB receive DOTS

under the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India. The reader is referred to the chapter “Revised National Tuberculosis Control Programme” [Chapter 63] for more details. Prevention As TB is quite common in patients with silicosis, there is a strong case for considering antituberculosis chemoprophylaxis in patients with silicosis. The currently accepted regimen of administering isoniazid for six to twelve months has been shown to be highly effective in individuals without silicosis but has been associated with appreciable risk of hepatic toxicity, particularly in older age groups (56). Poor compliance is a common problem with the chemoprophylaxis regimens and is inevitably related to their long duration (57). Therefore, it is important to develop shorter chemoprophylaxis regimens for patients with silicosis. In a preliminary study, the rate of development of active TB in patients with silicosis has been shown to be reduced to half when they were given rifampicin for 12 weeks, isoniazid and rifampicin for 12 weeks, and isoniazid for 24 weeks (3). However, this figure is less than that seen in individuals without silicosis, when isoniazid alone is used as prophylactic agent (57). This suggests that the local immune response is less efficient in subjects with silicosis, probably because of direct impairment of macrophage function by free silica (45,58). Further, the trials on prophylaxis suggest a need to develop a regimen which would prevent the occurrence of TB in a majority of patients with silicosis. At present, the Centers for Disease Control and Prevention recommends isoniazid prophylaxis for one year to all patients with silicosis who are tuberculin positive. Besides chemoprophylaxis, engineering measures to reduce or eliminate the exposure to silica dust are important in reducing the incidence of both silicosis and silicotuberculosis. There is a strong evidence to support the view that silica dust control is associated with a major reduction in risk of TB in silica-exposed patients (59). An active surveillance of the workers should be carried out in both pre-employment and post-employment periods. This involves performing periodic chest radiographs and tuberculin skin tests. Careful clinical investigations and close follow-up of tuberculin converters are essential to reduce the risk of TB.

Silicotuberculosis REFERENCES 1. Rees D, Murray J. Silica, silicosis and tuberculosis. Int J Tuberc Lung Dis 2007;11:474-84. 2. Qu Y, Tang Y, Cao D, Wu F, Liu J, Lu G, et al. Genetic polymorphisms in alveolar macrophage response-related genes, and risk of silicosis and pulmonary tuberculosis in Chinese iron miners. Int J Hyg Environ Health 2007 Jan 12;[Epub ahead of print]. 3. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. A double-blind placebo-controlled clinical trial of three antituberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong. Am Rev Respir Dis 1992;145:36-41. 4. International Labour Office. Encyclopedia of occupational health and safety. Vol II. Geneva: International Labour Organization;1976.p.1085-92. 5. Gupta SP, Garg AK, Gupta OP. Silicosis amongst stonecutters. J Assoc Physicians India 1969;17:163-72. 6. Gupta SP, Bajaj A, Jain AL, Vasudeva YL. Clinical and radiological studies in silicosis: based on a study of the disease amongst stone-cutters. Indian J Med Res 1972;60:1309-15. 7. Jain SM, Sepaha GC, Khare KC, Dubey VS. Silicosis in slate pencil workers. A clinicoradiologic study. Chest 1977;71:4236. 8. Cotes JE, Steel J. Work-related lung disorders. Oxford: Blackwell;1987.p.1-436. 9. Cowie RL. Silica-dust-exposed miners with scleroderma [systemic sclerosis]. Chest 1987;92:260-2. 10. Sluis-Cremer GK, Hessel PA, Hnizdo EH, Churchill AR, Zeiss EA. Silica, silicosis and progressive systemic sclerosis. Br J Ind Med 1985;42:838-43. 11. Kreiss K, Danilovs JA, Newman LS. Histocompatibility antigens in a population based silicosis series. Br J Ind Med 1989;46:364-9. 12. Sluis-Cremer GK, Maier G. HLA antigens of the A and B locus in relation to the development of silicosis. Br J Ind Med 1984;41:417-8. 13. Bailey WC, Brown M, Buechner HA, Weill H, Ichinose W, Ziskind M. Silico-mycobacterial disease in sand-blasters. Am Rev Respir Dis 1974;110:115-25. 14. Ziskind M, Jones RN, Weill H. Silicosis. Am Rev Respir Dis 1976;113:643-65. 15. Sharma SK, Pande JN, Verma K. Bronchoalveolar lavage fluid [BALF] analysis in silicosis. Indian J Chest Dis Allied Sci 1988;30:257-61. 16. Sharma SK, Pande JN, Verma K. Effect of prednisolone treatment in chronic silicosis. Am Rev Respir Dis 1991;143:81421. 17. Hughes JM, Weill H, Rando RJ, Shi R, Mcdonald AD, Mcdonald JC. Cohort mortality study of North American industrial sand workers. II. Case-reference analysis of lung cancer and silicosis deaths. Ann Occup Hyg 2001;45:201-7. 18. Mosquera JA. Epidemiologia de la Silico-tuberculosis en Mineros Asturianos: Tasa de Nuevos Casos Bacetriologicamente Positivos. Periodo 1971-1985. Proceedings of the

19.

20.

21.

22.

23.

24. 25.

26. 27. 28.

29.

30.

31.

32.

33. 34. 35. 36.

37.

273

7th International Pneumoconiosis Conference. Washington DC: National Institute of Occupational Safety and Health;1990.p.683-4. Lou J, Zhou C. The prevention of silicosis and prediction of its future prevalence in China. Am J Public Health 1989;79:1613-6. Forastiere F, Lagorio S, Michelozzi P, Perucci CA. Mortality pattern of silicotic subjects in the Latium region, Italy. Br J Ind Med 1989;46:877-80. Huang J, Shibata E, Takeuchi Y, Okutani H. Comprehensive health evaluation of workers in the ceramic industry. Br J Ind Med 1993;50:112-6. Ogawa S, Imai H, Ikeda M. Mortality due to silicotuberculosis and lung cancer among 200 whetstone cutters. Ind Health 2003;41:231-5. Kleinschmidt I, Churchyard G. Variation in incidences of tuberculosis in subgroups of South African gold miners. Occup Environ Med 1997;54:636-41. Cowie RL. The epidemiology of tuberculosis in gold miners with silicosis. Am J Respir Crit Care Med 1994;150:1460-2. Sikand BK, Pamra SP. Preliminary report on the occurrence of silicosis amongst stone masons. Proceedings of the seventh Tuberculosis Workers’ Conference, Bombay 1949. Westerholm P. Silicosis: Observations on a case register. Scand J Work Environ Health 1980;6[Suppl2]:5-86. Ng TP, Chan SL, Lee J. Predictors of mortality in silicosis. Respir Med 1992;86:115-9. Westerholm P, Ahlmark A, Maasing R, Segelberg I. Silicosis and risk of lung cancer or lung tuberculosis. Environ Res 1986;41:339-50. Peters JM. Silicosis. In: Merchant JM, editor. Occupational respiratory diseases. Washington DC: Department of Health and Human Services [NIOSH Pub. No. 86-102];1986.p.21937. Cowie RL, Langton ME, Becklake MR. Pulmonary tuberculosis in South African gold miners. Am Rev Respir Dis 1989;139:1086-9. Policard A, Gernez-Rieux C, Tacquet A, Martin JC, Devulder B, Le Bouffant L. Influence of pulmonary dust load on the development of experimental infection by Mycobacterium kansasii. Nature 1967;216:177-8. Ebina T, Takahashi Y, Hasuike T. Effects of quartz powder on tubercle bacilli and phagocytes. Am Rev Respir Dis 1960;82:516-27. Green GM. In defence of the lung. Am Rev Respir Dis 1970;102:691-703. Ng TP, Allan WGL, Tsin TW, O’Kelly FJ. Silicosis in jade workers. Br J Ind Med 1985;42:761-4. Ng TP, Chan SL. Factors associated with massive fibrosis in silicosis. Thorax 1991;46:229-32. Piguet PF, Collart MA, Graau GE, Sappino A-P, Vassalli P. Requirement of tumour necrosis factors for development of silica-induced pulmonary fibrosis. Nature 1990;344:245-7. Ghio AJ, Kennedy TP, Schapira RM, Crumbliss AL, Hiodal JR. Hypothesis: is lung disease after silicate inhalation caused by oxidant generation? Lancet 1990;336:967-9.

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Tuberculosis

38. Niculescu T, Dumitru R, Burnea D. Changes of copper, iron and zinc in the serum of patients with silicosis, silicotuberculosis, and active lung tuberculosis. Environ Res 1981;25:2608. 39. Guest L. The endogenous iron content, by Mossbauer spectroscopy, of human lungs: lungs from various occupational groups. Ann Occup Hyg 1978;21:151-7. 40. Murray MJ, Murray AB, Murray MB, Murray CJ. The adverse effect of iron repletion on the course of certain infections. Br Med J 1978;2:1113-5. 41. Barras G. Silico-tuberculose en Suisse. Schweiz Med Wochenschr 1970;100:1802-8. 42. Ng TP. Occupational lung diseases - mineral dusts. In: Jeyaratnam J, editor. Occupational health in developing countries. Oxford: Oxford University Press;1992.p.287-303. 43. Malik SK, Behera D, Awasthi GK, Singh JP. Pulmonary silicosis in emery polish workers. Indian J Chest Dis Allied Sci 1985;27:116-21. 44. de la Hoz R. Tuberculosis and silicosis. In: Rom WN, Garay S, editors. Tuberculosis. Boston: Little, Brown and Company; 1996.p. 525-30. 45. Snider DE. The relationship between tuberculosis and silicosis. Am Rev Respir Dis 1978;118:455-60. 46. Palmer PES, Daynes WG. Transkei silicosis. S Afr Med J 1967;41:1182-8. 47. Grobbelaar JP, Bateman ED. Hut lung: a domestically acquired pneumoconiosis of mixed aetiology in rural women. Thorax 1991;46:334-40. 48. Marrow CS. The results of chemotherapy in silicotuberculosis. Am Rev Respir Dis 1960;82:831-4.

49. Ramsay JHR, Pines A. The late results of chemotherapy in pneumoconiosis complicated by tuberculosis. Tubercle 1963;44:99-109. 50. Allison AC, D’Arey Hart P. Potentiation by silica of the growth of M. tuberculosis in macrophage cultures. Br J Exp Pathol 1968;49:465-76. 51. Morgan EJ. Silicosis and tuberculosis. Chest 1979;75:202-3. 52. Escreet BC, Langton ME, Cowie RL. Short-course chemotherapy for silicotuberculosis. S Afr Med J 1984;66:327-30. 53. Cowie RL. Silicotuberculosis: long-term outcome after shortcourse chemotherapy. Tuber Lung Dis 1995;76:39-42. 54. Lin TP, Suo J, Lee CN, Yang SP. Short-course chemotherapy for pulmonary tuberculosis in pneumoconiotic patients. Am Rev Respir Dis 1987;136:808-10. 55. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. A controlled clinical trial comparison of 6 months and 8 months of antituberculosis chemotherapy in the patients with silicotuberculosis in Hong Kong. Am Rev Respir Dis 1991;143:262-70. 56. Edwards PQ. Isoniazid associated hepatitis. Bull Int Union Tuber 1976;51:209-12. 57. International Union Against Tuberculosis Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. Bull World Health Organ 1982;60: 555-64. 58. Lowrie DB. What goes wrong with the macrophage in silicosis? Eur J Respir Dis 1982;63:180-2. 59. Costello J, Graham WGB. Vermont granite worker’s mortality study. Am J Ind Med 1988;13:483-97.

Abdominal Tuberculosis

19

M Tewari, SP Sahoo, HS Shukla

INTRODUCTION Abdominal tuberculosis [TB] includes TB of the gastrointestinal tract, peritoneum, omentum, mesentery, lymph nodes and other solid intra-abdominal organs like liver, spleen and pancreas. It is one of the most common forms of extra-pulmonary TB (1,2). Mycobacterium tuberculosis, Mycobacterium bovis and nontuberculous mycobacteria [NTM] can cause abdominal TB. With widespread pasteurization of milk and the strict control of TB in dairy herds, abdominal TB caused by Mycobacterium bovis is rarely seen in the present era and Mycobacterium tuberculosis is the most frequently isolated organism. Classification of abdominal TB is listed in Table 19.1. PERITONEAL TUBERCULOSIS Epidemiology Tuberculosis peritonitis constitutes four to ten per cent of all patients with extra-pulmonary TB and has been estimated to occur in 0.1 to 3.5 per cent of patients with pulmonary TB (1,5-11). Pathogenesis Activation of long-standing latent foci of TB infection of the peritoneum or haematogenous spread of bacilli from an active pulmonary lesion results in the development of TB peritonitis. Contiguous spread of infection from an intestinal lesion or fallopian tube is a relatively infrequent mechanism. Very rarely, TB peritonitis has been described as a complication of peritoneal dialysis (12).

Table 19.1: Classification of abdominal tuberculosis Gastrointestinal tuberculosis Ulcerative Hypertrophic Hypertrophic or hyperplastic Sclerotic or fibrous Diffuse colitis Peritoneal tuberculosis Tuberculosis of the peritoneum Acute tuberculosis peritonitis Chronic peritoneal tuberculosis Ascitic form Encysted [loculated] form Fibrous form Adhesive type Plastic type Tuberculosis of the mesentery and its contents Mesenteric adenitis Mesenteric cyst[s] Mesenteric abscess[es] Bowel adhesions Rolled-up omentum Tuberculosis of the solid viscera Liver, biliary tract and gall bladder Pancreas Spleen Miscellaneous Retroperitoneal lymph node tuberculosis etc. Based on references 3,4

Clinical Presentation Clinical presentation of TB peritonitis is detailed in Table 19.2 (1,6-11).

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Table 19.2: Clinical presentation of tuberculosis peritonitis Variable Abdominal swelling Abdominal pain Weight loss Diarrhoea Ascites on physical examination Abdominal tenderness Ascitic peritonitis Fibroadhesive peritonitis without ascites Anaemia Positive tuberculin test Abnormal chest radiograph Associated active pulmonary tuberculosis

Frequency [%] 65-100 36-93 37-87 9-27 51-100 65-87 92-100 0-8 48-68 55-100 37-63 4-21

Data are derived from references 6-11 Adapted from reference 1

Tuberculosis of the Peritoneum Acute Tuberculosis Peritonitis Tuberculosis peritonitis may have an onset closely resembling acute abdomen and such patients may often be subjected to emergency surgery (2-4). In this setting, when the abdomen is opened, straw-coloured fluid may be present and tubercles may be found scattered over the peritoneum and greater omentum. Sometimes, in addition to acute abdominal symptoms, ascites may be clinically demonstrable making the diagnosis of peritonitis reasonably evident (2-4). Chronic Tuberculosis Peritonitis Most often, persons between 25 and 45 years of age are affected and a slight female preponderance has been observed (1,6-11). Abdominal pain and swelling are the most common presenting symptoms. Symptoms of TB toxaemia such as fever, weight loss and night sweats are often present. In about a quarter of the patients, an abdominal mass may be felt (1,6-11). Three varieties of chronic TB peritonitis have been described, namely, ascitic, encysted [loculated], and fibrous forms. Ascitic form Ascitic form of TB peritonitis often has an insidious onset. History of fatigue, weight loss, fever, anorexia, facial pallor, and abdominal distension are frequently present. Abdominal pain is usually absent. Sometimes, considerable abdominal discomfort, diarrhoea or constipation may be present. On physical examination, abdomen may be distended and dilated veins may be apparent coursing beneath the skin.

Congenital hydrocoele may be present in a male child due to the processus vaginales becoming filled with the peritoneal fluid. Umbilical herniation due to increased abdominal pressure is a common observation (2-4). The rolled-up greater omentum infiltrated with tubercles may be felt as a transverse solid mass in the abdomen. Encysted [loculated] form The clinical presentation of encysted TB peritonitis resembles that of the ascitic form. Patients often present with localized abdominal swelling. Diagnosis is difficult and is often made retrospectively. A child with a suspected mesenteric cyst or a female with a suspected ovarian cyst, for example, may undergo a laparotomy and an encapsulated collection of fluid may be discovered. In some patients, intestinal obstruction may develop late in the disease. Fibrous form Widespread adhesions may cause coils of intestine especially in the ileal region to be matted together and distended. These matted coils may act as “blind-loop” leading to the development of steatorrhoea, malabsorption syndrome and abdominal pain. The disease may present as acute or subacute intestinal obstruction. On physical examination, the adherent loops of intestine and the thickened mesentery may be felt as lump[s] in the abdomen. Tuberculosis of Mesentery and Its Contents Purulent form of TB peritonitis is rare and is often secondary to TB salpingitis. Tuberculosis pus may be present amidst the mass of adherent intestines and omentum. Cold abscess, entero-cutaneous and entero-enteric fistulae can develop (3,4). Patients with mesenteric lymph node TB may present with general symptoms of TB toxaemia and abdominal pain. Enlarged mesenteric lymph nodes may be felt as lump[s] in the abdomen, usually in the right iliac fossa (3,4). Uncommonly, the presentation may mimic acute appendicitis. Tuberculosis pseudomesenteric cyst has also been described (3). Sometimes, calcified mesenteric lymph nodes may be evident on a plain radiograph of the abdomen. GASTROINTESTINAL TUBERCULOSIS Epidemiology Gastrointestinal TB, though rare in industrialized countries, continues to be a common problem in the developing countries. Although exact estimates are not available, presently, gastrointestinal TB is less commonly

Abdominal Tuberculosis 277 encountered than in the pre-antibiotic era (1,2). Reliable epidemiologic data on abdominal TB are lacking from India. Incidence of isolated intestinal TB in unselected autopsy series from India has been reported to vary from 0.02 to 5.1 per cent (13,14). In Delhi, 0.8 per cent of all hospital admissions were reported to be due to intestinal TB (15). In India, TB has been reported to be the cause in three to twenty per cent of patients with intestinal obstruction (16). About five to seven per cent of all gastrointestinal perforations [excluding appendix perforations] have been reported to be due to TB (17). Pathogenesis Gastrointestinal TB can occur primarily or it can be secondary to a TB focus elsewhere in the body (1,2). Ingestion of milk or food material contaminated with Mycobacterium bovis can result in primary intestinal TB. This form of the disease is rare in the present era. Infection more often reaches the abdomen by: [i] swallowing of infected sputum containing the bacilli; [ii] haematogenous dissemination from a focus of active pulmonary TB, miliary TB, or silent bacteraemic phase of primary TB; and [iii] spread of the disease from infected adjacent viscera. The organism may disseminate in the bile from a hepatic granuloma (2,3). Tuberculosis of Small Bowel and Colon Pathology Any region of the gastrointestinal tract from mouth to anus can be affected by TB. Ileocaecal area is commonly affected site (18-21). The striking prediliction for this region is thought to be due to the abundance of lymphoid tissue [Peyer’s patches]. Increased physiological stasis, increased rate of fluid and electrolyte absorption and minimal digestive activity permitting greater contact time between the organism and the mucosal surface in the ileocaecal area render this region more vulnerable to the development of intestinal TB. The vulnerability of ileocaecal region has also been attributed directly to Peyer’s patches and the associated microfold-cells [M-cells]. The bacille Calmette-Guérin [BCG] has been shown to be phagocytised by the M-cells and transported to the antigen presenting cells in the Peyer’s patches without any evidence of epithelial inflammation (22). Often, intestinal lesion starts as crypt abscess, followed by infection of Peyer’s patches. As the disease progresses,

the lymphoid follicles become infiltrated and inflammation extends throughout the submucosa. Eventually, the epithelial layers above the Peyer’s patches ulcerate giving rise to characteristic histopathologic appearance of ulcerative TB enteritis. Gastrointestinal TB can be of ulcerative, hypertrophic, ulcerohypertrophic, diffuse colitis and sclerotic forms. Ulcerative form The ulcerative form of intestinal TB usually occurs in adult patients who are malnourished. There is induration and oedema of the diseased segment of the intestine with an increase in serosal fat. Tuberculosis ulcers can be solitary or multiple and usually lie transverse to the long-axis of the gut girdle ulcers. Longitudinal or irregularly shaped ulcers may occasionally be seen. Areas of normal appearing mucosa may be found amidst the diseased segment skip lesions. The ulcers are of varying depth extending from the submucosa to muscularis propria or even serosa. As TB ulcers are most often horizontally located, healing and fibrosis result in stricture formation napkin ring strictures and lead to obstructive symptoms. Adhesions between the bowel loops prevent free perforation but promote formation of intestinal fistula. Severe haemorrhage due to endarteritis is rare. The related mesenteric lymph nodes enlarge and may caseate to form mesenteric abscesses. Hypertrophic form Unlike the ulcerative form, hypertrophic intestinal TB commonly occurs in young patients who are relatively well nourished. Caecum is the most commonly affected site. Hypertrophic intestinal TB occurs due to a low volume infection by less virulent organisms in a host with good resistance and wound healing capacity. This form is characterized by extensive inflammation and fibrosis that often results in the adherence of bowel, mesentery and lymph nodes into a mass. This mass may occasionally appear to be an exophytic neoplasm from the mucosal surface. On histopathological examination, lymphoid follicular overgrowth and hyperplastic germinal centre with infiltration by eosinophils, lymphocytes, plasma cells and giant cells are present. Caseation, though not always present in the gut, is often seen in the mesenteric lymph nodes. Caseation may occasionally be absent in tuberculosis granulomas. These non-caseating granulomas may be difficult to distinguish from those seen in Crohn’s disease. Confluence of the granulomas, relative absence of cracks and fissures and submucosal oedema are

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important findings that favour the diagnosis of TB (23). Das and Shukla (24) experimentally produced hypertrophic tuberculosis by intraperitoneal inoculation of infective tissue into guinea pigs. Inspite of non-specific histology, acid-fast bacilli [AFB] could be demonstrated in the gut and mesenteric lymph nodes in all four guinea pigs. While in a similar experiment, Crohn’s disease tissue failed to produce any lesion (24). Ulcerohypertrophic form Ulcerohypertrophic form of intestinal TB displays characteristics of both forms of the disease. Diffuse colitis Another much less common form of intestinal TB is diffuse colitis, which is endoscopically very similar to ulcerative colitis. Diffuse colitis cannot be easily distinguished from ulcerative colitis on the basis of mucosal appearance alone. Sclerotic form Sclerotic variety is associated with stricture that can be solitary or multiple (23). Entero-enteric, entero-vesical and entero-cutaneous fistulae can occur. In the gastrointestinal tuberculosis, luminal narrowing is often caused by adjacent TB lymphadenitis that results in traction, diverticula formation, narrowing, fixation and sinus tract formation. Clinical Features Demographic characteristics and clinical features of abdominal TB are summarized in Tables 19.3 and 19.4. Abdominal TB is a chronic illness with protean manifestations. Although the disease can affect any age group, subjects in the age group between 20 to 40 years are most often affected and slight female preponderance has been described (1,18-21). In the series reported by Bhansali (20), 171 patients complained of insidious onset of illness. The remaining 139 patients presented with acute manifestations. Of these 139 patients, 92 [66.2%] presented with intestinal obstruction, 23 [16.6%] presented with perforation while 19 patients [13.6%] had a presentation simulating peritonitis and in five patients [3.6%] the presentation mimicked acute appendicitis. In these patients, the cardinal presenting feature was abdominal pain. In 56 of these 139 patients [40.3%], the acute episode was the first manifestation of tuberculosis, while the remaining 83 patients [59.7%] gave a history of chronic intermittent abdominal pain in the past (20).

Symptoms Abdominal pain is the most common symptom and is present in almost all the patients (1,1821). The pain is most commonly located in right lower quadrant of the abdomen, though a significant proportion of patients may complain of diffuse, central, epigastric or left lower quadrant pain. The pain, particularly in patients presenting with intestinal obstruction has a cramp-like or colicky character. Pain may be diffuse or dull in character, especially when the peritoneum or mesenteric lymph nodes are involved. Sometimes, abdominal pain may be severe. Tuberculosis duodenitis may produce distress mimicking duodenal ulcer disease. Tuberculosis of the appendix mimics acute appendicitis. Diarrhoea occurs in 11 to 20 per cent of the patients (1,18-21). Liquid to semisolid stools are passed six to eight times a day. Mucus is usually present. Blood or frank pus may be passed rarely. Diarrhoea is almost always associated with intestinal ulceration, although it can sometimes occur in the absence of any mucosal disease and is thought to occur due to a generalized inflammatory response. Diarrhoea alternating with constipation has been described in 8.8 to 20 per cent of the patients (1,18-21). Weight loss is a common complaint. Anorexia contributes to marked diminution of food intake. Patients may also present with features of malabsorption. Decreased total absorptive area due to extensive ulceration, lymphatic obstruction or bacterial overgrowth are thought to be the causes of malabsorption. Bacterial overgrowth secondary to stagnant loop syndrome is found in 15 to 20 per cent patients presenting with intestinal TB and obstruction (1,18-21). Other abdominal symptoms include moving lump in the abdomen, nausea, vomiting, malaena, and constipation. Fever has been reported in 40 to 70 per cent of the patients (1,18-21). Menstrual abnormalities have been described in nearly one third of the female patients (1,1821). Signs Most patients appear ill and malnourished. Examination of the abdomen generally reveals tenderness most frequently in right iliac fossa. A palpable abdominal mass may be present. The mass is due to hyperplastic caecal TB, lymph node enlargement and rolled-up omentum. The classic “doughy abdomen” has been described in only six to eleven per cent patients in Indian studies [Table 19.3]. Abdominal

Abdominal Tuberculosis 279 Table 19.3: Demographic characteristics and symptoms at presentation in patients with abdominal tuberculosis Variable

Das and Shukla (19) [n = 182]

Bhansali (20) [n = 310]*

Singh et al (21) [n = 145]

Place of study

Allahabad

Mumbai

Banaras

Duration of study [years]

7

Male : Female Symptoms [%]

1:2.6†

13 1:0.9

5 1:2

Fever

44.2

49.2

66.2

Abdominal pain

94.0

100.0

88.3

Vomiting

69.6

29.9

55.2

Constipation

46.7

40.5

24.1

Diarrhoea

11.1

15.4

20.7

8.8

11.4

20.0

Weight loss

35.0

25.6

21.4

Anorexia

44.4

ND

71.7

8.8

ND

11.0

Moving lump in abdomen

28.8

ND

26.2

Borborygmi

25.5

ND

ND

Diarrhoea alternating with constipation

Cough

Postprandial distress

27.2

ND

ND

Abdominal distension

45.0

ND

41.4 35.0 [n = 97]

Menstrual abnormalities‡

35.6 [n = 132]

14.6 [n = 160]

Dysphagia

ND

ND

0.7

Bleeding per rectum

ND

ND

4.8

* Of the 310 patients included in the study, break-up of symptoms at presentation was provided for 254 chronic cases. Of these 254 chronic cases, 171 presented with a chronic ailment and 83 presented with acute on chronic disease † While the overall male:female ratio was 1:2.6, it was 1:8.5 in patients with hyperplastic ileocaecal tuberculosis [n = 38] 1:3 in patients with ascites [n = 20]: 1:2.8 in patients with stricture of ileum [n = 50]; 1:1.5 in those with mesenteric lymphadenitis and 1:1.5 in those with chronic miliary tuberculosis peritonitis [n=48] ‡ Numbers in square brackets indicate the number of female patients in the study ND = not described

distension with increased peristaltic activity is generally associated with intestinal obstruction [Figure 19.1]. There may be free intestinal perforation when signs of peritonitis may be apparent.

Oesophageal Tuberculosis Tuberculosis of oesophagus is very rare. In an autopsy study, oesophageal TB accounted for 0.2 per cent of the cases (25). Oesophageal involvement usually occurs due

Figure 19.1: Intestinal tuberculosis. Abdominal distenstion due to distended bowel loops, everted umbilicus [white arrow] and visible peristalisis [black arrow] can be seen

280

Tuberculosis Table 19.4: Physical signs at presentation in patients with abdominal tuberculosis

Variable

Das and Shukla (19) [n = 182]

Bhansali (20) [n = 310]*

Singh et al (21) [n = 145]

Anaemia

56.5

29.0*

Malnutrition

45.6

21.7†

ND

9.0§

ND

Peripheral lymphadenopathy

1.6‡

Features of intestinal obstruction

51.0

30.0

Abdominal tenderness

65.9

62.6

Distension of abdomen

58.2

Doughy feel of the abdomen

6.0

81.3ll ND

ND

50.0 ND 41.4 11.7

Visible peristalsis

35.1

66.2ll

31.7

Ascites

18.6

1.9

20.0

8.7

31.7

Rigidity/guarding Lump abdomen

28.6¶

59.1**

ND 31.0††

All values are shown as percentages * 90 of the 310 cases had haemoglobin less than 60 per cent † 55 of the 254 chronic cases were in a state of malnutrition ‡ Cervical lymphadenopathy § Cervical, axillary and inguinal lymphadenopathy ll Described in 139 of the 310 patients with acute presentation ¶ In 18.5% of the patients, right iliac fossa mass was present. Other sites included umbilical region [4.2%], epigastrium [3.2%], right hypochondrium [1.6%]. A vague mass was palpable in 1.1% of the cases ** Abdominal lump was described in 101 of the 171 [59.1%] patients with chronic presentation. In 80 of them [46.7%], the mass was located in the right iliac fossa and was due to hyperplastic ileocaecal tuberculosis; in 19 [11.1%], it was due to lymphadenopathy and in two [1.2%], the mass was due to rolled-up omentum †† The lump was situated in the right iliac fossa ND = not described

to direct extension of infection from adjacent affected structures, such as mediastinal lymph nodes or the lung (26-29). Less frequently, oesophageal involvement occurs in the absence of TB elsewhere in the body (30). Upper part of the oesophagus is more often involved than the lower part. Patients commonly present with dysphagia and odynophagia. Pulmonary aspiration can occur in patients who go on to develop tracheo-oesophageal or broncho-oesophageal fistula. Mild, rarely massive haematemesis due to aorto-oesophageal fistula has been described (31,32). However, none of these findings are specific to oesophageal TB, and endoscopic biopsy is mandatory for confirmation of the diagnosis. Gastric Tuberculosis Gastric TB is also rare due to the presence of gastric acid and the paucity of lymphoid tissue in stomach. In an autopsy series of TB patients, an incidence of 0.6 per cent

has been reported (33,34). Symptoms are non-specific and include abdominal pain, nausea, vomiting, gastrointestinal bleeding, fever and weight loss (35,36). Ulcerative form is the commonest and is encountered in 80 per cent of patients with gastric TB (35,36). The ulcers are found on the lesser curvature of the stomach. Very rarely, fistulous communications with adjacent organs may be evident. Gastric TB often is not suspected until the time of surgery and is usually a retrospective diagnosis. Duodenal Tuberculosis Duodenal TB is a rare form of gastrointestinal TB (21,3740). In the series described by Singh et al (21), duodenal involvement occurred in five of the 145 patients [3.4%] with abdominal TB. Usually patients present with obstructive symptoms or with non-specific dyspeptic symptoms. Fever and weight loss may be present. The obstruction is more often due to extrinsic compression

Abdominal Tuberculosis 281 rather than luminal obstruction. Extrinsic obstruction may be caused by lymph nodes or adhesions. Very rarely, patients may develop obstructive jaundice. Endoscopic biopsy has been found to have a low diagnostic yield. Tuberculosis of Appendix Incidental TB involvement of the vermiform appendix is fairly common in patients with active ileocaecal TB (1), but the incidence of isolated TB of the appendix is rare even in areas where TB is highly endemic (41). In India, TB has been reported in two per cent of all appendicectomies (42). The clinical features of TB appendicitis may be very vague, with the disease being diagnosed only on abdominal exploration. Very rarely, appendicular perforation may be the presenting feature (43). Anal Tuberculosis Anal and perianal TB are rare but pose diagnostic problems clinically. These lesions are mostly ulcerative, although lupoid, verrucus and miliary lesions have been described (44). The TB ulcers are shallow with bluish undermined edges and progress very slowly. Associated inguinal lymphadenopathy may be present. Tuberculosis fistula-in-ano and perianal abscess may be present. Tuberculosis fistula-in-ano should be considered when multiple or recurrent fistulae are seen along with inguinal lymphadenopathy (45). Anal lesions of Crohn’s disease, squamous cell carcinoma, lymphogranuloma venereum and syphilis can be differentiated by histopathological examination.

tructive jaundice have all been described (46). Pancreatic TB may present as acute or chronic pancreatitis or may mimic malignancy (47,48). Investigations generally do not contribute to the diagnosis and confirmation of the diagnosis is sometimes not possible even at operation. Fine-needle aspiration cytology [FNAC] and biopsy may be helpful in differentiating TB from carcinoma, lymphoma, sarcoidosis or chronic pancreatitis. SPLENIC TUBERCULOSIS Tuberculosis involvement of the spleen can occur due to disseminated or miliary form of the disease [Figure 19.2] (49-51). In developed countries, the disease is most commonly encountered in human immunodeficiency virus [HIV] seropositive individuals. Fever, left upper quadrant abdominal pain, weight loss and diarrhoea are common features (49-51). Multiple TB abscesses have been described in patients with HIV infection (51,52). Clinically, these patients may manifest with splenomegaly or hepatosplenomegaly and can present with a fever of unknown origin. Rarely, isolated splenic TB may occur in immunocompetent individuals (53-55). The clinical presentation may mimic splenic abscess due to other causes. Associated vertebral TB with a psoas abscess may facilitate involvement of the spleen by contiguous spread. In earlier days, pre-operative diagnosis was often difficult and used to be confirmed on histopathological examination of the splenectomy specimens. However, with the availability of modern imaging techniques, splenic TB lesions are increasingly being recognized.

HEPATOBILIARY TUBERCULOSIS The reader is referred to the chapter “Granulomatous hepatitis” [Chapter 20] for more details. PANCREATIC TUBERCULOSIS Pancreatic TB is rare. It is often associated with miliary TB and occurs more often in immunocompromised patients (46). Pancreatic TB is most often the result of lymphohaematogenous dissemination or direct spread from other adjacent organs. The clinical manifestations are protean and depend on the site and extent of disease. Anorexia, malaise, low-grade fever, weight loss, night sweats, malaena, pancreatic mass or abscess or obs-

Figure 19.2: Splenic tuberculosis. Extensive areas of caseation necrosis can be seen

282

Tuberculosis

Splenomegaly can also occur in TB patients with haematological abnormalities, such as pancytopenia, myelodysplasia, acute leukaemia, chronic myeloid leukaemia (56-59). In some patients splenomegaly is thought to contribute to the haematological abnormalities, as it has been reported that splenectomy resulted resolution of these abnormalities (60,61). ABDOMINAL TUBERCULOSIS IN PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND ACQUIRED IMMUNODEFICIENCY SYNDROME The epidemic of acquired immunodeficiency syndrome [AIDS] has been accompanied by a resurgence of TB. The incidence of extra-pulmonary TB is about 50 per cent in patients with AIDS, whereas, it is 10 to 15 per cent in patients without HIV infection (2,11,62). Fee et al (63) compared the presentation of abdominal TB in 43 patients infected with HIV and 35 patients without HIV infection. Fever, weight loss, and extra-abdominal lymphadenopathy were more common in patients with HIV infection, whereas ascites and jaundice were more frequent in patients without HIV infection. Intra-abdominal lymphadenopathy and visceral lesions, visualized on computed tomography [CT], were more common in patients with HIV infection, whereas ascites and omental thickening were more frequent in patients without HIV infection. Disseminated TB was present in 93 per cent of the HIV infected patients, compared with 31 per cent of those without HIV infection. In HIV-seropositive patients, abdominal TB appears to be a manifestation of disseminated disease and results in significant mortality. ABDOMINAL INVOLVEMENT IN NONTUBERCULOUS MYCOBACTERIAL INFECTION Abdominal involvement is uncommon in patients with nontuberculous mycobacterial [NTM] infections. Occasionally, intra-abdominal infection and disseminated disease caused by NTM have been described. The reader is referred to the chapter “Nontuberculous mycobacterial infections” [Chapter 48] for more details. DIAGNOSIS Abdominal paracentesis and ascitic fluid examination, laparoscopy with biopsy, needle biopsy of the peritoneum, diagnostic laparotomy are useful in confirming the diagnosis of TB peritonitis. In patients with

Table 19.5: Diagnostic criteria of abdominal tuberculosis Histopathological evidence of caseating granulomas, acidfast bacilli Presence of Mycobacterium tuberculosis in sputum, tissue or ascitic fluid Clinical, radiological or operative evidence of proven tuberculosis elsewhere with good therapeutic response Good therapeutic response to antituberculosis treatment Based on reference 64

gastrointestinal TB, barium meal studies, endoscopy with biopsy, exploratory laparotomy are potentially helpful in confirming the diagnosis. Biopsies are preferred from ulcer margins. Culture of the biopsy material increases the diagnostic yield. Diagnostic criteria for abdominal TB (64) are summarized in Table 19.5. Haematology and Serum Biochemistry There is a varying degree of anaemia, leucopenia with relative lymphocytosis. The erythrocyte sedimentation rate [ESR] is increased. Raised ESR was reported in 50 to 100 per cent patients in several studies (1,5-11,18-21). However, ESR was found to be normal in many histologically proven patients with abdominal TB (1,5-11,18-21). Serum albumin levels tend to be depressed. Serum transaminase levels tend to be normal. Serum alkaline phosphatase may be raised (1,5-11,18-21). Laboratory investigations are non-specific and do not contribute to the diagnosis. Tuberculin Skin Test A positive tuberculin skin test [TST] has been reported in 55 to 100 per cent patients with abdominal TB (1,511,18-21). However, in areas where TB is highly endemic, positive TST neither confirms the diagnosis of abdominal TB nor excludes it. Imaging Studies Chest Radiograph Associated pulmonary TB has been described in 24 to 28 per cent of patients with abdominal TB [Table 19.6]. Plain X-ray Abdomen Plain radiograph of the abdomen may show calcified lymph nodes or calcified granulomas in the spleen, liver

Abdominal Tuberculosis 283 Table 19.6: Evidence of associated pulmonary tuberculosis in patients with abdominal tuberculosis Variable

Das and Shukla (19) [n=182]*

Active pulmonary TB 15.1 Pleural effusion 6.9 Healed or calcified pulmonary TB 5.8 Total 27.8

Bhansali (20) [n=310] 10.6 ND 14.2 24.8

Singh et al (21) [n=145] 16.6 ND 3.4 20.0

All values are shown as percentages * Chest radiograph was done in 86 of the 182 patients ND = not described; TB = tuberculosis

and pancreas (65). Other radiographic features include dilated loops with fluid levels, dilatation of terminal ileum and ascites. Pneumoperitoneum may be evident in patients with intestinal perforation.

Barium contrast studies have been the most useful investigation for the diagnosis of intestinal TB till recently. Although the radiological features of intestinal TB are non-specific, several findings are highly suggestive of the disease. Enteroclysis [a fluoroscopic procedure to evaluate the small intestine, done by inserting a tube through the nose to the duodenum, infusing radiocontrast, like barium and air through it

and recording images in real time as the contrast moves through] followed by barium enema is useful for evaluation of intestinal TB. Increased transit time with hypersegmentation and flocculation of barium is one of the earliest signs of intestinal involvement. Localized areas of irregular thickened folds, mucosal ulceration, dilated segments and strictures may be seen [Figures 19.3A and l9.3B]. The ulcers may be linear or stellate and are situated along the circumference of the wall. Rarely, there may be deep ulcers with fistulae. The ileocaecal valve may be thickened initially and gives a broad triangular appearance with the base towards the caecum. This is referred to as the inverted umbrella sign or Fleischner’s sign. Other features include rapid transit and

Figure 19.3A: Barium meal follow through study showing grossly dilated terminal ileum [black arrow], stricture in the ileocaecal region [white arrow], contracted caecum and part of the ascending colon [asterisk] suggestive of ileocaecal tuberculosis with ascending colon involvement

Figure 19.3B: Enteroclysis study showing multiple strictures [arrows] in the jejunum

Barium Studies

284

Tuberculosis

lack of barium retention in an inflamed segment of the small bowel because of extreme irritability due to ulceration [Stierlin’s sign] and persistent narrow stream of barium in the bowel suggestive of stenosis [string sign]. Both Stierlin’s and string signs are also seen in Crohn’s disease and hence not specific for TB. Barium meal follow through findings in intestinal TB have been classified into four groups (66) as presented in Table 19.7. In patients with oesophageal TB, common radiographic features on barium oesophagogram include ulcerative oesophagitis, stricture, pseudotumour masses, fistulous communication with airway, sinus tract formation, and traction diverticulae. In patients with duodenal TB, barium studies usually reveal segmental narrowing of the duodenum. Hypertrophic type most commonly mimics neoplasm while the ulcerative type mimics peptic ulcer disease. Widening of “C” loop of duodenum due to lymphadenopathy may simulate superior mesenteric artery syndrome. Abdominal Ultrasonography Abdominal ultrasonography often reveals a mass made up of matted loops of small bowel with thickened walls, diseased omentum, mesentery and loculated ascites (65). However, these findings are not specific for TB. Fine septae may be seen in the ascitic fluid. These strands

usually arise from the serosa of the small bowel and are due to high fibrin content of the exudative ascitic fluid. They are considered to be diagnostic of abdominal TB (65). But this finding may be observed in patients with malignant ascites also (67). Loculated ascites probably represents walled-off peritoneal inflammation. Fluid collection in the pelvis produces thick septae and can mimic ovarian cysts. Interloop ascites gives rise to characteristic club sandwich appearance of alternating echogenic and echo-free layers of the bowel wall and interloop fluid (68). Mesenteric thickening is better detected in presence of ascites and is often seen as the stellate sign of bowel loops radiating out from its root. Enteritis with diffuse mural thickening is non-specific and must be distinguished from Crohn’s disease (69). In intestinal TB, bowel wall thickening is usually uniform and concentric as opposed to the eccentric thickening at the mesenteric border seen in Crohn’s disease and the variegated appearance seen in malignancy. This may be difficult to appreciate on ultrasonography. Lymphoma of the bowel remains an important differential diagnosis. Lymphadenopathy may be discrete [Figure 19.4] or matted. There is a predilection for periportal, peripancreatic and mesenteric locations. Calcification and heterogeneous echotexture may also be seen (70).

Table 19.7: Barium meal follow through findings in intestinal tuberculosis Group I

Group II

Group III

Group IV

Highly suggestive of intestinal tuberculosis if one or more of the following features are present Deformed ileocaecal valve with dilatation of terminal ileum Contracted caecum with an abnormal ileocaecal valve and/or terminal ileum Stricture of the ascending colon with shortening and involvement of ileocaecal region Suggestive of intestinal tuberculosis if one of the following features is present Contracted caecum Ulceration or narrowing of the terminal ileum Stricture of the ascending colon Multiple areas of dilatation, narrowing and matting of small bowel loops Non-specific changes Features of matting, dilatation and mucosal thickening of small bowel loops Normal study

Based on reference 66

Figure 19.4: Ultrasonography of the abdomen showing extensive hypoechoic lesions in the retroperitoneum suggestive of lymphadenopathy [N]

Abdominal Tuberculosis 285 include, thickened bowel loops and ascites. Balthazar et al (72) described preferential thickening of the medial caecal wall with an exophytic mass engulfing the terminal ileum associated with massive lymphadenopathy as characteristic findings in TB. This florid response was observed in patients who had AIDS (72). Short segments of homogeneous circumferential or eccentric mural thickening [Figures 19.7A and 19.7B] with normal intervening bowel associated with ileocaecal involvement strongly suggest TB (66). Granulomas or abscess in the liver, pancreas and spleen may be seen [Figure 19.8]. In most of the patients with splenic TB, multiple hypoechoic foci [< 2 cm] may be evident on contrast enhanced CT of the abdomen [Figures 19.9A, 19.9B, 19.10, Figure 19.5: CECT of the abdomen showing marked ascites [asterisks] and streakiness of the mesentery [arrows]

Although caseation of lymph node is common in TB, necrosis within the metastatic lymphadenopathy may have a similar appearance (71). Abdominal Computed Tomography Abdominal CT is better than ultrasonography for detecting high density ascites [Figure 19.5] (65). Abdominal CT also detects retroperitoneal, peripancreatic, porta hepatis, mesenteric and omental lymph node enlargement; caseation necrosis in the lymph node may appear as low attenuating, necrotic centres and thick, enhancing inflammatory rim (65) [Figure 19.6]. Other CT findings

Figure 19.6: CECT of the abdomen showing extensive retroperitoneal lymphadenopathy [arrows]

Figure 19.7A: CECT of the abdomen showing ileocaecal tuberculosis with stricture in the ileocaecal region [arrow]

Figure 19.7B: CECT of the abdomen showing caecal tuberculosis. Thickening of the caecal wall due to inflammation can be seen [arrow]

286

Tuberculosis

Figure 19.8: CECT of the abdomen showing multiple, low attenuation lesions in the liver Figure 19.9B: CECT of the abdomen showing solitary, low attenuation lesion in the spleen [arrow]

Ascitic Fluid Examination

Figure 19.9A: CECT of the abdomen showing multiple, low attenuation lesions in the spleen [arrows]

19.11 and 19.12] (51). Occasionally, a large solitary splenic tuberculoma has been described (62). In addition to ascites, mesenteric infiltration, omental masses peritoneal enhancement or thickening and disorganized masses of soft tissue densities may be seen. Most of the features can be seen individually in a variety of conditions like peritoneal mesothelioma, carcinomatosis and peritonitis of any form (73). However, when a combination of these findings is associated with lymphadenopathy and mural thickening of ileocaecal region, it would favour a diagnosis of TB.

The serum-ascitic fluid albumin gradient is less than 1.1 in more than 90 per cent of the patients (1,5-11,74,75). Ascitic fluid white blood cell count is usually 150 to 4000 cells/mm3 and consists of lymphocytes predominantly. For unknown reasons, neutrophilic response has been observed in the ascitic fluid in patients with TB peritonitis associated with peritoneal dialysis (12). Red blood cells may be found often in the ascitic fluid. Ascitic fluid reveals AFB in less than three per cent of the cases (1,511). In most of the studies (1,5-11), ascitic fluid culture for Mycobacterium tuberculosis is positive in less than 20 per cent of the patients. Singh et al (6) reported that the yield of ascitic fluid culture was as high as 83 per cent when one liter of fluid was concentrated by centrifugation and then cultured. Adenosine deaminase [ADA] activity in ascitic fluid is a sensitive and specific marker for TB (76-78). The reader is also referred to the chapter “Tuberculosis pleural effusion” [Chapter 17] for a detailed discussion on ADA estimation. When a cut-off value of 32 IU/l is chosen, the specificity and sensitivity of ascitic fluid ADA estimation are found to be 95 and 98 per cent, respectively (76-78). In low protein ascites, false-negative results are more frequent (77). In patients with HIV infection and TB peritonitis, the ADA levels may be lower (77). False-positive ADA result has also been reported in

Abdominal Tuberculosis 287

Figure 19.10: Abdominal tuberculosis. CECT of the abdomen showing multiple low attenuation lesions [black arrows] in the spleen [A,B]; ascites [white arrows], [B,C]; dilated bowel loops [asterisk] [C,D]; and extensive retroperitoneal lymphadenopathy [D], [square]

Figure 19.11: Ultrasonography showing a large, regular hypoechoic lesion [arrow] located peripherally along the inferior aspect of the spleen [A]. CECT of the abdomen of the same patient shows a large irregular hypodense lesion [arrow] in the inferior aspect of the spleen suggestive of an abscess [B] Reproduced with permission from “Sharma SK, Smith-Rohrberg D, Tahir M, Mohan A, Seith A. Radiological manifestations of splenic tuberculosis: a 23-patient case series from India. Indian J Med Res 2007;125:669-78 (reference 51)”

288

Tuberculosis

Figure 19.12: Ultrasonography showing multiple large hypoechoic lesions [arrows] [A]. CECT of the abdomen of the same patient shows multiple large hypodense lesions seen within the spleen [B] [arrows] Reproduced with permission from “Sharma SK, Smith-Rohrberg D, Tahir M, Mohan A, Seith A. Radiological manifestations of splenic tuberculosis: a 23-patient case series from India. Indian J Med Res 2007;125:669-78 (reference 51)”

patients with malignant ascites (76,79). The level of interferon-γ [IFN-γ] in ascitic fluid is significantly higher in TB peritonitis than in malignancy and cirrhosis (79). Using an optimal cut-off point of 112 pg/ml, IFN-γ was useful in distinguishing TB ascites from non-TB ascites (76). Estimation of both ADA and IFN-γ levels is simple, rapid and non-invasive with high sensitivity and specificity. However, estimation of IFN-γ is almost twice expensive than ADA test. Thus, ADA is particularly useful in developing countries where more sophisticated and expensive tests such as laparoscopy may not be available (76). Serodiagnosis Conventional histopathological and microbiological methods are often inadequate for diagnosing abdominal TB. In these instances, immunodiagnostic procedures seem to have a major role to play, even if they are only moderately sensitive. However, the results of various serological techniques are variable due to uncertainty of antibody response to mycobacteria, poor reproducibility and lack of specificity (80). The serum CA-125 level that is normally elevated in ovarian malignancy is also raised in some patients with abdominal TB. The level falls with antituberculosis treatment. This at times leads to diagnostic difficulty in patients with abdominopelvic mass with or without ascites mimicking an ovarian malignancy (81,82).

Polymerase Chain Reaction The scope of molecular biological methods in the diagnosis of abdominal TB is being explored. Anand et al (83) have used polymerase chain reaction [PCR] assay on endoscopic biopsy specimens to diagnose intestinal TB in a patient with chronic diarrhoea. The patient was treated with antituberculosis drugs with complete resolution of endoscopic abnormalities. The PCR can be used to complement the diagnosis of TB in processed and paraffin embedded tissue materials, especially in situations where a definite conclusion cannot be obtained by conventional methods (83,84). However, empirical antituberculosis treatment is justified in patients with clinical and histological features highly suggestive of peritoneal TB, even in cases with negative results from microscopy, culture and PCR analysis (85). Scintigraphy, Positron Emission Tomography Radionuclide scintigraphy detects serosal inflammation and peritonitis. Gallium67 citrate is superior to Indium111 labeled leucocytes for detecting areas of abdominal disease (86). 18Fluorine fluorodeoxyglucose positron emission tomography [18FDG-PET] has been found to be useful in the diagnosis of peritoneal TB (87). Exact role of these modalities is not clear at present and they should not be used indiscriminately.

Abdominal Tuberculosis 289 Endoscopy Colonoscopy Colonoscopy is the easiest and most direct method for establishing the diagnosis of TB colitis and when combined with directed colonoscopic biopsy, it has a clear advantage over radiographic approaches (88-90). On colonoscopy, the ileocaecal valve may be oedematous or deformed [Figure 19.13]. Nodules, ulcers, pseudopolypoid folds and strictures may be seen. Ulceration is the most common finding and is observed in the ileocaecal region. However, as with most diagnostic procedures in intestinal TB, endoscopic findings are not pathognomonic. Tuberculosis granulomas are found in the submucosa, hence multiple and deep biopsies will increase the diagnostic yield (88-90). A combination of histology and culture of the biopsy material can establish the diagnosis in 80 per cent of the cases (88-90).

Peritoneal Biopsy Blind percutaneous peritoneal needle biopsy and open parietal peritoneal biopsy under local anaesthesia are also useful procedures for confirming the diagnosis of abdominal TB (19-21,93). These techniques are relatively safe, although blind needle biopsy can cause fatal bowel perforation. Shukla et al (93) carried out open peritoneal biopsy by a grid iron incision in right iliac fossa under local anaesthesia and reported 80 per cent diagnostic accuracy. The needle biopsy of peritoneum has an added limitation that an involved part of peritoneum may not be obtained (94). Laparoscopy Direct inspection and biopsy of the peritoneum are perhaps the most effective method of diagnosing TB peritonitis [Figure 19.14]. Laparoscopy alone will facilitate an accurate presumptive diagnosis in 80 to 95 per cent of patients (1,89,95). Laparoscopy biopsy specimens may reveal AFB in 75 per cent and caseating granulomas in 85 to 90 per cent patients (1,8,95,96). Characteristic laparoscopic findings include multiple, yellowish-white miliary nodules over visceral and parietal peritoneum, erythematous, thickened and hyperaemic peritoneum, turbid ascites and adhesions. Chances of perforation are high when patients with fibroadhesive peritoneal TB are subjected to laparoscopy.

Figure 19.13: Colonoscopy showing oedematous and deformed ileocaecal valve [arrow]

Fine-Needle Aspiration Cytology In patients with palpable masses, FNAC has been shown to have a high diagnostic accuracy (91,92). In patients with lymphadenopathy, abscesses, and focal lesions of the viscera, FNAC confirms the diagnosis (70). Lowenstein-Jensen culture of the FNAC material increases the yield further. The FNAC during colonoscopy is likely to add to the diagnostic yield in patients with ileocaecal or colonic TB (91).

Figure 19.14: Laparoscopy showing multiple peritoneal tubercles. Biopsy confirmed the diagnosis of peritoneal tuberculosis

290

Tuberculosis

In these patients, use of open exposure of the peritoneum to introduce the laparoscope will significantly reduce the risk of perforation (1). The safety of laparoscopy has been well established in both HIV and non-HIV patients with suspected TB peritonitis. TREATMENT Management of patients with abdominal TB includes medical treatment and conservative or radical surgery wherever appropriate. Medical Treatment Earlier, patients with abdominal TB have been treated with antituberculosis drug regimens of eight to twelve months duration (97,98). However, recent evidence suggests that six month short-course chemotherapy regimens are effective in the treatment of all forms of abdominal TB (99). The reader is referred to the chapter “Treatment of tuberculosis” [Chapter 52] for more details. In India, majority of patients with abdominal TB get treated with DOTS using standardized intermittent treatment regimens under the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India. A decade of experience with the RNTCP suggests encouraging results (100,101). Corticosteroids The role of corticosteroid treatment in patients with abdominal TB is not well established and these should not be routinely administered to all patients. Surgery When the diagnosis of TB enteritis is confirmed, antituberculosis treatment should be initiated. Wherever appropriate, elective surgery may be performed after four to six weeks of antituberculosis treatment. Surgical Options Bypass surgery, such as entero-enterostomy, ileo-transverse colostomy, is not recommended for obstructive lesions as these procedures may facilitate the formation of blind loops leading to obstruction, malabsorption, or both (102). Stricturoplasty is recommended for these lesions. Strictures are present in a short segment, therefore, resection of the diseased segment [Figure 19.15]

Figure 19.15: Resected specimen of the small intestine showing tuberculosis ulcers and perforation [arrow]

with end-to-end anastomosis is recommended (97). Hypertrophic ileocaecal TB requires a limited ileocaecal resection with a five-cm margin from a visibly abnormal tissue or a limited right hemicolectomy and end-to-end anastomosis (103). Perforating ulcers are treated by excision of the perforated segment with primary anastomosis. Acute intestinal obstruction, perforation and peritonitis are treated conservatively, if possible. Operation undertaken during the acute stage carries a high mortality rate. However, surgery is essential when conservative treatment fails. REFERENCES 1. Marshall JB. Tuberculosis of the gastrointestinal tract and peritoneum. Am J Gastroenterol 1993;88:989-99. 2. Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316-53. 3. Rangabashyam N. Abdominal tuberculosis. In: Morris PJ, Malt RA, editors. Oxford textbook of surgery. New York: Oxford University Press; 1994.p.2484-92. 4. Mann CV, Russel RCG, Williams NS, editors. Bailey and Love’s short practice of surgery. London: English Language Book Society;1995. 5. Sohocky S. Tuberculous peritonitis: a review of 100 cases. Am Rev Respir Dis 1967;95:398-401. 6. Singh MM, Bhargava AN, Jain KP. Tuberculosis peritonitis: an evaluation of pathogenic mechanisms, diagnostic proce-

Abdominal Tuberculosis 291

7.

8.

9.

10. 11.

12.

13. 14. 15.

16. 17. 18.

19. 20. 21.

22.

23. 24.

25. 26.

dures and therapeutic measures. N Engl J Med 1969;289:10914. Dineen P, Homan WP, Grafe WR. Tuberculous peritonitis: 43 years’ experience in diagnosis and treatment. Ann Surg 1976;184:717-22. Manohar A. Simjee AE, Haffejee AA, Pettengell KE. Symptoms and investigative findings in 145 patients with tuberculous peritonitis diagnosed by peritoneoscopy and biopsy over a five-year period. Gut 1990;31:1130-2. Bhargava DK, Shriniwas, Chopra P, Nijhawan S, Dasarathy S, Kushwaha AK. Peritoneal tuberculosis: laparoscopic patterns and its diagnostic accuracy. Am J Gastroenterol 1992;87:109-11. Hyman S, Villa F, Alvarez S, Steigmann F. The enigma of tuberculous peritonitis. Gastroenterology 1962;42:1-6. Aguado JM, Pons F, Casafont F, san Miguel G, Valle R. Tuberculous peritonitis: a study comparing cirrhotic and noncirrhotic patients. J Clin Gastroenterol 1990;12:550-4. Malik GH, Al-Harbi AS, Al-Mohaya S, Kechrid M, Sheita MS, Azhari O. Tuberculous peritonitis in patients on chronic peritoneal dialysis: case reports. Saudi J Kidney Dis Transpl 2003;14:65-9. Tribedi BD, Gupta DM. Intestinal tuberculosis in Bengal. J Indian Med Assoc 1941;11:41. Ukil AC. Early diagnosis and treatment of intestinal tuberculosis. Indian Med Gazette 1942;77:613. Chuttani HK. Intestinal tuberculosis. In: Card WI, Creamer B, editors. Modern trends in gastroenterology. London: Butterworth;1970.p.309-27. Bhansali SK, Sethna JR. Intestinal obstruction: a clinical analysis of 348 cases. Indian J Surg 1970;32:57-70. Bhansali SK. Gastrointestinal perforations: clinical study of 96 cases. J Postgrad Med 1967;13:1-12. Pimparkar BD, Donde UM. Intestinal tuberculosis. I. Clinical and radiological studies. J Assoc Physicians India 1974; 22:20518. Das P, Shukla HS. Clinical diagnosis of abdominal tuberculosis. Br J Surg 1976;63:941-6. Bhansali SK. The challenge of abdominal tuberculosis in 310 cases. Indian J Surg 1978;40:65-77. Singh V, Jain AK, Agrawal AK, Khanna S, Khanna AK, Gupta JP. Clinicopathological profile of abdominal tuberculosis. Br J Clin Pract 1995;49:22-4. Fujimura Y. Functional morphology of microfold cells [M cells] in Peyer’s patches-phagocytosis and transport of BCG by M cells into rabbit Peyer’s patches. Gastroenterol Jpn 1986;21:325-35. Tandon HD, Prakash A. Pathology of intestinal tuberculosis and its distinction from Crohn’s disease. Gut 1972:13:260-9. Das P, Shukla HS. Abdominal tuberculosis: demonstration of tubercle bacilli in tissues and experimental production of hyperplastic enteric lesion. Br J Surg 1975;62:610-9. Lockard LB. Esophageal tuberculosis: a critical review. Laryngoscope 1913;23:561-84. Dow CJ. Oesophageal tuberculosis: four cases. Gut 1981; 22:234-6.

27. Fagundes RB, Dalcin RP, Rocha MP, Moraes CC, Carlotto VS, Wink MO. Esophageal tuberculosis. Endoscopy 2007 Jul 4;[Epub ahead of print]. 28. Gordon AH, Marshall JB. Esophageal tuberculosis: definitive diagnosis by endoscopy. Am J Gastroenterol 1990;85:1747. 29. Eng J, Sabanathan S. Tuberculosis of the esophagus. Dig Dis Sci 1991;36:536-40. 30. Laajam MA. Primary tuberculosis of the esophagus: pseudotumoral presentation. Am J Gastroenterol 1984;79:839-41. 31. Hancock BW, Barnett DB. Case of post-primary tuberculosis and massive haematemesis. BMJ 1974;3:722-3. 32. Robbs JV, Bhoola KD. Aorto-oesophageal fistula complicating tuberculous aortitis: a case report. S Afr Med J 1976;50:702-4. 33. Good RW. Tuberculosis of the stomach: an analysis of cases recently reviewed. Arch Surg 1931;22:415-25. 34. Palmer ED. Tuberculosis of the stomach and the stomach in tuberculosis: a review with particular reference to gross pathology and gastroscopic diagnosis. Am Rev Tuberc 1950;61:116-30. 35. Page RE, Williams RE, Benson EA. Primary gastric tuberculosis: a case report. Br J Surg 1975;62:618-20. 36. Talukdar R, Khanna S, Saikia N, Vij JC. Gastric tuberculosis presenting as linitis plastica: a case report and review of the literature. Eur J Gastroenterol Hepatol 2006;18:299-303. 37. Vijayraghavan M, Arunabh, Sarda AK, Sharma AK, Chatterjee TK. Duodenal tuberculosis: a review of the clinicopathologic features and management of twelve cases. Jpn J Surg 1990;20:526-9. 38. Deshpande SG, Mehta MJ. Tuberculous strictures of duodenum. J Indian Med Assoc 1975;65:306-7. 39. Tandon RK, Pastakia B. Duodenal tuberculosis as seen by duodenoscopy. Am J Gastroenterol 1976;66:483-6. 40. Deshmukh J. Value of exploratory laparotomy in the diagnosis of duodenal tuberculosis. J Postgrad Med 1969; 15:114-9. 41. Singh MK, Arunabh, Kapoor VK. Tuberculosis of the appendix: a report of 17 cases and a suggested aetiopathological classification. Postgrad Med J 1987;63:855-7. 42. Agarwal P, Sharma D, Agarwal A, Agarwal V, Tandon A, Baghel KD, et al. Tuberculous appendicitis in India. Trop Doct 2004;34:36-8. 43. Al-Hilaly MA, Abu-Zidan FM, Zayed FF, Suleiman JD, Farid LS. Tuberculous appendicitis with perforation. Br J Clin Pract 1990;44:632-3. 44. Colin JF, Stewart RJ. Ano-rectal tuberculosis-a reminder. Tubercle 1971;52:301-2. 45. Shukla HS, Gupta SC, Singh G, Singh PA. Tubercular fistulain-ano. Br J Surg 1988;75:38-9. 46. Brusko G, Melvin WS, Fromkes JJ, Ellison EC. Pancreatic tuberculosis. Am Surg 1995;61:513-5. 47. Levine R, Tenner S, Steinberg W, Ginsberg A, Borum M, Huntington D. Tuberculous abscess of the pancreas. Case report and review of the literature. Dig Dis Sci 1992;37:11414. 48. Varshney S, Johnson CD. Tuberculosis of the pancreas. Postgrad Med J 1995;71:564-6.

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Tuberculosis

49. Sharma SK, Mohan A, Pande JN, Prasad KL, Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. QJM 1995;88:29-37. 50. Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis 2005;5:415-30. 51. Sharma SK, Smith-Rohrberg D, Tahir M, Mohan A, Seith A. Radiological manifestations of splenic tuberculosis: a 23patient case series from India. Indian J Med Res 2007;125:66978. 52. Soriano V, Tor J, Gabarre E, Gros T, Muga R. Multifocal splenic abscesses caused by Mycobacterium tuberculosis in HIV-infected drug users. AIDS 1991;5:901-2. 53. Sharma S, Dey AB, Agarwal N, Nagarkar KM, Gujral S. Tuberculosis: a rare cause of splenic abscess. J Assoc Physicians India 1999;47:740-1. 54. Chandra S, Srivastava DN, Gandhi D. Splenic tuberculosis: an unusual sonographic presentation. Int J Clin Pract 1999;53:318-9. 55. Sheen-Chen SM, Chou FF, Wan YL, Eng HL. Tuberculosis presenting as a solitary splenic tumour. Tuber Lung Dis 1995; 76:80-3. 56. Twomey JJ, Leavell BS. Leukemoid reactions to tuberculosis. Arch Intern Med 1965;116:21-8. 57. Cameron SJ. Tuberculosis and the blood-a special relationship? Tubercle 1974;55:55-72. 58. Oswald NC. Acute tuberculosis and granulocytic disorders. BMJ 1963;2:1489-96. 59. Dawborn JA, Cowling DC. Disseminated tuberculosis in bone marrow dyscrasias. Aust Ann Med 1961;10:230-6. 60. Chapman AZ, Reeder PS, Baker LA. Neutropenia secondary to tuberculosis splenomegaly: report of a case. Ann Intern Med 1954;41:1225-31. 61. Cooper W. Pancytopenia associated with disseminated tuberculosis. Ann Intern Med 1959;50:1497-1501. 62. Clarke DL, Thomson SR, Bissetty T, Madiba TE, Buccimazza I, Anderson F. A single surgical unit’s experience with abdominal tuberculosis in the HIV/AIDS era. World J Surg 2007;31:1087-96. 63. Fee MJ, Oo MM, Gabayan AE, Radin DR, Barnes PF. Abdominal tuberculosis in patients infected with the human immunodeficiency virus. Clin Infect Dis 1995;20:938-44. 64. Lingenfelser T, Zak J, Marks IN, Steyn E, Halkett J, Price SK. Abdominal tuberculosis: still a potentially lethal disease. Am J Gastroenterol 1993;88:744-9. 65. Denton T, Hossain J. A radiological study of abdominal tuberculosis in a Saudi population, with special reference to ultrasound and computed tomography. Clin Radiol 1993;47:409-14. 66. Suri S, Kaur H, Wig JD, Singh K. CT in abdominal tuberculosis-comparison with barium studies. Indian J Radiol Imaging 1993;3:237-42. 67. Gompels BM, Darlington LG. Ultrasonic diagnosis of tuberculous peritonitis. Br J Radiol 1978;51:1018-9. 68. Kedar RP, Shah PP, Shivde RS, Malde HM. Sonographic findings in gastrointestinal and peritoneal tuberculosis. Clin Radiol 1994;49:24-9.

69. Lim JH, Ko YT, Lee DH, Lim JW, Kim TH. Sonography of inflammatory bowel disease: findings and value in differential diagnosis. AJR Am J Roentgenol 1994;163:343-7. 70. Malik A, Saxena NC. Ultrasound in abdominal tuberculosis. Abdom Imaging 2003;28:574-9. 71. Rubaltelli L, Proto E, Salmaso R, Bortoletto P, Candiani F, Cagol P. Sonography of abnormal lymph nodes in vitro: correlation of sonographic and histologic findings. AJR Am J Roentgenol 1990;155:1241-4. 72. Balthazar EJ, Gordon R, Hulnick D. Ileocecal tuberculosis: CT and radiologic evaluation. AJR Am J Roentgenol 1990;154:499-503. 73. Epstein BM, Mann JH. CT of abdominal tuberculosis. AJR Am J Roentgenol 1982;139:861-6. 74. Marshall JB, Vogele KA. Serum-ascites albumin difference in tuberculous peritonitis. Am J Gastroenterol 1988;83:59-61. 75. Runyon BA, Montano AA, Akriviadis EA, Antillon MR, Irving MA, McHutchison JG. The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Ann Intern Med 1992; 117:215-20. 76. Sharma SK, Tahir M, Mohan A, Smith-Rohrberg D, Mishra HK, Pandey RM. Diagnostic accuracy of ascitic fluid IFNgamma and adenosine deaminase assays in the diagnosis of tuberculous ascites. J Interferon Cytokine Res 2006;26:484-8. 77. Voigt MD, Kalvaria I, Trey C, Berman P, Lombard C, Kirsch RE. Diagnostic value of ascites adenosine deaminase in tuberculous peritonitis. Lancet 1989;1:751-4. 78. Bhargava DK, Gupta M, Nijhawan S, Dasarathy S, Kushwaha AK. Adenosine deaminase [ADA] in peritoneal tuberculosis: diagnostic value in ascitic fluid and serum. Tubercle 1990;71:121-6. 79. Sathar MA, Simjee AE, Coovadia YM, Soni PN, Moola SA, Insam B, et al. Ascitic fluid gamma interferon concentrations and adenosine deaminase activity in tuberculous peritonitis. Gut 1995;36:419-21. 80. Daniel TM. Antibody and antigen detection for the immunodiagnosis of tuberculosis: why not? what more is needed? where do we stand today? J Infect Dis 1988;158:678-80. 81. Thakur V, Mukherjee U, Kumar K. Elevated serum cancer antigen 125 levels in advanced abdominal tuberculosis. Med Oncol 2001;18:289-91. 82. Anuradha S, Kaur R, Singh NP, Baveja UK. Serodiagnosis of extrapulmonary tuberculosis using A-60 antigen. J Commun Dis 2001;33:12-6. 83. Anand BS, Schneider FE, El-Zaatari FA, Shawar RM, Clarridge JE, Graham DY. Diagnosis of intestinal tuberculosis by polymerase chain reaction on endoscopic biopsy specimens. Am J Gastroenterol 1994;89:2248-9. 84. Moatter T, Mirza S, Siddiqui MS, Soomro IN. Detection of Mycobacterium tuberculosis in paraffin embedded intestinal tissue specimens by polymerase chain reaction characterization of IS6110 element negative strains. J Pak Med Assoc 1998;48:174-8. 85. Schwake L, Von Herbay A, Junghanss T, Stremmel W, Mueller M. Peritoneal tuberculosis with negative polymerase

Abdominal Tuberculosis 293

86.

87.

88.

89.

90.

91.

92.

93.

chain reaction results: report of two cases. Scand J Gastroenterol. 2003;38:221-4. Pettengell KE, Larsen C, Garb M, Mayet FG, Simjee AE, Pirie D. Gastrointestinal tuberculosis in patients with pulmonary tuberculosis. Q J Med 1990;74:303-8. Shimamoto H, Hamada K, Higuchi I, Tsujihata M, Nonomura N, Tomita Y, et al. Abdominal Tuberculosis: peritoneal involvement shown by F-18 FDG PET. Clin Nucl Med 2007;32: 716-8. Singh V, Kumar P, Kamal J, Prakash V, Vaiphei K, Singh KW. Clinicocolonoscopic profile of colonic tuberculosis. Am J Gastroenterol 1996;91:565-8. Ibrarullah M, Mohan A, Sarkari A, Srinivas M, Mishra A, Sundar TS. Abdominal tuberculosis: diagnosis by laparoscopy and colonoscopy. Trop Gastroenterol 2002;23:150-3. Shah S, Thomas V, Mathan M, Chacko A, Chandy G. Ramakrishna BS, et al. Colonoscopic study of 50 patients with colonic tuberculosis. Gut 1992;33:347-51. Radhika S, Gupta SK, Chakrabarti A, Rajwanshi A, Joshi K. Role of culture for mycobacteria in fine-needle aspiration diagnosis of tuberculous lymphadenitis. Diagn Cytopathol 1989;5:260-2. Rajwanshi A, Bhambhani S, Das DK. Fine-needle aspiration cytology diagnosis of tuberculosis. Diagn Cytopathol 1987;3:13-6. Shukla HS, Bhatia S, Naitrani YP, Das P, Gupta SC. Peritoneal biopsy for the diagnosis of Koch’s abdomen. Postgrad Med J 1982;58:226-8.

94. Mehrotra MP, Mathur KS, Agrawal AN. Value of peritoneal biopsy in clinically diagnosed cases of tuberculosis. J Assoc Physicians India 1966;12:625. 95. Wolfe JH, Behn AR, Jackson BT. Tuberculous peritonitis and role of diagnostic laparoscopy. Lancet 1979;1:852-3. 96. Menzies RI, Fitzgerald JM, Mulpeter K. Laparoscopic diagnosis of ascites. Br Med J 1985;291:473-5. 97. Anand BS, Nanda R, Sachdev GK. Response of tuberculous stricture to antituberculous treatment. Gut 1988;29:62-9. 98. Chuttani HK, Sarin SK. Intestinal tuberculosis. Indian J Tuberc 1985;32:117-9. 99. Balasubramanian R, Narayan M, Balambal R, Tripathy SP, Sundararaman R, Venkatesan P. Randomised, controlled trial of short-course chemotherapy in abdominal tuberculosis: a five-year report. Int J Tuberc Lung Dis 1997;1:44-51. 100. Sharma SK, Liu JJ. Progress of DOTS in global tuberculosis control. Lancet 2006;367:951-2. 101. Tahir M, Sharma SK, Rohrberg DS, Gupta D, Singh UB, Sinha PK. DOTS at a tertiary care center in northern India: successes, challenges and the next steps in tuberculosis control. Indian J Med Res 2006;123:702-6. 102. Bennani A, Ouazzani H, Fadli F, Dafiri N, Ouazzani L. Diagnostic and therapeutic aspects of peritoneal tuberculosis in Morocco. Apropos of 300 cases. Ann Gastroenterol Hepatol 1988;24:347-54. 103. Pujari BD. Modified surgical procedures in intestinal tuberculosis. Br J Surg 1979;66:180-1.

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Granulomatous Hepatitis

20

Vineet Ahuja, SK Acharya

INTRODUCTION Granulomas in the liver may be found incidentally and perplex the clinician, but more often reflect an underlying clinically relevant disease. The search for an aetiology of granulomas usually suggests a systemic disorder rather than primary liver disease. Granulomas represent the inflammatory response of the mononuclear phagocytic system to the presence of a foreign antigen. An extremely diverse array of inciting agents can result in the formation of granulomas in the liver. These granulomas often have a common histopathological pattern but may sometimes differ in detail (1-4). However, in spite of an extensive work-up and evaluation, the aetiology remains obscure in 10 to 25 per cent patients with hepatic granulomas and these patients have been labelled as having “granulomatous hepatitis” (2-6). The word “hepatitis” implies that there is hepatic cell destruction. However, in most patients with hepatic granulomas, hepatic destruction is seldom seen. Therefore, several workers have proposed that the term “granulomatous hepatitis” should be avoided and have suggested “hepatic granulomatous disease” or “hepatic granulomas” as alternatives (3,4,7). AETIOLOGY Hepatic granulomas have varied aetiology and show considerable geographic variation. There are numerous causes of hepatic granulomas, both infective and noninfective. While the occurrence of sarcoidosis, primary biliary cirrhosis and fungal disease is high in the Western

hemisphere, tuberculosis [TB] is the most common cause in India. Hepatic granulomas usually represent a generalized disease process and have been described in five to ten per cent of needle liver biopsy specimens (2,4). The causes of hepatic granulomas are listed in Table 20.1. However, this list is by no means exhaustive. The relative frequency of occurrence of hepatic granulomas in some of the published studies is shown in Table 20.2. In many studies, TB and sarcoidosis have been the two most common causes of hepatic granulomas [Table 20.2]. With the advent of the human immunodeficiency virus [HIV] infection and the acquired immunodeficiency syndrome [AIDS], hepatic granulomas due to rare causes such as nontuberculous mycobacteria [NTM], cryptococcosis, etc., are being increasingly encountered (1-4). Table 20.1: Common causes of hepatic granulomas Infections Bacterial: Brucella, Salmonella Mycobacterial: Tuberculosis, Leprosy, NTM Rickettsiae: Q fever Spirochaetal: Syphilis Fungal: Histoplasma, Coccidioidomycosis, Cryptococcosis Parasitic: Schistosomiasis Viral: Hepatitis C, Cytomegalovirus Sarcoidosis Primary biliary cirrhosis Hodgkin’s disease AIDS related opportunistic infections Drugs: Carbamazepine, chlorpromazine, chlorpropamide, phenylbutazone, procainamide AIDS = acquired immunodeficiency syndrome; NTM = nontuberculous mycobacteria

Granulomatous Hepatitis 295 Table 20.2: Major causes of hepatic granulomas in various case series Variable

Guckian and Perry (8) [n = 63]

Tuberculosis

53

Neville et al (1) [n = 54] 2

Klatskin (9) [n = 565]

Cunnigham et al (10) [n = 77]

12.4

10.4 10.4

Sarcoidosis

12

54

38

Primary biliary cirrhosis

ND

19

10.4

Malignancy Unknown

5 20

1.4 10

6.5

4.4

7.8

6.5

31.2

Ferrell (11) [n = 35]* 2.5 20 22.8 8.5 20

Kanel and Reynolds (3) [n = 202]

Sabharwal et al (12) [n = 51]

25.2

55

27.2 0† 3.5 17.3

1.9 0 7.8 12

All values are shown as percentages ND = not described * Patients with epithelioid cell granulomas only † Patients with primary biliary cirrhosis were excluded

PATHOLOGY Hepatic granulomas are the result of a cell mediated immune response by hepatic reticuloendothelial system to antigen or foreign substances (1-4). Histopathological features of hepatic granulomas depend on the aetiology. Generally, hepatic granulomas consist of pale-staining epithelioid cells with surrounding lymphocytes. Sometimes, the foreign body or infecting organism can be identified within the granuloma. Central area of caseation necrosis, foreign body and Langhans’ giant cells can also be seen. Fibrous capsule and hyaline change representing healing may also be found. Several morphological types of hepatic granulomas have been described [Table 20.3]. Epithelioid granulomas are often encountered in patients with TB [Figure 20.1], sarcoidosis, primary biliary cirrhosis among other conditions. Caseating [necrotizing] granulomas have been classically associated with TB. Fibrin ring granulomas with a characteristic “doughnut” appearance occur in Q fever and have been described in several other conditions (13-15). Granulomatoid reaction with poorly Table 20.3: Morphological types of hepatic granulomas Epithelioid cell granulomas Caseating [necrotizing] granulomas Non-caseating granulomas Fibrin ring granulomas Granulomatoid reactions with poorly formed granulomas Bile granulomas Lipogranulomas Microgranulomas

formed granulomas occurs in patients with haematological malignancies and AIDS (3). Bile granulomas have been described in areas of cholestasis. Lipogranulomas can be seen in fatty liver. Microgranulomas can sometimes occur in patients with AIDS, cytomegalovirus [CMV] hepatitis and can occur along with other types of granulomas. Klatskin (9) estimated that in a patient with one granuloma in the needle biopsy specimen, the entire liver would contain about 15 million granulomas assuming that there is a generalized distribution. Hepatomegaly is, therefore, commonly observed in patients with granulomatous liver disease (1-4,16-18). CLINICAL PRESENTATION Clinical presentation of patients with hepatic granulomas depends on the causative disorder. These patients often present with pyrexia of unknown origin [PUO]. Mild to moderate hepatomegaly, which is usually non-tender, is common. When the disease is due to TB, sarcoidosis, associated peripheral mediastinal lymphadenopathy, erythema nodosum, clinically apparent jaundice may be found. In some conditions such as Hodgkin’s lymphoma and primary biliary cirrhosis where hepatic granulomas are an incidental finding, jaundice may be prominent. LABORATORY ABNORMALITIES In a patient with PUO, marked elevation of serum alkaline phosphatase [SAP] [3 to 6 times the normal] with mild elevation of serum transaminases [2 to 6 times the

296

Tuberculosis Table 20.4: Clinical syndromes of hepatobiliary tuberculosis Congenital tuberculosis Primary hepatic tuberculosis Disseminated/miliary tuberculosis Tuberculoma Tuberculosis of the biliary tract Drug induced hepatic failure Granulomatous hepatitis Tuberculosis pylephlebitis

pulmonary TB, is usually clinically silent. Occasionally, local signs and symptoms may be prominent in hepatic TB, and may constitute the initial or sole presenting feature of the disease. Using needle biopsy specimen, epithelioid granulomas can be demonstrated in hepatic TB in 80 to 100 per cent of cases; caseation necrosis in 30 to 83 per cent and acid-fast bacilli [AFB] in up to 59 per cent of cases (2-4). Congenital Tuberculosis

Figure 20.1: Granulomatous hepatitis. Photomicrograph showing a well-defined epithelioid granuloma [arrow], Langhans’ giant cells, ballooning and fatty degeneration [asterisk] of hepatocytes [A], [Haematoxylin and eosin × 200]. Epithelioid granuloma and Langhans’ giant cells [arrow] are also seen amidst hepatocytes showing ballooning degeneration [B] [Haematoxylin and eosin × 400]

normal], well preserved hepatic synthetic function, normal prothrombin time, serum albumin and a normal to slight increase in serum bilirubin should arouse a suspicion regarding the presence of hepatic granulomas (2-4). Anaemia and elevated erythrocyte sedimentation rate may be found. Peripheral blood eosinophilia may suggest Hodgkin’s disease, parasitic infestation and drug sensitivity (2-4). DIFFERENTIAL DIAGNOSIS Hepatobiliary Tuberculosis Tuberculosis involvement of the hepatobiliary system can occur in several ways [Table 20.4]. Liver involvement in TB, though common both in pulmonary and extra-

Hepatic involvement is very common in congenital TB and has been recently incorporated into the diagnostic criteria for this condition (19). When an infant born to a mother with active TB manifests hepatomegaly, jaundice and failure to thrive, congenital TB should be considered in the differential diagnosis. The reader is referred to the chapter “Tuberculosis in pregnancy” [Chapter 30] for details on this topic. Primary Hepatic Tuberculosis Primary hepatic TB is said to occur when there is involvement of the hepatobiliary tract by TB without apparent involvement elsewhere, or, only with local lymph node and splenic involvement (18). Some workers have called this condition “local hepatic tuberculosis” (18,19). Cinque et al (20) suggested that the tubercle bacilli reach the liver via the portal vein as opposed to miliary TB where the organism reaches the liver via the hepatic artery. Alvarez and Carpio (21) reported clinical and histopathological features of 130 patients with localized hepatic TB seen over a 20-year period at Manila, Philippines. The disease was more common in males and most patients were in the 11 to 30 years age range. Most of them were symptomatic for one to two years prior to the time of confirmation of the diagnosis. The paper described two major

Granulomatous Hepatitis 297 forms of clinical presentation. A hard, nodular liver with fever and weight loss mimicking cancer was observed in 65 per cent of the patients. In the remaining 35 per cent patients, chronic recurrent jaundice mimicking extra-hepatic obstruction was observed. Percutaneous liver biopsy [positive in 48 of 71 patients; 67%] and laparoscopy [positive in 49 of the 53 patients; 92%] were the main methods of confirmation of the diagnosis. On laparoscopy, hepatic lesions appeared as cheesy white, irregular nodules. Hepatic calcification was evident in 49 per cent of the patients. In patients with jaundice, serum aminotransferases were elevated in more than 90 per cent and SAP was elevated in 100 per cent patients. In those without jaundice, serum aminotransferases were elevated in about five per cent and SAP was elevated in 60 per cent patients. Overall, 12 per cent patients died in this series (21). In the series reported by Essop et al (22), hepatic TB was confirmed in 96 patients presenting with the features of liver disease, only 14 of whom had other concomitant hepatic pathology. Although respiratory symptoms occurred in 74 per cent of cases, these were overshadowed by the abdominal manifestations which included pain in the right hypochondrium, abdominal distension, firm, tender hepatomegaly, splenomegaly and ascites. Icterus was observed in 11 cases [only one of whom had concurrent hepatic pathology] and liver failure was found in 10 patients. A surgical presentation occurred in three patients. Coagulation abnormalities were noted in 26 patients [24 with low prothrombin index and 2 with moderately raised fibrinogen degradation products]. The characteristic serum profile included hyponatraemia [64%], raised SAP [3%] and γ-glutamyl transferase [77%], hypoalbuminaemia [63%] and hypergammaglobulinaemia [83%]. Transaminase levels were moderately elevated in 78 per cent of the cases. Hepatic imaging techniques were frequently misleading. Chest radiographs were normal in 25 per cent of cases. Liver biopsy was the most useful aid to correct diagnosis which was suspected clinically in only 47 per cent of cases. Histopathologically, AFB, caseation [Figure 20.2] and granulomas were seen in nine, 83 and 96 per cent of cases, respectively. The overall mortality was 42 per cent (22). Yu et al (23) have described computed tomography [CT] in hepatic TB in 12 cases. The findings included: [i] multiple nodular lesions in the subcapsule of liver;

Figure 20.2: Granulomatous hepatitis. Photomicrograph showing ballooning degeneration of hepatocytes [asterisk] and caseation necrosis [arrow] [Haematoxylin and eosin × 400]

[ii] multiple, miliary, micronodular and low-density lesions with miliary calcifications; [iii] singular, lowdensity mass with multiple flecked calcifications; [iv] multiple cystic lesions; and [v] multiple micronodular and low-density lesions fusing into multiloculated cystic mass or “cluster” sign. Balci et al (24) reported the spectrum of MRI features in 18 patients with a histopathological diagnosis of granulomatous hepatitis. Diffuse nodular liver involvement was visualized in all patients. Nodules were consistent with granulomas and were 0.5 to 4.5 cm in diameter. Caseating granulomas were of intermediate and high signal intensity on T2weighted images and low signal on T1-weighted images. Non-caseating granulomas revealed intermediate signal on T1- and T2-weighted images and increased enhancement in arterial phase images with persisting enhancement in late phase images. Most patients respond to antituberculosis treatment. For patients with obstructive jaundice, in addition to antituberculosis treatment, biliary decompression should be performed either by stent insertion during endoscopic retrograde cholangiopancreatography, by percutaneous transhepatic biliary drainage or by surgical decompression whenever feasible (25). Disseminated and Miliary Tuberculosis Hepatic involvement is a common finding in patients with disseminated and miliary TB (17). Granulomas has been reported in 75 to 100 per cent patients in autopsy

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series (26-28) and in 25 to 100 per cent needle biopsy specimens in patients with miliary TB (17,29,30). Miliary lesions are small 1 to 2 mm epithelioid granulomas. The reader is also referred to the chapter “Disseminated and miliary tuberculosis” [Chapter 34] for more details. Pulmonary Tuberculosis Up to two-thirds of the patients with pulmonary TB have been shown to have evidence of hepatic involvement (2,4,16). In patients with pulmonary TB, hyperglobulinaemia is frequently present and mild hyperbilirubinaemia may occasionally be present (30). Serum aminotransferase levels are usually normal. Kupffer cell hyperplasia is often present (16,31,32). Tuberculoma Sometimes, hepatic TB lesions can present as masses larger than 2 mm in diameter (33). Symptoms of fever, malaise and weight loss are common. Occasionally, abdominal pain and diarrhoea may occur. Hepatomegaly is frequently present. Jaundice and a palpable abdominal mass are uncommon presenting signs. Obstruction to bile flow due to compression at the porta hepatis by a tuberculoma has been postulated to be the cause of jaundice. Bleeding into a solitary tuberculoma presenting as an acute abdomen and progressive anaemia have also been reported (34). Consistent with a pattern characteristic of space occupying lesions of the liver, serum transaminases are normal or only slightly elevated; SAP levels are moderately elevated. On liver scan and arteriography, these lesions may mimic the appearance of a primary or metastatic carcinoma. They may also be confused with pyogenic or amoebic liver abscess (31,35). While blind percutaneous needle biopsy was not very helpful in the diagnosis (31,36), aspiration cytology at the time of laparoscopy was more useful in confirming the diagnosis (37). Most often these lesions resolve with effective antituberculosis treatment. Tuberculosis of Bile Ducts Tuberculosis of the bile ducts is uncommon. The disease is thought to result from rupture of tubercles in the periportal region into the walls of contiguous biliary ductules or by primary infection of bile ducts (38). Stemmerman (39) found TB of the biliary ducts in 45 of 1500 autopsies and estimated the incidence to be

three per cent. In these patients, symptoms and signs attributable to the biliary ducts are seldom found. Only three of the 45 patients [6.7%] reported by Stemmerman (39) manifested clinical jaundice, and hepatomegaly was evident only in one-third of them. However, evidence of TB of other organ systems draining into the portal circulation [e.g., caseous TB mesenteric lymphadenitis, intestinal TB, and TB peritonitis] was observed in 41 of the 45 patients in this series (39). Biliary stricture (40) and cholangitis (2) due to TB have also been described. Tuberculosis of Gall Bladder Gall bladder is an uncommon site of involvement by TB. Most cases occur in association with other organ involvement. Rarely, isolated TB of the gall bladder can occur (41,42) and is usually a retrospective diagnosis, becoming evident on histopathological examination of the cholecystectomy specimen. Management consists of administration of antituberculosis treatment (2,31,41,42). Hepatobiliary Tuberculosis in Patients with Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome Hepatobiliary involvement is very common in patients with HIV infection and AIDS (7). Both, Mycobacterium tuberculosis and NTM can cause the disease (2,31). In patients with AIDS, it is important to distinguish hepatic granulomas due to TB from other causes. Other Hepatic Lesions Granulomatous hepatitis has been described in 12 to 28 per cent patients receiving bacille Calmette-Guerin [BCG] vaccination (43-45). Clinically, constitutional symptoms, hepatomegaly, mildly elevated serum transaminases, bilirubin and moderately elevated SAP levels are present. Focal defects or non-homogeneous uptake on technetium liver scan may be present. On histopathological examination, granulomas, hepatocellular necrosis, lymphohistiocytic aggregates and Kupffer cell hyperplasia have been described (43-45). Direct effect of viable BCG bacilli and hypersensitivity reaction have been proposed as the underlying pathogenetic mechanisms (46). Amyloidosis has been described in 10 per cent of patients with concomitant hepatic TB which may occasionally present as marked hepatomegaly (28). Most of these patients have long standing advanced disease

Granulomatous Hepatitis 299 frequently involving the intestinal tract (28,47). Nodular regenerative hyperplasia had been described in TB and several other disorders such as collagen vascular disorders [e.g., systemic lupus erythematosus, rheumatoid arthritis, progressive systemic sclerosis], antiphospholipid antibody syndrome, macroglobulinaemia, among others (48,49). In Bantus of Africa, haemosiderosis of the liver has often been described (50). Whether these are mere associations or the cause/effect of TB needs further clarification. Hepatobiliary TB can rarely present as hepatic failure (51). Severe degree of immunosuppression following liver transplantation also predisposes to the development of hepatic TB (52).

giant cells are not common and necrosis is not present. Sometimes epithelioid cells may surround the interlobular bile ducts undergoing non-suppurative destruction. Liver granulomas may also be seen in primary sclerosing cholangitis (14).

Sarcoidosis

Hepatitis C Infection

Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology. In patients with sarcoidosis, hepatic granulomas are widely distributed in the liver; very often in the portal and periportal regions. Often, hepatic involvement seems incidental, but a few patients may present with signs and symptoms of hepatic dysfunction. In some patients, the clinical presentation may resemble primary biliary cirrhosis (52). The granulomas are numerous enough to make it unlikely that could be missed in a liver biopsy sample of even moderate size (53). Central necrosis in these granulomas is less frequent than in TB and they contain abundant reticulin. The granulomas are made of epithelioid cells [often with a thin rim of lymphocytes] and giant cells, some of them containing stellate [asteroid] bodies. The granulomas may show characteristic clustering which is also seen in the lymph nodes. As the granuloma ages, there may be deposition of collagen in a lamellar manner at the periphery of granuloma. Sarcoidosis may present with chronic cholestasis, destruction of interlobular ducts and limiting plates may be evident in liver biopsy specimens (54-56).

Chronic hepatitis C virus [HCV] infection has recently been recognized as an aetiological cause of hepatic granulomas (60). Hepatic granulomas have been described in up to 10 per cent patients with chronic HCV infection. Development of hepatic granulomas following interferon treatment has been reported in patients with HCV infection (61). A recent multicentre study (60) evaluated a total of 725 liver biopsies from 605 patients with chronic HCV infection to identify an association between the presence of granuloma and response to interferon treatment and also to see whether interferon treatment leads to the formation of hepatic granulomas. In eight patients, hepatic granulomas were detected in the initial liver biopsies. Four patients had repeat biopsies, and all had hepatic granulomas again. The prevalence of hepatic granulomas in patients with chronic hepatitis C was calculated to be 1.3 per cent. The presence of granulomas was not found to be a predictor of response to interferon therapy. The development of hepatic granulomas during interferon therapy was also not found to be a common phenomenon in this study. Hence, the clinical relevance of finding hepatic granulomas in HCV infected patients still needs further studies. Development of systemic sarcoidosis many years after interferon-α treatment for chronic HCV infection has also been documented (62).

Primary Biliary Cirrhosis In the early stages, the hepatic granulomas in patients with primary biliary cirrhosis may be indistinguishable from sarcoidosis. The granulomas are epithelioid and are most often found in the portal tracts. Lymphocytes are scattered within the granuloma. Plasma cells are often present in perigranulomatous location. Multinucleated

Drugs Many drugs have the potential to produce hepatic granulomas [Table 20.3] that may be eosinophil rich (57). Pyrazinamide which is given for the treatment of TB has also been implicated as a cause of granulomatous liver disease (58,59). Chronic Hepatitis

Hepatitis B Infection Tahan et al (63) studied the prevalence of hepatic granulomas in 663 patients with chronic hepatitis B virus

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[HBV] infection, to determine its significance regarding treatment outcome. Hepatic granulomas were found in 10 cases [1.5%]. Of these, four responded to interferon therapy, two dropped out, and four were nonresponders. This study (63) concluded that hepatic granuloma is a rare finding in chronic HBV infection and its presence does not seem to predict the response to interferon therapy. Brucellosis Brucella suis, Brucella abortus, Brucella melitensis and Brucella canis cause granulomatous reaction in the liver. Brucellosis is acquired by contact with cattle, goats, dogs or by ingestion of unpasteurized dairy products. The infection presents as undulating fever with remissions and relapses. Excessive weakness and depression are present during the acute illness. The diagnosis is made by brucella serology and positive reactions in titres of 1:320 or more are considered diagnostic. The most reliable method of establishing the diagnosis is by blood or bone marrow culture.

of abundant epithelioid cells with scattered lymphocytes. Multinucleated cells may be present and these granulomas are most often present in the parenchyma. It is seldom possible to identify the bacilli even when special stains are used. The lepromatous type granuloma is inflammatory in nature and consists of histiocytes with clear to foamy cytoplasm. Lymphocytes are infrequent and multinucleated giant cells are not present. These granulomas can be seen within the portal tracts or the parenchyma and contain abundant numbers of acid-fast organisms identified by Fite stain. The intermediate type granulomas consist of epithelioid cells with only scanty number of lymphocytes. Giant cells are seldom seen. Schistosomiasis Hepatic granulomas are caused by Schistosoma mansoni and Schistosoma japonicum. The granulomas are quite disease specific and ova may be seen in the centre of the granuloma. Presence of eosinophils may point to parasitic aetiology (4).

Systemic Mycoses

Hodgkin’s Lymphoma

Histoplasma capsulatum and Coccidioides immitis usually infect humans by inhalation of organisms with primary infection occurring in the lungs. Chronic pulmonary lesions develop in a few and rarely there is a widespread dissemination to other organs including the liver. The hepatic reaction to these fungi is usually by granuloma formation (2-4). Histoplasma usually colonizes in immunosuppressed patients but occasionally immunocompetent individuals may also be affected. The disease usually manifests as fever with hepatosplenomegaly and oral ulcers. Commonly there is an associated adrenal involvement with Addison’s disease. Liver usually contains granulomatous lesions, sometimes with central caseation necrosis resembling TB. Use of special stains like methenamine silver, Hotchkiss-McManus stain makes identification easier although the organism can often be found in the granuloma by haematoxylin and eosin staining. Diagnosis is best confirmed by culture of the organisms from blood, bone marrow, sputum and oral ulcer scrapings (2,4).

Hepatic granulomas have been described in eight to seventeen per cent patients with Hodgkin’s disease (64,65). The presence of hepatic granulomas does not appear to be related to disease outcome or prognosis in Hodgkin’s lymphoma.

Leprosy

Acquired Immunodeficiency Syndrome

Three types of granulomas have been described in patients with leprosy (3). The tuberculoid type, consists

Several conditions result in hepatic granulomas in patients with AIDS (4,15,16,57). These are listed in

Typhoid Fever Hepatic granuloma is a rare complication of typhoid fever. A report has described two cases of typhoid fever with hepatic, splenic and bone marrow granulomas (66). Q Fever Fibrin ring granulomas are often present in patients with Q fever. These granuloma contain a ring-like array of fibrin [stainable with phosphotungstic acid-haematoxylin] producing a “halo” effect around a central empty space (2-4). These granulomas have also been described in allopurinol hypersensitivity, CMV hepatitis, leishmaniasis, toxoplasmosis, hepatitis A and systemic lupus erythematosus (2-4).

Granulomatous Hepatitis 301 Table 20.5. The diagnosis is confirmed with histopathological and microbiological examination of the liver biopsy specimen. Idiopathic Granulomatous Hepatitis Despite extensive investigations, 10 to 25 per cent of patients are labelled as having “idiopathic” hepatic granulomas (2-6,67). Idiopathic granulomatous hepatitis is a condition characterized by recurrent fever and granulomas in the liver and other organs where other causes of hepatic granulomas have been carefully excluded (5,68,69). Patients are usually in the age range of 16 to 60 years. The prominent symptom is fever, which is often relapsing in character, although continuous and remittent fever patterns have also been described. Fortyfour per cent of patients first presented as PUO in one series (5). Other symptoms, include malaise, chills, weight loss, abdominal pain, anorexia, night sweats, nausea, jaundice, diarrhoea and abdominal distension. The natural history of the disease is marked by multiple remissions and exacerbations. Response to corticosteroids is usually dramatic (5,68,69). DIAGNOSIS Patients with hepatic granulomas must be thoroughly investigated for a possible aetiological cause. Detailed history must be obtained specifically focusing on exposure to an infectious source, and occupational or environmental agents including drugs. Several laboratory tests are often employed in the work-up of a patient with granulomatous hepatitis. Cultures of blood, body fluids and biopsy material must be done keeping in mind the common infectious causes of hepatic granulomas. Table 20.5: Causes of hepatic granulomas in patients with acquired immunodeficiency syndrome Mycobacterium tuberculosis Mycobacterium avium-intracellulare complex Cytomegalovirus Histoplasmosis Toxoplasmosis Cryptococcosis Neoplasms Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Drugs Adapted from references 2-4

Anti-mitochondrial antibodies may be helpful in the diagnosis of primary biliary cirrhosis. Elevated serum angiotensin converting enzyme levels may suggest a diagnosis of sarcoidosis. Liver biopsy is essential for the diagnosis. Biopsy material must be subjected to microbiological and histopathological examination. Type and location of granulomas may offer a clue to the aetiology. Special stains may be required to identify infectious agents. Examination under polarized light may help in visualizing foreign bodies. TREATMENT When the investigations are conclusive, treatment should be directed towards the aetiological agent. In a country like India, when the aetiological cause of granulomatous hepatitis is unclear, a therapeutic trial with antituberculosis agents is often given. If this fails, then corticosteroid treatment may be tried. In the study of idiopathic granulomatous hepatitis reported by Zoutman et al (5), the disease resolved spontaneously in seven patients, two patients responded with less than three months of oral corticosteroids or indomethacin treatment and seven patients required steroid treatment for two years or longer to maintain asymptomatic state. PROGNOSIS Outcome of hepatic granulomatous disease depends on the underlying cause. In the study of TB hepatitis reported by Essop et al (22), age below 20 years, acute presentation, presence of coagulopathy and a high mean caseation score were found to be predictors of a poor outcome. Drug-related granulomas often resolve when the offending agent is withdrawn (59). The presence of hepatic granulomas in patients with Crohn’s disease, Hodgkin’s disease and primary biliary cirrhosis is thought to indicate a better prognosis (69-71). REFERENCES 1. Neville E, Piyasena KH, James DG. Granulomas of the liver. Postgrad Med J 1975;51:361-5. 2. Sherlock S, Dooley J. Diseases of the liver and biliary system. Oxford: Blackwell Scientific Publications;1993.p.461-7. 3. Kanel GC, Reynolds TB. Hepatic granulomas. In: Kaplowitz N, editor. Liver and biliary disease. Baltimore: Williams and Wilkins;1992.p.455-62.

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4. Lefkowitch JH. Hepatic granulomas. In: Haubrich WS, Schaffner F, Berk JE, editors. Bockus gastroenterology. Philadelphia: W.B. Saunders Company;1995.p.2317-24. 5. Zoutman DE, Ralph ED, Frei JV. Granulomatous hepatitis and fever of unknown origin. An 11-year experience of 23 cases with three years’ follow-up. J Clin Gastroenterol 1991;13:69-75. 6. Simon HB, Wolff SM. Granulomatous hepatitis and prolonged fever of unknown origin - a study of 13 patients. Medicine [Baltimore] 1973;52:1-21. 7. Tobias H, Sherman A. Hepatobiliary tuberculosis. In: Rom WN, Gray SM, editors. Tuberculosis. Boston: Little, Brown and Company;1996.p.599-608. 8. Guckian JC, Perry JE. Granulomatous hepatitis. An analysis of 63 cases and review of the literature. Ann Intern Med 1966;65:1081-100. 9. Klatskin G. Hepatic granulomata: problems in interpretation. Mt Sinai J Med 1977;44:798-812. 10. Cunnigham D, Mills PR, Quigley EM, Patrick RS, Watkinson G, MacKenzie JF, et al. Hepatic granulomas: experience over a 10-year period in the West of Scotland. Q J Med 1982;202:162-70. 11. Ferrell LD. Hepatic granulomas: a morphologic approach to diagnosis. Surg Pathol 1990;3:87-106. 12. Sabharwal BD, Malhotra N, Garg R, Malhotra V. Granulomatous hepatitis: a retrospective study. Indian J Pathol Microbiol 1995;38:413-6. 13. Bernstein M, Edmondson HA, Barbour BH. The liver lesion in Q fever. Clinical and pathologic features. Arch Intern Med 1965;116:491-8. 14. Hoffmann CE, Heaton JW. Q fever hepatitis: clinical manifestations and pathological findings. Gastroenterology 1982;83:474-9. 15. Marazuela M, Moreno A, Yebra M, Cerezo E, Gomez-Gesto C, Vargas JA. Hepatic fibrin-ring granulomas: a clinicopathologic study of 23 patients. Hum Pathol 1991;22:607-13. 16. Bowry S, Chan CH, Weiss H, Katz S, Zimmerman HJ. Hepatic involvement in pulmonary tuberculosis. Am Rev Respir Dis 1970;101:941-8. 17. Sharma SK, Mohan A, Prasad KL, Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. QJM 1995;88:29-37. 18. Essop AR, Moosa MR, Segal I, Posen J. Primary tuberculosis of the liver-a case report. Tubercle 1983;64:291-3. 19. Cantwell MF, Shehab ZM, Costello AM, Sands L, Green WF, Ewing EP Jr, et al. Brief report: congenital tuberculosis. N Engl J Med 1994;330:1051-4. 20. Cinque TJ, Gary NE, Palladino VS. “Primary” miliary tuberculosis of the liver. Am J Gastroenterol 1964;42:611-9. 21. Alvarez SZ, Carpio R. Hepatobiliary tuberculosis. Dig Dis Sci 1983;28:193-200. 22. Essop AR, Posen JA, Hodkinson JH, Segal I. Tuberculosis hepatitis: a clinical review of 96 cases. Q J Med 1984;53:46577. 23. Yu RS, Zhang SZ, Wu JJ, Li RF. Imaging diagnosis of 12 patients with hepatic tuberculosis. World J Gastroenterol 2004;10:1639-42.

24. Balci NC, Tunaci A, Akinci A, Cevikbas U. Granulomatous hepatitis: MRI findings. Magn Reson Imaging 2001;19:110711. 25. Alvarez SZ. Hepatobiliary tuberculosis. J Gastroenterol Hepatol 1998;13:833-9. 26. Saphir O. Changes in the liver and pancreas in chronic tuberculosis. Arch Pathol 1929;7:1025-39. 27. Torrey RG. The occurrence of miliary tuberculosis of the liver in the course of pulmonary tuberculosis. Am J Med Sci 1916;151:549-56. 28. Ullom JT. The liver in tuberculosis. Am J Med Sci 1909; 137:694-9. 29. Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis 2005;5:415-30. 30. Sahn SA, Neff TA. Miliary tuberculosis. Am J Med 1974;56:495-505. 31. Lewis JH, Zimmerman HY. Tuberculosis of the liver and biliary tract. In: Schlossberg D, editor. Tuberculosis. New York: Springer Verlag;1988.p.149-69. 32. Arora MM, Ali A, D’Souza AJ, Pawar KN. Clinical, function and needle biopsy studies of the liver in tuberculosis. J Indian Med Assoc 1956;26:341-4. 33. Achem SR, Kolts BE, Grisnik J, MacMath T, Monteiro CB, Goldstein J. Pseudotumoral hepataic tuberculosis. Atypical presentation and comprehensive review of the literature. J Clin Gastroenterol 1992;14:72-7. 34. Prochazka M, Vyhnanek F, Vorreith V, Jirasek M. Bleeding into solitary hepatic tuberculoma. Report of a case treated by resection. Acta Chir Scand 1986;152:73-5. 35. Tahiliani RR, Parikh JA, Hegde AV, Bhatia SJ, Deodhar KP, Kapadia NM, et al. Hepatic tuberculosis simulating hepatic amoebiasis. J Assoc Physicians India 1983;31:679-80. 36. Duckworth WC. Tuberculosis of the liver. S Afr Med J 1964;38:945. 37. Bhargava DK, Verma K, Malaviya AN. Solitary tuberculoma of the liver; laparoscopic, histologic and cytologic diagnosis. Gastrointest Endosc 1983;29:329-30. 38. Rosenkranz K, Howard LD. Tubular necrosis of the liver. Arch Pathol 1936;22:743-54. 39. Stemmerman M. Bile ductal tuberculosis. Q Bull Sea View Hosp 1941;6:316-24. 40. Fan ST, Ng IO, Choi TK, Lai EC. Tuberculosis of the bile duct: a rare cause of biliary stricture. Am J Gastroenterol 1989;84:413-4. 41. Wang CT. Hepatobiliary tuberculosis. Chin J Tuberc Respir Dis1991;14:40-1. 42. Leader SA. Tuberculosis of the liver and gallbladder with abscess formation. Ann Intern Med 1951;37:594-605. 43. Bodurtha A, Kim YH, Laucius JF, Donato RA, Mastrangelo MJ. Hepatic granulomas and other hepatic lesions associated with BCG immunotherapy for cancer. Am J Clin Pathol 1974;61:747-52. 44. Ersoy O, Aran R, Aydinli M, Yonem O, Harmanci O, Akdogan B, et al. Granulomatous hepatitis after intravesical BCG treatment for bladder cancer. Indian J Gastroenterol 2006;25:258-9.

Granulomatous Hepatitis 303 45. Hristea A, Neacsu A, Ion DA, Streinu-Cercel A, St´niceanu F. BCG-related granulomatous hepatitis. Pneumologia 2007;56:32-4. 46. Obrien TF, Hysolp NE Jr. Case records of the Massachusetts General Hospital, weekly clinicopathological exercises. Case 34-1975. N Engl J Med 1975;293:443-8. 47. Jones K, Peck WM. Incidence of fatty liver in tuberculosis with special reference to tuberculosis enteritis. Arch Intern Med 1944;75:371-4. 48. Rougier P, Degott C, Rueff B, Benhamou JP. Nodular regenerative hyperplasia of the liver. Report of six cases and review of the literature. Gastroenterology 1978;75:169-72. 49. Foster JM, Litwin A, Gibbs JF, Intengen M, Kuvshinoff BW. Diagnosing regenerative nodular hyperplasia, the “great masquerader” of liver tumors. J Gastrointest Surg 2006;10:727-33. 50. Hersch C. Tuberculosis of the liver: a study of 200 cases. S Afr Med J 1964;38:857-63. 51. Sharma SK, Shamim SQ, Bannerjee CK, Sharma BK. Disseminated tuberculosis presenting as massive hepatosplenomegaly and hepatic failure: case report. Am J Gastroenterol 1981;76:153-6. 52. Sharma SK, Mohan A. Sarcoidosis: global scenario and Indian perspective. Indian J Med Res 2002;116:221-47. 53. Devaney K, Goodman ZD, Epstein MS, Zimmerman HJ, Ishak KG. Hepatic sarcoidosis.Clinicopathologic features in 100 patients. Am J Surg Pathol 1993;17:1272-80. 54. Rudzki C, Ishak KG, Zimmerman HJ. Chronic intrahepatic cholestasis of sarcoidosis. Am J Med 1975;59:373-87. 55. Bass NM, Burroughs AK, Scheuer PJ, James DG, Sherlock S. Chronic intrahepatic cholestasis due to sarcoidosis. Gut 1982;23:417-21. 56. Sharma SK, Mohan A. Uncommon manifestations of sarcoidosis. J Assoc Physicians India 2004;52:210-4. 57. Ishak KG. Granulomas of the liver. In: Ioachim HL, editor. Pathology of granulomas. New York: Raven Press; 1993.p.307-70. 58. Knobel B, Bunyanowsky G, Dan M, Zaidel L. Pyrazinamide induced granulomatous hepatitis. J Clin Gastroenterol 1997;24:264-6.

59. McMaster KR, Hennigar GR. Drug-induced granulomatous hepatitis. Lab Invest 1981;44:61-73. 60. Ozaras R, Tahan V, Mert A, Uraz S, Kanat M, Tabak F, et al. The prevalence of hepatic granulomas in chronic hepatitis C. J Clin Gastroenterol 2004;38:449-52. 61. Fiel MI, Shukla D, Saraf N, Xu R, Schiano TD. Development of hepatic granulomas in patients receiving pegylated interferon therapy for recurrent hepatitis C virus post liver transplantation. Transpl Infect Dis 2007 Oct 1;[Epub ahead of print]. 62. Tortorella C, Napoli N, Panella E, Antonaci A, Gentile A, Antonaci S. Asymptomatic systemic sarcoidosis arising 5 years after IFN-alpha treatment for chronic hepatitis C: a new challenge for clinicians. J Interferon Cytokine Res 2004;24:6558. 63. Tahan V, Ozaras R, Lacevic N, Ozden E, Yemisen M, Ozdogan O, et al. Prevalence of hepatic granulomas in chronic hepatitis B. Dig Dis Sci 2004;49:1575-7. 64. Abt AB, Kirschner RH, Belliveau RE, O’Connell MJ, Sklansky BD, Green WH, et al. Hepatic pathology associated with Hodgkin’s disease. Cancer 1974;33:1564-71. 65. Kadin ME, Donaldson SS, Dorfman RF. Isolated granulomas in Hodgkin’s disease. N Engl J Med 1970;283:859-61. 66. Mert A, Tabak F, Ozaras R, Ozturk R, Aki H, Aktuglu Y. Typhoid fever as a rare cause of hepatic, splenic, and bone marrow granulomas. Intern Med 2004;43:436-9. 67. Sartin JS, Walker RC. Granulomatous hepatitis: a retrospective review of 88 cases at the Mayo Clinic. Mayo Clin Proc 1991;66:914-8. 68. Telenti A, Hermans PE. Idiopathic granulomatosis manifesting as fever of unknown origin. Mayo Clin Proc 1989;65:44-50. 69. Beswick DR, Klatskin G, Boyer JL. Asymptomatic primary biliary cirrhosis. A progress report on long-term followup and natural history. Gastroenterology 1985;89:267-71. 70. O’Connell MJ, Schimpff SC, Kirschner RH, Abt AB, Wiernik PH. Epithelioid granulomas in Hodgkin’s disease. A favorable prognostic sign. JAMA 1975;233:886-9. 71. Gaya DR, Thorburn D, Oien KA, Morris AJ, Stanley AJ. Hepatic granulomas: a 10 year single centre experience. J Clin Pathol 2003;56:850-3.

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Neurological Tuberculosis

21

PS Mathuranath, K Radhakrishnan

INTRODUCTION Neurological tuberculosis [TB] comprises five to ten per cent of the cases of extra-pulmonary TB and occurs more frequently in children (1,2). With the emergence of TB as an increasingly common secondary infection in patients with human immunodeficiency virus [HIV] infection and acquired immunodeficiency syndrome [AIDS], there is a resurgence of neurological TB across the globe, including in the developing countries (3-5). Even with the modern day antituberculosis treatment, neurological TB continues to have a high morbidity and mortality rate, especially in children (6,7). The fact that the neurological TB is responsible for two to ten per cent of hospitalizations is a testimony to this fact (2). Neurological TB may be classified into three clinicopathological categories: tuberculosis meningitis [TBM], tuberculoma, and arachnoiditis, which is also referred to as TB radiculomyelitis [TBRM] [Table 21.1]. In addition, there is the less common clinicopathological entity of TB abscess. In this chapter, TBM, intracranial tuberculoma and TBRM are described. In addition, Table 21.1: Classification of neurological tuberculosis Tuberculosis meningitis Tuberculosis arachnoiditis Basal Opticochiasmatic Spinal Tuberculoma Intracranial Spinal Tuberculosis abscess

diagnosis and management of chronic meningitis and single, small, contrast enhancing brain lesions are also detailed. Spinal TB is covered in the chapter “Skeletal tuberculosis” [Chapter 23]. Indian investigators have contributed considerably to the understanding of the pathogenesis, pathology, diagnosis and treatment of neurological TB (8-12). Last two decades have witnessed major changes in several aspects of neurological TB. These include a change in the clinical picture of neurological TB with an increasing number of cases with atypical presentation and an alarming increase in the number of patients with multidrug-resistant tuberculosis [MDR-TB]. Intense research is being carried out for discovering an accurate serological marker for early diagnosis of neurological TB. Widespread availability and utilization of computed tomography [CT] and magnetic resonance imaging [MRI], have facilitated an early diagnosis of complications. TUBERCULOSIS MENINGITIS Tuberculosis meningitis, which accounts for 70 to 80 per cent of cases of neurological TB, is still an important public health problem in developing countries (2,13). In spite of its common occurrence, extensive research and widespread public awareness, there is often a delay in the diagnosis and institution of specific therapy for TBM. This is unfortunate as the promptness with which antituberculosis treatment is initiated is the single most important physician-controlled factor influencing the prospects for recovery without serious neurological sequelae.

Neurological Tuberculosis 305 Pathogenesis A majority of cases of TBM are caused by Mycobacterium tuberculosis. Isolated cases of meningitis caused by bovine, avian and nontuberculous mycobacteria [NTM] have also been documented (2). Central nervous system [CNS] TB is invariably secondary to TB elsewhere in the body. It is generally believed that the critical event in the development of meningitis is the rupture of a subependymally located tubercle [Rich focus] resulting in the delivery of infectious material into the subarachnoid space (14). In the bacteraemic phase of primary lung infection, metastatic foci can get established in any organ, which can undergo reactivation active after a variable period of clinical latency. Whether the critical subependymal tubercle develops during primary haematogenous dissemination or due to secondary haematogenous spread from an area of extra-cranial extra-pulmonary TB is still a matter of dispute. Several co-morbid conditions such as intercurrent viral infections, advanced age, malnutrition, alcoholism, HIV/AIDS, use of corticosteroids and other immunosuppressive drugs may compromise cellular immunity of the host leading to reactivation of a latent infection. However, a majority of cases of TBM occur in the absence of any clinically demonstrable extra-cranial infection or overt disturbance in host immune function. Pathology The pathology of TBM comprises of: [i] inflammatory meningeal exudate; [ii] ependymitis; [iii] vasculitis; [iv] encephalitis; and [v] disturbance of cerebrospinal fluid [CSF] circulation and absorption [Table 21.2].

The leptomeningeal reaction is characterized by a serofibrinous exudate lying between the pia and arachnoid intermixed with areas of caseous necrosis [Figure 21.1]. The cellular exudate consists predominantly of lymphocytes and plasma cells with infrequent epithelioid cells and giant cells. The proliferative arachnoiditis is most marked at the base of the brain, most prominent in the area of the optic chiasma. As the process of opticochiasmatic arachnoiditis becomes more chronic, it may progress and encircle the brainstem to involve the function of other cranial nerves. Ependymitis is almost a constant feature of TBM and may even be more severe than the meningeal reaction. The choroid plexus may show varying degrees of inflammatory process. The terminal portion of the internal carotid artery and proximal middle cerebral artery in the Sylvian fissure are the vessels most frequently involved by vasculitis with inflammation, spasm, constriction and thrombosis. The meningeal veins traversing the inflammatory exudate show varying degrees of phlebitis and thrombosis. The brain parenchyma immediately underlying the meningeal exudate as well as the subependymal region shows a variable degree of oedema, perivascular inflammation and microglial reaction. A majority of infarcts occur in the territory of the middle cerebral artery. Hydrocephalus develops in the majority of patients with TBM who have been symptomatic for more than two to three weeks (2,15). In the majority, it is a communicating hydrocephalus due to the blockage of the basal cisterns by the exudate in the acute stage and

Table 21.2: Pathology of tuberculosis meningitis Meningitis Inflammatory leptomeningeal exudate Caseous necrosis Proliferative opticochiasmatic arachnoiditis Vasculitis Arteritis Phlebitis Ependymitis and choroid plexitis Encephalitis Cortical Subependymal Vasculitis and infarction Hydrocephalus Communicating Obstructive

Figure 21.1: Tuberculosis meningitis. The meningeal blood vessels show vasculitis. They are surrounded by granulomas with epithelioid cells and necrosis [Haematoxylin and eosin × 250]

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adhesive leptomeningitis in the chronic stage. Less frequently, the hydrocephalus is obstructive due to either narrowing or occlusion of aqueduct by ependymal inflammation or by a strategically placed brainstem tuberculoma, or at the outlet foraminae of the fourth ventricle. Hydrocephalus is more frequent and severe in children than in adults. Udani and Dastur (10) described a pathological entity predominantly seen in the pediatric age group, designated as TB encephalopathy, characterized by diffuse brain oedema, perivascular myelinolysis and haemorrhagic leucoencephalitis with little evidence of meningitis. They ascribed the syndrome to hypersensitivity reaction to tuberculoproteins. Clinical and pathological distinction of this entity from Reye’s syndrome, acute disseminated encephalomyelitis and acute haemorrhagic leucoencephalitis will be difficult. There is little evidence for the existence of TB encephalopathy without meningitis. Clinical Features In developing countries, TBM is still a disease of childhood with the highest incidence in the first three years of life (2,13). Recent contact with TB, when elicited, can be found in 70 to 90 per cent of children with TBM (16). The disease usually evolves gradually over two to six weeks although an acute onset of illness can occur in 50 per cent of children and in 14 per cent of adults (16). The prodromal phase is non-specific and usually lasts two to three weeks with a history of vague ill-health, apathy, irritability, anorexia and behavioural changes. As a part of the prodrome, headache, vomiting or fever may occur in 13 to 30 per cent of patients and heralds the onset of meningitis. Focal neurological deficits and features of raised intracranial tension may precede signs of meningeal irritation. Focal or generalized convulsions are encountered in 20 to 30 per cent of patients sometime during the course of illness and are particularly common in children and the elderly. The underlying mechanism could include hydrocephalus, tuberculoma, cerebral oedema, and hyponatraemia due to syndrome of inappropriate antidiuretic hormone [SIADH] secretion. Cranial nerve palsies can occur in 20 to 30 per cent of patients, the sixth nerve involvement being the most common (2,8,16,17). Exudate around the optic chiasma is the central feature of the pathology in TBM. Hence, complete or

partial loss of vision is a major complication of the disease. The mechanisms for this may include arteritis or compression of the anterior visual pathways due to hydrocephalus or tuberculoma. Ethambutol toxicity too may contribute to the visual impairment. The frequency of optic nerve involvement in clinical reports varies from four to thirty-five per cent (2,17), although visual evoked potentials testing has shown disturbance in over 50 per cent of patients examined in the acute stage of the disease (18). The clinical presentation of TBM as documented at a teaching hospital in North-west India is shown in Table 21.3 (17). In untreated cases, adhesions in the basal brain progress and result in extensive cranial nerve palsies, internal carotid constriction and stroke, increasing hydrocephalus with tentorial herniation, pupillary abnormalities, pyramidal signs and progressive deterioration in the consciousness state. The terminal illness is characterized by deep coma and decerebrate or decorticate posturing. Without treatment, death usually occurs in five to eight weeks. According to the severity of the illness, patients with TBM can be categorized into three or four clinical stages Table 21.3: Percentage frequency of presenting symptoms and signs in 232 patients with tuberculosis meningitis seen at Postgraduate Institute of Medical Education and Research, Chandigarh* Clinical presentation

%

Symptoms Fever Altered sensorium Semiconscious Unconscious Seizures Behavioural changes

29.3 23.3 21.5 12.9

Signs Neck rigidity Papilloedema Abducens nerve palsy Hemiplegia Facial nerve palsy Optic atrophy Decerebration Abnormal movements Oculomotor nerve palsy Choroidal tubercles

64.2 33.6 18.5 18.5 17.7 11.6 11.2 6.5 6.0 3.4

* Data from reference 17

78.4

Neurological Tuberculosis 307 Table 21.4: Clinical staging system for tuberculosis meningitis Stage 1

2 3 4

Description Conscious and rational, with or without neck stiffness, but no focal neurological signs or signs of hydrocephalus Conscious but confused or has focal signs, such as cranial nerve palsies or hemiparesis Comatose or delirious with or without dense neurological deficit Deeply comatose with decerebrate or decorticate posturing

Adapted from references 19,20

[Table 21.4] (19,20). The clinical staging helps to optimize therapy [e.g., addition of dexamethasone to antituberculosis drugs] and to predict the prognosis. The prognosis of TBM is determined by the clinical stage at the time of initiation of treatment. During the last two decades, the picture of TBM has changed in developed countries with an increasing number of atypical cases (15,16). Atypical presentations of TBM include acute meningitic syndrome simulating pyogenic meningitis, progressive dementia, status epilepticus, psychosis, stroke syndrome, locked-in-state, trigeminal neuralgia, infantile spasm and movement disorders (2,17,21). The factors that are thought to be responsible for this changing pattern include delay in the age of onset of primary infection, immunization, problems related to immigrant populations and HIV infection (22,23). Tuberculosis Meningitis and Human Immunodeficiency Virus Infection One of the major causes for re-emergence of TB in the west has been the HIV epidemic. The CNS involvement is five times more frequent in HIV-seropositive compared to HIV-seronegative patients (22,24). Berenguer et al (22) reported that 10 per cent of 455 patients co-infected with both TB and HIV developed TBM. Yechoor et al (25) observed that 20 of the 31 patients [65%] identified as definite or probable TBM over a 12-year period were coinfected with HIV. Neurotuberculosis, either alone or associated with other opportunistic infections, was found in 35 of the 100 HIV-seropositive patients seen over seven years at the National Institute for Mental Health and

Neurosciences [NIMHANS] in Bengaluru [earlier called Bangalore], in south India (26). Although HIV infected patients are at an increased risk for TBM, the HIV status does not alter the clinical manifestations, CSF findings and response to therapy (5,22,25,27). However, CSF examination may frequently be normal in HIV-seropositive subjects with TBM (23). In such patients, radiographic clues to the diagnosis of neurotuberculosis include multiloculated abscess, cisternal enhancement, basal ganglia infarction and communicating hydrocephalus, which are not the findings associated with the more commonly encountered CNS lymphoma or toxoplasma encephalitis. Extra-meningeal TB is seen more often [65% to 77%] in patients co-infected with HIV and TB compared to HIVseronegative individuals [9%] (22,28). Likewise, an associated tuberculoma may be present in more than half of HIV infected patients with TBM (5). Neurological TB can also be the initial presentation of AIDS (29). Bishburg et al (24) noted that intravenous drug abusers with AIDS were more likely to develop TB of the CNS and TB brain abscesses. Diagnosis Tuberculosis meningitis should be differentiated from other causes of subacute and chronic meningitis [Table 21.5]. Early and accurate diagnosis of TBM can substantially reduce the morbidity and mortality, especially in children. Diagnosis of TBM is based on history, neurological symptoms, signs and CSF findings. Supporting features include radiological evidence from CT or MRI, such as basal exudates, hydrocephalus, infarcts, tuberculomas and gyral enhancement. However, the diagnosis of TBM is fraught with difficulties because demonstration of Mycobacterium tuberculosis in CSF is difficult and is often time-consuming. Table 21.5: Differential diagnosis of tuberculosis meningitis Partially-treated bacterial meningitis Cryptococcal meningitis Viral meningoencephalitis Carcinomatous meningitis Parameningeal infection Neurosarcoidosis Neurosyphilis

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Exposure to TB is important supportive evidence, especially in children. In a retrospective analysis spread over 20 years of 38 children with CNS TB, Farinha et al (30) reported presence of epidemiological evidence for TB in 71 per cent. Evidence of TB outside the CNS with appropriate microbiological, radiological or histopathological proof, a positive tuberculin skin test [TST] in the absence of a previous subclinical infection or bacille Calmette-Guérin [BCG] vaccination, and a resolution of the symptoms and signs of TBM after initiation of antituberculosis treatment are also important supportive features for a diagnosis of TBM. Investigations Routine laboratory studies are rarely helpful in establishing the diagnosis of TBM. Elevated erythrocyte sedimentation rate [ESR], anaemia and lymphocytosis are not seen in majority of the patients. Radiological Studies Chest radiograph The chest radiographs reveal findings consistent with pulmonary TB in 25 to 50 per cent of adult patients and 50 to 90 per cent of children with TBM seen in western countries (31). Neuroimaging Plain radiograph of the skull is no longer a diagnostic tool for any form of neurotuberculosis. The CT or MRI of the brain may reveal thickening and enhancement of basal meninges, hydrocephalus, infarction, oedema [often periventricular], and mass lesions due to associated tuberculoma or TB abscess. Common sites of exudates are basal cisterna ambiens, suprasellar cistern and Sylvian fissures. Bhargava et al (32) classified exudates as: [i] mild, when cisterns were obliterated but not enhanced; [ii] moderate, when the cisterns were outlined by high attenuating exudates; and [iii] severe, when attenuating exudates enlarged the cisterns. Hydrocephalus is the single most common abnormality and is reported in 50 to 80 per cent of the cases. The degree of hydrocephalus generally correlates with the duration of disease. Enhancements of basal meninges [60%] followed by cerebral infarction [28%], most frequently in the middle cerebral artery territory, are other common findings. Bhargava et al (32) demonstrated the presence of hydrocephalus [83%], cerebral infarction [28%] and tuberculoma [10%] on CT in patients with TBM. Vasculitis and thrombosis associated with

TBM are seen on CT as multiple areas of hypodensity secondary to ischaemia. Serial CT imaging is very helpful in assessing the course of tuberculomas and hydrocephalus. Gadolinium enhanced MRI is superior to the CT in detection of basal meningeal enhancement and small tuberculomas. Contrast enhanced MRI has been found to be superior to contrast enhanced CT in the detection of diffuse and focal meningeal granulomatous lesions. The MRI is also superior to CT in delineating focal infarcts of the basal ganglia and diencephalon. Furthermore, MRI is superior to CT in defining the presence, location and extent of associated brainstem lesions. Interestingly, in a very large retrospective series of more than 500 Filipino children, Lee (33) found cranial sonography a very useful diagnostic tool for intracranial TB, especially in children below the age of two years. Tuberculin Skin Test Tuberculin skin test [TST] with purified protein derivative [PPD] has been reported to be positive in 40 to 65 per cent of adults and in 85 to 90 per cent of children with TBM in western studies (15,16,30,31). However, TST lacks specificity in developing countries because of the possibility of previous sensitization to environmental mycobacteria and BCG vaccination. Interferon-Gamma Release Assays Recently, interferon-gamma release assays [IGRAs] have been found to be useful for detecting infection with Mycobacterium tuberculosis. The reader is referred to the chapter “Diagnosis of latent tuberculosis infection: recent advances and future directions [Chapter 12]” for more details. Cerebrospinal Fluid Study Cytology and biochemistry Clear CSF with moderately raised cells and protein and low glucose constitute the typical CSF picture of TBM. However, these characteristics are shared by other forms of chronic meningitis and partially treated pyogenic meningitis. In TBM, the leucocyte count is usually between 100 to 500 cells/μl, but rarely can exceed 1000 cells/μl. Median leucocyte counts in various reports range from 63 to 283 cells/μl. Predominantly, lymphocytes are increased in the CSF, although in the acute stage a polymorphonuclear response is not unusual. This response is transient and is

Neurological Tuberculosis 309 replaced by lymphocytic reaction in the course of days to weeks. Occasionally, the cell count may be normal. Rarely, the CSF may be haemorrhagic because of fibrinoid necrosis of vessels. A negative cytology for malignant cells in the CSF is essential for the diagnosis of TBM. The CSF protein is generally between 100 to 200 mg/dl. In the presence of co-existing spinal meningitis and spinal block, the values can exceed 1 g/dl and the fluid may be xanthochromic. If allowed to stand, a pellicle or cobweb may form, indicating the presence of fibrinogen. The pellicle is highly suggestive but not pathognomonic of TBM. The CSF protein has been reported to be normal in some patients with AIDS and TBM (22,34). The CSF glucose level is abnormal in majority of cases, being less than 40 per cent of the corresponding blood glucose level. Median glucose levels are reported to be between 18 to 45 mg/dl. In patients with TBM, CSF glucose levels are never undetectable as in patients with pyogenic meningitis. Low CSF chloride level was previously considered to be a non-specific marker for TBM. It is actually a reflection of co-existent serum hypochloraemia and is presently not considered to be helpful in discriminating between TBM, bacterial and viral meningitis. Thomas et al (17) observed the classical TB pattern in 66.8 per cent; pseudopyogenic pattern in 14.5 per cent; and normal CSF in five per cent of the cases. Patients with miliary TB and CNS involvement can sometimes present with a normal CSF profile and absence of neurologic signs. An acellular CSF may also be found in elderly patients suffering from TBM (28). Such cases are usually diagnosed by the findings on neuroimaging (35,36). Microbiological tests A negative Gram stain, negative India ink stain and a sterile culture for bacteria and fungi are pre-requisites for the diagnosis of TBM. Demonstration of acid-fast bacilli [AFB] in the CSF by microscopy is the most crucial part of the investigation and the rate of detection varies in different reports from 12.5 to 69 per cent (27,30). The yield of CSF smears by ZiehlNeelsen staining and auramine staining is low, ranging from four to forty per cent in various reports and is found to be a function of the volume and the number of samples of CSF. Centrifuging the CSF [10 to 20 ml] for 30 minutes and thick smear examination from the pellicle and repeat CSF examination enhance the detection rate. Kennedy and Fallon (20) in a series of 52 patients with TBM

reported a higher yield of AFB with examination of four CSF smear samples [37% in the first, and a further 25%, 19% and 3% in the second, third and fourth samples, respectively]. Lowenstein-Jensen [L-J] culture of CSF takes four to eight weeks to isolate the organisms because of the slow growth of mycobacteria. The reported positivity of CSF culture ranges from 25 to 70 per cent of cases, but is less than 50 per cent in most reports. In many Indian reports, the yield has been much lower, around 19 per cent (2,17). The yield can be increased by using liquid culture media, such as Septi-Chek AFB system, and Middlebrook 7H9 instead of the conventional L-J medium. The isolation rate of Mycobacterium tuberculosis is higher from cisternal and ventricular CSF than lumbar CSF (37), but in routine practice, CSF is seldom collected from the ventricles. Similar to AFB smear examination, repeated cultures of CSF samples increased the sensitivity from 52 per cent for the first culture up to 83 per cent after four cultures (20). In patients with disseminated and miliary TB with CNS involvement, cultures from extra-neural sites such as the sputum, lymph node and bone marrow may be positive. Immunological tests As the CSF picture in patients with TBM can be variable and non-specific, there is urgent need for a reliable and rapid test to diagnose TBM. In the Indian context, the difficulty in differentiating TBM from partially treated pyogenic meningitis is an added problem. Several tests have been devised for these reasons and they are broadly divided into direct tests that measure the chemical components or antigens of Mycobacterium tuberculosis and indirect tests that measure the components of the host response to Mycobacterium tuberculosis. The specificity of immunodiagnosis depends on the specificity of the antigens or antibodies used. Nonavailability of a clear cut gold standard has hampered the validation of the usefulness of newer diagnostic tests for the diagnosis of TBM. As the yield of conventional methods such as culture is low when applied to the CSF in patients with suspected TBM, these methods cannot be considered to be a gold standard against which immunodiagnosis or other tests can be compared with tests such as enzyme linked immunosorbent assay [ELISA], a significant overlap between the results of patients with and without TBM necessitates specification of a cut-off point to separate positive from negative test

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results. When establishing such a cut-off, there is usually a trade-off between sensitivity and specificity. With regard to immunoassays, it is also important to understand that the sensitivity of any immunoassay depends on standardization and evaluation of the assay system, whereas specificity depends on the type of the probe employed in the system (38). Furthermore, falsenegative results of antigen detecting immunoassays can also result from masking of the antigens by specific circulating antibodies. Mycobacterial antibodies Antibodies against glycolipids and proteins isolated from Mycobacterium tuberculosis, BCG, PPD, antigen 5, and lipoarabinomannan have all been used as a supporting test in the diagnosis of TBM. Radioimmunoassay, ELISA, and immunoblot methods have all been used to detect these antibodies. Various authors have reported sensitivity ranging from 61 to 90 per cent and specificity ranging from 58 to 100 per cent with these antibodies (39-44). Assay of antibodies against Mycobacterium tuberculosis antigens has a better sensitivity and specificity than PPD or BCG. Recent antibody targets have included antibodies against A-60 antigen. They have shown a greater sensitivity in sera [95%] compared to CSF and a greater specificity in the CSF [100%] compared to the sera (45,46). Mycobacterial antigens There are many reports of detection of mycobacterial antigens using ELISA and latex particle agglutination (12,47-49). Antigen detection has been shown to be more specific than antibody assays. Rabbit immunoglobulin [IgG] raised against BCG, culture filtrate antigen, antigen 5, and immunoabsorbent affinity column-purified antigen have all been used for antigen detection. The diagnostic yield is considerably improved by performing both antigen and antibody assays (42,50). Other mycobacterial antigen targets have included the 35kDa antigen (51). Unfortunately, many assays showing early promise in highly controlled studies do not perform with high sensitivity and specificity in clinical practice. Circulating immune complexes Circulating immune complexes in the serum and CSF of patients have been used in the diagnosis of TBM by isolating these complexes and confirming the presence of mycobacterial antigens and antibodies by ELISA test. Mathai et al (42) demonstrated antigen 5 in the immune complexes of CSF in 30 per cent of their patients with TBM. The antigen concentration in the immune complexes declined during the course of

treatment. Though antimycobacterial antibodies were present in 70 per cent patients, the immune complexes were not formed probably because of the non-availability of antigen 5 in optimal concentration. Patil et al (50) detected immune complexes in the CSF in 60 per cent and antimycobacterial antibodies in 55 per cent and both in 82 per cent patients with suspected TBM. Other indirect measures of host response Adenosine deaminase, an enzyme produced by T-lymphocytes, is elevated in the CSF of 60 to 100 per cent of patients with TBM (52-54). However, false-positive results have been reported in other forms of meningitis. The CSF lymphocyte transformation assay, detection of anti-BCG secreting cells in CSF, leucocyte migration inhibition assay, and T-cell immunoblotting are other tests used as indirect evidence of host response to Mycobacterium tuberculosis. The bromide partition test (55) is not routinely used these days. Biochemical detection of mycobacterial products Detection of tuberculostearic acid [TSA], a structural component of Mycobacterium tuberculosis has been reported to have a sensitivity of about 75 per cent and specificity of 96 per cent (56). Requirement of complex instrumentation is a major limitation to its wide application. Detection of 3-[2’-ketohexyl] indoline has also been used as an evidence of Mycobacterium tuberculosis infection (57). Molecular methods Amplification of the Myobacterium tuberculosis specific deoxyribonucleic acid [DNA] sequences by polymerase chain reaction [PCR] has been evaluated as a means of rapid diagnosis of neurotuberculosis (58-62). The use of primers derived from the insertion sequence IS6110, which is a multiple repetitive element in the genome of the Mycobacterium tuberculosis complex, has yielded amplification of high analytical sensitivity. One-step amplification used in conventional methods has a low sensitivity, which is attributed to the low copy numbers of the DNA template that could be extracted from CSF samples of patients with TBM. In comparison, two-step nested amplification can enhance the sensitivity by several folds. Using this technique, Liu et al (60) detected Mycobacterium tuberculosis genome in 19 of the 21 [90.5%] patients with clinically suspected TBM. The PCR has the advantage of being the only available technique besides AFB smear test, which can confirm the diagnosis of TB on the same day. While sensitivity of

Neurological Tuberculosis 311 CSF smear microscopy in TBM is nine per cent, the sensitivity of PCR for the CSF specimens is 48 per cent (63). In some studies, PCR was more sensitive than L-J culture and, hence, could be considered a superior method. The PCR can be applied to the CSF obtained after initiation of antituberculosis treatment. The PCR for Mycobacterium tuberculosis is not affected by the presence of other infecting bacteria as may occur in an immunocompromised host. However, in some reports, the sensitivity of PCR was not much higher than that of mycobacterial culture. Hence, a negative PCR, like culture, cannot exclude the diagnosis of TBM (64). False-negative PCR results are attributed to several factors, like prior treatment, presence of inhibitory factors to PCR in the CSF, extremely low bacterial numbers in the CSF, small volume of CSF tested, and the method of DNA extraction. When performing PCR, samples that may have large quantities of bacteria, such as sputum, should not be simultaneously tested because of the high risk of cross contamination and hence, higher false-positivity. Even in PCR-positive cases, culture remains important for testing drug sensitivity, especially with the emergence of drug-resistant strains (65). In a comparative study, Shankar et al (59) found PCR to be more sensitive than antibody assay. Comparing antibody assay, immune complex assay and PCR, Miorner et al (66) found that antibody immunoassays were non-specific. They also reported that detection of mycobacterial immune complexes strongly correlated with infection and was positive in 64 per cent of TBM cases, PCR was positive in 54 per cent of cases. All culturepositive and 74 per cent of culture-negative samples were found to be positive when immune complex assay was combined with PCR (60). Thus, a combination of tests may be more useful than a single test in arriving at treatment decisions. An inherent defect in many of the older studies stems from the lack of a gold standard, a problem of circularity [using the clinical diagnosis of TBM to validate the tests and subsequently recommending the tests to substantiate the clinical diagnosis], small sample size and the lack of reproducibility of the tests (67). Kox et al (63) have suggested that the PCR could detect Mycobacterium tuberculosis up to six weeks after starting treatment. The sensitivity of PCR in CSF samples seems to be better than that of culture and the specificity is comparable, but depends on scrupulous implementation

of precautions to avoid DNA contamination. More recently, microscopic observation drug susceptibility [MODS] assay has also been found to be useful in the rapid diagnosis of TBM and multidrug-resistant TB (68,69). Thus, even though there are many recently introduced rapid diagnostic methods for TBM, most of them lack the required combination of reproducibility, high sensitivity and specificity. A negative test, does not exclude TBM and many immunodiagnositc tests show false-positive results in other forms of meningitis. Unless stringent measures are adopted to prevent cross contamination in laboratories, false-positive results could limit the use of PCR. Treatment Once the disease has been diagnosed, the decision regarding initiation of antituberculosis treatment is the most important step in the management of TBM. Though a delay in the commencement of therapy should be minimized, adequate evidence favouring the presence of TBM should be gathered before starting therapy, as antituberculosis treatment is both potentially toxic and is required for a long period. Confirmation of the diagnosis, either by PCR or by immunological methods is seldom possible in every case, because of the limited facilities available in the developing countries. Apart from the investigations, there are indirect evidences of the disease being TBM, especially in countries with a high prevalence of TB infection. These include, clinical diagnosis of chronic meningitis; a history of pulmonary TB, especially if inadequately treated; exposure to a patient with pulmonary TB; evidence in the chest radiograph of an old TB lesion; a persistently elevated ESR; a positive TST and CT or MRI evidence of basal meningitis and/or its sequelae. Though none of the above information in isolation is sufficient, a combination of these factors should raise the suspicion of a diagnosis of TBM. Following this, a CSF study is mandatory if there is no contraindication for a lumbar puncture. If suspicion of TBM is high then antituberculosis treatment should be initiated at the earliest. The pros and cons of initiating antituberculosis treatment before the confirmation of the diagnosis should be carefully weighed in each patient. However, the most important principle of therapy is that antituberculosis treatment should be initiated when the disease is suspected. It

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should not be delayed until proof of diagnosis of TBM has been obtained (15). The following situations can be considered as separate management issues in TBM. Uncomplicated Tuberculosis Meningitis It is important to stage TBM patients according to one of the clinical stages described earlier before the initiation of treatment (19,20,70). Primary management of this condition is with first-line antituberculosis agents. Experimental studies indicate that meningeal permeability is enhanced by non-ionization of a drug, small molecular weight, low protein-binding, and high lipid solubility of the unionized moiety (71-73). Isoniazid is non-protein bound and rapidly penetrates into CSF, whether or not the meninges are inflammed, to give concentrations more than 30 times the minimum inhibitory concentration [MIC] for Mycobacterium tuberculosis (74-76). Rifampicin is highly protein bound and only up to 20 per cent is available to penetrate into the CSF. Though peak plasma levels are achieved at around four hours following administration of the drug, the maximum CSF concentration, which is 10 per cent of the plasma concentration, is achieved only at eight hours (77). Even this concentration is only marginally above the MIC (77,78). However, in spite of these facts clinical experience suggests that rifampicin is almost equally effective in both TBM as well as pulmonary TB. Pyrazinamide has excellent penetration into the CSF, which is uninfluenced by the state of the meninges. In view of its unique sterilizing activity and the significant reduction in relapse rates (79,80), it is highly recommended in the treatment of TBM. Ethambutol penetrates into the CSF only when the meninges are inflamed. Accurate estimates of its concentration in CSF are unavailable. In contrast, ethionamide at a dose of 250 mg crosses both the healthy and inflamed meninges and attains a CSF concentration that is comparable to that of serum and is well above the MIC for Mycobacterium tuberculosis (81). The concentration of streptomycin in CSF varies with the severity of the disease. As the meningeal inflammation reduces, its penetration declines. With a daily dose of 750 mg, its concentration in CSF is only slightly above the MIC for Mycobacterium tuberculosis (81). Intrathecal route of administration, which can provide better

concentration of this agent, has now been abandoned, as this has not improved the outcome (82). Treatment Regimens There are no convincing randomized, controlled clinical trials to suggest that any particular regimen is superior in the treatment of TBM. However, enormous clinical experience has accumulated to recommend some treatment regimens (2,15,16,83,84). It is advisable to commence a four-drug regimen. The recommended drugs are isoniazid, rifampicin, pyrazinamide and ethambutol or streptomycin. Ethambutol is preferred over streptomycin because of its better CSF penetration. Though a drug susceptibility result is preferred prior to, or, soon after starting the treatment, it is seldom practical, especially in the developing countries. Unless there is a very high suspicion of drug-resistant organism in a particular patient, the proposed four-drug-regimen is generally effective. After two months of treatment, pyrazinamide and ethambutol [or streptomycin] are stopped and isoniazid and rifampicin are continued. Pyridoxine is usually administered along with antituberculosis treatment to reduce the risk of isoniazidrelated peripheral neuropathy. In India, patients with TBM get treated with DOTS under the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India and receive Category I treatment. Patients receive treatment for six months; in individual patients, there is a provision for extending the treatment on a monthly basis for a further period of three to six months. The reader is referred to the chapters “Treatment of tuberculosis” [Chapter 52] and “Revised National Tuberculosis Control Programme” [Chapter 63] for more details. Duration of Treatment The optimum duration of treatment for TBM is unknown (85). Longer duration of treatment possibly lowers the relapse rates, though the cost, risk of toxicity and chances of poor compliance are greater. The only evidence-based recommendation possible is that a minimum of six months of treatment is necessary. In a large series of 95 children treated with a four-drug regimen, with 96 per cent of cases presenting in the MRC stage 2 or 3, a high rate of success and a mortality of as low as 16 per cent was achieved (6), while in yet another large series

Neurological Tuberculosis 313 of 781 cases of TBM, nearly all patients with relapse had received less than six months of therapy (86). The maximum duration of treatment has varied. The National Institute for Health and Clinical Excellence [NICE] (87) and the American Thoracic Society [ATS], Centers for Disease Control and Prevention [CDC], and Infectious Diseases Society of America [IDSA] (88) guidelines recommend 12 months of treatment for uncomplicated TBM. Although 18 to 24 months treatment was recommended in the past, there is substantial evidence to suggest that a duration ranging between six to twelve months may be adequate (89,90). According to Humphries (83), patients in clinical stage 1 or 2 can be treated for nine or twelve months, while those in clinical stage 3 or 4 should be preferably treated for at least 12 months and often for 18 months. Additional factors that need to be considered prior to initiation of treatment include age, co-existent renal or hepatic disease and pregnancy. One of the most common drug-induced side effect during the treatment of tuberculosis is development of hepatotoxicity (91). It is practically impossible to differentiate drug-induced hepatotoxicity from coincidental viral hepatitis that is highly prevalent in developing countries. The reader is referred to the chapter “Antituberculosis treatment induced hepatotoxicity” [Chapter 54] for more details. A greater clinical and radiological improvement, a significant reduction in CSF tumour necorsis factoralpha and a negligible side-effect profile with an adjunctive thalidomide therapy of childhood TBM in South African children with stage 2 disease in a recent report, has drawn attention to this agent (92). Role of Corticosteroids The role of corticosteroids in the treatment of TBM has been a subject of intense and interesting debate for many decades, with both proponents (93,94) and opponents (95,96) for its use. Administration of corticosteroids has been found to be most beneficial in patients with complications of TBM. The role of steroid therapy in majority of these situations remains to be established. Seven trials of various degrees of rigor have investigated the effects of corticosteroids on TBM (97-103). Five of these seven trials, including the best-analysed (97) clearly demonstrated an advantage of adjunctive corticosteroid therapy over standard therapy for survival, frequency of sequelae or both. The CSF abnormalities

and elevated pressures resolved significantly faster in corticosteroid recipients. Two of the studies (97,100) stratified participants by severity and found no benefit in either mild or severe disease, but significant benefit for patients with intermediate disease. Studies with longer regimens [4 weeks to ‘months’] demonstrated significant beneficial effects while those with shorter regimens [2 to 4 weeks] did not. Dexamethasone at 8 to 12 mg/day (97,98,100) or prednisolone of equivalent dose (103,104) was effective and had fewer side effects than higher doses. In addition to these studies, a comprehensive review in 1966 (105) and a large Chinese study in 1984 (106) also provided some evidence to recommend use of steroids to reduce mortality in patients with clinical stage 2 and 3 but found no benefit in those with clinical stage 1 of the disease. In a randomized prospective study, Kumaravelu et al (107) from India [n = 47] reported that the addition of dexamethasone to antituberculosis treatment resulted in better outcome in patients who had severe disease at three months. Girgis et al (97) from Egypt found that corticosteroids also reduced the morbidity and complications, if administered early in the course of treatment. However, they reported no benefit with steroids in patients with very advanced disease [stage 3 or 4]. In a randomized, double-blind, placebo-controlled trial [n = 545] from Vietnam, Thwaites et al (108) studied whether adjunctive treatment with dexamethasone reduced the risk of death or severe disability after nine months of follow-up. In this study, 545 patients were randomly assigned to groups that received either dexamethasone [n = 274] or placebo [n = 271]. It was observed that treatment with dexamethasone was associated with a reduced risk of death. However, dexamethasone treatment did not result in a significant reduction in the proportion of severely disabled patients [18.2% among survivors in the dexamethasone group vs 13.8% in the placebo group] or in the proportion of patients who had either died or were severely disabled after nine months. The treatment effect was consistent across subgroups that were defined by disease severity grade and by HIV status. Published evidence also favours the use of corticosteroids in the management of children with TBM, as it has been shown to decrease mortality, long-term neurological complications and permanent sequelae (97,109)

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It may also be useful in the management of complications of TBM, such as raised intracranial pressure, cerebral oedema, stupor, focal neurological signs, spinal block, hydrocephalus and basal opticochiasmatic pachymeningitis [Table 21.6]. The recommended daily dose of prednisolone is 0.75 to 1 mg/kg/day in adults and 1 to 2.5 mg/ kg/day in children. Drug-resistant Tuberculosis Meningitis The reader is referred to the chapter “Drug-resistant tuberculosis” [Chapter 49]. Treatment of Tuberculosis Meningitis Associated with Human Immunodeficiency Virus Infection Treatment of CNS TB in patients with HIV infection is the same as in patients without HIV infection (110). The reader is referred to the chapter “Tuberculosis and human immunodeficiency virus infection” [Chapter 40] for further details on this topic. Monitoring Therapy Once antituberculosis treatment is initiated, the mononuclear pleocytosis in CSF may briefly become polymorphonuclear. At two months of antituberculosis treatment CSF glucose levels normalize in almost all patients. Normalization of CSF protein level takes between four to twenty-six months, with a median period of eight months (16). The CSF cell counts normalize in one-third of the patients by 16 months and in almost all patients by three years (16). Clinical improvement in the form of abatement of fever and decrease in meningeal signs occurs over a variable period of time. However, clinical improvement

may not be reflected in the improvement in CSF parameters. Any clinical worsening during treatment warrants neuroimaging to rule out complications, such as hydrocephalus, tuberculoma, TB abscess or arteritis leading to infarction. Vigilance should also be maintained to detect the development of antituberculosis treatment induced hepatotoxicity, ethambutol induced optic neuritis and streptomycin induced vestibulopathy. These complications develop at varying intervals and are dose related. A repeat CSF examination may not be required in patients showing a steady clinical improvement. However, in patients showing neither clinical improvement nor deterioration, CSF parameters should be monitored along with neuroimaging, if required. In those patients showing deterioration in clinical status, neuroimaging should precede a CSF examination. Complications of Tuberculosis Meningitis Hydrocephalus, tuberculoma and rarely TB abscess are important complications of TBM that require surgical interventions [Table 21.7]. Both hydrocephalus and tuberculoma can develop after initial improvement with antituberculosis agents and can contribute to clinical deterioration. Table 21.7: Complications of tuberculosis meningitis Raised intracranial pressure, cerebral oedema, stupor Basal meningitis with cranial nerve palsies Focal neurological deficits Hydrocephalus Tuberculoma Tuberculosis abscess Opticochiasmatic pachymeningitis resulting in visual loss

Table 21.6: Possible indications for corticosteroids in tuberculosis meningitis

Tuberculosis arteritis and stroke Endocrine disturbances

Clinical Clinical stages 2 and above Evidence of raised intracranial pressure Focal neurological deficits suggesting arteritis

Hypothalamic disorder leading to loss of control of blood pressure and body temperature

Radiological Cerebral or perilesional oedema Hydrocephalus Infarcts Opticochiasmatic pachymeningitis

Internuclear ophthalmoplegia

Diabetes insipidus Syndrome of inappropriate antidiuretic hormone secretion Hemichorea Spinal block Spinal arachnoiditis

Neurological Tuberculosis 315 Ventriculomegaly in TBM need not always be due to hydrocephalus. Cerebral atrophy can also cause ventriculomegaly. Moderate to severe hydrocephalus is often associated with features of raised intracranial pressure. In children with TBM, hydrocephalus is almost always present after six weeks of illness (32). Early drainage of hydrocephalus by vetriculoperitoneal or ventriculoatrial shunt has been recommended (70,111, 112). High protein content or raised polymorphonuclear cell count in CSF often increases the chances of shunt complication. In such situations, external ventricular drainage may have to precede the shunt surgery. Mortality appears to be related to the severity of hydrocephalus (70). Patients in clinical stage 3 and 4, unlike those in clinical stage 1 and 2 often have a poor outcome despite shunt surgery. There is no convincing evidence to recommend subarachnoid or intraventricular use of hyaluronidase for hydrocephalus and optochiasmatic arachnoiditis (113). Other common complications of TBM include arteritis causing stroke, and opticochiasmatic arachnoiditis causing visual loss. Early institution of antituberculosis treatment helps in preventing the occurrence of these complications. Treatment for these conditions has been disappointing. Steroids have been recommended for the prevention of these complications. The reader is referred to the chapter “Endocrine implications of tuberculosis” [Chapter 39] for discussion on SIADH and diabetes insipidus. Tuberculosis abscess is an uncommon manifestation of CNS TB, most often occurring as a complication in patients with reduced immune resistance who are often on antituberculosis therapy for systemic or CNS TB. It is characterized by an encapsulated collection of pus containing viable tubercular bacilli without evidence of the classic TB granuloma. It must be distinguished from a granuloma with central caseation and liquefaction mimicking pus. It develops in the brain parenchyma although intraventricular (114) and subdural (115) sites have also been reported. Differentiation from pyogenic abscess can often be difficult and presence of indirect evidence of TB, culture of the aspirate or response to antituberculosis treatment may be needed. Recently, Gupta et al (116) reported that elevated lipid and lactate levels if accompanied by an elevated amino acid levels favour a pyogenic abscess over a TB abscess on magnetic resonance spectroscopy. They also found a significantly

higher magnetization transfer ratio in the wall of the pyogenic abscess compared to that in the tuberculosis abscess. Surgical aspiration of the abscess or excision of a multiloculated abscess may be required as these lesions harbour TB bacilli and their thick capsules are often impervious to antituberculosis agents. Draining the abscess decreases the mycobacterial load. Development of fulminant TB meningitis following surgical excision of TB abscess remains a problem (117). CHRONIC MENINGITIS Definition and Aetiology Chronic meningitis is defined as the clinical syndrome characterized by symptoms and signs of meningitis or meningoencephalitis developing in a subacute or chronic fashion associated with CSF abnormalities and persisting for at least four weeks (118,119). In general, chronic meningitis has an insidious evolution and a gradual progressive course. Sometimes chronic meningitis may begin relatively acutely and may become chronic later on. Chronic meningitis is a potential manifestation of several infectious and non-infectious diseases [Table 21.8] (119,120). As the aetiology of chronic meningitis is diverse, these patients require a thorough diagnostic evaluation to establish the cause. Partially treated pyogenic meningitis often needs to be differentiated from chronic meningitis. In our country, majority of patients with chronic meningitis are presumed to have TBM and are treated accordingly. A detailed account of various aetiological causes of chronic meningitis is beyond the scope of this chapter. However, the diagnostic and therapeutic approach in patients with chronic meningitis will be discussed briefly. Tuberculosis is the most common cause of chronic meningitis in the developing world, where TB is highly endemic. By contrast, in areas with a low prevalence of TB, the scenario may be different. In a study from Mayo Clinic (121), sarcoidosis [31%] and metastatic adenocarcinoma [25%] were the most frequent causes of chronic meningitis. Clinical Evaluation The history is critical to distinguish partially treated pyogenic meningitis and TBM [which may present as

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Tuberculosis Table 21.8: Causes of chronic meningitis

Infectious causes Mycobacterium tuberculosis Partially-treated bacterial meningitis Cryptococcus neoformans Treponema pallidum Borrelia burgdorferi Candida Brucella Leptospira icterohaemorrhagiae Coccidioides immitis Histoplasma capsulatum Aspergillus Toxoplasma gondii Actinomyces Nocardia Zygomycetes Larva migrans Non-infectious causes Neoplasms Sarcoidosis Vasculitis Connective tissue disorders Systemic lupus erythematosus Behcet’s disease Vogt-Koyanagi-Harada syndrome Chronic benign lymphocytic meningitis Mollaret’s meningitis Drug and chemical exposure: iodophendylate dye, sulphonamides, isoniazid, ibuprofen, and tolmentin

acute onset chronic meningitis], chronic meningitis with remissions and exacerbations; and recurrent meningitis [Mollaret’s meningitis]. Useful aetiological clues such as a known systemic disease, immunocompromised state, exposure to drugs and infectious agents [such as Borrelia, Treponema, Leptospira and Brucella] can be obtained from a carefully taken history. Physical examination may reveal a systemic disease, erythema nodosum [which may occur in TB, sarcoidosis, histoplasmosis, coccidioidomycosis], erythema chronicum migrans [Lyme disease], oral and genital ulcers [Behcet’s disease], pulmonary abnormalities [suggestive of TB, sarcoidosis, fungal infections], heart murmurs [bacterial endocarditis] and splenomegaly [lymphoproliferative diseases, brucellosis]. Ophthalmoscopic examination may show choroid tubercles, sarcoid granulomas or uveitis [Behcet’s disease, Vogt-Koyanagi-Harada syndrome]. Granulomatous myositis [tender, nodular muscles and proximal weakness] may be found in sarcoidosis.

Diagnostic Evaluation Chest radiograph, bronchoscopy with transbronchial lung biopsy, open lung biopsy, and lymph node or liver biopsy may help in identifying systemic diseases. Neutrophilic CSF pleocytosis may occur in chemical meningitis, systemic lupus erythematosus, bacterial [Actinomycetes, Listeria, Nocardia] and fungal [Aspergillus, Candida, Zygomycetes] meningitis. Eosinophilic CSF pleocytosis favours a parasitic aetiology. Low glucose in the CSF is non-specific and can occur in a variety of infectious and non-infectious causes of chronic meningitis. The CSF should be exhaustively searched for specific aetiologic clues utilizing the currently available facilities. In a retrospective study (122) of patients with chronic meningitis [n = 168] seen during the period 1986 to 1992 at the Sree Chitra Tirunal Institute for Medical Sciences and Technology [SCTIMST], Thiruvanananthapuram [earlier called Trivandrum], India, chest radiographs revealed evidence of pulmonary TB in 12.5 per cent; CSF smear or culture were positive for Mycobacterium tuberculosis in 16 per cent; and CSF ELISA for Mycobacterium tuberculosis antigen or antibody was positive in 59 per cent of the patients. Neuroimaging Studies Contrast enhanced CT or MRI of the head, in addition to revealing hydrocephalus and parenchymal lesions, may demonstrate meningeal enhancement. In the study from the Mayo Clinic (121), MRI with gadolinium contrast was the most useful diagnostic imaging technique demonstrating meningeal enhancement in 15 of 32 patients [47%] while only two of 32 [6%] CT showed meningeal enhancement. In the study (122) from SCTIMST, Thiruvananthapuram, India, CT was abnormal in 62 per cent of the 168 patients with chronic meningitis. Meningeal Biopsy Despite numerous diagnostic advances, the cause of chronic meningitis frequently remains a diagnostic dilemma. Few patients eventually require a leptomeningeal biopsy, with or without sampling of underlying cortex through suboccipital and pterional craniotomy. In a recent study, a definitive aetiologic diagnosis of chronic meningitis was made in 16 of

Neurological Tuberculosis 317 41 biopsies [39%] (121). In patients in whom meningeal enhancement was present on CT or MRI, a diagnosis was obtained in 80 per cent, while only nine per cent of nonenhancing regions were diagnostic. Therefore, contrast enhanced CT or MRI findings provide valuable assistance in predicting the yield and selecting the site for biopsy. Management In patients with inconclusive clinical and laboratory data concerning the aetiology of chronic meningitis, the decision between empirical therapeutic trial and meningeal biopsy is critical. The clinical presentation, especially the pace of progression of course of the disease will often dictate the choice. Antituberculosis treatment is indicated early in the course of chronic meningitis in a patient whose clinical condition shows deterioration. If PCR, serological tests and culture of the CSF for Mycobacterium tuberculosis are all negative, TST continues to remain non-reactive even after re-testing at two weeks, and no clinical response occurs, then antituberculosis treatment may be stopped after six weeks. The decision to empirically use potentially toxic antifungal, drugs such as amphotericin-B, in chronic meningitis is more difficult. In the absence of a positive proof for a fungal aetiology the following situations may warrant such a strategy: [i] a host with neutropenia or compromised cell-mediated immunity; [ii] presence of unequivocal clinical evidence or culture or biopsy proven systemic fungal disease, and [iii] a patient with obscure chronic meningitis, hypoglycorrhachia and progressive neurological deterioration inspite of antituberculosis treatment. A well-preserved patient with undiagnosed chronic meningitis and a static or slowly progressive course is a candidate for meningeal biopsy, especially when the neuroimaging studies suggest an enhancing lesion accessible through a pterional or suboccipital craniotomy. Empirical corticosteroid therapy in chronic meningitis is inappropriate because it can result in the rapid progression of an undiagnosed fungal disease. Of the 168 patients with chronic meningitis who were treated with antituberculosis drugs at the SCTIMST, Thiruvananthapuram, India (122), 19 per cent required ventriculo-peritoneal shunt for symptomatic hydrocephalus. In this study (122), 19.6 per cent patients died. At one and half years follow-up, 44 per cent of patients were fully functional, the remaining 36 per cent of patients had significant neurological sequelae.

INTRACRANIAL TUBERCULOMAS Definition and Pathology Tuberculoma is a mass of granulation tissue made up of a conglomeration of microscopic small tubercles [Figure 21.2]. A tubercle consists of a central core of epithelioid cells surrounded by lymphocytes. Giant cells are scattered among epithelioid cells. The centre of the tuberculoma becomes necrotic, forming caseous material, while the periphery tends to be encapsulated with fibrous tissue. There may be liquefaction of the caseous material resulting in the formation of a TB abscess. The size of cerebral tuberculomas is highly variable. In most cases their diameters range from a few mm to 3 to 4 cm (123). Intracranial tuberculomas in patients under the age of 20 years are usually infratentorial, but supratentorial lesions predominate in adults. Solitary tuberculomas are more frequent than multiple lesions. Epidemiology In the early decades of the twentieth century, cerebral tuberculoma was a common lesion, accounting for 20 to 40 per cent of all intracranial tumours (124). Since then the incidence of tuberculoma has declined dramatically in industrialized nations. In 1972, Maurice-Williams (125) from Great Britain reported a frequency of 0.15 per cent. Ramamurthi and Varadarajan (8) noted that the tuberculomas formed 20 per cent of all intracranial tumours at Chennai [then called Madras] in the 1950s. Although

Figure 21.2: Tuberculoma. Photomicrograph showing granulomatous reaction with epithelioid cells, Langhans’ giant cells [arrows] and central necrosis, characteristic of a tuberculoma [Haematoxylin and eosin x 250]

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the frequency has decreased in the last two to three decades, tuberculomas still constitute about five to ten per cent of intracranial space occupying lesions in the developing world (2,126). Diagnosis The CT and MRI have facilitated the diagnosis and assessment of intracranial tuberculomas. The characteristic CT and MRI finding is a nodular enhancing lesion with a central hypointensity (127) [Figures 21.3A, 21.3B, 21.4 and 21.5]. The pattern of enhancement can be

quite variable; homogeneous, patchy, serpentine and ring enhancement, have all been observed. Unless treated with steroids, oedema is nearly always present and can be quite marked. These CT findings are non-specific and may simulate the appearance of gliomas, metastasis, abscess, cysticercosis and fungal granulomas. In a study from Saudi Arabia (126), the initial diagnosis based on the CT appearance was wrong in 80 per cent of cases. The rupture of a parenchymal tuberculoma or tuberculoma en plaque of the meninges [Figures 21.6A and 21.6B] can result in TBM. In a study reported by Bhargava et al (32), tuberculomas occurred in 10 per cent of patients with TBM. Brainstem tuberculomas, although uncommon, constitute two to eight per cent of all intracranial tuberculomas and are more commonly seen in children (128). Ventricles form a relatively rare site for the tuberculoma (129). Management

Figure 21.3A: Contrast-enhanced T1-weighted MRI showing a round, well-defined lesion with central hypodensity [arrow] and surrounding oedema and conglomerate lesions

Figure 21.3B: Repeat MRI of the same patient showing complete disappearance of the lesions after eight months of antituberculosis treatment

In the past, management of tuberculoma was mainly surgical (130). With the availability of CT and MRI, a trial of antituberculosis treatment without pathological confirmation has been tried (127,131,132). Short-course chemotherapy may be adequate for the treatment of tuberculoma (133), although its efficacy is not yet established. Corticosteroids are helpful in selected patients who have cerebral oedema and are symptomatic. Tuberculomas begin to decrease in size within the first two months of antituberculosis treatment. Paradoxical expansion of intracranial tuberculomas during antituberculosis treatment for neural or extra-neural TB has been observed (134,135). Although the exact mechanism is unclear, it is thought to have an immunological basis. Surgery is still indicated for large lesions producing midline shift and severe intracranial hypertension, expanding lesions during antituberculosis treatment, when clinical and neuroimaging findings favour alternate possibilities such as glioma or metastasis and when the expected improvement is not forthcoming in the clinical and CT picture during follow-up of medical treatment. Therapeutic trial with antituberculosis treatment in patients with a solitary lesion suspicious of a tuberculoma is a widely accepted option. However, many workers advise a CT-guided excision biopsy for lesions larger than 2 cm in size, as these lesions could have a varied aetiology.

Neurological Tuberculosis 319

Figure 21.4: MRI of the brain [T2-weighted image, axial view] showing characteristic appearance of a tuberculoma [A]. Close-up view of the lesion showing central hyperintense area [solid arrow] suggestive of caseation necrosis; surrounding hypointense rim [white arrow head] of fibrousis capsule; and a significant perilesional white matter oedema [black arrrow head]

Figure 21.5: MRI of the brain [T2-weighted image, axial view] showing multiple tuberculomas [white arrows] and basal meningeal enhancement [black arrows] suggestive of tuberculosis meningitis [A]. Magnetic resonance spectroscopy of the largest lesion showing a large lipid peak with reduced n-acetyl aspartate peak compatible with tuberculoma [B]

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Tuberculosis from India (136-139). The enhancing lesion is less than two centimeters, but may show considerable oedema around it. A majority of them resolve over a six-to-twelveweek period without any specific therapy other than anticonvulsant medication. These lesions have been described under various names, such as “disappearing CT lesions” (138), “appearing and disappearing CT lesions” (136) and “solitary microlesions in CT” (140), but are currently called single, small, enhancing lesions [SSEL] (141,142). Aetiology

Figure 21.6A: Contrast enhanced T1-weighted coronal MRI showing an en plaque enhancing lesion with oedema [arrow] in a patient with tuberculoma en plaque with meningitis

Because of the exclusive geographical distribution, an infection, such as TB [Figure 21.7], focal encephalitis, microabscess, or infestation [cysticercosis] was suspected to be the aetiologic agent for SSEL. Currently, there is fairly a convincing evidence to incriminate cysticercosis as the major cause of SSEL. Epidemiologically, the reported occurrence of SSEL corresponds with the endemicity of cysticercosis. For example, in Kerala, where cysticercosis is non-existent, SSEL is encountered only in subjects who have lived outside Kerala. Serologically, Ahuja et al (139) showed that a significant proportion of patients with SSEL had positive serology for cysticercosis compared to healthy control subjects. Radiologically, most of SSEL on high resolution imaging, such as MRI, show pathognomonic features of cysticercosis [Figures 21.8A and 21.8B]. The biopsy studies by Chandy et al

Figure 21.6B: The lesion and oedema decreased while the patient was on antituberculosis treatment. Ipsilateral dilatation of lateral ventricle is also seen. The CSF data supported the diagnosis of tuberculosis meningitis and PCR was positive

SINGLE, SMALL, ENHANCING BRAIN LESION ON COMPUTED TOMOGRAPHY AND SEIZURES Definition Patients with seizures, who showed ring enhancing single CT lesions, have been described almost exclusively

Figure 21.7: MRI of the brain [post-gadolinium T1-weighted, axial view] showing ring enhancing lesions in the brain [black arrow] and cervical cord [white arrow]

Neurological Tuberculosis 321 the end of three months, the reduction in size or total resolution of the lesion was comparable in both the groups. There was no statistically significant difference between the albendazole or placebo groups. Natural involution of the cyst may account for the spontaneous resolution of lesions (145). Neuroimaging

Figure 21.8A: Contrast enhanced CT in a 17-year-old girl showing small enhancing ring lesion with a mural nodule [arrow] and surrounding oedema. The findings are suggestive of cysticercosis in the early dying stage

Rajashekhar et al (146) compared clinical and CT data of six consecutive patients with histologically proven tuberculomas and 25 consecutive patients with histologically verified cysticercus granulomas. Evidence of raised intracranial pressure and a progressive focal neurological deficit was seen only in patients with tuberculomas. On CT, all tuberculomas were greater than 2 cm in size and majority were irregular in outline. In contrast, all cysticercous granulomas were less than 20 mm and majority were regular in outline. Only tuberculomas were associated with a midline shift on CT. The authors (146) concluded that based on clinical findings [evidence of raised intracranial tension and a progressive neurological deficit] and CT appearance [size, shape and association with a midline shift] it is possible to distinguish these two entities in a majority of patients presenting with seizures and SSEL. Management Management of a patient with seizure and SSEL poses many problems. A series of Consensus Meetings held under the auspices of Neurological Society of India made the following recommendations in 1994 (147). First Visit

Figure 21.8B: The T1-weighted contrast enhanced MRI image [left panel] showing a small enhancing ring lesion [arrow] and a zoomed T-2 view [right panel] of the same patient showing the lesion [arrow]

(143) from Vellore in south India showed evidence of cysticercosis in 12 of 15 patients with SSEL. Follow-up A majority of these lesions disappear without any specific therapy. Padma et al (144) carried out a double-blind, randomized, placebo-controlled study by comparing the resolution of SSEL on CT in 40 patients who received albendazole and 35 patients who received placebo. By

If the patient did not have a contrast enhanced CT, then the study needs to be done. Plain CT has no place in the management of this disorder. After a careful neurological and systemic evaluation, routine blood tests and chest radiograph should be performed. If a subcutaneous nodule is detected, it should be biopsied. Reliable immunological diagnostic tests are available only in certain selected institutions and the reports from elsewhere should not be relied upon. Lumbar puncture need not be performed as a routine. Treatment should be started with an anticonvulsant drug, usually phenytoin or carbamazepine. If the patient is neurologically normal and seizure free, a follow-up CT is done at three-

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months; if neurological symptoms or signs or seizures recur then a follow-up CT is done at four to six weeks. Second Visit Contrast enhanced CT of the head is repeated. If CT shows the lesion to be of the same size as before, smaller than before, the oedema is less and the patient is seizure free, anticonvulsant drugs are continued. If the CT shows enlargement of lesion, but the lesion is still less than 2 cm in size with no shift or ventricular compression, then, albendazole is started and anticonvulsant drugs are continued. If the CT shows lesion larger than two centimeters with shift or compression of ventricle or gyri, there are two options: biopsy of the lesion or institution of antituberculosis treatment. All biopsies should be open biopsies with stereotaxic localization, whenever feasible.

to 90 per cent have been observed. Clinical stage 3 and 4 are usually accompanied by very high morbidity and mortality. In a multivariate analysis of 199 Chinese patients with TBM, Humphries et al (82) showed that only the age and the stage of presentation affected the outcome and with respect to the disease stage and the mortality raises from none to four per cent in stage 1, to 22 to 30 per cent in stage 2, to 78 to 79 per cent in stage 3 or 4. Age The outcome of TBM, particularly in children, is often poor irrespective of the region where they live. Extremes of age have poorer outcome; children below three years and adults above 50 years of age generally have a poor prognosis (30,82). Highest mortality due to intracranial TB has been observed in patients above 50 years of age (148).

Third Visit

Cerebrospinal Fluid Parameters

Third visit is scheduled at three months after the second visit for patients receiving anticonvulsant drug alone and at six to eight weeks for those receiving albendazole and antituberculosis treatment. If the repeat enhanced CT shows either enlargement or no change in the size of the lesion, a biopsy should be done to establish the diagnosis. Those who have responded to anticonvulsant therapy or albendazole and antituberculosis treatment by a decrease in size or disappearance of the lesion should be followed-up at three to six monthly intervals. Anticonvulsant drugs are continued till the time the lesion disappears, calcifies and/or if the patient remains seizure free for one to two years.

Though earlier studies suggested that lower glucose levels in CSF had a poorer outcome, more recent studies with larger number of patients have failed to show any correlation between CSF sugar levels and the clinical outcome (16). The only CSF parameter that correlated with a poor outcome was high protein levels [greater than 2 g/l], as it was associated with a more advanced stage of the disease at presentation.

PROGNOSIS AND OUTCOME OF INTRACRANIAL TUBERCULOSIS The most important factor determining the outcome of intracranial TB, as mentioned earlier, remains early diagnosis and prompt initiation of antituberculosis treatment. The following factors have been found to influence the prognosis of TBM. Clinical Stage of the Disease When antituberculosis treatment and corticosteroids are initiated before patient’s progress beyond clinical stage 1 or early stage 2 disease, high cure rates ranging from 85

Neuroimaging of the Head Patients with dense exudates in the basal cisterns and visual loss due to organized exudates over optico-chiasmatic region respond poorly to treatment (32). Similarly, patients with diencephalic infarcts and angiographic evidence of narrowing in the middle or anterior cerebral arteries have higher morbidity (2,148). It is also important to note that diencephalic infarcts give rise to syndrome of inappropriate antidiuretic hormone secretion, which is a poor prognostic indicator. Others Variables Poor outcome has also been associated with raised intracranial pressure with hydrocephalus and infection with drug-resistant mycobacterial strains. Children who have not received BCG vaccination also have a poor outcome. Infection with HIV does not seem to alter the

Neurological Tuberculosis 323 prognosis of TBM, except in patients with CD4+ Tlymphocyte counts below 0.2 × 109/l (22,25). These patients have reduced survival even otherwise (22). In a recently published study of 65 patients from Lucknow, India (149), neurological sequelae were observed in 78.5 per cent patients [cognitive impairment in 55%, motor deficit in 40%, optic atrophy in 37% and other cranial nerve palsy in 23%]. Logistic regression analysis revealed that focal motor deficit at admission was the most important predictor of neurologic deficits at one year follow-up. Sequelae The sequelae that have been identified following intracranial TB occur in patients with advanced disease [late clinical stage 2 or beyond], and especially in children [Table 21.9]. On an average, about 20 to 25 per cent of children with TBM suffer some sequelae. In a series from a teaching hospital from North-west India (17), only 58 of the 170 surviving patients [34%] with TBM were left with no sequelae. In the west, permanent neurological sequelae was noticed in 47 to 80 per cent of children with TBM, with motor disorders [25% to 27%], visual loss [20%] and cognitive and behavioural changes [17% to 40%] being the three of the commonest consequences in long-term follow-up studies (30,150). Intracranial tuberculomas generally grow without causing the tissue destruction that usually accompanies a malignant tumour. Therefore, they tend to resolve with minimum residual deficits. Conservative medical management seems to result in superior functional recovery. Choudhury (131) reported that 17 [68%] of 24 patients treated conservatively showed complete recovery, while only two patients [8%] had significant residual neurological problems. In the series reported by Gropper et al (151), of the five patients with tuberculoma who underwent surgical excision followed by antituber-

culosis treatment, four had an excellent outcome while one died. TUBERCULOSIS RADICULOMYELITIS Tuberculosis radiculomyelitis is a form of spinal TB and may develop in one of the three ways: [i] as a primary TB lesion; [ii] as a downward extension of TBM; and [iii] as a secondary extension from vertebral TB. The first two varieties of TBRM are discussed here briefly. Wadia and Dastur (9) suggested TBRM as a generic term to include cases designated as arachnoiditis, intradural spinal tuberculoma or granuloma and spinal cord complications of TBM. Pathology and Clinical Features Although common in clinical experience in India, TBRM is less reported in literature. Hernandez-Albujar et al (152) identified 74 cases of TBRM in the published literature from 1966 to 1999. Pathologically, it is characterized by extensive, copious and tenacious exudates that may occupy the entire space between the spinal dura mater and the leptomeninges that may encase the cord and impinge on the roots. Clinical features include a subacute to chronic progressive flaccid paraparesis, often in the presence of a positive Babinski’s sign, that is frequently preceded by root pains, paraesthesias, bladder disturbances and focal muscle wasting. Secondary TBRM may follow TBM during the acute stage but can also occur after a variable periods of months to years (153). Furthermore, it is known to occur in patients with TBM on inadequate or adequate antituberculosis treatment regimens (154,155). Lumbosacral region is the most commonly affected site in TBRM that is primary or follows TBM, although cervical involvement is not unknown. In contrast, TBRM secondary to vertebral TB is relatively more common in the dorsal region. Investigations

Table 21.9: Sequelae of tuberculosis meningitis Psychological or psychiatric disturbances Visual defects Hearing defects [often drug-induced] Focal neurological deficit Endocrine disturbances Seizures Intracranial calcification

In most patients with TBRM, if the lumbar puncture is not a dry tap, CSF shows lymphocytic pleocytosis, hypoglycorrhachia and characteristically, a very high protein level [probably secondary to a CSF flow block]. These findings may persist despite sterilization of CSF. Although in practice, CT myelography or contrast MRI of the spine is often preferred over the conventional spinal

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myelography in patients with TBRM, Chang et al (153), in their comparison of these modalities of imaging found conventional myelography to be the primary radiological method for diagnosis of suspected TBRM, particularly in those cases that are characterized by chronic adhesive changes. In patients with active intrathecal inflammatory process or with myelopathy, they reported gadolinum enhanced MRI to be optimal [Figures 21.9, 21.10 and 21.11]. In contrast to this observation, Gupta et al (156) favoured MRI as the primary imaging modality for screening patients with suspected intraspinal TB, regardless of the stage of the disease, an opinion that may find wider acceptance in view of the non-invasive nature of the investigation and the recent advances in spinal MRI technology. The CT myelography has no superiority over contrast enhanced MRI, except perhaps in cases with extensive vertebral tuberculosis. The MRI features of TBRM include loculation and obliteration of the spinal subarachnoid spaces, loss of outline of the spinal cord in the affected region, clumping or matting of the nerve roots in lumbar region, a syringomyelic cavity [as a late complication] and nodular, thick, linear intradural and meningeal enhancement on gadolinum enhanced MRI. Spinal meningeal enhancement in the

Figure 21.9: Contrast enhanced MRI in a patient with spinal pachy arachnoiditis showing post-gadolinium enhancement of meninges [arrow] [A]; and nerve roots [arrow] [B] in a patient with spinal pachy arachnoiditis

Figure 21.10: Contrast enhanced MRI in a patient with spinal pachy arachnoiditis showing post-gadolinium enhancement of clumped nerve roots after emergence from spinal forimina [1]; in spinal canal [2]; and at emergence from spinal forimina [3]

Figure 21.11: Contrast enhanced MRI in a patient with spinal pachy arachnoiditis showing post-gadolinium enhancement of anterior spinal nerve root [arrow] [A] and clumped nerve roots in spinal canal [arrow] [B]

Neurological Tuberculosis 325 cervical and thoracic region is highly suggestive of TBRM, if a clinical suspicion exists (157). It must, however, be noted that in chronic TBRM, enhancement may be conspicuous by its absence. Management Some authors consider TBRM as a form of paradoxical reaction to TB treatment, which might represent a delayed hypersensitivity response in a recovering patient to mycobacterial antigens liberated after antituberculosis treatment. Although this view might support the use of corticosteroids to prevent and treat TBRM, reports on the efficacy of corticosteroids for this condition are conflicting (158-160), and the studies are handicapped by lack of randomization. Nevertheless, given the exuberant nature of the inflammatory process at spinal level and the consequent risk for vasculitis of the spinal vessels, most clinicians consider the use of corticosteroids, in conjunction with antituberculosis treatment, as beneficial in the prevention and treatment of TBRM. Except in cases with vertebral TB that need vertebral stabilization, the role of decompressive spinal surgery in the treatment of TBRM is very limited, and often fails to arrest the relentless progression of the related neurological deficits. ACKNOWLEDGEMENTS The authors are grateful to Dr V.V. Radhakrishnan, Professor and Head, Department of Pathology and Dr A.K. Gupta, Professor and Head, Department of Radiology, Sree Chitra Tirunal Institute of Medical Sciences and Technology, Thiruvananthapuram, Kerala for providing the figures. The authors thank Ms C.V. Ambili for secretarial assistance.

REFERENCES 1. Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316-53. 2. Tandon PN, Bhatia R, Bhargava S. Tuberculous meningitis. In: Harris AA, editor. Handbook of clinical neurology [revised series]. Amsterdam: Elsevier Science; 1988.p.195-226. 3. Glynn JR. Resurgence of tuberculosis and the impact of HIV infection. Br Med Bull 1998;54:579-93. 4. Kumar D, Watson JM, Charlett A, Nicholas S, Darbyshire JH. Tuberculosis in England and Wales in 1993: results of a national survey. Public Health Laboratory Service/British Thoracic Society/Department of Health Collaborative Group. Thorax 1997;52:1060-7.

5. Dube MP, Holtom PD, Larsen RA. Tuberculous meningitis in patients with and without human immunodeficiency virus infection. Am J Med 1992;93:520-4. 6. Donald PR, Schoeman JF, Van Zyl LE, De Villiers JN, Pretorius M, Springer P. Intensive short course chemotherapy in the management of tuberculous meningitis. Int J Tuberc Lung Dis 1998;2:704-11. 7. Auerbach O. Tuberculous meningitis: correlation of therapeutic results with the pathogenesis and pathologic changes. I. General considerations and pathogenesis. Am Rev Tuberc 1951;64:408-18. 8. Ramamurthi B, Varadarajan MG. Diagnosis of tuberculomas of brain. Clinical and radiological correlation. J Neurosurg 1961;18:1-7. 9. Wadia NH, Dastur DK. Spinal meningitides with radiculomyelopathy. 1. Clinical and radiological features. J Neurol Sci 1969;8:239-60. 10. Udani PM, Dastur DK. Tuberculous encephalopathy with and without meningitis. Clinical features and pathological correlations. J Neurol Sci 1970;10:541-61. 11. Ahuja GK, Mohan KK, Prasad K, Behari M. Diagnostic criteria for tuberculous meningitis and their validation. Tuber Lung Dis 1994;75:149-52. 12. Radhakrishnan VV, Mathai A. Detection of mycobacterial antigen in cerebrospinal fluid: diagnostic and prognostic significance. J Neurol Sci 1990;99:93-9. 13. Donald PR. The epidemiology of tuberculosis in South Africa. Novartis Found Symp 1998;217:24-35; discussion 35-41. 14. Rich AR, Mc Cordock HA. Pathogenesis of tuberculous meningitis. Bull John Hopkins Hosp 1933;52:5-37. 15. Sheller JR, Des Prez RM. CNS tuberculosis. Neurol Clin 1986;4:143-58. 16. Kent SJ, Crowe SM, Yung A, Lucas CR, Mijch AM. Tuberculous meningitis: a 30-year review. Clin Infect Dis 1993;17:987-94. 17. Thomas MD, Chopra JS, Walia BN. Tuberculous meningitis. A clinical study of 232 cases. J Assoc Physicians India 1977;25:633-9. 18. Sridharan R, Krishnamurthy L. Visual evoked potentials in tuberculous meningitis. Neurol India 1984;32:27-33. 19. Medical Research Council. Streptomycin treatment of tuberculous meningitis: report of the committee on sterptomycin in tuberculosis trials. Lancet 1948;1:582-97. 20. Kennedy DH, Fallon RJ. Tuberculous meningitis. JAMA 1979;241:264-8. 21. Kocen RS, Parsons M. Neurological complications of tuberculosis: some unusual manifestations. QJM 1970;39:17-30. 22. Berenguer J, Moreno S, Laguna F, Vicente T, Adrados M, Ortega A, et al. Tuberculous meningitis in patients infected with the human immunodeficiency virus. N Engl J Med 1992;326:668-72. 23. Traub B, Colchester AE, Kingsley DP, Swash M. Tuberculosis of the central nervous system. QJM 1984;3:81-100. 24. Bishburg E, Sunderam G, Reichman LB, Kapila R. Central nervous system tuberculosis with the acquired immunodefi-

326

25.

26.

27.

28.

29.

30.

31. 32. 33.

34.

35.

36.

37.

38.

39.

40.

Tuberculosis ciency syndrome and its related complex. Ann Intern Med 1986;105:210-3. Yechoor VK, Shandera WX, Rodriguez P, Cate TR. Tuberculous meningitis among adults with and without HIV infection. Experience in an urban public hospital. Arch Intern Med 1996;156:1710-6. Satishchandra P, Nalini A, Gourie-Devi M, Khanna N, Santosh V, Ravi V, et al. Profile of neurologic disorders associated with HIV/AIDS from Bangalore, south India [1989-96]. Indian J Med Res 2000;111:14-23. Verdon R, Chevret S, Laissy JP, Wolff M. Tuberculous meningitis in adults: review of 48 cases. Clin Infect Dis 1996;22:9828. Karstaedt AS, Valtchanova S, Barriere R, Crewe-Brown HH. Tuberculous meningitis in South African urban adults. QJM 1988;91:743-7. Whiteman M, Espinoza L, Post MJ, Bell MD, Falcone S. Central nervous system tuberculosis in HIV-infected patients: clinical and radiographic findings. AJNR Am J Neuroradiol 1995;16:1319-27. Farinha NJ, Razali KA, Holzel H, Morgan G, Novelli VM. Tuberculosis of the central nervous system in children: a 20year survey. J Infect 2000;41:61-8. Berger JR. Tuberculous meningitis. Curr Opin Neurol 1994;7:191-200. Bhargava S, Gupta AK, Tandon PN. Tuberculous meningitisa CT study. Br J Radiol 1982;55:189-96. Lee LV. Neurotuberculosis among Filipino children: an 11 years experience at the Philippine Children’s Medical Center. Brain Dev 2000;22:469-74. Laguna F, Adrados M, Ortega A, Gonzalez-Lahoz JM. Tuberculous meningitis with acellular cerebrospinal fluid in AIDS patients. AIDS 1992;6:1165-7. Gupta RK, Kohli A, Gaur V, Lal JH, Kishore J. MRI of the brain in patients with miliary pulmonary tuberculosis without symptoms or signs of central nervous system involvement. Neuroradiology 1997;39:699-704. Janner D, Kirk S, McLeary M. Cerebral tuberculosis without neurologic signs and with normal cerebrospinal fluid. Pediatr Infect Dis J 2000;19:763-4. Radhakrishnan VV, Mathai A. Correlation between the isolation of Mycobacterium tuberculosis and estimation of mycobacterial antigen in cisternal, ventricular and lumbar cerebrospinal fluids of patients with tuberculous meningitis. Indian J Pathol Microbiol 1993;36:341-7. Katti MK. Are enzyme-linked immunosorbent assay and immunoblot assay independent in immunodiagnosis of infectious diseases? Clin Infect Dis 2001;32:1114. Chandramuki A, Bothamley GH, Brennan PJ, Ivanyi J. Levels of antibody to defined antigens of Mycobacterium tuberculosis in tuberculous meningitis. J Clin Microbiol 1989;27:821-5. Ashtekar MD, Dhalla AS, Mazarello TB, Samuel AM. A study of Mycobacterium tuberculosis antigen and antibody in cerebrospinal fluid and blood in tuberculous meningitis. Clin Immunol Immunopathol 1987;45:29-34.

41. Behari M, Raj M, Ahuja GK, Shrinivas. Soluble antigen fluorescent antibody test in the serodiagnosis of tuberculous meningitis. J Assoc Physicians India 1989;37:499-501. 42. Mathai A, Radhakrishnan VV, Sehgal S. Circulating immune complexes in cerebrospinal fluid of patients with tuberculous meningitis. Indian J Exp Biol 1991;29:973-6. 43. Park SC, Lee BI, Cho SN, Kim WJ, Lee BC, Kim SM, et al. Diagnosis of tuberculous meningitis by detection of immunoglobulin G antibodies to purified protein derivative and lipoarabinomannan antigen in cerebrospinal fluid. Tuber Lung Dis 1993;74:317-22. 44. Srivastava L, Prasanna S, Srivastava VK. Diagnosis of tuberculous meningitis by ELISA test. Indian J Med Res 1994;99:8-12. 45. Ghoshal U, Kishore J, Kumar B, Ayyagari A. Serodiagnosis of smear and culture-negative neurotuberculosis with enzyme linked immunosorbent assay for anti A-60 immunoglobulins. Indian J Pathol Microbiol 2003;46:530-4. 46. Maheshwari A, Gupta HL, Gupta S, Bhatia R, Datta KK. Diagnostic utility of estimation of mycobacterial antigen A60 specific immunoglobulins in serum and CSF in adult neurotuberculosis. J Commun Dis 2000;32:54-60. 47. Kadival GV, Mazarelo TB, Chaparas SD. Sensitivity and specificity of enzyme-linked immunosorbent assay in the detection of antigen in tuberculous meningitis cerebrospinal fluids. J Clin Microbiol 1986;23:901-4. 48. Wagle N, Vaidya A, Joshi S, Merchant SM. Detection of tubercle antigen in cerebrospinal fluids by ELISA for diagnosis of tuberculous meningitis. Indian J Pediatr 1990;57:679-83. 49. Desai T, Gogate A, Deodhar L, Toddywalla S, Kelkar M. Enzyme-linked immunosorbent-assay for antigen detection in tuberculous meningitis. Indian J Pathol Microbiol 1993;36:348-55. 50. Patil SA, Gourie-Devi M, Anand AR, Vijaya AN, Pratima N, Neelam K, et al. Significance of mycobacterial immune complexes [IgG] in the diagnosis of tuberculous meningitis. Tuber Lung Dis 1996;77:164-7. 51. Mathai A, Radhakrishnan VV, Shobha S. Diagnosis of tuberculous meningitis confirmed by means of an immunoblot method. J Infect 1994;29:33-9. 52. Ribera E, Martinez-Vazquez JM, Ocana I, Segura RM, Pascual C. Activity of adenosine deaminase in cerebrospinal fluid for the diagnosis and follow-up of tuberculous meningitis in adults. J Infect Dis 1987;155:603-7. 53. Gautam N, Aryal M, Bhatta N, Bhattacharya SK, Baral N, Lamsal M. Comparative study of cerebrospinal fluid adenosine deaminase activity in patients with meningitis. Nepal Med Coll J 2007;9:104-6. 54. Coovadia YM, Dawood A, Ellis ME, Coovadia HM, Daniel TM. Evaluation of adenosine deaminase activity and antibody to Mycobacterium tuberculosis antigen 5 in cerebrospinal fluid and the radioactive bromide partition test for the early diagnosis of tuberculosis meningitis. Arch Dis Child 1986;61:428-35.

Neurological Tuberculosis 327 55. Wiggelinkhuizen J, Mann M. The radioactive bromide partition test in the diagnosis of tuberculous meningitis in children. J Pediatr 1980;97:843-7. 56. Mardh PA, Larsson L, Hoiby N, Engbaek HC, Odham G. Tuberculostearic acid as a diagnostic marker in tuberculous meningitis. Lancet 1983;1:367. 57. Brooks JB, Choudhary G, Craven RB, Alley CC, Liddle JA, Edman DC, et al. Electron capture gas chromatography detection and mass spectrum identification of 3-[2'-ketohexyl] indoline in spinal fluids of patients with tuberculous meningitis. J Clin Microbiol 1977;5:625-8. 58. Kaneko K, Onodera O, Miyatake T, Tsuji S. Rapid diagnosis of tuberculous meningitis by polymerase chain reaction [PCR]. Neurology 1990;40:1617-8. 59. Shankar P, Manjunath N, Mohan KK, Prasad K, Behari M, Shriniwas, et al. Rapid diagnosis of tuberculous meningitis by polymerase chain reaction. Lancet 1991;337:5-7. 60. Liu PY, Shi ZY, Lau YJ, Hu BS. Rapid diagnosis of tuberculous meningitis by a simplified nested amplification protocol. Neurology 1994;44:1161-4. 61. Folgueira L, Delgado R, Palenque E, Noriega AR. Polymerase chain reaction for rapid diagnosis of tuberculous meningitis in AIDS patients. Neurology 1994;44:1336-8. 62. Deshpande PS, Kashyap RS, Ramteke SS, Nagdev KJ, Purohit HJ, Taori GM, et al. Evaluation of the IS6110 PCR assay for the rapid diagnosis of tuberculous meningitis. Cerebrospinal Fluid Res 2007;4:10 [Epub ahead of print]. 63. Kox LF, Kuijper S, Kolk AH. Early diagnosis of tuberculous meningitis by polymerase chain reaction. Neurology 1995;45:2228-32. 64. Grosset J, Mouton Y. Is PCR a useful tool for the diagnosis of tuberculosis in 1995? Tuber Lung Dis 1995;76:183-4. 65. Meybeck A, Calbet J, Ruimy R, Mashri K, Jachym M, Joly V, et al. Multidrug-resistant tuberculous meningitis in an HIVpositive patient: a challenging disease. AIDS Patient Care STDS 2007;21:149-53. 66. Miorner H, Sjobring U, Nayak P, Chandramuki A. Diagnosis of tuberculous meningitis: a comparative analysis of 3 immunoassays, an immune complex assay and the polymerase chain reaction. Tuber Lung Dis 1995;76:381-6. 67. Prasad K, Menon GR. Tuberculous meningitis. J Assoc Physicians India 1977;45:722-9. 68. Caws M, Ha DT, Torok E, Campbell J, Thu do DA, Chau TT, et al. Evaluation of the MODS culture technique for the diagnosis of tuberculous meningitis. PLoS ONE 2007;2:e1173. 69. Arias M, Mello FC, Pavón A, Marsico AG, Alvarado-Gálvez C, Rosales S, et al. Clinical evaluation of the microscopicobservation drug-susceptibility assay for detection of tuberculosis. Clin Infect Dis 2007;44:674-80. Epub 2007 Jan 22. 70. Palur R, Rajshekhar V, Chandy MJ, Joseph T, Abraham J. Shunt surgery for hydrocephalus in tuberculous meningitis: a long-term follow-up study. J Neurosurg 1991;74:64-9. 71. Brodie BB, Kurz H, Schanker LS. The importance of dissociation constant and lipid-solubility in influencing the passage of drugs into the cerebrospinal fluid. J Pharmacol Exp Ther 1960;130:20-5.

72. Barling RW, Selkon JB. The penetration of antibiotics into cerebrospinal fluid and brain tissue. J Antimicrob Chemother 1978;4:203-27. 73. Schanker LS. Passage of drugs into and out of the central nervous system. Antimicrobial Agents Chemother 1965;5:1044-50. 74. Barclay WR, Ebert RH, Le Roy GV, Manthei RW, Roth LJ. Distribution and excretion of radioactive isoniazid in tuberculous patients. J Am Med Assoc 1953;151:1384-8. 75. Fletcher AP. CSF-isoniazid levels in tuberculous meningitis. Lancet 1953;2:694-7. 76. Elmendorf DF Jr, Cawthon WU, Muschenheim C, McDermott W. The absorption, distribution, excretion, and short-term toxicity of isonicotinic acid hydrazide [nydrazid] in man. Am Rev Tuberc 1952;65:429-42. 77. Woo J, Humphries MJ, Chan K, O’Mahony G, Teoh R. Cerebrospinal fluid and serum levels of pyrazinamide and rifampicin in patients with tuberculous meningitis. Curr Ther Res 1987;47:235-42. 78. Kaojarern S, Supmonchai K, Phuapradit P, Mokkhavesa C, Krittiyanunt S. Effect of steroids on cerebrospinal fluid penetration of antituberculous drugs in tuberculous meningitis. Clin Pharmacol Ther 1991;49:6-12. 79. Mitchison DA. Mechanism of the action of drugs in shortcourse chemotherapy. Bull Int Union Tuberc Lung Dis 1985;60:34-7. 80. Donald PR, Seifart H. Cerebrospinal fluid pyrazinamide concentrations in children with tuberculous meningitis. Pediatr Infect Dis J 1988;7:469-71. 81. Mitchison DA, Ellard GA. Antituberculosis drugs. In: Reevs DS, Philipps I, Williams JD, Wise R, editors. Laboratory methods in antimicrobial chemotherapy. Edinburgh: Churchill Livingstone; 1978.p.244-8. 82. Humphries MJ, Teoh R, Lau J, Gabriel M. Factors of prognostic significance in Chinese children with tuberculous meningitis. Tubercle 1990;71:161-8. 83. Humphries M. The management of tuberculous meningitis. Thorax 1992;47:577-81. 84. Ramachandran P, Duraipandian M, Nagarajan M, Prabhakar R, Ramakrishnan CV, Tripathy SP. Three chemotherapy studies of tuberculous meningitis in children. Tubercle 1986;67:17-29. 85. Thwaites GE, Tran TH. Tuberculous meningitis: many questions, too few answers. Lancet Neurol 2005;4:160-70. 86. Goel A, Pandya SK, Satoskar AR. Whither short-course chemotherapy for tuberculous meningitis? Neurosurgery 1990;27:418-21. 87. National Institute for Health and Clinical Excellence, National Collaborating Centre for Chronic Conditions. Management of non-respiratory tuberculosis. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London: Royal College of Physicians; 2006.p.63-76. 88. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al; American Thoracic Society, Centers for Disease Control and Prevention and the Infectious

328

89.

90.

91.

92.

93. 94. 95. 96.

97.

98.

99. 100.

101.

102.

103.

104.

105. 106.

Tuberculosis Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603-62. Phuapradit P, Vejjajiva A. Treatment of tuberculous meningitis: role of short course chemotherapy. QJM 1987;239: 249-58. Acharya VN, Kudva BT, Retnam VJ, Mehta PJ. Adult tuberculous meningitis: comparative study of different chemotherapeutic regimens. J Assoc Physicians India 1985;33:583-5. Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 2002;166:916-9. Schoeman JF, Springer P, van Rensburg AJ, Swanevelder S, Hanekom WA, Haslett PA, et al. Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study. J Child Neurol 2004;19:250-7. Wasz-Hockert O. Late prognosis in tuberculous meningitis. Acta Paediatr 1962;51:1-119. Lorber J. Treatment of tuberculous meningitis. Br Med J 1960;1:1309-12. Smith H. Tuberculous meningitis. Int J Neurol 1964;4:13457. Hockaday JM, Smith HM. Corticosteroids as an adjuvant to the chemotherapy of tuberculous meningitis. Tubercle 1966; 47:75-91. Girgis NI, Farid Z, Kilpatrick ME, Sultan Y, Mikhail IA. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991;10:179-83. Grigis NI, Farid Z, Hanna LS, Yassin MW, Wallace CK. The use of dexamethazone in preventing ocular complications in tuberculous meningitis. Trans R Soc Trop Med Hyg 1983;77:658-9. Ashby M, Grant H. Tuberculous meningitis treated with cortisone. Lancet 1955;1:65-6. Voljarec BF, Corpe RF. The influence of corticosteroid hormones in the treatment of tuberculous meningitis in Negroes. Am Rev Respir Dis 1960;81:539-45. Lepper MH, Spies HW. The present system of the treatment of tuberculosis of the central nervous system. Ann NY Acad Sci 1963;106:106-23. O’Toole RD, Thronton GF, Mukherjee MK, Nath RL. Dexamethasone in tuberculosis meningitis: relationship of cerebrospinal fluid effects to therapeutic efficacy. Ann Intern Med 1969;70:39-48. Escobar JA, Belsey MA, Duenas A, Medina P. Mortality from tuberculous meningitis reduced by steroid therapy. Paediatrics 1975;56:1050-5. Dooley DP, Carpenter JL, Rademacher S. Adjunctive corticosteroid therapy for tuberculosis: A critical reappraisal of the literature. Clin Infect Dis 1997;25:872-87. Horne NW. A critical evaluation of corticosteroids in tuberculosis. Adv Tuberc Res 1966;15:1-54. Shao PP, Wang SM, Tung SG. Clinical analysis of 445 adults cases of tuberculous meningitis. Tuber Respir Dis 1980;3:1312.

107. Kumaravelu S, Prasad K, Khosla A, Behari M, Ahuja GK. Randomized controlled trial of dexamethasone in tuberculous meningitis. Tuber Lung Dis 1994;75:203-7. 108. Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT, Nguyen TC, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351:1741-51. 109. Schoeman JF, Van Zyl LE, Laubscher JA, Donald PR. Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics 1997;99:226-31. 110. Tuberculosis and human immunodeficiency virus infection: recommendations of the Advisory Committee for the Elimination of Tuberculosis [ACET]. MMWR Morb Mortal Wkly Rep 1989;38:236-8. 111. Smith HV. Tuberculous meningitis. Int J Neurol 1964;4:13457. 112. Roy TK, Sircar PK, Chandar V. Peritoneal ventriculo shunt in the management of tuberculous meningitis. Indian Pediatr 1979;16:1023-7. 113. Gourie-Devi M, Satish P. Hyaluronidase as an adjuvant in the treatment of cranial arachnoiditis [hydrocephalus and optochiasmatic arachnoiditis] complicating tuberculous meningitis. Acta Neurol Scand 1980;62:368-81. 114. Vajramani GV, Devi BI, Hegde T, Santosh V, Khanna N, Vasudev MK. Intraventricular tuberculous abscess: a case report. Neurol India 1999;47:327-9. 115. van Dellen A, Nadvi SS, Nathoo N, Ramdial PK. Intracranial tuberculous subdural empyema: case report. Neurosurgery 1998;43:370-3. 116. Gupta RK, Vatsal DK, Husain N, Chawla S, Prasad KN, Roy R, et al. Differentiation of tuberculous from pyogenic brain abscesses with in vivo proton MR spectroscopy and magnetization transfer MR imaging. AJNR Am J Neuroradiol 2001;22:1503-9. 117. Kumar R, Pandey CK, Bose N, Sahay S. Tuberculous brain abscess: clinical presentation, pathophysiology and treatment [in children]. Childs Nerv Syst 2002;18:118-23. Epub 2002 Mar 22. 118. Anderson NE, Willoughby EW. Chronic meningitis without predisposing illness—a review of 83 cases. QJM 1987;63:28395. 119. Ellner JJ, Bennett JE. Chronic meningitis. Medicine [Baltimore] 1976;55:341-69. 120. Wilhelm C, Ellner JJ. Chronic meningitis. Neurol Clin 1986;4:115-41. 121. Cheng TM, O’Neill BP, Scheithauer BW, Piepgras DG. Chronic meningitis: the role of meningeal or cortical biopsy. Neurosurgery 1994;34:590-5; discussion 596. 122. Radhakrishnan K, Kishore A, Mathuranath PS. Neurological tuberculosis. In: Sharma SK, editor. Tuberculosis. First edition. New Delhi: Jaypee Brothers Medical Publishers; 2001.p.209-28. 123. Dastur HM, Desai AD. A comparative study of brain tuberculomas and gliomas based upon 107 case records of each. Brain 1965;88:375-96.

Neurological Tuberculosis 329 124. Armstrong FB, Edwards AM. Intracranial tuberculoma in native races of Canada: with special reference to symptomatic epilepsy and neurologic features. Can Med Assoc J 1963;89:56-65. 125. Maurice-Williams RS. Tuberculomas of the brain in Britain. Postgrad Med J 1972;48:678-81. 126. Naim-Ur-Rahman. Intracranial tuberculomas: diagnosis and management. Acta Neurochir [Wien] 1987;88:109-15. 127. Tandon PN, Bhargava S. Effect of medical treatment on intracranial tuberculoma — a CT study. Tubercle 1985;66:85-97. 128. Kumar R, Jain R, Kaur A, Chhabra DK. Brain stem tuberculosis in children. Br J Neurosurg 2000;14:356-61. 129. Desai K, Nadkarni T, Bhatjiwale M, Goel A. Intraventricular tuberculoma. Neurol Med Chir [Tokyo] 2002;42:501-3. 130. Arseni C. Two hundred and one cases of intracranial tuberculoma treated surgically. J Neurochem 1958;21:308-11. 131. Choudhury AR. Non-surgical treatment of tuberculomas of the brain. Br J Neurosurg 1989;3:643-53. 132. Tandon PN. Brain biopsy in tuberculoma: the risks and benefits. Neurosurgery 1992;30:301. 133. Rajeswari R, Sivasubramanian S, Balambal R, Parthasarathy R, Ranjani R, Santha T, et al. A controlled clinical trial of shortcourse chemotherapy for tuberculoma of the brain. Tuber Lung Dis 1995;76:311-7. 134. Teoh R, Humphries MJ, O’Mahony G. Symptomatic intracranial tuberculoma developing during treatment of tuberculosis: a report of 10 patients and review of the literature. QJM 1987;63:449-60. 135. Chambers ST, Hendrickse WA, Record C, Rudge P, Smith H. Paradoxical expansion of intracranial tuberculomas during chemotherapy. Lancet 1984;2:181-4. 136. Sethi PK, Kumar BR, Madan VS, Mohan V. Appearing and disappearing CT scan abnormalities and seizures. J Neurol Neurosurg Psychiatry 1985;48:866-9. 137. Wadia RS, Makhale CN, Kelkar AV, Grant KB. Focal epilepsy in India with special reference to lesions showing ring or disclike enhancement on contrast computed tomography. J Neurol Neurosurg Psychiatry 1987;50:1298-301. 138. Goulatia RK, Verma A, Mishra NK, Ahuja GK. Disappearing CT lesions in epilepsy. Epilepsia 1987;28:523-7. 139. Ahuja GK, Behari M, Prasad K, Goulatia RK, Jailkhani BL. Disappearing CT lesion in epilepsy: is tuberculosis or cysticercosis the cause? J Neurol Neurosurg Psychiatry 1989;30:915-6. 140. Bhatia S, Tandon PN. Solitary ‘microlesions’ in CT: a clinical study and follow-up. Neurol India 1988;36:139-50. 141. Singhal BS, Ladiwala U, Singhal P. Neurocysticercosis in the Indian context [with special reference to solitary parenchymatous cyst]. Neurol India 1997;45:211-7. 142. Rajshekhar V. Etiology and management of single small CT lesions in patients with seizures: understanding a controversy. Acta Neurol Scand 1991;84:465-70. 143. Chandy MJ, Rajshekhar V, Ghosh S, Prakash S, Joseph T, Abraham J, et al. Single small enhancing CT lesions in Indian patients with epilepsy: clinical, radiological and pathological considerations. J Neurol Neurosurg Psychiatry 1991;54:702-5.

144. Padma MV, Behari M, Misra NK, Ahuja GK. Albendazole in single CT ring lesions in epilepsy. Neurology 1994;44:1344-6. 145. Mitchell WG, Crawford TO. Intraparenchymal cerebral cysticercosis in children: diagnosis and treatment. Pediatrics 1988;82:76-82. 146. Rajashekhar V, Haran RP, Prakash GS, Chandy MJ. Differentiating solitary small cysticercus granulomas and tuberculomas in patients with epilepsy. Clinical and computerized tomographic criteria. J Neurosurg 1993;78:402-7. 147. Abraham J. Preliminary findings of the 4 consensus meetings held on convulsive disorder associated with a single small enhancing brain lesion on CT scan [SSECTL]. World Federation of Neurosurgery Society [India] Circular; 1994. 148. Falk A. US veterans administration-armed forces cooperative study on the chemotherapy of tuberculosis.13. Tuberculous meningitis in adults, with special reference to survival, neurologic residuals, and work status. Am Rev Respir Dis 1965;91:823-31. 149. Kalita J, Misra UK, Ranjan P. Predictors of long-term neurological sequelae of tuberculous meningitis: a multivariate analysis. Eur J Neurol 2007;14:33-7. 150. Schoeman J, Wait J, Burger M, van Zyl F, Fertig G, van Rensburg AJ, et al. Long-term follow up of childhood tuberculous meningitis. Dev Med Child Neurol 2002;44:522-6. 151. Gropper MR, Schulder M, Sharan AD, Cho ES. Central nervous system tuberculosis: medical management and surgical indications. Surg Neurol 1995;44:378-84; discussion 384-5. 152. Hernandez-Albujar S, Arribas JR, Royo A, Gonzalez-Garcia JJ, Pena JM, Vazquez JJ. Tuberculous radiculomyelitis complicating tuberculous meningitis: case report and review. Clin Infect Dis 2000;30:915-21. 153. Chang KH, Han MH, Choi YW, Kim IO, Han MC, Kim CW. Tuberculous arachnoiditis of the spine: findings on myelography, CT, and MR imaging. AJNR Am J Neuroradiol 1989;10:1255-62. 154. Leonard JM, Des Prez RM. Tuberculous meningitis. Infect Dis Clin North Am 1990;4:769-87. 155. Wadia NH. Radioculomyelopathy associated with spinal meningitis [arachnoiditis] with special reference to the spinal tuberculous variety. In: Spillane JD, editor. Tropical neurology. Oxford: Oxford University Press; 1973.p.63-9. 156. Gupta RK, Gupta S, Kumar S, Kohli A, Misra UK, Gujral RB. MRI in intraspinal tuberculosis. Neuroradiology 1994;36:3943. 157. Villoria MF, Fortea F, Moreno S, Munoz L, Manero M, Benito C. MR imaging and CT of central nervous system tuberculosis in the patient with AIDS. Radiol Clin North Am 1995;33:80520. 158. Naidoo DP, Desai D, Kranidiotis L. Tuberculous meningiomyeloradiculitis–a report of two cases. Tubercle 1991;72:65-9. 159. Fehlings MG, Bernstein M. Syringomyelia as a complication of tuberculous meningitis. Can J Neurol Sci 1992;19:84-7. 160. John JF Jr, Douglas RG Jr. Tuberculous arachnoiditis. J Pediatr 1975;86:235-7.

330

Tuberculosis

Tuberculosis and Heart

22 SS Kothari, A Roy

INTRODUCTION Cardiovascular involvement is a relatively uncommon manifestation in patients with tuberculosis [TB] and has been described in one to two per cent of patients (1). It mainly affects pericardium, but very rarely myocardium, the valves and large arteries are involved. Although cardiovascular involvement is always secondary to TB elsewhere in the body, it may be the only clinical manifestation of TB. Mycobacterium tuberculosis is the usual infecting agent. Cardiovascular TB caused by nontuberculous mycobacteria [NTM] has been documented in patients with human immunodeficiency virus [HIV] infection (2). TUBERCULOSIS PERICARDITIS Pericardial TB may present as acute pericarditis, chronic pericardial effusion, cardiac tamponade or pericardial constriction. Hence, TB should always be considered in the differential diagnosis of pericardial disease. In developing countries where the disease is highly endemic, TB is an important cause of pericardial disease (3-5). Tuberculosis pericarditis, caused by Mycobacterium tuberculosis, is found in about one per cent of all autopsied cases of TB and in one to two per cent of cases of pulmonary TB (1). In India, TB is responsible for nearly two-thirds of the cases of constrictive pericarditis (3,4). Overall, TB accounts for 60 to 80 per cent of cases of acute pericarditis in the developing countries. However, recently published literature suggests that, in the developed world, TB is a relatively rare cause of pericardial disease in HIV negative, immunocompetent persons and accounts for two per cent of the cases of

acute pericarditis (6,7), two per cent of cardiac tamponade (8) and zero to one per cent of constrictive pericarditis (9,10). However, with emergence of the global pandemic of the acquired immunodeficiency syndrome [AIDS], these numbers are likely to increase again (11). Tuberculosis pericarditis is the predominant form of cardiovascular TB. Before the advent of antituberculosis treatment, TB pericarditis carried a grave prognosis. The reported mortality rate in TB pericarditis is more than 80 per cent during the acute phase of illness and still more at a later stage due to constrictive pericarditis (12-14). With the advent of modern multiple drug short-course treatment, the mortality rate in patients with TB pericarditis has decreased but still remains worrisome with reported death rates of three to seventeen per cent in the pre-HIV era (15,16) and as high as 27 per cent in HIV-seropositive patients (17). Pathogenesis Pericardial involvement most commonly results from direct extension of infection from adjacent mediastinal lymph node or through lymphohaematogenous route from a focus in lungs, kidneys, or bones. The TB pericarditis has following stages: [i] dry stage; [ii] effusive stage; [iii] absorptive stage; and [iv] constrictive stage (18). The disease may progress sequentially from first to fourth stage or may present as any of the stages. The factors that lead to a dominant exudative inflammation in some patients or fibrosis in others are not known (19). While acute pericarditis appears to be a primary hypersensitivity response to tuberculoprotein[s], chronic effusion and constriction reflect granuloma formation

Tuberculosis and Heart 331 and fibrosis. Epithelioid granulomas, Langhans’ giant cells and caseation necrosis are evident on histopathological examination (20). The T-lymphocytes, in addition to activated macrophages, are important in granuloma formation. The accompanying exudative pericardial fluid may contain polymorphonuclear leucocytes in the initial one to two weeks, but later on, it is predominantly lymphocytic with high protein content. In 80 per cent of the cases, the fluid is straw coloured or sero-sanguinous, and may be grossly bloody resembling venous blood at times (1). Very rarely, severe inflammation may result in pyopericardium due to TB (21). The amount of pericardial fluid may vary from 15 to 3500 ml (22). Development of cardiac tamponade due to TB pericarditis depends on the rapidity of collection of pericardial fluid. It may occur with small amount of pericardial fluid collected rapidly and may not occur even with a slowly accumulating large pericardial effusion. Fibrinous exudates, pericardial effusion and thickening of pericardium from fibrosis [especially the visceral layer] result in features of effuso-constrictive pericarditis within weeks of development of TB pericarditis. Continued inflammation and fibrotic activity may lead to chronic constrictive pericarditis [CCP]. With effective antituberculosis treatment, the pericardial effusion may resolve without development of CCP in nearly half the patients (5). Many patients with CCP, however, have no history of previous TB pericarditis. Complete obliteration of pericardial space by a fibrotic constricting shell results in impairment of cardiac function. In chronic cases the inflammatory process may extend into myocardium resulting in myonecrosis and muscle atrophy. The constriction at times may be patchy and localized to certain areas, like mitral or tricuspid annulus (23). The space around transverse and oblique sinus is often spared from fibrosis, and therefore, some degree of left atrial enlargement commonly occurs in CCP. Clinical Features Tuberculosis pericarditis can develop at any age but commonly occurs in the middle age. In the series, reported by Strang et al (16) more than 80 per cent patients were older than 35 years with nearly half of them being more than 55 years old. Like other forms of TB, it is more common in patients who are immunosuppressed. However, the majority of patients do not have any other co-morbid conditions. It is more common among the

black race as compared to whites in the western world (1,23,24). The clinical features depend on the stage and severity of the disease. The pericarditis is often insidious in onset and presents with fever, malaise and weakness. Attention to the diagnosis is drawn by presence of pericardial rub, vague chest pain or cardiomegaly on chest radiograph. Dyspnoea, non-productive cough and weight loss are common symptoms. Chest pain, orthopnoea and ankle oedema occur in nearly 40 to 70 per cent of patients (1,22,25). Chest pain is usually pleuritic in nature and is characteristically relieved by sitting up and leaning forward. This manoeuvre relieves increased pericardial tissue tension due to inspiration and truncal extension and also splints the diaphragm (26). Pain radiation to shoulder and jaw can mimic angina rarely. Radiation of pain to trapezius ridge through the phrenic nerve is virtually pathognomonic of pericardial pain (26). However, TB pericarditis may also present with an acute illness in 20 per cent of the cases (5). The reported frequency of various symptoms in different series is shown in Table 22.1 (1,24,25,28,29). Fever, pericardial rub and systemic congestive failure are important signs that are commonly seen [Table 22.2]. Exudative pleural effusion is seen in nearly half the patients. The typical features of pericardial effusion and constrictive pericarditis are described below. Pericardial Effusion Patients with TB pericarditis may develop chronic pericardial effusion with mild or severe constitutional symptoms (1,25). Patients may also present acutely with cardiac tamponade and may manifest severe distress, retrosternal compression, tachycardia and raised jugular venous pressure [JVP] with blunted y descent. In patients with cardiac tamponade, the heart sounds are usually distant. A pericardial rub may be heard despite significant pericardial effusion being present. Pulsus paradoxus [inspiratory decline of systolic blood pressure of more than 10 mm Hg] is the hallmark of bedside diagnosis. Subacute Effusive-Constrictive Pericarditis This subacute stage of TB pericarditis is also termed as subacute “elastic” pericarditis. It has features of both pericardial effusion and constriction. The fluid-fibrin layer leads to relatively elastic compression of heart, which has been compared to “wrapping the heart tightly

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Tuberculosis Table 22.1: Clinical symptoms in patients with tuberculosis pericarditis

Variable

Hageman et al (24) Rooney et al (25) [n = 35] [n = 44]

Weight loss Night sweats Chest pain Cough Haemoptysis Dyspnoea Orthopnoea

ND 14 39 48 ND 80 39

Fowler (1) [n = 19]

85 37 57 85 17 74 66

Komsuoglu et al (27) Yang et al (28) [n = 20] [n = 19]

40 58 76 94 14 88 53

ND 10 40 50 ND 60 ND

32 ND 37 47 ND 84 ND

Reuter et al (29) [n = 162] 79 62 27 90 ND 86 38

All values are shown as percentages n = number of patients; ND = not described

Table 22.2: Physical signs in patients with tuberculosis pericarditis Variable

Hageman et al (24) Rooney et al (25) [n = 35] [n = 44]

Fever Tachycardia [> 100/min] Pulsus paradoxus Ankle oedema Raised JVP Pericardial rub Cardiomegaly Pleural effusion Hepatomegaly Ascites Pulmonary infiltrates

73 68 45 64 70 41 90 ND 68 34 ND

97 94 23 49 46 37 85 71 63 3 ND

Fowler (1) [n = 19] 83 83 71 39 61 84 95 58 65 ND ND

Komsuoglu et al (27) Yang et al (28) Reuter et al (29) [n = 20] [n = 19] [n = 162] NA 73 33 24 47 ND 98 10 67 ND ND

58 47 11 42 68 32 79 42 26 26 42

75 74 27 38 78 ND ND 38 62 ND ND

All values are shown as percentages n = number of patients; JVP = jugular venous pressure; ND = not described

with rubber bands” (30). The haemodynamics of the nonrigid fibroelastic form of constrictive pericarditis resembles tamponade because the fibroelastic constriction compresses the heart throughout the cardiac cycle, and respiratory changes in intrathoracic pressure are transmitted to the cardiac chambers (30). Thus, the pattern of ventricular filling is similar to cardiac tamponade rather than constrictive pericarditis and includes a systemic venous waveform with a dominant x descent or equal x and y descent, an inconspicuous early diastolic dip in the ventricular waveforms, an inspiratory dip in systemic venous and right atrial pressures, and presence of pulsus paradoxus. This stage can develop within weeks of TB pericarditis. With effective antituberculosis treatment, the disease may resolve in some patients, but, commonly chronic constriction supervenes (5,16).

Chronic Constrictive Pericarditis In hearts with CCP, the inflow of blood is impeded due to thickened unyielding pericardium, especially in the late diastole. Thus, patients usually present with symptoms of systemic and pulmonary venous congestion. Abdominal swelling [from ascites or hepatomegaly] and peripheral oedema are the most common presenting symptoms. Dyspnoea and orthopnoea are also present in nearly half the patients requiring surgical intervention (31). Cardiac output is mildly reduced at rest. These patients have compensatory tachycardia to maintain cardiac output. Since more than 75 per cent of diastolic filling occurs in the first 25 per cent of the diastole, shortening of diastole does not reduce stroke volume much but helps in augmenting cardiac output. Other clinical signs include raised JVP with rapid y descent [Friedrich’s sign], which further increases on

Tuberculosis and Heart 333 inspiration [Kussmaul’s sign]. Pulsatile hepatomegaly, ascites, with an impalpable apex or systolic retraction of the precordium [Broadbent’s sign] are also seen commonly. A pericardial knock that occurs 0.11 to 0.12 seconds after the second heart sound may be present; murmurs are uncommon. In an Indian study (32), atrioventricular regurgitation was present in 78 per cent of patients with CCP on Doppler examination, but an audible murmur was present in only two of the 33 patients. In general, presence of cardiomegaly, third and fourth heart sounds, significant mitral or tricuspid regurgitation, and severe pulmonary hypertension favour the diagnosis of restrictive cardiomyopathy. Other atypical manifestations include clinical presentation with ascites that is disproportionate to the peripheral oedema [ascites precox] which may masquerade as primary liver disease. Sometimes, patients may also present with subtle signs, such as like fatigue, without obvious clinical findings of CCP. These patients with “occult” constrictive pericarditis often manifest pericardial thickening on radiological imaging. The clinical signs of constrictive pericarditis may become evident on fluid challenge in such patients. These patients improve with pericardiectomy. Other patients may present with congestive splenomegaly and protein losing enteropathy resulting in hypoproteinaemia. Rarely, nephrotic syndrome due to CCP has been described (31). Cardiac cirrhosis may also develop after many years of hepatic venous congestion. The disease worsens gradually and in chronic cases, significant myocardial atrophy occurs due to extension of inflammation and possibly disuse of cardiac muscle. These patients have suboptimal results and higher mortality with pericardiectomy (23). Differential Diagnosis The differential diagnosis of pericardial disease involves a number of conditions, such as idiopathic, viral, or, infectious pericarditis and pericarditis due to neoplasia, collagen vascular disorders and uraemia among others. The aetiological diagnosis in pericarditis is often established on the basis of “guilt by association”. Majority of patients with idiopathic or viral pericarditis have acute onset with characteristic chest pain. Pericardial effusion may be small or absent. Idiopathic or viral pericarditis is a self-limited illness lasting two to

three weeks (33). However, a more protracted course, large pericardial effusion or cardiac tamponade are not infrequent in idiopathic or viral pericarditis. On the other hand, TB pericarditis may have an acute onset. The differentiation of TB pericarditis from idiopathic or viral pericarditis may present a diagnostic dilemma. Diagnosis Chest Radiograph Cardiomegaly has been commonly reported in various published series on TB pericarditis. It was present in 40 of 44 patients described in one study (24) and in 190 of the 193 patients in another (16). Active pulmonary TB has been reported in nearly 30 per cent patients with TB pericarditis (1,16,34,35). However, pericarditis may be the only manifestation of extra-pulmonary TB in several patients. Reduced cardiac pulsations on fluroscopy has been reported in 76 per cent patients (24). Pleural effusion has also been frequently described and may be bilateral in some patients (25). Pericardial calcification [Figures 22.1A and 22.1B] commonly occurs around the annulus and has been observed in 15 per cent patients in Indian series and in about 75 per cent patients in Western series (3,23). Electrocardiogram The most common electrocardiogram [ECG] findings in patients with TB pericarditis are presence of low voltage complexes and T-wave inversion with or without STsegment changes [Figure 22.2]. One of these findings is present in over 90 per cent patients (24,25). In a recent study of 88 patients with TB pericarditis, presence of low voltage in the extremity and/or precordial leads correlated with the presence of greater than 750 ml of pericardial fluid. However, no ECG parameters were predictive of cardiac tamponade (36). The presence of classical ST-segment elevation of acute pericarditis is rare and is seen in two to nine per cent of patients (24,25). Pericardial Fluid The pericardial fluid is usually straw coloured or serosanguinous and has a high protein content. The cell count is high with predominance of lymphocytes and monocytes. In the initial weeks, predominantly polymorphonuclear leucocytes may be seen and very rarely TB

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Figure 22.2: Three-channel recording of a 12-lead electrocardiogram at 25 mm/s in a child with chronic constrictive pericarditis. Limb leads show a low-voltage graph and non-specific T-wave inversion in leads V4-V6. Left atrial enlargement is also evident

Figure 22.1A: Chest radiograph [postero-anterior view] showing moderate cardiomegaly, dense, plaque-like calcification of the pericardium in the anterior and inferior atrioventricular groove. Right basal pneumonitis and pleural effusion are also seen. Extensive calcification of hilar, anterior mediastinal and right paratracheal lymph nodes is indicative of tuberculosis

may cause a purulent pericarditis (21). A smear of pericardial fluid rarely identifies acid-fast bacilli [AFB] on Ziehl-Neelsen [Z-N] staining. Flurochrome staining is a more sensitive technique for identifying mycobacteria than conventional Z-N staining (37). Culture of pericardial fluid grows Mycobacterium tuberculosis in about 50 to 60 per cent cases using Lowenstein-Jensen [L-J] or double strength Kirchner medium (16,25). However, the major drawback is that six to eight weeks are needed for the cultures to yield results. Newer radiometric culture techniques like BACTEC yield quicker results. Application of polymerase chain reaction [PCR] to the pericardial fluid (38) and tissue (39) has also been found to be useful in the diagnosis of TB pericarditis. Elevated pericardial fluid adenosine deaminase [ADA] [cut-off > 40 IU/l, sensitivity 87%, specificity 89%]; and interferon-γ [IFN-γ] [cut-off > 50 pg/ml, sensitivity 92%, specificity 100%] have been found to be useful for the diagnosis of TB pericardial disease (29). However, a recent study (40) demonstrated that ADA, which is produced by activated macrophages and lymphocytes may also be raised in malignant effusions. The authors (41) proposed that simultaneous measurement of lysozyme, which is raised in TB effusions, along with ADA may help in distinguishing TB pericardial effusion from malignant pericardial effusion. Pericardial Biopsy

Figure 22.1B: Chest radiograph [lateral view] of the same patient. Pericardial calcification [arrow] is better appreciated in this view

Pericardial biopsy is another useful method for confirming the aetiology of pericarditis and it gives results earlier than pericardial fluid culture. Tissue can be obtained by open biopsy or percutaneously using a bioptome (41,42). Pecutaneous biopsy is taken from multiple sites and has been shown to be safe in a selected

Tuberculosis and Heart 335 group of patients, including children. Histopathological examination of pericardial tissue may be diagnostic of TB in 70 per cent of cases when performed prior to initiation of therapy (16). However, it is important to note that in some patients with culture positive TB, histopathology may show non-specific changes. Thus, a nonspecific histopathological change in the pericardial biopsy does not exclude TB (16). The pericardial tissue culture also provides an additional source for isolating Mycobacterium tuberculosis and increases the diagnostic yield (16,42). Echocardiogram The echocardiogram is highly sensitive and specific for the diagnosis of pericardial effusion and cardiac tamponade [Figure 22.3]. When 1 cm of posterior echofree space is evident in systole and diastole, with or without fluid accumulation elsewhere, the pericardial effusion is classified as ‘small’. When a posterior clear space of 1 to 2 cm is maintained in systole and diastole, the effusion is classified as ‘moderate’. In ‘large’ pericardial effusions, a clear space of 2 cm or more is evident; or an anterior and posterior clear space can be seen in systole and diastole (43). Collapse of right atrial and right ventricular free wall in diastole by pericardial fluid and exaggerated respiratory variation in atrio-ventricular valve flow velocities are diagnostic of tamponade and may precede clinical

Figure 22.3: Two-dimensional echocardiogram in parasternal long axis view of a child with tuberculosis pericardial effusion RV = right ventricle; LV= left ventricle; PEff = pericardial effusion

evidence. Pericardial fluid often contains fibrinous exudates. Rarely, these exudates may appear as a fleshy tumour that disappears with antituberculosis treatment (44). Thickened pericardium and pericardial effusion are seen in the effusive-constrictive stage. Pericardial thickening is best visualized anteriorly over the right ventricular free wall. Transoesophageal echocardiography is superior to transthoracic echocardiography in the detection of pericardial thickening. The normal pericardium is a thin, bright line of 1.2 [± 0.8 mm]. In one study (45), the pericardium in patients with constrictive pericarditis measured 9.8 [± 1.6 mm]. Pericardial thickness as measured by transoesophageal echocardiography was found to have an excellent correlation with the measurements obtained by electron beam computed tomography (46). When a value of 3 mm was used as a cut-off for defining pericardial thickness as measured by transoesophageal echocardiography, the sensitivity and specificity of this technique for CCP were calculated to be 95 per cent and 86 per cent, respectively (46). The other findings in CCP include abrupt flattening of mid to late diastolic movement of the left ventricular posterior wall on M-mode, reflecting a sudden decline in diastolic filling (47). Other M-mode features include rapid early closure of the mitral valve and, uncommonly, premature pulmonary valve opening from increased right-sided diastolic pressures. A diastolic septal bounce is also commonly seen. Diastolic septal motion is controlled by the pressure gradient across the septum. The abrupt bounce may be caused by sudden changes in the transseptal gradient during diastole, when filling is particularly rapid (48). Additional echocardiographic abnormalities include mild atrial and inferior vena cava [IVC] dilatation. Doppler studies also help in diagnosing CCP and differentiating it from restrictive cardiomyopathy. The mitral flow velocities show more than 25 per cent respiratory variation [decrease with inspiration], most pronounced in the first heartbeat after inspiration from apnoea (49). Similarly, an expiratory increase in diastolic flow reversal [> 25%] of the hepatic venous flow velocities is suggestive of CCP. Tissue doppler velocities are usually preserved in CCP and this feature helps to distinguish it from restrictive cardiomyopathy wherein tissue velocities are commonly impaired.

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Cross-Sectional Imaging

Cardiac Catheterization

Cross-sectional imaging with computed tomography [CT] or magnetic resonance imaging [MRI] is very useful in the diagnosis of CCP and in distinguishing it from restrictive cardiomyopathy in difficult cases. The diagnostic hallmark is the presence of pericardial thickening with or without calcification [Figure 22.4]. Additionally, CT is useful in demonstrating mediastinal lymphadenopathy [Figure 22.5]. While CT scores over MRI in detection of minimal amounts of pericardial calcification, MRI provides better soft tissue characterization (50). Pericardial thickening of more than 3 mm is usually considered abnormal. Often a localized process, pericardial thickening is most frequently seen over the right ventricle. In a study of 29 patients (51), MRI was found to be 88 per cent sensitive and 100 per cent specific, with a diagnostic accuracy of 93 per cent for detecting CCP. However, pericardial thickening can be seen without constrictive physiology. Similarly, in a small percentage of patients with constrictive physiology, no pericardial thickening can be identified. Therefore, it is important to search for additional findings suggestive of CCP like tubular shaped ventricles, enlarged atria, focal contour abnormalities of the ventricles, dilated IVC, ascites and pleural effusion on CT or MRI (50).

Cardiac tamponade or CCP due to any cause produces a similarly elevated right, left atrial [or pulmonary arterial wedge], right and left ventricular end-diastolic pressures. These pressures are within 5 mm Hg of each other [Figure 22.6]. The other classical haemodynamic criteria favouring CCP over restrictive cardiomyopathy (52) are a right ventricular systolic pressure less than or equal to 50 mm Hg and a ratio of right ventricular end-diastolic pressure to right ventricular systolic pressure greater than or equal to 1:3. If all these three criteria are met the probability of correctly diagnosing CCP is over 90 per cent. If one or none of these criteria is present then probability of having CCP is less than 10 per cent. However, one-fourth of patients could not be classified by these haemodynamic criteria (53). Measuring respiratory variation in ventricular haemodynamics during catheterization is another useful criteria for the diagnosis of CCP (49,53). As a manifestation of ventricular interdependence, respiratory discordance occurs in peak right ventricular systolic pressure and left ventricular systolic pressure. In CCP, right ventricular systolic pressure increases with inspiration while left ventricular systolic pressure simultaneously decreases. Wedge pressure declines more than the left ventricular diastolic pressure during inspiration, and the reduction in mitral flow translates into the observed reduction in left ventricular systolic pressure. These criteria have 100 per cent sensitivity and 95 per cent specificity for the diagnosis of CCP (53). In restrictive cardiomyopathy, both right and left ventricular systolic pressure decrease concordantly with inspiration (53). Treatment

Figure 22.4: Sagittal reconstruction of a contrast enhanced CT of the chest showing shell-like thickening [11 mm] of the pericardium [arrow] in a patient with tuberculosis pericardial effusion. Echocardiography did not reveal any evidence of constriction

Once diagnosis of TB pericarditis is established, prompt initiation of antituberculosis treatment is mandatory. Recommended therapy consists of four drug regimens consisting of isoniazid, rifampicin, pyrazinamide and ethambutol or streptomycin for two months followed by isoniazid and rifampicin for next four months. Some physicians prefer to administer longer duration of treatment. However, no randomized controlled trials have compared different durations of antituberculosis drug regimens in TB pericarditis. Similar duration of treatment is recommended for HIV-seropositive patients, though patients with NTM infection may require longer

Tuberculosis and Heart 337

Figure 22.5: Tuberculosis effusive-constrictive pericarditis. Chest radiograph [postero-anterior view] showing cardiomegaly [A]. CT of the chest of the same patient [mediastinal window] showing pericardial effusion along with well-defined pericardial thickening [arrows] [B] and mediastinal lymphadenopathy [arrow] [C]. The lymph nodes show the characteristic peripheral rim enhancement with central attenuation. Repeat CT after completion of antituberculosis treatment showing significant regression in pericardial effusion and thickening [D] and mediastinal lymphadenopathy [E]

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Figure 22.6: Left and right ventricular pressure tracing at paper speed of 100 mm/s and 100 mm Hg gain [each small square = 5 mm Hg]. Early [thick arrow] and late [thin arrow] diastolic pressures of the two ventricles are similar [30 mm Hg] and markedly elevated. Right ventricular systolic pressure is also elevated to 60 to 65 mm Hg LV = left ventricular pressure tracing; RV = right ventricular pressure tracing

duration of therapy. The reader is referred to the chapter “Treatment of tuberculosis” [Chapter 52] for more details. Under the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India, pericardial TB is categorized as serious form of extrapulmonary TB and is treated with Category I DOTS treatment. The reader is referred to chapter “Revised National Tuberculosis Control Programme” [Chapter 63] for more details. Role of Adjuvant Corticosteroid Treatment In controlled clinical trials, the addition of prednisolone to antituberculosis treatment has been shown to reduce mortality and the need for repeated pericardiocentesis in patients with TB pericarditis and effusion (5,16). In a double-blind comparison of prednisolone vs placebo as an adjuvant to six months of antituberculosis treatment in patients with active TB constrictive pericarditis (5), addition of prednisolone increased the rate of clinical improvement, reduced the risk of death from pericarditis and the need for pericardiectomy, and was associated with a higher proportion of patients with an

overall favourable status. In a subsequent randomized controlled trial with a factorial design by the same group (16): [i] immediate, complete, open surgical drainage of pericardial fluid versus percutaneous pericardiocentesis as required; and [ii] prednisolone versus placebo, doubleblind, as a supplement to six months of antituberculosis treatment, the authors (16) reported that open drainage eliminated the need for repeat pericardiocentesis. They also observed that prednisolone reduced the risk of death from pericarditis and the need for repeat pericardiocentesis, and was associated with a higher proportion of patients with an overall favourable status. In both trials, prednisolone was used for a period of 11 weeks of antituberculosis treatment in a dosage of 40 to 60 mg/ day for four to six weeks and tapered over the next five weeks. The authors (54), recently reported results of 10 years follow-up of the same cohort. Multivariate survival analysis [stratified by type of pericarditis], adjuvant prednisolone treatment reduced the overall death rate after adjusting for age and sex, and substantially reduced the risk of death from pericarditis. In another trial (17) in HIV-seropositive patients with TB pericarditis, there was a significant reduction in all cause mortality with use of steroids at 18 months of follow-up (17). Therefore, unless contraindicated, it appears appropriate to recommend steroids in all patients with TB pericarditis and pericardial effusion along with antituberculosis treatment (55). The higher dose of prednisolone is due to concurrent use of rifampicin which influences corticosteroid metabolism. Pericardiocentesis and Pericardiectomy Pericardiocentesis is life saving in patients with cardiac tamponade and also provides an opportunity to confirm the aetiology of the pericardial effusion. This can be performed percutaneously and by open surgical drainage. The latter method abolishes the need for repeat pericardiocentesis but does not reduce subsequent mortality or need for pericardiectomy (16). Furthermore, open surgical drainage requires general anaesthesia unlike percutaneously performed procedure, but provides an opportunity to obtain pericardial tissue for histopathological examination. Reuter et al (56) from South Africa studied 233 patients with TB pericardial effusion and reported that these patients responded well to closed pericardiocentesis and a six-month course of antituberculosis treatment.

Tuberculosis and Heart 339 Chronic constrictive pericarditis requires pericardiectomy, which is preferably avoided in the subacute stage when a plane of cleavage has not clearly developed (56). However, pericardiectomy can be done after two to four weeks of chemotherapy and should not be unduly delayed if indicated. Various approaches to pericardiectomy, i.e. median sternotomy, lateral thoracotomy, bilateral thoracotomy, with or without use of cardiopulmonary by pass; and anterior or total removal of pericardium have been described depending on patient population or personal preferences. Cardiopulmonary bypass is needed for more difficult cases with extensive calcification, coronary involvement or large vessel involvement. Surgical mortality of pericardiectomy is still high, especially in patients with calcification, in whom it was reported as 19 per cent in a recent series (58). Other poor predictors of outcome are long standing disease, baseline functional class, low voltage ECG complex, significantly increased atrial pressure, associated organ failure and myocardial involvement. MYOCARDIAL TUBERCULOSIS Myocardial TB is very rare (59,60). In patients with diffuse cardiac TB, myocardial involvement occurs but is overshadowed by the diffuse involvement. Nodular myocardial TB can sometimes produce a tumour-like granulomatous mass causing right atrial or right ventricular obstruction. Caseation necrosis of myocardium may cause aneurysm in submitral or left ventricular anterior wall (61). Occasionally, a lymphocytic myocarditis without demonstration of Mycobacterium tuberculosis has been described in patients with TB (59). Coronary arteritis from TB occurs infrequently in patients with TB pericarditis (61). TAKAYASU’S ARTERITIS Takayasu’s arteritis is an inflammatory disease involving aorta and its large branches and pulmonary arteries. The disease occurs more commonly in Asia, Africa, Mexico and South America. The role of Mycobacterium tuberculosis in aetiopathogenesis of Takayasu’s arteritis has been the subject of debate for a long time. As many as one-third of patients with Takayasu’s arteritis have associated past or present TB and a large number of patients have strongly positive Mantoux test. Evidence of mycobacterial involvement has also emerged from recent cytochemical

and serological studies (62). There is no consensus regarding the role of antituberculosis treatment in patients with Takayasu’s arteritis. However, patients with evidence of active tuberculosis should be treated with antituberculosis treatment and corticosteroids. REFERENCES 1. Fowler NO. Tuberculous pericarditis. JAMA 1991;266:99-103. 2. Palmer JA, Watanakunakorn C. Mycobacterium kansasii pericarditis. Thorax 1984;39:876-7. 3. Bashi VV, John S, Ravikumar E, Jairaj PS, Shyamsunder K, Krishnaswamy S. Early and late results of pericardiectomy in 118 cases of constrictive pericarditis. Thorax 1988;43:637-41. 4. Das PB, Gupta RP, Sukumar IP, Cherian G, John S. Pericardiectomy: indications and results. J Thoracic Cardiovasc Surg 1973;66:58-70. 5. Strang JI, Kakaza HH, Gibson DG, Girling DJ, Nunn AJ, Fox W. Controlled trial of prednisolone as adjuvant in treatment of tuberculous constrictive pericarditis in Transkei. Lancet 1987;2:1418-22. 6. Bruch C, Schmermund A, Dagres N, Bartel T, Caspari G, Sack S, et al. Changes in QRS voltage in cardiac tamponade and pericardial effusion: reversibility after pericardiocentesis and after anti-inflammatory drug treatment. J Am Coll Cardiol 2001;38:219-26. 7. Zayas R, Anguita M, Torres F, Gimenez D, Bergillos F, Ruiz M, et al. Incidence of specific etiology and role of methods for specific etiologic diagnosis of primary acute pericarditis. Am J Cardiol 1995;75:378-82. 8. Oliver Navarrete C, Marin Ortuno F, Pineda Rocamora J, Lujan Martinez J, Garcia Fernandez A, Climent Paya VE, et al. Should we try to determine the specific cause of cardiac tamponade? Rev Esp Cardiol 2002;55:493-8. 9. Ling LH, Oh JK, Schaff HV, Danielson GK, Mahoney DW, Seward JB, et al. Constrictive pericarditis in the modern era: evolving clinical spectrum and impact on outcome after pericardiectomy. Circulation 1999;100:1380-6. 10. Oh KY, Shimizu M, Edwards WD, Tazelaar HD, Danielson GK. Surgical pathology of the parietal pericardium: a study of 344 cases [1993-1999]. Cardiovasc Pathol 2001;10:157-68. 11. Mayosi BM, Wiysonge CS, Ntsekhe M, Volmink JA, Gumedze F, Maartens G, et al. Clinical characteristics and initial management of patients with tuberculous pericarditis in the HIV era: the Investigation of the Management of Pericarditis in Africa [IMPI Africa] registry. BMC Infect Dis 2006;6:2. 12. Mcguire J, Kotte JH, Helm RA. Acute pericarditis. Circulation 1954;9:425-42. 13. Harvey AM, Whitehill MR. Tubercular pericarditis. Medicine 1937;16:45-94. 14. Myers TM, Hamburger M. Tubercular pericaditis; its treatment with streptomycin and some observation on the natural history of disease. Am J Med 1952;12:302-10. 15. Desai HN. Tubercular pericarditis. A review of 100 cases. S Afr Med J 1979;55:877-80.

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16. Strang JI, Kakaza HH, Gibson DG, Allen BW, Mitchison DA, Evans DJ, et al. Controlled clinical trial of complete open surgical drainage and of prednisolone in treatment of tuberculous pericardial effusion in Transkei. Lancet 1988;2:759-64. 17. Hakim J, Ternouth I, Mushangi E, Siziya S, Robertson V, Malin A. Double blind randomised placebo controlled trial of adjuvant prednisolone in the treatment of effusive tuberculous pericarditis in HIV seropositive patients. Heart 2000;84:183-8. 18. Fewell JW, Cohen RV, Miller CL. Tubercular pericarditis. In: Cortes FM, editor. The pericardium and its disorders. Springfield: Charles C Thomas;1971.p.140. 19. Suwan PK, Potjalongsilp S. Predictors of constrictive pericarditis after tuberculous pericarditis. Br Heart J 1995;73:1879. 20. Sheffield EA. The pathology of tuberculosis. In: Davis PDO, editor. Clinical tuberculosis. London: Chapman and Hall Medical;1994.p.44-54. 21. Delacroix I, Thomas F, Godart J, Ravaud Y. Purulent tuberculous pericarditis with cardiac tamponade. Am J Med 1992;93:105. 22. Ortbals DW, Avioli LV. Tuberculous pericarditis. Arch Intern Med 1979;139:231-4. 23. Talwar JR, Bhatia ML. Constrictive pericarditis. In: Ahuja MMS, editor. Progress in clinical medicine in India. New Delhi: Arnold-Heinemann; 1981.p.177-89. 24. Hageman JH, D’esopo ND, Glenn WW. Tuberculosis of the pericardium. A long-term analysis of forty-four proved cases. N Engl J Med 1964;270:327-32. 25. Rooney JJ, Crocco JA, Lyons HA. Tuberculous pericarditis. Ann Intern Med 1970;72:73-81. 26. Spodick DH. Acute, clinically noneffusive [“dry”] pericarditis. In: Spodick DH, editor. The pericardium: a comprehensive textbook. New York: Marcel Dekker;1997.p.94-113. 27. Komsuoglu B, Goldeli O, Kulan K, Komsuoglu SS. The diagnostic and prognostic value of adenosine deaminase in tubercular pericarditis. Eur Heart J 1995;16:1126-30. 28. Yang CC, Lee MH, Liu JW, Leu HS. Diagnosis of tuberculous pericarditis and treatment without corticosteroids at a tertiary teaching hospital in Taiwan: a 14-year experience. J Microbiol Immunol Infect 2005;38:47-52. 29. Reuter H, Burgess L, van Vuuren W, Doubell A. Diagnosing tuberculous pericarditis. QJM 2006;99:827-39. 30. Hancock EW. On the elastic and rigid forms of constrictive pericarditis. Am Heart J 1980;100:917-23. 31. Myers RB, Spodick DH. Constrictive pericarditis: Clinical and pathophysiologic characteristics. Am Heart J 1999;138:21932. 32. Mantri RR, Radhakrishnan S, Sinha N, Goel PK, Bajaj R, Bidwai PS. Atrio-ventricular regurgitations in constrictive pericarditis: incidence and post-operative outcome. Int J Cardiol 1993;38:273-9. 33. Permanyer-Miralda G, Sagrista-Sauleda J, Soler-Soler J. Primary acute pericardial disease: a prospective series of 231 consecutive patients. Am J Cardiol 1985;56:623-30.

34. Humphries MJ, Lam WK, Teoh R. Non-respiratory tuberculosis. In: Davis PDO, editor. Clinical Tuberculosis. London: Chapman and Hall Medical;1994.p.111-9. 35. Marshall A, Ring N, Lewis T. Constrictive pericarditis: lessons from the past five years’ experience in the South West Cardiothoracic Centre. Clin Med 2006;6:592-7. 36. Smedema JP, Katjitae I, Reuter H, Burgess L, Louw V, Pretorius M, et al. Twelve-lead electrocardiography in tuberculous pericarditis. Cardiovasc J S Afr 2001;12:31-4. 37. Nelson CT, Taber LH. Diagnosis of tuberculous pericarditis with a fluorochrome stain. Pediatr Infect Dis J 1995;14:10047. 38. Lee JH, Lee CW, Lee SG, Yang HS, Hong MK, Kim JJ, et al. Comparison of polymerase chain reaction with adenosine deaminase activity in pericardial fluid for the diagnosis of tuberculous pericarditis. Am J Med 2002;113:519-21. 39. Zamirian M, Mokhtarian M, Motazedian MH, Monabati A, Reza Rezaian G. Constrictive pericarditis: detection of mycobacterium tuberculosis in paraffin-embedded pericardial tissues by polymerase chain reaction. Clin Biochem 2007;40:355-8. Epub 2007 Jan 13. 40. Aggeli C, Pitsavos C, Brili S, Hasapis D, Frogoudaki A, Stefanadis C, et al. Relevance of adenosine deaminase and lysozyme measurements in the diagnosis of tuberculous pericarditis. Cardiology 2000;94:81-5. 41. Endrys J, Simo M, Shafie MZ, Uthaman B, Kiwan Y, Chugh T, et al. New nonsurgical technique for multiple pericardial biopsies. Cathet Cardiovasc Diagn 1988;15:92-4. 42. Uthaman B, Endrys J, Abushaban L, Khan S, Anim JT. Percutaneous pericardial biopsy: technique, efficacy, safety, and value in the management of pericardial effusion in children and adolescents. Pediatr Cardiol 1997;18:414-8. 43. Feigenbaum H, Armstrong WF, Ryan T. Feigenbaum’s echocardiography. Sixth edition. Philadelphia: Lippincott Williams and Wilkins;2005.p.250. 44. Agrawal S, Radhakrishnan S, Sinha N. Echocardiographic demonstration of resolving intrapericardial mass in tuberculous pericardial effusion. Int J Cardiol 1990;26:240-1. 45. Hutchison SJ, Smalling RG, Albornoz M, Colletti P, Tak T, et al. Comparison of transthoracic and transesophageal echocardiography in clinically overt or suspected pericardial heart disease. Am J Cardiol 1994;74:962-5. 46. Ling LH, Oh JK, Tei C, Click RL, Breen JF, Seward JB, et al. Pericardial thickness measured with transesophageal echocardiography: Feasibility and potential clinical usefulness. J Am Coll Cardiol 1997;29:1317-23. 47. Engel PJ, Fowler NO, Tei CW, Shah PM, Driedger HJ, Shabetai R, et al. M-mode echocardiography in constrictive pericarditis. J Am Coll Cardiol 1985;6:471-4. 48. Voelkel AG, Pietro DA, Folland ED, Fisher ML, Parisi AF. Echocardiographic features of constrictive pericarditis. Circulation 1978;58:871-5. 49. Hatle LK, Appleton CP, Popp RL. Differentiation of constrictive pericarditis from restrictive cardiomyopathy by Doppler echocardiography. Circulation 1989;79:357-70.

Tuberculosis and Heart 341 50. Glockner JF. Imaging of pericardial disease. Magn Reson Imaging Clin N Am 2003;11:149-62. 51. Masui T, Finck S, Higgins CB. Constrictive pericarditis and restrictive cardiomyopathy: evaluation with MR imaging. Radiology 1992;182:369-73. 52. Vaitkus PT, Kussmaul WG. Constrictive pericarditis versus restrictive cardiomyopathy: a reappraisal and update of diagnostic criteria. Am Heart J 1991;122:1431-41. 53. Hurrell DG, Nishimura RA, Higano ST, Appleton CP, Danielson GK, Holmes DR Jr, et al. Value of dynamic respiratory changes in left and right ventricular pressures for the diagnosis of constrictive pericarditis. Circulation 1996; 93:2007-13. 54. Strang JI, Nunn AJ, Johnson DA, Casbard A, Gibson DG, Girling DJ. Management of tuberculous constrictive pericarditis and tuberculous pericardial effusion in Transkei: results at 10 years follow-up. QJM 2004;97:525-35. 55. Ntsekhe M, Wiysonge C, Volmink JA, Commerford PJ, Mayosi BM. Adjuvant corticosteroids for tuberculous pericarditis: promising, but not proven. QJM 2003;96:593-9.

56. Reuter H, Burgess LJ, Louw VJ, Doubell AF. The management of tuberculous pericardial effusion: experience in 233 consecutive patients. Cardiovasc J S Afr 2007;18:20-5. 57. Gibson DG. Pericardial disease. In: Weatherall DJ, Ledingham JGG, Warell DA, editors. Oxford textbook of medicine. Oxford: Oxford University Press; 1989. p.13.304-12. 58. Ling LH, Oh JK, Breen JF, Schaff HV, Danielson GK, Mahoney DW, et al. Calcific constrictive pericarditis: is it still with us? Ann Intern Med 2000;132:444-50. 59. Rose AG. Cardiac tuberculosis. A study of 19 patients. Arch Pathol Lab Med 1987;111:422-6. 60. Kinare SG. Interesting facets of cardiovascular tuberculosis. Indian J Surg 1975;37:145-51. 61. Daxini BV, Mandke JV, Sharma S. Echocardiographic recognition of tubercular submitral left ventricular aneurysm extending into left atrium. Am Heart J 1990;119:970-2. 62. Kothari SS. Aetiopathogenesis of Takayasu’s arteritis and BCG vaccination: the missing link? Med Hypotheses 1995;45:227-30.

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Skeletal Tuberculosis

23 S Bhan, HL Nag

INTRODUCTION Existence of “tuberculosis-like” disease has been known since time immemorial. Evidence of osteoarticular tuberculosis [TB] has been found in pre-historic humans (1). In immunocompetent individuals, the osteoarticular involvement occurs in 10 per cent of patients with extrapulmonary TB (2). Commonly, TB affects the spine and the hip joint; other sites of involvement include knee joint, foot bones, elbow joint and hand bones; rarely, it also affects the shoulder joint (3-5). SKELETAL TUBERCULOSIS Skeletal TB occurs due to haematogenous spread and affects almost all bones. The disease process can start either in the bone or in the synovial membrane. Thereafter, it spreads to other structures in a short time. Typically, an active focus forms in the metaphysis [in children] or epiphysis [in adults] and the inflammation extends peripherally along the shaft to reach the subperiosteal space. The inflammatory exudate may extend outwards through the soft tissues to form cold abscess and sinuses. Frequently, secondary infection occurs through the sinus tract. The epiphyseal plate is not destroyed as the cartilage is resistant to destruction by the TB inflammatory process. The granulation tissue can, however, invade the area of calcified cartilage and interfere with longitudinal growth. Metaphyseal infection reaches the joint through subperiosteal space by penetrating the capsular attachment. In adults, the inflammation can spread up to the subchondral area and enter the joint at the periphery where synovium joins the cartilage. Destruction of the subchondral bone loosens

the attachments of the articular cartilage which may become displaced in the joint. Sometimes the synovium may be infected first and the bone becomes infected secondarily. Usually, there is a low-grade synovial infection with moderate increase in joint fluid and formation of tubercles and fibrin deposits. Caseation necrosis of the synovium and the joint capsule is rare. When a destructive caseating lesion of the bone penetrates into the joint, the synovium too gets affected. Two classical forms of the disease have been described: granular and exudative [caseous] that involve the bone and synovium. Though both the patterns have been observed in patients with skeletal TB, one form may predominate. Types Osseous Granular Type In the osseous granular type, the bone involvement occurs at metaphysis or epiphysis often following trauma. The onset is insidious. Hydrarthrosis of the adjacent joint is non-specific and appears following exertion. Constitutional symptoms are rare. Overlying soft tissues are slightly warm and tender. Muscle atrophy appears rapidly. Osseous Exudative [Caseating] Type Onset of the osseous exudative [caseating] type is more rapid. Constitutional symptoms, muscle pain and spasm are more marked. The overlying soft tissues are warm, swollen, indurated and tender. When the caseous material penetrates into the joint, a severe destructive arthritis ensues.

Skeletal Tuberculosis 343 Synovial Granular Type The synovial granular type is characterized by intermittent joint effusion with little or no pain. Later, joint effusion occurs more frequently and becomes persistent. Constitutional symptoms are mild and muscle atrophy gradually sets in. This form of synovitis can continue for a long time without involving the bone. Rarely, the synovial granular form may get converted into caseous form and the patient may experience increase in the local and constitutional symptoms. Synovial Exudative [Caseous] Type The synovial exudative [caseous] type has an acute onset with marked local and constitutional symptoms. Overlying soft tissues are very tender. The joint movements are painful and regional lymph nodes are enlarged. Abscess and sinus formation is common. Prognosis The availability of modern antituberculosis drugs has changed the outlook of patients with bone and joint TB. In the granular form of disease, healing is possible without residual joint scarring and ankylosis. Effective antituberculosis treatment combined with resection of large caseous destructive foci ensures early healing and prevents the spread of infection into joint and soft tissues. In recent years, the occurrence of multidrug-resistant tuberculosis has, however, become a matter of concern. SPINAL TUBERCULOSIS Spinal TB is the most common form of skeletal involvement. Pathology of Spinal Tuberculosis Infection of Bone Lower thoracic and lumbar vertebrae are the most common sites for spinal TB followed by middle thoracic and cervical vertebrae. Usually, two contiguous vertebrae are involved, but several vertebrae can be affected and skip lesions may also be seen. The infection begins in the cancellous area of vertebral body, commonly in epiphyseal location and less commonly in the central or anterior area of vertebral body. Tuberculosis infection produces an exudative reaction with marked hyperaemia. The

infection spreads and destroys the epiphyseal cortex, the intervertebral disc and the adjacent vertebrae. It may spread beneath the anterior longitudinal ligament to reach neighbouring vertebrae. The vertebral body becomes soft and gets easily compressed to produce either wedging or total collapse. Anterior wedging is commonly seen in the thoracic spine where the normal kyphotic curve accentuates the pressure on the anterior part of vertebrae. In the cervical and lumbar spine, the centre of gravity is posteriorly located due to lordotic curve and, therefore, wedging is minimal. A single large caseating lesion of the vertebral body is rare. This type of lesion remains isolated and calcifies centrally, appearing as a sequestrum. In this form, mechanical strength of vertebral body is reduced to lesser extent and deformity may not occur. Adjacent intervertebral disc is affected gradually. Tuberculosis infection starting in the posterior bony arch and transverse processes is uncommon. With healing, the exudate is resorbed, osteoporosis decreases and density of body gradually increases to normal. When the intervertebral discs have been completely destroyed, the adjacent bodies fuse with each other. Formation of Cold Abscess Vertebral TB develops as an exudative lesion due to hypersensitivity reaction to Mycobacterium tuberculosis. The exudate consists of serum, leucocytes, caseous material, bone fragments and tubercle bacilli. It penetrates ligaments and follows the path of least resistance along fascial planes, blood vessels and nerves, to distant sites from the original bony lesion and forms a swelling commonly called as “cold abscess”. In the cervical region, the exudate collects behind prevertebral fascia and may protrude forward as a retropharyngeal abscess. The abscess may track down in mediastinum to enter into the trachea, oesophagus or the pleural cavity. It may spread laterally into the sternomastoid muscle and form an abscess in the neck. In the thoracic spine, the exudate may remain confined locally for a long time and may appear in the radiographs as a fusiform or bulbous paravertebral abscess. Tension may force the exudate to enter into the spinal canal and compress the spinal cord. Rarely, a thoracic cold abscess may follow the intercostal nerve to appear anywhere along the course of nerve. It can also penetrate the anterior longitudinal ligament to form a

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mediastinal abscess or pass downwards through medial arcuate ligament to form a lumbar abscess. The exudate formed at lumbar vertebrae most commonly enters the psoas sheath to manifest radiologically as a psoas abscess or clinically as a palpable abscess in the iliac fossa. Abscess can gravitate beneath the inguinal ligament to appear on the medial aspect of thigh. It can spread laterally beneath the iliac fascia to emerge at the iliac crest near the anterior superior iliac spine. Sometimes an abscess forms above the iliac crest posteriorly. Collection can follow the vessels to form an abscess in Scarpa’s triangle or gluteal region, if it follows femoral or gluteal vessels respectively. Paraplegia While neurological complications of spinal TB are rarely encountered in developed countries, their incidence remains quite high in the developing world. Paraplegia is the most serious complication of spinal TB and its occurrence is reported to be as high as 30 per cent in patients with spinal TB (6,7). Neurological involvement is common when the dorsal spine is involved because: [i] diameter and space of the spinal canal are smallest in the dorsal region; [ii] the abscess remains confined under tension and is thereby forced into the spinal canal; [iii] tuberculosis infection is common in this area; and [iv] the spinal cord terminates below the first lumbar vertebra. Paraplegia due to spinal TB has been known for a very long time. It is also known as Pott’s paraplegia. It can be of early or late onset (8-11). Early onset paraplegia develops during the active phase of infection. Paraplegia of late onset can appear many years after the disease has become quiescent even without any evidence of reactivation. Most commonly paraplegia develops due to mechanical pressure on the cord, but in a small number of patients, it may occur due to non-mechanical causes as well. The mechanisms underlying the development of Pott’s paraplegia are listed in Table 23.1. Frequently, more than one of these mechanisms may be operative in a given patient. The fact that paraplegia can sometimes recover even after many years suggests that the inflammatory exudate and the resultant oedema may temporarily inhibit the nerve cell function (12). In most cases, early onset paraplegia results from cord compression due to multiple causes and these include inflammatory oedema, caseous

Table 23.1: Mechanisms underlying the development of Pott’s paraplegia Extrinsic or mechanical causes During active disease Cold abscess [fluid or caseous material] Granulation tissue Sequestrated bone and disc fragments Pathological subluxation or dislocation of vertebra Following healing of lesions Pressure of ridge of bone anterior to cord Fibrosis of dura matter Gliosis of cord Intrinstic or non-mechanical causes Spread of tuberculosis inflammation through the dura to meninges and eventually to the spinal cord Rare causes Spinal tumour syndrome Thrombosis of anterior spinal artery Adapted from reference 11

material, pus and the granulation tissue. Recovery in these cases is favourable. Late onset paraplegia occurs due to long-standing persistent mechanical causes. These include internal gibbus, severe kyphotic deformity, dural fibrosis and stenosis of spinal canal. Prognosis in these cases is much less favourable (13). Clinical Features Spinal TB, once a disease of children and adolescents, is now often seen in the adults. Majority of the patients are under 30 years of age at the time of diagnosis. Constitutional symptoms, such as weakness, loss of appetite and weight, evening rise of temperature and night sweats, generally occur before the symptoms related to the spine manifest. Vertebral Disease A young child may be disinclined to play and may not complain of anything else. Localized pain over the site of involvement is the most common early symptom and the pain may worsen with activity or unguarded movements. Pain may be referred along the spinal nerves to be misdiagnosed as neuralgia, sciatica or intraabdominal pathology. As the infection progresses, pain increases and paraspinal muscle spasm occurs. Relaxation of muscles during sleep permits painful movements which may cause the child to cry during night [night cries].

Skeletal Tuberculosis 345 Patient walks carefully to avoid sudden jerks which can exacerbate the pain. With the involvement of cervical spine, head may be held with hands. Muscle spasm obliterates normal spinal curves and all spinal movements become restricted and painful. Careful palpation, percussion or pressure will reveal tenderness over the affected vertebrae. Sometimes a boggy, dusky thickening of skin may be seen over the affected area. In patients presenting late, when vertebral wedging and collapse have occurred, a localized knuckle kyphosis becomes quite obvious especially in the dorsal spine. Occasionally, patients with dorsal spine involvement present very late with an extensive destruction of multiple vertebrae. These patients have deformity of thoracic cage with a large gibbus. Cold Abscess Local pressure effects, such as dysphagia, dyspnoea, or hoarseness of voice may occur due to a retropharyngeal abscess. Further, dysphagia may also occur due to a mediastinal abscess. Flexion deformity of the hip develops due to a psoas abscess. The abscesses may be visible and palpable if they are superficially located. Therefore, in addition to the physical examination of the bony lesion, a careful search for the presence of cold abscess in the neck, chest wall, groin, inguinal areas and thighs can be rewarding. Paraplegia Rarely, paraplegia may be the presenting symptom. But, in a majority of cases, the diagnosis of TB of the spine is already established when paraplegia develops. Spontaneous twitching of muscles in lower limbs and clumsiness in walking due to muscle weakness and spasticity are the earliest signs of neurological involvement. With passage of time, paralysis progresses through various stages. These include muscle weakness, spasticity, incoordination, difficulty in walking and paraplegia in extension. Subsequently, paraplegia in flexion, sensory loss and loss of sphincteric control occur. Exaggerated deep tendon reflexes, clonus, and extensor plantar reflex can be elicited. Anteriorly located motor tracts in the spinal cord are in close proximity to the disease process and are sensitive to pressure effect. Therefore, the motor functions are affected first due to the cord compression. Increasing compression of cord produces uncontrolled flexor spasms. In later stages, limbs remain in flexion

[paraplegia in flexion] with complete loss of conduction in pyramidal and extrapyramidal tracts. The sense of position and vibration is the last to disappear. In severe cases, spasticity disappears and flaccid paralysis, sensory loss and loss of sphincter control [areflexic paraplegia] can develop. Rarely, the cord compression may be so sudden and complete that the patient presents with sudden onset of flaccid paralysis simulating the picture of spinal shock. This may occur due to rapid accumulation of TB pus and caseation, pathological dislocation of vertebra and ischaemia of cord due to thromboembolic phenomenon. Rarely, presenting features may simulate the features of spinal tumour syndrome. These features occur due to localized tuberculoma, granuloma or peridural fibrosis producing partial or complete block without any pathology being visible on radiographs. Such cases should be differentiated from lathyrism in endemic areas since lathyrism also presents as pure motor paraplegia of insidious onset. However, patients with lathyrism will not reveal block to cerebrospinal fluid flow on lumbar puncture, myelography and magnetic resonance imaging [MRI]. Clinically, the severity of paraplegia has been classified into four grades (14-16). Grade I Negligible paraplegia The patient is unaware of the neurological deficit but examination reveals clonus and extensor plantar response. Grade II Mild paraplegia The patient is aware of weakness and difficulty in walking but manages to walk with or without support. Grade III Moderate paraplegia The patient is bedridden and cannot walk due to severe weakness. Examination reveals paraplegia in extension and sensory deficit in less than 50 per cent. Grade IV Severe paraplegia Features of grade III with flexor spasm or paralysis in flexion or flaccid paralysis and sensory deficit of more than 50 per cent. The higher the grade of paralysis, more severe is the compression of cord and poorer is the prognosis for recovery of neurological deficit. Radiological Features On an average, involvement of 2.5 to 3.8 vertebrae has been described (17-19). There are mainly four sites of

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infection in the vertebra: paradiscal, central, anterior and appendicial. The most common site of vertebral involvement is paradiscal. The appendicial type includes the involvement of pedicle, lamina, spinous process and transverse process. Nearly seven per cent of patients may show skipped lesions (17-19). Some of the vertebral bodies may become eroded not necessarily due to the disease process per se, but due to the pressure effect of the paravertebral cold abscess. Radiologically, paradiscal infection first appears as demineralization with indistinct bony margins adjoining the disc [Figure 23.1]. Gradually, the disc space narrows signifying either atrophy of disc tissue due to lack of nutrition, or, prolapse of nucleus into the soft necrotic vertebral body. The disc space may eventually disappear and vertebral bodies reveal an enlarging area of destruction and wedging. Rarely, disc space may remain intact for a long time. It takes about three to five months for the bony destruction to become visible on a radiograph. More than 30 per cent of mineral must be removed from the bone for a radiolucent lesion to be discernable on the plain radiograph. Computed tomography [CT] and MRI allow identification of bony lesions including prevertebral and paravertebral abscess shadows at an early stage [Figures 23.2, 23.3, and 23.4]. Abscess in the cervical region presents as a soft tissue shadow between the vertebral bodies, pharynx and trachea. Early detection of an abscess in the area of seventh cervical to fourth dorsal vertebrae requires a good quality radiograph. Abscess in the dorsal spine area produces a typical fusiform shape [bird-nest appearance] and a large abscess in this region may appear as

Figure 23.1: Plain radiograph of the lumbosacral spine [lateral view] showing early changes of paradiscal involvement of L2 and L3 vertebrae, indistinct bony margins of adjacent vertebrae along with loss of disc space [arrow]

mediastinal widening. An abscess arising below the attachment of diaphragm forms a psoas abscess and in a good quality radiograph appears as a bulge of the lateral border of the psoas muscle shadow. A long-standing, tense paravertebral abscess [usually in the dorsal spine] may produce concave erosions along the margin of vertebral bodies [aneurysmal phenomenon]. Canal compromise and cord status are best demonstrated by CT or MRI [Figures 23.5 and 23.6]. Central type lesion starts in the centre of the vertebral body. Infection at this site probably reaches through Batson’s venous plexus or through branches of posterior vertebral artery. A lytic area develops in the centre of

Figure 23.2: Chest radiograph [postero-anterior view] showing left sided empyema [arrow]. CECT of the chest [sagittal reconstruction] [B] and [C] showing destruction of vertebral body [black arrow], paraspinal cold abscess [white arrow] and left sided empyema [asterisk]

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Figure 23.3: Plain radiograph of the dorsolumbar spine [anteroposterior view] [A] showing the involvement of D10 and D11 vertebrae, narrowing of intervening disc and paravertebral abscess [arrows]. CT of the dorsal spine [B] showing bilateral psoas abscesses [arrows]

Figure 23.4: CECT of the lower abdomen showing hypodense collections [asterisks] in bilateral psoas muscles [bigger on the left side] in a patient with disseminated tuberculosis. The adjacent vertebral body appears normal

the vertebral body and may gradually enlarge resulting in the ballooning out of the vertebral body mimicking a tumour. In the later stages of advanced destruction, a concentric collapse occurs almost resembling vertebra plana. In this type of lesion, the disc space is either not affected or affected minimally and paravertebral shadow is also usually not well-marked. Therefore, this type of lesion should be differentiated from a tumour or Calve’s disease. Anterior type lesion occurs when the infection starts in front or on sides of the vertebral body beneath the anterior longitudinal ligament and periosteum. Radio-

Figure 23.5: CT [transverse section through the body of C7 vertebra] showing its destruction and anterior compromise of canal by bony fragments [arrow]

logically, it is seen as a shallow excavation on anterior or lateral surface of vertebral body. Similar excavations will also appear due to the aneurysmal phenomenon in patients with paradiscal type of lesion and a longstanding, tense, paravertebral abscess. Tuberculosis of the posterior elements of vertebra is not detected in its early stage in the plain radiographs. In the late stage of disease, the erosive bony lesions of posterior elements can be seen in the radiographs. However, CT or MRI is invaluable in detecting these lesions at an early stage. Paravertebral abscess shadow may be present but the disc space remains intact. Sometimes more than one lesion may be present in vertebral column with one or more healthy vertebrae intervening between the diseased vertebrae [called skip lesions]. In late stages, anterior wedging or vertebral collapse results in the development of kyphotic deformity. Sometimes this deformity can be very severe. Destruction of vertebral body on one side can produce lateral deviation and rotation similar to that seen in patients with hemivertebra, especially when the disease affects the lower dorsal and lumbar spine [Figure 23.7]. On very rare occasions, a vertebral body may dislocate anteriorly due to destruction of the pedicles. The severity of a gibbus can be predicted with 90 per cent accuracy using the following formula (20) y = a + bx where: y = final angle of gibbus a = constant with a value of 5.5 b = constant with a value of 30.5 x = amount of initial loss of height of vertebral body

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Figure 23.6: MRI of the dorsolumbar spine. Sagittal view showing profound destruction of D10 and D11 vertebrae with anterior compression of the cord [A] [arrow]. Sagittal spin-echo T1 weighted image showing hypointense L1 and L2 vertebral bodies, intervening disc and an epidural soft tissue component at L1 level [B][arrow]. The bodies of L1 and L2 vertebrae and epidural soft tissues are brightly enhanced in T2-weighted image [C] [arrow]

Amount of initial loss of height of vertebral body is calculated as follows. Height of vertebral body on lateral radiograph is divided into 10 equal parts. Loss of height of all contiguous affected vertebrae is then added together to get the value of ‘x’. Differential Diagnosis

Figure 23.7: Plain radiograph of the lumbosacral spine [anteroposterior view] showing mild scoliotic chage due to the relative destruction of one side of vertebra involving L2 and L3 levels [arrows]

Usually, clinical presentation and radiological findings of spinal TB are characteristic. However, in doubtful cases, clinical examination and radiological investigations including CT or MRI will help in making an accurate diagnosis. In a very small percentage of cases, biopsy of the diseased vertebra for histopathological and microbiological examinations may be required to confirm the diagnosis. However, some conditions [Table 23.2] may mimic TB of the spine and these conditions need to be differentiated from spinal TB, especially in patients with atypical clinical presentation.

Skeletal Tuberculosis 349 Table 23.2: Conditions resembling spinal tuberculosis Developmental defects like hemivertebra, Calve’s disease, Schmorl’s nodes and Scheuermann’s disease Infections like pyogenic osteomyelitis, enteric fever, brucellosis, mycotic infections and syphilis Benign neoplasms like haemangioma, aneurysmal bone cyst, giant cell tumour Primary malignant tumours like Ewing’s tumour, chordoma, osteosarcoma, fibrosarcoma, chondrosarcoma, multiple myeloma and lymphoma Secondary neoplastic deposits Langerhan’s cell histiocytosis Paget’s disease Traumatic fracture Hydatid disease

Management Antituberculosis Treatment Antituberculosis drug treatment for skeletal TB is essentially the same as for TB elsewhere in the body. However, there is a difference of opinion regarding the duration of drug therapy. Though many orthpaedicians favour 18 to 24 months of antituberculosis drug treatment (21,22), short-course chemotherapy for nine months has also been shown to be equally effective in patients with disease caused by drug-susceptible microorganisms in whom the diagnosis has been established early (23). The DOTS should be administered as it takes care of compliance and cost and is associated with lesser adverse events. Community DOT providers facilitate administration of drugs in non-ambulatory patients. The reader is referred to the chapters “Treatment of tuberculosis” [Chapter 52] and “Revised National Tuberculosis Control Programme” [Chapter 63] for more details. Antibiotics Persistently draining sinuses are often secondarily infected and, therefore, appropriate antibiotic[s] should be administered along with antituberculosis drugs after culture and sensitivity testing. Surgery Efficacy of antituberculosis treatment has significantly reduced the need for operative intervention. Indications for adjunct surgery in patients with spinal TB lesions per se [regardless of paraplegia] are listed in Table 23.3. Common operative procedures include anterolateral decompression with interbody bone grafting or costo-

Table 23.3: Indications for surgery in patients with spinal tuberculosis regardless of paraplegia Doubtful diagnosis where open biopsy is necessary Failure to respond to antituberculosis drugs Radiological evidence of progression of bony lesion and/or paraspinal abscess shadow Imminent vertebral collapse Prevention of severe kyphosis Instability of spine and subluxation or dislocation of vertebral body

transversectomy with decompression. If a large gap is left behind after debridement, adequate bone grafting must always be done. Anteriorly placed grafts provide good stability and heal well. An additional use of metallic implants and titanium cage filled with cancellous bone grafts may be required when nearly whole of the vertebral body has been removed during debridement. Surgical prevention of severe kyphotic deformity requires extensive panvertebral operative procedures. These consist of anterior debridement, anterior interbody fusion and posterior fusion of the affected vertebrae (15,24). It has also been suggested that, a severe deformity in the presence of active disease should be an absolute indication for debridement, correction and stabilization since late correction of TB kyphosis is difficult and dangerous. Correction of a fixed spinal curve and severe kyphosis is a formidable surgical undertaking and should only be done in selected patients by a specially trained surgeon (25). Formerly, posterior spinal fusion by the methods of Hibbs [fusion between laminae, articular facets and spinous processes] and Albee [fusion between spinous processes with tibial cortical graft] were frequently used. Fusion was successful because posterior elements were seldom involved in disease process. However, by these interventions, progression of lesion in body was not affected. Posterior spinal fusion is now rarely used except to reinforce an anterior spinal fusion in regions of greatest stress at junctional areas like cervicothoracic and dorsolumbar junctions; and for panvertebral fusion in children who are at risk of developing severe kyphosis. Cold Abscess With antituberculosis treatment, a small cold abscess will heal along with the bony lesion. Tense and large cold abscesses are usually located in the neck, chest wall, iliac fossa, lumbar triangle, inguinal region and thigh. These abscesses are frequently painful and tend to burst and

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form sinuses. Therefore, these abscesses must be drained as early as possible by the standard surgical approach which depends on the location of the abscess. Most surgeons do not use a drain after evacuation of abscess for fear of sinus formation. Paravertebral abscess need not be drained on its own but should be evacuated at the time of debridement of bony lesion when indicated. Paraplegia Three schools of thought exist in the treatment of Pott’s paraplegia. One of the views is that immediate operative decompression of the cord by extensive anterior debridement results in maximum improvement in the shortest possible time (26). According to these workers, operation should be performed at an earliest because they feel that the TB infection can penetrate into the dura matter and infect the cord making recovery impossible. This view recommends early radical anterior debridement, decompression and arthrodesis in all patients with Pott’s paraplegia, except in patients with spinal tumour syndrome and those with paraplegia resulting from posterior spinal disease. The second view favours initial treatment with immobilization or complete bed rest. If this does not produce improvement and recovery within a specified time period then the surgical decompression of the spinal cord is performed (9,10,27-29). The widely accepted indications for surgical treatment are listed in Table 23.4. The third view proposes the “middle path regimen”(6) and advocates rest and antituberculosis treatment for four weeks and surgical decompression if there is no improvement in the neurological deficit by this time. This regimen is useful for developing countries with limited resources. Treatment of paraplegia in severe kyphosis is by excising internal gibbus through anterolateral approach or by anterior transposition of cord through laminectomy. Anterolateral decompression is a surgery of lesser magnitude compared to anterior decompression and is preferred in resource limited settings. Details of surgical techniques are beyond the scope of this chapter. However, it must be pointed out that obtaining adequate surgical exposure of junctional areas of spine is difficult and this type of surgery must be undertaken only by experienced and well-trained surgeons. Laminectomy and intraspinal exposure must be deferred if the neurological deficit is non-progressive or

Table 23.4: Indications for surgical treatment in patients with spinal tuberculosis and paraplegia Absolute indications Onset of paraplegia during conservative treatment Surgery is not performed for pyramidal tract signs but delayed till motor weakness is evident Paraplegia getting worse or remaining stationary despite adequate conservative treatment Persistence or complete loss of motor power for one month despite sufficient conservative treatment Paraplegia accompanied by uncontrolled spasticity of such severity that reasonable rest and immobilization are impossible or there is a risk of pressure necrosis of skin Severe paraplegia of rapid onset. This usually indicates severe mechanical pressure but may also be due to vascular thrombosis. Surgery is not helpful when thrombosis causes paraplegia Severe paraplegia, paraplegia in flexion, flaccid paraplegia, complete sensory loss or complete loss of motor power for more than six months. All these are indications for immediate surgery without trial of conservative treatment Relative indications Recurrent paraplegia even with paraplegia that would cause no concern in the first attack Paraplegia with onset in old age to avoid hazards of immobilization Painful paraplegia. Pain may be due to spasm or root compression Complications such as urinary tract infection and stones Rare indications Posterior spinal disease Spinal tumour syndrome Severe paralysis from cervical disease Severe cauda equina paralysis Adapted from references 28 and 29

if the radiographs are normal. Following decompression with or without bone grafting, bed rest for a period of 10 to 12 weeks is indicated. Thereafter, the patient is gradually mobilized with a suitable brace. Reactivation or reinfection may result in a relapse in a small percentage of cases and may be complicated by neurological involvement. In such situations, early operation and administration of appropriate antituberculosis drugs are indicated. TUBERCULOSIS OF HIP JOINT Tuberculosis of the hip joint occurs in about 15 per cent of all cases of osteoarticular TB and is the next common form after spinal TB.

Skeletal Tuberculosis 351 Pathology Tuberculosis of the hip joint almost always starts in bone and the initial focus is in the acetabular roof [Figures 23.8 and 23.9], femoral epiphysis, proximal femoral metaphysis or greater trochanter. Rarely, the initial focus may be in the synovial membrane and the disease may remain as synovitis for a few months. In these patients, the diagnosis may be considerably delayed. Tuberculosis of the greater trochanter may involve the overlying trochanteric bursa. Since the head and neck of femur are intracapsular, a bony lesion here invades the joint early and later spreads to involve the acetabulum as well. When the disease starts in the acetabulum, symptoms related to joint involvement appear late [Figure 23.10]. Extensive destruction may result in pathological dislocation of the hip joint. A cold abscess forms in the joint, may perforate the capsule and extend anywhere around the hip joint. It may perforate the thinned acetabular floor to form an intrapelvic abscess. Clinical Features Tuberculosis of the hip frequently affects the children. Constitutional symptoms may precede the joint symptoms. Pain around the hip joint or along the thigh or inner aspect of the knee joint. Particularly on weight bearing, is usually the first symptom. The patient limps while walking and avoids weight bearing on the affected side. During the acute stage, muscle spasm is severe. At night, relaxation of muscle spasm and unguarded movements produce night cries. All movements of the hip joint are painful and limited to a variable degree. As the acute

Figure 23.8: Plain radiograph of the hip joint showing lesions [arrows] at the acetabulum in a six-year-old boy at the beginning of treatment

stage subsides, pain and muscle spasm become less severe and muscle atrophy develops. Classical untreated TB of the hip joint passes through following three clinicopathological stages and each stage has a definite pattern of clinical deformity. Stage of Synovitis [Stage I] This stage is the earliest manifestation of disease. Intrasynovial effusion and exudate distend the joint capsule. The hip joint assumes a position of flexion, abduction and external rotation. During this stage, capacity of the hip joint is maximum. Limb appears lengthened but there is no real lengthening. This is the stage when the disease

Figure 23.9: Plain radiograph of the hip joint showing early tuberculosis lesion at the acetabulum [circle] in a 34-year-old man which was missed initially [panel A]. Same lesion, three months later [rectangle] when treatment was started [B]

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Tuberculosis is seldom diagnosed since similar physical findings are seen in traumatic synovitis, non-specific transient synovitis, rheumatic disease, low-grade pyogenic infection, Perthes’ disease and spasm of iliopsoas muscle due to an abscess in its sheath or nearby inflammed lymph nodes. In such situations, clinical and radiological examinations must be repeated at two to three weeks intervals till a definitive diagnosis has been made. Stage of Early Arthritis [Stage II] As the capsule thickens by fibrosis and contracts, and damage to the articular surface progresses, the hip joint assumes a position of flexion, adduction and internal rotation. Limb appears short but true shortening may not be present and if present is not more than one centimetre. All movements of the hip joint remain painful and limited. Stage of Advanced Arthritis [Stage III] The capsule becomes further destroyed, thickened and contracted along with advanced bony destruction producing true shortening of the limb. The joint movements become more restricted and the flexion, adduction, internal rotation deformity may become severe. With further destruction of the acetabulum, femoral head, capsule and ligaments, the joint dislocates with the destroyed head coming to lie proximally and posteriorly in wandering or migrating acetabulum. Instead of proximal migration sometimes protrusio acetabuli can develop with destruction of medial wall of acetabulum. Radiological Features

Figure 23.10: Plain radiograph of the hip joint of the patient shown in Figure 23.9 showing increase in the size of the lesion [square] despite five months of treatment [A]. Destruction of acetabulum and granulation tissues [arrows] are seen better in transverse section in MRI [B]. Biopsy confirmed the diagnosis of tuberculosis. Radiograph at 13 months of treatment showing regression of lesion with extension into the hip joint [square] limiting the movements [C]

In the earliest stage, radiographs may reveal diffuse decalcification of upper end of femur. Osteolytic bony focus of infection may be visible in the acetabulum or femur a little later and this lesion may be seen to be enlarging on sequential radiographs. Soft tissue swelling may be evident on the radiograph, but ultrasonography is useful at this stage to confirm soft tissue swelling. Late stages of the disease will reveal increasing destruction of acetabulum, wandering acetabulum, small atrophic femoral head, subluxation or dislocation of the femoral head. Seven different types of radiological appearances have been described in advanced stage of TB arthritis of hip joint (30) and are described below [Figure 23.11].

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Figure 23.11: Different radiological types of the hip joint tuberculosis

Normal Type The disease is mainly synovial. There may be cysts in the femoral neck, head or acetabulum, but there is no gross destruction of subchondral bone and the joint space is normal. Perthes’ Type Most patients are under five years of age. The whole femoral head is sclerotic and differentiation from Perthes’ disease can be difficult though metaphyseal changes seen in the classical Perthes’ disease are not seen. Dislocating Type Subluxation or dislocation of the femoral head occurs. This is mainly due to capsular laxity and synovial hypertrophy and not due to accumulation of pus. Results are better after open relocation of the hip joint. Wandering Acetabulum, Protrusio Acetabuli, Mortar and Pestle Type These appearances occur due to the erosion of subchondral bone [Figure 23.12]. Results of surgery are generally poor in these types of TB of the hip joint.

Figure 23.12: Plain radiograph of the hip joint showing the “protrusio acetabuli” type of hip involvement

Atrophic Type The femoral head is irregular and the joint space is narrow. It is seen almost exclusively in adults and the results of treatment are poor and the condition almost always progresses to fibrous ankylosis [Figure 23.13]. These radiological appearences in general also correspond to the duration of the disease before diagno-

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Figure 23.13: Plain radiograph of the hip joint [antero-posterior view] showing marked atrophy of head and neck of femur [A]. Radiograph of the hip joint [lateral view] of the same patient showing extensive involvement of upper shaft of the femur [B]

Figure 23.14: Plain radiograph of the hip joint [antero-posterior view] showing good healing of the lesion involving superior portion of acetabulum following antituberculosis treatment

sis. In the normal, Perthes’, dislocating and atrophic types, the mean duration of symptoms varies from four to seven months. In wandering acetabulum, protrusio acetabuli and mortar and pestle types, the mean duration of symptoms is usually longer, ranging from 10 to 14 months. Management In patients with TB of the hip joint, the prognosis depends on the stage of disease when treatment is initiated. Antituberculosis drug therapy started at stages I and II of the disease may allow an almost or near normal hip joint at the end [Figures 23.14 and 23.15]. The deformities should also be corrected as early as possible, or else fibrous ankylosis in the position of deformity will occur. Neglected cases will eventually have a markedly deformed hip joint and a short limb. The shortening is partly due to gross bony destruction and partly due to growth arrest at proximal femoral epiphysis. Occasionally, if the limb has been immobilized for more than one year, premature fusion of distal femoral epiphyseal plate can result in shortening. Antituberculosis drugs should be administered in adequate dosages for a sufficient length of time along with supportive measures to improve the general health. Skin traction is usually required initially in all cases. Traction corrects deformity, relieves muscle spasm and

Figure 23.15: Plain radiograph the hip joint [antero-posterior view] of the patient shown in Figure 23.8, showing healed lesion [square] at completion of treatment. The patient recovered with a good function of the hip joint

pain. It also maintains joint space, minimizes chances of development of wandering acetabulum and prevents dislocation. In the presence of abduction deformity, traction should be applied to both limbs to stabilize the pelvis. Otherwise, traction to the deformed limb alone would further increase the abduction deformity. In stage I and II, a prolonged period of traction [up to 12-weeks] may be required. Traction should be continued till disease activity is well-controlled, hip movements improve and become pain free and muscle spasm does not recur.

Skeletal Tuberculosis 355 Gentle hip mobilization and sitting in bed for short periods are started during the period of traction. For the next 12 weeks, non-weight bearing walking is allowed with crutches followed by another 12 weeks period of partial weight bearing. Unprotected weight bearing should not be permitted early since chances of collapse and deformity of the acetabulum and femoral head may persist till bones have become fully calcified after control of infection. Drainage of the cold abscess should be done without undue delay to prevent sinus formation. In patients with stage II disease, partial synovectomy and curettage of large or enlarging osteolytic lesions in the acetabulum [Figure 23.10] and femoral head should be done. At operation, the hip joint should not be dislocated in order to remove all TB tissue. After curettage, large lesions may be filled with cancellous grafts. Curettage of extra-articular lesions prevents spread of infection in the joint if done early enough. Postoperatively, the regimen of traction, non-weight bearing mobilization, partial weight bearing and then unprotected weight bearing are followed as described above. In patients presenting with advanced arthritis, or stage III disease, the aim is to achieve fibrous ankylosis in a functional position. Traction is applied first and if indicated, limited operative procedure of partial synovectomy and curettage of extra-articular lesions and joint debridement are done. Once the deformities are corrected and operative wound has healed well, a plaster spica is applied. Immobilisation in the plaster is continued for six to nine months followed by partial weight bearing for another six months. Unprotected weight bearing is usually possible after about 12 to 18 months from the beginning of treatment. Corrective osteotomy of proximal femur at a level just above the lesser trochanter is required in patients presenting with ankylosis in an unacceptable position. Further, with corrective femoral osteotomy, a painful, fibrous ankylosis may be converted into a painless, bony ankylosis. Arthrodesis to achieve bony ankylosis and painless hip joint is done after about 20 years of age when proximal femur has no more potential for longitudinal growth. In the era prior to the availability of antituberculosis drugs, extra-articular arthrodesis was done due to fear of reactivation of infection if the joint was opened. Two popular methods of arthrodesis were iliofemoral arthrodesis [Hibb’s arthrodesis] (31) and ischiofemoral

arthrodesis [Brittain’s arthrodesis] (32). Now-a-days, with effective antituberculosis treatment being available, a direct intra-articular fusion between the raw surfaces of femoral head and acetabulum is performed when arthrodesis is indicated. Excision arthroplasty of the hip joint (33) [Girdlestone arthroplasty] consists of excision of head and neck of femur along with debridement. Postoperatively, 10 to 12 weeks of traction is required and this is followed by gradual weight bearing. The limb becomes shorter by about two centimeters in addition to the preoperative shortening and the joint also becomes unstable. But this procedure offers the advantage of retaining a good range of movements; the patient can even squat and sit crosslegged. Replacement arthroplasty, which has been so successful in osteoarthritis and rheumatoid arthritis, is also now being performed in selected patients. For this procedure the disease must be clinically healed for over five years. TUBERCULOSIS OF KNEE JOINT Knee joint is the third common site for osteoarticular TB. It accounts for more than 10 per cent of cases of osteoarticular TB. Pathology In the past, the knee joint involvement was mainly a disease of children presenting as “synovial type”. Presently, it is increasingly being seen in adults and presents as an osseous metaphyseal lesion which spreads to the joint. The synovial type of infection is a low-grade inflammation. The synovial membrane becomes congested, oedematous and is studded with tubercles. The synovial fluid is increased. It is thin, watery, opalescent and contains flakes of fibrin and an increased number of mononuclear cells. Healing at this stage leaves the synovial membrane thickened with fibrosis and the articular surfaces remain largely intact. If healing does not occur and the infection persists, the granulation tissue forms and the synovial space is obliterated by fibrous adhesions. The granulation tissue erodes the cartilage, invades the subchondral bone, capsule and cruciate ligaments. When initial infection starts in metaphysis, it produces an acute exudative infection with caseation necrosis. This lesion can invade the joint to produce

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granulation tissue and extensive destruction of the articular cartilage [Figure 23.16]. Sinus formation can occur [Figure 23.17]. Wasting of thigh and calf muscles occurs early in this type of infection [Figure 23.18]. A low-grade synovial infection stimulates osteogenesis and ossification centers in adjoining tibia and femur. These bones may become longer than on the opposite side. If infection is not controlled early, a

premature closure of neighbouring growth plate can occur and in this situation, the limb becomes shorter. Clinical Features The synovial type of infection is insidious in onset and starts as intermittent episodes of synovial effusion. The affected joint remains normal in appearance and function during each remission. Excessive activity and strain tend

Figure 23.16: Tuberculosis synovitis with osteomyelitis. Photomicrograph showing synovial lining, chronic inflammatory changes and small necrotic bone spicules [arrow] [upper panel, left: Haematoxylin and eosin, x 100], epithelioid granuloma with lymphocytic infiltration [arrow] [upper panel, right; Haematoxylin and eosin x 200], caseation necrosis, Langhans’ giant cells [arrow], foreign body giant cells [lower panel, left; Haematoxylin and eosin, × 400] and caseation necrosis, giant cells [arrow] and lymphocytes [lower panel, right; Haematoxylin and eosin × 400]

Figure 23.17: Clinical photograph showing healed tuberculosis sinus and flexion deformity of the left knee joint at eight months of treatment

Figure 23.18: Clinical photograph showing early quadriceps wasting due to tuberculosis synovitis in the right knee joint

Skeletal Tuberculosis 357 to precipitate effusion. Aspirated joint fluid is not abnormal except for the presence of some mononuclear cells. At this stage, other causes must be considered in the differential diagnosis. These include meniscal tear and synovitis due to trauma, rheumatic fever, rheumatoid arthritis and pyogenic arthritis, osteochondritis dessicans, chondromalacia patellae, haemarthrosis, villonodular synovitis and synovial chondromatosis. In doubtful cases, synovial biopsy for histopathological and microbiological investigations are necessary. When a patient presents with recurrent or persistent knee joint swelling of insidious onset, a possibility of TB must be considered. Caution must be exercised while administering intra-articular corticosteroids in such patients as a flare-up of TB can occur. Gradually, the attacks of synovitis become more intense and presistent. The synovium and capsule become palpably thickened and tender. This feel of swelling of the knee joint in synovial TB is classically described as “doughy swelling” [Figure 23.18]. At first, the muscles, particularly hamstrings develop spasm, atrophy and contractures may develop later. The biceps femoris muscle pulls the leg in deformity of flexion [Figure 23.19], abduction and external rotation. If this deformity persists, capsular contracture occurs and tibia gradually subluxates posteriorly. The synovial fluid is thin, opalescent and contains a large number of mononuclear cells and flakes of fibrin. When healing takes place in the early stage of intermittent synovial effusion, the knee joint may almost remain near normal. Healing in the later stages leaves behind thickened and fibrotic synovial membrane and capsule. Intra-articular adhesions lead to fibrous ankylosis. In the form commonly seen in adults, metaphyseal focus of infection spreads to the joint. Inflammatory signs develop suddenly and include severe pain, muscle spasm, local warmth, tenderness and restriction of movements. Constitutional symptoms are present and include fever, anorexia and night sweats. Destruction is greater and abscess and sinus formation are frequent. Gradual of ossification may result in bony enlargement, most notably in the medial femoral condyle, and valgus deformity of the knee joint. A premature epiphyseal fusion results in retardation of longitudinal growth. In advanced cases, characteristic “triple deformity” of flexion, abduction, external rotation and posterior

Figure 23.19: Clinical photograph showing hamstrings spasm due to tuberculosis synovitis leading to early flexion deformity of the left knee joint

subluxation of tibia, painful fibrous ankylosis, abscess and sinus formation become evident. Radiological Features In the first stage of intermittent synovitis, radiographs are normal [Figure 23.20]. In the next stage of persistent synovitis, radiographs show generalized osteoporosis, loss of definition of articular margins [Figure 23.21]. Occasionally, marginal erosions are also seen. Thickened synovium and capsule may cast soft tissue shadow. In patients with advanced disease, radiographs may reveal marked narrowing of the joint space and the joint appears

Figure 23.20: Plain radiograph of the knee joint [antero-posterior view] in a patient with tuberculosis synovitis showing normal bones

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Figure 23.21: Sequentially taken plain radiographs of the left knee joint in a 54-year-old man, showing stage of synovitis with the knee in flexion before initiation of treatment [A and B]. Three months later, while on treatment, juxtaarticular rarefaction of bones in early arthritis stage is evident [C and D]. The radiograph taken at the completion of treatment showing ankylosed knee joint approximately at 100° flexion despite skeletal traction [E]

grossly disorganized. Osteolytic cavities and TB sequestra in bones may also be evident in an advanced stage of the disease and, the classical triple deformity [Figure 23.22] is seen. When the clinical presentation is atypical, and the findings on the plain radiograph do not support the clinical features, an MRI of the knee joint can be helpful [Figure 23.23]. Management In the early stages of synovial disease, a synovial biopsy and histopathological and microbiological examination

Figure 23.22: Plain radiograph of the knee joint in a patient with advanced knee joint tuberculosis. Antero-posterior view showing gross destruction of bones, lateral subluxation, flexion deformity and tricompartmental involvement can be seen [A]. Lateral view [B] of the same patient showing flexion deformity

of the material obtained may facilitate confirmation of the diagnosis. In the stage of intermittent effusion, administration of standard antituberculosis treatment alone may be sufficient. Traction is useful in all stages of the disease in children and only in the stage of persistent synovitis in adults. Preoperative traction is used in the acute fulminating form and surgery is deferred till the acute stage of disease has been controlled. Traction is also necessary in the postoperative period following synovectomy and debridement. Simple skin traction is adequate in patients with minimal flexion deformity. But, in cases where triple deformity has developed, the double traction technique should be used. It consists of applying both horizontal and vertical tractions from a pin passed in proximal tibia. But traction has its limitations in correction of deformity in patients with advanced disease of the knee joint [Figure 23.21E]. Double traction helps in correction of deformity and prevents posterior subluxation of tibia. With quiescence of acute local signs, intermittent, gentle active and passive knee bending exercises are started. Gradual mobilization and weight bearing are started with clinical and radiological improvement. Clinical improvement is indicated by improvement in local and constitutional symptoms. Reossification of radiolucent areas and increased density of joint margins are signs of radiological improvement. In the early period of mobilisation, a bivalved plaster cast or brace can be used to prevent recurrence of flexion deformity. If synovitis persists despite of adequate antituberculosis treatment for three months, an open arthrotomy and subtotal synovectomy are indicated. The

Skeletal Tuberculosis 359

Figure 23.23: Plain radiograph of the left knee joint in an 18-year-old boy with a history of significant injury who developed pain and stiffness in the left knee joint not responding to symptomatic treatment, showing rarefaction [small oval] [A], and patellofemoral sclerosis [large oval] [B]. MRI [sagittal section] of the same patient showing infective changes affecting epiphyseal part of the femur more than tibia [C]. Biopsy confirmed the diagnosis of tuberculosis

main objective is the removal of infected tissues to render the chemotherapy more effective. Moderately advanced disease, in addition, requires debridement with removal of loose bodies and debris. Excision of pannus covering the articular cartilage and curettage of superficial cartilage erosions and osseous necrotic foci are also done. If large metaphyseal lesions are present, they are exposed through a window at a distance from joint, curetted and packed with cancellous bone grafts. Postoperatively, traction must be continued for at least six weeks in order to prevent or to correct flexion deformity and avoid compressive forces acting against the articular surface. Thereafter, the knee joint must be protected in a bivalved plaster cast or brace and the weight bearing is started slowly and cautiously. The range of knee joint flexion is likely to remain limited to moderate or significant extent. In patients with advanced or progressive destructive arthritis or a painful fibrous ankylosis, arthrodesis may be required. During surgery, sufficient bone is removed to overcome deformity and expose normal cancellous bone and a compression device is used to obtain rapid fusion (34). Whenever possible, arthrodesis must be deferred till the completion of growth in distal femur and proximal tibia. With arthrodesis, the knee joint remains stable and allows long hours of standing and walking. However, arthrodesis does not allow flexion of the knee joint and the leg remains sticking out while sitting.

Healing of the wound after surgery in patients with advanced arthritis is often slow and wound dehiscence may occur. This is because, the capsule, subcutaneous tissue and the skin [that is often scarred] may also be affected by the disease process. TUBERCULOSIS OF ANKLE AND FOOT Tuberculosis of the ankle joint and foot accounts for less than five per cent of all cases of osteoarticular TB. Tarsals and the ankle joint are usually involved together in TB. This occurs due to spread of the TB infection through intercommunicating synovial channels or along soft tissue planes. The extent of bony involvement and the clinically evident swelling around the ankle joint and foot are more extensive than what is discernible on the plain radiograph. Pathology Tuberculosis of the ankle joint and foot most commonly starts as synovitis which may be either due to infection of the synovium or less often due to inflammatory response to an adjacent focus of TB in the bone. Usually, the disease presents as synovial disease or extra-synovial soft tissue disease associated with a bony focus. The disease spreads fast to involve several joints and is clinically characterized by early occurrence of signs of inflammation. Sometimes, a central bony focus may

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remain clinically quiescent for some time or may produce low-grade symptoms for some weeks. Local inflammatory signs develop late, only after the cortex has been penetrated and when the adjacent soft tissues and synovium are involved. The most commonly affected bone is calcaneum, followed in frequency by talus, first metatarsal, navicular and medial two cuneiform bones. Certain bones appear to be predisposed to TB at different ages. In infants, metatarsals are most often affected. Tarsal bones in children and bones of the ankle joint in adults are frequently involved. Talus is most often affected in old age. Multiple lesions, abscess and sinus formation are common in adults. On the other hand, fulminating synovial disease is more common in children. A metaphyseal focus in tibia can involve the growth plate and produce deformity of the ankle joint. An infective focus can develop in the epiphysis and destroy a part of it. In a child, intramedullary extension of the bony focus may precede the perforation of cortex. Clinical Features In the common variety of synovial disease, the onset is insidious. The clinical presentation includes pain, limp, local warmth, tenderness and a diffuse doughy swelling [Figures 23.24 and 23.25]. The soft tissue swelling is initially intermittent; subsides with rest and reappears with walking. Eventually, the swelling becomes persistent, pain increases and movements of the ankle joint become restricted. The boggy and tender swelling

Figure 23.24: Clinical photograph of the left ankle joint showing doughy swelling [arrows] due to tuberculosis arthritis

Figure 23.25: Clinical photograph of a young girl showing midfoot swelling [A] [arrow] extending up to ankle [B] [arrow] due to tuberculosis arthritis involving right foot and ankle joint

usually starts at dorsolateral aspect of tarsal areas and with the spread of infection it extends towards tarsometatarsal joints. In the less common type of disease, which starts as a central bony focus, usual clinical features include dull aching pain of a few weeks duration. The foot may appear deceptively normal. A careful clinical examination may reveal minimal swelling, tenderness and warmth. Sometimes, a sinus may form adjacent to the bony lesion [Figure 22.26]. Radiological Features An isolated destructive lesion may be seen in tarsal bones, commonly in calcaneum and talus [Figure 23.27]. In small tarsal and metatarsal bones and phalanges, single

Figure 23.26: Clinical photograph of the left foot showing healed tuberculosis sinus [arrow] overlying the bony lesion which responded well to treatment

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Figure 23.27: Plain radiograph of the calcaneum [axial view] [A] showing lytic lesion [arrow] in a patient with histopathologically proven calcaneal tuberculosis. The lytic lesion [arrow] is evident in the posterior part of the calcaneum in the lateral view [B]

intraosseous lesion usually first produces expansion of bone. Early diffuse osteoporosis is a prominent feature. Early radiological signs, before bony destruction becomes evident, are narrowing of joint space, cortical irregularities and minimal destruction of cortical margins. In late stages of the disease, radiographs show complete obliteration and disorganization of joint, large bony lesions and soft tissue swelling. In selected clinical situations where either the diagnosis is not clear or radiological features are inconclusive, MRI is helpful. This will show the extent of the bony as well as soft tissue lesions [Figures 23.28 and 23.29]. Management Synovial biopsy may be needed at times for confirmation of diagnosis. Antituberculosis drugs should be given in appropriate dosages for adequate length of time. Plaster of paris cast is used to give rest to the affected area. The ankle joint should be immobilized in 10° equinus position. This allows ankylosis, if at all it occurs, to develop in functional position. Immobilization and nonweight bearing should be continued till the disease becomes quiescent as evidenced by improvement in local signs. When treatment is started early, this conservative treatment will produce either completely normal or functionally normal ankle joint in over 80 per cent of the cases. An extensive, long-standing synovial disease requires arthrotomy and synovectomy. Along with synovectomy, pannus should be carefully peeled off the articular

Figure 23.28: Plain radiograph of the right foot of the patient shown in Figure 23.25 antero-posterior [A] and oblique [B] views showing loss of outline of individual tarsal bones. An MRI [sagittal section] of the right foot shows involvement of talus, navicular, calcaneum, and cuboid by tuberculosis [C, D, E, and F]

362

Tuberculosis involvement of shoulder joint by TB occurs more frequently in adults than children (35-37). Pathology

Figure 23.29: Plain radiograph of the foot showing no lesions in antero-posterior [A] and lateral [B] views. But MRI reveals extensive tuberculosis involvement of the mid-tarsal bone in the sagittal [arrow] [C] and transverse [arrow] [D] sections

Tuberculosis of the shoulder joint seldom begins in the synovium and the clinical presentation as synovitis is rare. Commonly, the disease starts as an osseous lesion in the humeral head or glenoid. The joint is involved early and is filled with granulation tissue. Capsular contracture and fibrous ankylosis occur early and, therefore, stiffness and limitation of movements also appear early. Small osseous foci gradually enlarge and become confluent. Subsequently, a large fibrocaseous cavity forms which may lead to deformity of the humeral head and glenoid. This common variety of TB of the shoulder joint is considered to be a dry and atrophic type, and hence the name caries sicca. Swelling, abscess and sinus formation occur rarely. In children, osseous lesion may start in metaphyseal region of humerus and interfere with the longitudinal growth. Clinical Features

cartilage. The articular cartilage tends to survive for long periods and destroyed articular cartilage heals by formation of fibrocartilage. An isolated bony lesion should be curetted and large cavities should be packed with bone grafts. This ensures early healing and prevents spread of disease into the joint and adjoining bones. An extensive destruction of one or multiple tarsal bones requires complete excision of the affected bone. Any portion of tarsus can be excised from the level of neck of talus proximally to metatarsal bases distally by two transverse saw cuts. The cut bone surfaces are approximated and cast applied. This results in a shortened but a well-functioning foot. When the joint destruction is so extensive that a functional joint can not be expected, arthrodesis of ankle or subtalar joint alone or together can result in a painless albeit stiff foot. The technique of arthrodesis is beyond the scope of this chapter.

The onset is insidious, the early symptoms are nonspecific and include sensation of heaviness or muscle weakness. Pain on movements of the shoulder joint, appears next and progressively worsens. Muscle spasm fixes the shoulder joint in adduction. Examination reveals painful limitation of all movements of the shoulder joint especially external rotation and abduction. In early stages of the disease, some swelling, thickening and tenderness in soft tissues around the shoulder joint may be present. A marked wasting of deltoid and supraspinatus muscles may occur. Axillary lymph nodes may be enlarged and rarely a cold abscess may be present. In early stages, TB of the shoulder joint has to be differentiated from periarthritis of the shoulder joint. In the advanced stage, rheumatoid arthritis must be considered in the differential diagnosis. In rheumatoid arthritis, the marked soft tissue swelling and synovial effusion occur. In doubtful cases, synovial biopsy should be submitted for microbiological and histopathological examinations.

TUBERCULOSIS OF THE SHOULDER JOINT

Radiological Features

Tuberculosis of the shoulder joint is relatively rare. It accounts for only one to two per cent of all cases of osteoarticular TB. In contrast to TB at other skeletal sites,

Diffuse osteoporosis is an important radiological feature in early stages. Later, some soft tissue swelling occurs and cortical margins become indistinct. Osteolytic

Skeletal Tuberculosis 363 osseous lesions, narrowing of the joint space and deformity of the humeral head and glenoid develop in the late stages of the disease [Figure 23.30]. Rarely, pathological subluxation or dislocation of the shoulder joint may develop [Figures 23.31 and 23.32]. Management In patients with a doubtful diagnosis, a synovial biopsy should be performed early to confirm the diagnosis. In addition to the general measures, the affected shoulder joint should be immobilized in plaster spica for

Figure 23.32: Plain radiograph of the shoulder joint [anteroposterior view] showing pathological superior migration and osteoporosis of the right humeral head [arrow] in treated tuberculosis arthritis of the right shoulder joint

Figure 23.30: Plain radiograph of the shoulder joint [anteroposterior view] showing late tuberculosis arthritis with destruction of the humeroscapular joint

Figure 23.31: Plain radiograph of the shoulder joint [anteroposterior view] showing pathological dislocation and a large cold abscess in axilla [arrow]. Patient had multiple sinuses located posteriorly

three months. Currently, removable polythene brace is commonly used for this purpose. Immobilization of the joint should be in functional position in the event of eventual healing with ankylosis. The optimum position for immobilization is 80° abduction, 30° forward flexion and 30° of internal rotation. Usually, fibrous ankylosis occurs. Patient can perform routine activities due to compensatory movements at the scapulothoracic level. Tuberculosis of the shoulder joint responds well to antituberculosis treatment. Occasionally, despite adequate antituberculosis treatment, fibrous ankylosis of the shoulder joint remains painful and has to be distinguished from a relapse. In selected cases with fibrous ankylosis, surgical arthrodesis of the glenohumeral joint in the optimum functional position is helpful. This relieves pain and provides a stable joint. A shoulder spica or internal fixation with metallic implants is necessary for the success of arthrodesis. Shoulder spica is to be continued for two to three months till the radiological confirmation of arthrodesis. Subsequently, limb is supported on a sling after removal of the spica. Gradual physiotherapy is started to encourage the scapulothoracic movement. An alternative to arthrodesis is available for patients with a painful shoulder joint due to TB. In the procedure known as excision arthroplasty of the shoulder joint, the diseased tissues are removed by thorough debridement, and the affected bony parts are removed from proximal humerus and glenoid. The resultant pseudoarthrosis

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preserves the movement at the shoulder joint. However, this procedure may render the joint unstable. Possibility of development of future relapses of the disease is also another risk with this procedure. All major surgical procedures are to be undertaken under the cover of antituberculosis drugs. TUBERCULOSIS OF ELBOW JOINT Tuberculosis of the elbow joint accounts for about two per cent or less of all osteoarticular TB. Children are less often affected as compared to adults. Pathology The disease commonly begins as an osseous focus in the olecranon, coronoid, lower end of the humerus or upper end of the radius in order of decreasing frequency. These caseous bony lesions involve the joint to produce destruction of cartilage and pannus formation. At this stage, if healing occurs, the eventual outcome will be a fibrous ankylosis. If caseous arthritis continues for a long period, discharging sinuses also develop. Tuberculosis starting as a synovial disease is uncommon in the elbow joint.

joint tenderness, boggy oedema of periarticular tissues and increased synovial effusion occur [Figure 23.33]. Swelling is most easily appreciated at the back of the elbow on both sides of the olecranon and triceps tendon. Wasting of arm and forearm muscles occurs early. Supratrochlear or axillary lymph nodes are enlarged in about one-third of the cases. In advanced untreated disease, discharging sinuses may be present. Radiological Features In the early stage of the disease, bones around the joint show generalized osteoporosis and the articular margins become fuzzy and irregular [Figure 23.34]. Osteolytic bony lesions can be seen in the olecranon, coronoid, distal humerus or radial head [Figure 23.35]. In the late stage of the disease, marked joint space narrowing and destruction of articular margins appear. Rarely, due to marked destruction of ligaments and bones, the elbow joint may develop pathological posterior dislocation. As the disease heals, fibrous ankylosis develops more frequently than bony ankylosis. Management

Clinical Features Disease is generally insidious in onset and produces pain, muscle spasm and limitation of movements. Generalized

If the disease starts from an osseous focus or has progressed to an advanced stage of arthritis, clinical and radiological features are usually diagnostic. In the stage

Figure 23.33: Clinical photograph with arms abducted [A] and held by the side [B] showing a doughy swelling at the left elbow joint, more marked on lateral and posterior aspects. Flexion of the elbow joint and muscle wasting in the arm are also evident

Skeletal Tuberculosis 365

Figure 23.34: Plain radiograph of the elbow joint, antero-posterior [A] and lateral [B] views showing generalized rarefaction, fuzziness of joint surfaces [rectangles]. Plain radiograph [antero-posterior view] [C], [lateral view] [D] of the patient shown in Figure 23.33 showing soft tissue swelling and fuzziness of joint surfaces [circles] [C and D]

Figure 23.35: Plain radiograph of the elbow joint [lateral view] involved by tuberculosis showing lytic lesion in olecranon [arrow] and loss of joint space with flexion deformity

of synovitis and during early stages of the joint destruction, differentiating TB of the elbow joint from rheumatoid arthritis can be difficult. In doubtful cases, an open biopsy of the synovium should be done to ascertain a definitive diagnosis. The principles underlying the management of TB of the elbow joint are similar to those applicable to TB of other synovial joints. Antituberculosis drugs form the mainstay of therapy. In cases where sinuses have formed,

secondary infection with pyogenic bacteria is likely. In these cases, a broad spectrum antibiotic should also be administered. In all stages of the disease, with or without operative intervention, the elbow joint should be immobilized for about three months in a plaster cast or removable polythene brace. When the disease is unilateral, immobilization of the elbow joint in 90° flexion and forearm in the midprone position is recommended to avoid the development of ankylosis in non-functional position. After removal of splintage, overuse of the joint should be avoided for further six to nine months. Functionally, satisfactory range of movements at the elbow joint is retained in a majority of the cases. Results, however, also depend on the stage and extent of the disease and joint destruction when treatment is started. The results are much better in the early stage disease of synovitis and in unicompartmental disease. In advanced arthritis with involvement of all compartments of the joint, the usual end result is fibrous ankylosis in a majority of patients. The bony ankylosis is uncommon. A localized destructive lesion near the joint [usually in the olecranon or coronoid] should be curetted early to eradicate a source of future relapses and extension of disease into the joint. Synovectomy and joint debridement are indicated in patients with early arthritis, when

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response to chemotherapy and immobilization is not adequate. When advanced arthritis has healed with elbow joint in tight fibrous anklylosis or anklyosis in unacceptable position, a good and functionally useful range of movements at the elbow joint can be regained with excision arthroplasty. The surgery should be deferred till growth is complete and should not be done in persons engaged in heavy manual work. The surgery consists of removing an “inverted V-shaped” segment of the lower end of humerus with the apex of “V” reaching the olecranon fossa. Supracondylar ridges, epicondyles and collateral ligaments should be carefully preserved. Upper end of the ulna [rarely along with upper end of the radius] should be sparingly trimmed and allowed to slide in the “inverted V-gap” in the humerus. After seven to ten days of operation, movements of active and assisted active flexion, extension, supination and pronation are started. Night splint should be used for three months. Light work without splint is allowed three months after the surgery (19). In heavy manual workers, arthrodesis of the elbow joint is indicated when the joint has become extensively disorganized. For unilateral disease, a position of 90° of flexion is desirable. For bilateral cases, one elbow joint should be placed in 110° flexion to enable the hand to reach mouth and face and the other in 65° flexion to attend to personal hygiene. The optimum position is best decided after a trial immobilization of the elbow joint in plaster cast for few weeks before operation. The surgical technique of arthrodesis of the elbow joint is beyond the scope of this chapter.

the infected tenosynovitis (38,39). Abscess and sinus formation are common. Clinical Features The onset of the disease is insidious. Exacerbation of pain by movements is the early symptom. Soft tissue swelling, tenderness and limitation of flexion and extension movements at the wrist joint occur later. In progressive disease with destruction of bones and ligaments, subluxation or dislocation of radiocarpal joints occurs. This gives rise to a marked deformity and further limitation of movements. Abscess and sinus formation are frequent in advanced disease. Extension of disease to flexor and extensor tendon sheaths produces a localized boggy swelling and difficulty in movements of fingers. A monoarticular rheumatoid arthritis may be difficult to differentiate from TB. Radiological Features In the early stages, radiographs show demineralization of bones, bony erosions and some reduction of the joint space. Osteolytic bony lesions in the radius and carpal bones may be seen. In advanced stages of the disease, joint spaces of both wrist and intercarpal joints become obliterated. Bony destruction and even subluxation or dislocation of the wrist joint may occur [Figures 23.36 and 22.37].

TUBERCULOSIS OF WRIST JOINT Tuberculosis of the wrist joint is rare and is seen mainly in adults. Pathology The most common site of initial focus of TB in the wrist joint is in the distal radius and capitate. The disease spreads to involve the wrist and intercarpal joints. Less often, the disease starts from a primary focus in the synovium and infection soon gets disseminated to intercarpal and wrist joints. Infection then spreads to involve both flexor and extensor tendon sheaths. Still less commonly, the infection may spread to wrist joint from

Figure 23.36: Post-treatment radiograph of the wrist joint [anteroposterior view] [A] showing ankylosed wrist, gross destruction of carpals, loss of intercarpal and radiocarpal joints. Mild volar subluxation of carpals with loss of radiocarpal joints can be seen in the lateral view [B]

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Figure 23.37: Plain radiograph of the right wrist, antero-posterior [A] and lateral [B] views of a patient who has received a full course of antituberculosis treatment showing bony ankylosis [rectangles] of distal radioulnar, radiocarpal and intercarpal joints

Management Tuberculosis of the wrist joint is quite likely to be misdiagnosed as monoarticular rheumatoid arthritis and, therefore, it is essential to confirm the diagnosis with synovial biopsy. Subsequent to an early diagnosis, the patient should be treated with DOTS. Periodic follow-up with imaging is required. If indicated, the continuation phase may be extended and this practice of extension of treatment should be individualized. More clinical trials are required to say definitely about the efficacy as well as duration of antituberculosis treatment. A prolonged splintage in plaster cast or polythene splint with wrist in 10° dorsiflexion and in midprone position is always required. Splintage should be gradually discarded during daytime but night splint is used for nearly one year. Heavy physical work should be avoided for 18 to 24 months in order to avoid collapse of the bones and minimizing the risk of development of deformity. The combination of modern antituberculosis treatment and proper splintage are adequate in nearly two-thirds of the patients. Good functional range of movements can be regained with these if the treatment is started at an early stage of the disease. Gross fibrous ankylosis occurs in one-third of the patients. Synovectomy of the joint or tendon sheaths [if involved] and curettage of bony lesions are indicated in patients not responding to treatment or whenever there

is doubt regarding the diagnosis. With the availability of better imaging modalities for an early diagnosis, effective drugs, use of better orthopaedic splintage and surgical intervention is rarely required (38,39). Arthrodesis of the wrist joint is the treatment of choice to minimize the disability in patients where wrist joint has dislocated due to the advanced destruction, in patients with painful fibrous ankylosis or ankylosis in non-functional position [e.g., flexion]. Thorough debridement and arthrodesis are also useful for painful wrist joint with a history of recurrence of infection. Arthrodesis of both wrist and intercarpal joints is performed together from a dorsal approach. The diseased tissue, synovium and articular cartilage are removed as far as possible and joint spaces are packed with cancellous grafts. In the Darrach’s procedure, a large cortico-cancellous graft is placed in a trough made in distal radius, lunate, capitate and proximal part of the third metacarpal. Along with this, the distal end of ulna should be excised to provide useful range of pronation and supination. Optimum position of the wrist joint arthrodesis is in 10° to 15° of dorsiflexion. TUBERCULOSIS OF SACROILIAC JOINT Sacroiliac joint is a true synovial joint. This joint is involved in two to five per cent cases of osteoarticular TB (40). Pathology Tuberculosis of the sacroiliac joint may start in the synovium, in lateral masses of sacrum or ilium. Infection can either start at these sites or occur as an extension of TB from ipsilateral hip joint and lumbosacral area of spine. Destructive caseous lesions form and destroy the joint. Abscess formation is common and the abscess may present dorsally or inside the pelvis. Intrapelvic extension can lead to severe visceral lesions making the prognosis quite serious. Dorsal abscess or its extension along the iliac crest is likely to result in sinus formation. These sinuses heal with difficulty. Superadded bacterial infection through the sinuses is common. Clinical Features Sacroiliac TB is rare in infancy and childhood and affects adults more frequently. The females are affected more frequently than males [male:female ratio = 2:5].

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Concomitant TB infection at some other site is present in about half the patients. In patients with a poor general health and nutritional status, bilateral sacroiliac joint involvement is common. The onset of the disease is insidious and it may follow trauma or pregnancy. Pain over the affected joint is the main symptom. It is referred to groin and less commonly in the sciatic nerve distribution. Pain worsens on lying either supine or on affected side. Prolonged standing and walking also aggravate pain. Sitting on the buttock on affected side is painful, whereas sitting on opposite buttock relieves pain. Bending forwards with the knee joints in extension produces tension on the hamstrings and exacerbates the pain, but, bending forwards with the knee joints in flexion is less painful as this manoeuvre relaxes the hamstrings. Sudden jerks, coughing and sneezing also worsen the pain. Localized tenderness and some boggy swelling or abscess are present. Stressing the involved sacroiliac joints by any one of the following three manoeuvres increases pain: [i] distraction of both sacroiliac joints by simultaneous pressure on both anterior superior iliac spines; [ii] stressing the sacroiliac joint with forced flexion, abduction and external rotation of ipsilateral hip joint [Faber’s test]; and [iii] by performing the Gaenslen’s test of rotating the ilium on sacrum. In the Gaenslen’s test, the hip on the unaffected side is first firmly flexed to fix the pelvis and lumbosacral junction. The affected hip is then hyperextended thereby rotating the corresponding ilium forwards. This stresses the inflammed ligamentous structures about the sacroiliac joint and produces pain. Rectal examination is important to detect intrapelvic abscess. In advanced disease, large cold abscesses and sinuses may be present. Radiological Features In the early stages, the plain radiographs are normal. The earliest radiological evidence is in the form of haziness or loss of definition of joint margins. Thereafter, an irregularity of the articular surface with areas of erosions may become evident. If the disease is controlled at this early stage, the joint space narrowing and sclerosis of the joint margins occur. Progressive destruction causes marked cavitation in the bone and narrowing of the joint space. Healing of advanced disease occurs by bony ankylosis and increased density of the joint margins. Ankylozing spondylitis, rheumatoid arthritis, pyogenic

infection and juxta-articular bony lesions should be considered in the differential diagnosis. The CT and MRI are of great value in detecting early joint erosions, cavitation and abscess. Management Tuberculosis of the sacroiliac joint is difficult to diagnose in the early stages, as the clinical manifestations are atypical. Also, it responds slowly and less favourably to antituberculosis treatment and surgery becomes necessary quite often. In the pre-chemotherapeutic era, TB of the sacroiliac joint was commonly encountered in patients with generalized severe infection and the mortality was high in these patients. Standard antituberculosis treatment and general supportive therapy are initiated. Surgical intervention is indicated in patients not responding to drugs and in those with recurrence of infection or when the diagnosis is in doubt. It consists of debridement of joint, freshening of joint margins and packing the area with adequate bone grafts to achieve arthrodesis. Post-operative bed rest is required for about three months followed by gradual mobilization in a lumbosacral belt or plaster jacket till clear bony fusion of the joint is evident radiologically. TUBERCULOSIS AT RARE SITES Sternoclavicular Joint Tuberculosis of the sternoclavicular joint is rare. Frequently, the disease may be misdiagnosed to be lowgrade pyogenic infection, rheumatoid arthritis, multiple myeloma or metastases. The disease usually starts in the bone at the medial end of clavicle and presents with a painful swelling of an insidious onset. The swelling may be warm, tender and boggy. A cold abscess and a sinus can form in late stages of the disease. Radiographic examination of this joint is very difficult; MRI is useful to detect early erosion and soft tissue swelling. Biopsy is necessary if the diagnosis is in doubt. Response to antituberculosis treatment is usually good. Acromioclavicular Joint Acromioclavicular joint is also a rare site for TB and the disease may start from the lateral end of clavicle or acromion and spreads to the joint. Clinical features include pain and swelling of an insidious onset. The

Skeletal Tuberculosis 369 diagnosis is often missed. Antituberculosis treatment often yields satisfactory results. Symphysis Pubis Tuberculosis of symphysis pubis is rare. The disease usually begins in pubic bone and spreads to symphysis. Localised pain and sometimes abscess and sinuses are presenting features. Radiological assessment of this area reveals osteolytic areas in pubic bones and destruction of margins of pubic symphysis. Concomitant TB lesions in sacroiliac joint are not uncommon and some of these patients may develop displacement of symphysis. Treatment is essentially with antituberculosis drugs. Cold abscess may require antigravity aspiration. Ilium, Ischium and Ischiopubic Ramus Isolated TB lesions are rarely seen in one of these bones. Usual presenting features include pain, swelling, tenderness, cold abscess and discharging sinuses. Radiologically these lesions show varying number of lytic areas and some of these lesions may contain sequestra. Superimposed pyogenic infection will produce sclerosis around lytic areas. One must be aware of these conditions in order to diagnose them at an early stage. Treatment is with antituberculosis drugs. Exploration and debridement of bony lesions is indicated in the following situations: [i] patients with doubtful diagnosis; [ii] disease not responding to antituberculosis treatment; and [iii] recurrent disease.

inferior or superior angle of scapula. Pain and occasionally swelling are the presenting clinical features. This is another bone where radiological evaluation is difficult. CT or MRI can be helpful to detect early lesion of the disease in scapula. Treatment is with antituberculosis drugs. Clavicle Tuberculosis of the clavicle without involvement of acromioclavicular or sternoclavicular joint is rare. Children are most often affected. Presenting clinical features include painful swelling of clavicle with or without cold abscess or sinuses. Radiograph shows any one of the following types of appearances: diffuse thickening and honeycombing, multiple cystic cavities and sequestra formation similar to pyogenic infection. The mainstay of management is antituberculosis treatment. The role of surgery is limited. Biopsy may be done to confirm the diagnosis. Debridement may be helpful in patients with slow or no response to drugs. Large sequestrum should be removed surgically. If necessary, a part of clavicle can be excised without loss of function (41). TUBERCULOSIS TENOSYNOVITIS AND BURSITIS Tuberculosis of the tendon sheaths and bursa is rare. Any synovial sheath or bursa can be affected but tendon sheaths around hand are more commonly affected as compared to other sites.

Sternum and Ribs

Tuberculosis Tenosynovitis

Tuberculosis very rarely involves the sternum and ribs. Often, the disease is not diagnosed till sinuses have formed. Nearly one-third of patients will have detectable TB lesion in lungs or other parts of the skeleton. Radiological assessment of both these sites is very difficult and may reveal irregular destruction and cavities. The diseased ribs may be thickened very much or expanded with “punched out” erosions. Surgery is not required routinely in these patients. However, it may be done to establish the diagnosis or for the removal of sequestrum. Response to antituberculosis treatment is good.

Hand is the most common site of involvement. People who work with cattle are predisposed to disease caused by Mycobacterium bovis. Infection can also reach the tendon sheath by haematogenous route or from neighbouring affected bone and joint. The disease usually starts as a simple inflammation of the tendon sheath with serous exudate and fibrinous deposits covering the inner surface. Gradually, the tendon sheath thickens and the exudate becomes seropurulent. With movement and friction, the broken villi and fibrinous exudate get moulded to resemble rice bodies mimicking rice bodies sometimes seen in rheumatoid arthritis. The tendon sheath may undergo caseation necrosis and the exudate penetrates the soft tissues to form sinuses. Rarely, necrosis of underlying tendons may occur. With healing,

Scapula The scapula is another rare site for TB. Infection may start in the angle of acromion, spine, neck of scapula and

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the sheath becomes fibrotic. The infection spreads in the sheath to involve all areas from muscle to tendinous insertion. Paratendon and fascial structures are involved by the spread of disease. Tuberculosis tenosynovitis of the common sheath of forearm flexor tendons distends the sheath both proximally and distally up to flexor retinaculum. This produces a dumb-bell shaped swelling, classically known as compound palmar ganglion. Cross fluctuation can be demonstrated between the swelling proximal and distal to flexor retinaculum. The clinical course of TB tenosynovitis is slow and insidious. Presenting features include pain, swelling, tenderness, weakness of grip and limitation of movements. The latter is minimal to start with but progressively worsens with adherence of tendons. Spontaneous tendon rupture and sinus formation are uncommon and occur as late complications. Fever and general constitutional symptoms are unusual until neighbouring bone and joint have been involved. Management in early stage consists of antituberculosis treatment and immobilization. In extensive and long standing disease, surgical resection of the diseased tissue followed by immobilization should be done. Function becomes better after radical excision. If tendon has become necrotic, it should be excised and tendon grafting should be done. When infection has spread to bone and joint, especially the wrist joint, wide excision, debridement and arthrodesis will give best functional result. Tuberculosis Bursitis Bursa over greater trochanter, subdeltoid bursa and pes anserinus bursa are known to develop tuberculosis. All are rare lesions. Clinical presentation includes mild pain, localized swelling and tenderness. Differentiation from rheumatoid arthritis, ganglion and synovial tumours can be difficult and biopsy may be required for an accurate diagnosis. Tuberculosis bursitis responds well to antituberculosis drugs. Large swellings may require aspiration.

common presenting features include pain, swelling of bone with warmth, tenderness, boggy soft tissue swelling and regional lymphadenopathy. In late cases, abscess and sinus formation occur. A high index of suspicion is required for the diagnosis. Radiographs show irregular cavities and areas of destruction with little surrounding sclerosis [Figures 23.38 and 23.39]. This commonly produces a honeycomb appearance. Some of the cavities may contain feathery sequestra. After sinus formation, superadded bacterial infection produces marked sclerosis and occasionally sequestration of cortical bone resembling pyogenic chronic osteomyelitis. Differential diagnosis includes chronic pyogenic osteomyelitis, Brodie’s abscess and tumours. Biopsy for histopathological and microbiological investigations may help in the diagnosis. Occasionally, a presumptive diagnosis can

Figure 23.38: Plain radiograph of the forearm antero-posterior [A] and lateral [B] views showing tuberculosis osteomyelitis of entire ulna at the beginning of treatment [arrows]

TUBERCULOSIS OSTEOMYELITIS Tuberculosis of the bone alone can occur without involvement of the joint (42). Any bone can be affected but long tubular bones are rarely involved. These are often diagnosed and treated like bacterial chronic osteomyelitis (37). Usually, adults are affected. The

Figure 23.39: Plain radiograph of the forearm antero-posterior [A] and lateral [B] views of the patient shown in Figures 23.38A and 23.38B showing healed TB osteomyelitis of ulna at completion of treatment [arrows]

Skeletal Tuberculosis 371 be confirmed on the basis of favourable response to antituberculosis drugs. Tuberculosis osteomyelitis of short tubular bones, like phalanges, metacarpals and metatarsals is more often seen and is predominantly a disease of children. The disease process starts in the medullary cavity causing patchy destruction. The entire diaphysis sequestrates due to a combination of two interrelated pathological processes. First, the periosteum becomes lifted up due to granulation tissue. This results in the formation of involucrum and consequently sequestration of diaphysis occurs. Secondly, because of deficient anastomosis of the osseous arteries in childhood, the thrombosis caused by TB pathology leads to sequestration of diaphysis. Rarely, the sequestrated diaphysis may be extruded before involucrum formation. As a result, gross shortening of the bone occurs. The bone becomes thickened and spindle shaped. Usually, these patients present with gradual and almost painless swelling of one of the phalanges of hand and foot. Constitutional symptoms are usually absent and the bone may be minimally tender. Radiological features of sequestration of diaphysis and subperiosteal new bone formation are diagnostic. 18Fluorine fluorodeoxyglucose positron emission tomography [18FDGPET] [Figure 23.40] has been found to be useful in localizing TB disease in inaccessible or obscure sites. It also facilitates differentiating soft tissue infection as being separate from the osseous infection (43,44). Response to antituberculosis drugs is favourable. With early treatment, sequestra may revascularise and get incorporated

Figure 23.40: 18FDG-PET scan showing increased FDG uptake [arrow] in small bones of foot

like a graft and nearly complete restoration of osseous structure occurs. In refractory cases involving long and short tubular bones or in the presence of abscess around the involved bone, excision of the granulation tissue and infected bone should be done. Concomitant presence of bacterial infection in the same osseous lesion, usually through sinuses, causes a delay in healing. A short-course of additional antibiotic should be given to control bacterial infection. TUBERCULOSIS INFECTION OF PROSTHETIC JOINT As the prosthetic joint replacement is increasingly being done globally, several reports documenting TB of the prosthetic joint have been published (45-48). Prosthetic joint TB may develop due to the reactivation of the TB arthritis for which prosthetic replacement was performed. These patients present with slowly progressive joint pain. Diagnosis requires a high index of suspicion. Arthrocentesis must be done and specimens must be obtained from multiple sites for mycobacteriological studies. Eradication of TB focus is not possible without removing the prosthesis. Treatment consists of removal of the prosthesis followed by appropriate antituberculosis therapy. REFERENCES 1. Lichtor J, Lichtor A. Paleo-pathological evidence suggesting precolambian tuberculosis of spine. J Bone Joint Surg Am 1958;39-A:1938-9. 2. Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316-53. 3. Tuli SM. Tuberculosis of the spine: an historical review. Clin Orthop Relat Res 2007;460:29-38. 4. Jain AK, Dhammi IK. Tuberculosis of the spine: a review. Clin Orthop Relat Res 2007;460:2-3. 5. Oguz E, Sehirlioglu A, Altinmakas M, Ozturk C, Komurcu M, Solakoglu C, et al. A new classification and guide for surgical treatment of spinal tuberculosis. Int Orthop 2007;32:127-33. 6. Tuli SM. Treatment of neurological complications in tuberculosis of the spine. J Bone Joint Surg Am 1969;51-A:680-92. 7. Bailey HL, Gabriel M, Hodgson AR, Shin JS. Tuberculosis of the spine in children. Operative findings and results in one hundred consecutive patients treated by removal of the lesion and anterior grafting. J Bone Joint Surg 1972;54:1633-57. 8. Butler RW. Paraplegia in Pott’s disease with special reference to the pathology and etiology. Br J Surg 1935; 22:738-68. 9. Seddon HJ. Pott’s paraplegia, prognosis and treatment. Br J Surg 1935;22:769-99.

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10. Griffiths DL, Seddon HL, Roaf R. Pott’s paraplegia. London: Oxford University Press; 1956. 11. Hodgson AR, Skinsnes OK, Leong CY. The pathogenesis of Pott’s paraplegia. J Bone Joint Surg 1967;49:1147-56. 12. Bosworth DM, Della Pietra A, Rahilly G. Paraplegia resulting from tuberculosis of the spine. J Bone Joint Surg 1953;35A:735-40. 13. Choksey MS, Powell M, Gibb WR, Casey AT, Geddes JF. A conus tuberculoma mimicking an intramedullary tumour: a case report and review of literature. Br J Neurosurg 1989;31:117-21. 14. Goel MK. Treatment of Pott’s paraplegia by operation. J Bone Joint Surg 1967;49:674-81. 15. Tuli SM. Judicious management of tuberculosis of bones, joints and spine. Indian J Orthop 1985;19:147-66. 16. Kumar K. Tuberculosis of spine: natural history of disease and its judicious management. West Pac Orthop Assoc 1988;25:1-18. 17. Mukopadhaya B, Mishra NK. Tuberculosis of the spine. J Bone Joint Surg Br 1957;39-B:326-33. 18. Martin NS. Tuberculosis of the spine. A study of the results of treatment during the last twenty five years. J Bone Joint Surg Br 1970;52:613-28. 19. Tuli SM. Tuberculosis of the skeletal system [Bones, joints, spine and bursal sheaths]. New Delhi: Jaypee Brothers Medical Publishers 1993. 20. Rajasekaran S, Shanmugasundaram TK. Prediction of angle of gibbus deformity in tuberculosis of spine. J Bone Joint Surg Br 1987;69:503-9. 21. Hodgson AR, Stock FE. Anterior spine fusion. A preliminary communication on the radical treatment of Pott’s disease and Pott’s paraplegia. Br J Surg 1956;44:266-75. 22. Hodgson AR, Stock FE. Anterior spinal fusion for the treatment of tuberculosis of the spine. J Bone Joint Surg 1960;42-A:295-310. 23. Dutt AK, Moers D, Stead WW. Short-course chemotherapy for extrapulmonary tuberculosis. Nine-year experience. Ann Intern Med 1986;104:7-12. 24. Rajasekaran S, Soundarapandian S. Progression of kyphosis in tuberculosis of the spine treated by anterior arthrodesis. J Bone Joint Surg Am 1989;71:1314-23. 25. Yau AC, Hsu LCS, O’Brien JP, Hodgson AR. Tuberculous kyphosis: correction with spinal osteotomy, halopelvic distraction, and anterior and posterior fusion. J Bone Joint Surg 1947;56:1419-34. 26. Hodgson AR, Yau A, Kwon JS, Kim D. A clinical study of 100 consecutive cases of Pott’s paraplegia. Clin Orthop 1964;36:128-50. 27. Roaf R, Kirkaldy-Willis WH, Cathro AJM. Surgical treatment of bone and joint tuberculosis. Edinburgh: E and S Livingstone 1959. 28. Griffiths DL. Tuberculosis of the spine: a review. Adv Tuberc Res 1980;20:92-110. 29. Seddon HJ. The choice of treatment in Pott’s disease. J Bone Joint Surg Br 1976;58-B:395-7.

30. Shanmugasundaram TK. A clinicoradiological classification of tuberculosis of hip. In: Shanmugasundaram TK, editor. Current concepts in bone joint tuberculosis. Madras: International Bone and Joint Club; 1983. 31. Hibbs RA. A preliminary report of 20 cases of hip joint tuberculosis treated by operation fixing the joint. J Bone Joint Surg 1926;8:422 32. Brittain HA. Ischiofemoral arthrodesis. Br J Surg 1941; 29:93. 33. Girdlestone GR. Tuberculosis of bones and joints. Modern trends in orthopaedics. Series I. London: Butterworth and Company; 1950.p.35. 34. Charnley J. Compression arthrodesis. London: E and S Livingstone; 1953. 35. Tang SC, Chow SP. Tuberculosis of the shoulder. Report of 5 cases treated conservatively. J R Coll Surg Edinb 1983;28: 188-90. 36. Srivastava TP, Singh S. Osteo-articular tuberculosis in children. M.S. Thesis. Varanasi: Banaras Hindu University; 1987. 37. Martini M. Tuberculosis of the bones and joints. Heidelberg: Springer-Verlag; 1988. 38. Leung PC. Tuberculosis of hand. Hand 1978;10:285-91. 39. Hodgson AR, Smith TK, Gabriel Sister. Tuberculosis of the wrist. With a note on chemotherapy. Clin Orthop Relat Res 1972;83:73-83. 40. Tuli SM, Sinha GP. Skeletal tuberculosis-“unusual” lesions. Indian J Orthop 1969;3:5-18. 41. Srivastava KK, Garg LD, Kocchar VL. Tuberculous osteomyelitis of the clavicle. Acta Orthop Scand 1974; 45:668-72. 42. Gardam M, Lim S. Mycobacterial osteomyelitis and arthritis. Infect Dis Clin North Am 2005;19:819-30. 43. Yago Y, Yukihiro M, Kuroki H, Katsuragawa Y, Kubota K. Cold tuberculous abscess identified by FDG PET. Ann Nucl Med 2005;19:515-8. 44. James SL, Davies AM. Imaging of infectious spinal disorders in children and adults. Eur J Radiol 2006;58:27-40. Epub 2006 Jan 18. 45. Berbari EF, Hanssen AD, Duffy MC, Steckelberg JM, Osmon DR. Prosthetic joint infection due to Mycobacterium tuberculosis: a case series and review of the literature. Am J Orthop 1998;27:219-27. 46. Shanbhag V, Kotwal R, Gaitonde A, Singhal K. Total hip replacement infected with Mycobacterium tuberculosis. A case report with review of literature. Acta Orthop Belg 2007;73:268-74. 47. Khater FJ, Samnani IQ, Mehta JB, Moorman JP, Myers JW. Prosthetic joint infection by Mycobacterium tuberculosis: an unusual case report with literature review. South Med J 2007;100:66-9. 48. Kaya M, Nagoya S, Yamashita T, Niiro N, Fujita M. Periprosthetic tuberculous infection of the hip in a patient with no previous history of tuberculosis. J Bone Joint Surg Br 2006;88:394-5.

Musculoskeletal Manifestations of Tuberculosis

24

Ashok Kumar, AN Malaviya

INTRODUCTION Tuberculosis [TB] of the musculoskeletal [MSK] system is an important form of extra-pulmonary disease. With increasing numbers of extra-pulmonary TB cases, it is expected that the global burden of MSK-TB would increase. Rheumatologists, especially in ‘high burden’ TB regions of the world would be expected to diagnose and manage such cases. EPIDEMIOLOGY Published data suggest that MSK involvement is seen in about two per cent of patients with all forms of TB and in 10 per cent of the patients with extra-pulmonary TB; associated pulmonary TB being present in 50 per cent of these patients (1-3). It is of interest to compare the burden of MSK-TB with that of rheumatoid arthritis [RA]. The average incidence rate of RA was approximately 26 cases per 100 000 population per year with rates varying from 3.8 to 75.3 (4,5). On this basis the comparative figures for RA and MSK-TB are summarized in Table 24.1.

These data show that RA is much more common than TB arthritis. Moreover, RA is just one of the several idiopathic inflammatory arthritides. The incidence figures quoted above did not include spondyloarthritides, juvenile idiopathic arthritis, psoriatic arthritis, systemic connective tissue diseases and other less common causes of inflammatory arthritides. Thus, despite high incidence of TB in the world, rheumatologists would still be seeing much bigger numbers of patients with RA than patients with TB arthritis. This would be true even for so-called ‘high burden’ countries. Yet, TB arthritis remains a curable condition if diagnosed and treated early. Therefore, rheumatologists should have a high index of suspicion with emphasis on early diagnosis and treatment. Generally, MSK-TB is classified into TB of the spine [which constitutes nearly 50% of all MSK-TB] and the TB of the peripheral joints (6). Various rheumatic syndromes resulting from TB are listed in Table 24.2 (7). Tuberculosis of the spine and peripheral joints has been covered in the chapter “Skeletal tuberculosis” [Chapter 23].

Table 24.1: Comparative rates of incidence of musculoskeletal tuberculosis and rheumatoid arthritis Disease

Average incidence [per 100 000 population per year] Incidence range [per 100 000 population per year]

MSK-TB

RA

World

High burden countries

2.88

3.7

26

0.04- 11.68

1.36-11.68

3.8-75.3

MSK-TB = musculoskeletal tuberculosis; RA = rheumatoid arthritis

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Tuberculosis Table 24.2: Rheumatic syndromes resulting from tuberculosis

Invasive TB arthritis Poncet’s disease [para-infective TB arthritis] TB soft tissue rheumatism Iatrogenic rheumatism TB osteomyelitis Pott’s spine TB = tuberculosis Reproduced with permission from “Malaviya AN, Kumar A, Muralidhar R, Pande I. Rheumatological manifestations of tuberculosis–a short review. J Indian Rheumatism Assoc 1994;2:145-8 (reference 7)”

In this chapter, the focus will be on Poncet’s disease [parainfective TB arthritis]; TB soft tissue rheumatism; and iatrogenic rheumatism, especially from the perspective of rheumatologists. AETIOPATHOGENESIS AND PATHOLOGY The reader is referred to the chapter “Skeletal tuberculosis” [Chapter 23] for details regarding TB of the spine peripheral joints. It has already been mentioned above that TB arthritis is not as common as idiopathic inflammatory arthritis [prototype RA]. But, it is potentially a ‘curable’ condition, which the rheumatologists cannot afford to overlook. Therefore, it becomes mandatory to be aware of the clinical settings where TB arthritis should be high on the list of differential diagnoses. In endemic regions of the world extra-pulmonary TB including its MSK form, is a disease of children, juveniles, young and middle-aged adults (3,810). On the other hand, in non-endemic regions it mainly affects people in older age group with compromised host defence [e.g., neglected inmates of homes for elderly, poor and homeless people from inner city, prisoners and jail inmates, alcoholics, racial and ethnic minorities and immigrants from high-TB burden countries] (3,11,12). Among immigrants from high TB burden countries, as in their native countries, MSK-TB occurs primarily in children, and young and middle-aged adults who commonly present with a solitary osteolytic lesion in the axial skeleton distant from the initial focus strongly indicative of reactivation of a metastatic focus (12). Immunosuppressed state due to diabetes mellitus, malnutrition, other debilitating illnesses [chronic renal failure, pneumoconiosis, liver cirrhosis, disseminated cancer], haemodialysis (13,14), immunosuppressive and

cytotoxic drugs, corticosteroid therapy [including local depot-preparation of steroid injections] (15), intravenous substance abuse (16), human immunodeficiency virus [HIV] infection and acquired immunodeficiency syndrome [AIDS] (17) also predisposes to TB. Bone TB but not TB arthritis has been reported in patients having received anti-tumour necrosis factor agents [e.g., infliximab and etanercept] for the treatment of rheumatoid arthritis (18). Local factors related to joint integrity and health [e.g., pre-existing joint or bone disease, joint, bone trauma, including surgical trauma] appear to play an important role in the reactivation of disease (19,20). Consideration of local risk factors for MSK-TB is of great importance to rheumatologists, especially from the standpoint of pre-existing systemic rheumatic diseases (21,22). It is not uncommon to see MSK-TB [arthritis, osteomyelitis] in patients who already have an underlying inflammatory joint disease [e.g., systemic lupus erythematosus, Sjögren’s syndrome, gout, osteonecrosis of the hip due to sickle-cell disease and prosthetic joint] (23-27). CLINICAL SETTING FOR SUSPECTING TUBERCULOSIS ARTHRITIS In majority of the cases [nearly 85%], TB of the joint manifests as chronic monoarthritis involving large and medium weight bearing joints, hip and shoulder being the most common sites (3,6,28). Therefore, in persons with TB risk-factors or those from high-burden regions presenting with chronic monoarthritis, TB arthritis should be the first consideration till excluded with appropriate investigations. Uncommonly, TB arthritis can present as a polyarticular or oligoarticular disease. However, this clinical form is mostly restricted to debilitated children or the elderly in high-burden regions with a background of close contact with TB, or in other immunocompromised settings mentioned above. Rheumatologists would rarely be confronted with TB osteomyelitis, which in adults most commonly involves long bones [femur, tibia and ulna]. In children, the common sites include short [e.g., phalanges] or small bones [carpals, tarsals] and closely resemble the so-called ‘spindle-like’ swelling, typically seen in psoriatic arthritis and other spondylarthropathies or arthritis of the wrist or midfoot region. In early stages, TB dactylitis spares the adjacent joint leaving the articular margins intact. This can be easily appreciated in a plain X-ray, which is often helpful in diagnosis [Figures 24.1 and 24.2].

Musculoskeletal Manifestations of Tuberculosis

Figure 24.1: Multifocal tuberculosis dactylitis Reproduced with permission from “Malaviya AN, Kotwal PP. Arthritis associated with tuberculosis. Best Practice Res Clin Rheumatol 2003;17:319-43 (reference 6)” Copyright [2003] Elsevier

Figure 24.2: X-ray of right hand of an 11-year-old girl with tuberculosis dactylitis of the proximal phalanx in the right middle finger. Note the prominent periosteal reaction and soft tissue swelling adjacent to the proximal interphalangeal joint. Spindle-shaped swelling near the proximal interphalangeal joint may clinically resemble arthritis of that joint causing diagnostic confusion. The joint margin is preserved indicating that in early stages tuberculosis dactylitis spares the adjacent joint, the articular margins remain intact Reproduced with permission from “Malaviya AN, Kotwal PP. Arthritis associated with tuberculosis. Best Practice and Res Clin Rheumatol 2003;17:319-43 (reference 6)” Copyright [2003] Elsevier

Radioisotope bone scan may reveal ‘hot spots’ in the metaphysis, diaphysis of a short bone in hand or foot that favours the diagnosis of TB osteomyelitis. Tuber-

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culosis of the spine is an important differential diagnosis in certain types of back pain. Depending upon the presence or absence of symptoms considered red flags for possible serious spinous pathology, rheumatologists classify back pain as ‘specific’ and ‘non-specific’ (29,30). The red flag symptoms for back pain include constitutional symptoms, non-mechanical nature of pain that is characteristically acute, severe and persistent without precipitants, pains at night, pain worse in the morning, hyperextension of spine and walking. Involvement of thoracic spine presenting as pain on coughing or sneezing is also considered red flag symptom for spinous pathology. This is also seen in ankylosing spondylitis where thoracic cage involvement is very common. Presence of widespread neurologic features, localized tenderness in the spine without structural deformity, onset under 30 or above 50 years of age, often in an immunocompromised host [glucocorticoids, HIV, cytotoxic drugs, debilitating underlying illness, etc.], favour the diagnosis of serious spinous pathology. It is also to be noted that ‘specific’ back pain under the red flag category includes inflammatory back pain seen in spondylarthropathies and ankylosing spondylitis as well as ‘sinister’ back pain caused by infection [e.g., TB] or neoplasm. The former has typical features of inflammatory rheumatic disease including duration of spinal discomfort for at least three months, spinal morning stiffness, age less than 40 years, insidious onset of symptoms, and no relief from pain with rest, but improvement with exercise (31). These features are generally not seen in ‘sinister’ back pains caused by neoplasms and infection [TB spine]. However, even in TB spine occasionally the symptoms may resemble those of inflammatory back pain (31). In endemic areas, back pain due to TB spine is most often seen in children and young adults. However, in developed countries it is more often seen in older age with a mean of approximately 50 years (3). Therefore, as a rule, in any specific back pain TB spine should be one of the diagnostic considerations, especially if other risk factors are present. Tuberculosis infection of soft tissue may present as bursitis, tenosynovitis, myositis, or fasciitis [Figure 24.3]. However, these are uncommon presentations of MSKTB. Their clinical resemblance with local and focal soft tissue inflammatory disorders may cause delay in diagnosis (32). However, in patients with pre-existing systemic rheumatic diseases, and other risk factors

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Figure 24.3: Tuberculosis tenosynovitis of the extensor tendon of the hand with skin ulceration [A] and healed lesion after antituberculosis drug treatment [B]. Reproduced with permission from “Malaviya AN, Kotwal PK. Arthritis associated with tuberculosis. Best Practice Res Clin Rheumatol 2003;17:319-43 (reference 6)” Copyright [2003] Elsevier

discussed above, appearance of these soft tissue manifestations should raise the suspicion of soft tissue TB. CHANGING CLINICAL PATTERN OF TUBERCULOSIS ARTHRITIS As discussed elsewhere in the book, all forms of extrapulmonary TB are seen in endemic countries. Generally, TB arthritis is more common among children, juveniles or young adults typically presenting as chronic monoarthritis of the weight-bearing joints (3,33). However, in non-endemic countries it is generally a disease of older age with involvement of non-weight bearing joints presenting as oligoarthritis indicative of an immunocompromised host status (3,33,34). In recent years, this trend is changing even in developing countries where presentation with oligoarthritis of non-weightbearing joints in older patients is common (3,32). It has already been mentioned above that an immunocompromised state due to an increasing incidence of diabetes mellitus, wider use of immunosuppressive drugs including glucocorticoids, malnutrition, HIV, substance abuse, alcoholism and a host of other factors, is the likely cause for this change in pattern of the disease. REACTIVE [PARA-INFECTIOUS] ARTHRITIS [PONCET’S DISEASE] In 1887, Poncet described inflammatory arthritis in the joints of the hands and feet in 12 patients with a past or

current history of extra-pulmonary TB (35). However, Poncet’s concept of ‘tuberculosis rheumatism’ was rather broad and non-specific that tended to include all forms of polyarthritis associated with active or inactive TB, associated with a family history of TB or, evidence of foci of TB in any joint before, coincident with, or following a polyarthritis (36). The lack of diagnostic precision and specificity in this broad description led to unrelated diseases getting labelled as ‘Poncet’s disease’ and the concept became controversial. For the present, “tuberculosis rheumatism” [Poncet’s disease] is defined as a polyarthritis associated with extra-pulmonary TB in which there is no evidence of bacteriologic involvement of the joints themselves (37-42). Pathogenesis Pathogenesis of Poncet’s disease is uncertain. Most workers believe it to be a ‘reactive arthritis’ due to hypersensitive immune response against tuberculoprotein (3742). It is known that mycobacteria are arthritogenic. Injection of heat killed and desiccated Mycobacterium tuberculosis in oil [complete Freund’s adjuvant] in animals can produce a chronic synovitis resembling rheumatoid arthritis (43). Interestingly, bacillus Calmette-Guérin [BCG] immunotherapy given in cancer patients has been shown to produce arthritis as an adverse effect, possibly caused by a similar adjuvant effect (44). Molecular mimicry between mycobacterial antigens and host tissues resulting in immunologic cross-reactivity has been implicated in its causation. Thus, antigenic similarity between a fraction of Mycobacterium tuberculosis and human cartilage has been demonstrated (45) as has been the mycobacterial heat shock protein [HSP65] that crossreacts with human HSP (46). A T-cell mediated crossreactive autoimmune response might also be operative in the pathogenesis of Poncet’s disease. Increasing reports of Poncet’s disease in HIV infected persons have brought out the complexities of the relationship between host and pathogen leading to paradoxical activation of some immune responses causing immune-mediated tissue lesions (47). Since Poncet’s disease apparently occurs only in a small proportion of patients with active TB, a genetic predisposition might be involved. In one of the Poncet’s disease patients investigated by the authors’ group, the human leucocyte antigen [HLA] haplotype was DR2, DR4. It is interesting to note that genes coding for this allele are associated with RA and may also influence the

Musculoskeletal Manifestations of Tuberculosis immune response to mycobacterial antigens. The DR4+ patients are hyperresponsive to mycobacterial antigens (48). Poncet’s disease might result from a genetically determined HLA-linked hyper-responsiveness to mycobacterial antigens disseminating into the joint spaces (49). This issue needs further studies. A number of case reports and small series have been published describing patients with this disease (3742,50,51). Poncet’s disease has been mainly a disease of juveniles or young adults with a slight female preponderance. These patients present with fever and constitutional symptoms associated with acute or subacute symmetrical peripheral inflammatory polyarthritis predominantly involving the large joints [the knee being the most common, followed by ankle and wrist] (37-42,50,51). Small joints may be affected in a symmetrical fashion resembling RA, but asymmetrical involvement is also frequently seen. Joint effusions are not uncommon. Some of the patients have oligoarticular presentation (37-42,50,51). Several other workers have also described it as a pauciarticular symmetrical arthritis predominantly involving the large joints in the extremities (37-42,50,51). Lymph nodes are the most common extra-pulmonary site of TB (37-42,50-52). The cervical, supraclavicular, axillary mediastinal and retroperitoneal lymph nodes are often enlarged with demonstrable caseous granulomas. Hilar and paratracheal lymphadenopathy with or without pulmonary infiltrates may be encountered (37-42,50-52). Patients of Poncet’s disease presenting with fever, polyarthritis and TB lymphadenitis may also develop pleural or pulmonary TB during the course of their illness (51). The existence of this entity, however, has been questioned (53) and the concept still remains controversial because the search for active TB foci in these joints has not always been rigorous (49). Some patients clinically suspected of Poncet’s disease, on careful diagnostic work-up were proven to have polyarticular TB arthritis (54). Poncet’s disease is mainly a “diagnosis of exclusion” in a patient with polyarthritis associated with documented active TB. Investigations usually demonstrate non-specific findings with negative autoimmune serology. The synovial fluid shows inflammatory characteristics with no microbiological evidence of TB. The arthritis in Poncet’s disease is said to resolve completely with antituberculosis therapy.

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ARTHRITIS ASSOCIATED WITH ADJUVANT MYCOBACTERIAL TREATMENT OF URINARY BLADDER CANCER Use of BCG as an adjuvant in the therapy of bladder cancer for stimulating T-cell-mediated immunity is now a standard practice. Interestingly, 0.4 to 0.8 per cent of these patients develop inflammatory polyarthritis following intravesical administration of BCG (55). In approximately one-fifth of the patients, the disease simulated spondyloarthritis with lower limb asymmetrical inflammatory arthritis with sacroiliitis that was associated with HLA-B27 (55). In another study (44), synovial biopsy showed development of an inflammatory synovitis predominantly comprising of Tlymphocytes that resolved spontaneously within 14 days. Thus, arthritis associated with adjuvant BCG treatment of bladder cancer appears to be the human counterpart of ‘adjuvant arthritis’ routinely produced in experimental animals by injecting complete Freund’s adjuvant containing heat-killed Mycobacterium tuberculosis. The Tcell cross-reactivity between mycobacteria and human proteins could be the most likely common aetiological factor between all these three forms of reactive arthritis with HSP65 as the main candidate cross-reactive antigen. Besides 50 per cent homology with human HSP the mycobacterial HSP also has homologies with proteoglycan and HLA-DR (55). PANNICULITIS ASSOCIATED WITH TUBERCULOSIS The term “panniculitis” has been given to non-suppurative inflammation in the subcutaneous fat [i.e., panniculus] (56,57). Some forms of panniculitides have been considered to have TB aetiology. It is not uncommon for patients with panniculitis to present with arthralgias or frank arthritis, often associated with a characteristic periankle inflammatory oedematous lesion with overlying skin showing ecchymotic purplish discolouration and scaling. Other large and small peripheral joints may also be affected transiently. Rheumatologists often see such patients due to the presence of arthritis. The most common form of panniculitis in clinical practice is erythema nodosum [EN] which is a form of septal panniculitis without vasculitis (56-58). It has a strong gender bias, seen much more often in young women. Clinically, it is characterized by acute or subacute appearance of a few tender erythematous nodules on the

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anterior tibial surface that are better palpated than visualized. The overlying skin shows indurated inflammation. Healing starts within a few days with softening of the nodules that become less palpable. The skin colour changes to an unusual ecchymotic purplish discolouration associated with scaling of the skin. Usually, the healing is complete in four to six weeks without suppuration or scarring. In addition to the MSK symptoms and the nodules on the lower leg, fever, malaise, leucocytosis, are other common features. The EN is considered to be a form of hypersensitivity reaction mainly after primary contact with the implicated aetiological factors. These include streptococcal and upper respiratory infections, acute onset of sarcoidosis, and inflammatory bowel disease. Other less common aetiological factors include TB, histoplasmosis, coccidioidomycosis, psittacosis and other rare infections; oral contraceptives, several other drugs [sulphonamides, aspartame, bromides, iodides], and pregnancy (58). Another form of panniculitis that has close clinical and morphologic resemblance to EN is called erythema induratum [EI]. It is a form of lobular panniculitis associated with vasculitis of medium- or small-sized blood vessels in the panniculus. It has often been labelled as ‘nodular vasculitis’ (59). The patients usually have no constitutional symptoms and appear otherwise healthy. In contrast to EN, EI occurs without any gender bias. Despite its close clinical resemblance to EN, unlike EN the commonest site of the nodules is on the calves rather than the shin. Also, unlike EN, EI lesions may breakdown and ulcerate or heal with scar. A proportion of patients with lesions clinically and histopathologically indistinguishable from EI shows an adjacent suppurative or granulomatous panniculitis. This presentation, called Bazin’s disease, is considered rather specific for TB (56,60). Recent studies have shown that a significant number of these patients have a form of cutaneous TB; typically seen in young patients; the lesions being labelled as ‘tuberculid’ (47,60). Histopathology usually confirms the diagnosis of TB but in others it may require confirmation with other investigations, such as polymerase chain reaction [PCR] (61). Response to antituberculosis treatment is usually satisfactory. Therefore, distinction between EN and EI is crucial for appropriate treatment (60,62). It is important to note that the inflammatory arthritis/periarthritis of ankle often associated with peripheral polyarthritis characteristic of EN, may also

be seen with EI including Bazin’s disease (63-65). Therefore, with rising incidence of extra-pulmonary TB, vague arthralgias, arthritis and especially ankle-periankle arthritis associated with induration and inflammatory oedema with lesions of panniculitis need to be carefully worked up with TB as a distinct possibility. UNUSUAL PRESENTATIONS OF MUSCULOSKELETAL TUBERCULOSIS Literature is replete with a variety of unusual presentations of MSK-TB. Thus, a non-healing ulcerative mass of the elbow in a 69-year-old woman resembling synovial sarcoma, which on histopathology showed TB synovitis (66). A 51-year-old woman’s left hip pain was because of left trochanteric bursitis due to TB (67); a sternoclavicular mass in a haemodialysis patient was proven to be TB arthritis on culture (14); another patient had bilateral sternoclavicular joint TB (68). Four cases have been reported in the world literature with TB arthritis causing Baker’s cyst (69). Injury-related TB [injury tuberculosis] among immigrants from ‘high burden’ areas (19), TB arthritis of the right great toe (70); TB of the lower end of the fibula in a young patient presenting with symptoms of pain and swelling over the outer aspect of the right ankle (71), foot pain in a patient with spinal TB due to TB arthritis of midtarsal joints (72), sternal TB that developed following sternotomy performed for coronary artery bypass graft surgery (20), have all been reported. The TB dactylitis may resemble sickle cell anaemia and lytic lesions of neuroblastoma, Langerhans’ cell histiocytosis and leukaemia (73). The TB oesophageal ulcer has been described as an unusual presentation of Pott’s disease (74). Rare cases of multifocal skeletal TB have also been described. The disease may also resemble RA (75). Unusual manifestations of osteoarticular TB have also been reported (76). MUSCULOSKELETAL DISEASE ASSOCIATED WITH NONTUBERCULOUS MYCOBACTERIA Musculoskeletal TB caused by nontuberculous mycobacteria [NTM] is uncommon but not rare. Most common mycobacterial species to cause such problems is Mycobacterium kansasii (77-79), although other NTM, such as Mycobacterium xenopi (80,81), Mycobacterium marinum (82,83), Mycobacterium avium intracellulare, Mycobacterium chelonei (84), and Mycobacterium fortuitum (85) have also

Musculoskeletal Manifestations of Tuberculosis been implicated. For some reasons, synovial sheath infection is much more common than infection of the osseous tissue (86). Predisposing factors are discernible in most cases and may include history of trauma [including puncture wound], surgery, glucocorticoid therapy, plaque psoriasis, a pre-existing MSK disease, immunocompromised conditions, such as diabetes mellitus, haemodialysis, renal transplantation, Hodgkin’s disease, and HIV infection (76,86,87). Occasionally, arthritis due to NTM has also been reported in nonimmunocompromised host (88). Arthritis and bursitis due to Mycobacterium kansasii has been described in a patient with systemic lupus erythematosus [SLE] (78,89). An unusual form of arthritis due to NTM on exposure to contaminated marine life has been described (90,91). Recently, a case of tenosynovitis due to Mycobacterium marinum in association with Still’s disease was described (82). ANTITUBERCULOSIS TREATMENT INDUCED ARTHRALGIAS Patients initiated on antituberculosis therapy may often complain of polyarthralgias in the initial stages with occasional actual polyarthritis (92-96). It is usually a transient self-limiting condition that does not require treatment or, at the most may require symptomatic control of pains. Most commonly incriminated drug is pyrazinamide. The exact mechanism of these symptoms is not known. Hyperuricaemia is common in patients taking pyrazinamide but gouty arthritis is rare. Use of allopurinol should be individualized depending upon the severity of arthralgias along with elevation of serum uric acid to twice the upper limit of the normal. Interestingly, ethambutol also causes mild hyperuricaemia but does not cause joint pains. These adverse events are much more common with daily as compared with intermittent administration of antituberculosis drugs. IMAGING OF MUSCULOSKELETAL TUBERCULOSIS Imaging in patients with skeletal TB is covered in detail in the chapter “Skeletal tuberculosis” [Chapter 23]. Certain key issues related to imaging in MSK-TB are described here to supplement the content covered in the chapter “Skeletal tuberculosis” [Chapter 23]. Among the various available imaging techniques, computed tomography [CT] is superior in depicting the degree of bony destruction and facilitating image-guided biopsy for

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spinal TB [Figure 24.3]. On the other hand, for detailed anatomical evaluation and for distinguishing different densities of tissues [fibrous tissue, abscess, meninges, spinal cord, etc.,] magnetic resonance imaging [MRI] with contrast is considered superior (97). The characteristic ‘Phemister’s triad’ is considered rather typical of TB. Three components of the triad are: [i] juxtaarticular osteoporosis; [ii] peripherally located osseous erosions; and [iii] gradual narrowing of the joint space (98-100). On the other hand, in the course of RA and pyogenic arthritis, the joint space narrowing occurs early. For soft tissue TB, the ultrasonography is the method of choice as it shows the extent and degree of involvement. On the other hand, the MRI shows the extent of soft tissue, osseous and joint involvement (98). One of the other typical features of TB aetiology of the bones that have a relatively superficial cortical surface [e.g., metacarpals, metatarsals, phalanges, tibia and ulna] is the presence of lytic lesions surrounded by reactive subperiosteal new bone formation (86). It needs to be emphasized that despite these advances, the ‘gold standard’ for the diagnosis of TB of the MSK system still remains histopathological and/or microbiological confirmation; definitive treatment cannot be instituted before confirming the diagnosis (98). DIAGNOSIS A high index of suspicion is required for making the diagnosis of MSK-TB. The clinical presentation and the characteristic pattern of joint involvement should arouse the suspicion of MSK-TB. Imaging of the lesion and confirmation of the diagnosis by histopathological and microbiological techniques then follow. Adequate tissue biopsy of the representative lesion is the quickest method of confirming the diagnosis of TB. Synovial biopsy is usually satisfactory with more than 90 per cent yield (35). Synovial fluid smear for acid-fast bacilli [AFB] is positive in 20 to 40 per cent of cases, while culture could yield a positive result in up to 80 per cent cases (3). Indications for Synovial Biopsy The issues concerning procurement of adequate tissue for histopathological diagnosis of skeletal TB are discussed in the chapter “Skeletal tuberculosis” [Chapter 23]. The indications for a synovial biopsy in patients with MSK-TB from a rheumatologist’s perspective is discussed below.

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When clinical evaluation and routine investigations fail to provide a diagnosis, synovial biopsy is the logical next step. It is usually the only definitive method of diagnosing infection with fastidious organisms including TB. An absolute indication for synovial biopsy is a chronic inflammatory monoarthritis where synovial fluid examination including microbiological studies may have failed to give a definitive diagnosis. Another strong indication for synovial biopsy would be a patient with persistent disease activity in a single joint. TREATMENT Treatment consists of administration of standard antituberculosis drugs. Many workers suggest nine months of treatment for extra pulmonary TB including MSK-TB (101). The reader is referred to the chapter “Treatment of tuberculosis” [Chapter 52] for more details. REFERENCES 1. Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316-53. 2. Tuli SM. Tuberculosis of the skeletal system. New Delhi: Jaypee Brothers Medical Publishers;1997. 3. Mahowald ML. Arthritis due to mycobacteria, fungi and parasites. In: Koopman WJ, editor. Arthritis and allied conditions. Fourteenth edition. Baltimore: Lippincott Williams and Wilkins;2002. 4. Gabriel SE. Epidemiology of the rheumatic diseases. In: Ruddy S, Harris ED Jr., Sledge CB, editors. Kelley’s textbook of rheumatology. Philadelphia: W.B. Saunders;2001.p.321-33. 5. Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41:778-99. 6. Malaviya AN, Kotwal PP. Arthritis associated with tuberculosis. Best Practice Res Clin Rheumatol 2003;17:319-43. 7. Malaviya AN, Kumar A, Muralidhar R, Pande I. Rheumatological manifestations of tuberculosis–a short review. J Indian Rheumatism Assoc 1994;2:145-8. 8. Huebner RE, Castro KG. The changing face of tuberculosis. Annu Rev Med 1995;46:47-55. 9. Puttick MP, Stein HB, Chan RM, Elwood RK, How AR, Reid GD. Soft tissue tuberculosis: a series of 11 cases. J Rheumatol 1995;22:1321-5. 10. Abdelwahab IF, Bianchi S, Martinoli C, Klein M, Hermann G. Atypical extraspinal musculoskeletal tuberculosis in immunocompetent patients: part II, tuberculous myositis, tuberculous bursitis, and tuberculous tenosynovites. Can Assoc Radiol J 2006;57:278-86. 11. Payne K, Yang J. Joint and bone tuberculosis: a case report and discussion. CMAJ 2002;166:628-30.

12. Houshian S, Poulsen S, Riegels-Nielsen P. Bone and joint tuberculosis in Denmark: increase due to immigration. Acta Orthop Scand 2000;71:312-5. 13. Courtman NH,Weighill FJ. Systemic tuberculosis in association with intra-articular steroid therapy. J R Coll Surg Edinb 1992;37:425. 14. Fukasawa H, Suzuki H, Kato A, Yamamoto T, Fujigaki Y, Yonemura K. Tuberculous arthritis mimicking neoplasm in a hemodialysis patient. Am J Med Sci 2001;322:373-5. 15. Binymin K, Cooper RG. Late reactivation of spinal tuberculosis by low-dose methotrexate therapy in a patient with rheumatoid arthritis. Rheumatology [Oxford] 2001;40:341-2. 16. Belzunegui J, Rodriguez-Arrondo F, Gonzalez C, Queiro R, Martinez de Bujo M, Intxausti JJ, et al. Musculoskeletal infections in intravenous drug addicts: report of 34 cases with analysis of microbiological aspects and pathogenic mechanisms. Clin Exp Rheumatol 2000;18:383-6. 17. Jellis JE. Human immunodeficiency virus and joint and bone tuberculosis. Clin Orthop 2002;398:27-31. 18. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098-104. 19. Ferris BD, Goldie B, Weir W. An unusual presentation of tuberculosis—’injury TB’. Injury 1987;18:347-9. 20. Silber JS, Whitfield SB, Anbari K Vergillio J, Gannon F, Fitzgerald RH Jr. Insidious destruction of the hip by Mycobacterium tuberculosis and why early diagnosis is critical. J Arthroplasty 2000;15:392-7. 21. Hernandez-Cruz B, Sifuentes-Osornio J, Ponce-de-Leon Rosales S, Ponce-de-Leon Garduno A, Diaz-Jouanen E. Mycobacterium tuberculosis infection in patients with systemic rheumatic diseases. A case-series. Clin Exp Rheumatol 1999;17:289-96. 22. Yun JE, Lee SW, Kim TH, Jun JB, Jung S, Bae SC, et al. The incidence and clinical characteristics of Mycobacterium tuberculosis infection among systemic lupus erythematosus and rheumatoid arthritis patients in Korea. Clin Exp Rheumatol 2002;20:127-32. 23. Victorio-Navarra ST, Dy EE, Arroyo CG, Torralba TP. Tuberculosis among Filipino patients with systemic lupus erythematosus. Semin Arthritis Rheum 1996;26:628-34. 24. Chen YC, Hsu SW. Tuberculous arthritis mimics arthritis of the Sjogren’s syndrome: findings from sonography, computed tomography and magnetic resonance images. Eur J Radiol 2001;40:232-5. 25. Lorenzo JP, Csuka ME, Derfus BA, Gotoff RA, McCarthy GM. Concurrent gout and Mycobacterium tuberculosis arthritis. J Rheumatol 1997;24:184-6. 26. Berbari EF, Hanssen AD, Duffy MC, Steckelberg JM, Osmon DR. Prosthetic joint infection due to Mycobacterium tuberculosis: a case series and review of the literature. Am J Orthop 1998;27:219-27. 27. Varango G, Bamba I, Kodo M, Dao A, Lambin Y. Osteonecrosis of the hip in sickle-cell disease associated with tuberculous arthritis. A review of 15 cases. Int Orthop 1998;22:384-9.

Musculoskeletal Manifestations of Tuberculosis 28. Harrington JT. Mycobacterial and fungal infections. In: Ruddy S, Harris ED Jr, Sledge CB, editors. Kelley’s textbook of rheumatology. Sixth edition. Philadelphia: W.B. Saunders; 2001.p.1493-505. 29. Burton AK, Waddell G. Clinical guidelines in the management of low back pain. Baillières Clin Rheumatol 1998;12:1735. 30. Dieppe PA, Klippel JH. Disorders of the musculoskeletal system. In: Dieppe PA, Klippel JH, editors. Practical Rheumatology. London: Mosby;1995.p.1-2. 31. Cantini F, Salvarani C, Olivieri I, Niccoli L, Padula A, Bellandi F, et al. Tuberculous spondylitis as a cause of inflammatory spinal pain: a report of 4 cases. Clin Exp Rheumatol 1998; 16:305-8. 32. Chen WS, Eng HL. Tuberculous tenosynovitis of the wrist mimicking de Quervains’s disease. J Rheumatol 1994;21:7635. 33. Kosinski MA, Smith LC. Osteoarticular tuberculosis. Clin Podiatr Med Surg 1996;13:725-39. 34. Valdazo J, Perez-Ruiz F, Albarracin A, Sanchez-Nievas G, Perez-Benegas J, Gonzalez-Lanza M, et al. Tuberculous arthritis: report of a case with multiple joint involvement and periarticular tuberculous abscesses. J Rheumatol 1990;17:399401. 35. Poncet A. De La polyarthrite tuberculeuse deformante ou pseudorheumatisme chronique tuberculeux. Congres Francaise de Chirurgie 1887;1:732-9. 36. Isaacs AJ, Sturrock RD. Poncet’s disease: fact or fiction? A reappraisal of tuberculous rheumatism. Tubercle 1974;55:13542. 37. Bhargava AD, Malaviya AN, Kumar A. Tuberculous rheumatism [Poncet’s disease]: A case series. Indian J Tuberc 1998;45:215-9. 38. Qurttom MA, D’Almedia EA, Sattar SA, Malaviya AN. Reactive arthritis due to tuberculous lymphadenitis [Poncet’s disease] in a Sri Lankan woman. Med Princ Pract 1997;6:1626. 39. Kroot EJ, Hazes JM, Colin EM, Dolhain RJ. Poncet’s disease: reactive arthritis accompanying tuberculosis. Two case reports and a review of the literature. Rheumatology [Oxford] 2007;46:484-9. Epub 2006 Aug 25. 40. Hansen SE, Wallenquist A. A case of chronic polyarthritis with debut in 1771: rheumatoid arthritis or Poncet’s disease? Scand J Rheumatol 2007;36:322-4. 41. Ozgul A, Baylan O, Taskaynatan MA, Kalyon TA. Poncet’s disease [tuberculous rheumatism]: two case reports and review of the literature. Int J Tuberc Lung Dis 2005;9:822-4. 42. Kawsar M, D’Cruz D, Nathan M, Murphy M. Poncet’s disease in a patient with AIDS. Rheumatology [Oxford] 2001;40:3467. 43. Pearson CM. Development of arthritis, periarthritis, and periostitis in rats given adjuvants. Proc Soc Exp Biol Med 1956;91:95-101.

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44. Hughes RA, Allard SA, Maini RN. Arthritis associated with adjuvant mycobacterial treatment for carcinoma of the bladder. Ann Rheum Dis 1989;48:432-4. 45. Holoshitz J, Drucker I, Yaretzky A, Lapidot Z, Yaretzky A, Frenkel A, et al. T lymphocytes of patients with rheumatoid arthritis patients show augmented reactivity to a fraction of mycobacteria cross-reactive with cartilage. Lancet 1986;2:3059. 46. Iwata H, Kinoshita M, Sumiya M, Iwai A, Aotsuka S, Hirata D, et al. Emergence of erosive polyarthritis coincident with Mycobacterium kansasii pulmonary infection in a patient with systemic sclerosis-rheumatoid arthritis overlap syndrome. Clin Exp Rheumatol 1999;17:757-8. 47. Cuende E, Almeida V, Portu J, Aldamiz M, Erdozain MA, Vesga JC, et al. Poncet’s disease and papulonecrotic tuberculid in a patient infected with the human immunodeficiency virus. Arthritis Rheum 1998;41:1884-8. 48. Ottenhoff TH, Torres P, de las Aguas JT, Fernandez R, van Eden W, de Vries RR, et al. Evidence for an HLA-DR4-associated immune response gene for Mycobacteruim tuberculosis: a clue to the pathogenesis of rheumatoid arthritis. Lancet 1986;2:310-3. 49. Southwood TR, Gaston JSH. The molecular basis of Poncet’s disease? Br J Rheumatol 1990;29:491. 50. Kumar A. Rheumatic manifestations of tuberculosis. In: Sharma SK, editor. Tuberculosis. First edition. New Delhi: Jaypee Brothers Medical Publishers; 2001.p.593-6. 51. Sood R, Wali JP, Handa R. Poncet’s disease in a north Indian hospital. Trop Doct 1999;29:33-6. 52. Ku FS, Li CL, Shen LH, Hsing S. Differential diagnosis of rheumatic fever and allergic arthritis due to tuberculosis. Chin Med J [Engl] 1966;85:477-81. 53. Summers SD, Jayson MIV. Does Poncet’s disease exist? Rheumatol Rehab 1980;19:149-50. 54. Hameed K, Karim M, Islam N, Gibson T. The diagnosis of Poncet’s disease. Br J Rheumatol 1993;32:824-6. 55. Wollheim FA. Enteropathic arthritis. In: Ruddy S, Harris ED Jr, Sledge CB, editors. Kelley’s textbook of rheumatology. Philadelphia: W.B. Saunders;2001.p.994-5. 56. Barnhill RL, Busam KJ. Vascular diseases. In: Elder D, editor. Lever’s histopathology of the skin. Eighth edition. Philadelphia: Lippincott-Raven;1997.p.191-2. 57. Callen JP, Zax RH. Panniculitis. In: Maddison PJ, Isenberg DA, Woo P, Glass DN, editors. Oxford textbook of rheumatology. Second edition. Oxford: Oxford University Press; 1998.p.1450-6. 58. Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease. Am Fam Physician 2007;75:695-700. 59. Leow LJ, Pintens S, Pigott PC, Whitfeld MJ. Erythema induratum–a hypersensitivity reaction to Mycobacterium tuberculosis. Aust Fam Physician 2006;35:521-2. 60. Feuer J, Phelps RG, Kerr LD. Erythema nodosum versus erythema induratum: a crucial distinction enabling

382

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

Tuberculosis recognition of occult tuberculosis. J Clin Rheumatol 1995;1:357-62. Yen A, Fearneyhough P, Rady P, Tyring S, Diven D. Erythema induratum of Bazin as a tuberculid: confirmation of Mycobacterium tuberculosis DNA polymerase chain reaction analysis. J Am Acad Dermatol 1997;36:99-101. Malaviya AN, Francis IM, Kaushik P, Ayyash EH. Musculoskeletal manifestations with panniculitis–a hospital based study on 62 patients in Kuwait. Rheumatol Int 1999;19:51-7. McCune WJ, Golbus J. Monoarthritis. In: Ruddy S, Harris ED Jr, Sledge CB, editors. Kelley’s textbook of rheumatology. Philadelphia: W.B. Saunders; 2001.p.367-70. Zvaifler NJ. Uncommon arthropathies. In: Stein J, editor. Internal medicine. Third edition. Boston: Little Brown; 1990.p. 1774-7. Mana J, Gomez-vaquero C, Salazar A, Valverde J, Juanola X, Pujol R. Periarticular ankle sarcoidosis: a variant of Lofgren’s syndrome. J Rheumatol 1996;23:874-7. Ayhan S, Ozmen S, Uluoglu O, Demirtas Y, Boyacioglu M, Latifoglu O, et al. Nonhealing ulcerative mass of the elbow: do not forget tuberculosis. Ann Plast Surg 2002;48:557-61. Perez C, Rojas A, Baudrand R, Gonzalez S, Fontbote C. Tuberculosis bursitis: report of case. Rev Med Chil 2002; 130:319-21. Dhillon MS, Gupta R, Rao KS, Nagi ON. Bilateral sternoclavicular joint tuberculosis. Arch Orthop Trauma Surg 2000;120:363-5. Bianco G, Paris A, Venditti M, Calderini C, Anzivino C, Serra P. Popliteal [Baker’s] cyst in a patient with tubercular arthritis. Report of a case and review of the literature. Recenti Prog Med 2001;92:663-6. Garcia-Porrua C, Gonzalez-Gay MA, Sanchez-Andrade A, Vazquez-Caruncho M. Arthritis in the right great toe as the clinical presentation of tuberculosis. Arthritis Rheum 1998;41:374-5. Malhan K, Kumar A, Sherman KP. Use of polymerase chain reaction in diagnosis of occult tuberculosis of the fibula. Acta Orthop Belg 2001;67:510-2. Ong Y, Cheong PY, Low YP, Chong PY. Delayed diagnosis of tuberculosis presenting as small joint arthritis—a case report. Singapore Med J 1998;39:177-9. Wessels G, Hesseling PB, Beyers N. Skeletal tuberculosis: dactylitis and involvement of the skull. Pediatr Radiol 1998;28:234-6. Collazos J, Quintas L, Mayo J. Tuberculous esophageal ulcer as the mode of presentation of Pott’s disease [tuberculous spondylitis]. Am J Med 2002;112:737-9. Tsuduki E, Kawada H, Takeda Y, Toyoda E, Kobayashi N, Kudo K, et al. A case of multiple bone and joint tuberculosis which had been misdiagnosed as the rheumatoid arthritis and treated with prednisolone for eleven months. Kekkaku 2002;77:361-6. Babhulkar S, Pande S. Unusual manifestations of osteoarticular tuberculosis. Clin Orthop 2002;398:114-20.

77. Bernard L, Vincent V, Lortholary O, Raskine L, Vettier C, Colaitis D, et al. Mycobacterium kansasii septic arthritis: French retrospective study of 5 years and review. Clin Infect Dis 1999;29:1455-60. 78. Nakamura T, Yamamura Y, Tsuruta T, Tomoda K, Sakaguchi M, Tsukano M, et al. Mycobacterium kansasii arthritis of the foot in a patient with systemic lupus erythematosus. Intern Med 2001;40:1045-9. 79. Saphyakhajon P, Mukhopadhyay D, Spiegal P, Grossman BJ. Mycobacterium kansasii arthritis of the knee joint. Am J Dis Child 1977;131:573-5. 80. Libbrecht E, Bressieux JM, Chelius P, Roger M, Eloy C, Rezzouk L, et al. Mycobacterium xenopi osteoarthritis of the ankle in a patient followed for psoriatic rheumatism. Presse Med 2000;29:539-40. 81. Yuen K, Fam AG, Simor A. Mycobacterium xenopi arthritis. J Rheumatol 1998;25:1016-8. 82. Thariat J, Leveque L, Tavernier C, Maillefert JF. Mycobacterium marinum tenosynovitis in a patient with Still’s disease. Rheumatology [Oxford] 2001;40:1419-20. 83. Ekerot L, Jacobsson L, Forsgren A. Mycobacterium marinum wrist arthritis: local and systematic dissemination caused by concomitant immunosuppressive therapy. Scand J Infect Dis 1998;30:84-7. 84. Toussirot E, Chevrolet A, Wendling D. Tenosynovitis due to Mycobacterium avium intracellulare and Mycobacterium chelonei: report of two cases with review of the literature. Clin Rheumatol 1998;17:152-6. 85. Badelon O, David H, Meyer L, Radault A, Zucman J. Mycobacterium fortuitum infection after total hip prosthesis. A report of 3 cases. Rev Chir Orthop Reparatrice Appar Mot 1979;65:39-43. 86. Tuli SM. General principles of joint and bone tuberculosis. Clin Orthop Relat Res 2002;398:11-9. 87. Kelly M, Thibert L, Sinave C. Septic arthritis in the knee due to Mycobacterium xenopi in a patient undergoing hemodialysis. Clin Infect Dis 1999;29:1342-3. 88. Frosch M, Roth J, Ullrich K, Harms E. Successful treatment of Mycobacterium avium osteomyelitis and arthritis in a non-immunocompromised child. Scand J Infect Dis 2000;32:328-9. 89. Mok MY, Wong SS, Chan TM, Fong DY, Wong WS, Lau CS. Non-tuberculous mycobacterial infection in patients with systemic lupus erythematosus. Rheumatology [Oxford] 2007;46:280-4. Epub 2006 Jul 22. 90. Barton A, Bernstein RM, Struthers JK, O’Neill TW. Mycobacterium marinum infection causing septic arthritis and osteomyelitis. Br J Rheumatol 1997;36:1207-9. 91. Alloway JA, Evangelisti SM, Sartin JS. Mycobacterium marinum arthritis. Semin Arthritis Rheum 1995;24:382-90. 92. Inoue T, Ikeda N, Kurasawa T, Sato A, Nakatani K, Ikeda T, et al. Hyperuricemia and arthralgia during pyrazinamide treatment. Nihon Kokyuki Gakkai Zasshi 1999;37:115-8. 93. Koumbaniou C, Nicopoulos C, Vassiliou M, MandaStachouli C, Sakellariou K, Demou GS, et al. Is pyrazinamide

Musculoskeletal Manifestations of Tuberculosis really the third drug of choice in the treatment of tuberculosis? Int J Tuberc Lung Dis 1998;2:675-8. 94. Schaberg T, Rebhan K, Lode H. Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. Eur Respir J 1996;9:202630. 95. Lacroix C, Guyonnaud C, Chaou M, Duwoos H, Lafont O. Interaction between allopurinol and pyrazinamide. Eur Respir J 1988;1:807-11. 96. Marra F, Marra CA, Bruchet N, Richardson K, Moadebi S, Elwood RK, et al. Adverse drug reactions associated with first-line anti-tuberculosis drug regimens. Int J Tuberc Lung Dis 2007;11:868-75.

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97. De Backer AI, Mortele KJ, Vanhoenacker FM, Parizel PM. Imaging of extraspinal musculoskeletal tuberculosis. Eur J Radiol 2006;57:119-30. Epub 2005 Aug 31. 98. Griffith JF, Kumta SM, Leung PC, Cheng JC, Chow LT, Metreweli C. Imaging of musculoskeletal tuberculosis: a new look at an old disease. Clin Orthop 2002;398:32-9. 99. Engin G, Acunas B, Acunas G, Tunaci M. Imaging of extrapulmonary tuberculosis. Radiographics 2000; 20:471-88. 100. Harisinghani MG, McLoud TC, Shepard JA, Ko JP, Shroff MM, Mueller PR. Tuberculosis from head to toe. Radiographics 2000;20:449-70. 101. Sequeira W, Co H, Block JA. Osteoarticular tuberculosis: current diagnosis and treatment. Am J Ther 2000;7:393-8.

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Cutaneous Tuberculosis

25 M Ramam

INTRODUCTION Cutaneous tuberculosis [TB] is an ancient disease. Cutaneous lesions of TB were described long before Robert Koch identified Mycobacterium tuberculosis. The first description of cutaneous TB is attributed to Laennec (1) in 1826 who described his own prosector’s wart that followed an injury sustained while performing an autopsy on a patient with spinal TB. Mycobacterium tuberculosis was first demonstrated in tissue sections of lupus vulgaris by Demme (2) in 1883. In 1886, Reihl and Paltauf (3) established that the prosector’s wart was a TB lesion. Apple-jelly nodules in lupus vulgaris were first described in 1888 (4) and tuberculids in 1896 (5). EPIDEMIOLOGY World Scenario Cutaneous TB appears to have been frequently encountered by dermatologists all around the world during the early part of this century and comprised 0.1 to 2.6 per cent of the total number of dermatology patients in various hospitals at different periods of time (6-22). Some workers had suggested that cutaneous TB was uncommon in the tropics and ascribed this difference to the abundant sunshine and consequent high levels of vitamin D in the skin (9,23). However, this view appears erroneous as evidenced by the numerous reports of cutaneous TB from India (24-36). Indian Scene No systematic survey for the prevalence and incidence of cutaneous TB in the community appears to have been

carried out in India. Information on the epidemiology of the disease is, therefore, based on hospital records and suffers from the usual drawbacks of such data. Cutaneous TB accounts for 0.11 to 2.5 per cent of all patients with skin diseases seen at hospitals located in different parts and this figure seems to be constant for all regions of the country (24-36). In a study from Vishakapatnam (24), cutaneous TB constituted 0.025 per cent of all patients with TB and 15 per cent of all patients with extra-pulmonary TB. One study (34) found that cutaneous TB was associated with TB in other organs in 22.1 per cent of patients. The organs affected most commonly were lungs, followed by bones, abdomen, central nervous system and the heart. Most studies reveal a male preponderance and a significant proportion of those affected are children (24-36). The disease is more common in the poor. In a study from Chandigarh (34), about 70 per cent of the patients had developed the disease in spite of having been vaccinated with bacille Calmette-Guérin [BCG]. Patients who had not been vaccinated were more likely to have TB in another organ than those who had received BCG vaccine (34). CLINICAL FEATURES Cutaneous TB presents in a variety of ways. The presentation is determined by the host immune response, the route of inoculation and the previous sensitization of the host to the Mycobacterium tuberculosis. The clinical varieties of cutaneous TB can be divided into three broad groups [Table 25.1]. Lupus vulgaris is the most common variety reported from India followed by TB verrucosa cutis and scrofuloderma. The other types are distinctly rare.

Cutaneous Tuberculosis Table 25.1: Clinical varieties of cutaneous tuberculosis Lesions developing in those not previously exposed to Mycobacterium tuberculosis Tuberculosis chancre Acute miliary tuberculosis of the skin Lesions developing in previously sensitized hosts Lupus vulgaris Tuberculosis verrucosa cutis Scrofuloderma Tuberculids Lichen scrofulosorum Papulonecrotic tuberculids Erythema induratum Erythema nodosum

Tuberculosis Chancre Tuberculosis chancre develops at the site of inoculation of Mycobacterium tuberculosis in a previously nonsensitized host. The bacillus enters the skin following minor wounds and abrasions. It may also gain entry following trauma, injections, circumcision and ear piercing. A non-descript papule or nodule develops at the site followed by crusting and ulceration. Spontaneous healing may occur but lesions usually proceed to lupus vulgaris. The regional lymph nodes are enlarged and may break down to form a discharging sinus in three to six months. Acid-fast bacilli [AFB] can be demonstrated and grown from early lesions. Skin biopsy reveals necrosis, infiltration by neutrophils and numerous AFB in early lesions. Later, epithelioid cell granulomas develop accompanied by the disappearance of the bacilli from the lesion.

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indolent, asymptomatic, gradually progressive, firm plaque with central clearing and peripheral activity [Figure 25.2]. In some cases, the progressing border of the plaque reveals translucent, erythematous papules that show a residual yellowish brown colour when blanched with a glass slide, the so-called apple-jelly nodules. Though this term is associated with lupus vulgaris, it may be seen in other granulomatous diseases including sarcoidosis and leprosy. Further, apple-jelly nodules are often obscured by the hyperkeratosis and crusting of lupus vulgaris. Thus, this is not a particularly useful sign. As the lesion progresses, there is central healing with scarring while the periphery continues to spread [Figure 25.3]. The lesion may be atrophic or may

Figure 25.1: Miliary tuberculosis of the skin. Chest radiograph demonstrated bilateral miliary lesions. Polymerase chain reaction [PCR] from skin lesions detected mycobacterial DNA

Acute Miliary Tuberculosis of the Skin Miliary TB develops following the haematogenous dissemination of Mycobacterium tuberculosis (37). It may follow measles or other viral exanthems (38). The skin lesions of miliary TB present as pustules, vesicles and papules that have a non-specific appearance and lack any diagnostic features [Figure 25.1]. Constitutional symptoms are usually severe and the patient is usually gravely ill. The diagnosis may be suspected if the patient is known to have TB in another organ system. Mycobacterium tuberculosis can be demonstrated in the lesions. Lupus Vulgaris Lupus vulgaris is probably the most common manifestation of cutaneous TB. Classically, it presents as an

Figure 25.2: Lupus vulgaris. Central scarring and peripheral activity in a long-standing lesion

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Tuberculosis underlying focus. It has also been reported as a rare complication of BCG vaccination (40,41) [Figure 25.5]. The regional lymph nodes may be slightly enlarged but do not show any evidence of TB. In some patients, the presence of broad, atrophic scarring indicating the possibility of a previous TB infection of the regional lymph nodes may be noted [Figure 25.6]. Less commonly, the regional lymph nodes draining a lesion of lupus vulgaris may show active scrofuloderma. Most patients with lupus vulgaris are well preserved and do not have constitutional symptoms even when lesions are extensive and multiple. The tuberculin skin test [TST] is positive in almost all patients. Skin biopsy reveals epithelioid cell granulomas in the upper dermis abutting the epidermis

Figure 25.3: Lupus vulgaris. Annular plaque with erythematous and scaly papules at the periphery and a relatively clear centre

Figure 25.5: Lupus vulgaris following vaccination with BCG Figure 25.4: Lupus vulgaris. The buttocks are a common site

show varying degrees of hyperkeratosis that may be severe enough to produce cutaneous horns. The lesion is usually dry but may occasionally be accompanied by a thin sero-purulent discharge and moist crusts due to secondary infection. Lesions may reach enormous sizes over the years and cause considerable damage and mutilation. Squamous cell carcinoma has been described to complicate long-standing lesions (39). The classical site of lesion is the face but it is seen at least as commonly on the buttocks [Figure 25.4] and lower limbs in Indian patients. The lesion is usually single but less commonly, multiple lesions may develop in one anatomic area or may be scattered over the skin surface. Rarely, symmetrical lesions may develop. Lupus vulgaris may develop at the site of cutaneous extension of TB from an

Figure 25.6: Lupus vulgaris of the ear lobe. Note scars of healed scrofuloderma on the neck

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carefully from the least keratotic area and incised deep enough to include the underlying indurated plaque, else, only thickened stratum corneum will be seen. An adequate biopsy reveals an enormously thickened epidermis with small epithelioid granulomas amidst an infiltrate of lymphocytes and plasma cells in the upper and mid dermis. Necrosis is absent and AFB cannot usually be demonstrated or grown from biopsy material. Scrofuloderma

Figure 25.7: Indurated plaque with a horny, keratotic surface

Scrofuloderma is the term applied to lesions that develop in the skin from contiguous spread or extension of TB infection from an underlying or adjacent structure. Most often, the primary focus is in the lymph nodes [Figure 25.10] but bones [Figure 25.11] and joints may

Figure 25.8: Tuberculosis verrucosa cutis. The sole is often affected

which is usually thickened and hyperkeratotic. The granulomas may show necrosis; AFB cannot, as a rule, be demonstrated in the sections. Culture of the biopsy material is not rewarding.

Figure 25.9: Tuberculosis verrucosa cutis. Very advanced disease with the entire foot appearing to be encased in a keratotic boot

Tuberculosis Verrucosa Cutis Tuberculosis verrucosa cutis, probably a variant of lupus vulgaris is characterized by a striking degree of hyperkeratosis in the lesions. The lesion usually develops over the acral parts of the extremities as a gradually progressive indurated plaque with a rough, horny surface [Figures 25.7 and 25.8]. With time, the lesions become progressively larger and hyperkeratotic and may involve the entire foot [Figure 25.9]. Multiple lesions are unusual and lymph nodes show changes similar to those seen in lupus vulgaris. Constitutional signs are usually absent. The TST is positive. Skin biopsies must be taken

Figure 25.10: Scrofuloderma overlying tuberculosis of the cervical and axillary lymph nodes

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Tuberculosis

Figure 25.11: Scrofuloderma secondary to tuberculosis of the bone. Note the thickened metacarpals underlying the sinus on the dorsum of the hand

Figure 25.12: Esthiomene secondary to healed scrofuloderma of the inguinal and external iliac lymph nodes. Note the scars in the area of both inguinal ligaments

also be the source of infection. The cutaneous lesion is a sinus with 3 to 5 mm orifice discharging a thin, seropurulent material. The edge of the sinus usually shows a purple discolouration, is thinned and may be eroded. The sinus is usually attached to the underlying structure. Crusts are present and may be large. Some patients show episodic activity in lesions with the amount of discharge showing periodic variations and even drying up completely to recur after varying periods of time extending up to several months. In long standing lesions, there are usually broad atrophic scars that represent spontaneously healed sinuses. Scarring and fibrosis of lymph nodes may lead to lymphoedema and elephantiasis [Figure 25.12]. In contrast to filariasis, the skin of the lymphoedematous area often shows lesions of cutaneous TB, usually lupus vulgaris [Figure 25.13]. The TST is positive. The AFB can be demonstrated in the discharge from the lesions and Mycobacterium tuberculosis, and rarely nontuberculous mycobacteria [NTM] such as Mycobacterium avium complex, Mycobacterium scrofulaceum can also be cultured. Fine needle aspiration cytology [FNAC] of the underlying structure, usually lymph node, confirms the diagnosis of TB. Biopsy from the edge of the sinus reveals a mixed cell granuloma consisting of epithelioid cells and histiocytes admixed with neutrophils and eosinophils. There are areas of necrosis and AFB may be identified in the biopsy. Culture of biopsy material grows Mycobacterium tuberculosis or NTM in some patients.

Tuberculosis Gumma Tuberculosis gumma refers to soft, subcutaneous swellings which often break through the overlying skin to produce ulcers [Figure 25.14]. The lesions resemble scrofuloderma on clinical, histopathological and microbiological grounds and can be considered as a variant produced by haematogenous seeding of subcutaneous tissue with Mycobacterium tuberculosis. Tuberculosis Cutis Orificialis Tuberculosis cutis orificialis develops by the inoculation of Mycobacterium tuberculosis derived from visceral

Figure 25.13: Lymphoedema of the right lower limb with gummas on the skin

Cutaneous Tuberculosis

Figure 25.14: Tuberculosis gummas which have broken down to form ulcers

infection into the skin around the draining orifices. Usually, lesions develop around the perianal area [Figure 25.15] or around the mouth in patients with abdominal or pulmonary TB. The lesion is a nodule that breaks down to form an indolent, deep ulcer. The diagnosis is usually suspected when the ulcer does not heal in spite of antibiotic therapy. Biopsy from the edge of the ulcer reveals epithelioid granulomas. Acid-fast bacilli may occasionally be demonstrated or grown from the lesion. Tuberculids Tuberculids are skin lesions that develop as a hypersensitivity response to the presence of a TB focus elsewhere in the body. The following criteria must be

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fulfilled to designate a condition as tuberculid: [i] the skin lesion must show a tuberculoid histopathology; [ii] Mycobacterium tuberculosis must not be demonstrable in the lesion; [iii] the tuberculin test must be strongly positive; and [iv] treatment of the underlying TB focus must lead to resolution of the skin lesions. In some cases, it is easy to document the focus while in others this may not be possible. In clinical practice, physical examination and simple imaging procedures are undertaken to look for TB elsewhere. If these tests fail to reveal a focus and clinical suspicion of a tuberculid is high, presumptive treatment for TB can be attempted. Since Mycobacterium tuberculosis cannot be demonstrated in tuberculids, there has been considerable controversy over the existence of this entity. Historically, the label was applied to all skin conditions that showed a tuberculoid granuloma on histopathology that were not neccessarily due to TB. It was hypothesized that such skin lesions represented a hypersensitivity response to a manifest or occult TB focus elsewhere in the body. This led to the grouping together of a heterogenous group of conditions that were subsequently shown to share no aetiologic or pathogenetic similarity. Presently, three conditions are unequivocally accepted as tuberculids, namely, lichen scrofulosorum, papulonecrotic tuberculids and erythema induratum. In addition, TB is an important cause of erythema nodosum in Indian patients. Recent studies employing the polymerase chain reaction [PCR] have demonstrated the presence of mycobacterial DNA in biopsies from patients with erythema induratum (42,43) and papulonecrotic tuberculids (42,44) providing further evidence of the association between these conditions and TB. Lichen Scrofulosorum

Figure 25.15: Orificial tuberculosis. Indolent, non-healing ulcer of the anus. The patient had abdominal tuberculosis

Lichen scrofulosorum typically presents as a crop of 2 to 5 mm erythematous papules that show a tendency to grouping [Figure 25.16]. Many papules show crusting. The eruption has a predeliction for the trunk but may occur at other sites also. Individual papules tend to resolve in about two weeks with hyperpigmentation but crops of lesions may come and go over several months. Uncommonly, the eruption may develop after initiation of antituberculosis treatment; these lesions subsided on continuing treatment (45). The TST is strongly positive and may show ulceration. Biopsy reveals focal epithelioid cell granulomas within and around the hair follicle or

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Tuberculosis the epidermis and upper dermis with underlying epithelioid granulomas. A focus of active TB can usually be demonstrated in these patients. Erythema Induratum

Figure 25.16: Lichen scrofulosorum. Grouped, minute erythematous papules

the duct of the sweat gland. The underlying TB focus may be in the lymph nodes, lungs or at some other site.

Erythema induratum presents as indolent, mildly tender, dull red nodules ranging in size from 5 to 7.5 cm that usually develop on the calves. The nodules soften and break down to form deep persistent ulcers that gradually heal over several weeks with scarring [Figure 25.18]. New nodules may continue to develop while the old lesions are resolving. The TST is positive. Skin biopsy reveals a granulomatous panniculitis with vasculitis of the dermal vessels. A focus of TB is demonstrable in many patients. However, a significant proportion of patients who show the typical clinical and histopathological features of erythema induratum do not have TB. In these patients, the reaction pattern has presumably been triggered by some other cause.

Papulonecrotic Tuberculids Papulonecrotic tuberculids present as an eruption of multiple, papulonodular lesions ranging in size from 2 to 5 cm occurring over the trunk and extremities. The eruption may be preceded by fever and constitutional symptoms. Individual lesions show pustulation and crusting at the centre [Figure 25.17]. Removal of the crust reveals a deep ulcer. The lesions heal gradually over four to six weeks with scarring. Crops of lesions recur at variable intervals. The TST is strongly positive and often ulcerates. Skin biopsy reveals wedge-shaped necrosis of

Figure 25.17: Papulonecrotic tuberculid. Indurated papulo-nodules with a central necrotic crust

Erythema Nodosum Erythema nodosum presents as erythematous, tender, 2.5 to 5 cm nodules that usually develop on the shins [Figure 25.19] but may also involve the thighs, buttocks and forearms in severe cases. Low grade fever and swelling of the ankle joints accompany the skin lesions in some patients. The lesions regress spontaneously becoming dull red, violaceous, finally leaving behind macular hyperpigmentation. Ulceration and scarring are not features of erythema nodosum. Recurrent crops of

Figure 25.18: Erythema induratum. Persistent ulcers with underlying induration on the posterior aspect of the leg

Cutaneous Tuberculosis

Figure 25.19: Erythema nodosum. Tender, erythematous, non-ulcerated nodules on the shins

lesions may develop. Skin biopsy reveals a septal panniculitis with no evidence of vasculitis. Erythema nodosum is a reaction pattern that may be provoked by a variety of triggers, infective and non-infective. However, in India TB is still an important cause of this condition justifying its inclusion as a tuberculid. Others Multiple episodes of Sweet’s syndrome were recently reported during treatment of scrofuloderma and probably represent a hypersensitivity phenomenon similar to the tuberculids (46). The reader is referred to the chapter “Musculoskeletal manifestations of tuberculosis” [Chapter 24] for more details. CUTANEOUS TUBERCULOSIS IN IMMUNOCOMPROMISED HOSTS The human immunodeficiency virus [HIV] epidemic has focussed attention on the manifestations of TB in patients with acquired immunodeficiency syndrome [AIDS] (37,47-51). Similar features may, however, be seen in persons who are immunosuppressed due to other reasons as well (52,53). Clinically, the lesions do not fit into the above-described categories and usually present as papules, nodules, vesicles or induration. Ulceration and discharge from the surface of the lesions may be a feature [Figure 25.20]. The diagnosis is usually not suspected clinically and it has been suggested that all atypical cutaneous lesions developing in immunosuppressed individuals should be biopsied and subjected

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Figure 25.20: Nodules papules and pustules on the buttock of a patient with Cushing’s syndrome. Numerous acid-fast bacilli were seen on biopsy

to culture (47). Biopsy reveals a neutrophilic infiltrate which may be admixed with histiocytes. Epithelioid cells, giant cells and well-formed granulomas are uncommon; AFB are usually seen in large numbers. Culture from the lesions usually grows Mycobacterium tuberculosis or NTM. Most patients appear to recover with antituberculosis treatment but some may die inspite of appropriate treatment. LABORATORY DIAGNOSIS The laboratory diagnosis of cutaneous TB depends on the direct demonstration of Mycobacterium tuberculosis in smears or biopsy specimens, culture of the organism. Sometimes, in the absence of mycobacteriological confirmation, histopathology may provide a compatible diagnosis. It is easy to obtain tissue specimens in patients with cutaneous TB; however, the diagnostic yield is uniformly poor. The Mycobacterium tuberculosis has been demonstrated in four to nine per cent of cases (32,33) and is hardly ever seen in lupus vulgaris and tuberculosis verrucosa cutis. The AFB are found in about 35 per cent of cases (35,36). The results of culture of biopsy material are equally disappointing. Cultures were found to be positive in less than 10 per cent of cases (32,33,35,36). However, much higher yield has been reported from other studies ranging from 23.5% (31) to 56.9% (54). Availability of radiometric methods has decreased the time taken for culture but is expensive and is unlikely to be of much use in cutaneous TB which is paucibacillary (55).

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Histopathological examination reveals a granulomatous dermatitis in 82 to 100 per cent of cases (32-36). However, it is difficult to demonstrate Mycobacterium tuberculosis in tissue sections. The TST is positive in 73 to 100 per cent of patients (32-36). Increasing the cut-off for a positive test increases the specificity of the test but decreases the sensitivity (56,57). In 1992, Victor et al (44) first described the use of PCR in cutaneous TB. Several reports have since documented the use of the test in lupus vulgaris, scrofuloderma and the tuberculids (43,58-69). Some workers (67,68) have demonstrated a high sensitivity of the technique in cutaneous TB, though another group (69) did not find it useful in paucibacillary forms. In a study on 66 cases and 47 controls from India, a true positive rate of 25.8 per cent and a false positive rate of 27.7 per cent were reported with PCR (70). It appears that clinical decisions about the diagnosis and treatment of patients with cutaneous TB should not be based on PCR results alone. Finally, when all the diagnostic modalities are inconclusive, a therapeutic trial with antituberculosis treatment is frequently used to confirm the diagnosis in difficult cases (71-74). Evidence is available suggesting that when a therapeutic trial is undertaken in cutaneous TB, six weeks treatment with isoniazid, rifampicin, pyrazinamide and ethambutol drugs appears adequate to prove [or disprove] the diagnosis (71-74). If there is no improvement at all after six weeks, antituberculosis therapy should be stopped and the diagnosis should be revised. There is no benefit of continuing the trial for longer periods. BACILLE CALMETTE-GUÉRIN AND CUTANEOUS LESIONS Skin complications due to BCG vaccination have been classified into local and generalized forms (75,76). These details are shown in Table 25.2. CUTANEOUS LESIONS DUE TO NONTUBERCULOUS MYCOBACTERIA Skin involvement due to NTM such as Mycobacterium marinum and Mycobacterium ulcerans are clearly defined clinical entities and are considered first. This is followed by a description of miscellaneous lesions caused by a number of other NTM.

Table 25.2: Skin lesions due to BCG vaccination Local lesions Keloid Abnormally large ulcer Subcutaneous abscess Epithelial cyst Eczematous reaction Granulomatous reaction Lupus vulgaris Warty tuberculosis Generalized lesions Erythema nodosum Tuberculids Scrofuloderma Non-specific haemorrhagic eruptions BCG = bacille Calmette-Guérin Based on references 75 and 76

Humans acquire Mycobacterium marinum disease from infected fish or water through breaches in the skin, usually of the upper and the lower limb (77,78). These infections have been termed ‘fish tank granuloma’ and ‘swimming pool granuloma’. A nodule, or less commonly, an ulcer, pustule or abscess develops at the site of injury about two weeks following exposure. In one-third of the cases, lesions are arranged linearly along the lymphatics in a “sporotrichoid” pattern. The infection extends to the deeper tissues, usually the tenosynovium in one-third of the patients; joints and bone may also be involved. Systemic dissemination of infection is rare. Skin biopsy reveals a range of patterns from acute neutrophilic inflammation to granulomas admixed with neutrophils. The AFB are difficult to find in tissue sections (79). The organism grows best at 30 to 33 oC on mycobacterial media. Several antibiotics have been found to be effective including rifampicin and ethambutol, doxycycline and minocycline, clarithromycin and cotrimoxazole. Treatment is recommended for two months after clinical healing; deep infections require treatment for longer periods. Surgical debridement should be considered in deep infections, immunocompromised patients or if medical therapy fails. Buruli ulcer disease is the third most common mycobacterial disease in immunocompetent people, after TB and leprosy (80,81). It is caused by Mycobacterium ulcerans, a mycobacteria found in soil and vegetation in many parts of the world, especially in tropical rain forests. The organism enters the skin through abrasions and injuries

Cutaneous Tuberculosis and is more common on the extremities. Children are affected more frequently though no age is exempt. Three clinical stages are described: pre-ulcerative lesions may be papules, nodules or plaques. These progress to necrosis of the subcutaneous fat and undermined ulcers of the overlying skin. Untreated, ulcers may extend and attain large sizes. On skin biopsy, large numbers of AFB can be detected in about 60 per cent of cases at this stage accompanied by necrosis of the dermis and subcutaneous fat and minimal inflammation (82). The final stage of scarring follows spontaneous healing of the ulcers. Scarring can lead to contractures and ankylosis and is a major cause of disability. Surgery is the treatment of choice. Excision of pre-ulcerative and ulcerative lesions is curative. The excision should remove all necrotic material and extend into healthy tissue to prevent relapses. In vitro, Mycobacterium ulcerans is sensitive to some antimycobacterial agents but not in vivo; drug therapy is thus of little value. A large number of other NTM have been reported to cause cutaneous infections in immunocompetent and immunocompromised hosts (83-89). Most of these mycobacteria are present in the environment and gain access to the skin following an injury, including iatrogenic injuries following needle pricks and surgery. The organisms include Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium scrofulaceum, Mycobacterium kansasii, Mycobacterium szulgai, Mycobacterium haemophilium, Mycobacterium avium intracellulare, Mycobacterium gordonae, and Mycobacterium abscessus. A variety of clinical manifestations are described: papules, pustules, nodules, abscesses, cellulitis, ulcers and sinuses. The clinical features are not distinctive and the infection may be suspected from the setting. Skin biopsy reveals diverse inflammatory patterns including suppuration, granulomas, folliculitis, panniculitis and diffuse histiocytic infiltrates (60). The histopathological features are not specific for any organism. The AFB are easily seen in immunocompromised hosts but may be difficult to find in the immunocompetent individuals. Culture and sensitivity testing of the causative organism is helpful for confirmation of the diagnosis and treatment. TREATMENT The recommended therapy for cutaneous TB is the use of short-course regimens as used for pulmonary TB. The

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reader is referred to the chapter “Treatment of tuberculosis” [Chapter 52] for more details. Using these regimens, lupus vulgaris and TB verrucosa cutis were found to heal completely in four to five months. The skin lesions of scrofuloderma healed in five to six months while the lymph nodes regressed in seven to nine months. There were no relapses in the patients who were followed up for three and half years (71,90). Drug resistance in cutaneous TB appears to be rare though recent reports of culture-documented cases with drug resistant TB gummas and scrofuloderma are a worrisome development (91-93). Under the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India, DOTS is available for patients with all forms of TB including cutaneous TB. Under the RNTCP, patients with cutaneous TB [limited disease] receive Category III treatment. When cutaneous involvement is a part of miliary or disseminated TB, Category I treatment is administered. The reader is referred to the chapter “Revised National Tuberculosis Control Programme” [Chapter 63] for details on this topic. REFERENCES 1. Laennec RTH. Traite de l’auscultation mediate et des maladies des peumons et du coeur. Vol.1. Paris: Asselin and Cie; 1826. p.649-650. Quoted in Marmelzat WL. Laennec and the “prosector’s wart”. Arch Dermatol 1962;86:122-4. 2. Demme R. Zur diagnostischen Beleutung der Tuberkelbacillen fur das Kindesalter. Berlin Klin Wschr 1883;20:217. Quoted in Michelson HE. The history of lupus vulgaris. J Invest Dermatol 1946;7:261-7. 3. Riehl G, Paltauf R. Tuberculosis verrucosa cutis. Eine bisher noch nicht beschriebene Form von Hauttuberculose. Vjschr Derm Syph 1886;13:19. Quoted in Marmelzat WL. Laennec and the “prosector’s wart”. Arch Dermatol 1962;86:122-4. 4. Michelson HE. The history of lupus vulgaris. J Invest Dermatol 1946;7:261-7. 5. Darier J. Des tuberculides cutanees. Ann Derm Syph 1896;7:1431-6. 6. Horwitz O. Lupus vulgaris cutis in Denmark 1895-1954: its relation to the epidemiology of other forms of tuberculosis. Acta Tuberculosea Scandinavia 1960;49[Suppl]:1-145. 7. Forstrom L. Frequency of other types of tuberculosis in patients with tuberculosis of the skin. Scand J Clin Lab Invest 1969;23[Suppl]:1-37. 8. Choudhury AM, Ara S. Cutaneous tuberculosis-a study of 400 cases. Bangladesh Med Res Counc Bull 2006;32:60-5. 9. Fasal P, Rhodes R. Cutaneous tuberculosis and sarcoidosis in the American Negro and in inhabitants of tropical countries. In: Simons RDGP, editor. Handbook of tropical

394

10. 11.

12. 13.

14. 15. 16. 17. 18.

19. 20.

21.

22.

23. 24.

25.

26. 27. 28. 29.

Tuberculosis dermatology and medical mycology, Vol. 1. New York: Elsevier; 1952.p.578-603. Neves H. Incidence of skin diseases 1952-65. Trans St. Johns Hosp Dermatol Soc [London] 1966;52:255-70. de Noronha T, de Almeida Gonclaves JC. O tratamento da tuberculose cutanea. Acrhivo Pathol 1961;33:20-45. Abstracted in Excerpta Medica [Dermatology and Venereology] 1962;16:254. Ustvedt HJ, Ostensen IW. The relation between tuberculosis of the skin and primary infection. Tubercle 1951;32:36-9. Amezquita R. Tuberculosis cutanea. Aspectos clinicos epidemiologicos en Mexico. Tesis recepcional. Acta Leprologica 1963;16:1-103. Abstracted in Excerpta Medica [Dermatology and Venereology] 1965;19:674. Mitchell PC. Tuberculosis verrucosa cutis among Chinese in Hong Kong. Br J Dermatol 1954;66:444-8. Wong KO, Lee KP, Chiu SF. Tuberculosis of the skin in Hong Kong. Br J Dermatol 1968;80:424-9. Goh YS, Ong BH, Rajan VS. Tuberculosis cutis in Singapore: a two-year experience. Sing Med J 1974;15:223-6. Li HC. A preliminary study of tuberculosis of skin in Peking. Chinese J Dermatol 1957;5:13-22. Lee YB, Cho BK, Houh W. Clinical and histopathological study on skin tuberculosis during 5 years [1970-74]. Korean J Dermatol 1975;13:103-8. Kqn KS, Chung TA. A clinical study on skin tuberculosis. Korean J Dermatol 1977;15:181-9. Kitamura K. Geographische verteilung der Haut tuberculose der lepra und der sarcoidose in Japan. Hautarzt 1967;18:5246. Takanohashi K, Yamamoto K, Ishidoya K. Statistical observations of cutaneous tuberculosis in Hirosaki University during recent 8 years [1961-1968]. Japanese J Clin Dermatol 1971;25:451-7. Privat Y, Faye I, Bellossi A, Guberina I. Apropos of cutaneous tuberculosis in Senegal [presentation of 14 new cases. Bull Soc Med Afr Noire Langue Franc 1967;12:640-4. Zoon JJ. Tuberculosis of the skin. Consideration about pathogenesis. AMA Arch Dermatol 1957;75:161-70. Satyanarayana BV. “Tuberculoderma” a brief review together with statistical analysis and observations. Indian J Dermatol 1963;29:25-42. Ghosh LM. An analysis of 50,000 skin cases seen in the outpatient department of the School of Tropical Medicine, Calcutta, during the 5 years from 1942 to 1946. Indian Medical Gazette 1948;84:493-501. Lahiri KD. Etiology and pathology of skin tuberculosis in the tropics. Indian J Dermatol 1956;2:3-7. Banerjee BN. Tuberculosis of the skin and its relation with pulmonary tuberculosis. Indian J Dermatol 1957;2:69-72. Singh G. Lupus vulgaris in India. Indian J Dermatol Venereol 1974;40:257-60. Sobhanadri C, Gupta KG, Rao VK, Reddy DJ. Tuberculosis of the skin in Guntur [a clinico-pathological study]. Indian J Dermatol Venereol 1958;24:133-47.

30. Mammen A, Thambiah AS. Tuberculosis of the skin. Indian J Dermatol Venereol 1973;39:153-9. 31. Sharma RC, Singh R, Bhatia VN. Microbiology of cutaneous tuberculosis. Tubercle 1975;56:324-8. 32. Pandhi RK, Bedi TR, Kanwar AJ, Bhutani LK. Cutaneous tuberculosis: a clinical and investigative study. Indian J Dermatol 1977;22:99-107. 33. Ramesh V, Misra RS, Jain RK. Secondary tuberculosis of the skin. Clinical features and problems in laboratory diagnosis. Int J Dermatol 1987;26:578-81. 34. Kumar B, Muralidhar S. Cutaneous tuberculosis: a twentyyear prospective study. Int J Tuberc Lung Dis 1999;3:494-500. 35. Sehgal VN, Srivastava G, Khurana VK, Sharma VK, Bhalla P, Beohar PC. An appraisal of epidemiologic, clinical, bacteriologic, and immunologic parameters in cutaneous tuberculosis. Int J Dermatol 1987;26:521-6. 36. Sehgal VN, Jain MK, Srivastava G. Changing patterns of cutaneous tuberculosis. A prospective study. Int J Dermatol 1989;28:231-6. 37. Rohatgi PK, Palazzolo JV, Saini NB. Acute miliary tuberculosis of the skin in acquired immunodeficiency syndrome. J Am Acad Dermatol 1992;26:356-9. 38. Kennedy C, Knowles GK. Miliary tuberculosis presenting with skin lesions. Br Med J 1975;3:356. 39. Forstrom L. Carcinomatous changes in lupus vulgaris. Ann Clin Res 1969;1:213-9. 40. Horwitz O, Meyer J. The safety record of BCG vaccination, untoward reactions observed after vaccination. Bibl Tuberc 1957;13:245-71. 41. Hartston W. Uncommon skin reactions after BCG vaccination. Tubercle 1959;40:265-70. 42. Degitz K, Steidl M, Thomas P, Plewig G, Volkenandt M. Aetiology of tuberculids. Lancet 1993;341:239-40. 43. Schneider JW, Geiger DH, Rossouw DJ, Jordaan HF, Victor T, Van Helden PD. Mycobacterium tuberculosis DNA in erythema induratum of Bazin. Lancet 1993;342:747-8. 44. Victor T, Jordaan HF, Van Niekerk DJ, Louw M, Jordaan A, Van Helden PD. Papulonecrotic tuberculid: identification of Mycobacterium tuberculosis DNA by polymerase chain reaction. Am J Dermatopathol 1992;14:491-5. 45. Thami GP, Kaur S, Kanwar AJ, Mohan H. Lichen scrofulosorum: a rare manifestation of a common disease. Pediatr Dermatol 2002;19:122-6. 46. Mahaisavariya P, Chaiprasert A, Manonukul J, Khemngern S. Scrofuloderma and Sweet’s syndrome. Int J Dermatol 2002;41:28-31. 47. Freed JA, Pervez NK, Chen V, Damsker B. Cutaneous mycobacteriosis: occurrence and significance in two patients with the acquired immunodeficiency syndrome. Arch Dermatol 1987;123:1601-3. 48. Lombardo PC, Weitzman I. Isolation of Mycobacterium tuberculosis and M. avium complex from the same skin lesions in AIDS. N Engl J Med 1990;323:916-7. 49. Lanjewar DN, Bhosale A, Iyer A. Spectrum of dermatopathologic lesions associated with HIV/AIDS in India. Indian J Pathol Microbiol 2002;45:293-8.

Cutaneous Tuberculosis 50. Chiewchanvit S, Mahanupab P, Walker PF. Cutaneous tuberculosis in three HIV-infected patients. J Med Assoc Thai 2000;83:1550-4. 51. Daikos GL, Uttamchandani RB, Tuda C, Fischl MA, Miller N, Cleary T, et al. Disseminated miliary tuberculosis of the skin in patients with AIDS: report of four cases. Clin Infect Dis 1998;27:205-8. 52. Taylor AE, Corris PA. Cutaneous tuberculosis in an immunocompromised host: an unusual clinical presentation. Br J Dermatol 1995;132:155-6. 53. Quinibi WJ, Al-Sibai MB, Taher S, Harder EJ, deVol E, Furayh OL, et al. Mycobacterial infection after renal transplantation: report of 14 cases and review of the literature. QJM 1990;282:1039-60. 54. Gopinathan R, Pandit D, Joshi J, Jerajani H, Mathur M. Clinical and morphological variants of cutaneous tuberculosis and its relation to mycobacterium species. Indian J Med Microbiol 2001;19:193-6. 55. Weissler JC. Tuberculosis: immunopathogenesis and therapy. Am J Med Sci 1993;305:52-65. 56. Gupta D, Saiprakash BV, Aggarwal AN, Muralidhar S, Kumar B, Jindal SK. Value of different cut-off points of tuberculin skin test to diagnose tuberculosis among patients with respiratory symptoms in a chest clinic. J Assoc Physicians India 2001;49:332-5. 57. Menzies D. What does tuberculin reactivity after bacille Calmette-Guerin vaccination tell us? Clin Infect Dis. 2000; 31[Suppl 3]:S71-74. 58. Schneider JW, Jordaan HF, Geiger DH, Victor T, Van Helden PD, Rossouw DJ. Erythema induratum of Bazin. A clinicopathological study of 20 cases and detection of Mycobacterium tuberculosis DNA in skin lesions by polymerase chain reaction. Am J Dermatopathol 1995;17:350-6. 59. Ban M, Kanematsu M, Ehara H, Yanagihara M, Kitajima Y. A case of acute tuberculous ulcer diagnosed rapidly by the polymerase chain reaction. Acta Dermatol Venereol 1995;75:245. 60. Degitz K, Messer G, Schirren H, Classen V, Meurer M. Successful treatment of erythema induratum of Bazin following rapid detection of mycobacterial DNA by polymerase chain reaction. Arch Dermatol 1993;129:1619-20. 61. Taniguchi S, Chanoki M, Hamada T. Scrofuloderma: the DNA analysis of mycobacteria by the polymerase chain reaction. Arch Dermatol 1993;129:1618-9. 62. Penneys NS, Leonardi CL, Cook S, Blauvelt A, Rosenberg S, Eells LD, et al. Identification of Mycobacterium tuberculosis DNA in five different types of cutaneous lesions by the polymerase chain reaction. Arch Dermatol 1993;129:1594-8. 63. Steidl M, Neubert U, Volkenandt M, Chatelain R, Degitz K. Lupus vulgaris confirmed by polymerase-chain reaction. Br J Dermatol 1993;129:314-8. 64. Serfling U, Penneys NS, Leonardi CL. Identification of Mycobacterium tuberculosis DNA in a case of lupus vulgaris. J Am Acad Dermatol 1993;28:318-22. 65. Degitz K, Steidl M, Neubert U, Plewig G, Volkenandt M. Detection of mycobacterial DNA in paraffin-embedded

66.

67.

68.

69.

70.

71.

72.

73.

74.

75. 76. 77.

78. 79.

80. 81.

395

specimens of lupus vulgaris by polymerase-chain reaction. Arch Dermatol Res 1993;285:168-70. Welsh O, Vera-Cabrera L, Fernández-Reyes M, Gómez M, Ocampo J. Cutaneous tuberculosis confirmed by PCR in three patients with biopsy and culture negative for Mycobacterium tuberculosis. Int J Dermatol 2007;46:734-5. Quiros E, Bettinardi A, Quiros A, Piedrola G, Maroto MC. Detection of mycobacterial DNA in papulonecrotic tuberculid lesions by polymerase chain reaction. J Clin Lab Anal 2000;14:133- 5. Arora SK, Kumar B, Sehgal S. Development of a polymerase chain reaction dot-blotting system for detecting cutaneous tuberculosis. Br J Dermatol 2000;142:72-6. Tan SH, Tan BH, Goh CL, Tan KC, Tan MF, Ng WC, et al. Detection of Mycobacterium tuberculosis DNA using polymerase chain reaction in cutaneous tuberculosis and tuberculids. Int J Dermatol 1999;38:122-7. Ramam M, Ramesh V, Mittal R, Sirka CS, Achar A, Singh MK, et al. Polymerase chain reaction [PCR] for the diagnosis of cutaneous tuberculosis [Abstract]. Fourth joint meeting of the International Society of Dermatopathology. Washington DC; 2001. Ramam M, Mittal R, Ramesh V. How soon does cutaneous tuberculosis respond to treatment? Implications for a therapeutic test of diagnosis. Int J Dermatol 2005;44:121-4. Ramam M, Tejasvi T, Manchanda Y, Sharma S, Mittal R. Six weeks is an adequate period for a therapeutic trial in cutaneous tuberculosis [Abstract]. IX International Congress of Dermatology. Beijing; 2004. Ramam M, Tejasvi T, Manchanda Y, Sharma S, Mittal R. What is the appropriate duration of a therapeutic trial in cutaneous tuberculosis? Further observations. Indian J Dermatol Venereol Leprol 2007;73:243-6. Sehgal VN, Sardana K, Sharma S. Inadequacy of clinical and/ or laboratory criteria for the diagnosis of lupus vulgaris, reinfection cutaneous tuberculosis: fallout/implication of 6 weeks of anti-tubercular therapy [ATT] as a precise diagnostic supplement to complete the scheduled regimen. J Dermatolog Treat 2007 Oct 11:1-4 [Epub ahead of print]. Kakakhel KV, Fritsch P. Cutaneous tuberculosis. Int J Dermatol 1989;28:355-62. Dostrovsky A, Sagher F. Dermatologic complications of BCG vaccination. Br J Dermatol 1963;75:181-92. Aubry A, Chosidow O, Caumes E, Robert J, Cambau E. Sixtythree cases of Mycobacterium marinum infection: clinical features, treatment, and antibiotic susceptibility of causative isolates. Arch Intern Med 2002;162:1746-52. Lahey T. Invasive Mycobacterium marinum infections. Emerg Infect Dis 2003;9:1496-8. Travis WD, Travis LB, Roberts GD, Su DW, Weiland LW. The histopathologic spectrum in Mycobacterium marinum infection. Arch Pathol Lab Med 1985;109:1109-13. van der Werf TS, van der Graaf WT, Tappero JW, Asiedu K. Mycobacterium ulcerans infection. Lancet 1999;354:1013-8. Sizaire V, Nackers F, Comte E, Portaels F. Mycobacterium ulcerans infection: control, diagnosis, and treatment. Lancet Infect Dis 2006;6:288-96.

396

Tuberculosis

82. Guarner J, Bartlett J, Whitney EA, Raghunathan PL, Stienstra Y, Asamoa K, et al. Histopathologic features of Mycobacterium ulcerans infection. Emerg Infect Dis 2003;9:51-6. 83. Street ML, Umbert-Millet IJ, Roberts GD, Su WP. Nontuberculosis mycobacterium infection of the skin. Report of fourteen cases and review of the literature. J Am Acad Dermatol 1991;24:208-15. 84. Rotman DA, Blauvelt A, Kerdel FA. Widespread primary cutaneous infection with Mycobacterium fortuitum. Int J Dermatol 1993;32:512-4. 85. American Thoracic Society. Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med 2007;175:367-416. 86. Murray-Leisure KA, Egan N, Weitekamp MR. Skin lesion caused by Mycobacterium scrofulaceum. Arch Dermatol 1897;123:369-70. 87. Hanke CW, Temofeew RK, Slama SL. Mycobacterium kansasii infection with multiple cutaneous lesions. J Am Acad Dermatol 1987;16:1122-8.

88. Cox SK, Strausbough LJ. Chronic cutaneous infection caused by Mycobacterium intracellulare. Arch Dermatol 1981; 117:794-6. 89. McGovern J, Bix BC, Webster G. Mycobacterium haemophilum skin disease successfully treated with excision. J Am Acad Dermatol 1994;30:269-70. 90. Ramesh V, Misra RS, Saxena U, Mukherjee A. Comparative efficacy of drug regimens in skin tuberculosis. Clin Exp Dermatol 1991;16:106-9. 91. Sharma N, Kumar P, Mantoo S, Patnaik S. Primary multidrug resistant tuberculous gumma. J Commun Dis 2001;33:170-3. 92. Ramesh V, Murlidhar S, Kumar J, Srivastava L. Isolation of drug-resistant tubercle bacilli in cutaneous tuberculosis. Pediatr Dermatol 2001;18:393-5. 93. Olson DP, Day CL, Magula NP, Sahid F, Moosa MY. Cutaneous extensively drug-resistant tuberculosis. Am J Trop Med Hyg 2007;77:551-4.

Lymph Node Tuberculosis

26 Arvind Kumar

‘Tis called the evil: A most miraculous work in this good king; Which often since my here-remain in England I have seen him do. How he solicits heaven, Himself best knows; but strangely visited people, All swollen and ulcerous, pitiful to the eye, The mere despair of surgery, he cures, Hanging a golden stamp about their necks, Put on with holy prayers; and ‘tis spoken, To the succeeding royalty he leaves The healing benediction William Shakespeare Macbeth, IV, iii, 146

INTRODUCTION Mycobacterial lymphadenitis has plagued humanity since ancient times. It has been called as “scrofula” [a term derived from the Latin for “glandular swelling” or from the French “full necked sow”] and “King’s evil”. Peripheral lymph node involvement is the commonest form of extra-pulmonary mycobacterial disease and the cervical region is the most frequently affected site (1-3). In the present era, Mycobacterium tuberculosis is the most common cause of mycobacterial lymphadenitis and lymphadenitis due to nontuberculous mycobacteria [NTM] is also being increasingly encountered. Peripheral and mediastinal lymph node tuberculosis [TB] are commonly seen in patients with human immunodeficiency virus infection [HIV] and the acquired immunodeficiency syndrome [AIDS].

EPIDEMIOLOGY Myocobacterial lymphadenitis has shown marked geographical variation. In the developing and underdeveloped countries, TB lymphadenitis continues to be the most common and lymphadenitis due to NTM is seldom seen. In several studies from India Mycobacterium tuberculosis has been the most common pathogen isolated from patients with mycobacterial lymphadenitis accounting for almost all the cases (3-6). One year data from July 1, 2000 to June 30, 2001 [i.e., from Quarter 3, 2000 to Quarter 2, 2001] from 16 districts under the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India, lymph node TB constituted 1630 of the 2816 [58%] new extra-pulmonary TB cases (7). In another communitybased house-to-house survey of a population of 23 229 in 35 neighbouring villages with 7900 children aged 0 to 14 years in the rural area of Wardha district, Maharashtra State, Central India from May 1993 to May 1994 and from March 1995 to February 1996, the prevalence of lymph node TB was reported to be 4.43 per 1000 children (8). On the other hand, NTM are the most frequently isolated pathogens from the lymphadenitis specimens in several reports from the developed world (9,10). In Australia (11) and British Columbia (12), NTM have been detected 10 times more frequently than Mycobacterium tuberculosis. In studies reported from the USA, Mycobacterium tuberculosis accounted for 95 per cent of all mycobacterial lymphadenitis in adults, whereas in children, 92 per cent of the mycobacterial lymphadenitis was due to NTM (13,14).

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In addition to geographical variation, there has been a changing trend in the prevalence of these organisms over a period of time at some places. In England, there has been a decline in TB lymphadenitis and a rise in NTM lymphadenitis (15). A high frequency of disease has been reported in populations hailing from areas where TB is highly endemic. In the study reported by Thompson et al (2), patients from the Indian subcontinent, who otherwise constituted only 10 per cent of the population of that region, accounted for 81 per cent of 61 cases of mycobacterial lymphadenitis. Similar results have been reported among Native Americans and in patients from South-east Asia and Africa (16,17). A high frequency of disease has also been reported among Asians and Hispanic patients in the San Francisco area by Lee et al (17). Patients of Asian origin and African-Americans also seem to have a high predilection for developing lymphadenitis due to Mycobacterium tuberculosis (18-21). PATHOGENESIS Tuberculosis lymphadenitis is considered to be the local manifestation of a systemic disease, whereas lymphadenopathy due to NTM is truly a localized disease. Mycobacterium tuberculosis generally enters the body via the respiratory tract and undergoes haematogenous and lymphatic dissemination. Hilar and mediastinal lymph nodes are the first lymphoid tissues encountered in the lymphatic spread from the lung parenchyma. This involvement may occur at the time of primary infection or may occur later in life due to reactivation of previous infection. Tonsil is also an important portal of entry. The infection may then spread via the lymphatics to the nearest cervical lymph nodes. In the initial stages, the nodes may be discrete clinically. Periadenitis results in matting and fixity of the lymph nodes. The lymph nodes coalesce and break down to form caseous pus. This may perforate the deep fascia and present as a fluctuant swelling on the surface [collarstud abscess]. Overlying skin becomes indurated, breaks down and leads to the formation of a sinus which if untreated may remain unhealed for years. Healing may occur from each of the three stages with calcification and/ or scarring. In NTM lymphadenitis, the pathogens usually enter the lymph nodes directly via oropharyngeal mucosa, salivary glands, tonsils, gingiva or conjunctiva (14,22) and lymph node involvement represents a localized

disease. The reader is referred to the chapter “Nontuberculous mycobacterial infections” [Chapter 48] for more details. CLINICAL PRESENTATION Tuberculosis Lymphadenitis Clinical presentation of TB lymphadenitis is summarized in Tables 26.1, 26.2 and 26.3 (2-4,23,24). Tuberculosis cervical lymphadenitis tends to occur more often in females and in young adults [Table 26.1]. Patients usually present with slowly enlarging lymph nodes and may otherwise be asymptomatic. Cervical lymph nodes are most commonly affected, although axillary and inguinal lymph nodes may also be involved. Associated mediastinal lymphadenopathy may also be present sometimes. Some patients with lymph node TB may manifest systemic symptoms. These include fever, weight loss, fatigue and occasionally night sweats [Table 26.1]. Cough may be a prominent symptom in patients with mediastinal lymphadenopathy. Jones and Campbell (25) had classified peripheral TB lymphadenopathy into five stages [Table 26.4]. Physical examination findings depend upon the stage of the disease. The enlarged lymph nodes may be of varying size, discrete or matted. The lymph nodes may be firm or cystic in consistency [Figure 26.1], if necrosis and abscess formation has taken place. The lymph nodes are usually not tender unless secondary bacterial infection has occurred. Physical examination may be unremarkable but for palpable lymphadenopathy. Sometimes, lymph node abscess may burst leading to a chronic nonhealing TB sinus and ulcer [Figure 26.2]. The typical TB sinus has thin, bluish, undermined edges with scanty watery discharge. Various complications have also been described due to TB mediastinal lymphadenitis. These include dysphagia due to pressure on the oesophagus (26,27), oesophago-mediastinal fistula (28-30), tracheooesophageal fistula (31,32). Sometimes, TB tracheooesophageal fistula may mimick a malignant tracheooesophageal fistula. Occasionally, upper abdominal and mediastinal lymph nodes may cause thoracic duct obstruction and present as chylothorax, chylous ascites or chyluria (33). Rarely, jaundice occurs because of biliary obstruction due to enlarged lymph nodes (34). Cardiac tamponade (35) due to TB mediastinal lymphadenitis,

Lymph Node Tuberculosis 399 Table 26.1: Demographic characteristics and symptoms at presentation in adult patients with peripheral lymph node tuberculosis Variable

Studies from India Dandapat et al (3) [n = 80]

Subrahmanyam (4) [n = 105]

Studies from other parts of the world Chen et al (23) [n = 71]

Thompson et al (2) [n = 67] Asian group* [n = 54]

Place of study

Berhampur

Solapur

Duration of study [years]

1

1.5

Mean age [years]

†

‡

Male:Female

1:12

1:1.3

History of contact with a case ND of TB or family history [%]

5.7

Taipei 6 42 1:1.5 ND

White group [n = 13]

Leicester

Leicester

10

10

41.8

46.9

1:1.5

Fain et al (24) [n = 59]

1:2.3

Paris 4 37.6 1:1.5

48

7.7

23.7

9.9

13

7.7

30.5

9.9

13

Symptoms [%] Fever

40

45

Weight loss

85

78

Night sweats

37

35

Cough

10

ND

8.5

Others

ND

ND

§

ND

23.1

47.5

9.3

15.4

22

14.8

0

0

||

||

¶

* Patients from the Indian subcontinent † Mean age was not described. Age range = 1 to 65 years ‡ Mean age was not described. Age range = 1.5 to 68 years § Other symptoms included dysphagia [2.8%]; haemoptysis [2.8%]; vomiting [2.8%] || Anorexia occurred in 7.4% patients in the Indian subcontinent group and 15.4% patients in the White group ¶ Asthenia occurred in 47.5% cases TB = tuberculosis; ND = Not described

Tuberculosis Lymphadenitis in Patients with Human Immunodeficiency Virus Infection

Figure 26.1: Right sided cervical lymphadenitis due to tuberculosis

massive haemoptysis due to tracheo-pulmonary artery fistula and pseudoaneurysm of the pulmonary artery (36) have also been reported.

Lymph node enlargement is a common feature in patients with HIV infection and lymphadenopathy can result from primary HIV-induced pathology and from diseases, such as TB lymphadenitis, NTM lymphadenitis, nodal Kaposi’s sarcoma and nodal lymphoma (37,38). In HIV-seronegative patients, TB lymphadenitis often occurs as a focal cervical lymphadenopathy with other groups of lymph nodes being occasionally involved [Table 26.2]. The disease often presents as multifocal lymphadenopathy in HIV-seropositive patients. Comparison of clinical presentation of TB lymphadenitis in HIV-seropositive and HIV-seronegative patients is shown in Table 26.5 (37,38). Nontuberculous Mycobacterial Lymphadenitis Very little is known regarding lymphadenitis due to NTM from India. It often occurs in children. Constitu-

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Tuberculosis Table 26.2: Physical signs at presentation observed in adult patients with peripheral lymph node tuberculosis

Variable

Studies from India Dandapat et al (3) [n = 80]

Subrahmanyam (4) [n = 105]

Studies from other parts of the world Chen et al (23) [n = 71]

Thompson et al (2) [n = 67] Asian group* [n = 54]

Fain et al (24) [n = 59]

White group [n = 13]

Site of involvement [%] Cervical Axillary Inguinal Multiple sites

70 6 9 15

93.3 3.8 2.9 ND

91.5 12.7 7 14.0†

85 11.1 3.7 ND

84.5 7.7 7.7 ND

73.1 15.4 9.6 15.3‡

Physical findings [%] Matting and fixity Discrete nodes Abscess formation Sinuses Ulcers

55 22.5 15 13 ND

68 32 15.2 10.5 7.6

ND ND ND ND ND

ND ND ND ND ND

ND ND ND ND ND

ND ND ND ND ND

* Patients from the Indian subcontinent † Right elbow nodes were enlarged in 1.4% patients. Two sites were involved in 14%; three sites were involved in 7% and four sites were involved in 4.4% patients ‡ Of the 59 patients studied, 69 different lymph node sites were noted; 46 patients [78%] had exclusive lymph node disease. A superficial distribution was found in 52 cases [88.1%] and isolated superficial lymph node involvement was found in 32 patients [54.2%]. Deep lymph node involvement [mediastinal and abdominal] was observed in 17 patients [32.7%] and isolated deep lymph node involvement was found in 7 patients [11.9%] ND = not described Table 26.3: Evidence of associated pulmonary tuberculosis in adult patients with peripheral lymph node tuberculosis Variable

Studies from India Dandapat et al (3) [n = 80]

Associated pulmonary TB [%]

5

Subrahmanyam (4) [n = 105]

16.2

Studies from other parts of the world Chen et al (23) [n = 71]

42‡

Thompson et al (2) [n = 59]* Asian group† [n = 11]

White group [n = 48]

44

18

Fain et al (24) [n = 59]

ND

* Chest radiographs were done in 59 of the 67 patients studied † Patients from the Indian subcontinent ‡ Among those with cervical lymph node TB, 33% of those with upper-third cervical lymph node involvement and 58.7% of patients with lower-third cervical lymph node involvement had radiological features of pulmonary TB TB = tuberculosis; ND = not described

tional symptoms seldom occur and the disease generally remains localized to the upper cervical area [Table 26.6]. If untreated, the nodes often progress to softening,

rupture, sinus formation and heal with fibrosis and calcification (16,22,25). Appropriate laboratory tests must be performed to differentiate lymphadenitis due to NTM

Lymph Node Tuberculosis 401 Table 26.4: Physical appearance of lymph node tuberculosis Stage 1 Enlarged, firm, mobile, discrete nodes showing non-specific reactive hyperplasia Stage 2 Larger rubbery nodes fixed to surrounding tissue owing to periadenitis Stage 3 Central softening due to caseation necrosis and abscess formation Stage 4 Collar-stud abscess formation Stage 5 Sinus tract formation Based on “Jones PG, Campbell PE. Tuberculous lymphadenitis in childhood; the significance of anonymous mycobacteria. Br J Surg 1962;50:302-14 (reference 25)”

and Mycobacterium tuberculosis as response to antituberculosis drugs is not good in the former. The reader is referred to the chapter “Nontuberculous mycobacterial infections” [Chapter 48] for more details. DIFFERENTIAL DIAGNOSIS There are numerous causes of peripheral lymphadenopathy. This list includes reactive lymphadenitis [secondary to viral and bacterial infections], TB lymphoma, sarcoidosis, secondary carcinoma and uncommon causes like fungal diseases, toxoplasmosis and diseases of the reticulo-endothelial system among others (38). Multiplicity, matting and caseation are three features which help in the diagnosis of TB lymphadenitis. In patients with lymphoma, the lymph nodes are rubbery in consistency and are not matted. In patients with secondary deposits in the lymph node [from a primary

somewhere in the drainage area], the lymph node is usually hard and may be fixed to the surrounding structures. DIAGNOSIS Apart from a focussed history and a detailed clinical examination, several other studies are required for confirming the diagnosis of lymph node TB. Tuberculin Skin Test Tuberculin skin test [TST] is positive in about 75 per cent patients with lymph node TB while it is often nonreactive in patients with NTM lymphadenitis (1,9,10). However, a negative TST does not rule out the possibility of TB. The reader is referred to the chapter “Tuberculin skin test” [Chapter 11] for more details. More recently, interferon-gamma release assays [IGRAs] have become available and may be useful in the diagnosis of TB infection. The reader is referred to the chapter “Diagnosis of latent tuberculosis infection: recent advances and future directions [Chapter 12]” for details on this topic. Imaging In patients with TB lymphadenitis, abnormalities are often discernible on the chest radiograph [Table 26.3]. However, there is a wide variation in the reported incidence of chest radiographic abnormalities with the figure ranging from five to forty-four per cent [Table 26.3]. The reported incidence of paratracheal, hilar and mediastinal lymphadenopathy [seen on the chest radiograph] in patients with peripheral lymphadenopathy has varied widely from five to twelve per cent

Figure 26.2: Tuberculosis lymphadenitis. Clinical photograph showing chronic non-healing sinus and ulcers over right cervical region and chest wall [A]; suprahyoid, bilateral cervical and axillary lymphadenitis with chronic non-healing ulcers [B]; and suprasternal and left supraclavicular lymphadenitis with discharging sinuses [C]

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Table 26.5: Comparison of clinical characteristics of lymph node tuberculosis in HIV-positive and HIV-negative patients Variable

Bem (37) HIV-positive [n = 157]

Mean age [years] Male:Female Site of involvement [%] Cervical Axillary Inguinal Multiple sites Physical findings [%] Firm and mobile Matted, irregular/hard and additional local signs Histopathlogical type Epithelioid granulomas with caseation necrosis without caseation necrosis Suppurative variety Non-reactive Chest radiograph findings [%] Pulmonary infiltration Cavitation Pleural effusion Pericardial effusion

Mohan et al (38) HIV-negative [n = 71]

HIV-positive [n = 34]

HIV-negative [n = 390]

30.6 1:0.9

30.6 1:1.2

28.4 1:1.3

27.8 1:1.3

99* 82 84 90

96 43 14 39

96 82 71 89

90 37 10 33

51 49†

51 49

ND ND

ND ND

ND ND ND ND

ND ND ND ND

46‡ 3‡ 17‡ 13‡

60§ 0§ 13§ 0§

18 21 29 32 ND ND ND ND ND

75 23 01 01 ND ND ND ND ND

* Among patients with lymph node TB, lymphadenopathy was confined to the neck in 10% HIV-positive patients compared to 57% HIVnegative patients. Further, isolated unilateral TB cervical lymphadenitis was observed in only 1 of the 157 HIV-positive patients compared to 32% in HIV-negative patients † Among HIV-positive patients with lymph node TB, local signs included sinuses [n = 2]; cold abscess [n = 3]; tender nodes [n = 3]; inflammatory mass [n = 3]. Among HIV-negative patients with lymph node TB, local signs included sinuses [n = 2]; tender nodes [n = 1]; inflammatory mass [n = 1]. None of the patients with primary HIV lymphadenopathy demonstrated local signs ‡ Tested in 110 patients § Tested in 15 patients HIV = human immunodeficiency virus; TB = tuberculosis

(2,3,14,16). The other radiological investigations include an ultrasound of the abdomen and a computed tomography [CT] of the chest, when indicated. Ultrasonography and CT of the abdomen may be required to assess the status of retroperitoneal, porta hepatis or mesenteric lymph nodes. It may reveal enlarged lymph nodes or a confluent mass with central necrosis. Sometimes the nodes may show calcification. Computed tomography of the chest is required for accurate evaluation of the thoracic lymph nodes if the chest radiograph shows any evidence of mediastinal or hilar lymphadenopathy. The lymph nodes show enlargement

with hypodense areas, sometimes central necrosis with peripheral rim enhancement or calcification [Figures 13.5, 13.6, and 26.3]. The reader is referred to the chapter “Roentgenographic manifestations of pulmonary tuberculosis” [Chapter 13] for more details. Magnetic resonance imaging [MRI] also reveals lymph node enlargement with multiple hypodense areas (39). Imaging modalities are also helpful in identifying deeply located abscesses in the cervical and axillary regions and, therefore, facilitate radiologically-guided anti-gravity aspiration or surgical drainage of the abscesses if the pus collection is substantial.

Lymph Node Tuberculosis 403 Table 26.6: Comparison between tuberculosis lymphadenitis and nontuberculous mycobacterial lymphadenitis Variable

Tuberculosis lymphadenitis

NTM lymphadenitis

Age

Any age group

Children

Sex

Female preponderance

Equal between sexes

Constitutional symptoms

Common

Rare

Lymph node involvement

Cervical lymph nodes are most commonly involved Axillary and inguinal lymph nodes may also be involved. Bilateral involvement is common

Localized disease often involving cervical lymph nodes [jugulodigastric, submandibular, preauricular]. Unilateral involvement is common

Chest radiographic evidence of pulmonary or pleural TB

Common

Rare

Tuberculin skin test

Often reactive

Non-reactive

Response to antituberculosis treatment

Good

Poor

NTM = nontuberculous mycobacteria; TB = tuberculosis

Cytopathology and Histopathology The definitive diagnosis of lymph node TB is established by visualizing mycobacteria on histopathology sections or on smears stained for acid-fast bacilli [AFB] or by mycobacterial culture. Traditionally, excision biopsy of the lymph nodes has been done to diagnose lymph node TB [Figure 26.4]. In patients with mediastinal lymphadenopathy, various techniques including ultrasound or CT-guided percutaneous biopsy, cervical mediastinoscopy, video-assisted thoracoscopic surgery, endoscopic transbronchial or transoesophageal biopsy (40-41) have been used to obtain lymph node material for tissue diagnosis. As the mycobacteria are not documented in every case, certain histopathological changes have been accepted as suggestive of TB. These include granulomatous inflammation with caseation necrosis [Figure 26.4]. However, it must be clarified that, although highly suggestive, these changes are by no means specific and may sometimes be seen in other diseases also (42). Moreover, the surgical procedure of excision biopsy is associated with certain morbidity. Fine needle aspiration cytology [FNAC], a relatively non-invasive, pain-free, out-patient procedure with no morbidity is available nearly for two decades. Over a period of time, it has established itself as a safe, cheap and reliable procedure for the diagnosis of peripheral lymphadenopathy also (43-44). It has also been suggested

as the first diagnostic technique for the diagnosis of peripheral lymphadenopathy. The characteristics cytopathological changes include epithelioid cell granulomas with or without multinucleate giant cells and caseation necrosis (43-46). Several authors have evaluated the sensitivity and specificity of FNAC in the diagnosis of peripheral lymphadenopathy by comparing it with the gold standard [i.e., histopathological examination] and found it to be a useful technique (45-50). Lau et al (46) reported their experience with 108 patients whose FNAC samples showed granulomatous inflammation suggestive of TB. Of these, 68 patients underwent surgical excision of the lymph nodes. The authors reported the sensitivity and specificity of FNAC in the diagnosis of lymph node TB to be 77 per cent and 93 per cent respectively. They also noticed that smears with necrosis had a higher rate of AFB positivity [47%] compared to the smears with no necrosis [15%]. Dandapat et al (3) reported a true positive diagnosis in 83 per cent, a false negative result in 14 per cent and equivocal results in three per cent. Other authors [Table 26.7] have reported similar results. In another study (45) of 272 patients with FNAC proven TB lymphadenitis, mycobacterial cultures were positive in 49 per cent and AFB were present in 30 per cent of direct and concentrated smears. Combining the smear and culture methods together, the microbiological diagnosis was possible in 57 per cent patients. This figure went up to 63 per cent in the sub-group of patients with caseation necrosis (4-5).

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Figure 26.4: Tuberculosis lymphadenitis. Photomicrograph showing epithelioid granulomas with caseation necrosis and peripheral lymphocyte infiltration [upper panel, left; Haematoxylin and eosin, x 100], well-defined epithelioid granulomas with lymphocytic infiltration [upper panel, right; Haematoxylin and eosin x 200], epithelioid granuloma, caseation, lymphocytic infiltration [lower panel, left; Haematoxylin and eosin x 200] and multinucleated Langhans’ giant cell and lymphocytic infiltration [lower panel, right; Haematoxylin and eosin, × 400]

rate was only 16 per cent of the histopathology proved cases (51). Others have reported positive culture in up to 65 to 68 per cent cases (3,52). For transportation of the excised lymph node to the specialized centre for culture of mycobacteria, selective Kirchner’s liquid medium has been reported to be the best and specimens can be stored in this medium in the refrigerator for up to 15 days without any loss in culture positivity (52). Excision biopsy of the lymph node remains the gold standard for the diagnosis of lymph node TB. Figure 26.3: CECT of the neck and chest showing bilateral cervical [A] [asterisk]; right-sided axillary [asterisk] and intrathoracic [arrow] lymphadenopathy [B], [C]. Peripheral rim enhancement with central attenuation can be seen. Fine needle aspiration cytology of the cervical lymph node confirmed the diagnosis of tuberculosis

In a prospective study (51) comparing FNAC with excision biopsy conducted at the All India Institute of Medical Sciences hospital, New Delhi, where coded samples were submitted to the laboratory and the laboratory personnel were not aware of the clinical diagnosis, the author observed that the culture positivity

Molecular and Other Methods Polymerase chain reaction [PCR] has been used on fine needle aspirate specimens Papanicolaou-stained fine needle aspirated smears and formalin-fixed, paraffinembedded histopathological specimens have yielded varying results in the diagnosis of lymph node TB (51,53-56). Presently available evidence suggests that PCR may be helpful in establishing the aetiological diagnosis in some patients with granulomatous lymphadenitis in whom the conventional methods of FNAC, histopathology and mycobacterial culture are inconclusive.

Lymph Node Tuberculosis 405 Table 26.7: Method of diagnosis in adult patients with peripheral lymph node tuberculosis Variable

Fine needle aspiration cytology Lymph node biopsy Histopathology Microbiology

Studies from India

Studies from other parts of the world

Dandapat et al (3) [n = 80]

Subrahmanyam (4) [n = 105]

Chen et al (23) [n = 71]

Thompson et al (2)* [n = 67]

Fain et al (24) [n = 59]

83†

ND

ND

ND

38‡‡ [n = 26]

100‡

100

100|| [n = 64]

100** [n = 60]

100§§ [n = 39]

65

§

80¶ [n = 10]

100†† [n = 7]

36 [n = 39]

All values are shown as percentages Numbers in square brackets indicate number tested * Included 54 patients of Asian origin and 13 White patients † False-negative results were observed in 14% and equivocal results were observed in 3% patients ‡ 80% patients had caseating granulomas; and 20% had non-caseating granulomas § Microbiological examination was not done in this study || A total of 64 specimens were obtained for histopathological exmamination [excision biopsy [n = 32]; total excision [n = 29]; neck dissection [n = 3]. Acid-fast bacilli were found in 35 of the 64 specimens ¶ Only 10 of the 64 specimens were subjected to culture on Lowenstein-Jensen medium and eight yielded Mycobacterium tuberculosis. **Histopathological examination was done in only 60 of the 67 patients. Biopsy specimens were not sent for microbiological examination in 13 of these 60 patients. Histopathology was positive in all the 60 patients. In 13 of these 60 patients, both histopathological and microbiological methods yielded the diagnosis †† In 7 patients, histopathological exmination was not done and microbiological examination alone was done ‡‡ Of the 26 patients in whom fine needle aspiration was performed, bacteriological diagnosis was possible in 38% cases and acid-fast bacilli were positive in 2 of them §§ Of these 39 patients, histopathological examination revealed caseating granulomas in 82%, isolated granulomata in 13% and nonspecific inflammatory lesions which revealed Mycobacterium tuberculosis in 5%

TREATMENT Presently, it is generally agreed that antituberculosis treatment alone is sufficient in majority of the cases and surgical intervention is required only in selected cases for specific situations. In India, majority of the patients with lymph node TB receive DOTS under the RNTCP of the Government of India. The reader is referred to the chapters “Treatment of tuberculosis”[Chapter 52] and Evolution of chemotherapeutic regimens in the treatment of tuberculosis and their scientific rationale” [Chapter 51] for more details. The number of drugs required and the ideal duration of treatment for lymph node TB have been an area of intense research. Observations from a series of randomized clinical trials conducted by the British Thoracic Society [BTS] resulted in the shortening of the duration of treatment from 18 months to nine months

initially and later to six months (6). In 1990, the group from Tuberculosis Research Centre [TRC], Chennai (5) reported results of their prospective trial evaluating a supervized short-course [six months] intermittent chemotherapy regimen consisting of streptomycin, rifampicin, isoniazid and pyrazinamide three times a week for two months followed by streptomycin and isoniazid twice a week for four months on an out-patient basis in children with lymph node TB. Out of 168 patients finally analysed, favourable clinical response was noted in most patients at the end of the treatment. They concluded that in children, TB lymphadenitis can be successfully treated with a short-course chemotherapy regimen of six months. Thereafter, the BTS next trial (57,58) compared the following regimens: rifampicin, isoniazid, ethambutol for the initial two months, followed by rifampicin and isoniazid for the subsequent seven months; rifampicin, isoniazid, pyrazinamide for

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the initial two months, followed by rifampicin and isoniazid for the subsequent four months. The six-month regimen was found to be equally effective in terms of response with an advantage of increased convenience and reduced cost. There was no difference in the speed of resolution of nodes, in the percentage of patients with residual nodes at the end of the treatment or in the numbers developing fluctuation or sinuses. However, seven patients in the ethambutol group and only one in the pyrazinamide group required aspiration of pus from lymph nodes. This may be because pyrazinamide, being bactericidal kills bacteria which are intracellular, making glands less likely to become fluctuant on treatment. In a recent study (6), patients with biopsy confirmed superficial lymph node TB were randomly allocated to receive two-drug regimens of either a daily selfadministered six-month regimen [n = 136] of rifampicin and isoniazid, or a twice-weekly, directly observed, sixmonth regimen of rifampicin and isoniazid plus pyrazinamide for the first two-months, followed by rifampicin and isoniazid for the subsequent four months [n = 141]. Of the 277 enrolled patients, data were available for analysis in 268 patients [n = 134 from each group]. At the end of the treatment, 87 per cent patients in each treatment group had a favourable clinical response; 14 [11%]; and 17 [13%] patients had a doubtful response, and four [3%]; and one [1%] patients had an unfavourable response among those treated with the daily and twiceweekly regimen, respectively. The authors (6) suggested that these regimens may be considered as alternatives to the existing regimens. Experience at the Paediatric Tuberculosis Clinic at the AIIMS hospital, New Delhi (59) [n = 459], indicated that pulmonary TB was the commonest followed by lymph node TB. Of the 16 children with isolated lymph node TB who received category III treatment, 12 were cured with the primary regimen; three achieved cure with extended primary regimen; and one was lost to follow-up. The authors (59) suggest that it is feasible to classify and treat lymph node TB in children based on the World Health Organization’s guidelines for adult TB. The overall opinion in the literature at present seems to be in favour of a short-course chemotherapy with four drugs [rifampicin, isoniazid, ethambutol, pyrazinamide] given for the first two months with rifampicin and isoniazid being given for the subsequent four to seven months. However, in the author’s experience, patients

invariably require longer duration of treatment and sometimes require addition of second-line antituberculosis drugs. While response to antituberculosis treatment may be delayed in patients with TB lymphadenitis, it is a common practice among physicians and surgeons to label these patients with a diagnosis of MDR-TB lymphadenitis. But it must be understood that MDR-TB is a laboratory diagnosis and for establishing this, the organisms must be grown in the laboratory and in vitro resistance to rifampicin and isoniazid must be demonstrated. Since lymphadenitis is a paucibacillary disease, it is not easy to grow Mycobacterium tuberculosis in cultures in most instances. Therefore, a label of MDR-TB lymphadenitis should be used judiciously. Occasionally, treatment of TB lymphadenitis with Category II antituberculosis drugs may be gratifying but this can be tried on a case-to-case basis and cannot be recommended as a public health approach. In an occasional patient with delayed response to conventional treatment, addition of a fluoroquinolone and streptomycin to the existing treatment regimen has been found to be helpful. However, these measures should be undertaken by a well experienced clinician and the appropriate dosage schedule and duration of treatment should be tailored to the needs of the individual patient. These issues merit further study. The results of various studies have shown that lymph nodes may enlarge in size or, new nodes may appear during or after antituberculosis treatment (5,6,60). These nodes may show histopathological features characteristic of TB but are sterile on culture. The development of new nodes while on treatment may represent an immunological response. This phenomenon is usually transient and the nodes ultimately regress in size. Fluctuation may appear in some lymph nodes while on treatment and the pus should be aspirated under strict aseptic conditions. In case there is secondary bacterial infection presenting as a classical abscess, drainage and appropriate broad-spectrum antibiotics may be required in addition to antituberculosis treatment. While the term “immune reconstitution inflammatory syndrome [IRIS]” is usually used in HIV-seropositive patients who are receiving antiretroviral treatment [ART], the term “paradoxical reaction” is generally used to describe a clinical worsening of TB disease in HIVseropositive and HIV-seronegative patients after initiation of antituberculosis treatment (61). In the past,

Lymph Node Tuberculosis 407 studies on TB-associated IRIS have used a variety of nonstandardized general case definitions. Recently, case definitions for paradoxical TB-associated IRIS, ARTassociated TB [Figure 26.5] and unmasking TB-associated IRIS [provisional] have been described (62). These definitions can be used by clinicians and researchers in developing and developed world to promote standardization and comparability of data. Sometimes, there are residual lymph nodes at the end of a proper course of chemotherapy. These can be left as such and the patients kept under close follow-up as many of these nodes are expected to resolve over a period of time. If the nodes increase in size further or systemic features reappear, an excision biopsy of the gland for histology and culture followed by re-treatment is recommended. Some workers recommend biopsy of all significant [> 10 mm] residual nodes and re-treatment only if cultures are positive. Apart from the biopsy of the lymph nodes, surgical intervention is also required for aspiration or drainage of abcesses in a few patients. It is generally accepted that antituberculosis treatment is ineffective and complete surgical excision is recommended for lymphadenitis caused by NTM (63). Therefore, whenever a biopsy is being performed for diagnosis, especially if it happens to be from a preferred site for NTM lymphadenitis such as submandibular or pre-auricular area, a complete excision or preferably selective nodal dissection of that area should be performed. A macrolide-based regimen should be

Figure 26.5: Antiretroviral treatment associated immune reconstitution inflammatory syndrome manifesting as left sided cervical lymphadenitis in a human immunodeficiency virus-seropositive patient

considered for patients with extensive Mycobacterium avium intracellulare complex lymphadenitis or poor response to surgical therapy (63). The reader is referred to the chapter “Nontuberculous mycobacterial infections [Chapter 48]” for more details. REFERENCES 1. Lazarus AA, Thilagar B. Tuberculous lymphadenitis. Dis Mon 2007;53:10-5. 2. Thompson MM, Underwood MJ, Sayers RD, Dookeran KA, Bell PRF. Peripheral tuberculous lymphadenopathy: a review of 67 cases. Br J Surg 1992;79:763-4. 3. Dandapat MC, Mishra BM, Dash SP, Kar PK. Peripheral lymph node tuberculosis: a review of 80 cases. Br J Surg 1990;77:911-2. 4. Subrahmanyam M. Role of surgery and chemotherapy for peripheral lymph node tuberculosis. Br J Surg 1993;80:1547-8. 5. Jawahar MS, Sivasubramaniam S, Vijayan VK, Ramakrishnan CV, Paramasivan CN, Selvakumar V, et al. Short-course chemotherapy for tuberculous lymphadenitis in children. BMJ 1990;301:359-62. 6. Jawahar MS, Rajaram K, Sivasubramanian S, Paramasivan CN, Chandrasekar K, Kamaludeen MN, et al. Treatment of lymph node tuberculosis - a randomized clinical trial of two 6-month regimens. Trop Med Int Health 2005;10:1090-8. 7. Wares F, Balasubramanian R, Mohan A, Sharma SK. Extrapulmonary tuberculosis: management and control. In: Agarwal SP, Chauhan LS, editors. Tuberculosis control in India. New Delhi: Directorate General of Health Services, Ministry of Health and Family Welfare; 2005.p.95-114. 8. Narang P, Narang R, Narang R, Mendiratta DK, Sharma SM, Tyagi NK. Prevalence of tuberculous lymphadenitis in children in Wardha district, Maharashtra State, India. Int J Tuberc Lung Dis 2005;9:188-94. 9. Wright JE. Non-tuberculous mycobacterial lymphadenitis. Aust N Z J Surg 1996;66:225-8. 10. Bayazit YA, Bayazit N, Namiduru M. Mycobacterial cervical lymphadenitis. ORL J Otorhinolaryngol Relat Spec 2004;66:275-80. 11. Llewelyn DM, Dorman D. Mycobacterial lymphadenitis. Aust Paediatr J 1971;7:97-102. 12. Roba-Kiewicz M, Grzybowski S. Epidemiologic aspects of nontuberculous mycobacterial diseases and of tuberculosis in British Columbia. Am Rev Respir Dis 1974;109:613-20. 13. Shikhani A, Hadi UM, Mufarriz AA, Zaytoun GM. Mycobacterial cervical lymphadenitis. Ear Nose Throat J 1989; 68:660, 662-6, 668-72. 14. Manolidis S, Frenkiel S, Yoskovitch A, Black M. Mycobacterial infections of the head and neck. Otolaryngol Head Neck Surg 1993;109:427-33. 15. Yates MD, Grange JM. Bacteriological survey of tuberculous lymphadenitis in South-east England, 1981-1989. J Epidemiol Community Health 1992;46:332-5. 16. Pang SC. Mycobacterial lymphadenitis in Western Australia. Tuber Lung Dis 1992;73:362-7.

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Tuberculosis

17. Lee KC, Tami TA, Lalwani AK, Schecter G. Contemporary management of cervical tuberculosis. Laryngoscope 1992; 102:60-4. 18. Cantrell R, Jensen JH, Reid D. Diagnosis and management of tuberculous cervical adenitis. Arch Otolaryngol 1975;101:537. 19. Comstock GW, Edwards LB, Livesay VT. Tuberculosis morbidity in the US Navy: its distribution and decline. Am Rev Respir Dis 1974;110:571-80. 20. Rich AR. The pathogenesis of tuberculosis. Springfield: Thomas; 1950. 21. Kent DC. Tuberculous lymphadenitis: not a localized disease process. Am J Med Sci 1967;254:866. 22. Olson RN. Nontuberculous mycobacterial infections of the face and neck-practical considerations. Laryngoscope 1981;91:1714-26. 23. Chen Y-M, Lee P-Y, Su W-J, Perng R-P. Lymph node tuberculosis: 7-year experience in Veterans General Hospital, Taipei, Taiwan. Tuber Lung Dis 1992;73:368-71. 24. Fain O, Lortholary O, Djouab M, Amoura I, Bainet P, Beaudreuil J, et al. Lymph node tuberculosis in the suburbs of Paris: 59 cases in adults not infected by the human immunodeficiency virus. Int J Tuberc Lung Dis 1993;3:162-5. 25. Jones PG, Campbell PE. Tuberculous lymphadenitis in childhood: the significance of anonymous mycobacteria. Br J Surg 1962;50:302-14. 26. Singh B, Moodly M, Goga AD, Haffejee AA. Dysphagia secondary to tuberculous lymphadenitis. S Afr J Surg 1996;34:197-9. 27. Gupta SP, Arora A, Bhargava DK. An unusual presentation of oesophageal tuberculosis. Tuber Lung Dis 1992;73:174-6. 28. Ohtake M, Saito H, Okuno M, Yamamoto S, Ohgimi T. Esophagomediastinal fistula as a complication of tuberculous mediastinal lymphadenitis. Intern Med 1996;35:984-6. 29. Adkins MS, Raccuia JS, Acinapura AJ. Esophageal perforation in a patient with acquired immunodeficiency syndrome. Ann Thorac Surg 1990;50:299-300. 30. Im JG, Kim JH, Han MC. Computed tomography of esophagomediastinal fistula in tuberculous mediastinal lymphadenitis. J Comput Assist Tomogr 1990;14:89-92. 31. Macchiarini P, Delamare N, Beuzeboc P, Labussiere AS, Cerrina J, Chapelier A, et al. Tracheoesophageal fistula caused by mycobacterial tuberculous adenopathy. Ann Thorac Surg 1993;55:1561-3. 32. Lee JH, Shin DH, Kang KW, Park SS, Lee DH. The medical treatment of a tuberculous tracheo-oesophageal fistula. Tuber Lung Dis 1992;73:177-9. 33. Wilson RS, White RJ. Lymph node tuberculosis presenting as chyluria. Thorax 1976;31:617-20. 34. Kohn MD, Altman KA. Jaundice due to rare causes: tuberculous lymphadenitis. Am J Gastroenterol 1973;59:48-53. 35. Paredes C, DelCampo F, Zamarron C. Cardiac tamponade due to tuberculous mediastinal lymphadenitis. Tubercle 1990;71:219-20. 36. Fatimi SH, Javed MA, Ahmad U, Siddiqi BI, Salahuddin N. Tuberculous hilar lymph nodes leading to tracheopulmonary

37.

38.

39. 40.

41.

42. 43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

artery fistula and pseudoaneurysm of pulmonary artery. Ann Thorac Surg 2006;82:e35-6. Bem C. Human immunodeficiency virus-positive tuberculous lymphadenitis in Central Africa: clinical presentation of 157 cases. Int J Tuberc Lung Dis 1997;1:215-9. Mohan A, Reddy MK, Phaneendra BV, Chandra A. Aetiology of peripheral lymphadenopathy in adults: analysis of 1724 cases seen at a tertiary care teaching hospital in southern India. Natl Med J India 2007;20:78-80. Chakraborti KL, Jena A. MR evaluation of the mediastinal lymph nodes. Indian J Chest Dis Allied Sci 1997;39:19-25. Kumar A, Mohan A, Sharma SK, Kaul V, Parshad R, Chattopadhyay TK. Video assisted thoracoscopic surgery [VATS] in the diagnosis of intrathoracic pathology: initial experience. Indian J Chest Dis Allied Sci 1999;41:2-13. Baron KM, Aranda CP. Diagnosis of mediastinal mycobacterial lymphadenopathy by transbronchial needle aspiration. Chest 1991;100:1723-4. Bharucha NE, Ramamoorthy K, Sorabjee J, Kuruvilla T. All that caseates is not tuberculosis. Lancet 1996;348:1313. Gupta AK, Nayar M, Chandra M. Critical appraisal of fine needle aspiration cytology in tuberculous lymphadenitis. Acta Cytol 1992;36:391-4. Finfer M, Perchik A, Burstein DE. Fine needle aspiration biopsy diagnosis of tuberculous lymphadenitis in patients with and without the acquired immunodeficiency syndrome. Acta Cytol 1991;35:325-32. Gupta SK, Chugh TD, Shiekh XA, al-Rubah NA. Cytodiagnosis of tuberculous lymphadenitis. A correlative study with microbiologic examination. Acta Cytol 1993;35:329-32. Lau SK, Wei WI, Hsu C, Engzell UC. Efficacy of fine needle aspiration cytology in the diagnosis of tuberculous cervical lymphadenopathy. J Laryngol Otol 1990;104:24-7. Radhika S, Gupta SK, Chakrabarti A, Rajwanshi A, Joshi K. Role of culture for mycobacteria in fine-needle aspiration diagnosis of tuberculous lymphadenitis. Diagn Cytopathol 1989;5:260-2. Pithie AD, Chicksen B. Fine-needle extra-thoracic lymphnode aspiration in HIV associated sputum-negative tuberculosis. Lancet 1992;340:1504-5. Bem C, Patil PS, Elliott AM, Namammbo KM, Bharucha H, Porter JD. The value of wide-needle aspiration in the diagnosis of tuberculous lymphadenitis in Africa. AIDS 1993;7:1221-5. Simecek C. Diagnosis of mycobacterial mediastinal lymphadenopathy by transbronchial needle aspiration. Chest 1992;102:1919. Singh KK, Muralidhar M, Kumar A, Chattopadhyaya TK, Kapila K, Singh MK, et al. Comparison of in house polymerase chain reaction with conventional techniques for the detection of Mycobacterium tuberculosis DNA in granulomatous lymphadenopathy. J Clin Pathol 2000;53:355-61. Vanajakumar, Selvakumar N, Jawahar MS, Rajaram K, Paramasivan CN. Transportation of lymph node biopsy specimens in selective Kirchner’s liquid medium for culture of tubercle bacilli. J Med Microbiol 1997;46:260-2. Singh HB, Singh P, Jadaun GP, Srivastava K, Sharma VD, Chauhan DS, et al. Simultaneous use of two PCR systems

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54.

55.

56.

57.

58.

targeting IS6110 and MPB64 for confirmation of diagnosis of tuberculous lymphadenitis. J Commun Dis 2006;38:274-9. Hirunwiwatkul P, Tumwasorn S, Chantranuwat C, Sirichai U. A comparative study of diagnostic tests for tuberculous lymphadenitis: polymerase chain reaction vs histopathology and clinical diagnosis. J Med Assoc Thai 2002;85:320-6. Park DY, Kim JY, Choi KU, Lee JS, Lee CH, Sol MY, et al. Comparison of polymerase chain reaction with histopathologic features for diagnosis of tuberculosis in formalin-fixed, paraffin-embedded histologic specimens. Arch Pathol Lab Med 2003;127:326-30. Osores F, Nolasco O, Verdonck K, Arevalo J, Ferrufino JC, Agapito J, et al. Clinical evaluation of a 16S ribosomal RNA polymerase chain reaction test for the diagnosis of lymph node tuberculosis. Clin Infect Dis 2006;43:855-9. Epub 2006 Aug 22. British Thoracic Society Research Committee. Six months versus nine months chemotherapy for tuberculosis of lymph nodes: preliminary results. Respir Med 1992;86:15-9. British Thoracic Society Research Committee. Six months versus nine months chemotherapy for tuberculosis of lymph nodes: final results. Respir Med 1993;87:621-3.

59. Kabra SK, Lodha R, Seth V. Category based treatment of tuberculosis in children. Indian Pediatr 2004;41:927-37. 60. Cheng VC, Ho PL, Lee RA, Chan KS, Chan KK, Woo PC, et al. Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients. Eur J Clin Microbiol Infect Dis 2002;21:803-9. 61. Colebunders R, John L, Huyst V, Kambugu A, Scano F, Lynen L. Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources. Int J Tuberc Lung Dis 2006;10:946-53. 62. Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W, et al; International Network for the Study of HIV-associated IRIS. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008;8:51623. 63. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367-416.

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Tuberculosis in Otorhinolaryngology

27

Subirendra Kumar, BC Roy, SC Sharma

INTRODUCTION Granulomatous infections that involve head and neck include a number of well-known diseases. Infections due to mycobacteria are the most prominent amongst them. Patients with granulomatous lesions including tuberculosis [TB] in the head and neck region usually present with lymphadenopathy or chronic inflammation that does not respond to antibacterial therapy (1-3). In the pre-chemotherapeutic era, patients with active pulmonary TB often developed laryngeal, otological, nasal and paranasal sinus involvement and deteriorated progressively. Laryngeal involvement was a dreaded consequence and was considered to be a harbinger of death. The classical description of TB involving head and neck emanated from that period. With the advent of effective antituberculosis treatment the incidence of otolaryngological TB has come down significantly. The resurgence of TB as a consequence of human immunodeficiency virus [HIV] infection and acquired immunodeficiency syndrome [AIDS] has brought otolaryngological TB into focus once again.

The site of involvement in some of the recently published series on head and neck TB is shown in Table 27.1 (1-3). TUBERCULOSIS OF CERVICAL LYMPH NODES Cervical lymph node involvement is the most common form of lymph node TB and is also the most frequently seen head and neck manifestation of TB [Figures 27.1, 27.2A, 27.2B, 27.3, and 27.4]. The chapter “Lymph node tuberculosis” [Chapter 26] covers this topic in detail. TUBERCULOSIS OF SPINE Patients with TB of cervical spine may occasionally present to the otorhinolaryngologist with torticollis, stiffness of neck due to spasm of the neck muscles and

TUBERCULOSIS IN HEAD AND NECK REGION Although not as common as pulmonary TB, head and neck involvement by TB occurs in a significant proportion of cases. Head and neck TB develops due to: [i] spread of the bacilli to the upper airway by contaminated sputum from a pulmonary focus; [ii] haematogenous; and [iii] lymphatic dissemination. Primary involvement of the tonsil as the portal of entry with subsequent involvement of the cervical lymph nodes is also known.

Figure 27.1: Tuberculosis lymph node abscess in suprahyoid region

Tuberculosis in Otorhinolaryngology 411 Table 27.1: Site of involvement in some of the recently published series on head and neck TB Variable

Menon et al (1) [n = 128]

Nalini and Vinayak (2) [n = 117]

Prasad et al (3) [n = 165]*

Place of study Male:Female Site of involvement† Cervical lymph nodes Larynx Cervical spine Oropharynx Nasopharynx Ear Eyes Retropharyngeal abscess Salivary glands Thyroid Temporomandibular joint Skin Associated pulmonary TB and TB of other organs

Bradford, UK 68:60

Mumbai, India 41:76

Mangalore, India 108:57

111 [87] 02 [1.6] 0 02 [1.6] 01 02 [1.6] 02 [1.6] 01 05 [3.9] 01 0 01 20

111 [95] 02 [1.7] 01 01 0 01 0 01 0 0 0 0 31

121 [73.3] 24 [14.5] 03 [1.8] 08 [5] 01 04 [2.4] 0 0 03 [1.8] 0 01 0 24.2

* Of the 65 patients who were tested, 30% were found to have co-existing HIV infection † Values in square brackets indicate percentage UK = United Kingdom; HIV = human immunodeficiency virus

Figure 27.2A: Tuberculosis lymph node abscess

Figure 27.2B: Ruptured tuberculosis lymph node abscess in the same patient as in Figure 27.2A. Repeated aspirations did not prevent rupture of the abscess

painful movement of the spine. Difficulty in swallowing and breathing, and a midline bulge in the posterior pharyngeal wall suggest a retropharyngeal or paravertebral abscess. Children with this condition may present with stridor. Pus from the TB lesion of the spine may track downwards and laterally along the prevertebral

muscles and manifests in the neck as an abscess. Epidural sepsis in the neck can be the cause of musculoskeletal symptoms [polyradiculopathy] which can go undiagnosed before it manifests with some more obvious features (4). The reader is referred to the chapter “Skeletal tuberculosis” [Chapter 23] for more details.

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Figure 27.3: Tuberculosis sinus from a cold abscess. Note the scarring adjacent to the sinus opening

Figure 27.5: Tuberculosis of the tongue. Patient recovered completely with antituberculosis treatment

single or multiple, painful or painless (5). Usually, the lesions are well-circumscribed, but irregular ulcers may also occur. These lesions sometimes begin as nodules, fissures or plaques (6). Initial picture may resemble a malignant process and histopathology confirms the diagnosis of TB (7). Other sites of involvement include: floor of mouth, soft palate, anterior pillars and uvula (8). Secondary involvement of the draining lymph nodes may occur. Majority of these patients also have pulmonary TB (5,7, 9-11). TUBERCULOSIS OF LARYNX Pathogenesis Figure 27.4: Preauricular sinus with tuberculosis infection

TUBERCULOSIS OF ORAL CAVITY The oral cavity is an uncommon site of involvement by TB. Infection in the oral cavity is usually acquired through infected sputum coughed out by a patient with open pulmonary TB. Infection may also be acquired by haematogenous spread. In general, the intact mucosa of the oral cavity is relatively resistant to invasion and saliva has inhibitory effect on the growth of mycobacteria. A breach in the mucosa due to any reason is one of the important predisposing factors for the development of TB of the oral cavity. Tongue is the most common site of involvement and accounts for nearly half the cases [Figure 27.5]. The lesions are usually found over the tip, borders, dorsum and base of the tongue. They may be

Laryngeal TB classically develops due to direct spread to the larynx from contaminated sputum [bronchogenic spread]. This form of involvement, frequent in patients with sputum smear-positive pulmonary TB, most commonly involves the posterior glottis. It is thought to develop due to the pooling of infected sputum when the patient is in the recumbent position (12). The bronchogenic spread to the larynx results in localized oedema, granuloma or ulcerations (13). The laryngeal involvement may also occur due to lymphohaematogenous spread. Isolated laryngeal involvement may occur without any evidence of pulmonary TB. Recent evidence suggests that the occurrence of laryngeal TB with oedematous, polypoid panlaryngitis as a consequence of lymphohaematogenous spread that is not easily distinguishable from chronic laryngitis is increasing (14-18).

Tuberculosis in Otorhinolaryngology 413 Epidemiology Before the availability of antituberculosis chemotherapy, laryngeal involvement was considered a grave prognostic sign indicative of severe disease. It was seen in nearly one-third of cases with pulmonary TB (19). With the availability of effective antituberculosis treatment, there has been a gradual decline in the burden of laryngeal TB. However, with the advent of the HIV infection and the AIDS, the incidence of laryngeal TB is increasing (14,16). In the present era, it has been observed that in countries where TB is highly endemic, almost all patients with laryngeal TB have been found to have radiological evidence of pulmonary TB and many of them may be sputum smear-positive (19-21). On the contrary, most of the patients with laryngeal TB in countries with a low prevalence of TB seldom have any evidence of pulmonary TB (22,23). However, patients with a heavy bacillary load and strongly positive sputum specimens may not have laryngeal involvement. The incidence of laryngeal involvement in patients with pulmonary TB has ranged from 1.5 to 50 per cent in recently published studies (20,24-27). Pathology The tubercle bacilli induce low-grade inflammation with the formation of typical TB granulation tissue. Coagulation necrosis occurs in large TB granulomas. Later, caseation may develop. Laryngeal lesions reveal oedema and hyperaemia, granulomas or ulceration. Vocal cord thickening and palsy can occur. Epiglottis may show irregular margins and nibbled appearance. Mycobacterium tuberculosis may be found in the subepithelial tissue. The process of destruction and the repair often proceeds simultaneously. The submucosa of epiglottis and aryepiglottic folds are likely to undergo fibrous infiltration resulting in pseudoedema. Described as turban epiglottis, this lesion is not commonly seen in the present era.

In their study of laryngeal TB, Soni and Chatterjee (20) reported hoarseness in 98.6 per cent, dysphagia and odynophagia or pain in throat in 35.8 per cent and referred otalgia in 28.6 per cent of patients. In 14.3 per cent of their cases, the symptoms were not referred to larynx. The physical examination findings associated with laryngeal TB include oedema, hyperaemia, nodularity, ulceration, exophytic mass, vocal cord thickening, and obliteration of anatomic landmarks. The ulceroinfiltrative lesions which predominantly affected the posterior larynx were observed frequently in the past and are rare now. At the present time the macroscopic appearance corresponds to a diffuse oedema or to a pseudotumoral image located in any zone. The laryngeal TB should be suspected in a patient with non-specific chronic laryngitis of poor evolution (18). The epiglottis may be markedly oedematous [turban epiglottis] and the vocal cord oedema can resemble polypoid corditis. Subglottic oedema or granulation in the true vocal cords can result in stridor. Vocal cord paralysis secondary to mediastinal lymphadenopathy can also cause stridor (27). Any laryngeal structure can be affected by TB [Figure 27.6] and the common sites include true vocal cord, the epiglottis, the false vocal cord, the aryepiglottic fold, the arytenoids, the interarytenoid area and the subglottis (17,28,29). Occasionally, patients may present with rapid onset of hoarseness of voice similar to that encountered in acute viral laryngitis. Because of the acute onset, TB is rarely suspected as the cause. When these patients fail to

Clinical Features Patients often present with hoarseness of voice and laryngeal TB should be considered in the differential diagnosis in any patient with unexplained hoarseness of voice. Pain is also an important feature which may radiate to one or both ears and may lead to odynophagia.

Figure 27.6: Endoscopic view of the laryngeal tuberculosis

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respond to conservative management, microlaryngoscopic examination, biopsy and histopathological examination may confirm the diagnosis of vocal cord TB. Co-existence of laryngeal TB and carcinoma is wellknown. Clinical features of these conditions may overlap and the lesions may look similar (21,22). The incidence of this co-existent TB and cancer of larynx has been reported to be 1.4 per cent (30). Antituberculosis treatment should be given for at least two to three weeks period before the treatment of laryngeal carcinoma is initiated. In a study of 201 patient with TB complicating a neoplastic condition, 45 had head and neck cancers (31). When TB develops after antineoplastic therapy, the infection is more severe with a higher mortality (21-23,30,31). TUBERCULOSIS OF THE SALIVARY GLANDS Tuberculosis sialitis is usually secondary to TB of the oral cavity or pulmonary TB. Primary TB of the salivary glands is also known, but, is rare. Parotid is the most common salivary gland involved [Figures 27.7A and 27.7B]. Tuberculosis of the submandibular gland is also known (32). Clinical presentation can be acute or chronic. Acute presentation may resemble acute non-TB sialitis and clinical differentiation may be difficult. Occasionally, the diagnosis of TB may be a surprise following surgery performed for a suspected salivary gland tumour (33). Unsuspected TB parotid abscess may be wrongly drained mistaking it to be a pyogenic [non-TB] abscess. This may lead to the formation of a persistent sinus. In one such case (34), the diagnosis of TB was made when superficial parotidectomy was performed as part of the treatment for fistula. In patients with suspected TB sialitis, chest radiograph and fine needle aspiration cytology are useful in confirming the diagnosis. TUBERCULOSIS OF PHARYNX Tuberculosis involvement of the tonsils and pharynx is uncommon at present. These cases may be confused with carcinoma at the time of presentation (35). The presenting features include: [i] ulcer on the tonsil or oropharyngeal wall; [ii] granuloma of the nasopharynx; and [iii] neck abscess. Co-existence of TB (36) and cancer of pharynx could be: [i] a mere coincidence; [ii] metastatic carcinoma developing secondarily in a recent or old TB lesion; [iii] TB infection engrafted on cancer in

Figure 27.7A: Tuberculosis parotitis with facial nerve palsy before antituberculosis treatment

Figure 27.7B: Following antituberculosis treatment, facial nerve palsy recovered and parotid gland swelling subsided

full evolution; and [iv] chronic progressive TB in which cancer develops (37). Lymphoreticular malignancy may be associated with TB abscess and sinus of the neck [Figure 27.8]. Rarely, malignancy and TB may involve two different organs (36). TUBERCULOSIS OF THE EAR While the association between pulmonary TB and TB infection of the middle ear cleft is known since early nineteenth century, primary infection of ear is rare (38-40).

Tuberculosis in Otorhinolaryngology 415

Figure 27.8: Tuberculosis sinuses associated with lymphoma of cervical lymph nodes

Pathogenesis Ear can become infected with Mycobacterium tuberculosis by the bacilli invading the Eustachian tube while the infant is being fed, or, by haematogenous spread to the mastoid process. Clinical Manifestations Patients with aural TB present with painless otorrhoea and hearing loss. However, patients with TB mastoiditis may complain of otalgia. Pale granulation tissue may be present in the middle ear with dilatation of vessels in the anterior part of the tympanic membrane (41-44). Multiple perforations of tympanic membrane may occur as a result of caseation necrosis. These perforations may coalesce to form a large perforation which may involve annulus as well. Pars flaccida is usually not involved by TB. Facial nerve palsy may occur in patients with TB of the ear with or without a sequestrum [Figure 27.9]. Persistent non-healing granulations in a post-mastoidectomy patient may occasionally be the result of TB infection. Pre-auricular lymphadenopathy with post-auricular fistula has been considered to be pathognomonic of TB otitis media (43). Tuberculosis of the external ear is uncommon. However, lupus vulgaris of the external ear has been reported (45). TUBERCULOSIS OF THE NASOPHARYNX Tuberculosis of the nasopharynx is uncommon. The most common complaint is nasal obstruction and rhinorrhoea.

Figure 27.9: Facial nerve palsy in a patient with tuberculosis of middle ear and mastoid. Ear became dry with antituberculosis treatment. Facial nerve palsy did not recover as it was long-standing

Physical examination may show adenoid hypertrophy without any distinguishing features. In a study of 40 patients reported by Tse et al (46), young femlaes in the age range of 20 to 40 years were frequently affected by nasopharyngeal TB. The most common clinical manifestation was cervical lymphadenopathy [53%], followed by hearing loss [12%], tinnitus, otalgia, nasal obstruction and postnasal drip [6% each]. Systemic symptoms such as fever, weight loss and night sweats were evident in 12 per cent patients. Direct endoscopic examination showed nasopharyngeal mucosal irregularity or mass in the nasopharynx in a majority [70%] of the patients. Primary infection of nasopharynx by TB is very rare (47). Nasal obstruction or middle ear effusion is the common presenting feature. TUBERCULOSIS OF THE PARANASAL SINUSES Paranasal sinus TB is a rare entity and is nearly always secondary to pulmonary or extra-pulmonary TB (48-50). The sinuses most frequently affected are maxillary and ethmoid, though any sinus may be affected. The infection reaches the sinus either via the blood stream or by a direct extension from TB of the skull base (51). In sinonasal TB, infection may be limited to the submucosa only. Here, the sinus mucosa may be thickened or filled with a polyp, which has a pale and boggy appearance with minimal purulent discharge. This form is more common than the second type, which is characterized by the bony involvement [osteomyelitis] with a sequestrum and fistula formation. The latter form is more difficult to treat. Like any other pyogenic infection, the sinonasal TB can also

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spread to the brain or orbit resulting in brain abscess, epiphora and deterioration of vision. Rarely, TB of the maxillary sinus may be associated with a carcinoma (52). Tuberculosis of the sphenoid sinus can present with blindness and features of cavernous sinus thrombosis with gradual onset and slow progression (50). Computed tomography [CT] may show a heterogeneous soft tissue mass lesion in a sinus with bone erosion and extension to the surrounding tissue. Magnetic resonance imaging [MRI] may delineate the soft tissue extension better. NASAL TUBERCULOSIS Tuberculosis of nasal cavity usually manifests as nasal obstruction and catarrh. Physical examination may reveal pallor of the nasal mucosa with minute apple-jelly nodules that do not blanch with nasal decongestants. Other sites which can be involved include inferior turbinate, septal mucosa and the vestibular skin. These nodules may coalesce to form a granular lesion with subsequent perforation of the septal cartilage (14). Involvement of nasolacrimal duct can occur rarely. Tuberculosis of the nose can cause complications, like septal perforation, atrophic rhinitis and scarring of nasal vestibule.

smear microscopy, culture and the chest radiography (14,45,53). A high index of suspicion is required to diagnose TB of the ear. Tissue biopsy should be done to confirm the diagnosis. However, due to the atypical nature of the clinical presentation, TB is not suspected initially and the patient may frequently undergo middle ear exploration. The diagnosis may become evident subsequently when histopathology reveals the classical changes. Diagnosis of TB otitis media is ascertained by smear and mycobacterial culture examination of the ear discharge and histopathologic study of the affected tissue. Smear and culture examination of the nasal discharge, nasopharyngeal secretions collected by nasal endoscopy along with histopathological examination of biopsy material are useful in the diagnosis of TB of the nose, paranasal sinuses and pharynx. Histopathological and microbiological examination of biopsy material is useful in confirming the diagnosis of TB of the tongue, oral cavity and salivary glands. Diagnosis of cervical lymph node TB is covered in the chapter “Lymph node tuberculosis” [Chapter 26]. Molecular methods of diagnosis, such as polymerase chain reaction [PCR] seem to be useful in the diagnosis of otolaryngological TB. Their usefulness needs to be confirmed in large studies.

DIFFERENTIAL DIAGNOSIS Laryngeal TB must be differentiated from squamous cell carcinoma and other granulomatous inflammatory diseases, such as fungal infections, syphilis, leprosy, Wegener’s granulomatosis, and sarcoidosis. Multiple biopsies may be required to confirm the diagnosis. Tuberculosis of the nose and paranasal sinuses results in ulceration, granuloma formation and pain in the nose and the infected sinus cavity. Usually, other granulomatous disorders of the paranasal sinuses are painless. Tuberculosis of the oral cavity should be differentiated from primary syphilis, fungal infections, chronic traumatic ulcers and squamous cell carcinoma. DIAGNOSIS Diagnosis of laryngeal TB involves demonstration of Mycobacterium tuberculosis in sputum, laryngeal swab by smear and culture methods and histopathological examination of the biopsy material (40). Co-existent pulmonary TB should be carefully looked for by sputum

IMAGING IN HEAD AND NECK TUBERCULOSIS Although CT and MRI scanning can accurately demonstrate the site, pattern and extent of the disease, however, both these modalities have limitations in the evaluation of head and neck TB (47). The radiological features are variable and non-specific. However, CT and MRI have a definitive role in the diagnosis of TB of spine. Tuberculosis lymphadenitis is often characterized by areas of low attenuation or low signal intensity with peripheral rim enhancement or calcification on the CT. The CT findings in laryngeal TB are also non-specific. There may be a diffuse thickening of the epiglottis or vocal cords. Deep submucosal infiltration to preepiglottic or paraglottic space and cartilage destruction is usually not seen unlike laryngeal carcinoma. Kim et al (54) described the CT findings in 12 patients with laryngeal TB. Bilateral involvement was noted in nine patients [75%], while unilateral involvement was seen in three [25%]. Diffuse thickening of free margin of the epiglottis was a characteristic and frequent finding in

Tuberculosis in Otorhinolaryngology 417 TB [50%]. No deep submucosal infiltration of the preepiglottic and paralaryngeal fat spaces was seen even when there was extensive involvement of the laryngeal mucosa. Cartilage destruction was not found in any case. By comparison, laryngeal carcinoma presented with unilateral involvement, infiltration of the pre-epiglottic and paralaryngeal fat spaces by a submucosal mass, cartilage destruction, and extra-laryngeal invasion. In patients with TB mastoiditis, the plain radiograph or the CT may reveal the presence of a sequestrum. Further, in patients with aural TB, the CT of temporal bone may demonstrate destruction of the osseous chain, sclerosis of the mastoid cortex, and opacification of the middle ear and mastoid air cells. The CT evidence of widespread bone destruction without clinical signs of aggressive infection, should suggest TB mastoiditis (55). The MRI may show thickened seventh and eighth nerve complex in the internal auditory meatus. This finding is frequently seen in the post-contrast scans in patients with sensory neural hearing loss and facial nerve paralysis [Figure 27.10]. IMPACT OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION Sparse literature is available on otorhinolaryngological TB in patients with HIV infection and AIDS (53,56-58). Singh et al (58) reviewed the clinical presentation of laryngeal TB in HIV-positive patients. In this study, eight of the 146 patients with head and neck TB had laryngeal

Figure 27.10: Post-contrast MRI scan showing thickened seventh and eighth nerve complex in the internal auditory meatus and arachnoiditis [arrow]

involvement and two of these patients were HIVpositive. The most common symptoms were hoarseness, odynophagia and shortness of breath. The majority of the patients had white exophytic lesions involving any area of the larynx and these lesions resembled carcinoma or chronic laryngitis. Systemic symptoms, such as fever, night sweats, and weight loss were very common in patients with AIDS and coupled with other illnesses masked the possibility of laryngeal disease and resulted in a delay in the diagnosis. In another retrospective study (53), the characteristics of TB confined to the head and neck region in 38 patients infected with HIV were reported. These patients were divided into two groups on the basis of the HIV status at presentation. Group 1 included 11 patients [29%] with AIDS at presentation. Group 2 included 27 patients [71%] with HIV infection but without AIDS. The authors reported that the cervical lymphatics were the most common site for isolated head and neck TB [89%], with the supraclavicular lymph nodes most often involved [53%]. Extra-lymphatic involvement was less common [11%], but involved a variety of anatomic locations [skin, spinal cord, larynx, parotid salivary gland]. The presenting history and physical examination had a low sensitivity for TB in patients with HIV infection, mainly because of the presence of multiple confounding factors. Purified protein derivative testing was highly sensitive for TB in patients with HIV infection alone [61%]; however, its usefulness was diminished in patients with AIDS [14%]. Fine needle aspiration biopsy was 94 per cent sensitive for diagnosing TB and was not affected by the status of HIV infection. Surgical biopsy was the gold standard for diagnosing TB but was associated with chronically draining fistulas in a significant number of cases [14%]. These data suggest that TB should be considered in the differential diagnosis of all head and neck lesions in patients infected with HIV, even in the absence of pulmonary involvement. Six of the fourteen children with HIV-1 infection described by Schaaf et al (57) presented with otorrhoea. Ear swabs were the source of Mycobacterium tuberculosis culture in three of them. Chest radiographs were abnormal in all of them. TREATMENT OF TUBERCULOSIS IN THE HEAD AND NECK Antituberculosis chemotherapy is the mainstay of treatment for patients with TB of head and neck region.

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The reader is referred to the chapter “Treatment of tuberculosis” [Chapter 52]. Patients should be treated for six months; however, prolongation of therapy should be considered in a patient if response to treatment is inadequate and slow (59). As the larynx heals, fibrosis of laryngeal tissue can occur resulting in the following sequelae: cricoarytenoid joint fixation, posterior glottic stenosis and anterior glottic web, subglottic stenosis, vocal cord scarring [Figure 27.3]. These specific complications are to be treated accordingly (21,23). Indications for surgery in patients with head and neck TB are outlined in Table 27.2. Superior laryngeal nerve block has been advocated for odynophagia (23), but, is rarely required at present as effective antituberculosis drugs are available. In patients with TB of the cervical spine and cold abscess, repeated aspirations may be required to decompress the abcess and relieve the difficulty in breathing and swallowing. Usually, open drainage is avoided. However, if required, external approach rather than peroral drainage is recommended to avoid sinus formation and prevent the abscess from draining into the oropharynx. Occasionally, debridement of the diseased bone and bone grafting may be required. Paraplegia may develop in patients with severe and advanced involvement of the cervical spine. To prevent this, prophylactic neck collar support is helpful. Neck collar support also relieves the pain when there is severe spasm of neck muscles. Occasionally, second-line antituberculosis drugs may be required in patients with atypical mycobacterial infection or drug-resistant TB [DR-TB]. Therefore, diligent efforts should be made to procure and subject Table 27.2: Indications for surgery in patients with head and neck tuberculosis Diagnostic Biopsy of mucosal lesions Lymph node biopsy where the fine needle aspiration cytopathology fails to give conclusive result Therapeutic Excision of a sinus or fistula with tuberculosis infection which fails to heal even after adequate antituberculosis therapy Drainage of neck abscess Repeated drainage or external drainage of retropharyngeal abscess Presence of sequestrum in the mastoid region Revision of cosmetically bad scars left after the tuberculosis infection has healed

the tissue specimens to culture and sensitivity whenever nontuberculous mycobacterial infection or DR-TB is suspected. REFERENCES 1. Menon K, Bem C, Gouldesbrough D, Strachan DR. A clinical review of 128 cases of head and neck tuberculosis presenting over a 10-year period in Bradford, UK. J Laryngol Otol 2007;121:362-8. Epub 2006 Aug 21. 2. Nalini B, Vinayak S. Tuberculosis in ear, nose, and throat practice: its presentation and diagnosis. Am J Otolaryngol 2006;27:39-45. 3. Prasad KC, Sreedharan S, Chakravarthy Y, Prasad SC. Tuberculosis in the head and neck: experience in India. J Laryngol Otol 2007;121:979-85. Epub 2007 Mar 19. 4. Smith DF, Smith FW, Douglas JG. Tuberculous polyradiculopathy: the value of magnetic resonance imaging of the neck. Tubercle 1989;70:213-6. 5. Soni NK, Chatterji P, Chhimpa I. Lingual tuberculosis. Indian J Otolaryngol 1979;31:92-2. 6. Tyldesley WR. Oral tuberculosis–an unusual presentation. Br Med J 1978;2:928. 7. Brennan TF, Vrabec DP. Tuberculosis of the oral mucosa. Ann Otol Rhinol Laryngol 1970;79:601-5. 8. Komet H, Schaefer RF, Mahoney PL, Antonio S. Bilateral tuberculosis granulomas of the tongue. Arch Otolaryngol 1965;82:649-51. 9. Fujibayashi T, Takahashi Y, Yoneda T, Tagani Y, Kusama M. Tuberculosis of the tongue. Oral Surg 1979;47:427-35. 10. Mcandrew PG, Adekeye EO, Ajdukiewicz AB. Miliary tuberculosis presenting with multifocal oral lesions. Br Med J 1976;1:1320. 11. Weaver RA. Tuberculosis of the tongue. JAMA 1976;235: 2418. 12. Houghton DJ, Bennett JD, Rapado F, Small M. Laryngeal tuberculosis: an unsuspected danger. Br J Clin Pract 1997;51:61-2. 13. Bull TR. Tuberculosis of the larynx. Br Med J 1966;2:991-2. 14. Williams RG, Douglas-Jones T. Mycobacterium marches back. J Laryngol Otol 1995;109:5-13. 15. Soda A, Rubio H, Salazar M, Genem J, Berlanga D, Sanchez A. Tuberculosis of the larynx: clinical aspects in 19 patients. Laryngoscope 1989;99:1147-50. 16. Lazarus AA, Thilagar B. Tuberculosis of pericardium, larynx, and other uncommon sites. Dis Mon 2007;53:46-54. 17. Levenson MJ, Ingerman M, Grimes C, Robbett WF. Laryngeal tuberculosis: review of twenty cases. Laryngoscope 1984;94:1094-7. 18. Porras AE, Martin MA, Perez RJ, Avalos SE. Laryngeal tuberculosis. Rev Laryngol Otol Rhinol 2002;123:47-8. 19. Looper EA, Lyon IB. Laryngeal tuberculosis. Ann Otol Rhinol Laryngol 1948;57:754-68. 20. Soni NK, Chatterjee P. Laryngeal tuberculosis. Indian J Otolaryngol 1978;30:115-7. 21. Rupa V, Bhanu TS. Laryngeal tuberculosis in the eighties– an Indian experience. J Laryngol Otol 1989;103:864-8.

Tuberculosis in Otorhinolaryngology 419 22. Thaller SR, Gross JR, Pilch BZ, Goodman M. Laryngeal tuberculosis as manifested in the decades 1963-1983. Laryngoscope 1987;97:848-50. 23. Street I, Gillett D, Sawyer A, Weighill J. Laryngeal tuberculosis: not the usual suspect. Br J Hosp Med [Lond] 2006;67:212-3. 24. Topak M, Oysu C, Yelken K, Sahin-Yilmaz A, Kulekci M. Laryngeal involvement in patients with active pulmonary tuberculosis. Eur Arch Otorhinolaryngol 2008;265:327-30. Epub 2007 Oct 6. 25. Iqbal K, Udaipurwala IH, Khan SA, Jan AA, Jalisi M. Laryngeal involvement in pulmonary tuberculosis. J Pak Med Assoc 1996;46:274-6. 26. Lim JY, Kim KM, Choi EC, Kim YH, Kim HS, Choi HS. Current clinical propensity of laryngeal tuberculosis: review of 60 cases. Eur Arch Otorhinolaryngol 2006;263:838-42. Epub 2006 Jul 12. 27. Shin JE, Nam SY, Yoo SJ, Kim SY. Changing trends in clinical manifestations of laryngeal tuberculosis. Laryngoscope 2000;110:1950-3. 28. Smallman LA, Clark DR, Raine CH, Proops DW, Shenoi PM. The presentation of laryngeal tuberculosis. Clin Otolaryngol 1987;12:221-5. 29. Galietti F, Giorgis GE, Gandolfi G, Astesiano A, Miravalle C, Ardizzi A, et al. Examination of 41 cases of laryngeal tuberculosis observed between 1975-1985. Eur Respir J 1989;2:731-2. 30. Feld R, Bodey GP, Groschell D. Mycobacteriosis in patients with malignant disease. Arch Intern Med 1976;136:67-70. 31. Kaplan MH, Armstrong D, Rosen P. Tuberculosis complicating neoplastic disease. A review of 201 cases. Cancer 1974;33:850-8. 32. Kumar S, Dev A. Primary tuberculosis of bilateral submandibular salivary glands. Indian J Otolaryngol 1990;42:69-70. 33. El Hakim IE, Langdon JD. Unusual presentation of tuberculosis of the head and neck region. Report of three cases. Int J Oral Maxillofacial Surg 1989;18:194-6. 34. Kant R, Sahi RP, Mahendra NN, Agarwal PK, Shankhdhar R. Primary tuberculosis of the parotid gland. J Indian Med Assoc 1977;68:212. 35. Srirompotong S, Yimtae K, Srirompotong S. Clinical aspects of tonsillar tuberculosis. Southeast Asian J Trop Med Public Health 2002;33:147-50. 36. Raman R, Bakthavizian A. Tuberculosis associated with malignancy of the nasopharynx. Indian J Otolaryngol 1981;33:149-50. 37. Broders AC. Tuberculosis associated with malignant neoplasia. JAMA 1919;72:390-4. 38. Hasan SA, Malik A. Tuberculosis otitis media. Indian J Otolaryngol 1981;33:145-6. 39. Skolink PR, Nadol JR Jr, Baker AS. Tuberculosis of the middle ear: review of literature with an instructive case report. Rev Infect Dis 1986;8:403-10.

40. Mittal OP, Singh RP, Katiyar SK, Nath N, Gupta SC. Tubercular osteomyelitis of the mastoid temporal bone. Int J Otolaryngol 1977;29:20. 41. Awan MS, Salahuddin I. Tuberculous otitis media: two case reports and literature review. Ear Nose Throat J 2002;81:792-4. 42. Di Rienzo L, Tirelli GC, D’Ottavi LR, Cerqua N. Primary tuberculosis of the middle ear: description of 2 cases and review of literature. Acta Otorhinolaryngol Ital 2001;21:365-70. 43. Greenfield BJ, Selesnick AH, Fisher L, Ward RF, Kimmelman CP, Harrison WG. Aural tuberculosis. Am J Otol 1995;16:17582. 44. Vital V, Printza A, Zaraboukas T. Tuberculous otitis media: a difficult diagnosis and report of four cases. Pathol Res Pract 2002;198:31-5. 45. Sachdeva OP, Kukreja SM, Mohan C. Lupus vulgaris of external ear. Indian J Otolaryngol 1978;30:136-7. 46. Tse GM, Ma TK, Chan AB, Ho FN, King AD, Fung KS, et al. Tuberculosis of the nasopharynx: a rare entity revisited. Laryngoscope 2003;113:737-40. 47. Mair IWS, Johannessen TA. Nasopharyngeal tuberculosis. Arch Otolaryngol 1970;92:392-3. 48. Kukreja HK, Sacha BS, Joshi KC. Tuberculosis of maxillary sinus. Indian J Otolaryngol 1977;29:27-8. 49. Krishnan E, Rudraksha MR. Paranasal sinus tuberculosis. India J Otolaryngol 1978;3:125-6. 50. Sharma SC, Baruah P. Sphenoid sinus tuberculosis in children–a rare entity. Int J Pediatr Otorhinolaryngol 2003;67:399-401. 51. Page JR, Jash DK. Tuberculosis of the nose and paranasal sinuses. J Laryngol Otol 1974;88:579-83. 52. Vrat V, Saharia PS, Nayyer M. Co-existing tuberculosis and malignancy in the maxillary sinus. J Laryngol Otol 1985;99:397-8. 53. Singh B, Balwally AN, Har-El G, Lucente FE. Isolated cervical tuberculosis in patients with HIV infection. Otolaryngol Head Neck Surg 1998;118:766-70. 54. Kim MD, Kim DI, Yune HY, Lee BH, Sung KJ, Chung TS, et al. CT findings of laryngeal tuberculosis: comparison to laryngeal carcinoma. J Comput Assist Tomogr 1997;21:29-34. 55. Mandpe AH, Lee KC. Tuberculous infections of the head and neck. Curr Opin Otolaryngol Head Neck Surg 1998;6:190-6. 56. Srirompotong S, Yimtae K, Srirompotong S. Tuberculosis in the upper aerodigestive tract and human immunodeficiency virus coinfections. J Otolaryngol 2003;32:230-3. 57. Schaaf HS, Geldenduys A, Gie RP, Cotton MF. Culturepositive tuberculosis in human immunodeficiency virus type 1-infected children. Pediatr Infect Dis J 1998;17:599-604. 58. Singh B, Balwally AN, Nash M, Har-El G, Lucente FE. Laryngeal tuberculosis in HIV-infected patients: a difficult diagnosis. Laryngoscope 1996;106:1238-40. 59. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al; American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society. Am J Respir Crit Care Med 2003;167:603-62.

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Ocular Tuberculosis

28

SP Garg, Rohan Chawla, Pradeep Venkatesh

INTRODUCTION Tuberculosis [TB] is a serious global public health problem (1). The incidence of ocular TB in a population is difficult to estimate (2). Estimates of incidence and prevalence of ocular TB have usually been drawn from reports of histopathologically proven ocular TB, studies on experimental ocular TB and surveys of ocular disease in patients with proven systemic TB (3). In a report (4) from a sanatorium in the USA, 1.4 per cent of 10 524 patients were treated for ocular TB between 1940 and 1966. In a 10-year review of cases from Romania the incidence of ocular TB has also been reported as being one per cent of all the TB patients (5). The incidence of TB uveitis in India has varied from two to thirty per cent (6,7). The large variation in the incidence rates in different reports possibly stems from differences in the diagnostic criteria used. In the studies reporting higher incidence rates, the diagnosis of TB uveitis was often based on a positive tuberculin skin test [TST]. Ocular manifestations of TB are protean. While TB can affect all areas of the visual system, the choroid is probably the most commonly affected intraocular structure. Choroidal tubercles constitute the most common intraocular manifestation of TB (8). Woods (9) estimated that the choroid is involved in about one per cent of patients with pulmonary TB. Primary TB of the eyelid, conjunctival sac and optic nerve is rare. Rarely, serious manifestations, such as panophthalmitis or endophthalmitis can also occur. Certain ocular manifestations, such as vasculitis due to TB [e.g., Eale’s disease] are presumably due to hypersensitivity to a sequestered antigen rather than TB disease per se (10).

The impact of acquired immunodeficiency syndrome [AIDS] epidemic on various ocular manifestations of TB remains unclear and ocular TB is uncommon in patients with human immunodeficiency virus [HIV] infection and AIDS (11-17). PRIMARY AND SECONDARY OCULAR TUBERCULOSIS Two different definitions have been given to “primary” ocular TB. The term “primary ocular TB” has been used when the TB lesions are confined to the eyes and no systemic lesions are clinically evident. The term has also been used to describe the cases where the eye has been the initial portal of entry (18,19). “Secondary” ocular TB has been defined as ocular infection resulting from contiguous spread from adjacent structures or haematogeneous spread from the lungs (20). Well-documented cases of primary ocular TB have been rarely described in the literature (17,21-23). Primary ocular infection rarely results in disseminated TB (24). Intraocular and orbital TB are considered to represent secondary infections (25,26). Studies to detect the ability of Mycobacterium tuberculosis to penetrate intact conjunctival or corneal epithelium have revealed conflicting results. Finnoff (26) reported that a breach in the epithelium was necessary to initiate an infection. Therefore, epithelial injury to the cornea may lead to primary ocular TB (27,28). However, Bruckner (29), experimenting on guinea pigs observed that Mycobacterium tuberculosis could be carried into the subepithelial tissue by phagocytosis despite an intact epithelium in the presence of chronic conjunctivitis.

Ocular Tuberculosis Besides Mycobacterium tuberculosis, nontuberculous mycobacteria [NTM] can also cause ocular TB. EYELID TUBERCULOSIS Tuberculosis affects the eyelids infrequently. The disease occurs as a result of spread of infection from the face and lymph nodes or by the haematogenous route. Primary eyelid involvement is extremely rare. Tuberculosis eyelid abscess has been reported in the literature in conjunction with lung infection or sinus disease (30-32). Eyelid lesion begins as a red papule that becomes indurated. Eventually, it enlarges to form a nodule or plaque that ulcerates. The ulcer is chronic and painless. In majority of the cases, regional lymphadenopathy also occurs. Rarely, the skin lesion is hyperkeratotic and papular. Lupus vulgaris of the face may spread to involve the eyelid. The disease progresses slowly leading to the characteristic soft “apple-jelly” nodule appearance. This feature is best appreciated on diascopy. Atrophic scars, ectropion and destruction of the lid may develop. Tuberculosis of the tarsal plate can simulate recurrent chalazion and finally causes its destruction (33). When lid involvement occurs by spread from the underlying bone, lacrimal sac or lymph node, the initial manifestation is a red, fluctuant nodule with induration. This lesion ulcerates in several cases and a fistula surrounded by granulation tissue develops in the ulcer crater. Tuberculids of the eyelid present as small, multiple papular and chronic lesions. It is not clear whether they are a non-specific form of granuloma or a hypersensitivity reaction to tuberculoprotein. The reader is referred to the chapter “Cutaneous tuberculosis” [Chapter 25] for more details. CONJUNCTIVAL TUBERCULOSIS Tuberculosis can involve the conjunctiva primarily or secondarily. Conjunctival TB and lupus vulgaris are manifestations of primary infection while tuberculids and phlyctenulosis are manifestations of secondary conjunctival infection. Primary lesions present as unilateral nodular or ulcerative conjuctivitis (34,35) associated with regional lymphadenopathy. Children are most commonly affected (34). Secondary lesions due to spread from contiguous disease or haematogenous dissemination are more common in older patients. The disease may be bilateral and may cause regional lymphadenopathy (34,35).

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Conjunctival tuberculomas start insidiously and three to four weeks later lead to regional lymphadenopathy. The enlarged preauricular and rarely the submandibular lymph nodes may suppurate resulting in sinus formation. Thus, conjunctival TB is one of the causes of Parinaud’s oculoglandular syndrome of an infectious conjunctivitis accompanied by regional lymph node enlargement. Very rarely, the disease may start as an acute purulent or mucopurulent conjunctivitis with symptoms of fever and malaise. Several types of conjunctival granulomas have been described (36,37) and include ulcerative, nodular, polypoid or hyperplastic lesions. These lesions may be solitary or multiple. Solitary tuberculomas involving the bulbar conjunctiva are observed in two to thirty per cent of the cases (38). The nodular prototype may simulate a trachomatous lesion. It has a propensity to involve the bulbar and upper forniceal conjunctiva (17). Associated follicles and corneal infiltration may be present. The nodule may enlarge to assume a cauliflower-like lesion with central ulceration. The ulcerative form has a propensity to involve the inferior cul-de-sac. It can also involve the bulbar conjunctiva and tarsus and may also spread to involve the cornea, lid or sclera. Mycobacterium tuberculosis can often be found in the ulcer crater (36,37). The hyperplastic variety develops most commonly in the fornix and rarely on the tarsus. This form is associated with severe conjunctival chemosis and lid oedema. It may assume a pedunculated appearance like the polypoid form. Conjunctival tuberculids are a manifestation of hypersensitivity reaction. They appear as small conjunctival nodules. They could be evanescent or remain localized. They are associated with TB involvement of the uveal tract, sclera, skin or other regions of the body. Tuberculosis of the bulbar conjunctiva is usually associated with an interstitial keratitis. Phlyctenulosis can involve the lid margin, cornea or conjunctiva. A phlycten [from the greek word for blister] is a hypersensitivity reaction to tuberculoprotein. In the conjunctiva, it can affect the bulbar, conjunctival or limbal region. However, the most common site is the limbal region. It usually appears as a small nodule with surrounding hyperaemia. It gradually ulcerates and heals without scarring. This is in contrast to the corneal phlyctenulosis, which leaves a scar on healing. Limbal phlyctenules leave a characteristic triangular scar because the conjunctival portion, unlike the corneal portion heals

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without scar formation. Tuberculosis phlcytenular keratoconjunctivitis also occurs. Mycobacterium tuberculosis has been demonstrated in only one-fourth of patients with conjunctival TB (17). In the west, Staphylococcal infection has replaced TB as the leading cause of phlyctenular keratoconjunctivitis. Phlyctenular keratoconjunctivitis due to TB usually occurs in malnourished older children and is more common in girls. Symptoms usually last for one to two weeks and consist of excessive lacrimation, pain, photophobia and blepharospasm. The severity of symptoms depends on the site of involvement. Corneal involvement indicates a much more severe form of the disease. Recurrence is frequent and may occur at a different site.

presentation is also known (48,49). Physical examination may reveal preauricular and submandibular lymphadenopathy. The scleritis develops due to direct scleral infection or, by spread from the conjunctiva, uveal tract or by haematogenous route and produces a nodular lesion [Figure 28.1]. Peripheral cornea is often secondarily affected and granulomatous uveitis may also develop. The scleral nodules may undergo caseous necrosis and ulceration. Subsequently, perforation may develop.

CORNEAL TUBERCULOSIS Manifestations of TB in the cornea include phlyctenulosis, interstitial keratitis, ulceration and infiltrations (39-42). Rarely, these patients may also have active pulmonary TB (43,44). Phlyctens of the cornea usually arise from limbus. Corneal involvement is characterized by intense photophobia, pain and blepharospasm. Marginal, miliary and fasicular phlyctenular patterns have been described. Corneal phlyctenules heal with a variable degree of scarring and vascularization. Interstitial keratitis is uncommon in TB. However, as compared to syphilis, TB interstitial keratitis is associated with more intense scarring and vascularization in the deeper layers (45). Besides being usually unilateral, TB often has selective propensity to involve the lower part of the cornea. Sclerosing keratitis may occur as sequelae to TB involvement of the sclera. Clinically, sclerosing keratitis appears as peripheral corneal scleralization. On resolution, it leaves behind a triangular or tongue-shaped opacity with the base directed towards the limbus. Corneal ulceration due to TB usually develops from the contiguous spread of infection from the conjunctiva or uveal tract. These ulcers are indolent and refractory to treatment. SCLERAL TUBERCULOSIS Although TB was reported as a frequent cause of scleritis earlier, it was considered rare by 1926 (46). Watson and Hayreh (47) found TB of the sclera in only one of the 217 cases of episcleritis. Tuberculosis of the sclera is characterized by scleral and conjunctival ulceration. Focal necrotising anterior scleritis is the most common presentation, but a diffuse

Figure 28.1: Nodular scleritis in a patient with miliary tuberculosis

TUBERCULOSIS OF LACRIMAL SYSTEM Tuberculosis involvement of the lacrimal gland, lacrimal canaliculi and lacrimal sac is unusual. Tuberculosis dacryoadenitis usually develops during haematogenous dissemination, occasionally due to spread from conjunctival or corneal disease and still infrequently due to an injury. It appears as a gradually enlarging painless swelling. When the eyelid is involved, lid oedema and pseudoproptosis are prominent features. If the orbit is involved, proptosis and restriction of upward gaze are evident. Abscess formation with a chronic draining fistula in the upper lid can also occur. Regional lymphadenopathy is a prominent manifestation in patients with TB of the lacrimal system. ORBITAL TUBERCULOSIS Abadie in 1881 (50) was the first to describe orbital TB. Since then, several cases of orbital TB have been reported.

Ocular Tuberculosis Orbital TB can occur in several forms, notably, periostitis, tuberculomas and myositis. A case of TB osteomyelitis involving the orbit and masquerading as post-traumatic haematoma has also been reported (51). Orbital TB occurs by haematogenous spread or by extension of infection from adjacent structures, such as the paranasal sinuses. It is usually unilateral and typically occurs in the first two decades of life. It usually has a protracted course. Tuberculosis periostitis has an insidious onset and presents as a chronic, painless inflammation, most commonly of the malar bone. Over months, oedema and discolouration of the overlying skin can progress to cold abscess, fistula formation, cicatrization and regional lymphadenitis. Tuberculomas, firm masses of chronic granulomatous inflammation, can occur anywhere in the orbit. These lesions can occur at any age. They cause gradual painless proptosis and sclerosis and, thus, mimic benign and malignant tumours, orbital pseudotumours and fungal infections. Occasionally, they involve extraocular muscles and are bilateral in location. Tuberculomas may also start in the maxillary or ethmoid sinuses, erode into the orbit and form fistula in the skin. Overt signs of chronic sinusitis accompany this presentation. Epiphora and epistaxis are also common symptoms. TUBERCULOSIS OF THE UVEAL TRACT Mycobacterium tuberculosis can involve the two principal internal layers of the eye: the uveal and the retinal layers. Rarely, it can cause a panophthalmitis (52-59). Tuberculosis involving the uvea may present as choroidal tubercles or granulomas, disseminated choroiditis, chronic or acute granulomatous iridocyclitis, pars planitis, ciliary body granulomas or endophthalmitis. It involves the choroid more frequently than the iris and ciliary body. In a series of 40 patients with histopathological evidence of Mycobacterium tuberculosis infection affecting the internal layers of the eye (3), the mean age at diagnosis was 32 years. Males and females were equally affected and the disease was mostly unilateral.

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TB usually results from haematogenous dissemination. However, their presence is not diagnostic of miliary TB (60-63), although investigation for the same in a patient may be rewarding. The finding of choroidal tubercles in TB meningitis is still rarer. In one study, 28 to 60 per cent of patients with miliary TB were reported to have choroidal tubercles on ophthalmoscopic examination (63). However, in the same study (63), only one of the 18 patients [0.05%] with TB meningitis without miliary disease had choroidal tubercles. Sharma et al (64) found choroidal tubercles in only 4.5 per cent [4 of the 88 patients] HIV-seronegative patients with miliary TB at New Delhi. Massaro et al (62) found choroidal tubercles in 30 per cent of patients with pulmonary TB. Patients with choroidal tubercles may be asymptomatic or the only symptom may be blurring of vision. On clinical examination, choroidal tubercles may be solitary [Figure 28.2] or multiple [Figure 28.3] and of varying dimensions ranging from about a quarter of the disc diameter to several disc diameters [Figures 28.4A and 28.4B]. They are most frequently situated in the posterior pole (62). Up to 60 choroidal tubercles have been described but, usually less than five are seen. They appear as yellowishgrey elevated nodules with or without overlying inflammation in the vitreous during the active stage [Figure 28.5]. The overlying and surrounding retina may be detached. Though suggestive of TB they are not diagnostic and may occur in other conditions such as fungal infections, sarcoidosis, syphilis and metastatic deposits in the choroid.

CHOROIDAL TUBERCULOSIS Choroidal tubercles and tuberculomata [large, solitary masses] are the most common ocular manifestations of TB. Choroid is a highly vascular structure and choroidal

Figure 28.2: Solitary tuberculoma in miliary tuberculosis

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Figure 28.3: Multiple choroidal tubercles in miliary tuberculosis [arrows]

Figure 28.4B: Post-treatment photograph of the same patient showing significant resolution of the choroidal tuberculoma

Figure 28.4A: Pre-treatment photograph in a patient with a large solitary choroidal tuberculoma

Figure 28.5: Choroidal lesion in a patient with intestinal tuberculosis

There is no typical diagnostic pattern of these lesions [small and large tuberculomas] on fluorescein angiography or ultrasonography. Thus, these investigations in cases of tuberculomas are more helpful in ruling out other causes, such as haemangioma or melanoma, which have a more characteristic presentation. On ultrasonography most choroidal tuberculomas appear as domeshaped choroidal masses with low to moderate internal reflectivity. In cases with extensive caseous necrosis leading to formation of cold abscess, sonography may show a loculated anechoic area within the mass [Figure 28.6]. Fluorescein angiography of choroidal tubercles, tuberculomas may reveal early hypofluorescence

followed by late hyperfluorescence (65) or hyperfluorescence from the early phases itself which increases in intensity with time (66). However, intense hyperfluorescence in the late phases of the angiogram is always seen in large tuberculomas [Figure 28.7]. Most patients with miliary TB and choroidal tubercles have no anterior segment involvement (67,68) perhaps because these patients are unable to mount an effective immunologic response to infection. Rarely, however, choroidal tubercles may co-exist with panuveitis (69,70). Tuberculosis can affect the retina either by direct infection or because of a hypersensitivity reaction. Isolated involvement of the retina by direct infection is

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Traditionally, mutton fat keratic precipitates, early formation of dense synechiae and formation of iris nodules of Koeppe or Bussaca were considered to be characteristic of TB iridocyclitis. Such lesions must be distinguished from sarcoid nodules which are larger and more pink. Tuberculosis Endophthalmitis and Panophthalmitis

Figure 28.6: Ultrasonography showing a choroidal tuberculoma

Figure 28.7: Fluorescein angiogram in a patient with choroidal tuberculoma

extremely rare. Experimental and clinical studies have revealed that Mycobacterium tuberculosis rarely affects the retina directly (4,43,44,71). The retina is more commonly affected secondarily from adjacent choroidal lesions. Some workers have attributed retinal periphlebitis to direct infection (72,73). In an atypical presentation, Saini et al (74) found histopathological evidence of TB in an eye that had been enucleated for presumed retinoblastoma.

Rarely, TB infection may lead to an endogeneous panophthalmitis [Figure 28.7] or endophthalmitis (52-59). Most of these cases have been reported in debilitated and immunocompromised individuals, drug abusers or children. Certain features that might point to TB aetiology include painless loss of vision despite significant intraocular inflammation, presence of iris or scleral nodules, spontaneous perforation of the ocular coats and early development of neovascularization of the anterior chamber starting from the angle and progressing centrally. Pain may develop due to secondary glaucoma. Endophthalmitis might begin as a posterior or an anterior diffuse type [Figure 28.8]. In the anterior diffuse type the primary involvement is restricted to the anterior chamber and iris. The patient may present with significant exudation, hypopyon with a silent posterior segment. It is important to identify and treat such cases early to avoid enucleation. Also, a complete systemic workup to rule out any focus of systemic infection must be carried out.

TUBERCULOSIS IRITIS AND IRIDOCYCLITIS Gradenigo in 1869 (70) first reported histopathological evidence of TB of the iris in a patient with miliary TB at autopsy. Tuberculosis was considered an important cause of granulomatous uveitis until the early 1960s. However, there has been a dramatic decline in the number of these cases probably due to identification of other diseases, like sarcoidosis and toxoplasmosis.

Figure 28.8: Anterior segment photograph in a patient with tuberculosis panophthalmitis

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Presumed Intraocular Tuberculosis There are certain ocular conditions which are presumed to be due to TB, however, actual demonstration of tubercle bacilli in such cases is lacking. The list includes Eale’s disease and serpigeneous choroiditis. Eale’s disease, an idiopathic, non-infective, inflammatory vasculitis of the retinal vasculature has been attributed to hypersensitivity to tuberculoprotein. This disease is an important cause of visual morbidity in healthy young adults, especially from the Indian subcontinent. It affects persons in their second and third decades of life (75). Males are more frequently affected (76). In about 90 per cent of the patients, the disease becomes bilateral within a few years. Most patients present with painless, sudden visual loss in one eye due to vitreous haemorrhage. Eale’s disease is characterized by retinal periphlebitis and capillary non-perfusion that result in hypoxia. This leads to neovascularization either on the retinal surface or on the optic nerve head. The new vessels being extremely fragile have a propensity to bleed into the vitreous. In some cases, this can lead to retinal detachment and an irreversible visual loss. The reasons for associating Eale’s disease with TB include increased prevalence of tuberculoprotein hypersensitivity (25,76-79); presence of concurrent active or healed pulmonary TB (77,79); and response to antituberculosis treatment in some patients. Recently, Mycobacterium tuberculosis deoxyribonucleic acid [DNA] has been identified using polymerase chain reaction [PCR] on vitreous and epiretinal membrane samples in a significantly greater proportion of patients with Eale’s disease as compared to controls (10,80). This, however, is not an indicator of active TB infection. But it provides support to the hypothesis that a sequestered TB antigen might be involved in the cascade of events leading to a hypersensitivity reaction. Histopathologically, no features typical of TB inflammation have been described in Eale’s disease (77,81,82). In most cases, a non-specific perivascular cuff of lymphocytes has been described. Thus, empirical antituberculosis therapy in patients with Eale’s disease is not recommended presently. However, it is important to identify a subset of patients with Eale’s disease, who apart from the typical features of vasculitis and neovascularization also show significant perivascular exudation, vitritis, snowball vitreous opacities, pars plana exudation or extensive anterior

segment inflammation [Figures 28.9A, 28.9B, and 28.10]. These cases must be investigated thoroughly for any evidence of TB. High positivity of PCR for Mycobacterium tuberculosis in the ocular fluids in these patients needs to be investigated further. Another disease attributed recently to TB is serpigineous choroiditis. Gupta et al (83) have demonstrated Mycobacterium tuberculosis DNA in ocular fluids of cases with serpigineous choroiditis. These patients also had systemic evidence of TB. However, classically described serpigineous choroiditis is idiopathic and responds to corticosteroid and immunosuppressive therapy. Further

Figure 28.9A: Pre-treatment photograph of a patient with tuberculosis anterior diffuse endophthalmitis

Figure 28.9B: Post-treatment photograph of the same patient showing considerable resolution of the lesion

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PATHOLOGY Histopathologically phlyctenules are characterized by a dense accumulation of lymphocytes, histiocytes and plasma cells. Neutrophils may be seen in the acute stage. There is a notable absence of giant ells and eosinophils. Mycobacterium tuberculosis is seldom seen. Choroidal tubercles are similar to the tubercles found elsewhere in the body. Granulomas may be caseating or non-caseating. The characteristic giant cells may also be seen. In contrast to the histopathology of choroidal tubercles, TB endophthalmitis is characterized by marked caseation necrosis and exudation. The reader is also referred to the chapter “Pathology” [Chapter 5] for more details. Figure 28.10: Fundus photographs of a case showing vasculitis due to tuberculosis

studies are required to clarify as to which subset of patients with serpigineous choroiditis might have TB aetiology. Tuberculosis can rarely cause pars planitis (84). OCULAR TUBERCULOSIS IN HUMAN IMMUNODEFICIENCY VIRUS INFECTED INDIVIDUALS Though there are some published case reports of ocular TB in HIV-infected patients (13-15), ocular TB appears to be a rare manifestation in these patients. Shafer and associates (11) did not report a single case of ocular TB in a study of 199 consecutive patients with HIV infection and extra-pulmonary TB. Small et al (12) reviewed 132 patients with AIDS and TB. In this study (12), TB was entirely extra-pulmonary in 30 per cent and both pulmonary and extra-pulmonary in 32 per cent of patients and no ocular involvement was reported. In another study (16), ocular TB was seen in 15 [2%] of the 766 consecutive patients with HIV infection and AIDS. In a recent report (17) from New Delhi, ocular manifestations were present in six of the 135 [4.4%] HIVseropositive patients studied; five patients had TB choroiditis [unilateral in 2, bilateral in 3 patients] and one patient had optic atrophy due to TB meningitis. Paradoxical worsening of the ocular TB lesions in HIVseropositive patients receiving antiretroviral treatment [ART] has also been described (85).

DIAGNOSIS Definitive diagnosis of ocular TB can be made only by demonstrating Mycobacterium tuberculosis in the ocular tissues. However, obtaining ocular tissue for diagnostic purposes is not only difficult, but is also associated with significant ocular morbidity. Hence, the diagnosis of TB can rarely be definitely confirmed before enucleation. Only 25 per cent of patients with ocular TB give past history of TB and 50 per cent have normal chest radiographs (9,86). Orbital radiographs may reveal bony erosions. A high degree of clinical suspicion is, therefore, the key to early diagnosis. Easily accessible sites, such as eyelid, conjunctiva (48), lacrimal gland and sclera (87), should preferably be biopsied to demonstrate the characteristic findings of caseating granulomas with Langhans’ giant cells and Mycobacterium tuberculosis. Despite all investigations patients with clinically suspicious lesions should receive empirical standard antituberculosis treatment and should be carefully followed-up for therapeutic response. Tuberculin Skin Test A positive TST in a patient with granulomatous uveitis was considered to be a positive evidence of ocular TB. A positive TST is, however, only indicative of infection with Mycobacterium tuberculosis and does not necessarily reflect the disease activity (36,39,62,88-91). Rosenbaum and Wernik (92,93) calculated that a patient with uveitis and a positive TST test has only one per cent probability of

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having active TB. However, recent conversion of a previous non-reactor favours the diagnosis of TB. Use of systemic corticosteroids for severe ocular inflammation can interfere with the TST results. Therefore, though a routine TST has been advocated in patients with uveitis, it is rarely diagnostic (91,94-96). In countries where TB is highly endemic, a caution is advocated before interpreting a positive TST result in isolation. A positive TST can be considered to be supporting evidence in a patient with a clinical picture highly suggestive of TB such as choroidal tubercles or tuberculoma or when other investigations such as a chest radiograph also have findings compatible with TB. On the other hand, a negative TST is considered by some as being more relevant as it rules out TB if the patient is immunocompetent. This, however, is also not always true as there are several causes of anergy (97).

Table 28.1: Suggested criteria for the diagnosis of intraocular tuberculosis in patients presenting with a compatible clinical picture in whom there is no definite histopathological or microbiological evidence of tuberculosis Major criteria Evidence of pulmonary or other systemic pathology consistent with TB occurring concurrently with the ocular disease Response of ocular and systemic disease to antituberculosis treatment [with or without steroids] Exclusion of other aetiological causes, like sarcoidosis, tumours, secondary metastases Minor criteria Positive IGRAs or TST Positive PCR for Mycobacterium tuberculosis in ocular fluids or biopsy All major criteria fulfilled = highly probable intraocular TB; 2 major and 1 minor criterion fulfilled = probable intraocular TB TST = tuberculin skin test; IGRAs = interferon-gamma release assays; PCR = polymerase chain reaction; TB = tuberculosis

Serological and Molecular Methods In patients with ocular TB, it is seldom possible to procure adequate tissue for diagnosis and the number of organisms present may be too small to be detected by conventional methods. The utility of serological tests in the diagnosis of ocular TB needs further evaluation in well-designed studies with a large sample size. Polymerase chain reaction appears to be a promising tool to establish the definitive diagnosis of ocular TB (98-101). Despite rapid advances in medicine, ocular TB still remains an important diagnostic challenge. The criteria for the diagnosis of ocular TB differ greatly and very often the diagnosis is based on a compatible clinical picture and good therapeutic response to antituberculosis treatment rather than mycobacterial isolation. Earlier, it has been suggested that clinical diagnosis of ocular TB be based on the presence of at least three of the following five features (102): [i] suggestive clinical picture; [ii] exclusion of other aetiology; [iii] positive TST; [iv] therapeutic response to antituberculosis treatment; and [v] present or past history of TB. In patients with a clinical picture suggestive of intraocular TB [including all clinical manifestations described above except those which come under presumed intraocular TB] in whom there is no definite histopathological or microbiological evidence of TB, the criteria shown in Table 28.1 can be helpful.

TREATMENT When patients with TB elsewhere in the body develop clinical features of ocular involvement, thorough ophthalmologic evaluation is warranted. Similarly when patients are detected to have ocular involvement, a complete systemic evaluation must be done. Treatment of ocular TB is on the same lines as treatment of TB elsewhere in the body. The disease is said to respond well to standard antituberculosis treatment and there is no role for topical treatment. The reader is referred to the chapter “Treatment of tuberculosis” [Chapter 52] for more details. However, as significant damage can occur to ocular tissues from infection as well as inflammation, it is prudent to add systemic corticosteroids as an adjuvant to the standard antituberculosis treatment. This must be done in consultation with a physician keeping in mind the general condition of the patient and the presence of associated co-morbidities. It is not clear how soon after initiation of antituberculosis treatment one should start corticosteroids in patients with ocular TB. However, as in cases of TB meningitis starting steroids early may be beneficial. Under the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India, patients with giant TB granulomas in the choroid and

Ocular Tuberculosis those with vision threatening disease, constitute serious form of extra-pulmonary TB similar to meningeal and spinal TB and should receive Category I DOTS treatment. The reader is referred to the chapter “Revised National Tuberculosis Control Programme [RNTCP]” [Chapter 63] for more details. Anterior segment inflammation should be managed with topical steroids and cycloplegics. Treatment of TB phlyctenulosis also involves topical corticosteroids and cycloplegic agents in addition to standard antituberculosis treatment. Conjunctival lesions causing only mild symptoms may respond to local astringents. Mucopurulent discharge suggests secondary bacterial infection and should be treated accordingly. Conjuctival lesions heal without scarring, but corneal phlyctenules leave superficial scars of variable severity. Adjunctive therapy with topical antibiotics, such as streptomycin, amikacin or isoniazid has also been tried in the treatment of TB scleritis with varying results (87). Antituberculosis Treatment Induced Ocular Toxicity Several antituberculosis drugs can cause ocular adverse effects, which if not recognized early can result in an irreversible loss of vision. Often patients are referred to ophthalmologists for evaluation of ocular toxicity following prescription of drugs for TB elsewhere in the body. Sometimes patients themselves notice a diminution in vision while on antituberculosis treatment and get evaluated by an ophthalmologist. Ocular toxicity due to ethambutol, isoniazid and streptomycin has been well documented. Of these, ethambutol has the greatest potential to cause ocular toxicity. In general, adverse drug reactions occur less frequently in patients receiving intermittent regimens as compared to daily regimens. Three types of optic neuritis have been described with ethambutol (103). These include the axial, the periaxial and the mixed type. Both eyes are usually involved and the visual loss may vary from mild to severe. Colour vision is also variably affected. In the axial form of optic neuritis, on visual field recording pericentral or peripheral scotoma may be evident. Quadrantic field defects have also been commonly found. Although mild disc hyperaemia and disc oedema have been reported, fundus examination may be normal in the acute phase of ethambutol toxicity (104). Peripapillary splinter haemorrhages, macular oedema and focal pigmentary changes have also been described (105,106). Electrophysiological studies

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including visual evoked responses [VER] are useful in confirming the involvement of the optic nerve and retina in patients receiving ethambutol. Ethambutol related ocular toxicity is strongly dose related (107-117). In a study reported by Carr and Henkind in 1962 (107), 45 per cent of patients receiving 60 to 100 mg/kg/day developed ocular toxicity. At that time the older racemic mixture of ethambutol was used (116). Another report showed the incidence of ocular toxicity to be 18.6 per cent in patients receiving more than 53 mg/kg/day of ethambutol (109). With 25 mg/kg/day, the reported incidence of ethambutol related optic neuritis was 1.3 to 15 per cent (110). However, less than two per cent patients develop this complication with doses below 15 mg/kg/day (111-116). Most cases of ethambutol optic neuropathy occur six to eight weeks after starting chemotherapy (118). As the incidence of ethambutol toxicity is low with the currently favoured dose of 15 to 20 mg/kg/day, and also because it is reversible in most cases, sophisticated electrophysiological tests like electroretinography and VER are not required in all cases. However, in all patients receiving ethambutol, a baseline best corrected visual acuity and colour vision record should be routinely obtained. Thereafter, patients should be questioned monthly about any changes in vision. Any significant alteration in vision needs to be promptly investigated. Isoniazid has also been reported to cause optic neuritis (119-125). In these cases, the dose of isoniazid has ranged from 200 to 900 mg/day and symptoms have been reported as early as the tenth day. Isoniazid has to be discontinued at the first sign of ocular toxicity and pyridoxine may probably be beneficial both in the treatment as well as prophylaxis (122,123). There have been few reports of ocular toxicity due to streptomycin of which, only the report by Sykowski (124) has been widely accepted. The most common adverse effect of rifampicin in the eye is conjunctivitis. It can result in the production of tears that are orange coloured and this can stain contact lenses (125). Rifabutin has been associated with the development of an endophthalmitis-like response (126). Clofazimine has been associated with several ocular side effects; these include: a brownish discolouration of the conjunctiva, brown swirls in the cornea (127,128) and bull’s eye maculopathy resulting in visual loss due to macular degeneration (129,130).

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REFERENCES 1. Brudney K, Dobkin J. Resurgent tuberculosis in New York city. Am Rev Respir Dis 1991;144:745-9. 2. Dinning WJ, Starston S. Cutaneous and ocular tuberculosis: a review. J Royal Soc Med 1985;78:576-81. 3. Helm CJ, Holland GN. Ocular tuberculosis. Surv Ophthalmol 1993;38:229-56. 4. Donahue HC. Ophthalmologic experience in a tuberculosis sanatorium. Am J Ophthalmol 1967;64:742-8. 5. Cepoi M, Mocanu C, Cioroianu L. Clinical and epidemiological aspects in ocular tuberculosis. Oftalmologia 2001;54:47-52. 6. Sen DK. Tuberculosis of the orbit and lacrimal gland: a clinical study of 14 cases. J Paed Ophthalmol 1980;17:232-8. 7. Agrawal PK, Nath J, Jain BS. Orbital involvement in tuberculosis. Indian J Ophthalmol 1977;25:12-6. 8. Grewal A, Kim RY, Cunningham ET. Miliary tuberculosis. Arch Ophthalmol 1998;116:953-4. 9. Woods AC. Chronic bacterial infections: ocular tuberculosis. In: Sorsby A, editor. Modern ophthalmology. Second edition. London: Butterworths; 1973.p.2-105. 10. Madhavan HN, Therese L, Gunisha P, Jayanthi U, Biswas J. Polymerase chain reaction for detection of Mycobacterium tuberculosis in epiretinal membrane in Eales disease. Invest Ophthalmol Vis Sci 2000;41:822-5. 11. Shafer RW, Kim DS, Weiss JP, Quale JM. Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine 1991;70:384-97. 12. Small PM, Schecter GF, Goodman PC, Sande MA, Chaisson RE, Hopewell PC. Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection. N Engl J Med 1991;324:289-94. 13. Blodi BA, Johnson MW, Mlash MW, Glass JD. Presumed choroidal tuberculosis in a human immunodeficiency virus infected host. Am J Ophthalmol 1989;108:605-7. 14. Croxatto JO, Mestre C, Puente S, Gonzalez G. Nonreactive tuberculosis in a patient with acquired immune-deficiency syndrome. Am J Ophthalmol 1986;102:659-60. 15. Bouza E, Merino P, Munoz P, Sanchez-Carrillo C, Yanez J, Cortes C. Ocular tuberculosis. A prospective study in a general hospital. Medicine [Baltimore] 1997;76:53-61. 16. Babu RB, Sudharshan S, Kumarasamy N, Therese L, Biswas J. Ocular tuberculosis in acquired immunodeficiency syndrome. Am J Ophthalmol 2006;142:413-8. 17. Gharai S, Venkatesh P, Garg S, Sharma SK, Vohra R. Ophthalmic manifestations of HIV infections in India in the era of HAART: analysis of 100 consecutive patients evaluated at a tertiary eye care center in India. Ophthalmic Epidemiol 2008;15:264-71. 18. Charles V, Charles SZ. Primary tuberculosis of conjunctiva. J Indian Med Assoc 1980;74:74-5. 19. Saini JS, Mukherjee AK, Nadkarni N. Primary tuberculosis of the retina. Br J Opthalmol 1986;70:533-5.

20. Cook CD, Hainsworth M. Tuberculosis of the conjunctiva occurring in association with a neighbouring lupus vulgaris lesion. Br J Ophthalmol 1990;74:315-6. 21. Anhalt EF, Zovell S, Chang G, Byron HM. Conjunctival tuberculosis. Am J Ophthalmol 1960;50:265-9. 22. Whitford J, Hansman D. Primary tuberculosis of the conjunctiva. Med J Aust 1977;1:486-7. 23. Champman CB, Whorton CM. Acute generalized miliary tuberculosis in adults: clinicopathological study based on sixty-three cases diagnosed at autopsy. N Engl J Med 1946;235:239-48. 24. Licheri G. Su di un caso di tuberculosis della conjunctiva clinicomente prinotiva. Lethura Oftal 1938;15:403-17. 25. Duke-Elder S, Perkins ES. Diseases of the uveal tract. In: Duke-Elder S, editor. System of ophthalmology. Vol. 9. St. Louis: CV Mosby company; 1966.p.246-85. 26. Finnoff WC. The relation of tuberculosis to chronic uveitis. Am J Ophthalmol 1931;14:1208-77. 27. Mckenzie WH. Tuberculosis of the conjunctiva. Report of a case. Am J Ophthalmol 1939;22:744-9. 28. Torres RA, Mani S, Altholz J, Bricker PW. Human immunodeficiency virus infection among homeless men in a New York City shelter: association with Mycobacterium tuberculosis infection. Arch Intern Med 1990;150:2030-6. 29. Bruckner Z. Erude histolyique de la permeability de la conjunctive aux bacilles tuberculeus. Ann Ocul 1929;166:80424. 30. Mehta DK, Sahnikamal, Ashok P. Bilateral tubercular lid abscess-a case report. Indian J Ophthalmol 1989;37:98. 31. Mohan K, Prasad P, Banerjee AK, Dhir SP. Tubercular tarsitis. Indian J Ophthalmol 1985;33:115-6. 32. Watrin E, Mendelsohn P. Palpebral cold abscess revealing a tuberculous maxillary sinusitis. Bul Soc Ophthalmol Fr 1967;67:1124-9. 33. Duke-Elder S, Macfaul PA. The ocular adnexa. Part I. Diseases of the eyelids. In: Duke-Elder S, editor. System of ophthalmology. Vol. 13. St. Louis: CV Mosby Company; 1974. 34. Woods AC. Ocular tuberculosis. In: Sorsby A, editor. Modern ophthalmology. Philadelphia: Lippincott; 1972.p.105-40. 35. Archer D, Bird A. Primary tuberculosis of conjuctiva. Br J Ophthalmol 1967;51:679-84. 36. Eyre JWH. Tuberculosis of the conjuctiva: its etiology, pathology and diagnosis. Lancet 1912;1:1319-28. 37. Duke-Elder S. Diseases of the outer eye. Part I. In: Duke-Elder S, editor. System of ophthalmology. Vol. 8. London: Henry Kimpton; 1965. 38. Boschoff PH, Grasset E. Two unusual ocular tuberculosis cases. Arch Ophthalmol 1944;32:120-2. 39. Gibson WS. The etiology of phlyctenular conjunctivitis. Am J Dis Child 1918;15:81-115. 40. Thygeson P, Diaz-Bonnet V, Okumoto M. Phlyctenulosis. Attempts to produce an experimental model with BCG. Invest Ophthalmol 1962;1:262-6.

Ocular Tuberculosis 41. Aclimandos WA, Kerr-Muir M. Tuberculosis keratoconjunctivitis. Br J Ophthalmol 1992;76:175-6. 42. Ginsberg SP. Corneal problems in systemic diseases. In: Tasman W, Jaeges EA, editors. Duane’s clinical ophthalmology. Vol. 5. Philadephia: JB Lippincott; 1982.p.1-23. 43. Glover LP. Some observations in tuberculosis patients at the state sanatorium, Cresson, Pennsylavania. Am J Ophthalmol 1930;13:411-2. 44. Goldenburg M, Fabricant ND. The eye in the tuberculous patient. Transact Ophthalmol Am Med Assoc 1930;135-65. 45. Mooney AJ. Further observations on the ocular complications of tuberculous meningitis and their implications. Am J Ophthalmol 1959;48:297-312. 46. Weeks JE. Tuberculosis of the eye. Am J Ophthalmol 1926;9:243-6. 47. Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol 1976;60:163-91. 48. Nanda M, Pflugfelder SC, Holland S. Mycobacterium tuberculosis scleritis. Am J Ophthalmol 1989;108:736-7. 49. Saini JS, Sharma A, Pillai P. Scleral tuberculosis. Trop Geogr Med 1988;40:350-2. 50. Abadie C. Jumeurs Rares symebioues des paupieres. Arch Ophthalmol 1881;1:432-7. 51. Prasad N. Tubercular osteomyelitis. Bulletin of the Delhi Ophthalmological Society. DOS Times 1995. 52. Dvorak-Theobald G. Acute tuberculous endophthalmitis; report of a case. Am J Ophthalmol 1958;45:403-7. 53. Darrell RW. Acute tuberculous panophthalmitis. Arch Ophthalmol 1967;78:51-4. 54. Ni C, Papale JJ, Robinson NL, Wu BF. Uveal tuberculosis. Int Ophthalmol Clin 1982;22:103-24. 55. Sheu SJ, Shyu JS, Chen LM, Chen YY, Chirn SC, Wang JS. Ocular manifestations of tuberculosis. Ophthalmology 2001;108:1580-5. 56. Anders N, Wollensak G. Ocular tuberculosis in systemic lupus erythematosis and immunosuppressive therapy. Klin Monatsbl Augenheilkd 1995;207:368-71. 57. Menezo JL, Martinez-Costa R, Marin F, Vilanova E, CortesVizcaino V. Tuberculous panophthalmitis associated with drug abuse. Int Ophthalmol 1987;10:235-40. 58. McMoli TE, Mordi VP, Grange A, Abiose A. Tuberculous panophthalmitis. J Pediatr Ophthalmol Strabismus 1978;15:383-5. 59. Chawla R, Garg S, Venkatesh P, Kashyap S, Tewari HK. Case report of tuberculous panophthalmitis. Med Sci Monit 2004;10:CS57-9. Epub 2004 Sep 23. 60. Illingworth RS, Wright T. Tuberculosis of the choroid. Br Med J 1948;365:8. 61. Jabbour NM, Faris B, Trempe CL. A case of pulmonary tuberculosis presenting with a choroidal tuberculoma. Ophthalmology 1985;92:834-7. 62. Massaro D, Katz S, Sachs M. Choroidal tubercles: a clue to haematogenous tuberculosis. Ann Intern Med 1964;60: 231-41. 63. Olazabal F Jr. Choroidal tubercles - a neglected sign. JAMA 1967;200:374-7.

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64. Sharma SK, Mohan A, Pande JN, Prasad KL, Gupta AK, Khilnani GC. Clinical profile laboratory characteristics and outcome in miliary tuberculosis. QJM 1995;88:29-37. 65. Santoni G, Fiore C, Lupidi G, Galuppo L. Choroidal miliary tuberculosis: fluoroangiographic study. Ophthalmologica 1982;184:6-12. 66. Cangemi FE, Friedman AH, Josephberg R. Tuberculoma of the choroid. Ophthalmology 1980;87:252-8. 67. Chung YM, Yeh TS, Sheu SJ, Liu JH. Macular subretinal neovascularization in choroidal tuberculosis. Ann Ophthalmol 1989;21:225-9. 68. Gur S, Silverstone BZ, Zylberman R, Berson D. Chorioretinitis and extrapulmonary tuberculosis. Ann Ophthalmol 1987; 19:112-5. 69. Welton TH, Townsend JC, Bright DC, Anderson SF, Nguyen AT, Ilsen PF. Presumed ocular tuberculosis in an AIDS patient. J Am Optom Assoc 1996;67:350-7. 70. Gradenigo PN. Tuberculosis of the iris. Boston Med Surg J 1869;4:285-7. 71. Ohmart WA. Experimental tuberculosis of the eye. Am J Ophthalmol 1933;16:773-8. 72. Fries JW, Patel RJ, Piesseno WF, Wirth DF. Genus - and species - specific DNA probes to identify mycobacteria using the polymerase chain reaction. Mol Cell Probes 1990;4:87105. 73. Rosen PH, Spalton DJ, Graham EM. Intraocular tuberculosis. Eye 1990;4:486-92. 74. Saini JS, Mukherjee AK, Nadkarni N. Primary tuberculosis of the retina. Br J Ophthalmol 1986;70:533-5. 75. Gieser SC, Murphy RP. Eale’s disease. In: Tasman W, Jaeger EA, editors. Duane’s clinical ophthalmology. Philadelphia: J.B. Lippincott; 1989. 76. Elliot AJ. 30-year observation of patient with Eale’s diseases. Am J Ophthalmol 1975;80:404-8. 77. Elliot AJ. Recurrent intraocular haemorrhages in young adults [Eale’s Diseases]: a report of thirty-one cases. Trans Am Ophthalmol Soc 1954;52:811-75. 78. Elliot AJ, Harris GS. The present status of the diagnosis and treatment of periphlebits retinae [Eale’s disease]. Can J Ophthalmol 1969;4:117-22. 79. Renie WA, Murphy RP, Anderson KC, Lippman SM, McKusick VA, Proctor LR, et al. The evaluation of patients with Eale’s Disease. Retina 1983;3:243-8. 80. Madhavan HN, Therese KL, Doraiswamy K. Further investigations on the association of Mycobacterium tuberculosis with Eales disease. Indian J Ophthalmology 2002;50:35-9. 81. Ballantyne AJ, Michaelson IC. A case of perivasculitis retinae associated with symptoms of cerebral disease. Br J Ophthalmol 1937;21:22-35. 82. Finnoff WC. Some impressions derived from the study of recurrent haemorrhages into the retina and vitreous of young patients. Trans Am Ophthalmol Soc 1921;19:238-58. 83. Gupta V, Gupta A, Arora S, Bambery P, Dogra MR, Agarwal A. Presumed tubercular serpiginous like choroiditis: clinical presentations and management. Ophthalmology 2003;110:1744-9.

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Tuberculosis

84. Vitale AT, Zierhut M, Foster CS. Intermediate uveitis. In: Foster CS, Vitale AT. editors. Diagnosis and treatment of uveitis. Philadelphia: W.B. Saunders Company; 2002. p.844-57. 85. Rathinam SR, Lalitha P. Paradoxical worsening of ocular tuberculosis in HIV patients after antiretroviral therapy. Eye 2007;21:667-8. Epub 2006 Dec 1. 86. Traquir HM. Manifestations of tuberculosis in ophthalmic practice. Edinburgh Med J 1940;47:57-66. 87. Bloomfield SE, Mondino B, Gray GF. Scleral tuberculosis. Arch Ophthalmol 1976;94:954-6. 88. Knapp A. On some forms of retinal tuberculosis. Trans Am Ophthalmol Soc 1913;13:486-9. 89. Verhoeff FH. The histologic findings in a case of tuberculous cyclitis, and a theory as to the origin of tuberculous scleritis and keratitis. Trans Am Ophthalmol Soc 1910;12:566-86. 90. Werdenberg E. Zur frage der tuberkulosen aetiologie der periphlebitis retinae. Klin Monatsbl Augenheilkd 1940;105: 285-93. 91. Schlaegel TF Jr, Weber JC. Double blind therapeutic trial of isoniazid in 344 patients with uveitis. Br J Ophthalmol 1969;53:425-7. 92. Rosenbaum JT, Wernick R. Selection and interpretation of laboratory tests for patients with uveitis. Int Ophthalmol Clin 1990;30:238-43. 93. Rosenbaum JT, Wernick R. The utility of routine screening of patients with uveitis for systemic lupus erythematosus or tuberculosis. A bayesian analysis. Arch Ophthalmol 1990;108:1291-3. 94. Mohamed MA. Tuberculous chorioretinitis: report of a florid case. Bull Ophthalmol Soc Egypt 1970;63:213-6. 95. Ni C, Papale JJ, Robinson NL, Wu BF. Uveal tuberculosis. Int Ophthalmol Clin 1982;22:103-24. 96. Smith RE. Tuberculoma of the choroid. Ophthalmology 1980;87:257-8. 97. Abrams J, Schlaegel TF Jr. The tuberculin skin test in the diagnosis of tuberculous uveitis. Am J Ophthalmol 1983;96:295-8. 98. Kotake S, Kimura K, Yoshikawa K, Sasamoto Y, Matsuda A, Nishikawa T, et al. Polymerase chain reaction for the detection of Mycobacterium tuberculosis in ocular tuberculosis. Am J Ophthalmol 1994;117:805-6. 99. Yamaguchi R, Matsuo K, Yamazaki A, Abe C, Nagai S, Terasaka K, et al. Cloning and characterization of the gene for immunogenic protein MPB64 of Mycobacterium bovis BCG. Infect Immune 1989;57:283-8. 100. Eisenach KD, Cave MD, Bates JH, Crawford JD. Polymerase chain reaction amplification of a repetitive DNA sequence specific for Mycobacterium tuberculosis. J Infect Dis 1990;161:977-81. 101. Schluger NW, Kinney D, Harkin TJ, Rom WN. Clinical utility of the polymerase chain reaction in the diagnosis of infections due to Mycobacterium tuberculosis. Chest 1994;105:1116-21. 102. Khosla PK, Garg SP. Role of tuberculosis in intraocular inflammation in India. In: Shimigu K, editor. Current aspects in ophthalmology practice; 1992.p.1981-2.

103. Leibold JE. Drugs having a toxic effect on the optic nerve. Int Ophthalmol Clin 1971;11:137-57. 104. Kakisu Y, Adachi-Usami E, Mizota A. Pattern electroretinogram and visual evoked cortical potential in ethambutol optic neuropathy. Doc Ophthalmol 1987;67:327-34. 105. Kuming BS, Braude L. Anterior optic neuritis caused by ethambutol toxicity. S Afr Med J 1979;55:4. 106. Roussos T, Tsolkas A. The toxicity of ethambutol in the human eye. Ann Ophthalmol 1970;2:577-80. 107. Carr RE, Henkind P. Ocular manifestations of ethambutol toxicity, toxic amblyopia after administration of an experimental antituberculous drug. Arch Ophthalmol 1962;67:566-71. 108. Place VA, Peets EA, Buyske DA, Little RR. Metabolic and special studies of ethambutol in normal volunteers and tuberculous patients. Ann N Y Acad Sci 1966;135:775-95. 109. Leibold JE. The ocular toxicity of ethambutol and its relation to dose. Ann N Y Acad Sci 1966;135:904-9. 110. Bobrowitz ID. Ethambutol in the retreatment of pulmonary tuberculosis. Ann N Y Acad Sci 1966;135:796-822. 111. Citron KM. Ethambutol: a review with special reference to ocular toxicity. Tubercle 1969;50[Suppl]:32-6. 112. Barron GJ. Tepper L, Iovine G. Ocular toxicity from ethambutol. Am J Ophthalmol 1974;77:256-60. 113. Donomae I, Yamamoto K. Clinical evaluation of ethambutol in pulmonary tuberculosis. Ann N Y Acad Sci 1966;135:84981. 114. Fledelius HC, Petrera JE, Skjodt K, Trojaborq W. Ocular ethambutol toxicity. A case report with electrophysiological considerations and a review of Danish cases 1972-81. Acta Ophthalmol 1987;65:251-5. 115. Gomez-Pimienta JL, Shibayama Hernandez H, Perez Fernandez LF, Perez Herrera R, Garcia Oranday O. Retreatment of pulmonary tuberculosis with ethambutol. Ann N Y Acad Sci 1966;135:882-9. 116. Pyle MM. Ethambutol in the retreatment and primary treatment of tuberculosis: four-year clinical investigation. Ann N Y Acad Sci 1966;135:835-45. 117. Chatterjee VK, Buchanan DR, Friedmann AI, Green M. Ocular toxicity following ethambutol in standard dosage. Br J Dis Chest 1986;80:288-91. 118. Lessell S. Toxic and deficiency optic neuropathies. In: Miller NR, Newman NJ, editors. Walsh and Hoyt’s clinical neuroophthalmology. Fifth edition. Baltimore: Williams and Wilkins; 1998.p.663-79. 119. Kokkada SB, Barthakur R, Natarajan M, Palaian S, Chhetri AK, Mishra P. Ocular side effects of antitubercular drugs - a focus on prevention, early detection and management. Kathmandu Univ Med J [KUMJ] 2005;3:438-41. 120. Sutton PH, Beattic A. Optic atrophy after administration of isoniazid with P.A.S. Lancet 1955;268:650-1. 121. Kass I, Mandel W, Cohen H, Dressler SH. Isoniazid as a cause of optic neuritis and atrophy. JAMA 1957;164:1740-3. 122. Neff TA. Isoniazid toxicity: reports of lactic acidosis and keratitits. Chest 1971;59:245-8. 123. Ahmad I, Clark LA Jr. Isoniazid hypersensitivity reaction involving the eyes. Report of a case. Dis Chest 1967;52:112-3.

Ocular Tuberculosis 124. Sykowski P. Streptomycin causing retrobulbar optic neuritis. Am J Ophthalmol 1951;34:1446. 125. Fraunfelder FT, Meyer SM. Drug-induced ocular side effects and drug interaction. Second edition. Philadelphia: Lea and Febiger;1982. 126. Saran BR, Maguire AM, Nichols C, Frank I, Hertle RW, Brucker AJ, et al. Hypopyon uveitis in patients with acquired immunodeficiency syndrome treated for systemic Mycobacterium avium complex infection with rifabutin. Arch Ophthalmol 1994;112:1159-65.

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127. Negrel AD, Chovet M, Baquillon G, Lagadec R. Clofazimine and the eye: preliminary communication. Lepr Rev 1984;55:349-52. 128. Walinder PE, Gip L, Stempa M. Corneal changes in patients treated with cloflazimine. Br J Ophthalmol 1976;60:526-8. 129. Cunningham CA, Friedberg DN, Carr RE. Clofazimineinduced generalized retinal degeneration. Retina 1990;10: 131-4. 130. Craythorn JM, Schwartz M, Creel DL. Clofazimine inducedbull’s eye retinopathy. Retina 1986;6:50-2.

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Breast Tuberculosis

29

Puneet Gupta, M. Tewari, HS Shukla

INTRODUCTION Tuberculosis [TB] of the breast is extremely rare (1). It is uncommon even in those countries where the incidence of pulmonary and extra-pulmonary TB is high (2-8). Because of non-specific clinical features, the condition remains undiagnosed and is often mistaken for carcinoma or pyogenic breast abscess. It also presents as a diagnostic problem on radiological and microbiological investigations. EPIDEMIOLOGY Tuberculosis involves breast infrequently as compared with other organs of the body. This is due to the fact that, like skeletal muscles and spleen, it provides infertile environment for survival and multiplication of Mycobacterium tuberculosis (9). Sir Astley Cooper reported the first case of mammary TB in 1829 and called it “scrofulous swelling of the bosom” (10). Morgan reviewed literature in 1931 and found 439 cases of TB mastitis and estimated the incidence to be between 0.5 and 1.04 per cent (11). In 1944, Klossner (12) reported 50 cases of breast TB in women, out of 75 000 with pulmonary involvement. Haagensen (13) could detect only five cases of breast TB out of approximately 8000 breast specimens studied between 1938 and 1967. Similarly, at the New York Hospital, only two cases of breast TB were encountered among 2 141 breast specimens studied between 1949 and 1954 (13). In 1952, Mckeown and Wilkinson (14) described the primary and secondary forms of breast TB. Hamit and Ragsdale (15) in 1985 could document only 500 cases

from the world literature. In developing countries, the incidence of breast TB in surgically treated breast disease was found to be 3 to 4.5 per cent (15). Although the first case of TB mastitis from India was reported by Chaudhary (16) in 1957, there have been occasional reports on breast TB from India (2,17-19). The prevalence of breast TB in India has been reported by several authors to vary between 0.64 and 3.59 per cent (18,19). In an extensive review of benign breast disorders in India, Shukla and Kumar (20) found a high prevalence of breast TB [5.2% of all breast disorders and 32% of all infective lesions]. Tuberculosis of the breast is rare in the western countries, with the prevalence being less than 0.1 per cent of breast lesions examined histologically (21,22). But with the dynamics of global spread of acquired immunodeficiency syndrome [AIDS], mammary TB may no longer be uncommon even in the developed world (23). MODE OF INFECTION According to Mckeown and Wilkinson (14), the breast TB could be primary when the breast lesion is the only manifestation of TB, or secondary when demonstrable TB lesion is present elsewhere in the body. However, it is now increasingly accepted that the breast TB is almost invariably secondary to a lesion elsewhere in the body (17,18,24). The breast may become infected in several ways: [i] haematogenous spread; [ii] lymphatic route; [iii] spread from contiguous structures; [iv] direct inoculation; and [v] ductal infection. Of these, the most

Breast Tuberculosis 435 accepted view for spread of infection is centripetal lymphatic spread from lungs to breast tissue via the tracheobronchial, paratracheal, mediastinal lymph trunk and internal mammary nodes (2,14). The infection may also spread through retrograde lymphatic spread from the axillary lymph nodes. A communication between the axillary glands and the breast emphasizes the Cooper’s theory of secondary involvement of the breast by lymphatic extension (25). The retrograde flow may also occur from cervical and less commonly from paratracheal and internal mammary lymph nodes (17,18). Direct extension from contiguous structures such as infected rib, costochondral cartilage, sternum, shoulder joint and even through the chest wall from TB pleurisy or via abrasions in the skin has been described (24,26). In all cases the bacilli infect the ducts and spare the lobules. CLINICAL PRESENTATION Age and Sex Tuberculosis of the breast commonly affects young women in their reproductive age group [21 to 30 years] (20,27). It is relatively uncommon in older women and in the prepubertal age (27). Pregnant and lactating women are more susceptible to develop breast TB since the lactating breast is vascular with dilated ducts, predisposed to trauma making it more susceptible to TB infection (17,27). Wilson and MacGregor (28) proposed an interesting hypothesis by correlating the

prevalence of TB in the faucial tonsils of suckling infants with the higher incidence of breast TB in lactating women in India; thereby suggesting the spread of infection orally from the suckling infant to the nipple, and in turn, to the lactating breast via lacticiferous ducts (28). Tuberculosis of the breast is rare in males (11,29). Clinical Presentation Tuberculosis of the breast usually presents as a unilateral disease and bilateral involvement is uncommon, being reported in less than three per cent of the cases (17). In patients with TB of the breast, the duration of symptoms varies from a few months to several years but, is usually less than a year (19,30). The clinical findings in TB of the breast are summarized in Table 29.1. A lump in the breast is the most common presentation (9,31). It is commonly found in the central or upper outer quadrant of the breast (20) [Figure 29.1], due to frequent extension of TB from axillary lymph nodes to the breast. Presentation with multiple lumps is less frequent (18). A lump of TB mastitis is irregular, ill-defined and hard Table 29.1: Clinical findings in tuberculosis of the breast Lump[s] in the breast with and without axillary nodes Ulcer Breast abscess with and without discharging sinuses Peau d’orange Purulent nipple discharge Persistent discharging sinus

Figure 29.1: Breast tuberculosis. Clinical photograph showing a lump, overlying ulceration [arrow] with undermined margins in the upper outer quadrant of the right breast and nipple retraction [A], and clinical photograph of the same patient with the arm abducted showing the lump with ulceration [arrow] [B]

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similar to carcinoma. The lump may be painful, mobile or fixed to either skin or muscle or even chest wall (27). The breast remains mobile unless involvement is secondary to TB of the underlying chest wall (17). An ulcer in the skin overlying the breast and breast abscess can also occur (20). Nipple retraction and peau d’orange are at times seen. Breast oedema is evident in patients with extensive axillary nodal TB. CLASSIFICATION OF BREAST TUBERCULOSIS The breast TB has been classified into different types as described in Table 29.2 (14). Table 29.2: Classification of breast tuberculosis Older classification Nodular TB mastitis Disseminated or confluent TB mastitis Sclerosing TB mastitis TB mastitis obliterans Acute miliary TB mastitis Recent classification Nodular TB mastitis Disseminated or confluent TB mastitis Breast abscess Source: reference 2 TB = tuberculosis

Nodular Tuberculosis Mastitis Nodular TB mastitis is the most common form of breast TB. It presents as a well-circumscribed, slowly growing painless mass[es] that progress to involve the overlying skin, may ulcerate, form sinuses and may become painful. In early stage it is difficult to differentiate from a fibroadenoma, while in later stages it mimics a carcinoma (32,33). Disseminated or Confluent Tuberculosis Mastitis Disseminated or confluent TB mastitis is a rare form of breast TB and is characterized by multiple foci throughout the breast that later caseate leading to sinus formation. The overlying skin is thickened and stretched with or without painful ulcers. The breast may be tense and tender. The draining axillary lymph nodes are enlarged and matted (27). Sclerosing Tuberculosis Mastitis Sclerosing TB mastitis usually affects involuting breasts of older females. Excessive fibrosis rather than caseation

is the dominating feature. It presents as a hard painless slow growing lump with nipple retraction. Suppuration is rare. It may be misdiagnosed as a schirrotic carcinoma (27). Often the entire breast becomes hard because of dense fibrous tissue. Tuberculosis Mastitis Obliterans Tuberculosis mastitis obliterans is characterized by duct infection that produces proliferation of lining epithelium and marked epithelial and periductal fibrosis. Cystic spaces are formed due to occlusion of ducts and the condition resembles ‘cystic mastitis’. Acute Miliary Tuberculosis Mastitis Sometimes, breast involvement can occur as a part of generalized miliary TB. INVESTIGATIONS Investigations are done with the aim to establish TB infection of the breast, presence of active or dormant TB focus elsewhere in the body and to rule out other lesions of the breast which closely resemble breast TB, especially breast cancer. Tuberculin Skin Test A positive tuberculin skin test [TST] indicates infection with Mycobacterium tuberculosis and is not a marker for active disease. Therefore, it is of no diagnsotic value in patients with breast TB in areas where TB is highly endemic. Chest Radiograph The chest radiograph may show evidence of active or healed TB lesion[s] in the lungs in a few cases (19). It may also reveal clustered calcifications in the axilla suggesting the possibility of healed TB of the lymph nodes (34). Mammography The mammographic findings in breast TB are nonspecific and may include mass, coarse calcification [but absence of microcalcification], asymmetric density of breast parenchyma with spiculated margin, skin thickening, nipple retraction and axillary lymph node enlargement (35). A dense tract connecting an ill-defined

Breast Tuberculosis 437 breast mass to a localized skin thickening and bulge [skin bulge and sinus tract-sign] suggests the possibility of a TB abscess (36). Mammographically, nodular, disseminated and sclerosing types of TB mastitis can be differentiated. The mammographic picture of nodular breast TB is very similar to carcinoma except the size of the lesion, which correlates with the clinical size (27). Usually, a dense round area with indistinct margins is seen without the classic ‘halo sign’ found in fibroadenoma (37). The disseminated variety mimics inflammatory carcinoma and the radiographs show dense breast with thickened skin (37). Sclerosing TB mastitis reveals a homogeneous dense mass with fibrous septae and nipple retraction (17,27,36,38). However, the mammogram is of limited value in the diagnosis of breast TB as the findings are often indistinguishable from carcinoma of the breast. The age of the patient is considered while evaluating the mammogram for suspected breast TB. Ultrasonography of the Breast No sonographic details of breast TB are available (37). The ultrasonography is useful in characterizing the illdefined densities seen in mammogram and differentiating cystic from solid mass. It also reveals heterogeneous, intermediate internal echoes in the breast parenchyma or retromammary region (35). In nodular form of the disease lesions are either hypoechoic with ill-defined margins or complex cystic masses (37). In diffuse breast TB, ill-defined hypoechoic masses are seen whereas in patients with sclerosing breast TB, increased echogenecity of the breast parenchyma often with no definite mass is seen (35,37). At times, a beak-like fistulous connection between retromammary abscess and thoracic wall is seen in the sonogram (36,39,40). Ultrasound-guided fine needle aspiration can be done for cytological and microbiological studies (38). Computed Tomography of the Breast Although basic imaging techniques used for the diagnosis of breast TB are mammography and ultrasonography, computed tomography [CT] may be helpful in defining the involvement of thoracic wall in patients presenting with deeply adherent breast lump (41). Tuberculosis abscesses are seen as smoothly marginated, inhomogeneous, hypodense lesions with

surrounding enchancing rim on contrast CT. A direct fistulous connection with the pleura or a destroyed rib fragment in the abscess can also be seen (40). The CT also shows area[s] of lung destruction beneath the pleural disease (41,42). The TB breast abscess can also be drained percutaneously under CT guidance (41). It is a valuable tool in demonstrating extent of the disease, and is therefore, useful in planning for surgery and in assessing the response to treatment. Magnetic Resonance Imaging of the Breast Only a few reports on magnetic resonance imaging [MRI] findings in breast TB are available (35,42,43). A breast abscess is identified by T2-weighted images as a smooth or irregular ring like bright signal intensity. However, this finding in gadolinium diethylenetriaminepentaacetic acid [Gd-DTPA] enhanced MRI scan is non-specific and is also seen in breast carcinoma and bacterial and fungal abscesses. Despite these limitations, MRI is very useful in demonstrating the extra-mammary extent of the lesion (35,42,43). Fine Needle Aspiration Cytology Fine needle aspiration cytology [FNAC] from the breast lump is useful in the diagnosis of breast TB (1,44). Up to 73 per cent of breast TB can be confidently diagnosed when both epithelioid cell granulomas and necrosis are present (1). Failure to demonstrate necrosis on FNAC does not exclude the diagnosis of TB in view of small quantity of the sample examined. Sometimes, acid-fast bacilli [AFB] can also be detected on FNAC examination (45). In regions endemic for TB like India, the diagnosis of granulomatous mastitis must be made with caution, even in the absence of AFB. An alternative diagnosis should be suspected if the patient fails to respond to adequate antituberculosis treatment (44). In TB breast abscess, the FNAC picture may be dominated by an acute inflammatory exudate. In this situation presence of AFB or histopathological evidence of TB is mandatory for the diagnosis of breast TB (1). A breast abscess, which fails to heal despite adequate drainage and antibiotic therapy and with persistent discharging sinuses should raise suspicion of underlying TB. Biopsy of the abscess wall will confirm the diagnosis of breast TB (1).

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Open Biopsy The FNAC examination may be inconclusive in several cases. Open biopsy [incision or excision] is the most reliable examination in doubtful cases (27). Biopsy from the wall of a suspected TB breast abscess cavity leads to a definite diagnosis (1). Histopathologically, TB mastitis [Figure 29.2] is a form of granulomatous inflammation. There are a considerable number of other conditions that are characterized histologically by a tuberculoid type of tissue reaction. These conditions include sarcoidosis, various fungal infections, and granulomatous reactions to altered fatty material. Sometimes the microscopic picture in these conditions is indistinguishable from that seen in breast TB (24).

Carcinoma and TB of the breast are occasionally found coincidentally in the same patient. Similar findings in the axillary lymph nodes may also be seen (13,34). In assessing diagnosis, it is therefore, important to remember that recognition of the presence of breast TB does not exclude concomitant breast cancer. TREATMENT The management of breast TB consists of antituberculosis treatment and surgery with specific indications. Antituberculosis Treatment Antituberculosis treatment is the mainstay of therapy (46-49). All patients should be treated for at least six months following surgery (27). Antituberculosis treatment is administered as in pulmonary TB (28,47). The reader is referred to the chapter “Treatment of tuberculosis” [Chapter 52] for more details. Surgical Treatment

Figure 29.2: Tuberculosis mastitis. Photomicrograph showing breast parenchyma, Langhans’ giant cells and granulomas [asterisk] [Haematoxylin and eosin × 100]

DIFFERENTIATION FROM CARCINOMA BREAST Clinical examination usually fails to differentiate carcinoma from TB of the breast. The features that suggest breast TB include presence of pain, constitutional symptoms, lack of fixation of the lump to deeper structures, multiple sinuses and an intact nipple and areola (17). In addition, patients are young, married, multiparous or lactating (27). Nipple retraction, peau d’orange and involvement of axillary lymph nodes are more common in malignancy than in breast TB. Mammography is not of much help as the findings in carcinoma in advanced stage are similar to that of TB lesion (27,36).

Sir Astley Cooper was the first to suggest the role of surgery in breast TB (10). Wilson and MacGregor (28) advocated simple mastectomy for most cases of breast TB and emphasized that the lesions tend to persist and reappear with conservative management with antituberculosis treatment. Currently, most investigators agree that breast TB is eminently treatable without mutilating surgery (50,51). Surgical management may include drainage of abscess, biopsy from abscess wall, scraping of sinuses in the breast, excisional biopsy, segmentectomy and rarely simple mastectomy (9,17,27). Generally, an excision biopsy followed by a full course of antituberculosis treatment is suitable for small lesions (27). Residual lump following antituberculosis treatment may also be removed. Only rarely, simple mastectomy with or without axillary clearance is required for extensive disease comprising of large, painful ulcerated mass involving the entire breast and draining axillary lymph nodes rendering organ preservation impossible (27). Modified radical mastectomy is best avoided unless there is a coexisting malignancy. REFERENCES 1. Kakkar S, Kapila K, Singh MK, Verma K. Tuberculosis of the breast. A cytomorphologic study. Acta Cytol 2000;44:292-6.

Breast Tuberculosis 439 2. Tewari M, Shukla HS. Breast tuberculosis: diagnosis, clinical features and management. Indian J Med Res 2005;122:10310. 3. Mirsaeidi SM, Masjedi MR, Mansouri SD, Velayati AA. Tuberculosis of the breast: report of 4 clinical cases and literature review. East Mediterr Health J 2007;13:670-6. 4. Morino GF, Rizzardi G, Gobbi F, Baldan M. Breast tuberculosis mimicking other diseases. Trop Doct 2007;37:177-8. 5. Bahadur P, Aurora AL, Sibbal RM, Prabhu SS. Tuberculosis of the mammary gland. J Indian Med Assoc 1983;21:67-80. 6. Rangabashyam N, Gnanaprakasm D, Krishnaraj B, Manohar V, Vijayalakshmi SR. Spectrum of benign breast lesions in Madras. J R Coll Surg Edinb 1983;28:369-73. 7. Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C. Tuberculosis. Lancet 2003;362:887-99. 8. Miller B, Schieffelbein C. Tuberculosis. Bull World Health Organ 1998;76[Suppl2]:141-3. 9. Gupta R, Gupta AS, Duggal N. Tubercular mastitis. Int Surg 1982;67:422-4. 10. Cooper A. Illustrations of the diseases of the breast. Part I. London: Longman, Rees, Orme, Brown and Green; 1829.p.73. 11. Morgan M. Tuberculosis of the breast. Surg Gynaecol Obstet 1931;53:593-605. 12. Klossner AR. Uber die Brustdrusentuberculose. Eine pathologisch-anatomische und klinische studie. Acta Chir Scand 1944; 90[Suppl85]:1-181. 13. Haagensen CD. Infections in the breast. In: Haagensen CD, editor. Diseases of the breast. Third edition. Philadelphia: W.B. Saunders Company; 1986.p.384-93. 14. Mckeown KC, Wilkinson KW. Tuberculous diseases of the breast. Br J Surg 1952;39:420-9. 15. Hamit HF, Ragsdale TH. Mammary tuberculosis. J R Soc Med 1982;75:764-5. 16. Chaudhary M. Tuberculosis of the breast. Br J Dis Chest 1957;23:195-9. 17. Banerjee SN, Ananthakrishnan N, Mehta RB, Prakash S. Tuberculous mastitis: a continuing problem. World J Surg 1987;11:105-9. 18. Dharkar RS, Kanhere MH, Vaishya ND, Bisarya AK. Tuberculosis of the breast. J Indian Med Assoc 1968;50:207-9. 19. Mukerjee P, George M, Maheshwari HB, Rao CP. Tuberculosis of the breast. J Indian Med Assoc 1974;62:410-2. 20. Shukla HS, Kumar S. Benign breast disorders in nonwestern populations. Part II. Benign breast disorders in India. World J Surg 1989;13:746-9. 21. O’Reilly M, Patel KR, Cummins R. Tuberculosis of the breast presenting as carcinoma. Mil Med 2000;165:800-2. 22. Al-Marri MR, Almosleh A, Almoslmani Y. Primary tuberculosis of the breast in Qatar: ten year experience and review of literature. Eur J Surg 2000;166:687-90. 23. Hartstein M, Leaf HL. Tuberculosis of the breast as a presenting manifestation of AIDS. Clin Infect Dis 1992;15:692-3. 24. Symmers St WC. The breast. In: Symmers St WC, editor. Systemic pathology. Vol. 4. Second edition. New York: Churchill Livingstone; 1978.p.759-1861.

25. Domingo C, Ruiz J, Roig J, Texido A, Aguilar X, Morera J. Tuberculosis of the breast: a rare modern disease. Tubercle 1990;71:221-3. 26. Hale JA, Peters GN, Cheek JH. Tuberculosis of the breast: rare but still exists. Review of literature and report of additional case. Am J Surg 1985;150:620-4. 27. Shinde SR, Chandawarkar RY, Deshmukh SP. Tuberculosis of the breast masquerading as carcinoma: a study of 100 patients. World J Surg 1995;19:379-81. 28. Wilson TS, MacGregor JW. The diagnosis and treatment of tuberculosis of the breast. Can Med Assoc J 1963;89:1118-24. 29. Jaideep C, Kumar M, Khanna AK. Male breast tuberculosis. Postgrad Med J 1997;73:428-9. 30. Dubey MM, Agarwal S. Tuberculosis of the breast. J Indian Med Assoc 1968;51:358-9. 31. Alagaratnam TT, Ong GB. Tuberculosis of the breast. Br J Surg 1980;67:125-6. 32. Gransman RI, Goldman MI. Tuberculosis of the breast- report of 9 cases including 2 cases of co-existing cancer and tuberculosis. Am J Surg 1945;67:48. 33. Inoue Y, Nishi M, Hirose T. Tuberculosis of the breast- a case which could not be mammographically distinguished from breast cancer. Rinsho Hoshasen 1986;31:321-2. 34. Fujii T, Kimura M, Yanagita Y, Koida T, Kuwano H. Tuberculosis of axillary lymph nodes with primary breast cancer. Breast Cancer 2003;10:175-8. 35. Oh KK, Kim JH, Kook SH. Imaging of tuberculous disease involving breast. Eur Radiol 1998;8:1475-80. 36. Makanjuola D, Murshid K, Al Sulaimani S, Al Saleh M. Mammographic features of breast tuberculosis: the skin bulge and sinus tract sign. Clin Radiol 1996;51:354-8. 37. Popli MB. Pictorial essay: tuberculosis of the breast. Indian J Radiol Imag 1999;9:127-32. 38. Schnarkowski P, Schmidt D, Kessler M, Reiser MF. Tuberculosis of the breast: US, mammographic, and CT findings. J Comput Assist Tomogr 1994;18:970-1. 39. Bassett LW, Kimme-Smith C. Breast sonography. AJR Am J Roentgenol 1991;156:449-55. 40. Chung SY, Yang I, Bae SH, Lee Y, Park HJ, Kim HH, et al. Tuberculous abscess in retromammary region: CT findings. J Comput Assist Tomogr 1996;20:766-9. 41. Romero C, Carrerira C, Cereceda C, Pinto J, Lopez R, Bolanos F. Mammary tuberculosis: percutaneous treatment of mammary tuberculous abscess. Eur Radiol 2000;10:531-3. 42. Bhatt GM, Austin HM. CT demonstration of empyema necessitates. J Comput Assist Tomogr 1985;9:1108-9. 43. Heywang SH. Contrast-enhanced MRI of the breast. Basel: Karger; 1990. 44. Gupta D, Rajwanshi A, Gupta SK, Nijhawan R, Saran RK, Singh R. Fine needle aspiration cytology in diagnosis of tuberculous mastitis. Acta Cytol 1999;43:191-4. 45. Pagel W, Simmonds FAH, Macdonald J, Nassan E. Pulmonary tuberculosis. Fourth edition. London: Oxford University Press; 1964.p.245.

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46. Elmrabet F, Ferhati D, Amenssag L, Kharbach A, Chaoui A. Breast tuberculosis. Med Trop [Mars] 2002;62:77-80. 47. Kalac N, Ozkan B, Bayiz H, Dursun AB, Demirag F. Breast tuberculosis. Breast 2002;11:346-9. 48. Kumar P, Sharma N. Primary MDR-TB of the breast. Indian J Chest Dis Allied Sci 2003;45:63-5. 49. Tran JH, Montakantikul P. The safety of antituberculosis

medications during breast feeding. J Hum Lact 1998;14:33740. 50. Goksoy E, Duren M, Durgun V, Uygun N. Tuberculosis of the breast. Eur J Surg 1995;161:471-3. 51. Fadaei-Araghi M, Geranpayeh L, Irani S, Matloob R, Kuraki S. Breast tuberculosis: report of eight cases. Arch Iran Med 2008;11:463-5.

Tuberculosis in Pregnancy

30 Sunesh Kumar

INTRODUCTION Since the days of Hippocrates, the initial presentation of tuberculosis [TB] in temporal relation to pregnancy has been a subject of concern and controversy. Tuberculosis in a pregnant woman can present in several ways. Pregnant women may give a past history of TB. Occasionally, the disease may be diagnosed in a pregnant woman when she develops symptoms and signs suggestive of TB. Many a times, pregnant women may remain asymptomatic and TB may be diagnosed either incidentally or by way of a screening programme. Atypical presentation of TB in pregnant women poses difficulties in confirmation of the diagnosis. Tuberculosis in pregnancy, thus, has important implications for the mother and child (1,2). EPIDEMIOLOGY During the year 1985, the Centers for Disease Control and Prevention [CDC], Atlanta, estimated that TB in association with pregnancy occurred at a rate of 49.6/ 100 000 population among the Asians and the Pacific Islanders compared to a figure of 5.7/100 000 in the American whites and 26.7/100 000 in the AfricanAmericans (3,4). In the series reported by Schaefer et al (5), between 1966 and 1972, 3.2 per cent of patients with active TB at the New York Lying-in Hospital were first diagnosed during pregnancy. Bailey et al (6) estimated the incidence of TB during pregnancy to be 4.8 per cent at New Orleans. Margono et al (7) reported that, between 1985-1990, 12.4 cases of active TB were identified per 100 000 deliveries and during 1991-1992, this number increased to 94.8 per 100 000 deliveries. In another study (8) from a district general hospital in a high prevalence

area in London, UK, the incidence of active TB disease during pregnancy was reported to be 252/100 000 deliveries. Reliable epidemiological data regarding TB in pregnancy are not available from India. In a prospective study from Pune (9), 24 of the 715 human immunodeficiency virus [HIV] infected women who were followed-up for 480 postpartum person-years developed TB, yielding a TB incidence of 5 cases per 100 person-years. A baseline CD4+ cell count less than 200 cells/mm3, an HIV load greater than 50 000 copies/ml and a positive tuberculin skin test [TST] result were found to be predictors for the development of active postpartum TB disease in HIVseropositive women. During pregnancy, pulmonary TB is the most common lesion and extra-pulmonary TB occurs less commonly. Miliary TB and TB of lymph nodes, bones and kidneys are also encountered during pregnancy (10). Tuberculosis meningitis (11,12), TB mastitits (13), TB peritonitis (14), and perineal TB (15) have also been described. CLINICAL PRESENTATION OF TUBERCULOSIS DURING PREGNANCY About one-half to two-thirds of pregnant women with TB remain asymptomatic (16). Some of the symptoms, such as increased respiratory rate and fatigue may mimic the physiological changes that occur in pregnancy and, thus, make the diagnosis difficult. In the series reported by Schaefer et al (5), minimal symptoms were observed in 65 per cent pregnant women with TB. Good et al (17) found 19 per cent women to be asymptomatic among 371 women admitted to the National Jewish Hospital, Colorado. Of these, 27 patients had reactivation of TB

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during or within 12 months after pregnancy. They also reported cough [74%], weight loss [41%], fever [30%], malaise and fatigue [30%], and haemoptysis [19%] as the common presenting symptoms. Maurya and Sapre (18) screened 209 pregnant women for TB by tuberculin test, direct sputum examination for acid-fast bacilli [AFB] and chest radiograph [done after 12 weeks of gestation with abdominal shielding]. Of these 209 patients, 12 per cent had active TB; 70.3 per cent were sputum smear-negative, but had chest radiographic evidence of TB and a raised erythrocyte sedimentation rate [ESR], 14 per cent had a past history of adequately treated TB but no evidence of active disease; and 2.9 per cent had no evidence of TB and were tuberculin negative. They found cough [75%], weight loss [23%], fever [15%] and malaise [30%] to be the common symptoms in 100 symptomatic women. Clinical presentation of TB in pregnancy as reported in some published studies is shown in Table 30.1. EFFECT OF PREGNANCY ON TUBERCULOSIS At the start of the twentieth century it was believed that pregnancy had a deleterious effect on TB (10). In fact,

therapeutic abortion was advocated for pregnant women with pulmonary TB. During this period, a number of conflicting reports evaluating the impact of pregnancy on TB appeared (10). However, it is currently believed that pregnancy neither predisposes to the development of TB nor results in the progression of the disease. Two large studies (19,20), although somewhat old, clearly showed that pregnancy does not appear to result in the progression of the disease. One study (19) described 250 pregnant women; 189 with pulmonary and 61 with extra-pulmonary TB. None of them were given antituberculosis treatment and the treatment largely consisted of sanatorium therapy. It was found that TB improved in 9.1 per cent women while the disease progressed in seven per cent and most of the women remained stable (19). In another study, de March (20) evaluated the influence of pregnancy as a relapse factor for pulmonary TB in 215 patients who received adequate treatment and concluded that pregnancy, labour, puerperium, and lactation did not predispose to the risk of relapse of pulmonary TB when the disease was adequately treated.

Table 30.1: Clinical presentation of tuberculosis in pregnancy Variable

Good et al (17)

Margono et al (7)

Maurya and Sapre (18)

Study period

1965-1974

1985-1992

1989-1992

Place of study

Denver

New York

Gwalior

No. of patients Pulmonary TB Extra-pulmonary TB Total

27* 0 27

10 6† 16

172‡ 0 17

HIV-seropositive [%]

ND

64 [n = 11]

ND

Tuberculin positive [%]

96

40 [n = 15]

ND

Method of diagnosis Microbiological [%] Histopathological [%]

100§ 0

100|| 19||

¶ ¶

Numbers in parantheses indicate number of patients tested * In 6 patients TB was diagnosed during pregnancy [first trimester n = 3; second trimester n = 1; third trimester n = 2]. In the remaining 11 patients, TB was diagnosed during the postpartum period [up to 12 months following delivery] † Included 2 patients with TB meningitis and 1 each with mediastinal, renal, gastrointestinal and pleural TB ‡ Of the 209 patients studied, 6 patients had no evidence of TB and were tuberculin negative; 31 patients had past history of adequately treated TB § 16 patients had drug-resistant TB || Patients with cultures of sputum, urine or cerebrospinal fluid positive for Mycobacterium tuberculosis whether or not smears were positive were included. In patients with mediastinal, pleural and gastrointestinal TB [1 patient each], diagnosis of TB was confirmed by histopathological examination ¶ Detailed break up not given TB = tuberculosis; HIV = human immunodeficiency virus; ND = not described

Tuberculosis in Pregnancy 443 Schaefer et al (5) compared the course and outcome of TB in pregnant women during the pre-chemotherapy and chemotherapy era; 88 per cent women in prechemotherapy and 91 per cent in the chemotherapy era remained stable during pregnancy. Eleven of the 27 cases of reactivation or relapse of pulmonary TB described by Good et al (17) occurred in the postpartum period. However, these and other studies highlight a small but definite risk of relapse and deterioration in the postpartum period (10). EFFECT OF TUBERCULOSIS ON PREGNANCY Contrary to old reports, following the advent of effective antituberculosis treatment, current literature does not suggest that TB has an adverse impact either on the course of pregnancy or labour (1,2). Abortions Selikoff and Dorfmann (21) reported seven early spontaneous abortions and nine antepartum or intrapartum foetal deaths in 616 pregnant women with TB, where 600 pregnancies resulted in the birth of 602 normal live infants. Maurya and Sapre (18) reported four spontaneous abortions in the group previously treated for TB. Preterm Delivery Schaefer et al (5) did not find any evidence of increased risk of prematurity in their series. Maurya and Sapre (18) reported only two premature deliveries among 31 pregnant women with a past history of TB. Bjerkedal et al from Norway (22) described the course and outcome of pregnancy in 542 women with TB [study group] and 112 530 women without TB [control subjects]. Study group had increased frequency of pregnancy induced hypertension [7.4% vs 4.7%] and vaginal bleeding [4.1% vs 2.2%]. Labour was induced more often in the study group than among the control subjects [14.6% vs 9.1%]. Labour was also reported to be more often complicated in the study group than in control subjects [15.1% vs 9.6%] and interventions during labour were required more often in the study group [12.6% vs 7.7%]. Intrauterine foetal death rate between 16 and 28 weeks was nine-fold higher in the study group [20.1/1000 in cases versus 2.3/1000 control subjects]. However, no difference was found in the number of congenital anomalies or subsequent conception rate. There was no

difference in mean gestational age, preterm births or mean birth weight among live births. Maurya and Sapre (18) reported two preterm deliveries and one intrauterine foetal death in the subgroup with active TB. Maternal mortality and foetal complications were more frequent in pregnant women with drug-resistant TB compared to those with drugsensitive disease in the study by Good et al (17). In the study reported by Jana et al (23), 33 patients with extra-pulmonary TB [12 with TB lymphadenitis and 9 with intestinal, 7 with skeletal, 2 with renal, 2 with meningeal, and 1 with endometrial TB] were followed through their deliveries. Of the 33 patients, 29 received antituberculosis treatment during pregnancy. The antenatal complications, intrapartum events, and perinatal outcomes were compared with those among 132 healthy pregnant women without TB who were matched for age, parity and socio-economic status. It was observed that TB lymphadenitis did not affect the course of pregnancy or labour or the perinatal outcome. However, as compared with the control subjects, 21 women with involvement of other extra-pulmonary sites had significantly higher rates of antenatal hospitalization [24% vs 2%], infants with low Apgar scores [< 6] soon after birth [19% vs 3%], and low birth-weight [less than 2.5 kg] infants [33% vs 11%]. The authors concluded that extrapulmonary TB that is confined to the lymph-nodes has no effect on obstetrical outcomes, but TB at other extrapulmonary sites does adversely affect the outcome of pregnancy (23). Outcome of pregnancy in patients with active pulmonary TB as reported in some of the published studies is shown in Table 30.2. PLACENTAL TRANSMISSION OF TUBERCULOSIS Placental transmission of TB infection has now been conclusively proven by a number of case reports (24-26). In the literature, cases where newborn babies were found to have acquired TB from the diseased endometrium have been described. Nemir and O’Hare (24) described one female child carefully investigated and treated for congenital TB in neonatal period. This child had positive subumbilical lymph nodes indicating umbilical vein as the route of transmission. Myocbacterium tuberculosis has also been demonstrated in placental specimens and tissues from stillborn infants (27,28). Kalpan et al (29) reported two interesting

444

Tuberculosis Table 30.2: Outcome of pregnancy in patients with active pulmonary tuberculosis Variable

Maurya and Sapre (18)

Schaeffer et al (5)

Study period

1989-1992 [n = 172]

1933-1951 [n = 506]

1952-1972 [n = 1059]

Pregnancy outcome [%] Normal delivery Forceps delivery Breech

87 0 0

61.6 27.6 4.5

64.5 28.7 2.7

Caesarean section Elective Emergency

13 9 4

6.3 ND ND

4.1 ND ND

n = number of subjects studied; ND = not described

cases. In the first case, a 25-year-old pregnant woman had been treated with multiple drugs for cavitary pulmonary TB. She desired an elective abortion at six weeks of gestation. Endometrial curettage smear revealed Mycobacterium tuberculosis. In the second case, a 24-yearold pregnant woman presented at 34 weeks of gestation with premature rupture of membranes. An emergency caesarean section performed 24 hours later revealed fibrinous exudates on peritoneal surface and a placenta densely adherent to the uterus. Both exudates and tissue from the endometrium grew Mycobacterium tuberculosis. These findings suggest that subclinical endometrial infections can be an important source for transplacental transmission of disease in patients with congenital TB. CONGENITAL TUBERCULOSIS The reader is referred to the chapters “Pathology” [Chapter 5] and “Tuberculosis in children” [Chapter 41] for more details. DIAGNOSIS It is important to identify pregnant women suffering from TB as it may help to prevent transmission of disease to the newborn and close contacts. Chest Radiograph In the past, a routine chest radiograph was advocated during pregnancy in order to detect active and inactive TB (21,30,31). Bonebrake et al (32) advised against such a policy as most patients with significant findings on chest radiograph also had positive findings on physical examination and a positive TST result. Concern about

radiation exposure to foetus does not justify the policy of routine chest radiograph examination during pregnancy [34 to 36 weeks]. However, if a chest radiograph is indicated, pregnancy should not be considered as an absolute contraindication. A chest radiograph should be taken with abdominal shielding, preferably after the first trimester of pregnancy. Estimated radiation from a chest radiograph is approximately 50 mrad to the chest and 2.5 to 5 mrad to the gonads (32,33-35). Prenatal radiation exposure has been correlated with subsequent risk of malformations and cancer. Mole (36), in a detailed analysis estimated such a risk to be zero to one case per 1000 patients if irradiated by one rad in utero during the first four months of pregnancy. Therefore, a chest radiograph carried out during pregnancy does not seem to carry a measurable risk to the foetus since radiation exposure from a chest radiograph is much less (32-35). Detection of Tuberculosis Infection The TST identifies persons infected by Mycobacterium tuberculosis but does not define the activity or extent of disease. Generally, the TST becomes positive two to ten weeks after initial exposure (37). In the past, a concern had been expressed regarding the effect of pregnancy on TST positivity (38). However, subsequent studies have not found pregnancy to affect the TST reactivity (39,40). Present and Comstock (40) evaluated 25 000 patients over a one-year period and reported that pregnancy did not affect the TST results. There appears to be no risk either to the pregnant woman or her foetus from the TST (41). Carter and Mates (42) while reviewing cases of TB during pregnancy over a four-year span in Rhode Island

Tuberculosis in Pregnancy 445 found that most patients with TB infection remain asymptomatic. They concluded that the TST screening in pregnancy may prevent risk to the foetus, newborn and the obstetric ward workers. However, usefulness of such a policy in areas where TB is highly endemic remains doubtful. The recently available interferon-gamma release assays [IGRAs], offer several advantages over the TST and are increasingly being used for the diagnosis of latent TB infection. The reader is referred to the chapters “Tuberculin skin test” [Chapter 11] and “Diagnosis of latent tuberculosis infection: recent advances and future directions” [Chapter 12] for more details. Microbiological Methods

regimen has been shown to prevent seizures in neonates born to mothers treated with isoniazid during pregnancy (1). The reader is referred to the chapter “Antituberculosis treatment induced hepatotoxicity” [Chapter 54] for further details. Rifampicin Although increase in limb defects have been observed in foetuses of mothers taking rifampicin (1). Snider et al (44) failed to detect increased incidence of teratogenicity among mothers taking rifampicin during pregnancy. Presently, rifampicin is considered to be an essential component of antituberculous treatment during pregnancy (1,47).

Demonstration of Mycobacterium tuberculosis in sputum, body fluids or material by Ziehl-Neelsen staining and Lowenstein-Jensen culture confirms the diagnosis of TB disease. However, low yield in these specimens remains a practical problem.

Ethambutol

TREATMENT OF ACTIVE TUBERCULOSIS DURING PREGNANCY

Streptomycin

Pregnant women with active TB should be immediately started on antituberculosis treatment as untreated TB is far more hazardous to a pregnant woman and her foetus than the adverse effects related to the treatment of the disease (43). Though first-line drugs, such as isoniazid, rifampicin, streptomycin and ethambutol cross the placenta, with exception of streptomycin induced ototoxicity, none of these drugs appear to be teratogenic or toxic to the foetus (44). Isoniazid Even though isoniazid crosses the placenta, no significant teratogenic effects have been noted even when used during the first four months of pregnancy (45). However, one report mentioned about two-fold increase in the risk of malformations when mothers were exposed to isoniazid (46). Hepatitis is a frequently observed side-effect of isoniazid. Pregnant and postpartum women may be particularly at higher risk for isoniazid induced hepatitis. An addition of pyridoxine in a dose of 50mg/day has been recommended during pregnancy to prevent neurotoxicity in the mother and the foetus (43). This

Although ethambutol is known to be teratogenic in experimental animals, there are no reports of maldevelopment including ocular injury in human foetuses (48-50).

Use of streptomycin during pregnancy has been reported to be associated with vestibular and auditory impairment in the newborns (51,52). Streptomycin induced ototoxicity has been reported irrespective of period of gestation. Therefore, streptomycin should not be used during pregnancy. Pyrazinamide Due to faster sputum conversion rate, this drug is commonly used in the short-course treatment regimens. As recommended by the World Health Organization [WHO] and International Union Against Tuberculosis and Lung Disease [IUATLD], pyrazinamide can be safely used in pregnancy (53). If pyrazinamide is not included in the initial treatment regimen, the minimum duration of treatment is nine months. Benefits of the use of pyrazinamide in HIV-seropositive pregnant women outweigh the undetermined potential risks to the foetus. Principles of Treatment Active disease discovered in antenatal period should be promptly treated. Isoniazid, rifampicin, pyrazinamide and ethambutol should be initially used. The reader is referred to the chapter “Treatment of tuberculosis” [Chapter

446

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52] for more details. Duration of antituberculosis treatment need not be modified because of pregnancy. Active TB disease discovered close to the time of delivery should also be actively treated. Neonate should be carefully examined and kept under surveillance for development of TB. Placenta should be examined for possible infection by Mycobacterium tuberculosis. If patients receiving antituberculosis drugs conceive, pregnancy should be allowed to continue while the patient continues antitubercuolsis treatment. Appropriate steps should be taken to prevent TB infection in the newborn. Second-Line Drugs Little is known about the teratogenic effects of the secondline antituberculosis drugs. Due to high incidence of sideeffects, their usefulness is limited. Teratogenic effect has been attributed to ethionamide (54). Kanamycin and capreomycin theoretically share the potential for producing ototoxicity with streptomycin. The potential hazard of such treatment must be considered by the parents and the treating physician. Treatment of Drug-resistant Tuberculosis During Pregnancy Women who are being treated for drug-resistant TB should receive counselling concerning the risk to the foetus because of the known and unknown risks of second-line antituberculosis drugs. There have been occasional case reports and small case series in the published literature regarding the management of multidrug-resistant TB [MDR-TB] during pregnancy using second-line drugs (55-58). These data suggest that treatment of MDR-TB during pregnancy is beneficial both to the mother and the child. However, studies involving large sample size with a long-term follow up are awaited. As the majority of teratogenic effects occur in the first trimester, treatment should be delayed until the second trimester. The decision to postpone the treatment should be based on the analysis of the risks and benefits and should be acceptable to both the doctor and patient. Injectable agents, aminoglycosides and capreomycin should be avoided during pregnancy and if possible ethionamide should also be avoided (59). The decision should also take into consideration the severity of illness.

Treatment should consist of combination of three or four drugs with demonstrated efficacy against the infecting strain. TREATMENT OF LATENT TUBERCULOSIS INFECTION The reader is referred to references 60 and 61 for details regarding treatment of latent TB infection in pregnancy. Efficacy and safety of isoniazid chemoprophylaxis during pregnancy, in areas where TB is highly endemic, like India, are unclear. MANAGEMENT OF TUBERCULOSIS IN INFANTS BORN TO MOTHERS WITH TUBERCULOSIS If the mother had been receiving treatment for TB during pregnancy, the newborn should be assessed for symptoms and signs of congenital TB. Infant should undergo the TST at birth. Chest radiograph and smear and culture examination of the gastric aspirate should be performed. If active TB is ruled out, the child should be treated with isoniazid for two to three months, or till such time the mother, known to be complying with treatment, becomes smear and culture negative (10). The child should be carefully followed up thereafter. If active disease is detected, the child should receive a full course of antituberculosis treatment with rifampicin, isoniazid and pyrazinamide. Ethambutol should preferably be avoided in neonates as it is difficult to monitor the ocular toxicity. Breast Feeding Breast feeding should not be discouraged in nursing mothers receiving antituberculosis treatment as the concentrations of these drugs secreted in the breast milk seldom attain toxic levels (10). However, drugs in breast milk should not be considered to serve as effective treatment for the disease or as chemoprophylaxis in a nursing infant (62,63). Pyridoxine supplementation should be given to breast feeding women taking isoniazid. ANTITUBERCULOSIS TREATMENT AND CONTRACEPTION Rifampicin induces the P-450 mixed function oxidase system that metabolises oral contraceptives and other

Tuberculosis in Pregnancy 447 drugs (10). Reliability of oral contraceptives is diminished in women taking rifampicin (64,65). Alternative contraceptive measures should be considered for postpartum women who require antituberculosis treatment. REFERENCES 1. Efferen LS. Tuberculosis and pregnancy. Curr Opin Pulm Med 2007;13:205-11. 2. Laibl VR, Sheffield JS. Tuberculosis in pregnancy. Clin Perinatol 2005;32:739-47. 3. Centers for Disease Control. Leads from the MMWR. Tuberculosis in minorities –United States. JAMA 1987;257:1291-2. 4. Centers for Disease Control. Lead from the MMWR. Tuberculosis in blacks-United States. JAMA 1987;257:2407-8. 5. Schaefer G, Zervoudakis IA, Fuchs FF, David S. Pregnancy and tuberculosis. Obstet Gynecol 1975;46:706-15. 6. Bailey WC, Thompson DH, Greenberg HB. Indigent pregnant women of New Orleans require tuberculosis control measures. Health Serv Rep 1972;87:737-42. 7. Margono F, Mroueh J, Garely A, White D, Duerr A, Minkoff HL. Resurgence of active tuberculosis among pregnant women. Obstet Gynecol 1994;83:911-4. 8. Kothari A, Mahadevan N, Girling J. Tuberculosis and pregnancy–results of a study in a high prevalence area in London. Eur J Obstet Gynecol Reprod Biol 2006;126:48-55. Epub 2005 Sep 9. 9. Gupta A, Nayak U, Ram M, Bhosale R, Patil S, Basavraj A, et al. Byramjee Jeejeebhoy Medical College-Johns Hopkins University Study Group. Postpartum tuberculosis incidence and mortality among HIV-infected women and their infants in Pune, India, 2002-2005. Clin Infect Dis 2007;45:241-9. Epub 2007 Jun 4. 10. Hamadeh MA, Glassroth J. Tuberculosis and pregnancy. Chest 1992;101:1114-20. 11. Golditch IM. Tuberculous meningitis and pregnancy. Am J Obstet Gynecol 1971;110:1144-6. 12. Stands JW, Jowers RG, Bryan CS. Miliary-meningeal tuberculosis during pregnancy: case report and brief survey of the problem of extra-pulmonary tuberculosis. JSC Med Assoc 1977;73:282-5. 13. Banerjee SN, Ananthakrishnan N, Mehta RB, Prakash S. Tuberculosis mastitis: a continuing problem. World J Surg 1987;11:105-9. 14. Lee GS, Kim SJ, Park IY, Shin JC, Kim SP. Tuberculous peritonitis in pregnancy. J Obstet Gynaecol Res 2005;31:436-8. 15. Pal A, Mahadevan N. Perineal tuberculosis diagnosed in pregnancy: a case report. J Obstet Gynaecol 2005;25:307-8. 16. Wilson EA, Thelin TJ, Dilts PV Jr. Tuberculosis complicated by pregnancy. Am J Obstet Gynecol 1973;115:526-9. 17. Good JT Jr, Iseman MD, Davidson PT, Lakshminarayan S, Sahn SA. Tuberculosis in association with pregnancy. Am J Obstet Gynecol 1981;140:492-8. 18. Maurya U, Sapre S. Tuberculosis and pregnancy. J Obstet Gynecol India 1996;46:460-3.

19. Hedvall E. Pregnancy and tuberculosis. Acta Med Scand Suppl 1953;286:1-101. 20. de March P. Tuberculosis and pregnancy. Five-to ten-year review of 215 patients in their fertile age. Chest 1975;68:800-4. 21. Selikoff IJ, Dorfmann HL. Management of tuberculosis. In: Rovinskey JJ, Gulmatcher AF, editors. Medical, surgical and gynecologic complications of pregnancy. Baltimore: Williams and Wilkins; 1965.p.111. 22. Bjerkedal T, Bahna SL, Lehmann EH. Course and outcome of pregnancy in women with pulmonary tuberculosis. Scand J Respir Dis 1975;56:245-50. 23. Jana N, Vasishta K, Saha SC, Ghosh K. Obstetrical outcomes among women with extrapulmonary tuberculosis. N Engl J Med 1999;341:645-9. 24. Nemir RL, O’Hare D. Congenital tuberculosis. Review and diagnostic guidelines. Am J Dis Child 1985;139:284-7. 25. Myers JP, Perlstein PH, Light IJ, Towbin, Dincsoy HP, Dincsoy MY. Tuberculosis in pregnancy with fatal congenital infection. Pediatrics 1981;67:89-94. 26. Niles RA. Puerperal tuberculosis with death of infant. Am J Obstet Gynecol 1982;144:131-2. 27. Snider D. Pregnancy and tuberculosis. Chest 1984;86[3 suppl]:10S-13S. 28. Siegel M. Pathological findings and pathogenesis of congenital tuberculosis. Am Rev Tuberc 1934;29:297-309. 29. Kaplan C, Benirschke K, Tarzy B. Placental tuberculosis in early and late pregnancy. Am J Obstet Gynecol 1980;137:858-60. 30. Freeth A. Routine X-ray examination of the chest at an antenatal clinic. Lancet 1953;1:287-8. 31. Stanton SL. Routine radiology of the chest in antenatal care. J Obstet Gynaecol Br Commonw 1968;75:1161-4. 32. Bonebrake CR, Noller KL, Loehnen CP, Muhm JR, Fish CR. Routine chest roentgenography in pregnancy. JAMA 1978;240:2747-8. 33. Mattox JH. The value of a routine prenatal chest X-ray. Obstet Gynecol 1973;41:243-5. 34. Swartz HM, Reichling BA. Hazards of radiation exposure for pregnant woman. JAMA 1978;239:1907-8. 35. Turner AF. The chest radiograph in pregnancy. Clin Obstet Gynecol 1975;18:65-74. 36. Mole RH. Radiation effects on prenatal development and their radiological significance. Br J Radiol 1979;52:89-101. 37. American Thoracic Society and Centers for Disease Control. The tuberculin skin test. Am Rev Respir Dis 1971;104:769-75. 38. Finn R, St Hill CA, Govan AJ, Ralfs IG, Gurney FJ, Denye V. Immunological responses in pregnancy and survival of foetal homograft. BMJ 1972;3:150-2. 39. Montgomery WP, Young RC Jr, Allen MP, Harden KA. The tuberculin test in pregnancy. Am J Obstet Gynecol 1968;100: 829-31. 40. Present PA, Comstock GW. Tuberculin sensitivity in pregnancy. Am Rev Respir Dis 1975;112:413-6. 41. Snider DE Jr, Farer LS. Package inserts of antituberculosis drugs and tuberculin. Am Rev Respir Dis 1985;131:809-10. 42. Carter EJ, Mates S. Tuberculosis during pregnancy. The Rhode Island experience, 1987 to 1991. Chest 1994;106:146670.

448

Tuberculosis

43. Warkany J. Antituberculosis drugs. Teratology 1979;20:133-7. 44. Snider DE Jr, Layde PM, Johnson MW, Lyle MA. Treatment of tuberculosis during pregnancy. Am Rev Respir Dis 1980;145:494-8. 45. Scheinhorn DJ, Angelillo VA. Antituberculosis therapy in pregnancy. Risks to the fetus. West Med J 1977;127:195-8. 46. Brost BC, Newman RB. The maternal and fetal effects of tuberculosis therapy. Obstet Gynecol Clin North Am 1997;24:659-73. 47. Vallejo JG, Starke JR. Tuberculosis and pregnancy. Clin Chest Med 1992;13:693-707. 48. Bothamley G. Drug treatment for tuberculosis during pregnancy: safety considerations. Drug Saf 2001;24:553-65. 49. Bobrowitz ID. Ethambutol in pregnancy. Chest 1974;66:20-4. 50. Lewit T, Nebel L, Terracina S, Karman S. Ethambutol in pregnancy: observation on embryogenesis. Chest 1974;66:25-6. 51. Conway N, Birt BD. Streptomycin in pregnancy. Effects of foetal ear. BMJ 1965;2:260-3. 52. Robinson GC, Cambon KG. Hearing loss in infants of tuberculous mothers treated with streptomycin during pregnancy. N Engl J Med 1964;271:949-51. 53. World Health Organization. Treatment of tuberculosis: Guidelines for national programmes. Third edition. WHO/ CDS/TB/2003.313. Geneva: World Health Organization;2003. 54. Potworowska M, Sianozecke E, Szufladowicz R. Ethionamide treatment and pregnancy. Pol Med J 1966;5:1152-8. 55. Khan M, Pillay T, Moodley J, Ramjee A, Padayatchi N. Pregnancies complicated by multidrug-resistant tuberculosis and HIV co-infection in Durban, South Africa. Int J Tuberc Lung Dis 2007;11:706-8. 56. Takashima T, Danno K, Tamura Y, Nagai T, Matsumoto T, Han Y, et al. Treatment outcome of patients with multidrug-

57.

58.

59.

60.

61.

62. 63.

64. 65.

resistant pulmonary tuberculosis during pregnancy. Kekkaku 2006;81:413-8. Drobac PC, del Castillo H, Sweetland A, Anca G, Joseph JK, Furin J, et al. Treatment of multidrug-resistant tuberculosis during pregnancy: long-term follow-up of 6 children with intrauterine exposure to second-line agents. Clin Infect Dis 2005;40:1689-92. Epub 2005 Apr 18. Shin S, Guerra D, Rich M, Seung KJ, Mukherjee J, Joseph K, et al. Treatment of multidrug-resistant tuberculosis during pregnancy: a report of 7 cases. Clin Infect Dis 2003;36:9961003. Epub 2003 Apr 4. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/ TB/ 2006.361. Geneva: World Health Organization; 2006. Centers for Disease Control and Prevention [CDC]; American Thoracic Society. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection - United States, 2003. MMWR Morb Mortal Wkly Rep 2003;52:735-9. American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep 2000;49[RR-]:1-51. Snider DE Jr, Powell KE. Should women taking antituberculosis drugs breast feed? Arch Int Med 1984;144:494-8. Tran JH, Montakantikul P. The safety of antituberculosis medications during breastfeeding. J Hum Lact 1998;14:33740. Skolnick JL, Stoler BS, Katz DB, Anderson WH. Rifampin, oral contraceptives and pregnancy. JAMA 1976;236:1382. Finch CK, Chrisman CR, Baciewicz AM, Self TH. Rifampin and rifabutin drug interactions: an update. Arch Intern Med 2002;162:985-92.

Female Genital Tuberculosis

31 Sunesh Kumar

INTRODUCTION

Genital Tuberculosis in Infertile Women

Female genital tuberculosis [TB], though known to have existed for centuries, was first described by Morgagni in 1744 during an autopsy on a 20-year-old girl known to have died of TB peritonitis (1). Infertility, menstrual irregularities and chronic pelvic or lower abdominal pain are the most common manifestations of female genital TB (2-4). It is almost always secondary to a focus elsewhere in the body. Fallopian tubes are the first and the most commonly affected genital organs, followed by endometrium, ovary and cervix (5). Occasionally, other sites may also be affected. A number of patients may remain asymptomatic and the disease may also be discovered incidentally (6). The last century has witnessed changing trends in incidence of female genital TB, initially due to improvement in economic standards in developed countries and subsequently by the global pandemic of the human immunodeficiency virus [HIV] infection.

Schaefer (7) estimated the worldwide incidence of genital TB in infertile women to be five to ten per cent. Incidence of genital TB has been estimated to range from 1 to 26.7 per cent in various studies from India (8,11-15). Malkani and Rajani (13), based on endometrial biopsies from infertile women, reported the incidence of genital TB to be 9.3 per cent. Deshmukh et al (8) reported a similar incidence at laparoscopy in 500 infertile women. Dam et al (14) from Kolkata, India reported that genital TB was an important aetiological cause in patients [n = 81] with unexplained infertility with apparently normal pelvic and non-endometrial tubal factors and repeated in vitro fertilization [IVF] failure. In another recent study (15) from New Delhi, India, 26.7 per cent of the 150 women with infertility were found to have genital TB. In a study (16) from Islamabad, Pakistan, 2.43 per cent of the 543 women with infertility were found to have female genital TB. The incidence of female genital TB among patients with infertility in the USA has been reported to be less than one per cent in various series (5-7,17).

EPIDEMIOLOGY Genital tract TB has been reported in patients presenting with infertility, chronic pelvic pain and menstrual irregularities, in autopsy series, and recently in laparoscopy series of infertility cases (5-8). Twentieth century witnessed dramatic reduction of female genital TB cases in the developed world. However, a similar trend has not been observed in the developing countries. Incidence of genital TB varies greatly depending upon the geographical location ranging from 10.3 per cent in India (9) to being less than one per cent in the USA (6) and Sweden (10).

Genital Tuberculosis in Women with Abnormal Uterine Bleeding Sutherland (18) described endometrial TB in 10 out of 1000 patients with abnormal uterine bleeding. Roy et al (19) described a series of 246 patients with abnormal uterine bleeding between 15 and 60 years of age. Histopathological evidence of TB was found in 20 patients. Further, mycobacterial cultures were reported to be positive in 21 specimens and guinea pig inoculation was positive in 18 specimens. Tripathy and Tripathy (20)

450

Tuberculosis

studied 62 women with sputum positive pulmonary TB using laparoscopy, they observed various findings such as bands of adhesion, tubercles and hyperaemia in 37, intestinal adhesions in 15, tubercles on fallopian tubes in 14 and adhesions in pouch of Douglas in seven women. The incidence of female genital tract TB has been estimated to be four to twelve per cent in autopsy studies (21). Rarely, female genital TB can present with postmenopausal vaginal bleeding (22). Age Distribution Schaefer (7) reported that 80 to 90 per cent of his patients were between 20 and 40 years of age. A changing trend in the age at diagnosis has been highlighted by Sutherland (2) in a large series of 704 patients with female genital TB seen between 1951 and 1980. The mean age was 28.2 years in the initial 10 years compared to 38.9 years observed in the last decade of the study (2). Reports from Swedish hospitals showed that 46 per cent patients with female genital TB were older than 50 years in the period between 1968 and 1972 and the figure increased to 62 per cent between 1972 to 1977 (10). A series from Turkey reported 29.2 per cent cases of female genital TB to be older than 40 years of age (23). In India, however, it is not uncommon to find TB endometritis at an younger age in patients undergoing investigations for amenorrhoea or infertility. In several series reported from India (11,24-27), 68 to 89 per cent cases of genital TB were between 20 and 30 years of age [Table 31.1]. PATHOGENESIS Genital tract TB is almost always secondary to TB infection elsewhere in the body. Although pulmonary

TB is most common, extra-pulmonary organs such as kidneys, gastrointestinal tract, bone or joints may also be the primary source of infection (10). In patients with miliary TB, genital organs may be one of the many organs involved. Primary genital TB, though extremely rare, has been described in the female partners of males affected by active genitourinary TB. Lattimer et al (28) first reported the presence of Mycobacterium tuberculosis in the semen of male partners of women with genital TB. Sutherland et al (29) in a series of 128 women with proven genital TB found five of their husbands to have active genitourinary TB. Female partners of three of these five husbands had evidence of a focus of TB elsewhere in the body. In patients with primary genital TB, cervix or vulva may be the site of involvement. Haematogenous or lymphatic route is the usual mode of spread. However, direct contiguous spread from other intraperitoneal organs may occur in a minority of patients (7,30). Simultaneous occurrence of peritoneal TB in patients with genital TB increases the possibility of ruptured caseous lymph nodes or involvement of genital organs during the haematogenous spread. Fallopian tube is usually the initial site of focus, being affected in 90 to 100 per cent cases, with subsequent spread to other genital organs. Other affected sites include endometrium in 50 to 60 per cent, ovaries in 20 to 30 per cent, cervix in five to fifteen per cent and vagina in one per cent of the cases (31). Fallopian Tube Tuberculosis Fallopian tubes are involved in almost all patients with genital TB (5,7). Ampullary portion of the fallopian tube is the most common site of the disease. Isthmus is less commonly involved and involvement of the interstitial

Table 31.1: Age distribution of patients with genital tuberculosis Study (reference)

Gupta (11) Devi (24) Hafeez and Tandon (25) Chhabra (26) Rattan et al (27)

No. of patients

47 144 120 58 50

Age group [years] 40

13.0 12.0 3.3 1.7 0

68.0 70.0 89.0 74.2 76.0

19.0 14.0 6.0 8.6 24.0

0 4.0 1.7 15.5 0

Distribution of patients in various age groups is shown as percentage All values are corrected to first decimal place

Female Genital Tuberculosis 451 portion is unusual. Generally, the disease tends to be bilateral. Disease may start on the peritoneal surface or in the muscularis mucosa of the tube, however, involvement of the mucosal layer is almost universal. Gross appearance of the fallopian tube may vary depending upon the severity of disease and stage at which it is encountered. In early cases, congestion of tubes and other pelvic organs with flimsy adhesions and fine miliary tubercles on the surface of the tube and other pelvic organs may be seen. In severe disease, dense plastic adhesions between the fallopian tubes and surrounding organs are seen. In old healed cases, hydrosalpinx or pyosalpinx may be present. Failure to visualize pelvic organs at laparoscopy or laparotomy may be due to dense adhesions in patients with pelvic TB. In 25 to 50 per cent cases, the fallopian tubes remain patent with everted fimbriae giving rise to so called “tobacco pouch appearance” (32). Microscopically, presence of chronic inflammatory cells, with or without caseation, granulomas with Langhans’ giant cells may be evident. However, microscopic appearance may be variable depending upon the severity of the disease and whether the disease is in active or healing phase. The tubal mucosa may be totally destroyed or may have hyperplastic or adenomatous appearance which may be confused with adenocarcinoma (33). Papillae in the endosalpinx are usually fused, and may lead to implantation of embryo in the fallopian tubes resulting in ectopic pregnancy.

Microscopically [Figure 31.1], diagnosis is based upon the presence of chronic inflammatory cells with or without caseation, granulomas with lymphocytes, Langhans’ giant cells and epithelioid cells. Such lesions may be focal or generalized. Due to cyclical shedding of endometrium such lesions may be seen close to the surface of endometrium. Granulomas may be better seen in premenstrual phase or within 12 hours after onset of menstruation (35). However, typical granulomas may not be seen in all cases (36). Bazaz-Malik et al (3) in a series of 1000 cases of TB endometritis noted discrete granulomas and caseation in 60 per cent cases only. They suggested presence of dilated glands, destruction of epithelium, inflammatory exudates in the lumen as additional criteria for diagnosis of TB endometritis. Bourno and Williams (37) suggest that focal collection of lymphocytes in the endometrium should be considered to be of TB origin unless proved otherwise. Ovarian Tuberculosis Ovarian involvement occurs in 15 to 25 per cent cases (5) and most often results from direct extension of the

Endometrial Tuberculosis Endometrial involvement in genital TB is secondary to tubal involvement (31,32). Schaefer (31) reported endometrial involvement in 50 to 80 per cent cases of genital TB. In a large series of 1436 cases of genital TB, Norgales-Ortiz et al (32) reported endometrial involvement in 79 per cent of cases. Oosthuizen et al (34) in a study of 109 patients with infertility, found evidence of genital TB in the form of positive culture in menstrual blood in 16 and positive endometrial tissue for Mycobacterium tuberculosis in four patients. Gross appearance of endometrium is mostly unremarkable. However, in advanced cases, ulcerative or atrophic endometrium or an obliterated endometrial cavity due to extensive intrauterine adhesions may be seen. Total destruction of endometrium by the disease process with resultant secondary amenorrhoea has been reported in a few cases (32).

Figure 31.1: Endometrial tuberculosis. Photomicrograph showing endometrial glands with clusters of epithelioid cells and lymphocytic infiltration [asterisk] [upper panel, left; Haematoxylin and eosin, × 60], stroma of endometrium, epithelioid granulomas [asterisk], Langhans’ giant cell [arrow] and lymphocytic infiltration [upper panel, right; Haematoxylin and eosin × 200]. Fallopian tube tuberculosis. Photomicrograph showing congested tubal plicae with epithelioid clusters and lymphocytic infiltration [asterisk] [lower panel, left; Haematoxylin and eosin, × 60], epithelioid granulomas in the fallopian tube [asterisk] [lower panel, right; Haematoxylin and eosin × 60]

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Tuberculosis

disease from fallopian tubes (10). In such cases, ovary may be surrounded by adhesions or may be the site of tubo-ovarian cyst formation or tubo-ovarian mass with adhesions surrounding them. In patients with haematogenous spread caseating granulomas may be seen in the parenchyma of ovary (7,32). Tuberculosis of Cervix Tuberculosis of the cervix may be seen in five to fifteen per cent cases of genital TB (5). Cervix mostly gets affected by downward spread of the disease from the endometrium. However, rarely cervical disease may occur secondary to deposition of infected semen by the male partner (29). Mostly, cervical lesions tend to be hypertrophic resembling cervical carcinoma (38) and less often an ulcerative lesion may be seen (32). Microscopic examination reveals granulomatous inflammation. Inflammatory atypia with frequent hyperplastic mucosal changes may be seen along with caseation (1). The endocervical involvement is common (32) and may explain increased mucus production. Cervical TB has been diagnosed cytologically by various workers (39-41). Multinucleated giant cells, histiocytes, epithelioid cells arranged in clusters simulating the appearance of granulomas are characteristic of the disease in Papanicolaou smear examination. Cytological diagnosis of genital TB in association with carcinoma in situ and Trichomonas vaginalis has been described (40,41). Tuberculosis of the Vagina, Vulva and Bartholin Gland Tuberculosis of the vulva and vagina occurs in one per cent of cases (5). Tuberculosis of Bartholin gland and vesicovaginal fistula due to genital TB has been described (42,43). Involvement of the vagina or vulva is usually secondary to the involvement of other parts of genital tract. However, transmission of the disease by a male partner due to involvement of epididymis or seminal vesicles has been reported (28). Lesions on vulva and vagina may present as hypertrophic lesions resembling malignancy, less often nonhealing ulcers in the vulva may be seen. Histopathological examination of the lesion is useful in confirming the diagnosis.

CLINICAL PRESENTATION Symptoms The most frequent presenting symptoms in patients with female genital TB include infertility, pelvic pain, menstrual disturbances, vaginal discharge and poor general condition [Table 31.2]. However, none of these are specific for female genital TB. Infertility Primary and secondary infertility are the most common presenting symptoms in patients with female genital TB. All reported series have identified this association [Table 31.2]. Chronic Lower Abdominal or Pelvic Pain Chronic lower abdominal or pelvic pain is the second most common symptoms in patients with female genital TB [Table 31.2]. Pain is non-characteristic and is usually localized in the lower abdomen or pelvis. Pain tends to be chronic and is usually dull aching. Occasionally, acute pain may occur similar to that of acute pelvic inflammatory disease or a twisted pelvic organ. Episodes of acute pain, as a result of superadded bacterial infection, can occur and require administration of antibiotics. Acute episodes of pain may occur after diagnostic procedures, such as endometrial biopsy, dilatation and curettage or hysterosalpingography [HSG]. Patients with chronic pain are more likely to have abnormal findings on pelvic examination. Alterations in Menstrual Pattern All types of menstrual irregularities, such as amenorrhoea, menorrhagia, oligomenorrhoea or even postmenopausal bleeding can occur [Table 31.2]. Persistent and Abnormal Vaginal Discharge Occasionally, patients with persistent vaginal discharge may be found to have genital TB affecting cervix or vagina (38-40). Such a symptom is more likely to occur in women with endocervical TB or in patients with TB of the cervix or vagina. Unusual Symptoms Several unusual symptoms as presentation of female genital TB have been described from time to time. These

Female Genital Tuberculosis 453 Table 31.2: Clinical presentation of patients with genital tuberculosis Study (reference)

No. of patients

Infertility

Amenorrhoea

Menorrhagia or Postmenopausal Oligomenorrhoea bleeding

Chronic pelvic pain

Sutherland (18)

250

40

10

18

20

ND

Malkani and Rajani (13)

106

ND

43.4

43

ND

ND

Mukherjee et al (44)

138

100

ND

ND

Munjal et al (36)

140

Klein et al (4)

20

Falk et al (10)

187

Bazaz-Malik et al (3)

19.7

42.8

41.4

1.4

ND

70

20

ND

ND

30

12.8

41.2

ND

ND

ND

47

26

337

58.6

26.4

Chhabra (26)

58

29.3

Sfar et al (45)

118

Bohate et al (12)*

1000

60

37.1

18.9

81

15 ND 15.5

ND

ND

1.0 ND 3.4 ND

2.4 ND 43.1 ND

Saracoglu et al (23)

72

47

11

ND

ND

32

Gupta et al (15)

40

40

10

40

ND

20

All values are shown as percentages * These series included patients with tuberculosis endometritis only ND = not described

include vulval lesions, Bartholin gland swelling (42), vesicovaginal fistula (43), pelvic masses (46), uterocutaneous fistula (47), retention of urine due to pelvic masses of TB origin (48). Miranda et al (49) described a case where pelvic TB presented as an asymptomatic pelvic mass with rising levels of serum cancer antigen-125 [CA-125]. Physical Signs No physical sign on abdominal or pelvic examination is characteristic of genital TB. A high index of suspicion is, therefore, required to make an early diagnosis. Minimal induration in adnexal areas on both sides is the most commonly noted physical finding during pelvic examination in these patients. However, it is not specific for female genital TB. Bilateral tubo-ovarian masses, especially in nullipara or unmarried girls in the absence of fever should raise a strong suspicion of genital TB (5). Sutherland (2), in a large series of patients over a 30-year period, found a decreasing incidence of palpable adnexal masses. Falk et al (10), in a series of 187 patients from 47 Swedish hospitals, found tubo-ovarian masses in 46 patients. However, on exploration, five of these 46 patients had adnexal malignancy and two had benign ovarian tumours. Lack of tenderness during palpation may be an indication of TB mass (46). Physical examination may be entirely normal in 31.6 to 50 per cent cases (24,50).

Presence of ascites or doughy feel of the abdomen especially in young unmarried girls with low-grade fever and alteration in menstrual pattern should raise suspicion of genital TB. Enlargement of uterus due to pyometra especially in a postmenopausal patient may be due to pelvic TB (48,51). Tuberculosis of cervix, vagina and vulva usually presents as hypertrophic or ulcerative lesions. Biopsy helps to differentiate such a lesion from malignancy. DIAGNOSIS As genital TB is a pauci-bacillary disease, it is not possible to demonstrate Mycobacterium tuberculosis in every case. Therefore, one has to rely on imaging and histopathology. Endometrial biopsy for histopathological examination and mycobacterial culture remain the most commonly used procedures for the diagnosis of female genital TB. Laparoscopy, HSG, ultrasonography of pelvic organs, computed tomography [CT] and magnetic resonance imaging [MRI] are other investigative procedures which are carried out if the endometrial biopsy is not conclusive. Recently, a number of newer investigations, such as polymerase chain reaction [PCR] have been applied for the diagnosis of genital TB [Table 31.3] with variable results. However, diagnostic hysteroscopy and laparoscopy have emerged as the most useful investigations. These investigations not only facilitate the visual

454

Tuberculosis

examination of the lesions and confirmation of the diagnosis, but also help in picking up unsuspected pathology such as endometriosis or malignancy in a number of cases.

or by dilatation of the cervix and curettage of the endometrium [D and C] is useful for the diagnosis of TB [Figure 31.1]. Best time to perform such a procedure is shortly before the menstruation (5) as lesions are likely to be close to surface of endometrium during this phase of the menstrual cycle. Histopathologically proven TB is present in 50 to 76 per cent patients with genital TB [Table 31.4]. In the absence of granulomas and caseation necrosis, other features such as dilatation of glands, destruction of epithelium and presence of inflammatory cells are seen on histopathology (3). Malkani and Rajani (13) suggested that the focal collection of chronic inflammatory cells or presence of proliferative endometrium in the premenstrual week in a patient with past history of TB in other parts of the body or a family history of TB would favour a diagnosis of female genital TB. A negative endometrial biopsy does not rule out the pelvic involvement since sampling errors are common and disease may have involved other pelvic organs without associated TB endometritis (1).

Endometrial Biopsy

Mycobacterial Isolation

Endometrial tissue obtained by endometrial biopsy curette or by aspiration with a plastic disposable cannula

Endometrial biopsy specimen, menstrual blood, cervical and vaginal secretions, tubal biopsy material or

Table 31.3: Diagnostic modalities for female genital tuberculosis Site

Diagnostic procedures

Fallopian tube

Laparoscopy, hysterosalpingography, peritoneal fluid for Mycobacterium tuberculosis smear and culture, tubal biopsy, serological tests Endometrial histology Endometrial smear and culture for Mycobacterium tuberculosis Hysteroscopy Menstrual blood culture for Mycobacterium tuberculosis Biopsy Exfoliative cytology Biopsy

Endometrium

Cervix Vagina and vulva

Table 31.4: Comparison of the mycobacterial culture and histopathological examination of endometrium in the diagnosis of female genital tuberculosis Study (reference) Malkani and Rajani et al (13) Halbrecht and Tiqva (52) Klien et al (4)

No. of patients

Culture positive

HPE positive

Both culture and HPE positive

57

17.5

100.0

*

103

36.9

10.6

52.5

20

37.5†

62.5†

ND

1436

100.0‡

76.1§

ND

Falk et al (10)

187

29.4

69.5

ND

Chhabra et al (53)

150

6.0

6.7

Sfar et al (45)

118

7.0

46.0

Roy et al (19)

800

10.9

9.8

40

2.5

Nogales-Ortiz et al (29)

Gupta et al (15)

Positive yield is shown as percentage All values have been corrected to first decimal place * 57 endometrial biopsy proven patients were included in the study † Culture and histopathology yield available for 16 patients ‡ Culture yield available for 30 patients § Histopathology yield available for 201 patients ND = not described; HPE = histopathological examination

25

1.3 ND 11.8 2.5

Female Genital Tuberculosis 455 peritoneal fluid obtained during diagnostic laparoscopy have been subjected to mycobacterial smear and culture examination (4,10,13,54-56). Endometrial Culture versus Histopathology A number of studies have evaluated histopathology and mycobacterial culture for the diagnosis of endometrial TB [Table 31.4]. Most studies have found a higher diagnostic yield with histopathological examination of endometrium than culture of biopsy material (10). Hysterosalpingography The HSG visualization of uterine cavity and fallopian tubes by injecting a radio-opaque contrast medium into the uterus through cervix is routinely performed for investigation of infertility [Figure 31.2]. A number of findings on HSG may suggest genital tract TB (57,58). The HSG performed during the acute stage of the disease may, however, result in exacerbation of the disease and is, therefore, contraindicated. Winifred (59) noted such an event in four of the fourteen cases subjected to HSG. Seigler (60) reported fever as the most common complication following HSG. Serious pelvic infections have been reported in 0.3 to 1.3 per cent cases (60). Magnusson (61) described two typical forms of the disease based upon HSG findings: [i] ragged and jagged tubal contour with small lumen defects [Figure 31.3]; and [ii] straight rigid contour of the lumen with stem pipelike configuration of the tube. Seigler (62) described rigid

tubes, irregular tubal outline, calcification of the tubes and ovary, filling defects in the line of tubal shadow and fistulous tracts on HSG as suggestive of TB . Rozin (63) has described several radiographic signs that were presumptive of TB. These include: [i] golf club appearance, when only isthmus and proximal ampulla are visualized, isthmic segment has a rigid stove pipe appearance [Figure 31.4]; [ii] a beaded appearance due to alternate areas of tube filled with and without radiographic contrast [Figure 31.5]; [iii] maltese cross appearance, completely filled tube with rigid, irregular outline [Figure 31.6]; [iv] rosette appearance, where the

Figure 31.2: Hysterosalpingogram with normal findings. The uterine cavity has a normal outline. Both the fallopian tubes are outlined with free peritoneal spill of radio-opaque contrast

Figure 31.4: Hysterosalpingogram showing rigid stove pipe-like appearance of the fallopian tubes. There is a small area of irregularity along the right uterine wall

Figure 31.3: Hysterosalpingogram showing ragged and jagged contour of the tube. Only one tube could be visualized in this case. Terminal end of the tube presents leopard skin-like speckled appearance

456

Tuberculosis

distal end of tube is filled with dye [Figure 31.7]; [v] numerous diverticula in isthmic area; and [vi] leopard skinlike speckled appearance, of the ampulla due to tube being partially filled with the contrast [Figure 31.3]. The presence of calcified tubes, ovary or pelvic lymph nodes is considered as the most significant finding. In addition, uterine cavity may be shrivelled and deformed [Figure 31.8]. The tubes may be patent in 37 per cent of cases with TB endometritis (64).

Figure 31.7: Hysterosalpingogram showing dilated portion of the left fallopian tube without any spill of dye. Only proximal part of the right fallopian tube is seen

Laparoscopy and Hysteroscopy

Figure 31.5: Hysterosalpingogram showing irregular uterine outline and patchy filling of the dye in the right fallopian tube resulting in beaded appearance

Figure 31.6: Hysterosalpingogram showing completely filled tube on the right side with a rigid outline. Dilatation of the distal half of the left tube with doubtful spill of the contrast is seen. A small filling defect is also seen in the uterine cavity

Laparoscopy and hysteroscopy are important procedures in the diagnostic work-up of patients with infertility. Laparoscopy provides direct visualization of the pelvic organs and peritoneal surfaces. In addition, it helps in confirming tubal patency. A number of observations may be made during laparoscopy in these cases. These include endometriosis, pelvic inflammatory disease or fibroids. Despite normal physical examination, several abnormalities can be detected in about 60 per cent of the cases during laparoscopy (65) [Figures 31.9A, 31.9B, and

Figure 31.8: Hysterosalpingogram showing extensive extravasation of radio-opaque contrast in pelvic vessels. Fallopian tubes are not visualized indicating bilateral cornual occlusion

Female Genital Tuberculosis 457 31.9C]. Diagnostic yield of laparoscopy in patients with infertility due to suspected female genital TB has been documented in several studies [Table 31.5]. Based upon various laparoscopic findings and guided biopsy, Palmer and Olivera (67) have described a subacute and chronic stages in the natural history of pelvic TB. Subacute Stage The subacute stage of female genital TB is characterized by the presence of whitish-yellow and opaque miliary granulations, surrounded by hyperaemic areas over the fallopian tubes and uterus. The pelvic organs may be congested, red and oedematous with adhesions. Multiple fluid filled pockets may also be seen. Figure 31.9C: Laparoscopic view of pelvis in a patient with pelvic tuberculosis showing tubercles on the surface of uterus and fluid in the Pouch of Douglas

Table 31.5: Incidence of genital tuberculosis at laparoscopy Study (reference)

No. of patients

Incidence (%)

Krishna et al (9)

697

Deshmukh et al (8)

500

10.3 9.0

Merchant (66)

687

14.1

Gupta et al (15)

150

26.7

Chronic Stage Figure 31.9A: Laparoscopy view in a patient with pelvic tuberculosis showing vascular adhesions on the posterior surface of uterus. The fallopian tube is congested and oedematous with tobacco pouch appearance of the fimbrial end

The chronic stage of female genital TB is recognized by the presence of the following findings. Nodular salpingitis A series of yellow coloured small nodes may be seen on a normal looking tube. Patchy salpingitis Short and swollen tubes with agglutinated fimbriae may be seen. Hydrosalpinx Fallopian tubes are distended at their terminal end due to agglutination of fimbriae. These tubes tend to be “retort shaped”. Bilateral involvement of the tubes is almost always seen. Caseosalpinx Ampulla of the tube is deformed by an ovoid dilatation which is whitish-yellow with poor vascularization. The tube is distended with caseous material. This finding also tends to be bilateral.

Figure 31.9B: Laparoscopic view of pelvis in a patient with pelvic tuberculosis showing surface tubercles on pelvic organs. Distal end of the tube is dilated

Adhesions Bands of adhesions may be seen between loops of intestine and the omentum. Sometimes broad bands may mask the whole adnexae. Laminar adhesions

458

Tuberculosis

covering the tubes and ovary and fixing them, are occasionally seen in the chronic phase of genital TB. Tripathy and Tripathy (20) performed laparoscopy in 62 sputum smear-positive pulmonary TB patients. They found bands of adhesion, tubercles and hyperaemia in 59.6 per cent cases and intestinal adhesions in 24.2 per cent patients. Tubercles were observed on the fallopian tubes in 22.6 per cent cases and adhesions in the pouch of Douglas were evident in 11.3 per cent patients. Bhide et al (68), in a laparoscopy study of 71 patients with genital TB, reported pelvic adhesions in 48 per cent, tubercles in 33.8 per cent, unilateral adnexal mass in 11.3 per cent and bilateral adnexal masses in 21.1 per cent patients. Further, encysted effusion [8.45%] and lesions on the bowel and/or omentum [25.4%] were also observed. Marana et al (69), in a laparoscopy study of 254 patients with primary or secondary infertility from Italy, found tubal factor to be responsible in 101 patients. Of these, only two patients had histopathological and culture-positive endometrial TB. In a third patient with laparoscopic findings suggestive of TB, the organisms were cultured from urine. In a recent study on female genital TB in infertile women from New Delhi [n = 40] (15), laparoscopic examination revealed abnormally dilated, tortuous, and blocked fallopian tubes [n = 13]; peritubal and periovarian adhesions [n = 18]; Fitz-HughCurtis syndrome [n = 15]; omental adhesions [n = 18]; and bowel adhesions [n = 15]. Hysteroscopy revealed flimsy intrauterine adhesions [n = 7]. Hysteroscopic observations also suggest that the female genital TB is an important cause of Asherman’s syndrome in India (70). The frequent use of laparoscopy and hysteroscopy has made it possible to diagnose a number of cases of genital TB among women with infertility and chronic pelvic pain.

has encountered a number of patients with infertility or chronic pelvic pain with adnexal masses and free fluid in the pelvis on ultrasonography who were found to have genital TB on subsequent investigations [Figure 31.10]. Computed Tomography A number of findings have been described on CT as suggestive of abdominal and pelvic TB. These include low density ascites, uncommon patterns of adenopathy, presence of multiple pelvic lesions, hepatic, adrenal and splenic lesions. Though these lesions may mimic malignancy, they should raise a suspicion of TB especially if they encountered in young patients suffering from infertility (72). Magnetic Resonance Imaging Magnetic resonance imaging is being increasingly used for evaluating pelvic and other abdominal masses [Figures 31.11A and 31.11B] and has been found to be useful in localizing soft tissue abnormalities in patients with female genital TB (73). Serodiagnosis Due to a low positivity rate of demonstration of Mycobacterium tuberculosis in smear and culture in patients with female genital TB, there has been a search

Ultrasonography Ultrasonography, being non-invasive with no radiation hazard, has been increasingly used in evaluating pelvic and other abdominal masses. Lee et al (71) described sonographic features of TB endometritis in a 59-year-old female. Demonstration of bilateral, predominantly solid, adnexal masses containing scattered small calcifications is highly indicative of TB involvement (72). The author

Figure 31.10: Ultrasonography in pelvic tuberculosis. A longitudinal scan in a 33-year-old parous woman with a history of oligomenorrhoea. The scan shows fluid collection in the Pouch of Douglas [asterisk]. Investigations confirmed the diagnosis of genital tuberculosis

Female Genital Tuberculosis 459

Figure 31.11A: Magnetic resonance imaging in pelvic tuberculosis. Post-gadolinium T1-weighted coronal scan in a 26-year-old nullipara with history of chronic pelvic pain unresponsive to usual treatment. Hypointense masses with rim enhancement [arrows] abutting the left pelvic wall and tracking to subgluteal region suggestive of abscesses

for serological tests to diagnose the disease in these patients. A number of reports on serological tests for diagnosis of TB have appeared in the literature. Early promising results have repeatedly given way to a low specificity. Polymerase Chain Reaction The PCR is a useful supporting test for the diagnosis of female genital TB (15,74,75). Used judiciously, the PCR can help in the diagnosis of TB in certain clinical situations. In a double-blind study (75) from New Delhi, India, endometrial aspirates, endometrial biopsies, fluid from the Pouch of Douglas were investigated for the presence of the mpt64 gene of Mycobacterium tuberculosis by PCR in 25 women with infertility and the PCR results were correlated with laparoscopic findings (71). The PCR was positive in 14 out of 25 patients [56%], compared to one smear with acid-fast bacilli [1.6 %] and two culturepositive samples [3.2%]. All patients with laparoscopy findings suggestive of TB, 60 per cent of those with a probable diagnosis and 33 per cent of those with incidental findings were positive by PCR. However, one

Figure 31.11B: Magnetic resonance imaging T1-weighted coronal scan of the same patient one year after antituberculosis treatment. Scan shows complete resolution of abscesses

endometrial aspirate sample from an infertile patient with normal laparoscopy was also positive. Multiple sampling from different sites increased the diagnostic yield by the PCR. The reader is referred to the chapter “Laboratory diagnosis” [Chapter 10] for more details. TREATMENT Treatment of genital TB is similar to treatment of TB elsewhere in the body. Availability of effective antituberculosis drugs has significantly decreased the requirement for surgical treatment in patients with female genital TB. In India, patients with female genital TB receive DOTS under the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India. The reader is referred to the chapters “Treatment of tuberculosis” [Chapter 52], and Revised National Tuberculosis Control Programme” [Chapter 63] for more details. Prior to the availability of effective drug therapy, surgery produced a significant degree of morbidity and complications. These included bowel fistula [14%] and an operative mortality rate of 2.2 per cent (76). These complications are rarely seen now. Indications for surgical intervention in patients with female genital TB are shown in Table 31.6.

460

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Table 31.6: Indications for surgical intervention in genital tuberculosis Persistence or increase of pelvic masses after a six-month course of antituberculosis treatment Recurrence of positive endometrial culture or histology after a six-month course of antituberculosis treatment Persistence or recurrence of pain or bleeding after six-months of antituberculosis treatment Postmenopausal patient with a recurrent pyometra due to tuberculosis Adapted from reference 5

Minimal Genital Tuberculosis Minimal disease is usually asymptomatic, except for infertility and is diagnosed by finding TB endometritis on curettage or biopsy or tubercle bacilli on culture of the curettings of menstrual blood. The patient is started on standard antituberculosis treatment and is examined at monthly intervals. After six months, a procedure of dilatation and curettage is done and the endometrial curettings are examined histologically and bacteriologically. Wherever feasible, the patient should be followed up annually for an indefinite period of time as exacerbations have been reported up to 10 years after apparent cure before the advent of modern short-course treatment. This is highly unlikely with current therapy. Advanced Genital Tuberculosis Advanced genital TB is diagnosed by the presence of palpable tubo-ovarian masses and histopathologic or bacteriologic evidence of TB. The patient is started on standard antituberculosis treatment and is examined at monthly intervals. Schaefer (5) has suggested that, if palpable adnexal masses persist after six months of antituberculosis treatment, total abdominal hysterectomy and bilateral salpingo-oophorectomy are performed (5). However, there is no consensus regarding this view (5) as a number of these patients suffer from infertility and are also young. With reports of successful pregnancies in patients with female genital TB following in vitro fertilization and embryo transfer [IVF-ET] procedures (77), adequate therapy with standard antituberculosis treatment regimens is desirable before surgical intervention is undertaken.

Pregnancy Following Treatment of Female Genital Tuberculosis Full-term pregnancy is uncommon after treatment of histopathologically proven genital TB (78). From time to time occasional case reports have appeared about successful term pregnancies in patients with genital TB who have undergone treatment (79,80). If pregnancy takes place in a treated patient with female genital TB, it is more likely to result in ectopic pregnancy or abortion (81). Among 206 patients with female genital TB treated by Sutherland (82), 45 pregnancies were reported in 26 women. Of these, 11 were ectopic pregnancies and 11 pregnancies ended in abortions. Fourteen women had 23 live births (82). Merchant (66) in a study of 101 patients with female genital TB, diagnosed on laparoscopy, reported three ectopic pregnancies, 11 intrauterine pregnancies and nine term pregnancies. In two patients abortion was induced for medical reasons. Jindal et al (79) reported three pregnancies among 14 women with histopathologically proven endometrial TB. Falk et al (10) in a study of 187 patients from 47 Swedish hospitals reported four ectopic pregnancies and no intrauterine pregnancy after antituberculosis treatment. Saracoglu et al (23), in a series of 72 patients with pelvic TB from Turkey, reported one intrauterine pregnancy without any surgical or medical treatment of pelvic TB. Tuboplasty Since infertility is the most common symptom in patients with genital TB, reconstructive tubal surgery is often performed after adequate medical treatment. Reactivation of silent pelvic TB following tuboplasty procedure has been reported by Ballon et al (83). Schaefer (5) advocates against such procedures in patients with female genital TB. In Vitro Fertilization In the last few years a number of reports have appeared in the literature highlighting the role of in vitro fertilization in patients with treated female genital TB (77,84). However, the results of IVF-ET have been disappointing in patients with female genital TB as compared to the success rates observed in non-TB tubal factors.

Female Genital Tuberculosis 461 REFERENCES 1. Anderson JR. Genital tuberculosis. In: Jones HW, Wentz AC, Burnett LS, editors. Novak’s text book of gynecology. Eleventh edition. Baltimore: Williams and Wilkins; 1988.p.557-69. 2. Sutherland AM. The changing pattern of tuberculosis of the female genital tract. A thirty-year survey. Arch Gynaecol 1983;234:95-101. 3. Bazaz-Malik G, Maheshwari B, Lal N. Tuberculous endometritis: a clinicopathological study of 1000 cases. Br J Obstet Gynecol 1983;90:84-6. 4. Klein TA, Richmond JA, Mishell DR Jr. Pelvic tuberculosis. Obstet Gynecol 1976l48:99-104. 5. Schaefer G. Female genital tuberculosis. In: Zuspan FP, Quillingan EJ, editors. Current therapy in obstetrics and gynecology. Fourth edition. Philadelphia: W.B. Saunders Company; 1994.p.51-5. 6. Goldin AG, Baker WT. Tuberculosis of the female genital tract. J Ky Med Assoc 1985;83:75-6. 7. Schaefer G. Female genital tuberculosis. Clin Obstet Gynecol 1976;19:223-39. 8. Deshmukh KK, Lopez JA, Naidu TAK, Gaurkhede MD, Kashbhawala MV. Place of laparoscopy in pelvic tuberculosis in infertile women. Arch Gynecol 1985;237[Suppl]:197. 9. Krishna UR, Saathe AV, Mehta H, Wagle S, Purandare VN. Tubal factors in sterility. J Obstet Gynecol India 1979;29: 663-7. 10. Falk V, Ludviksson K, Agren G. Genital tuberculosis in women. Analysis of 187 newly diagnosed cases from 47 Swedish hospitals during the ten-year period, 1968 to 1977. Am J Obstet Gynecol 1980;138:974-7. 11. Gupta S. Pelvic tuberculosis in women. J Obstet Gynecol India 1956;7:181-98. 12. Bobhate SK, Kadar GP, Khan A, Grover S. Female genital tuberculosis. A pathological appraisal. J Obstet Gynecol India 1986;36:676-80. 13. Malkani PK, Rajani CK. Endometrial tuberculosis. Indian J Med Sci 1954;8:684-97. 14. Dam P, Shirazee HH, Goswami SK, Ghosh S, Ganesh A, Chaudhury K, et al. Role of latent genital tuberculosis in repeated IVF failure in the Indian clinical setting. Gynecol Obstet Invest 2006;61:223-7. Epub 2006 Feb 13. 15. Gupta N, Sharma JB, Mittal S, Singh N, Misra R, Kukreja M. Genital tuberculosis in Indian infertility patients. Int J Gynaecol Obstet 2007;97:135-8. Epub 2007 Mar 23. 16. Shaheen R, Subhan F, Tahir F. Epidemiology of genital tuberculosis in infertile population. J Pak Med Assoc 2006;56:306-9. 17. Seiglar AM. Female genital tuberculosis and the role of HSG. Infertility 1984;7:175-86. 18. Sutherland AM. Functional uterine hemorrhage. A critical review of literature since 1938. Glasgow Med J 1949;30:1-28. 19. Roy A, Mukherjee S, Bhattacharya S, Adhya S, Chakraborty P. Tuberculous endometritis in hills of Darjeeling: a clinicopathological and bacteriological study. Indian J Pathol Microbiol 1993;36:361-9.

20. Tripathy SN, Tripathy S. Laparoscopic observation of pelvic organs in pulmonary tuberculosis. Int J Gynecol Obstet 1990;32:129-31. 21. Schaefer G. Tuberculosis of the female genital tract. Clin Obstet Gynecol 1970;13:965-98. 22. Gungorduk K, Ulker V, Sahbaz A, Ark C, Tekirdag AI. Postmenopausal tuberculosis endometritis. Infect Dis Obstet Gynecol 2007;2007:27028. Epub 2007 May 8. 23. Saracoglu OF, Mungan T, Tanzer F. Pelvic tuberculosis. Int J Gynecol Obstet 1992;37:115-20. 24. Devi PK. Genital tuberculosis in the female. J Indian Med Assoc 1962;38:164-6. 25. Haffeez MA, Tandon PL. Tubercular endometritits– a clinicopathologic study of 120 cases. J Indian Med Assoc 1966;46:610-16. 26. Chhabra S. Genital tuberculosis–a baffing disease. J Obstet Gynecol India 1990;40:569-73. 27. Rattan A, Gupta SK, Singh S, Takkar D, Kumar S, Bai P, et al. Detection of antigens of Mycobacterium tuberculosis in patients of infertility by monoclonal antibody based sandwiched ELISA assay. Tuber Lung Dis 1993;74:200-3. 28. Lattimer JK, Colmore HP, Sanger G, Robertson DH, McLellan FC. Transmission of genital tuberculosis from husband to wife via the semen. Am Rev Tuberc 1954;69:618-24. 29. Sutherland AM, Glean ES, MacFarlane JR. Transmission of genitourinary tuberculosis. Health Bull 1982;40:87-91. 30. Siegler AM, Kontopoulos V. Female genital tuberculosis and the role of hysterosalpingography. Semin Roentgenol 1979;14:295-304. 31. Schaefer G. Tuberculosis of the genital organs. Am J Obstet Gynecol 1965;14:295-304. 32. Nogales-Ortiz F, Tarancon I, Nogales FF Jr. The pathology of female genital tuberculosis–a 31-year study of 1436 cases. Obstet Gynecol 1979;53:422-8. 33. Daly JW, Monif GRG. Mycobacteria. In: Monif GRG, editor. Infectious diseases in obstetrics and gynaecology. Second edition. Philadelphia: Harper and Row; 1982.p.301. 34. Oosthuizen AP, Wessels PH, Hefer JN. Tuberculosis of the female genital tract in patients attending an infertility clinic. S Afr Med J 1990;77:562-4. 35. Czernobilsky B. Endometritis and infertility. Fertil Steril 1978;30:119-30. 36. Munjal S, Tandon PL, Hafeez MA. Tuberculous endometritis [clinicopathological study of 140 cases]. J Obstet Gynecol India 1970;20:106-11. 37. Bourno AW, Williams LH, editors. Recent advances in obstetrics and gynaecology. Tenth edition. London: J and AA Churchill; 1962.p.285-318. 38. Chahtane A, Rhrab B, Jirari A, Ferhati D, Kharbach A, Chaoui A. Hypertrophic tuberculosis of the cervix. Three cases. J Gynecol Obstet Biol Reprod Paris 1992;21:424-7. 39. Angrish K, Verma K. Cytologic detection of tuberculosis of the uterine cervix. Acta Cytol 1981;25:160-2. 40. Bhambani S, Das DK, Singh V, Luthra UK. Cervical tuberculosis with carcinoma in situ: a cytodiagnosis. Acta Cytol 1985;29:87-8. 41. Kumar N, Kapila K, Verma K. Cervical tuberculosis coexisting with Trichomonas vaginalis. Acta Cytol 1989;33:945-6.

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42. Dhall K, Das SS, Dey P. Tuberculosis of Bartholin’s gland. Int J Gynecol Obstet 1995;48:223-4. 43. Ba-Thike K, Than-Aye, Nan OO. Tuberculous vesicovaginal fistula. Int J Gynecol Obstet 1992;37:127-30. 44. Mukherjee K, Wagh KV, Agarwal S. Tubercular endometritis in primary infertility. J Obstet Gynecol India 1967;17:619-24. 45. Sfar E, Ourada C, Kharouf M. Female genital tuberculosis in Tunisia. Apropos of 118 cases at the Rabta Neonatology and Maternity Center in Tunis [January 1984-December 1988]. Rev Fr Gynecol Obstet 1990;85:359-63. 46. Jones NC, Savage EW, Salem F, Yeager C, Davidson EC Jr. Tuberculosis presenting as a pelvic mass. J Natl Med Assoc 1981;73:758-61. 47. Malhotra D, Vasisht K, Srinivasan R, Singh G. Tuberculous uterocutaneous fistula–a rare postcaesarean complication. Aust NZ J Obstet Gynecol 1995;35:342-4. 48. Yanagizawa R, Inoue S, Itakura H, Kishi H, Fujimaaru J, Wada Y. A case of urinary retention due to tuberculous pyometra. Nippon Hinyokika Gakkai Zasshi 1992;83:690-3. 49. Miranda P, Jacob AJ, Rosef L. Pelvic tuberculosis presenting as an symptomatic pelvic mass with rising serum CA-125 levels – a case report. J Reprod Med 1996;41:273-5. 50. Sutherland AM. Postmenopausal tuberculosis of the female genital tract. Obstet Gynecol 1982;59:6[Suppl]:548-78. 51. Schaefer G, Marcus RS, Kramer EE. Postmenopausal endometrial tuberculosis. Am J Obstet Gynecol 1972;112: 681-7. 52. Halbrecht I, Tiqva P. The relative value of culture and endometrial biopsy in the diagnosis of genital tuberculosis. Am J Obstet Gynecol 1958;75:899-903. 53. Chhabra S, Narang P, Gupte N. A study of 150 cases of endometrial cultures for Mycobacterium tuberculosis. J Obstet Gynecol India 1986;36:146-9. 54. Seward PGR, Mitchel RW. Guinea pig inoculation and culture for mycobacteria in tuberculosis in infertile women. A study of cost effectiveness. S Afr Med J 1985;67:126-7. 55. Morris CA, Norma Boxall F, Cayton HR. Genital tract tuberculosis in subfertile women. J Med Microbiol 1970;3: 85-90. 56. Sheth SS. Lack of diagnostic value of guinea pig test for tuberculosis. Lancet 1990;336:1440. 57. Robinson SA, Shapira AA. The value of hysterosalpingography. N Engl J Med 1931;205:380. 58. Rioux JE, Yuzpee AA. HSG in diagnosis of tuberculosis. Contempt Obstet Gynecol 1981;17:184. 59. Winifred JAF. Female genital tuberculosis. J Obstet Gynecol Br Common 1964;71:418-28. 60. Seigler AM. Hysterosalpingography. Fertil Steril 1983;40:13958. 61. Magnusson WP. Liber das rant genbild ber tuberculoser slpingitus. Acta Radiol 1945;25:263. 62. Seigler AM. Tuberculosis of uterine tubes. A roentgenologic study of eight cases. Obstet Gynecol 1955;6:180-5. 63. Rozin S. The X-ray diagnosis of genital tuberculosis. J Obstet Gynecol Br Empire 1952;59:59-63. 64. Sharman A. Genital tuberculosis in the female. J Obstet Gynecol Br Empire 1952;59:740-2.

65. Ambiya VR, Sarogi RM, Rawal MY. Diagnostic laparoscopy. J Obstet Gynecol India 1981;31:623-5. 66. Merchant R. Endoscopy in the diagnosis of genital tuberculosis. J Reprod Med 1989;34:468-74. 67. Palmar R, Olivera EM. Coelioscopy and coelioscopic biopsies in latent genital tuberculosis. In: Wenner R, Rippman ET editor. Latent female genital tuberculosis. Basel: Karger; 1966.p.143. 68. Bhide AG, Parulekar SV, Bhattacharya MS. Genital tuberculosis in females. J Obstet Gynecol India 1987;37:576-8. 69. Marana R, Muzii L, Lucisano A, Ardito F, Muscatello P, BilancioniE, et al. Incidence of genital tuberculosis in infertile patients submitted to diagnostic laparoscopy: recent experience in an Italian University Hospital. Int J Fertil 1991;36: 104-7. 70. Sharma JB, Roy KK, Pushparaj M, Gupta N, Jain SK, Malhotra N, et al. Genital tuberculosis: an important cause of Asherman’s syndrome in India. Arch Gynecol Obstet 2008;277:37-41. Epub 2007 Jul 25. 71. Lee J, Warner L, Khalleghian R. Sonographic features of tuberculous endometritis. J Clin Ultrasound 1983;11:331-3. 72. Walzer A, Koenigsberg M. Ultrasonographic demonstration of pelvic tuberculosis. J Ultrasound Med 1983;2:139-40. 73. Bankier AA, Fleischmann D, Wiesmayr MN, Putzd, Konstrus M, Hubsch P, et al. Update: abdominal tuberculosis-unusual findings on CT. Clin Radiol 1995;50:223-8. 74. Manjunath N, Shankar P, Rajan L, Bhargava A, Saluja S, Shriniwas. Evaluation of a polymerase chain reaction for the diagnosis of tuberculosis. Tubercle 1991;72:21-7. 75. Bhanu NV, Singh UB, Chakraborty M, Suresh N, Arora J, Rana T, et al. Improved diagnostic value of PCR in the diagnosis of female genital tuberculosis leading to infertility. J Med Microbiol 2005;54:927-31. 76. Jodberg H. A study on genital tuberculosis in women. Acta Obstet Gynecol Scand 1950;31[Suppl]:7-176. 77. Gurgan T, Urman B, Yarali H. Results of in vitro fertilization and embryo transfer in women with infertility due to genital tuberculosis. Fertil Steril 1996;65:367-70. 78. Tripathy SN, Tripathy SN. Infertility and pregnancy outcome in female genital tuberculosis. Int J Gynaecol Obstet 2002;76: 159-63. 79. Jindal UN, Jindal SK, Dhall GI. Short–course chemotherapy for endometrial tuberculosis in infertile women. Int J Gynecol Obstet 1990;32:75-6. 80. Schaefer G. Full-term pregnancy following genital tuberculosis [review]. Obstet Gynecol Surv 1964;19:81-124. 81. Varma TR. Genital tuberculosis and subsequent fertility. Int J Gynecol Obstet 1991;35:1-11. 82. Sutherland AM. The treatment of tuberculosis of the female genital tract with streptomycin, PAS and isoniazid. Tubercle 1976;57:137-44. 83. Ballon SC, Clewell WH, Lamb EJ. Reactivation of silent pelvic tuberculosis by reconstructive tubal surgery. Am J Obstet Gynecol 1975;122:991. 84. Parikh FR, Nandkarni SG, Kamat SA, Naik S, Soonawala SB, Parkh RM. Genital tuberculosis – a major pelvic factor causing infertility in Indian women. Fertil Steril 1997;67:497-500.

Genitourinary Tuberculosis 463

Genitourinary Tuberculosis

32 AK Hemal

INTRODUCTION Genitourinary tuberculosis [TB] is still a major problem in developing countries. Nearly all patients can be cured by effective antituberculosis treatment if the disease is diagnosed early. However, more often than not, the diagnosis is delayed, and a number of patients present with non-functioning kidney, ureteric stricture and shrunken urinary bladder. Early diagnosis and treatment of genitourinary TB is important because undiagnosed and untreated disease can result in renal failure and death. EPIDEMIOLOGY With the advent of modern chemotherapy and effective treatment of pulmonary TB, the incidence of genitourinary TB has shown a decline in the developed world. However, genitourinary TB remains to be a major problem in the developing world. Urogenital TB complicates three to four per cent of all cases of pulmonary TB and constitutes at least 30 per cent of all cases of extra-pulmonary disease (1-3). Medlar (4) found bilateral renal cortical lesions in patients with pulmonary TB and suggested haematogenous spread from the primary lesion in the lungs. Colabawalla (5) in a multicentric study from India reported the incidence of TB to be in 10 to 34 per cent in patients with various urological diseases. In a study conducted by the Indian Council of Medical Research in 2240 patients suspected to have urinary tract TB, the incidence of microbiological and/or histopathological proven diagnosis of TB was 10.7 per cent (6).

Acquired immunodeficiency syndrome [AIDS] has caused a worldwide resurgence of TB. Tuberculosis occurs in approximately 10 per cent of patients with AIDS and involves at least one extra-pulmonary site in nearly 50 per cent of the cases (7), with kidney being the most common genitourinary site of involvement (8). Therefore, a proportional increase in urogenital TB can be expected after an appropriate latent period, especially if survival rates in patients with AIDS improve. PATHOGENESIS Mycobacterium tuberculosis is the usual cause of urinary tract TB. Haematogenous dissemination from an active site of infection [often pulmonary] leads to the formation of metastatic lesions in the kidneys. The bacilli are initially disseminated throughout the cortices of both kidneys and form microscopic granulomas (9). The intensity of infection depends upon the infecting dose, virulence of the organism and the resistance of the host. Macroscopic progression of the disease is mostly unilateral (10). Usually, these multiple tubercles heal either spontaneously or as a result of antituberculosis treatment administered to control the clinically active primary focus. Nevertheless, one or more tubercles may enlarge after years of inactivity and rupture into the nephrons producing bacilluria without a radiographic lesion (9). The bacilli descend along the nephrons and form more granulomas within the medulla and papilla. These granulomas may coalesce and form cavities which may communicate with the pelvicalyceal system [PCS] following rupture. They may also result in necrosis and sloughing. Tuberculomas in the renal parenchyma can

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result in displacement of the calyces without communicating with the PCS. The appearance of a renal mass can also be produced by localized hydrocalycosis due to stricture of the infundibular or calyceal neck. The bacilli when shed into urine infect the walls of the calyces leading to ulceration, granuloma formation and ultimately result in fibrosis with strictures. Early scarring is reversible by adequate steroid treatment, but end-stage fibrotic strictures are irreversible (8). These changes are summarized in Table 32.1. Renal TB progresses slowly and often silently. In addition to loss of renal parenchyma by caseation, intrarenal scars and infundibular strictures lead to obstruction and dilatation of segments of the PCS. The intrarenal scars may also cause sharp kinking of the renal pelvis with resultant obstruction. Urinary obstruction from the strictures and caseation of the renal parenchyma results in destruction of the kidney or its parts. Obstruction may predominate, in which case, massive hydronephrosis or hydrocalyx may be the final stage. If parenchymal caseation, necrosis and calcification predominate, the kidney will be destroyed. Usually, both the processes occur and may lead to a malfunctioning, calcified kidney [Figures 32.1A and 32.1B]. This process is called “autonephrectomy”. From the kidney, the disease passes to the perirenal tissues. The fat is greatly thickened and becomes densely adherent to the kidney. When the renal capsule bursts, a

Figure 32.1A: Plain X-ray of the kidney, ureter and bladder [KUB] showing calcified kidney [arrows] on the left side resulting in autonephrectomy

Table 32.1: Changes that occur in renal tuberculosis Early changes Papillary necrosis or papillitis Cavity formation From sloughed off papilla From rupture of abscess into the pelvi-calyceal system Strictures Cortical scars Caliectasis Biked up pelvis Hydronephrosis Pelvi-ureteric junction stricture causing back pressure changes Perinephric abscess Rupture of tuberculosis abscess into the perinephric space Pseudocalculi Due to calcification in the lesions Caseous masses Caseous transformation of renal lobes Diffuse miliary involvement Diffuse involvement of the kidney

Figure 32.1B: Intravenous urogram of same patient showing normally functioning kidney on the right side and calcified nonfunctioning kidney [arrow] on the left side

peri-nephritis occurs. Later, peri-ureteritis and perinephric abscess may follow. The cut surface of a TB kidney has the following characteristics: [i] the papillae are destroyed; [ii] the calyces are deeply ulcerated; [iii] yellowish, caseous, tuberculous masses may be seen at the base of pyramids;

Genitourinary Tuberculosis 465 and [iv] numerous cavities of varying sizes with ragged edges and containing creamy, sterile pus are seen in the cortex. Renal calcification is a major sequelae of the renal TB (11). Its aetiology remains obscure. These calcific shadows tend to be ill-defined and irregular in outline. They are neither as dense nor as well-defined as radio-opaque renal calculi. These lie in the cortex and strongly suggest the presence of TB. It is an unfavourable prognostic sign when non-surgical treatment is used. In spite of antituberculosis treatment, there is less likelihood of stable urinary conversion, and a greater propensity for deterioration of renal function. Radiographs should be repeated every six months to determine an increase in size of the calcification in which case surgical intervention may be indicated. Ureteric involvement occurs due to the antegrade flow of urine from an infected kidney. Tuberculosis of the ureter produces mucosal and wall ulceration, fibrosis, stricture and calcification. The ragged, saw-tooth ureter seen in ureteric TB develops due to multiple active ulcers and spasm of the ureteric wall. The bacilli also descend to the bladder, affecting the collecting system and ureter and cause obstruction, reflux or both due to involvement of ureteric orifices and intramural ureter (12). Gradually, the bladder becomes small and contracted and even a “thimble bladder” may develop. Stiffening or fibrosis of the bladder wall can result in compromise of the valve mechanism at the ureterovesical junction, leading to vesico-ureteric reflux or occasionally obstruction. Genital TB is almost always acquired by haematogenous dissemination from an extra-genital source (13,14). The most common primary site is the lung. Direct extension from an adjacent affected organ, such as urinary tract, may occur. The primary focus of genital TB in the female is the fallopian tube. Spread from the fallopian tube to the uterus can occur in up to 50 per cent of patients with tubal infection (15). Tuberculosis of the fallopian tubes can rarely occur as a sexually transmitted infection when a woman acquires the infection from a man with epididymal TB (14). In men, the prostate, seminal vesicles and epididymis may be involved, where caseating granulomas, abscesses and calcification may ensue (10). The bacilli may also descend rarely to the urethra and may result in

urethral stricture and periurethral abscess or fistula formation (9). CLINICAL PRESENTATION The clinical presentation of genitourinary TB is summarized in Table 32.2. Active urogenital disease usually occurs five to twenty years after primary pulmonary infection. Therefore, renal involvement is rare before the age of 20 years. The disease is usually encountered between the second and fourth decades of life. Genitourinary TB is rare in children and in persons over 50 years of age (1-6,16). In a recently published retrospective series from the All India Institute of Medical Sciences [AIIMS], New Delhi (17), 241 patients with genitourinary TB [mean age 34.6 years] were studied. Majority of them presented with irritative voiding symptoms. Azotaemia was seen in 54 [22.4%] cases. The most commonly involved organ was the kidney in 130 [53.94%] cases. Preoperative bacteriologic diagnosis was confirmed in 70 [29%] cases. In the author’s experience, the duration of clinical history did not correlate with the severity of the disease. Table 32.2: Clinical presentation of genitourinary tuberculosis Common Irritative voiding symptoms Haematuria Flank pain Renal mass Sterile pyuria Recurrent urinary tract infection Chronic renal failure Urinary calculi Acute presentation mimicking pyelonephritis Rare Non-healing wound, sinuses or fistula Spontaneous vesico-vaginal fistula “Hour-glass” bladder Haemospermia Suprapubic fistula Nephro-colo-cutaneous fistula

Tuberculosis of the Kidney Specific symptoms include dysuria, haematuria, frequency and nocturia. These symptoms worsen as TB cystitis develops. Backache, abdominal and flank pain are common and may occasionally be due to a renal cold

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abscess or perirenal abscess. These symptoms worsen with fluid overload and pelvicalyceal obstruction. Nonspecific constitutional symptoms, such as fever, anorexia, weight loss and anaemia may occur. Tuberculosis of the Ureter Tuberculosis ureteric stricture is a common complication of the disease and may be present at the time of diagnosis of renal TB. However, it often develops or progresses during otherwise effective treatment with antituberculosis agents. The most common site for TB stricture is ureterovesical junction followed by pelviureteric junction. Occasionally, the middle third of ureter is affected and rarely the entire ureter can be affected resulting in complete stenosis, fibrosis and even calcification. In the author’s experience (18), of 34 cases of ureteric stricture seen during a 10-year period, ureteric lesions occurred on the right side in 18 patients, on the left side in eight patients, while eight patients had bilateral lesions. The most common site of involvement was the lower ureter [n = 18], followed by middle [n = 7] and upper ureter [n = 4]. Five patients had extensive involvement including two patients with complete involvement of ureter. Of the eight patients with bilateral disease, five had deranged renal functions. Six patients had TB in the past and had received adequate antituberculosis treatment. One patient had discontinued treatment after a month of therapy.

becomes withdrawn, rigid and dilated assuming the “golf hole” appearance. The ureters become rigid in their lower third and give rise to ureteric reflux. With the use of modern chemotherapy, this is a rare occurrence now. Occasionally, whole of the bladder is covered by angrylooking inflammed, velvety granulations with ulcerations. Once the disease reaches this stage, it is unlikely that even with modern chemotherapy, there will be sufficient recovery of the bladder from the sequelae of the disease. Gradually, the bladder becomes small and contracted and even a “thimble bladder” may develop. Genital Tuberculosis Genital TB may present with painless haemospermia, scrotal pain and swelling or nodularity of the epididymis, vas deferens, seminal vesicle or prostate. Testicular involvement is rare. Chronic infection in any of these sites can lead to sinus formation, such as nephrocutaneous fistula, nephro-colo-cutaneous fistula, perineal fistula and vesico-vaginal fistula (19,20). In the female, infection of the ovaries, fallopian tube, endometrium, vagina and urethra may cause infertility, vaginal discharge, menstrual dysfunction, dyspareunia or pelvic pain. Generalized abdominal tenderness can occur due to pelvic abscess. Other presentations include hypertension from total or partial ischaemia of the kidney and chronic renal failure. Occasionally, calcification in the renal area may be detected on an abdominal radiograph. Tuberculosis of the Testis

Tuberculosis of the Urinary Bladder Bladder lesions are secondary to renal TB. The earliest form of infection starts around one or the other ureteric orifice which becomes red, inflammed and oedematous. Later, bullous granulations appear and completely obscure the ureteric orifice. Tuberculosis ulcers may be present, but they are rare and are a late finding. These ulcers are irregular in outline. They are superficial with a central inflammed area which is usually surrounded by raised granulations. In the initial stage, they are close to the ureteric orifices. However, as the disease progresses, they can appear in any part of the bladder. If the disease progresses further, the inflammation spreads deep and the muscle is eventually replaced by fibrous tissue. The fibrosis starts around the ureteric orifice, which contracts and can either produce a stricture or

Tuberculosis of the testis is always secondary to infection of the epididymis, which in most cases is haematogenous. Tuberculosis orchitis without epididymal involvement is very rare. If the orchitis is secondary to epididymal TB, the testicular lesion rapidly responds to chemotherapy after the epididymis has been removed, provided the destruction of the testicular tissue is not extensive. Tuberculosis of the Epididymis Foci of TB in the epididymis are caused by metastatic spread of the organisms through the blood stream. The disease usually starts in the globus minor, because of its rich blood supply than the other parts of the epididymis. Tuberculosis epididymitis may be the first and only presenting symptom of genitourinary TB (21,22). The

Genitourinary Tuberculosis 467 disease usually develops in young, sexually active males and in 70 per cent of patients there is a previous history of TB. The usual presentation is a painful, inflammed scrotal swelling. The globus minor alone is affected in 40 per cent of the cases. In extensive disease, there may be generalized epididymal induration with beading of the palpable vas deferens (21,22). Tuberculosis of the Prostate Tuberculosis of the prostate is rare. In many cases it is diagnosed by the pathologist or is found incidentally after a transurethral resection. Very rarely, the disease spreads rapidly and cavitation may lead to a perineal sinus (23). Advanced lesions may cause a reduction in the volume of semen, a sign that may help in the diagnosis. The route of infection may be either haematogenous or descending. On palpation most often the gland is nodular, non-tender and rarely enlarged, with soft areas being extremely uncommon. Sometimes, the chronic granulomatous inflammation of the prostate leads to caseation necrosis which heals by fibrosis or due to poor host defense results in cavitation and sloughing. This has been termed “autoprostatectomy” by the author (24). The transmission of genital TB from male to female is rare. This is quite surprising because many men with genital TB have Mycobacterium tuberculosis in the semen. This form of the disease is unlikely to be seen in the developed world, but it does appear in developing countries. A painful swollen inguinal gland in a woman, if it is proven to be TB, should alert the clinician to a possible diagnosis of genital TB in the male partner. The lesion responds well to antituberculosis treatment. Infertility is also one of the presentations. Tuberculosis of the Penis Tuberculosis of the penis is very rare. Earlier, it was seen as a complication of ritual circumcision, when it was the usual practice for the operators, many of whom had open pulmonary TB, to suck the penis (25). Primary TB of penis occurs after coital contact with organisms already present in the female genital tract or by contamination from infected clothing (26). Secondary penile TB occurs as a secondary manifestation of active pulmonary TB. The lesion appears as a superficial ulcer of the glans penis. It is indistinguishable from malignant disease, although it

can progress to cause a TB cavernositis with involvement of the urethra. The diagnosis is confirmed by biopsy. Tuberculosis of the Urethra Tuberculosis of the urethra is also rare (27). It is caused by spread from a focus in the genital tract. Its rarity is difficult to understand as there is almost constant exposure of the urethra to infected urine. It may present in either acute or chronic form. In the acute phase, there will be urethral discharge with involvement of the epididymis, prostate and other parts of the renal tract. The diagnosis is not difficult at this stage as the organism is always isolated. In the chronic form, the diagnosis is difficult because the disease presents as urethral obstruction or stricture. In such cases, urethral biopsy is required for confirmation of the diagnosis. DIAGNOSIS Undiagnosed and untreated urinary tract TB can cause renal failure and finally death. Diagnostic difficulties in genitourinary TB are usually due to failure to consider the disease from the symptoms described. The diagnosis is considered as a path of four steps, each being slippery enough to trip even the most careful urologist. These are: [i] clinical suspicion; [ii] bacteriological confirmation of diagnosis; [iii] radiological localization; and [iv] endourological evaluation and biopsy. A full blood count, erythrocyte sedimentation rate [ESR], urea and electrolyte values should be obtained in every case. In addition, if calcification is present, a complete biochemical assessment of calcium metabolism is performed. In cases with elevated ESR, measurement at monthly intervals may give some indication regarding response to treatment. Tuberculin skin test is usually positive in most patients with genitourinary TB. Urine Examination Urine is examined for red blood cells and pus cells, the pH and concentration are noted. Urine culture and sensitivity tests are performed to isolate the non-specific organisms. Secondary bacterial infection is found in about 20 per cent of patients with TB. The usual organism is Escherichia coli. Persistent sterile pyuria and haematuria in the absence of recent antibiotic treatment is a common finding and in such a context urological TB must always be considered.

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Microbiological Methods

Plain Radiograph

Since urinary bacillary excretion is intermittent, at least three, but preferably five, consecutive early morning specimens of urine should be cultured, each on two slopes: [i] Lowenstein-Jensen culture medium; and [ii] a pyruvate egg medium containing penicillin to identify Mycobacterium bovis, which is partially anaerobic and grows on the surface of the culture medium. If the cultures are positive, sensitivity tests are always conducted, in order to rule out drug-resistant TB. Smear and culture examination of urine and secretions from a discharging sinus or material procured by fine-needle aspiration are helpful in confirming the diagnosis. However, urine smears for Ziehl-Neelsen staining are often negative and urine mycobacterial culture results are available only after six to eight weeks.

Plain radiographs of the urinary tract may show calcification in the renal areas [Figures 32.2A and 32.2B] and in the lower genitourinary tract. Ureteric calcification due to TB is very rare, unless there is extensive renal calcification. It must be distinguished from that seen in schistosomiasis. In ureteric TB, the calcification is intraluminal and appears as a cast of ureter which is

Polymerase Chain Reaction Polymerase chain reaction [PCR] has been applied for the early diagnosis of genitourinary TB. In a study of 42 patients with clinical suspicion of genitourinary TB from India (28), radiographic abnormalities suggestive of genitourinary were found in 37 [88%]; Mycobacterium tuberculosis TB was isolated from the urine in 13 [31%]; histopathology of the urinary bladder was suggestive of TB in 11 [46%]; and the urine PCR for Mycobacterium tuberculosis was positive in 34 cases [81%]. Of 35 cases with proven genitourinary TB, the urine PCR for Mycobacterium tuberculosis was positive in 33 [94.3%]. In another study from Egypt (29), urine specimens from 1000 patients with clinical suspicion of urinary TB were examined using conventional methods of smear and culture examination and two PCR protocols; the Mycobacterium tuberculosis species-specific insertion sequence, IS6110 and mycobacterium genus-specific sequence encoding ribosomal ribonucleic acid [16S rRNA] for nontuberculous mycobacteria. Compared with mycobacterial culture, the sensitivity and specificity of acid-fast bacilli staining were 52.1 per cent and 96.7 per cent respectively; the overall sensitivity and specificity of the IS6110-PCR assay was 95.6 per cent and 98.1 per cent respectively. The corresponding results for the 16S rRNA gene-PCR were 87.1 per cent and 98.9 per cent. These results suggest that urine PCR is a useful test for the rapid diagnosis of genitourinary TB in the appropriate clinical setting. The reader is referred to the chapter “Laboratory diagnosis” [Chapter 10] for more details.

Figure 32.2A: Plain radiograph of the abdomen showing bilateral calyceal calcification [arrows]

Figure 32.2B: Intravenous urogram showing lobar calcification of the inferior pole [white arrow] and dilated upper and middle calyces in the left kidney [black arrow]

Genitourinary Tuberculosis 469 thickened and not dilated. In schistosomiasis, the calcification is mural and the ureter is dilated and tortuous. Plain radiographs of the chest and spine are also performed to exclude pulmonary or spinal disease. Intravenous Urography Intravenous urography [IVU] is still the mainstay of investigation for renal tract pathology (30). In patients with genitourinary TB, it helps in localization of the disease besides functional and anatomical delineation [Figure 32.3]. The renal lesion may appear as distortion of a calyx, a calyx that is fibrosed and completely occluded [lost calyx], multiple small calyceal deformities, or a severe calyceal and parenchymal destruction. Urography may reveal a hydroureteronephrosis, a poorly functioning or a non-functioning kidney. Irreversible TB ureteritis is manifested by dilatation above a ureterovesical stricture, or if the disease is more advanced, by a rigid fibrotic ureter with multiple strictures [Figure 32.4]. The cystographic phase of the urogram can give valuable information about the condition of the bladder, which may be small and contracted or irregular with filling defects and bladder asymmetry [Figure 32.5].

Figure 32.3: Intravenous urogram showing no excretion of contrast on the right side and hydroureteronephrosis on the left side [arrows]

Figure 32.4: Intravenous urogram showing stricture of the lower end of the ureter in a solitary functioning kidney [arrow]

Figure 32.5: Intravenous urogram showing non-functioning kidney on the right side, hydronephrosis [black arrow] on the left side and thimble bladder [white arrows]

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Magnetic Resonance Urography Magnetic resonance urography imaging can also be done in these cases to delineate the anatomy of the urinary tract without the need for contrast. However, it gives an idea of anatomy alone. Hence, it needs to be supplemented by a functional study. Retrograde Pyelography Presently, retrograde pyelography is sparingly done. There are two indications for its use: [i] stricture at the lower end of the ureter where it is necessary to delineate the length of the stricture and the amount of obstruction and dilatation above the stricture [Figure 32.6]; and [ii] to obtain urine samples for culture from each kidney.

kidney can be assessed by measurement of creatinine clearance by leaving percutaneous nephrostomy tube, if desired. Nephrostogram [Figure 32.7] can be performed through the percutaneous nephrostomy tube. Arteriography Arteriography is an invasive investigation and is of limited value in the routine evaluation of a patient with genitourinary TB. It is useful when there is a suspicion of coincidental renal tumour. Voiding Cystourethrogram

Percutaneous antegrade pyelography is becoming more important as an alternative to retrograde ureterography in patients with large hydronephrotic obstructed kidneys. It is useful in visualizing a non-functioning kidney or in determining the condition of all excretory pathways above an obstruction. It can be used to aspirate the contents of the renal pelvis so that they can be sent for diagnostic examination. An isolated function of ipsilateral

Voiding cystourethrogram is a very useful investigation to delineate bladder pathology. The bladder outline may be irregular due to localized deformity from cicatrization or due to a hyperplastic inflammatory lesion (12). Tuberculosis in the vesical wall produces large, multiple lesions and may manifest radiologically as filling defects simulating carcinoma (9). In patients with TB cystitis, chronic ulceration produces hypertrophy of the bladder wall and marked cicatricial contraction of the bladder. Fibrosis in the region of the trigone produces gaping ureteric orifices, which may show vesico-ureteric reflux on voiding cystourethrogram [Figure 32.8].

Figure 32.6: Retrograde ureteropyelogram showing reno-colocutaneous fistula, narrow ureter [back arrow], colon, extravasation of the contrast through the sinus tract [white arrows]

Figure 32.7: Right nephrostogram showing multiple strictures in upper and lower ureter [arrows]

Percutaneous Antegrade Pyelography

Genitourinary Tuberculosis 471 urography gives an accurate picture. Computed tomography may help in case of a difficult intrarenal lesion or if there is a possibility of a co-existing renal carcinoma. Subtle ureteric changes are better appreciated with a combination of a ureterogram and an image intensifier. Computed tomography may be useful to delineate granulomatous lesion, mass lesion [Figure 32.9] and diseased seminal vesicles that were not originally thought to be infected (31).

Figure 32.8: Voiding cystourethrogram showing no excretion of contrast on the right side and hydroureteronephrosis on the left side [arrows]

Retrograde Urethrography Retrograde urethrography is performed to delineate the urethral anatomy and to rule out narrowing or stricture of urethra due to urogenital TB. Ultrasonography Ultrasonography as the initial investigation for genitourinary TB is of limited value. However, it is a noninvasive technique and can be used to monitor kidney lesions found by an intravenous urogram while the patient is receiving antituberculosis treatment. It can show whether a cavity is increasing or decreasing in size and helps in avoiding repeated radiographic examinations. It can also be used to monitor the volume of a contracted bladder during treatment and is of value in assessing the need for bladder augmentation. Ultrasound-guided fine-needle aspiration and cytopathological examination and biopsy of an abscess or a renal mass can be performed. Computed Tomography Computed tomography [CT], as an early investigation of genitourinary TB, is of limited value as intravenous

Figure 32.9: CECT of the abdomen showing an irregular hypodense lesion in the right kidney [arrow]

Cystoscopy Cystoscopy has important place in the evaluation of a patient with suspected urinary tract TB, especially when there is haematuria and persistent irritative voiding symptoms [frequency, urgency and dysuria]. It helps to evaluate the capacity of the bladder, any obvious bladder lesions and the nature of efflux from either ureter. Above all, biopsy can be taken from a suspicious lesion for histopathological diagnosis. Thus, urethroscopy, sampling of urine from both the kidneys and bladder biopsy must be attempted in patients with suspected genitourinary TB. TREATMENT Antituberculosis Treatment Antituberculosis treatment is an essential component of the treatment of genitourinary TB. Modern antituberculosis treatment is highly successful in the treatment of genitourinary TB, although the optimum duration is not yet fully defined (8,32). The reader is referred to the

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chapter “Treatment of tuberculosis” [Chapter 52] for more details. Surgery Surgery still has a vital role in the management of obstructive and advanced lesions in the urinary tract in conjunction with antituberculosis treatment [Table 32.3]. Advanced lesions are rare in the west, but are still commonly encountered in the developing countries. Howsoever, normal the upper urinary tract may seem at the first instance, a second IVU must be performed within three to four weeks as TB lesion contracts on healing and may result in hydroureter and hydronephrosis. Renal abscess not resolving within two weeks of the treatment can be drained with ultrasound guidance [Figure 32.10]. Strictures may occur in any part of the urinary tract. In the kidney, these may be seen at the neck of the calyx producing a hydrocalyx. Earlier these lesions had to be unroofed and drained [cavernostomy]. Now, hydrocalyx can be managed by ultrasound-guided aspiration. A silent blocked-off calyx can be left to resolve with antituberculosis treatment (33).

together with hypertension and ureteropelvic junction [UPJ] obstruction; and [iii] co-existing renal carcinoma. When kidney is destroyed completely or is not functioning [as identified on renal scan], nephrectomy may be the simplest answer. Laparoscopic [retroperitoneoscopic] nephrectomy and nephroureterectomy may be performed safely and successfully for non-functioning kidneys (35). However, this procedure may be difficult and complex when extensive perirenal fibrosis is present. In such cases, segmental nephrectomy should be considered. Obstruction of the pelviureteric junction can be dealt with endourological treatment [endopyelotomy antegrade and retrograde], or, with open pyeloplasty depending on the grade and severity. However, if an area of the hilum is severely cicatrized, ureterocalycostomy may be required. In a kidney affected by TB, renal stone leading to pyeloduodenal fistula is rare. Surgical treatment consists of nephrectomy and primary repair of duodenum [Figures 32.11A, 32.11B and 32.11C]. Partial Nephrectomy Partial nephrectomy is rarely carried out, because with modern antituberculosis treatment, the response of a

Nephrectomy Nephrectomy is indicated in the following situations (34): [i] a non-functioning kidney with or without calcification; [ii] extensive disease involving the whole kidney,

Figure 32.10: Ultrasonography showing an enlarged hypoechoic left kidney [thick arrow] with an anechoic cavity in the lower pole [asterisk] due to tuberculosis. A large psoas abscess [thin arrows] is also seen

Figure 32.11A: Intravenous urogram showing functioning right kidney with hydronephrosis [long arrow]. The left kidney is not visualized. A radio-opaque shadow can be seen in the upper ureter [small arrow]

Genitourinary Tuberculosis 473 Table 32.3: Surgical management of genitourinary tuberculosis Renal tuberculosis Nephrectomy or nephroureterectomy by conventional open surgery or by laparoscopic [retroperitoneoscopic] nephroureterectomy Partial nephrectomy Partial nephrectomy with fistulectomy Nephrectomy with excision of fistula with primary repair of gut Pyeloplasty Ureterocalycostomy Ureteric stricture Lower part Dilatation or balloon dilatation or endoureterotomy and stenting Ureteroneocystostomy Ureteroneocystostomy + psoas hitch or Boari’s flap Middle part Dilatation or balloon dilatation or endoureterotomy and stenting, or ureteroneocystostomy + psoas hitch or Boari’s flap according to the nature and location of the stricture Intubated ureterotomy Interposition with appendix on the right side ileal replacement Upper part Dilatation or balloon dilatation or endoureterotomy and stenting Percutaneous nephrostomy Pyeloureteroplasty Ureterocalycostomy Pyeloplasty Ileal replacement Multiple strictures or total stricture of the urethra Ileal replacement of the ureter Diversion Permanent ureterostomy Ureterosigmoidostomy Nephrostomy Urinary bladder tuberculosis Step I: Antituberculosis treatment Step II: If cystitis is severe, bladder capacity is moderate, corticosteroids can be added to antituberculosis treatment Step III: Bladder neck incision Hydraulic dilatation Step IV: Augmentation Small capacity bladder [30 to 150 ml] Ileal patch Ileocystoplasty Ileocaecoplasty Sigmoidcolocystoplasty Thimble bladder [10 to 30 ml] Cystectomy + orthotopic neobladder Tuberculosis of urethra Endoscopic dilatation Internal urethroplasty Staged urethroplasty Meatoplasty Genital tuberculosis Epididymectomy Orchiectomy Excision of fistula Partial penectomy

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Figure 32.11B: Intraoperative photograph of the same patient showing pyeloduodenal fistula

Figure 32.11C: Cut section of the kidney specimen removed during operation

local lesion in the kidney is rapid and effective. It is indicated in the following situations: [i] localized polar lesion containing calcification that has failed to respond after six weeks of intensive chemotherapy; and [ii] an area of calcification that is slowly increasing in size and is threatening to gradually destroy the whole kidney. Renal calcification is increasingly becoming a hazard in renal TB. In one study, 28 per cent of all large areas of calcification that were excised had viable Mycobacterium tuberculosis in the calcified matrix (33). Small lesions can be kept under review on an annual basis. Larger areas of calcification should be excised and non-functioning kidneys with extensive calcification should be removed. A reno-colo-cutaneous fistula due to TB is extremely rare, and so far only six such cases have been documented in the literature. Two such cases were managed by singlestage surgery [nephroureterectomy, fistulectomy and primary repair of the colon] and antituberculosis treatment (20).

If there is stricture in upper ureter or at UPJ, endoscopic stenting may first be attempted provided it is passable. The stent is left for six to twelve weeks. The result is assessed after removal of the stent with an intravenous urogram. In cases, where stenting is not possible, percutaneous nephrostomy is indicated. After adequate antituberculosis treatment for at least four weeks, pyeloplasty is performed. Both Anderson-Hynes technique and the Culp technique give satisfactory results. Pyelostomy is an essential part of the technique in cases in which a previous nephrostomy has not been performed. The pyelostomy tube is clamped the day after the silicone stent is removed and is removed after urine is shown to be draining satisfactorily. However, if there is involvement of the upper ureter with a poorly functioning kidney, nephroureterectomy is advisable. If UPJ is totally obliterated and pyeloplasty is not feasible, then ureterocalycostomy may be performed.

Stricture of the Upper Third of the Ureter

Usually this part of ureter is involved with extensive stricture. Isolated stricture of the middle third of the ureter is rare. The management starts with an endourological procedure if the stricture is passable, failing which,

Stricture at UPJ is seen infrequently. Probably by the time the stricture develops at the UPJ, the kidney may already have been destroyed.

Stricture of the Middle Third of the Ureter

Genitourinary Tuberculosis 475 one may resort to Davis’ intubated ureterostomy technique over a silastic stent with the hope that ureteral mucosa will regenerate around it. The silastic stent should be left in place for at least six to eight weeks. Possible complications include recurrent stricture or total narrowing after stent removal. Occasionally, interposition of appendix has been attempted on the right side for midureteric strictures. Stricture of the Lower Third of the Ureter Lower ureter is the commonest site of ureteric stricture in genitourinary TB. Once obstruction is identified, it necessitates careful follow-up and the patients are started on antituberculosis treatment. Tailored IVU should be done at the end of three weeks or earlier to assess the progression or stabilization of the stricture. If it starts worsening, then corticosteroids should be added to antituberculosis treatment. Early stenting should be considered in such cases. Endoscopic dilatation of the ureteral stricture has been suggested by Murphy et al (36) who reported 64 per cent success. Ureteric dilatation can be performed with the help of simple ureteric catheters, Brasch catheters or a ureteral balloon dilator. With the recent availability of miniature ureteroscopes, ureterotomy can be performed with the help of cold knife, diathermy or laser followed by stenting (37). However, a stricture not yielding to endoscopic maneuvering should be dealt with ureteroneocystostomy. The ureteric stricture should be assessed with retrograde ureterography and on cystoscopy the bladder is assessed. For strictures less than 5 cm, ureteroneocystostomy can be performed in a good capacity bladder. However, in long strictures, either a psoas hitch or a Boari’s flap may be required. When the ureteric stricture is associated with small capacity bladder, then, bladder is augmented and ureteroneocystostomy is performed. Similarly, in small capacity [thimble] bladder, simple cystectomy is done and ureteric reimplantation is performed in the neobladder. The author had encountered an unusual case with stricture at the lower end of the ureter leading to spontaneous extravasation of contrast in a solitary nonfunctioning kidney [Figure 32.12]. This patient was treated with antituberculosis drugs, unilateral dilatation and stenting. Later, the patient was carefully followedup and dilatation was regularly performed at six monthly intervals.

Figure 32.12: Intravenous urogram showing stricture of the lower end of the ureter [black arrows] with spontaneous extravasation of the contrast in solitary functioning kidney [white arrow]

Complete Ureteric Stricture In patients with complete ureteric stricture, ileal replacement of ureter [Figure 32.13], joining a tailored or plicated ileum to the calyx of the kidney cranially, and to the urinary bladder caudally is a useful surgical technique. Surgery for Urinary Bladder Tuberculosis If urinary bladder is small in capacity [< 100 ml], augmentation is warranted to take care of frequency on account of storage problem. Bladder augmentation can be done utilizing ileal segment, ileocaecal segment, sigmoid colon and even incorporating a segment of stomach [Figures 32.14A and 32.14B] (38-41). Detubularization is not always essential, as low pressure bladder achieved by this means may not have enough contractile power to empty itself. Augmentation does not work in all cases in thimble bladder [10 to 30 ml capacity] and can give rise to problems of diverticulation of augmented segment, anastomotic site stricture and suprapubic pain. Therefore, the author’s technique of simple cystectomy and orthotopic neobladder may be most useful in this

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Tuberculosis situation (40). The author has reported good long-term results in four patients with thimble bladder employing the orthotopic bladder replacement using the ileocaecal segment in three patients and sigmoid colon in the fourth [Figures 32.5, 32.15A and 32.15B] (40). Surgery for Other Forms of Genitourinary Tuberculosis

Figure 32.13: Intravenous urogram showing ileal replacement of ureter [arrows]

Figure 32.14A: Intravenous urogram showing small capacity thimble bladder [arrows]. The kidney is not visualized on the right side

Tuberculosis of the prostate can vary from infiltration of stroma to an abscess cavity, bursting into perineum or rectum. These lesions respond very well to antituberculosis treatment. The residual bladder neck obstruction, if required can be dealt endoscopically. The author had come across an unusual case of TB vesico-vaginal fistula which was treated with antituberculosis treatment and surgical repair of the fistula with omental interposition. The author also has experience of managing vesico-sigmoid fistula with antituberculosis treatment and surgical repair (18). Involvement of seminal vesicles and vas deferens gives rise to infertility. While many patients may respond to antituberculosis treatment, some may require surgical intervention. Direct involvement of epididymis may be

Figure 32.14B: Cystogram in the same patient following augmentation cystoplasty utilizing sigmoid colon [arrows]

Genitourinary Tuberculosis 477

Figure 32.15A: Reconstruction of orthotopic neobladder with ileocaecal segment after simple cystectomy [arrows]

Figure 32.15B: Post-void cystogram of the same patient demonstrating complete clearance [arrows]

difficult to differentiate from bacterial epididymis. Sometimes epididymectomy may be required for chronic fistula and orchalgia. Antituberculosis treatment combined with judicious surgery as and when indicated is the ideal treatment for genitourinary TB. All attempts must be made to reconstruct the urinary tract as the results are most gratifying. Infected and destroyed tissue, however, is best ablated. Increasing tendency towards performing endoscopic and reconstructive procedures at present suggests that the number of cases managed endoscopically is likely to increase in the future. In a recently published series on genitourinary TB from India [n = 241] (17), a total of 248 procedures, [33 endoscopic, 87 ablative and 128 reconstructive], were performed with some patients requiring more than one procedure. Early complications, which mainly involved the bowel, were seen in 19 [8%] cases. Bacteriologic cure was achieved in all culture positive cases. Renal functional parameters stabilized or improved in 44 of 54 patients [81.5%] in whom they were deranged at presentation. The authors suggest that a combination of antituberculosis treatment and judicious surgery achieves satisfactory results in majority of the cases. In

patients who undergo reconstructive procedures, a rigorous and prolonged follow-up would be required. REFERENCES 1. Teklu B, Ostrow JH. Urinary tuberculosis: a review of 44 cases treated since 1963. J Urol 1976;115:507-9. 2. Weinberg AC, Boyd SD. Genitourinary tuberculosis. Urology 1988;31:95-9. 3. Medical Research Council Tuberculosis and Chest Disease Unit. National survey of tuberculosis notifications in England and Wales in 1983. BMJ 1985;291:658-61. 4. Medlar EM. Cases of renal infection in pulmonary tuberculosis: evidence of healed tubercular lesions. Am J Pathol 1926;2:401-7. 5. Colabawalla BN. Diagnostic evaluation in renal tuberculosis. Indian J Surg 1978;40:109-12. 6. Colabawalla BN. Reflections on urogenital tuberculosis. Indian J Urol 1990;6:51-9. 7. Naidich DP, Garay SM, Leitman BS, McCauley DI. Radiographic manifestations of pulmonary disease in the acquired immunodeficiency syndrome. Semin Roentgenol 1987;12:14-30. 8. Becker JA. Renal tuberculosis. Urol Radiol 1988;10:25-30. 9. Elkin M. Urogenital tuberculosis. In: Pollack HM, editor. Clinical urography. Philadelphia: W.B. Saunders Company; 1990.p.1020-52.

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10. Amis SE Jr, Newhouse JH. Essentials of uroradiology. Boston: Little, Brown and Company; 1990.p.1640-66. 11. Gow JG. Renal calcification in genito-urinary tuberculosis. Br J Surg 1965;52:283-8. 12. Elkin M. Radiology of the urinary system. Boston: Little, Brown and Company; 1980.p.148-56. 13. Elkin M. Urogenital tuberculosis. In: Pollack HM, editor. Clinical urography. Philadelphia: W.B. Saunders Company; 1990.p.985-6. 14. Yoder IC. Hysterosalpingography and pelvis ultrasound imaging in infertility and gynecology. Boston: Little Brown and Company; 1988.p.1166-78. 15. Greenberg JP. Tuberculous salpingitis. A clinical study of 200 cases. Johns Hopkins Hosp Rep 1991;21:97-103. 16. Langemeier J. Tuberculosis of the genitourinary system. Urol Nurs 2007;27:279-84,321. 17. Gupta NP, Kumar R, Mundada OP, Aron M, Hemal AK, Dogra PN, et al. Reconstructive surgery for the management of genitourinary tuberculosis: a single center experience. J Urol 2006;175:2150-4. 18. Hemal AK. Genitourinary tuberculosis. In: Sharma SK, Mohan A, editors. Tuberculosis. First edition. New Delhi: Jaypee Brothers Medical Publishers; 2001.p.325-37. 19. Qureshi MA. Spontaneous nephrocutaneous fistula in tuberculous pyelonephritis. J Coll Physicians Surg Pak 2007;17:367-8. 20. Hemal AK, Gupta NP, Wadhwa SN, Songra MC, Batura D, Bhuyan UN. Primary repair of colorenocutaneous fistula in patients with genitourinary tuberculosis. Urol Int 1994;52:414. 21. Kumar R, Hemal AK. Bilateral epididymal masses with infertility. ANZ J Surg 2004;74:391. 22. Bhargava P. Epididymal tuberculosis: presentations and diagnosis. ANZ J Surg 2007;77:495-6. 23. Sporer A, Auerback MD. Tuberculosis of the prostate. Urol 1978;11:362-5. 24. Hemal AK, Aron M, Nair M, Wadhwa SN. ‘Autoprostatectomy’: a unusual manifestation in genitourinary tuberculosis. Br J Urol 1998;82:140-1. 25. Lewis EL. Tuberculosis of the penis: a report of 5 new cases and a complete review of the literature. J Urol 1946;56:737-45. 26. Agarwalla B, Mohanty GP, Sahu LK, Rath RC. Tuberculosis of the penis: report of two cases. J Urol 1980;124:927.

27. Singh I, Hemal AK. Primary urethral tuberculosis masquerading as a urethral caruncle: a diagnostic curiosity! Int Urol Nephrol 2002;34:101-3. 28. Hemal AK, Gupta NP, Rajeev TP, Kumar R, Dar L, Seth P. Polymerase chain reaction in clinically suspected genitourinary tuberculosis: comparison with intravenous urography, bladder biopsy, and urine acid fast bacilli culture. Urology 2000;56:570-4. 29. Moussa OM, Eraky I, El-Far MA, Osman HG, Ghoneim MA. Rapid diagnosis of genitourinary tuberculosis by polymerase chain reaction and non-radioactive DNA hybridization. J Urol 2000;164:584-8. 30. Valentini AL, Summaria V, Marano P. Diagnostic imaging of genitourinary tuberculosis. Rays 1998;23:126-43. 31. Premkumar A, Newhouse JH. Seminal vesicle tuberculosis: CT appearance. J Comput Assist Tomogr 1988;12:676-7. 32. Kadhiravan T, Sharma SK. Medical management of genitourinary tuberculosis. Indian J Urol 2008;24:362-8. 33. Wong SH, Lan WY. The surgical management of nonfunctioning tuberculous kidneys. J Urol 1980;124:187-91. 34. Flechner SM, Gow JG. Role of nephrectomy in the treatment of nonfunctioning or poorly functioning unilateral tuberculous kidney. J Urol 1980;123:822-5. 35. Hemal AK, Gupta NP, Kumar R. Comparison of retroperitoneoscopic nephrectomy with open surgery for tuberculous nonfunctioning kidneys. J Urol 2000;164:32-5. 36. Murphy DM, Fallon B, Lane V. Tuberculous stricture of ureter. Urology 1982;20:382-4. 37. Shin KY, Park HJ, Lee JJ, Park HY, Woo YN, Lee TY. Role of early endourologic management of tuberculous ureteral strictures. J Endourol 2002;16:755-8. 38. Gow JG. Genitourinary tuberculosis. In: Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr, editors. Campbell’s urology. Vol. 1. Sixth edition. Philadelphia: W.B. Saunders Company; 1992.p.951-74. 39. Chan SL, Ankenman GJ, Wright JE, McLoughlin MG. Caecocystoplasty in the surgical management of the small contracted bladder. J Urol 1980;124:338-40. 40. Hemal AK, Aron M. Orthotopic neobladder in management of tubercular thimble bladders: initial experience and longterm results. Urology 1999;53:298-301. 41. Dounis A, Gow JG. Bladder augmentation: a long term review. Br J Urol 1979;51:264-8.

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33 SK Agarwal

INTRODUCTION Tuberculosis [TB] is one of the major causes of morbidity and mortality throughout the world. Susceptibility to TB has been attributed to host resistance, socioeconomic (1) and environmental factors (2). Because of the immunosuppressive effect of uraemia, use of corticosteroids and immunosuppressive drugs during renal transplantation [RT], these patients are at a high risk of developing TB. Consequently, TB has been found to occur more frequently in patients with chronic renal failure [CRF], during maintenance haemodialysis [MHD] and following RT than in general population (3-7). PATHOGENESIS Uraemia is also an acquired immunodeficiency state leading to excessive morbidity and mortality related to infections. Functional abnormalities of neutrophils, Tand B- lymphocytes, monocytes and natural killer [NK] cells have been described in these patients. These abnormalities are often exacerbated by chronic haemodialysis and following RT. Bio-incompatibility during haemodialysis frequently leads to immune activation and subsequent leucocyte dysfunction, thus exacerbating the underlying immune defect of uraemia. Granulocyte functions, like chemotaxis, adherence and phagocytosis, are marginally defective in uraemia but patients on haemodialysis have pronounced defects in these functions. Leucocyte chemotaxis has been reported to be diminished in patients with end stage renal disease [ESRD] and MHD. In these patients, in vitro and in vivo administration of 1,25[OH]2D3 has been shown

to improve leucocyte adhesion and chemotaxis (8,9). Use of conventional cellulose membrane causes activation of the alternate complement pathway leading to changes in granulocyte cell adhesion molecules CD11b, CD18 [MAC-1] and L-selectin. These changes correlate with the development of leucopenia and its reversal (10). Similarly, phagocytosis is impaired both before and during haemodialysis. Impairment of phagocytosis during haemodialysis is more often encountered with cuprophane membrane than with newer membranes (11). Dialysis with cuprophane membrane also increases production of reactive oxygen species, thus decreasing responsiveness to an infectious challenge (12). Another major defect in lymphocyte function in uraemia and in patients on haemodialysis is decreased interleukin-2 [IL-2] production by activated T-helper cells (13). Whether the major defect is in the T-cells, antigen presentation to the T-cell or is monocyte derived, is still controversial. Altered macrophage Fc-receptor function in vivo and in vitro has been demonstrated in persons undergoing haemodialysis. This correlated very well with the incidence of severe infection during a two-year follow-up period. Defective antigen presentation by monocyte has also been demonstrated in patients on haemodialysis (14). Following successful RT, infection remains the leading cause of morbidity and mortality. The inflammatory response to microbial invasion in the transplant patients is attenuated by concomitant immunosuppressive therapy. The risk of infection in these patients is primarily determined by the interaction between exposure to mycobacteria and immune status of the

480

Tuberculosis

patient. Immunosuppression is a complex state determined by the interaction of a number of factors, the most important of which are the dose, duration and temporal sequence of immunosuppressive drugs employed. MAGNITUDE OF THE PROBLEM There is limited information on the magnitude of the problem of TB in patients with CRF. However, a recently published study from China (15) reported 30 times higher prevalence of TB in patients with CRF as compared to general population of same city (15). The study reported inverse association between renal function and TB. Problem of TB in patients already on MHD has been more commonly studied (3-6,16,17). All available studies are retrospective and the incidence of TB in such patients has varied from 1 to 13.3 per cent (4-6,18-21). It has been estimated that patients undergoing dialysis have a 10to 12-fold higher risk of developing TB compared to the general population (5,6). The incidence of TB in Indian patients receiving MHD has been reported to be 3.7 to 13.3 per cent (16,17). Majority of these patients have undergone haemodialysis for 12 to 24 months only. An increasing trend of TB has been observed in patients undergoing haemodialysis during the 1990s compared with the previous decade at author’s centre [personal observation]. A recent report also indicates transmission of TB from a health care worker to 29 patients and 13 employees in a dialysis centre (22). The incidence of TB in RT recipients has been more systematically studied as these patients are regularly followed-up. Incidence of TB in RT patients has ranged from one to four per cent in Northern Europe (23-26); 0.5 to 1 per cent in North America (26,27) and nearly five to ten per cent in several studies reported from India (28-33). Incidence of TB in RT patients has been found to be more or less similar among those who received cyclosporine and those who did not (18,30,31,33). However, few differences have been reported in these two groups. Higgins et al (7) reported that among RT patients who received cyclosporine based protocols, TB developed only in those patients who were clearly at risk of developing the disease due to previous exposure. Similarly, John et al (33) suggested that TB developed in the early post-RT period in patients on cyclosporine, as compared to those patients who did not receive cyclosporine. At another hospital in north India, early

occurrence of TB, especially miliary TB has been observed in RT patients receiving cyclosporine compared with those who did not [unpublished observations]. There is a limited information on the occurrence of TB in RT recipients on newer immunosuppressive medication like tacrolimus, mycophenolate, among others. In a recent study (34), a higher incidence of TB was found in patients receiving these drugs as compared to cyclosporine and also TB developed earlier in these patients (34). However, these results have not been confirmed by another study (35). Possible transmission of TB by renal allograft has been reported (26,36-38). The most definitive report (38) was concerning a donor with culture proven TB meningitis, whose kidneys were transplanted in two patients. Both of them developed definitive TB on days 35 and 39 respectively. In other published studies, disseminated TB developed in four of the six patients who acquired the disease through renal allograft (36,37). Graham et al (39) have documented definite donor organ transmitted TB using hemi-nested inverse PCR of the IS6110 region both in the donor and recipient (39). CLINICAL PRESENTATION Clinical Presentation of Tuberculosis during Maintenance Haemodialysis Clinical presentation of TB in patients on MHD is summarized in [Table 33.1]. The age distribution of patients on MHD who developed TB was similar to that observed in general population (4). Males were nearly twice as commonly affected as compared to females (4,18). This probably reflects the sex difference observed in patients with CRF. Regular MHD usually tends to improve the general immune status of the patients with CRF. Therefore, a majority of these patients develop TB prior to initiation or within a short period from the beginning of MHD, a time when effect of uraemia on immune status is still pronounced. Sasaki et al (4) and Andrew et al (5) have reported the development of TB within six months of MHD, however, this period was much longer in another study (6). Prior exposure to TB and diabetes mellitus were found as risk factors in nearly 50 per cent of the patients for the development of TB (6). Constitutional symptoms attributable to TB have been reported in 30 to 92 per cent patients in various series

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481

Table 33.1: Clinical presentation of tuberculosis in patients on maintenance haemodialysis Variable

Sasaki et al (4) [n = 367]

No. of TB patients [%] Mean age [years] Male:female Time of diagnosis of TB in relation to duration of HD [%] Prior HD Less than 6 months Six months to 1 year More than 1 year Site of TB [%]§ Pulmonary Pleural Lymph node Miliary or disseminated Neurological Colon Peritoneal Bone and joints Renal Hepatic Clinical presentation [%] Fever Appetite loss Weight loss Cough Neurological deficit Diagnosis [%]§§ Microbiology |||| Histopathology|||| Autopsy Mortality [%] TB mortality Overall mortality

Andrew et al (5) [n = 172]

Rutsky et al (6) [n = 885]

Malhotra et al (17) Venkata et al (40) [n = 150] [n = 900]

12 [3.3] 45 2:1

10 [5.8] 49 1.5:1

9 [1] 48 2:1

20 [13.3] 20 3:1

36 [4] 52 11:1

42

40

ND

0

42 8 8

50† 0 0

ND ND ND

ND ND ND

8 8 17 50 8 8 0 0 0 0

60 10 10 0 10 0 10 0 10 0

33 33 11 11 0 0 11 0 0 0

95‡ 5 0 || 10 45 30¶ 0 0 0 5 5 0 0

92 100 75 25 50

** ** ** ** **

†† †† †† †† ††

‡‡ ‡‡ ‡‡ ‡‡ ‡‡

72 72 25 ND ND

33 17 50

50 40 10

90¶¶ 20 0

20 45 5***

16.6 30.5 ND

75 75

0 20

22 44

10 60

25 ND

61.1*

36 28 14 11 0 0 0 8 0 0

* 14 patients were on regular dialysis [13 on HD, 1 patient was on continuous ambulatory peritoneal dialysis], and 8 were on irregular dialysis. Among patients on regular dialysis, TB was identified within 1 year of dialysis in 4, and in the remaining, TB was diagnosed between 1 and 9 years of dialysis † In 1 patient [10%], the diagnosis of TB was made concurrent with the initiation of HD ‡ In 3 patients [15%], the diagnosis of TB was made concurrent with the initiation of HD § More than one site was involved in some patients || The site of TB was not clear in one patient. This patient responded well to antituberculosis treatment ¶ One patient had left hilar lymphadenopathy ** Details of clinical presentation were not described. The presenting symptoms were non-specfic and constitutional in nature. Fever, malaise, anorexia and weight loss were most commonly encountered. Headache, chills, and shortness of breath were less common [< 30% of the patients] †† Of the 885 patients studied, a diagnosis of TB was made in 9 patients on HD and 8 patients who had CRF but did not require long-term dialysis. The clinical symptoms were not separately described for these 2 groups of patients ‡‡ Consolidated break-up of clinical features was not provided. Of the 20 patients in whom TB was diagnosed, 75% presented with fever, 50% with pleural effusion; 30% had lymphadenopathy, pulmonary abnormalities were found in 20% and ascites and hepatomegaly were observed in 10% patients. Other features included marked anorexia [10%], abnormal weight loss [5%] and bony swelling [5%] §§ More than 1 method was positive in some patients |||| Cumulative yield from various tissue and fluid specimens ¶¶ NTM were isolated from 3 of the 9 patients *** A patient who had shown TB peripheral lymphadenopathy during life revealed histopathological evidence of TB in hilar and tracheobronchial lymph nodes on autopsy TB = tuberculosis; HD = haemodialysis; ND = not described; CRF = chronic renal failure; NTM = nontuberculous mycobacteria

482

Tuberculosis

(4-6,16) and may include low- or high-grade fever. Malhotra et al (17) reported that 15 per cent of their patients on MHD who developed TB presented with pyrexia of unknown origin [PUO]. In other studies (6,1821,40), this presentation has been rarely observed. In majority of the studies (6,17-21,40), lung is the most common site of involvement in patients on MHD. In these studies (6,17-21,40), incidence of pulmonary TB ranged between 40 to 92 per cent. However, in some studies (5,6,40), isolated extra-pulmonary TB has been found in 56 to 60 per cent cases. Malhotra et al (17) have reported that pleural effusion occurred more frequently than pulmonary parenchymal lesions. However, this observation has not been corroborated by other workers who have found parenchymal lesions to be more common than pleural effusion (6,18-21). Lymph node involvement has been found to be the most common extra-pulmonary site of TB in patients on MHD [15% to 30%] (4,6,1719,33,40). In the series reported by Malhotra et al (17), lymph node TB occurred in 30 per cent of patients; in 25 per cent of the patients, this was the only presenting feature (17). Other sites of extra-pulmonary involvement include abdomen (4-6), meninges (4), bone and joints (19,33). Chuang et al (41) while describing extrapulmonary TB in dialysis patients, have reported involvement of peritoneum [35.3%] cervical lymph nodes [17.6%], involvement of bone marrow, spine, knee joint, brain, pericardium, cutaneous tissue and genitourinary system [5.7% each]. These observations suggest that, almost any organ can be affected by TB in these patients. Disseminated TB miliary TB have also been observed as the presenting feature in these patients. Nearly half of the patients studied by Sasaki et al (4) presented with disseminated or miliary TB. In most of the other series, the incidence of miliary TB ranged between 10 to 15 per cent (6,19). None of the patients described by Malhotra et al (17) had miliary TB. Two of the 100 patients with miliary TB reported by Sharma et al (42) had CRF as a predisposing factor. Tuberculosis peritonitis has been described in patients on continuous ambulatory peritoneal dialysis [CAPD] (43-45). In these patients, the ascitic fluid may reveal predominance of polymorphonuclear leucocytes. In addition to causing morbidity, it can also cause ultrafiltration failure of CAPD and require shifting to other modality of renal replacement therapy.

In a retrospective cohort study (46) of TB disease in 272 024 patients in the US Renal Data System initiated on dialysis therapy between April 1995 and December 1999, cumulative incidence of TB in patients undergoing either peritoneal or haemodialysis was found to be 1.2 per cent and 1.6 per cent, respectively. In this study (46), advanced age, unemployment, availing health insurance [Medicaid], reduced body mass index, decreased serum albumin, haemodialysis, both Asian and Native American race, ischaemic heart disease, smoking, illicit drug use and anaemia were found to be risk factors for the development of TB in patients receiving peritoneal or haemodialysis. Furthermore, in patients receiving dialysis, TB was independently associated with increased mortality. Clinical Presentation of Tuberculosis following Renal Transplantation Tuberculosis can be encountered in RT patients in two settings. First, a patient with renal failure suffering from TB in the pre-transplant phase may continue to suffer from TB in the post-RT phase as well. On the other hand, patients may develop TB for the first time following RT. The present description is regarding patients in the latter category. Patients who develop TB following RT [Table 33.2] are usually younger. Males are more often affected. This could be because of the fact that young males undergo RT more often in a country like India (30-32). Similar observations have been reported from the west as well as from other countries (47). Past history of TB has been reported in 5.6 to 8.9 per cent patients in studies reported from India [Table 33.2]. When TB develops, constitutional symptoms are more often encountered in RT patients than in patients on MHD (31-33). The lung is the most common site of involvement in RT patients who develop TB (29-33). Other sites of TB involvement in RT patients include abdomen (7,33); pericardium (30,33); thalamus (30); bone and joints (7,30). Miliary TB has also been reported in seven to thirty-six per cent of RT patients (7,30-33,36-38). Thus, RT patients develop pulmonary TB more often, and manifest constitutional symptoms more commonly compared with patients on MHD. Comparison of presentation of TB during haemodialysis and after RT [n = 923] at the author’s centre is shown in [Table 33.3] [unpublished data]. Pleuropulmonary TB appears to be more common in both

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483

Table 33.2: Clinical presentation of tuberculosis in renal transplant patients Variable

Hariharan et al (32) [n = 550]

Higgins et al (7) [n = 633]

John et al (33) [n = 808]

Sakhuja et al (31) [n = 305]

Agarwal et al (30)* [n = 461]

No. of patients with TB [%]

46 [8.4]

11 [1.7]

41 [5.1]

36 [11.8]

67 [14.5]

Mean age [years]

32.5

43.9

†

33.9

14

Male:Female

4.1:1

1.8:1

4.9:1

6.2:1

20

26.4

‡

Past history of TB

ND

ND

ND

5.6

8.9

Immunosuppression

D

D/T

D/T

D/T

D/T

Site of TB [%] § Pulmonary

20.7

3.5:1

Mean time interval between renal transplantation and detection of TB [months]

24

39

18

49

31

37

Pleural

13

9

0

14

22

Lymph node

17

0

2

3

8 8

Disseminated or miliary TB

7

36

27

25

Neurological

4

0

0

0

5

Abdominal

4

18

7

3

5

Genitourinary

0

9

5

3

0

Skin, soft tissue

0

0

7

3

0

Pericarditis

0

0

0

0

0

Bone and joints

0

0

2

0

1.5

Diagnosis [%]ll Microbiology¶

52

55**

98††

14

3

Histopathology¶

26

27

10

33

12

4

0

0

3

11

Autopsy Mortality [%] TB related mortality

4

9

12

6

0

Overall mortality

9

9

46

19.4

0

Percentage values are corrected to the nearest round figures * Figures from 1992 have been revised and updated till 1997 † Mean age of patients receiving cyclosporine immunosuppression and conventional immunosuppression was 39.9 and 37.3 years respectively ‡ Median time [months] of diagnosis of myobacterial infection after transplantation in patients receiving cyclosporine immunosuppression and conventional immunosuppression was 5.5 and 2.4 months respectively § Some patients had involvement of more than 1 site ll More than 1 method was positive in some patients ¶ Cumulative yield from various tissue fluids and specimens ** 1 patient had infection with Mycobacterium kansasii †† 2 patients had nontuberculous mycobacterial infection TB = tuberculosis; ND = not described; D = double immunosuppression; T = triple immunosuppression

484

Tuberculosis

settings. In RT recipients, presentation with PUO and miliary TB is significantly more common as compared to patients on MHD. Furthermore, abdominal TB was significantly more common during dialysis while neurological TB was more common after transplantation. Overall, patients with renal failure while on MHD manifest extra-pulmonary TB more frequently [60%] as compared to pulmonary TB [40%] [Table 33.1]. By contrast, site of involvement in RT-recipients resembles that observed in immunocompetent individuals; pulmonary TB is more frequent [60%] [Table 33.2], probably due to improvement in their immune status.

culosis treatment in a country like India where TB is endemic. Diagnosis of TB in patients with uraemia is difficult. Patients with uraemia can have a high erythrocyte sedimentation rate [ESR] due to anaemia and various other reasons and, therefore, ESR is not of much use in these patients. The tuberculin skin test [TST] is often negative in patients on MHD and following RT (21,48,49). The newer diagnostic methods for detecting latent TB infection such as interferon-gamma release assays [IGRAs] appear to have a potential role in the diagnosis of TB infection in these patients (50). Radiological findings in immunocompromised patients with pulmonary TB are often atypical. In these patients cavitary lesions are seldom seen and lower lung field and multiple lobar involvement are often seen. Patients on MHD can develop pleural effusion due to heart failure, uraemic pleuritis or hypoproteinaemia. Similarly, pericarditis and/or pericardial effusion and ascites in these patients are often due to dialysis associated pericarditis and/or ascites (51). Pleural fluid in uraemic pleuritis can also be exudative and haemorrhagic with high protein and lactate dehydrogenase levels with a predominance of lymphocytes (52,53). These findings are often encountered in TB pleural effusion and are therefore, unreliable. Diagnostic value of adenosine deaminase activity in pleural fluid even in RT patients is also unreliable (54). The acid-fast bacilli [AFB] can seldom be seen and mycobacteria are rarely cultured from the pleural fluid. Usefulness of modern diagnostic tests, such as polymerase chain reaction [PCR], has not been systematically explored in the diagnosis of TB in patients with renal disease. Studies with a large sample size are required to establish the usefulness of these investigations.

DIAGNOSIS

MANAGEMENT

Definitive diagnosis of TB requires demonstration or isolation of Mycobacterium tuberculosis. In majority of the studies published from the west, diagnosis of TB was based on demonstration of the organism in the body fluids and/or tissues or on the basis of histopathological findings (5-7). In contrast, 8.6 to 68 per cent of the patients in various Indian studies have been diagnosed to have TB only on clinical grounds (30-32). This is probably due to the low threshold for therapeutic trial with antituber-

Principles of antituberculosis treatment during dialysis and following RT remain similar to that in other patients with TB. The choice of safe and effective antituberculosis treatment for these patients depends upon the pharmacology of drugs in the setting of renal failure and during MHD and their interaction with immunosuppressive drugs used in patients with RT. Pharmacological properties of antituberculosis drugs that determine how the levels of these drugs are likely to be influenced by

Table 33.3: Comparison of site of tuberculosis involvement in patients with chronic renal failure [n = 923] pre- and postrenal transplantation Site of tuberculosis

Pre-RT No. [%]

Post-RT No. [%]

Number of cases Pleural* Pulmonary Abdominal* Nodal Pericardial* Presentation as PUO* Genitourinary Bone and joints Miliary* Neurological* Miscellaneous Laryngeal Orchitis Skin Psoas abscess Gluteal abscess

152 50 [32.9] 44 [28.9] 16 [10.5] 14 [9.2] 11 [7.2] 10 [6.6] 3 [1.9] 2 [1.3] 1 [0.6] 1 [0.6] 0 0 0 0 0 0

156 17 [10.9] 45 [28.8] 4 [2.6] 13 [8.3] 0 46 [29.5] 0 2 [1.3] 14 [8.9] 9 [5.8] 6 [3.9] 2 1 1 1 1

* Statistically significant difference RT = renal transplant; PUO = pyrexia of unknown origin

Tuberculosis in Chronic Renal Failure renal impairment have been extensively reviewed by several workers (55-58). Renal insufficiency complicates the management of TB because some antituberculosis medications are cleared by the kidneys. Management may be further complicated by the removal of some antituberculosis drugs via haemodialysis. Thus, some alteration in the dosage of antituberculosis medications is commonly necessary in patients with renal failure and ESRD receiving haemodialysis. Decreasing the dose of selected antituberculosis drugs may not be the best method of treating TB because, although toxicity may be avoided, the peak serum concentrations may be too low. Therefore, increasing the dosing interval instead of decreasing the dosage of the antituberculosis drugs is recommended (59). Isoniazid Ninety-six per cent of the administered dose of isoniazid is recoverable in the urine as unchanged drug together with its metabolites (60). All metabolites of isoniazid are devoid of antituberculosis activity. They are less toxic than isoniazid and are more rapidly excreted through the kidneys (61). In anuric patients, half-life of isoniazid varies with acetylator status. Half-life is essentially unaltered in rapid acetylators while in those who are slow acetylators, it has been observed to increase by 40 per cent. It is, therefore, recommended that normal daily dosage of isoniazid [300 mg or 5 mg/kg body weight] should be given in patients with severe renal impairment including anuric patients. In slow acetylators with severe renal impairment and who are not on dialysis, 5 to 6 mg/kg body weight isoniazid will be equivalent to daily dose of 7 to 9 mg/kg body weight in normal subjects. It has been shown that isoniazid is well tolerated at this dose in these patients (62). Therefore, previous recommendation to reduce the daily dose of isoniazid to 150 mg in patients with severe CRF is unjustified (63,64). Also, there is convincing evidence that isoniazid at a dosage less than 200 mg/day significantly decreases therapeutic response (65). Some suggestions regarding administering isoniazid eight hourly are unwarranted (66) and there is no justification for estimation of isoniazid levels in these patients (60). Rifampicin Serum half-life of rifampicin and the proportion of the unchanged drug excreted in the urine increase steadily

485

as the individual dosage is increased from 300 to 900 mg, probably as a result of biliary excretion route becoming saturated. Daily treatment with rifampicin for a period of one week or more, results in the induction of hepatic enzymes, which deacetylate the drug. Such induction significantly reduces half-life of rifampicin and probably reduces urinary excretion of the unchanged drug. About 14 per cent of the dose is recovered in urine whether or not liver enzymes have been induced. It is thought that effect of renal impairment on rifampicin excretion is negligible at a dose of 450 mg, modest at 600 mg and substantial at 900 mg (56). Therefore, rifampicin up to a dose of 600 mg/day does not require reduction at any degree of renal failure (56). Pyrazinamide As little as three to four per cent of ingested pyrazinamide is excreted unchanged in the urine. Its half-life is six to ten hours and very little change is expected even in patients with severe renal failure (67,68). However, Fabre et al (68), suggested to avoid its use in severe renal failure, while Anderson et al (69), and Andrew et al (5), suggested reduction in the dose to 12 to 20 mg/kg/day. However, such a dosage schedule will cause suboptimal therapeutic levels (70). Controlled clinical trials have shown that thrice weekly treatment is therapeutically more effective than daily administration (71). It is, therefore, recommended that patients with renal impairment should be treated either thrice or twice weekly with 40 to 60 mg/kg pyrazinamide. However, in most of the published studies, patients had received daily dose of pyrazinamide (67,68). Streptomycin Nearly 80 per cent of the dose of streptomycin, like other aminoglycosides, is excreted unchanged in the urine. Aminoglycosides are excreted by glomerular filtration and not by active secretion (72,73). Line et al (72) demonstrated significant correlation between degree of renal failure and serum levels of streptomycin. Therefore, if streptomycin is to be used in the treatment of TB in presence of renal failure, its dosage must be decreased. It is preferable to give streptomycin twice or thrice weekly without decreasing the usual dose. If possible, drug trough level should be measured and should not exceed 4 mg/l.

486

Tuberculosis

Ethambutol About 80 per cent of the dose of ethambutol is excreted unchanged in urine and major reduction in daily ethambutol doses are recommended in patients with renal failure. Recommended dosage in presence of renal failure varies from 5 to 10 mg/kg/day by various workers (6,74,75). Ethambutol can result in blindness. If treatment of TB in renal failure requires administration of a fourth drug, in addition to rifampicin, isoniazid and pyrazinamide, streptomycin seems to be a better choice as compared to ethambutol. As the measurement of streptomycin levels is much easier compared to measuring ethambutol levels, better therapeutic drug monitoring is possible with the use of streptomycin. There is report of irreversible blindness in a patient of ESRD treated with ethambutol for TB and, thus, periodic ophthalmic examination should be done in these patients (76). Second Line Antituberculosis Drugs Dosages of kanamycin, amikacin, and capreomycin must be adjusted in patients with renal failure because of renal excretion of these drugs. Administration of these drugs just prior to haemodialysis, removes approximately 40 per cent of the dosage (77). Dosing interval of these drugs should be increased. Ethionamide is not cleared by the kidneys, nor is the drug removed with haemodialysis, so no dose adjustment is necessary (78). Para-amino salicylic acid [PAS] is moderately cleared by haemodialysis [6.3%] but its metabolite, acetyl-PAS, is substantially removed by haemodialysis; twice daily dosing [4 g] should be adequate (78). Cycloserine is excreted primarily by the kidney, and is cleared by haemodialysis [56%]. Thus, an increase in the dosing interval is necessary to avoid accumulation between haemodialysis sessions, and the drug should be given after hemodialysis to avoid underdosing (78). The fluoroquinolones undergo some degree of renal clearance that varies from drug to drug. For example, levofloxacin undergoes greater renal clearance than moxifloxacin (79). It should be noted that the fluoroquinolone dosing recommendations for ESRD provided by the manufacturers were developed for treating pyogenic bacterial infections. These recommendations may not be applicable to the treatment of TB in patients with ESRD. It is important to monitor serum drug concentrations in persons with renal insufficiency who are taking cycloserine, ethambutol, or

any of the injectable agents to minimize dose-related toxicity, while providing effective doses. Currently, enough data are not available on antituberculosis drug dosage modification in patients receiving peritoneal dialysis and the drug removal mechanisms differ between haemodialysis and peritoneal dialysis. Therefore, such patients may require close follow-up and therapeutic drug monitoring. Treatment of Tuberculosis in Patients on Dialysis Treatment of TB is imperative as soon as the diagnosis is confirmed or strongly suspected. Isoniazid and rifampicin have been used in majority of the studies (4-6,16,21). Streptomycin is not so commonly used now a days in patients with renal failure. Isoniazid at a dosage of 200 to 300 mg/day does not cause significant toxicity in adult patients with renal failure. However, vitamin B6 in a dose of 10 to 20 mg should be administered prophylactically in all these patients. Dosage modification is not required for rifampicin but it should be administered cautiously in patients with CRF who are not on haemodialysis as it can result in acute renal failure or deterioration in the renal functions (80). Dosing recommendations for adult patients with reduced renal function [creatinine clearance < 30 ml/min] and for adult patients receiving haemodialysis are presented in Table 33.4 (59). The antituberculosis drugs should be administered after haemodialysis to avoid any loss of the drugs during the procedure, and to facilitate direct observation of the treatment (59). The possibility of impaired absorption of antituberculosis drugs because of co-morbid clinical conditions, such as diabetes mellitus with gastroparesis that are frequently present in these patients should also be kept in mind. Under the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India, patients receive DOTS. Under the programme, standard intermittent antituberculosis treatment has been advocated for all patients including those with renal failure on conservative management, MHD or following RT. Monitoring of renal or hepatic function is not done under programme conditions. As of now, there are no published data on the efficacy and safety of these regimens in patients with CRF on conservative management or MHD. There is no consensus for the duration of antituberculosis treatment in these patients. These issues merit further studies.

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487

Table 33.4: Dosing recommendations for adult patients with reduced renal function* and for adult patients receiving haemodialysis Drug

Change in frequency of administration

Dosage schedule

Isoniazid

No change

5 mg/kg [maximum 300 mg] once daily, or 15 mg/kg [maximum 900 mg] per dose, three times per week

Rifampicin

No change

10 mg/kg [maximum 600 mg] once daily, or 10 mg/kg [maximum 600 mg] per dose, three times per week

Pyrazinamide

Yes

25 to 35 mg/kg per dose three times per week [not daily]

First-line drugs

Ethambutol

Yes

15 to 25 mg/kg per dose three times per week [not daily]

Streptomycin

Yes

12 to 15 mg/kg per dose two or three times per week [not daily]

Second-line drugs Cycloserine

Yes

250 mg once daily, or 500 mg per dose three times per week†

Ethionamide

No change

15 to 20 mg/kg/day [maximum 1 g; usually 500 to 750 mg] in a single daily dose or two divided doses‡

Para-aminosalicylic acid

No change

8 to 12 g/day, in two or three doses

Capreomycin

Yes

12 to 15 mg/kg per dose two or three times per week [not daily]

Kanamycin

Yes

12 to 15 mg/kg per dose two or three times per week [not daily]

Amikacin

Yes

12 to 15 mg/kg per dose two or three times per week [not daily]

Levofloxacin

Yes

750 to 1000 mg per dose three times per week [not daily]

* Creatinine clearance less than 30 ml/min † The appropriateness of 250 mg daily doses has not been established ‡ The single daily dose can be given at bed time or with the main meal. No data to support intermittent administration The medications should be given after haemodialysis on the day of haemodialysis Monitoring of serum drug concentrations should be considered to ensure adequate drug absorption without excessive accumulation, and to assist in avoiding toxicity Data currently are not available for patients receiving peritoneal dialysis. Until data become available, begin with doses recommended for patients receiving haemodialysis and verify adequacy of dosing, using monitoring of serum concentration Adapted from reference 59

Rifampicin is an inducer of hepatic enzymes and is known to alter the metabolism of many drugs. In this regard, rifampicin use becomes an important issue in patients before and following RT. Majority of these patients also receive antihypertensive drugs, and with the use of rifampicin, an adequate blood pressure control may not be achieved and the dose modification may be required for the antihypertensive drugs. Rifampicin also decreases the efficacy of other drugs such as corticosteroids, cyclosporine and tacrolimus. Therefore, dosages of these drugs also need to be modified. This has lead to use of non-rifampicin based protocols for treatment of TB in RT recipients with an aim of decreasing the cost of therapy as well as avoiding frequent monitoring (81,82).

However, these findings require validation in future studies. There are no published data on the efficacy and safety of the standard intermittent regimens used in the DOTS strategy used in the RNTCP of Government of India in RT recipients. Controlled trials with large sample size are required to establish the efficacy, safety, and optimum duration of the standard treatment regimens used in the RNTCP in patients with CRF. Treatment of Latent Tuberculosis Infection in Patients with Chronic Renal Failure on Dialysis Treatment The ATS guidelines (83) mention the relative risk of developing TB in patients with CRF and those on MHD

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to be 10 to 25.3 and targeted tuberculin testing and treatment of latent TB infection is a well-accepted strategy in developed countries with low transmisison of TB such as the USA (59,83). However, this approach does not seem to have much relevance in highly endemic areas. Published data suggest that TST is not a reliable test for diagnosis of latent TB in patients with CRF (84-86). The potential role of IGRAs in this setting merits further study. The reader is referred to the chapter “Diagnosis of latent tuberculosis infection: recent advances and future directions” [Chapter 12] for more details. In a randomized, double-blind, placebo-controlled, prospective trial of isoniazid prophylaxis in patients on haemodialysis from India (87), some degree of protection was shown. This protection appeared to be insignificant when the number of cases who dropped out due to various reasons and significant number of patients developing TB in the treatment group were also taken into consideration. Another recently published trial on isoniazid prophylaxis in patients due to undergo RT who were receiving MHD (88) documented that TB developed in 16.7 per cent patients in the isoniazid group compared with 32.7 per cent patients in the control group, suggesting that there was a significant reduction in the incidence of TB if isoniazid was started early. These issues need further clarification. Another issue, which is not clear, is the optimum duration of antituberculosis treatment before a patient with CRF can be safely taken up for RT. Controlled trials have not been conducted to answer this question and there is no consensus. Possibly, four to six weeks treatment with an adequate antituberculosis drug regimen should be enough before the surgery especially if the patient is showing a good clinical response to treatment. Treatment of Tuberculosis in Recipients of Renal Transplantation Management of TB after RT is similar to management of TB in patients on MHD with few differences. First, following successful RT, renal function become normal and dosage modification done during MHD is no longer required. Secondly, antituberculosis drug interaction with immunosuppressive drugs is an important issue in these patients. Three most commonly used immunosuppressive drugs in these patients are prednisolone, cyclosporine and azathioprine. Sometimes, cyclophosphamide is also used. Recently, newer drugs like tacrolimus,

rapamycin [sirolimus], mycophenolate mofetil, misoribin have been used in some western countries. There have been no recommendations to decrease the dosage of immunosuppressive medication if patients develop TB after RT. During rifampicin therapy, daily dosage of corticosteroids should be increased or maintained to nearly one and a half times the baseline dosage, as rifampicin is known to be an inducer of the enzymes involved in the hepatic metabolism of corticosteroids (89). Azathioprine sometimes causes hepatotoxicity, which has to be differentiated from hepatotoxicity due to antituberculosis drugs. The major interaction of antituberculosis drugs is with cyclosporine A. Rifampicin produces lowering of blood levels of cyclosporine A by producing an increase in its hepatic metabolism (90). Ideally, cyclosporine A blood levels should be monitored and its dose adjusted if the patient is also receiving rifampicin. Fluoroquinolones decrease the metabolism of cyclosporine A and replace it from the bound form, thus, increasing its toxicity. Optimum duration of antituberculosis treatment in RT recipients is again controversial. Patients who receive DOTS under the RNTCP of Government of India are treated for six months with standard intermittent treatment regimens. In individual cases, treatment duration may be prolonged by another three [e.g., extrapulmonary TB] to six [e.g., TB meningitis] months. However, in some studies most patients have received treatment for 12 months or more (29-32,91). The efficacy of short-course chemotherapy has not been studied in detail in these patients. Treatment of Latent Tuberculosis Infection in Renal Transplant Recipients The relative risk of a RT patient developing TB has been estimated to be 37 (83). Therefore, the recent American Thoracic Society [ATS] guidelines recommend treatment of latent TB infection in RT recipients (83). However, it is possible for a person to develop TB inspite of chemoprophylaxis (92). In a recent study published from India (93), isoniazid prophylaxis started at the time of RT offered some protection from the development of TB (93). In this study, 11.1 per cent patients receiving isoniazid prophylaxis developed TB as compared to 25.8 per cent in the control group [relative risk 0.36]. However, these differences were not statistically significant. With the advent of IGRAs as more reliable indicators of detecting

Tuberculosis in Chronic Renal Failure latent TB infection as compared with TST, more information is expected to be available. Therapeutic Response and Prognosis With the proper use of currently available antituberculosis drugs, there is a potential for complete cure in a compliant patient. Major factors which determine the response to antituberculosis drugs are extent of disease at the time of diagnosis, treatment regimen given to the patients, sensitivity of the mycobacteria to given drugs and compliance with drug treatment. In the studies, where the response to antituberculosis treatment was clearly reported, the cure rate varied from 50 to 80 per cent (5-6,17). Mortality varied from 7.7 to 75 per cent but TB was seldom the cause of death in these patients. Mortality due to TB occurs in nearly 10 per cent of the RT patients (29,32,33). In RT patients, antituberculosis treatment induced hepatotoxicity has been estimated to be about 20 per cent in two major studies (31,32). The magnitude of the problem of multidrugresistant tuberculosis [MDR-TB] in patients with CRF and following RT needs to be studied in detail. NONTUBERCULOUS MYCOBACTERIAL INFECTION IN CHRONIC RENAL FAILURE Infection with nontuberculous mycobacteria [NTM] is uncommon in patients with renal failure and following RT. In one study (6), 17.6 per cent of mycobacterial infections in dialysis patients were caused by Mycobacterium avium-intracellulare and Mycobacterium fortuitium. Infection with NTM has been reported more frequently in RT recipients than in patients on MHD. Among these patients, about 10 per cent of mycobacterial infections are due to NTM, of which Mycobacterium kansasii and Mycobacterium chelonae are frequent (26,27, 93-98). Usually, these organisms cause chronic infection of bone and soft tissues. In India, mycobacterial culture and sensitivity testing facilities in reliable, accredited, quality assured laboratories are seldom available and it is therefore, possible that NTM infections are being missed. REFERENCES 1. Ogg CS, Toseland PA, Cameson JS. Pulmonary tuberculosis in a patient on intermittent haemodialysis. BMJ 1968;2:283-4.

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2. Comstock GW. Frost revisited: the modern epidemiology of tuberculosis. Am J Epidemiol 1975;101:363-82. 3. Papadimitriou M, Memmos D, Metaxas P. Tuberculosis in patients on regular haemodialysis. Nephron 1979;24:53-7. 4. Sasaki S, Akiba T, Suenaga M, Tomura S, Yoshiyama N, Nakagawa S, et al. Ten years survey of dialysis associated tuberculosis. Nephron 1979;24:141-5. 5. Andrew OT, Schoenfeld PY, Hopewell PC, Humphreys MH. Tuberculosis in patients with end-stage renal disease. Am J Med 1980;68:59-65. 6. Rutsky EA, Rostand SG. Mycobacteriosis in patients with chronic renal failure. Arch Intern Med 1980;140:57-61. 7. Higgins RM, Cahn AP, Porter D, Richardson AJ, Mitchell RG, Hopkin JM, et al. Mycobacterial infection after renal transplantation. QJM 1991;78:145-53. 8. Tabata T, Suzuki R, Kikunami K, Matsushita Y, Inoue T, Inove T, et al. The effect of 1 alpha hydroxy-vitamin D3 on cell mediated immunity in hemodialysed patients. J Clin Endocrinol Metabol 1986;63:1218-21. 9. Venezio FR, Koseny FA, Divincenzo CA, Hano JE. Effect of 1,25 dihydroxy vitamin D3 on leukocyte functions in patients receiving chronic hemodialysis. J Infect Dis 1988;158:1102-5. 10. Himmelfarb J, Zaoui P, Hakim RM. Modulation of granulocyte LAM-1 and MAC-1 during dialysis: a prospective randomised, controlled trial. Kidney Int 1992;41:388-95. 11. Descamps-Latscha B, Goldfarb B, Nguygen AT, Landais P, London G, Cavaillon NH, et al. Establishing the relationship between complement activation and stimulation of phagocyte oxidation metabolism in randomised study. Nephron 1991;59:279-85. 12. Himmelfarb J, Ault KA, Holbrook D, Leeber DA, Hakim RM. Intradialysis granulocyte reactive oxygen species production: a prospective crossover trial. J Am Soc Nephrol 1993;4:17886. 13. Beaurain G, Naret C, Marcon L, Grateau G, Drueke T, Urena P, et al. In vivo T-cell reactivation in chronic uremic haemodialysed and non-haemodialysed patients. Kidney Int 1989;36:636-44. 14. Gibbons RA, Martinez OM, Garovoy MR. Altered monocyte function in uraemia. Clin Immunol Immunopathol 1990;56:66-71. 15. Yuan FH, Guang LX, Zhao SJ. Clinical comparison of 1498 chronic renal failure patients with and without tuberculosis. Ren Fail 2005;27:149-53. 16. Narula AS, Misra A, Oberoi HS, Anand AC, Chatterjee SK, Waryam S. Tuberculosis in patients of chronic renal failure on maintenance haemodialysis. Indian J Nephrol 1991;1:67. 17. Malhotra KK, Parashar MK, Sharma RK, Bhuyan UN, Dash SC, Kumar R, et al. Tuberculosis in maintenance hemodialysis patients. Postgrad Med J 1981;57:492-8. 18. Pradhan RP, Katz LA, Nidus BD, Matalon R, Eisinger RP. Tuberculosis in a dialysed patient. JAMA 1974;229:798-800. 19. Basok A, Vorobiov M, Rogachev B, Avnon L, Tovbin D, Hausmann M, et al. Spectrum of mycobacterial infections: tuberculosis and Mycobacterium other than tuberculosis in dialysis patients. Isr Med Assoc J 2007;9:448-51.

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Tuberculosis

20. Christopoulos AI, Diamantopoulos AA, Dimopoulos PA, Gumenos DS, Barbalias GA. Risk of tuberculosis in dialysis patients: association of tuberculin and 2,4-dinitrochlorobenzene reactivity with risk of tuberculosis. Int Urol Nephrol 2006;38:745-51. 21. Zyga S, Tourouki G. Tuberculosis in haemodialysis: a problem making a comeback. EDTNA ERCA J 2006;32:176-8. 22. Centers for Disease Control and Prevention [CDC]. Tuberculosis transmission in a renal dialysis center-Nevada, 2003. MMWR Morb Mortal Wkly Rep 2004;53:873-5. 23. Coutts II, Jegarajah S, Stark JE. Tuberculosis in renal transplant recipients. Br J Dis Chest 1979;73:141-8. 24. Riska H, Gronhagen-Riska C, Ahonen J. Tuberculosis and renal allograft transplantation. Transplant Proc 1987;19: 4096-7. 25. McWhinney N, Khan O, Williams G. Tuberculosis in patients undergoing maintenance haemodialysis and renal transplantation. Br J Surg 1981;68:408-11. 26. Lichtenstein IH, Macgregor RR. Mycobacterial infection in renal transplant recipients: report of five cases and review of literature. Rev Infect Dis 1983;5:216-26. 27. Lloveras J, Peterson PK, Simmons RL, Najarian JS. Mycobacterial infections in renal transplant patients. Arch Intern Med 1982;142:888-92. 28. Govil S, Ojha RK, Bhatia RK, Zope JD, Shah PR, Trivedi HL. Tuberculosis and renal allograft dysfunction. Indian J Nephrol 1995;5:96-7. 29. Agarwal DK, Ammanna N, Murthy BVR, Neela P, Ratnakar KS. High incidence of posttransplant tuberculosis in India. Indian J Nephrol 1994;4:91. 30. Agarwal SK, Dash SC, Tiwari SC, Agarwal R, Mehta SN. Spectrum of tuberculosis in renal transplant recipients in northern India. Indian J Nephrol 1992;2:39-43. 31. Sakhuja V, Jha V, Varma PP, Joshi K, Chugh KS. The high incidence of tuberculosis among renal transplant recipients in India. Transplantation 1996;61:211-5. 32. Hariharan S, Date A, Gopalkrishnan G, Pandey AP, Jacob CK, Kirubakaran MG, et al. Tuberculosis after renal transplantation. Dialysis Transpl 1987;16:311-2. 33. John GT, Vincent L, Jeyaseelan L, Jacob CK, Shastry JCM. Cyclosporin immunosuppression and mycobacterial infections. Transplantation 1994;58:247-9. 34. Atasever A, Bacakoglu F, Toz H, Basoglu OK, Duman S, Basak K, et al. Tuberculosis in renal transplant recipients on various immunosuppressive regimens. Nephrol Dial Transplant 2005;20:797-802. 35. Vandermarliere A, Van Audenhove A, Peetermans WE, Vanrenterghem Y, Maes B. Mycobacterial infection after renal transplantation in a Western population. Transpl Infect Dis 2003;5:9-15. 36. Laxminarayan S, Sahn SA. Tuberculosis in patients after renal transplantation. Tubercle 1973;54:72-6. 37. Mourad G, Soulillou JP, Chong G, Pouliquen M, Hourmant M, Mion C. Transmission of Mycobacterium tuberculosis with renal allograft. Nephron 1985;41:82-5.

38. Peters TG, Reiter CG, Boswell RL. Transmission of tuberculosis by kidney transplantation. Transplantation 1984; 38:514-6. 39. Graham JC, Kearns AM, Magee JG, El-Sheikh MF, Hudson M, Manas D, et al. Tuberculosis transmitted through transplantation. J Infect 2001;43:251-4. 40. Venkata RKC, Kumar S, Krishna RP, Kumar SB, Padmanabhan S, Kumar S. Tuberculosis in chronic kidney disease. Clin Nephrol 2007;67:217-20. 41. Chuang FR, Lee CH, Wang IK, Chen JB, Wu MS. Extrapulmonary tuberculosis in chronic haemodialysis patients. Ren Fail 2003;25:739-46. 42. Sharma SK, Mohan A, Pande JN, Prasad KL, Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis QJM 1995;88:29-37. 43. Karayaylali I, Seyrek N, Akpolat T, Ates K, Ozener C, Yilmaz ME, et al. The prevalence and clinical features of tuberculous peritonitis in CAPD patients in Turkey, report of ten cases from multi-centers. Ren Fail 2003;25:819-27. 44. Abraham G, Mathews M, Sekar L, Srikanth A, Sekar U, Soundarajan P. Tuberculous peritonitis in a cohort of continuous ambulatory peritoneal dialysis patients. Perit Dial Int 2001;21[Supp3]:S202-4. 45. Gupta N, Prakash KC. Asymptomatic tuberculous peritonitis in a CAPD patient. Perit Dial Int 2001;21:416-7. 46. Klote MM, Agodoa LY, Abbott KC.Risk factors for Mycobacterium tuberculosis in US chronic dialysis patients. Nephrol Dial Transplant 2006;21:3287-92. Epub 2006 Sep 12. 47. el-Agroudy AE, Refaie AF, Moussa OM, Ghoneim MA. Tuberculosis in Egyptian kidney transplant recipients: study of clinical course and outcome. J Nephrol 2003;16:404-11. 48. Amedia C, Oettinger CW. Unusual presentation of tuberculosis in chronic haemodialysed patients. Clin Nephrol 1977;8:363-6. 49. Habesoglu MA, Torun D, Demiroglu YZ, Karatasli M, Sen N, Ermis H, et al. Value of the tuberculin skin test in screening for tuberculosis in dialysis patients. Transplant Proc 2007;39:883-6. 50. Passalent L, Khan K, Richardson R, Wang J, Dedier H, Gardam M.Detecting latent tuberculosis infection in hemodialysis patients: a head-to-head comparison of the TSPOT.TB test, tuberculin skin test, and an expert physician panel. Clin J Am Soc Nephrol 2007;2:68-73. Epub 2006 Oct 18. 51. Cinque TJ, Letteri JM. Idiopathic ascites in chronic renal failure. N Y State J Med 1973;73:781-4. 52. Berger HW, Rammadan G, Neff MS, Buhain WJ. Uremic pleural effusion: a study of 14 patients on chronic dialysis. Ann Intern Med 1975;82:362-4. 53. Fairshter RD, Vazin ND, Mirahmudi MK. Lung pathology in chronic hemodialysed patients. Int J Artif Organs 1982;5:97100. 54. Chung JH, Kim YS, Kim SI, Park K, Park MS, Kim YS, et al. The diagnostic value of the adenosine deaminase activity in the pleural fluid of renal transplant patients with tuberculous pleural effusion. Yonsei Med J 2004;45:661-4.

Tuberculosis in Chronic Renal Failure 55. Weber WW, Hein DW. Clinical pharmacokinetics of isoniazid. Clin Pharmacokinet 1979;4:401-22. 56. Kenny MT, Strates B. Metabolism and pharmacokinetics of the antibiotic rifampicin. Drug Metab Rev 1981;12:159-218. 57. Holdiness MR. Clinical pharmacokinetics of the antitubercular drugs. Clin Pharmacokinet 1984;9:511-44. 58. Holdiness MR. Chromatographic analysis of antitubercular drugs in biological samples. J Chromatogr 1985;340:321-59. 59. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Morb Mortal Wkly Rep 2003;55:1-77. 60. Ellard GA, Gammon PT. Pharmacokinetics of isoniazid metabolism in man. J Pharmacokinetics Biopharma 1976;4:83-113. 61. Ellard GA. A slow release preparation of isoniazid: pharmacological aspects. Bull Int Union Tuberc 1976;51:144-54. 62. Hong Kong Treatment Services and East African and British Medical Research Council. First-line chemotherapy in the treatment of bacteriological relapse of pulmonary tuberculosis following a short-course regimen. Lancet 1976;1:162-3. 63. Anonymous. Tuberculosis in patients having dialysis. BMJ 1980;280:349. 64. Whelton A. Antibacterial chemotherapy in renal insufficiency: a review. Antibiotics Chemother 1974;81:1-48. 65. East African/British Medical Research Council. Isoniazid with thiacetazone in the treatment of pulmonary tuberculosis in east Africa. Second investigation. Tubercle 1963;44:301-33. 66. Bennett WM. Guide to drug dosage in renal failure. Clin Pharmacokinetics 1988;15:326-54. 67. Stamatakis G, Montes C, Trouvin JH, Farinotti R, Fessi H, Kenouch S, et al. Pyrazinamide and pyrazanoic acid pharmacokinetics in patients with chronic renal failure. Clin Nephrol 1988;30:230-4. 68. Fabre J, Fox HM, Dayer P, Balant L. Difference in kinetic properties of drugs: implication as to the selection of a particular drug for use in patients with renal failure with special emphasis on antibiotic and beta–adrenoreceptor blocking agents. Clin Pharmacokinetics 1980;5:441-64. 69. Anderson RJ, Gambertoglio JG, Schrier RW. Drugs used in the treatment of tuberculosis and fungal infections. In: Clinical use of drugs in renal failure. Springfield: Thomas 1976. p. 90-101. 70. Ellard GA. Absorption, metabolism and excretion of pyrazinamide in man. Tubercle 1969;50:144-58. 71. East African/British Medical Research Council. A controlled comparison of four regimens of streptomycin plus pyrazinamide in the retreatment of pulmonary tuberculosis. Tubercle 1969;50:81-114. 72. Line DH, Poole GW, Waterworth PM. Serum streptomycin levels and dizziness. Tubercle 1970;51:76-81. 73. Mitchison DA, Ellard GA. Tuberculosis in patients having dialysis. BMJ 1980;280:1533. 74. Anonymous. Tuberculosis in chronic renal failure. Lancet 1980;1:909-10. 75. Varughese A, Brater DG, Benet LZ, Lee CC. Ethambutol kinetics in patients with impaired renal function. Am Rev Respir Dis 1986;134:84-8.

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76. Fang JT, Chen YC, Chang MY. Ethambutol induced optic neuritis in patients with end stage renal disease on haemodialysis: two case reports and literature review. Ren Fail 2004;26:189-93. 77. Matzke GR, Halstenson CE, Keane WF. Hemodialysis elimination rates and clearance of gentamicin and tobramycin. Antimicrob Agents Chemother 1984;25:128-30. 78. Malone RS, Fish DN, Spiegel DM, Childs JM, Peloquin CA. The effect of hemodialysis on cycloserine, ethionamide, paraaminosalicylate, and clofazimine. Chest 1999;116:984-90. 79. Fish DN, Chow AT. The clinical pharmacokinetics of levofloxacin. Clin Pharmacokinet 1997;32:101-19. 80. Mittal R, Saxena S, Agarwal SK, Tiwari SC, Bhuyan UN, Dash SC. Acute interstitial nephritis following first exposure to continuous rifampicin therapy. Indian J Nephrol 1993;3:546. 81. Vachharajani TJ, Oza UG, Phadke AG, Kirpalani AL. Tuberculosis in renal transplant recipients: rifampicin sparing treatment protocol. Int Urol Nephrol 2002;34:551-3. 82. Jha V, Sakhuja V. Rifampicin sparing treatment protocols in posttransplant tuberculosis. Int Urol Nephrol 2004;36:287-8. 83. Joint Statement of the American Thoracic Society [ATS], and the Centers for Disease Control and Prevention [CDC], endorsed by the Council of the Infectious Diseases Society of America [IDSA], September 1999, and the sections of this statement. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221-47. 84. Sester M, Sester U, Clauer P, Heine G, Mack U, Moll T, et al. Tuberculin skin testing underestimates a high prevalence of latent tuberculosis infection in haemodialysis patients. Kidney Int 2004;65:1826-34. 85. Poduval RD, Hammes MD. Tuberculosis screening in dialysis patients–is the tuberculin test effective? Clin Nephrol 2003;59:436-40. 86. Fang HC, Chou KJ, Chen CL, Lee PT, Chiou YH, Hung SY, et al. Tuberculin skin test and anergy in dialysis patients of a tuberculosis-endemic area. Nephron 2002;91:682-7. 87. John GT, Thomas PP, Thomas M, Jeyaseelan L, Jacob CK, Shastry JC. A double-blind, randomised trial of primary isoniazid prophylaxis in dialysis and transplant patients. Transplantation 1994;57:1683-4. 88. Vikrant S, Agarwal SK, Gupta S, Bhowmik D, Tiwari SC, Dash SC, et al. Prospective randomised controlled trial of isoniazid chemoprophylaxis during renal replacement therapy. Trans Infect Dis 2005;7:99-108. 89. Edwards OM, Courtenary Evans RJ, Galley JM, Hunter J, Tait AD. Changes in cortisol metabolism following rifampicin therapy. Lancet 1974;2:548-51. 90. Cutler RE. Cyclosporin drug interaction. Dialysis Transpl 1988;17:139-51. 91. British Thoracic and Tuberculosis Association. Short-course chemotherapy in pulmonary tuberculosis. Lancet 1976;2: 1102-4. 92. Kuruvila KC, Colabawalla BN, Joshi SS. Problem of transplantation in India. Transpl Proc 1979;2:1296.

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Tuberculosis

93. Agarwal SK, Gupta S, Dash SC, Bhowmik D, Tiwari SC. Prospective randomised trial of isoniazid prophylaxis in renal transplant recipient. Int Urol Nephrol 2004;36:425-31. 94. Rosen T. Cutaneous Mycobacterium kansasii infection presenting as cellulitis. Cutis 1983;31:87-9. 95. Fraser DW, Buxton AE, Naji A, Barker C, Rudnick M, Weinstein AJ. Disseminated Mycobacterium kansasii infections presenting with cellulitis in a recipient of a renal homograft. Am Infect Dis 1975;112:125-9.

96. Spence RK, Dafoe DC, Rabin G, Grossman RA, Naji A, Barker CF, et al. Mycobacterium infections in renal allograft recipients. Arch Surg 1983;118:356-9. 97. Cruz N, Ramirex-Muxo O, Bermudez RH, Santiago-Delpin EA. Pulmonary infection with Mycobacterium kansasii in a renal transplant patient. Nephron 1980;26:187-8. 98. Sanger JR, Stampfl D, Franson T. Recurrent granulomatous synovitis due to Mycobacterium kansasii in renal transplant patient. Am J Hand Surg 1987;12:436-41.

Disseminated and Miliary Tuberculosis

34

SK Sharma, Alladi Mohan

The whole surface, in front and behind, as well as within the interstitium of the major lobes, was covered with firm small white corpuscles, of the size of millet seeds….

deficiency virus [HIV] infection, acquired immunodeficiency syndrome [AIDS], disseminated and miliary TB are particularly common (1,3,10,11).

— John Jacob Manget EPIDEMIOLOGY INTRODUCTION Disseminated tuberculosis TB refers to concurrent involvement of at least two non-contiguous organ sites of the body, or, involvement of the blood or bone marrow by tuberculosis [TB] process (1-3). One form of disseminated TB, miliary TB, results from a massive haematogenous dissemination of tubercle bacilli which results in tiny discrete foci usually the size of millet seeds [1 to 2 mm] more or less uniformly distributed in the lungs and the other viscera (4-9). Miliary pattern on the chest radiograph is the hallmark of miliary TB. Miliary and disseminated TB continue to be a diagnostic problem even in areas endemic to TB, where clinical suspicion is very high. Mortality from miliary TB disease has remained high despite effective therapy being available. In patients with human immuno-

The epidemiology of miliary TB as documented in several published studies is depicted in Table 34.1 (12-36). Miliary TB accounts for less than two per cent of all cases of TB and up to 20 per cent of all extra-pulmonary TB cases in various clinical studies in immunocompetent individuals; the corresponding figures in autopsy studies have been higher [Table 34.1]. Caution must be exercised while comparing these epidemiological data as these studies are hospital based or autopsy studies. The emergence of the HIV/AIDS pandemic and widespread use of immunosuppressive drugs have changed the epidemiology of miliary TB. Since its first description by John Jacob Manget, the clinical presentation of miliary TB has changed dramatically. Especially, its occurrence as a complication of childhood infection is diminishing and the “cryptic form” [vide infra] in a

Table 34.1: Epidemiology of miliary tuberculosis Study (reference)

Frequency of miliary TB Overall [%]

Adults, autopsy studies (12-18) Adults, clinical studies (19-22) Children, clinical studies (23-26) All age groups, epidemiological studies, public health data (27-36) TB = tuberculosis Adapted from reference 4

0.3-13.3 1.3-2.0 0.7-41.3 —

Among extra-pulmonary TB [%] 11.9-40.5 0.64-20 1.3-3.2 0.4-10.7

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much older group is emerging (37-39). The modulating effect of bacille Calmette-Guerin [BCG] vaccination resulting in substantial reduction in miliary TB and TB meningitis among young vaccinees, increasing use of computed tomography [CT], and wider application of invasive diagnostic methods could also have contributed to the demographic shift (4). Age and Gender Distribution In patients with miliary TB, presently two additional peaks are evident–one involving adolescents and young adults and another later in life among elderly people (4-9). Sparse published data are available on disseminated TB. In a recently published series from northern Taiwan (2), patients with HIV/AIDS who had disseminated TB [n = 23] were younger [mean age 37.1 years], compared with HIV-seronegative disseminated TB patients with [n = 64; mean age 61.4 years] and without other co-morbid conditions [n = 77; mean age 58.9 years]. Males seem to be more frequently affected by miliary TB in children as well as adults (4-9). Similarly, 119 of the 164 patients [73%] with disseminated TB reported by Wang et al (2) were men. However, a few recent adult series on miliary TB (16,20,40,41) describe a female preponderance. This shift probably reflects increased awareness and use of health services by women. Further work is required to understand the influence of other factors such as socio-economic and nutritional status, comorbid illnesses, and host genetic factors other than ethnic variations in the causation of disseminated and miliary TB. PATHOGENESIS Miliary TB develops due to a massive lymphohaematogenous dissemination of Mycobacterium tuberculosis from a pulmonary or extra-pulmonary focus and embolization to the vascular beds of various organs [Figure 34.1] (4). Less commonly, simultaneous reactivation of multiple foci in various organs can result in miliary TB. This reactivation can occur either at the time of primary infection or later during reactivation of dormant foci. When miliary TB develops during primary disease [early generalization], the disease has an acute onset and is rapidly progressive. Late generalization during post-primary TB can be rapidly progressive [resulting in acute miliary TB], episodic, or protracted, leading to chronic miliary TB. Re-infection also has an important role, especially in areas where TB is highly endemic. Rarely, miliary TB can also develop due

to caseation of an extra-pulmonary site, discharge of caseous material into the portal circulation and initial hepatic involvement with the classical pulmonary involvement occurring late (4-9). The reader is referred to the chapter “Immunology of tuberculosis” [Chapter 7] for more details regarding the molecular mechanisms underlying the pathogenesis of disseminated and miliary TB. Miliary TB is a common manifestation of congenital TB in neonates. Acquisition of infection during the perinatal period through aspiration and ingestion of infected maternal genital tissues and fluid and subsequent haematogenous dissemination may rarely lead to the development of MTB in neonates. The reader is referred to the chapter “Pathology” [Chapter 5] for more details regarding congenital TB. CLINICAL PRESENTATION Most of the patients with disseminated and miliary TB often have non-specific predisposing or associated conditions [Table 34.2]. Their pathogenetic role is unclear. Table 34.2: Conditions predisposing to or associated with disseminated and miliary tuberculosis Childhood infections Malnutrition HIV infection and AIDS Alcoholism Diabetes mellitus Chronic renal failure, haemodialysis Post-surgery [e.g., gastrectomy*] Organ transplantation Drugs Corticosteroids Immunosuppressive and cytotoxic drugs Immunomodulator drugs [e.g., infliximab, etanercept] Connective tissue disorders Pregnancy, postpartum Underlying malignancy Silicosis Iatrogenic causes Ureteral catheterization* Extracorporeal shockwave lithotripsy† Laser lithotripsy† Cardiac valve homograft replacement‡ Intravesical BCG therapy for urinary bladder carcinoma * Predisposes to TB in general † Patient had undiagnosed genitourinary TB ‡ Contamination of homografts, probably occurred at the time of harvest from cadavers HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome; BCG = bacille Calmette-Guerin; TB = tuberculosis Adapted from reference 4

Disseminated and Miliary Tuberculosis 495

Figure 34.1: Gross pathology of miliary tuberculosis. Multiple lesions of miliary tuberculosis in both lung fields with areas of haemorrhage [A]; liver slice showing multiple confluent as well as discrete tubercles [B]; spleen showing multiple grey-white varying sized lesions [C]; cut-section of spleen showing miliary seeding [D]; omentum showing multiple tubercles, caseation is evident in larger lesions [E]; kidney with tubercles seen over the surface [F]

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Tuberculosis

Common presenting symptoms and signs noted at presentation in patients with disseminated and miliary TB are listed in Table 34.3 (40-56). Although disseminated and miliary TB involves almost all organs, most often the involvement is asymptomatic. Clinical manifestations of disseminated and miliary TB are protean and can be obscure till late in the disease. Fever and inanition are relatively common. Cough and dyspnoea are often present. Chills and rigors, usually seen in patients with malaria, or, sepsis and bacteraemia, have often been described in adult patients with miliary TB (2,17-23).

Organomegaly is also a frequent physical finding. Choroidal tubercles are bilateral, pale, greyish-white and oblong patches which occur less commonly in adult patients with miliary TB than children (4). If present, choroidal tubercles are pathognomonic of miliary TB and offer a valuable clue to the diagnosis [Figure 28.3]. Therefore, systematic ophthalmoscopic examination after mydriatic administration must be done in every suspected patient with miliary TB. Skin involvement in the form of erythematous macules and papules have also been described (4-9). Signs of hepatic involvement may

Table 34.3: Presenting symptoms in miliary and disseminated tuberculosis Variable

Miliary TB

Disseminated TB‡

Adults [%]*

Children [%]†

Symptoms Fever Chills Anorexia Weight loss Night sweats Weakness/fatigue Cough/sputum Chest pain Dyspnoea Haemoptysis Headache Altered sensorium Seizures Nausea Abdominal pain Diarrhoea Urinary symptoms

35-100 15-28 24-100 20-100 08-100 25-100 27-82 03-49 08-100 03-15 02-18 05-26 ND 01-19 05-19 02-03 02-06

61-98 ND 04-81 04-60 08-75 14-54 17-90 01-03 07-25 01 02-08 02-08 07-30 ND 03-15 ND ND

48 ND 06 07-46 03 10-75 23-33 ND 11-17 ND 02 09 ND ND 06 ND 04

Signs Fever Pallor Cyanosis Icterus Lymphadenopathy Chest signs Hepatomegaly Splenomegaly Ascites Choroidal tubercles Neurological signs

35-100 36-59 01-02 05-09 02-30 29-84 14-62 02-32 04-38 02-12 03-26

39-75 31 ND 03 05 34-72 39-82 24-54 06-09 02-05 19-35

48 ND 06 07-46 03 10-75 23-33 ND 11-17 ND 02

All values are expressed as percentages corrected to the nearest round figure * Data from references 13,20,40-54 † Data from references 21,23,26,55,56 ‡ Data from reference 2. In this series, 23 of the 164 patients were HIV seropositive TB = tuberculosis; HIV = human immunodeficiency virus; ND = not described

Disseminated and Miliary Tuberculosis 497 be evident in the form of icterus and hepatomegaly. Neurological involvement in the form of meningitis or tuberculomas is common. Tuberculosis meningitis has been described in 10 to 30 per cent of adult patients with miliary TB (14,20,40-53). Conversely, about one-third of patients presenting with TB meningitis have underlying miliary TB (57). Clinically significant cardiac or renal involvement is uncommon in patients with miliary TB (4-9). Overt adrenal insufficiency at presentation, or during treatment has also been described in miliary TB (58). In some studies, headache and abdominal pain when present are supposed to have specific implications in miliary TB, headache signifying the presence of meningitis and abdominal pain signifying abdominal involvement (4-9). Clinical presentation of miliary TB in children is similar to that observed in adults, but with important differences [Table 34.3]. In children with miliary TB, chills, night sweats, haemoptysis, and productive cough have been reported less frequently, while peripheral lymphadenopathy and hepatosplenomegaly are more common, compared with adults. Likewise, a higher proportion of children with miliary TB have TB meningitis compared with adults. Rare Manifestations Table 34.4 shows various atypical manifestations in patients with miliary TB. Atypical presentations can delay the diagnosis and disseminated and miliary TB is often a missed diagnosis. Patients with occult disseminated and miliary TB can present with “pyrexia of unknown origin” without any localizing clue. Clinical presentation such as absence of fever, and progressive wasting strongly mimicking a metastatic carcinoma can occur, especially in the elderly. Proudfoot et al (37) suggested the term “cryptic miliary TB” for this presentation. Table 34.5 (37-39) highlights the important differences between classical and cryptic forms of miliary TB. The reader is referred to the chapter “Tuberculosis and acute lung injury” [Chapter 36] for details regarding TB and acute respiratory distress syndrome [ARDS]. Disseminated and Miliary Tuberculosis in the Immunosuppressed Patients The clinical presentation of TB in early HIV infection [CD4+ cell counts > 500/μl] is similar to that observed in immunocompetent individuals. With progression of

Table 34.4: Atypical clinical manifestations in miliary tuberculosis Cryptic miliary tuberculosis Pyrexia of unknown origin Acute respiratory distress syndrome “Air-leak” syndrome [pneumothorax, pneumomediastinum] Myelophthisic anaemia , myelofibrosis, pancytopenia, immune haemolytic anaemia Acute empyema Septic shock, multiple organ dysfunction syndrome Thyrotoxicosis Renal failure due to granulomatous destruction of the interstitium Immune complex glomerulonephritis Sudden cardiac death Mycotic aneurysm of aorta Native valve and prosthetic valve endocarditis Myocarditis, congestive heart failure, intracardiac masses Cholestatic jaundice Presentation as focal extra-pulmonary tuberculosis Incidental diagnosis Syndrome of inappropriate antidiuretic hormone secretion Deep vein thrombosis Data from references 37,39-53, 58-75

immunosuppression in advanced HIV infection [CD4+ cell counts < 200/μl], disseminated and miliary TB are seen more frequently (54,76,77). Cutaneous involvement is unusual in MTB but is more commonly seen in HIV-seropositive patients with CD4+ cell counts below 100/μl (78). The cutaneous lesions that have been described include tiny papules or vesiculopapules variously described as ‘tuberculosis cutis miliaris disseminata’, ‘tuberculosis cutis acuta generalisita’, and disseminated TB of the skin (79). Rarely, macular, pustular, or purpuric lesions, indurated ulcerating plaques, and subcutaneous abscesses have also been reported (79). In HIV/AIDS patients with disseminated and miliary TB, intrathoracic lymphadenopathy and tuberculin anergy are more common; sputum smears are seldom positive and blood culture may grow Mycobacterium tuberculosis, especially in patients with profound immunosuppression (1,2,4-9,54). Immune reconstitution inflammatory syndrome [IRIS] has been implicated as the cause of paradoxical worsening of lesions in patients with TB. Consequently, HIV-seropositive patients with miliary TB may develop acute renal failure (80) or ARDS (81). The reader is

498

Tuberculosis Table 34.5: Comparison of classical and cryptic miliary tuberculosis Variable

Classical miliary TB

Cryptic miliary TB

Age at diagnosis

Majority < 40 years

Majority > 60 years

Fever

Present in > 90%

Rarely present, few localizing signs evident

Weight loss

Present in 60%-80%

Dominant clinical feature

Meningitis

Seen in 20%-30% adults 30%-40% children

Rare unless terminal

Lymphadenopathy

Present in 20%

Rarely present

Chest radiograph

Classical miliary pattern common

Normal

HRCT of the chest

Required only when classical miliary pattern is not evident. May also reveal additional findings

Required for diagnosis

Tuberculin skin test

Positive in 60%

Rarely positive

Confirmation of diagnosis

Invasive procedures

Usually made at autopsy*

* Diagnosis can be made with computed tomography at present during life time TB = tuberculosis; HRCT = high resolution computed tomography Adapted from references 37-39

referred to the chapter “Tuberculosis and human immunodeficiency virus infection” [Chapter 40] for more details. LABORATORY FINDINGS Haematology and Serum Biochemistry A number of haematological and biochemical abnormalities are known to occur in disseminated and miliary TB but their significance is controversial [Table 34.6]. Anaemia of chronic disease, leucocytosis, leucopenia, leukaemoid reactions, thrombocytopenia and disseminated intravascular coagulation are all known to occur. Erythrocyte sedimentation rate is usually elevated in patients with disseminated and miliary TB (4-9). The reader is referred to the chapter “Haematological manifestations of tuberculosis” [Chapter 37] for more details. Hyponatraemia in miliary TB was first described in 1938 by Winkler and Crankshaw (82). Shalhoub and Antoniou (83) postulated an acquired disturbance of neurohypophyseal function resulting in unregulated antidiuretic hormone [ADH] release as the underlying mechanism. Vorherr et al (84) demonstrated an antidiuretic principle in the lung tissue affected by TB and suggested that it may either produce ADH or absorb an inappropriately released hormone from the posterior pituitary. Hyponatraemia in miliary TB has also been attributed to meningeal involvement (43). Presence of hyponatraemia in patients with miliary TB is thought to be of prognostic significance [vide infra]. Hypercalcaemia

Table 34.6: Laboratory abnormalities in disseminated and miliary tuberculosis Haematological Anaemia Leucocytosis Neutrophilia Lymphocytosis Monocytosis Thrombocytosis Leucopenia Lymphopenia Thrombocytopenia Leukaemoid reaction Elevated ESR, CRP levels Biochemical Hyponatraemia Hypoalbuminaemia Hyperbilirubinaemia Elevated tranaminases Elevated serum alkaline phosphatase Hypercalcaemia ESR = erythrocyte sedimentation rate; CRP = C-reactive protein

has been documented in miliary TB but is uncommon (4-9). Tuberculin Skin Test Majority of patients with disseminated and miliary TB are tuberculin skin test [TST] positive [Table 34.7]. The reader is referred to the chapter “Tuberculin skin test” [Chapter 11] for more details.

Disseminated and Miliary Tuberculosis 499 Table 34.7: Results of tuberculin skin test in miliary tuberculosis** Study (reference)

No. studied

No. tested

Negative TST [%]

Paediatric series Kim et al (23)

84

84

51

Aderele (55)

44

26

35

Rahajoe (56)

80

80

54

Hussey et al (21)

94

94

62

Gurkan et al (26)

23

23

74

Adult series Biehl (42)

68

26

39

Munt (43)

69

57

48

Campbell (44)

48

30

20

Gelb et al (45)

44

109

72

Grieco et al (46)

28

21

52

Onadeko (47)

41

23

65

Prout et al (49)

62

21

62

Kim et al (50)

38

38

68

Maartens (51)

109

47

57

Mert et al (40) Sharma SK [unpublished observations]

38

38

62

134

107

70

have patterns that are indistinguishable from interstitial pneumonia (4,52). Some of the patients may manifest coalescent opacities [Figures 34.2A, 34.2B, and 34.3]. When patients with miliary TB develop ARDS, the chest radiograph may be identical to that seen in ARDS due to other causes (4,59). Majority of the patients [88%] in the study reported by Sharma et al (52) had chest radiographs consistent with miliary TB and in some, these classical radiological changes evolved over the course of the disease. The diagnosis of miliary TB is easier when patient presents with classical miliary shadowing on chest radiograph in an appropriate setting. However, the diagnosis may be difficult in those situations where chest radiograph does not show classical miliary shadows. This fact is highlighted by 12 patients in the series reported by Sharma et al (52) who had atypical chest radiographs and the case of a patient with fever of unknown origin who presented with a very subtle suggestion of miliary mottling on the chest radiograph. This chest radiograph was passed off as normal in a busy outpatient department [Figure 34.4]. High resolution CT [HRCT] [vide infra]

* Varying strengths and methods were employed for TST in different studies TST = tuberculin skin test

Interferon-gamma Release Assays Newer in-vitro T-cell based interferon-gamma release assays [IGRAs] appear to be promising in detecting TB infection as compared to the TST and may be useful in patients with disseminated and miliary TB. The reader is referred to the chapter “Diagnosis of latent tuberculosis infection: recent advances and future directions” [Chapter 12] for further details on this topic. Imaging Chest Radiograph The radiographic hallmark of miliary TB is the miliary pattern on chest radiograph [Figure 13.3]. The term miliary refers to the “millet seed” size of the nodules [< 2 mm] seen on classical chest radiographs (4). Some patients with miliary TB, however, may have normal chest radiographs when they seek medical care and some

Figure 34.2A: Chest radiograph [postero-anterior view] showing confluent shadows instead of miliary mottling in a patient with miliary tuberculosis Reproduced with permission from “Sharma SK, Mohan A, Prasad KL, Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. QJM 1995;88:29-37 (reference 52)”

500

Tuberculosis

Figure 34.2B: HRCT of the chest of the same patient in Figure 34.2A, showing miliary pattern Reproduced with permission from “Sharma SK, Mohan A, Prasad KL, Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. QJM 1995;88:29-37 (reference 52)”

Figure 34.4: Chest radiograph [postero-anterior view] showing subtle miliary shadows Reproduced with permission from “Sharma SK, Mohan A, Prasad KL, Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. QJM 1995;88:29-37 (reference 52)”

Figure 34.5: CT of the chest of the same patient in Figure 34.4 showing extensive miliary shadows Reproduced with permission from “Sharma SK, Mohan A, Prasad KL, Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. QJM 1995;88:29-37 (reference 52)”

Figure 34.3: Chest radiograph [postero-anterior view] showing miliary mottling and a cavity in the left upper lobe

suggested a miliary pattern [Figure 34.5] and excision biopsy of the supraclavicular lymph node which developed over the course of the disease confirmed the

diagnosis in this patient [Figure 34.6]. This re-emphasizes the fact that though the clinical and laboratory parameters are indicative of the disease, they are not sensitive enough to allow an accurate provisional diagnosis. Thus, if there is a high index of suspicion of miliary TB and the chest radiograph is atypical, it is suggested that HRCT be done to support the diagnosis.

Disseminated and Miliary Tuberculosis 501

Figure 34.6: Lymph node biopsy showing confluent, caseating epithelioid cell granulomas with giant cells suggestive of tuberculosis [Haematoxylin and eosin × 80] Reproduced with permission from “Sharma SK, Mohan A, Prasad KL, Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. QJM 1995;88: 29-37 (reference 52)”

Ultrasonography In patients with disseminated and miliary TB, ultrasonography is useful in the detection of associated lesions, such as loculated ascites, focal hepatic and splenic lesions, adnexal masses [in women] and cold abscess. Diagnostic thoracic or abdominal paracentesis under ultrasound guidance is useful to procure fluid for diagnostic testing, especially when it is loculated. Computed Tomography and Magnetic Resonance Imaging High resolution computed tomography has considerably improved the antemortem diagnosis of disseminated and miliary TB. The interlobular septal thickening or intralobular fine network that is evident on HRCT in miliary TB seems to be caused by the presence of tubercles in the interlobular septa and alveolar walls. Centrilobular nodules and branching linear structures producing a treein-bud appearance–a pattern seen in active post-primary pulmonary TB–may sometimes be evident in miliary TB. Contrast enhanced CT [CECT] is better for detecting intrathoracic lymphadenopathy, calcification, and pleural lesions (3,4). Magnetic resonance imaging [MRI] and CECT are also useful in demonstrating miliary lesions at occult

extra-pulmonary sites, an exercise that was earlier possible only at post-mortem examination. Abdominal CECT is useful in identifying lesions in the liver and spleen, intra-abdominal lymphadenopathy, and cold abscesses (3,4,85). Miliary lesions in the liver and spleen may appear as confluent or discrete hypodense lesions, sometimes with peripheral rim enhancement on the CECT of the abdomen (3,4,85). Ultrasonography, CECT, and MRI may help in identifying adnexal masses, ascites in women, and epididymitis and seminal vesicle lesions in men with genital tract involvement. The CECT or MRI of the brain and spine are useful in the evaluation of patients with concomitant TB meningitis [Figure 34.7] or spinal TB. Interventional radiological procedures such as fine needle aspiration cytology and biopsy under CT or MRI guidance are useful for procuring tissue fluid for confirmation of diagnosis. Imaging findings which are commonly encountered in patients with disseminated TB are shown in Figures 34.8A, 34.8B, 34.9A, 34.9B, 34.10A, 34.10B, 34.11, and 34.12] . Sharma et al (86) assessed the CT appearances of miliary TB [Figures 34.13, 34.14, 34.15, 34.16A, 34.16B, and 34.17] and the CT findings were correlated with pulmonary functions and gas exchange. The effect of antituberculosis treatment on various observed findings was also studied. It was found that the HRCT was superior to the conventional CT in defining the parenchymal details. A significant positive correlation was observed between the visual chest radiograph and CT scores (86). Further, CT of the chest also revealed lymph nodal enlargement, calcification and pleural lesions in more patients than plain films. Curiously, Sharma et al (86) also described air trapping on CT both at presentation and during follow-up period and attributed this to TB bronchiolitis [Figures 34.15, 34.16A, 34.16B, and 34.17]. The clinical significance of these findings is unclear at present. Pipavath et al (87) in a recent report [n = 16] documented the following changes on HRCT in patients with miliary TB: miliary pattern [n = 16]; intrathoracic lymphadenopathy [n = 8]; alveolar lesions such as ground glass attenuation and/or consolidation [n = 5]; pleural and pericardial effusions [2 patients each]; and

502

Tuberculosis

Figure 34.8A: CECT of the chest of a patient with disseminated tuberculosis showing bilateral parenchymal lesions

Figure 34.8B: CECT of the abdomen of the same patient showing multiple, low attenuation lesions in the liver and spleen

Figure 34.7: MRI of the brain [T1-weighted image, axial view] in a patient with miliary tuberculosis showing multiple hyperintense disk-like lesions [tubercles] [A] that are enhanced after the administration of contrast medium [arrows] [B]. Contrast enhanced MRI of the brain [T1-weighted image, axial section] showing multiple hyperintense enhancing disk-like lesions of varying sizes scattered within the brain [C,D, and E]. Some of them have coalesced to produce a hyperintense enhancing irregularly shaped lesions [arrows] [F].

peribronchovascular interstitial thickening and emphysema [1 patient each]. Pulmonary Functions, Gas Exchange Abnormalities Miliary TB is associated with abnormalities of pulmonary functions typical of diffuse interstitial disease of the lungs (4). The impairment of diffusion has been the most frequent and severe abnormality encountered (4). Sharma et al (88) studied the pulmonary functions

Disseminated and Miliary Tuberculosis 503

Figure 34.9A: CECT of the abdomen of a patient with disseminated tuberculosis showing a large, low attenuation lesion in the spleen [arrow]

Figure 34.10A: CECT of the abdomen of a patient with disseminated tuberculosis showing multiple, low attenuation lesions in the spleen

Figure 34.10B: CECT of the abdomen of the same patient showing ascites with loculations [arrows]

Figure 34.9B: CECT of the abdomen of the same patient showing psoas abscess [asterisk] on the right side. Erosion of the vertebral body [arrow] can also be seen

[n = 31] and gas exchange abnormalities on arterial blood gas analysis [n = 13] in patients with miliary TB. They found a mild restrictive ventilatory defect, impairment of diffusing capacity and hypoxaemia due to widening of alveolar-arterial oxygen gradient. A mild reduction in the flow rates suggestive of peripheral airways involvement was also observed.

With antituberculosis treatment, mean arterial oxygen tension [PaO2] showed a significant increase from the pre-treatment values [Figure 34.18]. The mean posttreatment values of forced vital capacity [FVC], forced expiratory volume in the first second [FEV1], peak expiratory flow rate [PEFR], maximal mid expiratory flow rate FEF 25-75, forced expiratory flow at 50 per cent vital • capacity [V50] and forced expiratory flow at 25 per cent • vital capacity [V25] did not show a significant increase at the end of treatment (88). The functional residual capacity [FRC] and residual volume [RV]/total lung capacity

504

Tuberculosis

Figure 34.11: CECT of the chest of a young woman who presented with low-grade fever for 3 months, cough and dysphagia showing subcarinal [A] and right hilar [B] lymph nodes. Arrows point to hypodensities which indicate necrosis in the lymph nodes. CECT of the abdomen of the same patient showing bilateral psoas abscesses [C] [arrows]. Coronal reconstruction of the CECT of the abdomen of the same patient showing bilateral psoas abscesses [D] [arrows]. CT guided fine needle aspirate from the psoas abscess revealed numerous acid-fast bacilli Reproduced with permission from “Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316-53 (reference 3)”

[TLC] [%] also did not decrease significantly at the end of treatment. Antituberculosis treatment resulted in improvement in gas exchange [Figure 34.18]. Pipavath et al (87) assessed the correlation between the disease extent score as evaluated by a visual scoring

system and the pulmonary functions in 16 patients with miliary TB. They observed a significant correlation between the disease extent score and the FVC, FEV1, TLC, arterial oxygen saturation [SaO2], and diffusion capacity of the lung for carbon monoxide [DLCO].

Disseminated and Miliary Tuberculosis 505

Figure 34.12: Tuberculosisof the spleen. CECT of the abdomen [A] showing multiple hypodense lesions in the spleen [A]. CECT of the abdomen [B] showing multiple hypodense lesions in the spleen [black arrows] and liver [white arrows]

Figure 34.13: HRCT of the chest at intermediate bronchus level showing non-uniform distribution of nodular lesions in both the lungs with areas of conglomeration Reproduced with permission from “Sharma SK, Mukhopadhyay S, Arora R, Varma K, Pande JN, Khilnani GC. Computed tomography in miliary tuberculosis: comparison with plain films, bronchoalveolar lavage, pulmonary functions and gas exchange. Australasian Radiol 1996;40:113-8 (reference 86)”

Cardiopulmonary Exercise Testing Patients with miliary TB have abnormal cardiopulmonary exercise performance with lower maximum oxygen consumption, maximal work rate, anaerobic threshold, peak minute ventilation, breathing reserve, and low maximal heart rate (89,90). Other abnormalities include higher respiratory frequency, peak minute ventilation at submaximal work, and high physiological dead space/ tidal volume ratio. Some of these patients manifest a demonstrable fall in oxygen saturation [4% or more] with

Figure 34.14: CT of the chest through upper lobes showing extensive, fine nodules in both the lungs with relative peripheral sparing Reproduced with permission from “Sharma SK, Mukhopadhyay S, Arora R, Varma K, Pande JN, Khilnani GC. Computed tomography in miliary tuberculosis: comparison with plain films, bronchoalveolar lavage, pulmonary functions and gas exchange. Australasian Radiol 1996;40:113-8 (reference 86)”

exercise. Following successful treatment, most patients reveal reversal of abnormalities. However, some of these abnormalities may persist following treatment (89,90). Immunologic Abnormalities and Bronchoalveolar Lavage Sharma et al (88) reported that patients with miliary TB had a significantly higher total cell count and increased proportion of lymphocytes, CD3+, and CD4+ T-lymphocytes in the bronchoalveolar lavage [BAL] fluid

506

Tuberculosis

Figure 34.15: HRCT of the chest at carina showing extensive nodular lesions with confluence mainly in the right lung and focal area of bronchiectasis or a thin walled cavity in the left lung along with scattered areas of air trapping Reproduced with permission from “Sharma SK, Mukhopadhyay S, Arora R, Varma K, Pande JN, Khilnani GC. Computed tomography in miliary tuberculosis: comparison with plain films, bronchoalveolar lavage, pulmonary functions and gas exchange. Australasian Radiol 1996;40:113-8 (reference 86)”

Figure 34.16B: Follow-up CT of the same patient after 7 months of antituberculosis therapy. The nodules have disappeared and air trapping has increased significantly Reproduced with permission from “Sharma SK, Mukhopadhyay S, Arora R, Varma K, Pande JN, Khilnani GC. Computed tomography in miliary tuberculosis: comparison with plain films, bronchoalveolar lavage, pulmonary functions and gas exchange. Australasian Radiol 1996;40:113-8 (reference 86)”

Figure 34.16A: CT through upper lobes showing non-uniform distribution of nodules with areas of air trapping in both the lungs Reproduced with permission from “Sharma SK, Mukhopadhyay S, Arora R, Varma K, Pande JN, Khilnani GC. Computed tomography in miliary tuberculosis: comparison with plain films, bronchoalveolar lavage, pulmonary functions and gas exchange. Australasian Radiol 1996;40:113-8 (reference 86)”

Figure 34.17: Follow-up CT of a patient at the end of antituberculosis therapy. The nodules have disappeared but air trapping has increased Reproduced with permission from “Sharma SK, Mukhopadhyay S, Arora R, Varma K, Pande JN, Khilnani GC. Computed tomography in miliary tuberculosis: comparison with plain films, bronchoalveolar lavage, pulmonary functions and gas exchange. Australasian Radiol 1996;40:113-8 (reference 86)”

[Figures 34.19, 34.20 and 34.21]. In patients with miliary TB, BAL showed lymphocytic alveolitis (88,91). The finding of increased CD4+ lymphocytes in the BAL fluid and their depletion in the peripheral blood suggested compartmentalization of lymphocytes at the site of

inflammation. With antituberculosis treatment, total cell count in BAL fluid decreased but continued to be higher than that in normal control subjects. The proportion of lymphocytes did not change significantly [Figure 34.22 upper panel].

Disseminated and Miliary Tuberculosis 507

Figure 34.18: Effect of antituberculosis treatment on lung volumes and maximal expiratory flow rates [upper panel (A)] and gas exchange, Raw and SGaw [lower panel (B)]. Single asterisk indicates p < 0.05; double asterisk indicates p < 0.01; solid bars = pre-treatment; hatched bars = post-treatment Reproduced with permission from “Sharma SK, Pande JN, Singh YN, Verma K, Kathait SS, Khare SD, et al. Pulmonary function and immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 1992;145:1167-71 (reference 88)” FVC = forced vital capacity; FEV1 = forced expiratory volume in the first second; PEFR = peak expiratory flow rate; FEF25-75 = maximal • • mid expiratory flow rate; forced expiratory flow at 50 per cent vital capacity = V50 ; V25 = forced expiratory flow at 25 per cent vital capacity; FRC = functional residual capacity; RV = residual volume; TLC = total lung capacity; Raw = airway resistance; SGaw = airway conductance

Figure 34.19: Absolute number of pre-treatment T- and B-lymphocytes in the peripheral blood of patients with miliary tuberculosis [MTB] and normal control subjects [N] Reproduced with permission from “Sharma SK, Pande JN, Singh YN, Verma K, Kathait SS, Khare SD, et al. Pulmonary function and immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 1992;145:1167-71 (reference 88)”

508

Tuberculosis

Figure 34.20: Lymphocyte subsets in bronchoalveolar [BAL] fluid in normal controls [N] and patients with miliary tuberculosis [MTB] NS = not significant Reproduced with permission from “Sharma SK, Pande JN, Singh YN, Verma K, Kathait SS, Khare SD, et al. Pulmonary function and immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 1992;145:1167-71 (reference 88)”

Sharma et al (88) also observed that the immunoglobulins [Ig] G, IgA, IgM were increased in the peripheral blood and BAL fluid in 18 patients [Tables 34.8 and 34.9]; suggesting polyclonal hypergammaglobulinaemia. With antituberculosis treatment, serum immunoglobulins, IgG and IgA showed an insignificant increase. The decrease in serum IgM value was not statistically significant. The mean BAL fluid IgG, IgA values showed a decline following antituberculosis treatment, but the difference did not attain statistical significance. Although BAL fluid IgM did not show a significant fall with antituberculosis treatment, the mean post-treatment value in MTB patients was quite close to the mean in normal control subjects [Figure 34.22, lower panel]. Sharma et al (88) postulated that elevation of IgM occurred in the acute and active phase of the infection only, whereas, IgG and IgA continued to be raised even after apparent cure of infection. These increased levels

Figure 34.21: CD4+/CD8+ ratio in the peripheral blood and BAL fluid in normal controls [N] and patients with miliary tuberculosis [MTB] NS = not significant Reproduced with permission from “Sharma SK, Pande JN, Singh YN, Verma K, Kathait SS, Khare SD, et al. Pulmonary function and immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 1992;145:1167-71 (reference 88)”

were thought to be due to persistent mycobacterial antigenic stimulus. Increased BAL fluid fibronectin (88,92) and serum complement [C3] (88) have also been described in patients with miliary TB [Table 34.9]. The increase in serum C3 has been thought to be the result of “acute phase response” to ongoing inflammation and elevated BAL fluid fibronectin compared with peripheral blood suggested local synthesis in the lung. DIAGNOSIS Even in an endemic area, the diagnosis of disseminated and miliary TB can be difficult as the clinical symptoms have been non-specific, the chest radiographs do not always reveal the classical miliary changes and atypical presentations such as ARDS, and shadows larger than miliary on chest radiograph commonly occur. In patients with suspected disseminated and miliary TB, attempts

Disseminated and Miliary Tuberculosis 509

Figure 34.22: Effect of antituberculosis treatment on bronchoalveolar lavage [BAL] fluid findings in patients with miliary tuberculosis FR = fluid recovery, AM = alveolar macrophages, LYM = lymphocytes, TC = total cells, POLY = polymorphs, FN = fibronectin, Ig = immunoglobulin; Single asterisk indicates p < 0.05; solid bars = pre-treatment; hatched bars = post-treatment Reproduced with permission from “Sharma SK, Pande JN, Singh YN, Verma K, Kathait SS, Khare SD, et al. Pulmonary function and immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 1992;145:1167-71 (reference 88)” Table 34.8: Pre-treatment serum immunoglobulins and complement [C3] in patients with miliary tuberculosis and normal control subjects* Measurement

Normal control subjects

Miliary TB BMI < 18

BMI > 18

Total patients

IgG [mg/dl]

1868 [1.161] [n = 10]

1969 [505] [n = 8]

1913 [906]† [n = 8]

1063 [371] [n = 70]

IgA [mg/dl]

321 [86.5] [n = 10]

350 [155] [n = 8]

333.8 [118.4]† [n = 8]

139 [65] [n = 70]

IgM [mg/dl]

240 [130] [n = 9]

193.5 [65.4] [n = 8]

218 [104]† [n = 17]

94.32 [26.3] [n = 70]

Complement C3 [mg/dl]

234 [129] [n = 13]

299 [104] [n = 10]

262 [121]† [n = 23]

124.7 [31.9] [n = 10]

* All values are expressed as mean [SD] † p < 0.001, miliary TB versus normal control subjects Modified and reproduced with permission from “Sharma SK, Pande JN, Singh YN, Verma K, Kathait SS, Khare SD, et al. Pulmonary function and immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 1992;145:1167-71 (reference 88)” BMI = body mass index [kg/m2]; TB = tuberculosis

510

Tuberculosis Table 34.9: Pre-treatment bronchoalveolar lavage findings in patients with miliary tuberculosis and normal control subjects* Measurement

Miliary TB

Normal control subjects [n = 17]

Total patients

BMI < 18

BMI > 18

Fluid recovery [%]

44.35 [11.32]

53.4 [11.9] [n = 16]

54.8 [17.5] [n = 15]

54.10 [14.65]‡ [n = 31]

Total cell count [106 cells/ml]

0.76 [0.36]

2.22 [1.47] [n = 13]

4.39 [3.86] [n = 14]

4.39 [3.86] [n = 27]

Alveolar macrophages [%]

86 [12.3]

39 [12.8] [n = 14]

39.2 [21.7] [n = 13]

39.11 [17.29]‡ [n = 27]

Lymphocytes [%]

10.58 [10.25]

53.4 [12.5] [n = 14]

54.9 [20.8] [n = 13]

54.15 [16.7]‡ [n = 27]

Neutrophils [%]

5 [12.23]

7.57 [6.58] [n = 14]

5.69 [4.89] [n = 13]

6.67 [5.80] [n = 27]

Fibronectin [μg/mg albumin]

6.69 [1.44]

34.6 [19.7]§ [n = 12]

19.8 [8.88] [n = 10]

27.89 [17.15]‡ [n = 22]

IgG [μg/mg albumin]

254 [90.2]

1973 [671] [n = 8]

1634 [916] [n = 9]

1794 [804]‡ [n = 17]

IgA [μg/mg albumin]

155 [22.4]

799 [473] [n = 9]

719 [571] [n = 10]

757 [514]‡ [n = 19]

IgM [μg/mg albumin]

3.33 [3.13]

7.57 [3.86] [n = 9]

5.78 [3.49] [n = 9]

6.67 [3.68]|| [n = 18]

* All values are expressed as mean [SD] † Cell count for four patients not included because of the presence of epithelioid cell granulomas in the BAL fluid ‡ p 2.5 g/dl]

Usually high [> 2.5 g/dl] Serum–ascitic fluid albumin gradient < 1.1

Usually high

Usually high [100-500 mg/dl] Can be very high with blockage or chronicity

Glucose

Usually less than simultaneously collected peripheral blood value

Low

Low

Usually 40-50 mg/dl [about 50% of blood glucose]

Differential count

Smear microscopy [%]

< 10

39.3 oC, icterus, hepatomegaly, hypoalbuminaemia, hyponatraemia, elevated serum alkaline phosphatase

Long et al (20)

1997

Presence of one or more risk factors†

Mert et al (40)

2001

Male sex, presence of atypical chest radiographic pattern, delay in starting antituberculosis treatment

Hussain et al (41)

2004

Presence of altered mental status, lung crackles, leucocytosis, thrombocytopenia, need for ventilation

Wang et al (2)‡

2007

Hypoalbuminaemia, hyperbilirubinemia, renal insufficiency, and delay in starting antituberculosis treatment

* No statistical analysis was performed † Listed in Table 34.2 ‡ Disseminated TB TB = disseminated tuberculosis Modified and adapted from reference 4

REFERENCES 1. Sharma SK, Mohan A, Gupta R, Gupta AK, Singhal VK, Kumar A, et al. Clinical presentation of tuberculosis in patients with AIDS: an Indian experience. Indian J Chest Dis Allied Sci 1997;39:213-20.

2. Wang JY, Hsueh PR, Wang SK, Jan IS, Lee LN, Liaw YS, et al. Disseminated tuberculosis: a 10-year experience in a medical center. Medicine [Baltimore] 2007;86:39-46. 3. Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316-53. 4. Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary

516

5. 6.

7.

8.

9.

10.

11.

12.

13.

14.

15. 16.

17.

18.

19.

20.

Tuberculosis tuberculosis: new insights into an old disease. Lancet Infect Dis 2005;5:415-30. Sahn SA, Neff TA. Miliary tuberculosis. Am J Med 1974;56:494-505. Sharma SK, Mohan A. Disseminated/miliary tuberculosis. In: Sharma SK, Mohan A, editors. Tuberculosis. First edition. New Delhi: Jaypee Brothers Medical Publishers;2001.p.348-61. Baker SK, Glassroth J. Miliary tuberculosis. In: Rom WN, Garay SM, editors. Tuberculosis. Philadelphia: Lippincott Williams and Wilkins; 2004.p.427-44. Divinagracia R, Harris HW. Miliary tuberculosis. In: Schlossberg D, editors. Tuberculosis and nontuberculous mycobacterial infection. Philadelphia: W.B. Saunders Company; 1999.p.271-84. Sharma SK, Mohan A. Miliary tuberculosis. In: Agarwal AK, editor. Clinical medicine update – 2006. New Delhi: Indian Academy of Clinical Medicine; 2006.p.353-60. Hill AR, Premkumar S, Brustein S, Vaidya K, Powell S, Li PW, et al. Disseminated tuberculosis in the acquired immunodeficiency syndrome era. Am Rev Respir Dis 1991;144:116470. Sharma SK, Mohan A, Kadhiravan T. HIV-TB co-infection: epidemiology, diagnosis and management. Indian J Med Res 2005;121:550-67. Lewison M, Frelich EB, Ragins OB. Correlation of clinical diagnosis and pathological diagnosis with special reference to tuberculosis: analysis of autopsy findings in 893 cases. Am Rev Tuberc 1931;24:152-71. Chapman CB, Whorton CM. Acute generalised miliary tuberculosis in adults. A clinicopathological study based on sixty three cases diagnosed at autopsy. N Engl J Med 1946;235:239-48. Slavin RE, Walsh TJ, Pollack AD. Late generalized tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine [Baltimore] 1980;59:352-66. Jacques J, Sloan JM. The changing pattern of miliary tuberculosis. Thorax 1970;25:237-40. Vasankari T, Liippo K, Tala E. Overt and cryptic miliary tuberculosis misdiagnosed until autopsy. Scand J Infect Dis 2003;35:794-6. Jagirdar J, Zagzag D. Pathology and insights into pathogenesis of tuberculosis. In: Rom WN, Garay SM, editors. Tuberculosis. Philadelphia: Lippincott Williams and Wilkins; 2004.p.323-44. Ansari NA, Kombe AH, Kenyon TA, Hone NM, Tappero JW, Nyirenda ST, et al. Pathology and causes of death in a group of 128 predominantly HIV-positive patients in Botswana, 1997-1998. Int J Tuberc Lung Dis 2002;6:55-63. Alvarez S, McCabe WR. Extrapulmonary tuberculosis revisited: a review of experience at Boston City and other hospitals. Medicine [Baltimore] 1984;63:25-55. Long R, O’Connor R, Palayew M, Hershfield E, Manfreda J. Disseminated tuberculosis with and without a miliary pattern on chest radiograph: a clinical-pathologic-radiologic correlation. Int J Tuberc Lung Dis 1997;1:52-8.

21. Hussey G, Chisholm T, Kibel M. Miliary tuberculosis in children: a review of 94 cases. Pediatr Infect Dis J 1991;10:832-6. 22. Noertjojo K, Tam CM, Chan SL, Chan-Yeung MM. Extrapulmonary and pulmonary tuberculosis in Hong Kong. Int J Tuberc Lung Dis 2002;6:879-86. 23. Kim PK, Lee JS, Yun DJ. Clinical review of miliary tuberculosis in Korean children. 84 cases and review of the literature. Yonsei Med J 1969;10:146-52. 24. Udani PM, Bhat US, Bhave SK, Ezuthachan SG, Shetty VV. Problem of tuberculosis in children in India: epidemiology, morbidity, mortality and control programme. Indian Pediatr 1976;13:881-90. 25. Somu N, Vijayasekaran D, Ravikumar T, Balachandran A, Subramanyam L, Chandrabhushanam A. Tuberculous disease in a pediatric referral centre: 16 years experience. Indian Pediatr 1994;31:1245-9. 26. Gurkan F, Bosnak M, Dikici B, Bosnak V, Yaramis A, Tas MA, et al. Miliary tuberculosis in children: a clinical review. Scand J Infect Dis 1998;30:359-62. 27. Centers for Disease Control and Prevention. Tuberculosis statistics in the United States, 1990. Atlanta: US Department of Health and Human Services, Centers for Disease Control: 1992. 28. Farer LS, Lowell AM, Meador MP. Extrapulmonary tuberculosis in the United States. Am J Epidemiol 1979;109:205-17. 29. Rieder HL, Snider DE Jr, Cauthen GM. Extrapulmonary tuberculosis in the United States. Am Rev Respir Dis 1990;141:347-51. 30. Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 1997. Tuberculosis cases by form of disease: States, 1997. Available at URL: http:// www.cdc.gov/nchstp/tb/ surv/surv97/surv97pdf/ table12.pdf. Accessed on October 17, 2008. 31. Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 1998. Tuberculosis cases by form of disease: States, 1998. Available at URL: http:// www.cdc.gov/nchstp/ tb/surv/surv98/surv98pdf/ table12.pdf. Accessed on October 17, 2008. 32. Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 1999. Tuberculosis cases by form of disease: States, 1999. Available at URL: http:// www.cdc.gov/nchstp/ tb/surv/surv99/pdfs/table21.pdf. Accessed on October 17, 2008. 33. Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2000. Tuberculosis cases by form of disease: States, 2000. Available at URL: http:// www.cdc.gov/nchstp/ tb/surv/surv2000/pdfs/t21.pdf. Accessed on October 17, 2008. 34. Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2001. Tuberculosis cases by form of disease: States, 2001. Available at URL: http:// www.cdc.gov/nchstp/tb/ surv/surv2001/pdf/t23.pdf. Accessed on October 17, 2008. 35. Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2002. Tuberculosis cases by

Disseminated and Miliary Tuberculosis 517

36.

37. 38. 39.

40.

41.

42.

43.

44. 45. 46.

47. 48.

49. 50.

51.

52.

53.

form of disease: States, 2002. Available at URL: http:// www.cdc.gov/nchstp/tb/ surv/surv2002/PDF/T23.pdf. Accessed on October 17, 2008. Wares F, Balasubramanian R, Mohan A, Sharma SK. Extrapulmonary tuberculosis: management and control. In: Agarwal SP, Chauhan LS, editors. Tuberculosis control in India. New Delhi: Central TB Division. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India; 2005.p.95-114. Proudfoot AT, Akhtar AJ, Douglas AC, Horne NW. Miliary tuberculosis in adults. BMJ 1969;2:273-6. Yu YL, Chow WH, Humphries MJ, Wong RW, Gabriel M. Cryptic miliary tuberculosis. QJM 1986;59:421-8. Ormerod LP. Respiratory tuberculosis. In: Davies PDO, editor. Clinical tuberculosis. London: Chapman and Hall Medical; 1997.p.76. Mert A, Bilir M, Tabak F, Ozaras R, Ozturk R, Senturk H, et al. Miliary tuberculosis: clinical manifestations, diagnosis and outcome in 38 adults. Respirology 2001;6:217-24. Hussain SF, Irfan M, Abbasi M, Anwer SS, Davidson S, Haqqee R, et al. Clinical characteristics of 110 miliary tuberculosis patients from a low HIV prevalence country. Int J Tuberc Lung Dis 2004;8:493-9. Biehl JP. Miliary tuberculosis; a review of sixty-eight adult patients admitted to a municipal general hospital. Am Rev Tuberc 1958;77:605-22. Munt PW. Miliary tuberculosis in the chemotherapy era: with a clinical review in 69 American adults. Medicine [Baltimore] 1972;51:139-55. Campbell IG. Miliary tuberculosis in British Columbia. Can Med Assoc J 1973;108:1517-9. Gelb AF, Leffler C, Brewin A, Mascatello V, Lyons HA. Miliary tuberculosis. Am Rev Respir Dis 1973;108:1327-33. Grieco MH, Chmel H. Acute disseminated tuberculosis as a diagnostic problem. A clinical study based on twenty-eight cases. Am Rev Respir Dis 1974;109:554-60. Onadeko BO, Dickinson R, Sofowora EO. Miliary tuberculosis of the lung in Nigerian adults. East Afr Med J 1975;52:390-5. Teklu B, Butler J, Ostrow JH. Miliary tuberculosis. A review of 83 cases treated between 1950 and 1968. Ethiop Med J 1977;15:39-48. Prout S, Benatar SR. Disseminated tuberculosis. A study of 62 cases. S Afr Med J 1980;58:835-42. Kim JH, Langston AA, Gallis HA. Miliary tuberculosis: epidemiology, clinical manifestations, diagnosis, and outcome. Rev Infect Dis 1990;12:583-90. Maartens G, Willcox PA, Benatar SR. Miliary tuberculosis: rapid diagnosis, hematologic abnormalities, and outcome in 109 treated adults. Am J Med 1990;89:291-6. Sharma SK, Mohan A, Pande JN, Prasad KL, Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. Q J Med 1995;88:29-37. Al-Jahdali H, Al-Zahrani K, Amene P, Memish Z, AlShimemeri A, Moamary M, et al. Clinical aspects of miliary tuberculosis in Saudi adults. Int J Tuberc Lung Dis 2000;4:2525.

54. Swaminathan S, Padmapriyadarsini C, Ponnuraja C, Sumathi CH, Rajasekaran S, Amerandran VA, et al. Miliary tuberculosis in human immunodeficiency virus infected patients not on antiretroviral therapy: clinical profile and response to short course chemotherapy. J Postgrad Med 2007;53:228-31. 55. Aderele WI. Miliary tuberculosis in Nigerian children. East Afr Med J 1978;55:166-71. 56. Rahajoe NN. Miliary tuberculosis in children. A clinical review. Paediatr Indones 1990;30:233-40. 57. Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT, Nguyen TC, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351:1741-51. 58. Braidy J, Pothel C, Amra S. Miliary tuberculosis presenting as adrenal failure. J Can Med Assoc 1981;82:254-6. 59. Sharma SK, Mohan A, Banga A, Saha PK, Guntupalli KK. Predictors of development and outcome in patients with acute respiratory distress syndrome due to tuberculosis. Int J Tuberc Lung Dis 2006;10:429-35. 60. Penner C, Roberts D, Kunimoto D, Manfreda J, Long R. Tuberculosis as a primary cause of respiratory failure requiring mechanical ventilation. Am J Respir Crit Care Med 1995;151:867-72. 61. Mohan A, Sharma SK, Pande JN. Acute respiratory distress syndrome in miliary tuberculosis: a 12-year experience. Indian J Chest Dis Allied Sci 1996;38:147-52. 62. Sharma N, Kumar P. Miliary tuberculosis with bilateral pneumothorax: a rare complication. Indian J Chest Dis Allied Sci 2002;44:125-7. 63. Das M, Chandra U, Natchu M, Lodha R, Kabra SK. Pneumomediastinum and subcutaneous emphysema in acute miliary tuberculosis. Indian J Pediatr 2004;71:553-4. 64. Singh KJ, Ahluwalia G, Sharma SK, Saxena R, Chaudhary VP, Anant M. Significance of haematological manifestations in patients with tuberculosis. J Assoc Physicians India 2001;49:790-4. 65. Kuo PH, Yang PC, Kuo SS, Luh KT. Severe immune hemolytic anemia in disseminated tuberculosis with response to antituberculosis therapy. Chest 2001;119:1961-3. 66. Runo JR, Welch DC, Ness EM, Robbins IM, Milstone AP. Miliary tuberculosis as a cause of acute empyema. Respiration 2003;70:529-32. 67. Sydow M, Schauer A, Crozier TA, Burchardi H. Multiple organ failure in generalized disseminated tuberculosis. Respir Med 1992;86:517-9. 68. Nieuwland Y, Tan KY, Elte JW. Miliary tuberculosis presenting with thyrotoxicosis. Postgrad Med J 1992;68:677-9. 69. Mallinson WJ, Fuller RW, Levison DA, Baker LR, Cattell WR. Diffuse interstitial renal tuberculosis—an unusual cause of renal failure. Q J Med 1981;50:137-48. 70. Shribman JH, Eastwood JB, Uff J. Immune complex nephritis complicating miliary tuberculosis. Br Med J [Clin Res Ed] 1983;287:1593-4. 71. Wallis PJ, Branfoot AC, Emerson PA. Sudden death due to myocardial tuberculosis. Thorax 1984;39:155-6.

518

Tuberculosis

72. Cope AP, Heber M, Wilkins EG. Valvular tuberculous endocarditis: a case report and review of the literature. J Infect 1990;21:293-6. 73. Wainwright J. Tuberculous endocarditis: a report of 2 cases. S Afr Med J 1979;56:731-3. 74. Rose AG. Cardiac tuberculosis. A study of 19 patients. Pathol Lab Med 1987;111:422-6. 75. Haas DW, Des Prez RM. Tuberculosis and acquired immunodeficiency syndrome: a historical perspective on recent developments. Am J Med 1994;96:439-50. 76. Jones BE, Young SM, Antoniskis D, Davidson PT, Kramer F, Barnes PF. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993;148:1292-7. 77. Lado Lado FL, Barrio Gomez E, Carballo Arceo E, Cabarcos Ortiz de Barron A. Clinical presentation of tuberculosis and the degree of immunodeficiency in patients with HIV infection. Scand J Infect Dis 1999;31:387-91. 78. Daikos GL, Uttamchandani RB, Tuda C, Fischl MA, Miller N, Cleary T, et al. Disseminated miliary tuberculosis of the skin in patients with AIDS: report of four cases. Clin Infect Dis 1998;27:205-8. 79. del Giudice P, Bernard E, Perrin C, Bernardin G, Fouché R, Boissy C, et al. Unusual cutaneous manifestations of miliary tuberculosis. Clin Infect Dis 2000;30:201-4. 80. Jehle AW, Khanna N, Sigle JP, Glatz-Krieger K, Battegay M, Steiger J, et al. Acute renal failure on immune reconstitution in an HIV-positive patient with miliary tuberculosis. Clin Infect Dis 2004;38:e32-5. 81. Goldsack NR, Allen S, Lipman MC. Adult respiratory distress syndrome as a severe immune reconstitution disease following the commencement of highly active antiretroviral therapy. Sex Transm Infect 2003;79:337-8. 82. Winkler AW, Crankshaw DF. Chloride depletion in conditions other than Addison’s disease. J Clin Invest 1938;17:1-6. 83. Shalhoub RJ, Antoniou LD. The mechanism of hyponatremia in pulmonary tuberculosis. Ann Intern Med 1969;70:943-62. 84. Vorherr H, Massry SG, Fallet R, Kaplan L, Kleeman CR. Antidiuretic principle in tuberculous lung tissue of a patient with pulmonary tuberculosis and hyponatremia. Ann Intern Med 1970;72:383-7. 85. Yu RS, Zhang SZ, Wu JJ, Li RF. Imaging diagnosis of 12 patients with hepatic tuberculosis. World J Gastroenterol 2004;10:1639-42. 86. Sharma SK, Mukhopadhyay S, Arora R, Varma K, Pande JN, Khilnani GC. Computed tomography in miliary tuberculosis: comparison with plain films, bronchoalveolar lavage, pulmonary functions and gas exchange. Australasian Radiol 1996;40:113-8. 87. Pipavath SN, Sharma SK, Sinha S, Mukhopadhyay S, Gulati MS. High resolution CT [HRCT] in miliary tuberculosis

88.

89. 90.

91. 92.

93.

94.

95.

96.

97.

98.

99.

100.

[MTB] of the lung: correlation with pulmonary function tests and gas exchange parameters in north Indian patients. Indian J Med Res 2007;126:193-8. Sharma SK, Pande JN, Singh YN, Verma K, Kathait SS, Khare SD, et al. Pulmonary function and immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 1992;145:116771. Sharma SK, Ahluwalia G. Exercise testing in miliary tuberculosis–some facts. Indian J Med Res 2007;125:182-3. Sharma SK, Ahluwalia G. Effect of antituberculosis treatment on cardiopulmonary responses to exercise in miliary tuberculosis. Indian J Med Res 2006;124:411-8. Sharma SK, Pande JN, Verma K. Bronchoalveolar lavage [BAL] in miliary tuberculosis. Tubercle 1988;69:175-8. Prabhakaran D, Sharma SK, Verma K, Pande JN. Estimation of fibronectin in bronchoalveolar lavage fluid in various diffuse interstitial lung diseases. Am Rev Respir Dis 1990;141:A51. Willcox PA, Potgieter PD, Bateman ED, Benatar SR. Rapid diagnosis of sputum negative miliary tuberculosis using the flexible fibreoptic bronchoscope. Thorax 1986;41:681-4. World Health Organization. Treatment of tuberculosis: guidelines for national programmes. WHO/CDS/TB/ 2003.313. Third edition. Geneva: World Health Organization; 2003. World Health Organization. Revised guidelines for national programmes. WHO/CDS/TB/2003.313. Third edition 2003. Revision approved by STAG, June 2004. Available at URL: http:// www.who.int/docstore/gtb/publications/ttgnp/ PDF/tb_2003_313chap4_rev.pdf. Accessed on October 17, 2008. American Academy of Pediatrics Committee on Infectious Diseases. Chemotherapy for tuberculosis in infants and children. Pediatrics 1992;89:161-5. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:60362. National Institute for Health and Clinical Excellence, National Collaborating Centre for Chronic Conditions. Management of non-respiratory tuberculosis. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London: Royal College of Physicians; 2006.p.63-76. Sun TN, Yang JY, Zheng LY, Deng WW, Sui ZY. Chemotherapy and its combination with corticosteroids in acute miliary tuberculosis in adolescents and adults: analysis of 55 cases. Chin Med J [Engl] 1981;94:309-14. Massaro D, Katz S, Sachs M. Choroidal tubercles. A clue to hematogenous tuberculosis. Ann Intern Med 1964;60:231-41.

Complications of Pulmonary Tuberculosis

35 D Behera

INTRODUCTION Complications of pulmonary tuberculosis [TB] significantly contribute to morbidity and mortality of patients and are listed in Table 35.1. HAEMOPTYSIS

35.1 and 35.2]. Important causes of haemoptysis in patients with pulmonary TB are listed in Table 35.2. Walls of a TB cavity may be affected by inflammation and necrosis and may become atrophic. Increased pressure can lead to weakening of the walls, dilatation of blood vessels and formation of Rasmussen’s aneurysms (5,6) [Figure 35.3]. Further, these blood vessels rupture

Haemoptysis is a common and potentially serious complication of pulmonary TB (1-4). The incidence of haemoptysis in patients with pulmonary TB is reported to range from 30 to 35 per cent (1-3). Occurrence of haemoptysis does not imply that the TB is active. Haemoptysis may occur as the initial manifestation of active TB, during the course of treatment, or, even after the disease is apparently cured. Haemoptysis can be streaky or massive and life-threatening. Massive haemoptysis may be associated with atelectasis [Figures

Table 35.1: Complications of pulmonary tuberculosis Local Haemoptysis Post-tuberculosis bronchiectasis Fungal ball [aspergilloma] Tuberculosis endobronchitis and tracheitis Spontaneous pneumothorax Scar carcinoma Disseminated calcification of the lungs Pulmonary function changes, obstructive airways disease Secondary pyogenic infections Systemic Secondary amyloidosis Chronic respiratory failure Chronic cor-pulmonale

Figure 35.1: Chest radiograph [postero-anterior view] of a patient who presented with massive haemoptysis showing collapse of the left lung Reproduced with permission from “Sharma SK, Mohan A. Pulmonary tuberculosis: typical and atypical cases. Case track series 1. Mumbai: Merind; 1997 (reference 3)”

520

Tuberculosis

Figure 35.2: Chest radiograph [postero-anterior view] of the same patient following vigorous chest physiotherapy and suction showing bilateral infiltration of both the lung fields. Sputum smear revealed Mycobacterium tuberculosis Reproduced with permission from “Sharma SK, Mohan A. Pulmonary tuberculosis: typical and atypical cases. Case track series 1. Mumbai: Merind; 1997 (reference 3)”

Table 35.2: Causes of haemoptysis in pulmonary tuberculosis Bleeding from cavity wall Rupture of Rasmussen’s aneurysm Direct erosion of capillaries or arteries by granulomatous inflammation Tuberculosis endobronchitis Post-tuberculosis bronchiectasis Aspergilloma Broncholith, cavernolith Scar carcinoma

due to increased pressure during strenuous exercise or coughing and can result in haemoptysis. The vessel walls can also be eroded directly either because of endarteritis, or, vasculitis secondary to TB. Sometimes intense allergic response to antigen[s] of Mycobacterium tuberculosis damages the vessel wall and gives rise to haemoptysis. Bleeding from TB granulomas in the bronchi can result in haemoptysis. Blood vessels with aneurysmal dilatation and accentuated bronchopulmonary communications are present surrounding these granulomas. In this setting,

Figure 35.3: Rasmussen’s aneurysm. Dynamic and threedimensional views of the pulmonary and bronchial vasculature on computed tomography obtained after the injection of contrast material demonstrated a large pulmonary aneurysm [panels A and B, arrows] obtained from a 54-year-old man who presented with a 3-month history of haemoptysis. The patient underwent successful embolization of the pulmonary artery aneurysm and its feeding vessel. However, the haemoptysis resolved only after subsequent embolization of the bronchial artery Reproduced with permission from “van den Heuvel MM, van Rensburg JJ. Images in clinical medicine. Rasmussen’s aneurysm. N Engl J Med 2006;355:e17 (reference 5)” Copyright [2006] Massachusetts Medical Society. All rights reserved

the bronchial blood vessels which are under systemic pressure can be the source of bleeding. All these factors should be taken into consideration while managing haemoptysis in patients with TB. In most instances bed rest, sedation, and resuscitative measures aimed at restoring fluid balance and

Complications of Pulmonary Tuberculosis 521 haemodynamic status control the bleeding. Broad spectrum antibiotics are administered to treat superadded bacterial infection. Antituberculosis treatment is indicated in patients with active TB. However, if the bleeding is massive, and repetitive, fibreoptic bronchoscopy [to localize the site of bleeding] and high resolution computed tomography [HRCT] are performed. Angiography along with bronchial artery embolization is done in patients with massive haemoptysis [Figures 35.4A and 35.4B] (7,8). Rarely, resection of the site of bleeding may be indicated (9,10).

Figure 35.4: Intra-arterial digital subtraction angiograpy [IA-DSA] in a patient with right upper lobe pulmonary tuberculosis showing a hypertrophied intercosto-bronchial trunck producing contrast extravasation and pulmonary artery filling in the region of fibrocavitary lesion [A]. The IA-DSA after embolization with polyvinyl alcohol particles showing obliteration of the angiographic abnormality with patent parent artery [B] Kind courtesy: Dr Sanjiv Sharma, Department of Cardioradiology, All India Institute of Medical Sciences, New Delhi

ASPERGILLOMA [MYCETOMA; “FUNGUS BALL”] Mycetoma is a mass of fungal hyphal material that grows in a lung cavity. Although other fungi like Zygomycetes [mucor] and Fusarium may cause the formation of a fungal ball, Aspergillus species, particularly, Aspergillus fumigatus, are by far the most common aetiological agents. The overall incidence of aspergilloma in general population has been estimated to be between 0.01 per cent in Great Britain to 0.017 per cent in the USA (11,12). In a large multicentric study by the British Tuberculosis Association (11), which surveyed 544 patients with healed TB cavities on chest films, measuring 2.5 cm or greater in diameter, 25 per cent had precipitins to Aspergillus in serum and 11 per cent had radiologic evidence of aspergilloma. Aspergilloma occurred as frequently in patients with recently healed TB as in those with inactive disease for long periods (11). A follow-up study (12) of this group, three years after the first survey, revealed an increase in incidence of aspergilloma to 17 per cent. The new aspergilloma cases were generally patients who had only serum precipitins during the first survey (11,12). Aspergillomas have been identified in cavities associated with tuberculosis, histoplasmosis, sarcoidosis, bronchial cysts, bullae, neoplasms, pulmonary infarctions, asbestosis, ankylosing spondylitis, bronchiectasis, and malignant diseases (13,14). Of these, TB is the most frequently associated condition (15). Occasionally, they are described in cavities due to other fungal infections (16,17). The natural history of an aspergilloma is highly variable and it may remain stable, increase in size or spontaneously resolve. In the early phase of its development, the fungus ball grows inside a lung cavity consisting of both living and dead fungus. The future course depends upon the predominance of these living or dead fungi. If local conditions favour death, the fungus ball liquifies and the secretions are expectorated out. Calcification occurs less frequently. Clinical Features The fungus ball may be present for long periods without any clinical symptoms and may be an incidental finding in majority of cases and the lesion remains stable. In approximately 10 per cent of cases, it may increase in size or resolve spontaneously without treatment (18). Rarely, the aspergilloma increases in size (11). But

522

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eventually, most of them will manifest with some symptoms. The most common presentation in such cases is haemoptysis and the estimated frequency varies from five to ninety per cent. The amount may be very minimal to severe particularly in patients with associated TB (19). Bleeding usually occurs from the bronchial blood vessels. The exact cause of haemoptysis associated with aspergilloma is not certain, but has been variously ascribed to mechanical friction of mycetoma, an endotoxin with haemolytic properties, an anticoagulant factor derived from Aspergillus, local vasculitis, and direct vascular invasion in cavity wall vessels (20-23). The mortality rate varies between two and fourteen per cent. Other features include chronic cough, weight loss, and rarely fever and dyspnoea (20-23). Risk factors associated with poor prognosis of aspergilloma include severe underlying disease, increasing size or number of lesions as seen on chest radiograph, immunocompromised state including corticosteroid therapy, increasing Aspergillus-specific immunoglobulin G [IgG] titres, recurrent large volume haemoptysis, and underlying sarcoidosis or human immunodeficiency virus [HIV] infection (24). Diagnosis Aspergilloma usually comes to clinical attention as an incidental finding on a routine chest radiographic examination or during an evaluation of haemoptysis. The typical radiographic appearance of aspergilloma is described as a bell-like image, with the fungus ball appearing as a clapper inside a bell. A semicircular crescentic air shadow appears around the radio-opaque fungus ball located in an upper lobe lung cavity (25). The fungus ball is mobile and changes its position as the patient moves, which is best seen on fluoroscopy or by taking chest radiographs or computed tomography [CT] [Figure 35.5] at different positions. A change in position of the aspergilloma with the change in position of the patient is an interesting but a variable sign (26). Occasionally, it may be difficult to recognize the mass on a routine chest radiograph, and tomography or chest CT may be necessary to visualize the aspergilloma. The adjacent pleura may be thickened. The radiographic differential diagnosis includes organized haematoma or pus inside a cavity, neoplasm, abscess, Wegener’s granulomatosis and a ruptured hydatid cyst. An aspergilloma may co-exist with any of these conditions also.

The initial suspicion of a fungus ball is raised from the chest radiograph. Sputum culture may confirm the presence of fungus, but may be negative in about 50 per cent of cases (27). The serum precipitins [IgG antibodies] to Aspergillus are positive in almost 100 per cent of cases except in cases of aspergilloma due to other Aspergillus species or if the patient is on corticosteroid therapy (28). Skin tests are less helpful and may be positive only in a minority of patients (27). In some cases bronchoscopy may be helpful in identifying the site of bleeding and sometimes one may see the fungus ball in direct continuity with the bronchial lumen. Bronchial washings, brushings and forceps biopsy may be carried out to isolate Aspergillus. Treatment The treatment of aspergilloma is controversial because of variability in its natural history. No therapy is warranted in asymptomatic cases. Systemic antifungal therapy is ineffective in treating these lesions. The anti-fungal drugs cannot penetrate into the intracavitary fungi (29). Attempts are made to instill local intrabronchial intracavitary or inhalational antifungal agents [amphotericin B, nystatin, sodium iodide] with varying success (30-32). Systemic antifungal therapy using intravenous Amphotericin B has no effect (33). Itraconazole therapy has been tried with varying success (34). Bronchial artery embolization rarely controls haemoptysis because of extensive collateral blood vessels. This procedure may, however, be used as a temporary measure to control massive, life-threatening haemoptysis (35). Some advocate routine surgery because of the fear of haemoptysis in future. However, the clinical approach should be individualized. In some cases the severity of the underlying lung disease will not allow surgical resection, even in the presence of life-threatening haemoptysis. The surgical treatment of aspergilloma is associated with a relatively high mortality rate that ranges between seven and twenty-three per cent (36,37). The most common causes of death following surgery are severe underlying lung disease, pneumonia, acute myocardial infarction, and invasive pulmonary aspergillosis. In addition, there is a significant postoperative morbidity, including bleeding, residual pleural space, bronchopleural fistula, empyema, and respiratory failure. In younger patients with adequate lung reserve the morbidity and mortality are lower (38,39).

Complications of Pulmonary Tuberculosis 523

Figure 35.5: CT of the chest [lung window, supine position] showing a cavity in the left upper lobe [A and B] containing a radio-opaque shadow with a semi-circular air crescent around it [arrow] suggestive of a fungal ball [asterisk]. When the CT is repeated with the patient in the prone position [C and D], the fungal ball can be seen to have changed its position

The best approach seems to wait and watch and surgery is indicated only when there is repeated and severe haemoptysis. Patients with mild infrequent haemoptysis or without symptoms may be observed carefully. Surgical approach needs to be considered in patients with massive haemoptysis and adequate pulmonary reserve (36-40). Mycetoma and Human Immunodeficiency Virus Infection Pulmonary mycetomas have also been documented in human immunodeficiency virus [HIV] seropositive individuals (21,41-43). Although life-threatening haemoptysis has occasionally been documented (41), it

appears to be a relatively rare manifestation in HIVseropositive patients with pulmonary mycetoma. In a study (21) comparing the clinical presentation, disease progression, treatment, and outcome of pulmonary mycetoma in patients with [n = 10], and without [n = 15] HIV infection, the following observations were documented. Although TB and sarcoidosis were the most prevalent predisposing diseases, a history of Pneumocystis jirovecii pneumonia and the consequent cavitation was found to be a risk factor for pulmonary aspergilloma in HIV infected individuals. In HIV-positive patients with a CD4+ count of less than or equal to 100 cells/μl, the disease progressed disease despite treatment. Compared with HIV-positive patients, significant haemoptysis

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requiring intervention was more likely in HIV-negative individuals. In another study (43), Pneumocystis jirovecii pneumonia was found to be a risk factor for pulmonary mycetoma in the HIV infected individuals. These workers (43) also reported that though the disease progressed rapidly, life-threatening haemoptysis rarely occurred in HIV-infected patients with mycetoma. A combination of anti-fungal and anti-retroviral therapy may improve the clinical outcome in HIV-infected patients with pulmonary mycetoma. POST-TUBERCULOSIS BRONCHIECTASIS The pathogenesis of bronchiectasis in TB is multifactorial (44). Caseation necrosis and granulomatous inflammation in the wall of the dilated and destroyed bronchi suggest that this may represent an extension of the TB process. Scarring that follows TB inflammation produces bronchial stenosis. This, when followed by mixed bacterial infection and retention of purulent bacterial secretions, leads to destruction and dilatation of the bronchi as is the case with other types of bronchiectasis. The ongoing pathological changes may be perpetuated by products of inflammation. Compression of the bronchial lumen by enlarged lymph nodes produces consequences similar to those of an intraluminal obstruction. This is more so in the case of young children and adolescents in whom TB hilar lymphadenitis is more common. In both these situations, inflammatory destruction of the bronchial wall is by and large the sequelae of secondary bacterial infection rather than the direct effect of Mycobacterium tuberculosis. Another rare, but important cause of bronchial obstruction is penetration of the airway by a calcified TB lymph node and the formation of broncholith. Some or all of the bronchiectatic cavities may represent healing or healed TB cavities that have been re-lined with ciliated columnar epithelium. Bronchiectasis structurally resembles small/ large cavities in the bronchial wall. Recently, it has been reported that, Mycobacterium avium-intracellulare infection of the lungs is associated with bronchiectasis in apparently healthy individuals, or, in persons with emphysema. It seems that such an association may either be due to a primary infection or colonization. Post-TB bronchiectasis is commonly seen in the upper lobes, since the disease is more common at this site. It is a “dry” or

“sicca” type of bronchiectasis because of the effective drainage of the upper lobes by gravity. The usual presentation is with haemoptysis or repeated episodes of secondary bacterial infection. Although the chest radiograph is important in the evaluation of a patient with suspected post-TB bronchiectasis, the findings are often non-specific. Bronchography performed with a radio-opaque, iodinated lipid dye, provides an excellent visualization of the dilated airways [Figure 35.6]. However, in the recent years, it has been replaced by HRCT. As compared to the bronchography, the CT is a relatively non-invasive investigation. TUBERCULOSIS ENDOBRONCHITIS AND TRACHEITIS Tuberculosis endobronchitis and tracheitis are observed in about one-third of the patients with pulmonary TB (45). These structures can be infected by direct implantation of Mycobacterium tuberculosis, through submucosal lymphatics, haematogenous spread or from the lymph nodes. Clinical manifestations include cough, haemoptysis, breathlessness and soreness or constriction in the sub-sternal region. Healing can lead to bronchostenosis.

Figure 35.6: Bronchography showing right upper lobe posttuberculosis bronchiectasis

Complications of Pulmonary Tuberculosis 525 The reader is referred to the chapter “Endobronchial tuberculosis” [Chapter 16] for more details. SPONTANEOUS PNEUMOTHORAX Spontaneous pneumothorax has been reported in five to fifteen per cent of patients with pulmonary TB (46,47). In countries where TB is a common problem, it is an important cause of pneumothorax [Figure 35.7]. Spontaneous pneumothorax may result from rupture of a subpleural TB cavity into the pleural space. Infection of pleural cavity results in pyopneumothorax. Other causes of pneumothorax include rupture of an open healed cavity or rupture of a bleb or bulla [Figure 35.8] secondary to fibrosis and destruction of the lung (48).

may also give history of coughing out calcified stones in the sputum [broncholiths or pneumoliths]. Extensive calcification, may result in respiratory failure or chronic cor-pulmonale. TUBERCULOSIS LARYNGITIS Involvement of larynx during the course of pulmonary TB occurs in about four to forty per cent of cases (49). The incidence increases with extensive involvement of lungs and presence of cavitary disease. The usual mode of infection is by direct implantation or through lymphatics and blood vessels. The symptoms include soreness or pain in the throat, dry, hacking cough and hoarseness of voice. Laryngoscopy may reveal an ulcer, granuloma, paresis or paralysis, destruction of cords, or stenosis of the vocal cords. The vocal cords, arytenoids and the interarytenoid space are most commonly affected. The sputum is usually positive for Mycobacterium tuberculosis. The reader is referred to the Chapter “Tuberculosis in otorhinolaryngology” [Chapter 27] for details. TUBERCULOSIS ENTERITIS Tuberculosis enteritis seldom occurs as a complication of pulmonary TB in the present era. The reader is referred to the chapter “Abdominal tuberculosis” [Chapter 19] for further details. “OPEN-NEGATIVE” SYNDROME

Figure 35.7: Chest radiograph [postero-anterior view] showing hydropneumothorax on the right side

CALCIFICATION Tuberculosis lung lesions heal by calcification. In fact, localized or extensive calcification of the lungs is a feature of healed primary TB (47). Calcification can either be microscopic or macroscopic. Most often these calcifications are innocuous and present as discrete radio-opaque shadows in patients with parenchymal disease [Figure 35.9] and sheet-like calcification in patients with pleural disease [Figure 35.10]. Occasionally, however, these calcified concretions may get detached from the lung tissue and erode through a bronchial wall or blood vessel and result in massive haemoptysis. The patient

Patients with “open-negative syndrome” have thin walled cavities with epithelialization extending from bronchioles down to the inner lining of the cavity (5052). These are observed more frequently following the advent of chemotherapy. Although they are known as “isoniazid cavities”, they can also occur due to other antituberculosis drugs. Complete epithelialization prevents these cavities to collapse and fibrose but renders them innocuous. From a clinical point of view, they are regarded as inactive cavities. However, histopathological examination of such cavities may reveal incomplete epithelialization and necrotic foci showing Mycobacterium tuberculosis. These present radiologically as “ring shadows” with thin walls. Although the cavities themselves will not produce any symptoms, they are associated with certain hazards like secondary infection, colonization with fungi

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Figure 35.8: Chest radiograph [poster-anterior view] [A], CT of the chest [coronal reconstruction, B], [C], and [D] of a patient who presented with breathlessness showing bilateral bullous lung disease [arrows]. This patient had sputum smear-positive pulmonary tuberculosis a decade ago and had received adequate antituberculosis treatment

Figure 35.9: Chest radiograph [postero-anterior view] showing parenchymal calcification on the left side

Figure 35.10: Chest radiograph [postero-anterior view] showing sheet-like pleural calcification on the right side

Complications of Pulmonary Tuberculosis 527 producing fungal balls, scar carcinoma, spontaneous pneumothorax, and loss of effective volume of the lungs. SCAR CARCINOMA Development of lung cancer in association with old scars [scar carcinoma] is common in conditions, such as progressive systemic sclerosis with lung involvement. The relationship between the scars of pulmonary TB and lung cancer has been a matter of debate for a long time. In the series reported by Auerbach et al (53), scar cancer was observed in 82 of the 1186 autopsied cases [1%]; 23.2 per cent of these had originated from TB scars. A similar association between scars of TB and lung cancer has been documented in several other reports (54,55). However, other reports indicate that the association between TB and lung cancer was merely coincidental (56,57). Impaired lung ventilation and concomitant increase in pulmonary carbon dioxide levels, which in turn causes pronounced hyperplasia of pulmonary neuroendocrine cells have been postulated as the possible mechanisms underlying the genesis of lung cancer in patients with chronic lung diseases. A receptor with sensitivity for oxygen and carbon dioxide which produce a number of autocrine growth factors is considered to be crucial in the malignant transformation (58-60). These issues merit further study.

Figure 35.11: Chest radiograph [postero-anterior view] of a patient with old, healed pulmonary tuberculosis showing extensive parenchymal destruction, bronchiectatic changes and pleural thickening on the left side. On the right side, compensatory emphysema and pseudobulla formation can be seen

PULMONARY FUNCTION CHANGES Thirty to sixty per cent of cases with pulmonary TB suffer from diffuse airways obstruction (61,62), which is distinct from chronic bronchitis. Further, because of diffuse parenchymal fibrosis, pleural effusion and thickening, and fibrothorax, a restrictive type of pulmonary function defect is also possible. Thus, in a patient with pulmonary TB an obstructive, restrictive, or a mixed type of lung function abnormality is possible depending upon the type and extent of involvement or residual damage (63). CHRONIC RESPIRATORY FAILURE Chronic respiratory failure may complicate pulmonary TB, especially if the disease had been extensive and the patient survived because of adequate treatment. Respiratory failure develops due to extensive destruction of pulmonary parenchyma [Figures 35.11 and 35.12] and • • the resultant ventilation-perfusion [V/Q ]mismatch.

Figure 33.12: Chest radiograph [postero-anterior view] of a patient with pulmonary tuberculosis showing extensive parenchymal destruction, bronchiectatic changes and pleural thickening on the left side. On the right side, compensatory emphysema can be seen

Associated pleural thickening and fibrothorax result in thoracic wall malfunction and further add to the mechanical disadvantage of the lung, thus contributing

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to the pump failure (64-66). Atrophy or disuse of the respiratory muscles can also contribute to chronic respiratory failure. Tachypnoea, hypoxia and hypercapnia develop ultimately and the patient may die from these abnormalities. PULMONARY ARTERY HYPERTENSION AND CHRONIC COR-PULMONALE Cor-pulmonale is defined as enlargement [dilatation and/or hypertrophy] of the right ventricle due to increased right ventricular afterload from intrinsic pulmonary diseases including those of pulmonary circulation, inadequate function of the chest bellows or inadequate ventilatory drive from the respiratory centres; when right heart abnormalities secondary to left heart failure or congenital heart disease are excluded. Right heart failure need not be present, although this is a clinical manifestation of the overloaded right ventricle that precedes the clinically unrecognizable cor-pulmonale. Except in rare instances when the disease is complicated by massive pulmonary thromboembolism, cor-pulmonale is usually chronic. The possible causes of chronic cor-pulmonale in pulmonary TB include abnormalities of the pulmonary parenchyma or thoracic wall. The underlying basic pathophysiology of chronic cor-pulmonale is an increase in the pulmonary artery vascular resistance and pulmonary hypertension. Mechanisms causing these changes include occlusion or destruction of vascular bed due to lung parenchymal destruction, vasculitis, and endarteritis with diminished cross-sectional area of the pulmonary circulation (67,68). Other less important causes include hypoxia, acidosis with hypercapnia, and increased blood viscosity due to polycythaemia. The latter may not be important in developing nations because of a high prevalence of malnutrition and anaemia. These causes also happen to be important in the causation of chronic cor-pulmonale in patients with chronic obstructive pulmonary disease. Normally, pulmonary circulation is a highly distensible, low pressure and low-resistance circulation that transmits the entire cardiac output without much change in pressure because the pulmonary arteries are thinwalled with little resting muscular tone. In adults, there is a negligible response in terms of capacity, distensibility, or resistance to flow following autonomic nervous system stimulation. Many small arterioles and capillaries are

non-perfused at rest, but can be recruited when needed to expand the pulmonary vascular bed causing a decrease in pulmonary vascular resistance. There is no humoral counterpart of the renin-angiotensin system that is capable of evoking sustained pulmonary artery hypertension. Normal mean pulmonary artery pressure is 13 to 14 mm Hg in a young adult and is less than 18 mm Hg in 80 per cent of subjects of all ages. Pulmonary artery pressure of greater than 20 mm Hg signifies pulmonary artery hypertension. Blood flow through the pulmonary capillaries is achieved by a pressure drop of only 5 to 9 mm Hg [pulmonary artery to left atrial pressure] compared to 90 mm Hg for the systemic circuit. Accordingly, the normal pulmonary vascular resistance is 10 to 20 times less than systemic vascular resistance. It is generally agreed that the decrease in extent of the pulmonary vascular bed is insufficient to play a predominant role in the pathogenesis of pulmonary hypertension unless the reduction is extreme. The effective cross-sectional area of the pulmonary vascular bed must be reduced by more than 50 per cent before any change in pulmonary artery pressure can be detected at rest, although exercise will increase the pressure at lower levels of increased blood flow. Experiments in dogs have shown that more than two-thirds of the lungs had to be ablated before pulmonary artery pressures approach hypertensive levels (67,68). Obliterative vascular diseases increase pulmonary vascular resistance by vascular occlusion, while diffuse interstitial and parenchymal diseases act primarily by compressing and obliterating small vessels. The diagnosis of chronic cor-pulmonale is often not made until significant right ventricular hypertrophy or overt right ventricular failure is present. Heart failure occurs insidiously, causing further impairment of lung function and is frequently misinterpreted as worsening of the underlying lung disease. Episodes of leg oedema, atypical chest pain, exertional dyspnoea, exerciseinduced cyanosis in the periphery, prior respiratory failure, and excessive daytime sleepiness are non-specific but important historical clues suggesting the possibility of cor-pulmonale. General physical examination reveals distended neck veins, peripheral oedema, and cyanosis. Oedema in chronic cor-pulmonale may not be necessarily due to overt heart failure. Signs and symptoms suggestive of

Complications of Pulmonary Tuberculosis 529 heart failure like dyspnoea, orthopnoea, oedema, hepatomegaly, and raised jugular venous pressure [JVP] can also occur due to chronic obstructive airways disease without right heart failure. However, the raised JVP is present in both phases of respiration in right heart failure. The apical impulse and the right ventricular lift are often not palpable. The second heart sound may be palpable in the pulmonary area. The earliest sign of pulmonary hypertension is an accentuated pulmonic component of the second heart sound. A right ventricular S3 gallop is heard in the epigastrium along the sternum. With advanced pulmonary artery hypertension, characteristic diastolic murmur of pulmonary regurgitation and pansystolic murmur of tricuspid regurgitation which accentuates during inspiration can be heard along with a systolic ejection sound. Right ventricular failure is usually precipitated by some acute episode like pneumonia. Associated clinical features of the underlying basic disease will be present. Cor-pulmonale due to restricted vascular bed is manifested by a strikingly high pulmonary arterial pressure associated with a low cardiac output. Hypoxaemia is often mild. Tachypnoea which persists even during sleep is the rule, particularly with multiple pulmonary emboli. Chest pain is common. Enlargement of right ventricle in its pure form is manifested in these disorders. Prominent “a” and “v” waves appear in the jugular veins. The classic radiographic evidence of right ventricular enlargement [crossing the right vertebral border] will be present. This is manifested by enlargement of the outflow tract of the right ventricle, the main pulmonary arteries, and their central branches, in association with attenuated peripheral branches of the pulmonary arterial tree. Enlargement of the pulmonary artery is considered to exist when the diameter of the right descending pulmonary artery is greater than 16 mm and the left descending pulmonary artery is greater than 18 mm, although the true sensitivity and specificity of these measurements are not known. The “suggestive” indices of pulmonary hypertension [right ventricular enlargement] in the electrocardiogram include: p pulmonale in leads II, III, aVF, S1Q3, or S1-S2S3 patterns, right axis deviation, R:S ratio in V6 of 1.0, rSR pattern in the right precordial leads, and partial or complete right bundle branch block (69-71). Dominant R or R’ in lead V1 or V3R in association with inverted T

waves in the right precordial leads in combination with “suggestive” criteria, are more definite indices. Noninvasive investigations such as Doppler and 2-D transthoracic echocardiography may be used periodically to monitor pulmonary artery pressure and right ventricular function. AMYLOIDOSIS Secondary amyloidosis is known to occur in a wide variety of clinical situations and is characterized by the deposition of an extracellular eosinophilic substance in various organs. Although the name suggests carbohydrate deposition, in fact, the substance is predominantly, if not exclusively, protein in origin (72). Several cytokines including interleukin-1 [IL-1], interleukin-6 [IL-6] and tumour necrosis factor-α [TNF]-α stimulate hepatic synthesis of serum amyloid A precursor during TB inflammation. The incidence of renal amyloidosis in TB has been reported to range from eight to thirty-three per cent (73-77). Differences in the method used to detect amyloidosis could also have contributed to this wide variation. The incidence of amyloidosis was 1.01 per cent of 6431 postmortems and 8.4 per cent of 1980 renal biopsies at the Postgraduate Institute of Medical Education and Research, Chandigarh (76). While 87.1 per cent had secondary amyloidosis, 3.5 per cent had primary amyloidosis and the remaining had multiple myeloma. Tuberculosis of various organs was the most common predisposing cause accounting for 59.1 per cent of secondary amyloidosis, followed by chronic suppurative lung diseases (76). Pulmonary TB was the leading cause in 81.6 per cent of cases followed by glandular and abdominal TB. The interval between the onset of the predisposing disease and the first evidence of secondary renal amyloidosis varied from one to thirty years with a mean of 6.9 years in this study. The interval was greater than five years in 67 per cent of patients. However, other reports suggest that this interval varies widely and may be as short as six months or as long as 43 years (77). Secondary amyloidosis is now rare as a complication of pulmonary TB because of the availability of effective antituberculosis treatment. Nonetheless, TB is still the commonest cause of secondary amyloidosis in Indian patients (76). Abdominal fat pad, rectal, mucosal, liver, or kidney biopsy specimens are useful in confirming the diagnosis of secondary amyloidosis.

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REFERENCES 1. Bidwell JL, Pachner RW. Hemoptysis: diagnosis and management. Am Fam Physician 2005;72:1253-60. 2. Pamra SP, Goyal SS, Raj B, Mathur GP. Epidemiology of haemoptysis. Indian J Tuberc 1970;17:111-8. 3. Sharma SK, Mohan A. Pulmonary tuberculosis: typical and atypical cases. Case track series 1. Mumbai: Merind; 1997. 4. Reechaipichitkul W, Latong S. Etiology and treatment outcomes of massive hemoptysis. Southeast Asian J Trop Med Public Health 2005;36:474-80. 5. van den Heuvel MM, van Rensburg JJ. Images in clinical medicine. Rasmussen’s aneurysm. N Engl J Med 2006;355:e17 6. Keeling AN, Costello R, Lee MJ. Rasmussen’s aneurysm: a forgotten entity? Cardiovasc Intervent Radiol 2007;30:12347. Epub 2007 Sep 5. 7. Kato A, Kudo S, Matsumoto K, Fukahori T, Shimizu T, Uchino A, et al. Bronchial artery embolization for hemoptysis due to benign diseases: immediate and long-term results. Cardiovasc Intervent Radiol 2000;23:351-7. 8. Lee JH, Kwon SY, Yoon HI, Yoon CJ, Lee KW, Kang SG, et al. Haemoptysis due to chronic tuberculosis vs. bronchiectasis: comparison of long-term outcome of arterial embolisation. Int J Tuberc Lung Dis 2007;11:781-7. 9. Metin M, Sayar A, Turna A, Solak O, Erkan L, Dincer SI, et al. Emergency surgery for massive haemoptysis. Acta Chir Belg 2005;105:639-43. 10. Naidoo R. Active pulmonary tuberculosis: experience with resection in 106 cases. Asian Cardiovasc Thorac Ann 2007;15:134-8. 11. British Tuberculosis Association. Aspergillus in persistent lung cavities after tuberculosis. A report from the Research Committee of the British Tuberculosis Association. Tubercle 1968;49:1-11. 12. British Thoracic and Tuberculosis Association. Aspergilloma and residual tuberculous cavities–the results of a resurvey. Tubercle 1970;51:227-45. 13. Kauffman CA. Quandry about treatment of aspergillomas persists. Lancet 1996;347:1640. 14. Zizzo G, Castriota-Scanderbeg A, Zarrelli N, Nardella G, Daly J, Cammisa M. Pulmonary aspergillosis complicating ankylosing spondylitis. Radiol Med [Torino] 1996;91:817-8. 15. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med 2000;39:209-12. 16. Rosenheim SH, Schwartz J. Cavitary pulmonary cryptococcosis complicated by aspergilloma. Am Rev Respir Dis 1975;111:549-53. 17. Sarosi GA, Silberfarb PM, Saliba NA, Huggin PM, Tosh FE. Aspergillomas occurring in blastomycotic cavities. Am Rev Respir Dis 1971;104:581-4. 18. Gefter WB. The spectrum of pulmonary aspergillosis. J Thoracic Imaging 1992;7:56-74. 19. Faulkner SL, Vernon R, Brown PP, Fisher RD, Bender HW Jr. Hemoptysis and pulmonary aspergilloma: operative versus nonoperative treatment. Ann Thorac Surg 1978;25:389-92. 20. Tomee JF, van der Werf TS, Latge JP, Koeter GH, Dubois AE, Kauffman HF. Serologic monitoring of disease and treatment

21.

22.

23. 24.

25. 26.

27. 28.

29. 30.

31.

32.

33.

34.

35.

36.

37.

in a patient with pulmonary aspergilloma. Am J Respir Crit Care Med 1995;151:199-204. Addrizzo-Harris DJ, Harkin TJ, McGuinness G, Naidich DP, Rom WN. Pulmonary aspergilloma and AIDS. A comparison of HIV-infected and HIV-negative individuals. Chest 1997;111:612-8. Wallace JM, Lim R, Browdy BL, Hopewell PC, Glassroth J, Rosen MJ, et al. Pulmonary Complications of HIV Infection Study Group. Risk factors and outcomes associated with identification of Aspergillus in respiratory specimens from persons with HIV disease. Chest 1998;114:131-7. Aslam PA, Eastridge CE, Hughes FA Jr. Aspergillosis of the lung. An eighteen year experience. Chest 1971;59:28-32. Stevens DA, Kan VL, Judson MA, Morrison VA, Dummer S, Denning DW, et al. Practice guidelines for diseases caused by Aspergillus. Infectious Diseases Society of America. Clin Infect Dis 2000;30:696-709. Epub 2000 Apr 20. Tuncel E. Pulmonary air meniscus sign. Respiration 1984;46:139-44. Roberts CM, Citron KM, Strickland B. Intrathoracic aspergilloma. Role of CT in diagnosis and treatment. Radiology 1987;165:123-8. McCarthy DS, Pepys J. Pulmonary aspergilloma: clinical immunology. Clin Allergy 1973;3:57-70. Rafferty P, Biggs BA, Crompton GK, Grant IW. What happens to patients with pulmonary aspergilloma? Analysis of 23 cases. Thorax 1983;38:579-83. Pennington JE. Aspergillus lung disease. Med Clin North Am 1980;64:475-90. Jewkes J, Kay PH, Paneth M, Citron KM. Pulmonary aspergilloma: analysis of prognosis in relation to haemoptysis and survey of treatment. Thorax 1983;38:572-8. Yamada H, Kohno S, Koga H, Maesaki S, Kaku M. Topical treatment of pulmonary aspergilloma by antifungals. Relationship between duration of the disease and efficacy of therapy. Chest 1993;103:1421-5. Munk PL, Vellet AD, Rankin RN, Muller NL, Ahmad D. Intracavitary aspergilloma: transthoracic percutaneous injection of amphotericin gelatin solution. Radiology 1993;188:821-3. Hammermann KJ, Sarosi GA, Tosh FE. Amphotericin B in the treatment of saprophytic forms of pulmonary aspergillosis. Am Rev Respir Dis 1974;109:57-62. Campbell JH, Winter JH, Richardson MD, Shankland GS, Banham SW. Treatment of pulmonary aspergilloma with itraconazole. Thorax 1991;46:839-41. Uflacker R, Kaemmerer A, Picon PD, Rizzon CF, Neves CM, Oliveira ES, et al. Bronchial artery embolization in the management of hemoptysis: technical aspects and long-term results. Radiology 1985;157:637-44. Okubo K, Kobayashi M, Morikawa H, Hayatsu E, Ueno Y. Favorable acute and long-term outcomes after the resection of pulmonary aspergillomas. Thorac Cardiovasc Surg 2007;55:108-11. Pratap H, Dewan RK, Singh L, Gill S, Vaddadi S. Surgical treatment of pulmonary aspergilloma: a series of 72 cases. Indian J Chest Dis Allied Sci 2007;49:23-7.

Complications of Pulmonary Tuberculosis 531 38. Chen JC, Chang YL, Luh SP, Lee JM, Lee YC. Surgical treatment for pulmonary aspergilloma: a 28 year experience. Thorax 1997;52:810-3. 39. Regnard JF, Icard P, Nicolosi M, Spagiarri L, Magdeleinat P, Jauffret B, et al. Aspergilloma: a series of 89 surgical cases. Ann Thorac Surg 2000;69:898-903. 40. Glimp RA, Bayer AS. Pulmonary aspergilloma: diagnostic and therapeutic considerations. Ann Intern Med 1983;143: 303-8. 41. Lombardo GT, Anandarao N, Lin CS, Abbate A, Becker WH. Fatal hemoptysis in a patient with AIDS-related complex and pulmonary aspergilloma. N Y State J Med 1987;87:306-8. 42. Hohler T, Schnutgen M, Mayet WJ, Meyer zum Buschenfelde KH. Pulmonary aspergilloma in a patient with AIDS. Thorax 1995;50:312-3. 43. Greenberg AK, Knapp J, Rom WN, Addrizzo-Harris DJ. Clinical presentation of pulmonary mycetoma in HIVinfected patients. Chest 2002;122:886-92. 44. Rosenzweig DY, Stead WW. The role of tuberculosis and other forms of bronchopulmonary necrosis in the pathogenesis of bronchiectasis. Am Rev Respir Dis 1966;93:769-85. 45. Rikimaru T. Endobronchial tuberculosis. Expert Rev Anti Infect Ther 2004;2:245-51. 46. Kim HY, Song KS, Goo JM, Lee JS, Lee KS, Lim TH. Thoracic sequelae and complications of tuberculosis. Radiographics 2001;21:839-58. 47. Hussain SF, Aziz A, Fatima H. Pneumothorax: a review of 146 adult cases admitted at a university teaching hospital in Pakistan. J Pak Med Assoc 1999;49:243-6. 48. Borrego Galan JC, Rivas Lopez P, Remacha Esteras MA. Recurrent tuberculous pneumothorax and tuberculous empyema: an association of two rare complications. Arch Bronconeumol 2003;39:478-9. 49. Lim JY, Kim KM, Choi EC, Kim YH, Kim HS, Choi HS. Current clinical propensity of laryngeal tuberculosis: review of 60 cases. Eur Arch Otorhinolaryngol 2006;263:838-42. Epub 2006 Jul 12. 50. Elemanov MG, Kharcheva KA, Vavillin GI. Evaluation of the “open-negative” syndrome in the clinical course of tuberculosis. Probl Tuberk 1974;52:19-23. 51. Miyagi Y. “Open-negative” syndrome. Clinical course of its development and subsequent destiny. Jpn J Tuberc 1966;13 [Suppl]:54-9. 52. Breuer J, Abeles H, Chaves AD, Robins AB. Observations on ambulatory tuberculous patients with pulmonary cavities and noninfectious sputum [the open-negative syndrome]. Am Rev Tuberc 1958;78:725-34. 53. Auerbach O, Garfinkel L, Parks VR. Scar cancer of the lung: increase over a 21 year period. Cancer 1979;43:636-42. 54. Gao YT. Risk factors for lung cancer among nonsmokers with emphasis on lifestyle factors. Lung Cancer 1996;14 Suppl 1:S39-45. 55. Wu-Williams AH, Dai XD, Blot W, Xu ZY, Sun XW, Xiao HP, et al. Lung cancer among women in north-east China. Br J Cancer 1990;62:982-7. 56. Jindal SK, Malik SK, Bedi RS, Gupta SK. Risk of lung cancer

57.

58.

59. 60.

61.

62.

63.

64. 65.

66.

67. 68. 69.

70. 71. 72. 73.

74. 75. 76.

77.

in patients with old tuberculosis – a prospective study. Lung India 1986;4:59-61. Hinds MW, Cohen HI, Kolonel LN. Tuberculosis and cancer risk in nonsmoking women. Am Rev Respir Dis 1982;125: 776-8. Johnson DE, Geogieff MK. Pulmonary perspective: neuroendocrine cells in health and disease. Am Rev Respir Dis 1989;140:1807-12. Youngson C, Nurse C, Yeger H, Cutz E. Oxygen sensing in airway chemoreceptors. Nature 1993;365:153-5. Schuller HM, Miller MS, Park PD, Orloff MS. Promoting mechanisms of CO2 on neuroendocrine cell proliferation mediated by nicotine receptor stimulation. Significance for lung cancer risk in individuals with chronic lung disease. Chest 1996;109[Suppl]:20S-21S. Hallett WY, Martin CJ. The diffuse obstructive pulmonary syndrome in a tuberculosis sanatorium. I. Etiologic factors. Ann Intern Med 1961;54:1146-55. Snider GL, Doctor L, Demas TA, Shaw AR. Obstructive airway disease in patients with treated pulmonary tuberculosis. Am Rev Respir Dis 1971;103:625-40. Lee JH, Chang JH. Lung function in patients with chronic airflow obstruction due to tuberculous destroyed lung. Respir Med 2003;97:1237-42. Macklem PT. Respiratory muscles: the vital pump. Chest 1980;78:753-8. Park JH, Na JO, Kim EK, Lim CM, Shim TS, Lee SD, et al. The prognosis of respiratory failure in patients with tuberculous destroyed lung. Int J Tuberc Lung Dis 2001;5:963-7. Bone RC. Treatment of respiratory failure due to advanced chronic obstructive lung disease. Arch Intern Med 1980;140:1018-21. Ferrer MI. Cor pulmonale [pulmonary heart disease]: presentday status. Am Heart J 1975;89:657-64. Fishman AP. State of the art: chronic cor pulmonale. Am Rev Respir Dis 1976;114:775-94. Kleiger RE, Senior RM. Longterm electrocardiographic monitoring of ambulatory patients with chronic airway obstruction. Chest 1974;65:483. Padmavati S, Raizada V. Electrocardiogram in chronic cor pulmonale. Br Heart J 1975;34:648. Prabhakar R. Laboratory aspects of tuberculosis. Indian J Tuberc 1987;34:67-80. Glenner GG, Terry WD, Isersky C. Amyloidosis: its nature and pathogenesis. Semin Hematol 1973;10:65-86. Shah PKD, Jain MK, Mangal HN, Singhvi NM. Kidney changes in pulmonary tuberculosis–a study by kidney biopsy. Indian J Tuberc 1975;1:23-7. Mittal OP, Sharma GS, Singh SK, Agarwala MC. Renal biopsy in pulmonary tuberculosis. Indian J Chest Dis 1966;8:20-4. Abdulpurkar AG, Desai MG, Shankar PS. Renal changes in pulmonary tuberculosis. Lung India 1987;5:82-5. Chugh KS, Singhal PC, Sakhuja V, Datta BN, Jain SK, Dash SC. Pattern of renal amyloidosis in Indian patients. Postgrad Med J 1981;57:31-5. Kennedy AC, Burton JA, Allison ME. Tuberculosis as a continuing cause of renal amyloidosis. Br Med J 1974;3:795-7.

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Tuberculosis and Acute Lung Injury

36 DR Karnad, KK Guntupalli

INTRODUCTION Acute lung injury [ALI] is a disorder characterized by inflammatory damage to the alveolar capillary membrane producing severe derangement of gas exchange, which could result from a variety of insults, ultimately resulting in severe hypoxaemia, non-cardiogenic pulmonary oedema, and the acute respiratory distress syndrome [ARDS] (1). In general, abnormalities of gas exchange are uncommon in pulmonary tuberculosis [TB] because concomitant involvement of ventilation and perfusion results in maintenance of the normal ventilation-perfusion relationship (2). However, severe hypoxic respiratory failure due to ALI can sometimes complicate severe forms of pulmonary including miliary TB (3-5). This complication is associated with a very high mortality despite treatment. Hence, early recognition and appropriate management of this uncommon complication is of utmost importance. DEFINITION The term ALI has been loosely used until the 1994 American-European Consensus Conference laid down a specific definition for this condition in order to ensure uniformity in research, diagnosis and management (1,6). It is essentially used to identify an earlier stage of the ARDS. Both ALI and ARDS require the following common diagnostic features (6): [i] acute onset; [ii] bilateral infiltrates on chest radiograph; and [iii] pulmonary artery wedge pressure of less than or equal to 18 mm Hg or absence of clinical evidence of left atrial hypertension. The fourth criterion, which defines the oxygenation defect, is used to differentiate ALI from ARDS. The ratio

of arterial oxygen tension [PaO2] to fraction of oxygen in inspired air [FIO2] is normally close to 450. A value of 200 or less, in the presence of the above-mentioned three criteria, is diagnostic of ARDS and a value between 201 and 300 is diagnostic of ALI. Thus, ALI represents a milder form of the pulmonary abnormalities that characterize ARDS (1,6). PATHOGENESIS Acute lung injury and ARDS occur in approximately 40 per cent of patients with sepsis and the systemic inflammatory response syndrome (6). Initially, there is an inflammatory damage to the pulmonary endothelial cell barrier, resulting in increased pulmonary capillary permeability. This produces leakage of protein-rich pulmonary oedema at normal pulmonary artery wedge pressure. A series of inflammatory events then damages the alveolar epithelial cells [Figures 36.1 and 36.2]. Damage to the Type I cells further worsens alveolar flooding and gas-exchange. Type II cuboidal cells, which produce surfactant, too are damaged in later stages of the disease resulting in collapse of the more severely affected alveoli during end-expiration. Pro-inflammatory cytokines interleukin-1 [IL-1], interleukin-6 [IL-6], interleukin-8 [IL-8], and tumour necrosis factor-α [TNF-α] attract and activate inflammatory cells like neutrophils, macrophages. These cells release other inflammatory substances like elastases, other proteases, oxygen free radicals, leukotrienes and platelet activating factor. Endogenous anti-inflammatory substances like soluble IL-1 receptor antagonist [sIL-1RA], soluble tumour necrosis factor receptor [sTNF-R] and anti-inflammatory cytokines, interleukin-10 [IL-10] and interleukin-11

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Figure 36.1: The normal alveolus [left-hand side] and the injured alveolus in the acute phase of acute lung injury and the acute respiratory distress syndrome [right-hand side]. In the acute phase of the syndrome [right-hand side], there is sloughing of both the bronchial and alveolar epithelial cells, with the formation of protein-rich hyaline membranes on the denuded basement membrane. Neutrophils are shown adhering to the injured capillary endothelium and marginating through the interstitium into the air space, which is filled with protein-rich oedema fluid. In the air space, an alveloar macrophage is secreting cytokines, interleukin-1, 6, 8, and 10, [IL-1, 6, 8, and 10] and tumour necrosis factor-α [TNF-α], which act locally to stimulate chemotaxis and activate neutrophils. Macrophages also secrete other cytokines, including interleukin-1, 6, and 10. Interleukin-1 can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other proinflammatory molecules, such as platelet-activating factor [PAF]. A number of anti-inflammatory mediators are also present in the alveolar milieu, including interleukin-1-receptor antagonist, soluble tumour necrosis factor receptor, autoantibodies against interleukin-8, and cytokines such as interleukin-10 and 11 [not shown]. The influx of protein rich oedema fluid into the alveolus has led to the inactivation of surfactant. MIF denotes macrophage inhibitory factor Reproduced with permission from “Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-49 (reference 6)” Copyright [2000] Massachusetts Medical Society. All rights reserved

[IL-11] too are present in the alveoli, but their role in the pathogenesis of ALI is not clear (6). The inflammatory process is not limited to the lung (7,8). Activation of coagulation is common and frank disseminated intravascular coagulation may develop in some patients. Inflammatory mediators arising from the lung may also play a role in the development of the multiple organ dysfunction syndrome in these patients (7). In patients with TB, ALI is believed to result from the release of mycobacteria or their products into the

pulmonary circulation (9,10). This classical situation is present in severe miliary TB where widespread distribution of the bacterial load may result in diffuse lung injury and ARDS (11). Mycobacterial cell wall component lipoarabinomannan [LAM] and mycobacterial cytosolic heat-shock protein-65kD [HSP-65] have been shown to induce release of inflammatory cytokines (12). Lipoarabinomannan binds to CD14 receptors on human mononuclear macrophages and induces the production and release of cytokines including interleukin-1β [IL-

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Figure 36.2: Mechanisms important in the resolution of acute lung injury and the acute respiratory distress syndrome. On the left side of the alveolus, the alveolar epithelium is being repopulated by the proliferation and differentiation of alveolar type II cells. Resorption of alveolar oedema fluid is shown at the base of the alveolus, with sodium and chloride being transported through the apical membrane of type II cells. Sodium is taken up by the epithelial sodium channel [ENaC] and through the basolateral membrane of type II cells by the sodium pump [Na+/K+–ATPase]. The relevant pathways for chloride transport are unclear. Water is shown moving through water channels, the aquaporins, located primarily on type I cells. Some water may also cross by a paracellular route. Soluble protein is probably cleared primarily by paracellular diffusion and secondarily by endocytosis by alveolar epithelial cells. Macrophages remove insoluble protein and apoptotic neutrophils by phagocytosis. On the right side of the alveolus, the gradual remodelling and resolution of intra-alveolar and interstitial granulation tissue and fibrosis are shown Reproduced with permission from “Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-49” (reference 6)” Copyright [2000] Massachusetts Medical Society. All rights reserved

1β], TNF-α, interleukin-1α [IL-1α], IL-6, IL-8, IL-10, and granulocyte macrophage colony-stimulating factor [GM-CSF]. Heat-shock protein-65kD too induces the release of cytokines, but to a lesser extent than LAM, and by a mechanism that does not involve the CD14 receptor (12). Mycobacteria also induce expression of the intercellular adhesion molecule-1 [ICAM-1] on endothelial cells, which facilitates adhesion of activated neutrophils to capillary walls (12). Another compound, muramyl dipeptide, stimulates chemotaxis, and enhances phagocytosis and release of inflammatory mediators (13). The subsequent series of events are

probably similar to those seen in gram-negative bacterial sepsis (9,10,12). Some authors have also suggested that ALI may be partly due to a cell-mediated immune response to mycobacterial antigens (13). This could result either from an enhancement of the delayed hypersensitivity response or from a decrease in suppressor mechanisms (13,14). This may probably play an important role in ALI that develops in some patients after institution of antituberculosis treatment and in patients with human immunodeficiency virus [HIV] infection receiving antiretroviral drugs (11-15).

Tuberculosis and Acute Lung Injury INCIDENCE Even though ALI and ARDS are well recognized complications in patients with pulmonary and miliary TB, sparse epidemiological data are available on this entity. Varying denominators have been used in the published studies because of which meaningful comparison of these data is not possible. In a study from Korea, Choi et al (16) found that 1.7 per cent of 1010 patients with pulmonary TB had acute respiratory failure. The incidence is as high as 20 per cent in patients with miliary TB and 0.8 per cent in TB pneumonia (1). The incidence increases with any delay in diagnosis and institution of appropriate therapy for miliary TB (17). In a study from Mumbai, ALI due to TB accounted for 1.7 per cent of admissions to the medical intensive care unit [ICU] (18). In a report from Chandigarh (19), nine of the 187 patients [4.8%] admitted to a respiratory ICU had TB-ARDS. In a large study from India, Sharma et al (5) reported that of 2733 TB patients treated during 1980-2003, 29 [1.06%; 1.21 patients per year] developed ARDS. PREDISPOSING FACTORS Acute lung injury invariably occurs in patients with severe TB such as miliary TB, or TB bronchopneumonia (9,10). A number of predisposing factors have been described. Malnutrition is the commonest predisposing factor seen in patients with pulmonary TB developing acute respiratory failure (11,20,21). Other factors include alcoholism, diabetes mellitus, immunosuppressive therapy with corticosteroids or other drugs, HIV infection, drug addiction, chronic liver disease and pregnancy (2,11,13,21,22). In the study reported by Sharma et al (5), presence of miliary TB, duration of illness beyond 30 days at presentation, absolute lymphocyte count less than 1625/mm3 and serum alanine aminotransferase [ALT] greater than 100 IU/l were independent predictors of ARDS development. CLINICAL SYNDROMES Acute Lung Injury in Miliary Tuberculosis Kim et al (23) reported that 8 of the 34 South Korean patients [24%] with miliary TB seen during the period 1990 to 1999 [0.9 patients per year] developed ARDS. Penner et al (11) reported that, over a 10-year period in the province of Manitoba, Canada, 13 patients [miliary

535

or disseminated TB, n = 7; and TB pneumonia, n = 6] were identified with TB as a primary cause requiring mechanical ventilation. Eight of these patients developed ARDS. In contrast, ARDS occurred in only five per cent of 100 Indian patients with miliary TB studied by Sharma et al (3), and in seven per cent of 109 South African patients studied by Maartens et al (20). It can occur in patients at all ages and the youngest patient reported is a seven-month-old child (24). Fever, non-productive cough, chest discomfort and dyspnoea are the common symptoms and the average interval between onset of symptoms and diagnosis is 14 days (20,21). In more than 50 per cent of patients, the diagnosis of TB is not known at the time of admission with respiratory failure (11). In these patients, radiological features of ARDS usually mask the typical miliary mottling (9). The interval between admission and diagnosis in a large series was one to twenty days (11). In up to 10 per cent of patients with ALI, the miliary TB may be cryptic with systemic dissemination and a normal chest radiograph (17,21,25). A large proportion of these patients may harbour HIV infection (17). Other clinical findings include hepatosplenomegaly, mild hepatic dysfunction and pancytopenia (21). In a patient with unexplained ARDS, a history of fever of more than 15 days duration and elevation of serum alkaline phosphatase should arouse the suspicion of disseminated TB as the underlying cause (21). In less than half the number of cases, ALI develops in diagnosed patients with miliary TB after antituberculosis treatment is initiated (11). In patients with miliary TB, auscultation of the chest is generally normal. Tachypnoea and presence of diffuse rales while on drug therapy are ominous signs of early ALI. Mortality in patients with ARDS due to miliary TB is between 40 to 80 per cent, despite use of mechanical ventilation and corticosteroids (9,11,23,26). At autopsy, alveoli may show intense perifocal inflammation, interstitial granulomas and obliterative endarteritis, characteristic of miliary TB (27). In addition, changes of ALI may be present [Figures 36.3 and 36.4], in the form of increased vascularity, presence of dense exudates in the alveoli, and hyaline membrane formation (27,28). Acute Lung Injury in Tuberculosis Pneumonia Nodular lesions resulting from air-space consolidation due to endobronchial spread to lobar or multilobar

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Tuberculosis 45 days. Seven of the 29 patients in the series reported by Sharma et al (5) had pulmonary TB. Chest radiographs show nodular lesions, with mixed consolidation and ground glass opacities [Figures 36.5 and 36.6] (3,11). High resolution computed tomography [HRCT] shows

Figure 36.3: Tuberculosis pneumonia presenting as acute respiratory distress syndrome. Epithelioid cells are identified within the alveoli [Haematoxylin and eosin x 100]

Figure 36.5: Chest radiograph [done bedside, with a portable machine] showing consolidation with air-bronchogram Reproduced with permission from “Sharma SK, Mohan A, Pande JN, Prasad KL, Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. QJM 1995; 88:29-37 (reference 3)”

Figure 36.4: Acute respiratory distress syndrome in tuberculosis. There is an inflammatory exudate in the alveolus and fibrin deposition [arrows] along the alveoli [Haematoxylin and eosin x 400]

locations is termed TB pneumonia (11). The development of ALI due to TB pneumonia was first reported in 1977 by Agarwal et al (2). They reported 16 patients with acute respiratory failure, 10 of whom required mechanical ventilation. Alcholism and chronic liver disease were the predisposing factors in almost all cases. In a ten-year review of patients with TB requiring mechanical ventilation for ARDS, Penner et al (11) found that 50 per cent of his cases had TB pneumonia. These patients formed 0.8 per cent of patients with non-miliary TB that were seen during the study period. The mean interval between the onset of symptoms of TB and treatment was

Figure 36.6: Chest radiograph [postero-anterior view] of the same patient in Figure 36.5 showing classical miliary shadows evolving after a few days Reproduced with permission from “Sharma SK, Mohan A, Pande JN, Prasad KL, Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. QJM 1995;88:29-37 (reference 3)”

Tuberculosis and Acute Lung Injury bronchogenic dissemination with ground glass attenuation (9). The classical tree-in-bud appearance is seen on computed tomography [CT] in less than 50 per cent of cases (16). Acute Lung Injury in Cavitary Pulmonary Tuberculosis In a retrospective analysis of patients with TB and acute respiratory failure, Zahar et al (17) found that 11 per cent of patients had an isolated apical cavity on chest radiograph preceding the onset of ALI. Choi et al (16) found cavities in HRCT of 45 per cent of patients with ALI. Extensive endobronchial spread of TB following rupture of a cavity into the bronchus is thought to initiate ALI (29). The initial symptoms of TB in these patients are fever and cough, which are followed after two weeks to two months by acute onset of dyspnoea and severe hypoxaemia (29). The chest radiograph shows diffuse bilateral alveolar infiltrates as in ARDS, but unlike in miliary TB complicated by ARDS, these patients tend to have unilateral preponderance of the infiltrates and physical signs (29). They may have systemic manifestations like disseminated intravascular coagulation [DIC] and hypotension. Mycobacteria are easily demonstrable in tracheal aspirates in almost all cases. Acute Lung Injury After Initiation of Antituberculosis Treatment In 1986, Onwubalili et al (13) described two alcoholic, malnourished patients with bilateral extensive sputum smear-positive pulmonary TB, who developed paradoxical worsening of the disease resulting in ARDS during the second week of antituberculosis treatment. One of them had TB bronchopneumonia. Baseline tests of immune function revealed a negative tuberculin skin test [TST] with 10 tuberculin units [TU] of purified protein derivative [PPD], lymphopenia, failure of peripheral blood mononuclear cells to respond to stimulation with PPD and severely depressed natural killer cell activity. This patient experienced severe breathlessness, worsening of radiological lesions and hypoxaemia 11 days after starting antituberculosis treatment. At this time, the erythrocyte sedimentation rate [ESR] had increased to 110 mm at the end of first hour, TST [1 TU of PPD] revealed an induration of 8 mm, and there was considerable improvement in the tests of immune function. The second patient had fibrocavitary disease

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and a TST [1 TU of PPD] reading of 7 mm. His condition deteriorated eight days after starting treatment; ESR increased to 100 mm at the end of first hour and there was an increase in all the parameters of immune function. He required mechanical ventilation for ARDS, and methylprednisolone was administered to reduce pulmonary inflammation. This patient died 13 days after starting treatment. The authors (13) mention that both patients had in vivo and in vitro anergy and depression of lymphocyte function, probably due to poor nutritional status, excess alcohol consumption and the severe infection itself. On treatment, there was a progressive reversal of the immune deficiency and the ALI may have been due to an exaggerated delayed hypersensitivity reaction to mycobacterial antigens released by the dying organisms. Tuberculoprotein and muramyl dipeptide have been implicated as possible immunogenic cell-wall components (13). Cell-mediated damage to the pulmonary alveolar-capillary membrane is believed to cause ARDS in these patients (13). Akira and Sakatani (14) have reported the radiological features in five patients who developed ALI due to paradoxical worsening after treatment of TB. All five patients had unilateral cavitary TB restricted to one lobe. After treatment, chest radiographs revealed progression of the original lesion, and appearance of new lesions in the other lung and other regions in the same lung. The HRCT revealed that in addition to the segmental or lobar cavitation in the original locations, extensive areas of ground glass opacities were present bilaterally in all the cases. However, a predominantly dependent distribution, which is characteristic of ARDS due to sepsis, was not seen. Transbronchial lung biopsy [TBLB] showed the presence of intra-alveolar and interstitial pulmonary oedema. Two of these five patients died. Transient radiological worsening of pulmonary lesions has been reported in three to fourteen per cent of patients receiving antituberculosis treatment (30). However, the patients may remain asymptomatic in this setting. In 0.6 per cent of cases, the process may be severe enough to cause respiratory failure due to ALI (14). Paradoxical worsening is more frequent and also more severe in patients with HIV infection, especially those also receiving antiretroviral drugs due to the immune reconstitution inflammatory syndrome (15,31). However, Wendel et al (31) showed that 11 per cent of patients with

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HIV infection receiving antiretroviral drugs along with antituberculosis treatment developed clinically relevant paradoxical worsening compared to seven per cent receiving antituberculosis treatment alone; the difference was not statistically significant. Increase in severity of fever and a rising ESR may help identify patients who are likely to develop severe paradoxical worsening (13,14). Injectable methylprednisolone or oral prednisolone in a dose of 1 to 2 mg per kg body weight, daily for one to two weeks which is gradually tapered is recommended in patients with paradoxical worsening, although there are no randomized controlled trials to prove their benefit (15). Other Manifestations As in severe systemic sepsis, dysfunction of other organs is seen in 35 per cent of patients with ALI due to TB even in the absence of other bacterial infections (17,22,32). These manifestations are encountered more often in miliary TB than in TB pneumonia (11). Mycobacterial infection itself can cause septic shock, with increased cardiac index, and low systemic vascular resistance (33). Non-mycobacterial sepsis due to secondary infection may supervene in approximately 40 per cent of patients receiving mechanical ventilation (11). A significant number of patients also have co-existing DIC (20). Mortality in these patients is close to 100 per cent (34). Up to 10 per cent of patients may also have acute renal failure (17). Pancytopenia has been frequently reported in ARDS due to miliary TB (20,21). Mechanisms include bone marrow infiltration by TB granulomas and cytokine-induced bone marrow suppression. Pancytopenia responds well to antituberculosis treatment, but these patients have poor survival rates (21). DIAGNOSIS Acute lung injury is suspected in patients with severe hypoxaemia, bilateral extensive rales on auscultation, presence of bilateral confluent alveolar opacities on chest radiograph in patients with proven pulmonary TB or prolonged fever (9,10,32). Arterial blood gas analysis will reveal a widened alveolar-arterial oxygen gradient and the PaO2/FIO2 ratio would help to differentiate between ALI and ARDS. Type I respiratory failure with normal or low arterial carbon dioxide tension [PaCO2] is usually seen (7,10,27,32). The diagnosis is made by the American-

European Consensus Conference diagnostic criteria mentioned earlier (1). Recently ARDS Network has proposed pulse oximetric saturation [SpO2] to FIO2 ratio [S/F ratio] as a surrogate to diagnose ALI and ARDS when PaO2/FIO2 ratio is not available (35). An S/F ratio of 235 corresponded with a PaO2/FIO2 ratio of 200 while an S/F ratio of 315 corresponded with a PaO2/ FIO2 ratio of 300. The non-invasive measurements can be used to facilitate an early diagnosis of ARDS even in resourcelimited settings. The diagnosis of TB in patients presenting with ARDS is difficult, and needs a high index of suspicion. Early diagnosis is important as delay in treatment may worsen the respiratory failure and increase mortality. Radiographic changes of ARDS may mask underlying TB and alveolar infiltrates that are more organized or appear more nodular than usual should arouse suspicion (28). Choi et al (16) systematically reviewed the chest radiographic and HRCT findings in 17 patients with ALI due to TB [Table 36.1]. During resolution, HRCT may reveal bilateral extensive thin-walled cystic lesions. Whether these represent parenchymal damage due to TB or ventilator-induced lung injury is not clear. These cysts resolve completely over several months (16). The TST is invariably negative (9,21). Detection of immunoglobulin G [IgG] or immunoglobulin M [IgM] antibodies to Mycobacterium tuberculosis antigens in serum by enzyme linked immunosorbent assay is of little value in endemic areas since up to 50 of normal healthy adults have a positive test (9). The yield of acid-fast bacilli in the tracheal secretions depends on the type of underlying pulmonary TB lesion. In fibrocavitary disease, TB pneumonia and endobronchial spread leading to bronchopneumonia, endotracheal aspirate will be positive for Mycobacterium tuberculosis in over 60 to 100 per cent of cases (5,17). In miliary TB, the yield is much lower at approximately 33 per cent (20). Fiberoptic bronchoscopy with TBLB or bronchoalveolar lavage may increase the yield to 88 per cent (20). In many cases, especially those with cryptic miliary TB who do not have miliary mottling on chest radiograph, the diagnosis is invariably established by demonstration of TB granulomas in the liver biopsy specimen (21,25). MANAGEMENT The basic principles of management of ALI in TB are the same as for ALI due to other causes: treatment of basic

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Table 36.1: Radiological findings in patients with acute respiratory failure due to pulmonary tuberculosis Plain radiograph

High resolution computed tomography

Findings

%

Findings

Small [ < 10 mm] nodular lesions Air space consolidation Ground glass opacities Reticular lesions Cavitary lesions

96 76 70 24 24

Nodular lesions Ground glass opacities Air space consolidation Septal thickening Tree-in-bud appearance Cavities Mediastinal lymphadenopathy Pleural effusion Pericardial effusion Spontaneous pneumothorax

% 100 91 73 73 45 45 27 27 27 9

Adapted from reference 16

cause, maintenance of optimum oxygen delivery, provision of adequate nutrition [preferably by the enteral route] and prevention of complications like nosocomial infections, upper gastrointestinal haemorrhage and deep vein thrombosis (6). Oxygen Therapy Initial treatment of hypocapnoeic acute respiratory failure consists of oxygen administration. The aim of therapy is to maintain arterial PaO2 above 60 mm Hg and arterial oxygen saturation [SaO2] above 90 per cent. Using an oxygen mask can increase FIO2 to 50 to 60 per cent. Pulse oximetry helps in rapidly adjusting the FIO2 to provide adequate oxygenation. If the desired SaO2 cannot be achieved, oxygen administered by a nonrebreathing mask with a reservoir bag may help. If these measures fail, or respiratory distress is severe, or patient appears fatigued, tracheal intubation and mechanical ventilation may be needed (3,6,10,32). Mechanical Ventilation The initial ventilatory strategy in patients with ALI or ARDS is to deliver tidal volume of 6 ml/kg of ideal body weight, using 100 per cent FIO2 with positive end-expiratory pressure (6). After PaO2/FIO2 ratio reaches the desired levels, the FIO2 can be reduced gradually to less than 60 per cent, provided SaO2 remains above 90 per cent. Most patients will require sedation and neuromuscular blockade to prevent discomfort (6). In patients with refractory hypoxaemia, lung recruitment manoeu-

vres and prone positioning of the patient may sometimes help. The possibility of barotrauma and ventilatorinduced lung injury should be kept in mind while changing ventilator settings (6). The risk of developing pneumothorax due to barotrauma is particularly high in patients with TB as a cause of ARDS. Antituberculosis Drugs Antituberculosis treatment should be instituted as early as possible. Administration of parenteral drugs is not superior to enteral therapy. Enteral therapy may not be possible in all patients. In these cases, parenteral therapy with aminoglycoside and isoniazid should be initiated. Injectable rifampicin may be added where available. Corticosteroids Corticosteroids have been used in TB causing ALI in various dosages (9,13,15,20,26,36). In addition to their immunosuppressive effects, corticosteroids also inhibit synthesis of several mediators of inflammation including cytokines like IL-1, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-α and GM-CSF (36). They also prevent induction of the inducible forms of nitric oxide synthase and cyclooxygenase-2 (36). In a recent update on the use of corticosteroids in pulmonary disease, Jantiz and Sahn (36) have reviewed the evidence for the use of corticosteroids in pulmonary TB. There is only one controlled trial (36) in which 28 patients with miliary TB were treated with isoniazid, streptomycin, and paraaminosalicylic acid alone, and 27 patients also received

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prednisone in addition to these drugs. The dose of prednisone was 10 mg four times a day for one week, followed by 20 mg daily for six weeks (36). It was then gradually tapered and the total course lasted for three to five months. Mortality was seven per cent in the corticosteroid group compared with 18 per cent in the control group (36). Most workers recommend that corticosteroids be given to all patients with ALI due to TB along with antituberculosis drugs, especially since up to 10 per cent of these patients also have adrenal TB leading to adrenal insufficiency (15,20,37). The increased risk of upper gastrointestinal bleeding and secondary bacterial sepsis must be weighed before instituting corticosteroid therapy (37). PROGNOSIS Overall mortality in ALI due to TB is between 40 to 80 per cent. Non-survivors of ARDS, regardless of the cause, die of respiratory failure in less than 20 per cent of cases (38). Most deaths are primarily related to the underlying disease, the severity of the acute illness, and the degree of dysfunction of other organs (38). In the study reported by Sharma et al (5), acute physiology and chronic health evaluation II [APACHE II] score greater than 18; APACHE II score less than 18 in the presence of hyponatraemia and PaO2/FIO2 ratio less than 108.5 were predictors of death in patients with TB-ARDS. Zahar et al (17) have shown that patients receiving treatment more than one month after onset of symptoms have a 3.5 times higher risk of death than those in whom treatment is started early. REFERENCES 1. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149:818-24. 2. Agarwal MK, Muthuswamy PP, Banner AS, Shah RS, Addington WW. Respiratory failure in pulmonary tuberculosis. Chest 1977;72:605-9. 3. Sharma SK, Mohan A, Pande JN, Prasad KL, Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. QJM 1995;88:29-37. 4. Mohan A, Sharma SK, Pande JN. Acute respiratory distress syndrome in miliary tuberculosis: a 12-year experience. Indian J Chest Dis Allied Sci 1996;38:147-52.

5. Sharma SK, Mohan A, Banga A, Saha PK, Guntupalli KK. Predictors of development and outcome in patients with acute respiratory distress syndrome due to tuberculosis. Int J Tuberc Lung Dis 2006;10:429-35. 6. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-49. 7. Ranieri VM, Suter PM, Tortorella C, De Tullio R, Dayer JM, Brienza A, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999;282:54-61. 8. Ranieri VM, Giunta F, Suter PM, Slutsky AS. Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome. JAMA 2000;284:43-4. 9. Jindal SK, Aggarwal AN, Gupta D. Adult respiratory distress syndrome in the tropics. Clin Chest Med 2002;23:445-55. 10. Chandana I. Tuberculosis and acute lung injury. In: Sharma SK, Mohan A, editors. Tuberculosis. First edition. New Delhi: Jaypee Brothers Medical Publishers; 2001.p.507-13. 11. Penner C, Roberts D, Kunimoto D, Manfreda J, Long R. Tuberculosis as a primary cause of respiratory failure requiring ventilation. Am J Respir Crit Care Med 1995;151:867-72. 12. Zhang Y, Doerfler M, Lee TC, Guillemin B, Rom WN. Mechanisms of stimulation of interleukin-1 beta and tumour necrosis factor alpha by Mycobacterium tuberculosis components. J Clin Invest 1993;91:2076-83. 13. Onwubalili JK, Scott GM, Smith H. Acute respiratory distress related to chemotherapy of advanced pulmonary tuberculosis: a study of two cases and a review of literature. QJM 1986;230:599-610. 14. Akira M, Sakatani M. Clinical and high-resolution computed tomographic findings in five patients with pulmonary tuberculosis who developed respiratory failure following chemotherapy. Clin Radiol 2001;56:550-5. 15. American Thoracic Society, Centers for Disease Control and Prevention, Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:606-62. 16. Choi D, Lee KS, Suh GY, Kim TS, Kwon OJ, Rhee CH, et al. Pulmonary tuberculosis presenting as acute respiratory failure: radiologic findings. J Comput Assist Tomogr 1999;23:107-13. 17. Zahar JR, Azoulay E, Klement E, De Lassence A, Lucet JC, Regnier B, et al. Delayed treatment contributes to mortality in ICU patients with severe active pulmonary tuberculosis and acute respiratory failure. Intensive Care Med 2001;27: 513-20. 18. Parikh CR, Karnad DR. Quality, cost, and outcome of intensive care in a public hospital in Bombay, India. Crit Care Med 1999;27:1754-9. 19. Agarwal R, Gupta D, Aggarwal AN, Behera D, Jindal SK. Experience with ARDS caused by tuberculosis in a respiratory intensive care unit. Intensive Care Med 2005;31:1284-7. 20. Maartens G, Willcox PA, Benatar SR. Miliary tuberculosis: rapid diagnosis, hematologic abnormalities, and outcome in 109 treated adults. Am J Med 1990;89:291-6.

Tuberculosis and Acute Lung Injury 21. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 23-1995. A 44-year-old woman with pulmonary infiltrates, respiratory failure and pancytopenia. N Engl J Med 1995;333:241-8. 22. Gachot B, Wolff M, Clair B, Regnier B. Severe tuberculosis in patients with human immunodeficiency virus infection. Intensive Care Med 1990;16:491-3. 23. Kim JY, Park YB, Kim YS, Kang SB, Shin JW, Park IW, et al. Miliary tuberculosis and acute respiratory distress syndrome. Int J Tuberc Lung Dis 2003;7:359-64. 24. Kruger M, Woenckhaus J, Berner R, Hentschel R, Brandis M. Miliary tuberculosis and adult respiratory distress syndrome in an infant. Klin Pediatr 1998;210:425-7. 25. Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis 2005;5:415-30. 26. Tanaka G, Nagai H, Hebisawa A, Kawabe Y, Machida K, Kurashima A, et al. Acute respiratory failure caused by tuberculosis requiring mechanical ventilation. Kekkaku 2000;75:395-401. 27. Bhalla A, Mahapatra M, Singh R, D’Cruz SD. Acute lung injury in miliary tuberculosis. Indian J Tuberc 2002;49:125-8. 28. Dee P, Teja K, Korzeniowski O, Suratt PM. Miliary tuberculosis resulting in adult respiratory distress syndrome: a surviving case. AJR Am J Roentgenol 1980;134:569-72. 29. Dyer RA, Potgieter PD. The adult respiratory distress syndrome bronchogenic pulmonary tuberculosis. Thorax 1984;39:383-7.

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30. Akira M, Sakatani M, Ishikawa H. Transient radiographic progression during initial treatment of pulmonary tuberculosis: CT findings. J Comput Assist Tomogr 2000;24:426-31. 31. Wendel KA, Alwood AS, Gachuhi R, Chaisson RE, Bishai WR, Sterling TR. Paradoxical worsening of tuberculosis in HIV-infected persons. Chest 2001;120:193-7. 32. Udwadia FE. Multiple organ dysfunction syndrome due to tropical infections. Indian J Crit Care Med 2003;7:233-6. 33. Ahuja SS, Ahuja SK, Phelps KR, Thelmo W, Hill AR. Hemodynamic confirmation of septic shock in disseminated tuberculosis. Crit Care Med 1992;20:901-3. 34. Piqueras AR, Marruecos L, Artigas A, Rodriguez C. Miliary tuberculosis and adult respiratory distress syndrome. Intensive Care Med 1987;13:175-82. 35. Rice TW, Wheeler AP, Bernard GR, Hayden DL, Schoenfeld DA, Ware LB; for the National Institutes of Health, National Heart, Lung, and Blood Institute ARDS Network. Comparison of the SpO2/FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS. Chest 2007;132:410-7. Epub 2007 Jun 15. 36. Jantiz MA, Sahn SA. Corticosteroids in acute respiratory failure. Am J Respir Crit Care Med 1999;160:1079-100. 37. Sun TN, Yang JY, Zheng LY, Deng WW, Sui ZY. Chemotherapy and its combination with corticosteroids in acute miliary tuberculosis in adolescents and adults: analysis of 55 cases. Chin Med J [Engl] 1981;94:309-14. 38. Vincent JL, Sakr Y, Ranieri VM. Epidemiology and outcome of acute respiratory failure in intensive care unit patients. Crit Care Med 2003;31[Suppl4]:S296-9.

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Haematological Manifestations of Tuberculosis

37 Shaji Kumar

INTRODUCTION The interactions between the mycobacteria and the haematopoietic system have been a major focus of interest for haematologists and mycobacteriologists alike for several decades. Patients with mycobacterial infections can present with myriad different, often puzzling, haematological abnormalities (1,2) [Table 37.1] and different mycobacterial infections often afflict patients with haematological disorders. Though haematological abnormalities associated with tuberculosis [TB] have been well recognised, few studies have carefully evaluated their prevalence and relationship with disease severity. Haematological changes have been observed with focal as well as disseminated TB and are usually reversible with antituberculosis treatment. Haematological manifestations of TB can be due to direct effect of the infectious process itself or may be a consequence of antituberculosis treatment. While haematological changes are also commonly seen in children with TB, a study (3) from a developing nation suggested that they may not Table 37.1: Haematological changes in tuberculosis Anaemia Leucocyte changes Leucopenia or leucocytosis Lymphocytopenia Neutropenia or neutrophilia Monocytopenia or monocytosis Thrombocytopenia or thrombocytosis Pancytopenia Deep vein thrombosis Disseminated intravascular coagulation

be significantly different compared to a matched group of children without TB. In general, the reported haematological changes in TB appear to be more frequent and profound among patients with disseminated TB compared to localized disease. ANAEMIA Anaemia is the most common haematological manifestation of TB, and is seen in 16 to 94 per cent of patients with pulmonary or extra-pulmonary TB. The prevalence of anaemia is likely to be higher in the developing nations, given the high rates of nutritional deficiencies as well as other causes of iron deficiency anaemia, such as worm infestations. Morris et al (4) observed anaemia in 60 per cent of patients with pulmonary TB, males being more frequently affected than females. In this study (4) there was a correlation between the degree of anaemia and the presence of acid-fast bacilli [AFB] in the sputum and failure to correct anaemia was associated with persistence of AFB in the sputum. The anaemia observed with TB is multifactorial in aetiology [Table 37.2] and tends to be mostly normocytic, normochromic and less often microcytic anaemia. The peripheral blood picture and the haematological indices usually indicate an anaemia of chronic disease. The inflammatory response seen in TB leads to increased secretion of cytokines such as tumour necrosis factor-α [TNF-α] from the monocytes, which result in a blunted response to erythropoietin and decreased ability to utilize the marrow iron stores. Morris et al (4) found that 81 per cent of patients with pulmonary TB had increased iron stores, suggesting decreased release of marrow iron stores and suppression of

Haematological Manifestations of Tuberculosis Table 37.2: Aetiological factors for anaemia in tuberculosis Anaemia of chronic disease Iron deficiency Nutritional deficiency Secondary to chronic blood loss Folate deficiency Vitamin B12 deficiency Myelophthisic anaemia Haemolytic anaemia Hypoplastic or aplastic anaemia Pure red cell aplasia Sideroblastic anaemia Drug-induced anaemia [includes marrow aplasia and haemolysis] Primary haematological disorder with tuberculosis disease

erythropoiesis by inflammatory response mediators. However, the bone marrow iron was found to be decreased in another study (5). Similarly, serum iron and total iron binding capacity have been observed to be decreased in patients with pulmonary TB and anaemia compared to those without anaemia. In addition, erythropoietin level itself has been noted to be low in patients with TB (6). Ebrahim et al (6) using an in vitro system of hepatocellular carcinoma cell lines demonstrated suppression of erythropoietin secretion by monocyte supernatants from patients with pulmonary TB. The levels of TNF-α were higher in these sera and addition of neutralizing antibodies to TNF-α reversed some of these effects. Serum ferritin levels have been found to be an unreliable marker for iron deficiency in patients with TB (4,7). The inflammatory process in TB results in increased ferritin synthesis and high levels of ferritin in spite of decrease in iron stores. Ferritin acts as an acute phase reactant and the levels correlate with C-reactive protein concentration. In patients with TB, raising the cut-off values of serum ferritin to 30 μg/l or less, correctly diagnosed 88 per cent patients with iron deficiency compared with a figure of 61 per cent when a cut-off value of 10 μg/l or less was used (8). A higher red blood cell volume distribution width [RDW] similar to that observed in iron deficiency anaemia has been reported in untreated anaemic patients with TB. The RDW values tended to become normal with antituberculosis treatment (9). In a study (10) from Indonesia, the distribution of three polymorphisms in the solute carrier family 11

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member 1 gene [SLC11A1], previously known as natural resistance-associated macrophage protein 1 [NRAMP1], including INT4, D543N and 3’UTR was examined for a possible association with susceptibility to TB. The authors (10) studied 378 patients with active pulmonary TB and 436 healthy control subjects from the same neighbourhood with the same socio-economic status. Anaemia was present in 63.2 per cent of the patients with active pulmonary TB compared with 6.8 per cent of the control subjects. Anaemia was more pronounced in female patients and those with extensive disease as assessed by the chest radiograph. Patients with active pulmonary TB and anaemia had lower plasma iron levels, iron binding capacity and higher ferritin levels. Even without iron supplementation, antituberculosis treatment resulted in normalization of the plasma iron, iron binding capacity and ferritin levels. However, NRAMP1 gene polymorphisms were not associated with TB susceptibility, TB severity or anaemia. The authors (10) concluded that anaemia in patients with active pulmonary TB was probably due to inflammation and not to iron deficiency. Macrocytic anaemia is less frequently associated with TB and is usually unrelated to folate or vitamin B12 deficiency (4,11). In a study of 138 patients with megaloblastic haematopoiesis, who were also life-long vegetarians, 17 patients were found to have TB (11). However, Morris et al (4) found that the serum vitamin B12 levels were elevated in over half of the patients with pulmonary TB, while serum and red cell folate levels were normal in most of them. The vitamin B12 levels were higher in patients with leucocytosis possibly because of the elevated levels of R-binders which lead to increased concentration of vitamin B12. In a study (12) of Nigerian patients with TB, the cobalamin status did not appear to influence the severity of anaemia seen in pulmonary or disseminated TB. Administration of vitamin B12 does not correct the anaemia in these patients. Low serum folate levels have been observed in a study (5), while no relationship between folate levels and megaloblastic haematopoiesis was found in another study (4). Autoimmune haemolytic anaemia has been reported in association with both pulmonary and disseminated TB and may disappear with treatment (13-15). Pure red cell aplasia [PRCA] has been seen in association with TB in children (16,17). Sideroblastic changes have been reported in the marrow of patients with localized or disseminated TB and the anaemia has been reported to respond to pyridoxine administration (18).

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There are only limited studies on the haematological changes in patients with disseminated and miliary TB (19-24). In a study (21) comparing patients with disseminated and miliary TB and those with pulmonary TB, normocytic, normochromic anaemia was the most common abnormality observed in both the groups. Moderate degree of anaemia has been observed in 52 to 72 per cent of the patients in most series (22,23,25). The anaemia is predominantly normocytic and normochromic (26). Autoimmune haemolytic anaemia [AIHA] and PRCA have been reported in association with disseminated TB (27-29). Anaemia can be a prominent finding in patients with gastrointestinal TB, where blood loss can complicate the anaemia of chronic disease (30). LEUCOCYTE CHANGES Mild leucocytosis and a left shift with increased myelocytes and metamyelocytes, in the peripheral blood is the most common finding in most of the studies and has been seen in six to twenty-two per cent of patients (31). Patients with pulmonary TB more frequently have leucocytosis whereas leucopenia is rare. Tuberculosis can result in increased myelopoiesis and the bone marrow and peripheral blood may show a leukaemoid reaction (32-34). Patients with advanced TB often have higher counts than those with minimal disease. Mild leucopenia with counts less than 4 x 109/l has been documented in 1.5 to 4 per cent of patients (4). Prevalence of leucopenia in most studies is either equal to or higher than leucocytosis (31). Leucopenia and neutropenia were significantly higher in patients with disseminated TB. Neutrophilia has been observed in 20 to 60 per cent of patients while leucopenia has been documented in 10 to 30 per cent patients with miliary TB (19,20,35). Neutropenia has been observed in patients with disseminated TB (31). The mechanisms of neutropenia may include hypersplenism, increased neutrophil demand, or excessive margination of neutrophils. Cell-mediated autoimmune mechanisms may be responsible for neutropenia in some of the patients (36). Presence of Pelger-Huet anomaly [two symmetric, usually rounded nuclear lobes joined by a thin-strand formed by hypercondensation of nuclear chromatin that creates a spectacle-like appearance] has been described in TB (37). Decrease in the peripheral blood CD4+ subset of T-lymphocytes has also been documented and may be seen in up to 15 per cent of patients and is more common

in disseminated and miliary TB (38,39). Lymphopenia appear to be more common than lymphocytosis in patients with pulmonary TB (31,39,40). The decreased count usually returns to the normal level following effective therapy (41). While the reasons behind the lymphopenia in TB are not entirely clear, it may reflect continued recruitment of CD4+ T-lymphocytes to the sites of granuloma formation (41). In a study (42) of lymphocyte populations in peripheral blood, pleural fluid, and ascites during TB infection, recent infection was associated with peripheral blood lymphocytosis involving both CD4+ and CD8+ cells compared to no changes in previously diagnosed patients. No changes were found in the numbers of B-lymphocytes or natural killer cells in either recently infected or previously diagnosed patients. The pleural effusion and ascitic fluid samples contained T-lymphocytes, the majority of which were CD4+ cells. These lymphocytes also showed an inverted CD45RA-to-CD45RO ratio, and had high-level expression of the interleukin-2 receptor [CD25] in some patients. Both monocytosis and monocytopenia have been documented in patients with TB (4). Monocytopenia has been reported in as many as 50 per cent of the patients and may correlate with the disease severity (43). Basophilia has been reported in patients with disseminated TB (32). Hypereosinophilic syndrome with organ damage (44) as well as isolated eosinophilia (45,46) have also been reported in association with TB. PLATELET ABNORMALITIES Patients with pulmonary or disseminated TB usually have mild thrombocytosis, probably due to increased thrombopoiesis reflecting an acute phase reaction (31,47). The increased thrombopoiesis may be in part be driven by inflammatory cytokines, such as interleukin-6 [IL-6]. The IL-6 is known to increase the megakaryocytes in vitro (48). In a study comparing patients with pulmonary TB with healthy volunteers, the median IL-6 concentrations were higher among those patients with thrombocytosis compared to those with normal platelet counts (49). The IL-6 concentrations were significantly correlated with AFB positivity. Hence, it appears that IL-6 might play a contributory part in reactive thrombocytosis and acute phase response in TB. Thrombocytopenia is more common in patients with disseminated TB, whereas, thrombocytosis is more

Haematological Manifestations of Tuberculosis common in pulmonary TB. However, isolated thrombocytopenia has occasionally been described in pulmonary TB and its pathogenesis is believed to be immune mediated (31,50,51). Anti-platelet antibodies and platelet associated immunoglobulin G [IgG] have been demonstrated in some patients. Boots et al (50) reported a case of immune thrombocytopenia with pulmonary TB, where additional studies showed presence of platelet bound IgG antibodies without any circulating anti-platelet antibodies. In contrast to antibodies in patients with idiopathic thrombocytopenic purpura, the antibodies in this patient did not react with normal donor platelets and the thrombocytopenia resolved with intravenous immunoglobulin therapy (50,51). There is an inverse correlation between platelet count and the mean platelet volume, and increased numbers of small platelets have been described in these patients which have a shortened survival (52). Thrombocytopenia is more common in patients with disseminated TB and has been reported in 23 to43 per cent of patients (20,53,54). Majority of these patients, however, does not have any significant bleeding. Thrombotic thombocytopenic purpura has been seen with lymph node as well as pulmonary TB and has been hypothesized to be due to an increased procoagulant activity of interleukin-1 [IL-1] on endothelial cells (55,56). PANCYTOPENIA Pancytopenia is infrequent and has been observed in only three to twelve per cent of cases (57). Pancytopenia is rare in patients with pulmonary TB and may occcur occasionally as a result of drug toxicity in these patients (53,57-61). It is mostly associated with an underlying haematological disease although cases associated with severe miliary TB alone have been described. Patients with disseminated TB may have splenomegaly as a result of the disease process, underlying haematological disease or both. Splenomegaly may contribute to the haematological abnormalities including pancytopenia in some of these patients (62). The pancytopenia may resolve after splenectomy in some of these patients, suggesting that hypersplenism may be one of the mechanisms of pancytopenia in these patients. Pancytopenia in disseminated TB has also been attributed to haemophagocytosis, even though hypocellularity of the marrow has also been reported (62-64). All these haematological abnormalities,

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including pancytopenia often reverse with effective therapy (61). COAGULATION ABNORMALITIES Various coagulation abnormalities have been described in patients with pulmonary as well as disseminated TB. Disseminated intravascular coagulation [DIC] has been documented in disseminated as well as pulmonary TB and often is accompanied by a high mortality rate (59, 65-70). In these patients activated partial thromboplastin time and thrombin time are increased and the antithrombin-III [AT-III] activity is often reduced. In a retrospective study of 833 culture-proven TB patients with DIC were evaluated before starting antituberculosis treatment (71). Nearly 3.2 per cent of them had TB induced DIC with a mortality rate of 63 per cent. Seven of the 27 patients with DIC [25.9%] had disseminated TB. An early institution of antituberculosis treatment significantly improved survival in this study. Acquired Factor V deficiency with variable bleeding manifestations has been described in patients with pulmonary TB. This abnormality disappears with antituberculosis treatment (72). Sarode et al (71) reported the presence of platelet hyperaggregation in 88 per cent patients with intestinal TB. Serum and plasma from 15 of these patients, when incubated with normal platelets caused hyperaggregation as well (71). This abnormality may be related to increased levels of C-reactive protein in these patients. Transient thrombasthenia has been reported in patients with TB (73). Transient protein S deficiency has been reported in association with TB and deep vein thrombosis [DVT]; however, a direct pathological relationship could not be established. Deep vein thrombosis confirmed by venography has been observed in three to four per cent of patients with pulmonary TB (74). In a group of patients with active pulmonary TB, thrombocytosis, elevations in plasma fibrinogen, fibrin degradation products [FDP], tissue plasminogen activator [t-PA] and inhibitor [PAI-1] with depressed AT-III levels were seen (75). In another study (76) comparing 45 patients of active pulmonary TB with healthy volunteers, elevated levels of plasma fibrinogen, Factor VIII, PAI-1 and depressed AT-III and protein C levels were observed. Following treatment, fibrinogen and Factor VIII, protein C and AT-III levels normalized. There was no evidence of activated protein C resistance.

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Platelet aggregation studies demonstrated increased platelet activation. Age, sex and disease matched individuals with venographically proven DVT had higher FDP, t-PA, and functional PAI-1 activity. Fibrinogen levels in all patients rose during the first two weeks of therapy and, together with related disturbances, corrected within 12 weeks. Bone marrow emboli have been reported in patients with miliary TB (77). Budd Chiari syndrome has been reported in a child with hepatic TB (78). Portal vein thrombosis has been reported in association with abdominal TB (79). BONE MARROW CHANGES IN TUBERCULOSIS Both localized and disseminated TB, can lead to a spectrum of histopathological changes in the bone marrow [Table 37.3]. These changes include typical caseating granuloma formation, non-caseating granulomas, marrow hypoplasia, red cell aplasia, megaloblastosis, haemophagocytosis, and necrosis of the marrow (24,80). In majority of the patients, the bone marrow shows normal to increased cellularity and myeloid hyperplasia (66). In most patients with pulmonary TB, the marrow shows “reactive changes” with increased granulocytic hyperplasia with mild to moderate plasmacytosis (4). Bone marrow plasmacytosis is seen less frequently in miliary TB and can be a helpful differentiating feature (4,24,81). Bone marrow granulomas [Figures 37.1 and 37.2] are present in 50 to 100 per cent of patients with miliary TB and are usually absent in pulmonary TB (82). In a study (83) of 6 988 bone marrow biopsies, six per cent of patients in whom granulomas were present in the bone marrow had TB as the inciting cause. Patients with peripheral blood abnormalities are more likely to have granulomas in the bone marrow (35). Tuberculosis granulomas Table 37.3: Bone marrow changes in tuberculosis Myeloid hyperplasia Plasmacytosis Megaloblastoid maturation Hypoplasia or aplasia Haemophagocytosis Caseating and non-caseating granulomas Bone marrow necrosis Myelofibrosis

Figure 37.1: Bone biopsy showing a well-defined tuberculosis granuloma composed of epithelioid cells and Langhans’ giant cells [arrow] [Haematoxylin and eosin × 100]

Figure 37.2: Bone biopsy showing a tuberculosis granuloma composed of epithelioid cells [asterisk] and Langhans’ giant cells [arrows] [Haematoxylin and eosin × 400]

usually show the presence of Langhans’ giant cells and caseation necrosis in 60 to 70 per cent of cases (20,24). Caseation necrosis and the presence of AFB in the granulomas is diagnostic of TB. It has been observed that near these granulomas the marrow cellularity is often greater or lower, and there may be an increase in reticulin fibres and in severe cases myelofibrosis may occur (84). Reticuloendothelial cells in the bone marrow may show phagocytosis of erythrocytes, leucocytes and platelets, commonly referred to as haemophagocytosis. It is more often seen in disseminated TB and disappears with treatment (85,86). Haemophagocytic syndrome has been reported with localized extra-pulmonary TB as well (87). Rarely, life-threatening haemophagocytic syndrome

Haematological Manifestations of Tuberculosis related to Mycobacterium tuberculosis can occur (88). Bone marrow necrosis has been described in patients with disseminated TB (89,90). The bone marrow in patients with untreated TB may show megaloblastic changes in as many as 60 per cent of patients with disseminated TB, but this does not reflect vitamin B12 or folate deficiency in these patients (24). Bone marrow aspirate iron stores are usually increased reflecting poor iron usage, though they may be decreased in some patients. Patients with poor nutritional status may have decreased iron status on bone marrow examination (27). Bone marrow examination is often a helpful diagnostic tool in TB. The AFB may be demonstrated in the bone marrow morphologically within the granulomas or by mycobacterial culture. In a study of patients with pulmonary TB (91), AFB were detected in 55 per cent cases in the buffy coat, and in 48.3 per cent cases in the bone marrow. In 38.3 per cent cases, the AFB could be demonstrated both in the buffy coat as well as the bone marrow. It is possible to use polymerase chain reaction [PCR] to detect Mycobacterium tuberculosis in bone marrow aspirate material and this technique may be more sensitive than the conventional culture methods. The PCR technique has the added advantage of being a rapid test compared to cultures. Lombard et al (46) reported that the overall sensitivity for the detection of Mycobacterium tuberculosis in the bone marrow aspirate improved to 58 per cent by using both conventional culture and PCR techniques. NONTUBERCULOUS MYCOBACTERIAL INFECTION Haematological abnormalities are commonly observed in patients with localized or disseminated infection caused by nontuberculous mycobacteria [NTM], but a causal relationship is often difficult to confirm given the usual immunocompromised status of the typical host and other predisposing illnesses. Nontuberculous mycobacterial infections are on the rise globally, especially due to the ongoing acquired immunodeficiency syndrome [AIDS] epidemic. Anaemia can be seen in almost all patients with NTM (92). Leucopenia, thrombocytopenia and pancytopenia have been observed in nearly half of the patients (93). Plasmacytosis and granulocytic hyperplasia are common findings in the bone marrow (92). Granulomas can be found in approximately half of the patients and range from small and lymphohistiocytic aggregates to larger lymphohistiocytic

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lesions and clusters of epithelioid cells and lymphocytes (92). Unlike the granulomas associated with TB, necrosis is not commonly seen in these granulomas. Usually, few bacteria are demonstrable in the bone marrow biopsy in patients with TB, whereas numerous AFB can be seen in patients with disease due to Mycobacterium avium intracellulare complex [MAIC]. Farhi et al (92) found granulomas in the bone marrow in 12 of 24 patients with disseminated MAIC infection (92). DRUG-INDUCED HAEMATOLOGICAL CHANGES Many of the abnormalities seen with TB can also be induced by the antituberculosis drugs and often makes the diagnosis difficult in a patient initiated on therapy [Table 37.4]. Drug-induced AIHA can be precipitated by isoniazid, rifampicin, streptomycin as well as paraaminosalicyclic acid [PAS] (94-96). In patients receiving rifampicin, a flu-like prodrome may precede the onset of the intravascular haemolysis. In many of these patients, direct Coomb’s test will become positive. Sideroblastic anaemia is a well-documented adverse Table 37.4: Haematological changes due to antituberculosis treatment Autoimmune haemolytic anaemia Rifampicin Para-aminosalicylic acid Isoniazid Megaloblastic anaemia Para-aminosalicylic acid Sideroblastic anaemia Isoniazid Cycloserine Pyrazinamide Pure red cell aplasia Isoniazid Agranulocytosis Streptomycin Thioacetazone Para-aminosalicylic acid Autoimmune thrombocytopenia Rifampicin Para-aminosalicylic acid Isoniazid Aplastic anaemia Streptomycin Para-aminosalicylic acid Disseminated intravascular coagulation Isoniazid

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effect of isoniazid therapy and usually occurs after several weeks of therapy (97,98). The bone marrow usually shows normoblastic hyperplasia with ring sideroblasts and the indices of iron metabolism are usually within normal range. The anaemia reverses on withdrawal of the drug and administration of pyridoxine. Sideroblastic anaemia has also been occasionally reported with pyrazinamide (99). Isoniazid may also produce an immune-mediated PRCA which reverses on withdrawal of the drug (100). Aplastic anaemia has been documented with disseminated bacille Calmette-Guerin [BCG] infection (101). Treatment with PAS may cause malabsorption and result in vitamin B 12 deficient megaloblastic anaemia (102). Leucopenia, agranulocytosis and aplastic anaemia have been observed following isoniazid, rifampicin and PAS administration (77,103-107). Antituberculosis treatment induced leucopenia appears to be more commonly seen in elderly patients (108). Leucopenia is rare with ethambutol use (104). Para-aminosalicylic acid can produce atypical lymphocytosis simulating infectious mononucleosis. Eosinophilia can occur with rifampicin therapy (109) and also has been reported with ethambutol (110). The use of rifampicin may produce immunemediated thrombocytopenia and the antibodies may be directed against the glycoprotein Ib/IX complex (111114). Antibodies of IgG and immunoglobulin M [IgM] type have been demonstrated in many of these patients. Thrombocytopenia has been more frequently observed when twice weekly regimen of 900 mg rifampicin was used and it resolves with reduction of dose to 150 to 300 mg/day. Isoniazid, pyrazinamide (115), streptomycin, ethambutol (116,117), and PAS (118) may also produce thrombocytopenia. Thrombotic thrombocytopenic purpura has been reported in association with rifampicin (119). Coagulation abnormalities are rare with antituberculosis drugs. Rarely, DIC following isoniazid and rifampicin therapy has been documented (120). Acquired Factor XIII deficiency due to inhibitors has been reported with isoniazid therapy (121). In most cases, the inhibitors have been shown to be IgG antibodies and these patients may present with severe subcutaneous and retroperitoneal bleeding. The pathogenesis of isoniazid associated Factor XIII inhibitor is not fully understood. Lorand et al (122) have proposed that isoniazid binds to Factor XIII

or one of its substrates and antigenically modifies the protein resulting in autoantibody production. Paraaminosalicylic acid can produce hypothrombinemia (4). Increased incidence of DVT has been reported among patients with TB receiving rifampicin (4). This may be related to the induction of enzyme cytochrome P-450 system by rifampicin which alters the balance between anticoagulant and coagulant proteins resulting in a state of hypercoagulability. A relationship between administration of isoniazid alone or in combination with rifampicin and fibrinogen as well as AT-III blood levels has been seen in one study (123). These observations indicate a protective effect of the synchronous administration of rifampicin in the preservation of fibrinogen blood levels by enzyme induction mechanisms. ACQUIRED IMMUNODEFICIENCY SYNDROME Various haematological abnormalities have been described in patients with human immunodeficiency virus [HIV] infection and AIDS (124-127). In patients with AIDS, isolated thrombocytopenia has been observed during early part of the disease (128); severe degree of anaemia, leucopenia and pancytopenia are more often observed in advanced disease (129,130). Leucocytosis is more often observed in patients with extra-pulmonary TB without HIV infection than in patients with AIDS (131). Hill et al (132) have observed absolute lymphocyte count of less 1 x 109/l in 80 per cent of HIV-seropositive patients and in only 40 per cent of HIV-seronegative patients. Approximately 60 per cent of these patients have granulomas in the bone marrow (131,132). Nongranulomatous reaction occurs in the presence of severe overwhelming infection. The granulomas may have areas of necrosis with many AFB. The surrounding inflammation when present consists mainly of polymorphonuclear cells and macrophages in contrast to usual cellular components of a granuloma seen in HIV-seronegative patients with TB (131). In a study from India (133), AFB could be demonstrated in 12.9 per cent of the 140 bone marrow aspirates obtained from HIV-seropositive patients suggesting that in countries with a high prevalence of TB, AFB staining of the bone marrow aspirate is useful in establishing the diagnosis of TB. In a study from sub-Saharan Africa (134), low selenium concentrations, high viral load, and high IL-6

Haematological Manifestations of Tuberculosis concentrations were associated with anaemia in HIVseropositive adults with active pulmonary TB. These manifestations could be partly secondary to antiretroviral drug treatment or hypersplenism. Several antiretroviral drugs, particularly zidovudine have a propensity to cause haematological manifestations, especially anaemia (135). However, a direct effect of mycobacterial infection and HIV on the haematopoietic system cannot be excluded. The underlying defect of the haematological system may also be responsible for the haematological changes and increased susceptibility to mycobacterial infection in patients with or without HIV infection. These observations merit further evaluation. REFERENCES 1. Dawborn JK, Cowling DC. Disseminated tuberculosis and bone marrow dyscrasias. Australas Ann Med 1961;10:230-6. 2. Corr WP Jr, Kyle RA, Bowie EJ. Hematologic changes in tuberculosis. Am J Med Sci 1964;248:709-14. 3. Wessels G, Schaaf HS, Beyers N, Gie RP, Nel E, Donald PR. Haematological abnormalities in children with tuberculosis. J Trop Pediatr 1999;45:307-10. 4. Morris CD, Bird AR, Nell H. The haematological and biochemical changes in severe pulmonary tuberculosis. QJM 1989;73:1151-9. 5. Roberts PD, Hoffbrand AV, Mollin DL. Iron and folate metabolism in tuberculosis. Br Med J 1966;2:198-202. 6. Ebrahim O, Folb PI, Robson SC, Jacobs P. Blunted erythropoietin response to anaemia in tuberculosis. Eur J Haematol 1995;55:251-4. 7. Baynes RD, Flax H, Bothwell TH, Bezwoda WR, MacPhail AP, Atkinson P, et al. Haematological and iron-related measurements in active pulmonary tuberculosis. Scand J Haematol 1986;36:280-7. 8. Kotru M, Rusia U, Sikka M, Chaturvedi S, Jain AK. Evaluation of serum ferritin in screening for iron deficiency in tuberculosis. Ann Hematol 2004;83:95-100. 9. Baynes RD, Flax H, Bothwell TH, Bezwoda WR, Atkinson P, Mendelow B. Red blood cell distribution width in the anemia secondary to tuberculosis. Am J Clin Pathol 1986;85:226-9. 10. Sahiratmadja E, Wieringa FT, van Crevel R, de Visser AW, Adnan I, Alisjahbana B, et al. Iron deficiency and NRAMP1 polymorphisms [INT4, D543N and 3’UTR] do not contribute to severity of anaemia in tuberculosis in the Indonesian population. Br J Nutr 2007;98:684-90. Epub 2007 Apr 30. 11. Chanarin I, Malkowska V, O’Hea AM, Rinsler MG, Price AB. Megaloblastic anaemia in a vegetarian Hindu community. Lancet 1985;2:1168-72. 12. Knox-Macaulay HH. Serum cobalamin concentration in tuberculosis. A study in the Guinea savanna of Nigeria. Trop Geogr Med 1990;42:146-50. 13. Murray HW. Transient autoimmune hemolytic anemia and pulmonary tuberculosis. N Engl J Med 1978;299:488.

549

14. Siribaddana SH, Wijesundera A. Autoimmune haemolytic anaemia responding to anti-tuberculous treatment. Trop Doct 1997;27:243-4. 15. Kuo PH, Yang PC, Kuo SS, Luh KT. Severe immune hemolytic anemia in disseminated tuberculosis with response to antituberculosis therapy. Chest 2001;119:1961-3. 16. Rani S, Singh T, Prakash S. Pure red cell aplasia. Indian Pediatr 1990;27:366-70. 17. Dutta S, Mohta R, Pati HP. Tuberculosis pure red cell aplasia. Int J Tuberc Lung Dis 1999;3:361-2. 18. Demiroglu H, Dundar S. Vitamin B6 responsive sideroblastic anaemia in a patient with tuberculosis. Br J Clin Pract 1997;51:51-2. 19. Sharma SK, Mohan A, Pande JN, Prasad KL, Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. QJM 1995;88:29-37. 20. Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis 2005;5:415-30. 21. Singh KJ, Ahluwalia G, Sharma SK, Saxena R, Chaudhary VP, Mohan A. Significance of haematological manifestations in patients with tuberculosis. J Assoc Physicians India 2001;49:788,790-4. 22. Hussain SF, Irfan M, Abbasi M, Anwer SS, Davidson S, Haqqee R, et al. Clinical characteristics of 110 miliary tuberculosis patients from a low HIV prevalence country. Int J Tuberc Lung Dis 2004;8:493-9. 23. Yoon HJ, Song YG, Park WI, Choi JP, Chang KH, Kim JM. Clinical manifestations and diagnosis of extrapulmonary tuberculosis. Yonsei Med J 2004;45:453-61. 24. Lombard EH, Mansvelt EP. Haematological changes associated with miliary tuberculosis of the bone marrow. Tuber Lung Dis 1993;74:131-5. 25. Al-Jahdali H, Al-Zahrani K, Amene P, Memish Z, AlShimemeri A, Moamary M, et al. Clinical aspects of miliary tuberculosis in Saudi adults. Int J Tuberc Lung Dis 2000; 4:252-5. 26. al-Majed SA, al-Momen AK, al-Kassimi FA, al-Zeer A, Kambal AM, Baaqil H. Tuberculosis presenting as immune thrombocytopenic purpura. Acta Haematol 1995;94:135-8. 27. Bakhshi S, Rao IS, Jain V, Arya LS. Autoimmune hemolytic anemia complicating disseminated childhood tuberculosis. Indian J Pediatr 2004;71:549-51. 28. Sinha AK, Agarwal A, Lakhey M, Ansari J, Rani S. Pure red cell aplasia - report of 11 cases from eastern Nepal. Indian J Pathol Microbiol 2003;46:405-8. 29. Blanche P, Rigolet A, Massault PP, Bouscary D, Dreyfus F, Sicard D. Autoimmune haemolytic anaemia revealing miliary tuberculosis. J Infect 2000;40:292. 30. Ismail Y, Muhamad A. Protean manifestations of gastrointestinal tuberculosis. Med J Malaysia 2003;58:345-9 31. Olaniyi JA, Aken’Ova YA. Haematological profile of patients with pulmonary tuberculosis in Ibadan, Nigeria. Afr J Med Med Sci 2003;32:239-42. 32. Paar JA, Scheinman MM, Weaver RA. Disseminated nonreactive tuberculosis with basophilia, leukemoid reaction and terminal pancytopenia. N Engl J Med 1966;274:335.

550

Tuberculosis

33. Keeton GR, Naidoo G, Jacobs P. Leukaemoid reaction and disseminated tuberculosis. A case report. S Afr Med J 1975; 49:1930-2. 34. Tripathi K, Prakash J, Misra KM, Srivastava PK, Dube B. Leukaemoid reaction in tuberculosis. J Indian Med Assoc 1984;82:63-4. 35. Maartens G, Willcox PA, Benatar SR. Miliary tuberculosis: rapid diagnosis, hematologic abnormalities, and outcome in 109 treated adults. Am J Med 1990;89:291-6. 36. Bagby GC Jr, Gilbert DN. Suppression of granulopoiesis by T-lymphocytes in two patients with disseminated mycobacterial infection. Ann Intern Med 1981;94:478-81. 37. Shenkenberg TD, Rice L, Waddell CC. Acquired Pelger-Huet nuclear anomaly with tuberculosis. Arch Intern Med 1982;142:153-4. 38. Kony SJ, Hane AA, Larouzé B, Samb A, Cissoko S, Sow PS, et al. Tuberculosis-associated severe CD4+ T-lymphocytopenia in HIV-seronegative patients from Dakar. SIDAK Research Group. J Infect 2000;41:167-71. 39. Sharma SK, Pande JN, Singh YN, Verma K, Kathait SS, Khare SD, et al. Pulmonary function and immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 1992;145:1167-71. 40. Akintunde EO, Shokunbi WA, Adekunle CO. Leucocyte count, platelet count and erythrocyte sedimentation rate in pulmonary tuberculosis. Afr J Med Med Sci 1995;24:131-4. 41. Onwubalili JK, Edwards AJ, Palmer L. T4 lymphopenia in human tuberculosis. Tubercle 1987;68:195-200. 42. Gambon-Deza F, Pacheco Carracedo M, Cerda Mota T, Montes Santiago J. Lymphocyte populations during tuberculosis infection: V beta repertoires. Infect Immun 1995;63: 1235-40. 43. Venter JP. Hematological, blood biochemical and certain clinical aspects of tuberculosis in the Bantu. S Afr Med J 1974;48:1559-62. 44. Farcet JP, Binaghi M, Kuentz M, Merlier JF, Mayaud C, Nebout T, et al. A hypereosinophilic syndrome with retinal arteritis and tuberculosis. Arch Intern Med 1982;142:625-7. 45. Flores M, Merino-Angulo J, Tanago JG, Aquirre C. Late generalized tuberculosis and eosinophilia. Arch Intern Med 1983;143:182. 46. Lombard EH, Victor T, Jordaan A, van Helden PD. The detection of Mycobacterium tuberculosis in bone marrow aspirate using the polymerase chain reaction. Tuber Lung Dis 1994; 75:65-9. 47. Omar MA, Jogessar VB, Kamdar MC. Thrombocytosis associated with tuberculous peritonitis. Tubercle 1983;64:295-6. 48. Asano S, Okano A, Ozawa K, Nakahata T, Ishibashi T, Koike K, et al. In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets. Blood 1990; 75:1602-5. 49. Unsal E, Aksaray S, Koksal D, Sipit T. Potential role of interleukin 6 in reactive thrombocytosis and acute phase response in pulmonary tuberculosis. Postgrad Med J 2005;81:604-7. 50. Boots RJ, Roberts AW, McEvoy D. Immune thrombocytopenia complicating pulmonary tuberculosis: case report and investigation of mechanisms. Thorax 1992;47:396-7.

51. Hernandez-Maraver D, Pelaez J, Pinilla J, Navarro FH. Immune thrombocytopenic purpura due to disseminated tuberculosis. Acta Haematol 1996;96:266. 52. Baynes RD, Bothwell TH, Flax H, McDonald TP, Atkinson P, Chetty N, et al. Reactive thrombocytosis in pulmonary tuberculosis. J Clin Pathol 1987;40:676-9. 53. Cockcroft DW, Donevan RE, Copland GM, Ibbott JW. Miliary tuberculosis presenting with hyponatremia and thrombocytopenia. Can Med Assoc J 1976;115:871-3. 54. Cummins D, Markham D, Ardeman S, Lubenko A. Severe thrombocytopenia in tuberculosis. Clin Lab Haematol 1993;15:150-2. 55. Pavithran K, Vijayalekshmi N. Thrombocytopenic purpura with tuberculous adenitis. Indian J Med Sci 1993;47:239-40. 56. Toscano V, Bontadini A, Falsone G, Conte R, Fois F, Fabiani A, et al. Thrombotic thrombocytopenic purpura associated with primary tuberculosis. Infection 1995;23:58-9. 57. De SRJL, Vidanapathirana NN, Rajakariar R. Pancytopenia in a paediatric unit. Ceylon Med J 1977;22:132-6. 58. Ulku B, Ilkova HM, Celikoglu SI, Aykan TB. Pancytopenia associated with disseminated tuberculosis. Haematologica 1982;67:630-5. 59. Sarma PS, Viswanathan KA, Budhiraja A, Mukherjee MM. Pancytopenia and DIC. in disseminated tuberculosis. J Assoc Physicians India 1984;32:601-2. 60. Hunt BJ, Andrews V, Pettingale KW. The significance of pancytopenia in miliary tuberculosis. Postgrad Med J 1987;63:801-4. 61. Yadav TP, Mishra S, Sachdeva KJ, Gupta VK, Siddhu KK, Bakshi G, et al. Pancytopenia in disseminated tuberculosis. Indian Pediatr 1996;33:597-9. 62. Cassim KM, Gathiram V, Jogessar VB. Pancytopaenia associated with disseminated tuberculosis, reactive histiocytic haemophagocytic syndrome and tuberculous hypersplenism. Tuber Lung Dis 1993;74:208-10. 63. Demiroglu H, Ozcebe OI, Ozdemir L, Sungur A, Dundar S. Pancytopenia with hypocellular bone marrow due to miliary tuberculosis: an unusual presentation. Acta Haematol 1994;91:49-51. 64. Basu S, Mohan H, Malhotra H. Pancytopenia due to hemophagocytic syndrome as the presenting manifestation of tuberculosis. J Assoc Physicians India 2000;48:845-6. 65. Mavligit GM, Binder RA, Crosby WH. Disseminated intravascular coagulation in miliary tuberculosis. Arch Intern Med 1972;130:388-9. 66. Oluboyede OA, Onadeko BO. Observation on haematological patterns in pulmonary tuberculosis in Nigerians. J Trop Med Hyg 1978;81:91-5. 67. Stein DS, Libertin CR. Disseminated intravascular coagulation in association with cavitary tuberculosis. South Med J 1990;83:60-3. 68. Eliopoulos G, Vaiopoulos G, Kittas C, Fessas P. Tuberculosis associated hemophagocytic syndrome complicated with severe bone marrow failure and disseminated intravascular coagulation. Nouv Rev Fr Hematol 1992;34:273-6. 69. Fujita M, Kunitake R, Nagano Y, Maeda F. Disseminated intravascular coagulation associated with pulmonary tuberculosis. Intern Med 1997;36:218-20.

Haematological Manifestations of Tuberculosis 70. Wang JY, Hsueh PR, Lee LN, Liaw YS, Shau WY, Yang PC, et al. Mycobacterium tuberculosis inducing disseminated intravascular coagulation. Thromb Haemost 2005;93:729-34. 71. Sarode R, Bhasin D, Marwaha N, Roy P, Singh K, Panigrahi D, et al. Hyperaggregation of platelets in intestinal tuberculosis: role of platelets in chronic inflammation. Am J Hematol 1995;48:52-4. 72. Aliaga JL, de Gracia J, Vidal R, Pico M, Flores P, Sampol G. Acquired factor V deficiency in a patient with pulmonary tuberculosis. Eur Respir J 1990;3:109-10. 73. Du PHA, Retief FP, Richter G, Badenhorst PN. Transient thrombasthenia in a patient with tuberculosis. S Afr Med J 1974;48:2454-6. 74. Cowie RL, Dansey RD, Hay M. Deep-vein thrombosis and pulmonary tuberculosis. Lancet 1989;2:1397. 75. Robson SC, White NW, Aronson I, Woollgar R, Goodman H, Jacobs P. Acute-phase response and the hypercoagulable state in pulmonary tuberculosis. Br J Haematol 1996;93:943-9. 76. Turken O, Kunter E, Sezer M, Solmazgul E, Cerrahoglu K, Bozkanat E, et al. Hemostatic changes in active pulmonary tuberculosis. Int J Tuberc Lung Dis 2002;6:927-32. 77. Witham RR, Burton JA. Bone marrow emboli in a patient with miliary tuberculosis. Chest 1979;75:208. 78. Gomber S, Khalil A, Vij JC, Bahl VK, Kapoor R, Saini L. Budd Chiari syndrome in a child with hepatic tuberculosis. Indian Heart J 1986;38:226-9. 79. Ruttenberg D, Graham S, Burns D, Solomon D, Bornman P. Abdominal tuberculosis–a cause of portal vein thrombosis and portal hypertension. Dig Dis Sci 1991;36:112-5. 80. Knox-Macaulay HH. Tuberculosis and the haemopoietic system. Baillieres Clin Haematol 1992;5:101-29. 81. Kinoshita M, Ichikawa Y, Koga H, Sumita S, Oizumi K. Reevaluation of bone marrow aspiration in the diagnosis of miliary tuberculosis. Chest 1994;106:690-2. 82. Morris CD. The radiography, haematology and biochemistry of pulmonary tuberculosis in the aged. QJM 1989;71:529-36. 83. Bhargava V, Farhi DC. Bone marrow granulomas: clinicopathologic findings in 72 cases and review of the literature. Hematol Pathol 1988;2:43-50. 84. Samuelsson SM, Killander A, Werner I, Stenkvist B. Myelofibrosis associated with tuberculous lymphadenitis. Acta Med Scand Suppl 1966;445:326-5. 85. Campo E, Condom E, Miro MJ, Cid MC, Romagosa V. Tuberculosis-associated hemophagocytic syndrome. A systemic process. Cancer 1986;58:2640-5. 86. Undar L, Karpuzoglu G, Karadogan I, Gelen T, Artvinli M. Tuberculosis-associated haemophagocytic syndrome: a report of two cases and a review of the literature. Acta Haematol 1996;96:73-8. 87. Shin BC, Kim SW, Ha SW, Sohn JW, Lee JM, Kim NS. Hemophagocytic syndrome associated with bilateral adrenal gland tuberculosis. Korean J Intern Med 2004;19:70-3. 88. Claessens YE, Pene F, Tulliez M, Cariou A, Chiche JD. Lifethreatening hemophagocytic syndrome related to mycobacterium tuberculosis. Eur J Emerg Med 2006;13:172-4 89. Katzen H, Spagnolo SV. Bone marrow necrosis from miliary tuberculosis. JAMA 1980;244:2438-9.

551

90. Paydas S, Ergin M, Baslamisli F, Yavuz S, Zorludemir S, Sahin B, et al. Bone marrow necrosis: clinicopathologic analysis of 20 cases and review of the literature. Am J Hematol 2002;70:300-5. 91. Garcia MJ, Rodriguez L, Vandervoort P. Pulmonary vein thrombosis and peripheral embolization. Chest 1996;109: 846-7. 92. Farhi DC, Mason UG 3rd, Horsburgh CR, Jr. The bone marrow in disseminated Mycobacterium aviumintracellulare infection. Am J Clin Pathol 1985;83:463-8. 93. Horsburgh CR Jr, Mason UG 3rd, Farhi DC, Iseman MD. Disseminated infection with Mycobacterium aviumintracellulare. A report of 13 cases and a review of the literature. Medicine [Baltimore] 1985;64:36-48. 94. Oguz A, Kanra T, Gokalp A, Gultekin A. Acute hemolytic anemia caused by irregular rifampicin therapy. Turk J Pediatr 1989;31:83-8. 95. Yeo CT, Wang YT, Poh SC. Mild haemolysis associated with flu-syndrome during daily rifampicin treatment–a case report. Singapore Med J 1989;30:215-6. 96. Letona JM, Barbolla L, Frieyro E, Bouza E, Gilsanz F, Fernandez MN. Immune haemolytic anaemia and renal failure induced by streptomycin. Br J Haematol 1977;35:561-71. 97. McCurdy PR, Donohoe RF. Pyridoxine-responsive anemia conditioned by isonicotinic acid hydrazide. Blood. 1966;27:352-62. 98. Tomkin GH. Isoniazid as a cause of neuropathy and sideroblastic anaemia. Practitioner 1973;211:773-7. 99. McCurdy PR, Donohoe RF, Magovern M. Reversible sideroblastic anemia caused by pyrazinoic acid [pyrazinamide]. Ann Intern Med 1966;64:1280-4. 100. Claiborne RA, Dutt AK. Isoniazid-induced pure red cell aplasia. Am Rev Respir Dis 1985;131:947-9. 101. Long HJ. Aplastic anemia, a rare complication of disseminated BCG infection: case report. Mil Med 1982;147:1067-70. 102. Paaby P, Norvin E. The absorption of vitamin B12 during treatment with para-aminosalicylic acid. Acta Med Scand 1966;180:561-4. 103. Williams CK, Aderoju EA, Adenle AD, Sekoni G, Esan GJ. Aplastic anaemia associated with anti-tuberculosis chemotherapy. Acta Haematol 1982;68:329-32. 104. Mehrotra TN, Gupta SK. Agranulocytosis following isoniazid. Report of a case. Indian J Med Sci 1973;27:392-3. 105. van Assendelft AH. Leucopenia caused by two rifampicin preparations. Eur J Respir Dis 1984;65:251-8. 106. Carrington CB, Addington WW, Goff AM, Madoff IM, Marks A, Schwaber JR, et al. Chronic eosinophilic pneumonia. N Engl J Med 1969;280:787-98. 107. van Assendelft AH. Leucopenia in rifampicin chemotherapy. J Antimicrob Chemother 1985;16:407-8. 108. Umeki S. Clinical features of pulmonary tuberculosis in young and elderly men. Jpn J Med 1989;28:341-7. 109. Nigam P, Goyal BM, Saxena HN. Eosinophilia as a result of rifampicin therapy. J Indian Med Assoc 1981;77:158-9. 110. Wong PC, Yew WW, Wong CF, Choi HY. Ethambutolinduced pulmonary infiltrates with eosinophilia and skin involvement. Eur Respir J 1995;8:866-8.

552

Tuberculosis

111. Leggat PO. Rifampicin and thrombocytopenia. Lancet 1971;2:103-4. 112. Burnette PK, Ameer B, Hoang V, Phifer W. Rifampinassociated thrombocytopenia secondary to poor compliance. DICP 1989;23:382-4. 113. Lee CH, Lee CJ. Thrombocytopenia–a rare but potentially serious side effect of initial daily and interrupted use of rifampicin. Chest 1989;96:202-3. 114. Mehta YS, Jijina FF, Badakere SS, Pathare AV, Mohanty D. Rifampicin-induced immune thrombocytopenia. Tuber Lung Dis 1996;77:558-62. 115. Jain VK, Vardhan H, Prakash OM. Pyrazinamide induced thrombocytopenia. Tubercle 1988;69:217-8. 116. Rabinovitz M, Pitlik SD, Halevy J, Rosenfeld JB. Ethambutolinduced thrombocytopenia. Chest 1982;81:765-6. 117. Prasad R, Mukerji PK. Ethambutol-induced thrombocytopaenia. Tubercle 1989;70:211-2. 118. Feigin RD, Zarkowsky HF, Shearer W, Anderson DC. Thrombocytopenia following administration of paraaminosalicylic acid. J Pediatr 1973;83:502-3. 119. Fahal IH, Williams PS, Clark RE, Bell GM. Thrombotic thrombocytopenic purpura due to rifampicin. BMJ 1992;304:882. 120. Ip M, Cheng KP, Cheung WC. Disseminated intravascular coagulopathy associated with rifampicin. Tubercle 1991;72:291-3. 121. Krumdieck R, Shaw DR, Huang ST, Poon MC, Rustagi PK. Hemorrhagic disorder due to an isoniazid-associated acquired factor XIII inhibitor in a patient with Waldenstrom’s macroglobulinemia. Am J Med 1991;90:639-45. 122. Lorand L, Maldonado N, Fradera J, Atencio AC, Robertson B, Urayama T. Haemorrhagic syndrome of autoimmune origin with a specific inhibitor against fibrin stabilizing factor [factor XIII]. Br J Haematol 1972;23:17-27. 123. Farmakis M, Travlou O, Aroni S, Fertakis A. Fibrinogen and antithrombin III blood levels fluctuations during isoniazid or isoniazid plus rifampicin administration. Arzneimittelforschung 1992;42:1041-4. 124. Evans RH, Scadden DT. Haematological aspects of HIV infection. Baillieres Best Pract Res Clin Haematol 2000;13:21530.

125. Adias TC, Uko E, Erhabor O. Anaemia in human immunodeficiency virus infection: a review. Niger J Med 2006;15:2036. 126. Lee SW, Kang YA, Yoon YS, Um SW, Lee SM, Yoo CG, et al. The prevalence and evolution of anemia associated with tuberculosis. J Korean Med Sci. 2006;21:1028-32. 127. Subbaraman R, Chaguturu SK, Mayer KH, Flanigan TP, Kumarasamy N. Adverse effects of highly active antiretroviral therapy in developing countries. Clin Infect Dis 2007;45:1093-101. Epub 2007 Sep 6. 128. Karpatkin S. HIV-1 related thrombocytopenia. Hematol Oncol Clin North Am 1990;4:193-218. 129. Treacy M, Lai L, Costello C, Clark A. Peripheral blood and bone marrow abnormalities in patients with HIV related diseases. Br J Haematol 1987;65;289-94. 130. Zon Li, Arkin C, Groopman JE. Haematologic manifestations of human immunodeficiency virus [HIV] infection. Br J Haematol 1987;66:251-6. 131. Shafer RW, Kim DS, Weiss JP, Quale JM. Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine [Baltimore] 1991;70:384-97. 132. Hill AR, Premkumar S, Brustein S, Vaidya K, Powell S, Li PW, et al. Disseminated tuberculosis in the acquired immunodeficiency syndrome era. Am Rev Respir Dis 1991;144:116470. 133. Khandekar MM, Deshmukh SD, Holla VV, Rane SR, Kakrani AL, Sangale SA, et al. Profile of bone marrow examination in HIV/AIDS patients to detect opportunistic infections, especially tuberculosis. Indian J Pathol Microbiol 2005;48:712. 134. van Lettow M, West CE, van der Meer JW, Wieringa FT, Semba RD. Low plasma selenium concentrations, high plasma human immunodeficiency virus load and high interleukin-6 concentrations are risk factors associated with anemia in adults presenting with pulmonary tuberculosis in Zomba district, Malawi. Eur J Clin Nutr 2005;59:526-32. 135. Antoniskis D, Easley AC, Espina BM, Davidson PT, Barnes PF. Combined toxicity of zidovudine and antituberculosis chemotherapy. Am Rev Respir Dis 1992;145:430-4.

Adrenocortical Reserve in Tuberculosis

38

GA Prasad, SK Sharma, N Kochupillai

INTRODUCTION Overt clinical features of adrenal insufficiency appear only after the destruction of more than 80 to 90 per cent of both the adrenal glands (1). However, subclinical adrenal insufficiency which may exist without any evidence may be important in stressful situations such as acute and chronic infections, which require increased release of adrenocortical hormones to meet heightened metabolic demands. The rich vascularity, and the high local levels of corticosteroids which suppress cellmediated immune response, make the adrenal glands an ideal nidus for organisms, such as mycobacteria, Histoplasma species and involvement of the adrenal gland frequently occurs following haematogenous dissemination in tuberculosis [TB] and histoplasmosis. Acute infections are usually associated with increased release of adrenal steroids (2). However, adrenal reserve in chronic infections, especially in TB has been a subject of great controversy (3,4). Estimation of adrenal reserve assumes greater importance in view of the appearance of reports of clinical deterioration and sudden death in patients with TB on commencement of antituberculosis therapy, especially rifampicin (5). Rifampicin, a potent inducer of hepatic microsomal enzymes, is known to reduce the half-life and tissue availability of corticosteroids (6). Hence, it may unmask subclinical adrenal insufficiency which may lead to clinical Addisonian crisis. TUBERCULOSIS ADDISON’S DISEASE In 1855, Thomas Addison first described the chronic type of hypoadrenalism (7). Presently, the term ‘Addison’s

disease’ is now used to refer to all forms of chronic primary adrenocortical insufficiency (8). Seventy five years ago, Guttman (9) reviewed 403 autopsy reports of patients with adrenal insufficiency and reported that adrenal TB was present in 70% patients, while idiopathic atrophy occurred in 20 per cent of the patients. In 1956, Sanford and Favour (10) reported that TB was the aetiological cause of adrenal insufficiency in 25 per cent of the cases. Dunlop (11) reported that 79 per cent of the cases had TB as the cause of Addison’s disease in an autopsy series of 24 patients during 1928 to 1938. However, subsequent studies have generally reported a declining proportion of TB. Nerup (12) reported that the majority [66%] had the idiopathic type of Addison’s disease while only seven per cent of patients had a TB aetiology. Ethnic variations have been described in the aetiology of hypoadrenalism (13). Tuberculosis as a cause of hypoadrenalism was seen in only four per cent of Caucasians [92% due to autoimmune disease] while in Polynesians, who have a 10-fold higher incidence of TB than Caucasians, hypoadrenalism due to TB was detected in 63 per cent of cases (13). In a study from South Africa (14), it has been reported that the probable aetiology of Addison’s disease was idiopathic in 42 per cent, related to active TB in 18 per cent, old TB in 16 per cent and autoimmune in 12 per cent. In another recent autopsy study (15), adrenal TB was seen in six per cent of the patients with active TB and in 25 per cent of them the adrenal gland was the only organ involved by TB. Thus, autoimmune adrenalitis is the most common cause of adrenal insufficiency in developed countries, TB is still a common cause in the developing world (1,16).

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Activated hypothalamo-pituitary-adrenal axis in TB causes increased cortisol secretion which results in a shift in the Th1/Th2 balance towards Th2 T-cell dysfunction due to high cortisol and low dehydroepiandrosterone levels. This may be responsible for immunologicallymediated tissue damage in TB (1). Clinical Manifestations Patients with acute adrenal insufficiency present with severe hypotension or hypovolaemic shock, acute abdominal pain, vomiting, and fever. Patients with chronic adrenal insufficiency complain of fatigue, lack of stamina and energy, reduced muscle strength, and increased irritability. Weight loss, nausea, and anorexia or failure to thrive [in children], and arthralgias are also present (1,7,8). The combined measurement of early morning serum cortisol and plasma adrenocorticotrophic hormone [ACTH] separates patients with primary adrenal insufficiency from healthy individuals and those with secondary disease (17). Imaging Appearances In patients with Addison’s disease due to TB with recent or active infection, the adrenal glands may appear enlarged (1,18). Non-homogeneous appearance and presence of non-enhancing areas may indicate foci of caseous necrosis (19). In patients with remote infection, the gland may be atrophied or calcified (18). On the contrary, adrenocortical functions may be normal despite adrenal involvement by TB (1,18,19). ESTIMATION OF ADRENOCORTICAL RESERVE Before the advent of synthetic analogues, corticotrophin derived from the bovine or porcine pituitary gland was used for the stimulation and estimation of adrenal gland reserve. However, its use often led to allergic reactions. Cosyntropin, a synthetic polypeptide, contains the first 24 of the 39 amino acids of ACTH responsible for the biological activity of ACTH (9). The advantages of using the cosyntropin test to assess adrenal function include a reduced incidence of hypersensitivity reactions (20,21), ease of performance of the test, [as only three intravenous punctures are required] and reliability of the method in excluding or confirming adrenal insufficiency (22).

Various methods to estimate adrenal reserve using cosyntropin have been advocated. Intramuscular injection of cosyntropin with estimation of serum cortisol before, 20 and 60 minutes has been used (23). The need to measure serum cortisol early i.e., within 60 minutes of injection of 250 μg of cosyntropin intramuscularly was emphasized in a study done by Danowski et al (24). Some workers (25-27) felt that 250 μg of synthetic ACTH provides a very high blood ACTH concentration resulting in a ‘supraphysiological’ dose. Therefore, it has been postulated that this dosage may induce falsepositive cortisol responses and may result in underdiagnosis of adrenal insufficiency. Therefore, 1 μg of ACTH has been considered to be an adequate dose to provide ‘physiological’ adrenocortical stimulation and has been used in some studies (25-27). Effect of Rifampicin on Corticosteroids Rifampicin, a well-known inducer of hepatic microsomal enzymes, causes serious reduction in the plasma concentration of concomitantly administered drugs metabolized in the liver. These drugs include corticosteroids, oral contraceptives, oral hypoglycaemic agents and digitalis (6). Hence, it may unmask subclinical adrenal insufficiency which may lead to clinical Addisonian crisis. McAllister et al (28) studied the pharmacokinetics of prednisolone to quantify the effect of rifampicin on prednisolone and found that the clearance of prednisolone increased by 45 per cent and the tissue availability reduced by 66 per cent. Therefore, they recommended doubling of prednisolone dosage when given in combination with rifampicin. This observation was supported by Edwards et al (29) who cite the case of a patient with Addison’s disease who required a three-fold higher dose of corticosteroids when put on rifampicin. Instances of acute adrenal insufficiency being precipitated following introduction of antituberculosis treatment [including rifampicin] have also been reported in the literature (5,30). The diagnosis of acute adrenal insufficiency was confirmed by Wilkins et al (5) by a short cosyntropin test. The altered pharmacokinetics of corticosteroids was also reported by Buffington et al (31) in their study on recipients of renal allografts.

Adrenocortical Reserve in Tuberculosis Effect of Malnutrition of Adrenal Function Adrenal function in malnutrition has also been a subject of controversy as views expressed range from hypofunction to hyperfunction. Bajaj et al (32) induced protein malnutrition in rhesus monkeys to study their adrenal function and observed hypoproteinaemia, fasting hypoglycaemia and a rise of basal serum cortisol with loss of diurnal variation. They proposed that the hypercortisolism observed could be due to: [i] the metabolic stress induced by protein malnutrition; [ii] the fasting hypoglycaemia; and [iii] reduction in the clearance of cortisol. The adrenal reserve was found to be normal despite increased adrenal activity. Loss of diurnal variation was interpreted to be due to the sustained ACTH release because of hypoglycaemia. Enwonwu et al (33) also made similar observations in their study on malnourished non-human primates. Mean plasma 11-hydroxy-corticosteroid levels were found to be higher in malnourished children by Alleyne and Young (34). They did not observe any evidence of reduced adrenal reserve in these patients either. Overview of Past Experience Table 38.1 briefly summarizes the previously published studies on this subject (3,4,35-43). Basal cortisol was reported to be either normal or increased [Table 38.1], except in one study (41), where the mean basal serum cortisol level was low. The most common explanation advanced for raised levels of basal cortisol was hyperfunctioning of the adrenal glands in response to the stress caused by infection (35). Chan et al (36) demonstrated a direct correlation between elevated serum cortisol at presentation and subsequent mortality during treatment. They also demonstrated in their autopsy series that the only patient with demonstrable granulomas in the adrenals had the highest basal cortisol concentration. Srivastava and colleagues (35) found that the duration of symptoms was inversely proportional to basal cortisol levels, while a direct correlation existed with parameters like sputum positivity for Mycobacterium tuberculosis, extent of disease, fever, and raised erythrocyte sedimentation rate. Measurement of serum cortisol after stimulation of the adrenals by ACTH or synthetic analogues of ACTH is a very reliable method of estimating adrenal reserves, as compared to measurement of basal cortisol alone, which

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may yield fallacious information. The extent of compromise of adrenal reserve reported in these studies [Table 38.1] ranged from normal (36) to a very significant extent (3,37). Chan et al (36) reported that about 41 per cent of patients were negative responders to the cosyntropin stimulation test. However, about 75 per cent of these patients had basal cortisol in the supranormal range. Hence, this lack of rise following cosyntropin administration was attributed to the basal hyperstimulation of the gland. Matah and co-workers (38) reported that five per cent of patients showed a subnormal response, while 12.5 per cent of patients did not respond at all to cosyntropin administration. However, criteria used for defining the response were not mentioned in the study. Reversibility of changes in adrenal reserve following the administration of antituberculosis therapy has also been investigated. Ellis and Tayoub (3) repeated the ACTH stimulation test two weeks after starting treatment. They found that the proportion of negative responders dropped to 30 per cent from the figure of 55 per cent observed before treatment. Interestingly, all 12 patients who remained negative responders after two weeks of therapy were on rifampicin containing regimens. The authors concluded that though therapy does improve adrenal reserve, rifampicin possibly prevented a similar improvement when given as part of the antituberculosis treatment. Barnes et al (4) re-assessed adrenal function three to four weeks after starting antituberculosis treatment and concluded that therapy significantly improves adrenal function, as only one out of seven patients had a negative response to cosyntropin stimulation. However, unlike the observations reported by Ellis and Tayoub (3), rifampicin did not appear to have any adverse effect on adrenal function in this study (4) or in the study reported by Francois Venter et al (44). Chan and co-workers (36) also measured both basal and post-ACTH cortisol levels two months after antituberculosis treatment in 22 of their 39 patients. They found that basal cortisol concentrations were normal in all the cases studied. The incremental response to cosyntropin in these patients was significantly higher than the response at presentation. Analysis of three patients, who had developed hypotension after antituberculosis was started, revealed that serum cortisol was extremely high in all three patients [> 1000 nmol/l]. Post-mortem examination revealed normal adrenal glands in one patient and granulomas in the adrenal glands in two other patients.

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Tuberculosis Table 38.1: Summary of studies on adrenocortical reserve in tuberculosis

Study (reference)

No. of subjects, Type of TB

Parameters studied

Results

Comments

Basal cortisol

PostACTH cortisol

Diurnal variation

Others

Basal cortisol

Post-ACTH cortisol

Diurnal variation

Srivastava et al (35)

84, PTB

Y

NS

NS

–

Elevated in all patients

–

–

Cortisol levels reduced with increasing duration of symptoms. SS+ patients had higher serum cortisol

Ellis and Tayoub (3)

41, PTB

NS

Y

NS

–

–

55% patients had negative cosyntropin test

–

–

Barnes et al (4)

30, PTB 30, MTB 30, EPTB

Y

Y

NS

–

Normal 61% Elevated 39%

8% patients had negative cosyntropin test

–

–

Chan et al (36)

39, PTB

Y

Y

NS

–

Normal 82% Elevated 18%

41% patients had negative cosyntropin test

–

Basal cortisol significantly higher in patients who died. 11 of 16 patients with abnormal response had elevated basal cortisol

Sarma et al (37)

39, PTB

NS

Y

Y

DST

–

50% patients had negative cosyntropin test

Lost in patients with PTB

DST positive hence normal pituitary activity; primary adrenal insufficiency

Matah et al (38)

40, PTB

Y

Y

NS

Serum sodium

Elevated in all patients

17.5% patients had negative cosyntropin test

–

Hyponatraemia due to adrenal insufficiency or due to SIADH

York et al (39)

37, PTB

Y

NS

Y

–

Normal

–

Lost in patient – with active disease

Keven et al (40)

21, PTB 1, Pleural TB

Y

Y

NS

DST

Normal in 7 [32%], elevated in 14 [64%] and low in one patient

–

–

Insufficient suppression of plasma cortisol levels in 9 [41%] patients before treatment

Prasad et al (41)

30, PTB 33, DTB/MTB 34, DR-TB

Y

Y

NS

–

Low in patients

Compromised in 49.5% of patients

–

–

Kaplan et al (42)

18, HIV+, PTB 22, HIV–PTB 32, Control subjects

Y

Y

NS

T3, T4, TSH Serum sodium Plasma osmolality

Higher in patients

–

–

Mean cortisol after stimulation with 1 µg did not differ either in HIV+ and HIV–patients or the control. Primary hypoadrenalism was present in a single patient

Zargar et al (43)

28, PTB 12, EPTB 10, Control subjects

Y

Y

Y

-

Comparable between the patients and controls subjects

14 [35%] patients exhibited sub-optimal cortisol response

ACTH stimuAdrenocortical reserve lation revealed was inversely related to significant the radiological severity cortisol rise in and chronicity of PTB patients with active TB at 4 and 8 hours only, whereas in healthy controls, the cortisol rise was more prolonged and continued up to 24 hours

ACTH = adrenocorticotrophic hormone; PTB = pulmonary tuberculosis; MTB = miliary tuberculosis; EPTB = extra-pulmonary tuberculosis; DTB = disseminated tuberculosis; DR-TB = drug-resistant tuberculosis; TB = tuberculosis; HIV+ = human immunodeficiency virus-seropositive; HIV– = human immunodeficiency virus-seronegative; SS+ = sputum smear-positive; DST = dexamethasone suppression test; T3 = serum tri-iodothyronine; T4 = serum thyroxine; TSH = serum thyroid stimulating hormone; SIADH = syndrome of inappropriate antidiuretic hormone secretion; NS = not studied; Y = studied

Adrenocortical Reserve in Tuberculosis Sharma et al (45) prospectively studied the adrenal reserve and morphology in 105 human immunodeficiency virus [HIV] negative patients with various forms of TB [pulmonary TB in 72 and extra-pulmonary TB in 33] and 27 normal control subjects. Baseline standarddose ACTH stimulation test was done on all the subjects, before starting the treatment and all of them received standard antituberculosis treatment, depending on the type of disease and were followed up for a period of 30 months. Adrenocorticotrophic hormone stimulation test was performed at follow-up, every six months. Before antituberculosis treatment was started, ACTH stimulation test revealed that 52 of 105 patients [49.5%] were found to have compromised adrenal reserve. At six months, the percentage of responders had increased to 71 per cent with a gradual increasing trend noted thereafter. At 24 months, 31 of the 32 patients [97%] who were followed up demonstrated a normal response to ACTH stimulation. The percentage of responders was comparable in both pulmonary [21 of 22 patients; 95%] and extra-pulmonary TB [10 of 10 patients; 100%] groups at follow-up. The authors (45) suggested that nearly half of the patients with active TB have a subclinical adrenal insufficiency indicated by an impaired response to ACTH stimulation test. It is important to recognize this fact as this has clinical relevance in the acute stressful setting. However, with antituberculosis treatment, the adrenal insufficiency seems to reverse completely in a majority of the patients. Serum cortisol estimations over 24 hours reveal a normal diurnal variation with maximal values attained in the mornings and a normal nadir in the evenings (46). However, Sarma et al (37) and York et al (39), reported loss of this normal diurnal variation in all their patients with TB. No definite reason was advanced by these workers to explain this loss of diurnal rhythm. A possible explanation could be the basal hyperstimulation of the adrenal gland due to the stress of infection. But, basal cortisol was not elevated in any of these studies. An interesting observation made by Matah et al (38) was the presence of significant hyponatraemia in 27.5 per cent of the patients with pulmonary TB. The possible reasons could be, firstly due to adrenocortical insufficiency itself; and secondly, due to dilutional hyponatraemia occurring secondary to the syndrome of inappropriate secretion of antidiuretic hormone (47). Computed tomography [CT] can be used as an imaging modality to assess the adrenal gland morpho-

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logy due to its high spatial and density resolution which allows precise demonstration of normal [Figure 38.1] and abnormal [Figures 38.2, 38.3, 38.4A and 38.4B] glands. Calcification of the adrenal glands can also be identified much earlier on CT. Appearance of radiological abnormalities of the adrenal gland depends on the duration of TB. Initial involvement often leads to gland enlargement and as the disease progresses the gland size decreases and finally atrophy may occur (13,48). Kelestimur et al (49) on comparing the adrenal gland size measured on CT, have found a similar correlation between gland size and duration of the disease. A study from India (41) revealed that 14 of the 86 patients [16.3%] had adrenal gland enlargement on CT. Further, patients with enlarged glands had a longer duration of disease

Figure 38.1: CECT of the abdomen showing normal suprarenal glands [arrows]

Figure 38.2: CECT of the abdomen showing bilateral and diffuse enlargement of suprarenal glands [arrows]

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Tuberculosis as compared to those with normal glands. Majority of the patients with enlarged glands in this study had drugresistant TB. These patients remain sputum-positive for a long time thereby leading to a greater bacteriologic load providing greater opportunity for dissemination of disease. It was observed that patients with enlarged glands had lower basal, 30 and 60 minutes cortisol values than those with normal glands. These facts and the observation that 13 of the 14 patients [92.8%] had unilateral enlargement of the gland supports the hypothesis that gland enlargement is due to involvement of the gland by the TB process rather than due to stress induced hyperplasia.

Figure 38.3: CECT of the abdomen showing unilateral focal left adrenal gland enlargement [arrow]

Figure 38.4A: CECT of the abdomen showing enlargement of left suprarenal gland before treatment [arrow]

Figure 38.4B: CECT of the abdomen showing regression of suprarenal gland enlargement after one year of antituberculosis treatment [arrow]

Adrenocortical Reserve in Patients Co-infected with Human Immunodeficiency Virus and Tuberculosis Sparse literature is available regarding adrenocortical reserve in patients co-infected with HIV and TB. In a report from Kenya [n = 174] (50), 90 HIV-positive and 84 HIV-seronegative patients with active TB were assessed for adrenocortical insufficiency using the 30 minutes synacthen stimulation test. Overall, a sub-normal cortisol response was observed in 51 per cent patients with pulmonary TB and 56 per cent patients with extrapulmonary TB. There was no statistically significant difference in the prevalence of compromised adrenocortical reserve in HIV-seropositive and negative patients with active TB. In another study from Uganda (51), 21 of the 113 [19%] critically ill HIV-infected adults not receiving corticosteroids were found to have functional adrenal insufficiency [defined as morning total serum cortisol level of < 25 μg/dl]. Of the 46 patients with clinical suspicion of TB disease, eight [17%] had functional adrenal insufficiency. Five patients [24%] with functional adrenal insufficiency [n = 21] were being treated with rifampicin compared to four [4%] of those with normal adrenal function [n = 92] indicating that rifampicin use was associated with the occurrence of functional adrenal insufficiency. The authors (51) postulated Mycobacterium tuberculosis infection of the adrenal gland or induction of the cytochrome enzyme system which enhances the metabolism of cortisol as the likely explanations for this phenomenon. In conclusion, it is evident from the above studies that the exact status of adrenal reserve in patients with TB is far from clear. This difference in opinion in these studies is in part, due to the different patient groups selected,

Adrenocortical Reserve in Tuberculosis the differences in methodology, and different standards used for interpreting the results of adrenal stimulation tests. Several questions, such as the relationship between the adrenal reserve and the severity of the disease and the nutritional status of the patient; the influence of cellmediated immune response on the spread of the disease and hence on the status of adrenal reserve and morphology in patients with multidrug-resistant TB need to be addressed in future studies. REFERENCES 1. Kelestimur F. The endocrinology of adrenal tuberculosis: the effects of tuberculosis on the hypothalamo-pituitary-adrenal axis and adrenocortical function. J Endocrinol Invest 2004;27:380-6. 2. Melby JC, Spink WW. Comparative studies on adrenal cortical function and cortisol metabolism in healthy adults and in patients with shock due to infection. J Clin Invest 1958;37:1791-8. 3. Ellis ME, Tayoub F. Adrenal function in tuberculosis. Br J Dis Chest 1986;80:7-12. 4. Barnes DJ, Naraqi S, Temu P, Turtle JR. Adrenal function in patients with active tuberculosis. Thorax 1989;44:422-4. 5. Wilkins EG, Hnizdo E, Cope A. Addisonian crisis induced by treatment with rifampicin. Tubercle 1989;70:69-73. 6. Kyriazopoulou V, Parparousi O, Vagenakis AG. Rifampicininduced adrenal crisis in addisonian patients receiving corticosteroid replacement therapy. J Clin Endocrinol Metab 1984;59:1204-6. 7. Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003;361:188193. 8. Lovas K, Husebye ES. Addison’s disease. Lancet 2005;365: 2058-61. 9. Guttman PH. Addison’s disease: statistical analysis of 566 cases and a study of the pathology. Arch Pathol 1930;10:74285, 896-935. 10. Sanford JP, Favour CB. The interrelationships between Addison’s disease and active tuberculosis: a review of 125 cases of Addison’s disease. Ann Intern Med 1956;45:56-72. 11. Dunlop D. Eighty-six cases of Addison’s disease. Br Med J 1963;5362:887-91. 12. Nerup J. Addison’s disease - clinical studies. A report of 108 cases. Acta Endocrinol [Copenh] 1974;76:127-41. 13. Eason RJ, Croxson MS, Perry MC, Somerfield SD. Addison’s disease, adrenal autoantibodies and computerised adrenal tomography. N Z Med J 1982;95:569-73. 14. Soule S. Addison’s disease in Africa–a teaching hospital experience. Clin Endocrinol [Oxf] 1999;50:115-20. 15. Lam KY, Lo CY. A critical examination of adrenal tuberculosis and a 28-year autopsy experience of active tuberculosis. Clin Endocrinol [Oxf] 2001;54:633-9. 16. Kong MF, Jeffcoate W. Eighty-six cases of Addison’s disease. Clin Endocrinol [Oxf] 1994;41:757-61.

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17. Oelkers W, Diederich S, Bahr V. Diagnosis and therapy surveillance in Addison’s disease: rapid adrenocorticotropin [ACTH] test and measurement of plasma ACTH, renin activity, and aldosterone. J Clin Endocrinol Metab 1992;75:25964. 18. McMurry JF Jr, Long D, McClure R, Kotchen TA. Addison’s disease with adrenal enlargement on computed tomographic scanning. Report on two cases of tuberculosis and review of the literature. Am J Med 1984;77:365-8. 19. Jayakar DV, Condemi G, DeSoto-LaPaix F, Plawker M, Farag A, Ghosh BC. Adrenal tuberculosis. Eur J Surg 1998;164:975-8. 20. Kehlet H, Blichert-Toft M, Lindholm J, Rasmussen P. Short ACTH test in assessing hypothalamic-pituitary-adrenocortical function. Br Med J 1976;1:249-51. 21. Greig WR, Maxwell JD, Boyle JA, Lindsay RM, Browning MC. Criteria for distinguishing normal from subnormal adrenocortical function using the Synacthen test. Postgrad Med J 1969;45:307-13. 22. El-Shaboury AH. Effect of a synthetic corticotrophic polypeptide on adrenal function in hypersensitive asthmatics. Lancet 1965;17:298-301. 23. Speckart PF, Nicoloff JT, Bethune JE. Screening for adrenocortical insufficiency with cosyntropin [synthetic ACTH]. Arch Intern Med 1971;128:761-3. 24. Danowski TS, Hofmann K, Weigand FA, Sunder JH. Steroid responses to ACTH-like polypeptides. J Clin Endocrinol Metab 1968;28:1120-6. 25. Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, Adawi F, et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991;72:773-8. 26. Dokmetas HS, Colak R, Kelestimur F, Selcuklu A, Unluhizarci K, Bayram F. A comparison between the 1-microg adrenocorticotropin [ACTH] test, the short ACTH [250 microg] test, and the insulin tolerance test in the assessment of hypothalamo-pituitary-adrenal axis immediately after pituitary surgery. J Clin Endocrinol Metab 2000;85:3713-9. 27. Kelestimur F, Goktas Z, Gulmez I, Unluhizarci K, Bayram F, Ozesmi M, et al. Low dose [1 microg] adrenocorticotropin stimulation test in the evaluation of hypothalamo-pituitaryadrenal axis in patients with active pulmonary tuberculosis. J Endocrinol Invest 2000;23:235-9. 28. McAllister WA, Thompson PJ, Al-Habet SM, Rogers HJ. Rifampicin reduces effectiveness and bioavailability of prednisolone. Br Med J [Clin Res Ed] 1983;286:923-5. 29. Edwards OM, Courtenay-Evans RJ, Galley JM, Hunter J, Tait AD. Changes in cortisol metabolism following rifampicin therapy. Lancet 1974;2:548-51. 30. Elansary EH, Earis JE. Rifampicin and adrenal crisis. Br Med J [Clin Res Ed] 1983;286:1861-2. 31. Buffington GA, Dominguez JH, Piering WF, Hebert LA, Kauffman HM Jr, Lemann J Jr. Interaction of rifampin and glucocorticoids. Adverse effect on renal allograft function. JAMA 1976;236:1958-60. 32. Bajaj JS, Khardori R, Deo MG, Bansal DD. Adrenocortical function in experimental protein malnutrition. Metabolism 1979;28:594-8.

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Tuberculosis

33. Enwonwu CO, Stambaugh RV, Jacobson KL. Protein–energy deficiency in nonhuman primates: biochemical and morphological alterations. Am J Clin Nutr 1973;26:1287-302. 34. Alleyne GA, Young VH. Adrenal function in malnutrition. Lancet 1966;1:911-2. 35. Srivastava RML, Mukerji PK, Bhargava KP, Khanna BK. A study on plasma cortisol in pulmonary tuberculosis. Indian J Tuberc 1980;27:3-6. 36. Chan CH, Arnold M, Mak TW, Chan RC, Hoheisel GB, Chow CC, et al. Adrenocortical function and involvement in high risk cases of pulmonary tuberculosis. Tuber Lung Dis 1993;74:395-8. 37. Sarma GR, Immanuel C, Ramachandran G, Krishnamurthy PV, Kumaraswami V, Prabhakar R. Adrenocortical function in patients with pulmonary tuberculosis. Tubercle 1990;71:277-82. 38. Matah SC, Kesharwani GL, Srivastava GN, Singh SK, Agrawal JK. Adrenocortical insufficiency in smear positive pulmonary tuberculosis. Indian J Chest Dis Allied Sci 1992;34:133-6. 39. York EL, Enarson DA, Nobert EJ, Fanning FA, Sproule BJ. Adrenocortical function in patients investigated for active tuberculosis. Chest 1992;101:1338-41. 40. Keven K, Uysal AR, Erdogan G. Adrenal function during tuberculous infection and effects of antituberculosis treatment on endogenous and exogenous steroids. Int J Tuberc Lung Dis 1998;2:419-24. 41. Prasad GA, Sharma SK, Mohan A, Gupta N, Bajaj S, Saha PK, et al. Adrenocortical reserve and morphology in tuberculosis. Indian J Chest Dis Allied Sci 2000;42:83-93. 42. Kaplan FJ, Levitt NS, Soule SG. Primary hypoadrenalism assessed by the 1 microg ACTH test in hospitalized patients with active pulmonary tuberculosis. QJM 2000;93:603-9.

43. Zargar AH, Sofi FA, Akhtar MA, Salahuddin M, Masoodi SR, Laway BA. Adrenocortical reserve in patients with active tuberculosis. J Pak Med Assoc 2001;51:427-33. 44. Francois Venter WD, Panz VR, Feldman C, Joffe BI. Adrenocortical function in hospitalised patients with active pulmonary tuberculosis receiving a rifampicin-based regimen–a pilot study. S Afr Med J 2006;96:62-6. 45. Sharma SK, Tandan SM, Saha PK, Gupta N, Kochupillai N, Misra NK. Reversal of subclinical adrenal insufficiency through antituberculosis treatment in TB patients: a longitudinal follow up. Indian J Med Res 2005;122:127-31. 46. Orth DN, Kovacs WJ, DeBold CR. The adrenal cortex. In: Wilson JD, Foster DW, editors. Williams textbook of endocrinology. Eighth edition. Philadelphia: W.B. Saunders Company; 1992.p.508. 47. Shalhoub RJ, Antoniou LD. The mechanism of hyponatremia in pulmonary tuberculosis. Ann Intern Med 1969;70:943-62. 48. Sun ZH, Nomura K, Toraya S, Ujihara M, Horiba N, Suda T, et al. Clinical significance of adrenal computed tomography in Addison’s disease. Endocrinol Jpn 1992;39:563-9. 49. Kelestimur F, Unlu Y, Ozesmi M, Tolu I. A hormonal and radiological evaluation of adrenal gland in patients with acute or chronic pulmonary tuberculosis. Clin Endocrinol [Oxf] 1994;41:53-6. 50. Hawken MP, Ojoo JC, Morris JS, Kariuki EW, Githui WA, Juma ES, et al. No increased prevalence of adrenocortical insufficiency in human immunodeficiency virus-associated tuberculosis. Tuber Lung Dis 1996;77:444-8. 51. Meya DB, Katabira E, Otim M, Ronald A, Colebunders R, Njama D, et al. Functional adrenal insufficiency among critically ill patients with human immunodeficiency virus in a resource-limited setting. Afr Health Sci 2007;7:101-7.

Endocrine Implications of Tuberculosis

39

R Goswami, S Mishra, N Kochupillai

INTRODUCTION Being a systemic disease with a capacity for widespread dissemination, it is obvious that tuberculosis [TB] can affect various endocrine glands in the body. Moreover, antituberculosis drugs are known to induce cytochrome P-450 oxidase enzymes, thereby enhancing the catabolism of endogenous cortisol in the liver. In active pulmonary TB, endocrine abnormalities including sick euthyroid syndrome, hypogonadotropic hypogonadism and hypoadrenalism are common (1). In a similar manner, due to a variety of factors other endocrine glands may also be the target organs for lodgement and tissue invasion by Mycobacterium tuberculosis. The present chapter deals with the endocrine implications of TB. The reader is also referred to the chapter “Adrenocortical reserve in tuberculosis” [Chapter 38] for more details. TUBERCULOSIS AND HYPOTHALAMUSPITUITARY INVOLVEMENT Hypothalamus-pituitary involvement in TB may arise either from haematogenous spread or due to extension of the local lesions (2). Generally, TB of the adenohypophysis is observed in patients with a past history of TB meningitis (3). It may manifest as a space occupying lesion [tuberculoma] or as sellar or suprasellar calcification (4-9). Intrasellar tuberculoma may also present as apoplexy (10). The reported frequency of sellar tuberculomas is between 0.25 per cent and 4 per cent in western countries (11). Sellar tuberculomas usually present at younger age with female preponderance. The most common present-

ing complaint is headache followed by visual changes (12). These lesions may also lead to erosion of the sella (2). It is difficult to differentiate them from pituitary adenomas, but radiological findings like leptomeningeal enhancement, parenchymatous brain tuberculomas, intense enhancement of a lesion or a thickened pituitary stalk on contrast magnetic resonance imaging [MRI], suggest the diagnosis of a sellar tuberculoma (12-14). Though hypothalamic-pituitary dysfunction is common in patients with a history of TB who also have radiological abnormalities in hypothalamic region, endocrine dysfunction can occur even when there are no gross anatomical changes (9). Recently, MRI in these patients has revealed areas of abnormal enhancement in the suprasellar region possibly related to the granulomatous tissue at these sites (9). The long time interval between the occurrence of TB meningitis and the development of endocrine dysfunction suggests a chronic process of necrosis and scarring possibly due to devascularization of the hypothalamus or pituitary (8). Endocrine dysfunction related to pituitary or hypothalamic involvement can occur secondary to intracranial TB in several ways, the most common being growth hormone and gonadotrophin deficiency (5,1517). In a review of 13 adult cases of sellar tuberculoma, 86 per cent had suprasellar extension and 78.6 per cent had anterior pituitary dysfunction. Only a few cases of suprasellar tuberculoma have been reported in children and usual presentation includes both anterior and posterior pituitary involvement or compressive features (18). Though pituitary is the usual site of abnormality, hypothalamus may be the primary site in some. In the

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latter subset of patients, growth hormone response through insulin induced hypoglycaemia [acting through hypothalamus] is abnormal but response following growth hormone releasing hormone infusion is normal (15). Clinically, these abnormalities manifest as short stature or hypogonadism. The adverse effect of growth hormone deficiency on adult height is observed in patients who suffer from TB meningitis before completion of the growth spurt (17). It is important for the clinicians caring for children with TB meningitis to be aware of this preventable cause of short stature. The diagnosis of hypopituitarism due to TB should be considered in patients with sellar or suprasellar calcification. However, sellar and suprasellar calcification following meningitis may not be accompanied by endocrine disturbances (19). Suprasellar calcification in a young male with diabetes insipidus and anterior pituitary hormone deficiency may also be seen in craniopharyngioma and should be considered in the differential diagnosis of TB hypopituitarism (20). Less common endocrine abnormalities seen with TB are deficiency of the corticotrophic and thyrotrophin hormones manifesting as secondary adrenocortical insufficiency and hypothyroidism (5,15). Posterior pituitary deficiency can also occur and manifest as diabetes insipidus (5,21-23). Though hypopituitarism is the most common abnormality with hypothalamic-pituitary involvement due to TB, patients may also present with hormonal overactivity presenting as central precocious puberty (24-26) or hyperprolactinaemia (5,15). In fact, Desai et al (26) reported preceding history of TB meningitis in as many as 31 per cent of girls and 27 per cent of boys with centrally mediated precocious puberty in India (26). Hyperprolactinaemia occurs as a result of stalk compression due to tuberculoma and release of anterior pituitary from the inhibiting effect of dopamine (5,15). ALTERED WATER AND ELECTROLYTE METABOLISM IN TUBERCULOSIS The syndrome of hyponatraemia and renal loss of sodium in patients with advanced pulmonary TB was first recognized by Winkler and Crankshaw in 1930 (27). Subsequently, Westwater et al (28) detected hyponatraemia in 48 per cent of patients with pulmonary TB. The possible mechanism responsible for this syndrome was

studied by Sims and associates (29) and they found that primary renal or adrenal abnormality did not explain hyponatraemia in patients with pulmonary TB. Schwartz et al (30) defined the syndrome of inappropriate antidiuretic hormone secretion [SIADH] as incomplete suppression of peripheral arginine vasopressin [AVP] secretion in the presence of subnormal plasma osmolality with no volume depletion. Weiss and Katz (31) first suggested that hyponatraemia of pulmonary TB fulfilled these criteria. The syndrome is usually accompanied by hyponatraemia, elevated urine osmolality and urinary sodium concentration. Since then several cases of hyponatraemia associated with pulmonary TB have been described (32,33). This syndrome is also observed in patients with extra-pulmonary TB, such as TB meningitis (34-36), TB epididymoorchitis (37) and miliary TB (38). The source of increased vasopressin hormone and defects in vasopressin action in these patients are not clear. Vorherr et al (39) could isolate bioassayable hormone from lung tissue of a patient with fatal pulmonary TB. He concluded that increased AVP in the lung tissue was due to adsorption of the hormone produced from the posterior pituitary (39). There is only one study where AVP has been measured by radioimmunoassay and the nature of diluting defect systematically studied by water load test (32). Hill et al (32) studied 28 patients with pulmonary TB and hyponatraemia, [mean serum sodium level 126 ± 3 mmol/l] and reported measurable levels of AVP at a time when it should have been undetectable by virtue of reduced plasma tonicity. They postulated that hyponatraemia of TB may be regarded as a form of SIADH (32). Since vasopressin was partially suppressed by a further decrement in tonicity [following water load test], the source of inappropriate AVP was likely to be the hypothalamic neurohypophyseal osmoregulatory centre. This study excluded release of hormone from ectopic sites because AVP hormone could be suppressed by water load test (39,40). A variable water load response has also been observed in these hyponatraemic patients (32,41). Majority of these hyponatraemic patients demonstrate impaired water excretion. However, a subset of them also showed normal response to water load and can be considered to have ‘reset osmostat’ (32,41). Thus, a disturbed or downset osmoregulatory mechanism occurring as a remote effect of active TB is the mechanism for hyponatraemia and water excretion abnormalities observed in patients with TB. The

Endocrine Implications of Tuberculosis 563 stimulus for abnormally increased AVP levels is not precisely known but could be the circulating mediators of the acute phase reaction, fever or inflammatory cytokines acting on posterior pituitary (32,42,43). The reader is referred to the chapter “Disseminated and miliary tuberculosis” [Chapter 34] for more details regarding the significance of hyponatraemia in patients with miliary TB. The hyponatraemia of TB is generally mild, asymptomatic and self-limiting. Water restriction, the conventional therapy for SIADH, has been effective in reversing the hyponatraemia in these patients (30,32,44) but is usually reserved for patients with symptomatic and/or severe hyponatraemia [serum sodium < 120 to 125 mmol/l]. Occurrence of this syndrome in patients with TB meningitis carries a poor prognosis (34) and herein lies the importance of its prompt recognition and management. TUBERCULOSIS AND THE THYROID GLAND In 1862, Lebert (45) first described a case of TB of the thyroid gland in a patient with disseminated TB (46). In 1878, Chiari (47) described seven cases of microscopic involvement of thyroid in 1000 autopsies in patients who died from disseminated TB. Bruns (48) in 1893, first described a case of TB of the thyroid gland even when there was no clinical evidence of pulmonary TB. With increasing prevalence of HIV, concomitant infection of thyroid TB is being reported (49). The true incidence of TB thyroiditis, however, is difficult to determine because clinical suspicion is rarely made by the physician. On the other hand, the TB involvement of the thyroid is not uncommon [2% to 7%] in autopsy studies (50,51). Prevalence of the disease was first recognized when Coller and Huggins (52) in 1926 found evidence of TB in 5 of 1 200 histopathological specimens of goitre operated between 1921 to 1926. Rankin and Graham (53) studied a large series of 20 758 partial thyroidectomy specimens from the Mayo Clinic between 1920 and 1931 and diagnosed TB in 21 cases (53). A similar incidence was reported by Levitt (54) who found only two cases of TB among 2 114 consecutive thyroidectomy specimens (54). In a study from India, Das et al (55) reported the prevalence of TB to be 0.6 per cent among 1 283 thyroid lesions subjected to aspiration cytology. The mode of spread of TB infection to the thyroid gland is not known. Besides disseminated TB and cervical lymphadenopathy, thyroid involvement

can also occur via congenital transmission (56,57). The newborns of mothers with untreated TB have been reported to have thyroid TB at birth (56,57). Miliary involvement of the thyroid gland is more common (58). Less commonly, focal TB of the thyroid may occur, presenting as a localized swelling (58), cold abscess appearing superficially (59), acute abscess (60) or as diffuse thyroid enlargement (44,47). Fibrosis and adherence to adjacent structures may occasionally give rise to pressure symptoms (61) with dyspnoea or recurrent laryngeal nerve palsy (62). Presence of cervical lymphadenopathy and pressure symptoms have often resulted in erroneous diagnosis of malignancy in patients with TB goitre (59). Chronic fibrosis of the thyroid has been described in association with TB (58). However, the aetiological relationship of TB with sclerosing thyroiditis remains doubtful. Clinically patients with thyroid TB may present with features of hyperthyroidism and acute thyroiditis (50,63-65). Diagnosis of thyroid TB is not difficult to make if the possibility is considered. Seed (66) in 1939 proposed three prerequisites for making this diagnosis. These include: [i] demonstration of Mycobacterium tuberculosis within the thyroid gland; [ii] a necrotic gland or TB abscess having epithelioid cell granulomas with peripheral lymphocyte cuffing, Langhans’ giant cells and central caseation necrosis; and [iii] demonstration of a definite focus of TB outside thyroid. Presently, it is believed that histological and bacteriological confirmation is adequate to make a diagnosis and fulfillment of the third criterion is not essential (55). Fine needle aspiration cytology demonstrates abundance of lymphocytes and is a cost effective approach for the diagnosis of thyroid TB. However, the stained smear may be negative for acid-fast bacilli [AFB], and in such situations, detection of Mycobacterium tuberculosis by polymerase chain reaction may be helpful (67,68). Microscopic features of the disease resemble sarcoidosis and subacute [giant cell] thyroiditis. The granulomatous inflammation in subacute thyroiditis is characterized by scattered disorganized follicles lined with necrotic epithelium and infiltration by neutrophils, macrophages and multinucleate cells. However, unlike TB, subacute thyroiditis is not associated with caseation necrosis (69). Mycobacterium tuberculosis does not grow in the centre of caseating lesions because of its high oxygen requirement. However, thyroid gland is an exception because of its rich vascularity (69). Computed

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tomography of the thyroid may reveal peripheral enhancing low density abscess and ultrasound demonstrates heterogeneous hypoechoic mass with regional lymphadenopathy (70). The treatment of TB with para-aminosalicylic acid and ethionamide may produce goitre (71). Both drugs have actions similar to propylthiouracil and complete resolution of the goitre occurs when these drugs are withdrawn (72). A few patients with thyroid TB also have dysfunction of the thyroid gland. Mosiman (73) observed nine such patients with seven of them having thyrotoxicosis on clinical examination. Kapoor et al (74) described a patient of hyperthyroidism [high 131I uptake with uniform tracer distribution] with histopathological specimen of the thyroid showing evidence of TB. However, such occurrence of thyrotoxicosis does not prove the cause and effect relationship. Hypothyroidism as a result of progressive thyroid destruction is expected and has been more commonly observed (55). Alterations in circulating thyroid hormones levels are also frequent in chronic non-thyroid illnesses (75,76). Serum thyroid hormones levels in patients with TB may show low or normal serum total T4, low serum total T3, normal thyroid stimulating hormone [TSH] and increase in reverse T3, a profile consistent with sick euthyroid syndrome. Chow et al (75) reported 63 per cent prevalence of this syndrome in pulmonary TB. They also observed that patients with severe illness had lower free T3 values and higher mortality. HYPERCALCAEMIA AND TUBERCULOSIS Hypercalcaemia has been described in up to 50 per cent of adult patients with TB (77-80). Differences in the dietary intake of calcium and vitamin D account for the wide variation in the prevalence of this disorder (77,78). In a hospital-based study from Hong Kong, Shek et al (80) observed that TB constituted six per cent of all cases of hypercalcaemia and was the second most common cause of hypercalcaemia after malignancy. Hypercalcaemia has also been reported among children with TB though exact prevalence is not known (81-83). Abnormal vitamin D metabolism has been implicated in the pathogenesis of hypercalcaemia in TB. A higher mean serum 1,25[OH]2D3 has been reported in patients with TB compared with control subjects (83-86) and the

raised level has also been observed in those with normal serum calcium (85). The presence of hypercalcaemia has been observed even in anephric patients with TB (87). The finding of increased concentration of 1,25[OH]2D3 in patients with end-stage renal failure and TB is in marked contrast to that observed in other patients with end-stage renal failure with no TB (87). Lung is the extrarenal site of 1,25[OH]2D3 synthesis as is supported by detection of high concentration of this hormone in the pleural fluid of patients with TB pleuritis (88). In vitro studies have shown that alveolar macrophages and lymphocytes are important source of 1,25[OH] 2 D 3 production in patients with TB (89-91). The hormone production does not seem to be regulated by the factors that normally modulate renal 1-α-hydroxylase activity as there is hypercalcaemia and increased circulating 1,25[OH]2D3 despite suppressed serum parathyroid hormone and high normal serum phosphate (77,92). Decline in serum parathyroid hormone and increase in serum calcium and phosphorus concentrations are the physiologic factors that reduce vitamin D synthesis in healthy subjects. Studies on culture of alveolar macrophages recovered from patients with sarcoidosis have suggested that some lymphokines produced locally or systemically may be the main factors regulating 1-αhydroxylase activity in granulomatous tissue (93). The production of 1,25[OH]2D3 by the granulomatous tissue may also play an important role in the regulation of the antituberculosis immune response (94,95). Indeed it has been shown in patients with active pulmonary TB that CD4+ T-lymphocytes recovered from bronchoalveolar lavage fluid express 1,25[OH]2D3 (96,97). Production of ectopic 1,25[OH]2D3 within granulomatous tissue could be regulated by antimycobacterial products, independent of parathyroid hormone and 25[OH]2D 3. Increased 1,25[OH]2D3 can exert its effect locally and enhance antimycobacterial activity of human monocytes and macrophages. Further experiments on cultured macrophage (97) and supplementation studies on TB patients have shown that the efficacy of pyrazinamide is enhanced by vitamin D and its active metabolites. Thus, hypercalcaemia observed in TB and other granulomatous disorders may be the result of an antigen driven host defense. Asymptomatic hypercalcaemia may be present in up to one-third of newly diagnosed patients with TB. Presence of hypercalcaemia has also been reported in extra-pulmonary TB as, e.g., abdominal and hepatic

Endocrine Implications of Tuberculosis 565 (98-100). Infection with nontuberculous mycobacteria such as Mycobacterium avium-intracellulare complex in acquired immunodeficiency syndrome [AIDS] is also associated with hypercalcaemia (101,102). However, hypercalcaemia may be masked at the time of initial presentation because of low serum albumin levels and manifests only when serum albumin levels become normal with antituberculosis treatment (79). Besides hypercalcaemia, hypercalciuria has also been observed in some patients with TB. Calcium absorption studies have shown that this hypercalciuria is of absorptive nature, possibly related to increased serum calcitriol levels (103-105). Patients with TB [and sarcoidosis] may be abnormally sensitive to vitamin D supplementation (79). If TB occurs in a patient with renal failure, serum calcium levels may increase and vitamin D supplementation may have to be withdrawn (87). Despite the apparent similarity with the pathogenesis of hypercalcaemia and hypercalciuria in sarcoidosis, there are important differences in the presentation, clinical course and prognosis of abnormal calcium metabolism in these two disorders. In sarcoidosis, hypercalcaemia frequently occurs during the summer months following exposure to sunlight and patients are often hypercalcaemic at the time of presentation. Further, the hypercalcaemia and hypercalciuria are often protracted and may lead to lithiasis, nephrocalcinosis, urinary tract infection, chronic renal failure and even death. In contrast, hypercalcaemia associated with TB is usually mild and asymptomatic (105), occurs after several months of antituberculosis treatment (106) and generally carries a good prognosis (107). In both the diseases, hypercalcaemia is corrected by the administration of glucocorticoids (108). Ketoconazole administration inhibits cytochrome P-450 dependent 1-α-hydroxylase and reduces serum 1,25[OH]2D3 in healthy subjects (109). Administration of this drug for hypercalcaemia in patients with TB resulted in normalization of serum calcium levels and decline of 1,25[OH]2D3 levels within 48 hours (110). The problem of hypercalcaemia in TB and its exacerbation with antituberculosis drugs may not be common in India because of the wide prevalence of vitamin D deficiency in India (111). Antituberculosis drugs are known to affect calcium and phosphorus metabolism (112-118). Both rifampicin and isoniazid have been shown to decrease serum levels of 25[OH]D 3 and

1,25[OH]2D3 (91-98) and serum levels of parathyroid hormone may rise by 36 per cent in response to hypocalcaemia induced by isoniazid therapy (111). Addition of rifampicin increases stress on calcium metabolism and parathyroid hormone levels may further rise by 57 per cent (112). Mechanism by which these drugs produce their effects are different. Rifampicin acts through hepatic enzyme induction and conversion of 25[OH]D3 to an inactive metabolite (111). Isoniazid induces inhibition of 1-α-hydroxylation and decreases calcitriol synthesis (111). In developing countries antituberculosis treatment may trigger osteomalacia (98). This may be related to preexisting vitamin D deficiency in these patients because it is not observed in places like Hong Kong where vitamin D status is normal (119). VITAMIN D DEFICIENCY AND TUBERCULOSIS A role of vitamin D in TB has been speculated for a long time. Cod liver oil was first advocated for the treatment of TB in 1770 and was widely used till the nineteenth century (120-122). Many workers tried calciferol in the late 1940s and rationalized this treatment by suggesting its role in the calcification of TB lesions. It was believed to be effective in the treatment of skin TB (121,122). It was also claimed that in both guinea pigs (123) and humans (124), severe late disease would be fatal if treated with tuberculostatic drugs alone and could be cured if calciferol was also added to the treatment. With the advent of effective antituberculosis drugs in the mid 1950s, enthusiasm for treating TB with vitamin D subsided. However, it formed the basis of subsequent investigations linking vitamin D deficiency in Asian Indians to their susceptibility to develop pulmonary TB (84,114,125-129). Davies et al (114) compared 25[OH]D3 levels in untreated TB patients with healthy control subjects and found significantly lowered levels in patients with TB. In a similar study, Grange et al (129) showed that patients with higher 25[OH]D3 levels had less extensive radiographic disease. In an another retrospective study, foreign-born persons in London with TB were found to have significantly lower level of 25[OH]2D3 (130). Recently, vitamin D deficiency and single nucleotide polymorphisms in the vitamin D receptor [VDR] gene have been shown to be associated with post-primary pulmonary TB in Asian Gujarati community living in London (131). There was high prevalence of 25[OH]D3

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deficiency among this community with lowest serum concentration found in patients with active disease. Undetectable 25[OH]2D3 levels were associated with a 10-fold increased risk of TB. This study (131) further revealed the synergistic association between the presence of T-allele related to TaqI single nucleotide polymorphism [SNP] of the VDR gene and 25[OH]D3 deficiency. The presence of f-allele related to FokI SNP of the VDR gene was also observed to be frequent in patients with extrapulmonary disease (131). There are variable reports related to VDR expression and SNP of common VDR polymorphisms, i.e., FokI, BsmI and TaqI (132,133). In a case-control study, Babb et al (134) did not find an association between VDR genotype and TB, however, the time taken to convert to sputum negativity while on antituberculosis treatment was independently predicted by the VDR genotype (134). Till date no study has assessed expression of VDR in pulmonary macrophages and its association with pulmonary TB. Therefore, the exact mechanism linking the SNPs of VDR with TB, is not known. It has, therefore, been postulated that vitamin D plays a protective role in TB by reducing the incidence of infection developing into overt disease and later by retarding its progression. Douglas et al (135) have provided further evidence in support of vitamin D deficiency and susceptibility to TB. They reported a striking seasonal variation of TB incidence, with peak after the summer and nadir in the spring; unlike that observed in other respiratory diseases. They suggested seasonal changes in vitamin D levels as the cause for the paradoxical reversed seasonality of TB (135). In the post-winter period, low levels of vitamin D may result in reactivation of dormant mycobacteria (136,137). Cellular basis for vitamin D deficiency and susceptibility to TB has been explained by an effect of vitamin D deficiency on cell-mediated immunity (136-137). Monocytes have been shown to have receptors for 1,25[OH] 2D 3. Rook et al (136) have shown that incubation of macrophages with physiological concentration [10 –9 M] of 1,25[OH] 2 D 3 results in inhibition of intracellular growth of Mycobacterium tuberculosis which is in addition to the effect of interferon-γ. Mycobacterial killing is enhanced by 1,25[OH]2D3 by an increased nitric oxide production (138). Mice deficient in nitric oxide synthase 2 and vitamin D had more severe form of pulmonary lesion (138).

DIABETES MELLITUS AND TUBERCULOSIS Several retrospective (139,140) and prospective (141,142) studies have highlighted that patients with diabetes mellitus are at higher risk for the development of TB. In a retrospective study involving 1529 patients with diabetes mellitus, the risk of acquiring TB was found to be 4.8 per cent compared to 0.8 per cent for the general population (139). The risk was highest [24%] in patients with Type I diabetes mellitus [38 times more compared to the general population under 40 years of age] (139). Lester (141) found TB to be the most common complicating illness [16.5%] in Ethiopian patients with Type I diabetes mellitus. In India, Patel (140) found TB to be most common complicating illness [5.9%] in a large cohort of 8 793 patients with diabetes mellitus. Similar findings have been reported by Swai et al (142) who prospectively followed 1250 African patients with diabetes mellitus for seven years. Seventy of them [5.4%] developed pulmonary TB and 0.2 per cent developed spinal TB. In 25.7 per cent, TB was diagnosed prior to the onset of diabetes mellitus and in 45.7 per cent diagnosis was made subsequently (142). In 20.6 per cent, TB and diabetes mellitus were diagnosed simultaneously. The prevalence of TB was greater in the young, in those with a low body mass index [BMI], in insulin dependent diabetes mellitus patients compared to those with noninsulin dependent diabetes mellitus [9% vs 2.7%] and in those with poorly controlled diabetes mellitus (142). Mortality rate in these 70 patients was 24.3 per cent. In another study (143) in 702 patients with diabetes mellitus, the morbidity due to pulmonary TB was found to be 9.4 times higher as compared to the general population. Recently, diabetes mellitus has been found to be associated with a progressive shift of male predominance in pulmonary TB (144). Pulmonary TB has been reported to be a common complication among diabetic patients from Africa (145). Diabetes mellitus is the most common co-morbidity in pulmonary TB followed by malignancy and is associated with a higher probability of cavitary nodules (146). Though the relative risk for developing pulmonary TB disease is 3.5 times higher in patients with diabetes mellitus than in the matched control subjects (147), rate of infection with Mycobacterium tuberculosis is not different. Similar prevalence of tuberculin skin test reactivity has been observed in patients with diabetes mellitus and normal subjects (148). The sputum positivity

Endocrine Implications of Tuberculosis 567 rate in patients with diabetes mellitus and co-existent TB has been variable in comparison to subjects without diabetes mellitus with pulmonary TB. Sputum AFB positivity has been variably reported to be relatively higher (148) to less than usual (149) in subjects with diabetes mellitus. Recently, the impact of diabetes mellitus as a risk factor for incident pulmonary TB cases was estimated using India as an example (150). Diabetes mellitus accounted for 14.8 per cent of pulmonary TB and 20.2 per cent sputum smear-positive TB cases. The incidence of smear-positive cases was about 15 per cent higher in urban as compared to rural areas (150). These observations suggest that diabetes mellitus significantly contributes to the burden of incident TB cases in India and the association is particularly strong for the infectious form of TB. These findings are important for planning TB control activities as future projections indicate that the burden of diabetes mellitus in India is likely to increase in coming years (150). Clinical symptoms and presentation of pulmonary TB are similar in patients with and without diabetes mellitus (151). Pulmonary TB occurs predominantly in lung apices. It has been suggested that in patients with diabetes mellitus, TB occurs predominantly in the lower lobes with frequent cavitary lesions (151). Lower lung field TB was found to be significantly associated with female gender and, in patients older than 40 years of age (152). However, in a recent case-control study, distribution of lesions including cavitary disease was found to be similar in chest radiographs of TB patients with or without diabetes mellitus (153). The reader is referred to the chapter “Lower lung field tuberculosis” [Chapter 15] for more details. The cause of an increased susceptibility of diabetic patients to develop TB is not known. In a recent study analysing the association between human leucocyte antigen-[HLA-] DRB[1], DQB[1] gene and pulmonary TB complicated with diabetes mellitus, the presence of DRB[1]*09 allele was found to increase the susceptibility towards pulmonary TB, while DQB[1]*05 was observed to be protective for TB in patients with diabetes mellitus (154). An increased susceptibility of patients with diabetes mellitus to develop TB could be due to neutrophilic dysfunction and impaired cytokines production (155). Interferon-α [IFN-α] production capacity of white blood cell culture has been found to be reduced in patients with

diabetes mellitus as well as TB patients (155). Tsukaguchi et al (156) have reported significantly lowered production of interleukin-1β [IL-1β] and tumour necrosis factor-α [TNF-α] by the peripheral blood monocytes in patients with TB and co-existent diabetes mellitus compared to patients with TB who do not suffer from diabetes mellitus. The production of IL-1β and TNF-α was significantly lower in patients with poor glycaemic control (156). An increased susceptibility to TB could also be due to thickened alveolar epithelium and pulmonary basal lamina, reduced pulmonary diffusion capacity, lung volumes and elastic recoil in patients with diabetes mellitus. Pathogenesis of these changes is currently thought to be due to non-enzymatic glycosylation of tissue proteins inducing an alteration in connective tissue in diabetes mellitus (157). Further, diabetic autonomic neuropathy also leads to abnormal basal airway tone due to an alteration in vagal pathways and, thus, causes a reduced bronchial reactivity and bronchodilation (157). The side-effects of modern antituberculosis treatment do not differ in patients with and without diabetes mellitus (158) except peripheral neuropathy which is much more common in patients with diabetes mellitus (128). Insulin requirements may also occasionally increase in patients with diabetes mellitus receiving rifampicin (159). Bacteriological conversion rates have been found to be similar for TB patients with and without diabetes mellitus (160). The degree of control of diabetes mellitus does not influence this conversion rate. Relapse rates after short-course antituberculosis treatment have been found to be similar for TB patients [10%] with and without diabetes mellitus and relapse occurred at a similar time interval [6 to 30 months] in both the groups (160). However, most of the TB patients without diabetes mellitus relapsed with sensitive strains and a good response was observed on re-treatment while patients with diabetes mellitus relapsed more often with resistant strains (160). Bashar et al (161) found significant increase in multidrug-resistant TB in patients with diabetes mellitus [36% vs. 10%] compared to individuals without diabetes mellitus. Kameda et al (160) found no relationship between degree of glycaemic control and relapse rate. However, a significant negative correlation was observed between the glycaemic control and the relapse rate by Kado et al (162). Thus, TB patients with diabetes mellitus seem to

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have a response rate and long-term relapse rate similar to those without diabetes mellitus. However, they have a poor prognosis once the relapse occurs. TUBERCULOSIS AND DIABETES MELLITUS Though the evidence that diabetic patients are at increased risk of developing TB is well-known, the converse relationship, i.e., the patients with TB have a higher prevalence of diabetes was not known till 1950s (163,164). When oral glucose tolerance test was used for diagnosis, as in the study reported by Nichols in 1957 (163), a high prevalence of diabetes was observed in patients with TB. Since then, several studies have shown high prevalence of impaired glucose tolerance test in patients with TB (165-169) with rates varying from 1.9 to 41 per cent. Comparison between these studies is difficult due to different criteria used for the diagnosis of diabetes mellitus. In 1985, the World Health Organization proposed criteria for the diagnosis of diabetes mellitus and glucose tolerance test which gained wide acceptance (170). Adopting these criteria, Mugusi et al (171) investigated the prevalence of glucose tolerance abnormalities in 506 Tanzanian patients with active TB. He reported a crude prevalence rate of four per cent for diabetes mellitus in these patients, which is four times higher compared to that for the general population [0.9%]. Impaired glucose tolerance was observed in additional 16.2 per cent of patients, a prevalence which was twice the rate observed in general population [8.8%]. In another study Jawad et al (172) reported glucose intolerance in as many as 49 per cent of the patients with active TB [impaired glucose tolerance in 29% and diabetes mellitus in 20%]. After antituberculosis treatment, 50 per cent of them had normalization of glucose intolerance. Some authors have reported an association between severity of TB and abnormal glucose tolerance (171). However, no association has been found with age, family history of TB, ethnicity or duration of treatment (163,165). A number of postulations have been made to explain the increased prevalence of diabetes mellitus in TB. Nichols (163) suggested that whenever two diseases are associated, a reciprocal relationship is expected. Others have suggested that occult glucose intolerance predisposes to TB infection (173). Most TB patients in developing countries have malnutrition and low (174). Malnutrition has been postulated as a modulatory factor

in the pathogenesis of diabetes mellitus (174-176). Roychowdhury and Sen (169) have suggested TB of the pancreas to be a possible cause of glucose intolerance. However, pancreatic involvement is rare in TB. Another suggested possibility is stress induced diabetes mellitus which can occur in major illnesses like TB (171). The evidence that mycobacteria are linked to diabetes mellitus has been increasing rapidly. The pancreatic islet amyloid deposits have been observed in patients with systemic TB and undergo resolution following rifampicin treatment. Transitory changes in carbohydrate metabolism in patients with TB may lead to insulin deficiency with persistent hyperglycaemia (177). Abnormalities of glucose tolerance in TB improve following commencement of antituberculosis treatment. However, some patients with rifampicin induced early phase hyperglycaemia have been reported (159). Augmented intestinal absorption of glucose has been postulated to be the cause of this abnormality as the intravenous glucose tolerance is normal in these patients (159). The widespread involvement of endocrine glands in clinical TB is an important consideration to be kept in mind by the physicians managing TB. Further studies are required to conclusively explore the reported predisposition of certain endocrine disorders, such as vitamin D deficiency to TB and causes of increased prevalence of diabetes mellitus in TB. REFERENCES 1. Post FA, Soule SG, Willcox PA, Levitt NS. The spectrum of endocrine dysfunction in active pulmonary tuberculosis. Clin Endocrinol [Oxf] 1994;40:367-71. 2. Berger SA, Edberg SC, David G. Infectious disease in the sella turcica. Rev Infect Dis 1986;8:745-55. 3. Mohasseb G, Nasr B, Lahoud S, Halaby G. Hypophyseal tuberculosis. A case report. J Neurochirurgie 1983;29:16770. 4. Taparia SC, Tyagi G, Singh AK, Gondal R, Prakash B. Sellar tuberculoma. J Neurol Neurosurg Psychiatry 1992;55:629. 5. Tomono N, Mori M, Kikuchi N, Imagawa, Katakura S, Aihara Y, et al. A case of tuberculous meningitis followed by tuberculoma with panhypopituitarism. Kansenshogaku Zasshi 1995;69:1402-7. 6. Brooks MH, Dumlao JS, Bronsky D, Waldstein SS. Hypophysial tuberculoma with hypopituitarism. Am J Med 1973;54:777-81. 7. Esposito V, Fraioli B, Ferrante L, Palma L. Intrasellar tuberculoma: case report. Neurosurgery 1987;21:721-3.

Endocrine Implications of Tuberculosis 569 8. Sherman BM, Di Chiro G. Postmeningitic selective hypopituitarism with suprasellar calcification. Arch Intern Med 1971;128:600-4. 9. Asherson RA, Jackson WP, Lewis B. Abnormalities of development associated with hypothalamic calcifications after tuberculous meningitis. BMJ 1965;2:839-43. 10. Arunkumar MJ, Rajshekhar V. Intrasellar tuberculoma presenting as pituitary apoplexy. Neurol India 2001;49:40710. 11. von Kummer R, Storch B, Rauch M, Krause KH. A case of multiple intracranial tuberculomas followed by serial computerized tomography. Nervenarzt 1981;52:344-7. 12. Sharma MC, Arora R, Mahapatra AK, Sarat Chandra P, Gaikwad SB, Sarkar C. Intrasellar tuberculoma–an enigmatic pituitary infection: a series of 18 cases. Clin Neurol Neurosurg 2000;102:72-7. 13. Desai KI, Nadkarni TD, Goel A. Tuberculomas of the hypophysis cerebri: report of five cases. J Clin Neurosci 2003;10:562-6. 14. Harzallah L, Migaw H, Harzallah F, Kraiem CH. Imaging features of intrasellar tuberculoma: two cases. Ann Endocrinol [Paris] 2004;65:209-12. 15. Lam KS, Sham MM, Tam SC, Ng MM, Ma HT. Hypopituitarism after tuberculous meningitis in childhood. Ann Intern Med 1993;118:701-6. 16. Bartsocas CS, Pantelakis SN. Human growth hormone therapy in hypopituitarism due to tuberculous meningitis. Acta Paediatr Scand 1973;62:304-6. 17. Lanigan CJ, Buckley MP. Adult panhypopituitarism with normal stature following tuberculous meningitis: a case report. Ir Med J 1983;76:353-4. 18. Jain R, Kumar R. Suprasellar tuberculoma presenting with diabetes insipidus and hypothyroidism–a case report. Neurol India 2001;49:314-6. 19. Haslam RH, Winternitz WW, Howieson J. Selective hypopituitarism following tubercular meningitis. Am J Dis Child 1969;118:903-8. 20. Daniels DL, Williams AL, Thornton RS, Meyer GA, Cusick JF, Haughton VM. Differential diagnosis of intrasellar tumors by computed tomography. Radiology 1981;141:697-701. 21. Fruchtman SM, Banerji MA. Tuberculous meningitis; diagnostic problem of visual loss and diabetes insipidus. N Y State Med J 1980;5:963-5. 22. Lorber J. Diabetes insipidus following tubercular meningitis. Arch Dis Child 1958;33:315-9. 23. Shenoi A, Deshpande SA, Marwaha RK. Diabetes insipidus and growth hormone deficiency following tubercular meninigitis. Indian Pediatr 1990;27:624-6. 24. Wasz-Hockert O, Donner M. A follow up of 103 children recovered from tuberculous meningitis. Acta Pediatr 1962;51[Suppl141]:26-33. 25. Illingworth RS. Sexual precocity following recovery from tuberculous meningits with hydrocephalus. Calcifying intracranial tuberculoma. Cerebral cyst. Optic atrophy with good vision. Proc R Soc Med 1951;44:726-8.

26. Desai M, Colaco MP, Choksi CS, Ambadkar MC, Vaz FE, Gupte C. Isosexual precocity: the clinical and etiologic profile. Indian Pediatr 1993;30:607-23. 27. Winkler AW, Crankshaw OF. Chloride depletion in conditions other than Addison’s disease. J Clin Invest 1938;17:1-6. 28. Westwater JO, Stiven D, Garry RC. A note on the serum sodium level in patients suffering from tuberculosis. Clin Sci 1939;4:73-7. 29. Sims EAH, Welt LG, Orloff J, Needham JW. Asymptomatic hyponatraemia in pulmonary tuberculosis. J Clin Invest 1950;29:1545-57. 30. Schwartz WB, Bennett W, Curelop S. A syndrome of renal sodium loss and hyponatraemia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 1957;23:529-42. 31. Weiss H, Katz S. Hyponatraemia resulting from apparently inappropriate secretion of antidiuretic hormone in patients with pulmonary tuberculosis. Am Rev Respir Dis 1965;92:60916. 32. Hill AR, Uribarri J, Mann J, Berl T. Altered water metabolism in tuberculosis: role of vasopressin. Am J Med 1990;88:35764. 33. Berliner S, Garfinkel D, Shoenfeld Y, Pinkhas J. Inappropriate antidiuretic hormone [ADH] secretion in a patient with extensive fibrothorax. Respiration 1980;39:283-5. 34. Cotton MF, Donald PR, Schoeman JF, Aalbers C, Van-Zyl LE, Lombard C. Plasma arginine vasopressin and the syndrome of inappropriate antidiuretic hormone secretion in tuberculous meningitis. Pediatr Infect Dis J 1991; 10:837-42. 35. Cotton MF, Donald PR, Schoeman JF, Van-Zyl LE, Aalbers C, Lombard CJ. Raised intracranial pressure, the syndrome of inappropriate antidiuretic hormone secretion, and arginine vasopressin in tuberculous meningitis. Childs Nerv Syst 1993;9:10-5. 36. Erduran E, Mocan H, Aslan Y. Syndrome of inappropriate secretion of antidiuretic hormone in tuberculous meningits. Pediatr Nephrol 1996;10:127. 37. Motiwala HG, Sanghvi NP, Barjatiya MK, Patel SM. Syndrome of inappropriate antidiuretic hormone following tuberculous epididymo-orchitis in renal transplant recipient: case report. J Urol 1991;146:1366-7. 38. Ando T, Tanaka T, Saeki A, Ogawa K, Honda K, Sasamoto M, et al. Syndrome of inappropriate secretion of antidiuretic hormone associated with miliary tuberculosis. Kekkaku 1997;72:161-5. 39. Vorherr H, Massry SG, Fallet R, Kaplan L, Kleeman CR. Antidiuretic principle in tuberculous lung tissue of a patient with pulmonary tuberculosis and hyponatraemia. Ann Intern Med 1970;72:383-7. 40. Valiquette G. The neurohypophysis. Neurol Clin 1987;5:291331. 41. DeFronzo RA, Goldberg M, Agus ZS. Normal diluting capacity in hyponatremic patients. Reset osmostat or a variant of the syndrome of inappropriate antidiuretic hormone secretion. Ann Intern Med 1976;84:538-42.

570

Tuberculosis

42. Dinarello CA. Interleukin-1 and its biologically related cytokines. Adv Immunol 1989;44:153-205. 43. Silva CL, Faccioli LH. Tumour necrosis [cachectin] factor mediates induction of cachexia by cord factor from mycobacteria. Infect Immun 1988;56:3067-71. 44. Peltier P, Grossette R, Daboius G, Corroller J. Hyponatremie edilution arec natriure se conservee au Cours d’une tuberculose pulmonaire. Sem Hosp 1980;56:484-6. 45. Lebert H. Die Kranheiten der Schilddruse and ihre Behandlung. Breslau;1862.p.264. 46. Virchow R. Die Kranhaften Geschivulste. Vorlesung;1864.p.3. 47. Chiari H. Uber Tuberculose der Schiddruse Medsche Jahrbuch; 1878.p.66. 48. Burns P. Stuma tuberculosis. Beitr Klin Chir 1893;10:1. 49. Kiertiburanakul S, Sungkanuparph S, Malathum K, Pracharktam R. Concomitant tuberculous and cryptococcal thyroid abscess in a human immunodeficiency virus-infected patient. Scand J Infect Dis 2003;35:68-70. 50. Neimark II. Diagnostika tuberkulioza shchitovidnoj zhelezy [Diagnosis of tuberculosis of the thyroid gland]. Klin Med [Mosk]1974;52:42-7. 51. Talwar VK, Gupta H, Kumar A. Isolated tuberculous thyroiditis. JIACM 2003;4:238-9. 52. Coller FA, Huggins CB. Tuberculosis of the thyroid gland. A review of literature and report of five new cases. Ann Surg 1926;84:804-20. 53. Rankin FW, Graham AS. Tuberculosis of the thyroid gland. Ann Surg 1932;96:625-48. 54. Levitt T. The status of lymphadenoid goiter: Hashimoto’s and Riedel’s disease. Ann Royal Coll Surg 1952;10;369-404. 55. Das DK, Pant CS, Chachra KL, Gupta AK. Fine needle aspiration cytology diagnosis of tuberculous thyroiditis. A report of eight cases. Acta cytol 1992;36:517-22. 56. Wanh JH, Chen WP, Soong WJ, Yu IT, Chou NS, Wang HC, et al. Congenital tuberculosis: a case report. Zhonghua Yi Xue Za Zhi [Taipei] 1990;45:266-71. 57. Kang GH, Chi-JG. Congenital tuberculosis–report of an autopsy case. J Korean Med Sci 1990;5:59-64. 58. Barnes P, Weatherstone R. Tuberculosis of the thyroid: two case reports. Br J Dis Chest 1979;73:187-91. 59. Magboo MI, Clark OH. Primary tuberculous thyroid abscess mimicking carcinoma diagnosed by fine needle aspiration biopsy. West J Med 1990;153:657-9. 60. Johnson AG, Phillips ME, Thomas RJS. Acute tuberculous abscess of the thyroid gland. Br J Surg 1973;60:668-9. 61. Chandrcharoensin C, Viranuvatti V. Tuberculous abscess of the retrosternal thyroid gland displacing the oesophagus. Diagn Imaging 1981;50:29-31. 62. Emery P. Tuberculous abscess of the thyroid with recurrent laryngeal nerve palsy: case report and review of literature. J Laryngol Otol 1980;94:553-8. 63. Tom A, Dean D, Wilson K. To be or not TB. Thyroid 2008;18:77-80. 64. Karakhanian E. O roli tuberkulioznoj infekciji v etiologiji I patogeneze juvenilnovo zoba [Role of tuberculosis infection in etiology and pathogenesis of juvenile goiter]. Pediatriia 1978;9:48-50.

65. Ghosh A, Saha S, Bhattacharya B, Chattopadhay S. Primary tuberculosis of thyroid gland: a rare case report. Am J Otolaryngol 2007;28:267-70. 66. Seed L. Tuberculosis of the thyroid gland. In: Goldburg’s clinical tuberculosis. Philadelphia: FA Davis; 1939. 67. Mondal A, Patra DK. Efficacy of fine needle aspiration cytology in diagnosis of tuberculosis of the thyroid gland: a study of 18 cases. J Laryngol Otol 1995;109:36-8. 68. Pazaitou K, Chrisoulidou A, Ginikopoulou E, Angel J, Destouni C, Vainas I. Primary tuberculosis of the thyroid gland: report of three cases. Thyroid 2002;12:1137-40. 69. Das DK, Bhambhani S, Pant JN, Parkash S, Murthy NS, Hedau ST, et al. Superficial and deep seated tuberculous lesions: fine needle aspiration cytology diagnosis of 574 cases. Diagn Cytopathol 1992;8:211-5. 70. Kang BC, Lee SW, Shim SS, Choi HY, Baek SY, Cheon YJ. US and CT finding of tuberculosis of the thyroid: three case reports. Clin Imaging 2000;24:283-6. 71. Clausen KH, Kjerulf Jensen K. Artificial myxoedema during para-aminosalicylic acid. Nord Med 1951;45:475-7. 72. Moulding T, Fraser R. Hypothyroidism related to ethionamide. Am Rev Respir Dis 1970;101:90-4. 73. Mosiman RE. Tuberculosis of the thyroid. Surg Gynec Obstet 1917;24:680. 74. Kapoor VK, Subramani K, Das SK, Mukhopadhyay AK, Chattopadhyay TK. Tuberculosis of the thyroid gland associated with thyrotoxicosis. Postgrad Med J 1985;61:339-40. 75. Chow CC, Mak TW, Chan CH, Cockram CS. Euthyroid sick syndrome in pulmonary tuberculosis before and after treatment. Ann Clin Biochem 1995;32:385-91. 76. Yan SM. Clinical study on thyroid hormone level in tuberculous patients. Zhonghua Jie He He Hu Xi Za Zhi 1991;14:298-300. 77. Abbasi AA, Chemplavil JK, Farah S, Muller BF, Arnstein AR. Hypercalcaemia in active pulmonary tuberculosis. Ann Intern Med 1979;90:324-8. 78. Chan TY. Differences in vitamin D status and calcium intake: possible explanations for the regional variation in the prevalence of hypercalcaemia in tuberculosis. Calcif Tissue Int 1997;60:91-3. 79. Need AG, Philips PJ, Chiu F, Prisk HM. Hypercalcaemia associated with tuberculosis. BMJ 1980;282:831. 80. Shek CC, Natkunam A, Tsang V, Cockram CS, Swaminathan R. Incidence, causes and mechanism of hypercal-caemia in a hospital population in Hong Kong. QJM 1990;284:1277-85. 81. Gerritsen J, Knol K. Hypercalcaemia in a child with miliary tuberculosis. Eur J Pediatr 1989;148:650-1. 82. Saggese G, Bertelloni S, Baroncelli GI, Di Nero G. Ketoconazole decreases the serum ionized calcium and 1,25 dihydroxy vitamin D levels in tuberculosis associated hypercalcaemia. Am J Dis Child 1993;147:270-3. 83. Saggese G, Bertelloni S, Baroncelli GI, Fusara C, Gualtiers M. Abnormal synthesis of 1,25 dihydroxy vitamin D and hypercalcaemia in children with tuberculosis. Pediatr Med Chir 1989;11:529-32. 84. Cadranel J, Milleron B, Garabedian M, Aroun G. Serum concentrations of vitamin D metabolites in untreated tuberculosis. Thorax 1985;40:639-40.

Endocrine Implications of Tuberculosis 571 85. Epstein S, Stern PH, Bell NH, Dowdeswell I, Turner RT. Evidence for abnormal regulation of circulating 1 alpha, 25 dihydroxyvitamin D in patients with pulmonary tuberculosis and normal calcium metabolism. Calcif Tissue Int 1984;36:5414. 86. Bell NH, Shary J, Shaw S, Turner RT. Hypercalcaemia associated with increased circulating 1,25 dihydroxy vitamin D in patients with pulmonary tuberculosis. Calcif Tissue Int 1985;37:588-91. 87. Felsenfeld AJ, Drezner MK, Llacch F. Hypercalcemia and elevated calcitriol levels in a maintenance dialysis patient with tuberculosis. Arch Intern Med 1986;146:1941-5. 88. Barnes PF, Modlin RL, Bikle DD, Adams JJ. Transpleural gradient of 1,25 dihydroxy vitamin D in tuberculosis pleuritis. J Clin Invest 1989;83:1527-32. 89. Cadranel J, Garabedian M, Milleron B, Guillozo H, Akoun G, Hance AJ. 1,25[OH]2D3 production by lymphocytes and alveolar macrophages recovered by lavage from normocalcemic patients with tuberculosis. J Clin Invest 1990;85:1588-93. 90. Reichel H, Koeffler HP, Barbers R, Norman AW. Regulation of 1,25 dihydroxyvitamin D production by cultured alveolar macrophages from normal human donors and from patients with pulmonary sarcoidosis. J Clin Endocrinol Metab 1987;65:1201-9. 91. Caldranel J, Hance AJ, Milleron B, Paillard F, Akoun GM, Garabedian M. Vitamin D metabolism in tuberculosis: production of 1,25 [OH]2D3 by cells recovered by bronchoalveolar lavage and the role of this metabolite in calcium homeostasis. Am Rev Respir Dis 1988;138:984-9. 92. Singhellakis PN, Kitrou MP, Demertzi FD, Tzannes SE, Alevizaki CC, Mountokalkis TD, et al. Serum parathyroid hormone levels in active pulmonary tuberculosis. Acta Endocrinol Suppl [Copenh] 1984;265:52-4. 93. Adams JS, Gacad MA. Characterization of 1 alpha–hydroxylation of vitamin D3 sterols by cultured alveolar macrophage from patients with sarcoidosis. J Exp Med 1985;161:755-65. 94. Crowle AJ, Ross EJ, May MH. Inhibition by 1,25[OH]2 vitamin D3 of the multiplication of virulent tubercle bacilli in cultured human macrophage. Infect Immun 1987;55:294550. 95. Rook GA, Taverne J, Leveton C, Steele J. The role of gamma interferon, vitamin D3 metabolites and tumour necrosis factor in the pathogenesis of tuberculosis. Immunology 1987;62:22934. 96. Rigby WFC. The immunobiology of vitamin D. Immunol Today 1988;9:54-8. 97. Biyoudi-Vouenze R, Cadranel J, Valeyre D, Milleron B, Hance AJ, Soler P. Expression of 1,25[OH]2D3 receptors on alveolar lymphocytes from patients with pulmonary granulomatous disease. Am Rev Respir Dis 1991;143:1376-80. 98. Liam CK, Lim KH, Srinivas P, Poi PJ. Hypercalcaemia in patients with newly diagnosed tuberculosis in Malaysia. Int J Tuberc Lung Dis 1998;2:818-23. 99. Ramanathan M, Abdullah AD, Sivadas T. Hypercalcaemic crisis as the presenting manifestation of abdominal tuberculosis:a case report. Med J Malaysia 1998;53:432-4.

100. Kang ES, Do MY, Park SY, Hur KY, Ahn CW, Cha BS, et al. Hypercalcemia in hepatic tuberculosis: a case report in Korea. Am J Trop Med Hyg 2005;72:368-9. 101. Aly ES, Baig M, Khanna D, Baumann MA. Hypercalcemia: a clue to Mycobacterium avium intracellulare infection in a patients with AIDS. Int J Clin Pract 1999;53:227-8. 102. Playford EG, Bansal AS, Looke DF, Whitby M, Hogan PG. Hyperalcemia and elevated 1, 25[OH]2D3 levels associated with disseminated Mycobacterium avium infection in AIDS. J Infect 2001;42:157-8. 103. Narang NK, Meratwal S, Jain D. Effect of vitamin D on efficacy of pyrazinamide in pulmonary tuberculosis. J Assoc Physicians India 1991;39:425-6. 104. Martinez ME, Gonzalez J, Sanchez-Cabezudo MJ, Peria JM, Vazquez JJ, Felsenfeld A. Evidence of absorption hypercalciuria in tuberculosis patients. Calcif Tissue Int 1993;53:384-7. 105. Shai F, Baker RK, Addrizzo JR, Wallach S. Hypercalcaemia in mycobacterial infection. J Clin Endocrinol Metab 1972;34:251-6. 106. Martinez ME, Gonzaloz J, Sanchez-Cabezulo MJ, Pena JM, Vazquez JJ. Remission of hypercalciuria in patients with tuberculosis after treatment. Calcif Tissue Int 1996; 59:17-20. 107. Sharma SC. Serum calcium in pulmonary tuberculosis. Postgrad Med J 1981;57:694-6. 108. Pruitt B, Onarecker C, Coniglione T. Hypercalcemic crisis in a patient with pulmonary tuberculosis. J Okla State Med Assoc 1995;88:518-20. 109. Braman SS, Goldman AL, Schwarz MI. Steroid responsive hypercalcemia in disseminated bone tuberculosis. Arch Int Med 1973;132;269-71. 110. Adams JJ, Sharma OP, Diz MM, Endres DB. Ketoconazole decreases the serum 1,25 dihydroxy vitamin D and calcium concentrations in sarcoidosis associated hypercalcemia. J Clin Endocrinol Metab 1990;70:1090-5. 111. Harinarayan CV, Ramalakshmi T, Prasad UV, Sudhakar D, Srinivasarao PV, Sarma KV, et al. High prevalence of low dietary calcium, high phytate consumption, and vitamin D deficiency in healthy south Indians. Am J Clin Nutr 2007;85:1062-7. 112. Brodie MJ, Boobis AR, Hillyard CJ, Abeyasekera G, Stevenson JC, Macintyre I, et al. Effect of rifampicin and isoniazid on vitamin D metabolism. Clin Pharmacol Ther 1982;32:52530. 113. Brodie MJ, Boobis AR, Dollery CT, Hillyard CJ, Brown DJ, Macintyre I, et al. Rifampin and vitamin D metabolism. Clin Pharmacol Ther 1980;27:810-4. 114. Davies PD, Brown RC, Church HA, Woodhead JJ. The effect of antituberculous chemotherapy on vitamin D and calcium metabolism. Tubercle 1987;38:261-6. 115. Perry W, Brown J, Erooga MA, Stang TC. Calcium metabolism during rifampicin and isoniazid therapy for tuberculosis. J Royal Soc Med 1982;75:533-6. 116. Williams SE, Wardman AG, Taylor GA, Peacock M, Cooke NJ. Long-term study of the effects of rifampicin and isoniazid on vitamin D metabolism. Tubercle 1985;66:49-54.

572

Tuberculosis

117. Toppet M, Vainsel M, Contrainc F, Franckson M. Course of serum alkaline phosphatase during treatment with isoniazid and rifampicin. Arch Fr Pediatr 1985;42:79-80. 118. Shah SC, Sharma RK, Hemangini, Chitle AR. Rifampicin induced osteomalacia. Tubercle 1981;62:207-9. 119. Chan TY. Osteomalacia during rifampicin and isoniazid therapy is rare in Hong Kong. Int J Clin Pharmacol Ther 1996;34:533-4. 120. Cod liver oil treatment of tuberculosis. Brompton Hospital Records; 1849. p.39. 121. Dowling GB, Prosser-Thomas EW. Treatment of lupus vulgaris with calciferol. Lancet 1946;1:919-22. 122. Charpy J. Quelques traitements vitamines ou par substances fonctionnelles en dermatologie. Bull Med 1950;24:505. 123. Chmeler NA. Les recidives de la tuberculose et al probleme du renforcement des preparations tuberculostatiques. Bull Int Union Tuber 1959;29:683. 124. Brincourt J. Does calciferol have a liquifying action on caseum? Poumon Coeur 1967;23:841-51. 125. Davies PD. A possible link between vitamin D deficiency and impaired host defence to Mycobacterial tuberculosis. Tubercle 1985;66:301-6. 126. Rook GAW. The role of vitamin D in tuberculosis. Am Rev Respir Dis 1988;138:768-70. 127. Davies PD. The role of vitamin D in tuberculosis [letter]. Am Rev Respir Dis 1989;139:1571. 128. Rook GAW. Vitamin D and tuberculosis [letter]. Tubercle 1986;67:155-6. 129. Grange JM, Davies PD, Brown RC, Woodhead JS, Kardjito T. Vitamin D levels in Indonesian patients with untreated pulmonary tuberculosis. Tubercle 1985;66:187-91. 130. Ustianowski A, Shaffer R, Collin S, Wilkinson RJ, Davidson RN. Prevalence and associations of vitamin D deficiency in foreign-born persons with tuberculosis in London. J Infect 2005;50:432-7. 131. Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 2000;355:618-21. 132. Søborg C, Andersen AB, Range N, Malenganisho W, Friis H, Magnussen P, et al. Influence of candidate susceptibility genes on tuberculosis in a high endemic region. Mol Immunol 2007;44:2213-20. Epub 2006 Dec 6. 133. Lombard Z, Dalton DL, Venter PA, Williams RC, Bornman L. Association of HLA-DR, -DQ, and vitamin D receptor alleles and haplotypes with tuberculosis in the Venda of South Africa. Hum Immunol 2006;67:643-54. Epub 2006 May 22. 134. Babb C, van der Merwe L, Beyers N, Pheiffer C, Walzl G, Duncan K, et al . Vitamin D receptor gene polymorphisms and sputum conversion time in pulmonary tuberculosis patients. Tuberculosis [Edinb] 2007;87:295-302. 135. Douglas AS, Strachan DP, Maxwell JD. Seasonality of tuberculosis: the reverse of other respiratory diseases in the U.K. Thorax 1996;51:944-6.

136. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O Riordan J, et al. Vitamin D3, gamma interferon and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 1986;57:159-63. 137. Crowle AJ, Ross FJ. Comparative abilities of various metabolites of vitamin D to protect cultured human macrophages against tubercle bacilli. J Leukol Biol 1990;47:545-50. 138. Waters WR, Palmer MV, Nonnecke BJ, Whipple DL, Horst RL. Mycobacterium bovis infection of vitamin D-deficient NOS2-/- mice. Microb Pathog 2004;36:11-7. 139. Olmos P, Donoso J, Rojas N, Landeros P, Schurmann R, Retamal G, et al. Tuberculosis and diabetes mellitus: a longitudinal-retrospective study in a teaching hospital. Rev Med Chil 1989;117:979-83. 140. Patel JC. Complications in 8793 cases of diabetes mellitus 14 years study in Bombay Hospital, Bombay, India. Indian J Med Sci 1989;43:177-83. 141. Lester FT. Clinical features, complications and mortality in type I [insulin dependent] diabetic patients in Addis Ababa, Ethiopia, 1976-1990. QJM 1992;83:389-99. 142. Swai AB, Mclarty DG, Mugusi F. Tuberculosis in diabetic patients in Tanzania. Trop Doct 1990;20:147-50. 143. Liu-CY. Pulmonary tuberculosis and diabetes mellitus. A clinical analysis of 42 cases. Zhonghua Jie He He Hu Xi Za Zhi 1989;12:288-9. 144. Perez-Guzman C, Vargas MH, Torres-Cruz A, Perez-Padilla JR, Furuya ME, Villarreal-Velarde H. Diabetes modifies the male:female ratio in pulmonary tuberculosis. Int J Tuberc Lung Dis 2003;7:354-8. 145. Sidibe EH. Main complications of diabetes mellitus in Africa. Ann Med Interne [Paris] 2000;151:624-8. 146. Wang JY, Lee LN, Hsueh PR. Factors changing the manifestation of pulmonary tuberculosis. Int J Tuberc Lung Dis 2005;9:777-83. 147. Kim SJ, Hong YP, Lew WJ, Yang SC, Lee EG. Incidence of pulmonary tuberculosis among diabetics. Tuber Lung Dis 1995;76:529-33. 148. Garcia PH, Cruz MF, Martinez CT. PPD and chemoprophylaxis in diabetes mellitus. Aten Primaria 1992;9:106-8. 149. Bacakoglu F, Basoglu OK, Cok G, Sayiner A, Ates M. Pulmonary tuberculosis in patients with diabetes mellitus. Respiration 2001;68:595-600. 150. Stevenson CR, Forouhi NG, Roglic G, Williams BG, Lauer JA, Dye C, et al. Diabetes and tuberculosis: the impact of the diabetes epidemic on tuberculosis incidence. BMC Public Health 2007;7:234. 151. Al Wabel AH, Teklu B, Mahfouz AA, Al Ghamdi AS, El Amin OB, Khan AS. Symptomatology and chest roentgenographic changes of pulmonary tuberculosis among diabetics. East Afr Med J 1987;74:62-4. 152. Bacakoglu F, Basoglu OK, Cok G, Sayiner A, Ates M. Pulmonary tuberculosis in patients with diabetes mellitus. Respiration 2001;68:595-600. 153. Morris JT, Seaworth BJ, McAllister CK. Pulmonary tuberculosis in diabetics. Chest 1992;102:539-41.

Endocrine Implications of Tuberculosis 573 154. Zhao Y, Duanmu H, Song C. Analysis of the association between HLA-DRB[1], DQB[1] gene and pulmonary tuberculosis complicated with diabetes mellitus. Zhonghua Jie He He Hu Xi Za Zhi 2001;24:75-9. 155. Uno K, Nakano K, Maruo N, Onodera H, Mata H, Kurosu I, et al. Determination of interferon-alpha-producing capacity in whole blood cultures from patients with various diseases and from healthy persons. J Interferon Cytokine Res 1996;16:911-8. 156. Tsukaguchi K, Yoneda T, Yoshikawa M, Tokuyama T, Fu A, Tomoda K, et al. Case study of interleukin-1beta, tumor necrosis factor alpha and interleukin-6 production in peripheral blood monocytes in patients with diabetes complicated by pulmonary tuberculosis. Kekkaku 1992; 67:755-60. 157. Marvisi M, Marani G, Brianti M, Della Porta R. Pulmonary complications in diabetes mellitus. Recent Prog Med 1996;97:623-7. 158. Cheren’ko SA. Intensive chemotherapy regimens in pulmonary tuberculosis with concomitant diabetes mellitus. Vrach Delo 1990;9:87-8. 159. Atkin SL, Masson EA, Bodmer CW, Walker BA, White MC. Increased insulin requirement in a patient with type 1 diabetes on rifampicin. Diabet Med 1993;10:392. 160. Kameda K, Kawabata S, Masuda N. Follow-up study of shortcourse chemotherapy of pulmonary tuberculosis complicated with diabetes mellitus. Kekkaku 1990;65: 791-803. 161. Bashar M, Alcabes P, Rom WN, Condos R. Increased Incidence of multidrug-resistant tuberculosis in diabetic patients on the Bellevue Chest Service, 1987 to 1997. Chest 2001;120:1514-9. 162. Kado S, Isobe T, Ishioka S, Yamakido M, Shibata Y, Kuraoka T. Clinical features of diabetic patients with recurrent pulmonary tuberculosis. Kekkaku 1992;67:313-8. 163. Nichols GP. Diabetes among young tuberculosis patients; a review of the association of the two diseases. Am Rev Tuber 1957;76:1016-30.

164. Root HF. The association of diabetes and pulmonary tuberculosis. N Engl J Med 1934;210:1-13. 165. Zack MD, Fulkerson LL, Stein E. Glucose intolerance in pulmonary tuberculosis. Am Rev Respir Dis 1973;108:1164-9. 166. Kishore B, Nagrath SP, Mathur KS, Hazra DK, Agarwal BD. Manifest, chemical and latent chemical diabetes in pulmonary tuberculosis. J Assoc Phycicians India 1973;21:875-81. 167. Singh V, Goyal RK, Mathur MN. Glucose tolerance in patients with pulmonary tuberculosis. J Indian Med Assoc 1978;70: 81-3. 168. Seth SC, Parmar MS, Saini AS, Lal H. Glucose tolerance in pulmonary tuberculosis. Hormone Metab Res 1982;14:50. 169. Roychowdhury AB, Sen PK. Diabetes in tuberculous patients. J Indian Med Assoc 1980;74:8-15. 170. WHO Study Group on Diabetes Mellitus. WHO Technical Report Series 727. Geneva: World Health Organization; 1985. 171. Mugusi F, Swai AB, Alberti KG, Mclarty DG. Increased prevalence of diabetes mellitus in patients with pulmonary tuberculosis in Tanzania. Tubercle 1990;71:271-6. 172. Jawad F, Shera AS, Memon R, Ansari G. Glucose intolerance in pulmonary tuberculosis. JPMA J Pak Med Assoc 1995;45:237-8. 173. Bloom JD. Glucose intolerance in pulmonary tuberculosis. Am Rev Respir Dis 1969;100:38-41. 174. Samal KC, Tripathy BB, Das S. Profile of childhood onset diabetes in Orissa. Int J Diab Dev Countries 1990;10:27-34. 175. Hadden DR. Glucose, free fatty acid and insulin interrelations in Kwashiorkor and marasmus. Lancet 1967;2:58992. 176. McLarty DG, Swai ABM, Kitange HM, Masuki G, Mtinangi BL, Kilima PM, et al. Prevalence of diabetes and impaired glucose tolerance in rural Tanzania. Lancet 1989;1:871-5. 177. Broxmeyer L. Diabetes mellitus, tuberculosis and the mycobacteria: two millenia of enigma. Med Hypotheses 2005;65:433-9.

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Tuberculosis and Human Immunodeficiency Virus Infection

40

Srikanth Tripathy, Myo Paing, Jai P Narain

INTRODUCTION Tuberculosis [TB], an ancient disease, continues to remain even today a major public health problem in much of the developing world (1). The problem is now further complicated by relentless spread of the human immunodeficiency virus [HIV], which causes acquired immunodeficiency syndrome [AIDS] pandemic (2,3). The rapid growth of HIV epidemic in many countries of the world resulted in an equally dramatic rise in the estimated number of new TB cases. Human immunodeficiency virus related TB continues to increase even in the countries with well-organized national TB control programmes that are successfully implementing the DOTS, the internationally recommended strategy for TB control (4). Infection with HIV results in progressive immunodeficiency and renders the infected person increasingly vulnerable to a wide range of pathogens. In many parts of the world, TB is the most common opportunistic infection [OI] in HIV infected persons (5,6). The immune defects produced by HIV influence the natural history of TB infection. Thus, the HIV pandemic has altered both the epidemiology of TB and the measures for approaches to its control. In populations where the risk of TB and HIV infection is high, the incidence of TB is expected to increase particularly in a number of developing countries in Africa and Asia. EPIDEMIOLOGY Mycobacterium tuberculosis infects a third of the world’s population. Globally, in 2006, there were about 9.2 million new cases of TB of which nearly 700 000 were infected with HIV (6). In 2006, there were 1.7 million TB

deaths, including 230 000 infected with HIV (7). These deaths comprise 25 per cent of all avoidable deaths in developing countries. Ninety-five per cent of TB cases and 98 per cent of TB deaths occur in developing countries. Three-fourths of TB cases in developing countries occur among the economically productive age group i.e., 15 to 40 years. The situation is further complicated by the rapidly spreading HIV pandemic (8). According to the recent World Health Organization [WHO] and the Joint United Nations Programme on HIV/AIDS [UNAIDS] update on AIDS epidemic, the revised global estimate of people living with HIV/AIDS [PLHIV] has been calculated to be 33.2 million [range 30.6 to 36.1 million], a reduction of 16 per cent compared with the estimate of 39.5 million in 2006 (9,10). The major contribution to this new estimate has been from the revised figures for India. According to the new estimates, 2.5 million people [range 2 to 3.1 million]; or about 0.4 per cent of adult population in India are HIV-seropositive and these estimates are less than half the earlier reported figures of 5.7 million [range 3.4 to 9.4 million] people (11). In light of these data, it is likely that the estimates related to HIV-TB co-infection will be revised in near future. The HIV epidemic has reached a generalized stage at the national level in three countries of Asia: Cambodia, Myanmar and Thailand (12-14). In 2003, in Cambodia the prevalence of HIV infection among those aged 15 to 49 years was estimated to be 2.6 per cent, in Myanmar the prevalence was 0.7 per cent and in Thailand the prevalence was 1.4 per cent. The HIV epidemic is generalized in five states of India, namely, Andhra Pradesh, Karnataka, Maharashtra, Manipur, and Nagaland (13).

Tuberculosis and Human Immunodeficiency Virus Infection 575 As per WHO/UNAIDS estimates [2004] (12), up to 50 per cent of people with HIV or AIDS develop TB. At least 11 per cent of AIDS deaths and possibly 50 per cent are caused by TB. Of the 3.6 million adults with HIV infection in the South-East Asia Region, nearly half are likely to be infected with TB. Tuberculosis is the most important lifethreatening associated with HIV infection. In Thailand 60 per cent of AIDS patients have had pulmonary TB. This was 80 per cent in Myanmar, 56 per cent in India and 75 per cent in Nepal (6). Figure 40.1 (7) and Table 40.1 (15,16) show geographical distribution of HIV-TB cases and incidence of TB among HIV-positive adults respectively, in countries with a high TB/HIV burden in Asia (6,7,15,16). The threefold higher proportion in South-East Asia could be attributed primarily to the high burden in India (8). Table 40.2 shows the proportion of estimated TB deaths [numbers and rates] among those infected with HIV for some countries in the two regions. In the SouthEast Asia Region, 0.7 per cent of prevalent TB cases are co-infected with HIV and four per cent of TB deaths [11% in Thailand] occurred among HIV infected cases (6,7).

Table 40.1: Estimated prevalence of human immunodeficiency virus in new tuberculosis cases and estimated incidence of tuberculosis in human immunodeficiency viruspositive adults aged 15-49 years* Prevalence of HIV Incident cases of TB [all forms] in HIV+ in new adult TB cases [%]† adults [thousands]‡ Cambodia

13.0

6.5

China

0.7

5.8

Myanmar

6.8

5.5

Nepal

2.9

0.9

India

5.2

54.4

Indonesia

0.5

2.3

Thailand

8.7

5.3

Vietnam

2.8

1.7

*Detailed methodology as per reference 15 † Source: reference 6 ‡ Year 2002 estimates. Source: reference 16 TB = tuberculosis, HIV = human immunodeficiency virus; + = positive

Figure 40.1: Geographical distribution of HIV-positive TB cases in 2006. For each country or region, the number of incident TB cases arising in people with HIV is shown as a percentage of the global total of such cases AFR* is all countries in the WHO African Region except those shown separately; AMR* excludes Brazil; EUR* excludes the Russian Federation; SEAR* excludes India HIV = human immunodeficiency virus; TB = tuberculosis; WHO = World Health Organization; AFR = African region; AMR = American region; EMR = Eastern Mediterranean region; EUR = European region; WPR = Western Pacific region; SEAR = South-East Asian region Reproduced with permission from “WHO Report 2008. Global Tuberculosis Control: surveillance, planning, financing. Geneva: World Health Organization;2008. WHO/HTM/TB/2008.393 (reference 7)” The World Health Organization updates these data annually. The reader can access theupdated information from the WHO report of the current year available at the URL: http:/www.who.int/topics/tuberculosis/en/

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Table 40.2: Deaths due to tuberculosis in human immunodeficiency virus positive patients in countries with high tuberculosis and human immunodeficiency virus burden Numbers [thousands] India Myanmar Thailand South-East Asia

Rate [per 100 000 population]

22.2

2.1

1.4

2.9

1.3

2.1

26.0

Cambodia

2.4

17.6

China

2.2

0.2

Malaysia

0.1

0.3

Papua New Guinea

0.1

2.2

Philippines

0.2

0.3

Vietnam

0.4

0.5

Western Pacific Total

5.5 31.5

Source: reference 6

Given the annual risk of clinical TB, which varies from five to eight per cent, among individuals dually infected with HIV and TB, further increases in TB incidence seem inevitable. Rapid increase in TB is attributed primarily to HIV in countries of sub-Saharan Africa, such as Tanzania, Zambia, Malawi and Burundi (6,7). The HIV epidemic is already having a profound and prolonged impact on TB in Asia and the Pacific. In the Chiang Rai province in Northern Thailand a case control study between 1990 and 1998 has shown that the proportion of TB cases attributable to HIV rose to 72 per cent in male patients and 66 per cent in female patients. This continuing increase in TB cases attributable to HIV has occurred even when there is marked reduction in HIV prevalence in the area (12-14). The incidence of TB in HIV infected patients is about a 100-fold greater than that in the general population. Even more dramatic is the effect seen when persons who are already infected with HIV become newly infected with Mycobacterium tuberculosis. In two outbreaks, in which HIV infected persons were exposed to infectious TB cases, 40 per cent of the infected persons developed active TB within a few months (8). In HIV infected persons, active TB seems to develop soon after infection and progress rapidly, often resulting in death (8,12,13).

The HIV sentinel surveillance carried out among TB patients in many countries of the world shows that HIV prevalence rates are increasing quite rapidly. The HIV seroprevalence among TB patients in different regions of India varies [Table 40.3] (17-34). These differences could be due to selection bias, but a trend could be noted for the individual site. Clinical and surveillance data show that TB is now the most important life-threatening OI associated with the HIV in Asia. For example, in Thailand, 60 per cent of AIDS patients seen in a Bangkok hospital between 1985 and 1993 had pulmonary TB. Similar data have been reported from Myanmar [80%], India [56%] and Nepal [75%] (12,13). The HIV is clearly the most potent risk factor for the development of clinical TB in many individuals. PATHOGENESIS The reader is referred to the chapters “Pathology” [Chapter 5] and “Reactivation and reinfection tuberculosis” [Chapter 47] for more details regarding the natural history and pathogenesis of TB including HIV-TB. CLINICAL PRESENTATION Unlike other OI which occur at CD4+ counts below 200/ mm3, active TB occurs throughout the course of HIV disease (3). The clinical presentation of TB in HIV infected patients varies depending on the severity of immunosuppression. In patients with earlier stages of HIV disease, clinical presentation of TB tends to be similar to that observed in persons without immunodeficiency. Pulmonary disease is the most common, often with focal infiltrates and cavities. In patients with more marked immunodeficiency, with CD4+ counts of less than 200/mm3, the features of TB are often atypical, with a much greater frequency of extra-pulmonary involvement, especially of the lymph nodes. Diffuse pulmonary disease without cavitation often involving the lower lobes and prominent mediastinal or paratracheal adenopathy are often seen in patients with advanced HIV disease. The radiological shadows in the lungs may change rapidly. Patients with advanced HIV disease more often have miliary TB and involvement of the lymphatic system, central nervous system [parenchymal and meningeal], soft tissue, bone marrow, liver and other viscera. Mycobacterium tuberculosis may be isolated from the blood or faeces in some cases (3).

Tuberculosis and Human Immunodeficiency Virus Infection 577 Table 40.3: Human immunodeficiency virus seroprevalence in tuberculosis patients as reported in various studies published from India Author (reference)

Place of study

Period of study

No. of TB patients

Sharma et al (17) Sharma et al (18) Piramanayagam et al (19) Ramachandran et al (20) Ahmad et al (21)

Delhi Delhi Delhi Chennai Aligarh

Shahab et al (22) Prasad et al (23)

Aligarh* Lucknow

1994-99 2000-02 2003-05 1997-98 1996-97 1997-98 1998-99 1999-00 2000-01 1996-2001 1999-2000 1995-96 1996-97 1997-98 1995-98 1993-95 1988-89 1989-90 1990-91 1991-92 1992-93 1993-94 1989-94 1991 1992 1993 1994 1995 1996 1991-96 1995 1991 1992 1993 1991-93 1996 1995 1994-95 1995-96 1995-96 1994 1995 1996 1994-96

500 555 374 2361 1006 1215 1126 1330 1204 5881 250 400 225 350 975 2448 468 707 641 678 596 788 3878 344 187 395 1046 1189 1457 4618 1256 392 680 358 1430 112 11657 1002 520 340 500 550 500 1600

Purohit et al (24) Mohanty and Basheer (25)

Paranjape et al (26)

Tripathy et al (27) Solomon et al (28)

Samuel et al (29) WHO/IUATLD Project (30) Banavaliker et al (31) Gupta et al (32) Talib et al (33) Vasudeviah (34)

Ajmer Mumbai

Pune

Pune Chennai

Chennai Delhi Delhi Udaipur Aurangabad Pondicherry

HIV-positive cases No. [%] 2 [0.4] 52 [9.4] 31 [8.3] 111 [4.7] 8 [0.8] 11 [0.9) 14 [1.2] 24 [1.8] 34 [2.8] 91 [1.6] 5 [2.0] † [1.3] † [1.8] † [4.3] 24 [3.1] 18 [0.7] 12 [2.6] 19 [2.7] 25 [3.9] 65 [9.6] 59 [9.9] 90 [10.2] 260 [6.7] 11 [3.2] 11 [5.9] 20 [5.0] 105 [10.0] 184 [15.5] 293 [20.1] 694 [15.0] 152 [12.1] 3 [0.8] 9 [1.3] 12 [3.4] 24 [1.7] 19 [17.0] * [1.0] 5 [0.5] 40 [7.7] 16 [4.7] 20 [4.0] 19 [3.5] 27 [4.9] 66 [4.1]

* Paediatric series † Exact number of HIV-seropositive patients not mentioned TB = tuberculosis; HIV = human immunodeficiency virus; WHO = World Health Organization; IUATLD = International Union Against Tuberculosis and Lung Disease

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Tuberculosis

In a patient with HIV infection, large lymph node size [> 4 cm], rapidly growing lymph nodes, asymmetrical lymphadenopathy, tender, painful lymph nodes not associated with local infection, matted or fluctuant lymph nodes, presence of constitutional features [fever, night sweats, weight loss] and hilar or mediastinal lymphadenopathy on chest radiograph warrant further investigation. In HIV infected persons with TB and severe immunosuppression, TB lymphadenopathy may be acute and resembles acute pyogenic lymphadenitis. Tuberculosis serositis, especially pleural effusion is more common in HIV-seropositive individuals. Tuberculosis may occur at unusual sites. Tuberculomas of the brain, abscesses of the chest wall, testes or elsewhere can occur. In the presence of marked immunosuppression sputum smears may be negative for acid-fast bacilli [AFB] even in the presence of extensive radiological changes and the tuberculin skin test [TST] may be negative. In a patient with TB, presence of generalized lymphadenopathy, oral candidiasis, chronic diarrhoea not responding to standard anti-diarrhoeal treatment for more than a month, herpes zoster, recurrent pneumonia, bacteraemia [especially caused by Salmonella typhimurium], oral hairy leukoplakia, persistent painful genital ulceration or Kaposi’s sarcoma suggest the possibility of associated HIV infection. The presence of symptoms such as weight loss more than 10 kg or more than 20 per cent of the original body weight, pain on swallowing [due to oral candidiasis] and burning sensation of the feet [peripheral sensory neuropathy] should also alert the clinician to the possibility of associated HIV infection in a patient with TB. According to the revised WHO clinical staging of HIV/AIDS for adults and adolescents [2005] (35), a patient with pulmonary TB diagnosed in last two years is staged as having clinical stage 3 disease, whereas a patient with extra-pulmonary TB is staged as having clinical stage 4 disease. Paediatric Tuberculosis The natural history of TB in a HIV infected child depends on the stage of the HIV disease. As in the case of adults, clinical presentation of TB in HIV infected children with early HIV disease is similar to that observed in immunocompetent children without HIV infection. However, TB bacilli are more likely to disseminate to other parts of the body in a child who has HIV infection. Tuberculosis meningitis, miliary TB, and generalized enlargement of lymph nodes are more likely to occur. It must also be

kept in mind that these HIV-positive children may have other OI apart from TB. Clinical signs suggesting HIV infection in children are weight loss or abnormally slow growth, chronic diarrhoea, more prolonged fever lasting more than a month, generalized lymphadenopathy, oropharyngeal candidiasis, recurrent common infections [ear infections, pharyngitis], persistent cough, generalized rash, neurological problems, delay in development, bilateral parotid gland enlargement, hepatosplenomegaly, recurrent abscesses, meningitis and recurrent herpes simplex. In India, provision is available under the Revised National Tuberculosis Control Programme [RNTCP] and the National AIDS Control Programme to evaluate patients with TB for HIV infection and vice versa to maximize the case detection rates (36). DIAGNOSIS Given the fact that most cases with HIV-TB have extrapulmonary TB and smear-negative or paucibacillary pulmonary TB, there is an urgent need for development of newer diagnostic tools to facilitate an early diagnosis. These tests should be cheaper, user friendly and should have wider application in field settings. This becomes more important in areas where HIV is highly prevalent in order to interrupt disease transmission and prevent morbidity and mortality. Published evidence suggests that sputum smears reveal AFB less frequently in HIV-seropositve patients with pulmonary TB, especially in late HIV disease (37-40). However, in one study the yield of sputum smear and culture was similar in pulmonary TB patients with and without HIV infection (41). Clinicians should also subject all bronchoscopy and biopsy specimens from an HIV infected patient to mycobacterial smear and culture examination (42). Diagnosis of extra-pulmonary, disseminated and miliary TB may require mycobacterial culture of bone marrow, lymph node, pleural or ascitic fluid, brain tissue, cerebrospinal fluid, urine, stool or blood. In HIV-seropositive patients with mild degree of immunosuppression, the histopathological appearance of TB lymph nodes shows caseating lesions with few or no AFB. In HIV infected individuals with a severe degree of immunosuppression, the lymph node histopathological appearance presents as little cellular reaction with many AFB. The reader is referred to the chapter “Pathology” [Chapter 5] for more details.

Tuberculosis and Human Immunodeficiency Virus Infection 579 The TST is commonly used to detect latent tuberculosis infection [LTBI]. More recently, interferon-gamma release assays [IGRAs] are increasingly being used to detect LTBI and have several advantages. The reader is referred to the chapters and “Diagnosis of latent tuberculosis infection: recent advances and future directions” [Chapter 10] “Tuberculin skin test” [Chapter 11] for more details. MANAGEMENT OF TUBERCULOSIS AND HUMAN IMMUNODEFICIENCY VIRUS CO-INFECTION Experiences from several countries have demonstrated that a continuum of care from hospital to home is the optimum to provide care and support to those affected with HIV. Patients co-infected with HIV-TB should benefit from HIV/AIDS care and support based on this approach. Community-and home-based care is one of the key activities to strengthen the continuum of care with referral linkages to TB services and vice versa. Comprehensive care should link the formal [hospitals and health services] and the informal [family and community care] sections of the health system in a cohesive network of services. The success of a comprehensive care model depends on the cooperation and collaboration of health care workers at all levels [primary, secondary and tertiary] and the active involvement of communities at risk, PLHIV and their families and care givers. If comprehensive care across the continuum operates successfully then it will facilitate reduction in the impact of illness, an improvement in the quality of life of PLHIV, and a reduction in the level of stigma and discrimination in clinical and community care settings. Providing comprehensive HIV/AIDS care includes (43); clinical and nursing care, in particular, the prevention and treatment of common OIs including TB, psychosocial support, financial support, housing and legal assistance, care and support of orphans and widows and information and training of care givers. The common HIV-related infections, e.g., Pneumocystis jiroveci, pneumonia and bacterial infections, cause considerable morbidity during treatment of HIVTB co-infection. Pneumonia due to Pneumocystis jiroveci, is commonly reported OI in Thailand and India (44,45). Preventive treatment against these intercurrent infections represents a possible way to decrease morbidity and mortality in HIV infected TB patients. Studies in PLHIV in Cote d’Ivoire showed the benefit of cotrimoxazole

prophylaxis against some bacterial causes of pneumonia and diarrhoea and their complications (46-48). The UNAIDS and WHO have recommended the use of cotrimoxazole preventive treatment [CPT] in HIV infected individuals as part of a minimum package of care (49,50). Cotrimoxazole preventive treatment is the gold standard in industrialized countries for HIV infected individuals with CD4+ T-lymphocyte count less than 200/mm 3 regardless of TB (51). The Thai Clinical Management Guidelines recommend the use of cotrimoxazole following clinical eligibility criteria for those who can not afford to have CD4+ counts done (52,53). Further studies are necessary to evaluate the best models for the use of co-trimoxazole in HIV infected TB patients in South-East Asia. For example in Thailand PLHIV groups and non-government organizations have launched an initiative to provide access to treatment for prevention of OIs for PLHIV (52). Highly Active Antiretroviral Therapy Rapid progress in developing antiretroviral therapy [ART] led in 1996 to the introduction of highly active antiretroviral therapy [HAART]. This includes a combination of at least three antiretroviral [ARV] drugs. This revolutionized the treatment of HIV infection. As with antituberculosis treatment, a combination of ARV drugs provides efficacy and decreases the risk of drug resistance. Antiretroviral therapy is the global standard of care in the treatment of HIV infection. Although not a cure for HIV infection, ART usually results in nearcomplete suppression of HIV replication. It is a lifelong treatment. The prime objectives of ART are to delay the onset of HIV disease progression; improve the quality of life of the infected individual; reduce the transmission of HIV infection and maintain the “health of the public”. These objectives are achieved by initiation of ART in patients at risk of disease progression and can be achieved only by using drug combinations of at least three antiretroviral agents. These drug combinations result in impairment of viral replication with restoration of immune function and reduced rates of clinical progression. The ART results in dramatic reductions in morbidity and mortality in HIV infected people. There are several requirements for successful use of ART. These include considerable efforts to maintain adherence to lifelong

580

Tuberculosis

treatment and to monitor response to treatment, drug toxicities and drug-drug interactions. Although the benefits of ART are considerable, administration is not easy. Many HIV infected persons cannot tolerate the toxic effects of the drugs. Adherence is difficult because of often large numbers of pills and complicated treatment regimens. Poor adherence to treatment leads to the emergence of drug-resistant viral strains which are very difficult to treat. Access to ART is limited to very few HIV infected people where the burden of HIV is greatest [in subSaharan Africa and Asia]. The WHO estimated that in 2002 there were six million people in developing countries in need of ART (54,55). Of these, only 230 000 had access to ART [and half of those were in one country, Brazil]. There were increasing international efforts to improve access to ART in resource-limited settings in recent years. The ART has become increasingly available in resource-poor countries since late 2003. The WHO/ UNAIDS estimated that in June 2005, the number of people receiving combination ART for HIV/AIDS in developing countries has increased significantly – more than doubling from 400 000 in December 2003 to approximately one million in June 2005 (54,55). National standardized approaches should be developed when deciding on first-line ART combinations in resource limited settings. The WHO recommends that antiretroviral treatment programmes choose few potent first-line ART regimen to start treatment in the majority of patients (56). Clinical trials of different triple drug regimens have generally revealed comparable antiviral potencies. Therefore, the choice among these regimens generally relies on other considerations including: sideeffect profiles, safety in pregnancy, potential drug-drug interactions [especially with medications used to treat TB], co-morbidities [e.g., TB, hepatitis], maintenance of alternative options in the setting of treatment failure, drug availability, cost, likely HIV [sub]-types and ‘cold chain’ requirements (56).

Zidovudine and Stavudine Zidovudine [ZDV] and stavudine [d4T] are thymidine NRTI inhibitors. They must not be co-administered due to competition for intracellular phosphorylation. The choice between d4T or ZDV should be made at the country level but both agents should be available. Use of ZDV essentially requires haemoglobin monitoring before and during therapy. The WHO haemoglobin colour scale can be used when laboratory-based haemoglobinometry methods are unavailable. While d4T is generally better tolerated, concerns exist about the development of lipoatrophy and other metabolic complications. Nevirapine Nevirapine [NVP] is a non-nucleoside reverse transcriptase inhibitor [NNRTI]. It is administered on a twice daily basis. Significant side effects include rash [which may evolve into Stevens-Johnson syndrome] and hepatitis. Nevirapine should be avoided in patients receiving rifampicin-based antituberculosis treatment. Further studies on the concomitant use of NVP and antituberculosis treatment are required. Efavirenz Efavirenz [EFV], an NNRTI, is administered on a once daily basis. This drug should be used with caution because of its teratogenic potential. The WHO recommends that it should not be used in women of child-bearing potential unless adequate contraception is used. This drug may be used in patients on antituberculosis treatment. The antiretroviral drug dosages and commonly encountered adverse drug reactions are listed in Tables 40.4 and 40.5. While there are many potential first-line ART combinations, the WHO currently suggests only four combinations consisting of five drugs. Using the “5-drug, formulary approach” outlined above [{d4T or ZDV} + 3TC + {NVP or EFV}], results in four possible firstline regimens: [i] d4T/3TC/NVP; [ii] d4T/3TC/EFV; [iii] ZDV/3TC/NVP; and [iv] ZDV/3TC/EFV (48,52,54).

Lamivudine Lamivudine [3TC] is a cytidine nucleoside reverse transcriptase inhibitor [NRTI]. It is well tolerated and can be administered either in a once or twice daily schedule. It has activity against hepatitis B virus as well as HIV. Resistance develops quickly to this drug if used as part of a sub-optimal combination.

Antituberculosis Treatment Due to the high prevalence of TB among HIV infected individuals living in the South-East Asia Region, many patients who are candidates for ART will have active TB (57). In addition, patients already receiving ART may develop clinical TB. Effective treatment and control of

Tuberculosis and Human Immunodeficiency Virus Infection 581 Table 40.4: Nucleoside reverse transcriptase inhibitors Name

Dose

Comments and common side-effects

Lamivudine [3TC]

150 mg twice daily

Generally well tolerated Active against HBV

Stavudine [d4T]

30 mg twice daily Peripheral neuropathy [1% to 4% in early studies; 24% in expanded access patients with CD4+ counts < 50/mm3]

Zidovudine [ZDV]

300 mg twice daily

Initial nausea, headache, fatigue, anaemia, neutropenia, neuropathy, myopathy

HBV = hepatitis B virus

Table 40.5: Non-nucleoside reverse transcriptase inhibitors Comments and common side effects

Name

Dose

Nevirapine [NVP]

200 mg daily for Rash, hepatitis two weeks, then 200 mg twice daily

Efavirenz [EFV]

600 mg daily [evening]

agents produce unacceptable drug interactions with antituberculosis agents and can increase toxicity of TB treatment (59-67). The DOTS strategy should be initiated promptly in HIV-seropositive patients diagnosed to have TB. The two major issues in the clinical management of patients with HIV and TB are when to start ART and which regimen to use. The optimum time at which to commence ART in a patient with HIV-TB co-infection is unknown. An early initiation of ART is recommended for TB patients at very high risk for HIV disease progression and mortality. For patients with a CD4+ count less than 200 cells/mm3, ART is recommended as soon as the antituberculosis treatment is tolerated, usually between two weeks and two months [Table 40.6, Figure 40.2]. For patients who develop TB with CD4+ counts in the 200 to 350 cells/mm3 range, ART should be started after the first two months of antituberculosis Table 40.6: Antiretroviral therapy for individuals co-infected with human immunodeficiency virus and tuberculosis Situation

Rash, hepatitis, neuropsychiatric manifestations

TB is a central priority when developing treatment strategies for HIV co-infected patients (58). The aims of antituberculosis treatment are to cure patients with TB, to prevent death from active TB or its late effects, to prevent relapse and to decrease TB transmission to others. The WHO recommends the same treatment regimen for TB patients with and without HIV co-infection. In India, the Revised National Tuberculosis Control Programme [RNTCP] uses intermittent thrice weekly DOTS both in the initial intensive phase as well as in the continuation phase of chemotherapy. While new patients are treated with Category I treatment, retreatment cases are treated with Category II treatment. For HIV-TB treatment, there is no Category III treatment. The reader is referred to the chapters “Treatment of tuberculosis” [Chapter 52], and “Revised national tuberculosis control program in India” [Chapter 63] for more details. Thioacetazone should not be used in HIV-seropositive patients. The management of HIV and TB coinfection is complicated because some antiretroviral

Recommendations

Start TB treatment. Start one of these CD4+ count < 200 cells/mm3 regimens as soon as TB treatment is tolerated [between 2 weeks and 2 months]: Recommended regimen: ZDV/3TC/EFV Alternatives: ZDV/3TC/SQV/r ZDV/3TC/ABC* d4T/3TC/ABC or SQ/r [for ZDV intolerance] CD4+ count 200 to 350 cells/mm3

Start TB treatment. Start one of these regimens after 2 months of TB treatment: Recommended regimen: ZDV/3TC/EFV Alternatives: ZDV/3TC/SQV/r ZDV/3TC/ABC

CD4+ count > 350 cells/mm3

Treat TB. Monitor CD4+ counts if available. Defer ART

* Although this regimen does not require modification of dosages when co-administered with rifampicin, it is inferior for HIV/AIDS treatment TB = tuberculosis; ZDV = zidovudine; 3TC = lamivudine; EFV = efavirenz; SQV/r = saquinavir/ritonavir; ABC = abacavir; d4T = stavudine; ART = antiretroviral treatment; HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome Source: references 50 and 56

582

Tuberculosis While protease inhibitors [PIs] should not be used concomitantly with rifampicin because rifampicin induces hepatic enzymes that reduce the PIs to subtherapeutic levels, however, saquinavir/ritonavir [SQV/ r] [1000/100 mg twice a day or 400/400 mg twice a day] and lopinavir/ritonavir [400/400 mg twice a day] can be co-administered with rifampicin (66,67). Highly Active Antiretroviral Treatment and Rifabutin-based Antituberculosis Treatment

Figure 40.2: World Health Organization guidelines on timing of antiretroviral treatment in patients with HIV-TB co-infection HIV = human immunodeficiency virus; TB = tuberculosis; HAART = highly active antiretroviral therapy; OI = opportunistic infection Reproduced with permission from “Sharma SK, Mohan A, Kadhiravan T. HIV-TB co-infection: epidemiology, diagnosis and management. Indian J Med Res 2005;121:550-67 (reference 3)”

therapy, because the toxicity of TB treatment is greatest during this period. In patients with CD4+ count greater than 350 cells/mm3, the ART should be deferred and the patient is monitored closely. Highly Active Antiretroviral Treatment and Rifampicin-based Antituberculosis Treatment Details of HAART and antituberculosis treatment are provided in Table 40.7. Co-administration of triple drug regimen of NRTI or nucleotide reverse transcriptase inhibitor [NtRTIs] with rifampicin does not require dose modification of antiretroviral drugs, as there are no drugdrug-interactions. However, the drug regimen is of lower potency for HIV/AIDS treatment. Non-nucleoside reverse transcriptase inhibitor-based regimen consists of two NRTI/NtRTIs in combination with a NNRTI [EFV or NVP] and rifampicin-based antituberculosis treatment. The standard dose of NVP [200 mg twice a day] can be used concomitantly with rifampicin (68,69). While both dosages of EFV [600 and 800 mg per day] have been used (70), CDC guidelines recommend daily dose of 800 mg of EFV when administered concomitantly with rifampicin (66,67)

While rifabutin [RBT] is costly, it provides a better option for concomitant use with PIs. Two NRTIs/NtRTIs in combination with any of the available PIs and NNRTI can be co-administered with RBT-based except for saquinavir, ritonavir or delavirdine (66,67). The dose of nelfinavir [750 mg to 1000 mg three times a day] and indinavir [800 mg to 1000 mg three times a day] should be increased. The dose of rifabutin [300 mg three times a week, when used with nelfinavir, indinavir, amprenavir and fosamprenavir and 150 mg three times a week when concurrently used with atazanavir or ritonvir-boosted PI regimens] should be decreased. The dose of rifabutin should be increased to 600 mg three times a day when co-administered with EFV (66,67). When patients already receiving ART develop TB, the ART regimen should be adjusted to be compatible with antituberculosis treatment. Following completion of antituberculosis treatment, the ART regimen can be continued or changed depending upon the clinical and immunologic status of the patient. When rifampicin is being used, ART regimens containing EFV and ABC are preferred for use in older and younger children respectively. However, in many countries in South-East Asia, ABC is not available in liquid formulation and the tablet form is expensive. If ABC and PIs are not available, NVP is an acceptable alternative. Serum NVP level is lowered by approximately 30 per cent when concurrently used with rifampicin. Therefore, it is reasonable to increase the dose of NVP by around 20 per cent when rifampicin is being coadministered. When used along with rifampicin, the dose of EFV should be increased by 20 to 30 per cent. Treatment and Response to Therapy While majority of the HIV seropositive patients with pulmonary TB will respond to the standard antituber-

Tuberculosis and Human Immunodeficiency Virus Infection 583 Table 40.7: Co-administration of highly active antiretroviral therapy and antituberculosis treatment Rifampicin-based antituberculosis drug regimen

NNRTI EFV NVP PI Saquinavir/ritonavir Lopinavir/ritonavir

Dose

NRTI/NtRTI backbone

600 or 800 mg qd 200 mg bid

2NRTI/NtRTIs 2NRTI/NtRTIs

1000/100 mg bid or 400/400 mg bid 400/400 mg bid

2NRTI/NtRTIs 2NRTI/NtRTIs

Rifabutin-based antituberculosis drug regimen

NNRTI EFV NVP PI Indinavir Nelfinavir Amprenavir Fosamprenavir Atazanavir Lopinavir/ritonavir Ritonavir combined with amprenavir, indinavir, fosamprenavir or saquinavir

Dose

Nucleoside backbone

Rifabutin dose

600 mg qd 200 mg bid

2NRTI/NtRTIs 2NRTI/NtRTIs

600 mg qd or 600 mg qod 300 mg qd or 300 mg three times a week

1000 mg tid 1000 mg tid 1200 mg bid 1400 mg bid 400 mg qd 400/100 mg bid

2NRTI/NtRTIs 2NRTI/NtRTIs 2NRTI/NtRTIs 2NRTI/NtRTIs 2NRTI/NtRTIs 2NRTI/NtRTIs

300 mg three times a week 300 mg three times a week 300 mg three times a week 300 mg three times a week 150 mg three times a week 150 mg three times a week

400/100 mg bid

2NRTI/NtRTIs

150 mg three times a week

NRTIs do not have drug-drug interaction with PIs Co-administration of three NRTIs is an inferior regimen NRTI = nucleoside reverse transcriptase inhibitor; NtRTI = nucleotide reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; EFV = efavirenz; NVP = nevirapine; qd = once daily; bid = twice daily; qod = every other day; tid = thrice daily; PI = protease inhibitor Adapted from reference 65

culosis treatment. Some evidence is available suggesting that the chances of relapse of TB in HIV-seropositive individuals are also higher than in HIV-seronegative individuals. Hence, it may be useful to prolong the continuation phase of treatment to reduce the chances of relapse. In intravenous drug users and in other cases where compliance is likely to be poor, a fully supervised regimen is recommended. The safety of streptomycin injections in areas with high prevalence of HIV infection must be taken into consideration, if the standards of sterilization are suspect. One should ensure high standards of sterilization. If at all possible, one should use disposable syringes and needles and make sure that they are destroyed after use (71).

IMMUNE RECONSTITUTION SYNDROME IN HUMAN IMMUNODEFICIENCY VIRUS– TUBERCULOSIS CO-INFECTED PATIENTS With increased co-prevalence of TB and HIV and increasing access to ART in the developing world, clinicians in these countries should be able to identify immune reconstitution inflammatory syndrome [IRIS] and relieve symptoms without compromising clinical care (3,72,73). The HAART for HIV infection suppresses viral replication, allowing the partial restoration of the immune system. This immune reconstitution, however, can result in an inflammatory response against infectious and non-infectious antigens and apparent clinical deterioration of the patient. This phenomenon has been

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described as IRIS. The IRIS can occur with many concomitant infections including Mycobacterium tuberculosis, nontuberculous mycobacteria [NTM], leishmania, fungal and viral infections. Other diseases, such as sarcoidosis, Grave’s disease and lymphomas, can also occur as a part of the IRIS. Though IRIS is a widely recognized phenomenon, various non-standardized general case definitions have been used to describe in the published literature. The case definitions for paradoxical TBassociated IRIS, ART-associated TB and unmasking TBassociated IRIS [provisional] have been recently described (73). These definitions can be used in resourcelimited settings also and their use is expected to facilitate standardization and comparability of data. Several risk factors for development of paradoxical IRIS include: [i] a low baseline CD4+ cell count; [ii] a higher baseline viral load; [iii] a shorter interval between commencing antituberculosis treatment and HAART; [iv] disseminated TB; [v] a greater increase in CD4+ cell count; and [vi] a greater reduction in viral load after starting HAART. The manifestations of IRIS include hectic fever, increase in size or development of lymphadenopathy, appearance of new lesions or worsening of existing pulmonary infiltrates, and development of respiratory failure. Other manifestations include occurrence or worsening of pleuritis, pericarditis, or ascites, intracranial tuberculomas, meningitis, disseminated skin lesions, epididymitis, hepatosplenomegaly, soft tissue abscesses (3,72,73). The IRIS is a diagnostic challenge and remains a diagnosis of exclusion. Drugresistant TB and alternative diagnoses [other OIs] must be ruled out. Conversion of TST from negative to positive is a common finding during IRIS. Paradoxical reactions have a median duration of about eight weeks but may last longer especially those associated with lymphadenopathy. Most of these cases are self-limiting. Usually, treatment with non-steroidal anti-inflammatory drugs [NSAIDs] is sufficient. Antituberculosis drugs and HAART treatment should be continued in patients with IRIS. However, corticosteroids may be indicated for very severe IRIS and HAART may be temporarily withheld in patients with very severe and life-threatening IRIS. Surgical intervention may be required for indications such as organ rupture and drainage of abscesses etc.

Drug-Resistant Tuberculosis In early 1990, several institutional outbreaks of multidrugresistant TB [MDR-TB] among HIV infected patients drew attention to the problem (70). However, HIV infection per se does not appear to be a predisposing factor for the development of MDR-TB. Recent studies have found that drug-resistant TB including MDR-TB is no more common among people infected with HIV (74,75). Several factors can contribute to outbreaks of MDRTB. Increasing incidence of TB in some areas will bring more persons with active, infectious TB into institutional settings such as health care and correctional facilities, many of which serve populations in which there is also a high proportion of HIV infected persons. This will create practices for controlling the transmission of airborne disease. In addition, recognition of drugresistant TB is often delayed because current methods for diagnosing TB and performing drug susceptibility tests require weeks to months, especially in resource limited settings. Furthermore, the selection of drugs available for treating TB is limited, which makes the treatment of drug-resistant cases particularly difficult. Recent findings suggest that once or twice weekly therapy including isoniazid and a rifamycin increases the risk of acquired rifamycin resistance among TB patients with advanced HIV disease with very low CD4+ cell count [< 60/mm 3 ] (76,77). It has, thus, been recommended that persons with HIV-TB and CD4+ cell counts less than or eual to 100/mm3 should not be treated with highly intermittent [i.e., once or twice weekly] regimens. These patients should receive daily therapy during the intensive phase and daily or three doses a week during the continuation phase, preferably under directly observed therapy (76,77). These issues merit further study. Treatment of MDR-TB is usually more problematic since both isoniazid and rifampicin become less effective. Commonly, regimens that include five or six drugs are necessary. Initial drugs must be chosen depending on the local pattern of drug susceptibility. Modifications may be required based on the results of susceptibility testing of the organisms isolated from the patient. The use of second-line antituberculosis drugs is frequently associated with toxicity and intolerance. Patients may need admission to hospital at the beginning of treatment.

Tuberculosis and Human Immunodeficiency Virus Infection 585 The reader is referred to the chapter “Drug resistant tuberculosis” [Chapter 49] for more details topic. Extensively Drug-resistant Tuberculosis [XDR-TB] Following an earlier description of a lethal outbreak in HIV infected patients in South Africa (78), extensively drug-resistant TB [XDR-TB] has been described worldwide (79-82). Extensively drug-resistant TB is defined as MDR-TB that includes resistance to any fluoroquinolones and one of the second-line antituberculosis injectable agents, kanamycin, amikacin, or capreomycin, is potentially untreatable. The reader is referred to the chapter “Drug-resistant tuberculosis” [Chapter 49] for more details topic. CONTROLLING TUBERCULOSIS TRANSMISSION IN SETTINGS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTED PERSONS Inexpensive infection control measures can be implemented to help reduce transmission of TB in health care facilities at the district or referral level hospitals. This will reduce exposure of Mycobacterium tuberculosis including drug-resistant strains to immunocompromised persons as well as health care workers. The reader is referred to the chapter “Tuberculosis in health care workers” [Chapter 45] for more details topic. ROLE OF BACILLE CALMETTE-GUERIN VACCINATION IN PREVENTING TUBERCULOSIS IN HUMAN IMMUNODEFICIENCY VIRUS INFECTED INDIVIDUALS The benefit of bacille Calmette-Guerin [BCG] is in protecting young children against disseminated and severe TB, such as TB meningitis and miliary TB. The BCG vaccine has little or no effect in reducing the number of adult cases with pulmonary TB. It is not known if HIV infection reduces the protection conferred by BCG against TB in children. There is some evidence that conversion to a positive TST after BCG is less frequent in HIV infected children. The significance of this finding for protection against TB is not clear. There have been a few case reports of local complications and disseminated BCG disease following BCG immunization in HIV infected children. However, prospective studies comparing BCG immunization in HIV infected and uninfected infants showed no difference in risk of complications. Therefore, in the

Table 40.8: World Health Organization recommended policy on bacille Calmette-Guerin in human immounodeficiency virus infection Country TB prevalence

WHO recommended policy

High

BCG for all children [according to standard programme] except children with symptoms of HIV disease/AIDS Do not give BCG immunization to HIV infected children

Low

WHO = World Health Organization; TB = tuberculosis; BCG = bacille Calmette-Guerin; HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome

vast majority of cases, BCG immunization is considered to be safe. The WHO recommended policy depends on the TB prevalence in a country, as shown in Table 40.8. In a country with high TB prevalence, the possible benefits of BCG immunization outweigh the possible disadvantages. PREVENTION Preventing HIV-associated TB as public health action goes beyond the full implementation of DOTS. It includes preventing HIV infection in the first place, as well as preventing progression of latent TB infection [LTBI] to active disease and the provision of HIV/AIDS care and treatment. In 2002, WHO Regional Office for South-East Asia developed a HIV/TB regional strategic plan following discussions held among the Joint National AIDS and TB Programme Managers and Global TB/HIV Working Group Meetings. The plan has adapted to the epidemiology and the ongoing national responses to HIV and TB in the region and it is also consistent with Global TB/HIV Strategic Framework (83,84). The goal of the strategy is to reduce HIV/TB-associated morbidity and mortality. To achieve the above goal the plan has proposed four strategies including preventing HIV transmission and progression of LTBI to active TB among HIV infected individuals. Interventions related to preventing increase in number of HIV-TB co-infection call for control of both epidemics as well as intensified efforts that require collaboration between two programmes. Since HIV fuels the TB epidemic, interventions to prevent HIV transmission should contribute to decreasing the TB burden. Reduction in the number of sexual partners, expanding

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Tuberculosis

access to condoms, syndromic management of sexually transmitted infections [STIs], harm reduction for injecting drug users [IDUs] and integrated counselling and testing [ICT], [earlier called voluntary counselling and testing, VCT] have all been shown to be effective in preventing HIV infection. The most efficient way to prevent the spread of HIV is to target populations with high HIV case reproduction number, e.g., those with the most sexual partners and IDUs who share needles and syringes. Among the range of measures with immediate impact in decreasing HIV transmission are 100 per cent condom use programme, management of STIs and needle-syringe exchange programmes. Thailand has shown the effectiveness of the “100 per cent condom programme” targeting commercial sex workers and their clients in brothels on a national scale. It is well known that the HIV epidemic started in IDU population in several Asian countries and then spread to other risk groups and the general population. Harm reduction through provision of sterile injecting equipment, peer education and continuing drug treatment are proven to be effective in preventing HIV transmission among IDUs. Majority of TB patients do not know their HIV status and several HIV infected TB patients receive antituberculosis treatment regardless of their HIV status. Such patients, therefore, do not have access to prevention and treatment of HIV associated OIs and ART. Similarly, many of the HIV-seropositive individuals may be harbouring TB which may be undetected unless specifically looked for. The ICT services can serve these purposes. The recommended intervention to obtain an HIV test result is voluntary and confidential process by which the client chooses to be tested. This process includes pre-test counselling, HIV testing, and post-test counselling for both HIV-seropositive and HIV-seronegative persons. Post-test counselling for HIV-seropositive individuals should always include information about the symptoms of common HIV-related illnesses in particular TB. The ICT can also be an effective entry point to HIV/TB activities directed towards preventing progression of LTBI to active disease and reducing HIV-related morbidity among TB patients. Intensified TB case finding is meant for screening HIV-seropositive people for TB symptoms. Intensified case finding has two-fold purpose – to consider those with LTBI for treatment and to refer those who are

symptomatic for investigation and treatment of active TB. Screening should occur both in the ICT setting and also in the HIV care setting on a regular basis. The HIV is the most potent known risk factor for progression to active TB both in people with recently acquired infection and those with latent Mycobacterium tuberculosis infection. The annual risk of developing TB in HIV infected individuals co-infected with Mycobacterium tuberculosis ranges from five to ten per cent. Up to 60 per cent of TST positive people with HIV/AIDS develop active TB during their lifetime compared to about 10 per cent of purified protein derivative [PPD] positive HIV-seronegative individuals [Figure 40.3]. The HIV increases the rate of recurrent TB, either due to endogenous reactivation or exogenous re-infection. An increase in the number of TB cases in PLHIV augments the risk of TB transmission to the general community. Treatment of LTBI is thought to decrease the risk of a first or recurrent episode of TB. The WHO and UNAIDS recommend treatment of LTBI for six months for TSTpositive, HIV infected individuals who do not have TB disease. A six-month course of treatment with daily isoniazid [5 mg/kg] is effective in preventing progression of Mycobacterium tuberculosis infection to disease. Among PLHIV, treatment of LTBI is likely to provide protection against the risk of developing TB through two mechanisms. First one is by decreasing the risk of progression of recent infection, and secondly, by decreasing the risk of reactivation of latent Mycobacterium tuberculosis infection. In populations with high TB prevalence, the duration of benefit following completion of a six-month course of isoniazid treatment is limited [up to 2.5 years]. This is probably due to continued exposure to Mycobacterium tuberculosis. The duration of protection depends on the duration of preventive treatment.

Figure 40.3: Lifetime risk of active TB TB = tuberculosis; TST = tuberculin skin test; HIV = human immunodeficiency virus; + = positive; – = negative

Tuberculosis and Human Immunodeficiency Virus Infection 587 Table 40.9: Potential disadvantages and necessary precautions of treatment of latent tuberculosis infection Potential disadvantage

Necessary precaution

Risk of drug toxicity [especially liver damage]

Do not give to people with chronic disease or who regularly drink excessive amounts of alcohol

Emergence of drug resistance [if the patient has undetected TB disease and not just Mycobacterium tuberculosis infection]

In all cases exclude TB disease by sputum microscopy and chest radiograph

Diversion of resources from NTP activities

Funding must be from sources other than NTP [e.g., AIDS control programme, voluntary sector] or extra funding sources for the NTP must be found. Treatment of latent TB infection could be integrated into HIV care package under responsibility of AIDS unit

TB = tuberculosis; NTP = National Tuberculosis Programme; HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome

Data from the former Zaire [now the Democratic Republic of Congo], and in Haiti showed a higher rate of recurrent TB in HIV infected individuals than in nonHIV-infected individuals treated with a six-month regimen containing rifampicin (85,86). In Zaire and Haiti, post-treatment prophylaxis [isoniazid and rifampicin in the study in Zaire and isoniazid in the study in Haiti] decreased the risk of TB recurrence in HIV-infected individuals, but did not prolong survival. Further studies are needed to confirm the benefit, establish the optimum regimen [drugs and duration] and assess operational feasibility, before widely recommending treatment aimed at decreasing risk of TB recurrence. Preventive treatment for all individuals infected with Mycobacterium tuberculosis is not a recommended TB control strategy. It may be cost-effective only if it is targeted to high-risk groups. Young children are at special risk, especially if they are HIV-infected since it is a potent cause of progression of Mycobacterium tuberculosis infection to TB disease, like in adults. A breastfeeding infant has a high risk of infection from a mother with pulmonary TB, and a high risk of developing TB. Similarly, children under six years of age with household contact of adults with sputum smear-positive pulmonary TB are at high risk. The theoretical benefits of treatment of LTBI are attractive. However, the Table 40.9 shows the potential disadvantages and necessary precautions. In India, the role of chemoprophylaxis with a single drug has not been clearly documented to be useful. But, because of the prevalence of a significant proportion of isoniazid-resistant strains of Mycobacterium tuberculosis

in the community in different studies done in India, a combination of drugs may be required to prevent onset of TB in HIV-seropositive individuals. However, it is worth to note that some studies indicate that short-course multi-drug regimens, compared to isoniazid monotherapy, were much more likely to require discontinuation of treatment due to adverse effects. The choice of regimen will depend on factors, such as costs, adverse effects, adherence and drug resistance. Appropriate policy on treatment of LTBI needs to be set up based on above scientific findings and feasible strategies should be identified where pertinent. REFERENCES 1. Raviglione MC, Snider DE, Kochi A. Global epidemiology of tuberculosis; morbidity and mortality of a worldwide epidemic. JAMA 1995;273:220-6. 2. Narain JP, Raviglione MC, Kochi A. HIV-associated tuberculosis in developing countries: epidemiology and strategies for prevention. Tuber Lung Dis 1992;73:311-21. 3. Sharma SK, Mohan A, Kadhiravan T. HIV-TB co-infection: epidemiology, diagnosis and management. Indian J Med Res 2005;121:550-67. 4. World Health Organization. A guide to monitoring and evaluation for collaborative TB/HIV activities. WHO/HTM/ TB/2004.342, WHO/HIV/2004.09. Geneva: World Health Organization; 2004. 5. Sharma SK, Kadhiravan T, Banga A, Goyal T, Bhatia I, Saha PK. Spectrum of clinical disease in a series of 135 hospitalised HIV-infected patients from north India. BMC Infect Dis 2004;4:52. 6. WHO Report 2005. Global Tuberculosis Control: surveillance, planning, financing. WHO/HTM/TB/2005.349. Geneva: World Health Organization; 2005.

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Tuberculosis

7. WHO Report 2008. Global Tuberculosis Control: surveillance, planning, financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008. 8. Narain JP. Tuberculosis and AIDS: the growing epidemic. AIDS watch 1997;1:1-2. 9. Dandona L, Dandona R. Drop of HIV estimate for India to less than half. Lancet 2007;370:1811-3. 10. UNAIDS, World Health Organization, AIDS epidemic update. Available at URL: http://data.unaids.org/pub/ EPISlides/2007/2007_epiupdate_en.pdf. Accessed on February 08, 2008. 11. Joint United Nations Programme on HIV/AIDS, 2006 report on the global AIDS epidemic.Available at URL: http:// www.unaids.org/en/HIV_data/2006GlobalReport/ default.asp. Accessed on January 31, 2008. 12. Tuberculosis Control in South-East Asia and Western Pacific Regions 2005. A Bi-Regional Report. Geneva: World Health Organization; 2005. 13. Narain JP. AIDS in Asia: the challenge ahead. New Delhi: Sage Publishers: 2004. 14. Narain JP, Lo YR. Epidemiology of HIV-TB in Asia. Indian J Med Res 2004;120:277-89. 15. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009-21. 16. Tuberculosis estimates 2002. Available at URL: http:// www.who.int/docstore/ gtb/tbestimates/2002tbestimates. xls. Accessed on August 08, 2008. 17. Sharma SK, Saha PK, Dixit Y, Siddaramaiah NH, Seth P, Pande JN. HIV seropositivity among adult tuberculosis patients in Delhi. Indian J Chest Dis Allied Sci 2000;42: 157-60. 18. Sharma SK, Aggarwal G, Seth P, Saha PK. Increasing HIV seropositivity among adult tuberculosis patients in Delhi. Indian J Med Res 2003;117:239-42. 19. Piramanayagam P, Tahir M, Sharma SK, Smith-Rohrberg D, Biswas A, Vajpayee M. Persistently high HIV seroprevalence among adult tuberculosis patients at a tertiary care centre in Delhi. Indian J Med Res 2007;125:163-7. 20. Ramachandran R, Datta M, Subramani R, Baskaran G, Paramasivan CN, Swaminathan S. Seroprevalence of human immunodeficiency virus [HIV] infection among tuberculosis patients in Tamil Nadu. Indian J Med Res 2003;118:147-51. 21. Ahmad Z, Bhargava R, Pandey RK, Sharma K. HIV infection seroprevalence in tuberculosis patients. Indian J Tuberc 2003;50:151-4. 22. Shahab T, Zoha MS, Malik MA, Malik A, Afzal K. Prevalence of human immunodeficiency virus infection in children with tuberculosis. Indian Pediatr 2004;41:595-9. 23. Prasad R, Saini JK, Kannaujia RK, Sarin S, Suryakant, Kulshreshth R, et al. Trend of HIV Infection in patients with pulmonary tuberculosis in Lucknow area. Indian J Tuberc 2003;50:39-42. 24. Purohit SD, Gupta RC, Bhattara VK. Pulmonary tuberculosis and human immunodeficiency virus infection in Ajmer. Lung India 1996;14:113-20.

25. Mohanty KC, Basheer PMM. Changing trend of HIV infection and tuberculosis in Bombay area since 1988. Indian J Tuberc 1995;42;117-20. 26. Paranjape RS, Tripathy SP, Menon PA, Mehendale SM, Khatavkar P, Joshi DR, et al. Increasing trend of HIV seroprevalence among pulmonary tuberculosis patients in Pune. Indian J Med Res 1997;106:207-11. 27. Tripathy SP, Joshi DR, Menon P, Paranjape RS, Mehendale SM, Khatavkar P. Seroprevalence of HIV-1 infection in tuberculosis patients at Pune, India. Paper presented at the XI international conference on AIDS, Vancouver, Canada July 7-12 1996. 28. Solomon S, Anuradha S, Rajasekaran S. Trend of HIV infection in patients with pulmonary tuberculosis in south India. Tuber Lung Dis 1995;76:17-9. 29. Samuel NM, Alamelu C, Jagannath K, Rajan BP. Detection of HIV infection in pulmonary tuberculosis patients. J Indian Med Assoc 1996;94:331-3. 30. Antituberculosis drug resistance in the world, 1997. The WHO/IUTALD Global Project on Anti-tuberculosis Drug Resistance Surveillance 1994-1997. WHO/TB/97.229. Geneva: World Health Organization; 1997. 31. Banavaliker JN, Gupta R, Sharma DC, Goel MK, Kumari S. HIV seropositivity in hospitalized pulmonary tuberculosis patients in Delhi. Indian J Tuberc 1999;44:17-20. 32. Gupta PR, Luhadia SK, Gupta SN, Joshi V. Tuberculosis in human immunodeficiency virus seropositives in Rajasthan. Indian J Tuberc 1998;16:147-9. 33. Talib SH, Bansal MP, Kamble MM. HIV-1 seropositivity in pulmonary tuberculosis. Indian J Pathol Microbiol 1993;36:383-8. 34. Vasudeviah V. HIV infection among tuberculosis patients. Indian J Tuberc 1997;44:97-8. 35. Interim WHO clinical staging of HIV/AIDS and HIV/AIDS case definitions for surveillance. WHO/HIV/2005.02. 36. National Framework for Joint TB/HIV Collaborative Activities [May 2007]. Available at URL: http:// www.tbcindia.org/pdfs/National%2 HIVTB%20 Action%20 Plan%20 November %202001.pdf. Accessed on January 31, 2008. 37. Pitchenik AE, Cole C, Russell BW, Fischl MA, Spira TJ, Snider DE Jr, et al. Tuberculosis, atypical mycobacteriosis and AIDS among Haitians and non-Haitian patients in South Florida. Ann Intern Med 1984;101:641-5. 38. Sunderam G, MacDonald RJ, Maniatis T, Oleske J, Kapila R, Reichman LB. Tuberculosis as a manifestation of AIDS. JAMA 1986;256:362-6. 39. Pitchenik AE, Fertel D, Bloch AB. Mycobacterial disease; epidemiology, diagnosis, treatment and prevention. Clin Chest Med 1988;94:25-41. 40. Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1999;340: 367-73. 41. Theuer CP, Hopewell PC, Elias D, Schecter GF, Rutherford GW, Chaisson DE. Human immunoiodeficiency virus infection in tuberculosis patients. J Infect Dis 1990;162:8-12. 42. Murray JF, Felton CP, Garay SM, Gottlieb MS, Hopewell PC, Stover DE, et al. Pulmonary complications of AIDS; report

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43.

44. 45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

of a nation heart, lung and blood workshop. N Engl J Med 1984;310:1682-8. Narain JP, Chela C, van Praag E. Planning and implementing HIV/AIDS care programmes: a step-by-step approach. WHO Project ICP OCD 041. SEA/AIDS/106. New Delhi: World Health Organization Regional Office for South-East Asia; 1998. Ministry of Public Health Thailand. Thai AIDS Newsletter; 2003. Hira SK, Dore GJ, Sirisanthana T. Clinical spectrum of HIV/ AIDS in the Asia-Pacific Region. AIDS 1998;12[SupplB]: S145-54. Wiktor SZ, Sassan-Morokro M, Grant AD, Abouya L, Karon JM, Maurice C, et al. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Côte d’Ivoire: a randomised controlled trial. Lancet 1999;353: 1469-75. Wagner KR, Bishai WR. Issues in the treatment of Mycobacterium tuberculosis in patients with human immunodeficiency virus infection. AIDS 2001;15[Suppl5]:S203-12. British HIV Association. BHIVA treatment guidelines for TB/ HIV infection September 2004; p 1-32. Available at http:// www.bhiva.org. Accessed on December 22, 2007. Joint WHO/UNAIDS/UNICEF statement on use of cotrimoxazole as prophylaxis in HIV exposed and HIV infected children. Available at URL: http://www.who.int/ 3by5/ mediacentre/news32/en/print.html. Accessed on August 08, 2008. World Health Organization. Scaling up antiretroviral therapy in resource-limited settings: treatment guidelines for a public health approach. 2003 revision. Geneva: World Health Organization; 2004. USPHA/IDSA Guidelines for the prevention of opportunistic infections in persons infected with Human Deficiency Virus; 2001. Available at URL: http://www.cdc.gov/mmwr/ preview/ mmwrhtml/rr5108a1.htm. Accessed on on August 08, 2008. Ministry of Public Health Thailand. National guidelines for the clinical management of HIV infection in children and adults. Sixth edition. Nonthaburi: AIDS Division, Department of Communicable Disease Control; 2000. World Health Organization. Involvement of people living with HIV/AIDS in treatment preparedness. Case Study. Geneva: World Health Organization; 2004. World Health Organization. Towards universal access by 2010: how WHO is working with countries to scale-up HIV prevention, treatment, care and support. Available at http: //www.who.int/hiv/toronto2006/towardsuniversalaccess.pdf. Accessed on August 08, 2007. Brinkhof MW, Egger M, Boulle A, May M, Hosseinipour M, Sprinz E, et al. Antiretroviral Therapy in Low-Income Countries Collaboration of the International epidemiological Databases to Evaluate AIDS (IeDEA); ART Cohort Collaboration, Tuberculosis after initiation of antiretroviral

56.

57. 58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

therapy in low-income and high-income countries. Clin Infect Dis 2007;45:1518-21. Epub 2007 Oct 22. Harries A, Maher D, Graham S. TB/HIV. A clinical manual. Second edition. WHO/HTM/TB/2004.329. Geneva: World Health Organization; 2004. Narain JP, Pontali E, Tripathy S. Epidemiology and control strategy. Indian J Tuberc 2002;49:3-9. Santora-Lopes G, de Pinho AM, Harrison LH, Schechter M. Reduced risk of TB among Brazilian patients with advanced human immunodeficiency virus infection treated with highly active antiretroviral therapy. Clin Infect Dis 2002;34:543-6. Oliva J, Moreno S, Sanz J, Ribera E, Molina JA, Rubio R, et al. Co-administration of rifampin and nevirapine in HIVinfected patients with tuberculosis. AIDS 2003;17:637-8. Ribera E, Pou L, Lopez RM, Crespo M, Falco V, Ocaña I, et al. Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients with tuberculosis. J Acquir Immune Defic Syndr 2001;28:450-3. Centers for Disease Control and Prevention. Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors. Atlanta: Centers for Disease Control and Prevention; 2004. Available at URL: www.cdc.gov/nchstp/ tb/TB_HIV_ Drugs/PDF /tbhiv.pdf. Accessed on February 03, 2008. Pedral-Samapio D, Alves C, Netto E, et al. Efficacy of efavirenz 600 mg dose in the ARV therapy regimen for HIV patients receiving rifampicin in the treatment tuberculosis. Boston: 10th Conference on Retroviruses and Opportunistic Infections, February 2003 [abstract 784] Available at URL: www.retroconference.org/2003/Abstract/Abstract.aspx? AbstractID51930. Accessed on February 03, 2008. Hung C-C, Lee H-C, Hsieh S-M, et al. Effectiveness of highly active antiretroviral therapy and antituberculous therapy combinations among HIV-infected patients with active tuberculosis. San Francisco, CA: 11th Conference on Retroviruses and Opportunistic Infections, February 2004. [abstract 763]. Available at URL: www.retroconference.org/ 2004/cd/ abstr act/763.htm. Accessed on February 03, 2008. Department of Health and Human Services [DHHS]. Guidelines for the use of antiretroviral agents in HIV-1infected adults and adolescents. Bethesda, MD: DHSS, National Institutes for Health, March 2004. Available at URL: http://www.aidsinfo.nih. gov/guidelines/adult/AA_ 111003.pdf. Accessed on February 03, 2008. Kwara A, Flanigan TP, Carter EJ. Highly active antiretroviral therapy HAART in adults with tuberculosis: current status. Int J Tuberc Lung Dis 2005;9:248-57. Burman WJ, Jones BE. Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy. Am J Respir Crit Care Med 2001;164:7-12. American Thoracic Society Documents. American Thoracic Society/Centers for Disease Control and Prevention/ Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603-62.

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Tuberculosis

68. Avihingsanon A, Manosuthi W, Kantipong P, Chuchotaworn C, Moolphate S, Sakornjun W, et al. Pharmacokinetics and 48-week efficacy of nevirapine: 400 mg versus 600 mg per day in HIV-tuberculosis coinfection receiving rifampicin. Antivir Ther 2008;13:529-36. 69. Aaron L, Saadoun D, Calatroni I, Launay O, Mémain N, Vincent V, et al. Tuberculosis in HIV-infected patients: a comprehensive review. Clin Microbiol Infect 2004;10:388-98. 70. Centers for Disease Control and Prevention. Transmission of multidrug-resistant tuberculosis among immunocompromised persons in a correctional system – New York, 1991. MMWR Morb Mortal Wkly Rep 1992; 41:507-9. 71. Tahir M, Sharma SK, Smith-Rohrberg D. Unsafe medical injections and HIV transmission in India. Lancet Infect Dis 2007;7:178-9. 72. McIlleron H, Meintjes G, Burman WJ, Maartens G. Complications of antiretroviral therapy in patients with tuberculosis: drug interactions, toxicity, and immune reconstitution inflammatory syndrome. J Infect Dis 2007;196 [Suppl 1]:S63-75. 73. Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W, et al; International Network for the Study of HIV-associated IRIS. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008;8:51623. 74. Asch S, Knowles L, Rai A, Jones BE, Pogoda J, Barnes PF. Relationship of isoniazid resistance to human immunodeficiency virus infection in patients with tuberculosis. Am J Respir Crit Care Med 1996;153:1708-10. 75. Spellman CW, Matty KJ, Weis SE. A survey of drug-resistant Mycobacterium tuberculosis and its relationship to HIV infection. AIDS 1998;12:191-5. 76. Burman W, Benator D, Vernon A, Khan A, Jones B, Silva C, et al; Tuberculosis Trials Consortium. Acquired rifamycin resistance with twice-weekly treatment of HIV-related tuberculosis. Am J Respir Crit Care Med 2006;173:350-6. Epub 2005 Aug 18.

77. Nahid P, Gonzalez LC, Rudoy I, de Jong BC, Unger A, Kawamura LM, et al. Treatment outcomes of patients with HIV and tuberculosis. Am J Respir Crit Care Med 2007;175: 1199-206. Epub 2007 Feb 8. 78. Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, Lalloo U, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006;368:1575-80. 79. Centers for Disease Control and Prevention [CDC]. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs–worldwide, 2000-2004. MMWR Morb Mortal Wkly Rep 2006;55:301-5. 80. Shah NS, Wright A, Bai GH, Barrera L, Boulahbal F, MartínCasabona N, et al. Worldwide emergence of extensively drugresistant tuberculosis. Emerg Infect Dis 2007;13:380-7. 81. World Health Organization . Case definition for extensively drug-resistant tuberculosis. Wkly Epidemiol Rec 2006;81:408. 82. World Health Organization. Addressing the threat of tuberculosis caused by extensively drug-resistant tuberculosis. Wkly Epidemiol Rec 2006;81:386-90. 83. World Health Organization Regional Office for South-East Asia. Regional strategic plan on HIV/TB. SEA/TB/261, SEA/ AIDS/140. New Delhi: World Health Organization Regional Office for South-East Asia; 2003. 84. World Health Organization Regional Office for South-East Asia. HIV/AIDS. SEARO Publications on HIV/AIDS, Tuberculosis and HIV–Some Questions and answers. Available at URL: http://www.searo.who.int/en/ Section10/Section18/Section356/ Section421_1624.htm. Accessed on November 3, 2008. 85. Perriëns JH, St.Louis ME, Mukadi YB, Brown C, Prignot J, Pouthier F, et al. Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled trial of treatment for either 6 or 12 months. N Engl J Med 1995;332:779-84. 86. Chaisson RE, Clermont HC, Holt EA, Cantave M, Johnson MP, Atkinson J, et al. Six-month supervised intermittent tuberculosis therapy in Haitian patients with and without HIV infection. Am J Respir Crit Care Med 1996;154:1034-8.

Tuberculosis in Children

41 SK Kabra, Rakesh Lodha

INTRODUCTION Tuberculosis [TB] is one of the major infections affecting children worldwide. It causes a significant morbidity and mortality, especially in infants and young children as TB infection can progress rapidly to disease, particularly in this group. Tuberculosis in children reflects the prevalence of the disease in adults as well as current transmission rates in the community. Children born to human immunodeficiency virus [HIV] infected parents, whether infected or not, are at high risk of developing TB because of the increased risk of exposure to the disease (1,2). Tuberculosis is more common among the disadvantaged and vulnerable groups in each society and the impact of overcrowding, undernutrition and poverty is particularly severe on children. Mycobacterium tuberculosis infects millions of children worldwide every year, yet accurate information on the extent and distribution of disease in children is not available for most of the world. Recent studies have documented an increase in the occurrence of TB in children, both in developed and developing countries. Mortality rates from TB are also highest in early childhood, mainly due to disseminated forms such as meningeal and miliary TB (3). EPIDEMIOLOGY Since most children acquire the organism from adults in their surroundings, the epidemiology of childhood TB follows that in adults. Global burden of childhood TB is unclear. This is because of the difficulty of confirming the diagnosis of childhood TB. The other important reason is that children do not make a significant

contribution to the spread of TB. In several estimates, childhood TB is estimated to constitute 10 per cent of the TB burden (4). However, available data linking the incidence of TB to the TB caseload represented by children suggest an exponential increase in the proportion of childhood TB. With the rise in the incidence of TB, children may constitute nearly 40 per cent of the caseload in certain high incidence communities (5). Tuberculosis infection and disease among children are much more prevalent in developing countries, where resources for TB control are scarce (6). It is estimated that in developing countries the annual risk of TB infection in children is two to five per cent and in India it is 1.5 per cent (7). The estimated lifetime risk of developing TB disease for a young child infected with Mycobacterium tuberculosis as indicated by positive tuberculin skin test [TST] is about 10 per cent (8). About five per cent of those infected are likely to develop disease in the first two years after infection and another five per cent in rest of their lifetime. These rates increase in HIV infected individuals. Nearly eight to twenty per cent of the deaths caused by TB occur in children (9). The age of the child at acquisition of TB infection has a great effect on the occurrence of TB disease. Approximately 40 per cent of infected children less than one year of age, if left untreated, develop radiologically significant lymphadenopathy or segmental lesions; the comparative figures for children in the age groups one to ten years and 11 to 15 years are 24 per cent and 16 per cent, respectively (10). TRANSMISSION Transmission of Mycobacterium tuberculosis occurs from person-to-person via the inhalation route. Several factors

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are associated with the risk of acquiring Mycobacterium tuberculosis infection (11). The risk of acquiring infection has been associated consistently with the extent of contact with the index case, bacillary burden in the sputum, and the frequency of cough in the index case. Patients with sputum smear-positive pulmonary TB are more likely to transmit infection. Markers of close contact such as residence in urban locality, overcrowding, and lower socio-economic status all are correlated with the acquisition of infection. An increased risk-developing infection has been demonstrated in multiple institutional settings, including nursing homes, correctional institutions, and homeless shelters. The risk of acquiring infection increases with age from infancy to early adulthood, likely attributable to increasing contact with other persons. NATURAL HISTORY The natural history of TB infection is covered in detail in the chapter “Pulmonary tuberculosis” [Chapter 14]. Progressive primary disease is a serious complication of the pulmonary primary complex [PPC] in which the PPC, instead of resolving and calcifying, enlarges steadily and develops into a large caseous centre. The latter then liquefies and may empty into an adjacent bronchus leading to formation of a cavity. This is associated with a large number of bacilli (12). During this stage, the bacilli may spread to other parts of the lobe or the entire lung. This may lead to consolidation of an area of the lung or the development of bronchopneumonia. The cavitary disease is uncommon in children. It may be difficult to differentiate progressive primary disease from a simple TB focus with superimposed acute bacterial pneumonia. On the chest radiograph, the segmental lesion appears as a fan-shaped opacity representing mainly atelectasis and almost always involves that very segment occupied by the primary pulmonary focus (13,14). Some of the manifestations are also the consequence of intrathoracic lymphadenopathy. The enlarged lymph nodes may compress the neighbouring airway (15,16). Ball-valve effect due to an incomplete obstruction may lead to distal air-trapping or focal emphysema (17,18). Enlarged paratracheal nodes may cause stridor and respiratory distress. The subcarinal nodes may impinge on the oesophagus and cause dysphagia. Atelectasis occurs due to complete bronchial obstruction.

Outcome of Bronchial Obstruction Bronchial obstruction may resolve in several ways including: [i] complete expansion and resolution of the chest radiograph findings; [ii] disappearance of the segmental lesions; and [iii] scarring and progressive compression of the lobe or segment leading to bronchiectasis. A caseous lymph node may erode through the wall of the bronchus, leading to TB bronchitis or endobronchial TB. Fibrosis and bronchiectatic changes may supervene. Discharge of Mycobacterium tuberculosis into the lumen may lead to bronchial dissemination of infection. Haematogenous dissemination of Mycobacterium tuberculosis occurs early in the course of the disease when the bacilli find their way into the blood stream through lymph nodes. This may result in foci of infection in various organs. If the host immune system is good, then these foci are contained and disease does not develop. Seeding of apex of the lung leads to development of Simon’s focus. Lowering of host immunity may lead to activation of these metastatic foci and development of disease especially seen in young infants, severely malnourished children, and children with immunodeficiency including HIV infection. Massive seeding of blood stream with Mycobacterium tuberculosis leads to miliary TB, where all lesions are of similar size. This usually occurs within three to six months after initial infection. Pulmonary TB resulting from endogenous reactivation of foci of infection is uncommon in children; but may be seen in adolescents. The commonest site for this type of disease is the apex of the lung [Puhl’s lesion], because the blood flow is sluggish at apex. Regional lymph nodes are usually not involved in this type of TB (19). CLINICAL FEATURES Childhood TB can be broadly classified as intra-thoracic and extra-thoracic TB. Most children develop pulmonary TB. Nonetheless, the recognition of extra-thoracic TB is equally important because of its great potential for causing morbidity. Intrathoracic Tuberculosis The onset of symptoms is generally insidious, but may be relatively acute in miliary TB. Primary infection

Tuberculosis in Children usually passes off unrecognized. Asymptomatic infection is defined as infection evident only as a positive TST, but without any clinical or radiographic manifestations. Children with primary complex predominantly manifest constitutional symptoms in the form of mild fever, anorexia, weight loss, and decreased physical activity. Cough is an inconsistent symptom and may be absent even in advanced disease. Irritating dry cough can be a symptom of bronchial and tracheal compression due to enlarged lymph nodes. In some children, the lymph nodes continue to enlarge even after resolution of parenchymal infiltrates (20,21). This may lead to compression of neighbouring regional bronchus. The PPC is the most commonly encountered presentation in the out-patient setting. In a community setting, primary infection may not be associated with significant constitutional symptoms to warrant medical advice. The PPC may be picked up accidentally during evaluation of intercurrent infections (22). Children with progressive primary disease may present with high-grade fever and cough. Expectoration of sputum and haemoptysis are usually associated with advanced disease and development of cavity or ulceration of the bronchus. Physical findings of consolidation or cavitation depend on the extent of the disease. Abnormal chest signs consist mainly of dullness, decreased air entry, and crepitations. Cavitary pulmonary TB is uncommon in children. However, this may not always be true as is evident from the study by Maniar (23) who reported a series of 75 children, less than two years of age presenting with primary cavitary pulmonary TB. Children with endobronchial TB may present with fever, troublesome cough with or without expectoration. Dyspnoea, wheezing and cyanosis may be present. Occasionally, the child may be misdiagnosed to have bronchial asthma. In a wheezing child less than two years of age, the possibility of endobronchial TB should always be considered, especially if there is a poor response to asthma medications. Partial compression of the airway can lead to emphysema. Features of collapse may be present if a large airway is completely compressed (21,22). Miliary TB is an illness characterized by heavy haematogenous spread and progressive development of innumerable small foci throughout the body. The disease is most common in infants and young children. The onset of illness is often sudden. The clinical manifestations depend on the numbers of disseminated organisms and

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the involved organs. The child may present with highgrade fever. Sometimes, dyspnoea may be a prominent symptom. The physical examination may be unremarkable and occasionally, cyanosis, fine crepitations and rhonchi may be present. These findings may be confused with other acute respiratory infections of childhood. The illness may be severe, with the child having a high fever with rigors and altered sensorium. In addition, these children may have lymphadenopathy and hepatosplenomegaly. Sometimes, miliary TB may present with insidious onset, with fever and loss of weight. Choroid tubercles may be seen in about 50 per cent children. Meningitis may occur in 20 to 30 per cent of cases (21-24). The rupture of a subpleural focus into the pleural cavity may result in pleural effusion. The pleura may also be involved by haematogenous spread from the primary focus. The effusion usually occurs due to hypersensitivity to tuberculoprotein[s]. Minor pleural effusions associated with the rupture of primary foci are usually not detected. Tuberculosis pleural effusion is uncommon in children younger than five years of age, is more common in boys, and is rarely associated with segmental lesion and miliary TB (19). The onset may be insidious or acute with fever, cough, dyspnoea and pleuritic chest pain on the affected side. There is usually no expectoration. The pleuritic pain may disappear once the fluid separates the inflammed pleural surfaces and a vague discomfort may then be felt. An increase in the pleural effusion may make breathing shallow and difficult. The clinical findings depend on the amount of fluid in the pleural sac. In early stages, a pleural rub may be present. Other early signs include decreased chest wall movement, impairment of percussion note and diminished air entry on the affected side. As the fluid collection increases, the signs of pleural effusion become more definite. Sometimes, acute secondary bacterial infection may also occur and the child may, present with a high-grade fever, cough and crepitations. The symptoms and signs respond partially to the conventional antibiotics, but the chest radiographic findings due to underlying TB persist. Calcification of the primary complex occurs more commonly in children. Extra-thoracic Tuberculosis A complete description of extra-thoracic TB is beyond the scope of this chapter, but clinicians must consider

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this possibility when evaluating children with a history of persistent fever. The most common forms of extrathoracic disease in children include TB of the peripheral lymph nodes and the central nervous system. Other rare forms of extra-thoracic disease in children include osteoarticular, abdominal, gastrointestinal, genitourinary, cutaneous, and congenital TB. Tuberculosis of the peripheral lymph nodes can rarely be associated with drinking unpasteurized cow’s milk or can be caused by extension of primary lesions located at the upper lung fields or abdomen leading to involvement of the supraclavicular, anterior cervical, tonsillar, and submandibular nodes. Although lymph nodes may become fixed to surrounding tissues, a low-grade fever may be the only systemic symptom. A primary focus is visible on the chest radiograph only in 30 to 70 per cent of children. The TST is usually reactive. Although spontaneous resolution may occur, in patients with untreated lymphadenitis caseation necrosis, capsular rupture, and spread to adjacent nodes and overlying skin, resulting in a draining sinus tract develop (25). Central nervous system disease is the most serious complication of TB in children and arises from a caseous lesion in the cerebral cortex or meninges that resulted from an early occult lymphohaematogenous spread. Infants and young children are more likely to experience a rapid progression to hydrocephalus, seizures, and cerebral oedema. In older children, signs and symptoms progress over several weeks, beginning non-specifically with fever, headache, irritability, and drowsiness. Disease abruptly advances with symptoms of lethargy, vomiting, nuchal rigidity, seizures, hypertonia, and focal neurologic signs. The final stage of disease is marked by coma, hypertension, decerebrate and decorticate postures, and eventually death. Rapid confirmation of TB meningitis can be extremely difficult because of the wide variability in cerebrospinal characteristics, non-reactive TST results in 40 per cent, and normal chest radiographs in 50 per cent of the cases. Because an improved outcome is associated with early treatment, an empirical antituberculosis treatment should be considered for any child with basilar meningitis and hydrocephalus or cranial nerve involvement that has no other apparent cause (26).

of Mycobacterium tuberculosis or one of its components; and [ii] demonstration of host’s response to exposure to Mycobacterium tuberculosis. The reader is referred to the chapter “Diagnosis of childhood tuberculosis: recent advances and applicability of new tools” [Chapter 42] for more details. Radiology On the chest radiograph, the PPC manifests as an area of airspace consolidation of varying size, usually unifocal, and homogeneous [Figure 41.1]. Enlarged lymph nodes may be seen in the hilar, or right paratracheal region. Sometimes, lymphadenopathy alone may be present in children with primary TB. Consolidation in progressive primary disease is usually heterogeneous, poorly marginated with predilection of involvement of apical or posterior segments of the upper lobe or superior segment of the lower lobe [Figure 41.2]. Features of collapse may as well be present [Figure 41.3]. Bronchiectasis may occur in a progressive primary disease because of: [i] destruction and fibrosis of lung parenchyma resulting in retraction and irreversible bronchial dilatation; and [ii] cicatricial bronchostenosis secondary to localized endobronchial infection resulting in obstructive pneumonitis and distal bronchiectasis. In children, cavitary disease is uncommon [Figure 41.4]. Pleural effusion may occur with or without lung lesions [Figure 41.5]. In miliary TB, the lesions are less than 2 mm in diameter [Figure 41.6].

DIAGNOSIS Laboratory Tests The diagnostic tests for pulmonary TB can be broadly divided into two categories: [i] demonstration/isolation

Figure 41.1: Chest radiograph [postero-anterior view] in a child with progressive primary complex showing left-sided hilar adenopathy and an ill-defined parenchymal lesion

Tuberculosis in Children

Figure 41.2: Chest radiograph [postero-anterior view] in a child with progressive primary disease showing consolidation in the right mid-zone

Figure 41.3: Chest radiograph [postero-anterior view] showing collapse consolidation of the right upper lobe

Occasionally, the chest radiograph may be normal and lymphadenopathy may be evident only on computed tomography [CT]. In addition, CT features such as low attenuation of lymph nodes with peripheral enhancement, calcification, branching centrilobular nodules and miliary nodules are helpful in suggesting the diagnosis in cases where the radiograph is normal or equivocal. Other features such as segmental or lobar consolidation and atelectasis are non-specific (27). In a study by Kim et al (28), CT including high-resolution CT [HRCT] revealed lymphadenopathy, and parenchymal lesions that were not evident in 21 per cent and 35 per cent of the chest radiographs, respectively. The

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Figure 41.4: Chest radiograph [postero-anterior view] showing a cavity [arrow] in the right mid-zone

Figure 41.5: Chest radiograph [postero-anterior view] showing massive pleural effusion on the left side

HRCT is more sensitive than chest radiograph for the detection of miliary TB and shows randomly distributed multiple, small [< 2 mm diameter] nodules (29). The nodules may be so numerous that they coalesce to form larger nodules greater than 2 mm in diameter and at times areas of consolidation with air bronchograms may be seen. Thickening of the interlobular septa may also be a feature. Mediastinal and hilar lymphadenopathy may also be present. Cavitation is reported to be rare on the chest radiograph in children with TB. However, children co-infected with HIV and TB may manifest atypical radiographic features (30,31). In children co-

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Tuberculosis Scoring Systems for Predicting Childhood Tuberculosis

Figure 41.6: Chest radiograph [postero-anterior view] showing miliary mottling and right-sided paratracheal adenopathy

infected with HIV and TB, CT may show areas of cavitation that are not apparent on the chest radiograph (30,31). The HRCT and colour doppler ultrasonography have been found to be useful in the diagnosis of cervical lymphadenopathy (32). Tuberculosis of the spine is the most common site of skeletal involvement. The utility of magnetic resonance imaging [MRI] has been documented in children with TB spondylitis (33,34). In a retrospective study (33), MRI of 53 children under the age of 13 years were interpreted by three readers using a consensus method. The salient observations included contiguous involvement of two or more vertebral bodies [85%]; an intraspinal or paraspinal soft tissue mass or abscess [98%]; and subligamentous extension [64%]. Rim enhancement of the soft tissue mass was seen in 65 per cent patients following gadolinium administration (33). Contrast enhanced MRI is emerging as a very useful technique for diagnosing neurological TB, as it demonstrates the localized lesions, meningeal enhancement and the brain stem lesions (34). Tuberculin Skin Test Tuberculin skin test is most widely available and commonly used for establishing the diagnosis of TB infection in children. The reader is referred to the chapter “Tuberculin skin test” [Chapter 11] for more details.

Though demonstration of mycobacterium in various clinical specimens remains gold standard, for diagnosis, this is often not possible in children due to the paucibacillary nature of the illness. Clinical features may be non-specific and the chest radiograph and TST results are difficult to interpret. In addition, these do not give conclusive evidence for the disease. To overcome these problems, a combination of clinical features, history of exposure to adult patients with TB, results of TST and radiological finding, have been evaluated by various workers (35,36). Various scoring systems have been developed after giving different weightage to these variables [Table 41.1] (35,36). In these scoring systems, more weightage is given to microbiological and histopathological evidence, suggestive radiographic picture and a reactive TST result [> 10 mm induration]. These scoring systems need to be validated in individual countries before use. Table 41.2 depicts the proposed criteria by Migliori et al (37) for diagnosis of pulmonary TB in children in countries where mycobacterial culture facilities are not available. DIAGNOSTIC ALGORITHM FOR PULMONARY TUBERCULOSIS The suggested algorithm for diagnosis of pulmonary TB in children is given in Figure 41.7. DRUG-RESISTANT TUBERCULOSIS Pattern of drug resistance among children with TB tends to reflect that found among adults in the same population. Table 41.1: Scoring systems for diagnosis of childhood tuberculosis Parameters Demonstration of acid-fast bacilli Histopathological evidence in biopsy specimens Tuberculin skin test > 10 mm Suggestive radiology Compatible physical examination Contact with TB family

Stengen et al (35)

Nair and Philip (36)

+3 +3

+5 +5

+3 +2 +1 +2

+3 +3 +3 +2

Scores 1-2 = TB unlikely; 3-4 = TB possible; 5-6 = TB probable; > 7 = TB unequivocal TB = tuberculosis

Tuberculosis in Children Table 41.2: Diagnostic criteria for pulmonary tuberculosis in children in countries where mycobacterial culture facilities are not available Gastric washings positive for AFB or Two or more of the following criteria History of contact with a TB adult Symptoms suggestive of pulmonary TB [cough for more than 2 weeks] 2 TU PPD reaction positive > 10 mm in unvaccinated BCG patients > 15 mm in vaccinated BCG patients Radiological findings compatible with pulmonary TB Response to treatment [body weight increase > 10% after 2 months of treatment, plus clinical improvement] TB = tuberculosis; TU = tuberculin units; PPD = purified protein derivative; BCG = bacille Calmette-Guerin; AFB = acid-fast bacilli Source: reference 28

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[RFLP] analysis. Six adult-child pairs with cultures positive for Mycobacterium tuberculosis were identified. Drug susceptibility pattern and RFLP analysis were identical for five adult-child pairs. The strain isolated from a child, in whom a source case was not evident, was different from that isolated from the source cases. However, the strain isolated from this child was prevalent in the community in which he resided. This study (38) supports the view that majority of the childhood contacts of adults with MDR-TB are likely to be infected by these source cases. Childhood contacts of adults with MDR-TB should, therefore, be treated according to the drug susceptibility patterns of Mycobacterium tuberculosis strains of the likely source cases unless the susceptibility pattern of the strain isolated from the child indicates otherwise. In a report from South Africa (39), of the 306 mycobacterial culture and sensitivity results available from 338 children [under 13 years of age], the prevalence of isoniazid resistance and multidrug-resistance [defined as isolates resistant to isoniazid and rifampicin with or without resistance to other antituberculosis drugs] were 6.9 per cent and 2.3 per cent, respectively (39). Clinical features were similar in children with drug-susceptible and drug-resistant TB (39). Only two of the children with culture proven drugresistant TB [n = 338] had received antituberculosis treatment in the past; of these, one isolate was monoresistant to isoniazid and the other was multidrugresistant. However, this study was conducted concurrently with a study of childhood contacts [under five years of age], of adults with multidrug-resistant pulmonary TB at the same hospital. Four of seven children identified with MDR-TB were part of the latter study. TREATMENT

Figure 41.7: Diagnostic algorithm for paediatric TB TB = tuberculosis; CXR = chest X-ray; TST = tuberculin skin test

A four-year prospective study (38) in the Western Cape province of South Africa evaluated 149 childhood contacts of 80 adult multidrug-resistant tuberculosis [MDR-TB] cases. Culture for Mycobacterium tuberculosis was obtained from both the adult source cases as well as the child contacts. Isolates were compared by drug susceptibility pattern and restriction fragment length polymorphism

The principles of treatment in children with TB are similar to that followed in adults (40). During the last few years, dramatic changes have occurred in the therapeutic approach to childhood TB. Short-course chemotherapy, with the treatment duration as short as six months, has become the standard of care. Intermittent regimens have been documented to be as effective as daily regimen in the paediatric population (41-45). The DOTS has been success-fully used in adults but there are sparse data regarding the utility of this approach in children. An observational trial (46) evaluated directly observed six-month regimen for pulmonary, pleural and lymph node TB in children using two weeks of daily

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isoniazid, rifampicin and pyrazinamide therapy; followed by six weeks of twice weekly isoniazid, rifampicin and pyrazinamide therapy; and 16 weeks of twice weekly isoniazid and rifampicin (46). Of the 175 children evaluated [159 with pulmonary and intrathoracic lymph node TB, 4 with pleural, and 12 with cervical lymph node TB], 81 per cent completed treatment in six months. Of the 33 patients who received extended treatment, three did so because of physician’s choice, 17 had an inadequate response to initial therapy, and two had significant adverse reactions to drugs, and 16 had poor adherence to the direct observation of treatment. Only 37 per cent of patients had complete resolution of disease at the end of treatment, but all continued to improve after therapy was stopped. Only one patient relapsed after four years. The major problem in inclusion of children in programmatic treatment is difficulty in demonstration of AFB and classification of different clinical manifestations according to categories described for adults. There have been efforts to develop classification of different types of childhood TB into three categories similar to those for adults. A classification was developed and evaluated in the TB clinic of a tertiary care hospital (47). In this study (47), of the 459 children with TB, 365 [80%] completed the treatment. Of these, 302 [82.7%] were cured with the primary regimen assigned to them in the beginning, 54 [14.8%] required extension of treatment for three months and nine [2.5%] patients required change in the treatment regimen. The authors (47) concluded that it is feasible to classify and manage various types of TB in children in different categories similar to World Health Organization [WHO] guidelines for adult TB. Recently, a consensus statement jointly prepared by the Indian Academy of Pediatrics and Revised National Tuberculosis Control Programme [RNTCP] of Government of India has also proposed a classification of different types of TB in children into three categories (48). The categorization and standardized treatment regimens for use in children under the RNTCP of Government of India are described in Tables 63.5A and 63.5B (49). Corticosteroids Corticosteroids, in addition to antituberculosis drugs, are useful in the treatment of children with neurological TB

and in some children with pulmonary TB. These are mainly useful in settings where the host inflammatory reaction contributes significantly to tissue damage. Shortcourses of corticosteroids are indicated in children with endobronchial TB that causes localized emphysema, segmental pulmonary lesions or respiratory distress. Some children with severe miliary TB may show dramatic improvement with corticosteroids, if alveolocapillary block is present. Management of an Infant Born to a Mother with Tuberculosis Congenital TB is rare. The diagnosis is frequently missed. The foetus may be infected either haematogenously through umbilical vessels or through ingestion of the infected amniotic fluid. In the former situation there will be primary focus in liver and in the latter it will be in the lungs. It is difficult to find the route of transmission in a newborn with multiple foci of infection. It is difficult to differentiate between congenital and postnatally acquired TB. According to the criteria proposed by Cantwell et al (50) in 1994, congenital TB is diagnosed if the infant has proven TB lesion[s] and at least one of the following criteria: [i] appearance of lesions in the first week of life; [ii] a primary hepatic complex or caseating hepatic granulomas; [iii] TB infection of the placenta or the maternal genital tract; and [iv] exclusion of the possibility of postnatal transmission by a thorough investigation of contacts including the infant’s hospital attendants or birth attendant. All infants born to mothers with active TB should be screened for evidence of disease by doing a good physical examination, TST and chest radiograph. If physical examination and investigations are negative for TB disease, the infant should be started on isoniazid prophylaxis [5 mg/kg/day] for six months. After three months, the child should be examined for evidence of TB and a repeat TST is done. If TST result is negative, the infant can be immunized with bacille Calmette-Guerin [BCG] vaccine and isoniazid can be stopped. If TST is positive but the infant is totally asymptomatic, isoniazid prophylaxis is continued for another three months. Infants with congenital TB should be treated with four drugs [isoniazid, rifampicin, pyrazinamide, streptomycin] in the intensive phase followed by two drugs

Tuberculosis in Children [isoniazid, rifampicin] during maintenance phase for the subsequent four months. Management of a Child in Contact with an Adult with Tuberculosis In a recent study (51), nearly one-third of children [aged < 5 years] in contact with adults with active TB disease had evidence of TB infection. The infection was more commonly associated with younger age, severe malnutrition, absence of BCG vaccination, contact with an adult who was sputum smearpositive, and exposure to environmental tobacco smoke (51). It is suggested that children below six years of age in contact with adult patients with sputum smear-positive TB should receive six months of isoniazid prophylaxis. It is mandatory to screen all children for evidence of TB in the household of an adult patient with sputum smear-positive TB. Monitoring of Therapy Response to treatment can be judged by using the following criteria: clinical, radiological, bacteriological, and laboratory test results. Clinical Criteria Clinical improvement in a child on antituberculosis therapy is the mainstay of judging response to treatment. The child should be seen once in every two to four weeks initially, and once in four to eight weeks thereafter. On each visit, improvement in fever, cough, appetite and subjective well-being is assessed. The child is examined for weight gain and improvement in findings on physical examination. Compliance is assessed by talking to parents, checking medications on each visit. Majority of children show improvement in symptoms within a few weeks. In the presence of poor response or worsening of symptoms or signs, the initial basis of diagnosis is reviewed, especially, if treatment compliance has been regular and the child should be assessed for the possibility of drug-resistant TB. After the treatment is over, follow-up every three to six months for next two years is desirable (48,52). Immune reconstitution inflammatory syndrome [IRIS] has been described in 32 to 36 per cent of patients with HIV-TB, usually within days to weeks after the

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initiation of highly active antiretroviral therapy (53,54). Rarely, paradoxical reactions have been described in HIV-seronegative patients as well. These can be brief or prolonged with multiple recurrences. Paradoxical reactions pose a diagnostic challenge and have to be distinguished from TB treatment failure, drug resistance and other opportunistic infections that are common among HIV-infected patients (53,54). Radiological Criteria Clinical improvement precedes radiological clearance of lesion on the chest radiograph. The optimal frequency of radiological monitoring in children with pulmonary TB is unclear. One protocol suggests obtaining chest radiographs after four to eight weeks of treatment. If it shows improvement in combination with clinical response, no further radiographic evaluation is required. In the authors’ opinion, the first follow-up chest radiograph during treatment should be done after eight weeks i.e., at the end of intensive phase. In patients who show increase or little change in radiological features coupled with delayed clinical response, prolongation of intensive phase by a month is suggested. Further films are taken after four weeks and the child, if better, should be shifted to continuation phase; else, the child is investigated for failure of treatment and drug resistance. The degree of radiological clearance can be graded as: [i] complete clearance; [ii] moderate to significant clearance [half to two-thirds clearance]; [iii] mild clearance [one-third or less decrease in size]; or [iv] no clearance or appearance of new lesion[s]. Treatment should not be continued till complete radiological clearance as improvement in the chest radiograph may continue even after discontinuation of treatment (55). Microbiological Criteria Most of the childhood pulmonary TB is paucibacillary. In children, where isolation of Mycobacterium tuberculosis was possible at the time of diagnosis, every effort should be made to document disappearance of bacilli during treatment. Other Measures Although an elevated erythrocyte sedimentation rate [ESR] may be expected in children with TB, a recent study found that one-third of children with TB had a normal

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ESR at the time of diagnosis, suggesting little value in using ESR as a diagnostic and monitoring test for childhood TB (56).

20.

REFERENCES

21.

1. Chintu C. Tuberculosis and human immunodeficiency virus co-infection in children: management challenges. Paediatr Respir Rev 2007;8:142-7. 2. Rekha B, Swaminathan S. Childhood tuberculosis-global epidemiology and the impact of HIV. Paediatr Respir Rev 2007;8:99-106. Epub 2007 Jun 4. 3. Datta M, Swaminathan S. Global aspects of tuberculosis in children. Paediatr Respir Rev 2001;2:91-6. 4. Mandalakas AM, Starke JR. Current concepts of childhood tuberculosis. Semin Pediatr Infect Dis 2005;16:93-104. 5. Donald PR. Childhood tuberculosis: out of control? Curr Opin Pulm Med 2002;8:178-82. 6. Enarson DA. The International Union Against Tuberculosis and Lung Disease Model National Tuberculosis Programmes. Tuber Lung Dis 1995;76:95-9. 7. Chadha VK, Kumar P, Jagannatha PS, Vaidyanathan PS, Unnikrishnan KP. Average annual risk of tuberculous infection in India. Int J Tuberc Lung Dis 2005;9:116-8. 8. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974;99:131-8. 9. Munoz FM, Starke JR. Tuberculosis in children. In: Tuberculosis: a comprehensive international approach. Second edition. NewYork: Marcel Dekker; 2000.p.553-95. 10. Miller FM, Seale RM. Tuberculosis in children. Boston: Little Brown and Company;1963. 11. Comstock G. Epidemiology of tuberculosis. In: Reichman LB, Hershfield E, editors. Tuberculosis: a comprehensive international approach. New York: Marcel Dekker; 2000.p.129-48. 12. Dannenberg AM, Sugimoto M. Liquefaction of caseous foci in tuberculosis. Am Rev Respir Dis 1976;113:257- 9. 13. Lamont AC, Cremin BJ, Pelteret RM. Radiologic patterns of pulmonary tuberculosis in the pediatric age group. Pediatr Radiol 1986;16:2-7. 14. Morrison JB. Natural history of segmental lesions in primary pulmonary tuberculosis: long-term review of 383 patients. Arch Dis Child 1973;48:90-8. 15. Schwartz P. Lymph node tuberculosis; a decisive factor in pulmonary pathology. Arch Pediatr 1957;74:201-18. 16. Stansberry SD. Tuberculosis in infants and children. J Thorac Imaging 1990;5:17-27. 17. Matsaniotis N, Kattanis C, Economou-Mavrou C, Kyriazakou M. Bullous emphysema in childhood tuberculosis. J Pediatr 1967;71:703-8. 18. Pray LG. Obstructive emphysema in infancy due to tuberculous mediastinal glands. J Pediatr 1944;25:253-6. 19. Seth V, Lodha R, Kabra SK. Pulmonary tuberculosis. In: Seth V, Kabra SK, editors. Essentials of tuberculosis in

22.

23. 24.

25.

26.

27. 28.

29.

30.

31. 32.

33.

34.

35. 36. 37.

children. Second edition. New Delhi: Jaypee Brothers; 2000.p.85-98. Seth V, Singhal PK, Semwal OP, Kabra SK, Jain Y. Childhood tuberculosis in a referral center: clinical profile and risk factors. Indian Pediatr 1993;30:479-85. Pamra SP. Tuberculosis in children. Indian J Tuberc 1987;34:55-6. Somu N, Vijayasekaran D, Ravikumar T, Balachandran A, Subramanyam L, Chandrabhushanam A. Tuberculous disease in a pediatric referral center: 16 years experience. Indian Pediatr 1994;31:1245-9. Maniar BM. Cavitating pulmonary tuberculosis below age of 2 years. Indian Pediatr 1994;31:181-90. Cruz AT, Starke JR. Clinical manifestations of tuberculosis in children. Paediatr Respir Rev 2007;8:107-17. Epub 2007 Jun 5. Seth V, Donald PR. Tuberculous lymphadenitis. In: Seth V, Kabra SK, editors. Essentials of tuberculosis in children. Second edition. New Delhi: Jaypee Brothers; 2000.p.99-107. Seth V, Gulati S, Udani PM. Clinical features and diagnosis of CNS tuberculosis. In: Seth V, Kabra SK, editors. Essentials of tuberculosis in children. Second edition. New Delhi: Jaypee Brothers; 2000.p.134-61. Copley SJ. Application of computed tomography in childhood respiratory infections. Br Med Bull 2002;61:263-79. Kim WS, Moon WK, Kim IO, Lee HJ, Im JG, Yeon KM, et al. Pulmonary tuberculosis in children: evaluation with CT. Am J Roentgenol 1997;168:1005-9. Jamieson DH, Cremin BJ. High resolution CT of the lungs in acute disseminated tuberculosis and a pediatric radiology perspective of the term ‘miliary’. Pediatr Radiol 1993;23: 380-3. Haller JO, Ginsburg KJ. Tuberculosis in children with acquired immunodeficiency syndrome. Pediatr Radiol 1997;27:186-8. Kornreich L, Goshen Y, Horev G, Grunebaum M. Mycobacterial respiratory infection in leukemic children. Eur J Radiol 1995;21:44-6. Papakonstantinou O, Bakantaki A, Paspalaki P, Charoulakis N, Gourtsoyiannis N. High-resolution and color Doppler ultrasonography of cervical lymphadenopathy in children. Acta Radiol 2001;42:470-6. Andronikou S, Jadwat S, Douis H. Patterns of disease on MRI in 53 children with tuberculous spondylitis and the role of gadolinium. Pediatr Radiol 2002;32:798-805. Uysal G, Kose G, Guven A, Diren B. Magnetic resonance imaging in diagnosis of childhood central nervous system tuberculosis. Infection 2001;29:148-53. Stegen G, Jones K, Kaplan P. Criteria for guidance in the diagnosis of tuberculosis. Pediatrics 1969;43:260-3. Nair PH, Philip E. A scoring system for diagnosis of tuberculosis in children. Indian Pediatrics 1981;18:299-303. Migliori GB, Borghesi A, Rossanigo P, Adriko C, Neri M, Santini S, et al. Proposal of an improved score method for the diagnosis of pulmonary tuberculosis in childhood in developing countries. Tuber Lung Dis 1992;73:145-9.

Tuberculosis in Children 38. Schaaf HS, Van Rie A, Gie RP, Beyers N, Victor TC, Van Helden PD, et al. Transmission of multidrug-resistant tuberculosis. Pediatr Infect Dis J 2000;19:695-9. 39. Schaaf HS, Gie RP, Beyers N, Sirgel FA, de Klerk PJ, Donald PR. Primary drug-resistant tuberculosis in children. Int J Tuberc Lung Dis 2000;4:1149-55. 40. Donald PR, Schaaf HS. Old and new drugs for the treatment of tuberculosis in children. Paediatr Respir Rev 2007;8:13441. Epub 2007 Jun 5. 41. Pablos-Mendez A, Raviglione MC, Laszlo A, Laszlo A, Binkin N, Rieder HL, et al. Global surveillance for antituberculosis drug resistance 1994-1997. World Health Organization-International Union Against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. N Engl J Med 1998;338:1641-9. 42. Biddulph J. Short-course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990;9:794-801. 43. Kumar L, Dhand R, Singhi PD, Rao KL, Katariya S. A randomized trial of fully intermittent vs. daily followed by intermittent short course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990;9:802- 6. 44. Kiper N, Gocmen A, Dilber E, Ozcelik U. Effectiveness of short-course intermittent chemotherapy for tuberculosis in young infants aged less than 6 months. Clin Pediatr 1998; 37:433-6. 45. Te Water Naude JM, Donald PR, Hussey GD, Kibel MA, Louw A, Perkins DR, et al. Twice weekly vs daily chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 2000;19:405-10. 46. Al-Dossary FS, Ong LT, Correa AG, Starke JR. Treatment of childhood tuberculosis with a six month directly observed regimen of only two weeks of daily therapy. Pediatr Infect Dis J 2002;21:91-7.

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47. Kabra SK, Lodha R, Seth V. Category based treatment tuberculosis in children. Indian Pediatr 2004;41:927-37. 48. Chauhan LS, Arora VK. Management of pediatric tuberculosis under the Revised National Tuberculosis Control Program [RNTCP]. Indian Pediatr 2004;41:901-5. 49. A joint statement of the Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, and experts from Indian Academy of Pediatrics Management of Pediatric TB under the Revised National Tuberculosis Control Programme [RNTCP]. Available at URL: http://www.tbcindia.org/pdfs/Consensus%20 statement.pdf. Accessed on July 04 2008. 50. Cantwell MF, Shehab ZM, Costello AM, Sands L, Green WF, Ewing EP Jr, et al. Brief report: congenital tuberculosis. N Engl J Med 1994;330:1051-4. 51. Singh M, Maynak ML, Kumar L, Mathew JL, Jindal SK. Prevalence and risk factors for transmission of infection among children in household contact with adults having pulmonary tuberculosis. Arch Dis Child 2005;90:624-8. 52. Kabra SK, Ratageri VH. Tuberculosis in children: monitoring of treatment and management of side effects. Paediatr Today 1999;2:81-4. 53. Sharma SK, Mohan A, Kadhiravan T. HIV-TB co-infection: epidemiology, diagnosis and management. Indian J Med Res 2005;121:550-67. 54. Cheng SL, Wang HC, Yang PC. Paradoxical response during antituberculosis treatment in HIV-negative patients with pulmonary tuberculosis. Int J Tuberc Lung Dis 2007;11:1290-5. 55. Starke JR. Current concepts of epidemiology, diagnosis and treatment of childhood tuberculosis in the United States. Indian Pediatr 1991;28:335-55. 56. Al-Marri MR, Kirkpatrick MB. Erythrocyte sedimentation rate in childhood tuberculosis: is it still worthwhile? Int J Tuberc Lung Dis 2000;4:237-9.

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Diagnosis of Childhood Tuberculosis: Recent Advances and Applicability of New Tools

42

Ben J Marais, Madhukar Pai

INTRODUCTION It is often stated that children with tuberculosis [TB] rarely have sputum smear-positive disease and contribute little to disease transmission within the community. For this reason the diagnosis and management of TB in children is not considered a priority by TB control programmes. However, children carry a huge disease burden (1,2) and adolescent children in particular do contribute to disease transmission within the community (3,4). Of the estimated 8.3 million new TB cases reported to the World Health Organization [WHO] in the year 2000, 884 019 [11%] were children (2). The severity of the childhood TB disease burden has been recognised in many developing countries (5-8). For example, a recent survey from South Africa reported that children under 13 years of age contribute 13.7 per cent of the TB disease burden with a calculated incidence rate in excess of 400 per 100 000 per year (8). The global epidemic of TB is closely linked to the spread and intensity of the human immunodeficiency virus [HIV] epidemic in many endemic areas, particularly in sub-Saharan Africa (9). Although HIV infected children are highly susceptible to develop TB following infection, the majority of child TB cases are HIVuninfected (10), even in sub-Saharan Africa (11), where TB/HIV co-infection is highly prevalent in adults. Another common misconception is that children usually develop mild forms of TB and that severe disease manifestations are the exception. In reality, children can and do develop severe forms of TB. It has been reported that TB accounts for 15 per cent of all paediatric deaths in some Indian hospitals (12), while a survey conducted

in Malawi reported a mortality rate of 17 per cent in children diagnosed with TB (13). An autopsy study from Zambia showed that TB rivals acute pneumonia as a major cause of death from respiratory disease in children from endemic areas, irrespective of the child’s HIV status (11). The complete spectrum of disease reported in children from a highly endemic area demonstrates the frequency with which severe TB disease manifestations do occur (14). Standard antituberculosis treatment is extremely effective, but unfortunately treatment is rarely available to diseased children in endemic areas. This is demonstrated by the fact that the Global Drug Facility, at present, provides no child friendly treatment option to countries with limited resources. In addition, TB control programmes largely focus on the treatment of adults with sputum smear-positive TB and establishing an accurate diagnosis of childhood TB is considered to be very difficult, especially in resource-limited settings. CHILDHOOD TUBERCULOSIS: A DIAGNOSTIC DILEMMA The diagnosis of childhood TB is complicated by the absence of a practical gold standard, as bacteriologic confirmation is rarely achieved (15,16). Sputum smear microscopy, often the only diagnostic test available in endemic areas, is positive in less than 10 to 15 per cent of children with probable TB (17,18), and culture yields are also low [< 30% to 40%] (17,18). For this reason, alternative strategies have been developed to diagnose childhood TB in non-endemic areas, the triad of [i] known contact with an adult index case [e.g., household contact]; [ii] a positive tuberculin skin test [TST] as

Diagnosis of Childhood Tuberculosis: Recent Advances and Applicability of New Tools evidence of Mycobacterium tuberculosis infection; and [iii] suggestive signs on the chest radiograph provides an accurate diagnosis. Although it has not been formally validated, this approach is widely applied in nonendemic areas and it has been incorporated into the International Standards for Tuberculosis Care (19). However, the diagnostic accuracy of the triad is greatly reduced in endemic areas where the majority of the population acquire infection during childhood, and where transmission is not restricted to household contact with a known index case (20,21). Consequently, in endemic settings where the discriminatory value of known Mycobacterium tuberculosis exposure and/or infection is drastically reduced, the diagnosis of childhood TB depends mainly on clinical features and the subjective interpretation of the chest radiograph (22,23). The WHO guidelines (24) categorize children as suspect, probable and confirmed cases. The application of these guidelines are limited by the frequency with which children are infected in endemic areas, reducing the diagnostic value of a positive TST, as well as the unavailability of radiology in most resource-limited settings and the subjectivity of chest radiograph findings. Hilar adenopathy is often regarded as the hallmark of primary TB (25). However, the natural history of disease demonstrates that asymptomatic hilar adenopathy is a transient phenomenon in the majority [50% to 60%] of children following recent primary infection. Despite the absence of antituberculosis treatment, very few children with asymptomatic hilar adenopathy develop progressive disease, indicating that hilar adenopathy is more indicative of recent primary infection than active disease in the absence of suspicious symptoms (26,27). The interpretation of radiologic signs is highly subjective and it should be interpreted with extreme caution in the absence of clinical data. However, chest radiograph remains the most widely used diagnostic test in clinical practice (23,28), and, when interpreted by an experienced clinician, it does provide a fairly accurate diagnosis in the presence of suspicious symptoms. The natural history of disease also demonstrates the importance of risk stratification. In immune competent children, age is the most important variable that determines the risk of disease progression following primary Mycobacterium tuberculosis infection (26). Children who become infected at a very young age [< 2 years], before immune maturation is complete, experience the

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highest risk. Disease progression occurs primarily within the first 12 months following primary infection (27), and therefore, it seems prudent to include all immune competent children less than three years of age in the high-risk group. Children infected with HIV and/or those with other forms of immune deficiency experience a similar high risk and they should be included in the high-risk group irrespective of age (26,29). Due to the frequency and rapidity with which disease progression may occur in these high-risk children, an important diagnostic challenge is to find a sensitive marker of Mycobacterium tuberculosis infection that will identify those who may benefit from preventive treatment. Current diagnostic approaches, together with recent advances that may be applicable to diagnosis of childhood TB in the near future, are summarized in Table 42.1 (30). ADVANCES IN SYMPTOM-BASED DIAGNOSIS Screening for Disease The WHO guidelines regard the TST and chest radiograph as prerequisite tests for adequate screening of household contacts (31). However, this limits access to preventive therapy in resource-limited settings where these test are rarely available and where children are frequently exposed to TB at a young and vulnerable age. A recent study evaluated the value of symptom-based screening compared with TST and chest radiographbased screening in children exposed to Mycobacterium tuberculosis (32). The findings suggest that simple symptom-based screening could have considerable value in resource-limited settings given the fact that more than 90 per cent of children diagnosed with TB on chest radiograph reported symptoms, and in those that reported no symptoms only isolated hilar adenopathy was observed, probably reflecting recent primary infection and not disease. These findings require confirmation, but the use of a simple symptom-based screening test would facilitate the provision of preventive chemotherapy to asymptomatic, high-risk household contacts; only symptomatic children would then be selected for further investigation to exclude active TB. Diagnosing Disease Due to the diagnostic limitations discussed and the difficulty in obtaining chest radiographs in many

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Table 42.1: Summary of various diagnostic approaches, their potential application and perceived problems and benefits Potential problems and benefits

Validation

Slow turn around time, too expensive for most poor countries Poor sensitivity in children

Accepted gold standard

Rarely available in endemic areas with limited resources Accurate disease classification essential Isolated hilar adenopthy may indicate recent primary infection and not disease

Marked inter- and intra-observer variability Reliable in expert hands and in presence of suspicious symptoms

Current clinical diagnostic Diagnosis of probable approaches active TB

Poor symptom definition

Not well validated

Tuberculin skin test

Rarely available in endemic areas with limited resources Does not differentiate LTBI from active disease Not specific for Mycobacterium tuberculosis infection Particularly insensitive in immune compromised children Simple to use and less expensive than blood-based LTBI tests

Various cut-offs advised in different settings

Diagnostic approach

Potential application

Current approaches TB culture using solid or Bacteriologic confirliquid broth media mation of active TB Chest radiography

Diagnosis of probable active TB

Diagnosis of Mycobacterium tuberculosis infection

Recent advances Symptom-based approaches Symptom-based screening

Screening child contacts Simple, limited resources required of adult TB cases Should improve access to preventive chemotherapy for asymptomatic high-risk contacts

Not well validated

Refined symptom-based diagnosis

Diagnosis of probable active TB

Simple, limited resources required Should improve access to chemotherapy in resource-limited setting Poor performance in HIV-infected children

Additional validation required

Immune-based approaches Antibody-based immune assays

Diagnosis of probable active TB

Simple, point of care testing Variable accuracy and difficulty in distinguishing between latent and active TB

Additional validation required

Antigen-based immune assay [e.g., LAM detection assay]

Diagnosis of probable active TB

Simple, point of care testing Limited clinical data on accuracy

Not well validated

MPB 64 skin patch test

Diagnosis of probable active TB

Simple and easy to use Limited clinical data on accuracy, but initial data suggests it distinguishes latent infection from active TB

Not well validated

Interferon-gamma release assay

Diagnosis of LTBI; potentially a “rule-out” test for active TB disease

Limited data in children Not well validated in children Inability to differentiate LTBI from active TB Particular relevance in high-risk children, where LTBI treatment is warranted Expensive, not easily applicable in resource limited settings -Contd-

Diagnosis of Childhood Tuberculosis: Recent Advances and Applicability of New Tools

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Table 42.1 -ContdDiagnostic approach

Potential application

Bacteriology and moleBacteriologic confirmacular based approaches tion of active TB Colorimetric culture systems [e.g., TK-Medium]

Potential problems and benefits

Validation

Simple and feasible, but limited data in children Potential for contamination in field conditions

Not well validated

Phage-based tests [e.g., FASTPlaque-TB]

Diagnosis of probable Limited data in children active TB, and detection Requires laboratory infrastructure of rifampicin resistance Performs relatively poorly when used on clinical specimens

Not well validated

Microscopic observation drug susceptibility assay

Diagnosis of probable Simple and feasible, but limited data in active TB, and detection children of drug resistance

Not well validated

Nucleic acid amplification tests

Diagnosis of probable Rarely available in endemic areas with Extensively validated, but active TB, and detection limited resources evidence not in favour of of rifampicin resistance Sensitivity tends to be poor in smearwidespread use negative and paucibacillary TB Specificity a concern in endemic areas, where LTBI is common Requires adequate quality control systems

TB = tuberculosis; LTBI = latent TB infection; HIV = human immunodeficiency virus; LAM = lipoarabinomannan Adapted from “Marais BJ, Pai M. Recent advances in the diagnosis of childhood tuberculosis. Arch Dis Child 2007;92:446-52 (reference 30)”

endemic areas, a variety of clinical scoring systems have been developed. A critical review of scoring systems concluded that they are severely limited by the absence of standard symptom definitions and a lack of adequate validation (33). Accurate symptom definition is important to differentiate TB from other common conditions. A recent community survey demonstrated that poorly defined symptoms [such as, a cough of > 3 weeks duration] are frequently reported in a random selection of healthy children and have poor discriminatory power (34). However, a follow-up study demonstrated that the use of well-defined symptoms with a persistent, nonremitting character significantly improves the diagnostic accuracy (35), although the diagnostic value of this approach required more extensive validation. This was partially achieved in a recently completed prospective, community-based study that enrolled 1024 children with suspicious symptoms over a three-year period in Cape Town, South Africa (36). Combining three variables at presentation: [i] persistent non-remitting cough of greater than two weeks duration; [ii] documented failure to thrive during the preceding three months and [iii] fatigue, performed well in low-risk immune competent children three years or older, with good

sensitivity [82.3%], specificity [90.2%], positive predictive value [82.3%]. Clinical follow-up served as a valuable additional diagnostic tool to differentiate active TB from other common diseases in those low-risk children who did not meet the diagnostic criteria at presentation. This approach also performed reasonably well in HIV uninfected children under three years of age, but more caution is required in this high-risk group due to the rapidity with which disease progression may occur. However, the approach performed poorly in HIV infected children, due to the presence of chronic symptoms caused by other opportunistic infections and/or HIV-related conditions, re-emphasizing the need for the provision of preventive chemotherapy following exposure and/or documented infection in these children. The most common extra-thoracic manifestation of TB in children is cervical adenopathy. A simple clinical algorithm that identified children with persistent [> 4 weeks] cervical adenopathy, without a visible local cause or response to first-line antibiotics, and a cervical mass of greater than or equal to 2 × 2 cm showed excellent diagnostic accuracy in a recent study from a TB endemic area (37). Regular clinical follow-up remains essential so that children who do not respond to standard antituber-

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culosis treatment are referred as soon as possible to establish a definitive diagnosis. In non-endemic areas, where the pre-test probability of TB is low and where the prevalence of latent TB infection [LTBI] is low, the addition of a positive TST result or the presence of other immune markers of Mycobacterium tuberculosis infection, such as a positive T-cell assay, may offer significant additional value. For the definitive diagnosis of TB cervical adenopathy in children, fine needle aspiration cytology has proven to be a robust and simple technique that provides a rapid result and excellent bacteriologic yields (37-40); the use of a small 23-gauge needle has been associated with minimal side-effects (37). ADVANCES IN IMMUNE-BASED DIAGNOSIS Serological Tests Serological tests for the detection of antibodies have been attempted for many years, and their performance has been extensively reviewed (41-43). Despite their long history and repeated attempts at improving these tests, no assay is currently accurate enough to replace microscopy and culture. However, commercial kits for antibody detection are widely available and they are primarily marketed in endemic countries where regulatory approval systems are weak. Several authors have analysed the reasons for the apparent failure of serological tests (41-43). A major challenge with immunological diagnosis is the wide clinical spectrum of TB, ranging from LTBI to various degrees of active disease. Several other factors may also affect the performance of antibodybased tests, including bacille Calmette-Guérin [BCG] vaccination, exposure to nontuberculous mycobacteria [NTM] and HIV co-infection; all of which are particularly prevalent in endemic areas. Early versions of serological assays used crude, nonspecific antigenic mixtures. This led to loss of specificity, and the inability to distinguish active TB from LTBI and infection with NTM. The development of well-defined, purified recombinant proteins specific to Mycobacterium tuberculosis partially overcame this problem, but antigen recognition remains highly variable and varies across the infection/disease spectrum, as Mycobacterium tuberculosis expresses different genes and proteins during different stages of the disease. Therefore, any immune-based test should include antigens that are expressed during all the various stages of disease progression and not a single

antigen that may not be recognized by the host immune system during all stages of disease. The development of Mycobacterium tuberculosis specific antigen cocktails partially addresses this problem. It has been suggested that each TB state is characterized by a specific “bacterial antigen signature”, and therefore, it seems important to study both negative as well as positive responses to a panel of antigens (44,45). A pattern of positive and negative responses [analogous to a bar code] may then be used to distinguish between various disease stages, but whether this approach will have clinical applicability remains to be seen. Because of the limitations of existing serological assays, efforts are underway to develop assays that focus on antigen rather than antibody detection. For example, antigen-capture enzyme linked immunosorbent assay [ELISA] for the detection of lipoarabinomannan in sputum and urine samples has shown good promise in early trials (46), but further work is necessary to determine their utility in clinical practice. Another innovative immune-based method uses transdermal application of MPB64 antigen as a patch test. The MPB64 is an immunogenic antigen specific to Mycobacterium tuberculosis complex. In studies conducted in Japan and the Philippines (47,48), the MPB64 skin patch test was able to distinguish active TB from LTBI with 88 to 98 per cent sensitivity and 100 per cent specificity. Although the exact biological mechanism behind the skin response remains unclear, the skin patch test is currently being developed into a commercial test by Sequella Inc., Rockville, MD, USA. Its ability to detect active TB in children has not been evaluated. Interferon-gamma Release Assays Due to advances in molecular biology and genomics, an alternative to the traditional TST has emerged in the form of blood-based assays that measure interferon-γ [IFN-γ] released by sensitized T-cells after stimulation by Mycobacterium tuberculosis antigens. The IFN-gamma release assays [IGRAs] use antigens that are more specific to Mycobacterium tuberculosis than purified protein derivative [PPD]. These antigens include early secreted antigenic target 6 [ESAT-6], culture filtrate protein 10 [CFP-10], and TB7.7 [Rv2654]. The ESAT-6 and CFP-10 are encoded by genes located within the region of difference 1 segment of the Mycobacterium tuberculosis genome; they are more specific than PPD because they are not shared with any of the BCG strains and several NTM species.

Diagnosis of Childhood Tuberculosis: Recent Advances and Applicability of New Tools Two IGRAs are currently available as commercial kits; the T-SPOT.TB® test [Oxford Immunotec, Oxford, UK], and the QuantiFERON®-TB Gold® [QFT-G] [Cellestis Ltd, Carnegie, Australia] assay. The QFT-G assay is approved by the US Food and Drug Administration [FDA]. The QFT-G In Tube, a simplified, improved version has been evaluated in field studies (49-51), and is currently FDA approved. The T-SPOT.TB is licensed for use in Europe, Canada, and other countries. Available evidence on IGRAs, reviewed extensively elsewhere (52-56), suggests that these assays have higher specificity than the TST and better correlation with surrogate measures of exposure to Mycobacterium tuberculosis in low incidence settings. However, given the lack of a gold standard for LTBI, the sensitivity and specificity for LTBI cannot be directly estimated, and there is some concern that the sensitivity for LTBI might be less than that of the TST, especially in vulnerable populations (55). The US Centers for Disease Control and Prevention recently recommended that the QFT-G assay can be used in place of the TST for all indications, including screening of children (55), despite a lack of published paediatric data. There are limited data on the performance of QFT-G assay in children. A study from Australia compared the performance of the TST and the QFT-G assay in 101 children considered to be at risk for LTBI; 17 per cent of the QFT-G assays yielded indeterminate results (57). In addition, the concordance between QFT-G and the TST was poor [kappa 0.30] with 26 [70%] of the 37 children defined as LTBI by TST having a negative QFT-G result (57). In contrast, a recent study among hospitalized children in rural India showed high agreement between TST and QFT-G In Tube, but data were inadequate to estimate sensitivity among bacteriologically proven cases of TB (58). In a study from Japan, five children diagnosed to have TB who had typical chest radiograph findings, such as cavitation, lymphadenopathy, and nodular hilar shadows, were positive by the QFT-G assay (56). Of three asymptomatic cases without radiologic abnormalities but with a positive QuantiFERON®-TB Gold® 2G [QFT-2G] response, one developed TB during follow-up. Among 12 QFT-2G negative children, no TB cases occurred during the follow-up period (59). Lastly, a recent case report suggested that the QFT-G assay may be useful in the diagnosis of perinatal TB, especially as the TST is not a reliable test in this population (60).

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Various studies have documented the experience with the enzyme linked immunospot [ELISPOT] assay in children. Compared to TST, the ELISPOT assay demonstrated improved sensitivity in children, as reflected by better correlation with the degree of exposure following a school TB outbreak in the UK (61). It also demonstrated higher sensitivity than TST in HIV-infected children with active TB, and was less affected by malnutrition (62). In a study from South Africa, ELISPOT responses to ESAT-6 and CFP-10 were detectable in twothirds of children with a clinical diagnosis of TB; however, the assay was more frequently positive [83%] in children with culture-proven disease (63). Overall, IGRAs appears to be a promising tool to diagnose LTBI and they may aid the diagnosis of active TB in children, but available evidence is inadequate to make any clinical recommendations at this time. It is important to emphasize that in the absence of symptoms or radiologic signs, IGRAs, like the TST, fail to make the crucial distinction between LTBI and active disease. The main application of these assays in non-endemic areas may be to assess LTBI in contact and/or immigrant screening. In endemic areas, its presumed superior ability to detect Mycobacterium tuberculosis infection in HIVinfected individuals (62), compared to the TST that performs poorly in this group (64), may be of particular value, as the diagnosis of Mycobacterium tuberculosis infection is highly relevant in these high-risk children. A sensitive test for Mycobacterium tuberculosis infection may also provide important supportive evidence to establish or refute a diagnosis of active TB, particularly in HIV-infected children where the value of symptombased diagnostic approaches is reduced by chronic HIVrelated symptomatology and chest radiograph interpretation is complicated by HIV-related lung disease (65). Further research is needed to document the role of IGRAs as “rule out” tests for active TB in children. ADVANCES IN BACTERIOLOGY-BASED AND MOLECULAR DIAGNOSIS Traditional Methods Although the bacteriologic yield in children is said to be low, it must be emphasized that adolescent children frequently develop sputum smear-positive adult-type disease and sputum microscopy has definite diagnostic value in these older children (4). In addition, a recent

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study demonstrated that the bacteriologic yield in children with TB depends on the specific intra-thoracic manifestation of the disease (66). A yield of 77 per cent was reported in children with advanced disease, while the yield in those with uncomplicated hilar adenopathy was only 35 per cent, using the liquid broth mycobacteria growth indicator tube [MGIT®] system [Beckton Dickinson, MD, USA]. Liquid broth systems as such, MGIT® and BACTEC® offer slightly superior sensitivity, reduced turn around time compared to the conventional Lowenstein-Jensen [L-J] solid media (67). However, their excessive cost and requirement for laboratory infrastructure remains a major limitation. This observation may explain the poor yield observed in developed countries, where active contact tracing programmes are well established and children are usually diagnosed at a very early stage of the disease. It also demonstrates the potential value of traditional, as well as more advanced bacteriology-based diagnostic approaches, particularly in endemic areas where children frequently present with advanced disease. In addition to poor bacteriologic yield, the collection of bacteriologic specimens is often problematic. Two to three fasting gastric aspirates collected on consecutive days and usually requiring hospital admission are routinely advised in young children who cannot cough up sputum. A retrospective study from California compared the bacteriologic yield achieved in gastric aspirates collected from hospitalized and non-hospitalized children (68). Although the yield in hospitalized children was higher [percentage of positive cultures 48% vs 37%], this difference was not statistically significant (68), which suggests that hospitalization may not be a prerequisite for the collection of a good gastric aspirate specimen. Bronchoalveolar lavage, using flexible fiberoptic bronschoscopy, has additive value when used in combination with gastric lavage, but this technique is highly specialized and is unavailable in most endemic areas (69). In a study from Peru, mid-morning nasopharyngeal aspiration was compared with early morning gastric aspiration; gastric aspiration provided a slightly better yield than nasopharyngeal aspiration [38% vs 30%], but the results were comparable (70). Nasopharyngeal aspiration is minimally invasive, does not require hospitalization or fasting, and can be performed any time of the day. A study from South Africa demonstrated that a single specimen, using hypertonic-saline induced sputum collection, may provide the same yield as three gastric aspirate specimens (18). However, the overall

yield in this study remained poor [15% with 1 and 20% with 3 induced sputum specimens], the technique has not been used outside the hospital setting and induced coughing may pose a transmission risk to health care workers, and also to other children if the procedure is not performed in a separate, well-ventilated room and/ or equipment is not adequately sterilized. Additional studies are awaited to confirm the feasibility, safety and diagnostic value of collecting induced sputum specimens in primary health care settings. The various methods that have been used to collect a bacteriologic specimen are summarized in Table 42.2 (71). The string test is another novel approach that has recently been evaluated for its ability to retrieve Mycobacterium tuberculosis from sputum smear-negative HIV infected adults with TB symptoms (72). This test demonstrated superior sensitivity compared to induced sputum in this study population and was generally well tolerated. A recent study (73) also showed that the string test is well tolerated and achievable for most childhood TB suspects as young as four years. Assessment of the bacteriologic yield and clinical utility of this test in children is eagerly awaited. Novel Culture Systems and Detection Methods The biggest limitations of traditional culture methods are sub-optimal sensitivity, slow turn around time and excessive cost. TK-Medium® [Salubris Inc., Cambridge, MA, USA] is a novel colorimetric system that indicates growth of mycobacteria and allows for early positive identification, before bacterial colonies appear (74). The TK-Medium also permits susceptibility testing for drug resistance, and can allow for differentiation between Mycobacterium tuberculosis and NTM. Although TKMedium promises to be a practical, low-cost, simple test, published evidence on this test is limited and the test is currently not US FDA approved (43). No data exist on its value in childhood TB diagnosis. Field studies are ongoing and they should help to define the accuracy and robustness of this new rapid culture system under field conditions. Mycobacteriophage-based tests use bacteriophages to infect live Mycobacterium tuberculosis and detect the presence of mycobacteria using either phage amplification on a bed of Mycobacterium smegmatis or the detection of light (75,76). In general, phage assays have a turn around time of two to three days, and require a laboratory infrastructure similar to that required for performing

Diagnosis of Childhood Tuberculosis: Recent Advances and Applicability of New Tools

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Table 42.2: Summary of various bacteriologic sample collection methods and perceived problems and/or benefits Sample collection method

Potential problems and benefits

Potential application

Sputum

Not feasible in very young children Assistance and supervision may improve the quality of the specimen

Routine sample to be collected in children > 7 years of age [all children who can produce a good quality specimen]

Induced sputum

Increased yield compared to gastric aspirate No age restriction; Specialized technique, which requires nebulization and suction facilities Use outside hospital setting not studied Potential transmission risk

To be considered in the hospital setting on an in- or outpatient basis

Gastric aspirate

Difficult and invasive procedure Not easily performed on an out-patient basis Requires prolonged fasting Sample collection advised on 3 consecutive days

Routine sample to be collected in hospitalized patients who cannot produce a good quality sputum specimen

Nasopharyngeal aspiration

Less invasive than gastric aspirate No fasting required Comparable yield to gastric aspirate

To be considered in primary health care clinics or on an out-patient basis

String test

Less invasive than gastric aspirate Tolerated well in children > 4 years of age Bacteriologic yield and feasibility requires further investigation

Potential to become the routine sample collected in children who can swallow the capsule, but cannot produce a good quality sputum specimen

Bronchoalveolar lavage

Extremely invasive

Only for use in patients who are intubated or who require diagnostic bronchoscopy

Urine, stool

Not invasive Excretion of Mycobacterium tuberculosis well documented

To be considered with novel sensitive bacteriologic or antigen-based tests

Blood, bone marrow

Good sample sources to consider in the case of probable disseminated TB

To be considered for the confirmation of probable disseminated TB in hospitalized patients

Adapted from: “Marais BJ, Pai M. Specimen collection methods in the diagnosis of childhood tuberculosis. Indian J Med Microbiol 2006; 24:249-51 (reference 71)”

cultures. Phage amplification assays are available as commercial kits; the FASTPlaque-TB® [Biotec Laboratories Ltd, Ipswich, Suffolk, UK] assay can be used directly on sputum specimens for diagnosis, and a variant, the FASTPlaque-TB Response® kit is designed to detect rifampicin resistance in sputum specimens. The FASTPlaqueTB® kits are currently not US FDA approved, but are CE marked for use in Europe. No information exists on its utility in the diagnosis of childhood TB. In adults, these assays are fairly accurate for rifampicin resistance, especially when used on culture isolates (76). Microscopic observation drug susceptibility assay [MODS] is a novel assay that uses an inverted light microscope and Middlebrook 7H9 broth culture to rapidly detect mycobacterial growth. The MODS uses inverted light microscopy to detect early growth of

Mycobacterium tuberculosis as “strings and tangles” of bacterial cells in the broth medium with or without antimicrobial drugs [for drug susceptibility testing]. In a recent, large study from Peru (77), MODS detected 94 per cent of 1908 positive sputum cultures, whereas the conventional L-J culture detected only 87 per cent. The MODS also had a shorter time to culture positivity [average of 8 days] compared to L-J culture. Although MODS is a promising and inexpensive tool, no information exists on its utility in the diagnosis of childhood TB or detection of drug resistance in children. Nucleic Acid Amplification Tests Nucleic acid amplification [NAA] tests amplify nucleic acid regions specific to the Mycobacterium tuberculosis complex. These tests can be directly used on clinical

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specimens [such as, sputum] and are available as either commercial kits or in-house assays. Commercial kits include the Amplified Mycobacterium tuberculosis Direct Test® [MTD] [Gen-Probe Inc., San Diego, CA, USA], the Amplicor® MTB tests [Roche Diagnostic Systems, Branchburg, NJ, USA], and the BD ProbeTec ET assay [Becton Dickinson Biosciences, Sparks, MD, USA]. The Amplicor® and MTD® tests are currently US FDA approved. The literature on NAA tests has been extensively reviewed (78-81). They have shown highly variable results and limited utility in children (82-85). Several recent metaanalyses (78,80,81,85) have shown that sensitivity estimates are low in paucibacillary forms of TB [extrapulmonary TB, and smear-negative pulmonary TB], which represents the vast majority of childhood TB cases. A negative test, therefore, does not rule out the diagnosis of TB. The same limitations apply to the use of NAA tests on cerebrospinal fluid samples for the diagnosis of TB meningitis (81). Good results have been reported with the use of a hemi-nested polymerase chain reaction [PCR] technique in Peru (85), but the study used uninfected children as the control group and could therefore, not

comment on the ability of this test to differentiate LTBI from active TB, which is a particular concern in endemic areas where LTBI is extremely common. In summary, available NAA tests have not lived up to their early promise. In addition to concerns about accuracy and reliability, their high costs and requirement for laboratory infrastructure reduce their applicability in resource-limited settings. Therefore, efforts are underway to simplify testing protocols and increase their accuracy (43,87). Many promising advances have been made in the development of novel tools to diagnose TB in adults (43,52,87), but none of these tests are currently in position to replace sputum smear microscopy or culture. Very few of these novel approaches have been tested in children, the group in whom the current diagnostic dilemma is most pronounced. At present, the uses of simple symptom-based diagnostic approaches with or without the use of TST or IGRAs and improved access to chest radiography seem to offer the most immediate benefit to children (88). A flow diagram has been included to guide the diagnosis and appropriate management of children with suspected TB exposure or disease [Figure 42.1]. Improving the provision of preventive chemotherapy to

Figure 42.1: Algorithm for diagnosis and management of children with suspected tuberculosis exposure and/or disease based on answering five simple questions. Question 5 refers to special circumstances such as human immunodeficiency virus infection, retreatment, or exposure to a drug-resistant source case Reproduced with permission from “Marais BJ, Gie RP, Schaaf HS, Beyers N, Donald PR, Starke JR. Childhood pulmonary tuberculosis: old wisdom and new challenges. Am J Respir Crit Care Med 2006;173:1078-90 (reference 88)”

Diagnosis of Childhood Tuberculosis: Recent Advances and Applicability of New Tools high-risk children following exposure and/or Mycobacterium tuberculosis infection, and antituberculosis treatment to those with active disease will drastically reduce the severe TB-related morbidity and mortality suffered by children in endemic areas (88). Ultimately, the burden of childhood TB is determined by the level of epidemic control achieved within a particular community (30,89-91). Current efforts to control the TB epidemic are mainly directed towards reducing transmission within the community by treating sputum smear-positive adults, and little emphasis is placed on reducing the vulnerability of communities where TB is endemic. There is a substantial body of evidence to suggest that this will depend mainly on breaking the cycle of poverty in these areas and achieving sustainable social upliftment (89). Several recent initiatives are attempting to address these issues, including the formulation of the UN Millennium Developmental Goals (92), the Global Plan to Stop TB 2006-2015 (93), the International Standards for TB Care (19), and the new Stop TB strategy (94). Global political commitment and sufficient funding is required to support these key initiatives. REFERENCES 1. Nelson LJ, Wells CD. Tuberculosis in children: considerations for children from developing countries. Semin Pediatr Infect Dis 2004;15:150-4. 2. Nelson LJ, Wells CD. Global epidemiology of childhood tuberculosis. Int J Tuberc Lung Dis 2004;8:636-47. 3. Curtis AB, Ridzon R, Vogel R, McDonough S, Hargreaves J, Ferry J, et al. Extensive transmission of Mycobacterium tuberculosis from a child. N Engl J Med 1999;341:1491-5. 4. Marais BJ, Gie RP, Hesseling AH, Beyers N. Adult-type pulmonary tuberculosis in children 10-14 years of age. Pediatr Infect Dis J 2005;24:743-4. 5. Gocmen A, Cengizlier R, Ozcelik U, Kiper N, Senuyar R. Childhood tuberculosis: a report of 2,205 cases. Turk J Pediatr 1997;39:149-58. 6. Somu N, Vijayasekaran D, Ravikumar T, Balachandran A, Subramanyam L, Chandrabhushanam A. Tuberculous disease in a pediatric referral centre: 16 years experience. Indian Pediatr 1994;31:1245-9. 7. Lemos AC, Matos ED, Pedral-Sampaio DB, Netto EM. Risk of tuberculosis among household contacts in Salvador, Bahia. Braz J Infect Dis 2004;8:424-30. 8. Marais BJ, Hesseling AC, Gie RP, Schaaf HS, Beyers N. The burden of childhood tuberculosis and the accuracy of community-based surveillance data. Int J Tuberc Lung Dis 2006;10:259-63.

611

9. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009-21. 10. Shahab T, Zoha MS, Malik MA, Malik A, Afzal K. Prevalence of human immunodeficiency virus infection in children with tuberculosis. Indian Pediatr 2004;41:595-9. 11. Chintu C, Mudenda V, Lucas S, Nunn A, Lishimpi K, Maswahu D, et al. Lung diseases at necropsy in African children dying from respiratory illnesses: a descriptive necropsy study. Lancet 2002;360:985-90. 12. Mubarik M, Nabi B, Ladakhi GM, Sethi AS. Childhood tuberculosis [Part-I]. Epidemiology, pathogenesis, clinical profile. JK Pract 2000;7:12-5. 13. Harries AD, Hargreaves NJ, Graham SM, Mwansambo C, Kazembe P, Broadhead RL, et al. Childhood tuberculosis in Malawi: nationwide case-finding and treatment outcomes. Int J Tuberc Lung Dis 2002;6:424-31. 14. Marais BJ, Gie RP, Schaaf HS, Hesseling AC, Enarson DA, Beyers N. The spectrum of disease in children treated for tuberculosis in a highly endemic area. Int J Tuberc Lung Dis 2006;10:732-8. 15. Starke JR. Childhood tuberculosis. A diagnostic dilemma. Chest 1993;104:329-30. 16. Eamranond P, Jaramillo E. Tuberculosis in children: reassessing the need for improved diagnosis in global control strategies. Int J Tuberc Lung Dis 2001;5:594-603. 17. Starke JR. Pediatric tuberculosis: time for a new approach. Tuberculosis [Edinb] 2003;83:208-12. 18. Zar HJ, Hanslo D, Apolles P, Swingler G, Hussey G. Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. Lancet 2005;365:130-4. 19. Tuberculosis Coalition for Technical Assistance. International Standards for Tuberculosis Care. http://www.tbcta.org The Hague: Tuberculosis Coalition for Technical Assistance; 2006. p.26-7. 20. Schaaf HS, Michaelis IA, Richardson M, Booysen CN, Gie RP, Warren R, et al. Adult-to-child transmission of tuberculosis: household or community contact? Int J Tuberc Lung Dis 2003;7:426-31. 21. Verver S, Warren RM, Munch Z, Richardson M, van der Spuy GD, Borgdorff MW, et al. Proportion of tuberculosis transmission that takes place in households in a highincidence area. Lancet 2004;363:212-4. 22. Enarson PM, Enarson DA, Gie R. Management of tuberculosis in children in low-income countries. Int J Tuberc Lung Dis 2005;9:1299-304. 23. Weismuller MM, Graham SM, Claessens NJ, Meijnen S, Salaniponi FM, Harries AD. Diagnosis of childhood tuberculosis in Malawi: an audit of hospital practice. Int J Tuberc Lung Dis 2002;6:432-8. 24. World Health Organization. Provisional guidelines for the diagnosis and classification of the EPI target diseases for primary health care, surveillance and special studies. PI/ GEN/83/4. Geneva: World Health Organization;1983.

612

Tuberculosis

25. Leung AN, Muller NL, Pineda PR, FitzGerald JM. Primary tuberculosis in childhood: radiographic manifestations. Radiology 1992;182:87-91. 26. Marais BJ, Gie RP, Schaaf HS, Hesseling AC, Obihara CC, Starke JJ, et al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the prechemotherapy era. Int J Tuberc Lung Dis 2004;8:392-402. 27. Marais BJ, Donald PR, Gie RP, Schaaf HS, Beyers N. Diversity of disease in childhood pulmonary tuberculosis. Ann Trop Paediatr 2005;25:79-86. 28. Theart AC, Marais BJ, Gie RP, Hesseling AC, Beyers N. Criteria used for the diagnosis of childhood tuberculosis at primary health care level in a high-burden, urban setting. Int J Tuberc Lung Dis 2005;9:1210-4. 29. Madhi SA, Huebner RE, Doedens L, Aduc T, Wesley D, Cooper PA. HIV-1 co-infection in children hospitalised with tuberculosis in South Africa. Int J Tuberc Lung Dis 2000;4:44854. 30. Marais BJ, Pai M. Recent advances in the diagnosis of childhood tuberculosis. Arch Dis Child 2007;92:446-52. 31. World Health Organization. Treatment of tuberculosis. Guidelines for national programmes. Geneva: World Health Organization; 2003. 32. Marais BJ, Gie RP, Hesseling AC, Schaaf HS, Enarson DA, Beyers N. Radiographic signs and symptoms in children treated for tuberculosis: possible implications for symptombased screening in resource-limited settings. Pediatr Infect Dis J 2006;25:237-40. 33. Hesseling AC, Schaaf HS, Gie RP, Starke JR, Beyers N. A critical review of diagnostic approaches used in the diagnosis of childhood tuberculosis. Int J Tuberc Lung Dis 2002;6:103845. 34. Marais BJ, Obihara CC, Gie RP, Schaaf HS, Hesseling AC, Lombard C, et al. The prevalence of symptoms associated with pulmonary tuberculosis in randomly selected children from a high burden community. Arch Dis Child 2005;90:116670. 35. Marais BJ, Gie RP, Obihara CC, Hesseling AC, Schaaf HS, Beyers N. Well defined symptoms are of value in the diagnosis of childhood pulmonary tuberculosis. Arch Dis Child 2005;90:1162-5. 36. Marais BJ, Gie RP, Hesseling AC, Schaaf HS, Lombard C, Enarson DA, et al. A refined symptom-based approach to diagnose pulmonary tuberculosis in children. Pediatrics 2006;118:1350-9. 37. Marais BJ, Wright CA, Schaaf HS, Gie RP, Hesseling AC, Enarson DA, et al. Tuberculous lymphadenitis as a cause of persistent cervical lymphadenopathy in children from a tuberculosis-endemic area. Pediatr Infect Dis J 2006;25:1426. 38. Handa U, Palta A, Mohan H, Punia RP. Fine needle aspiration diagnosis of tuberculous lymphadenitis. Trop Doct 2002;32:147-9. 39. Lau SK, Wei WI, Kwan S, Yew WW. Combined use of fineneedle aspiration cytologic examination and tuberculin skin

40.

41. 42.

43.

44.

45. 46.

47.

48.

49.

50.

51.

52.

53.

54.

test in the diagnosis of cervical tuberculous lymphadenitis. A prospective study. Arch Otolaryngol Head Neck Surg 1991;117:87-90. Thomas J, Adeyi AO, Olu-Eddo AO, Nwachokor N. Fine needle aspiration cytology in the management of childhood palpable masses: Ibadan experience. J Trop Pediatr 1999;45:378. Gennaro ML. Immunologic diagnosis of tuberculosis. Clin Infect Dis 2000;30:S243-6. Laal S, Skeiky YAW. Immune-based methods. In: Cole ST, Eisenach KD, McMurray DN, Jacobs WR Jr, editors. Tuberculosis and the tubercle bacillus. Washington, DC: ASM Press; 2005.p.71-83. Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: Part II. Active tuberculosis and drug resistance. Expert Rev Mol Diagn 2006;6:423-32. Davidow A, Kanaujia GV, Shi L, Kaviar J, Guo X, Sung N, et al. Antibody profiles characteristic of Mycobacterium tuberculosis infection state. Infect Immun 2005;73:6846-51. Gennaro ML. Serologic tests for TB: is there hope? Int J Tuberc Lung Dis 2005;9:S18. Boehme C, Molokova E, Minja F, Geis S, Loscher T, Maboko L, et al. Detection of mycobacterial lipoarabinomannan with an antigen-capture ELISA in unprocessed urine of Tanzanian patients with suspected tuberculosis. Trans R Soc Trop Med Hyg 2005;99:893-900. Nakamura RM, Einck L, Velmonte MA, Kawajiri K, Ang CF, Delasllagas CE, et al. Detection of active tuberculosis by an MPB-64 transdermal patch: a field study. Scand J Infect Dis 2001;33:405-7. Nakamura RM, Velmonte MA, Kawajiri K, Ang CF, Frias RA, Mendoza MT, et al. MPB64 mycobacterial antigen: a new skintest reagent through patch method for rapid diagnosis of active tuberculosis. Int J Tuberc Lung Dis 1998;2:541-6. Pai M, Gokhale K, Joshi R, Dogra S, Kalantri SP, Mendiratta DK, et al. Mycobacterium tuberculosis infection in health care workers in rural India: comparison of a whole-blood interferon-g assay with tuberculin skin testing. JAMA 2005;293:2746-55. Mahomed H, Hughes EJ, Hawkridge T, Minnies D, Simon E, Little F, et al. Comparison of Mantoux skin test with three generations of a whole blood IFN-g assay for tuberculosis infection. Int J Tuberc Lung Dis 2006;10:310-6. Brock I, Ruhwald M, Lundgren B, Westh H, Mathiesen LR, Ravn P. Latent tuberculosis in HIV positive, diagnosed by the M. tuberculosis specific interferon-gamma test. Respir Res 2006;7:56. Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: Part I. Latent tuberculosis. Expert Rev Mol Diagn 2006;6:413-22. Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4:761-76. Dheda K, Udwadia ZF, Huggett JF, Johnson MA, Rook GA. Utility of the antigen-specific interferon-gamma assay for the

Diagnosis of Childhood Tuberculosis: Recent Advances and Applicability of New Tools

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67. 68.

management of tuberculosis. Curr Opin Pulm Med 2005;11:195-202. Mazurek GH, Jereb J, Lobue P, Iademarco MF, Metchock B, Vernon A. Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR Recomm Rep 2005;54:49-55. Nahid P, Pai M, Hopewell PC. Advances in the diagnosis and treatment of tuberculosis. Proc Am Thorac Soc 2006;3: 103-10. Connell TG, Curtis N, Ranganathan SC, Buttery JP. Performance of a whole blood interferon gamma assay in detecting latent infection with Mycobacterium tuberculosis in children. Thorax 2006;61:616-20. Dogra S, Narang P, Mendiratta DK, Chaturvedi P, Reingold AL, Colford JM Jr, et al. Comparison of a whole blood interferon-gamma assay with tuberculin skin testing for the detection of tuberculosis infection in hospitalized children in rural India. J Infect 2007;54:267-76. Mori M, Kurosawa R, Imagawa T, Katakura S, Mitsuda T, Aihara Y, et al. Usefulness of interferon-gamma-based diagnosis of Mycobacterium tuberculosis infection in childhood tuberculosis. Kansenshogaku Zasshi 2005;79:93744. Connell T, Bar-Zeev N, Curtis N. Early detection of perinatal tuberculosis using a whole blood interferon-gamma release assay. Clin Infect Dis 2006;42:82-5. Ewer K, Deeks J, Alvarez L, Bryant G, Waller S, Andersen P, et al. Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet 2003;361:1168-73. Liebeschuetz S, Bamber S, Ewer K, Deeks J, Pathan AA, Lalvani A. Diagnosis of tuberculosis in South African children with a T-cell-based assay: a prospective cohort study. Lancet 2004;364:2196-203. Nicol MP, Pienaar D, Wood K, Eley B, Wilkinson RJ, Henderson H, et al. Enzyme-linked immunospot assay responses to early secretory antigenic target 6, culture filtrate protein 10, and purified protein derivative among children with tuberculosis: implications for diagnosis and monitoring of therapy. Clin Infect Dis 2005;40:1301-8. Madhi SA, Gray GE, Huebner RE, Sherman G, McKinnon D, Pettifor JM. Correlation between CD4+ lymphocyte counts, concurrent antigen skin test and tuberculin skin test reactivity in human immunodeficiency virus type 1-infected and uninfected children with tuberculosis. Pediatr Infect Dis J 1999;18:800-5. Graham SM, Coulter JB, Gilks CF. Pulmonary disease in HIVinfected African children. Int J Tuberc Lung Dis 2001;5:1223. Marais BJ, Hesseling AC, Gie RP, Schaaf HS, Enarson DA, Beyers N. The bacteriologic yield in children with intrathoracic tuberculosis. Clin Infect Dis 2006;42:69-71. Gray JW. Childhood tuberculosis and its early diagnosis. Clin Biochem 2004;37:450-5. Lobato MN, Loeffler AM, Furst K, Cole B, Hopewell PC. Detection of Mycobacterium tuberculosis in gastric aspirates

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

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collected from children: hospitalization is not necessary. Pediatrics1998;102:E40. Singh M, Moosa NV, Kumar L, Sharma M. Role of gastric lavage and broncho-alveolar lavage in the bacteriological diagnosis of childhood pulmonary tuberculosis. Indian Pediatr 2000;37:947-51. Franchi LM, Cama RI, Gilman RH, Montenegro-James S, Sheen P. Detection of Mycobacterium tuberculosis in nasopharyngeal aspirate samples in children. Lancet 1998;352:1681-2. Marais BJ, Pai M. Specimen collection methods in the diagnosis of childhood tuberculosis. Indian J Med Microbiol 2006; 24:249-51. Vargas D, Garcia L, Gilman RH, Evans C, Ticona E, Navincopa M, et al. Diagnosis of sputum-scarce HIVassociated pulmonary tuberculosis in Lima, Peru. Lancet 2005;365:150-2. Chow F, Espiritu N, Gilman RH, Gutierrez R, Lopez S, Escombe AR, et al. La cuerda dulce - a tolerability and acceptability study of a novel approach to specimen collection for diagnosis of paediatric pulmonary tuberculosis. BMC Infect Dis 2006;6:67. Kocagoz T, O’Brien R, Perkins M. A new colorimetric culture system for the diagnosis of tuberculosis. Int J Tuberc Lung Dis 2004;8:1512; author reply 3. Kalantri S, Pai M, Pascopella L, Riley L, Reingold A. Bacteriophage-based tests for the detection of Mycobacterium tuberculosis in clinical specimens: a systematic review and meta-analysis. BMC Infect Dis 2005;5:59. Pai M, Kalantri S, Pascopella L, Riley LW, Reingold AL. Bacteriophage-based assays for the rapid detection of rifampicin resistance in Mycobacterium tuberculosis: a metaanalysis. J Infect 2005;51:175-87. Moore DA, Mendoza D, Gilman RH, Evans CA, Hollm Delgado MG, Guerra J, et al. Microscopic observation drug susceptibility assay, a rapid, reliable diagnostic test for multidrug-resistant tuberculosis suitable for use in resourcepoor settings. J Clin Microbiol 2004;42:4432-7. Flores LL, Pai M, Colford JM Jr, Riley LW. In-house nucleic acid amplification tests for the detection of Mycobacterium tuberculosis in sputum specimens: meta-analysis and metaregression. BMC Microbiol 2005;5:55. Pai M. The accuracy and reliability of nucleic acid amplification tests in the diagnosis of tuberculosis. Natl Med J India 2004;17:233-6. Pai M, Flores LL, Hubbard A, Riley LW, Colford JM Jr. Nucleic acid amplification tests in the diagnosis of tuberculous pleuritis: a systematic review and meta-analysis. BMC Infect Dis 2004;4:6. Pai M, Flores LL, Pai N, Hubbard A, Riley LW, Colford JM Jr. Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and metaanalysis. Lancet Infect Dis 2003;3:633-43. Smith KC, Starke JR, Eisenach K, Ong LT, Denby M. Detection of Mycobacterium tuberculosis in clinical specimens from

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83. 84.

85.

86.

87.

Tuberculosis children using a polymerase chain reaction. Pediatrics 1996;97:155-60. Gomez-Pastrana D. Tuberculosis in children-is PCR the diagnostic solution? Clin Microbiol Infect 2002;8:541-4. Gomez-Pastrana D, Torronteras R, Caro P, Anguita ML, Barrio AM, Andres A, et al. Diagnosis of tuberculosis in children using a polymerase chain reaction. Pediatr Pulmonol 1999;28:344-51. Sarmiento OL, Weigle KA, Alexander J, Weber DJ, Miller WC. Assessment by meta-analysis of PCR for diagnosis of smear-negative pulmonary tuberculosis. J Clin Microbiol 2003;41:3233-40. Montenegro SH, Gilman RH, Sheen P, Cama R, Caviedes L, Hopper T, et al. Improved detection of Mycobacterium tuberculosis in Peruvian children by use of a heminested IS6110 polymerase chain reaction assay. Clin Infect Dis 2003;36:16-23. Perkins MD, Roscigno G, Zumla A. Progress towards improved tuberculosis diagnostics for developing countries. Lancet 2006;367:942-3.

88. Marais BJ, Gie RP, Schaaf HS, Beyers N, Donald PR, Starke JR. Childhood pulmonary tuberculosis: old wisdom and new challenges. Am J Respir Crit Care Med 2006;173:1078-90. 89. Marais BJ, Obihara CC, Warren RM, Schaaf HS, Gie RP, Donald PR. The burden of childhood tuberculosis: a public health perspective. Int J Tuberc Lung Dis 2005;9:1305-13. 90. Marais BJ, Pai M. New approaches and emerging technologies in the diagnosis of childhood tuberculosis. Paediatr Respir Rev 2007;8:124-33. Epub 2007 Jun 5. 91. Marais BJ, Graham SM, Cotton MF, Beyers N. Diagnostic and management challenges for childhood tuberculosis in the era of HIV. J Infect Dis 2007;196[Suppl1]:S76-85. 92. United Nations. The Millennium Development Goals Report 2005. New York: United Nations; 2005. 93. Stop TB Partnership and World Health Organization. The Global Plan to Stop TB 2006 - 2015. Geneva: World Health Organization; 2006. 94. Raviglione MC, Uplekar MW. WHO’s new Stop TB Strategy. Lancet 2006;367:952-5.

Surgical Aspects of Childhood Tuberculosis

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43

M Bajpai, V Jain, Arun K Gupta

INTRODUCTION Diagnosis of tuberculosis [TB] in children poses a major problem and a high degree of suspicion is warranted to make an early diagnosis even in endemic regions. In this chapter, the surgical aspects of TB in children will be discussed laying emphasis on the clinical, diagnostic and surgical principles involved. GENITOURINARY TUBERCULOSIS As there is a time lag of about four to twenty years between the initial infection and occurrence of genitourinary involvement, paediatric genitourinary TB presents usually in the adolescent period. The time lag noted is more than five years in two-thirds of the patients and is greater than 15 years in a quarter of the cases (1). Clinical Presentation Tuberculosis of the genital tract is uncommon before puberty. Majority of the young children with genitourinary TB are asymptomatic. Symptoms are seen in the more advanced stages and usually after vesical involvement. Symptoms and signs commonly observed in children with genitourinary TB are listed in Table 43.1. Tuberculosis of the genitourinary tract must be suspected if a child presents with chronic or recurrent urinary tract infection [cystitis] not responding to adequate standard antibiotic therapy for recommended duration. The clinical suspicion is enhanced when pus cells are found without bacteria in an acidic urine or on methylene blue staining of the urine sediment. Gross or microscopic haematuria; an enlarged, non-tender

Table 43.1: Clinical features of genitourinary tuberculosis Symptoms Progressive, diurnal urinary frequency Dysuria Macroscopic haematuria with back and flank pain Renal colic Systemic symptoms [fever, anorexia, night sweats, weight loss] Hypertension Chronic epididymitis Other symptoms Polyuria, hyponatraemia [with adrenal tuberculosis] Chronic renal insufficiency

epididymis with a thickened, beaded vas; a chronic, draining scrotal sinus in the setting of history of TB elsewhere in the body or definite history of contact further support the diagnosis of genitourinary TB. Urinary frequency is the earliest symptom which is diurnal and progressive in nature (2). Frequency is secondary to vesical irritation, decreased bladder capacity and rarely as a result of polyuria with tubular dysfunction. The urine may be opalescent. Occasionally, patients may present with pyuria. The child may initially complain of suprapubic pain with a moderately full bladder which gradually progresses to dysuria and strangury. Renal pain is usually absent but some patients may have a dull flankache. Painless haematuria may result because of ulcers at the renal papilla in five per cent cases (1,2). Renal and ureteric colic may occur due to passage of a blood clot, secondary calculi or debris. There is usually no renal enlargement or tenderness. Rarely, the contralateral kidney may show compensatory

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enlargement. Symptomatic chronic renal failure occurs rarely but subclinical impairment of renal functions may be seen more oftenly. Five to ten per cent of patients with renal TB may have hypertension (1-3). Ocon et al (3) have shown that in most patients the hypertension is not mediated by the renin-angiotensin system and is therefore, not cured by nephrectomy. Genitourinary TB may present with other complications, such as perinephric abscess, renal calculi, secondary amyloidosis and adenocarcinoma of the renal pelvis. Tuberculosis of the genital tract most often manifests as epididymitis in boys. Fever is seldom present. Enlarged epididymis may be felt as a hard, nodular swelling. A chronic draining scrotal sinus should suggest TB aetiology unless proved otherwise. A secondary hydrocoele may accompany epididymitis. The testis may be fixed by an extension of an epididymal abscess. The prostate may be nodular or indurated and the seminal vesicle is similarly involved. In the presence of prostatitis, TB may spread via the semen. Genital TB may be a

manifestation of sexual abuse and there are reports of urethral involvement and penile lesions following ritual circumcision. In girls, lower abdominal pain and amenorrhoea may be presenting symptoms of genital TB. Constitutional symptoms are rare. Free peritoneal fluid and lower abdominal mass may be evident. Role of Surgery Surgery is reserved for the management of local complications, such as ureteral strictures, perinephric abscesses and non-functioning kidneys. Algorithm for the surgical management of children with genitourinary TB is shown in Figure 43.1. Surgery should be preceded by at least three weeks and preferably four months of antituberculosis treatment with constant clinical and radiological monitoring. The principles of surgery for urogenital TB in children are same as those for adults. The reader is referred to the chapter “Genitourinary tuberculosis” [Chapter 32] for more details.

Figure 43.1: Algorithm for the surgical management children with genitourinary tuberculosis IVP = intravenous pyelography Adapted and reproduced with permission from reference 8

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ABDOMINAL TUBERCULOSIS The clinical manifestations of abdominal TB are protean [Figures 43.2, 43.3, 43.4, 43.5 and 43.6]. All age groups are at risk, and children between six and fourteen years of age are often affected (4,5). Clinical presentation of abdominal TB in children can be acute, sub-acute or with other manifestations. The reader is referred to the chapters “Tuberculosis in children” [Chapter 41A] and “Abdominal tuberculosis” [Chapter 19] for more details

Figure 43.2: CECT of the abdomen showing calcified retroperitoneal and mesenteric lymph nodes. A large psoas abscess can also be seen on the left side [arrow]

Figure 43.4: Ultrasonography of the abdomen showing ascites [A] and multiple hypoechoic masses in the prevertebral location [B] suggestive of lymphadenopathy

regarding the clinical presentation, diagnosis and medical management of this condition. Role of Surgery

Figure 43.3: Barium meal follow through examination showing ileocaecal tuberculosis [stricture marked by arrows]

Antituberculosis treatment is the mainstay of management (4-9). Surgical intervention is helpful in procuring tissue for confirmation of aetiological diagnosis in children with peritoneal and mesenteric lymph node TB. An algorithm for assessment of suspected abdominal TB is shown in Figure 43.7 (10). Surgery is also helpful in the management of complications of intestinal TB, such as perforation of intestinal ulcer and intestinal obstruction. The possible role of surgical intervention in children with abdominal TB is shown in Figures 43.8A and 43.8B.

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Tuberculosis Stricturoplasty is preferred to multiple resection anastomoses in multiple strictures as it conserves the bowel and obviates the occurrence of blind loop syndromes. Emergency surgery for intestinal obstruction is best avoided as it is associated with a high mortality (12). PERIPHERAL LYMPH NODE TUBERCULOSIS

Figure 43.5: Plain radiograph of the lumbosacral region [anteroposterior view] showing multiple calcified lymph nodes

Tuberculosis accounts for a high proportion of lymphadenopathy in children. Classically, the cervical nodes are involved in 67 to 90 per cent of cases (13,14). The exact incidence may vary in childhood but has been reported in up to 55 per cent in a cohort of 223 children under six years of age (15). Painless enlargement, matting, fluctuant neck mass or a discharging sinus may be evident. Multifocal [> 3 sites] or generalized lymphadenopathy is uncommon without co-existent disseminated or miliary TB. Associated extralymphatic TB has been described in five to fifteen per cent cases. These figures increase when human immunodeficiency virus [HIV] infection co-exists (13-16). Isolated TB lymphadenitis at sites other than cervical region has been reported rarely. Selective preauricular and intraparotid lymph nodal TB with or without parotid parenchymal involvement may sometimes be seen (17). The lower pole is usually involved presenting as a swelling antero-inferior to the ear and in front of the mastoid attachment of the sternocleidomastoid muscle. The dense parotid fascia limits the spread of infection and the resultant swelling may mimic a tumour on physical examination. Nontuberculous Mycobacterial Lymphadenitis in Children

Figure 43.6: Barium meal follow through examination showing short segment tuberculosis stricture [arrow] in the small bowel with proximal dilatation

Surgery for abdominal TB must be cautious and minimal as the risk of inadvertent bowel injury with subsequent entero-cutaneous fistulae is high. Procedures commonly adopted include closure of perforation, exteriorization of bowel, adhesiolysis and resectionanastomosis of the bowel. The choice of surgery is dependent on several factors. Tuberculosis perforations carry a high mortality [30% to 40%] despite surgery (11).

In lymphadenitis caused by nontuberculous mycobacteria [NTM], females are mostly affected and lymph node involvement is unilateral (13). High cervical lymph nodes near the mandible are characteristically involved and the enlarged lymph nodes are firm, rubbery and non-tender. They may not manifest the signs of inflammation and matting is exceedingly rare. Systemic symptoms are uncommon and history of exposure to TB is rarely obtained. The reader is referred to the chapter “Lymph node tuberculosis” [Chapter 26] for more details on the clinical presentation, diagnosis and management of lymph node TB.

Surgical Aspects of Childhood Tuberculosis

Figure 43.7: Algorithm for assessment of suspected abdominal TB. *Confirmatory investigations: 1. culture for Mycobacterium tuberculosis from accessible source; 2. peripheral lymph node biopsy for histopathology and culture; 3. adenosine deaminase levels in ascitic fluid; and 4. CT of the abdomen if ultrasonography is inconclusive TB = tuberculosis; AFB = acid-fast bacilli; TST = tuberculin skin test Adapted from reference 10

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Tuberculosis Table 43.2: Indications for lymph node sampling Difficulty in clinical diagnosis and/or non-diagnostic fine needle aspiration cytology Abscess formation History of rapid increase in size Further significant increase in size on treatment Supraclavicular lymph nodes Hard or matted lymph nodes Fixation to surrounding structures

Figure 43.8A: Surgical intervention in patients with peritoneal TB TB = tuberculosis Adapted from reference 9

Development of new signs and symptoms [fever, weight loss, night sweats] Significant lymph node [> 2 cm] not responding to antibiotic therapy in 4 to 6 weeks Non-resolution of the lymphadenopathy in 8 weeks

by the enlarged intrathoracic lymph nodes can result in atelectasis, obstructive emphysema, pulmonary infection and even asphyxia (19-21). The enlarged mediastinal lymph nodes can also cause perforation of the tracheobronchial tree. The aim of effective surgical treatment in childhood pulmonary TB includes restoring lung function to normal and managing complications. The indications for surgery are listed in Table 43.3 (19-23). Role of Surgery Figure 43.8B: Surgical intervention in patients with intestinal TB TB = tuberculosis Adapted from reference 9

Role of Surgery Antituberculosis treatment is the mainstay in management of lymph node TB. The surgeon aids in obtaining tissue for the confirmation of diagnosis [e.g., in performing excision biopsy of the lymph node]. The indications for the lymph node sampling are listed in Table 43.2. Nontuberculous mycobacterial lymphadenitis is treated primarily by surgical excision (13). Parotid lymph nodal TB may mandate superficial extirpation of an encapsulated mass with a 1 cm margin (17,18). Aspiration of fluctuant lesions may also be required in some patients. PULMONARY TUBERCULOSIS In children with primary pulmonary TB disease, compression of the relatively narrow and compliant airways

Major Airways Obstruction When there is an obstruction of the major airways and acute respiratory distress, administration of prednisolone [2 mg/kg/day] along with antituberculosis treatment and nebulized bronchodilator therapy is indicated. Lack of improvement within 48 to 72 hours is an indication Table 43.3: Indications of surgery in childhood pulmonary tuberculosis Major airway obstruction by extraluminal lymph node compression or intraluminal tissue Post-TB pulmonary destruction TB pleural disease Other indications Drainage of active TB lung abscess Repair of broncho-oesophageal and bronchopleural fistula using vascularized muscle flaps Resection of persistently discharging chest wall sinuses TB = tuberculosis

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for operative intervention. Following a pre-operative bronchoscopic assessment of the airway, usually a right thoracotomy is performed. An attempt to resect the entire nodal mass is hazardous and can lead to damage of the airway wall. Most of the nodes can be evacuated by incising the capsule and removing the caseous material or by removing the calcified contents piece-meal. When there is chronic compromise, these patients may be asymptomatic. Superinfection by pyogenic organisms can result in an acute presentation. Also, the distal atelectatic or collapsed lung can undergo progressive damage despite effective medical therapy [Figure 43.9]. Recent evidence suggests that the early surgical decompression prevents irreversible pulmonary parenchymal damage. The risk of airway damage during evacuation of lymph nodes is higher in this group. Nodal incision and curettage of the mass is recommended. When the obstruction is due to intraluminal tissue [endobronchial TB], the collapsed lung is at high risk of being permanently damaged by infection. Bronchoscopic suction and removal of granulomatous tissue with biopsy forceps results in re-inflation of the lobe or lung in more than 50 per cent of the cases. This usually requires multiple attempts which are repeated every five to seven days. Haemorrhage during removal of the granulation tissue is a possible complication. This procedure decreases the incidence of pulmonary resection and salvages lungs or lobes which are collapsed secondary to obstruction but are otherwise normal.

Post-tuberculosis Pulmonary Destruction

Figure 43.9: Chest radiograph [postero-anterior view] showing collapse of left lower lobe which can be seen as a triangular radiodensity [arrow] in the left retrocardiac region

Figure 43.10: CECT of the chest showing loculated encysted empyema in right hemithorax with enhancing walls. Thickening of extrapleural soft tissues can also be seen

Patients with post-TB pulmonary destruction present with definite evidence of extensive pulmonary damage and are usually symptomatic. Decision making regarding pulmonary resection is primarily based on symptomatology rather than the radiological findings. The risk to the remaining pulmonary tissue should be kept in mind while planning for surgery. Intensive pre-operative preparation involving physiotherapy and use of broadspectrum antibiotic treatment is mandatory. This regimen is continued till the sputum production is reduced to a minimum. One lung ventilation and prone position with head end lowered is recommended during surgery to avoid contamination of the normal lung. Tuberculosis Pleural Disease Late pleural fibrosis after a TB empyema requires decortication [Figure 43.10]. Patients with minimal or no respiratory symptoms despite radiographic evidence of pleural fibrosis do not require decortication unless there is a significant postural problem [scoliosis]. Patients with minimal symptoms cope well with pleural fibrosis which tends to regress with age and activity. It is also important to ensure that the underlying lung is not bronchiectatic and unsalvageable before undertaking decortication. Video-assisted thoracoscopic surgery [VATS] is also finding increasing use in the treatment of pleuropulmonary TB (24,25). Video-assisted thoracoscopic

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surgery is a safe approach and avoids the morbidity associated with conventional thoracotomy. The current role of VATS in the management of pleuropulmonary TB is unclear but VATS has been found to be useful in the following situations (25): [i] VATS is safe and effective in achieving the diagnosis of TB through pleural biopsies or wedge lung resection of indeterminate pulmonary nodules; it is particularly useful for those patients who are debilitated, thus making them poor candidates for conventional open surgery; and [ii] in patients with trapped lung or TB empyema, VATS could achieve full lung re-expansion with minimal morbidity. However, therapeutic lung resection using VATS in patients with TB is technically demanding and potentially hazardous. Its role is, at present, limited. The reader is also referred to the chapter “Surgery for pleuropulmonary tuberculosis” [Chapter 55] for more details. NEUROLOGICAL TUBERCULOSIS Neurological TB constitutes almost half the cases of childhood TB. Tuberculosis meningitis [TBM] is the most common type of central nervous system TB. The reader is referred to the chapter “Neurological tuberculosis” [Chapter 21] and “Tuberculosis in children” [Chapter 41] for more details. Surgical Therapy Intrathecal hyaluronidase has been used in children with thick basal exudates. Besides clearing up meningeal adhesions hyaluronidase helps in better diffusion of drugs and reverses or reduces vasculitis. A weekly dose of 1000 to 1500 units for five to ten weeks has been recommended as treatment (26). In 50 per cent or more cases, there is established hydrocephalus [Figures 43.11A and B] requiring treatment. Meningeal exudates not only obstruct cerebrospinal fluid [CSF] pathways but can occlude large vessels in the circle of Willis, the middle cerebral artery in the Sylvian fissure and the lenticulostriate vessels causing infarction. The aetiopathogenesis of hydrocephalus in TBM involves blockage of the basal cisterns by the TB exudates in the acute stage and adhesive leptomeningitis in the chronic stage resulting in communicating hydrocephalus. The aqueduct of Sylvius may be blocked by circumferential compression of the brainstem by the meningeal exudates leading to non-communicating

Figure 43.11: NCCT of the head showing obscured suprasellar cisterns [A] which manifest intense enhancement with intravenous contrast. Communicating hydrocephalus with periventricular ooze [arrow] is also seen [B]

hydrocephalus. Rarely, an intraluminal subependymal tuberculoma or a plug of ependymal exudate may block the acqueduct. In patients with hydrocephalus due to TBM, surgical management is indicated if the signs and symptoms suggestive of raised intracranial pressure persist despite adequate medical therapy. Increasing ventriculomegaly with periventricular ooze, recent onset papilloedema and signs and symptoms of raised intracranial pressure like vomiting, hypertonia, gaze palsies and bradycardia are indications for shunt surgery (27,28). Ventriculoperitoneal shunts are preferred over ventriculoatrial shunts unless the peritoneal cavity is involved in the disease. Various shunt systems are available and all of them involve a one-way pressure regulated valve. Cerebrospinal fluid examination is mandatory before shunt

Surgical Aspects of Childhood Tuberculosis

Figure 43.12: CECT of the head showing contrast enhancing granuloma with lobulated outline and surrounding oedema. Tuberculoma is difficult to differentiate reliably from other inflammatory granulomas on the basis of CT alone

placement. The presence of persistent infection in the CSF can lead to a low-grade peritoneal inflammation and pseudocyst formation. Further, the high protein content of the CSF has been implicated in the higher incidence of shunt blockage seen in this setting. Intraventricular septae and ependymal adhesions complicate the picture and cause incomplete decompression of ventricles. Ventriculoscopy and adhesiolysis may be required to break the loculations and allow free CSF drainage. It must be remembered that CSF shunting has definite serious complications and, therefore, the decision to place a shunt must be individualized and based on definite indications. If the tuberculoma is large or is located in the pathway of CSF circulation, surgical removal is essential [Figure 43.12]. However, in majority of the patients, tuberculomas respond well to antituberculosis treatment and corticosteroids. REFERENCES 1. Christensen WI. Genitourinary tuberculosis. Review of 102 cases. Medicine 1974;53:377-92. 2. Wechsler H, Westfall M, Lattimer KK. The earliest signs and symptoms in male patients with genitourinary tuberculosis. J Urol 1960;83:801-3. 3. Ocon J, Novillo R, Villavicencio H, Del Rio G, Castellet R, Izquierdo F, et al. Renal tuberculosis and hypertension: value of the renal vein renin ratio. Eur Urol 1984;10:114-20. 4. Millar AJW, Rode H, Cywes S. Abdominal tuberculosis in children - surgical management. A 10-year review of 95 cases. Pediatr Surg Int 1990;5:392-6.

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5. Aston NO. Abdominal tuberculosis. World J Surg 1997;21: 492-9. 6. al-Fadel Saleh M, al-Quorain A, Larbi E, al-Fawaz I, Taha O, Satti MB. Tuberculous peritonitis in children: report of two cases and literature review. J Pediatr Gastroenterol Nutr 1997;24:222-5. 7. Sharma AK, Agarwal LD, Sharma CS, Sarin YK. Abdominal tuberculosis in children. Experience over a decade. Indian Pediatr 1993;30:1149-52. 8. Bajpai M, Dave S. Genitourinary tuberculosis. In: Seth V, editor. Essentials of tuberculosis in children. New Delhi: Jaypee Brothers Medical Publishers; 1997.p.203. 9. Gupta DK, Bajpai M. Abdominal tuberculosis. In: Seth V, editor. Essentials of tuberculosis in children. New Delhi: Jaypee Brothers Medical Publishers; 1997.p.140. 10. Saczek KB, Schaaf HS, Voss M, Cotton MF, Moore SW. Diagnostic dilemmas in abdominal tuberculosis in children. Pediatr Surg Int 2001;17:111-5. 11. Bahari HM. Perforation of tuberculous enteritis: report of a case. Med J Malays 1978;32:282-4. 12. Bhansali SK. The challenge of abdominal tuberculosis in 310 cases. Indian J Surg 1978;40:65-77. 13. Venkatesh V, Everson NW, Johnstone MS. Atypical mycobacterial lymphadenopathy in children- is it underdiagnosed? J R Coll Surg Edinb 1994;39:301-3. 14. Harris BH, Webb HW, Wilkinson AH Jr, Santdices AA. Mycobacterial lymphadenitis. J Pediatr Surg 1982;17:589-90. 15. Herzog LW. Prevalence of lymphadenopathy of the head and neck in infants and children. Clin Pediatr 1983;22:485-7 16. Dandapat MC, Mishra BM, Dash SP, Kar PK. Peripheral lymph node tuberculosis: a review of 80 cases. Br J Surg 1990;77:911-2. 17. Zheng JW, Zhang QH. Tuberculosis of the parotid gland: a report of 12 cases. J Oral Maxillofac Surg 1995;53:849-51. 18. Lindeboom JA, Kuijper EJ, Bruijnesteijn van Coppenraet ES, Lindeboom R, Prins JM. Surgical excision versus antibiotic treatment for nontuberculous mycobacterial cervicofacial lymphadenitis in children: a multicenter, randomized, controlled trial. Clin Infect Dis 2007;44:1057-64. Epub 2007 Mar 2. 19. Goussard P, Gie R. Airway involvement in pulmonary tuberculosis. Paediatr Respir Rev 2007;8:118-23. Epub 2007 Jun 7. 20. Freixinet J, Varela A, Lopez Rivero L, Caminero JA, Rodriguez de Castro F, Serrano A. Surgical treatment of childhood mediastinal tuberculous lymphadenitis. Ann Thorac Surg 1995;59:644-6. 21. Papagiannopoulos KA, Linegar AG, Harris DG, Rossouw GJ. Surgical management of airway obstruction in primary tuberculosis in children. Ann Thorac Surg 1999;68:1182-6. 22. Rotman PE, Jones JC, Peterson HG. Endoscopic and surgical treatment of pulmonary tuberculosis in children. Am J Dis Child 1960;99:315-9. 23. Pomerantz M, Brown J. The surgical management of tuberculosis. Semin Thorac Cardiovasc Surg 1995;7:108-11.

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24. Yim AP, Low JM, Ng SK, Ho JK, Liu KK. Video-assisted thoracoscopic surgery in the paediatric population. J Paediatr Child Health 1995;31:192-6. 25. Yim AP. The role of video-assisted thoracoscopic surgery in the management of pulmonary tuberculosis. Chest 1996;110: 829-32. 26. Udani PM. Management of tuberculosis meningitis. Indian J Pediatr 1985;52:171-4.

27. Bajpai M. Management of hydrocephalus. Indian J Pediatr 1997;64:48-56. 28. Harold LR. Treatment of hydrocephalus. In: Cheek WR, Marlin AE, McLone DG, Reigel DH, Walker ML, editors. Pediatric neurosurgery. Third edition. Philadelphia: W.B. Saunders Company; 1994.p.202-20.

Tuberculosis in Elderly

44

M van Cleeff, PCFM Gondrie, J Veen

INTRODUCTION

EPIDEMIOLOGY

Population ageing was in the twentieth and still is in the twenty-first century, one of the most distinctive demographic events [Table 44.1] (1). Initially experienced by the more developed countries, in the near future virtually all countries will face population ageing. In absolute terms, the number of older persons has tripled over the last 50 years and will more than triple again over the next 50 years. In relative terms, the percentage of older persons is projected to more than double worldwide over the next half century. Although the highest proportions of older persons are found in the more developed regions, this age group is growing considerably more rapidly in the less developed regions. As a result, the older population will be increasingly concentrated in the less developed regions (2). The elderly population in India increased from 20 million [5.5% of total population] in 1950 to 55 million [6.5% of total population] in 1991 and almost 77 million [7.6% of total population] in the year 2000 (3,4). These figures emphasize the extent and the importance of this group of population in future.

The epidemiological pattern of tuberculosis [TB] in high incidence and low incidence countries shows a remarkable difference. In high incidence countries the peak of the epidemic is among young adults and low in older age. In low incidence countries there is an increase in the burden of TB with growing age. In England and Wales, from the year 1987 to 1989, while the increase in the incidence of TB was six per cent for all ages combined, it was 13 per cent in females and 16 per cent in males over the age of 75 years. The proportion of deaths due to extrapulmonary TB in the age group 75 and above increased by 3.2 per cent per annum from the year 1972 to 1992, while in the other age groups, the mortality rates declined (5). It has also been reported that adverse drug reactions to antituberculosis drugs occur more frequently in the elderly persons (6). A similar trend was also observed in Canada. During the year 1981, persons aged 65 years or more constituted only 9.7 per cent of the total population, but accounted for 28 per cent of all TB cases which occurred in that year (7). In the United States of America [USA], the incidence of TB in persons aged more than 65 years

Table 44.1: Number and proportion of population aged 60 years and older [1950 to 2050] Region

1950*

2000*

2050*

World

205 475 [8]

605 785 [10]

1 963 767 [21]

More developed regions

95 473 [12]

231 442 [19]

395 106 [34]

Less developed regions

110 003 [6]

374 343 [8]

1 568 660 [19]

Least developed regions

10 733 [5]

32 167 [5]

173 222 [10]

* Data expressed as thousands [%] Source: reference 1

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Tuberculosis

has been estimated to be as high as 150 to 200 per 100 000 in 1992 (8). In the USA, during the period 1986 to 1988, elderly subjects [more than 65 years of age] constituted 12 per cent of the population and accounted for about 28 per cent of the reported cases of TB. In the USA the incidence of TB is found to be higher in the elderly residing in nursing homes [old age homes] as compared to the elder ly in the community (9-11). This is attributed to clustering of elderly population in nursing homes. However, some studies (12,13) have found no significant difference in the incidence of TB in the institutionalized and noninstitutionalized elderly. As per the Revised National Tuberculosis Control Programme [RNTCP] of Government of India data 2006 [n = 563 778] (14), persons aged 65 years or above constituted eight per cent of the sputum smear-positive patients. It seems that the diagnosis of TB is often missed in the elderly subjects and is being misdiagnosed as bronchitis, bronchiecstasis or pneumonia, and while in many countries the population is ageing, TB in elderly becomes more important. Therefore, it is evident that TB can be a major health problem in some elderly populations. As an epilogue to Dubos’ book ‘The White Plague’ (15), the prevalence of TB among elderly citizens may well be titled ‘The Grey Plague’ (16).

promised, and these changes have serious implications for the elderly to control infection (21,22). Several risk factors contribute to this decline in immunity (23): [i] underweight and/or malnutrition; [ii] concomitant diseases, like cancer or diabetes mellitus; [iii] gastrointestinal surgery [gastrectomy, jejunoileal bypass]; [iv] immunosuppressive treatment like corticosteroids; [v] heavy tobacco smoking; and [vi] human immunodeficiency virus [HIV] infection. Recent data suggest that tumour necrosis factor-α blocking drugs [e.g., infliximab] have an unexpected influence on the T-cell balance and contributes to reactivation of latent TB infection [LTBI] (24). The higher age specific incidence of TB in elderly age group is attributed to enduring viability of Mycobacterium tuberculosis and to the steadily diminishing T-lymphocyte activity [immuno-senescence] (25,26). It has been demonstrated that high incidence of TB in elderly results from higher rate of infection experienced in early life (26,27). In developed countries, the prevalence of TB infection is higher in elderly as they have lived in highly endemic areas in their younger life and experienced high rates of infection. The reader is also referred to the chapter “Reactivation and reinfection tuberculosis” [Chapter 47] for more details.

REACTIVATION AND REINFECTION

LATENT TUBERCULOSIS INFECTION IN ELDERLY

Tuberculosis in old people can be either due to exogenous infection or reinfection or endogenous reactivation. Exogenous infection [or reinfection] is acquired from an outside source, usually a sputum smear-positive case, whereas endogenous reactivation arises from quiescent lesions in the lung or elsewhere in the body. It is difficult to be certain in individual cases, but there are theoretical reasons for believing that in old people endogenous reactivation is the predominant mechanism (17). When transmission in the community is low, increased incidence in older age in over 90 per cent represents reactivation of latent infection (18). However, when transmission in endemic environments is high, exogenous reinfection does occur, as has been shown by Canetti et al (19). In developed countries with a relatively large influx from refugees and asylum seekers, ongoing transmission in the elderly might even delay the elimination of TB (20). During the natural ageing process the immune system undergoes many alterations. In particular, both the CD4+ and CD8+ T-cell compartments become com-

Infection with Mycobacterium tuberculosis generally produces a positive tuberculin skin test [TST] indicated by greater than 10 mm induration with an intradermal injection of five tuberculin units [TU] of purified protein derivative [PPD]. Very often, the value of this test is questioned in elderly subjects. In a large study (27) where 45 000 residents in 227 nursing homes were tested with 5 TU of PPD, 20 to 30 per cent of those who were 60 years old were found to be TST positive. This figure dropped to 10 per cent at the age of 90 years. In this study, all the non-reactors had a booster effect on re-testing (28). American Thoracic Society [ATS] and Centers for Disease Control and Prevention [CDC] have recommended a two-stage TST (29,30). The TST positivity can be taken as a risk factor for developing active TB. Negative TST result, often found in elderly, is mainly due to failing immune response to the PPD that can be restored by repeated administration of this antigen. Care should be taken in not misinterpreting booster effect as the TST conversion.

Tuberculosis in Elderly 627 Although TST reactors have an increased risk of developing active TB, they live longer as this is an indicator of their immunocompetence. Among the non-reactors some are immunocompromised and die early in life due to some infection while the immunocompetent subjects are either not infected or have outlived the TB bacilli and, thus, have lost sensitivity to tuberculin (8). In fact, among elderly patients with active TB, tuberculin anergy has been reported in 20 to 30 per cent of those without acquired immunodeficiency syndrome [AIDS] and in up to 60 per cent in those with AIDS (30). Most patients with active TB without AIDS who are TST negative in the beginning become positive after recovery with therapy for TB. The reader is also referred to the chapter “Tuberculin skin test” [Chapter 11] for more details. There is a promising evidence suggesting that the interferon-gamma release assays [IGRAs] have a potential to perform better than the TST in the elderly population in detecting LTBI. The reader is referred to the chapter “Diagnosis of latent tuberculosis infection: recent advances and future directions” [Chapter 12] for more details.

Table 44.2: Comparison of clinical presentation of tuberculosis in the young and the elderly patients Variable Constitutional symptoms Fever Night sweats Non-specific symptoms* Respiratory symptoms Cough Haemoptysis Dyspnoea Co-morbid conditions † Hypoalbuminaemia TST positivity Adverse drug reactions

Young

Elderly

+ + +

– – –

+ + – – – + –

– – + + + – +

* dizziness, mental dullness † chronic obstructive pulmonary disease, diabetes mellitus, bronchiectasis, stroke + = more frequent; – = less frequent; TST = tuberculin skin test

clinical presentation of TB in the elderly may be atypical, especially if it is due to new infection (37,38). Pulmonary Tuberculosis

CLINICAL FEATURES Elderly subjects with TB may present with the systemic manifestations of TB such as fever, anorexia, weight loss, and symptoms attributable to the organ system involvement but with important differences (31,32). Some of the difficulties apply to diagnosis in old people in general. Elderly people may not give an accurate account of their symptoms, due to contributing factors such as poor memory or dementia, or loss of communicative skills due to deafness or impairment of speech. Other diseases like cancer may mask the symptoms of TB and confuse the clinical picture, both for the patient and the doctor. It is, therefore, not uncommon that the diagnosis of TB is only made at autopsy (33). Sometimes, apyrexial presentation with progressive wasting strongly mimicking a metastatic carcinoma has been described in elderly patients with miliary TB and has been described as cryptic miliary TB (34-36). The reader is referred to the chapter “Disseminated and miliary tuberculosis” [Chapter 34] for further details on this topic. Table 44.2 provides a comparison of clinical presentation of TB in young adults and elderly subjects. A paucity of respiratory symptoms is frequently observed in the elderly (31,32). As compared to young adults,

Pulmonary TB is defined as TB affecting the tracheobronchopulmonary tree. This excludes the mediastinum and the pleura. In the past the term ‘respiratory TB’ was used, which included TB of all intra-thoracic pulmonary structures. In some countries, especially in the former Soviet Republics, this terminology is still used. Comparison of the clinical presentation and diagnosis of pulmonary TB in elderly persons in some published studies (39-42) is shown in Table 44.3. Since primary infection at old age is rare, most clinical presentations of pulmonary TB is based on reactivation of old lesions. Typical sites are the apical segments of both upper and lower lobes and the posterior segments of the upper lobes. The disease may develop as pneumonia with caseation, liquefaction and cavity formation. In the pre-chemotherapy era complications like exudative pleuritis, or pneumothorax were common. Though these are encountered less frequently in the elderly in areas of low TB transmission, they are commonly seen in areas where TB is highly endemic (3946). Tuberculosis should be included in the differential diagnosis of any illness in an elderly patient, which consists of ill-defined pleuropulmonary symptoms or signs and pulmonary infiltrates of unknown cause.

628

Tuberculosis Table 44.3: Comparison of the clinical presentation, and diagnosis of pulmonary tuberculosis in elderly patients

Variable

Umeki (39)

Gupta et al (40)

Lee et al (41)

Das et al (42)

No. of patients Place of study Mean age [years] Predisposing/co-morbid conditions* Alcoholism COPD Hypertension or cardiovascular disease Diabetes mellitus Cancer Malnutrition Symptoms* Fever Cough Sputum Haemoptysis Chest pain Dyspnoea Fatigue Anorexia Weight loss Night sweats No symptoms Signs* Chest signs Hepatomegaly Altered consciousness Chest radiograph* Upper lobe involvement Bilateral disease Cavitation Pleural effusion Positive TST*† Diagnosis*† Sputum smear-positive

35 Japan 73.5

50 India 63.1

119 Korea 74.8

30 India 70.6

11 23 34 09 ND ND

ND 02 06 16 ND ND

ND 10.1 15.1 25.2 0.8 ND

ND 40 ND 17 ND 13

49 60 69 03 09 06 34 29 43 09 14

74 74 68 14 38 46 ND 90 80 50 ND

32.8 67.2 67.2 14.3 04.2 38.7 50.4 31.4 30.1 03.4 01.7

63 90 87.5 17 ND 93 ND 90 87 07 ND

49 14 11

60 ND ND

ND ND 13.4

ND ND ND

69 23 40 09 20 [n = 12]

ND ND 32 18 ND

77.3 ND ND ND ND

30 40 53.3 03.3 ND

43

70.7 [n = 41]

57.1

47

* All values shown as percentages † Numbers in square brackets indicate number of patients tested n = no. of patients studied; COPD = chronic obstructive pulmonary disease; TST = tuberculin skin test; ND = not described

Elderly subjects with reactivation or reinfection pulmonary TB present with fever, cough with expectoration, and haemoptysis. Chest radiographs may reveal fibronodular lesions in the upper zones with or without cavitation. Hilar and perihilar lesions may also be present and these need to be differentiated from other opportunistic infections, bronchogenic carcinoma and lymphoma. On the other hand, the clinical picture of primary TB infection in the elderly is different. Besides constitutional

symptoms and cough, the chest radiographic abnormalities are often seen in mid and lower zones (11). Due to this atypical presentation, the diagnosis may be missed unless a high index of suspicion is maintained and sputum or bronchial aspirate is subjected to smear and culture examination. Further, delay in the diagnosis results in transmission of infection to the fellow inmates, especially if they are living in a crowded nursing home. The reader is also referred to the chapter “Pulmonary tuberculosis” [Chapter 14] for more details.

Tuberculosis in Elderly 629 Extra-pulmonary Tuberculosis Extra-pulmonary TB is the result of reactivation of lesions that were the result of haematogenous spread of bacilli in the primary phase of infection. Extra-pulmonary TB becomes relatively more frequent than pulmonary TB with increasing age. Among 15 352 patients registered between 1993 and 2002 in the Netherlands the ratio of extra-pulmonary to pulmonary TB increased from 37 per cent in patients under 14 years of age to 64 per cent in persons aged 55 to 64 years. The most common sites affected in people over 65 years of age were bones and joints [24.3%], urogenital [17.6%], abdominal [6.3%] and meningeal [3.6%]. There was, however, a large proportion [48.2%] of ‘other’ i.e., undefined sites (45). They may often present with disseminated TB with involvement of two or more non-contiguous organs. In elderly patients, TB lymphadenitis usually presents as slowly enlarging lymphadenopathy. Cervical lymph nodes are most commonly affected. Fever and other systemic symptoms may not be evident and the patients may otherwise be asymptomatic. Rarely, axillary and inguinal lymphadenopathy may also be present. Physical examination may be unremarkable but for palpable peripheral lymphadenopathy. Cold abscess, chronic non-healing TB sinus and ulcer may rarely be seen. Elderly patients with TB pleural effusion present with an insidious onset of symptoms. Pleuritic pain and nonproductive cough are the usual presenting symptoms. Fever and other systemic symptoms may also be evident. However, many elderly patients with TB pleural effusion may remain asymptomatic and this may result in a delayed diagnosis. Tuberculosis of bones and joints tends to affect such weight bearing joints as the vertebrae, hip or knee, causing a combination of osteomyelitis and arthritis. The clinical presentation is not distinctive and should be suspected in any elderly patient with unexplained unifocal inflammation or destruction of bone or joint. Genitourinary TB often is a complication of reactivation of dormant haematogenous foci in the kidneys. The most common symptoms are dysuria and urinary frequency caused by secondary TB cystitis. The disease should be suspected in any patient with sterile pyuria.

Tuberculosis meningitis is also more commonly seen in elderly patients. These patients may present with nonspecific symptoms of headache, dizziness, confusion and the classical signs of meningitis in the form of neck rigidity and Kernig’s sign may be absent. Fever may or may not be present. Severe hyponatraemia due to syndrome of inappropriate antidiuretic hormone secretion may produce a confusional state in these patients. Thus, a high index of suspicion is necessary to diagnose this condition. Computed tomography [CT] of the head and lumbar puncture and cerebrospinal fluid [CSF] examination should be performed. Usually, treatment is based on limited clinical features and non-specific laboratory findings, such as elevated proteins, low sugar and lymphocytosis in the CSF. Generalized Tuberculosis Miliary TB is increasingly being seen in the elderly as compared to young adults (8,36). Miliary TB can be difficult to recognize. The symptoms are often nonspecific, e.g. fever, weakness, weight loss, with no further information from physical examination, TST or chest radiograph (11). A needle biopsy of liver or bone marrow may be needed to establish the diagnosis. But also a slowly, progressive wasting syndrome with low grade or absent fever, without localizing symptoms or signs and without a miliary pattern on the chest radiograph can be found (36,47). Computed tomography, especially high resolution CT, may reveal abnormalities in these patients (36,48). An elderly patient with disseminated TB may have palpable peripheral lymphadenopathy and hepatosplenomegaly as the only positive finding on clinical examination. One variety of TB in elderly people has been called ‘areactive’ or ‘sepsis tuberculosa acutissima’ (49). Usually, the disease is of the miliary type with distinctive pathological features. Contrary to the classical tubercle with a central core of caseous material surrounded by inflammatory cells, in areactive TB the tubercles consist of caseous and necrotic material containing large numbers of tubercle bacilli but with a notable absence of inflammatory cells (49). This characteristic is similar to that seen in HIV infected individuals and is the result of a declining cell-mediated immunity. The reader is referred to the chapter “Disseminated and miliary tuberculosis” [Chapter 34] for more details.

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Tuberculosis

Tuberculosis and Human Immunodeficiency Virus Co-infection in the Elderly Sparse published data are available on HIV-TB coinfection in the elderly. The diagnosis of HIV infection is often missed in elderly patients, as it is not suspected in them (50-53). Furthermore, atypical clinical presentation of TB in geriatric patients frequently results in a delayed diagnosis. DIAGNOSIS From the afore-mentioned description it is evident that a high index of suspicion is essential to make a diagnosis of various forms of TB in elderly subjects. All efforts should be made to obtain a microbiological and/or histopathological diagnosis. Occasionally, patients are treated empirically based on a strong clinical suspicion and suggestive chest radiographic and CT findings in the absence of microbiological or histopathological diagnosis. Sometimes, elderly patients with pulmonary TB may remain asymptomatic [Table 44.3] (39-42). Furthermore, physical examination may be unremarkable in most situations. Co-morbid conditions such as chronic obstructive pulmonary disease frequently co-exist and because of the associated long-standing cough, active pulmonary TB may not be suspected in these patients and the sputum smear examination may be delayed (54). In the elderly, congestive heart failure may mimic TB pleural effusion. Haematological parameters have been observed to be similar in young and elderly patients with TB (39-42). Serum biochemistry has also been similar except for a mild elevation of alkaline phosphatase and liver enzymes which has been attributed to asymptomatic involvement of liver by TB (39-42). However, significant hypoalbuminaemia may be present in elderly patients with TB (3942,55). The chest radiograph usually raises the suspicion of TB in elderly persons. But since it is only a two-dimensional shadow, it cannot be considered as a confirmation of the diagnosis. This holds also true for CT. All elderly patients with pneumonia who do not respond to antibiotics, should be investigated for TB (46). Spontaneously produced or induced sputum gives the best information about infectivity [Table 44.3] (39-42). Microscopy of a smear prepared by the Ziehl-Neelsen method or fluorescence staining and detecting the acid-fast bacilli, facilitates immediate diagnosis. However, elderly people

have insufficient strength to expectorate and may not be able to provide an adequate sputum sample for testing. If the clinical suspicion is high and the sputum smear is negative, more invasive methods such as laryngeal swab, fibreoptic bronchoscopy and examination of various bronchoscopic secretions and gastric aspirate can be undertaken. Sputum examination is more likely to give positive results in elderly with reactivation TB as compared to primary TB. In progressive primary disease, where the number of bacilli is usually small, their demonstration is usually difficult (9). Mycobacterial culture results take six to eight weeks to become known. The reader is referred to the chapter “Laboratory diagnosis” [Chapter 10] for details on the various conventional and modern diagnostic methods. The value of the TST for the diagnosis of active TB in elderly is limited. In a patient suspected to have TB, a strongly positive TST increases the likelihood of diagnosis. However, a negative TST does not rule out the diagnosis of TB. In patients with extra-pulmonary TB, all efforts should be made to obtain appropriate specimens for microbiological and/or histopathological diagnosis and these include fine needle aspiration cytology material from lymph nodes, cold abscess, and other body fluids and secretions depending upon the clinical situation. TREATMENT The principles of treatment of TB in elderly patients are broadly the same as in young adults. However, there are a few problems in the treatment of elderly which require emphasis. Old people notoriously are unreliable about taking tablets regularly, at the right time, or in the right dose, especially if several drugs have to be taken together. Again poor eyesight and memory or mental confusion are contributing factors. But additionally, old people become apathetic and lack the determination to complete a treatment that has to last six months or longer. Therefore, it is important to make a reliable person responsible for their drug intake, who could be a family member, a home help, or a nursing staff if the elderly is residing in the old age home. Drug interactions are common with antituberculosis medications, especially with isoniazid and rifampicin. For example, rifampicin increases the metabolic degradation of drugs, such as corticosteroids, digoxin, oral anticoagulants and hypoglycaemic agents. Hence, the

Tuberculosis in Elderly 631 dosages of these drugs need to be adjusted according to blood levels. Ideally, antituberculosis drugs should be administered according to body weight and pyridoxine [25 to 50 mg] should be considered with each dose of isoniazid. In the elderly, streptomycin is preferably avoided (56,57). In India, elderly patients receive DOTS under the RNTCP of the Government of India. The direct observation of treatment facilitates and aids regular drug intake. The reader is referred to the chapters “Treatment of tuberculosis” [Chapter 52], and “Revised National Tuberculosis Control Programme” [Chapter 63] for more details. It is thought that the problem of drug resistance is less common in the elderly subjects as most of these patients are thought to have reactivation of infection which was acquired many decades ago. Whenever drug resistance is suspected, it should be treated according to the results of culture and sensitivity. If the sputum smears remain positive despite DOTS for a period of five months, antituberculosis drug resistance should be suspected. The reader is referred to the chapter “Drug-resistant tuberculosis” [Chapter 49] for more details regarding the evaluation of such patients. Treatment Ex-juvantibus or ‘Trial Treatment’ If no other cause for disease can be found and TB is suspected, but cannot be proven with the available armamentarium of investigations, a trial with a full course of antituberculosis drugs is justified as the beneficial effects of treatment far outweigh the risk of relentless progression of untreated active TB which can be uniformly fatal. Subsequent clinical improvement lends support to the diagnosis and the course of standard chemotherapy should be completed. Adverse Effects of First-line Antituberculosis Drugs Similar to other medications, the adverse reactions to antituberculosis drugs are much more common in the elderly (46-52). The elderly patients usually suffer from more than one disease and take medications for more than one ailment at a time. Usually, antituberculosis regimens are well-tolerated. Advancing age is an important risk factor for the development of antituberculosis drug-induced hepatotoxicity (58) and should be carefully watched for. The reader is referred to the chapter

“Antituberculosis treatment induced hepatotoxicity” [Chapter 54] for more details. Ethambutol cannot be avoided, but it may cause retrobulbar neuritis, which may be difficult to detect early in elderly patients with some impairment of vision or with cataracts. Streptomycin is preferably avoided in elderly patients as it causes eighth nerve damage particularly affecting the vestibular component (18). Treatment of Tuberculosis and Human Immunodeficiency Virus Co-infection in the Elderly In addition to the usual concerns related to the treatment of HIV-TB co-infection, polypharmacy and the consequent drug interactions are a concern in elderly patients with HIV-TB (50-53). Careful consideration should be given to the medications being administered for comorbid conditions and the elderly patient with HIV-TB co-infection should be carefully monitored for adverse drug reactions. Treatment of Latent Tuberculosis Infection The administration of isoniazid aims at curing an established infection with a small bacterial load. Although theoretically other bactericidal drugs may also be used for chemoprophylaxis, most experience has been with isoniazid. The most important indication of giving isoniazid prophylaxis is recent conversion of the TST since these subjects have greater chances of developing active TB. Data from countries with a low burden of TB where targeted testing using the TST is practised suggest that isoniazid treatment of LTBI definitely leads to low incidence of TB disease in the elderly (59). However, there is a small but definite risk of hepatotoxicity. The overall gain in survival may be very small, especially in elderly aged more than 80 years and those with co-existing diseases like chronic obstructive pulmonary disease and congestive heart failure (60,61). Therefore, treatment of LTBI in elderly should be individualized and appears to be of no benefit in elderly subjects over the age of 80 years. In areas where the prevalence of TB is low, however, elderly patients who are TST positive, have negative sputum cultures and fibrotic pulmonary lesions compatible with old TB, or those that have certain risk factors [e.g., patients with diabetes mellitus, those receiving corticosteroid or other immunosuppressive

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agents] merit treatment of LTBI. In areas where TB is highly endemic, routine treatment of LTBI in elderly subjects, who are TST positive, is not recommended. The reader is referred to the chapter “Tuberculin skin test” [Chapter 11] for a detailed discussion on this subject. REFERENCES 1. United Nations. Department of Economic and Social Affairs. Population Division. World population prospects: the 2000 revision. Volume I. ST/ESA/SER.A/198. New York: United Nations; 2001. 2. Saad Paulo M. Demographic dimensions of population ageing and its impact. In: Report of an expert group meeting. Population ageing and development: social, health and gender issues with a focus on the poor in old age, 29-31 October 2001, Valetta, Malta. Population ageing and development. No.3. New York: United Nations Population Fund [UNFPA]; 2002. 3. Sharma SD, Agarwal S. Aging: the Indian perspective. In: Kumar V, editor. Aging: Indian perspective and global scenario. Proceedings of the International Symposium on Gerontology and Seventh Conference of the Association of Gerontology [India]. New Delhi: All India Institute of Medical Sciences; 1996.p.2-19. 4. Siva Raju S. Policies and programmes for meeting the needs of the older poor in India: issues, responses and challenges. In: Report of an expert group meeting. Population ageing and development: social, health and gender issues with a focus on the poor in old age, 29-31 October 2001, Valetta, Malta. New York: United Nations Population Fund [UNFPA]; 2002. 5. Doherty MJ, Spence DP, Davies PD. Trends in the mortality from tuberculosis in England and Wales: effect of age from non-respiratory disease. Thorax 1995;50:976-9. 6. Davies PD. Tuberculosis in the elderly. J Antimicrob Chemother 1994;34[Suppl]:93-100. 7. Tuberculosis statistics, morbidity and mortality. Statistics Canada Catalogue 82-212. 8. Dutt AK, Stead WW. Tuberculosis. Clin Geriatr Med 1992;8:761-75. 9. Stead WW. Tuberculosis among elderly persons: an outbreak in a nursing home. Ann Intern Med 1981;94:606-10. 10. Narain JP, Lofgren JP, Warren E, Stead WW. Epidemic tuberculosis in a nursing home: a retrospective cohort of study. J Am Geriatr Soc 1985;33:258-63. 11. Stead WW, Lofgren JP, Warren E, Thomas C. Tuberculosis as an epidemic and nosocomial infection among the elderly in nursing homes. N Engl J Med 1985;312:1483-7. 12. Macarthur C, Enarson DA, Fanning EA, Hessel PA, Newman S. Tuberculosis among institutionalized elderly in Alberta, Canada. Int J Epidemiol 1992;21:1175-9. 13. Lindberg MC, Winsemius D, Lawyer B, Erickson RV. Tuberculin reactivity is low among residents of a Connecticut nursing home. Conn Med 1993;57:197-200.

14. Central TB Division. Directorate General of Health Service, Ministry of Health and Family Welfare, Government of India. TB India 2007. RNTCP Status report. New Delhi: Central TB Division. Directorate General of Health Service, Ministry of Health and Family Welfare, Government of India; 2007. 15. Dubos R, Dubos J. The White Plague. Tuberculosis, man and society. Boston: Little, Brown and Company;1952. 16. Iseman MD. Tuberculosis in the elderly. The Grey Plague. J Am Geriatr Soc 1983;33:517. 17. Anonymous. Tuberculosis in old age. Leading Article. Tubercle 1983;64:69-71. 18. Nagami P, Yoshikawa TT. Aging and tuberculosis. Gerontology 1984;30:308-15. 19. Canetti G, Sutherland I, Svandova E. Endogenous reactivation and exogenous reinfection: their relative importance with regard to the development of non-primary tuberculosis. Bull Int Union Tuberc 1972;47:116-34. 20. Borgdorff Martien. Personal communication. 21. Turner J, Frank AA, Orme IM. Old mice express a transient early resistance to pulmonary tuberculosis that is mediated by CD8 T cells. Infect Immun 2002;70:4628-37. 22. Aspinall R. Age-related changes in the function of T cells. Microsc Res Tech 2003;62:508-13. 23. Hans RL. Epidemiologic basis of tuberculosis control. First edition. Paris: International Union Against Tuberculosis and Lung Disease;1999. 24. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis alpha-neutralizing agent. N Engl J Med 2001;345:1098-104. 25. National Tuberculosis Institute, Bangalore. Tuberculosis in a rural population of India: a five-year epidemiological study. Bull World Health Organ 1974;51:573-88. 26. Frost WH. The age selection of mortality from tuberculosis in successive decades. 1939. Am J Epidemiol 1995;30:91-6. 27. Grzybowski S, Mar WB. The unchanging pattern of pulmonary tuberculosis. Can Med Assoc J 1963;89:737-40. 28. Stead WW, To T. The significance of the tuberculin test in elderly persons. Ann Intern Med 1987;107:837-42. 29. American Thoracic Society. Diagnostic standards and classification of tuberculosis. Am Rev Respir Dis 1990;142:725-35. 30. Centers for Disease Control. Prevention and control of tuberculosis in facilities providing long-term care to elderly. Recommendations of Advisory Committee for Elimination of Tuberculosis. Morb Mortal Wkly Rep MMWR 1990;39 [No. RR-10]. 31. Treip C, Myers D. Fatal tuberculosis in a general hospital. Lancet 1959;1:164-6. 32. Cleeff MR, Kivihya-Ndugga L, Githui W, Nganga L, Odhiambo J, Klatser PR. A comprehensive study on the efficiency of the routine pulmonary tuberculosis diagnostic process in Nairobi. Int J Tuberc Lung Dis 2003;7:186-90. 33. Bobrowitz ID. Active tuberculosis undiagnosed till autopsy. Am J Med 1982;72:650-8. 34. Proudfoot AT, Akhtar AJ, Douglas AC, Horne NW. Miliary tuberculosis in adults. BMJ 1969;2:273-6.

Tuberculosis in Elderly 633 35. Yu YL, Chow WH, Humphries MJ, Wong RW, Gabriel M. Cryptic miliary tuberculosis. QJM 1986;59:421-8. 36. Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis 2005;5:415-30. 37. Khan MA, Kovnat DM, Bachus B, Whitcomb ME, Brody JS, Snider GL. Clinical and roentgenographic spectrum of pulmonary tuberculosis in the adult. Am J Med 1977;62:31-8. 38. Stead WW, Kerby GR, Schlueter DP, Jordahl CW. The clinical spectrum of primary tuberculosis in adults. Confusion with reinfection in the pathogenesis of chronic tuberculosis. Ann Intern Med 1968;68:731-45. 39. Umeki S. Clinical features of pulmonary tuberculosis in young and elderly men. Jpn J Med 1989;28:341-7. 40. Gupta D, Singh N, Kumar R, Jindal SK. Manifestations of pulmonary tuberculosis in the elderly: a prospective observational study from north India. Indian J Chest Dis Allied Sci 2008;50:263-7. 41. Lee JH, Han DH, Song JW, Chung HS. Diagnostic and therapeutic problems of pulmonary tuberculosis in elderly patients. J Korean Med Sci 2005;20:784-9. 42. Das SK, Mukherjee RS, Ghosh IN, Halder AK, Saha SK. A study of pulmonary tuberculosis in the elderly. J Indian Med Assoc 2007;105:432-9. 43. King D, Davies PDO. Disseminated tuberculosis in elderly: still a diagnosis overlooked. J Royal Soc Med 1992;85:48-50. 44. Katz PR, Reichman V, Dube D, Feather J. Clinical features of pulmonary tuberculosis in young and old veterans. J Am Geriatr Soc 1987;35:512-5. 45. Data from the Dutch surveillance database. KNCV Tuberculosis Foundation, The Hague. Data provided by N. Kalisvaart. 46. Chan CH, Cohen M, Pang J. A prospective study of community-acquired pneumonia in Hong Kong. Chest 1992;101: 442-6. 47. Slavin R, Walsh TJ, Pollack AD. Late generalised tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine [Baltimore] 1980;59:352-66. 48. Sharma SK, Mohan A, Pande JN, Prasad AK, Gupta AK,

49. 50.

51. 52. 53.

54.

55.

56. 57.

58.

59.

60.

61.

Khilnani GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. QJM 1995;88:29-37. Sahn SA, Neff TA. Miliary tuberculosis. Am J Med 1974;56: 495-505. Salazar JA, Poon I, Nair M. Clinical consequences of polypharmacy in elderly: expect the unexpected, think the unthinkable. Expert Opin Drug Saf 2007;6:695-704. Rajagopalan S, Yoshikawa TT. Tuberculosis in the elderly. Z Gerontol Geriatr 2000;33:374-80. Wooten-Bielski K. HIV and AIDS in older adults. Geriatr Nurs 1999;20:268-72. Wallace JI, Paauw DS, Spach DH. HIV infection in older patients: when to suspect the unexpected. Geriatrics 1993;48:61-4, 69-70. Gothi D, Shah DV, Joshi JM. Clinical profile of diseases causing chronic airflow limitation in a tertiary care centre in India. J Assoc Physicians India 2007;55:551-5. Chan CH, Woo J, Or KK, Chan RC, Cheung W. The effect of age on the presentation of patients with tuberculosis. Tuber Lung Dis 1995;76:290-4. Yoshikava TT. Tuberculosis in aging adults. J Am Geriatr Soc 1992;40:178-87. World Health Organization. Treatment of tuberculosis: guidelines for National Programmes. Third edition. WHO/ CDS/TB 2003.313. Geneva: World Health Organization;2003. Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 2002;166:916-9. Joint Statement of the American Thoracic Society [ATS] and the Centers for Disease Control and Prevention [CDC], endorsed by the Council of the Infectious Diseases Society of America [IDSA]. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221-47. Sarasin FP, Perrier A, Rochat T. Isoniazid preventive therapy for pulmonary tuberculosis sequelae: which patients up to which age? Tuber Lung Dis 1995;76:394-400. Chan CH, Or KK, Cheung W, Woo J. Adverse drug reactions and outcome of elderly patients on antituberculosis chemotherapy with and without rifampicin. J Med 1995;26:43-52.

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Tuberculosis in Health Care Workers

45 SK Jindal

INTRODUCTION There is a worldwide concern on the risk of acquiring tuberculosis [TB] by health care workers [HCWs] looking after patients suffering from an active infectious disease. This is particularly so since the infection is air-borne and the presentation of the disease after acquisition of infection is generally delayed. The contagious nature of TB was recognized long before the bacteriological aetiology was identified (1). Historically, there are innumerable examples of relatives and close contacts of patients with TB themselves developing the disease and often dying from the same. The occurrence of TB in HCWs especially the medical personnel, is a matter of concern for lay persons and is frequently talked about in the lay press (2). It seems quite appropriate to consider TB as an occupational disease as suggested in the recent medical literature (3). TUBERCULOSIS CARE AS AN OCCUPATIONAL HAZARD There is a large body of data to suggest that looking after patients with TB constitutes an occupational hazard. This belief was traced to the 1950s in an elegant historical review of the medical literature of the past 100 years (4). There was a great hesitation initially in accepting the risk to the hospital employees for the fear of frightening people to adopt a health care career. It was perhaps in 1938 when a high incidence of TB among nurses was demonstrated for the first time (5). Several other reports have appeared since then (6-9). Quite aptly, it has been recently termed as “the battle of a century” (10).

Most of the reports published in the recent past support a higher risk of occurrence of both TB infection and disease among HCWs (9). There is a paucity of data on this subject in spite of the fact that India accounts for about one-fifth of the total global TB burden and that most disease related indices are alarmingly high (11). A study from a teaching hosptial at Chandigarh (12) revealed that, among resident doctors, the overall risk of developing TB was calculated to be 11.2 cases per 1 000 person-years of exposure and the overall incidence of TB was found to be 17.3 per 1000. But the findings available from other places around the world can be considered as an indicator of the enormity of the problem in this country as well. RECOGNITION OF TRANSMISSION OF TUBERCULOSIS Diagnosis of clinical TB is made on the basis of clinical picture and microbiological positivity of sputum or other biological specimens. The presence of infection, however, is established long before the onset of disease symptoms. Based on the circumstantial evidence, it is somewhat easy to attribute the occurrence of new clinical symptoms and aetiology in a HCW to their exposure to TB. This, however, cannot be definitely said unless the mycobacterial transmission can be traced to the specific source in a health care setting. This can be done with the help of sophisticated molecular techniques, such as the deoxyribonucleic acid fingerprinting. Tuberculin Skin Test A positive tuberculin skin test [TST] result is the most frequently used marker of TB infection. There are several

Tuberculosis in Health Care Workers 635 difficulties in interpreting TST results and estimating TST conversion rates. This is generally attributed to factors such as the prior bacille Calmette Guerin [BCG] vaccination and/or previous exposure to environmental mycobacteria. The reader is referred to the chapter “Tuberculin skin test” [Chapter 11] for more details. It is, therefore, difficult to attribute the presence of TB infection in HCWs to occupational exposure merely from the presence of TST positivity unless a prospective study on TST conversion rate is undertaken. The author found a cut-off value of 10 mm useful in supporting the diagnosis in patients with strong clinical suspicion of TB; in other patients a 15 mm cut-off was more suitable (13). From retrospective analyses, it is perhaps more pertinent to compare the number of TB patients among HCWs versus general population in these areas, provided reliable data are available. Such comparisons are available from some of the developing countries (14-16). Besides TST, a few other markers of exposure to Mycobacteria have also been utilized. A Western blot antiMycobacterium bovis A60 complex antibody was evaluated on 127 exposed and 28 non-exposed HCWs from a hospital in Italy and 140 non-exposed BCGvaccinated control subjects; and positivity of the test was found to be significantly higher in the exposed HCWs and therefore, this was suggested as a more sensitive biological marker than the TST (17). Interferon-gamma Release Assays The advent of interferon-gamma release assays [IGRAs] in the recent years has heralded a new era in the field of TB diagnostics. The IGRAs, are emerging as the gold standard for the diagnosis of latent TB infection. Recent guidelines (14-16) are also available for the judicious use of these newer diagnostic modalities for detecting TB infection. In the near future, it is expected that IGRAs may replace TST as the investigation of choice to detect TB infection in HCWs. The reader is referred to the chapter. “Diagnosis of latent tuberculosis infection: recent advances and future directions” [Chapter 12] for more details. RISK OF INFECTION The annual risk of TB infection assessed using TST in HCWs varied from 0.09 to 10 per cent in different populations in various studies published between 1975

and 1994 (8-10,18-30). This was up to a hundred times higher than the estimated ARI in the general population of the Western Europe and the United States during the period 1973 to 1992 (31). The calculated risk for the home staff and the pulmonary fellows vis-a-vis general population was probably highest. Similarly, the annual incidence of TB disease was considerably more in the HCWs. The same observations are corroborated by the findings of later studies which have appeared since 1994. Both the TB infection and the disease are reported to be significantly higher in most studies among HCWs. The criteria used for assessment of TB risk are diverse in different studies. In the Western European countries, USA, Canada and Australia where the TB prevalence is rather low, the positive TST and/or TST conversion are the most frequently employed tests to detect the presence of infection. In a large study (32) involving 4070 HCWs and 4 298 non-HCWs, a positive TST was observed in 19.3 per cent HCW compared with 13.7 per cent in nonHCWs; the significant differences were not explained by the employees characteristics, such as age, country of birth and the past BCG status (32). High TST positivity has been recorded among physicians [45.9%] than in the general Canadian population (33). Similarly, physicians in USA had a high rate of tuberculin reactivity [7%] although the TST conversion rate was low (34). Higher infection rates among almost all categories of HCWs including nurses and other ancilliary staff have been shown in several other studies (35-38). A TST coversion rate of 1.7 per cent over a 12-month period was also seen in dental HCWs (39). In another report (40), nosocomial transmission was also reported to occur even from an extra-pulmonary site; 12 [13%] of 95 HCWs who were initially non-reactive to tuberculin developed a positive TST after exposure to an index patient with TB prostatic abscess who had undergone abscess drainage and bilateral orchiectomy and had expired after 27 days of hospitalization. In a study from Turkey (3), TB was seen three-fold more frequently among the HCW at four urban hospitals than the general population and the workers of chest diseases were found to have a higher risk than those of other departments (3). Similar high risk of TB infection was reported in several other studies (41-47).

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FACTORS INFLUENCING NOSOCOMIAL TRANSMISSION OF TUBERCULOSIS Although most investigators have reported an increased transmission of TB among HCWs, the rates have been significantly variable. Furthermore, no increased risk of transmission has been shown in other studies (48-50). These differences can be attributed to methodological or sampling variations and other factors affecting the disease transmission. Some of these factors are listed in Table 45.1. Table 45.1: Factors influencing nosocomial transmission of tuberculosis among health care workers Related to the health care facility Level of exposure High vs low exposure areas Inadequate isolation of infected patients Environmental Inadequate sanitation Inappropriate disposal of excreta Overcrowding in the wards Poor ventilation Host factors related to HCWs Immune status of an individual Co-morbid illnesses BCG vaccination status General clinical factors Delayed suspicion and diagnosis Delayed initiation of treatment Self administration of drug HCWs = health care workers; BCG = bacille Calmette-Guérin

Level of Exposure The HCWs directly involved in looking after patients with TB are more likely to get infected than others. Data from several studies indicate that medical and nursing personnel [especially chest physicians and HCWs in chest diseases wards] have higher risk ratios of TST conversion and development of active TB disease (3,34,41,43,51). A strong association has also been shown with type and duration of work; for example people working in respiratory therapy, physiotherapy and house-keeping have greater risks (10). Environmental Factors Environment of hospital wards and the methods employed for sanitation and disposal of waste materials

and excreta affect the disease transmission. The TST conversion rate has been shown to be strongly associated with inadequate ventilation of the general patient rooms (52). Some of these factors are of particular importance in this country where the wards are rather overcrowded and the ventilation is not adequate. Immune Status and Comorbidities The presence of diseases, which predispose to TB and the status of immunity are important factors that determine the prevalence of TB in HCWs. Prevalence of diseases such as diabetes mellitus, as well as many other conditions requiring use of corticosteroids or other immunosuppressive drugs, among HCWs is at least similar to their prevalence in the community. Their presence in HCWs is likely to augment their predisposition to TB. Intrinsic immune status of an individual HCW is a particular point of interest. Immunodeficiency is an independent risk factor for TB. In a study on the occupational transmission in a haemodialysis unit, the TB isolates from different sources showed the strains to be unrelated when tested with restriction fragment length polymorphism [RFLP] (53). Similarly, nosocomial transmission of TB in human immunodeficiency virus [HIV] infected patients is also known (54-56). The impact of HIV infection on increase in number of TB patients was demonstrated in a South African district hospital where the incidence rate of TB among HCWs and ancillary staff was not significantly different than the age specific rate in the community. But there was a five-fold increase in annualized incidence rate from 1991 to 1992 and 1993 to 1996 which was directly attributable to HIV infection (49). In another study (57), strains of tubercle bacilli infecting eight [89%] of nine HCWs with HIV seropositivity had a clustered RFLP pattern, implying a common source, i.e., an unrecognized occupational transmission. The HIV infected HCWs who developed TB following a hospital outbreak of multidrug-resistant TB [MDR-TB] had more severe disease and died (58). Bacille Calmette-Guérin Vaccination The protective efficacy of BCG vaccination has remained debatable. Nonetheless, it continues to be administered at birth or in early childhood as a general vaccination policy in countries with high TB prevalence. The reader

Tuberculosis in Health Care Workers 637 is referred to the chapter “Tuberculin skin test” [Chapter 11] for more details on the clinical implications of BCG vaccination on TST results. Clinical Factors Besides factors related to the host, i.e., HCWs and the environment in which they work, factors related to awareness of occupational transmission, preventive steps being used, the clinical suspicion and diagnosis of an early disease are important in influencing disease occurrence. There was an inadequacy of knowledge on TB transmission and infection control measures among HCWs in the USA in a questionnaire-based survey (59). The situation is likely to be worse in most hospitals of the developing world, including India. Many HCWs are likely to be more negligent in adopting routine measures while working in the hospitals and tend to ignore precautionary practices generally recommended for attendants and care providers of patients. This is somewhat akin to attitudinal desensitization in following guidelines, which might occur among workers with a callous attitude. RISK ASSESSMENT It is known that untreated patient with active TB transmits acid-fast bacilli [AFB] and infects other individuals. This risk is likely to be significant in the hospital surroundings with a larger number of patients staying in a closed door environment. More than the close personal contact; it is the inhalational route which is important in spreading TB. This was amply shown following a sharp outbreak of TB abroad the naval vessel “Richard E Byrd” (60). Of the 66 men who shared a compartment with an index patient with TB, 80 per cent had demonstrated TST conversion. Interestingly, 54 per cent of 81 men in another compartment had also developed TST conversion. Although there was no direct patient contact in the second compartment, about three quarters of the ventilation came through interconnecting ducts from the first compartment. It was, therefore, concluded that the rate of infection was proportional to the amount of contaminated air (61). The mathematical model for quantitative assessment of air, borne infection vis-a-vis room ventilation developed for measles epidemic has also been used for TB (61,62). The probability curve of TB infection clearly showed the diminishing effectiveness of high level of

ventilation. A similar curve was drawn for TB outbreak from a brief but intense exposure during bronchoscopy (63). It can be, therefore, concluded that TB transmission can be quantitatively assessed fairly well from the amount of room ventilation (64). CONTROLLING OCCUPATIONAL TUBERCULOSIS An increased occurrence of TB in HCWs has more serious ramifications than a mere addition to the total pool of TB patients. There is the fear of spreading a serious disease including that of MDR-TB, causing panic among the employees and the community and also scaring away people from hospital jobs. It is, therefore, an issue of great public and social importance. It has also the potential of forcing a return to the medieval practices of segregating patients to isolation chambers and wards. It is, thus important to adopt strategies to prevent and control TB in HCWs. Implementation of protection guidelines has been shown to effectively reduce the risk in HCWs (65,66). There are two important strategies to control occupational TB among HCWs: [i] early diagnosis and treatment; and [ii] prevention of infection and disease. Early Diagnosis and Treatment It is important to make diagnosis and institute antituberculosis treatment at the earliest. Hospital employees have the advantage of an easy availability of medical advice and investigations. It is, simpler to make an early diagnosis in a symptomatic individual. In fact better detection and notification of cases of TB among HCWs have been also considered as factors accounting for some of the apparent increased risk among them (47). While HCWs are better placed to seek early interventions, they tend to ignore early symptoms more than people in the community. It is a common observation that hospital personnel including doctors and nurses greatly rely on self-administered symptomatic treatment before seeking appropriate medical advice. This is particularly so in developing countries where medicines are relatively easily accessible and available to medical, nursing and paramedical personnel. These factors are likely to delay the diagnosis. Therefore, a careful approach to diagnosis among symptomatic individuals and routine screening programmes among HCWs are important for success.

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Considering the hospital work as a risk factor and the fact that more specialized expertise and care is available in a hospital setting one would tend to suggest a more aggressive approach for early diagnosis of TB disease among HCWs. A simplified algorithm [Figure 45.1] for diagnosis and treatment of TB, may be useful in the evaluation of HCWs who are TB suspects. It is worthwhile introducing a standardized questionnaire of symptoms as an instrument for active case finding for screening of all HCWs on a regular basis. Any individual who reports with respiratory and/or general consti-

tutional symptoms of even one week’s duration unless explained by a definite alternative aetiology should be considered as a TB suspect and investigated with the help of both sputum microscopy for AFB and a chest radiograph examination. In case sputum smear is positive for AFB, treatment is given accordingly. In case sputum smear is negative for AFB, and the chest radiograph findings suggest TB, treatment for AFB-negative TB should be instituted and an attempt should be made to demonstrate AFB in the bronchoalveolar lavage [BAL] fluid and/or other appropriate investigations. In case the

Figure 45.1: Suggested algorithm for early detection of tuberculosis in HCWs in resource-limited settings HCWs = health care workers; TB = tuberculosis; AFB = acid-fast bacilli; BCG = bacille CalmetteGuerin; TST = tuberculin skin test; IGRAs = interferon-gamma release assays; BAL = bronchoalveolar lavage

Tuberculosis in Health Care Workers 639 chest radiograph is clearly normal or negative for TB, other diagnoses should be considered and appropriate investigations done. Treatment regimens in HCWs do not differ than those recommended for TB in other groups. Preventive Strategies Different strategies are employed in different countries to prevent infection and mycobacterial transmission. The difference in approach in India is related more to the enormous disease burden and the existing health care infrastructure. Nonetheless, the infection control measures which are recommended anywhere are generally similar [Table 45.2]. The efficacy of preventive programmes has been clearly shown in several studies (36,37,66,67). The TST conversion rates were shown to significantly decrease following full implementation of expanded infection control measures in US medical school graduates (36). Similar observations were made at several other centres following infection control practices (37,66,67). The Centers for Disease Control and Prevention [CDC], published the “Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health Care Facilities” in 1994 (68). These guidelines were subsequently revised in 2005 by the CDC (16). According to the current guidelines (16) that have been expanded to address a broader concept, the term “health care Table 45.2: Measures used for control of tuberculosis transmission in health care workers General infection control measures Reduction of environmental load by reducing the release of mycobacteria Use of masks for patients Isolation rooms Preventing environmental spread Negative pressure rooms Use of HEPA filters Use of ultraviolet radiation Individual protection measures Inhalational prevention strategies Use of simple masks Use of respirators: HEPA filters/PAPR BCG vaccination Chemoprophylaxis Early detection and treatment HEPA = high-efficiency particulate air; PAPR = powered air purifying respirator

setting” has been chosen over the term “facility,” used in the previous guidelines. The term “health care setting” includes not only the hospital related scenario [e.g., inpatient, outpatient settings, TB clinics], but also settings in correctional facilities in which health care is delivered, settings in which home-based health care and emergency medical services are provided, and laboratories handling clinical specimens that might contain Mycobacterium tuberculosis. Important changes in the current guidelines (16) over the previously published one (68) are shown in Table 45.3. The reader is referred to reference (16) for a detailed account of these guidelines. In November 2007, The National Task Force [NTF] for the involvement of Medical Colleges in the Revised National Tuberculosis Control Programme [RNTCP], Government of India, constituted Expert Working Group to develop guidelines for Airborne Infection Control and build the capacity at the national and state level for advocating and ensuring implementation of airborne infection control measures in hospital settings (69). A coneptual framework for the control of TB in health care settings that conveys the key concepts outlined in the published guidelines is described below. Infection Control Measures The most important source of mycobacteria in the environment is an open patient with pulmonary TB who is excreting bacilli in the sputum. Bacteria are released during coughing, laughing and talking and transmitted to others through air-borne droplets. Infection control measures are, therefore, designed to focus on reduction of environmental load of mycobacteria by one or more of the following steps in transmission of infection. Reducing the release of mycobacteria and preventing environmental distribution The most efficient method to prevent dispersion of infectious particles from a patient in a hospital room is to trap the particles at the patient’s mouth. This can be achieved by the masks covering the mouth and nose. In resource limited settings, simple gauze masks or a piece of cloth are commonly used for this purpose. The respiratory droplets released on coughing are impinged on the mask. A mask is fairly effective but is not convenient for constant use. It gets wet very soon and cumbersome for use in a patient with constant cough and sputum production. Their use is, therefore, restricted to specific situations

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The risk assessment process includes the assessment of additional aspects of infection control These recommendations usually apply to an “entire health care setting” rather than “areas within a setting” The term TST is used instead of purified protein derivative The whole-blood interferon gamma release assay QuantiFERON®TB Gold test [Cellestis Limited, Carnegie, Victoria, Australia] might be used instead of TST in TB screening programmes for HCWs The frequency of TB screening for HCWs has been decreased in various settings, and the criteria for determination of screening frequency have been redefined The scope of settings in which the guidelines apply has been broadened to include laboratories and additional outpatient and nontraditional facility based settings Criteria for serial testing for Mycobacterium tuberculosis infection of HCWs are more clearly defined New terms, airborne infection precautions [airborne precautions] and airborne infection isolation room [aII rooms], are introduced. Recommendations for annual respirator training, initial respirator fit testing, and periodic respirator fit testing have been added The evidence of the need for respirator fit testing is summarized Information on ultraviolet germicidal irradiation and room-air recirculation units has been expanded Additional information regarding MDR-TB and HIV infection has been included * reference 16 † reference 68 TST = tuberculin skin test; TB = tuberculosis; HCWs = health care workers; MDR-TB = multidrug-resistant tuberculosis; HIV = human immunodeficiency virus

for limited time periods. Adequate ventilation is useful to dilute the environmental concentration of mycobacteria. While the indoor load within a hospital is reduced, the method may prove to be counter productive by spreading the infectious airborne droplets in the surrounding areas. This would pose the risk of infection to a larger number of employees and other people in the building. Such incidents of spread of infection in the entire building have been reported in the literature. These include the example of TB outbreak through ventilation in two adjoining compartments, in the naval vessel “Richard E. Byrd” (60) and another outbreak, where one worker with undiagnosed TB infected 27 of 67 colleagues over a four-week period (70). Similarly, it was shown that the exposure in the hospital building treating HIV patients with TB infection was universal and a sojourn of 40 or more hours per week was enough to get infection (71). This was attributable to recirculation of air from the infected source to the entire building. It is, therefore, more useful to contain the infection within, rather than ventilating it out. Internal containment includes the prevention of dissemination of infectious droplets in the air by entrapment procedures as well as the air disinfection.

Complete isolation of a TB patient is not feasible. As per current practice and recommendations in India, a sputum smear-positive patient need not be admitted in the hospital. If the medical indication for admission is strong, separate areas should be earmarked for such patients. The use of high-efficiency particulate air [HEPA] filter is useful to prevent dispersal. Separate cubicles and booths should be made available in the wards and laboratories for performance of procedures requiring coughing, such as induced sputum induction. Similarly, bronchoscopic examination in suspected TB patients should be performed in well equipped areas fitted with HEPA filters. Air filtration and disinfection The HEPA filters, permanently fixed for room ventilation remove droplet nuclei carrying tubercle bacilli from the air. They are capable of removing almost 100 per cent of the particles of over 0.3 μm in diameter (72). The filter units are fitted with blowers to recirculate air. The filtered air from the room or the booth can also be recirculated through a duct to create a negative pressure within. This type of HEPA filtered self-contained booths for some specified purposes as listed earlier are already available commercially.

Tuberculosis in Health Care Workers 641 Air disinfection by ultra-violet [UV] radiation has also been effectively used to kill or inactivate organisms in several field trials for infectious diseases, such as measles and influenza (73,74). Almost complete protection against TB was seen in medical and nursing students since none of them showed TST conversion while working in a TB ward in Milwaukee when UV air disinfection was employed over a 12-year period (75). The UV radiation can also be combined with filtration units. It is doubtful if there is any additional advantage of the combined system. The UV radiation has some advantages over HEPA air disinfection. The resistance to airflow is much less than with a HEPA filter. Therefore, the blowers used are smaller and quieter. But the main disadvantage is the possibility of causing excessive exposure to the germicidal UV causing painful superficial irritation of skin and eyes, although there are no serious long-term effects (76). There is no evidence of systemic immunosuppression from UV germicidal irradiation employed for room disinfection (77). To prevent personal exposure, the germicidal UV is directed at the air in the upper part of the room. The mixing of lower air with upper air permits disinfection of all indoor air. This mixing is promoted by convection and forced air movement by supplemental fans. But when the ceilings are low, the upper air UV radiation gets deflected downwards posing a greater risk to the occupants. The UV radiation can also be used in the ventilating ducts to make the re-circulated air germ free. Generally, the upper air disinfection in each room is more effective than central duct irradiation but it requires a more elaborate setting. Individual Protection Inhalational prevention strategies Protective measures which can be employed by an individual working in a health care facility include the use of devices to prevent inhalation of infectious droplet nuclei. Unfortunately, most of these methods have their fallacies and failures. Fortunately, the risk of infection in HCWs is minimal from paediatric patients with primary TB (78). Historically, surgical face-masks have been employed by visitors and HCWs attending upon TB patients. It is difficult to comment upon the usefulness of this method in the absence of any efficacy-study on their use. But there is a complete lack of standardization, besides the difficulties involved in wearing of a well-fitted face-mask all the time.

More effective than a simple mask is a respirator which removes the infectious particles through impaction by filtration and/or electrostatic attraction. If properly worn, a respirator can prevent up to 80 per cent of exposure. But it is cumbersome to wear respirators continuously in all situations. These are generally recommended for personnel attending upon sputum smearpositive patients and during cough induction and bronchoscopic procedures (68). Leakage of droplet nuclei from a filter depends upon the filtration efficiency and facial seal. Some of the important factors which determine the efficiency include the filter characteristics of mask size, distribution of particles and linear velocity through the material (30,68,79-82). Loading of particles and electrostatic charge on the filter as well as the ability of unfiltered air to penetrate a respirator between the respirator’s edge and the wearer’s face are also important. The CDC (16,68) recommends that a respirator should meet the following criteria: [i] it should be able to filter particles of 1 mm in size with 95 per cent efficiency; [ii] it should have a face seal leakage of 10 per cent or less; [iii] it should have the ability to fit the different facial sizes and characteristics of health personnel; and [iv] it should be checked for face piece fit by a HCW each time it is used. Different types of filters which include HEPA and powered air purifying respirator [PAPR] masks have been employed (16,68). The high cost of these gadgets is a deterrent for their use in resource-limited settings. Bacille Calmette-Guerin vaccination Unfortunately, the role of BCG vaccination in preventive TB has remained doubtful and debatable (83). The available evidence supports a good level of protection in children (84). As per current practices in India, BCG is administered at birth. Presumably, most adults including the HCWs should have received BCG vaccination in childhood. There is no recommendation at present to adopt the policy of revaccinating HCWs. The practice of prophylactic BCG vaccination in risk groups, such as HCWs, did exist in several countries in the past. The practice was discontinued in view of an unproven efficacy and the possibility of adverse reaction of BCG vaccination. Regular screening is considered a more effective strategy. The issue of BCG vaccination among HCWs, especially those who are tuberculin negative, remains to be reexamined (85).

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Treatment of latent tuberculosis infection The Advisory Council for Elimination of Tuberculosis [ACET] recommends treatment of latent TB infection [LTBI] for high risk groups with positive TST (86). Although there was no specific mention of HCWs, ‘the groups defined by local’ public health authorities to be at high risk for TB, with TST size greater than 10 mm were included to qualify for preventive isoniazid therapy. In a recent report (87), it is suggested that a TST reaction of 10 to 14 mm should not be used as an indication for the treatment of LTBI in HCWs born in the USA with no known exposure to TB. Two of the four subjects in this report with reaction of 10 to 14 mm were Mycobacterium avium sensitin dominant, one was purified protein derivative dominant and another was non-dominant (87). Stead (75) studied the protection of isoniazid treatment of LTBI in subjects with heavy TB exposure in six hospitals and 22 nursing homes in the USA. In this study (75), 98 of 336 non-reactors showed TST conversion; 19 of them had developed TB before preventive therapy could be started (75). Tuberculosis disease did not develop among 238 non-converters or 76 known TST reactors who were not treated. It was concluded that healthy persons who remained non-reactive to TB after heavy exposure had escaped infection and required no treatment. It was also recommended as wise to start preventive therapy if exposure was discovered immediately; treatment could be discontinued if the TST is negative at three months. Preventive isoniazid therapy after exposure is advisable in persons younger than 35 years of age, those with HIV infection or receiving any kind of immunosuppressive therapy (75). A focussed programme of counselling and active follow up of HCWs seems to facilitate satisfactory implementation of isoniazid treatment of LTBI (88). Presently, there is no consensus on these recommendations in India and other resource-limited settings. The reader is referred to the chapter “Treatment of latent tuberculosis infection” [Chapter 53] for more details. It is perhaps fair to conclude that, as of today, sparse evidence is available advocating treatment of LTBI in HCWs irrespective of their contact with sputum smear-positive patients. Personal protective measures and close supervision are important to detect the disease early and treat it immediately. The BCG vaccination policy also needs to be re-examined.

REFERENCES 1. Keers RY. Pulmonary Tuberculosis: journey down the centuries. First edition. London: Bailliere Tindall; 1978. 2. Doctors becoming more vulnerable to TB. Times of India. April 25 1995. 3. Kilinc O, Ucan ES, Cakan MD, Ellidokuz MD, Ozol MD, Sayiner A, et al. Risk of tuberculosis among health care workers: can tuberculosis be considered as an occupational disease? Respir Med 2002;96:506-10. 4. Sepkowitz KA. Tuberculosis and the health care worker: a historical perspective. Ann Intern Med 1994;120:71-9. 5. Heimbeck J. Incidence of tuberculosis in young adult women with special reference to employment. Br J Tuberc 1938;32: 154-66. 6. Badger TL, Ayvazian LF. Tuberculosis in nurses: clinical observation on its pathogenesis as seen in a fifteen-year follow up of 745 nurses. Am Rev Tuberc 1949;60:305-27. 7. Childress WG. Occupational tuberculosis in hospitals and sanatorium personnel. JAMA 1951;146:1188-90. 8. Price LE, Rutala WA, Samsa GP. Tuberculosis in hospital personnel. Infect Control 1987;8:97-101. 9. Menzies D, Fanning A, Yuan L, Fitzgerald M. Tuberculosis among health care workers. N Engl J Med 1995;332:92-8. 10. Fennelly KP, Iseman MD. Health care workers and tuberculosis: the battle of a century. Int J Tuberc Lung Dis 1999;3:363-4. 11. Mohan A, Sharma SK. Epidemiology. In: Sharma SK, Mohan A, editors. Tuberculosis. First edition. New Delhi: Jaypee Brothers Medical Publishers; 2001.p.14-29. 12. Rao KG, Aggarwal AN, Behera D. Tuberculosis among physicians in training. Int J Tuberc Lung Dis 2004;8:1392-4. 13. Gupta D, Saiprakash BV, Aggarwal AN, Muralidhar S, Kumar B, Jindal SK. Value of different cut-off points of tuberculin skin test to diagnose tuberculosis among patients with respiratory symptoms in a chest clinic. J Assoc Physicians India 2001;49:332-5. 14. Canadian Tuberculosis Committee. Interferon gamma release assays for latent tuberculosis infection. An Advisory Committee Statement [ACS]. Can Commun Dis Rep 2007;33[ACS-10]:1-18. 15. Mazurek GH, Jereb J, Lobue P, Iademarco MF, Metchock B, Vernon A; Division of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention [CDC]. Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR Recomm Rep 2005;54[RR-15]:49-55. 16. Jensen PA, Lambert LA, Iademarco MF, Ridzon R; Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Recomm Rep 2005;54:1141. 17. Franchi A, Amicosante M, Rovatti E, Bonini R, Marchegiano P, Girardi E, et al. Evaluation of a western blot test as a

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18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

potential screening tool for occupational exposure to Mycobacterium tuberculosis in health care workers. J Occup Environ Med 2000;42:64-8. Mahashur AA, Kamat A. Tuberculosis in health care workers. In: Sharma SK, Mohan A, editors. Tuberculosis. First edition. New Delhi: Jaypee Brothers Medical Publishers; 2001.p.56773. Berman J, Levin ML, Orr ST, Desi L. Tuberculosis risk for hospital employees: analysis of a five-year tuberculin skin testing program. Am J Public Health 1981;71:1217-22. Craven RB, Wenzel RP, Atuk N. Minimizing tuberculosis risk to hospital personnel and students exposed to unsuspected disease. Ann Intern Med 1975;82:628-32. Vogeler DM, Burke JP. Tuberculosis screening for hospital employees: a five-year experience in a large community hospital. Am Rev Respir Dis 1978;117:227-32. Ruben FL, Norden CW, Schuster N. Analysis of a community hospital employee tuberculosis screening program 31 months after its inception. Am Rev Respir Dis 1977;115:23-8. Chan JC, Tabak JI. Risk of tuberculous infection among house staff in an urban teaching hospital. South Med J 1985;78: 1061-4. Aitken ML, Anderson KM, Albert RK. Is the tuberculosis screening program of hospital employees still required? Am Rev Respir Dis 1987;136:805-7. Raad I, Cusick J, Sherertz RJ, Sabbagh M, Howell N. Annual tuberculin skin testing of employees at a university hospital: a cost-benefit analysis. Infect Control Hosp Epidemiol 1989;10:465-9. Condos R, Schluger N, Lacouture R, Rom W. Infections among house staff at Bellevue Hospital in an epidemic period. Am Rev Respir Dis 1993;147[Suppl]:A124. Redwood E, Anderson V, Felton CP, Findley S, Ford JG. Tuberculin conversions in hospital employees in a high tuberculosis prevalence area. Am Rev Respir Dis 1993; 147[Suppl]:A119. Ramirez AJ, Anderson P, Herp S, Raff MJ. Increased rate of tuberculin skin test conversion among workers at a university hospital. Infect Control Hosp Epidemiol 1992;13:579-81. Adal KA, Anglim AM, Palumbo CL, Titus MG, Coyner BJ, Farr BM. The use of high-efficiency particulate air-filter respirators to protect hospital workers from tuberculosis – a cost effectiveness analysis. N Engl J Med 1994;331:169-73. Pai M, Kalantri S, Aggarwal AN, Menzies D, Blumberg HM. Nosocomial tuberculosis in India. Emerg Infect Dis 2006;12:1311-8. American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221-S47. Stuart RL, Bennett NJ, Forbes AB, Grayson ML. Assessing the risk of tuberculosis infection among health care workers: the Melbourne Mantoux Study. Med J Aust 2001;174:569-73. Plitt SS, Soskolne CL, Fanning EA, Newman SC. Prevalence and determinants of tuberculin reactivity among physicians in Edmonton, Canada 1996-1997. Int J Epidemiol 2001;30: 1022-8.

34. Warren DK, Foley KM, Polish LB, Seiler SM, Fraser VJ. Tuberculin skin testing of physicians at a mid-western teaching hospital: a 6-year prospective study. Clin Infect Dis 2001;32:1331-7. 35. Kassim S, Zuber P, Wiktor SZ, Diomande FV, Coulibaly IM, Coulibaly D, et al. Tuberculin skin testing to assess the occupational risk of Mycobacterium tuberculosis infection among health care workers in Abidjan, Cote d’lvoire. Int J Tuberc Lung Dis 2000;4:321-6. 36. Blumberg HM, Sotir M, Erwin M, Bachman R, Shulman JA. Risk of house staff tuberculin skin test conversion in an area with a high incidence of tuberculosis. Clin Infect Dis 1998;27:826-33. 37. Louther J, Rivera P, Feldman J, Villa N, DeHovitz J, Sepkowitz KA. Risk of tuberculin conversion according to occupation among health care workers at a New York City Hospital. Am J Respir Crit Care Med 1997;156:201-5. 38. Schwartzman K, Loo V, Pasztor J, Menzies D. Tuberculosis infection among health care workers in Montreal. Am J Respir Crit Care Med 1996;154:1006-12. 39. Porteous NB, Brown JP. Tuberculin skin test conversion rate in dental health care workers – results of a prospective study. Am J Infect Control 1999;27:385-7. 40. D’Agata EM, Wise S, Stewart A, Lefkowitz LB Jr. Nosocomial transmission of Mycobacterium tuberculosis from an extrapulmonary site. Infect Control Hosp Epidemiol 2001;22:10-2. 41. Cuhadaroglu C, Erelel M, Tabak L, Kilicaslan Z. Increased risk of tuberculosis in health care workers: a retrospective survey at a teaching hospital in Istanbul, Turkey. BMC Infect Dis 2002;2:14. 42. Eyob G, Gebeyhu M, Goshu S, Girma M, Lemma E, Fontanet A. Increase in tuberculosis incidence among the staff working at the Tuberculosis Demonstration and Training Centre in Addis Ababa, Ethiopia: a retrospective cohort study [19891998]. Int J Tuberc Lung Dis 2002;6:85-8. 43. Kruuner A, Danilovitsh M, Pehme L, Laisaar T, Hoffner SE, Katila ML. Tuberculosis as an occupational hazard for health care workers in Estonia. Int J Tuberc Lung Dis 2001;5:170-6. 44. Skodric V, Savic B, Jovanovic M, Pesic I, Videnovic J, Zugic V, et al. Occupational risk of tuberculosis among health care workers at the Institute for Pulmonary Diseases of Serbia. Int J Tuberc Lung Dis 2000;4:827-31. 45. Usui T, Yamanaka K, Nomura H, Tokudome S. Elevated risk of tuberculosis by occupation with special reference to health care workers. J Epidemiol 2000;10:1-6. 46. Harries AD, Nyirenda TE, Banerjee A, Boeree MJ, Salaniponi FM. Tuberculosis in health care workers in Malawi. Trans R Soc Trop Med Hyg 1999;93:32-5. 47. Meredith S, Watson JM, Citron KM, Cockcroft A, Darbyshire JH. Are health care workers in England and Wales at increased risk of tuberculosis? BMJ 1996;313:522-5. 48. Raitio M, Tala E. Tuberculosis among health care workers during three recent decades. Eur Respir J 2000;15:304-7. 49. Wilkinson D, Gilks CF. Increasing frequency of tuberculosis among staff in a South African district hospital: impact of

644

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

Tuberculosis the HIV epidemic on the supply side of health care. Trans R Soc Trop Med Hyg 1998;92:500-2. Pleszewski B, FitzGerald JM. Tuberculosis among health care workers in British Columbia. Int J Tuberc Lung Dis 1998;2:898-903. Tokars JI, McKinley GF, Otten J, Woodley C, Sordillo EM, Caldwell J, et al. Use and efficacy of tuberculosis infection control practices at hospitals with previous outbreaks of multi-drug resistant tuberculosis. Infect Control Hosp Epidemiol 2001;22:449-55. Menzies D, Fanning A, Yuan L, FitzGerald JM. Hospital ventilation and risk for tuberculous infection in Canadian health care workers. Canadian Collaborative Group in Nosocomial Transmission of TB. Ann Intern Med 2000;133:779-89. Linquist JA, Rosaia CM, Riemer B, Heckman K, Alvarez F. Tuberculosis exposure of patients and staff in an outpatient hemodialysis unit. Am J Infect Control 2002;5:307-10. Sacks LV, Pendle S, Orlovic D, Blumberg L, Constantinou C. A comparison of outbreak- and nonoutbreak-related multidrug-resistant tuberculosis among human immunodeficiency virus-infected patients in a South African hospital. Clin Infect Dis 1999;29:96-101. Moro ML, Gori A, Errante I, Infuso A, Franzetti F, Sodano L, et al. An outbreak of multidrug-resistant tuberculosis involving HIV-infected patients of two hospitals in Milan, Italy. Italian Multidrug-Resistant Tuberculosis Outbreak Study Group. AIDS 1998;12:1095-102. Beck-Sagué C, Dooley SW, Hutton MD, Otten J, Breeden A, Crawford JT, et al. Hospital outbreak of multidrug-resistant Mycobacterium tuberculosis infections. Factors in transmission to staff and HIV-infected patients. JAMA 1992;268:1280-6. Sepkowitz KA, Friedman CR, Hafner A, Kwok D, Manoach S, Floris M, et al. Tuberculosis among urban health care workers: a study using restriction fragment length polymorphism typing. Clin Infect Dis 1995;21:1098-101. Jereb JA, Klevens RM, Privett TD, Smith PJ, Crawford JT, Sharp VL, et al. Tuberculosis in health care workers at a hospital with an outbreak of multi-drug resistant Mycobacterium tuberculosis. Arch Intern Med 1995;155:854-9. Lai KK, Fontecchio SA, Kelley AL, Melvin ZS. Knowledge of the transmission of tuberculosis and infection control measures for tuberculosis among health care workers. Infect Control Hosp Epidemiol 1996;17:168-70. Houk VN, Kent DC, Baker JH, Sorensen K. The epidemiology of tuberculosis infection in a closed environment. Arch Environ Health 1968;16:26-35. Riley EC, Murphy G, Riley RL. Airborne spread of measles in a suburban-elemental school. Am J Epidemiol 1978;107: 421-32. Nardell EA. Nosocomial tuberculosis in the AIDS era: strategies for interrupting transmission in developed countries. Bull Int Union Tuberc Lung Dis 1991;66:107-11. Catanzaro A. Nosocomial tuberculosis. Am Rev Respir Dis 1982;123:559-62.

64. Riley RL. Transmission and environmental control of tuberculosis. In: Reichman LB, Hershfield ES, editors. Tuberculosis: a comprehensive international approach. First edition. New York: Marcel Dekker Inc.; 1993.p.123-36. 65. Brotherton JM, Bartlett MJ, Muscatello DJ, Campbell-Lloyd S, Stewart K, McAnulty JM. Do we practice what we preach? Health care worker screening and vaccination. Am J Infect Control 2003;31:144-50. 66. Yanai H, Limpakarnjanarat K, Uthaivoravit W, Mastro TD, Mori T, Tappero JW. Risk of Mycobacterium tuberculosis infection and disease among health care workers, Chiang Rai, Thailand. Int J Tuberc Lung Dis 2003;7:36-45. 67. Cookson ST, Jarvis WR. Prevention of nosocomial transmission of Mycobacterium tuberculosis. Infect Dis Clin North Am 1997;11:385-409. 68. Centers for Disease Control. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health care facilities 1994. MMWR Morb Mortal Wkly Rep 1994;43[RR13]:1-132. 69. Central TB Division, Ministry of Health and Family Welfare, Government of India. Part-2: NTF group work recommendations. Available at URL: http://www.tbcindia.org/ Pdfs/Minutes%20and%20Recommendations%20of%20 NTF%202007.pdf. Accessed on July 27, 2008. 70. Nardell EA, Keegan J, Cheney SA, Etkind SC. Airborne infection: theoretical limits of protection achievable by building ventilation. Am Rev Respir Dis 1991;144:302-6. 71. Centers for Disease Control. Mycobacterium tuberculosis transmission in a health clinic – Florida 1988. MMWR Morb Mortal Wkly Rep 1989;38:256-64. 72. American College of Chest Physicians [ACCP] Consensus Statement. Institutional control measures for tuberculosis in the era of multiple drug resistance. Chest 1995;108:1690-710. 73. Medical Research Council. Air disinfection with ultraviolet irradiation: its effect on illness among school age children. London: Her Majesty’s Stationary Office, Special Report Series; 1954.p.283. 74. Perkins JE, Bahlke AM, Silverman HF. Effects of ultraviolet irradiation of classrooms on the spread of measles in large rural central schools. Am J Public Health 1947;37:529-37. 75. Stead WW. Management of health care workers after inadvertent exposure to tuberculosis: a guide for the use of preventive therapy. Ann Intern Med 1995;122:906-12. 76. Riley RL, Nardell EA. Clearing the air: the theory and application of ultra-violet air disinfection. Am Rev Respir Dis 1989;139:1286-94. 77. Zmudzka BZ, Beer JZ. Activation of human immunodeficiency virus by ultraviolet radiation. Photochem Photobiol 1990;52:1153-62. 78. Munoz FM, Ong LT, Seavy D, Medina D, Correa A, Starke JR. Tuberculosis among adult visitors of children with suspected tuberculosis and employees at a children’s hospital. Infect Control Hosp Epidemiol 2002;23:568-72. 79. Hinds WC, Kraske G. Performance of dust respirators with facial seal leaks: Experimental. Am Ind Hyg Assoc J 1987;48:836-41.

Tuberculosis in Health Care Workers 645 80. Chen CC, Lehtimaki M, Willeke K. Aerosol penetration through filtering face pieces and respiratory cartridges. Am Ind Hyg Assoc J 1992;53:566-74. 81. Chen CC, Ruuskanen J, Pilacinski W, Willeke K. Filter and leak penetration characteristics of a dust and mist filtering face piece. Am Ind Hyg Assoc J 1990;51:632-9. 82. National Institute for Occupational Safety and Health. NIOSH recommended guidelines for personal respiratory protection of workers in health care facilities potentially exposed to tuberculosis. Cincinnati US Department of Health and Human Services, Public Health Service, National Institute for Occupational Safety and Health; 1992.p.1-55. 83. Fine PE, Rodrigues LC. Modern vaccines: Mycobacterial diseases. Lancet 1990;335:1016-20. 84. Hershfield ES. BCG vaccination: Theoretical and practical applications. Bull Int Union Tuberc Lung Dis 1990;66:29-30.

85. Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, et al. Efficacy of BCG vaccine in the prevention of tuberculosis: meta-analysis of the published literature. JAMA 1994;271:698-702. 86. Centers for Disease Control. Use of BCG vaccines in the control of tuberculosis: a Joint Statement by the ACIP and the Advisory Committee for the Elimination of Tuberculosis. MMWR Morb Mortal Wkly Rep 1988;37:663-75. 87. Marsh BJ, San Vicente J, von Reyn CF. Utility of dual skin tests to evaluate tuberculin skin test reactions of 10 to 14 mm in health care workers. Infect Control Hosp Epidemiol 2003;24:821-4. 88. Shukla SJ, Warren DK, Woeltje KF, Gruber CA, Fraser VJ. Factors associated with the treatment of latent tuberculosis infection among health care workers at a Midwestern teaching hospital. Chest 2002;122:1609-14.

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Nutrition and Tuberculosis

46

Jason Andrews, Ramnath Subbaraman

INTRODUCTION Research has established clear connections between malnutrition and impairment of immune defense, including decreased cell-mediated protection, abnormal phagocytic function, and reduced immunoglobulin production (1-3). Among infectious diseases, tuberculosis [TB] has a particularly powerful historical association with malnutrition; its name has been linked to its wasting effect on the body since at least the time of Hippocrates in the fifth century BC. While many studies (1-3) have reinforced this millennia-old association between malnutrition and TB, remarkably few clarify the tangled relationship between the two. The probable bi-directional influence of one on the other [in which malnutrition predisposes to TB infection even as TB causes wasting], the co-occurrence of malnutrition with many other poverty-associated risk factors for TB [such as poor housing and sanitation], and the increasing incidence of TB patients co-infected with human immunodeficiency virus [HIV] [which itself causes a wasting syndrome] are just a few of the issues that confound the understanding of the relationship between malnutrition and TB. From a clinical perspective, literature on the impact of nutrition on the natural history of TB as well as evidence-based guidelines for nutritional management of such patients are also sparse. IMPACT OF NUTRITION ON THE RISK OF ACTIVE TUBERCULOSIS INFECTION AND ITS NATURAL HISTORY Despite India’s aggressive Revised National Tuberculosis Control Programme [RNTCP] and scaling up of DOTS,

the yearly incidence of the disease seems to only have reached a steady state with a possible mild downward curve at best (4). While the growing HIV epidemic is cited as one reason for the lack of decline in TB (4,5), the widespread prevalence of chronic malnutrition, the scale of which far exceeds HIV in India, is probably even more significant in fuelling the smouldering fire of the TB epidemic. While definitive data on the relative risk of TB among malnourished individuals are relatively scarce due to the ubiquity of confounding risk factors, the best available data suggest that the relative risk is six- to- ten fold after controlling for other factors (6). Like HIV, malnutrition can cause profound immunosuppression, rendering the body unable to control mycobacterial infection. The mechanisms of immunological dysfunction have been elucidated mostly in animal models (7-16), while the impact of malnutrition on the risk of TB activation at the population level has been demonstrated in clinical studies (17-35). Evidence from Animal Models Recent animal studies have better characterized the physiological connection between malnutrition, immunosuppression, and risk of active TB infection. Deficiency of protein, rather than of micronutrients, appears to play a larger role in blunting the immune response to TB. One common hypothesized mechanism of zinc and protein deficiencies is thymic atrophy, which impairs the generation of mature T-lymphocytes (7). A guinea pig model has yielded equivocal results on the question of vitamin D and zinc deficiency as the risk factors for susceptibility to TB (8,9). However, the same model shows, that protein deficiency markedly impairs

Nutrition and Tuberculosis 647 T-cell function in response to bacille Calmette-Guérin [BCG] vaccination as demonstrated by a decreased purified protein derivative response measured by the tuberculin skin test [TST] and decreased cytokine production, specifically interleukin-2 and interferon-γ (10,11). These malnourished animals also exhibit absolute and relative T-lymphocyte deficiencies of many types, including CD2+, CD4+, and CD8+ cells (12-14). In another set of experiments, lymphocytes transferred from protein deficient guinea pigs to syngeneic fully nourished animals did not protect the recipient guinea pigs from TB infection while the opposite was true (15), leading the authors to conclude that protein status has a direct influence on the potency of the lymphocytic response to TB. Similar observations in the mouse model described by Chan et al (16) make these guinea pig data more persuasive. Most importantly, both the guinea pig and the mouse models exhibited recovery of resistance to active TB with reversal of the protein malnourished state, an encouraging finding for public health specialists if also true in humans. Clinical Evidence This plethora of animal model data contrasts with the paucity of basic clinical studies clarifying the connection between malnutrition and TB risk in humans. Many studies describe multiple macro- and micro-nutrient deficiencies in TB patients (17-23). None of these studies can conclude, however, whether this malnourishment is primarily from TB preferentially activating in those with poor nutrition, or from the wasting induced by the infection itself. High population density, poor sanitation, social crises, and other poverty-associated risk factors also confound these analyses. Two classic studies (24,25) persuasively isolate the role of malnutrition in predisposing individuals to active TB. The first study (24), performed while the author himself was a prisoner-of-war, “controls” for other major factors in the external environment by observing two groups of soldiers [Russian versus British] held in the same living conditions in German prisoner-of-war camps. The Germans provided both groups the same meager rations vividly described by the author as meat “with high percentage of bone,” potatoes “largely frostbitten and inedible,” and a stew “full of small particles of grit and often containing large stones.” The British soldiers alone also received extra food rations from the

Red Cross, adding 1300 daily calories to their diet and nearly doubling their protein intake. The Russians, by contrast, underwent a process of slow starvation on the German rations, exhibiting much lower plasma protein levels and higher rates of anaemia. The Russians had an active pulmonary TB prevalence of 19 per cent while the relatively well-fed British soldiers had a prevalence of 1.2 per cent, a 16-fold greater relative risk attributable to undernourishment. Moreover, the character of the disease was different in the two populations. The Russians had rapidly progressive, highly fatal infection with massive tissue breakdown but little granuloma formation, while infection in British soldiers followed a normal chronic course with good granuloma formation. Furthermore, TB had the strongest association with malnutrition; the prevalence of malaria, dysentery, and other infections was similar between the two groups. The second classic study (25) was carried out in Norway in the 1940s, where the high rate of TB among naval recruits was initially believed to result from the young men’s overcrowded and unhygienic living conditions. However, improvements in hygiene and housing failed to reduce TB rates. Authorities then supplemented the recruits’ diets with milk, margarine, wheat bread, fruits, vegetables, and cod liver oil, after which TB rates quickly declined. While this does not, of course, disprove the prevailing wisdom of urban crowding and poor living conditions as major risk factors for the spread of TB, it does highlight the equal relevance of nutrition at a population level for TB control. More recent studies (26-28) attempt to identify specific diets and micro-nutrient deficiencies that may increase TB risk. Two studies (26,27) examining Hindu vegetarian versus Muslim omnivore South Asian immigrants in Britain found vegetarianism correlated with a three- to four-fold increase in the relative risk of active TB. Moreover, the latter study by Strachan et al (27) showed a dose response relationship; decreasing levels of fish and meat consumption correlated with an increased risk of TB. The studies speculate that B12 or vitamin D deficiency may be more specifically responsible for the increased TB risk in vegetarians, but neither examined these micro-nutrient levels in vivo. Another study (28) found that increased fruit, vegetable, and berry intake decreases the risk of active TB. A non-randomized trial of vitamin and mineral supplements by Downes (29) in New York City in the

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1940s suggested that micro-nutrients might independently protect against TB. The trial of supplementation versus no intervention was tested for five years in two groups of families with similar prevalence and incidence of TB as well as similar food and living indices. The group without micro-nutrient supplementation had a threetimes greater relative risk of active TB and the high rate of non-adherence in the experimental group suggests that protective effects of micronutrients may be even greater. Despite this evidence regarding micro-nutrients in general, the search for one single micro-nutrient that confers a high degree of protection against TB has not been fruitful. One cohort study (30) found that low levels of vitamins A and C increase TB risk, while another study (28) found vitamin C to be unassociated. Two other studies suggest that the active form of vitamin D may help mediate the actions of macrophages in killing mycobacteria (31,32). While multiple case-control studies show that TB patients have lower levels of vitamin D as compared to control subjects, it remains unclear whether this is from nutritional wasting secondary to TB or from vitamin D deficiency increasing risk of TB activation (22,33-35). While the data suggesting malnutrition predisposes to active TB infection are persuasive, little of this research has been translated into public health interventions aimed at curbing the epidemic. Correcting protein-energy malnutrition, the deficiency most powerfully connected with TB, may require larger public policy changes; however, mass multivitamin and mineral supplementation through public health programmes could also have an impact on TB rates (29). Finally, by encouraging increased protein intake and general micro-nutrient supplementation, as well as aggressively treating intestinal parasites and anemia, physicians can address malnutrition in all their patients as a method of TB prevention. THE IMPACT OF TUBERCULOSIS ON NUTRITION Tuberculosis has been understood as a disease of wasting since its earliest descriptions, and we now know that it causes significant deficiencies in nearly every nutritional marker. Body-mass index [kg/m2], skinfold thickness, mid-upper arm circumference, grip strength, body fat percentage, calorie stores, muscle mass, serum albumin, blood haemoglobin, plasma retinol, plasma zinc, selenium, iron, and vitamins A,C,D and E have all been found to be depressed in TB patients (17-20,23,36-39).

In TB, weight loss is one of the most obvious manifestations of nutritional wasting, though probably not the most clinically relevant in terms of impact on health and survival. The bulk of weight loss in patients with TB is fat mass, though the fat free component, which is also lost in significant amounts, certainly has more of an effect on the physical functioning of the patient. Protein deficiency has been well described in the context of TB, and albumin and prealbumin have been found to be useful markers both for the diagnosis of deficiency as well as the monitoring of its reversal (21,37,40,41). The predominant biochemical source of wasting is believed to be an increase in tumour necrosis factor-α [TNF-α], which causes a net catabolic state (42). While some (43) have further described an “anabolic block”, or decrease in protein synthesis, in the context of TB, other workers have failed to demonstrate this abnormal metabolism (44). Leptin, a well-known cytokine involved in energy metabolism, appears not to be involved in the wasting process in TB (45). Finally, while the little research that has been done comparing weight changes in pulmonary versus extra-pulmonary TB suggests that–at least as a subjective complaint–the loss is similar, the difference in nutrient deficiencies in these manifestations of TB are not well understood. Several vitamin deficiencies have been found to be common in TB patients and may be a result of TB wasting; however, most of these studies are cross-sectional. Furthermore, the risk of active TB has also been ascribed to vitamin deficiency. Therefore, it can be difficult to distinguish vitamin deficiency that resulted from the disease from vitamin deficiency that predisposed to the development of the disease. Vitamin A deficiency is perhaps the best studied micro-nutrient deficiency in TB, with several studies demonstrating greatly decreased serum levels in TB patients (20,21,39,46-48). In a study (37) from India, serum vitamin A levels in TB patients were found to be half than that in household contacts, who presumably had a similar diet, suggesting that the deficiency resulted from the disease. Because of the relatively recent surge in HIV, which is fuelling the TB epidemic worldwide, the impact of HIV-TB co-infection on nutrition merits special mention. Like TB, HIV often leads to nutritional deficiencies and clinical wasting, particularly in its later stages (49,50). “Acquired immunodeficiency syndrome [AIDS] cachexia” and “HIV wasting” are well-characterized

Nutrition and Tuberculosis 649 phenomena, with the latter carrying precise clinical definitions. While HIV disease is itself, like TB, a net catabolic state, evidence has suggested that, in regions in which it is endemic, TB is the predominant cause of severe wasting in patients with HIV (51). The combination of these two diseases produces a profound cachexia, rapidly obliterating a patient’s nutritional stores in a fashion more damaging to nutritional status than either HIV or TB alone (51-55). Given that malnutrition predicts survival in patients with HIV independent of the CD4+ count, such co-infection is particularly concerning. Furthermore, co-infection may blunt the normal improvements in nutrition that result from TB chemotherapy. A study (56) conducted in Tanzania found that HIV-TB co-infected patients had lower vitamin A levels than HIV-seronegative TB control. Interestingly, treating TB in HIV-seronegative patients significantly increased vitamin A levels while these levels did not increase at all in the HIV-seropositive patients on TB chemotherapy, suggesting that HIV blunted the nutritional recuperation. Several studies have described nutritional deficiencies in the setting of TB; however, the causality and implications of these deficiencies have not been well characterized. While it is difficult to sort out the predisposing nutrient deficiencies from those caused by TB, it is probably best to understand them as a spiraling force, with nutritional deficiencies causing immune compromise which enables TB to strengthen its hold in the body, and the proliferation of TB as leading to further nutritional deficiencies. The challenge for clinicians is to interrupt that cycle, perhaps through the augmentation of chemotherapy with nutritional adjuvant support, as will be discussed below. CLINICAL IMPLICATIONS AND INTERVENTIONS Nutritional status has implications for both the diagnosis and management of TB; however, there is a paucity of clinical studies assessing the impact of nutritional interventions on outcomes in TB patients. The following section will review the nexus of TB and nutrition from a clinical perspective, specifically considering the effects of malnutrition on the diagnosis of TB, the challenges that malnutrition poses in the prevention of TB, nutritional interventions in patients with active TB disease, the relatively recent advent of immunotherapy as adjunct treatment for TB, and the monitoring of nutritional markers in the clinical care of the TB patient.

Malnutrition and the bacille Calmette-Guerin Vaccine Existing evidence suggests that malnutrition drastically compromises the efficacy of the BCG vaccine in two different ways. First, maintenance of good nutrition is critical for continuing vaccine-induced immune protection. Deteriorating nutritional status between serial TSTs after BCG vaccination resulted in a marked decrease in the size of induration (57). Children with even mild levels of malnutrition in this study also had fewer positive TSTs after vaccination. These results suggest that vaccineinduced immune protection is a function of nutritional status at any given time. Similar findings in animal models support these data (14,15,58). Secondly, severe malnutrition at the time of BCG administration can permanently affect vaccine-induced immune protection. Children who had kwashiorkor at the time of BCG administration had very high rates of negative TSTs, despite much better nutrition between the time of vaccine administration and TST (59). This implies severe protein malnutrition prevented the vaccine from “registering” with the immune system in the first place. Severely protein malnourished children may therefore derive greater benefit from being vaccinated with the BCG after improvement in their nutritional status, if such delay is feasible. Diagnosis Weight loss has long been identified as one of the most common presenting complaints of patients with TB (60,61). In a population-based survey of TB symptoms carried out in the United States, weight loss was found to be a presenting complaint in 43 per cent of patients with pulmonary TB and 50 per cent of patients with extrapulmonary TB [in developing countries, where delays in seeking or obtaining medical care are often greater, these figures are likely higher]. Notably, there was not much difference in pulmonary versus extra-pulmonary TB in this aspect of the presentation. Nevertheless, evidence suggests that severely malnourished patients are more likely to have an atypical presentation of pulmonary TB, including dyspnoea and diarrhoea, and a less frequent presentation of haemoptysis and cavitation (24,62). This finding is similar to the presentation of TB in patients with HIV, and immunodeficiency may be a common pathway for these manifestations.

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Finally, there appears to be a relationship between the sensitivity of TST and the nutritional status of the patient. Studies have found a positive correlation between the size of a reaction and protein nutrition as reflected in serum albumin, leading to false negatives in those with low serum albumin levels (47,63). Similarly, evidence in animal studies shows an association between specific micro-nutrient deficiencies, such as vitamin D and zinc, and reduced TST reaction, perhaps as a result of fewer and less functional circulating T-cells. Again, these findings parallel TST studies in HIV patients, suggesting clinicians should err on the side of liberally interpreting borderline TST reaction in undernourished patients. Natural History of Tuberculosis in Malnourished Patients Malnutrition is independently associated with mortality in patients hospitalised for TB (64). In one study (65), nearly twice the number of moderate to severely malnourished hospitalized TB patients died within one month as compared to those with mild malnutrition, adjusting for all other risk factors. In another study, the initial body weight of a TB patient on presentation was found to be a better predictor of survival than the commonly used inpatient outcome instrument acute physiology and chronic health evaluation II [APACHE II] score (41). The same group (66) has also suggested that part of the adverse effect of poor nutrition on mortality may be through diminishing plasma drug concentrations during treatment. This hypothesis is supported by data showing that patients at less than 10 per cent of their ideal body weight had higher rates of treatment failure and relapse (67). Isoniazid and Vitamin B Deficiency Isoniazid-induced peripheral neuropathy is a wellrecognized adverse effect of TB treatment mediated by nutritional deficiency of pyridoxine, or vitamin B6 (68). Antituberculosis treatment has been shown to cause significant reductions in plasma pyridoxine levels within one week of therapy (69), and isoniazid may also compete with pyridoxine in its role as a cofactor for synthesis of neurotransmitters, such as gamma-aminobutyric acid. The result is a dose-dependent toxicity of numbness and tingling in the extremities in a glove and

stocking distribution, though it can also present as ataxia or muscle weakness. Central nervous symptoms such as seizures and confusion are less frequent presentations of B6 deficiency from isoniazid. Studies at the Tuberculosis Chemotherapy Centre, Madras [now called Tuberculosis Research Centre, Chennai] (70), in India in the 1960s first identified the role of low-dose pyridoxine supplementation [6 mg/day] in protecting against isoniazid-induced peripheral neuropathy. Current guidelines for pyridoxine supplementation are based on the patient’s risk for isoniazid toxicity. Malnourished individuals, the elderly, pregnant women, cancer patients, chronic alcoholics, chronic liver disease patients, and children [especially adolescent females] are at higher risk for pre-existing pyridoxine deficiency even before TB treatment. In addition, isoniazid peripheral neuropathy occurs more frequently in those already at risk for neuropathy from other causes, such as diabetes mellitus, renal failure, and HIV disease (68,71). Patients co-infected with HIV and TB on antiretroviral regimens containing stavudine or didanosine are at especially high risk, as these drugs can also cause peripheral neuropathy (72). Current guidelines (71) recommend 6 to 10 mg daily supplementation of pyridoxine for patients not at high risk for isoniazid toxicity. Patients with one or more risk factor-require dosages of 25 to 50 mg daily. For patients presenting with active isoniazids induced peripheral neuropathy, seizures, or mental status changes, 100 to 200 mg daily of pyridoxine is recommended for treatment (71). Finally, data are also available indicating increased rates of toxicity in patients with low baseline serum albumin levels (73,74), suggesting that malnutrition may predispose patients to higher rates of drug-induced hepatotoxicity from antituberculosis therapy treatment. Nutritional Interventions in Patients with Active Tuberculosis In light of the strong data demonstrating the impact of malnutrition on survival in TB patients, it would seem intuitive that nutritional support would decrease morbidity and mortality. This idea, traditional wisdom in the early days of TB therapy, has since come under question. In a classic study conducted by Ramakrishnan and colleagues (75) at Chennai in the late 1950s, 193

Nutrition and Tuberculosis 651 patients were randomized to treatment at home or in a TB sanatorium . The TB sanatorium provided nutritional supplementation such that sanatorium patients had significantly increased caloric, protein, carbohydrate, and micro-nutrient intake as compared to patients treated at home. Patients were followed for six months, after which response to therapy was assessed using time to culture negative sputum and improvement in chest radiograph. It was found that in spite of a markedly poorer diet and substantially less weight gain in the patients who received treatment at home, the overall response to therapy was similar in the two groups. In a multivariate analysis, none of the dietary factors studied [calories, carbohydrates, proteins, fats, minerals, and vitamins] were found to influence the time to attainment of quiescent disease. Another study (17) from Tanzania further questioned the utility of aggressive nutritional support for reducing mortality. Weight gain was found to be a poor predictor of clinical outcomes; however, the authors did suggest that there may be a positive influence on quality of life and reduction in some morbidities (17). In contrast, a recent randomized study (76) found that patients being treated for TB who were counselled to increase their intake through diet and high-energy supplements for six weeks after beginning therapy had significantly greater increase in body weight, total lean mass, and grip strength compared with patients who received standard nutritional counselling. While clinical outcomes including morbidity, mortality, and TB cure were not assessed, this study did find an overall improvement in physical well being and quality of life in those who received early nutritional support. In addition to increased caloric intake, micro-nutrient supplementation has been studied as a potential adjuvant for improving outcomes in TB patients. Some of the early efforts at micro-nutrient supplementation involved the use of vitamin D, the deficiency of which has been well associated with immune dysfunction [particularly impaired lymphocyte proliferation] and risk of active TB; however, the utility of supplementation has not been demonstrated by clinical trials and the potential side effects of excessive vitamin D intake need further examination. Equally controversial, perhaps, is the use of vitamin A supplementation as adjuvant therapy in patients with active TB. Hanekom et al (21) looked at a cohort of South African children with pulmonary TB

and found that 62 per cent were deficient in plasma vitamin A. Lower plasma levels were also associated with more extensive or severe disease, including higher rates of extra-pulmonary disease. However, high-dose vitamin A therapy in this population was found to have no effect on disease outcome, including physical and biochemical markers compared to placebo (21). Furthermore, at six weeks, respiratory complaints had resolved in more patients in the group receiving placebo [49%] than in those who received vitamin A [24%]. In contrast, a study (46) carried out in Indonesia found that patients receiving vitamin A and zinc supplementation had earlier conversion to culture-negative sputum and a greater improvement on chest radiograph at two months. Because the intervention group received both zinc and vitamin A, it is possible that the benefit was only from zinc and did not thereby contradict the aforementioned South African study (21). Finally, iron supplementation has been successful in improving haemoglobin levels in patients with pulmonary TB and mild to moderate anaemia by accelerating the normal resumption of haematopoiesis (77). The absence of a well-demonstrated reduction in TBassociated morbidity and mortality from nutritional interventions does not imply that nutritional support is inconsequential in the care of patients with TB. Rather, two important points should be kept in mind. The first is that further research is needed in this area, especially focussing on greater levels of protein and high-energy supplementation which may be necessary to overcome the “anabolic block” that may occur with TB. The other critical lesson is that nutritional support can contribute greatly in the restoration of physical function, which is critical in contexts where individuals are dependent upon their health to earn income for survival. Adjuvant Immunotherapy for Improving Nutritional Status in Tuberculosis With the understanding that TB wasting is a consequence of endogenous immune response, particularly involving TNF-α, immune modulation has been proposed as an adjuvant therapy for improving nutritional status in patients with TB, HIV, and TB/HIV co-infection. Simple corticosteroids have been used in several trials; however, in a review of these studies, Dooley et al (78) concluded that corticosteroids only contributed to short-term weight gains and had minimal long-term benefits or

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improvement in outcomes. Thalidomide has also been used in hopes of reversing wasting by suppressing TNF-α. Small controlled trials have found enhancement in weight gain compared with placebo in patients with TB and HIV-TB co-infection (79,80). However, the gains appear to be largely fat weight, rather than fat free mass, which is clinically a more important component. Thalidomide is not yet standard practice, and larger trials, looking at a wider range of clinical outcomes, are needed. Monitoring Nutritional Status in Tuberculosis Patients Despite the contribution of wasting towards morbidity and mortality from TB, the weight gains accompanying antituberculosis treatment have not been demonstrated to improve or predict survival. This may be a result of the type of mass that is gained. In one study, patients being treated for pulmonary TB had a 10 per cent gain in body weight during treatment; however, they had a 44 per cent gain in fat mass, with very little increase in fatfree mass, including protein mass and bone minerals. This is of great consequence, given that fat-free mass has been more closely correlated with improvements in quality of life and physical functioning. Thus, while protein is one of the major components lost during an episode of TB, it is not significantly regained during the course of treatment, making overall weight gain an inadequate clinical marker for following the reversal of

TB wasting. Serum albumin may be a more accurate indicator than weight of improving nutritional status [especially with regard to crucial fat-free mass] in patients being treated for TB, as was demonstrated in a review of cases in Nigeria (41). CONFRONTING THE VICIOUS CYCLE OF HUNGER AND DISEASE Table 46.1 summarizes the critical nutritional considerations in the prevention and management of TB. This chapter illuminates the synergistic interaction between TB and malnutrition, which induces a vicious downward spiral of hunger and ill health. Malnutrition compromises the immune system, allowing TB infection to take advantage of a fragile host environment. The mycobacteria then cause further wasting, confounding nutritional repletion and disease treatment. The ultimate result is lower quality of life for patients, poor clinical outcomes, and, often, death. Is it any surprise, then, that India, the country with the largest burden of chronic undernourishment in the world, also has the highest number of TB cases? Is it not unsurprising that the epidemic trend has been refractory to purely medical attempts to confront it? Dreze and Sen (82) have argued that hunger in the modern world is a crisis of both food security and health

Table 46.1: Critical nutritional considerations in the prevention and management of tuberculosis Prevention Reduction of protein-energy malnutrition is critical to controlling and reducing rates of TB Data supports wide scale daily multivitamin, mineral supplementation as an intervention to reduce TB rates BCG vaccine efficacy is severely compromised in malnourished recipients Protein repletion prior to BCG vaccine administration should be considered, if possible, in severely protein malnourished children Diagnosis Borderline PPDs in malnourished patients should be interpreted liberally, erring on the side of a positive read Severe malnutrition is associated with atypical presentations of TB, parallelling patterns in AIDS patients Treatment While comprehensive nutritional support of TB patients may not decrease mortality, studies show that it is probably crucial in improving quality of life Repletion of tissue mass in TB patients requires greater than normal levels of nutritional intake, including protein and high energy supplementation Iron supplementation is recommended for anaemia due to pulmonary TB Vitamin A and D supplementation for TB patients remains controversial Weight gain alone can be a deceptive measure of clinical improvement and should be augmented by serum albumin monitoring for a more accurate reflection of nutritional status Improvements of serum albumin may be the earliest sign of improving nutritional status in patients being treated for TB TB = tuberculosis; BCG = bacille Calmette-Guérin; PPD = purified protein derivative; AIDS = acquired immunodeficiency syndrome

Nutrition and Tuberculosis 653 care. Clinicians treating TB are in an ideal position to confront this combined entity of hunger and disease. They can do this not only by optimizing nutritional status in those with active TB [thereby improving quality of life for these patients], but also by addressing malnutrition in all their patients as a method of TB prevention. Specific interventions would include encouraging increased protein intake and general micronutrient supplementation, as well as aggressively treating intestinal parasites and anaemia. Nevertheless, perhaps the most powerful way doctors can confront TB is by moving beyond the purely medical approach and stepping outside of their hospitals into the realm of public action. Even as malnutrition is a medical problem, so is TB inseparable from hunger. By advocating for public policy which includes food security for the poor (83), doctors can confront TB as it needs to be confronted: at both the social and medical levels. REFERENCES 1. Macallan DC. Malnutrition in tuberculosis. Diagn Microbiol Infect Dis 1999;34:153-7. 2. Chandra RK. Nutrition and the immune system: an introduction. Am J Clin Nutr 1997;66:460S-3S. 3. Chandra RK. Nutrition and the immune system from birth to old age. Eur J Clin Nutr 2002;56[Suppl3]:S73-6. 4. Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248-76. 5. Williams BG, Granich R, Chauhan LS, Dharmshaktu NS, Dye C. The impact of HIV/AIDS on the control of tuberculosis in India. Proc Natl Acad Sci USA 2005;102:9619-24. 6. Cegielski JP, McMurray DN. The relationship between malnutrition and tuberculosis: evidence from studies in humans and experimental animals. Int J Tuberc Lung Dis 2004;8:286-98. 7. Dai G, Phalen S, McMurray DN. Nutritional modulation of host responses to mycobacteria. Front Biosci 1998;3:e110-22. 8. McMurray DN, Bartow RA, Mintzer CL, Hernandez-Frontera E. Micronutrient status and immune function in tuberculosis. Ann N Y Acad Sci 1990;587:59-69. 9. Hernandez-Frontera E, McMurray DN. Dietary vitamin D affects cell-mediated hypersensitivity but not resistance to experimental pulmonary tuberculosis in guinea pigs. Infect Immun 1993;61:2116-21. 10. McMurray DN, Carlomagno MA, Mintzer CL, Tetzlaff CL. Mycobacterium bovis BCG vaccine fails to protect proteindeficient guinea pigs against respiratory challenge with virulent Mycobacterium tuberculosis. Infect Immun 1985;50:555-9. 11. Dai G, McMurray DN. Altered cytokine production and impaired antimycobacterial immunity in proteinmalnourished guinea pigs. Infect Immun 1998;66:3562-8.

12. Bartow RA, McMurray DN. Erythrocyte receptor [CD2]bearing T lymphocytes are affected by diet in experimental pulmonary tuberculosis. Infect Immun 1990;58:1843-7. 13. Mainali ES, McMurray DN. Protein deficiency induces alterations in the distribution of T-cell subsets in experimental pulmonary tuberculosis. Infect Immun 1998;66:927-31. 14. McMurray DN, Bartow RA, Mintzer CL. Protein malnutrition alters the distribution of Fc gamma R+ [T gamma] and Fc mu R+ [T mu] T lymphocytes in experimental pulmonary tuberculosis. Infect Immun 1990;58:563-5. 15. Mainali ES, McMurray DN. Adoptive transfer of resistance to pulmonary tuberculosis in guinea pigs is altered by protein deficiency. Nutr Res 1998;18:309-17. 16. Chan J, Tian Y, Tanaka KE, Tsang MS, Yu K, Salgame P, et al. Effects of protein calorie malnutrition on tuberculosis in mice. Proc Natl Acad Sci USA 1996;93:14857-61. 17. Kennedy N, Ramsay A, Uiso L, Gutmann J, Ngowi FI, Gillespie SH. Nutritional status and weight gain in patients with pulmonary tuberculosis in Tanzania. Trans R Soc Trop Med Hyg 1996;90:162-6. 18. Onwubalili JK. Malnutrition among tuberculosis patients in Harrow, England. Eur J Clin Nutr 1988;42:363-6. 19. Harries AD, Nkhoma WA, Thompson PJ, Nyangulu DS, Wirima JJ. Nutritional status in Malawian patients with pulmonary tuberculosis and response to chemotherapy. Eur J Clin Nutr 1988;42:445-50. 20. Karyadi E, Schultink W, Nelwan RH, Gross R, Amin Z, Dolmans WM, et al. Poor micronutrient status of active pulmonary tuberculosis patients in Indonesia. J Nutr 2000;130:2953-8. 21. Hanekom WA, Potgieter S, Hughes EJ, Malan H, Kessow G, Hussey GD. Vitamin A status and therapy in childhood pulmonary tuberculosis. J Pediatr 1997;131:925-7. 22. Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 2000;355:618-21. 23. Kassu A, Yabutani T, Mahmud ZH, Mohammad A, Nguyen N, Huong BT, et al. Alterations in serum levels of trace elements in tuberculosis and HIV infections. Eur J Clin Nutr 2006;60:580-6. 24. Leyton GB. Effect of slow starvation. Lancet 1946;2:73-9. 25. Leitch I. Diet and tuberculosis. Proc Nutr Soc 1945;3:156. 26. Chanarin I, Stephenson E. Vegetarian diet and cobalamin deficiency: their association with tuberculosis. J Clin Pathol 1988;41:759-62. 27. Strachan DP, Powell KJ, Thaker A, Millard FJ, Maxwell JD. Vegetarian diet as a risk factor for tuberculosis in immigrant south London Asians. Thorax 1995;50:175-80. 28. Hemila H, Kaprio J, Pietinen P, Albanes D, Heinonen OP. Vitamin C and other compounds in vitamin C rich food in relation to risk of tuberculosis in male smokers. Am J Epidemiol 1999;150:632-41. 29. Downes J. An experiment in the control of tuberculosis among Negroes. Milbank Mem Fund Q 1950;28:127-59.

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30. Getz HR, Long ER, Henderson HJ. A study of the relation of nutrition to the development of tuberculosis; influence of ascorbic acid and vitamin A. Am Rev Tuberc 1951;64:381-93. 31. Biyoudi-Vouenze R, Cadranel J, Valeyre D, Milleron B, Hance AJ, Soler P. Expression of 1,25[OH]2D3 receptors on alveolar lymphocytes from patients with pulmonary granulomatous diseases. Am Rev Respir Dis 1991;143:137680. 32. Cadranel J, Garabedian M, Milleron B, Guillozo H, Akoun G, Hance AJ. 1,25[OH]2D2 production by T lymphocytes and alveolar macrophages recovered by lavage from normocalcemic patients with tuberculosis. J Clin Invest 1990;85: 1588-93. 33. Davies PD, Brown RC, Woodhead JS. Serum concentrations of vitamin D metabolites in untreated tuberculosis. Thorax 1985;40:187-90. 34. Sasidharan PK, Rajeev E, Vijayakumari V. Tuberculosis and vitamin D deficiency. J Assoc Physicians India 2002;50:554-8. Comment in: J Assoc Physicians India 2003;51:325-6. 35. Ustianowski A, Shaffer R, Collin S, Wilkinson RJ, Davidson RN. Prevalence and associations of vitamin D deficiency in foreign-born persons with tuberculosis in London. J Infect 2005;50:432-7. 36. Ramachandran G, Santha T, Garg R, Baskaran D, Iliayas SA, Venkatesan P, et al. Vitamin A levels in sputum-positive pulmonary tuberculosis patients in comparison with household contacts and healthy ‘normals’. Int J Tuberc Lung Dis 2004;8:1130-3. 37. Scalcini M, Occenac R, Manfreda J, Long R. Pulmonary tuberculosis, human immunodeficiency virus type-1 and malnutrition. Bull Int Union Tuberc Lung Dis 1991;66:37-41. 38. Ray M, Kumar L, Prasad R. Plasma zinc status in Indian childhood tuberculosis: impact of antituberculosis therapy. Int J Tuberc Lung Dis 1998;2:719-25. 39. Madebo T, Lindtjorn B, Aukrust P, Berge RK. Circulating antioxidants and lipid peroxidation products in untreated tuberculosis patients in Ethopia. Am J Clin Nutr 2003;78:11722. 40. Mehta JB, Fields CL, Byrd RP Jr, Roy TM. Nutritional status and mortality in respiratory failure caused by tuberculosis. Tenn Med 1996;89:369-71. 41. Adebisi SA, Oluboyo PO, Oladipo OO. The usefulness of serum albumin and urinary creatinine as biochemical indices for monitoring the nutritional status of Nigerians with pulmonary tuberculosis. Niger Postgrad Med J 2003;10:24750. 42. Bekker LG, Maartens G, Steyn L, Kaplan G. Selective increase in plasma tumor necrosis factor-alpha and concomitant clinical deterioration after initiating therapy in patients with severe tuberculosis. J Infect Dis 1998;178:580-4. 43. Macallan DC, McNurlan MA, Kurpad AV, de Souza G, Shetty PS, Calder AG, et al. Whole body protein metabolism in human pulmonary tuberculosis and undernutrition: evidence for anabolic block in tuberculosis. Clin Sci [Lond] 1998;94:32131.

44. Paton NI, Ng YM, Chee CB, Persaud C, Jackson AA. Effects of tuberculosis and HIV infection on whole-body protein metabolism during feeding, measured by the [15N]glycine method. Am J Clin Nutr 2003;78:319-25. 45. Schwenk A, Hodgson L, Rayner CF, Griffin GE, Macallan DC. Leptin and energy metabolism in pulmonary tuberculosis. Am J Clin Nutr 2003;77:392-8. 46. Karyadi E, West CE, Schultink W, Nelwan RH, Gross R, Amin Z, et al. A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status. Am J Clin Nutr 2002;75:720-7. 47. Evans DI, Attock B. Folate deficiency in pulmonary tuberculosis: relationship to treatment and to serum vitamin A and beta-carotene. Tubercle 1971;52:288-94. 48. Rwangabwoba JM, Fischman H, Semba RD. Serum vitamin A levels during tuberculosis and human immunodeficiency virus infection. Int J Tuberc Lung Dis 1998;2:771-3. 49. Suttmann U, Ockenga J, Selberg O, Hoogestraat L, Deicher H, Muller MJ. Incidence and prognostic value of malnutrition and wasting in human immunodeficiency virus-infected outpatients. J Acquir Immune Defic Syndr Hum Retrovirol 1995;8:239-46. 50. Tang AM, Forrester J, Spiegelman D, Knox TA, Tchetgen E, Gorbach SL. Weight loss and survival in HIV-positive patients in the era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2002;31:230-6. 51. Lucas SB, De Cock KM, Hounnou A, Peacock C, Diomande M, Honde M, et al. Contribution of tuberculosis to slim disease in Africa. BMJ 1994;308:1531-3. 52. Paton NI, Castello-Branco LR, Jennings G, Ortigao-deSampaio MB, Elia M, Costa S, et al. Impact of tuberculosis on the body composition of HIV-infected men in Brazil. J Acquir Immune Defic Syndr Hum Retrovirol 1999;20:265-71. 53. Niyongabo T, Henzel D, Idi M, Nimubona S, Gikoro E, Melchior JC, et al. Tuberculosis, human immunodeficiency virus infection, and malnutrition in Burundi. Nutrition 1999;15:289-93. 54. van Lettow M, Fawzi WW, Semba RD. Triple trouble: the role of malnutrition in tuberculosis and human immunodeficiency virus co-infection. Nutr Rev 2003;61:81-90. 55. van Lettow M, Harries AD, Kumwenda JJ, Zijlstra EE, Clark TD, Taha TE, et al. Micronutrient malnutrition and wasting in adults with pulmonary tuberculosis with and without HIV co-infection in Malawi. BMC Infect Dis 2004;4:61. 56. Mugusi FM, Rusizoka O, Habib N, Fawzi W. Vitamin A status of patients presenting with pulmonary tuberculosis and asymptomatic HIV-infected individuals, Dar-es-Salaam, Tanzania. Int J Tuberc Lung Dis 2003;7:804-7. 57. Kielmann AA, Uberoi IS, Chandra RK, Mehra VL. The effect of nutritional status on immune capacity and immune responses in preschool children in a rural community in India. Bull World Health Organ 1976;54:477-83. 58. McMurray DN, Mintzer CL, Tetzlaff CL, Carlomagno MA. The influence of dietary protein on the protective effect of BCG in guinea pigs. Tubercle 1986;67:31-9.

Nutrition and Tuberculosis 655 59. Satyanarayana K, Bhaskaram P, Seshu VC, Reddy V. Influence of nutrition on postvaccinial tuberculin sensitivity. Am J Clin Nutr 1980;33:2334-7. 60. Hira SK, Dupont HL, Lanjewar DN, Dholakia YN. Severe weight loss: the predominant clinical presentation of tuberculosis in patients with HIV infection in India. Natl Med J India 1998;11:256-8. 61. Miller LG, Asch SM, Yu EI, Knowles L, Gelberg L, Davidson P. A population-based survey of tuberculosis symptoms: how atypical are atypical presentations? Clin Infect Dis 2000;30:293-9. 62. Madebo T, Nysaeter G, Lindtjorn B. HIV infection and malnutrition change the clinical and radiological features of pulmonary tuberculosis. Scand J Infect Dis 1997;29:355-9. 63. Harrison BD, Tugwell P, Fawcett IW. Tuberculin reaction in adult Nigerians with sputum-positive pulmonary tuberculosis. Lancet 1975;1:421-4. 64. Rao VK, Iademarco EP, Fraser VJ, Kollef MH. The impact of comorbidity on mortality following in-hospital diagnosis of tuberculosis. Chest 1998;114:1244-52. 65. Zachariah R, Spielmann MP, Harries AD, Salaniponi FML. Moderate to severe malnutrition in patients with tuberculosis is a risk factor associated with early death. Trans R Soc Trop Med Hyg 2002;96:291-4. 66. Byrd RP Jr, Mehta JB, Roy TM. Malnutrition and pulmonary tuberculosis. Clin Infect Dis 2002;35:634-5; author reply 6356. 67. Benator D, Bhattacharya M, Bozeman L, Burman W, Cantazaro A, Chaisson R, et al. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet 2002;360:528-34. 68. Snider DE Jr. Pyridoxine supplementation during isoniazid therapy. Tubercle 1980;61:191-6. 69. Visser ME, Texeira-Swiegelaar C, Maartens G. The short-term effects of anti-tuberculosis therapy on plasma pyridoxine levels in patients with pulmonary tuberculosis. Int J Tuberc Lung Dis 2004;8:260-2. 70. Tuberculosis Chemotherapy Centre. The prevention and treatment of isoniazid toxicity in the therapy of pulmonary tuberculosis. II: an assessment of the prophylactic effect of pyridoxine low dosage. Bull World Health Organ 1963;29:45781. 71. World Health Organization. Treatment of tuberculosis: guidelines for national programmes. Third edition. Geneva:

World Health Organization; 2003. 72. Simpson DM, Tagliati M. Nucleoside analogue-associated peripheral neuropathy in human immunodeficiency virus syndrome. J Acquir Immune Defic Syndr Hum Retrovirol 1995;9:153-61. 73. Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax 1996;51:132-6. 74. Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 2002;166:916-9. 75. Ramakrishnan CV, Rajendran K, Jacob PG, Fox W, Radhakrishna S. The role of diet in the treatment of pulmonary tuberculosis: an evaluation in a controlled chemotherapy study in home and sanatorium patients in South India. Indian J Tuberc 1962;9:50-70. 76. Paton NI, Chua YK, Earnest A, Chee CB. Randomized controlled trial of nutritional supplementation in patients with newly diagnosed tuberculosis and wasting. Am J Clin Nutr 2004;80:460-5. 77. Das BS, Devi U, Mohan Rao C, Srivastava VK, Rath PK, Das BS. Effect of iron supplementation on mild to moderate anaemia in pulmonary tuberculosis. Br J Nutr 2003;90:54150. 78. Dooley DP, Carpenter JL, Rademacher S. Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 1997;25:872-87. 79. Tramontana JM, Utaipat U, Molloy A, Akarasewi P, Burroughs M, Makonkawkeyoon S, et al. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med 1995;1:384-97. 80. Klausner JD, Makonkawkeyoon S, Akarasewi P, Nakata K, Kasinrerk W, Corral L, et al. The effect of thalidomide on the pathogenesis of human immunodeficiency virus type 1 and M. tuberculosis infection. J Acquir Immune Defic Syndr Hum Retrovirol 1996;11:247-57. 81. Schwenk A, Hodgson L, Wright A, Ward LC, Rayner CF, Grubnic S, et al. Nutrient partitioning during treatment of tuberculosis: gain in body fat mass but not in protein mass. Am J Clin Nutr 2004;79:1006-12. 82. Dreze J, Sen AK. Hunger and public action. London: Oxford University Press; 1989. 83. Boelaert J, Gordeuk VR. Protein energy malnutrition and risk of tuberculosis infection. Lancet 2002;360:1102.

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Reactivation and Reinfection Tuberculosis

47

Sujatha Narayanan, JS Guleria

INTRODUCTION Exposure to Mycobacterium tuberculosis results in an asymptomatic period of incubation or latency which may progress to active disease. However, unlike most other infectious diseases, tuberculosis [TB] involves a delay between infection and disease that is extremely variable, ranging from a few weeks to a lifetime. Thus, the development of active TB in someone known to have been previously infected raises the question whether this represents a recrudescence of the initial infection [endogenous reactivation] or infection by a new strain [exogenous reinfection] (1-5). Some workers believe that post-primary TB occurs primarily as a result of endogenous reactivation pathway [the unitary concept of TB] (3,5). According to this theory, primary infection [which is usually acquired in the childhood in areas where TB is highly endemic] lies dormant for unknown reasons. Under certain circumstances, the dormant infection gets reactivated and results in post-primary TB. Others believe that exogenous reinfection pathway leads to the development of post-primary TB. These two pathways are thought to be mutually exclusive (2,3,5). Distinction between endogenous reactivation and exogenous reinfection has important implications in the planning of clinical trials and national TB control programmes. It would be catastrophic to assume that the elderly patients with TB have disease caused by infection that they acquired before the widespread emergence of drug-resistant organisms (2). If exogenous reinfection, which may be clinically indistinguishable from relapse, is common then the use of antituberculosis chemopro-

phylaxis in people who have recently been exposed to infectious TB may be prudent, regardless of whether they have evidence of prior infection. Furthermore, if exogenous reinfection is common, then new regimens that effectively eliminate infection or treat disease will be unfairly judged in clinical trials. The development of improved vaccines against TB will be especially challenging if natural infection does not confer protective immunity (2). NATURAL HISTORY OF TUBERCULOSIS INFECTION Natural history of TB infection is shown in Figure 47.1 (1). Recurrence of TB in a person who completes a full course of treatment and is cured could be due to reinfection by a different strain or reactivation of the original infecting strain (6). Retrospective analysis of mycobacterial culture and sensitivity data of several randomized clinical trials conducted at the Tuberculosis Research Centre [TRC], Chennai (7) indicates that active TB recurs in two to seven per cent of patients infected with drug susceptible isolates who were treated with contemporary short-course treatment. The earlier conventional methods like phage typing and antibiotic susceptibility could not discriminate between reactivation and reinfection. Only after the advent and widespread application of molecular biological techniques to genetically dissect the genome of Mycobacterium tuberculosis, has it been possible to understand whether the recurrence is due to relapse of the original infecting strain or due to exogenous reinfection.

Reactivation and Reinfection Tuberculosis 657

Figure 47.1: Natural history of Mycobacterium tuberculosis infection in immunocompetent and human immunodeficiency virus-infected individuals LTBI = latent tuberculosis infection; TB = tuberculosis; PTB = pulmonary TB; EPTB = extra-pulmonary TB; SS = sputum smear-positive; TST = tuberculin skin test; SS– = sputum smear-negative Adapted and reproduced with permission from “Sharma SK, Mohan A, Kadhiravan T. HIV-TB co-infection: epidemiology, diagnosis and management. Indian J Med Res 2005;121:550-67 (reference 1)”

CLINICAL PRESENTATION In areas where TB is highly endemic, primary TB is commonly encountered in childhood, whereas, the postprimary form of the disease is often seen in adults. In the developed world, where the prevalence of TB is low,

primary disease can be encountered in older age groups. While the primary lesion heals by calcification, the postprimary lesion heals by fibrosis and scar formation. Important differences exist in the location of the lesions in primary and post-primary TB [Table 47.1 and

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Table 47.1: Comparison of clinical presentation of primary and post-primary pulmonary tuberculosis in immunocompetent persons Variable

Primary tuberculosis

Post-primary tuberculosis

Location

Any part of the lung

Apical region

Size of the lesion

Small

Large

Cavitation

Uncommon

Frequent

Local spread

Uncommon

Frequent

Infectivity

Uncommon

Frequent

Lymphatic involvement

Common

Minimal

Tuberculin skin test

May be negative initially

Often positive

Figure 47.2]. While the primary lesion can occur anywhere in the lung and follows a random chance distribution; cavities, which are characteristic of postprimary TB, are almost always located in the apical region of the lungs (3). PATHOGENESIS Several factors, such as the dose of the infecting organism, immune status of the host among others, have been implicated in the pathogenesis of TB. Balasubramanian et al (3), critically reviewing the available evidence on this subject and their findings in a guinea-pig model of experimental TB (8), have postulated the “integrated model” which integrates the endogenous reactivation

Figure 47.2: Clinical presentation of primary and post-primary tuberculosis in immunocompetent individuals. Primary disease is usually characterized by a single lesion in the middle or lower right lobe with enlargement of the draining lymph nodes. Post-primary disease is often accompanied by a single [cavitary] lesion in the apical region

and exogenous reinfection pathways of pathogenesis of TB. The authors (3) propose that the interaction between virulence of the organism, prior immunological experience and the risk of infection were responsible to determine the route by which the apical implant is established, thereby determining whether the endogenous reactivation pathway or the exogenous reinfection pathway or both ensue. They (3) suggest that while the primary implant can occur anywhere in the lungs, the bacilli must gain access into the “vulnerable” regions in the apex of the lungs for the progression of infection to disease. In areas of the world where there is a low risk of infection with Mycobacterium tuberculosis, low incidence of vaccination or sensitization to environmental mycobacteria, or high incidence of high virulent isolates, the virulent tubercle bacilli reach the vulnerable region via a bacillaemia during the first infection. In areas of the world where there is a high risk of infection with Mycobacterium tuberculosis, high incidence of vaccination, or sensitization to environmental mycobacteria, or a high incidence of low virulent isolates, the organisms reach the vulnerable region via the airway which requires repeated episodes of infection, as the probability of the first implant occurring in the vulnerable region is low. Implantation having occurred in the apical area by either of the mechanisms, the primary complex eventually gets sterilized. Immunosuppressive events trigger the multiplication of the tubercle bacilli in the vulnerable apical area and the effect of cell-mediated immunity leads to caseation necrosis and cavity formation. Vynnycky and Fine (9) estimated the age-dependent risks of developing TB using the age-structured deterministic model of the dynamics of TB infection and disease in England and Wales since 1900. The best estimates of the risks of developing ‘primary’ disease [within 5 years of initial infection] for individuals infected at ages under 10 years, 15 years and over 20 years were found to be four per cent, nine per cent, and 14 per cent, respectively. A previous infection appeared to impart little protection against [further] reinfection, but, provided a 16 to 41 per cent protection against the development of active disease subsequent to reinfection for adolescents and adults. The authors (9) concluded that “risk of infection” is the single most important factor affecting the magnitude of TB morbidity in a population, as it determines both the age pattern of initial infection [and hence the risk of developing the disease] and the risk of reinfection.

Reactivation and Reinfection Tuberculosis 659 MOLECULAR EPIDEMIOLOGY The issue of reactivation or reinfection TB has been studied employing DNA fingerprinting using restriction fragment length polymorphism [RFLP] (10,11). In patients with recurrent TB, if the DNA fingerprinting results of the initial isolates are available, subsequent DNA fingerprinting can help in determining whether the second episode is due to reactivation or reinfection. The reader is referred to the chapter “Drug-resistant tuber-

culosis” [Chapter 49] for more details regarding these techniques. An alternative method of detecting exogenous reinfection or ongoing transmission has also been widely used. In this method, if two or more patients share the same RFLP pattern, they are categorized as belonging to a “cluster”. A given cluster denotes exogenous reinfection or ongoing transmission and unique RFLP pattern is suggestive of endogenous reactivation [Figure 47.3] (12).

Figure 47.3: Restriction fragment length polymorphism can distinguish two isolates of Mycobacterium tuberculosis. The chromosomal DNA from two clinical isolates of Mycobacterium tuberculosis was digested with restriction enzyme Pvu II. The resulting DNA fragments were run on agarose gel electrophoresis along with molecular weight marker. The DNA fragments were transferred from the agarose gel to nylon membrane by southern blotting and hybridized with non-radioactively labelled IS6110 repeat element Adapted and reproduced with permission from “Narayanan S. Molecular epidemiology of tuberculosis. Indian J Med Res 2004;120:23347 (reference 12)”

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The insertion sequence IS6110 has been most widely used for RFLP studies. However, in certain regions of the world, i.e., India and other South-East Asian countries, several clinical isolates of Mycobacterium tuberculosis harbour few or no copies of IS6110. In a multicentric study from India (13), 56 per cent of the isolates showed high copy number of IS6110 [6 to 19], 13 per cent showed intermediate copy number [3 to 5], 20 per cent showed low copy number [1 to 2], whereas 11 per cent isolates lacked IS6110 element. Such variations should be kept in mind while attempting to study the molecular epidemiology of TB and more number of genetic probes would have to be used. Use of convention epidemiological data in combination with the DNA techniques is helpful in answering important questions about the epidemiology of TB in larger populations by helping us trace the source of infection (14-21). These include RFLP using the insertion sequence IS6110, direct repeat sequence, polymerase chain reaction [PCR] based typing methods such as spacer oligonucleotide typing [spoligotyping] based on polymorphisms in the direct repeat locus and fingerprinting based on the variable number of tandem DNA repeats [VNTRs]. Patients whose isolates have identical patterns [i.e., cluster] are likely to have been infected recently and can be targeted for epidemiological investigation to identify a chain of transmission, whereas patients whose isolates demonstrate unique patterns are likely to have a latent infection (22). In geographical areas with a low incidence of TB, recurrent TB is generally due to reactivation of the disease. But this is not a universal finding. In several low incidence countries exogenous reinfection is more predominant. Although it was previously thought that 90 per cent of TB cases in the developed world occurred due to endogenous reactivation of latent infection, population-based RFLP studies conducted in the United States and western Europe, areas with relatively low incidence of TB, show that recent infection accounts for up to half of the cases among both human immunodeficiency virus [HIV]-seropositive and HIV-seronegative patients in urban areas (14-21). There have also been instances where, in high incidence countries like India, the endogenous reactivation is more predominant among HIV-seronegative TB patients (23). In Africa, where TB is endemic, it has generally been considered that most cases of TB in patients with and without HIV infection result from reactivation of a latent infection (24).

There have been a very few studies addressing the question of whether recurrences was due to relapse [endogenous reaction] or exogenous reinfection. The proportion of recurrent cases caused by reinfection in these studies has varied widely. Factors influencing the rate of recurrence are the rate of exposure to new strains [the prevalence of active TB in the community] and the presence of conditions that increase the likelihood of progression to active disease after exposure to new strains, the most common predisposing factor being advanced HIV disease. The HIV has a profound effect on the pathogenesis of TB. In patients with the acquired immunodeficiency syndrome [AIDS], TB infection progresses very rapidly to active disease, and the risk of a person co-infected with HIV and TB developing active disease over two years exceeds the lifetime risk in HIV-seronegative individuals. Patients with AIDS do not maintain protective immunity following infection, and thus, remain susceptible to exogenous reinfection. van Rie et al (25) used DNA fingerprinting to examine isolates of Mycobacterium tuberculosis obtained over a period of almost six years from 698 patients from a metropolitan area in South Africa that has one of the highest rates of TB in the world. They (25) identified 16 patients with recurrent TB after curative therapy for which complete data were available (25). Of these, 15 were HIV-seronegative. After comparing the DNA fingerprints of bacilli isolated during the initial episode with those of bacilli isolated during the subsequent episode, the authors concluded that 12 patients has been exogenously reinfected with a different strain. However, their analysis included only 16 of the 698 patients and their results must, therefore, be interpreted cautiously as patients with exogenous reinfection may be overrepresented in the analysis. The low overall rate of contamination [3.4%] in this study strongly supports their contention that laboratory error did not contribute to their result. A cohort study (26), where it was possible to distinguish relapse and reinfection, revealed an increased rate of recurrent TB among HIV-infected gold miners. Furthermore, the data from this study (26) suggested that recurrent TB was predominantly due to reinfection. In HIV-seropositive patients, 62 per cent recurrences were due to reinfection with a new organism, while in HIVseronegative patients, 94 per cent of the recurrences were due to relapse with the same organism. Overall, in

Reactivation and Reinfection Tuberculosis 661 patients with and without HIV infection, 93 per cent of recurrences within the first six months were due to relapse while 52 per cent of later recurrences were due to reinfection (26). Further studies are required to confirm these findings. DISTINGUISHING TREATMENT FAILURE AND EXOGENOUS REINFECTION Kruuner et al (27) from Estonia, studied patients with active pulmonary TB who were categorized as “treatment failure”. These patients had at least three isolates tested for drug susceptibility and were initially diagnosed to have been infected with drug-susceptible Mycobacterium tuberculosis. Eleven patients from whom 35 sequential isolates of Mycobacterium tuberculosis had been obtained were recruited into the study. Their clinical data and treatment charts were analysed and correlated with drug susceptibility patterns and IS6110 RFLP profiles. Six of the eleven isolates were found to harbour isogenic drugsusceptible Mycobacterium tuberculosis stains whereas in the other five patients, the isolated strain shifted from a susceptible to resistant phenotype. In all the cases, this shift correlated with a shift in the RFLP pattern, which points out to reinfection with a new strain. Exogenous reinfection with drug-resistant Mycobacterium tuberculosis may be misinterpreted as the emergence of drug resistance, if molecular testing techniques are not used (27). The detection of superinfection with a new strain of Mycobacterium tuberculosis during the treatment of an episode of active TB is also possible only through the use of molecular epidemiology tools. The results obtained by the use of these tools make it clear that those patients who are treated in more than one hospital setting can become infected with a new or more virulent strain of Mycobacterium tuberculosis, if infectious patient are not isolated. Molecular epidemiological studies in patients with recurrent TB also facilitate the identification of antituberculosis treatment regimens with low recurrence rates. The data from sub-Saharan Africa (28) suggest that the use of rifampicin both during the initial and continuation phase lowers the possibility of recurrent TB. India has the highest number of incident TB cases in the world. The limited numbers of molecular epidemiologic studies conducted in India were laboratory based and comprised of small number of patients (29,30). In a report from the TRC, Chennai (29), the pretreatment and relapse isolates of Mycobacterium tuberculosis were

obtained from patients with pulmonary TB who were recruited into controlled clinical trials. The isolates originated from 52 patients who received short-course chemotherapy for six to eight months. The initial isolate was obtained before starting treatment and the subsequent isolate was obtained after stopping treatment. Patients with quiescent disease were followed as long as 60 months by monthly sputum examination for up to 24 months from the start of treatment and at three-monthly intervals thereafter, in order to determine the stability of bacteriological relapse [true relapse], if two or more positive cultures were obtained within the six-month period. Coded samples of 44 pairs of clinical isolates were analysed by RFLP with direct repeat [DR] probe. On analysis, 30 different patterns were observed and the number of bands ranged from two to seven. On the basis of the number and molecular sizes of the bands similar RLFP patterns were grouped. This laboratory based study, (29) showed that the patterns of 69 per cent of the isolates from patients with relapses matched those with pre-treatment isolates, indicating that the rate of relapse caused by reactivation exceeded the rate of relapse caused by reinfection (29) [Figure 47.4]. Data are also available from a population based study (31) where molecular epidemiologic techniques were used to investigate mechanisms and risk factors for TB transmission in a high prevalence rural area in south India. The study was carried out at Tiruvallur district, Tamil Nadu with a population of 580 000 and incidence of sputum smear-positive TB of 76 per 100 000 population (32). The study subjects were all TB patients undergoing treatment according to the guidelines of the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India. Of 437 culture-positive patients, 378 isolates were available for RFLP analysis. The combined RFLP analysis with IS6110 and DR probes identified 236 [62%] patients with distinct patterns, and 142 [38%] patients were in one of the 35 clusters. More than two patients with identical RFLP patterns by IS6110 and DR probe were considered to be in a given cluster. Though not statistically significant, age above 45 years was associated with clustering suggestive of ongoing transmission [reinfection]. Furthermore, a majority of the patients who had a relapse and were in a cluster, harboured a strain with only a single copy of IS6110. Risk factors, such as multidrug-resistance, alcoholism, literacy status and family size, were not associated with clustering.

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Figure 47.4: Direct repeat restriction fragment length polymorphism patterns of the pre- and post-treatment isolates. Lanes 1 and 2 represent the pre- and post-treatment isolate of a patient and lanes 3 and 4 represent the pre- and post-treatment isolates of the second patient and so on

The findings of this study suggest that a majority of the TB cases in south India occur predominantly due to reactivation. These observations also have implications for the RNTCP of the Government of India. With the nation-wide coverage of DOTS, the transmission of infection appears to have been reduced due to the higher cure and lower relapse rates. However, reactivation of latent infection seems to contribute to the new cases for

years to come. These observations also suggest that the DOTS implementation should be sustained to control and eventually attempt to cure TB. The scenario has been different in patients co-infected with HIV and TB [Figure 47.5]. Follow-up data are available from the TRC, Chennai from patients coinfected with HIV and TB after completion of treatment. The positive mycobacterial cultures before treatment and

Figure 47.5: The direct repeat restriction fragment length polymorphism patterns before and after treatment in patients co-infected with human immunodeficiency virus and tuberculosis DR = direct-repeat

Reactivation and Reinfection Tuberculosis 663 after recurrent infection have been analysed by RFLP using more than two probes. In contrast to HIVseronegative patients co-infected with TB, preliminary results [unpublished observations] indicate that the recurrent TB is more frequently due to exogenous reinfection among patients co-infected with HIV and TB. These observations suggest the need for further studies in patients co-infected with HIV and TB. Elucidation of pathogenetic pathways of TB will enable more rational decision concerning the control measures that may have a bearing on the strategies for development of vaccines designed to protect against a specific stage of the pathogenesis (2,3). REFERENCES 1. Sharma SK, Mohan A, Kadhiravan T. HIV-TB co-infection: epidemiology, diagnosis and management. Indian J Med Res 2005;121:550-67. 2. Fine PE, Small PM. Exogenous reinfection in tuberculosis. N Engl J Med 1999;341:1226-7. 3. Balasubramanian V, Wiegeshaus EH, Taylor BT, Smith DW. Pathogenesis of tuberculosis: pathway to apical localization. Tuber Lung Dis 1994;75:168-78. 4. Stead WW. Pathogenesis of a first episode of chronic pulmonary tuberculosis in man: recrudescence of residuals of the primary infection or exogenous reinfection? Am Rev Respir Dis 1967;95:729-45. 5. Canetti G. Endogenous reactivation and exogenous reinfection. Their relative importance with regard to the development of non-primary tuberculosis. Bull Int Union Tuberc 1972;47:116-22. 6. American Thoracic Society. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 2000;161:1376-95. 7. Tuberculosis Research Centre, Indian Council of Medical Research, Chennai, India. Low rate of emergence of drug resistance in sputum positive patients treated with short course chemotherapy. Int J Tuberc Lung Dis 2001;5:40-5. 8. Balasubramanian V, Wiegeshaus E, Smith DW. Growth characteristics of recent sputum isolates of M.tuberculosis in guinea-pigs infected by the respiratory route. Infect Immun 1992;60:4762-7. 9. Vynnycky E, Fine PE. The natural history of tuberculosis: the implications of age-dependent risks of disease and the role of reinfection. Epidemiol Infect Dis 1997;119:183-201. 10. Lambert ML, Hasker E, Van Deun A, Roberfroid D, Boelaert M, Van der Stuyft P. Recurrence in tuberculosis: relapse or reinfection? Lancet Infect Dis 2003;3:282-7. 11. Cohn DL, O’Brien RJ. The use of restriction fragment length polymorphism [RFLP] analysis for epidemiological studies of tuberculosis in developing countries. Int J Tuberc Lung Dis 1998;2:16-26.

12. Narayanan S. Molecular epidemiology of tuberculosis. Indian J Med Res 2004;120:233-47. 13. Chauhan DS, Sharma VD, Parashar D, Chauhan A, Singh D, Singh HB, et al. Molecular typing of Mycobacterium tuberculosis isolates from different parts of India based on IS6110 element polymorphism using RFLP analysis. Indian J Med Res 2007;125:577-81. 14. Frothingham R, Meeker-O’Connell WA. Genetic diversity in the Mycobacterium tuberculosis complex based on variable numbers of tandem DNA repeats. Microbiology 1998;144:1189-96. 15. Barnes PF, Yang Z, Preston-Martin S, Pogoda JM, Jones BE, Otaya M, et al. Patterns of tuberculosis transmission in Central Los Angeles. JAMA 1997;278:1159-63. 16. Bishai WR, Graham NM, Harrington S, Pope DS, Hooper N, Astemborski J, et al. Molecular and geographic patterns of tuberculosis transmission after 15 years of directly observed therapy. JAMA 1998;280:1679-84. 17. Braden CR, Templeton GL, Cave MD, Valway S, Onorato IM, Castro KG, et al. Interpretation of restriction fragment length polymorphism analysis of Mycobacterium tuberculosis isolates from a state with a large rural population. J Infect Dis 1997;175:1446-52. 18. Genewein A, Telenti A, Bernasconi C, Mordasini C, Weiss S, Maurer AM, et al. Molecular approach to identifying route of transmission of tuberculosis in the community. Lancet 1993;342:841-4. 19. Hayward AC, Goss S, Drobniewski F, Saunders N, Shaw RJ, Goyal M, et al. The molecular epidemiology of tuberculosis in inner London. Epidemiol Infect 2002;128:175-4. 20. Small PM, Hopewell PC, Singh SP, Paz A, Personnet J, Ruston DC, et al. The epidemiology of tuberculosis in San Francisco: a population-based study using conventional and molecular methods. N Engl J Med 1994;330:1703-9. 21. van Deutekom H, Gerritsen JJ, van Soolingen D, van Ameijden EJ, van Embden JD, Coutinho RA. A molecular epidemiological approach to studying the transmission of tuberculosis in Amsterdam. Clin Infect Dis 1997;25:1071-7. 22. Easterbrook PJ, Gibson A, Murad S, Lamprecht D, Ives Natalie, Ferguson A, et al. High rates of strains causing tuberculosis in Harare, Zimbabwe: a molecular epidemiological study. J Clin Microbiol 2004;42:4536-44. 23. Narayanan S, Das S, Garg R, Hari L, Rao VB, Frieden TR, et al. Molecular epidemiology of tuberculosis in a rural area of high prevalence in south India: implications for disease control and prevention. J Clin Microbiol 2002;40:4785-8. 24. DeCock KM, Soro B, Coulibaly IM, Lucas SB. Tuberculosis and HIV infection in sub-Saharan Africa. JAMA 1992; 268:1581-7. 25. van Rie A, Warren R, Richardson M, Victor TC, Gie RP, Enarson DA, et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 1999;341:1174-9. 26. Sonnenberg P, Murray J, Glynn JR, Shearer S, Kambashi B, Godfrey-Faussett P. HIV-1 and recurrence, relapse and

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reinfection of tuberculosis after cure: a cohort study in South African mine workers. Lancet 2001;358:1687-93. 27. Kruuner A, Pehme L, Ghebremichael S, Koivula T, Hoffner SE, Mikelsaar M. Use of molecular techniques to distinguish between treatment failure and exogenous reinfection with Mycobacterium tuberculosis. Clin Infect Dis 2002;35:146-55. 28. Harries AD, Hargreaves NJ, Salaniponi FM. Design of regimens for treating tuberculosis in patients with HIV infection, with particular reference to sub-Saharan Africa. Int J Tuberc Lung Dis 2001;5:1109-15. 29. Sahadevan R, Narayanan S, Paramasivan CN, Prabhakar R, Narayanan PR. Restriction fragment length polymorphism typing of clinical isolates of Mycobacterium tuberculosis

from patients with pulmonary tuberculosis in Madras, India by use of direct-repeat probe. J Clin Microbiol 1995;33:30379. 30. Das S, Paramasivan CN, Lowrie DB, Prabhakar R, Narayanan PR. IS6110 RFLP typing of clinical isolates of Mycobacterium tuberculosis from patients with pulmonary tuberculosis in Madras, south India. Tuber Lung Dis 1995;76:550-4. 31. Tuberculosis Research Centre. Fifteen year follow up trial of BCG vaccines in South India for tuberculosis prevention. Indian J Med Res 1996;110:56-69. 32. Tuberculosis Research Centre. Trends in the prevalence and incidence of tuberculosis in south India. Int J Tuberc Lung Dis 2001;5:142-57.

Nontuberculous Mycobacterial Infections 665

Nontuberculous Mycobacterial Infections

48

VM Katoch, T Mohan Kumar

INTRODUCTION Mycobacteria other than Mycobacterium tuberculosis complex [MOTT] mainly exist in the environment as saprophytes. First such mycobacterium was recognized as a cause of human disease in 1908 (1). These organisms in the past have been called atypical mycobacteria, the term first coined by Pinner (2). Diseases caused by these organisms are uncommon compared with tuberculosis [TB], but there has been a significant increase in pulmonary and non-pulmonary infections due to these mycobacteria during the last two to three decades (3-8). This increase is in part explained by the increase in the number of susceptible and immunocompromised individuals but can also be attributed to the availability of better technology. While the infections caused by Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae are definite clinical entities, the diseases caused by other mycobacteria have varied manifestations, are not usually transmitted from man to man and have been broadly grouped as “other mycobacteriosis”. Even though these mycobacteria were always there, the emergence of human immunodeficiency virus [HIV] infection and acquired immunodeficiency syndrome [AIDS] has significantly increased the risk of TB and disease due to MOTT (9-11). In these individuals the infections due to nontuberculous mycobacteria [NTM] have been observed to be major causes of morbidity and mortality in western countries (11). The NTM cause pulmonary and generalized infections in immunocompromised individuals and cervical lymphadenitis in children (3-8,11). Of the 121 known species of mycobacteria so far, 45 species have been found to be associated with

disease in man (12,13). The important NTM species are listed in Tables 48.1A and 48.1B. Most of these NTM reveal in vitro resistance to many drugs that are used for the treatment of Mycobacterium tuberculosis. Some species like Mycobacterium celatum Mycobacterium genavense and Mycobacterium conspicuum were reported for the first time in AIDS patients. Mycobacterium paratuberculosis also appears to be the likely causative organism for Crohn’s disease. Besides being known as atypicals, these mycobacterial species have been given various names like ‘anonymous’, ‘nontuberculous’, ‘environmental’, ‘opportunistic’ mycobacteria and MOTT. None of these terms have become universally acceptable and the name NTM seems to have better consensus and is also endorsed by the American Thoracic Society [ATS] and the Infectious Diseases Society of America [IDSA] statement (11,14). DISTRIBUTION IN THE ENVIRONMENT Most of the NTM are ubiquitous in distribution and have been isolated from stagnant water, mud, soil and food items (15). Mycobacterium avium complex [MAC] have been isolated from natural waters; Mycobacterium kansasii from tap water; and rapidly growing mycobacteria are found in soil and natural waters as well as in tap water, water used for dialysis or even in surgical solution (3). Man-made changes in the environment may also have altered the risks of these infections. For example, hot water systems are growth nidus for some of these mycobacteria, such as Mycobacterium xenopi, in the hospital environment and use of showers may create droplet inhalation of the mycobacteria.

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Mycobacterium avium intracellulare complex Mycobacterium avium Mycobacterium intracellulare Mycobacterium kansasii Mycobacterium paratuberculosis Mycobacterium scrofulaceum Mycobacterium simiae Mycobacterium habana Mycobacterium interjectum Mycobacterium xenopi Mycobacterium heckeshornense Mycobacterium szulgai Mycobacterium fortuitum-Mycobacterium chelonae complex Mycobacterium fortuitum Mycobacterium chelonae Mycobacterium immunogenum Mycobacterium marinum Mycobacterium genavense Mycobacterium haemophilum Mycobacterium celatum Mycobacterium conspicuum Mycobacterium haemophilum Mycobacterium celatum Mycobacterium conspicuum Mycobacterium malmoense Mycobacterium ulcerans Mycobacterium smegmatis Mycobacterium terrae complex

Mycobacterium wolinskyi Mycobacterium goodii Mycobacterium thermoresistible Mycobacterium neoaurum Mycobacterium vaccae Mycobacterium palustre Mycobacterium elephantis Mycobacterium bohemicum Mycobacterium septicum Mycobacterium bolletti Mycobacterium phocaicum and Mycobacterium aubaganense Mycobacterium arupense Mycobacterium parmense Mycobacterium canariasense [closely related to Mycobacterium diernhoferi] Mycobacterium fortuitum third biovariant complex Mycobacterium boenickei Mycobacterium houstonense Mycobacterium neworleansese Mycobacterium brisbanense Mycobacterium porcinum Mycobacterium parascrofulaceum Mycobacterium gordonae Mycobacterium mucogeniceum Mycobacterium nonchromogenicm Mycobacterium shottsi Mycobacterium pseudoshotti

Table 48.1B: Species of nontuberculous mycobacteria causing infections in humans Mycobacterium arupense Mycobacterium aubaganense Mycobacterium avium Mycobacterium boenickei Mycobacterium bohemicum Mycobacterium bolletti Mycobacterium brisbanense Mycobacterium canariasnse Mycobacterium celatum Mycobacterium chelonae Mycobacterium conspicuum Mycobacterium diernhoferi Mycobacterium elephantis Mycobacterium fortuitum Mycobacterium genavense Mycobacterium goodii

Mycobacterium haemophilum Mycobacterium heckeshornense Mycobacterium houstonense Mycobacterium immunogenum Mycobacterium interjectum Mycobacterium intracellulare Mycobacterium kansasii Mycobacterium malmoense Mycobacterium marinum Mycobacterium neourum Mycobacterium neworleanense Mycobacterium nonchromogenicum Mycobacterium palustre Mycobacterium parascrofulaceum Mycobacterium paratuberculosis Mycobacterium parmense

Mycobacterium phocaicum Mycobacterium porcinum Mycobacterium pseudoshottsi Mycobacterium scrofulaceum Mycobacterium septicum Mycobacterium shottsi Mycobacterium simiae Mycobacterium smegmatis Mycobacterium szulgai Mycobacterium thermoresistible Mycobacterium terrae Mycobacterium triviale Mycobacterium ulcerans Mycobacterium vaccae Mycobacterium woliniskyi Mycobacterium xenopi

Nontuberculous Mycobacterial Infections 667 The distribution of NTM and the incidence of disease caused by them are difficult to determine since systems of notification vary from country to country. In USA there have been attempts to understand the trends in mycobacteriosis due to NTM (16). In 1980, NTM comprised of 33 per cent of total mycobacterial isolates in US laboratories and most of the isolates were Mycobacterium avium, Mycobacterium kansasii, Mycobacterium fortuitum (16). The picture did not significantly change during the next decade (17), however, the HIV/AIDS epidemic has changed the scenario. There have been some reports of NTM infection from Japan (18), UK (19) and India (20-27). In Indian studies (24-30). Mycobacterium tuberculosis has always been found as the major cause of mycobacterial infections and the proportion of NTM has varied from less than one to twenty-eight per cent. Species like Mycobacterium fortuitum, Mycobacterium avium, etc., have been isolated in different studies (2430). Mycobacterium fortuitum and Mycobacterium chelonae are among the frequently isolated from clinical specimens in hospitals from India (25,26,29). As the culture with strict criteria is still not routinely performed in most parts of the country, and there is a tendency to ignore such isolates and in the absence of clear-cut guidelines it is difficult to comment on the exact magnitude of the problem. Mycobacterium tuberculosis has been observed to be the most common cause of TB in Indian patients with HIV/AIDS (31). Environmental exposure to NTM is common. This results in sensitization which can be detected by tuberculin test to NTM antigens and differential tuberculin testing with antigens prepared from other mycobacteria, e.g. purified protein derivative [PPD]-A [Mycobacterium avium] or PPD-Y [Mycobacterium kansasii] has been considered as a satisfactory method of distinguishing sensitization due to NTM from Mycobacterium tuberculosis. The reader is referred to the chapter “Tuberculin skin test” [Chapter 11] for more details. PREDISPOSING FACTORS It is well known that these environmental mycobacteria cause disease in individuals who offer some opportunity due to altered local or systemic immunity (3,4,11,32-36). While the reasons may be less clear in children with cervical lymphadenitis such factors may be quite obvious in patients with bronchiectasis, surgical procedures,

injections, break in skin surface due to wounds and generalized immune deficiency states, like AIDS and use of immunosuppressive agents in transplant patients (11). The pathogenesis of NTM is not very clear and has not been adequately investigated. The lipid rich outer envelope of the organisms may be important as the first defence of these organisms but specific moeities on the surface may also be important factors. Some NTM species, such as Mycobacterium avium and Mycobacterium simiae have been reported in patients with AIDS in India (33). Very low CD4+ counts in patients with AIDS and defective cytokine response[s] have been linked to development of severe infections due to Mycobacterium avium from the common sources, such as potable water (37). Chronic obstructive pulmonary diseases, emphysema, pneumoconiosis, bronchiectasis, cystic fibrosis, thoracic scoliosis, aspiration due to oesophageal disease, previous gastrectomy and chronic alcoholism are some of the conditions which have been linked to disease due to NTM. CLINICALLY IMPORTANT MYCOBACTERIA Among the known 121 species of NTM, only one-third have been associated with human disease. Mycobacterium avium intracellulare Complex Members of Mycobacterium avium intracellulare complex group have gained a major prominence in the west, especially after an increased frequency of infections produced by these organisms in patients with AIDS (38-42). However, in western countries these organisms were also a major cause of pulmonary and other infections in the pre-AIDS era (11,16,17). Mycobacterium avium has been isolated from environment as well as clinical specimens including sputum from India (23,30). Certain specific serotypes of Mycobacterium avium (11,35), plasmid containing Mycobacterium avium (41) and in some European and African countries certain restriction fragment length polymorphism types of Mycobacterium avium have been found to be more commonly isolated from patients with AIDS (35,42). As compared to Mycobacterium intracellulare, Mycobacterium avium appears to have a greater predilection for causing disease in patients with AIDS (35). Further, these organisms may cause mixed infections along with other NTM, such as Mycobacterium kansasii (39) and Mycobacterium simiae (40), among others.

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Infections caused by Mycobacterium avium intracellulare complex were commonly observed in chronic bronchitis, bronchiectasis and chronic obstructive airways disease in the pre-AIDS era in geriatric patients. In non-HIV patients Mycobacterium avium has been associated with pulmonary disease, lymphadenitis and joint involvement (11). Unlike Mycobacterium tuberculosis, the Mycobacterium avium intracellulare complex strains have a low virulence and despite being commonly found in the environment rarely cause disease (15,37). These usually produce clinical disease only when the CD4+ count is very low [< 50 cells/μl] towards the end of natural history of disease, seen in four to five per cent of HIV/AIDS patients (34). Mycobacterium avium complex strains isolated from patients with AIDS in Africa have been shown to be different as compared with western strains (35). In AIDS patients, the portal of entry is thought to be mainly through the gut (37) and the most common presenting features include persistent highgrade fever, night sweats, anaemia and weight loss in addition to non-specific symptoms of malaise, anorexia, diarrhoea, myalgia and occasional painful adenopathy. On examination, there may be hepatomegaly and chest radiograph as well as computed tomography of the chest and abdomen may show a widespread intra-thoracic and intra-abdominal lymphadenopathy. The diagnosis is generally not difficult as clinical specimens yield numerous acid-fast bacilli [AFB] which can be cultured and identified. Mycobacterium kansasii These organisms are found in water and consequently in some sputum samples as non- significant commensals. Nevertheless, when repeatedly isolated from sputum they could be associated with pulmonary disease (11). Since long time Mycobacterium kansasii has been considered an important cause of pulmonary disease (3,11) and has become even more important in AIDS era (39,43-46). Although in vitro susceptibility tests suggest that members of these species are more resistant to antimicrobial agents than Mycobacterium tuberculosis, infections with Mycobacterium kansasii frequently respond well to multiple drug therapy (6,45,46). New biotypes of Mycobacterium kansasii have been isolated from patients with AIDS (44). As with MAC infections, these patients may present with advanced AIDS with very low CD4+ count [< 50 cells/μl].

Mycobacterium paratuberculosis Mycobacterium paratuberculosis species is closely related to Mycobacterium avium and has characteristic property of dependence on mycobactin J. Members of this species have been reported to be causative organisms of enteritis [Johne’s disease] in cattle, goats and sheep and can be characterised rapidly with molecular techniques (47,48). With the help of gene probes, strains belonging to this species have been linked to aetiology of Crohn’s disease in man (48). Demonstration of specific sequences in tissue sections by in situ hybridisation has provided a definitive evidence of an aetiological relationship of this organism with Crohn’s disease (49). Mycobacterium scrofulaceum The distribution of these pigmented organisms in nature is similar to that of Mycobacterium avium and Mycobacterium intracellulare complex (50). The most common disease caused by these organisms is cervical lymphadenitis in children as well as chronic ulcerative and nodular lesions (11). It may cause adult pulmonary disease and disseminated infections in patients with AIDS (11,50). Mycobacterium interjectum Mycobacterium interjectum is a new species found to be associated with chronic lymphadenitis (51). Mycobacterium xenopi Mycobacterium xenopi is an unusual bacterium with optimal growth temperature at 45 oC. It has been encountered as a pathogen in patients with other underlying lung diseases (52-54). It has been isolated from hot water reservoirs of hospitals and has been found to be associated with clinical problems (11,52,53). Clinical manifestations are similar to Mycobacterium avium complex in patients with advanced AIDS. An instance of an outbreak of pulmonary disease due to this organism from hot water supply of a hospital has been reported (11). Mycobacterium simiae Mycobacterium simiae organism was initially isolated from a monkey and later recognised as an agent of human pulmonary disease in AIDS as well as non-AIDS cases (3,4,11,33,40). Another closely related organism with similar pulmonary disease spectrum has been isolated in Cuba and named as Mycobacterium habana (8).

Nontuberculous Mycobacterial Infections 669 Mycobacterium szulgai

Mycobacterium genavense

Mycobacterium szulgai species has been isolated on several occasions from patients with pulmonary disease. It is confused often with some of the scotochromogenic mycobacteria. This organism is also been associated with disseminated disease and also involves skin, joint and lymph nodes (55). These mycobacteria have been isolated from India also (26,27).

These organisms were isolated for the first time from patients with AIDS. These organisms are grown with difficulty and need enrichment with mycobactin J. It grows in liquid media, often after prolonged incubation periods and has now been isolated from several countries (63-65). Patients are usually in advanced stage of AIDS and present with weight loss, fever, abdominal pain and diarrhoea. This organism has been found to be sensitive to clarithromycin.

Mycobacterium fortuitum-Mycobacterium chelonae complex Mycobacterium fortuitum-Mycobacterium chelonae complex are rapidly growing organisms that are commonly found in the soil and are now being reported with increasing frequency from human disease (4-8,11,25,27,29,30,56-58). These are widely distributed in the Indian environment and could emerge as important pathogens (25-30). Mycobacterium fortuitum causes pulmonary disease and also pyogenic lesions in the soft tissue, joints, bursae and injection abscesses (3,4,11). Besides their common causative association with soft tissue infections, Mycobacterium fortuitum and Mycobacterium chelonae can cause generalized disease in immunocompromised hosts and present as subcutaneous nodules, similar picture may be shared by other NTM, like Mycobacterium kansasii (11,56). Mycobacterium immunogenum, closely related to Mycobacterium abscessus has been reported as a cause of human infections (59).

Mycobacterium haemophilum

Mycobacterium marinum

Several species of NTM have been isolated from AIDS patients (71-74). Besides Mycobacterium genavense, other species isolated for the first time from AIDS patients include: Mycobacterium celatum (71) and Mycobacterium conspicuum (72). Mycobacterium malmoense (73,74) has emerged as another pathogen which has not been isolated from the environment (15). Mycobacterium ulcerans has been established as an important skin pathogen for a long time (3,4,75). Other mycobacteria rarely associated with disease are: Mycobacterium smegmatis (76), Mycobacterium thermoresistible (77), Mycobacterium neoaurum (78) and Mycobacterium vaccae (79). Due to wider use of gene sequencing [16S rRNA, rpoB] these days several new species have been identified which were earlier missed as variants of known species. These include several species from human clinical

This mycobacterial species has been recognized as a causative organism of “swimming pool granuloma” or fish tank granuloma. It causes papular lesions in the extremities and may be confused with sporotrichosis (3,4,60-62). This has also been reported as a cause of infections of hands and wrist (61) and bones, joints and tendon sheaths, especially in patients with AIDS (62). Mycobacterium terrae Complex This complex consists of three species, Mycobacterium terrae, Mycobacterium nonchromogenicum and Mycobacterium triviale. They appear to be harmless saprophytes but occasionally may be associated with disease (3,11,29).

This is a new emerging mycobacterial pathogen (66-70). This slow growing organism has been recognized as a cause of life-threatening infections in immunocompromised individuals, like AIDS, bone marrow transplant recipients. The organism has been isolated from the skin lesions, lymph nodes, synovial fluid, vitreous fluid, bronchoalveolar lavage fluid [BAL], bone marrow aspirate and blood. Recovery of this organism requires cultivation in enriched chocolate agar or haemin or ferric ammonium citrate supplement and incubation at 30 oC up to eight weeks. Information about its environmental reservoirs and spread is limited. Despite aggressive therapy with multiple antituberculosis drugs the recurrence is common. EMERGING NEW MYCOBACTERIAL PATHOGENS

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specimens (80-92) and also marine animals (93,94). Important examples are: Mycobacterium heckeshornense (80), Mycobacterium bohemicum (81), Mycobacterium woliniskyi and Mycobacterium goodii, both closely related to Mycobacterium smegmatis (82), Mycobacterium palustre (83), Mycobacterium elephantis (84), Mycobacterium septicum (85), Mycobacterium bolletti, Mycobacterium phocaicum and Mycobacterium aubaganense (87), Mycobacterium arupense (88), Mycobacterium parmense (89), Mycobacterium canariasense closely related to Mycobacterium diernhoferi (90), members of Mycobacterium fortuitum, third biovariant complex-Mycobacterium boenickei, Mycobacterium houstonense, Mycobacterium neworleansese, Mycobacterium brisbanense and Mycobacterium porcinum (91) and Mycobacterium parascrofulaceum (92). Mycobacterium shottsi (93) and Mycobacterium pseudoshottsi (94) have been isolated from lesions from fish and bass. These newly identified pathogens have been isolated from a variety of conditions such as cutaneous, soft tissue and wound infections (82,85,86,91), from patients with pulmonary disease (80,91,92), lymphadenitis (81,89), bacteraemia (85,91), febrile conditions (90) and disseminated disease. The exact importance of these potential pathogens in the causation of diseases will be better known with routine use of modern techniques for molecular characterization.

CLINICAL MANIFESTATIONS Nontuberculous mycobacteria have been reported to be associated with varied clinical manifestations (3,4-8,11). In non-HIV patients, NTM has been established to be responsible for pulmonary disease usually with some local predisposing conditions, lymphadenitis, soft tissue infections, infections of joints and bones, bursae, skin ulcers and generalized disease in individuals like leukaemia, transplant patients etc., (3,4,11,95). In patients with AIDS their spectrum may depend upon the degree of immune deficiency and the manifestations may range from localized pulmonary to intestinal and disseminated disease (11,96-98). Most of the NTM can be associated with both the localized as well as generalized disease depending upon degree of immune deficiency or local favourable conditions for their establishment and growth [Tables 48.2 and 48.3]. Diagnosis Diagnosis of the disease due to NTM depends upon the degree of suspicion and strict laboratory practices. Due to ubiquitous presence of these organisms in the environment, it is extremely important to rule out contamination. At present most of the experience is based on published findings from western countries and there is

Table 48.2: Localised clinical disease due to nontuberculous mycobacteria Type of lesion

Species

Pulmonary disease

Common: Mycobacterium avium complex, Mycobacterium abscessus, Mycobacterium kansasii, Mycobacterium malmoense, Mycobacterium xenopi Uncommon: Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium haemophilum, Mycobacterium celatum, Mycobacterium asiaticum, Mycobacterium scrofulaceum Common: Mycobacterium avium complex, Mycobacterium scrofulaceum, Mycobacterium malmoense Uncommon: Mycobacterium genavense, Mycobacterium haemophilum, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium fortuitum, Mycobacterium kansasii, Mycobacterium szulgai Common: Mycobacterium marinum, Mycobacterium ulcerans, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium abscessus Uncommon: Mycobacterium avium complex, Mycobacterium haemophilum, Mycobacterium mucogenicum, Mycobacterium nonchromogenicum, Mycobacterium kansasii, Mycobacterium malmoense, Mycobacterium smegmatis, Mycobacterium szulgai, Mycobacterium terrae complex Mycobacterium paratuberculosis

Lymphadenopathy

Skin, soft tissue, wound infections, bone disease

Crohn’s disease

Specimen contaminants: Mycobacterium gordonae, Mycobacterium haemophilum, Mycobacterium mucogenicum, Mycobacterium nonchromogenicum and Mycobacterium terrae complex

Nontuberculous Mycobacterial Infections 671 Table 48.3: Disseminated disease due to nontuberculous mycobacteria Condition

Species

Without AIDS [usually transplant patients, leukaemia etc.,

Mycobacterium avium complex, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium scrofulaceum, Mycobacterium fortuitum including members of Mycobacterium fortuitum, third biovariant complex-Mycobacterium boenickei, Mycobacterium houstonense, Mycobacterium neworleansese, Mycobacterium brisbanense, and Mycobacterium porcinum and Mycobacterium parascrofulaceum, Mycobacterium septicum, Mycobacterium canariasense closely related to Mycobacterium diernhoferi, Mycobacterium haemophilum Mycobacterium avium complex, Mycobacterium haemophilum, Mycobacterium simiae, Mycobacterium xenopi, Mycobacterium kansasii, Mycobacterium fortuitum-chelonae complex, Mycobacterium genavense, Mycobacterium malmoense, Mycobacterium celatum, Mycobacterium conspicuum

With AIDS

AIDS = acquired immunodeficiency syndrome

a general tendency of discarding these isolates as contaminants. These issues have been extensively debated and some broad guidelines have emerged. Pulmonary Disease Clinical presentation of the disease due to NTM may be like TB and pulmonary infections may present as chronic cough and infiltrates in the radiographs. Infection due to NTM should be suspected especially in patients in whom initial antituberculosis treatment has not produced clinical, radiographic and microbiological response. Sputum should always be sent for smear and culture examination and if the cough is non-productive it is better to do a bronchoscopy, BAL and or biopsy. Infection with NTM may be asymptomatic and may present with subacute or chronic illness. Symptoms include cough, sputum production, weight loss, haemoptysis, shortness of breath, malaise, pleuritic chest pain, low-grade fever and night sweats. Radiological appearances are similar to TB with cavities and infiltrates, though the upper lobes are more involved and the distribution is more variable than TB. Thin-walled cavities with lesser parenchymal infiltrates have been described as a suggestive feature (11). The changes may be unilateral or bilateral and more than one lobes may be involved. In high resolution computed tomography, clusters of small nodules associated with areas of bronchiectasis in the lower and middle zones are common. Asymptomatic solitary nodules due to MAC have been documented. Pleural thickening and effusion are not common. Bronchoscopy is very useful to obtain BAL samples for culture and biopsy samples for

histopathology. The gold standard for NTM disease compared to colonization is a tissue biopsy showing granulomatous inflammation, which may or may not contain AFB and a positive culture, even if the sample is smear-negative. Other Clinical Forms Most of other manifestations should be considered in the differential diagnosis of any chronic infection, pyrexia of unknown origin and localized clinical disease [abscess, ulcers, nodules, infiltrates, etc.,] not responding to antibiotics. Attempts should be made to demonstrate and isolate the NTM from such lesions using most stringent criteria and precautions. As most of the NTM are not sensitive to routine antituberculosis treatment, it is imperative to correctly identify the causative mycobacteria and if required determine their sensitivity profile. Specimens Because NTM are widely distributed in the environment and may be merely present as colonizing agents on the skin and mucous membranes, proper sample collection is very important. The specimen should be obtained directly from the lesion or organ concerned (11). For such purposes biopsies and procedures, like BAL have advantages. It is recommended to attempt repeated isolation in significant numbers to firmly link the isolate with the aetiology. Further, the decontamination has to be gentler than Mycobacterium tuberculosis. In case of the disseminated infections such as in patients with AIDS blood cultures have been shown to yield positive

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cultures. Diagnosis of Mycobacterium avium complex is generally done by growing the mycobacteria from the peripheral blood or bone marrow sample (99,100).

colony pigmentation. Since the days of Runyon it is conventional to initially classify the organisms as rapid and slow growers (106).

Histopathology

Biochemical Tests

Histopathological examination of bone marrow, liver or lymph nodes [aspirates or biopsy] showing granuloma may be helpful in the diagnosis, the greatest advantage of this approach over the culture being the speed (38). It may be advisable to include some in situ methods [antigen detection and gene probes] to confirm the histological diagnosis straightaway.

After classifying the mycobacteria on the basis of growth and pigmentation most of the mycobacteria can be identified by biochemical tests (106). A few simple biochemical and culture tests can usually identify a strain to clinical satisfaction. These common tests are: niacin production, nitrate reduction, tween-80 hydrolysis, arylsulphatase, urease, and catalase [qualitative and quantitative] production, tellurite reduction, thiophene2-carboxylic acid hydrazide sensitivity, growth on MaConkey agar, sodium chloride tolerance, among others (106).

Cultivation There has been a considerable progress in developing and testing methods for isolation of NTM from environment as well as clinical specimens (101-110). As these mycobacteria may be susceptible to decontaminating procedures like NaOH treatment (101), approaches like paraffin bating such as paraffin coated slides become attractive option (102,103). Most of these mycobacteria are easy to cultivate and these can be grown on ordinary media for mycobacteria like Lowenstein-Jensen, Middlebrook and Dubos Broth and Agar (11,104,106). Organisms like Mycobacterium haemophilum may have special requirements like hemin for which blood containing media-chocolate agar or supplement of ferric ammonium citrate may be required. Various radiometric systems, like BACTEC (104,105,108); non-radiometric methods like mycobacteria growth inhibitor tube [MGIT] and MB/Bac T (109,110) or liquid media like 13A or BACTEC 12B broth medium (33) as well as agar-based isolation systems have been described to be highly sensitive [up to 96%-98%] for MAC and other NTM (3,4,11,17,99,100,104-110). Pyruvate containing medium may be necessary for growth of Mycobacterium bovis or bacille Calmette-Guerin [BCG] (107). Mycobacterium genavense, Mycobacterium paratuberculosis will require supplementation with mycobactin J. Different incubation temperatures such as 30 oC for Mycobacterium ulcerans and Mycobacterium marinum, 37 oC for most pathogens, 45 oC for Mycobacterium xenopi etc will have to be selected depending upon the suspected organisms. Identification of Isolates The first scheme for identification and grouping of cultivable mycobacteria was based on growth rates and

Lipid Patterns Mycobacteria can be characterized at group, species and subspecies levels by analysis of their lipids by thin layer chromatography, high performance liquid chromatography. These techniques are simple and have been developed along with easy software programmes for rapid analysis (107,108) by which isolates from liquid and solid media can be rapidly identified. Identification Techniques for Established, Reference Laboratories Alternative methods for identification of mycobacteria which would require special laboratories and expertise are described below: Serotyping These methods have been well developed for the members of Mycobacterium avium intracellulare complex (99,111). Based on serotype specific sera, these strains can be correctly identified and assigned to serotypes. Some serotypes (11,99) of Mycobacterium avium have been shown to be preferentially associated with disease in patients with AIDS. Isoenzyme and protein electrophoregrams Simple electrophoretic techniques and schemes based on electrophoretic mobilities of proteins and isoenzymes for the characterization of strains of Mycobacterium tuberculosis and NTM have been developed which can be used to confirm identity of the isolate rapidly (112-114). These patterns may be used both for rapid identification and characterization of these mycobacteria (114).

Nontuberculous Mycobacterial Infections 673 Measurements of immunological relatedness Based on divergences in the structure of certain enzymes such as catalase (115) and superoxide dismutases (116), various clinically relevant mycobacterial species can be identified. This approach may also be evaluated in future studies. New Molecular Methods for Identification and Characterisation Recent years have witnessed many advances in the molecular genetics of various organisms including mycobacteria. As these are based on the complementarity of gene sequences, these techniques can achieve maximum sensitivity and specificity. By hybridization of isolated ribonucleic acid [RNA], deoxyribonucleic acid [DNA] from growth or tissue with specific probes, identity of isolates is rapidly established. Based on new knowledge about the gene sequences many gene probes for the identification of isolates as well as amplification of specific gene fragments from the lesions and mycobacterial culture isolates have been developed and are described below. Gene probes During the last 20 years, a number of gene probes for the identification of important NTM have been developed and some are also being commercially marketed (105,117-119). With the help of these probes, growth from solid slants and even liquid cultures [e.g., BACTEC] can be identified and these have been found to be fairly reliable and rapid. Gene amplification methods Advances in gene amplification methods especially polymerase chain reaction [PCR] technology have influenced almost every discipline of medicine. Several PCR techniques for rapid detection and identification of various clinically relevant mycobacteria have been developed (120-133). These include different types of PCR assays for detection of Mycobacterium avium, Mycobacterium intracellulare (120,123,124) and Mycobacterium paratuberculosis (47) from the clinical specimens. The PCR assays using genus and group specific amplification followed by restriction analysis have been developed for regions like 65 kD for Mycobacterium tuberculosis, Mycobacterium avium, etc., (121), rRNA gene region for Mycobacterium avium, Mycobacterium chelonae, Mycobacterium xenopi, etc., (129-133). A new PCR technique appears to be potentially useful for characterizing various pathogenic NTM (133). Another PCR strategy using amplification

followed by capture plate hybridization has been reported to be useful for Mycobacterium ulcerans (125) and Mycobacterium avium, Mycobacterium chelonae, Mycobacterium scrofulaceum (126). A reverse hybridization line probe assay [LipA][e.g., INNO-LiPA, Innogenetics, Ghent, Belgium] has been described to be quite useful for rapid identification of mycobacteria (127). Polymerase chain reaction targeting certain regions on rRNA has been observed to be useful for quick identification of various NTM (130). These PCR methods can be used for rapid identification of clinical isolates (121,122,124,125,129,130,133) as well direct detection of pathogens from the clinical specimens (123,128). Keeping in view the diversity of these organisms present in different geographical locations, it would be important to evaluate the usefulness of these techniques. Further, contamination from the environment will have to be carefully ruled out. DNA fingerprinting techniques Due to almost universal presence of these organisms in the environment, there has been interest in identifying the strains which would be more commonly associated with disease. Further, such identification would be important to investigate hospital infections as well other sources of such infections (134-145). The DNA fingerprinting techniques using procedures such as pulsed-field gel electrophoresis (134,143), random amplified polymorphic DNA [RAPD]arbitrary PCR (135), rRNA probes (136-138) and different insertion and repeat elements have been described for characterization of NTM (69,139,141,142). Insertion elements have been described to be useful for characterisation of Mycobacterium haemophilum (69), Mycobacterium avium (139,140,144,145), Mycobacterium scrofulaceum (142,144) as well as Mycobacterium kansasii (141). Using these probes and fingerprinting systems, the aetiology of Crohn’s disease due to Mycobacterium paratuberculosis has been established to a large extent (47,49). Further, some specific RFLP types of Mycobacterium avium have been shown to be closely linked with disease in Europe and Africa (35,42). The IS1245 based RFLP analysis of Indian isolates of Mycobacterium avium suggested birds as origin of most of human isolates (140). Determination of sensitivity profiles The NTM tend to be generally resistant to low concentrations of various anti-tuberculosis drugs (11). However, at high concentrations [within the therapeutic limits], these organisms may be sensitive. The media usually recommended for

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Tuberculosis Table 48.4: Recommended techniques to diagnose nontuberculous mycobacterial disease

Low resource settings

Good Institute with moderate resources

Reference laboratories

Repeated isolation on conventional media and identification by selected biochemical tests

Repeated isolation on conventional media and identification by selected biochemical tests

Repeated isolation on conventional media and identification by selected biochemical tests

Growth in any liquid medium and identification by lipid patterns

Growth in any standard liquid medium system, like BACTEC, MGIT, MB/Bac T, identification by probe hybridization and lipid patterns by TLC or HPLC

Growth in any liquid medium, like BACTEC, MGIT, MG/ Bac T and identification by probe hybridization and lipid patterns by TLC or HPLC

Histopathology

Histopathology; plus immunohistochemistry and in-situ hybridisation etc.,

Histopathology; plus immunohistochemistry and in-situ hybridization, in-situ PCR etc.,

PCR-RFLP [if PCR available]

PCR-RFLP

PCR-RFLP

Drug susceptibility testing

Drug susceptibility testing 16S rRNA/rpoB sequencing DNA fingerprinting

Fluorochrome staining technique is preferred for NTM Routine drug susceptibility testing of Mycobacterium avium complex isolates is recommended for clarithromycin only Routine drug susceptibility testing of Mycobacterium kansasii is recommended for rifampicin only Routine drug susceptibility testing of rapid growing mycobacteria [Mycobacterium fortuitum, Mycobacterium chelonae and Mycobacterium abscessus] should be with clarithromycin, cefoxitin, doxycycline, fluorinated quinolones, amikacin, a sulphonamide or trimethoprim-sulphamethoxazole, linezolid, imipenem [Mycobacterium fortuitum only] and tobramycin [Mycobacterium chelonae only] PCR = polymerase chain reaction; RFLP = restriction fragment length polymorphism; DNA = deoxyribonucleic acid; MGIT = mycobacteria growth inhibitor tube; TLC = thin layer chromatography; HPLC = high performance liquid chromatography

sensitivity screening of Mycobacterium tuberculosis are also used for NTM. However, due to differences in the levels of sensitivity in broth (11), a caution is required. Other media, like chocolate agar supplemented with ferric ammonium salts and mycobactins etc., will be required for sensitivity screening of other fastidious species. While newer techniques like BACTEC, MGIT and MB/Bac T (109,110) have been quite promising in early detection of growth of NTM from clinical specimens, only BACTEC and E-test have been found to be useful for sensitivity determination of rapid as well as slow growing NTM (146-148). Expert group of ATS (14) has suggested that there is no use of testing of sensitivity for rifampicin and isoniazid for rapid growers as they are usually resistant to these drugs and other drugs such as sulphones, clarithromycin, cefoxitin, amikacin etc., should be considered for the treatment of NTM disease. Likewise, higher cutoff values for determination of sensitivity should be considered for organisms, like Mycobacterium avium. Recombinant strain of Mycobacterium avium expressing beta galactosidase have been reported to be useful for screening of activity of anti-mycobacterial compounds (149).

Laboratories with different levels of infrastructure and financial commitment can follow different strategies to deal with diagnosis and characterisation of NTM for management [Table 48.4]. Table 48.5: Prevention of nontuberculous mycobacteria disease Health care-associated NTM disease Avoid exposure of injection sites, intravenous catheters and surgical wounds to tap water and tap water derived fluids Avoid cleaning of endoscopes with tap water Avoid contamination of clinical specimens with tap water and ice Disseminated MAIC disease Patients with AIDS [CD4+ T-lymphocyte count < 50 cells/µl] Azithromycin 1200 mg/week or Clarithromycin 1000 mg/day or Rifabutin 300 mg/day [less well tolerated] AIDS = acquired immunodeficiency syndrome; MAIC = Mycobacterium avium intracellulare complex; NTM = nontuberculous mycobacteria Adapted from reference 14

Nontuberculous Mycobacterial Infections 675 Table 48.6: Treatment of nontuberculous mycobacterial disease Disease

Drugs

Dose

Frequency

Duration

A regimen consisting of clarithromycin or azithromycin and rifampicin and ethambutol

1000 mg 500-600 mg 600 mg 25 mg/kg

3 times a week 3 times a week 3 times a week 3 times a week

After achieving culturenegative status, the same should be maintained while on treatment for a further period of 1 year

A regimen consisting of clarithromycin or azithromycin and rifampicin

500*-1000 mg 250 mg 10 mg/kg

Treat until culture-negative on treatment for 1 year

150 - 300 mg 15 mg/kg

Daily Daily Daily [maximum 600 mg] Daily Daily

A regimen consisting of clarithromycin or azithromycin and ethambutol ± rifabutin

1000 mg 500 mg 15 mg/kg 300 mg

Daily Daily Daily Daily

Patient should be treated until resolution of symptoms and reconstitution of cellmediated function

Mycobacterium kansasii pulmonary disease

A regimen consisting of isoniazid rifampicin and ethambutol

300 mg 600 mg 15 mg/kg

Daily Daily Daily

After achieving culturenegative status, the same should be maintained while on treatment for a further period of 1 year

Mycobacterium abscessus pulmonary disease

No drug regimen of proven efficacy available Surgical resection of localized disease with multidrug regimens that include clarithromycin

Pulmonary MAC Disease Nodular/bronchiectatic disease

Fibrocavitary MAC lung disease or severe nodular/ bronchiectatic disease

or rifabutin and ethambutol amikacin or streptomycin† Disseminated MAC disease

1000 mg

Daily

May produce symptomatic improvement and disease regression

NTM cervical lymphadenitis‡

Surgical excision is the treatment of choice

Patient with extensive MAC lymphadenitis or poor response to surgical treatment

Macrolide-based multidrug regimen such as that used for pulmonary disease

Non-pulmonary disease due to rapid growing NTM

The drug regimen is based on in vitro drug susceptibilities. Surgical debridement is an essential component of treatment. A macrolide-based drug regimen is frequently used for Mycobacterium abscessus

* Lower dose for body weight < 50 kg † The doses of streptomycin or amikacin will depend on the patient’s age, weight, and renal function and may range from 8 to 10 mg/ kg two to three times weekly [with a maximum dose of 500 mg for patients older than 50 years] to 25 mg/kg three times weekly ‡ The disease is due to MAC in majority of the cases NTM = nontuberculous mycobacteria ; MAC = Mycobacterium avium complex Adapted from reference 14

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MANAGEMENT Prevention Prevention of NTM is detailed in Table 48.5. Treatment Treatment of NTM is provided in Table 48.6. Monitoring for Toxicity Drugs required for management of various NTM infections have many potential adverse events. This is specially so in the elderly patients and multisystem involvement in AIDS patients. Combinations of drugs like rifabutin and macrolides have been reported to be accompanied by various side effects. It is advisable to carefully observe following side effects-visual [ethambutol], central nervous system [cycloserine, ciprofoxacin, ethambutol], hepatic [rifampicin, isoniazid, ethionamide], renal [streptomycin, rifampicin, ethionamide], auditory [streptomycin] and haemopoeitic system [sulphonamides, cefoxitins, tetracyclines]. Regular clinical as well as laboratory monitoring of these systems can help in detection of side effects and permit necessary changes in the treatment. REFERENCES 1. Duvall CW. Studies in atypical forms of tubercle bacilli isolated directly from the human tissues in cases of primary cervical adenitis. J Exp Med 1908;9:403-29. 2. Pinner M. Atypical acid-fast microorganisms. Am Rev Tuberc 1935;32:424-45. 3. Wolinsky E, Rynearson TK. Mycobacteria in soil and their relation to disease-associated strains. Am Rev Respir Dis 1968;97:1032-7. 4. Wolinsky E. Non-tuberculous mycobacteria and associated disease. Am Rev Respir Dis 1979;119:107-59. 5. Horsburgh CR Jr, Selik RM. The epidemiology of disseminated non-tuberculous mycobacterial infections in the acquired immunodeficiency syndrome [AIDS]. Am Rev Respir Dis 1989;139:4-7. 6. Good RC. Opportunistic pathogens in the genus Mycobacterium. Annu Rev Microbiol 1985;39:347-69. 7. Smith MJ, Grange JM. Deep tissue infections due to environmental bacteria. In: Ratledge C, Stanford J, Grange MJ, editors. Biology of mycobacteria. Volume 3. London: Academic Press;1989.p.511-64. 8. Wayne LG, Sramek HA. Agents of newly recognised or infrequently encountered mycobacterial diseases. Clin Microbiol Rev 1992;5:1-25.

9. Dolin PJ, Raviglione MC, Kochi A. Global tuberculosis incidence and mortality during 1990-2000. Bull World Health Organ 1994;72:213-20. 10. Narain JP, Raviglione MC, Kochi A. HIV-associated tuberculosis in developing countries: epidemiology and strategies for prevention. Tuber Lung Dis 1992;72:311-21. 11. American Thoracic Society. Diagnosis and treatment of disease caused by non-tuberculous mycobacteria. Am Rev Respir Dis 1990;142:940-53. 12. Katoch VM. Infections due to non-tuberculous mycobacteria [NTM]. Indian J Med Res 2004;120:290-304. 13. Euzeby JP. List of bacterial names with standing in nomenclature - Genus Mycobacterium. Available at URL: http://www.bacterio.cict.fr/m/mycobacterium.html. Accessed on September 08, 2008. 14. American Thoracic Society. Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367-416. 15. Kazda JF. The principles of ecology of mycobacteria. In: Stanford JL, Ratledge C, editors. Biology of mycobacteria. Volume 2. London: Academic Press;1983.p.323-42. 16. Good RC, Snider DE. Isolation of non-tuberculous mycobacteria in the United States, 1980. J Infect Dis 1982;146:829-33. 17. O’Brien RJ, Geiter LJ, Snider DE. The epidemiology of nontuberculous mycobacteria disease in the United States. Results from a national survey. Am Rev Respir Dis 1987;135:100714. 18. Tsukamura M, Kita N, Shimoide H, Arakawa H, Kuze A. Studies on the epidemiology of non-tuberculous mycobacteriosis in Japan. Am Rev Respir Dis 1988;137:1280-4. 19. Jervis PN, Lee JA, Bull PD. Management of non-tuberculous mycobacterial peri-sialadenitis in children: the Sheffield otolaryngology experience. Clin Otolaryngol Allied Sci 2001;26:243-8. 20. Thomas KL, Joseph S, Subbaiah TV, Selkon JB. Identification of tubercle bacilli from Indian patients with pulmonary tuberculosis. Bull World Health Organ 1961;25:747-58. 21. Patel IU, D’Souza TJ, Sayed BA. A bacteriological study of Mycobacterium tuberculosis in Baroda. Indian J Med Sci 1966;20:924-32. 22. Kulkarni KG, Frimodt-Moller J. Bacteriological study of mycobacteria isolated from cases of cervical lymphadenitis. Trivandrum: Proceedings of the 24th TB and Chest Diseases Workers Conference 1969.p.391. 23. Paramasivan CN, Govindan D, Prabhakar R, Somasundaram PR, Subbammal S, Tripathy SP. Species level identification of non-tuberculous mycobacteria from south India BCG trial area during 1981. Tubercle 1985;66:9-15. 24. Kaur H, Chitkara NL. A study of atypical acid-fast bacilli [culture and biochemical characateristics]. Indian J Tuberc 1964;12:16-8. 25. Katoch K, Katoch VM, Dutta AK, Sharma VD, Ramu G. Chest infection due to M. fortuitum in a case of lepromatous leprosy: a case report. Indian J Lepr 1985;57:399-403. 26. Chakrabarti A, Sharma M, Dubey ML. Isolation rates of different mycobacterial species from Chandigarh [north India]. Indian J Med Res 1990;91:111-4.

Nontuberculous Mycobacterial Infections 677 27. Singh S, Rattan A, Kumar S. Severe cutaneous Mycobacterium chelonei infection following a yellow jacket sting. Tuber Lung Dis 1992;73:305-6. 28. Sachdeva R, Gadre DV, Talwar V. Characterisation and susceptibility pattern of extrapulmonary isolates. Indian J Med Res 2002;115:102-7. 29. Jesudason MV, Gladstone P. Non-tuberculous mycobacteria isolated from clinical specimens at a tertiary care hospital in South India. Indian J Med Microbiol 2005;23:172-5. 30. Bannalikar AS, Verma R. Detection of Mycobacterium avium and M. tuberculosis from human sputum culture by PCRRFLP analysis of hsp 65 gene and pncA PCR. Indian J Med Res 2006;123:165-72. 31. Sharma SK, Kadhiravan T, Banga A, Goyal T, Bhatia I, Saha PK. Spectrum of clinical disease in a series of 135 hospitalised HIV-infected patients from north India. BMC Infect Dis 2004;4:52. 32. Ramachandran R, Swaminathan S, Somasundram S, Asgar VN, Paramesh P, Paramasivan CN. Mycobacteremia in tuberculosis patients with HIV infections. Indian J Tuberc 2002;50:29-31. 33. Narang P, Narang R, Mendiratta DK, Roy D, Deotale V, Yakrus MA, et al . Isolation of Mycobacterium avium complex and M. simiae from blood of AIDS patients from Sevagram, Maharashtra, India. Indian J Tuberc 2005;52:21-6. 34. Fauci AS, Macher AM, Longo DL, Lane HC, Rook AH, Masur H, et al. Acquired immunodeficiency syndrome: epidemiologic, clinical, immunologic and therapeutic considerations. Ann Intern Med 1984;100:92-106. 35. Portaels P, Kunze ZM, McFadden JJ, Fonteyne PA, Carpels G. AIDS and mycobacterial diseases in developing and developed countries. J Chemother 1991;4[Suppl]:449-50. 36. Hoover DR, Graham NM, Bacellar H, Murphy R, Visscher B, Anderson R, et al. An epidemiologic analysis of Mycobacterium avium complex disease in homosexual men infected with human immunodeficiency virus type 1. Clin Infect Dis 1995;20:1250-8. 37. von Reyn CF, Maslow JN, Barber TW, Falkinham JO, Arbeit RD. Persistent colonization of potable water as a source of Mycobacterium avium infection in patients with AIDS. Lancet 1994;343:1137-41. 38. Farhi DC, Mason UG, Horsburgh CR. Pathology of MAC infection AIDS. Human Pathol 1987;18:709-14. 39. Massenkeil G, Opravil M, Salfinger M, von Graeventz A, Luthy R. Disseminated coinfection with Myobacterium avium complex and Mycobacterium kansasii in a patient with acquired immunodeficiency syndrome and liver abscess. Clin Infect Dis 1992;14:618-9. 40 Levy-Frebault V, Pangon B, Bure A, Katlama C, Marche C, David HL. Mycobacterium simiae, Mycobacterium avium complex–M. intracellulare mixed infection in AIDS. J Clin Microbiol 1987;25:154-7. 41. Meissner PS, Falkinham JO. Plasmid DNA profiles as epidemiological markers for clinical and environmental isolates of Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium scrofulaceum. J Infect Dis 1986;153:325-31.

42. Hampson SJ, Portaels F, Thompson J, Green EP, Moss MT, Hermon-Taylor J, et al. DNA probes demonstrate single highly conserved strain of Mycobacterium avium infecting AIDS patients. Lancet 1989;1:65-8. 43. Echevarría MP, Martín G, Pérez J, Urkijo JC. Pulmonary infection by Mycobacterium kansasii. Presentation of 27 cases [1988-1992]. Enferm Infecc Microbiol Clin 1994;12:280-4. 44. Tortoli E, Simonetti MT, Lacchini C, Penati V, Urbano P. Tentative evidence of AIDS-associated biotype of Mycobacterium kansasii. J Clin Microbiol 1994;32:1779-82. 45. Levine B, Chaisson RE. Mycobacterium kansasii: a cause of treatable pulmonary disease associated with advanced human immunodeficiency virus [HIV] infection. Ann Intern Med 1991;114:861-8. 46. Witzig RS, Fazal BA, Mera RM, Mushatt DM, Dejace PM, Greer DL, et al. Clinical manifestations and implications of coinfection with Mycobacterium kansasii and human immunodeficiency virus type 1. Clin Infect Dis 1995;21:77-85. 47. Vary PH, Andersen PR, Green E, Hermon-Taylor J, McFadden JJ. Use of highly specific DNA probes and polymerase chain reaction for detection of Mycobacterium paratuberculosis in Johne’s disease. J Clin Microbiol 1990;28:933-7. 48. McFadden JJ, Butcher PD, Chiodini R, Hermon-Taylor J. Crohn’s disease-isolated related mycobacteria are identical to Mycobacterium paratuberculosis as determined by DNA probes that distinguish between mycobacterial species. J Clin Microbiol 1987;25:796-801. 49. Sechi LA, Manuela M, Francesco T, Amelia L, Antonello S, Giovanni F, et al. Identification of Mycobacterium avium subsp. paratuberculosis in biopsy specimens from patients with Crohn’s disease identified by in situ hybridization. J Clin Microbiol 2001;39:4514-7. 50. Sanders JW, Walsh AD, Snider RL, Sahn EE. Disseminated Mycobacterium scrofulaceum infection: a potentially treatable complication of AIDS. Clin Infect Dis 1995;20:549. 51. Springer B, Kirchner P, Rost-Meyer G, Schroder KH, Kroppenstedt RM, Bottger EC. Mycobacterium interjectum, a new species isolated from a patient with chronic lymphadenitis. J Clin Microbiol 1993;31:3083-9. 52. Banks J, Hunter AM, Campbell IA, Jenkins PA, Smith AP. Pulmonary infection with Mycobacterium xenopi; review of treatment and response. Thorax 1984;39:376-82. 53. Ausina V, Barrio J, Luquin M, Sambeat MA, Gurgui M, Verger G, et al. Mycobacterium xenopi infections in the acquired immunodeficiency syndrome. Ann Intern Med 1988;109:9278. 54. Shafer RW, Sierra MF. Mycobacterium xenopi, Mycobacterium fortuitum, Mycobacterium kansasii, and other nontuberculous mycobacteria in an area of endemicity for AIDS. Clin Infect Dis 1992;15:161-2. 55. Maloney JM, Gregg CR, Stephens DS, Manian FA, Rimland D. Infections caused by Mycobacterium szulgai in humans. Rev Infect Dis 1987;9:1120-6. 56. Sack JB. Disseminated infection due to Mycobacterium fortuitum in a patient with AIDS. Rev Infect Dis 1990;12: 961-3.

678

Tuberculosis

57. Kuritsky JN, Bullen M, Broome CV, Silcox V, Good R, Wallace RJ. Sternal wound infections and endocarditis due to organisms of the Mycobacterium fortuitum complex. Ann Intern Med 1983;98:938-9. 58. Safraneck TJ, Jarvis WR, Carson LA, Cusick LB, Bland LA, Swenson JM, et al. Mycobacterium chelonae wound infections after plastic surgery employing contaminated gentian violet skin-marking solution. N Engl J Med 1987;317:197-201. 59. Wilson RW, Steingrube VA, Bottger EC, Springer B, BrownElliott BA, Vincent V, et al. Mycobacterium immunogenum sp. nov., a novel species related to Mycobacterium abscessus and associated with clinical disease, pseudo-outbreaks and contaminated metal working fluids: an international cooperative study on mycobacterial taxonomy. Int J Syst Evol Microbiol 2001;51:1751-64. 60. Collins CH, Grange JM, Noble WC, Yates MD. Mycobacterium marinum infections in man. J Hyg [Lond] 1985;94:13549. 61. Chow SP, Ip FK, Lau JH, Collins RJ, Luk KD, So YC, et al. Mycobacterium marinum infection of the hand and wrist. Results of conservative treatment in twenty four cases. J Bone Joint Surg Am 1987;69:1161-8. 62. Lambertus MW, Mathiesen GE. Mycobacterium marinum infection in a patient with cryptosporidiosis and the acquired immunodeficiency syndrome. Cutis 1988;42:38-40. 63. Coyle MB, Carlson LC, Wallis CK, Leonard RB, Raisys VA, Kilburn JO, et al. Laboratory aspects of “Mycobacterium genavense”, a proposed species isolated from AIDS patients. J Clin Microbiol 1992;30:3206-12. 64. Bottger EC, Teske A, Kirschner P, Bost S, Chang HR, Beer V, et al. Disseminated Mycobacterium genavense infection in patients with AIDS. Lancet 1992;340:76-80. 65. Bessesen MT, Shlay J, Stone-Venohr B, Cohn DL, Reves RR. Disseminated Mycobacterium genavense infection; clinical and microbiological features and response to therapy. AIDS 1993;7:1357-61. 66. Dawson DJ, Blacklock ZM, Kane DW. Mycobacterium haemophilum causing lymphadenitis in otherwise healthy child. Med J Aust 1981;2:289-90. 67. Males BM, West TE, Bartholomew WR. Mycobacterium haemophilum infection in a patient with AIDS. J Clin Microbiol 1987;25:186-90. 68. Kiehn TE, White M, Pursell KJ, Boone N, Tsivitis M, Brown AE, et al. A cluster of four cases of Mycobacterium haemophilum infection. Eur J Clin Microbiol Infect Dis 1993;12:1148. 69. Kikuchi K, Bernard E, Kiehn TE, Armstrong D, Riley LW. Restriction fragment length polymorphism analysis of clinical isolates of Mycobacterium haemophilum. J Clin Microbiol 1994;32:1763-7. 70. Dever LL, Martin JW, Seaworth B, Jorgensen JH. Varied presentations and responses to treatment of infections caused by Mycobacterium haemophilum in patients with AIDS. Clin Infect Dis 1992;14:1195-1200. 71. Tortoli E, Piersimoni C, Bacosi D, Bartoloni A, Betti F, Bono L, et al. Isolation of newly described species Mycobacterium celatum from AIDS patients. J Clin Microbiol 1995;33:137-40.

72. Springer B, Tortoli E, Richter I, Grunewald R, Rusch-Gerdes S, Uschmann K, et al. Mycobacterium conspicuum sp. nov., a new species isolated from patients with disseminated infections. J Clin Microbiol 1995;33:2805-11. 73. Banks J, Jenkins PA, Smith AP. Pulmonary infections in Mycobacterium malmoense-a review of treatment and response. Tubercle 1985;66:197-203. 74. Claydon EJ, Coker RJ, Harris JR. Mycobacterium malmoense infection in HIV positive patients. J Infect 1991;23:191-4. 75. Josse R, Guedenon A, Darie H, Anagonou S, Portaels F, Meyers WM. Mycobacterium ulcerans cutaneous infections: Buruli ulcer. Med Trop [Mars] 1995;55:363-73. 76. Wallace RJ, Nash DR, Tsukamura M, Blacklock ZM, Silcox VA. Human disease due to Mycobacterium smegmatis. J Infect Dis 1988;158:52-9. 77. Weitzman I, Osadezyl D, Corrado NL, Karp D. Mycobacterium thermoresistible; a new pathogen for humans. J Clin Microbiol 1981;14:593-5. 78. Davison MR, McCormack JG, Blacklock AM, Dawson DJ, Tilse MH, Crimmins PB. Bacteremia caused by Mycobacterium neoaurum. J Clin Microbiol 1988;26:62-4. 79. Hachem R, Raad I, Rolston KV, Whimbey E, Katz R, Tarrand J, et al. Cutaneous and pulmonary infections caused by Mycobacterium vaccae. Clin Infect Dis 1996;23:173-5. 80. Roth A, Reischl U, Schonfeld N, Naumann L, Emler S, Fisher M, et al. Mycobacterium heckeshornense sp. nov., a new pathogenic slowly growing mycobacterium sp. causing cavitary lung disesase in an immunocompetent patient. J Clin Microbiol 2000;38:4102-7. 81. Tortoli E, Bartoloni A, Manfrin V, Mantella A, Scarparo C, Böttger E. Cervical lymphadenitis due to Mycobacterium bohemicum. Clin Infect Dis 2000;30:210-1. 82. Brown BA, Springer B, Steingrube VA, Wilson RW, Pfyffer GE, Garcia MJ, et al. Mycobacterium wolinskyi sp. nov. and Mycobacterium goodii sp. nov., two new rapidly growing species related to Mycobacterium smegmatis and associated with human wound infections: a cooperative study for the International Working Group on Mycobacterial Taxonomy. Int J Syst Bacteriol 1999;49:1493-511. 83 Torkko P, Suomalainen S, Iivanainen E, Tortoli E, Suutari M, Seppanen J, et al. Mycobacterium palustre sp. nov., a potentially pathogenic, slowly growing mycobacterium isolated from clinical and veterinary specimens and from Finnish stream waters. Int J Syst Evol Microbiol 2002;52:151925. 84. Turenne C, Chedore P, Wolfe J, Jamieson F, May K, Kabani A. Phenotypic and molecular characterization of clinical isolates of Mycobacterium elephantis from human specimens. J Clin Microbiol 2002;40:1230-6. 85. Schinsky MF, McNeil MM, Whitney AM, Steigerwalt AG, Lasker BA, Floyd MM, et al. Mycobacterium septicum sp. nov., a new rapidly growing species associated with catheterrelated bacteraemia. Int J Syst Evol Microbiol 2000;50:575-81. 86. Woo PC, Leung KW, Wong SS, Chong KT, Cheung EY, Yuen KY. Relatively alcohol-resistant mycobacteria are emerging pathogens in patients receiving acupuncture treatment. J Clin Microbiol 2002;40:219-24.

Nontuberculous Mycobacterial Infections 679 87. Adekambi T, Berger P, Raoult D, Drancourt M. rpoB gene sequence-based characterisation of emerging non-tuberculous mycobacteria with description of Mycobacterium bolletti sp. nov., Mycobacterium phocaicum sp. nov. and Mycobacterium aubagnense sp. nov. Int J Syst Evol Microbiol 2006;56:133-43. 88. Cloud JL, Meyer JJ, Pounder JI, Jost KC, Sweeney A, Carroll KC, et al. Mycobacterium arupense sp. nov., a noncromogenic bacterium isolated from clinical specimens. Int J Syst Evol Microbiol 2006;56:1413-8. 89. Fanti F, Tortoli E, Hall L, Roberts GD, Kroppenstedt RM, Dodi I, et al. Mycobacterium parmense sp. nov. Int J Syst Evol Microbiol 2004;54:1123-7. 90 Jimenez MS, Campos-Herrero MI, Garcia D, Luquin M, Herrera L, Garcia M. Mycobacterium canariasense sp. nov. Int J Syst Evol Microbiol 2004;54:1729-34. 91. Schinsky MF, Morey RE, Steigerwalt AG, Douglas MP, Wilson RW, Floyd MM, et al. Taxonomic variation in the Mycobacterium fortuitum third biovariant complex: description of Mycobacterium boenickei sp. nov. Mycobacterium houstenense sp. nov. Mycobacterium neworleansense sp. nov. and Mycobacterium brisbanense sp nov. and recognition of Mycobacterium porcinum from human clinical isolates. Int J Syst Evol Microbiol 2004;54:1653-67. 92. Turenne CY, Cook VJ, Burdz TV, Pauls RJ, Thibert L, Wolfe JN, et al. Mycobacterium parascrofulaceum sp. nov., novel slow growing, scotochromogenic clinical isolates related to Mycobacterium simiae. Int J Syst Evol Microbiol 2004;54:154351. 93 Rhodes MW, Kator H, Kotob S, van Berkum P, Kaattari I, Vogelbein W, et al. Mycobacterium shottsii sp. nov., a slowly growing species isolated from Chesapeake Bay striped bass [Morone saxatilis]. Int J Syst Evol Microbiol 2003;53:421-4. 94. Rhodes MW, Kator H, McNabb A, Deshayes C, Reyrat JM, Brown-Elliott BA, et al. Mycobacterium pseudoshottsii sp. nov., a slowly growing species isolated from Chesapeake Bay striped bass [Morone saxatilis]. Int J Syst Evol Microbiol 2005;55:1139-47. 95. Lai KK, Stottmeier KD, Sherman IH, McCabe WR. Mycobacterial cervical lymphadenopathy. Relation of etiologic agents to age. JAMA 1984;251:1286-8. 96. Wallace RJ, Swenson JM, Silcox VA, Good RC, Tschen JA, Stone MS. Spectrum of disease due to rapidly growing mycobacteria. Rev Infect Dis 1983;5:657-79. 97. Horsburgh DR, Mason UG, Farhi DC, Iseman MD. Disseminated infection with Mycobacterium aviumintracellulare. Medicine [Baltimore] 1985;64:36-48. 98. Ahn CH, McLarty JW, Ahn SS, Ahn SI, Hurst GA. Diagnostic criteria for pulmonary disease caused by M. kansasii and M. intracellulare. Am Rev Respir Dis 1982;125:388-91. 99. Kiehn TE, Edwards FF, Brannon P, Tsang AY, Mary M, Jonathan WH. Infections caused by MAC in immunocompromised patients; diagnosis by blood culture and fecal examination antimicrobial susceptibility tests, and morphological and seroagglutination characteristics. J Clin Microbiol 1985;21:168-73.

100. Shanson DC, Dryden MS. Comparison of methods for isolating Mycobacterium avium-intracellulare from the blood of patients with AIDS. J Clin Pathol 1988;41:687-90. 101. Parashar D, Chauhan DS, Sharma VD, Chauhan A, Chauhan SV, Katoch VM. Optimization of procedures for isolation of mycobacteria from soil and water samples obtained in northern India. Appl Environ Microbiol 2004;70:3751-3. 102. Ollar RA, Dale JW, Feddar MS, Favate A. The use of paraffin wax metabolism in the speciation of Mycobacterium avium intracellulare. Tubercle 1990;71:23-8. 103. Narang P, Narang R, Bhattacharya S, Mendiratta DK. Paraffin slide culture technique for isolating non tuberculous mycobacteria from stool and sputum of HIV seropositive patients. Indian J Tuberc 2004;51:23-6. 104. Anargyros P, Astill DS, Lim IS. Comparison of improved BACTEC and Lowenstein-Jensen media for culture of bacteria from clinical specimens. J Clin Microbiol 1990;28:1288-91. 105. Evans KD, Nakasone AS, Sutherland PA, de la Maza LM, Peterson EM. Identification of Mycobacterium tuberculosis and Mycobacterium avium-M. intracellulare directly from primary BACTEC cultures by using acridinium ester labelled DNA probes. J Clin Microbiol 1992;30:2427-31. 106. Vestal AL. Procedure for isolation of mycobacteria. Atlanta: US Department of Health, Education and Welfare Publication; 1977. 107. Katoch VM, Sharma VD. Advances in the diagnosis of mycobacterial infections. Indian J Med Microbiol 1997;15:4955. 108. Duffey PS, Guthertz LS, Evans GC. Improved rapid identification of mycobacteria by combining solid phase high performance liquid chromatography analysis of BACTEC cultures. J Clin Microbiol 1996;34:1939-43. 109. Piersimoni C, Scarparo C, Callegaro A, Tosi CP, Nista D, Bornigia S, et al . Comparison of MB/ Bact alert 3D system with radiometric BACTEC system and Lowenstein-Jensen medium for recovery and identification of mycobacteria from clinical specimens: a multicentre study. J Clin Microbiol 2001,39:651-7. 110. Leitritz L, Schubert S, Bucherl B, Masch A, Heesemann J, Roggenkamp A. Evaluation of BACTEC MGIT 960 and BACTEC 460 TB systems for recovery of mycobacteria from clinical specimens of a university hospital with low incidence of tuberculosis. J Clin Microbiol 2001;39:3764-7. 111. Schaefer WB. Serologic identification and classification of atypical mycobacteria by their agglutination. Am Rev Respir Dis 1965;92:85-93. 112. Sharma VD, Katoch VM, Shivannavar CT, Gupta UD, Sharma RK, Patil MA, et al. Protein and isoenzyme patterns of mycobacteria. I. Their role in identification of rapidly growing mycobacteria. Indian J Med Microbiol 1995;13:115-8. 113. Sharma VD, Katoch VM, Shivannavar CT, Gupta UD, Sharma RK, Patil MA, et al. Protein and isoenzyme patterns of mycobacteria. II. Their role in identification of slowly growing mycobacteria. Indian J Med Microbiol 1995;13:119-23. 114. Gupta P, Katoch VM, Gupta UD, Chauhan DS, Das R, Singh D, et al. A preliminary report on characterization and

680

115.

116.

117.

118.

119.

120.

121.

122

123.

124.

125.

126.

127.

Tuberculosis identification of non-tuberculous mycobacteria [NTM] on the basis of biochemical tests and protein/isoenzyme electrophoresis patterns. Indian J Med Microbiol 2002;20:137-40. Wayne LG, Diaz GA. Reciprocal immunological distances of catalase derived from strains of M. avium, M. tuberculosis and closely related species. Int J Syst Bacteriol 1979;29:19-24. Shivannavar CT, Katoch VM, Sharma VD, Patil MA, Katoch K, Bharadwaj VP, et al. Development of SOD ELISA to determine immunological relatedness among mycobacteria. Int J Lepr Other Mycobact Dis 1996;64:58-65. McFadden JJ, Kunze Z, Seechurn P. DNA probes for detection and identification of non-tuberculosis mycobacteria. In: Mc Fadden J, editor. Molecular biology of mycobacteria. Surrey: Surrey University Press;1990.p.139-72. Katoch VM, Kanaujia GV, Shivannavar CT, Katoch K, Sharma VD, Patil MA, et al. Progress in developing ribosomal RNA and rRNA gene[s]probes for diagnosis and epidemiology of infectious disease specially leprosy. In: Kumar S, Sen AK, Dutta GP, Sharma RN, editors. Molecular biology and control strategies. New Delhi: Council for Scientific and Industrial Research;1994.p.581-7. Kaminski DA, Hardy DJ. Selective utilization of DNA probes for identification of Mycobacterium species on the basis of cord formation in primary BACTEC 12B cultures. J Clin Microbiol 1995;33:1548-50. Stratmann J, Strommenger B, Stevenson K, Gerlach GF. Development of peptide mediated capture of PCR for detection of Mycobacterium avium subsp paratuberculosis in milk. J Clin Microbiol 2002;40:4244-50. Rodrigo G, Kallenius G, Hoffmann E, Svenson SB. Diagnosis of mycobacterial infection by PCR and restriction enzyme digestion. Lett Appl Microbiol 1992;15:41-4. Chen ZH, Butler WR, Baumstark BR, Ahearn DG. Identification and differentiation of Mycobacterium avium and M. intracellulare by PCR. J Clin Microbiol 1996;34:1267-9. Kulski JK, Khinsoe C, Pryce T, Christiansen K. Use of a multiplex PCR to detect and identify Mycobacterium avium and M. intracellulare in blood culture of AIDS patients. J Clin Microbiol 1995;33:668-74. De Beenhouwer H, Liang Z, de Rizk P, van Eekeren C, Portaels F.. Detection and identification of mycobacteria by DNA amplification and oligonucleotide specific capture plate hybridization. J Clin Microbiol 1995;33:2994-8. Portaels F, Agular J, Fissetle K, Fonteyne PA, de Beenhouwer H, de Rijk P, et al. Direct detection and identification of Mycobacterium ulcerans in clinical specimens by PCR and oligonucleotide-specific capture plate hybridization. J Clin Microbiol 1997;35:1091-1100. Ruiz P, Gutierrez J, Zerolo FJ, Casal M. Genotype Mycobacterium assay for identification of mycobacterial species isolated from human clinical samples by using liquid medium. J Clin Microbiol 2002;40:3076-8. Suffys PN, da Silva Rocha A, de Oliveira M, Dias Campos CE, Werneck Barreto AM, Portaels F, et al. Rapid identification of mycobacterium to the species level using INNO-

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139. 140.

141.

142.

LiPA mycobacterium, a reverse hybridization assay. J Clin Microbiol 2001;39:4477-82. Li Z, Bai GH, von Reyn CF, Marino P, Brennan MJ, Gine N, et al. Rapid detection of Mycobacterium avium in stool samples from AIDS patients by immunomagnetic PCR. J Clin Microbiol 1996;34:1903-7. Vaneechoutte M, Beenhouwer HD, Claeys G, Vershraegen G, De Rouck A, Paepe N, et al. Identification of Mycobacterium species by using amplified ribosomal DNA restriction analysis. J Clin Microbiol 1993;31:2061-5. Avanis Saghnjani E, Jones K, Holtzman A, Aronson T, Glover N, Boian M, et al. Molecular techniques for rapid identification of mycobacteria. J Clin Microbiol 1996;34:98-102. Dobner P, Feldmann K, Rifai M, Loscher T, Rinder H. Rapid identification of mycobacterial species by PCR amplification of hypervariable 16S rRNA gene promoter region. J Clin Microbiol 1996;34:866-9. Roth A, Reischl U, Streubel A, Naumann L, Kroppenstedt M, Habicht M, et al. Novel diagnostic algorithm for identification of mycobacteria using genus-specific amplification of 16S-23S rRNA gene spacer and restriction endonucleases. J Clin Microbiol 2000;38:1094-104. Katoch VM. WHO, Biennium Project Report. Identification of Mycobacterium tuberculosis and other pathogenic Mycobacteria by a ribosomal PCR-RFLP assay;2004. Slutsky AM, Arbeit RD, Barber TW, Rich J, von Reyn CF, Pieciak W, et al. Polyclonal infections due to Mycobacterium avium complex in patients with AIDS decided by pulsedfield gel electrophoresis of sequential clinical isolates. J Clin Microbiol 1994;32:1773-8. Kauppinen J, Mantyjarvi R, Katila ML. Random amplified polymorphic genotyping of Mycobacterium malmoense. J Clin Microbiol 1994;32:1827-9. Katoch VM, Shivannavar CT, Datta AK. Studies on ribosomal RNA genes of mycobacteria including M. leprae. Acta Leprol 1989;7[suppl1]:231-3. Kanaujia, Katoch VM, Shivannavar CT, Sharma VD, Patil MA. Rapid characterization of Mycobacterium fortuitum-chelonei complex by restriction fragment length polymorphism of ribosomal RNA genes. FEMS Microbiol Lett 1991;77:205-8. Chiodini RJ. Characterization of Mycobacterium paratuberculosis and organisation of Mycobacterium avium complex by restriction polymorphism of rRNA gene region. J Clin Microbiol 1990;28:489-94. Picardeau M, Vincent V. Typing of Mycobacterium avium isolates by PCR. J Clin Microbiol 1996;34:389-92. Kumar S, Bose M, Isa M. Genotype analysis of human Mycobacterium avium isolates from India. Indian J Med Res 2006;123:139-44. Yang M, Ross BC, Dwyer B. Identification of an insertion sequence like element in subspecies of M. kansasii. J Clin Microbiol 1993;31:2074-9. Falkinham JO. Molecular epidemiology: other mycobacteria. In: Ratledge C, Dale J, editors. Mycobacteria: molecular

Nontuberculous Mycobacterial Infections 681 biology and virulence. London: Blackwell Science Ltd; 1999.p.136-60. 143. Vanitha JD, Venkatasubramani R, Dharmalingam, Paramasivan CN. Large-restriction fragment polymorphism of Mycobacterium chelonae and Mycobacterium terrae isolates. Appl Environ Microbiol 2003;69:4337-41. 144. Jucker MT, Falkinham JO. Epidemiology of infections by nontuberculous mycobacteria. IX. Evidence for two DNA homology groups among small plasmids in Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium scrofulaceum. Am Rev Respir Dis 1990;142:858-62. 145. Soini H, Eerola E, Viljanen MK. Genetic diversity among Mycobacterium avium complex AccuProbe positive isolates. J Clin Microbiol 1996;34:55-7.

146. Steadham DE, Stall SK, Simmank JL. Use of the BACTEC system for drug susceptibility testing of Mycobacterium tuberculosis, M. kansasii, and M. avium complex. Diagn Microbiol Infect Dis 1985;3:33-40. 147. Biehle JR, Cavalieri SJ, Saubolle MA, Getsinger LJ. Evaluation of E test for susceptibility testing of rapidly growing mycobacteria. J Clin Microbiol 1995;33:1760-4. 148. Fabry W, Schmid EN, Ansorg R. Comparison of the E test and a proportion dilution method for suseptibility testing of Mycobacterium kansasii. Chemotherapy 1995;41:247-52. 149. Maisetta G, Batoni G, Pardini M, Boschi A, Bottai D, Esin S, et al. Use of recombinant strain of Mycobacterium avium expressing beta-galactosidase to evaluate the activities of the antimycobacterial agents inside macrophages. Antimicro Agents Chemother 2001;45:356-8.

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49

Sharmistha Banerjee, N Siddiqi, Seyed E Hasnain

INTRODUCTION At the end of nineteenth century, Dr. Robert Koch isolated the dreaded organism that was the aetiological agent of tuberculosis [TB] (1-3). Since then, there had been desultory experiments with a variety of medical applications in the management of pulmonary TB. The first success, marking the antibiotic era, came in the year 1944, with the introduction of streptomycin for TB treatment. With the availability of isoniazid, and paraaminosalicylic acid [PAS], in the mid 1940s, predictable, curative treatment for TB became a reality. With the introduction of rifampicin, pyrazinamide and ethambutol in the subsequent years, short-course treatment became possible. Initial euphoria of ability to cure TB led to indiscriminate use of antituberculosis drugs and the laxity in monitoring of tedious drug regimens led to the emergence of multidrug-resistant strains of Mycobacterium tuberculosis. Multidrug-resistant -TB [MDR-TB] caused by isolates of Mycobacterium tuberculosis resistant to isoniazid and rifampicin with or without resistance to other antituberculosis drugs, is a worrisome disease and is prevalent worldwide (4-10). Resistance to rifampicin and isoniazid, two frontline drugs that form the backbone of the short-course treatment, would necessitate using drugs that are more toxic, costly and are administered for a long period. The MDR-TB patients that fail treatment have a higher risk of death (5-7) . After the initial discovery of five or six antituberculosis drugs, no newer drugs have been discovered against Mycobacterium tuberculosis. The mechanism of resistance to most antituberculosis drugs remained

unknown till the last decade. Even today, TB, a curable disease, continues to be a major threat worldwide. EPIDEMIOLOGY The epidemiology of drug-resistant TB including MDRTB is extensively covered in the chapter “Antituberculosis drug resistance surveillance” [Chapter 50]. Molecular Epidemiology of Multiple Drug-Resistant Strains Tools for Studying Molecular Epidemiology Several methods are used for antituberculosis drug susceptibility testing, and are described in detail in the chapter “Laboratory diagnosis” [Chapter 10]. A new tool that has been applied to TB epidemiology is the restriction fragment length polymorphism [RFLP] analysis-based deoxyribonucleic acid [DNA] fingerprinting that identifies specific strain of a microorganism. This technique has found widespread use in Mycobacterium tuberculosis characterization by virtue of repetitive DNA sequences that are present in the genome in variable numbers and locations. These include the insertion sequences [IS], direct repeats [DR], polymorphic GC-rich sequences [PGRS], major polymorphic tandem repeats [MPTR] and enterobacterial repetitive intergenic consensus sequences [ERIC]. The greater polymorphism shown by these repetitive sequences offers better identification power over the earlier typing techniques, such as pulse field gel electrophoresis. Another advantage of these techniques is their standardization, which offers greater intra- and inter-laboratory

Drug-Resistant Tuberculosis comparisons of fingerprints. Few years back a new method spacer oligonucleotide typing [spoligotyping] was introduced for diagnosis and epidemiology of Mycobacterium tuberculosis [Figures 49.1A and 49.1B] (11). It is based on the detection of various nonrepetitive spacer sequences located between the direct repeats in the DR locus. It is a polymerase chain reaction [PCR] based method hence the results can be obtained in a shorter time (12). However, the discriminative power

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of spoligotyping compared to IS6110 fingerprinting is less, and consequently, its use for epidemiological studies of Mycobacterium tuberculosis is limited. The fluorescent amplified fragment length polymorphism [FAFLP] is a relatively new whole-genome DNA typing method (13-16). Newer methods such as heteroduplex and mismatch analyses, DNA sequencing, real-time PCR [RT-PCR], molecular beacons, and line probe assays have all been

Figure 49.1A: Chromosome of Mycobacterium tuberculosis hypothetical strain X and genotyping of Mycobacterium bovis bacille CalmetteGuérin [BCG], the Mycobacterium tuberculosis laboratory strain H37Rv, and strain X on the basis of IS6110 insertion sequences and mycobacterial interspersed repetitive units [MIRUs]. The top left-hand panel shows the chromosome of hypothetical strain X, as shown by the arrows. The top right-hand panel shows the results of IS6110-based genotyping. Mycobacterial DNA is digested with the restriction enzyme PvuII. The IS6110 probe hybridizes to IS6110 DNA to the right of the PvuII site in IS6110. The size of each hybridising fragment depends on the distance from this site to the next PvuII site in adjacent DNA [fragments, a through f], as reflected by gel electrophoresis of the DNA fragments of BCG, H37Rv, and X. The horizontal lines to the right of the electrophoretic strip indicate the extent of the distribution of fragments in the gel, including PvuII fragments that contain no IS6110. The three bottom panels show the results of MIRUbased genotyping. The MIRUs contain repeat units, and MIRU analysis involves the use of polymerase chain reaction [PCR] amplification and gel electrophoresis to categorize the number and size of repeats in 12 independent loci, each of which has a unique repeated sequence. The sizes of molecular-weight markers [M] and PCR products for the loci A, B, C, and D in BCG, H37Rv, and X are shown. The specific sizes of the various MIRUs in each strain result in a distinctive fingerprint for the strain Reproduced with permission from “Barnes PF, Cave MD. Molecular epidemiology of tuberculosis. N Engl J Med 2003;349:1149-56 (reference 11)” Copyright [2000] Massachusetts Medical Society. All rights reserved

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Figure 49.1B: Spoligotyping. The direct-repeat [DR] locus is a chromosomal region that contains 10 to 50 copies of a 36-bp direct repeat, separated by spacer DNA with various sequences, each of which is 37 to 41 bp. A copy of IS6110 is inserted within a 36-bp direct repeat in the middle of the DR locus in most strains. Mycobacterium tuberculosis strains have the same overall arrangement of spacers but differ in terms of the presence or absence of specific spacers. Spacer oligonucleotide typing [spoligotyping] involves polymerasechain reaction [PCR] amplification of the DR locus, followed by hybridization of the labeled PCR products to a membrane that contains covalently-bound oligonucleotides corresponding to each of 43 spacers. Individual strains have positive or negative signals for each spacer. The top section shows the 43 direct repeats [rectangles] and spacers [horizontal lines] used in spoligotyping. The middle section shows the products of PCR amplification of spacers 1 through 6 of Mycobacterium bovis bacille Calmette-Guérin [BCG], Mycobacterium tuberculosis strain H37Rv, and Mycobacterium tuberculosis hypothetical strain X, with the use of primers [white and black arrowheads] at each end of the DR locus. The bottom section shows the spoligotypes of the three strains Reproduced with permission from “Barnes PF, Cave MD. Molecular epidemiology of tuberculosis. N Engl J Med 2003;349:1149-56 (reference 11)” Copyright [2000] Massachusetts Medical Society. All rights reserved

used to screen for mutations that are responsible for the development of antituberculosis drug resistance. Multiplex PCR, followed by hybridization on an oligonucleotide microarray (17) or low-density DNA oligonucleotide array [macroarray] (18) have also been used to detect the DNA of Mycobacterium tuberculosis complex and to identify mutations associated with isoniazid and rifampicin resistance (6). Ahmed et al (19) described the population structure and dynamics of Mycobacterium tuberculosis strains for more than hundred independent isolates from 11 different countries by a chromosome-wide scan using

FAFLPs. Analysis of data revealed distinct geographic partitioning of Mycobacterium tuberculosis strains across these countries correlating genomic diversity with a possible geographic evolution. They (19) hypothesized that this might have occurred due to specific genomic deletions and substitutions selected rigorously against host defenses and environmental stresses on an evolutionary time-scale (19). Further, it suggests that the pathogen diversity may be a reflection of the host population diversity. W-Beijing genotype is well-known for its rapidity of spread and tenacity, and notably for its strong association

Drug-Resistant Tuberculosis with multidrug-resistance (20,21). It is highly prevalent in some regions of Asia and Eastern Europe, such as Estonia, Azerbaijan, and Russia. Outbreaks of drugresistant TB caused by W-Beijing strain have been described from South Africa as well (22-24). The strains belonging to the W-Beijing family have been shown to exhibit a constant spoligotype and high degrees of similarity among IS6110 RFLP, PGRS, RFLP, and variable numbers of tandem repeats profiles. However, caution must be exercised while interpreting these data as these observations need to be confirmed before definitely linking the clone to the given host population (25). Most of our understanding of TB dynamics in populations has been derived indirectly by inference from descriptive epidemiological data, as well as from clinical trials conducted to test the efficacy of antituberculosis drugs and vaccine immunization programmes. Usually a small number of infected individuals end up with the disease, also the long incubation period between infection and disease makes it difficult to identify source of infection and site of transmission. The diagnosis of TB can be established definitively, only by isolation of Mycobacterium tuberculosis by culture from the individual suspected of carrying the disease. Microscopic examination of sputum can detect organisms only when large numbers are present, thus it has sensitivity of no more than 50 to 70 per cent compared to culture. Because of high prevalence of TB and widespread use of bacille CalmetteGuérin [BCG] vaccine, a positive tuberculin skin test [TST] does not identify the source or duration of the infection. The ability to determine transmission links is, thus, limited by technology. The integration of molecular methods of strain identification with conventional epidemiology can be used to establish transmission links and to identify individual and environmental risk factors. With the discovery of polymorphic DNA in Mycobacterium tuberculosis, strain differentiation has become an important tool in the study of epidemiology of TB (26). While understanding the molecular basis of drug resistance is important for development of new drug targets, it is equally important to understand the relative virulence and dynamics of multidrug-resistant strains of Mycobacterium tuberculosis. Multidrug-resistant strains have to pay a price to attain resistance to drugs for their survival that comes in terms of highly reduced virulence and propagation (27). However, Ordway’s study (28) reveals no such relationship between virulence and drug resistance.

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MECHANISMS OF DRUG RESISTANCE Tuberculosis cavity usually contains 107 to 109 bacilli. Mutations causing resistance to isoniazid occur in about 1 in 106 replications, and the mutations causing resistance to rifampicin occur in about 1 in 108 replications, and the overall the probability of spontaneous mutations causing resistance to both isoniazid and rifampicin would be 106 × 108 which is equal to 1 in 1014 replications (6,7). Since this number of bacilli cannot be found even in patients with extensive cavitary pulmonary TB, the chance of the development of spontaneous dual resistance to rifampicin and isoniazid is very uncommon (5-7) and this forms the basis for administration of multiple drugs for the treatment of TB. MOLECULAR BASIS OF MULTIPLE DRUG-RESISTANCE Predominantly, the molecular basis of drug resistance could be traced to mutations in genes coding for drug target proteins (29). However, as an efficient pathogen, Mycoobacterium tuberculosis is equipped with several defence strategies, including a complex cell wall, drug efflux pumps and multi-functional proteins (29-36). Another mechanism for acquiring resistance that has been documented in other systems, but not yet in Mycobacterium tuberculosis, is ‘drug alteration’ (29). Rifampicin Resistance to rifampicin is a relatively rare event (37) and leads to selection of mutants that are already resistant to other components of short-course treatment. Therefore, rifampicin resistance is often regarded as an excellent surrogate marker for MDR-TB (38). The association of the ribonucleic acid [RNA] polymerase β subunit gene [rpoB] with resistance to rifampicin has been documented previously and subsequent reports from various groups have confirmed this association in clinical isolates of Mycobacterium tuberculosis (39-41). Introduced in the early 1970s, rifampicin is a lipophilic ansamycin and its efficacy as an antituberculosis drug lies in its ability to diffuse across the hydrophobic cell envelope (39). The ‘ansa’ designation connotes an aromatic centre that is bridged on both the ends by an aliphatic chain. The conformational relationship between the aromatic nucleus and the aliphatic chains is very important for microbiologic activity, probably because

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of the interaction of the drug with its target. It is a potent inhibitor of DNA dependent RNA polymerase. The RNA polymerase is a multisubunit protein consisting of a core enzyme having four polypeptide chains [α2ββ’]. The holoenzyme has an additional subunit ‘σ’ that allows

promoter recognition for initiation of transcription. The subunits α,β,β’ and σ are coded by the rpoA, rpoB, rpoC and rpoD genes, respectively (42). Rifampicin binds to the β subunit involved in the initiation and elongation of transcription [Figure 49.2].

Figure 49.2: Schematic representation of development of rifampicin resistance. Mutations in the rpoB leads to conformation change of the β subunit which fails to bind to rifampicin resulting in rifampicin resistance RIF = rifampicin; α,β,β’ and σ = subunits of RNA polymerase; rpoB = RNA polymerase gene subunit B; DNA = deoxyribonucleic acid; mRNA = messenger ribonucleic acid

Drug-Resistant Tuberculosis Rifampicin Resistance The molecular mechanism of rifampicin resistance has been thoroughly studied in Escherichia coli and supplemented with genetic studies in early 1980s (43-47). Mutations occurring in a discrete region of rpoB gene were identified and correlated with rifampicin resistance by several investigators (46-48). This agnate region of Mycobacterium tuberculosis rpoB was first cloned and sequenced by Telenti et al (49) on the basis of sequence information available from rpoB gene of Mycobacterium leprae (49,50). They identified a total of 15 distinct mutations clustered in a 23-amino acid stretch [69 bases]. Of the 15 mutations, eight were in the conserved amino acid residues. Essentially, all mutations were missense with major abundance of amino acid substitution in either residue 526 or 531 of the rpoB gene. Kapur et al (40) sequenced 121 rifampicin-resistant strains and concluded that 90 per cent of the rifampicin-resistant strains had sequence alteration in the 69 base pair [bp] hotspot that was present within the 350 bp region showing considerable polymorphism amongst the rifampicin-resistant strains. These earlier efforts led to a surprising discovery that certain mutations were relatively more abundant in one set of population than the other, and pointed to geographic partitioning and strain divergence amongst the rifampicin-resistant strains. Subsequent work has documented several other

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novel mutations that have been added to the list of mutations in the rpoB gene in rifampicin-resistant strains. A study from Japan (51) established for the first time a relationship of these mutations to the level of resistance demonstrated by the strains. Isolates with mutations in codons 513, 526 and 531 had high levels of drug resistance indicated by minimum inhibitory concentration [MIC] levels of greater than or equal to 50 μg/ml. In contrast, amino acid substitutions located at position 514, 521 or 533 resulted in low-level resistance [MIC < to 12.5 μg/ml]. These results have been confirmed by other studies (52-54). It is important to mention here that in some of the rifampicin-resistant strains studied earlier, no mutation either in the rpoB hotspot or its flanking region were found, suggesting that there must be supplementary molecular mechanisms associated with the rifampicin-resistance. Systematic studies on rifampicin-resistant strains related to its epidemiological relevance in India are urgently required as it has become apparent that there exists a distinct geographic variation in distribution of mutations in rpoB gene. Siddiqi et al (55) sequenced about 93 rifampicin-resistant isolates from various parts of India, majority of the samples being from North India. Amongst Indian isolates certain novel mutations were identified along with the already reported ones. Most rifampicin-resistant isolates had mutations at codon 531 [Figure 49.3]. Of the 93 rifampicin-resistant strains,

Figure 49.3: Summary of mutations at codons 508 to 532 in the rpoB gene. The wild type sequence and amino acids are shown in the middle frame. Nucleotide changes are marked with arrows in the top frame and the corresponding amino acid changes are denoted in the bottom frame. The amino acids are subscripted with numbers indicating the number of isolates harbouring the change. Amino acid changes in squares indicate novel mutations; those in circles are silent mutations Source: reference 55

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28 had the missense mutation Ser531Leu and eight had the substitution Ser531Trp. The next most common mutations were the amino acid substitutions Asp516Val/ Gly [20 isolates] and His526Tyr/Leu/Arg [19 isolates]. Novel mutations included Ser509Arg, Leu511Val, Asn518Thr, Ser522Gln, Lys527Asn, Arg528Pro and Arg528His. Silent mutations included Leu511 and Leu521. Interestingly, this mutation at position 511 never occurred alone and was only present in isolates having more than one mutation at the rpoB locus in this study (55). An important outcome of the study by Siddiqi et al (55) is the direct correlation of certain mutations in Indian isolates to high MIC values. Mutations in codons 516 and 521 conferred low-level resistance [MIC < 40 μg/ ml] to rifampicin, whereas mutations in codons 510, 526, 527, 528 and 531 were seen to confer high levels of resistance [MIC > 64 μg/ml]. The amino acids 526 to 531 appear to be very important in drug-target interactions, and mutations in them result in MIC levels in the range of 64 μg/ml and above. In a few cases double mutations were found to have an additive effect on the degree of resistance (55). Rifabutin Resistance Rifabutin, a derivative of rifamycin S, while most useful in the treatment of human immunodeficiency virus [HIV] and TB co-infection, can be used in some patients with rifampicin-resistant TB (56,57). The observation that rifabutin was effective only in some patients with rifampicin-resistant TB indicated that susceptibility to rifabutin may depend upon the position and type of mutation in rpoB gene. Bodmer et al (54) quantitatively tested rifampicin, rifabutin and some other antimycobacterial drugs. They could establish a direct correlation between specific mutations in rpoB and susceptibility to rifabutin. They found the strains with Leu-511 → Pro, Asp-516 → Tyr, Asp-516 → Val or Ser-522 → Leu were either susceptible [MIC < 0.5 μg/ml] or had low resistance to rifampicin. However, these investigations do indicate that certain group of patients with rifampicinresistant TB could possibly be treated with rifabutin (58,59). Isoniazid Isonicotinic acid hydrazide [isoniazid], one of the key drugs for the treatment of TB is considered to be an ideal antimicrobial agent because of its low cost, excellent intracellular penetration, bioavailability, and a narrow

spectrum of action. However, the high frequency of spontaneous development of resistance to this drug in Mycobacterium tuberculosis precludes its use as a singleagent to treat TB. Isoniazid Resistance Isoniazid is a pro-drug and is converted into active yet an unstable electrophilic intermediate that inhibits the biosynthesis of cell wall mycolic acids [long-chain αbranched β-hydroxylated fatty acids], thereby making the mycobacteria susceptible to reactive oxygen radicals, nitric oxide [NO] and other hostile environmental factors presented by the host. The mode of action of isoniazid is schematically represented in Figure 49.4. The formation of active intermediate requires the enzyme catalaseperoxidase, coded by the gene katG and an electron sink [hydrogen peroxide] (60). Therefore, it is apparent that mutation in katG gene would lead to isoniazid resistance in Mycobacterium tuberculosis. Experimental evidence to the mode of action of isoniazid was provided by Middlebrook (61) and Zhang et al (62,63). These investigators (61-63) directly correlated the involvement of catalase-peroxidase by restoring isoniazid susceptibility in isoniazid-resistant Mycobacterium smegmatis and Mycobacterium tuberculosis by providing the wild type katG (62). It was observed that complete deletion of katG led to the development of highlevel resistance [MIC > 50 μg/ml] (63). Furthermore, it was found that a subset of isoniazid-resistant strains of Mycobacterium tuberculosis had intact katG. Therefore, major deletions or insertions alone could not be the proper explanation of resistance to isoniazid due to mutations in katG (64). Later several workers (65-67) using PCR, single-strand conformation polymorphism [SSCP] and sequencing, reported the presence of several missense mutations in the gene, the most common being CGG → CTG [Arg → Leu] at amino acid position 463. Additional missense mutations identified by them included GTG → GCG [fMet → Ala at position 1], GAC → GCC [Thr-275Pro], AGC → ACC [Ser-315Thr] and CTG → ATG [Leu-587Met], occurring singly or more than one. In a report from India (55), 24 isoniazidresistant isolates were analysed for insertions, deletions and substitution mutations in the katG locus. The mutations in the 5' region [nt 3-239] and the mid-region [nt 1187-1600] of the katG gene, corresponding to amino acid positions 2-77 and 395-533, respectively were studied. Figure 49.5 summarizes the mutations observed,

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Figure 49.4: Schematic representation of the mode of action of isoniazid orf1 = open reading frame1; inhA = enoyl acyl-carrier protein reductase; H2O2 = hydrogen peroxide; ahpC = alkyl hydroperoxide reductase; NADH = reduced nicotinic acid dinucleotide; katG = catalase-peroxidase; acpM = acyl-carrier protein; kasA = β-ketocyl acyl-carrier protein synthase; ROs = reactive oxyen species

including some of the novel mutations. Apart from mutations, partial deletion of this locus was also observed in six isolates. Mutation Arg-463Leu [CGG → CTG] was most common, but represented polymorphism amongst isolates rather than drug resistance. It has been argued

previously that this polymorphism in the katG locus might be more important as a marker for evolution than resistance (68). However, to the pathogen, loss of catalase-peroxidase activity means susceptibility to organic peroxides and redox stress as catalase-peroxidase

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Figure 49.5: Summary of mutations in the katG gene. Deletions are indicated by a red arrow with minus sign. Insertions are depicted as blue arrows with a plus sign. Substitutions are shown as black arrows Source: reference 555

is the only peroxide-inducible protein of Mycobacterium tuberculosis (69). Overexpression of alkyl hydroperoxide reductase [ahpC] protein that can detoxify organic peroxides compensates for this loss. Sherman et al (70) demonstrated that all katG mutant Mycobacterium tuberculosis strains overexpressed ahpC protein at significantly higher levels than isoniazid-sensitive strains. Position 39 to 81 bp upstream from the ahpC start codon of each ahpC-upregulated and katG mutant isolate contained mutations that could increase the promoter activity (70). Hence, it was hypothesized that compensatory mutations in the ahpC promoters were selected naturally for survival of katG mutant Mycobacterium tuberculosis strains to withstand oxidative stress. There was, however, an apparent inconsistency in upregulation of ahpC in katG, such as, ahpC upregulation was not observed among Mycobacterium tuberculosis isolates with katG 315 codon mutations, even though it resulted in more than a 20-fold decrease in katG activity and conferred high MIC (66,71). This suggests that there is more complexity to acquiring isoniazid resistance than a simple downregulation of katG and upregulation of ahpC. This also underlined the search for new mechanisms and additional genes involved in isoniazid resistance. Banerjee et al (72) identified a locus containing two contiguous open reading frames [ORF], orf1 and inhA, that may participate in both resistance to isoniazid and ethionamide. The probable role of ORFs, orf 1 and inhA in the causation of isoniazid resistance has been schematically explained in Figure 49.4. In detail, two enzyme systems intervene in mycolic acid biosynthesis. One involves reduced form of nicotinamide adenine dinucleotide [NADH] dependent enoyl acyl-carrier protein [ACP] reductase [inhA] and other involves 3-oxyacyl ACPsynthase [kasA]. Enoyl-ACP reductase [inhA] catalyses the NADH-dependent reduction of the double bond at

second position of growing fatty acid chain linked to ACP. This is a common enzyme reaction in long chain fatty acid biosynthesis, including mycolic acid biosynthesis in Mycobacterium tuberculosis. The activated electrophilic form of isoniazid, isonicotinic acyl anion and isonicotinic acyl radicle, bind with NADH to form isonicotinic acyl-NADH (73). This modified NADH cannot participate in NADH-dependent reduction step of long chain fatty acid biosynthesis. Resistance to isoniazid has been linked to mutations in inhA within or near the NADH binding site, resulting in decreased affinity of inhA for iso-NADH (74,75). Therefore, isoniazid-dependent inhibition of mycolic acid biosynthesis in mutated inhA would require very high concentrations of NADH compared to wild type (74,75). Thus, there exists a correlation between the ability of the enzyme to bind NADH and to become inhibited by activated isoniazid. Furthermore, ACP substrates can prevent isoniazid-dependent inhibition of inhA, suggesting that activated isoniazid also interacts with the substrate binding region of inhA (72,76-78). A ‘T>G’ transversion, observed in few of the resistant strains, at position 280 [94ser → 94ala] or ‘ATC>ACC’ [Ile-16 → thr16] in the inhA gene, this alters the binding affinity of inhA to iso-NAD[H], and ultimately results in isoniazid resistance (66,79). Alternately, hyperexpression of inhA could result in weak isoniazid resistance owing to titrating out the drug. It has also been observed that, three isoniazid-resistant isolates carried mutations in the ribosomal binding site [RBS] upstream of the inhA gene [Figure 49.6]. These mutations, probably, confer resistance by a drug titration effect (55). However, further experiments with mutants along with clinical evidence dismissed the probability of inhA being the primary target for the activated form of isoniazid (80). The activated form of isoniazid binds to the complex of kasA and an ACP called ACP-M. This prevents it from

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Figure 49.6: A schematic representation of the mutations identified in the putative ribosomal binding site of the inhA gene. The inhA locus is composed of two contiguous open reading frames [designated mabA and inhA] which are separated by a 21 bp non-coding sequence mabA = mycolic acid biosynthesis A [reductase]; inhA = enoylacyl carrier protein reductase; RBS = ribosomal binding site; A = adenine; G = guanine; T = thymine; C = cytosine

participating in mycolic acid biosynthesis. Mutation in kasA also leads to isoniazid resistance. It is reported that kasA inhibition is detrimental to Mycobacterium tuberculosis growth, making it an important drug target (81). Comprehensively, resistance to isoniazid arises due to mutations in the katG (40,82,83) inhA (72,84), ahpC (85,86), oxidative stress regulator [oxyR] (85,86) and kasA gene loci (81). Broadly, katG and inhA mutations account for 70 to 80 per cent of isoniazid-resistant Mycobacterium tuberculosis isolates. Streptomycin The antibiotics aminoglycosides, macrolides and tetracyclines target protein translation machinery of the pathogen. Streptomycin is an aminocyclitol glycoside that binds to 16S ribosomal RNA [rRNA] interfering with proof-reading step in protein translation (87-89). Most of the eubacteria have multiple copies of rRNA operons including 16S rRNA, and therefore, mutations in one copy can be compensated by the active products of other copies. But slow growing mycobacteria like Mycobacterium tuberculosis or Mycobacterium leprae have a single copy of 16S rRNA, implying that any mutation in these genes would confer resistance to streptomycin (90,91). It is important to point out here that streptomycin resistance in Mycobacterium tuberculosis arises due to alteration of the target than drug itself. Mutations in two target genes are associated with streptomycin resistance in Mycobacterium tuberculosis, the 16S rRNA and

ribosomal protein S12. The latter is involved in the translation machinery indirectly where it stabilizes the quaternary ‘pseudoknot’ structure of 16S rRNA [Figure 49.7] (88,89). Therefore, any mutation in S12 can result in altered structure of 16S rRNA preventing binding of streptomycin, thus, conferring resistance (92). Polymorphism in 16S rRNA due to point mutations has been mapped into two discrete regions, the 530 loop and the 915 region in Mycobacterium tuberculosis. The A→G transition found at 904 along with a missense mutation in codon 88 of rpsL AAG→CAG [Lys→Gln] had been correlated with high resistance to streptomycin [greater than 60 μg/ml] (93). It has been shown in a clinical set-up that disruption of the 530 loop as a result of either base pairing between residue 524-526 or loss of adjacent bulge owing to base pairing between residue 504-507 results in streptomycin resistance (94,95). Mutations in the ribosomal protein subunit 12 [rpsL] gene accounted for more than two-third of streptomycin resistant cases (96,97). Fourteen isolates resistant to streptomycin were checked for mutations in the rpsL and 16S rRNA [rrs] loci in one study (55). A novel silent mutation in eight strains at amino acid position 121 in the rpsL locus where the codon AAA [Lys] was changed to AAG [Lys], but no mutations in the rrs genes were observed [Figure 49.8]. The reported mutations at the rpsL locus are generally Leu43Arg, Leu43Thr or Lys88Arg. It is still not clear that how this mutation leads to the development of streptomycin resistance (55).

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Overall, only two-third of the resistant isolates sequenced had demonstrable mutations in the above two loci. This indicates that there are more mechanisms conferring streptomycin resistance that are yet to be discovered.

Ethambutol Resistance to ethambutol is a typical case of drug resistance due to over-expression of the target gene. Exact mechanism of action of ethambutol is still not known,

Figure 49.7: The secondary structure of the 16S rRNA of Mycobacterium tuberculosis. The mutations in the 530 loop and 904 regions are marked by arrowheads, and these lead to streptomycin resistance Source: references 88,89

Figure 49.8: Schematic representation of mutations located in the rpsL gene encoding the S12 protein, associated with streptomycin resistance in Mycobacterium tuberculosis

Drug-Resistant Tuberculosis although several hypotheses have been put forward which indicate more than one target for the drug. Inhibition of RNA metabolism (98), spermidine synthesis (99), phospholipid biosynthesis (100,101), biosynthesis of arabinogalactan and transfer of arabinogalactan into the cell wall of the pathogen are some of the proposed mechanisms for ethambutol action. The ethambutol susceptibility, however, is mainly due to alteration in the mycobacterial cell wall structure (102-106) that makes it susceptible to host generated stress factors. Accumulation of trehalose mono- and di-mycolates in the medium led to hypothesis that ethambutol inhibits transfer of arabinogalactan to cell wall, which could also justify the accumulation of mycolic acid and subsequent change in morphology and declumping of mycobacteria after ethambutol treatment (100,105). Belanger et al (107) identified an operon of three genes in Mycobacterium avium designated as embC, embA, and embB. The corresponding genes in Mycobaterium tuberculosis are genes embC, embA, and embB (107,108). The embA, and embB genes encode for arabinosyl transferase III which is responsible for the polymerization of arabinose into the arabinan of arabinogalactan, the primary cellular target for ethambutol (109). The ubiquity of the ethambutol-resistance region was investigated by Southern blot analysis with genomic DNA from Mycobacterium avium, Mycobacterium smegmatis, Mycobacterium tuberculosis, and Mycobacterium leprae. Transposon insertion, however, narrowed down to the fact that the ethambutol resistant phenotype requires only embA and embB and further, their copy numbers determined the resistance levels. Mapping of embA and embB in Mycobacterium tuberculosis showed the presence of a secondary stem loop structure between the embA and the embB genes indicates that the embB gene in Mycobacterium tuberculosis could be differentially regulated (110). The most significant mutation found among ethambutol-resistant isolates was the missense substitution in the conserved embB codon 306 that coded for methionine (110). Their role in conferring resistance to ethambutol was confirmed by gene transfer assays (110). Mycobacterium tuberculosis strains with Met306Leu and Met306Val substitutions demonstrated a higher MIC for ethambutol [40 μg/ml] than those for organisms with Met306Ile substitutions [20 μg/ml]. Considerable polymorphism was detected in the 1.892 kb of 5’ segment of embB among ethambutol-resistant and ethambutol-

693

susceptible isolates (110). When, epidemiologically unassociated organisms alone are considered, 69 per cent of ethambutol-resistant bacteria had an amino acid change in the region of embB studied, and most replacements [89%] occurred at position 306. Structural and functional association with mutation at position 306 can be a promising area to further modify the drug to kill ethambutol-resistant Mycobacterium tuberculosis (110). Pyrazinamide Though antimycobacterial properties of pyrazinamide were known since 1952, its utility was realized only during 1980s when it became a crucial part of shortcourse therapy and contributed to the shortening of the treatment duration from 12 to six months. A structural analog of nicotinamide, pyrazinamide is transported as a neutral molecule to the cell where the pro-drug form is converted into its active form pyrizinoic acid by an enzyme pyrazinamidase. Evidence suggesting that intrinsic resistance of Mycobacterium bovis to pyrazinamide was due to absence of the enzyme pyrazinamidase led to the discovery of Mycobacterium tuberculosis pyrazinamidase [pncA] that had both pyrazinamidase and nicotinamidase activities (111). Sequence polymorphism because of mutations in pncA results in inactive pyrazinamidase and confers resistance to pyrazinamide. The mutations mapped onto Mycobacterium tuberculosis pncA from clinical isolates included missense alterations, termination mutations, nucleotide insertions and deletions [Figure 49.9]. However, some clinical isolates resistant to pyrazinamide were found to carry no detectable mutations and were also checked positive for pyrazinamidase activity (112115). This indicated that polymorphism in pncA could be exploited for screening pyrazinamide-resistant strains, but could not be considered to be the molecular mechanism underlining pyrazinamide resistance in all clinical isolates. Cellular target of pyrazinamide is still obscure and needs to be further explored. Fluoroquinolones Fluoroquinolones are synthetic derivatives of nalidixic acid, a family of antibiotics that inhibit replication of DNA in permeable cell system (116). Fluoroquinolones target the bacterial DNA gyrase, an ATP-dependent type II DNA topoisomerase that catalyses the negative

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Tuberculosis

Figure 49.9: Schematic representation of mutations in pncA associated with pyrazinamide resistance in Mycobacterium tuberculosis Source: references 112,113

supercoiling of DNA. This enzyme is made up of four units [α2β2] that are encoded by the gyrA and gyrB genes, respectively. Fluoroquinolones bind to the gyrase and inhibit the supercoiling of DNA (117). The eukaryotic homologue of gyrase, topoisomerase II, is less sensitive than gyrase to the quinolones; making the quinolones clinically useful antibacterials (118). The gyrA and gyrB genes of Mycobacterium tuberculosis have been cloned and mutations in the quinolone binding site have been mapped (119,120). In subsequent studies the hot spot region for mutations in the gyrA gene was identified. This extends from codon 81 to 95 and polymorphism at codons’ 87, 90, 91, 94 and 95 are common (121). Figure 49.10 schematically represents the reported mutations in gyrA locus. Siddiqi et al (55), reported that mutations in gyrA could be correlated with high levels of ofloxacin resistance, while gyrB mutations associated with low levels of resistance in 68 ofloxacin-resistant isolates. It has been argued that the S95T mutation does not correlate with drug resistance (68). It, therefore, appears that the isolates have acquired resistance to ofloxacin via other mechanisms (55). In another study (33), all the 52 ofloxacin-resistant isolates mapped for their mutations in gyrA were also subjected to whole genome microrestriction analysis by

Figure 49.10: A schematic representation of the reported mutations in gyrA of fluoroquinolone resistant strains of Mycobacterium tuberculosis. The codons 87 to 96 form the hot spot region for mutations at this locus. The middle panel has the wild type sequence. The top panel shows the nucleotide mutations and the bottom panel depicts the corresponding amino acid changes. The underlined mutations are the novel mutations found in the authors’ study

FAFLP. It revealed unique markers, especially the characteristic absence of the 383/384 base pair marker [corresponding to pst C2 gene] in all 52 clinical isolates with a documented ofloxacin resistance pattern in vitro [Figure 49.11] (33). Other Anti-mycobacterial Agents Several other drugs are used to treat drug-resistant TB and nontuberculous mycobacteria [NTM]. These include ethionamide, kanamycin, capreomycin, viomycin

Drug-Resistant Tuberculosis

695

Figure 49.11: Fluorescent amplified fragment length polymorphism [FAFLP] analysis results comparing ICC154, an ofloxacin-resistant isolate that also over-expresses a TAP-like efflux pump under drug pressure, to H37Rv. The FAFLP pattern was generated using primers EcoRI+G/MseI+0 [upper panel], EcoRI+A/MseI+0 [middle panel] and EcoRI+T/MseI+0 [lower panel]. Horizontal scale represents marker sizes in base pairs while vertical scale shows relative peak heights signifying quantitative variation in PCR products Source: reference 33

macrolides [clarithromycin, azithromycin, and roxithromycin]. Little is known about the mechanisms of antituberculosis drug resistance in these agents (121-129). Monotherapy with macrolides had resulted in emergence of resistance, mainly due to point mutations in domain V of 23S rRNA (128,129). Drug Efflux Pumps The drug efflux pumps are major contributors to drug resistance in human pathogens and cancer cells. Reports on presence of such pumps are available in bacterial pathogens to human cancers. Mycobacterial species are no exception and there are few reports on the presence of such pumps in Mycobacterium smegmatis (130-132),

Mycobacterium fortuitum (133) and Mycobacterium tuberculosis (120,134,135). The genome of Mycobacterium tuberculosis [H37Rv] revealed presence of 20 such putative efflux proteins. However, negligible evidence exists related to their involvement of any of these proteins to drug resistance in Mycobacterium tuberculosis. The fact that many researchers have been unable to relate the level of resistance in multidrug-resistant strains to the mutations in the target genes indicate that like other bacteria, Mycobacterium tuberculosis also may have more than one drug efflux pumps. Most bacterial drug-resistant pumps are from the major facilitator family of efflux pumps (136). These are membrane translocases and use a proton motive force

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Tuberculosis

as a source of energy. Few examples of this family include TetA, B and C proteins which mediate tetracycline export in Gram-negative bacteria, NorA, a quinolone resistance protein of Staphylococcus aureus and the multidrug resistance protein [Bmr] from Bacillus subtilis. Another family of transporters involved in drug efflux is the adenosine triphosphate binding cassette [ABC] transporters. These transporters contribute to resistance in eukaryotes and an interesting example of this family is P-glycoprotein (136). Few of the efflux protein genes of Mycobacterium tuberculosis that have been characterized are ABC-transporter drrABC, efpA and resistance to ethidium bromide [emrE] genes. Recently, it was shown that Rv1258c gene of Mycobacterium tuberculosis encodes an efflux protein that is similar to Tap protein in Mycobacterium fortuitum and confers weak resistance to tetracycline (133). Siddiqi et al (33) have reported a novel and definite association between drug resistance and transcription levels of Rv1258c in a multidrug-resistant clinical isolate of Mycobacterium tuberculosis [ICC154] which possesses a unique genotypic signature. In another study (126), the Mycobacterium bovis P55 gene, located downstream from the gene that encodes the immunogenic lipoprotein P27, was characterized (135). The gene was identical to the open reading frame of the Rv1410c gene in the genome of Mycobacterium tuberculosis H37Rv, annotated as a probable drug efflux protein. The presence of specific markers has implications in rapid identification of multidrug-resistant clinical isolates and consequent disease management Molecular mechanisms of antituberculosis drug resistance are summarized in Table 49.1. POTENTIAL CAUSES OF DRUG RESISTANCE Several factors have been implicated in the causation of MDR-TB [Table 49.2] and have been discussed in detail in a recent review (6). The various causes of inadequate treatment are listed in Table 49.3 (138). MULTIDRUG-RESISTANT TUBERCULOSIS IN THE IMMUNOCOMPROMISED While reports from the early 1990s documented several institutional outbreaks of MDR-TB among HIV infected patients (5-7), it is presently believed that HIV infection per se does not appear to be a predisposing factor for the development of MDR-TB. However, some studies

Table 49.1: Molecular mechanisms underlying antituberculosis drug resistance Drug

Genes involved in resistance

Group 1 First-line oral antituberculosis agents Isoniazid

Rifampicin

Enoyl acyl carrier protein [acp] reductase [inhA] Catalase-peroxidase [katG] Alkyl hydroperoxide reductase [ahpC] Oxidative stress regulator [oxyR] β-Ketocyl acyl carrier protein synthase [kasA] RNA polymerase subunit B [rpoB]

Pyrazinamide

Pyrazinamidase [pncA]

Ethambutol

Arabinosyl transferase [emb A, emb B, and emb C]

Group 2 Injectable antituberculosis agents Streptomycin

Ribosomal protein subunit 12 [rpsL] 16s ribosomal RNA [rrs] Aminoglycoside phosphotransferase gene [strA]

Capreomycin

Haemolysin [tlyA]*

Group 3 Fluoroquinolones

DNA gyrase [gyr A and gyr B]

* The tlyA gene in Mycobacterium tuberculosis encodes a 268amino acid polypeptide, which shows striking similarity to a haemolysin/cytotoxin, tlyA, from the spirochete Serpulina hyodysenteriae Adapted from reference 6 Table 49.2: Factors implicated in the causation of multidrug-resistant tuberculosis Factors related to previous treatment Incomplete and inadequate treatment Errors in management Use of a single drug Addition of a single drug to a failing regimen Failure to identify pre-existing resistance Initiation of an inadequate primary regimen Failure to identify and address non-adherence to treatment Inappropriate isoniazid treatment of latent tuberculosis infection Variations in the bioavailability of antituberculosis drugs Logistic issues Lack of good reliable laboratory services Virulence of the organism Host genetic factors HLA-DRB1*1, DRB1*14 HLA-DRB1*0803 Source: references 5-9,137

Drug-Resistant Tuberculosis Table 49.3: Causes of inadequate treatment Causes

Description

Lack of political commitment Noncompliance with available Providers/programmes: inadequate regimens guidelines Absence of guidelines Poor training Unsupervised treatment Poorly organized or funded tuberculosis control programmes Drugs: inadequate supply/quality

Patients: inadequate drug intake

Poor quality Unavailability of certain drugs [stockouts or delivery disruptions] Poor storage conditions Wrong dose or combination Poor adherence [or poor direct observation of treatment] Lack of information Lack of money [no free treatment available] Lack of transportation Side effects Social barriers Malabsorption Substance abuse disorders

Adapted and reproduced with permission from reference 138

(139,140) have found that MDR-TB is not more common among people infected with HIV. Factors predisposing for increased chances of MDR-TB occurring in persons with HIV infection and AIDS are listed in Table 49.4 (5-7). Epidemiological evidence reveals the Mycobacterium tuberculosis strains infecting HIV patients have a different lineage, clustering pattern and dynamics than those infecting immunocompetent hosts (141). Comparative genomics also showed that Mycobacterium tuberculosis infecting HIV seropositive and HIV seronegative population are distinct with a maximum genetic distance of 63 per cent (142). Clonal groupings were observed among Mycobacterium tuberculosis isolates obtained from patients with AIDS. However, isolates from HIV seronegative individuals were found to be relatively heterogeneous and nonclonal. Earlier reports by Yang et al (143), however, could not show any significant differences between the IS6110-based genotypes of HIV1-associated isolates and those from immunocompetent patients in Tanzania. This may be attributed to inherent

697

Table 49.4: Predisposing factors for development of multidrug-resistant tuberculosis in persons with human immunodeficiency virus infection/acquired immunodeficiency syndrome Increased susceptibility to TB Increased opportunity to acquire TB Overcrowding Exposure to patients with MDR-TB due to increased hospital visits Malabsorption of antituberculosis drugs Inadequate antituberculosis treatment Administration of poor quality drugs Frequent interruption of treatment with antituberculosis drugs and antiretroviral drugs MDR-TB = multidrug-resistant tuberculosis; TB = tuberculosis;

problems with IS6110 typing method (144). Further studies are required to understand these issues. Extensively Drug-resistant Tuberculosis Extensively drug-resistant TB [XDR-TB] is increasingly being reported from several parts of the world (145-148) including India (149) during the last two years. Among immunosuppressed patients, XDR-TB has been associated with an exceptionally high mortality with very few survivors as the treatment options are very few in these patients. The evolution, case definition and epidemiological aspects of extensively drug-resistant TB [XDR-TB] have been addressed in the chapter “Antituberculosis drug-resistance surveillance” [Chapter 50]. MANAGEMENT The treatment of MDR-TB and XDR-TB should be undertaken by experienced clinicians at centres equipped with reliable, periodically accredited laboratory services for mycobacterial culture and in vitro sensitivity testing (5-7,150). In the early reports of outbreaks of MDR-TB in HIV-co-infected patients in hospitals and prisons, the mortality rate was very high, ranging from 70 to 90 per cent (5-7). However, subsequent studies have documented better outcome in patients with MDR-TB (5-7). Principles of Management Need for Standard Definitions No randomized, controlled trials exist addressing the issue of the optimal management strategy for MDR-TB

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Tuberculosis

and XDR-TB. The standardization of definitions for MDR-TB case registration and treatment outcomes would permit the accumulation of evidence and would facilitate cross-programme comparisons. Table 49.5 lists the standard definitions that are useful in the management of patients with MDR-TB (151).

Principles of Treatment When a patient is suspected to have drug-resistant-TB, the sputum, body fluidm, secretion must be subjected to mycobacterial culture and antituberculosis drugsensitivity testing [DST]. Depending on the scenario

Table 49.5: Treatment outcome definitions for patients with multidrug-resistant tuberculosis New MDR-TB patients MDR-TB patients who have never received TB treatment, or who have received TB treatment for less than 1 month MDR-TB patients previously treated with only first-line drugs MDR-TB patients who were treated for more than 1 month with only first-line antituberculosis drugs*† MDR-TB patients previously treated with second-line drugs MDR-TB patients who were treated for more than 1 month with at least one second-line antituberculosis drug [with or without first-line drugs] † Transfer-in MDR-TB patients who have been transferred from another DOTS-Plus register to continue treatment. Their outcomes should be reported to the transferring unit so they can report their outcomes in the cohort in which they originally started MDR-TB treatment Others Includes MDR-TB patients who were treated outside DOTS programmes Cure An MDR-TB patient who has completed treatment according to country protocol and has been consistently culture-negative [with at least 5 results] for the final 12 months of treatment‡ Treatment completed An MDR-TB patient who has completed treatment according to country protocol but does not meet the definition for cure or treatment failure due to lack of bacteriologic results [i.e., fewer than 5 cultures were performed in the final 12 months of treatment] Death An MDR-TB patient who dies for any reason during the course of MDR-TB treatment Treatment default An MDR-TB patient whose MDR-TB treatment was interrupted for 2 or more consecutive months for any reason Treatment failure Treatment will be considered to have failed if 2 or more of the 5 cultures recorded in the final 12 months are positive, or if any one of the final 3 cultures is positive. Treatment will also be considered to have failed if a clinical decision has been made to terminate treatment early due to poor response or adverse events Transfer-out An MDR-TB patient who has been transferred to another reporting and recording unit and for whom the treatment outcome is unknown * It may also be useful to note if patients received a re-treatment regimen † Patients should be further defined by the outcome of the most recent previous treatment: failure, return after default, relapse, or transfer-in ‡ A positive culture requires more than 10 colonies on solid media; 2 consecutive positive cultures must be obtained if, less than 10 colonies are detected in the first culture; if the second culture also contains less than 10 colonies, the culture should be interpreted as positive. If only one positive culture is reported during that time, and there is no concomitant clinical evidence of deterioration, a patient may still be considered cured, provided that this positive culture is followed by a minimum of three consecutive negative cultures, taken at least 30 days apart TB = tuberculosis; MDR-TB = multidrug-resistant tuberculosis Adapted from reference 151

Drug-Resistant Tuberculosis where the patient is being cared for, these patients should be started on WHO Category II treatment (152) or the regimens suggested by the American Thoracic Society [ATS], the Centers for Disease Control and Prevention [CDC], and the Infectious Diseases Society of America [IDSA] (153) while the mycobacterial culture and sensitivty report is awaited. Further therapy is guided by the culture and sensitivity report. The treatment options are shown in Figure 49.12. A single drug should never be added to a failing regimen. Drugs with potential for cross-resistance should not be used. At least three previously unused drugs to which there is in vitro susceptibility must be employed when initiating treatment (153,154). Recent publications (155,156) suggest moxifloxacin to be the most potent among the currently available fluoroquinolones. The results of a study from Peru (157) suggest that community-based outpatient treatment of patients with MDR-TB is possible with high cure rates even in resourcepoor settings. Various drugs that are currently being used for the treatment of MDR-TB are listed in Table 49.6 (6,7,154). The reader is also referred to the chapters “Evolution of chemotherapeutic regimens in the treatment of tuberculosis and their scientific rationale” [Chapter 51] and “Treatment of tuberculosis” [Chapter 52] for more details regarding the adverse drug reactions and other treatment issues related to these drugs.

Figure 49.12: Treatment strategies for multidrug-resistant tuberculosis DRS = drug resistance surveillance; DST = drug sensitivity testing Reproduced with permission from “World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/TB/2006.361. Geneva: World Health Organization; 2006 (reference 154)”

699

DOTS-Plus Strategy While DOTS is a key ingredient in the TB control strategy, it has been found to be inadequate in populations where MDR-TB is endemic (158). The WHO and its international partners have been evolving the “DOTS-Plus for MDR-TB programmes” [Table 49.7] to facilitate the programmatic treatment of MDR-TB in low- and middleincome countries that have adopted the DOTS strategy. The Green Light Committee is a unique partnership established by the WHO to lower the prices of and to increase control over second-line antituberculosis drugs and close to 50 DOTS-Plus projects are underway across the globe (5,6,159-162). The Revised National Tuberculosis Control Programme [RNTCP] of the Government of India has also initiated the DOTS-Plus strategy (138,163). In this strategy, 24 RNTCP state level Intermediate Reference Laboratories [IRLs], accredited to perform culture and DST are being set up. The RNTCP has initiated the establishment of the IRLs network in a phased manner across the country, with support from the four National Reference Laboratories at Chennai, Bengaluru, New Delhi, and Agra. The treatment of MDR-TB patients is planned to begin at DOTS-Plus sites established in a limited number of highly specialized centres, at least one in each state. On the 29th of August 2007, Gujarat became the first state in the country to initiate MDR-TB patients on treatment under RNTCP with its Category IV regimen (163). Subsequently, another pilot study of MDR-TB treatment has started in the State of Maharashtra. The programme is expected to cover the whole country in a phased manner. The principles underlying constitution of individualised regimens design based on DST for first-line antituberculosis drugs suggested by the WHO are shown in Tables 49.8A and 49.8B (164). The recommended duration of treatment is guided by smear and culture conversion. The minimal suggested duration is for at least 18 months after culture conversion. Extension to 24 months may be indicated in patients defined as “chronic cases” (6,7,153,154) with extensive pulmonary damage. The Category IV regimen used in the RNTCP (138, 163,164) comprises of six drugs, kanamycin [K], ofloxacin (Ofl), ethionamide [Eto], pyrazinamide [Z], ethambutol [E] and cycloserine [Cs] during six to nine months of the intensive phase and four drugs [ofloxacin, ethionamide, ethambutol and cycloserine] during the 18 months of the

700

Tuberculosis Table 49.6: Antituberculosis drugs used in the treatment of multidrug-resistant tuberculosis

Drug

Daily dosage

Group 1 First-line oral antituberculosis agents Pyrazinamide Ethambutol Group 2 Injectable antituberculosis agents Capreomycin* Kanamycin Amikacin Group 3 Fluoroquinolones† Ofloxacin Levofloxacin Gatifloxacin Moxifloxacin Group 4 Oral bacteriostatic second-line antituberculosis drugs Thioamides‡ Ethionamide Prothionamide Cycloserine Terizodone§ Para-aminosalicylic acid [PAS]

20-30 mg/kg [1200 to 1600 mg] 15-20 mg/kg [1000 to 1200 mg] 15 mg/kg [750-1000 mg] 15 mg/kg [750 to 1000 mg] 15 mg/kg [750 to 1000 mg] 7.5-15 mg/kg [600 to 800 mg] 500 to 1000 mg 400 mg 400 mg

10-20 mg/kg [500 to750 mg] 10-20 mg/kg [500 to 750 mg] 15-20 mg/kg [500 to 750 mg] 15-20 mg/kg [600 mg] 150 mg/kg [10 to12 g]

* No cross-resistance with other aminoglycosides, such as kanamycin, streptomycin † Currently, the most potent available fluoroquinolones in descending order based on in vitro activity and animal studies are: moxifloxacin = gatifloxacin > levofloxacin > ofloxacin = ciprofloxacin. Moxifloxacin is better tolerated and causes fewer adverse events as compared with other fluoroquinolones ‡ Chemical structure resembles thioacetazone with which there is frequent and partial cross-resistance. However, strains resistant to thioacetazone are often sensitive to thioamides, but the reverse is seldom the case. More acceptable if it is administered with orange juice or milk, or after milk, or at bedtime to avoid nausea § Terizidone is a combination of two molecules of cycloserine Source: reference 154

Table 49.7: Components of DOTS-Plus strategy Sustained political and administrative commitment Accurate, timely diagnosis through quality-assured culture and drug susceptibility testing Uninterrupted supply of quality assured first-and second-line drugs; appropriate treatment strategies utilizing second-line drugs under strict supervision Directly observed treatment Standardized recording and reporting system that enables performance monitoring and evaluation of treatment outcome

continuation phase. Para-aminosalicylic acid [PAS] is included in the regimen as a substitute drug if any bactericidal drug [K, Ofl, Z and Eto] or any two bacteriostatic [E and Cs] drugs are not tolerated. The details regarding the clinical, microbiological and radiological follow-up protocol and schedule are too exhaustive and cumbersome to be listed in this chapter.

Similarly, details regarding the management of MDRTB in special situations, such as renal failure, pregnancy, base, line hepatic dysfunction, among others is also too technical for the general reader who is, anyway, not expected to undertake the management of MDR-TB on an individual basis. The interested reader is, therefore, referred to the websites of the WHO (154), or, the Central TB Division, Ministry of Health and Family Welfare, Government of India (138,163,164) for the latest details on this topic. The results from the retrospective study (165) of MDR-TB patients [n = 204], treated under the Latvian DOTS-Plus strategy following WHO guidelines, have been encouraging; 66 patients were cured or completed treatment, seven per cent died, 13 per cent defaulted, and 14 per cent did not respond to treatment. Data on adverse drug reactions [ADRs] collected from five DOTSPlus sites in Estonia, Latvia, Peru, the Philippines, and

Drug-Resistant Tuberculosis

701

Table 49.8A: Suggested regimens for mono- and poly-drug resistant tuberculosis other than multidrug-resistant tuberculosis Pattern of drug resistance

Suggested regimen

Minimum duration of treatment [months]

Comments

H [± S]

R, Z and E

6-9

A fluoroquinolone may strengthen the regimen for patients with extensive disease

H and Z

R, E and fluoroquinolones

9-12

A longer duration of treatment should be used for patients with extensive disease

H and E

R, Z and fluoroquinolones

9-12

A longer duration of treatment should be used for patients with extensive disease

R

H, E, fluoroquinolones, plus at least 2 months of Z

12-18

An injectable agent may strengthen the regimen for patients with extensive disease

R and E [± S]

H, Z, fluoroquinolones, plus an injectable agent for at least the first 2-3 months

18

A longer course [6 months] of the injectable agent may strengthen the regimen for patients with extensive disease

R and Z [± S]

H, E, fluoroquinolones, plus an injectable agent for at least the first 2-3 months

18

A longer course [6 months] of the injectable agent may strengthen the regimen for patients with extensive disease

H, E, Z [± S]

R, fluoroquinolones, plus an oral second-line agent, plus an injectable agent for the first 2–3 months

18

A longer course [6 months] of the injectable agent may strengthen the regimen for patients with extensive disease

H = isoniazid; S = streptomycin; R = rifampicin; Z = pyrazinamide; E = ethambutol Adapted with permission from reference 154

Table 49.8B: Suggested regimens for multidrug-resistant tuberculosis Pattern of drug resistance

Suggested regimen

Comments

H-R

Z-E-injectable agent-fluoroquinolone [± one or two Group 4 agents]*

One Group 4 agent is sufficient if E and Z susceptibility has been ascertained. Two Group 4 agents* should be used in extensive disease, or if the DST result is questionable [i.e., reported susceptibility to E or Z despite a history of these agents being used in a failing regimen]

H-R [± S] and E or Z

Z or E-injectable agent-fluoroquinolone [± two or more Group 4 agents]*

Only use the first-line agents to which the patient’s strain is susceptible. Use alternative injectable agent if S resistance is present. More than two Group 4 agents should be used in extensive disease or if resistance to E and Z is present or suspected Group 5 agents† can be considered if an adequate regimen of four drugs cannot be formed based on DST

H = isoniazid; R = rifampicin; S = streptomycin; Z = pyrazinamide; E = ethambutol; DST = drug sensitivity testing * Group 4 agents = ethionamide [Eto]; prothionamide [Pto]; cycloserine [Cs]; terizidone [Trd]; para-aminosalicylic acid [PAS]; thioacetazone [Th]. † Group 5 agents = clofazimine [Cfz]; amoxycillin/clavulanate [Amx/Clv]; clarithromycin [Clr]; linezolid [Lzd] Adapted with permission from reference 154

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Tuberculosis

the Russian Federation (166) showed that, among 818 patients enrolled for MDR-TB treatment, only two per cent of patients stopped treatment and 30 per cent required removal of the suspected drugs from the regimen and use of alternative drugs due to ADRs. Monitoring Response to Treatment Patients receiving treatment for MDR-TB should be closely followed up. Clinical, radiological, laboratory, and microbiological parameters should be frequently reviewed to assess the response to treatment. Additionally, considerable attention must be focussed on monitoring the ADRs (5-7).

Global Experience in the Management of Drugresistant Tuberculosis Multidrug-resistant Tuberculosis In the early reports of outbreaks of MDR-TB in HIVco-infected patients in hospitals and prisons, the mortality rate was very high, ranging from 70 to 90 per cent (5-7). However, subsequent studies have documented better outcome in patients with MDR-TB [Table 49.9A] (168-190). These results suggest that communitybased outpatient treatment of patients with MDR-TB is possible with high cure rates even in resource-limited settings.

Table 49.9A: Global experience in the treatment of drug-resistant tuberculosis Study (reference)

Year of Type of publication DR-TB

Treatment

Outcome

Goble et al (167)

1993

MDR-TB [n = 171]

Antituberculosis drugs, individualized treatment + resective surgery [n = 9]

Of 134 patients with sufficient follow-up data, cured 65%, treatment failure 35%

Telzak et al (168)

1995

MDR-TB [n = 25]

Antituberculosis drugs, individualized treatment + resective surgery [n = 3]

Clinical response 96%; all 17 patients for whom data were available had microbiologic response

Sharma et al (10)

1996

MDR-TB [n = 19]

Antituberculosis drugs, individualized treatment

Sputum conversion in 18 of the 19 patients

Viskum et al (169)

1997

1998 [n = 8]

Antituberculosis drugs, individualized treatment

8 of the 9 patients responded favourably to treatment; 1 patient died

Park et al (170)

1998

MDR-TB [n = 107]

Antituberculosis drugs, individualized treatment + resective surgery [n = 22]

Of 63 patients with sufficient follow-up data, cured 82.5%, treatment failure 17.5%

Avendano et al (171) 2000

MDR-TB [n = 40]

Antituberculosis drugs , individualized treatment + resective surgery [n = 6]

Bacteriological conversion achieved in 85%, died 12%

Geerligs et al (172)

2000

MDR-TB [n = 44]

Antituberculosis drugs, individualized treatment + resective surgery [n = 6]

Cured 75%, death 14%

Yew et al (173)

2000

MDR-TB [n = 63]

Antituberculosis drugs, individualized regimen

Cured 81%, treatment failure 14.3%, death 4.7%

Kim et al (174)

2001

MDR-TB [n = 1011]

Antituberculosis drugs, individualized treatment

Cured 48%, treatment failure 8.1%, default 39%, transferred out 4.3%, death 0.3%

Tahaoglu et al (175)

2001

MDR-TB [n = 158]

Antituberculosis drugs, individualized treatment + resective surgery [n = 36]

Cured or completed treatment 77%, default 11%, treatment failure 8%, death 4%

Suarez et al (176)

2002

Chronic TB [n = 466] Of these 298 had MDRTB

Antituberculosis drugs, Standard empirical treatment

Cured 48%, treatment failure 28%, default 11%, death 12% -Contd-

Drug-Resistant Tuberculosis

703

Table 49.9A -ContdStudy (reference)

Year of Type of publication DR-TB

Mitnick et al (177)

2003

MDR-TB [n = 75]

Narita et al (178)

2001

MDR-TB [n = 81]

Leimane et al (165)

2005

Treatment

Outcome

Antituberculosis drugs, individualized treatment + resective surgery [n = 3] Antituberculosis drugs

Among the 66 patients who completed 4 or more months of therapy, cured or completed treatment 83%, death 8% Completed treatment 57%, default 41%, death 32%

MDR-TB [n = 204]

Antituberculosis drugs, individualized treatment regimen

Cured or completed therapy 66%, treatment failure 14 %, default 13%, death 13%

Nathanson et al (179) 2006

MDR-TB [n = 1047]

Gandhi et al (180)

2006

XDR-TB [n = 53]

Antituberculosis drugs, individualized treatment regimen + resectional surgery [n = 114] Antituberculosis drugs

Cured or completed treatment 69.7%, treatment failure 6.7%, default 10.5%, death 13% 52 of the 53 patients died

TRC, Chennai (181)

2007

MDR-TB [n = 65] XDR-TB [n = 1]

Antituberculosis drugs, individualized treatment regimen

Cured 38%, treatment failure 26%, default 24%, death 12%

Sharma (182)

2007

Dhingra et al (183)

2008

MDR-TB [n = 172] XDR-TB [n = 1] MDR-TB [n = 27]

Antituberculosis drugs, individualized treatment regimen Antituberculosis drugs, individualized treatment regimen

Cured 41.6%, treatment failure 38.7%, default 15%, death 4.6% 13 patients were cured, 10 defaulted, one died, and 1 was still under treatment

Shean et al (184)

2008

MDR-TB [n = 491]

Antituberculosis drugs, individualized treatment regimen

Cured or completed treatment 49%, death 14%, default 29%, treatment failure 5%

Masjedi et al (185)

2008

MDR-TB [n = 43]

Mitnick et al (186)

2008

XDR-TB [n = 48] MDR-TB [n = 603]

Antituberculosis drugs, individualized treatment regimen Antituberculosis drugs, individualized treatment regimen + resectional surgery [n = 94; 7 patients with XDR-TB and 87 patients with MDR-TB]

Cured or completed treatment 67.5%, treatment failure 14%, death 18.6% 60.4% patients with XDR-TB completed treatment or were cured 66.3% patients with MDR-TB completed treatment or were cured

Bonilla et al (187)

2008

XDR-TB [n = 43]

Antituberculosis drugs individualized regimen [n = 37], standardized regimen [n = 6]

Cured or treatment completed 49%, treatment failure 14%, default 19%, death 19%

Kwon et al (188)

2008

XDR-TB [n = 27] MDR-TB [n = 128]

Antituberculosis drugs, individualized regimen + resectional surgery [n = 35; 22 patients with MDR-TB, 13 patients with XDR-TB]

Banerjee et al (189)

2008

XDR-TB [n = 18] MDR-TB [n = 406]

Antituberculosis drugs, individualized regimen

Overall, cured or completed treatment 66%, default 10%, treatment failure 14%, death 6% Treatment success rate [cured or completed treastment] was similar among patients with MDR-TB [66%] and XDR-TB [65%] Among 17 patients with XDR-TB with known outcomes, 41.2% completed treatment, 29.4% died, 1 patient continues to receive treatment

Keshavjee et al (190) 2008

XDR-TB [n = 29] MDR-TB [n = 579]

Antituberculosis drugs individualized regimen

Among patients with XDR-TB cured or treatment completed 48·3%, treatment failure 31% Among patients with MDR-TB, cured or treatment completed 66·7%, treatment failure rate 8.5%

DR-TB = drug resistant tuberculosis; MDR-TB = multidrug-resistant tuberculosis; TRC = Tuberculosis Research Centre; XDR-TB = extensively drug-resistant tuberculosis

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Extensively drug-resistant Tuberculosis Initial reports documenting XDR-TB were associated with an exceptionally high mortality rate. In the outbreak that occurred in a rural area in KwaZulu Natal Province in South Africa in (180), 52 of 53 patients with XDR-TB died. Forty four of the XDR-TB patients tested were HIVseropositive. The median survival was 16 days from the time of diagnosis among the 42 patients with confirmed dates of death. However, subsequently published data [Table 49.9A] suggest higher cure rates.

to correct remediable factors, such as malnutrition (6,7,157,165,167,168,175,191). Newer Antituberculosis Drugs Following the introduction of rifampicin, no worthwhile antituberculosis drug with new mechanism[s] of action has been developed in the last three decades. Some of the older drugs that are being evaluated again and the newer drugs with potential as antituberculosis agents that are at various stages of development are listed in Table 49.10.

Prognostic Markers

Surgery

Table 49.9B summarizes markers of poor prognosis in patients with MDR-TB. Recognition of these factors may help clinicians to monitor the patients more closely and

The role of surgery in the management of MDR-TB is discussed in detail in the chapter “Surgery for pleuropulmonary tuberculosis” [Chapter 55].

Table 49.9B: Markers of poor prognosis in patients with multidrug-resistant tuberculosis Study

Year of publication

No. of subjects [% HIV-positive]

Markers of poor prognosis

Park et al (170)

1996

173 [52]

Extra-pulmonary involvement

Telzak et al (168)

1999

156 [100]

History of prior tuberculosis treatment

Flament-Saillour et al (191)

1999

51 [16]

HIV-coinfection, treatment with less than two active drugs, and knowledge regarding the multidrug-resistant status at the time of diagnosis

Tahaoglu et al (175)

2001

158

Older age, history of previous treatment with a larger number of drugs

Drobniewski et al (192)

2002

90 [29]*

Immunocompromised status, failure to culture the bacterium in 30 days or to apply appropriate treatment with three drugs to which the organism is susceptible, and age

Mitnick et al (177)

2003

75 [1.5%]†

Low haematocrit and resistance to pyrazinamide or ethambutol

Leimane et al (165)

2005

204 [0.5]‡

Previous treatment for MDR-TB, the use of five or fewer drugs for > 3 months, resistance to ofloxacin, BMI 35 % in several countries of the former Soviet Union]. The countries of the former Soviet Union are facing a more serious and widespread epidemic, since the population weighted average of countries reporting indicates that almost half of all TB cases are resistant to at least one drug and MDR-TB accounted for one among every five cases of TB. In this region, MDR-TB cases had more extensive resistance patterns including some of the highest proportions of extensively drug-resistant TB [XDR-TB]. A similar high burden of MDR-TB was observed in some provinces in China, while Western Europe and some countries in Africa, reported the lowest proportions of MDR-TB. It is noteworthy that at least one country in all six WHO regions has reported greater than three per cent MDRTB among new cases. Data from surveys in 10 of 31 provinces in China over a ten-year period indicate that drug resistance is widespread and represent the highest burden of cases in the world. It is estimated that 130 548 MDR-TB cases emerged in 2006 accounting for over 25 per cent of the global burden. The high proportion of drug-resistant TB in new cases China suggests transmission of drugresistant strains. It is estimated that over 10 per cent of the MDR-TB cases that emerged globally in 2006 occurred in patients in China who had no prior history of

717

antituberculosis treatment (14). Since China has reached the global targets for case detection and treatment success, it was felt that the rapid implementation of services for the diagnosis and treatment of MDR-TB was necessary to ensure success of the TB control programme and to control transmission of drug-resistant strains. In 2006, 118 732 diagnostic were reported among 108 countries [with 74 % of these tests conducted in the European Region] (14). The proportion of new cases for whom DST was done was also highest in the Europe [45 countries with 78% of estimated MDR-TB cases accounted for in that region], followed by the Americas [17 countries with 50% of MDR-TB cases accounted in the region]. The South-East Asia Region showed the fewest cases, with only two countries reporting the 0.03 per cent cases accounted for in the region]. The proportion of DST for re-treatment cases also followed a similar pattern [Table 50.1] (13). The WHO Report 2008 (15) also indicated that a small number of MDR-TB cases were diagnosed compared with the large number of cases that were estimated to exist in the respective WHO regions. These observations suggest that an enormous amount of work remains to be done to improve the availability and provision of diagnosis and treatment for MDR-TB. These surveillance results suggest link between the quality of TB control programmes and levels of drug resistance. However, this relationship is complex (17). Extensively Drug-resistant Tuberculosis The Centers for Disease Control and Prevention [CDC], Atlanta, in March 2006 reported the extensively drugresistant tuberculosis [XDR-TB] (16). The XDR-TB is defined as cases in persons with TB whose isolates were resistant to isoniazid and rifampicin and at least three of the six main classes of second-line drugs, such as aminoglycosides, polypeptides, fluoroquinolones, thioamides, cycloserine, and para-aminosalicyclic acid (17,18). Subsequently, this definition has been modified and XDR-TB is defined as isolates resistant to at least rifampicin and isoniazid [which is the definition of MDRTB], in addition to any fluoroquinolone, and to at least one of the three following injectable drugs used in antituberculosis treatment, such as capreomycin, kanamycin and amikacin (19-25). A summary of the results of that survey, which was published in a Fact Sheet (18), determined that during 2000 and 2004, of 17 690 TB

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Tuberculosis

Figure 50.1: Countries/settings with prevalence of any resistance higher than 30% among new cases, 2002–2007 Reproduced with permission from “The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 2002-2007. Anti-tuberculosis drug resistance in the world. Fourth Global Report. WHO/HTM/TB/2004.343. Geneva: World Health Organization; 2008 (reference 14)”

Figure 50.2: Countries/settings with prevalence of MDR-TB higher than 5% among new cases 2002-2007 MDR-TB = multidrug-resistant tuberculosis Reproduced with permission from “The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 2002-2007. Anti-tuberculosis drug resistance in the world. Fourth Global Report. WHO/HTM/TB/2008.394. Geneva: World Health Organization; 2008 (reference 14)”

Antituberculosis Drug Resistance Surveillance

719

Figure 50.3: Countries/settings with a prevalence of MDR-TB higher than 30% among previously treated cases, 2002-2007 Reproduced with permission from “The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 2002-2007. Anti-tuberculosis drug resistance in the world. Fourth Global Report. WHO/HTM/TB/2008.394. Geneva: World Health Organization; 2008 (reference 14)”

Table 50.1: World Health Organization region-wise information on the number of countries reporting diagnostic drug sensitivity testing in 2006 and the estimated multidrug-resistant tuberculosis cases accounted for in each region Region

New cases No. of countries reporting

Africa

Re-treatment cases % of estimated MDR-TB cases accounted for in that region

No. of countries reporting

% of estimated MDR-TB cases accounted for in that region

8

10

11

14

Americas

17

50

15

65

Eastern Mediterranean

10

11

6

13

European

45

78

40

81

South-East Asia

2

3

2*

Western Pacific

15

12

0.03

12

3

World

97

19

87

19

* Data from India and China excluded because testing of only 26 [India] and 10 [China] re-treatment cases was reported MDR-TB = mulitdrug-resistant tuberculosis Source: reference 13

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Tuberculosis

Figure 50.4A: Prevalence of multidrug-resistant tuberculosis among new tuberculosis cases, 1994-2007 Reproduced with permission from “World Health Organization. Anti-tuberculosis drug resistance in the world. Report No. 4. WHO/ IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. WHO/HTM/TB/2008.394. Geneva: World Health Organization; 2008 (reference 14)”

Figure 50.4B: Prevalence of multidrug-resistant tuberculosis among previously treated tuberculosis cases, 1994-2007 Reproduced with permission from “World Health Organization. Anti-tuberculosis drug resistance in the world. Report No. 4. WHO/ IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. WHO/HTM/TB/2008.394. Geneva: World Health Organization; 2008 (reference 14)”

Antituberculosis Drug Resistance Surveillance convenient sample isolates from 49 countries, the XDRTB was approximately 10 per cent and was spread over 17 countries. In addition, population-based data on drug susceptibility of TB isolates were obtained from the United States [for the years 1993-2004], Latvia [for the years 2000-2002], and South Korea [for the year 2004], where four per cent, 19 per cent, and 15 per cent of MDRTB cases, respectively, were XDR-TB. A total of 12 [10.9%] of 113 MDR-TB strains in Iran were resistant to all eight second-line drugs tested and, therefore, were denoted as XDR-TB. Retrospective analysis of the cases of XDRTB showed that all of them belonged to one of the two epidemiological clusters, either a single-family cluster [4 cases] or a cluster of close contacts [8 cases] (19). An unpublished report from Tuberculosis Research Centre [TRC], Chennai, has indicated that XDR-TB to be approximately four per cent of 3173 isolates received in TRC during the period 2001 to 2004 from chronically ill patients with a prolonged and varying treatment history. The global burden of XDR-TB is shown in Figures 50.5A (25) and 50.5B (14). The XDR-TB has emerged worldwide as a threat to public health and TB control, raising concerns of a future epidemic of virtually untreatable TB. PREVALENCE OF DRUG-RESISTANT TUBERCULOSIS IN INDIA Drug-resistant TB has frequently been encountered in India and its presence has been known from the time antituberculosis drugs were introduced. Lack of comprehensive reports on this subject is mainly due to limited facilities for culture and susceptibility tests. Much of the drug resistance is presumed clinically when patients do not improve or the symptoms return after initial relief where sputum remains positive for acid-fast bacilli. Drug Resistance in Newly Diagnosed Cases Though drug resistance in newly diagnosed cases is found to be low in developed countries, it is common in India and varies widely in different regions. The Southeast Asia region is a major contributor, accounting for almost 30 per cent, of the global burden of MDR-TB among new and previously treated cases [Tables 50.2A and 50.2B] (14). The data on drug resistance in newly

721

diagnosed cases estimated by different investigators over the past 30 years are listed in Table 50.3. In the 1960s Indian Council of Medical Research [ICMR] conducted two nation wide surveys at nine urban chest clinics in India (26,27). The results of the first survey showed resistance level of 8.2 per cent to isoniazid alone, 5.8 per cent to streptomycin alone and 6.5 per cent to both the drugs. The resistance levels among new cases seen in these two surveys were 14.7 per cent and 15.5 per cent respectively to isoniazid and 12.5 per cent and 13.8 per cent respectively to streptomycin. A decade later, a study was conducted to assess the prevalence of resistance among new cases in Government Chest Institute and Chest [Tuberculosis] Clinic of Government Stanley Hospital, Chennai (28). The results of this study were almost similar to the earlier ICMR surveys and the authors reported that the prevalence of resistance among new cases has not risen during the span of 10 years. During the 1980s among five reports on primary drug resistance, while the levels of resistance among new cases to isoniazid and streptomycin were similar to that reported in earlier studies. Rifampicin resistance started appearing in North Arcot, Pondicherry, Bengaluru and Jaipur but not in Gujarat (29-34). The reason for the emergence of rifampicin resistance during this period may be the introduction of short-course chemotherapy [SCC] regimens containing rifampicin. Further, a higher level of resistance among new cases to isoniazid was observed among the rural population in Kolar compared to the urban patients contradicting a Korean study where a much higher level of initial resistance was seen among urban patients giving the reason of easy access to the antituberculosis drugs (4). There was also an increase in the proportion of resistance among new cases to rifampicin [4.4%] encountered in this rural population. In the early 1990s, a retrospective study done at New Delhi (35) showed a high level of resistance among new cases to isoniazid [18.5%] and a low level of rifampicin resistance. Overall, the prevalence rate of resistance among new cases to isoniazid as a single agent ranged from six per cent to thirteen per cent (26-31,33-35) except among the rural population in Kolar, Karnataka (32) where a high rate of 26.7 per cent has been reported. Prevalence of resistance in newly diagnosed cases to streptomycin as

722

Tuberculosis

Figure 50.5A: Global burden of extensively drug-resistant tuberculosis Reproduced with permission from “World Health Organization. Countries with XDR-TB Confirmed cases to date. Available at URL: http://www.who.int/ tb/challenges/xdr/xdrmap_oct07_en.pdf. Accessed on October 22, 2008 (reference 25)”

Figure 50.5B: Extensively drug-resistant tuberculosis: global scenario Reproduced with permission from “World Health Organization. Anti-tuberculosis drug resistance in the world. Report No.4. WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. WHO/HTM/TB/2008.394. Geneva: World Health Organization; 2008 (reference 14)”

Antituberculosis Drug Resistance Surveillance

723

Table 50.2A: Proportion of global mutidrug-resistant tuberculosis in new tuberculosis cases Region

No. of estimated new TB cases

Estimated MDR-TB cases % of global total

No. Established Market Economies

85 729

724

0.3

Central Europe

42 464

416

0.2

Eastern Europe

336 842

43 878

15.4

Latin America

315 216

7 196

2.5

Eastern Mediterranean Region

569 446

16 430

5.8

Africa, low HIV incidence

350 671

5 311

1.9

Africa, high HIV incidence

350 671

43 767

15.3

South-East Asia

3 100 354

85 908

30.1

Western Pacific Region

1 882 930

82 087

28.7

All countries [n = 175]

9 123 922

285 718

100.0

HIV = human immunodeficiency virus Source: reference 14 Table 50.2B: Proportion of global mutidrug-resistant tuberculosis in previously treated tuberculosis cases Region

No. of estimated new TB cases

Estimated MDR-TB cases No.

% of global total

Established Market Economies

5036

413

0.2

Central Europe

8038

785

0.4

Eastern Europe

79 474

36 179

17.8

Latin America

33 856

4 813

2.4

Eastern Mediterranean Region

31 286

9 040

4.4

Africa, low HIV incidence

25 130

3 105

1.5

Africa, high HIV incidence

216 152

14 528

7.2

South-East Asia

363 959

63 707

31.4

Western Pacific Region All countries [n = 175]

289 214

70 601

34.7

1 052 145

203 230

100.0

HIV = human immunodeficiency virus Source: reference 14

a single agent ranged from 1.0 to 5.8 per cent and to rifampicin from 0 to 1.9 per cent (26-35). In many of these surveys ethambutol susceptibility was not performed. In a recently conducted study in Bengaluru (33), the resistance in newly detected cases was 13.7 per cent to isoniazid, 22.5 per cent to streptomycin; and 2.2 per cent had MDR-TB. The resistance to any drug increased with age indicating the effect of improper implementation of TB control measures in Bengaluru before 1999.

For a correct evaluation of primary drug resistance, standardized methodology should have been used taking care of the following, namely, eliciting patient history, adequate sample size, uniform laboratory methods, external and internal quality control, reliable drugs for setting up media for DST, use of standard chemicals in the preparation of media, etc. Many Indian studies may have limitations related to these methodological issues.

2779 2127 436

1983-86

1985-89

Gujarat* (29)

North Arcot (30)

Puducherry (30) 1985-91

Bengaluru† (31)

271

1999

1987-89

1988-91

1990-91

Bengaluru (33)

Kolar§ (32)

Jaipur¶ (34)

New Delhi (35)

18.5

7.6 [10.1]

26.7 [32.8]

13.7

12.6 [17.4]

12.1 [17.4]

6

13

7.9 [13.9]

10.6

15.5

8.2 [14.7]

H

-

5.2 [7.6]

1 [5.1]

22.5

1.7 [4.8]

1.8 [5.7]

4

4

3.2 [7.4]

9.5

13.8

5.8 [12.5]

S

0.6

1.9 [3.0]

1 [4.4]

2.6

1.5 [2.3]

1.8 [3.0]

0.2 [0.9]

0.07 [2.0]

0

ND

ND

ND

R

-

2 [2.6]

0 [1.7]

1.8

0 [0.5]

0 [0.5]

ND

ND

2.5 [4.0]

ND

ND

ND

E

-

ND

ND

ND

ND

ND

ND

ND

0.5 [1.5]

ND

-

-

T

Resistance to single drug (%)

-

1.6

2.4

6.6

2.9

3.6

3

7

3.3

4.7

-

6.5

SH

-

0.7

3.2

2.2

1.2

0.9

0.4

0.7

0

-

-

-

HR

Resistance to multiple drugs (%)

-

0.1

0.7

1.1

0.2

0.2

0.3

0.9

-

-

-

-

SHR

-

19.9

34.9

27.7

20.5

21.1

13.9

26

20

-

22

20.4

Total resistance (%)

Urban

-

Rural

Urban

Urban

Urban

-

Rural

-

Urban

Urban

Urban

Location

H = isoniazid; S = streptomycin; R = rifampicin; E = ethambutol; T = thiacetazone; ND = not done Figures in square brackets indicate percentage of isolates resistant to a drug along with other drugs. [H] = H+SH+HR+SHR; [S] = S+SH+SR+SHR; [R] = R+SR+HR+SHR; [E] = E+HE+SE+SHE+HRE; [T] = T+HT * Multiple drug resistance patterns were also reported for HT [1.0%]: HE [0.7%]: SHE [0.9%] † Multiple drug resistance patterns were also reported for HE [0.5%] ‡ Multiple drug resistance patterns were also reported for HE [0.6%] § Multiple drug resistance patterns were also reported for HE [0.3%]; SHE [1.0%]; HRE [0.3%] ¶ Multiple drug resistance patterns were also reported for SR [0.2%]; SE [0.5%]; SHE [0.1%]

324

1009

292

588

Bengaluru‡ (32) 1985-86

1980s

254

1976

Chennai (28) 570

851

9 Urban Centres 1965-67 in India (27)

No. of isolates tested

1838

Year

9 Urban Centres 1964-65 in India (26)

Study (reference)

Table 50.3: Summary of studies on resistance among new cases in Mycobacterium tuberculosis isolates from India

724 Tuberculosis

Antituberculosis Drug Resistance Surveillance

725

was 63 per cent, out of which 23.5 per cent were resistant to single drug and 39.5 per cent resistant to more than one drug. In a recently conducted study in Bengaluru (38), the multidrug resistance in previously treated cases was found to be 12.8 per cent and ranged from 8.4 per cent to 17.2 per cent. The proportion of 12 per cent MDRTB in previously treated patients appears to be similar in other DOTS implemented areas, such as Hong Kong (39) and Nepal (40). The overall rates of resistance in previously treated patients to isoniazid ranged from 34.5 to 67 per cent, for streptomycin from 26.0 to 26.9 per cent and for rifampicin from 2.8 to 37.3 per cent (26-35).

Resistance in Previously Treated Tuberculosis Cases The rates of resistance in previously treated patients are invariably higher than the rates of resistance in newly diagnosed cases, though data on resistance in previously treated patients are limited. Studies on resistance patterns in previously treated patients are shown in Table 50.4. The longitudinal trend of drug resistance in Gujarat between 1980 and 1986 (34) showed that in treatment failure or relapsed patients, resistance to rifampicin increased from 2.8 per cent in 1980 to 37.3 per cent in 1986 and to isoniazid from 34.5 per cent to 55.8 per cent. From this study (34), it was presumed that high level of rifampicin resistance was almost entirely acquired. A study was conducted by the ICMR (36) to compare the efficacy of SCC with the conventional [non-SCC] chemotherapy in North Arcot district, Tamil Nadu. The population was examined during their follow-up period to confirm the bacterial quiescence and in turn the efficacy of SCC. It was found that there was an increase in the frequency of resistance in previously treated patients with 67 per cent resistance to isoniazid, 26 per cent to streptomycin and 12 per cent to rifampicin. In addition, six per cent of the strains tested were resistant to both isoniazid and rifampicin (36). A study from New Delhi in the 1990s (35) also showed a higher level of resistance in previously treated patients to isoniazid and rifampicin, which is almost similar to that of the Gujarat report (29). A study conducted by the Institute of Thoracic Medicine, Chennai (37) aimed at finding out the prevalence of TB resistance in four District Tuberculosis Centres of Tamil Nadu, showed that acquired resistance

Multidrug Resistance The rate of MDR-TB in new cases in India is very low, ranging from 0 to 3 per cent [Table 50.3]. The drug resistance in various DRS sites in India conducted by two national reference laboratories of India between 19852003, namely Tuberculosis Research Centre [TRC], Chennai and National Tuberculosis Institute [NTI], Bengaluru is shown in Figure 50.6 (33,41-43). The resistance varied from 0.5 to 3.4 per cent. The level of MDR-TB in previously treated cases was less than 13.0 per cent except in Gujarat where a high level was observed [11.4% to 18.5%] (29) [Table 50.4]. In the report from the Institute of Thoracic Medicine, Chennai (37) on the prevalence of MDR-TB among patients undergoing treatment for varying periods of time at four District Tuberculosis Centres in Tamil Nadu, 20.3 per cent were found to be harbouring multidrug-resistant strains. Majority of these patients had irregular and interrupted

Table 50.4: Summary of studies on resistance in previously treated patients in Mycobacterium tuberculosis isolates from India Study (reference)

Year

Resistance (%)

Number of isolates

Location

H

S

R

SH

HR

SR

SHR

-

-

-

Gujarat (29)

1980-86

1574

34.5-55.8

26.3-26.9

2.8-37.3

-

-

Gujarat (29)

1983-86

1267

-

-

-

-

11.4-18.5 1.2-3.5

14.5-15.3

-

North Arcot (36) 1988-89

560

67.0

26.0

12.0

19.0

6.0

-

-

Rural

New Delhi (35)

1990-91

81

50.7

-

33.7

-

-

-

-

Urban

Bengaluru (38)

1999-2000

226

4.7-12.1

5.4-13.2

0-3.6

0-1.3

8.4-17.2 0.2.1

0.2-4.2

Urban

H = isoniazid; S = streptomycin; R = rifampicin

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Tuberculosis

Figure 50.6: Drug resistance data from some surveillance sites in India [1985-2003]. Figures in square brackets indicate prevalence of Multidrug-resistant tuberculosis

treatment owing to the non-availability of drugs (37). Data documented at the TRC, Chennai (44) from 443 Category II patients from the model DOTS area in Tiruvallur district of Tamil Nadu [1999-2003] revealed that the prevalence of MDR-TB was 11.7 per cent. In another study (45) in HIV-TB co-infected patients from south India [n = 204], MDR-TB was observed in 4.2 per cent [7 of the 167] of new cases and 13.5 per cent [5 of the 37] of previously treated patients. Data of resistance among new cases from TRC, Chennai, for the past four decades are shown in the Figure 50.7. It is clearly evident that there was a gradual increase in the prevalence of resistance to antituberculosis drugs among new cases. For isoniazid, the resistance rates ranged from three to seventeen per cent and for streptomycin from three to thirteen per cent. Initial resistance to rifampicin started appearing in 1990s and still remains at one per cent. Resistance to more than one drug is observed to range from none to seven per cent for streptomycin and isoniazid and less than one per cent for isoniazid and rifampicin or streptomycin, isoniazid and rifampicin. The second ICMR survey (27) conducted in the 1960s showed a higher level of drug resistance among those with a history of previous chemotherapy and it was 7.0

Figure 50.7: Trend of prevalence of drug resistance in newly diagnosed cases of tuberculosis in various studies of Tuberculosis Research Centre [TRC], Chennai H = isoniazid; S = streptomycin; R = rifampcin

per cent to isoniazid, 9.1 per cent to streptomycin and 15.8 per cent to both the drugs. During the 1980s two surveys were conducted by the ICMR at Raichur district, Karnataka (46) and North Arcot district, Tamil Nadu (47) to estimate the prevalence of drug-resistant TB. The results of the survey showed a higher level of initial drug resistance in Raichur District compared to that in North Arcot district (46,47). The results of another study (43) in Wardha district of Maharashtra revealed resistance to isoniazid, rifampicin or both drugs to be 15.2 per cent, 0.5 per cent and 0.5 per cent respectively.

Antituberculosis Drug Resistance Surveillance A recently concluded study (43) in the Jabalpur district of Madhya Pradesh showed resistance in newly diagnosed cases to isoniazid, rifampicin and to both drugs to be 16.1 per cent, 1.8 per cent and 1.1 per cent, respectively. Since 1999, TRC has carried out several operational research studies in the model DOTS area in Tiruvallur district of Tamil Nadu, including, measurement of drug resistance among patients living in the trial area. Data from the period 1999-2003 revealed resistance to isoniazid and MDR-TB among new cases to be 10.4 and 1.7 per cent, respectively (44). Likewise, in a study (45) on drug resistance carried out in patients co-infected with HIV-TB [2000-2002], resistance to isoniazid and MDR-TB among new cases were reported to be 13 and 4.3 per cent, respectively. Data on the prevalence of drug resistance from Army Hospital, Pune (48) showed a very low level of initial resistance to isoniazid and the authors have reasoned

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that this lower level of drug resistance in this population could be due to the minimal chance of indiscriminate exposure of antituberculosis agents prior to reporting to the hospital. Overall the initial resistance to isoniazid as single agent ranges from 0.6 per cent to 13.2 per cent, to streptomycin from 2.2 per cent to 7.0 per cent and to rifampicin from none to 1.7 per cent. In the Fourth Global Report (13), India reported data from one state, Gujarat, and three districts: Ernakulam district, Kerala State, Hoogli district, West Bengal State, and Mayhurbhanj district, Orissa State [Figure 50.8]. Data from the nine sites in India show that drug resistance among new cases is relatively low; however, new data from Gujarat indicate that prevalance of MDR-TB among retreatment cases [17.2%] was higher than previously anticipated and it is estimated that 110 32 new MDR-TB cases emerged in India in 2006, representing over 20 per cent of the global burden (14). Although plans have been

Figure 50.8: Prevalence of multidrug-resistant TB in new and previously treated cases in South-East Asia region, 2002-2007 Reproduced with permission from “World Health Organization. Anti-tuberculosis drug resistance in the world. Report No.4. WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. WHO/HTM/TB/2008.394. Geneva: World Health Organization; 2008 (reference 14)”

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developed for management of 5000 MDR-TB cases annually by 2010, insufficient laboratory capacity is seen as the primary limitation in the implementation of these plans. Treatment Outcome of Drug-Resistant Tuberculosis The emergence of drug-resistant strains is known to reduce the efficacy of treatment. Strains resistant to isoniazid. streptomycin or both neither pose a major problem nor affect the result of treatment in a big way provided proper regimens are used (49,50). On the contrary, patients infected with organisms resistant to rifampicin, isoniazid or both have a high rate of treatment failure (30,35,49,50) and this forms a major threat to TB control programmes, particularly for countries like India with limited resources. Patients infected with MDR-TB strains require longer duration of therapy and may die of TB or continue to have active TB despite optimal therapy (2). The reader is referred to the chapter “Drugresistant tuberculosis” [Chapter 49]” for more details regarding the global experience in the treatment of drugresistant TB. The Relevance of These Studies In view of the results so far observed, there is no clear evidence of an increase in the prevalence of resistance among new cases in India over the years. However, relatively high prevalence of resistance in previously treated patients has been reported from Gujarat, New Delhi and North Arcot district (29,35,36). When compared to the prevalence of drug resistance globally, resistance among new cases is found to be marginally lower and a much higher level of resistance in previously treated patients is observed in India. The magnitude of drug resistance problem to a larger extent is due to acquired resistance. The prevalence of MDR-TB is also found to be at a very low level in most of the regions of India. Children seldom produce adequate sputum for culture and sensitivity testing. Resistance pattern observed in strains isolated from children were found to be similar to those of strains isolated from their adult contacts. Studies conducted at the TRC, Chennai in paediatric population revealed that resistance to isoniazid was five per cent to ten per cent; resistance to streptomycin without resistance to rifampicin was 2.0 per cent to 11.4 per cent (50-52). These observations

suggest that there is no alarming increase in the incidence of initial multidrug-resistant cases. A strong TB control programme that can reduce the incidence of drug resistance in a community and particularly DOTS, which is cost-effective, proved to be effective in treatment completion and in turn proved to be effective against emergence of drug resistance in New York (5). New drugs for TB are unlikely to come up in the near future, and hence, the key success remains in adequate case finding, prompt and correct diagnosis and effective treatment of infective patients for prevention of drug resistance. The longitudinal studies of TRC, Chennai (43) and many of the above-cited surveys including studies on the childhood TB show that there is no real threat by the increase of MDR-TB in India. However, there cannot be complacency among health care professionals, since in absolute number, considering the existing TB burden and population of this vast country, even a fraction in the increase of MDR-TB would literally mean millions of rupees of extra spending in the treatment of such cases. Reliablility of second-line antituberculosis DST also need to be ascertained before they are tried in India (53). Every physician and health care worker should strictly adhere to the treatment policies of the government and ensure early diagnosis and completion of treatment under direct observation of a committed DOT provider, which would eventually result in the reduction in the prevalence of MDR-TB in the community (54). Apart from a strong TB control programme, there is also a need for a continuous and/or periodic survey of drug resistance, which will provide information on the type of chemotherapy to be used for the treatment of patients and also serve as a useful parameter in the evaluation of current and past chemotherapy programmes (5,55). DOTS-PLUS The DOTS-Plus is a comprehensive management strategy based upon DOTS (57), under development and testing that includes the five tenets of the DOTS strategy. The DOTS-Plus takes into account specific issues such as the use of second-line antituberculosis drugs that need to be addressed in areas where there is high prevalence of MDR-TB. Thus, DOTS-Plus works as a supplement to the standard DOTS strategy. By definition, it is impossible

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to conduct DOTS-Plus in an area without having an effective DOTS-based TB control programme in place. DOTS-Plus is not intended as a universal strategy, and is not recommended in all settings. The DOTS-Plus is intended to be implemented in selected areas with moderate to high levels of MDR-TB in order to combat an emerging epidemic (57,58). The DOTS-Plus is being implemented in Bolivia, Costa Rica, Estonia, Haiti, Karakalpakstan [Uzbekistan], Latvia, Malawi, Mexico, Peru, Philippines and the Russian Federation [Arkhangelsk, Ivanono, Tomsk and Orel Oblasts]. The DOTS-Plus projects have also been approved for 27 sites in 24 countries including Georgia, Honduras, Jordan, Kenya, Kyrgyzstan, Lebanon, Nepal, Nicaragua, Romania and Syria (59,60), and are under review in six countries including Delhi, India. The DOTS-Plus projects are also in pipeline for 10 countries, including some other sites in India.

though as yet no products have been purchased; [iv] a plan for convergence of the drug procurement unit of the GLC mechanism with the GDF was agreed for implementation in 2006; [v] advice to WHO has enabled the formulation of new WHO Guidelines for the management of drug-resistant TB (62); [vi] through assistance to countries, several high TB and MDR-TB burden countries were approved for MDR-TB management in the fifth round of the Global Fund to Fight AIDS, Tuberculosis and Malaria [GF]; [vii] important modifications to the governance of the Working Group were introduced: drug resistance to the second line-drugs was included in the terms of reference of the Group, the Core Group was expanded with representatives of the community; and [viii] the first training for consultants on MDR-TB management was conducted at the newly established WHO Collaborating Centre for MDR-TB Control in Riga, Latvia (59).

The World Health Organization Working Group on DOTS-Plus for Multidrug-resistant Tuberculosis

PREVENTION OF MULTIDRUG-RESISTANT TUBERCULOSIS IN INDIA’S REVISED NATIONAL TUBERCULOSIS CONTROL PROGRAMME

The Stop TB Working Group on DOTS-Plus for MDR-TB has planned to produce feasible, effective and costeffective approaches to the prevention and management of MDR-TB (61). During 2005, it focussed on developing new guidelines for MDR-TB management in resourcelimited settings, producing the Strategic Plan of the Working Group for 2006-2015, refining a guide to policymaking in management of drug-resistant TB and submitting manuscripts on feasibility and cost-effectiveness of MDR-TB pilot projects to peer-reviewed journals. The main achievements during 2005 were: [i] new projects for the management of MDR-TB were approved for six countries and existing projects were expanded. There 47 projects for management of MDR-TB with a total cohort size of 12 215 MDR-TB patients in 29 countries; [ii] a manuscript reporting results from the first five Green Light Committee [GLC] approved projects was submitted to a peer-reviewed journal. These results showed that MDRTB management was feasible and that adverse events were manageable in resource-limited settings; [iii] as part of the prequalification of manufacturers of second-line drugs, nine manufacturers applied to the WHO prequalification project, 14 dossiers were submitted for assessment, and three inspections took place. The production plants of two manufacturers of second-line drugs were approved,

It is well known that resistance levels are higher in areas with a poorly performing DOTS programmes. Use of inadequate regimens and inappropriate direct observation of treatment [DOT] leads to increase in resistance levels in the community. It has been acknowledged that good treatment is a pre-requisite to the prevention of emergence of resistance. The Revised National Tuberculosis Control Programme [RNTCP], of the Government of India, recognizes that implementation of a good quality DOTS programme is the first priority for TB control in the country. Prevention of emergence of MDRTB in the community is more imperative rather than its treatment (63). DOTS-Plus in India’s Revised National Tuberculosis Control Programme Provision of DOTS-Plus is a supplementary service under the expanded framework of the DOTS package under RNTCP. Well administered first-line treatment for susceptible cases is the best method to prevent the development of resistance in such cases. Therefore, in every DOTS implementing unit of the country, DOTS would be prioritized above DOTS-Plus with the view that DOTS reduces the emergence of MDR-TB, and

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therefore, over time the need for DOTS-Plus also gets reduced. Timely identification of MDR-TB cases and adequately administered Category IV regimens are essential to stop primary transmission of MDR-TB. Although the standardized drug regimens used by RNTCP are highly effective, with low failure rates of around two per cent and six per cent amongst Category I and II cases, respectively, RNTCP has planned to address the issue of the treatment of those pulmonary TB patients who remain smear-positive following a fully supervised Category II re-treatment regimen. The RNTCP views the treatment of MDR-TB patients as a “standard of care” issue. Recognizing that the treatment of MDR-TB cases is very complex, treatment will follow the internationally recommended DOTS-Plus guidelines and will be done in designated RNTCP DOTSPlus sites. These sites will be in a limited number of highly specialized centres, at least one in each state, which will have ready access to an RNTCP accredited state-level intermediate reference laboratory [IRL] with facilities for culture and DST, with qualified staff available to manage patients, using standardized second-line drug regimens given under daily DOT and standardized follow-up protocols, have systems in place to deliver ambulatory DOT after an initial short period of in-patient care to stabilize the patient on the second-line drug regimen, and with a logistics system and standardized information system in place. The DOTS-Plus sites are planned to be initiated in a phased manner similar to that for the establishment of the culture and DST laboratory network, and these sites will be linked geographically to the establishment of the RNTCP accredited IRLs. The DOTSPlus has been developed as an integral component of RNTCP to manage MDR-TB to be implemented through the existing programme infrastructure. The reader is referred to the chapter “Revised National Tuberculosis Control Programme” [Chapter 63] for more details. Indian Efforts at Antituberculosis Drug Resistance Surveillance India has developed a plan to conduct nationwide surveillance of drug resistance in each state. At the national level, a generic protocol for the Central TB Division, Ministry of Health and Family Welfare, Government of India has been developed, as per WHO guidelines in line with international standards (6). The

DRS protocols as per international guidelines have been developed and are under progress with gradual addition and re-survey of states over time. The objectives of DRS in the state setting are to: [i] determine the levels and pattern of resistance to first-line antituberculosis drugs among “newly diagnosed” sputum-positive cases; [ii] estimate the levels and pattern of resistance to firstline antituberculosis drugs among “previously treated cases”; and [iii] establish the foundation for routine surveillance of drug resistance in order to observe trends over time. Another objective of nationwide surveillance of drug resistance in India includes strengthening of laboratory networks through the implementation of an external QA system for smear microscopy and QA of culture and DST in state laboratories. The plan of action also includes human resource development and enhancement of financial capacity before a nationwide survey is implemented. Currently there are three NRLs, 16 intermediate reference laboratories [IRLs] or State TB Demonstration and Training Centres in India. The DRS protocols for Indian states have adapted economic variant of proportion method for DST in DRS. The sample size for population proportionate cluster sampling [PPS] for each state has been calculated to be 1680 patients for ‘new’ smear-positive cases with an estimated prevalence of two per cent, precision of one per cent for 95 per cent confidence intervals [CI] including 10 per cent loss, after applying a design effect of two. The sample size for ‘previously treated’ smearpositive cases is 992 patients, estimated prevalence: 12 per cent, precision: two per cent, 95 per cent CI, 10 per cent loss after applying a design effect of 2. Intake for previously treated smear-positive cases would be from the designated microscopy centres selected for new cases. Intakes for both new and previously treated cases have been scheduled to be completed within one year. A national external QA document for Central TB Division has been developed, which has incorporated international guidelines established in 2002. Primary importance has been given for EQA of smear microscopy before start of DRS. A national RNTCP Laboratory Network Coordination Team consisting of microbiologists from national reference laboratories of TRC, NTI and L.R.S. Institute of Tuberculosis and Respiratory Diseases, New Delhi and representatives from intermediate reference laboratories, Central TB Division, Ministry of Health and Family Welfare, Government of

Antituberculosis Drug Resistance Surveillance India and WHO, South-East Asia Regional Office, New Delhi has been established. Assessment of state level laboratory is done using a modified WHO laboratory assessment tool. The state specific protocol development for the survey on the prevalence of antituberculosis drug resistance involves three major operational issues: [i] programme management [logistics, training, collection of clinical information, supervision of survey]; [ii] laboratory techniques [DST, proficiency testing, QA]; and [iii] epidemiology [sampling, data entry and analysis]. The state is considered as a survey area and should have at least one functioning state culture laboratory located at State TB Demonstration and Training Centre or at the state public health laboratory.This initiative is likely to provide reliable antituberculosis drug resistance surveillance data from India. GLOBAL EFFORTS TO PROVIDE ACCESS TO BETTER DIAGNOSTICS IN HIGH BURDEN COUNTRIES In the context of a global response to MDR-TB and XDRTB, the WHO-Stop TB Department, Partners in Health and the Foundation for Innovative New Diagnostics [FIND] assessed the National TB Laboratory in Lesotho in November 2006 to evaluate the operational feasibility of establishing an automated liquid culture system as a rapid DST detection tool. In order to expand and accelerate access to patients at risk for MDR-TB by facilitating MDR-TB diagnostics within appropriate laboratory systems in 16 high burden countries [8 in Eastern Europe, 4 each in Africa and in South-East Asia], the Global Laboratory Initiative [GLI], Global Development Fund [GDF], FIND and the drug purchase facility UNITAID have developed an ambitious plan to provide rapid liquid culture and nucleic acid amplification systems (64), including equipment and consumables, to these countries for a period of three years beginning in 2008 (65). These global efforts for better diagnostics in high burden countries are likely to facilitate better documentation and monitoring of drug-resistant TB. ACKNOWLEDGMENTS The authors gratefully acknowledge Ms J. Daisy Vanitha, for her painstaking help in the preparation of the first draft of the article and Mr P.R. Somasundaram, and Dr V.K. Vijayan, for their helpful comments.

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REFERENCES 1. Jacobs RF. Multiple-drug-resistant tuberculosis. Clin Infect Dis 1994;19:1-8. 2. Pablos-Mendez A, Sterling TR, Frieden TR. The relationship between delayed or incomplete treatment and all-cause mortality in patients with tuberculosis. JAMA 1996;276:1223-8. 3. Bustreo F, Migliori GB, Nardini S, Raviglione MC. Antituberculosis drug resistance: is it worth measuring? The WHO/ IUATLD Working Group on Antituberculosis Drug Resistance Surveillance. Monaldi Arch Chest Dis 1996;51:299-302. 4. Kim SJ, Hong YP. Drug resistance of Mycobacterium tuberculosis in Korea. Tuber Lung Dis 1992;73:219-24. 5. Fujiwara PI, Cook SV, Rutherford CM, Crawford JT, Glickman SE, Krieswirth BN, et al. A continuing survey of drug-resistant tuberculosis, New York City, April 1994. Arch Intern Med 1997;157:531-6. 6. Aziz MA, Laszlo A, Raviglione M, Rieder HL, Espinal M, Wright A. Guidelines for surveillance of drug resistance in tuberculosis. Second edition. WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Geneva: World Health Organization 2003. 7. Crofton J, Chaulet P, Mahler D. Guidelines for the management of drug resistant tuberculosis. Geneva: World Health Organization;1997. 8. Pablos-Méndez A, Raviglione MC, Laszlo A, Binkin N, Rieder HL, Bustero F, et al, for the WHO/IUATLD Working Group on Anti-tuberculosis Drug Resistance Surveillance. Global surveillance for antituberculosis-drug resistance: 1994-1997. N Engl J Med 1998;338:1641-9. 9. Raviglione MC, Snider DE, Kochi A. Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic. JAMA 1995;273:220-6. 10. Raviglione MC, Sudre P, Rieder HL, Spinaci S, Kochi A. Secular trends of tuberculosis in western Europe. Bull World Health Organ 1993;71:297-306. 11. The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance SurveillanceAnti-tuberculosis Drug Resistance in the World. Report no. 2: Prevalence and Trends. WHO/CDS/TB/2000.278. Geneva: World Health Organization; 2000. 12. The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 1999-2002. Anti-tuberculosis drug resistance in the world. Third Global Report. WHO/HTM/ TB/2004.343. Geneva: World Health Organization; 2004. 13. Zignol M, Hosseini MS, Wright A, Weezenbeek CL, Nunn P, Watt CJ, et al. Global incidence of multidrug-resistant tuberculosis. J Infect Dis 2006;194:479-85. 14. World Health Organization. Anti-tuberculosis drug resistance in the world. Report No. 4.. WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. WHO/HTM/TB/2008.394. Geneva: World Health Organization; 2008. 15. World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008.

732

Tuberculosis

16. Centers for Disease Control and Prevention. Emergence of Mycobacterium tuberculosis with extensive resistance to second line drugs-world wide, 2002-2004. MMWR 2006;55:301-5. 17. World Health Organization. XDR-TB Extensive Drug Resistant TB, September 2006. Available at URL: http:// www.who.int/tb/XDR_TB_Sept_06.pdf. Accessed on September 4, 2008. 18. Masjedi MR, Farnia P, Sorooch S, Pooramiri MV, Mansoori SD, Zariffi AZ, et al. Extensively drug-resistant tuberculosis: 2 years of surveillance in Iran. Clin Infect Dis 2006;43:841-7. 19. Raviglione MC. The new Stop TB Strategy and the Global Plan to Stop TB, 2006-2015. Bull World Health Organ 2007;85:327. 20. Blondal K. Barriers to reaching the targets for tuberculosis control: multidrug-resistant tuberculosis. Bull World Health Organ 2007;85:387-90. 21. World Health Organization. Countries with XDR-TB Confirmed cases to date. Available at URL: http:// www.who.int/ tb/challenges/xdr/xdrmap_oct07_en.pdf. Accessed on 22 October, 2008. 22. Bonilla CA, Crossa A, Jave HO, Mitnick CD, Jamanca RB, Herrera C, et al. Management of extensively drug-resistant tuberculosis in Peru: cure is possible. PLoS ONE 2008;3:e2957. 23. Kwon YS, Kim YH, Suh GY, Chung MP, Kim H, Kwon OJ, et al. Treatment outcomes for HIVuninfected patients with multidrug-resistant and extensively drug-resistant tuberculosis. Clin Infect Dis 2008;47:496-502. 24. Banerjee R, Allen J, Westenhouse J, Oh P, Elms W, Desmond E, et al. Extensively drug-resistant tuberculosis in California, 1993-2006. Clin Infect Dis 2008;47:450-7. 25. Keshavjee S, Gelmanova IY, Farmer PE, Mishustin SP, Strelis AK, Andreev YG, et al. Treatment of extensively drugresistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 2008;372:1403-9. 26. Prevalence of drug resistance in patients with pulmonary tuberculosis presenting for the first time with symptoms at chest clinics in India. I. Findings in urban clinics among patients giving no history of previous chemotherapy. Indian J Med Res 1968;56:1617-30. 27. Prevalence of drug resistance in patients with pulmonary tuberculosis presenting for the first time with symptoms at chest clinics in India. II. Findings in urban clinics among all patients, with or without history of previous chemotherapy. Indian J Med Res 1969;57:823-35. 28. Krishnaswami KV, Rahim MA. Primary drug resistance in pulmonary tuberculosis. Indian J Chest Dis Allied Sci 1976;18:233-7. 29. Trivedi SS, Desai SC. Primary antituberculosis drug resistance and acquired rifampicin resistance in Gujarat-India. Tubercle 1988;69:37-42. 30. Paramasivan CN, Chandrasekaran V, Santha T, Sudarsanam NM, Prabhakar R. Bacteriological investigations for shortcourse chemotherapy under the tuberculosis programme in two districts of India. Tuber Lung Dis 1993;74:23-7.

31. Chandrasekaran S, Jagota P, Chaudhuri K. Initial drug resistance to anti-tuberculosis drugs in urban and rural district tuberculosis programme. Indian J Tuberc 1992;39:171-5. 32. Chandrasekaran S, Chauhan MM, Rajalakshmi R, Chaudhuri K, Mahadev B. Initial drug resistance to anti-tuberculosis drugs in patients attending an urban district tuberculosis centre. Indian J Tuberc 1990;37:215-6. 33. Sophia V, Balasangameshwara VH, Jagannatha PS, Saorja VN, Kumar P. Initial drug resistance among tuberculosis patients under DOTS program in Bangalore city. Indian J Tuberc 2004;51:17-22. 34. Gupta PR, Singhal B, Sharma T]N, Gupta RB. Prevalence of initial drug resistance in tuberculosis patients attending a chest hospital. Indian J Med Res 1993;97:102-3. 35. Jain NK, Chopra KK, Prasad G. Initial acquired isoniazid and rifampicin resistance to M. tuberculosis and its implications for treatment. Indian J Tuberc 1992;39:121-4. 36. Datta M, Radhamani MP, Selvaraj R, Paramasivan CN, Gopalan BN, Sudeendra CR, et al. Critical assessment of smear-positive pulmonary tuberculosis patients after chemotherapy under the district tuberculosis programme. Tuber Lung Dis 1993;74:180-6. 37. Vasanthakumari R, Jagannath K. Multidrug resistant tuberculosis - A Tamil Nadu study. Lung India 1997;15:178-80. 38. Sophia V, Balasangameshwara VH, Jagannatha PS, Saroja VN, Shivashankar B, Jagota P. Re-treatment outcome of smear positive tuberculosis cases under DOTS in Bangalore City. Indian J Tuberc 2002;49:195-204. 39. Kam KM, Yip CW. Surveillance of Mycobacterium tuberculosis drug resistance in Hong Kong, 1986-1999, after the implementation of directly observed treatment. Int J Tuberc Lung Dis 2001;5:815-23. 40. Malla P, Bam DS, Shrestha B. Drug resistance surveillance of TB cases in Nepal. Int J Tuberc Lung Dis 2001;5:S 84. 41. Mahadev B, Jagota P, Srikantaramu N, Gnaneshwaran M. Surveillance of drug resistance in Mysore district, Karnataka. NTI Bulletin 2003;39:5-10. 42. Mahadev B, Kumar P, Agarwa SP, Chauhan LS, Srikantaramu N. Surveillance of drug resistance to anti-tuberculosis drugs in districts of Hoogli in West Bengal and Mayurbhanj in Orissa. Indian J Tuberc 2005;52:5-10. 43. Paramasivan CN, Venkataraman P. Drug resistance in tuberculosis in India. Indian J Med Res 2004;120:377-86. 44. Santha T, Thomas A, Chandrasekaran V, Selvakumar N, Gopi PG, Rajeswari R, et al. Initial drug susceptibility profile of M. tuberculosis among patients under TB programme in South India. Int J Tuberc Lung Dis 2006;10:52-7. 45. Swaminathan S, Paramasivan CN, Ponnuraja C, Iliayas S, Rajasekaran S, Narayanan PR. Anti-tuberculosis drug resistance in patients with HIV and tuberculosis in South India. Int J Tuberc Lung Dis 2005;9:896-900. 46. Gopi P, Vallishayee RS, Appe Gowda BN, Paramasivan CN, Ranganatha S, Venkataramu KV, et al. A tuberculosis prevalence survey based on symptoms questioning and sputum examination. Indian J Tuberc 1997;44:171-80.

Antituberculosis Drug Resistance Surveillance 47. Tuberculosis Research Centre. Median Annual Report. Chennai: Tuberculosis Research Centre [Indian Council of Medical Research]; 1990. 48. Jena J, Panda BN, Nema SK, Ohri VC, Pahwa RS. Drug resistance pattern of Mycobacterium tuberculosis in a chest diseases hospital of armed forces. Lung India 1995;13:56-9. 49. Mathew R, Santha T, Parthasarathy R, Rajaram K, Paramasivan CN, Janardhanam B, et al. Response of patients with initially drug-resistant organisms to treatment with short-course chemotherapy. Indian J Tuberc 1993;40:119-23. 50. Ramachandran P, Duraipandian M, Nagarajan M, Prabhakar R, Ramakrishnan CV, Tripathy SP. Three chemotherapy studies of tuberculous meningitis in children. Tubercle 1986;67:17-29. 51. Jawahar MS, Sivasubramanian S, Vijayan VK, Ramakrishnan CV, Paramasivan CN, Selvakumar V, et al. Short course chemotherapy for tuberculous lymphadenitis in children. BMJ 1990;301:359-62. 52. Somu N, Swaminathan S, Paramasivan CN, Vijayasekaran D, Chandrabhooshanam A, Vijayan VK, et al. Value of bronchoalveolar lavage and gastric lavage in the diagnosis of pulmonary tuberculosis in children. Tuber Lung Dis 1995;76:295-9. 53. Kim SJ, Espinal MA, Abe C, Bai GH, Boulahbal F, Fattorin L, et al. Is second-line anti-tuberculosis drug susceptibility testing reliable? Int J Tuberc Lung Dis 2004;8:1157-8. 54. Paramasivan CN. An overview on drug resistant tuberculosis in India. Lung India 1998;16:21-8. 55. Paramasivan CN, Bhaskaran K, Venkataraman P, Chandrasekaran V, Narayanan PR. Surveillance of drug resistance in tuberculosis in the state of Tamil Nadu. Indian J Tuberc 2000;47:27-33. 56. Farmer P, Kim JY. Community based approaches to the control of multidrug resistant tuberculosis: introducing “DOTS-plus”. BMJ 1998;317:671-4. 57. Espinal MA, Kim SJ, Suarez PG, Kam KM, Khomenko AG, Migliori GB, et al. Standard short-course chemotherapy for

58.

59.

60.

61.

62.

63.

64.

65.

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drug-resistant tuberculosis. Treatment outcomes in 6 countries. JAMA 2000;283:2537-45. Time Bomb: Multidrug-resistant tuberculosis. The Newsletter of The Global Partnership Movement to Stop TB. Issue 7, 2002. Available at URL: www.stoptb.org. Accessed on August 5,2008. World Health Organization. The Stop TB Partnership Annual Report, 2005. Geneva: World Health Organization;2006. WHO/HTM/STB/2006.36. Available at URL: http:// www.stoptb.org/resource_center/assets/documents/ TB_ANNUAL_REPORT_2005.pdf. World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2006. WHO/ HTM/TB/2006.362. Geneva: World Health Organization; 2006. Stop TB Working Group on DOTS-Plus for MDR-TB. A prioritized research agenda for DOTS-Plus for multidrug-resistant tuberculosis [MDR-TB]. Int J Tuberc Lung Dis 2003;7:410-4. Rich M, Cegielski P, Jaramillo E, Lambregts K, editors. Guidelines for the programmatic management of drugresistant tuberculosis. WHO/HTM/TB/2006.361. Geneva: World Health Organization; 2006.p.1-186. Central TB Division Revised National Tuberculosis Control Programme. Managing DOTS-Plus activities in your district. New Delhi: Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India; 2006:1-48. Barnard M, Albert H, Coetzee G, O’Brien R, Bosman ME. Rapid molecular screening for multidrugresistant tuberculosis in a high-volume public health laboratory in South Africa. Am J Respir Crit Care Med 2008;177:787-92. UNITAID, Resolution No. 4. TB/ MDR-TB Project. Expanding and accelerating access to diagnostics for patients at risk of MDR-TB. Available at the URL: http:// www.unitaid.eu/images/governance/EB7/eb7_res4_en. pdf. Accessed on September 13, 2008.

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Evolution of Chemotherapeutic Regimens in the Treatment of Tuberculosis and Their Scientific Rationale

51

Rani Balasubramanian, Rajeswari Ramachandran

INTRODUCTION Tuberculosis [TB] has been a scourge of mankind for thousands of years and remains one of the deadliest diseases in the world today. Nevertheless, TB can be cured in nearly all cases. The only way to stop the spread of disease in the community is to cure all smear-positive cases by treatment with appropriate chemotherapeutic regimens. SCIENTIFIC BASIS OF TUBERCULOSIS TREATMENT Mycobacterium tuberculosis is a slow-growing aerobic organism with doubling time of 18 hours and can remain dormant for a long period [Figure 51.1]. Therefore, prolonged treatment is required to ensure relapse-free cure. The effect of treatment is determined mainly by bacteriological, environmental [anatomical and biochemical] and pharmacological factors. Bacteriological Factors The Numerical Factor The number of tubercle bacilli varies widely with the type of lesion. Based on the data on resected lung specimens from untreated patients (1), the number of bacilli in a medium-sized cavity communicating with the bronchi is about 108. Resistant mutants are likely to be present even before treatment is started if the bacterial population is larger. This fact must be borne in mind when choosing the regimen. The Metabolic Factor Antituberculosis drugs kill tubercle bacilli that are metabolically active and are multiplying continuously.

Figure 51.1: Theoretical basis of chemotherapy of tuberculosis. Three populations of Mycobacterium tuberculosis are postulated to exist in a tuberculosis cavity, based on their anatomic and metabolic characteristics. Population A refers to rapidly multiplying bacteria found in caseous debris in pulmonary cavities. Compared with streptomycin [S], rifampicin [R], and ethambutol [E], isoniazid [H] is most active against this population. Slowly multiplying bacteria because of local acidic conditions are referred to as population B. Pyrazinamide [Z] is the most effective antituberculosis drug active against this group followed by rifampicin [R] and isoniazid [H]. “Elimination” of populations “A” and “B” results in negative sputum cultures, typically after two months of treatment. Bacilli in the host tissue capable of sporadic bursts of metabolism, multiplication constitute population “C”. This population is a potential source for relapses. Rifampicin [R] plays a major role in eliminating these organisms followed by H. Another population of bacilli designated as population “D” are dormant non-replicating bacilli that are not vulnerable to antimicrobial action and are also considered to be a potential source for relapse

But, in each bacterial population there are bacilli with a very low metabolic rate. Some are inhibited owing to a low pH; others are dormant most of the time and grow,

Evolution of Chemotherapeutic Regimens in the Treatment of Tuberculosis and Their Scientific Rationale if at all, only during short periods. These organisms remain unaffected by most drugs; only rifampicin or pyrazinamide may kill them effectively under certain conditions. They survive even in the presence of potent drugs such as isoniazid and streptomycin, in spite of being susceptible to these drugs. These organisms are called “persisters”. This phenomenon explains to some extent why all bacilli are not killed during treatment, and why drug-susceptible bacilli are coughed up for some time thereafter. Relapse with drug-susceptible organisms after being “cured” or endogenous reactivation may occur due to bacilli that have persisted in residual lesions in a dormant state for a long time. Environmental Factors The Anatomical Factors The type of tissue harbouring tubercle bacilli may modify drug action because all drugs are not able to penetrate into all tissues and cells or permeate biological membranes, including the normal blood-brain barrier. Isoniazid, rifampicin and pyrazinamide readily cross biological membranes, whereas streptomycin fails to enter many cells and is much less effective against intracellular bacilli than against extracellular bacilli (2). The Biochemical Factors Important biochemical factors influencing the antimicrobial effect of a drug are the environmental pH and the oxygen tension. In cavity walls, the pH is neutral or slightly alkaline, oxygen tension is high and mycobacterial multiplication is rapid. In cavitary lesions, all the bactericidal antituberculosis drugs are highly effective. Streptomycin is best active in a slightly alkaline [extracellular] environment. Mycobacterial growth is slowed by low oxygen tension. Pyrazinamide, is unique amongst antituberculosis drugs in having greater bactericidal activity as mycoabacterial metabolism slows down and is also effective in acidic environment. Thus, it is active against mycobacteria inside macrophages where, the pH is acidic, oxygen tension is low and mycobacterial growth is slow. Pharmacological Factors Dosage Drugs must be given in a dosage large enough to produce an inhibitory concentration at the site where bacilli are

735

present, but it is not necessary to keep this concentration at a constant level. In fact, studies on the role of dosage and serum levels of isoniazid showed that it was both the peak level and the total exposure to the drug [area under time concentration] that were important for the response to the drug (3). Thus, 400 mg of isoniazid given once daily was therapeutically superior to the same dose divided into two parts and administered at 12 hour intervals (3). Combinations of Drugs Regimens should contain a combination of three or more bactericidal drugs, particularly in the initial phase of treatment so that bacilli that are both susceptible and resistant to one drug are killed rapidly by various other drugs. Treatment of TB disease should never be attempted with a single drug. In patients having lesions like cavities which are likely to contain large numbers of bacilli, the regimen should include at least two new drugs to which the bacilli are likely to be susceptible especially for patients who had received antituberculosis drugs earlier and a single drug should never be added to a failing regimen. Otherwise, treatment failure due to the emergence of drug resistance is the likely result. The major landmarks in the evolution of modern antituberculosis Treatment are given in Table 51.1. CURRENT RECOMMENDATIONS FOR STANDARD REGIMENS All treatment regimens should have two phases, an initial intensive phase of three or four bactericidal drugs and a continuation phase of at least two drugs (4). Initial Intensive Phase The initial intensive phase is designed to kill actively growing and semi-dormant bacilli. This means a shorter duration of infectivity with usually a rapid smear conversion [80% to 90%] after two to three months of treatment. The initial phase of rifampicin-containing regimens should always be directly observed in order to ensure adherence. The initial phase usually comprises of three to four, or sometimes five drugs, especially for patients who had failed or relapsed after primary chemotherapy. If initial resistance rates are high, use of a three-drug regimen has the risk of selecting drugresistant mutants, especially in smear-positive pulmonary TB patients with high bacillary loads. In such

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Tuberculosis

Table 51.1: Evolution of modern treatment for tuberculosis Year

Major events

1946

Clinical use of streptomycin, monotherapy leads to resistance Double drug regimen [SP] prevents emergence of drug resistance Introduction of isoniazid and two drug regimens [PH and SH] Data from India suggest that supervised administration of treatment [direct observation of treatment] is essential Emergence of daily administered 3 drug regimens [STH/TH, SPH/PH, SRH/RH] Ambulatory chemotherapy is as effective as sanatorium treatment. There is no additional risk of disease to close contacts Peripheral neuropathy, related to isoniazid dose and is more common in slow acetylators Efficacy of twice weekly SH intermittent regimen [S2H2] is proved Twice weekly PH as effective as daily PH 12RE and 2RE/10R1E1 is effective salvage regimen Concept of two phase regimens evolves: SRH/R2H2 regimen proves to be effective Effective short-course daily regimens of 6 months including RZ 6-month fully intermittent effective short-course regimens evolved Possibility of 4-month ultra short-course short effective regimen containing quinolones is explored

1948 1952-55 1958

1958-67 1959

1961 1964 1969 1970 1972 1974 1980 2001

Numbers preceding the regimen indicate duration in months; numbers in subscript indicate the number of times the drug is administered per week S = streptomycin, P = para-aminosalicylic acid; H = isoniazid; R = rifampicin; T = thioacetazone; E = ethambutol; Z = pyrazinamide

situations, a four-drug regimen decreases the risk of developing drug resistance and reduces failure and relapse rates. Even if patients default after the initial intensive phase, relapse is less likely. There is ample experimental and clinical evidence that more than one drug, and particularly a three- or fourdrug regimen, when administered in the initial period of treatment, greatly improves the efficacy of treatment (5,6). At least two bactericidal drugs, such as isoniazid and streptomycin or isoniazid and rifampicin, are required in the initial phase. Pyrazinamide given in the initial intensive phase allows reduction in treatment duration from nine to six months. A fourth drug, like

ethambutol, is of benefit when initial drug resistance may be present or when the burden of organisms is high (7). The multiplication of susceptible organisms stops during the first few days of effective treatment, and the total number of bacilli in the sputum decreases rapidly, especially within the first two weeks of effective treatment (8). The key observations concerning antituberculosis treatment from laboratory and controlled clinical studies are described below. It is crucial for the outcome of treatment, especially in patients harbouring large bacterial populations, to rapidly stop bacterial multiplication and ensure that drug-susceptible bacilli are killed as soon as possible [“early kill”]. This will prevent early deterioration and death in the initial weeks of treatment. Furthermore, rapid reduction of bacterial population say, from 108 [a number commonly found in lung cavities] to 103, the likely emergence of new resistant mutants will be minimized, even after several generations of uninhibited multiplications. Appropriate multidrug combinations always contain two drugs capable of destroying single drug-resistant mutants pre-existing in wild strains. Thus, at the outset, in a cavity harbouring a population of 108 bacilli, about 5 000 isoniazid-resistant and several hundreds of streptomycin-resistant mutants could be present. When the patient is started on treatment, initially all the susceptible organisms get killed and also the bacilli resistant to isoniazid alone for example may get killed by the other drugs. Sometimes, the organisms resistant to rifampicin may get selected out and start multiplying. Such multiplication may be particularly dangerous in the early phase of the treatment as it will produce drugresistant disease (9). Thus, in patients with initial resistance to a single drug [except rifampicin], an initial treatment with three or four drugs is associated with good response to therapy. The addition of a fourth drug in the intensive phase may be beneficial in patients who harbour large numbers of Mycobacterium tuberculosis. Continuation Phase The continuation phase eliminates most residual bacilli and reduces failures and relapses. Because of a small number of bacilli in the beginning of the continuation phase, fewer drugs are required as the chance of emergence of drug-resistant mutants is low.

Evolution of Chemotherapeutic Regimens in the Treatment of Tuberculosis and Their Scientific Rationale Table 51.2A: Classification of currently used antituberculosis drugs First line drugs Rifampicin Isoniazid Pyrazinamide Ethambutol Streptomycin Second line drugs Broad spectrum agents Cycloserine Fluoroquinolones Ciprofloxacin Ofloxacin Levofloxacin Moxifloxacin Gatifloxacin Rifamycins [other than rifampicin] Rifabutin Rifapentene Macrolides Azithromycin Clarithromycin Narrow spectrum agents Capreomycin Kanamycin Amikacin Viomycin Ethionamide Prothionamide Clofazimine Para-aminosalicylic acid Thioacetazone Other drugs* * Listed in Table 49.10 Source: reference 10

Antituberculosis Drugs The classification of antituberculosis drugs is shown in Tables 51.2A and 51.2B (10,11). The reader is referred to the chapter “Treatment of tuberculosis” [Chapter 52] for more details regarding the dosing schedule and various therapeutic regimens that are currently used. THE SCIENTIFIC BASIS OF INTERMITTENT TREATMENT Intermittent regimens are those in which the individual drugs are given at intervals of more than one day, e.g., three or two times a week. Originally, it was believed that antituberculosis drugs require daily administration to maintain drug concentrations at inhibitory levels

737

Table 51.2B: Alternative classification of currently used antituberculosis drugs Group 1 First-line oral antituberculosis agents Isoniazid [H] Rifampicin [R] Ethambutol [E] Pyrazinamide [Z] Group 2 Injectable antituberculosis agents Streptomycin [S] Kanamycin [Km] Amikacin [Am] Capreomycin [Cm] Viomycin [Vi] Group 3 Fluoroquinolones Ciprofloxacin [Cfx] Ofloxacin [Ofx] Levofloxacin [Lfx] Moxifloxacin [Mfx]* Gatifloxacin [Gfx]* Group 4 Oral bacteriostatic second-line antituberculosis agents Ethionamide [Eto] Prothionamide [Pto] Cycloserine [Cs] Terizidone [Trd]* Para-aminosalicylic acid [PAS] Thioacetazone [Th]† * The long-term safety and efficacy for multidrug-resistant tuberculosis [MDR-TB] treatment have not yet been fully confirmed, and therefore, use is not yet recommended for treatment of MDR-TB † Thioacetazone should be used only in patients documented to be HIV-negative and should usually not be chosen over other drugs listed in Group 4 Source: reference 11

continuously. For the first time, it was observed among patients admitted to randomized controlled clinical trials at the Tuberculosis Research Centre [TRC], Chennai [formerly Tuberculosis Chemotherapy Centre, Madras] that even patients who had consumed less than 80 per cent of the scheduled chemotherapy had remained bacteriologically quiescent during a follow-up period of five years. Subsequently, in vitro experiments demonstrated that, after a culture of Mycobacterium tuberculosis is exposed to certain drugs for some time, it takes several days [the “lag period”] before new growth occurs (12,13). The long generation doubling time of Mycobacterium tuberculosis [about 18 hours] and the observation that the antituberculosis drugs can kill the tubercle bacilli only when they are metabolically active, intermittent treatment led to the evolution of intermittent antituberculosis treatment.

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Tuberculosis

Table 51.3: Lag in growth of Mycobacterium tuberculosis after temporary exposure to drugs Drug

Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin Ethionamide Cycloserine Thioacetazone

Concentration [mg/l] 1 0.2 50 10 5 5 100 10

Lag [days] after exposure for 6 hours

24 hours

0 2-3 5-40* 0 8-10 0 0 0

6-9 2-3 40* 4-5 8-10 10 408 0

* Depending on the pH of the medium Source: reference 13

Table 51.3 shows the lag in the growth of Mycobacterium tuberculosis after temporary exposure to different drugs for varying times. For each bactericidal drug there was a maximum lag [last column] that seems to indicate the practical limit beyond which the interval between two doses should not be extended. Thioacetazone did not produce any lag, even after exposure for 24 or 96 hours. This suggests that thioacetazone is unsuitable for intermittent treatment. Animal studies (13) showed conclusively that, with the exception of rifampicin, the longer the chosen interval between doses, the higher the doses of most of the drugs needed to be. Thus, with high doses of isoniazid, a three-day interval was shown to be the optimum, whereas an extension to eight days gave significantly worse results. A series of experiments in animal models demonstrated that intermittent administration of isoniazid, rifampicin and pyrazinamide actually increased the efficacy of treatment. Standard Intermittent Regimens Although experimental findings cannot be directly extrapolated to the clinical scenario in humans, these results were promising enough to be explored in clinical studies. The first such randomized controlled clinical trial [Table 51.4] was undertaken at the TRC, Chennai (14). A standard oral regimen of isoniazid plus para-aminosalicyclic acid [PAS] twice daily was compared with a twice-weekly regimen of streptomycin plus isoniazid. The oral regimen was dispensed for self-administration. For the intermittent regimens, the patients had to attend the clinic twice a week at three- to four-day intervals.

Table 51.4: Comparison of results at the end of 12 months treatment with streptomycin and isoniazid twice weekly vs para-aminosalicyclic acid plus isoniazid daily Status of disease SH Twice weekly *

Bacteriologically quiescent Bacteriologically active Death from tuberculosis Total no. of patients

PH Daily †

No.

%

No.

%

68

94

56

85

2

2

9

14

2

3

1

2

72

100

66

100

* SH = streptomycin 1 g intramuscular + oral isoniazid 14 mg/kg body weight †PH = sodium para-aminosalicylic acid 10 g + isoniazid 200 mg daily, divided into two equal doses Source: reference 13

Treatment was ‘fully supervised’, i.e., each patient first had to take isoniazid tablets in the presence of the staff [who verified that the tablets had actually been swallowed] and then receive the injection of streptomycin. The results at 12 months are shown in Table 51.4. The intermittent regimen was highly successful and perhaps slightly more effective than the daily regimen. All the patients admitted to the study had extensive, bilateral cavitary disease with sputum heavily positive by direct smear examination. The relapse rates at twoyears were eight per cent for the twice-weekly and 12 per cent for the daily regimen; after four years, the corresponding figures were 12 per cent and 15 per cent, respectively. In four out of five patients who relapsed on the intermittent regimen, the bacilli were susceptible to both isoniazid and streptomycin. These data suggest that had there been an intensive phase at the start of treatment, the susceptible bacilli would probably have been eliminated. In another study (15), the possibility of increasing the dosing interval to one week among out-patients was investigated at TRC, Chennai. Four intermittent regimens were studied concurrently. The regimen consisting of streptomycin and isoniazid administered twice weekly, was compared with streptomycin plus isoniazid administered once weekly. In both regimens, the dosage of streptomycin [0.75 g to 1 g given by intramuscular injection] and isoniazid [15 mg/kg body weight] were the same. The effect of a lower dose [0.75 g] of streptomycin was studied because it seemed likely that the

Evolution of Chemotherapeutic Regimens in the Treatment of Tuberculosis and Their Scientific Rationale smaller dose would be sufficient and better tolerated, particularly by elderly patients, than the usual 1 g dose. The twice-weekly regimen again proved to be highly successful and the once-weekly regimen was considerably less effective. Nevertheless, it was rather impressive that, despite severe disease, 71 per cent of patients on the latter regimen achieved bacteriological quiescence (15). The reasons for the inferiority of the once-weekly regimen were examined. In this analysis, patients were grouped according to the rate of inactivation of isoniazid and the dosage of streptomycin. The efficacy of the twiceweekly regimen was influenced neither by the inactivation rate of isoniazid nor by a 25 per cent reduction in the dosage of streptomycin. In contrast, the once-weekly regimen was clearly affected by the rate of isoniazid inactivation and, to a lesser extent, also by the reduction in the streptomycin dosage. The twice-weekly regimen was, therefore, robust and effective, even without an initial intensive phase. The isoniazid inactivation rate also influenced the response to other once-weekly regimens concurrently investigated. From the clinical studies done at TRC, Chennai and other places, the following conclusions may be drawn from the experience gained with intermittent treatment without rifampicin. Twice-weekly regimens containing isoniazid in a high dosage [14 to 15 mg/kg] and streptomycin [0.75 g to 1 g] are highly effective, whether given from the outset or after an initial intensive phase of treatment. Their efficacy in slow and rapid inactivators of isoniazid is similar. These regimens can be highly effective in patients with extensive disease and in populations with a high frequency of rapid inactivators. A once-weekly regimen of isoniazid [15 mg/kg] and streptomycin [1 g] after initial daily therapy with isoniazid and streptomycin given for four weeks, approached the efficacy of the twice-weekly regimen; however, unlike the latter, it was substantially inferior in rapid inactivators, and therefore, cannot be recommended. Evolution of Short-course Chemotherapeutic Regimens The monumental advance in the chemotherapy of TB in the last three decades has been the development of shortcourse chemotherapy [SCC] regimens of six to eight months duration as against 12 to 24 months of conventional chemotherapy. Animal studies had shown high

739

sterilizing activities of pyrazinamide and rifampicin implicating low relapses. The chances of failure due to initial drug resistance are greatly decreased because of the multiplicity and potency of the drugs used particularly in the intensive phase. Sputum conversion occurred rapidly. In view of all these factors it was possible to evolve highly effective short-course regimens consisting of rifampicin, isoniazid, and pyrazinamide with streptomycin or ethambutol for a period of two months followed by two or three drugs like rifampicin plus isoniazid with or without ethambutol or a non-rifampicin continuation phase consisting of streptomycin or thioacetazone plus isoniazid. These regimens were found to be highly effective with no failures among patients with drug-sensitive bacterial population. The relapse rates were less than five per cent during a two-year period of follow-up. Majority of relapses occurred within six months after stopping chemotherapy. In contrast, 12 month non-rifampicin conventional regimens had an overall maximum failure [failure plus relapse] rate of 18 per cent. Streptomycin resistance was of no consequence in the response to treatment among patients treated with short-course chemotherapeutic regimens. Initially either three or four bactericidal drugs were given daily for two or three months in the initial intensive phase followed by two or three drugs daily for the subsequent four or six months. Intermittent Short-course Chemotherapy Regimens As the daily SCC regimens were found to be highly effective, the efficacy of intermittent SCC regimens was studied. At first, regimens with a daily intensive phase followed by an intermittent continuation phase were studied with the risk of relapse being the key indicator of the effectiveness of the regimen (16). Many regimens achieve nearly 100 per cent cure; relapse was less than five per cent. A series of studies (17-28) have demonstrated that intermittent treatment following a daily intensive phase–which may be as short as two weeks–is highly effective, as long as treatment observation is ensured. Six-month SCC regimens achieve smear and culture conversion within two to three months in a majority of patients. Many regimens achieve a favourable response, as defined by culture negativity of 97 to 100 per cent (17-28) at the end of treatment. The challenge, however, lies in identifying practical regimens with low [< 5%] relapse rates.

740

Tuberculosis

Short-course Chemotherapy Regimens in the Treatment of Sputum Smear-positive Pulmonary Tuberculosis Several studies have demonstrated that a six-month SCC regimen containing rifampicin throughout and pyrazinamide in the intensive phase is highly effective in the treatment of sputum smear-positive TB (17-28). In the initial studies, drugs were given daily throughout or during the initial intensive phase at least. Studies conducted at the TRC, Chennai and Hong Kong Special Administrative Region of China [Hong Kong SAR] have shown that fully intermittent regimens are equally effective, and that the reduction in adverse reactions is significant, with near 100 per cent efficacy at the end of the treatment followed by a relapse rate of two to seven per cent (21,22,28,29). Thus, these data suggest that newly diagnosed sputum smear-positive pulmonary TB patients should be treated with daily or intermittent therapy for six to eight months; eight months being required if rifampicin is not used in the continuation phase of the treatment. The intensive phase should comprise of four drugs including rifampicin and pyrazinamide and should be given for at least two months. Terminology of Standard Tuberculosis Treatment Regimens It is essential to familiarize with the terminology used to describe various treatment regimens for TB (4). There are standard codes for TB treatment regimens. In this nomenclature, each antituberculosis drug has a standard abbreviation [H = isoniazid, R = rifampicin, Z = pyrazinamide, S = streptomycin, and E = ethambutol] and each regimen has two phases. The number before a phase indicates the duration of that phase of treatment in months. A number in subscript [e.g., 3] following a letter is the number of doses of that drug per week. If there is no number in subscript after a letter, then treatment with that drug is on a daily basis. An alternative drug [or drugs] appears as a letter [or letters] in parantheses. Some examples are described below to illustrate the standard code. In the regimen designated ‘2HRZE/4HR’, the prefix ‘2’ refers to an initial intensive phase of treatment for two months with isoniazid, rifampicin, pyrazinamide and ethambutol. As there is no subscript number following the letters, the drug treatment is daily.

The prefix ‘4’ refers to the continuation phase of treatment for four months with rifampicin and isoniazid. In the regimen designated 2H3R3Z3E3 /4H3R3 or 2 [HRZE]3/4[HR]3, the prefix ‘2’ refers to the initial phase of treatment for two months with isoniazid, rifampicin, pyrazinamide and ethambutol. The subscript ‘3’ following the letter[s] indicates thrice weekly administration of the drugs. The prefix ‘4’ refers to a continuation phase of four months with isoniazid and rifampicin. Short-course Chemotherpay Regimens of Less Than Six Months Two five-month regimens [2HRZS/3(HZS) 2 ] and [3HRZS/2(HZS)2] investigated at Chennai were found to be effective and had low relapse rates [4% to 5%] (16). This is the only study that investigated five-month regimens consisting of streptomycin for the entire duration of treatment and acceptable results were achieved (16). The efficacy of a three-month regimen [90 doses of RHZS] (30,31) has been studied in patients with pulmonary TB. Though this regimen achieved a near 100 per cent culture conversion rate at the end of the treatment, 20 per cent of patients had bacteriologically confirmed relapse during the follow-up period of five years (31). In contrast, when fewer doses were administered over a longer duration [thrice-weekly for 2 months; followed by twice-weekly for 4 months, making up a total of 63 doses in 6 months], relapse rates were only four to six per cent. Thus, the duration for which the drugs are administered appears to be of prime importance and not the number of doses. Similarly, fourmonth SCC regimens investigated in Singapore also had high relapse rates [8% to 16%] (23-25,31,32). With the advent of fluoroquinolones there appears to be a tentative possibilty of reducing the duration of treatment to four months in patients with pulmonary TB (33). However, more studies are needed to draw firm conclusions. Optimum Duration of Standard, Non-rifampicin Containing Regimens There are situations where rifampicin is either not available or rifampicin and pyrazinamide cannot be given to a patient. Before rifampicin and pyrazinamide became available, patients were treated for prolonged periods ranging from 12 to 18 months. For patients with initially sputum smear-positive TB, practically all-effective regimens reach the potential of bacteriological quiescence

Evolution of Chemotherapeutic Regimens in the Treatment of Tuberculosis and Their Scientific Rationale within six months of the start of treatment. However, relapse occurs in about one-fourth of patients treated with streptomycin, isoniazid and thioacetazone daily for six months (17). Hence if rifampicin and pyrazinamide are not used the total duration should be at least 12 months. With reference to study the optimum duration of initial supplement of streptomycin or the initial intensive phase in long-term treatment, studies in East Africa had shown that an initial supplement of streptomycin for eight weeks to the basic regimen of thioacetazone plus isoniazid daily for 12 months had a success rate of 96 per cent and the emergence of resistance was rare among patients who failed treatment. Two weeks of initial intensive treatment resulted in 10 per cent of failures, all with organisms resistant to isoniazid. Patients who received an initial supplement of streptomycin for four weeks had only a slightly [2%] less favourable bacteriological response than those in the eight weeks intensive phase (33). Other studies (34,35) investigating two weeks of initial intensive phase in the long-term treatment did not show any contribution to the overall results of the regimens. Thus, the optimum duration of intensive phase in a conventional long-term treatment is eight weeks. On the other hand, there is enough evidence that more than 18 months of good treatment produces little additional benefit, if any, in terms of treatment success or prevention of relapse (36). SMEAR-NEGATIVE PULMONARY TUBERCULOSIS The optimum duration of treatment for smear-negative pulmonary TB patients was addressed in studies done in Hong Kong SAR (37-40). Patients who had five smears negative for acid-fast bacilli [AFB] and had a chest radiograph suggestive of pulmonary TB were treated with two or four months of SHRZ (37-40). Relapse rates were higher with two to three months of treatment and the study concluded that smear-negative patients require at least four months of treatment. But for consistency and to allow a margin of safety, the World Health Organization [WHO] recommends six-month regimens for the treatment of smear-negative pulmonary TB. EXTRA-PULMONARY TUBERCULOSIS Challenges in Diagnosis Patients with extra-pulmonary TB are often treated empirically based on clinical and radiological grounds

741

without pathological and/or bacteriological confirmation of the diagnosis. This results in over-diagnosis and unnecessary treatment of a large number of patients (41). Extra-pulmonary TB may not be considered at all in the differential diagnosis; resulting in delay or deprivation of treatment (42). Extra-pulmonary TB is usually paucibacillary and any treatment regimen that is effective in pulmonary TB is likely to be effective as well in the treatment of extrapulmonary TB. For the purpose of treatment, extrapulmonary TB can be classified into severe and nonsevere forms. Severe forms of extra-pulmonary TB include meningeal TB, spinal TB [Pott’s disease], neurologicalTB, abdominal TB, bilateral or unilateral, moderate or extensive pleural effusion, pericardial effusion, and bone and joint TB involving more than one site. Limited disease involving other body sites are classified as non-severe forms. There are few reports of the use of SCC in the treatment of extra-pulmonary TB (43). The difficulty in defining a clear-cut “end-point” in assessing the efficacy of treatment of extra-pulmonary TB led to varying durations of treatment, and there have been relatively few controlled clinical trials in extra-pulmonary TB (44,45). The principles underlying the diagnosis and management of extra-pulmonary TB, therefore, have evolved mainly from the experience gained from randomized controlled clinical trials for pulmonary TB. However, studies on some forms of extra-pulmonary TB [e.g., TB of the spine, TB lymphadenitis, abdominal TB and brain tuberculoma] have clearly established the efficacy of SCC [6 to 9 months] in both children and adults. Table 51.5 describes the efficacy of treatment regimens in different forms of extra-pulmonary TB (46-50). The overall favourable response with these regimens varied from 87 to 99 per cent [Table 51.5]. Intermittent regimens have been proven to be as effective as daily regimens (46-50). The severe form of extra-pulmonary TB is preferably treated with four drugs in the initial intensive phase and if required, the total duration of treatment can be extended to nine to twelve months, especially in TB meningitis and neurological-TB. Corticosteroids should also be administered to patients with TB meningitis with neurological impairment, massive pleural effusion, some cases of TB pericarditis, and possibly other severe forms of extra-pulmonary TB. Lymph nodes can enlarge, persist and become superinfected with bacteria in the course of

742

Tuberculosis Table 51.5: Efficacy of treatment regimens in different forms of extra-pulmonary tuberculosis

Study (reference)

Treatment regimens

Duration [months]

No. of patients

Follow-up period [months]

Overall favourable response [%]

Spinal TB (46)

6HR + Modified Hong Kong Surgery 6HR 9HR

6

78

120

90

6 9

78 79

120 120

94 99

Radical surgery + 2HERS/7H2R2 2HERS/7H2R2

9 9

20 11

60 60

90 73

Pott’s paraplegia (47)

TB lymphadenitis (48)

2H3R3Z3S3/4H2S2

6

168

36

97

Abdominal TB (49)

2HRZ/4HR EHS/HE*

6 12

85 93

60 60

94 87

Brain tuberculoma (50)

3HRZ/6H2R2 3H3R3Z3/6H2R2

9 9

47 44

24 24

89 91

The number before the letters refers to the number of months of treatment The subscript after the letter refers to the number of doses per week * Daily regimen of streptomycin, ethambutol and isoniazid for 2 weeks, followed by ethambutol and isoniazid for rest of the subsequent 12 months TB = tuberculosis; H = isoniazid; R = rifampicin; E = ethambutol; S = streptomycin; Z = pyrazinamide

TB treatment. Paradoxical reactions or immune reconstitution inflammatory syndrome [IRIS] may occur. Generally, no modification or prolongation of antituberculosis treatment regimen is indicated. Even though treatment gives good results in most forms of extra-pulmonary TB, there are a few exceptions such as TB meningitis and spinal TB, where the treatment outcome depends on early initiation of antituberculosis the treatment. In TB meningitis, particularly, the outcome correlates with the stage of the disease at the time of initiation of treatment; only a minority of patients with severe disease recover completely (51). Predictors of poor outcome include younger age and advanced stage of the disease. However, Donald et al (52) had reported a mortality rate of 16 per cent and a relapse rate of two per cent among 95 children diagnosed to have TB meningitis treated with a SCC regimen of RHZE daily for six months. Similarly, in patients with spinal TB, the time taken for neurological recovery was not related to the nature of treatment regimen but appeared to be influenced by factors, such as initial motor power, presence or absence of bed sores and duration of kyphosis (47). The long-term efficacy of short-course treatment regimens of six to twelve months duration in various forms of extra-pulmonary TB has been proven by systematic follow-up of patients for five to ten years and

documentation of relapse rates of less than four per cent (46-50). SURGERY With the introduction of SCC, primary surgical treatment is less frequently used for the treatment of TB. The current status of surgery in the treatment of TB is discussed in the chapter “Surgery for pleuropulmonary tuberculosis” [Chapter 55] and in the respective chapters covering various forms of extra-pulmonary TB. Monitoring of Adverse Drug Reactions to Antituberculous Drugs Adverse reactions to antituberculosis drugs [Table 52.3] are relatively rare, but in some patients they may be severe. Clinicians who treat TB should be familiar with the methods of monitoring adverse reactions. Patients should be closely monitored for signs and symptoms suggestive of adverse drug reactions. The following are the definitions used to document adverse drug reactions [ADRs] and adverse events [AEs] (53). Adverse Drug Reaction An ADR is defined as a response to a drug which is noxious and unintended and which occurs at doses

Evolution of Chemotherapeutic Regimens in the Treatment of Tuberculosis and Their Scientific Rationale normally used in humans for diagnosis or therapy of diseases. The term ADR implies that a causal relationship between a medicinal product [drug] and an adverse event, is at least a reasonable possibility [i.e., the relationship cannot be ruled out] (53). Adverse Event An AE is defined as an untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can, therefore, be any unfavourable and unintended sign [including an abnormal laboratory finding] symptom, or disease temporarily associated with the use of a medicinal product, whether or not related to the medicinal [investigational] product (53). Serious Adverse Event A serious adverse event SAE is defined as a fatal or life threatening event or an event resulting in significant or persistent disability or incapacity or may necessitate hospitalization or prolongation of hospitalization or may jeopardize the subject and may require medical or surgical intervention to prevent serious outcomes. Ideally, adults treated for TB should have baseline measurements of hepatic enzymes, serum bilirubin and creatinine as well as complete blood and platelet counts. Serum uric acid should be measured if pyrazinamide is used and baseline examination of visual acuity should be obtained for patients for whom ethambutol is prescribed. The purpose of these baseline tests is to detect any abnormality that would complicate therapy or require a modified regimen. Monitoring of all adverse reactions to TB medications should be individualized. Type and frequency of monitoring should depend on the drugs used in a given regimen and the patients’ risk factors for adverse reactions, such as, age and alcohol use. Patients should be instructed to report if they develop any new symptoms. If the symptoms are suggestive of adverse reactions, appropriate laboratory testing should be performed. All patients receiving regimens containing isoniazid, rifampicin, and pyrazinamide should be closely monitored for drug induced hepatitis. The latter may be confused with acute viral hepatitis in developing nations, therefore, it is essential to check for markers for viral hepatitis in patients who develop

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abnormal liver functions while on antituberculosis drugs (54). The reader is referred to the chapter “Antituberculosis treatment induced hepatotoxicity [Chapter 54] for more details. Peripheral neuropathy is associated with use of isoniazid and is more likely among persons prone to develop neuropathy due to other causes. Hyperuricaemia may occur in patients receiving pyrazinamide but acute gout is uncommon. Asymptomatic hyperuricaemia is not an indication for discontinuing the drug. The reader is also referred to the chapter “Musculoskeletal manifestations of tuberculosis” [Chapter 24] for more details. Treatment of Tuberculosis Under Special Situations The reader is referred to the chapters “Granulomaotus hepatitis [Chapter 20], “Neurological tuberculosis” [Chapter 21], “Tuberculosis in pregnancy” [Chapter 30], and “Tuberculosis in chronic renal failure” [Chapter 33] for more details regarding the treatment of TB under special situations. Clinically Significant Drug Interactions Due to Rifampicin Several clinically significant drug interactions are known to occur with rifampicin and these are summarized in Table 52.5. TREATMENT OF TUBERCULOSIS IN PERSONS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND ACQUIRED IMMUNODEFICIENCY SYNDROME The treatment of TB in persons with the human immunodeficiency virus infection and acquired immunodeficiency syndrome is detailed covered in the chapter “Tuberculosis and human immunodeficiency virus infection” [Chapter 40]. Fixed-dose Combinations of Antituberculosis Drugs Fixed-dose combination antituberculosis drugs [FDC], which incorporate two or more drugs into one tablet in fixed proportions, have been used since the late 1980s and are registered in more than 40 countries (55). Combinations of isoniazid and thioacetazone and isoniazid and ethambutol have long been used. For SCC, the two most common FDC preparations combine

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isoniazid, rifampicin and pyrazinamide, used in the intensive phase of treatment, and isoniazid and rifampicin, often used in the continuation phase. Increasingly, a four-drug FDC consisting of isoniazid, rifampicin, pyrazinamide and ethambutol is being used (56). Potential Advantages Drug resistance may be less likely to emerge since multiple drugs are incorporated into the FDC (57-59). Further, with treatment interruption due to default, all drugs will be stopped, and thus, resistant organisms are unlikely to emerge. The use of FDC can simplify treatment, will reduce the number of pills to be consumed, and thus, minimise prescription errors and reduce the probability of monotherapy. Procurement, management and distribution of drugs are simplified by the use of FDC. A treatment regimen using FDC may improve patient’d compliance to treatment (59,60). The use of rifampicin in FDC may reduce inappropriate use of rifampicin for other infections (61). Several studies have shown that the FDC containing four drugs is bioequivalent to separate individual drugs at the same dose levels (61-64). Potential Disadvantages The bioavailability [the amount of an ingested drug absorbed into the blood] of rifampicin may decrease when it is combined with other drugs in the FDC (61-64). Therefore, use of FDC, particularly in three- and four-drug combinations, could result in sub-optimal therapeutic plasma levels of rifampicin, and thus, could lead to treatment failures, relapses and/or the generation of rifampicin-resistant strains of Mycobacterium tuberculosis (65). Therefore, only FDC of proven bioavailability should be used (66). A global mechanism for pre-qualification of FDC has been proposed to ensure that only quality FDC will be purchased and used. The optimal operational efficiency from using FDC may not be achieved as the doses required for all patients receiving treatment will vary with body weight of patients. The WHO recommended dosage schedule for FDC allows for easy adjustment of dosage by weight. Adverse effects, such as antituberculosis drug induced hepatotoxicity, may also necessitate dosing changes. Hence, any TB control programme using FDC must also supply single drugs for special circumstances to be used by TB specialists.

If at all they are used, only the formulations recommended by the WHO and International Union Against Tuberculosis and Lung Disease [IUATLD] should be used (66). When three- or four-drug FDC are used in the intensive phase of treatment, a different two-drug FDC is used in the continuation phase. If a country is using FDC, it will need to provide additional training on drug procurement, treatment recommendations, and patient and provider education (55). Although there are potential advantages in using FDC, the benefits may be difficult to realise given the existing operational, programmatic and regulatory constraints. Each country must carefully weigh the advantages, disadvantages and appropriate role of FDC within their programme. Phenomenon of Drug Resistance Clinical and laboratory observations and experimental studies have led to the understanding of development of drug resistance, its clinical and epidemiological significance, and its prevention and control. The phenomenon of resistance was detected when streptomycin alone was introduced in the treatment of TB in humans (67). At first a striking improvement in the patient’s symptoms, together with a rapid decrease in the number of bacilli in the sputum occurred. Subsequently, the number of bacilli soon increased again and the patient’s condition deteriorated. Bacilli isolated from the sputum of patients who had received streptomycin alone for a few months continued to grow in vitro in the presence of high concentrations of the drug. This showed that large bacterial populations contain a minute proportion of organisms that are barely or not at all susceptible to a particular drug, even before its administration. The susceptible bacteria are killed by the drug, the few resistant organisms survive and multiply, and their nonsusceptible descendants, generation after generation, replace the susceptible organisms. Thus, clinically relevant drug resistance is the result of a selection process. Resistance to any antituberculosis drug [including rifampicin] develops predictably if the drug is used alone. This was first described with streptomycin in 1947 as the “fall and rise” phenomenon. Such resistance can develop after relatively brief periods [i.e., over several days] of single drug treatment, especially in patients with large numbers of actively replicating bacilli [e.g., in patients with extensively active disease or severe immunosuppression, such as AIDS]. Similarly, resistance would be

Evolution of Chemotherapeutic Regimens in the Treatment of Tuberculosis and Their Scientific Rationale expected if only one drug in a regimen is effective [due to pre-existing resistance to the other agents of the regimen]. Development of resistance due to addition of a single drug to a failing regimen has also been well described (68). Multidrug-resistant TB [MDR-TB] caused by isolates resistant to isoniazid and rifampicin with or without resistance to other antituberculosis drugs is emerging as a threat to destabilize the global TB control (69,70). Extensively drug-resistant TB [XDR-TB] is also being documented in several parts of the world (71). The reader is referred to the chapters “Drug resistant tuberculosis” [Chapter 49], and “Antituberculosis drug resistance surveillance” [Chapter 50] for more details. Reasons for Special Precautions to Protect Rifampicin Rifampicin must be protected because it is the key sterilizing drug in short-course treatment (72). With rifampicin, treatment for drug-susceptible disease can be completed in six to nine months [depending on companion drugs], with combined rates of failure and relapse of less than five per cent. Without rifampicin, treatment must generally be given for at least 12 months to achieve low rates of failure and relapse. Resistance to rifampicin results in a substantial increase in the rate of failure and relapse when standard three- or four-drug regimens are used (73). In the British Medical Research Council trials (74), initial resistance to rifampicin was associated with a rate of failure of 45 per cent during treatment and half of the remaining patients relapsed [overall unfavourable treatment outcome of 72%]. This is in striking contrast to the experience of patients with initial resistance to isoniazid and or streptomycin. When rifampicin resistance is present, the minimum required duration of antituberculosis treatment with a feasible regimen is 12 to 15 months. If resistance to isoniazid is also present [i.e., multidrug resistance], then necessary treatment duration is likely to be 18 to 24 months or more. These problems can be prevented by restricting availability of rifampicin and related drugs [rifabutin, rifapentine] to TB control programmes [as is done in some developing countries with well functioning programmes], or to licensed or experienced practitioners [as is done in many developed and some developing countries]; and/or, making rifampicin available exclusively as a fixed-drug combination in products which include

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isoniazid, so that the rifampicin component cannot be administered alone. The consequences of restricted use of rifampicin are minimal, because rifampicin is occasionally indicated for the treatment of some deep-seated staphylococcal infections, and in prevention of meningococcal disease. Other alternative antibiotics that are available may be used in such conditions. RESEARCH AGENDA AND FUTURE FOR TUBERCULOSIS TREATMENT Newer Antituberculosis Drugs Newer antituberculosis drugs are needed for three reasons: to shorten or otherwise simplify treatment of TB caused by drug-susceptible organisms, to improve the treatment of patients with MDR-TB, and to provide more effective and efficient treatment of latent tuberculosis infection [LTBI] (75). Although treatment regimens for drug-susceptible TB are effective, they must be administered for a minimum of six months to achieve optimal results. Non-adherence to this relatively lengthy course of treatment remains a major problem. To address the problem of non-adherence, direct observation of treatment [DOT], as a component of the DOTS strategy is recommended as the standard of care worldwide. However, the administrative and financial burden of providing DOT to all patients is considerable. Current treatment regimens for drug-resistant TB utilize drugs that are less effective, more toxic, and more expensive than those used for standard treatment. Moreover, these treatment regimens often have to be given for 18 to 24 months. Although new drugs that are effective against resistant organisms would alone not solve the problem of drug resistance, their judicious use would greatly improve the treatment of many patients. With the advent of newer and more efficient diagnostic tests for the detection of LTBI, such as the inteferongamma release assays [IGRAs], there is a need for new drugs to provide for safe and effective “short-course” LTBI treatment. No truly novel compounds that are likely to have a significant impact on TB treatment are presently available for clinical study. Table 49.10 lists some of the newer drugs that are being evaluated for the treatment of TB. The reader is also referred to the chapter “Treatment of tuberculosis” [Chapter 52] for more details.

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OTHER INTERVENTIONS TO IMPROVE THE EFFICACY OF TUBERCULOSIS TREATMENT PROGRAMMES A number of other approaches have been suggested that might lead to improved treatment outcome, including alternative drug delivery systems and a variety of methods of immunomodulation and immunotherapy. Experimental studies have demonstrated that effective serum concentrations of isoniazid and pyrazinamide can be provided through incorporation of drug into slowrelease, biodegradable polymers that are implanted subcutaneously (76). However, there has been little apparent commercial interest in pursuing this approach. Liposomal encapsulation of antituberculosis drugs has been suggested as an approach to direct drug to the proposed site of infection [i.e., the macrophage] to provide more effective and better tolerated therapy; and for widely spaced treatment interval. Similarly, incorporation of drug into inhalable smaller particles may reduce dose requirements, minimize toxicity, and deliver drug to the infected alveolar macrophages. Although experimental studies have suggested that these approaches might be effective, little clinical work has been done in these areas (76,77). Because of possible detrimental effects of the cytokine, tumour necrosis factor-α [TNF-α] in HIV-associated TB, there has been some interest in the use of drugs, such as thalidomide and pentoxifylline, that block TNF-α production. Studies have shown that administration of thalidomide improves weight gain in both HIV-seropositive and HIV-seronegative patients with TB (78). Pentoxifylline has been associated with reduced circulating HIV viral load in patients with TB (79). However, the potential side effects of these drugs may outweigh possible benefits. A more promising intervention is the administration of “protective” cytokines, such as aerosolized interferon and subcutaneous interleukin-2, which have shown activity as adjuncts to chemotherapy in patients with MDR-TB (80,81). Another method of immunomodulation, the use of heat-killed preparations of Mycobacterium vaccae as a therapeutic vaccine, has not shown clinically significant benefits when carefully evaluated in randomized clinical trials (82). Nonetheless, there continues to be interest in this approach, especially for patients with advanced drug-resistant TB. Other vaccines that lead to expression of protective cytokines have shown more promise in

experimental studies (83). Finally, a study suggested that the administration of vitamin A and zinc to patients with pulmonary TB is associated with an increased rate of sputum conversion and improvement in chest radiographs (84). Further assessment of nutritional supplements in TB treatment is indicated. METHODS TO IDENTIFY AND MANAGE HIGH- AND LOW-RISK PATIENTS The sputum culture positivity at two months appears to be a marker for an increased risk of relapse for patients with pulmonary TB. Surrogate markers that could be measured earlier in therapy and have a greater sensitivity and specificity for a poor outcome could better select high risk patients for more intensive or longer therapy, thus, minimizing the likelihood of relapse. Studies of several molecular markers in the sputum have shown promise and deserve further evaluation (85). Conversely, markers that reliably identify patients at lower risk of an adverse treatment outcome would be helpful to select patients for less intense or shorter treatment. Whether or not lowrisk patients can be treated with shorter regimens using currently available drugs is a topic of considerable importance. DOTS The WHO (4) and the IUATLD (86) guidelines for the treatment of TB target, in general, countries in which mycobacterial culture, drug susceptibility testing, radiographic facilities, and second-line drugs are not widely available. Both these recommendations are built around a national case management strategy called “DOTS,” in which DOT is only one of five key elements (87). The essential principles of DOTS strategy are the products of India’s long and distinguished tradition of TB research. In the 1950s and 1960s, studies at the TRC, Chennai, demonstrated the efficiency and safety of home treatment of TB patients without additional risk of disease to close contacts (88). Wallace Fox (89) of TRC, Chennai identified the problems related to poor compliance to treatment and demonstrated the necessity and feasibility of supervised administration of every dose of treatment to TB patients and also provided evidence that intermittent chemotherapy was as effective as daily treatment. In the 1960s, studies at the National

Evolution of Chemotherapeutic Regimens in the Treatment of Tuberculosis and Their Scientific Rationale Tuberculosis Institute [NTI], Bengaluru [then Bangalore], documented the efficacy and feasibility of case detection by sputum smear microscopy even at the peripheral health institutions (90). Karel Styblo (91) combined all the above principles into a powerful treatment system that ensured monitoring, supervision, and accountability for every patient started on treatment and demonstrated that this system could provide effective TB treatment, affordable for developing countries. Thus, the principles of modern TB control, first developed in India, in the late 1950s have travelled around the world and finally returned home nearly 40 years later as DOTS. The reader is referred to the chapters “DOTS: the strategy that ensures cure of tuberculosis” [Chapter 56] and “Directly observed treatment” [Chapter 57] for more details.

4.

5. 6.

7.

8. 9. 10.

HEALTH EDUCATION Intensive health education should be initiated as soon as the patient is started on treatment for TB. The instruction should be at an educational level appropriate for the patient and should include information about TB, expected outcomes of treatment, the benefits and possible adverse effects of the drug regimen, methods of supervision, assessment of response, and a discussion of infectiousness and infection control measures. The medication regimen must be explained in clear, understandable language including written instructions. Health education materials should be appropriate for the culture, language, age, and reading level of the patient. Relevant information should be reinforced at each visit. Use of a record system, that quantifies the dosage and frequency of medication administered, indicates smear status, and notes symptom improvement as well as any adverse effects of treatment serves to facilitate regular reviews and also provides data for cohort analyses.

11.

12.

13.

14.

15.

16.

REFERENCES 1. Canetti G. The tubercle bacillus in pulmonary lesion of man; histobacteriology and its bearing on the therapy of pulmonary tuberculosis. New York: Springer; 1955. 2. Mitchison DA. Bacteriological mechanisms in recent controlled chemotherapy studies. Bull Int Union Tuberc 1970;43:322-31. 3. Tuberculosis Chemotherapy Centre, Madras. A concurrent comparison of isoniazid plus PAS with three regimens of isoniazid alone in the domiciliary treatment of pulmonary

17.

18.

747

tuberculosis in South India. Bull World Health Organ 1960;23:535-85. World Health Organization, Stop TB Department. Treatment of tuberculosis: guidelines for national programmes. Third edition. Geneva: World Health Organization;2003. Mitchison DA. Chemotherapy of tuberculosis: a bacteriologist’s viewpoint. Br Med J 1965;1:1333-40. Canetti G. Host factors and chemotherapy of tuberculosis. In: Barry VC, editor. Chemotherapy of tuberculosis. London: Butterworth; 1964.p.20-38. Harries A, Maher D, Uplekar M, Raviglione M, Chaulet P, Nunn P, et al. TB. A clinical manual for South-East Asia. WHO/TB/96.200 [SEA]. Geneva: World Health Organization;1997. Mitchison DA. Mechanisms of the action of drugs in the shortcourse chemotherapy. Bull Int Union Tuberc 1985;60:36-40. Mitchison DA. Basic mechanisms of chemotherapy. Chest 1979;76(6 Suppl):771-81. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al. American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603-62. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/ TB/ 2006.361. Geneva: World Health Organization; 2006. Dickinson JM, Mitchison DA. In vitro and in vivo studies to assess the suitability of antituberculous drugs for use in intermittent chemotherapy regimens. Tubercle 1968;49 [Suppl]:66-70. Grumbach F, Canetti G, Grosset J, le Lirzin M. Late results of long-term intermittent chemotherapy of advanced, murine tuberculosis: limits of the murine model. Tubercle 1967;48:1126. Lotte A, Hatton F, Perdrizet S, Rouillon A. Tuberculosis Chemotherapy Centre, Madras. A concurrent comparison of intermittent [twice-weekly] isoniazid plus streptomycin and daily isoniazid plus PAS in the domiciliary treatment of pulmonary tuberculosis. Bull World Health Organ 1964;31: 247-71. Tuberculosis Chemotherapy Centre, Madras. A controlled comparison of a twice-weekly and three once-weekly regimens in the initial treatment of pulmonary tuberculosis. Bull World Health Organ 1970;43:143-206. Santha T, Nazareth O, Krishnamurthy MS, Balasubramanian R, Vijayan VK, Janardhanam B, et al. Treatment of pulmonary tuberculosis with short course chemotherapy in south India– 5-year follow up. Tubercle 1989;70:229-34. East African-British Medical Research Councils. Controlled clinical trial of four short-course [6-month] regimens of chemotherapy for treatment of pulmonary tuberculosis. Third report. Lancet 1974;2:237-40. Second East African/British Medical Research Council Study. Controlled clinical trial of four 6-month regimens of chemotherapy for pulmonary tuberculosis. Second report. Am Rev Respir Dis 1976;114:471-5.

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Tuberculosis

19. East and Central African/British Medical Research Council Fifth Collaborative Study. Controlled clinical trial of 4 shortcourse regimens of chemotherapy [three 6-month and one 8month] for pulmonary tuberculosis. Tubercle 1983;64:153-66. 20. East and Central African/British Medical Research Council Fifth Collaborative Study. Controlled clinical trial of 4 shortcourse regimens of chemotherapy [three 6-month and one 8month] for pulmonary tuberculosis: final report. Tubercle 1986;67:5-15. 21. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 6-month and 8-month regimens in the treatment of pulmonary tuberculosis. First report. Am Rev Respir Dis 1978;118:219-28. 22. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 6-month and 8-month regimens in the treatment of pulmonary tuberculosis: the results up to 24 months. Tubercle 1979;60:201-10. 23. Singapore Tuberculosis Service/British Medical Research Council. Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1979;119:579-85. 24. Singapore Tuberculosis Service/British Medical Research Council. Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis: the results up to 30 months. Tubercle 1981;62:95-102. 25. Singapore Tuberculosis Service/British Medical Research Council. Long-term follow-up of a clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1986;133:77983. 26. Singapore Tuberculosis Service/British Medical Research Council. Five-year follow-up of a clinical trial of three 6-month regimens of chemotherapy given intermittently in the continuation phase in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1988;137:1147-50. 27. Singapore Tuberculosis Service/British Medical Research Council. Clinical trial of three 6-month regimens of chemotherapy given intermittently in the continuation phase in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1985;132:374-8. 28. Balasubramanian R. Fully intermittent 6 months regimen for pulmonary tuberculosis in South India. Indian J Tuberc 1991;38:51-3. 29. Tuberculosis Research Centre, Madras. . Low rate of emergence of drug resistance in sputum positive patients treated with short course chemotherapy. Int J Tuberc Lung Dis 2001;5:40-5. 30. Tuberculosis Research Centre, Madras, and National Tuberculosis Institute, Bangalore. A controlled clinical trial of 3- and 5-month regimens in the treatment of sputumpositive pulmonary tuberculosis in South India. Am Rev Respir Dis 1986;134:27-33. 31. Balasubramanian R, Sivasubramanian S, Vijayan VK, Ramachandran R, Jawahar MS, Paramasivan CN, et al. Five year results of a 3-month and two 5-month regimens for the

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

treatment of sputum-positive pulmonary tuberculosis in south India. Tubercle 1990;71:253-8. East African and British Medical Research Councils. Controlled clinical trial of five short-course [4-month] chemotherapy regimens in pulmonary tuberculosis. First report of 4th study. Lancet 1978;2:334-8. Tuberculosis Research Centre. Shortening short course chemotherapy: a randomised clinical trial for the treatment of smear positive pulmonary tuberculosis with regimens using ofloxacin in the intensive phase. Indian J Tuberc 2002;49:27-38. A co-operative study in East African hospitals, clinics and laboratories with the collaboration of the East African and British Medical Research Councils. Isoniazid with thioacetazone (thioacetazone) in the treatment of pulmonary tuberculosis in East Africa–fifth investigation. Tubercle 1970;51:123-51. Tuberculosis Chemotherapy Centre, Madras. Controlled comparison of oral twice-weekly and oral daily isoniazid plus PAS in newly diagnosed pulmonary tuberculosis. Br Med J 1973;2:7-11. Results at 5 years of a controlled comparison of a 6-month and a standard 18-month regimen of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1977;116:3-8. Hong Kong Chest Service/Tuberculosis Research Centre/ British Medical Research Council. Sputum-smear-negative pulmonary tuberculosis: controlled trial of 3-month and 2-month regimens of chemotherapy. Lancet 1979;1:1361-3. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. A controlled trial of a 2-month, 3-month, and 12-month regimens of chemotherapy for sputum smear-negative pulmonary tuberculosis: the results at 30 months. Am Rev Respir Dis 1981;124:138-42. Hong Kong Chest Service/Tuberculosis Research Centre/ British Medical Research Council. A controlled trial of 2month, 3-month, and 12-month regimens of chemotherapy for sputum-smear-negative pulmonary tuberculosis. Results at 60 months. Am Rev Respir Dis 1984;130:23-8. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. A controlled trial of 3-month, 4-month, and 6-month regimens of chemotherapy for sputum smear-negative pulmonary tuberculosis. Results at 5 years. Am Rev Respir Dis 1989;139:871-6. Ramanathan M, Wahinuddin S, Safari E, Sellaiah SP. Abdominal tuberculosis: a presumptive diagnosis. Singapore Med J 1997;38:364-8. Ormerod LP. The management of extra-pulmonary tuberculosis. In: Gangadharam PRJ, editor. Mycobacteria. New York: Chapman and Hall; 1997.p.236-78. Dutt AK, Moers D, Stead WW. Short-course chemotherapy for extrapulmonary tuberculosis. Nine years’ experience. Ann Intern Med 1986;104:7-12. British Thoracic Society Research Committee. Short course chemotherapy for tuberculosis of lymph nodes: a controlled trial. Br Med J [Clin Res Ed] 1985;290:1106-8.

Evolution of Chemotherapeutic Regimens in the Treatment of Tuberculosis and Their Scientific Rationale 45. Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316-53. 46. Balasubramanian R, Ramachandran R. Management of nonpulmonary forms of tuberculosis: review of TRC studies over two decades. Indian J Pediatr 2000;67[2 Suppl]:S34-40. 47. Parthasarathy R, Sriram K, Santha T, Prabhakar R, Somasundaram PR, Sivasubramanian S. Short-course chemotherapy for tuberculosis of the spine. A comparison between ambulant treatment and radical surgery–ten-year report. J Bone Joint Surg Br 1999;81:464-71. 48. Jawahar MS, Sivasubramanian S, Vijayan VK, Ramakrishnan CV, Paramasivan CN, Selvakumar V, et al. Short course chemotherapy for tuberculous lymphadenitis in children. BMJ 1990;301:359-62. 49. Balasubramanian R, Nagarajan M, Balambal R, Tripathy SP, Sundararaman R, Venkatesan P, et al. Randomised controlled clinical trial of short course chemotherapy in abdominal tuberculosis: a five-year report. Int J Tuberc Lung Dis 1997;1:44-51. 50. Rajeswari R, Sivasubramanian S, Balambal R, Parthasarathy R, Ranjani R, Santha T, et al. A controlled clinical trial of shortcourse chemotherapy for tuberculoma of the brain. Tuber Lung Dis 1995;76:311-7. 51. Ramachandran P, Duraipandian M, Nagarajan M, Prabhakar R, Ramakrishnan CV, Tripathy SP. Three chemotherapy studies of tuberculous meningitis in children. Tubercle 1986;67:17-29. 52. Donald PR, Schoeman JF, Van Zyl LE, De Villiers JN, Pretorius M, Springer P. Intensive short course chemotherapy in the management of tuberculous meningitis. Int J Tuberc Lung Dis 1998;2:704-11. 53. National Insitutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events v3.0 [CTCAE] Publish Date: August 9, 2006. Available at URL: http://ctep.cancer.gov/forms/CTCAEv3.pdf. Accessed on August 01, 2008. 54. Sarda P, Sharma SK, Mohan A, Makharia G, Jayaswal A, Pandey RM. Acute viral hepatitis confounds antituberculosis treatment induced hepatotoxicity in developing countries. Indian J Med Res 2008 [in press]. 55. Norval PY, Blomberg B, Kitler ME, Dye C, Spinaci S. Estimate of the global market for rifampicin-containing fixed-dose combination tablets. Int J Tuberc Lung Dis 1999;3[11 Suppl 3]:S292-300; discussion S317-21. 56. Fixed-dose combination tablets for the treatment of tuberculosis: report of an informal meeting held in Geneva Tuesday 27 April 1999: World Health Organization Communicable Diseases Cluster 1999. WHO/CDC/CPC/ TB/99.267. Geneva. World Health Organization; 1999. 57. Blomberg B, Spinaci S, Fourie B, Laing R. The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis. Bull World Health Organ 2001;79:61-8. Epub 2003 Nov 5. 58. Mitchison DA. How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis. Int J Tuberc Lung Dis 1998;2:10-5.

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59. Moulding T, Dutt AK, Reichman LB. Fixed-dose combinations of antituberculous medications to prevent drug resistance. Ann Intern Med 1995;122:951-4. 60. Hong Kong Chest Service/British Medical Research Council. Acceptability, compliance, and adverse reactions when isoniazid, rifampin, and pyrazinamide are given as a combined formulation or separately during three-timesweekly antituberculosis chemotherapy. Am Rev Respir Dis 1989;140:1618-22. 61. Acocella G. Human bioavailability studies. Bull Int Union Tuberc Lung Dis 1989;64:38-40; discussion 40-2. 62. Acocella G, Luisetti M, Grassi GG, Peona V, Pozzi E, Grassi C. Bioavailability of isoniazid, rifampicin and pyrazinamide [in free combination or fixed-triple formulation] in intermittent antituberculous chemotherapy. Monaldi Arch Chest Dis 1993;48:205-9. 63. Fox W. Drug combinations and the bioavailability of rifampicin. Tubercle 1990;71:241-5. 64. Pillai G, Fourie PB, Padayatchi N, Onyebujoh PC, McIlleron H, Smith PJ, et al. Recent bioequivalence studies on fixeddose combination anti-tuberculosis drug formulations available on the global market. Int J Tuberc Lung Dis 1999;3[11 Suppl 3]:S309-16; discussion S317-21. 65. Long MW, Snider DE Jr, Farer LS. U.S. Public Health Service Cooperative trial of three rifampin-isoniazid regimens in treatment of pulmonary tuberculosis. Am Rev Respir Dis 1979;119:879-94. 66. A joint statement of the International Union Against Tuberculosis and Lung Diseases and the World Health Organization. Assuring bioavailability of fixed-dose combinations of anti-tuberculosis medications. Int J Tuberc Lung Dis 1999;3[11 Suppl 3]:S282-3. 67. Pyle MM. Relative numbers of resistant tubercle bacilli in sputa of patients before and during treatment with streptomycin. Proc Staff Meet Mayo Clin 1947;22:465-73. 68. Mahmoudi A, Iseman MD. Pitfalls in the care of patients with tuberculosis. Common errors and their association with the acquisition of drug resistance. JAMA 1993;270:65-8. 69. Sharma SK, Mohan A. Multidrug-resistant tuberculosis: a menace that threatens to destabilize tuberculosis control. Chest 2006;130:261-72. 70. Zignol M, Hosseini MS, Wright A, Weezenbeek CL, Nunn P, Watt CJ, et al. Global incidence of multidrug-resistant tuberculosis. J Infect Dis 2006;194:479-85. Epub 2006 Jul 12. 71. Jeon CY, Hwang SH, Min JH, Prevots DR, Goldfeder LC, Lee H, et al. Extensively drug-resistant tuberculosis in South Korea: risk factors and treatment outcomes among patients at a tertiary referral hospital. Clin Infect Dis 2008;46:42-9. 72. Mitchison DA. Basic concepts in the chemotherapy of tuberculosis. In: Gangadharam PRJ, Jenkins PA, editors. Mycobacteria. Vol 2. Chemotherapy. New York: Chapman and Hall; 1998.p.15-50. 73. Espinal MA, Kim SJ, Suarez PG, Kam KM, Khomenko AG, Migliori GB, et al. Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries. JAMA 2000;283:2537-45.

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74. Mitchison DA, Nunn AJ. Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986;133:423-30. 75. O’Brien RJ, Nunn PP. The need for new drugs against tuberculosis. Obstacles, opportunities, and next steps. Am J Respir Crit Care Med 2001;163:1055-8. 76. Gangadharam PR, Geeta N, Hsu YY, Wise DL. Chemotherapy of tuberculosis in mice using single implants of isoniazid and pyrazinamide. Int J Tuberc Lung Dis 1999;3:515-20. 77. Sharma R, Saxena D, Dwivedi AK, Misra A. Inhalable microparticles containing drug combinations to target alveolar macrophages for treatment of pulmonary tuberculosis. Pharm Res 2001;18:1405-10. 78. Tramontana JM, Utaipat U, Molloy A, Akarasewi P, Burroughs M, Makonkawkeyoon S, et al. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med 1995;1:384-97. 79. Wallis RS, Nsubuga P, Whalen C, Mugerwa RD, Okwera A, Oette D, et al. Pentoxifylline therapy in human immunodeficiency virus-seropositive persons with tuberculosis: a randomized, controlled trial. J Infect Dis 1996;174:727-33. 80. Condos R, Rom WN, Schluger NW. Treatment of multidrugresistant pulmonary tuberculosis with interferon-gamma via aerosol. Lancet 1997;349:1513-5. 81. Johnson B, Bekker LG, Ress S, Kaplan G. Recombinant interleukin 2 adjunctive therapy in multidrug-resistant tuberculosis. Novartis Found Symp 1998;217:99-106; discussion 106-11. 82. Durban Immunotherapy Trial Group. Immunotherapy with Mycobacterium vaccae in patients with newly diagnosed pulmonary tuberculosis: a randomised controlled trial. Lancet 1999;354:116-9.

83. Moreira AL, Tsenova L, Murray PJ, Freeman S, Bergtold A, Chiriboga L, et al. Aerosol infection of mice with recombinant BCG secreting murine IFN-gamma partially reconstitutes local protective immunity. Microb Pathog 2000;29:175-85. 84. Karyadi E, West CE, Schultink W, Nelwan RH, Gross R, Amin Z, et al. A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status. Am J Clin Nutr 2002;75:720-7. 85. Desjardin LE, Perkins MD, Wolski K, Haun S, Teixeira L, Chen Y, et al. Measurement of sputum Mycobacterium tuberculosis messenger RNA as a surrogate for response to chemotherapy. Am J Respir Crit Care Med 1999;160:203-10. 86. International Union Against Tuberculosis and Lung Disease. Management of tuberculosis: a guide for low income countries. Fifth edition. Paris: International Union Against Tuberculosis and Lung Disease; 2000. 87. World Health Organization. What is DOTS? A guide to understanding the WHO-recommended TB control strategy known as DOTS. WHO/CDS/CPC/TB/99.270. Geneva: World Health Organization; 1999. 88. Tuberculosis Chemotherapy Centre, Madras. A concurrent comparison of home and sanatorium treatment of pulmonary tuberculosis patients in South India. Bull World Health Organ 1959;21:51. 89. Fox W. Self administration of medicaments. A review of published work and a study of the problems. Bull Int Union Tuberc 1961;31:307-31. 90. Baily GV, Savic D, Gothi GD, Naidu VB, Nair SS. Potential yield of pulmonary tuberculosis cases by direct microscopy of sputum in a district of South India. Bull World Health Organ 1967;37:875-92. 91. Styblo K. Epidemiology of tuberculosis. Second edition. The Hague: Royal Netherlands Tuberculosis Association; 1991.

Treatment of Tuberculosis 751

Treatment of Tuberculosis

52 WW Yew

INTRODUCTION Tuberculosis [TB] is one of the most common infectious diseases known to mankind. After some years of neglect, this important global problem is regaining the attention it deserves. Treatment of TB, largely based on drugs, has been evolving for several decades. HISTORY OF CHEMOTHERAPY OF TUBERCULOSIS Chemotherapy for TB became possible only after the discovery of streptomycin in 1944. Improvement in clinical state, sputum bacteriology and radiography was experienced by the patient after two to three months of therapy with the drug. Unfortunately, these good responses were short lasting as bacillary resistance to streptomycin would develop after the monotherapy resulting in disease deterioration again (1). A few years later, combined therapy with streptomycin and paraaminosalicylic acid was found to prevent drug resistance from developing and achieved better results (2). The subsequent introduction of isoniazid as a drug in the combination regimen for treating TB formed the basis of primary chemotherapy in the 1950s to 1960s (3). The standard regimen then comprised streptomycin, isoniazid and para-aminosalicylic acid for a few months followed by the latter two drugs up to a total period of 18 to 24 months. Para-aminosalicylic acid could be substituted by ethambutol or thioacetazone depending on their availability and acceptability in the community. Aside from adverse reactions to drugs, patients often absconded prematurely or took drugs irregularly when they became symptomless after a few weeks to months of

treatment. This could lead to treatment failure and development of drug resistance. In the early 1960s, the experience gained in Chennai [earlier called Madras] and Hong Kong from collaborative studies between the British Medical Research Council and relevant health care authorities demonstrated the effectiveness and efficacy of ambulatory antituberculosis treatment (4). Prolonged hospitalizsation in sanatoria became unnecessary. Fully supervised chemotherapy, directly observed therapy [DOT], in form of streptomycin and isoniazid given intermittently twice per week in the continuation phase, after the initial few months of the daily triple-drug therapy referred to earlier, was utilized. In 1965, rifampicin was discovered followed shortly by ethambutol and pyrazinamide. In the 1970s, short-course chemotherapy [SCC] was introduced for the treatment of TB (5). Biological Characteristics of Mycobacterium tuberculosis and Basis of Short-course Chemotherapy Mycobacterium tuberculosis is a slowly growing bacterium, and it can also enter a phase of dormancy which is basically drug refractory. A patient with TB can harbour four hypothetical populations of organisms. The first population is the actively growing extracellular organisms, which are present in abundance within aerated cavities. The second population consists of slow intermittently growing organisms in an unstable part of the lesion. The third population includes organisms surviving in low environmental pH, which can occur in inflammatory lesions or within phagolysosomes of macrophages. The last population refers to the completely dormant organisms surviving under anaerobic conditions [Figure 51.1].

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The three major actions of antituberculosis drugs (5) are: [i] bactericidal action, defined by the ability to kill actively growing bacilli rapidly; [ii] sterilizing action, defined by the capacity to kill the semi-dormant organisms; and [iii] prevention of emergence of drug resistance. Isoniazid is the most potent bactericidal drug. Rifampicin is also important as such. Rifampicin and pyrazinamide are important drugs for sterilizing the TB lesions and preventing disease relapse. Resistance to an antituberculosis drug is due to spontaneous chromosomal mutation at a frequency of 10-6 to 10-8 mycobacterial replications. As mutations resulting in drug resistance are unlinked, the probability of resistance to all three drugs used concomitantly becomes 10-18 to 10-20. Thus, the chance of drug resistance becomes practically nil when three effective drugs are used in combination for the treatment of TB. Among the first-line antituberculosis drugs, isoniazid and rifampicin are most effective in preventing the emergence of drug resistance (5). Streptomycin, ethambutol and pyrazinamide are less so. Thioacetazone and para-aminosalicylic acid are the least effective for the purpose. AIMS OF TREATMENT The aims of chemotherapy of TB are: [i] to cure patients of TB by the shortest duration of drug administration with minimum interference with their living; [ii] to prevent death from TB or late sequelae of disease; [iii] to prevent relapse of TB; [iv] to prevent emergence of drug resistance; and [v] to reduce transmission of disease to people both within and outside the community. The standard terminology used for describing antituberculosis drugs and various treatment regimens are described in the chapter “Evolution of chemotherapeutic regimens in the treatment of tuberculosis and thier scientific rationale” [Chapter 51]. Treatment of Smear-positive Pulmonary Tuberculosis In the last few decades, a number of effective drug regimens have been found, largely through clinical trials, for treating newly diagnosed patients with smearpositive pulmonary TB. These regimens are summarized in Table 52.1 (6-16). Most regimens are given for a total duration of six months, this being currently the shortest required.

Table 52.1: Drug regimens for treatment of new cases of smear-positive pulmonary tuberculosis Reference Standard 6-month daily regimens 2 EHRZ/4 HR 2 SHRZ/4 HR

6

Standard 6-month regimens when directly observed, intermittent chemotherapy can be organized 2 EHRZ/4 H3R3 2 SHRZ/4 H3R3 7 2 E3H3R3Z3/4 H3R3 2 S3H3R3Z3/4 H3R3 8, 9 10 0.5 EHRZ/1.5 E2H2R2Z2 / 4 H2R2 0.5 SHRZ/1.5 S2H2R2Z2 / 4 H2R2 2 EHRZ/4 H2R2 11 2 SHRZ/4 H2R2 Alternative less active regimens of longer durations With a highly active initial 4-drug phase 2 EHRZ/6 HT 2 SHRZ/6 HT 2 EHRZ/6 HE 2 SHRZ/6 HE 2 SHRZ/6 S2H2Z2 With a less active or no initial phase 2 SHR / 7 HR 2 EHR / 7 HR 9 HR

12

13 14 15 16

E = ethambutol; H = isoniazid; R = rifampicin; Z = pyrazinamide; S = streptomycin; T = thioacetazone; Number preceding abbreviation for a drug name = month[s] of treatment; numbers in subscript indicate the number of doses administered per week

Regimens that do not contain pyrazinamide in the initial intensive phase must be given for longer than six months. The relapse rates during six to thirty months posttreatment are generally less than five per cent. In countries or communities with a high rate of initial resistance to isoniazid [4% or more] (13), as in most Asian countries, a four-drug regimen [for 2 months] followed by two drugs used simultaneously [for 4 months] is recommended [Table 52.1]. This is currently the standard regimen recommended by the World Health Organization and International Union Against Tuberculosis and Lung Disease [IUATLD] (17). Furthermore, the administration of pyrazinamide beyond two months has not been shown to be of advantage (18,19). However, for individual cases with extensive disease and slow sputum bacteriological conversion to negative, prolongation of

Treatment of Tuberculosis 753 the administration of pyrazinamide with or without streptomycin or ethambutol beyond two months sounds acceptable. Prolongation of the total duration of treatment can also be considered. Presence of radiographic cavity and sputum culture positivity after two months have been found to be factors associated with an increased risk of failure and relapse (20,21), and thus possibly justify prolongation of short-course therapy to a total duration of nine months in individuals possessing these characteristics (22). The eight-month regimen where streptomycin [S], isoniazid [H], rifampicin [R] and pyrazinamide [Z] are administered for two months followed by subsequent six months of isonaizid [H] and thioacetazone [T] or ethambutol [E] [2SHRZ/6HT or 6HE] combined with hospitalization in the first two months has been proven to be effective in controlled clinical trials and programme settings in Africa (12). This regimen is, however, generally not recommended by health care authorities in the developed countries. In confirmed or suspected human immunodeficiency virus [HIV] infected patients, ethambutol should be used in place of thioacetazone in light of possibly severe cutaneous reaction to the latter drug (23). There is increasing indication that thioacetazone should be dropped from the antituberculosis regimens in the developing countries, as many of these are experiencing rising HIV infection rates. Regimens based almost entirely on isoniazid and rifampicin (14-16) are perhaps only good for pansusceptible TB with limited bacillary load, and has to be given for nine months [2HRE/7HR or 9HR]. These regimens are usually not applicable in Asian countries except for patients who cannot tolerate pyrazinamide. Intermittent regimens comprising two drugs in the continuation phase, following upon an intensive phase of four drugs given on a daily basis, have been shown to be highly effective [2SHRZ/4H3R3 or 2SHRZ/4H2R2] (7,11,22). The WHO, however, does not generally recommend twice-weekly regimens because of the higher risk of treatment failure with missing doses (17). Lately, clinical data from China [including Hong Kong] on 2S3H3R3Z3/4H3R3 also reveal the high efficacy of such a regimen (8,9). Intermittent short-course regimens that are administered thrice-weekly have largely equivalent efficacy to daily regimens. In addition, they have lower cost, greater feasibility for directly observed administration under ambulatory settings, and possibly also lower drug toxicity.

For the treatment of smear-positive relapse cases of pulmonary TB as well as retreatment after interruption, a eight-month regimen has been recommended by the WHO and IUATLD, namely 2SHRZE/1HRZE/5HRE or 5H3R3E3 (17). Bacillary drug susceptibility testing in vitro can help to guide modification of this regimen as required. The use of fixed-dose drug combination [FDC] tablets comprising two to three and even four drugs can enhance ease of prescription for physicians, reduction of inadvertent medication errors, simplification of drug procurement [WHO] and supply, and treatment adherence by patients (24). When used properly, FDC tablets should decrease the risk of development of multidrug-resistant tuberculosis [MDR-TB], i.e., TB caused by bacillary strains resistant to at least isoniazid and rifampicin in vitro (25). While FDC tablets by self-administered therapy may serve as an alternative to DOT when the latter cannot be practised, the delivery of DOT using FDC tablets should be advocated as there is still a potential risk of emergence of drug resistance when these FDC tablets are taken irregularly (26). The main concern in using FDC tablets is the quality and bioavailability of their component drugs, especially rifampicin (27). This would occur when proper manufacturing conditions and raw materials were not utilized (28). In 1994, the IUATLD and WHO issued a joint statement recommending that only FDC of proven good quality should be used in the treatment of TB (29). The WHO and IUATLD have also formulated model protocols for establishing the bioequivalence of rifampicin in the FDC tablets as compared with single drug reference preparations administered in loose combinations (30,31). The majority of clinical studies found no significant difference between FDC tablets and individual drugs regarding sputum smear conversion rates and frequency of side-effects and relapses (32). Some studies, however, have produced controversial results. The Singapore study (33), found higher relapse rates in patients who received FDC at two years and five years of follow-up. While more knowledge needs to be acquired on the optimal use of the FDC tablets, these have recently been recommended to be included in the list of essential drugs (34). Furthermore, the Global TB Drug Facility [under WHO] can supply quality drugs, including four-drug FDC to countries requesting assistance (35).

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DOTS Drug-resistant TB can result from poor patient adherence and other aspects of failure in implementation of an effectively functioning TB control programme (36). Although patient characteristics like homelessness, alcohol or drug abuse, behavioural problems, mental retardation, and lack of social or family support are more commonly associated with non-adherence to therapy, it is often difficult to identify poorly adherent patients because underlying reasons for such behaviour are indeed multifaceted and complex (37). The DOT was in fact shown to be highly efficacious in ensuring patient adherence through experience gained earlier in Chennai and Hong Kong (4). In order to facilitate delivery of DOT, other concomitant strategic interventions must be incorporated. Short-course chemotherapy has been shown to be the most important component. In 1993, the WHO officially announced the new global strategy for TB control known as DOTS (38,39). The DOTS strategy is clearly more than DOT alone. Some randomized controlled trials have not shown the benefit of DOT (40,41). However, these trials were compromised by suboptimal implementation of treatment observation, with success rates significantly below those of worldwide programmes of DOTS. Implementation of DOT depends on the setting, facilities, resources and environment. In its application, flexibility should be exercised (17). To reiterate, the DOTS strategy should be viewed as a comprehensive service, or an integral part thereof, which possesses ingredients also inclusive of enablers, incentives, education and holistic care that are conducive to the success of the programme. Regarding holistic care, resolution of social disadvantage particularly poverty is of paramount importance. Poverty predisposes to the development of TB through mechanisms including overcrowding and malnutrition, and TB perpetuates poverty by increasing the economic burden. In addition, a higher prevalence of multidrug resistance was found to be associated with a lower gross national product [GNP] per capita income (42). With the use of DOTS, treatment success of TB can be optimized and chances of development of drug resistance markedly curtailed (36,39). Indeed, this strategy should be regarded as the most cost-effective intervention in the control of TB (39). The reader is referred to the chapters “DOTS: the strategy that ensures cure of tuberculosis” [Chapter 56] and “Directly observed treatment” [Chapter 57] for more details.

Treatment of Smear-negative Pulmonary Tuberculosis In many countries, around 50 per cent of patients are diagnosed as having active pulmonary TB on clinical and radiographic grounds, without immediate bacteriological confirmation (17). In the first smear-negative study in Hong Kong (43), it was subsequently found that 36 per cent of these patients had one or more initial sputum cultures positive for Mycobacterium tuberculosis. When patients were observed until the appearance of radiographic and/or bacteriological evidence for active disease, 57 per cent of this control group of patients required treatment within 60 months. When smearnegative, culture-positive patients were treated with two to three months of daily streptomycin, isoniazid, rifampicin and pyrazinamide, relapses occurred in 32 per cent and 13 per cent, respectively, over 60 months of follow-up. The corresponding relapse rates for culturenegative patients for these two durations of therapy were eleven per cent and seven per cent respectively. In the second study carried out in smear-negative patients at Hong Kong (44), which again included 35 per cent of subjects with sputum cultures initially positive for Mycobacterium tuberculosis, all patients received streptomycin, isoniazid, rifampicin and pyrazinamide, daily or thrice weekly, for three to four months [culturenegative cases] and four to six months [culture-positive cases]. Over 60 months, the combined relapse rates for culture-negative patients who had three and four months of treatment were seven per cent and four per cent, respectively. The relapse rate for the four-month regimen was two per cent in patients with initially drugsusceptible bacilli and eight per cent in patients with bacilli initially resistant to isoniazid, streptomycin or both. There was no significant difference between the relapse rates among patients allocated four-month and six-month regimens of the same four drugs. The WHO recommends, in the latest guidelines (17), the use of six-month regimens consisting of daily isoniazid, rifampicin, ethambutol and pyrazinamide for two months followed by daily or thrice-weekly isoniazid and rifampicin for another four months in the treatment of new cases of smear-negative pulmonary TB (17). Ethambutol may be omitted during the initial phase of treatment for some patients with non-cavitary smearnegative pulmonary TB who are known to be HIVnegative, and children with primary TB (17). The

Treatment of Tuberculosis 755 American Thoracic Society, Centers for Disease Control and Prevention [CDC], Infectious Disease Society of America (22) recently recommended four to six months of treatment totally for smear-negative pulmonary TB basing on the culture status of the pre-treatment sputum (22). Treatment of Monodrug-resistant Pulmonary Tuberculosis For patients who are subsequently known to harbour bacilli resistant to streptomycin, it would obviously be reasonable to stick to the conventional short-course regimens just described for treatment of new cases. For patients with isoniazid-resistant TB, one of the following two approaches can be adopted. First, continuation of rifampicin, ethambutol and pyrazinamide for a further 10 months or rifampicin plus ethambutol for another 12 months after having administered rifampicin, isoniazid, ethambutol and pyrazinamide for two months before drug susceptibility testing [DST] results are known (45,46). Secondly, no modification of the initially administered four-drug regimen is made, with it being given for a total duration of six months (47). Reducing the drug components from four to two after two months, as in the management of drug-susceptible TB is also acceptable for programme purpose, except the relapse rate would be somewhat higher [10% v 3%] (19). When patients are already known to have isoniazid-resistant disease at the commencement of therapy, a nine-month regimen comprising streptomycin, rifampicin, pyrazinamide and ethambutol for two months, followed by rifampicin and ethambutol for seven months, has also been shown to be effective (48). On the other hand, for patients with rifampicin mono-resistant disease, which is generally of rare occurrence in clinical practice aside from HIV subjects, recommendation has been made to treat with isoniazid, pyrazinamide and ethambutol for 18 to 24 months (49). Some authorities currently feel that the duration of treatment can be shortened to nine to twelve months with addition of a fluoroquinolone to this three-drug regimen (22).

The reader is referred to the chapter “Antituberculosis drug resistance surveillance” [Chapter 50] for more details. Although DOTS is highly effective in the management of drug-susceptible TB, it is not sufficient for treating established MDR-TB (50). Even in settings using 100 per cent DOT, cases with MDR-TB had a higher failure rate than drug-susceptible TB (51). The frequency of recurrence of disease among MDR-TB declared cure after SCC is also high (52). Furthermore, SCC including standardized retreatment regimens can even cause an amplification of drug resistance when empiric treatment courses are repeatedly administered. The treatment success rates of patients with MDR-TB are generally much lower when compared to those of patients with drug-susceptible disease, namely 56 per cent to 80 per cent versus 90 per cent or more (53-57). Also, the standard retreatment SCC regimen [US$ 30 to 35] is about 50 per cent more costly than a first-line conventional SCC regimen [US$20], and the cheapest reserve chemotherapy regimen comprising second-line and new antimycobacterial drugs is at least 100 times more costly [US$ 2 000] (17). On the basis of available data, the WHO has recommended a three-part response to the global threat of MDR-TB (58): [i] widespread implementation of DOTS as the cornerstone of good TB control; [ii] improved DST and surveillance; and [iii] careful introduction of secondline [reserve] drugs [SLD] after a sound evaluation of cost, effectiveness and feasibility. Figure 52.1 depicts the concept of the combined chemotherapy strategy in the control of TB.

Treatment of Multidrug-resistant Pulmonary Tuberculosis The WHO/IUATLD global project on antituberculosis drug resistance surveillance (42) found that drug resistance was indeed a very widespread phenomenon.

Figure 52.1: Combined chemotherapy strategy in the control of tuberculosis TB = tuberculosis; MDR-TB = multidrug-resistant tuberculosis

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Preliminary evidence shows that investing in MDRTB control in middle-income countries is beneficial (59). However, it would not simply be logical for any country or community to divert significant resources to implement treatment strategy for MDR-TB, if a large proportion of new infectious cases remain ineffectively treated. The new initiative known as DOTS-Plus (60) is currently coordinated by the WHO in partnership with many agencies and institutions worldwide. Thus, for established MDR-TB, effective treatment should comprise alternative specific and perhaps even ideally individualized SLD regimens. It appears that the most important determinant in formulating a drug regimen for MDR-TB is the patient’s current drug susceptibility pattern in vitro (54,57). It has been well shown that patients given appropriate drugs based on DST in vitro had better outcomes (56,61). One practical obstacle to the usefulness of conventional DST in guiding regimen modification and design is its prolonged turnaround time. Rapid DST broth systems based on non-radiometric or radiometric technique have brought about improvement in this aspect (62), but these are more costly compared with the conventional ones. Advances in phenotypic or genotypic technology might help in further accelerating the delineation of drug resistance in the near future (62). Besides, the methodology of assessing drug susceptibilities for many SLD is not totally standardized yet, and therefore, there can be an observed discrepancy in microbiological response of the patient and results of the DST in vitro (56). More work apparently needs to be done in the relevant area (63). The fluoroquinolones, however, emerge as new antimycobacterial drugs that have consistent activities in vitro, often independent of culture medium, inoculum size, and method of assessment (57). A patient with MDR-TB should receive a regimen comprising at least four to five of these SLD, for the initial months, followed by three to four drugs subsequently. One regimen recommended by the WHO consists of treatment with ethambutol, ethionamide and prothionamide, ofloxacin or ciprofloxacin, pyrazinamide, and aminoglycoside, capreomycin, for six months, with the first four drugs being administered for a further 12 to 18 months (17). In fact, in a recent large-scale trial in Peru (59), 55 per cent of adherent patients given a similar regimen, namely kanamycin, ciprofloxacin, pyrazinamide, ethambutol,

and ethionamide, after failure of the standard retreatment SCC regimen that comprised streptomycin, rifampicin, isoniazid, ethambutol, and pyrazinamide could be cured. Indeed, ofloxacin-containing multidrug regimens could give rather impressive cure rates of about 80 per cent in MDR-TB in several reports (55-57). Preliminary data from two other reports (64,65) also suggest that levofloxacin possibly has better efficacy than ofloxacin in the treatment of MDR-TB. Among the agents used in the multidrug regimens, the fluoroquinolones are most likely the pivotal drugs with major contribution to the efficacy of the regimens. In a retrospective analysis of patients with MDR-TB treated with ofloxacin or levofloxacin together with similar accompanying drugs that principally included aminoglycosides, ethionamide or prothionamide, pyrazinamide, ethambutol, cycloserine, and para-aminosalicylic acid, resistance to ofloxacin in vitro was found to be a significant variable independently associated with adverse outcomes (57). Aside from their efficacy in vivo resulting from good bactericidal and sterilizing activities (57,66), though the latter is still apparently inferior to that of pyrazinamide especially in TB patients co-infected with HIV (67), fluoroquinolones such as ofloxacin or levofloxacin and ciprofloxacin also have the following favourable therapeutic characteristics: high peak serum drug concentration: minimal inhibitory concentration [MIC] ratio, good tissue penetration particularly into lungs, and good tolerance by patients during long-term administration even at high dosages (57,64,68,69). The good tolerance is therapeutically beneficial and sets the fluoroquinolones aside from most second-line [reserve] antituberculosis agents (57). However, interactive toxicities of fluoroquinolones with cycloserine can be of real concern (70). The good patient tolerance of fluoroquinolones is not a class effect. Sparfloxacin, for example, has better antituberculosis activity than ofloxacin or levofloxacin (71,72). However, potential phototoxicity and cardiotoxicity can jeopardize its future role in the clinical management of MDR-TB (73,74). By the same token, new fluoroquinolones with good antimycobacterial activities, like moxifloxacin (75-77), sitafloxacin [DU-6859a] (78) and gatifloxacin (79,80) might share a similar fate unless their safety profiles on long-term use can be established in the future. Moxifloxacin attracts the greatest interest because of its good oral bioavailability, long half-life

Treatment of Tuberculosis 757 [8-16 hours] and prominent sterilizing capacity (81-83). The Tuberculosis Trials Consortium [TBTC] of CDC, USA has launched “Study 27” officially to examine the efficacy and tolerance of moxifloxacin by substituting the fluoroquinolone for ethambutol in the standard fourdrug, short-course antituberculosis regimen (84). Preliminary clinical data have supported the satisfactory tolerance of moxifloxacin (85). Data from mouse model reveal moxifloxacin to be most efficacious when substituted for isoniazid instead of ethambutol in the standard first-line antituberculosis drug regimen (86). The TBTC “Study 28” is evaluating this combination treatment in a double-blind randomized controlled Phase Two two-month treatment trial. A Phase Three trial [REMox TB Trial] to evaluate ability of moxifloxacinbased drug regimens to shorten treatment to four months with safety and efficacy not inferior to standard six months treatment for drug-sensitive pulmonary TB in HIV-seropositive and HIV-seronegative adults has been planned. Further examples of new quinolones that might have roles in antimycobacterial treatment include garenoxacin or T-3811ME (87), [a broad-spectrum desF(6)-quinolone] and PD161148 [a C-8-methoxyl fluoroquinolone] (88). The optimum duration of treatment for patients with MDR-TB is currently unclear. While a number of authorities including the WHO has recommended a total duration of at least 18 months even for HIV-negative patients (17), there is some preliminary evidence that at least a proportion of immunocompetent patients who managed to achieve sustained sputum culture conversion early in the treatment course could perhaps be adequately treated with 12 months of fluoroquinolone-containing regimens (57). It does appear, however, that patients who are immunocompromised [including those with diabetes mellitus and silicosis], or have extensive radiographic evidence of disease [particularly with cavities], or extensive drug resistance in vitro, or delayed sputum culture conversion [i.e., after more than 3 months of treatment], or extrapulmonary involvement should receive longer than 12 months of treatment. In formulating the optimum duration of treatment for MDR-TB, the key factors that appear to be most relevant are the number of active agents, their bactericidal capacity, dosage, cost and toxicity, alongside the anticipated patient adherence (57). Finally, fluoroquinolones must be used with great vigilance in the management of MDR-TB to prevent

emergence of cross-resistance among members of this important class of drugs (53,72). This has already been reported in some communities (89,90), and might have negative impact on the potential usefulness of emerging members of this drug class with greater antimycobacterial activities. It also appears useful to delineate the correlation of fluoroquinolone-resistance phenotypes and genotypes to enable better choice of new fluoroquinolones in the face of MDR-TB caused by ofloxacinresistant bacillary strains (91). DEVELOPMENT OF NEW ANTITUBERCULOSIS DRUGS New antituberculosis drugs can hopefully offer advances in management of TB in the following areas (92): [i] shortening total duration of therapy and significantly reducing number of doses administered under the DOTS protocol; [ii] improving treatment success of MDR-TB; and [iii] providing more effective treatment of latent TB infection [LTBI]. A new drug for treatment of TB should have desirable biopharmaceutical, pharmacokinetic and pharmacodynamic properties. Considerations should include oral solubility, permeability and compatibility with other agents in combination. Furthermore, its oral bioavailability, tissue penetration especially into lung, disposition profile and elimination half-life are also issues of concern. Lastly, the MIC and post-antibiotic effect of the drug against Mycobacterium tuberculosis should be superior to those of existing agents. The fluoroquinolones have a role in the management of MDR-TB, and possibly also TB in the face of severe drug intolerance, such as hepatotoxicity (93). However, their role as primary treatment for TB is uncertain (94). Other potential new drugs will be briefly discussed below. Some of these are existing antimicrobial agents and classes for different indications, while others are novel classes of compounds. Rifabutin, a spiropiperidyl rifamycin with better in vitro activity against Mycobacteium tuberculosis than rifampicin, has also been shown to have activity against some MDR-TB bacillary strains though the crossresistance rate between the two rifamycins is high (95). Indeed, its clinical efficacy in MDR-TB was found to be disparate among two clinical studies (96,97). The better designed study (96) that compared patients randomized to receive rifabutin or rifampicin together with similar

758

Tuberculosis

accompanying drugs showed a low culture negativity rate [20%] even for the rifabutin group. Rifalazil [KRM1648], a benzoxazinorifamycin, has been found to have MICs about 10-2 those of rifampicin and less than or equal to 0.25 those of rifabutin against Mycobacterium tuberculosis (98). Results were also favourable when it was combined with isoniazid in long-term treatment of murine TB (99). However, it has been shown to possess partial crossresistance with rifampicin (98), and human Phase Two studies have not demonstrated any significantly positive result (100). Rifapentine, a long-acting cyclopentyl rifamycin, has been shown to yield encouraging results when given with isoniazid in a once-weekly dosing during the continuation phase of treating pulmonary TB, though delineation of the optimum dosage of this rifamycin to achieve a lower relapse rate is still required (9,20,21). A prospective, randomized, double-blind study (101) on the tolerability of rifapentine 600, 900, and 1200 mg plus isoniazid in the continuation phase of treatment has suggested that rifapentine 900 mg onceweekly dosing appears to be safe and well tolerated. This dosing schedule would have further evaluation in Phase Three efficacy trials on treatment of LTBI. As for 1200 mg once-weekly rifapentine, further exploration of the safety and tolerability is apparently warranted too (101). This approach of utilizing long-acting rifamycin can greatly facilitate the delivery of DOTS. However, data concerning the unsatisfactory clinical efficacy and development of acquired rifampicin mono-resistance among HIV infected patients given rifapentine therapy are somewhat disturbing (102). Rifametane, a 3-azinomethyl rifamycin was found to have a superior pharmacokinetic profile to rifampicin in terms of higher peak serum drug concentration and longer half-life (103). No relevant clinical data are yet available for this new rifamycin. Aminosidine [paromomycin] is an aminoglycoside that has been shown to have activities against Mycobacterium tuberculosis in vitro (104) and in vivo (104,105). Further evaluation of its role in the treatment of MDRTB is required. Also, aerosolized aminoglycoside, like tobramycin, might have a place in the treatment of TB, and is being further evaluated (106). Clarithromycin, an important macrolide active against Mycobacterium avium complex, was not found to have significant activity against Mycobacterium tuberculosis (107). Although there has been favourable

experience concerning the in vitro (108) and early bactericidal activity (109) of β-lactam-β-lactamase inhibitors against Mycobacterium tuberculosis, the role of these compounds in the treatment of TB especially MDRTB is still uncertain, given the scanty clinical data that are currently available (110,111). Clofazimine is a riminophenazine that has been extensively used for treatment of leprosy and Mycobacterium avium complex infection. It has recently been shown to possess in vitro and in vivo activities against some strains of Mycobacterium tuberculosis (112), including drug-resistant ones in the murine model. A few analogues of this drug, such as B746 and B4101 were found to have even better activities under both in vitro and in vivo settings (112). Thus, clofazimine and its analogues might have a place in the management of MDR-TB if sufficient evidence supporting their clinical efficacy and tolerance can be established. Other examples of new drug classes which might potentially merit further evaluation include oxazolidinones (113,114), nitroimidazopyrans (115), and 2pyridones (116). The oxazolidinones are new synthetic antibacterial agents, and preliminary studies have shown that the compound PNU100480 is as active as isoniazid (113). Furthermore, preliminary pharmacokinetic data in the murine model has shown good oral bioavailability (114). While another member linezolid has demonstrated some activity against Mycobacterium chelonae in vivo (117), its potential clinical use in mycobacterial infections is compromised by possible toxicity and high cost. The key compound of the nitroimidazopyran group is PA824 (115). This lead compound is active against MDR-TB strains and exhibits no cross-resistance with existing antituberculosis drugs. Its site of action is possibly on the synthesis of protein and cell wall lipid. Another class of related compound, namely the nitroimidazoles, with CGI 17341, an analogue of metronidazole as an important example, also has potentially significant antimycobacterial activity (118). TMC207, a diarylquinoline that has activity against drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis, is in clinical phase 2 development (119,120). Other new antimycobacterial compounds, a new pyrrole known as Sudoterb [LL-3858] (121), the compound, SQ-109 [an ethylenediamine] (122) and OPC-67683 [nitroimidazo-oxazole] (123) have entered clinical Phase One evaluation. It must be stressed that only scanty data concerning the antimycobacterial activities of these agents are currently available.

Treatment of Tuberculosis 759 Methods to design novel drugs based on the structure of a cellular component or genetic material have been repeatedly attempted. One possible target of intervention is the mycobacterial glyoxylate pathway (106) which involves key enzymes, like isocitrate lyase. It has been shown that the glyoxylate shunt is important for the longterm survival of Mycobacterium tuberculosis within pulmonary tissue (124). Another example is concerned with the lipids in the mycobacterial cell wall. Thiolactomycin, a unique thiolactone antibiotic isolated initially from the soil Nocardia species, possesses both in vitro and in vivo activities against Mycobacterium smegmatis and Mycobacterium tuberculosis (125). The likely targets of action are fatty acid and mycolic acid biosynthesis (126). Recently, a novel antimycobacterial compound Noctanesulphonyl-acetamide, by acting on similar sites through mimicking the transit state of the reaction catalysed by the β-ketoacyl synthase (127), may serve as a promising lead compound for future antituberculosis drug development. Aside from new drugs, novel methods of delivery of old drugs may facilitate better treatment of TB. Such possible innovative approaches include liposomal delivery (106) of aminoglycosides and fluoroquinolones, implant delivery (106) of isoniazid, and aerosolisation of cytokines (106), aminoglycosides (106), and rifampicin microparticles (128) for the treatment of TB. With the advent of gene therapy, a new strategy of antimycobacterial treatment might be developed in the future. Mycobacteriophages can be used to deliver antisense nucleic acids or other materials to combat mycobacteria including the drug-resistant strains (106). The latest developments in gene transfer technology have revealed the possibility of developing preventive or therapeutic vaccines for TB (129). The lack of interest of the pharmaceutical industry in pursuit of development of new antituberculosis drugs largely results from the conventional notion that the anticipated financial return would not justify the immense investment required. To circumvent this difficulty, public-private partnerships for the discovery and development of antituberculosis drugs should be the proper direction. In 2000, participants from a number of interested parties comprising public organizations as well as companies in the private sector joined hands in forming a coalition named Global Alliance for Tuberculosis Drug Development (92). This is a not-for-profit

venture aiming at accelerated discovery and development of antituberculosis drugs to combat this important foe. The vision of this Alliance is provision of new drugs with equitable access to communities and countries for better treatment of TB. The Alliance will function as a lean, virtual, research and development organization. The pipeline of research and development of new drugs essentially consists of relevant basic research, discovery of lead compounds, preclinical studies, clinical trials and finally technology transfer in drug production. This pipeline is currently filled with gaps accounting for the tremendous length of time required for development of new antituberculosis drugs. The formation and functioning of the Alliance may help to overcome some or all of these obstacles. Despite this, the final development of antituberculosis drugs for clinical use is still an arduous task. Efficacy trials are both complex and time-consuming. Regulatory authorities require that a new drug must be at least as safe and effective as the existing standard therapy to grant approval for registration for the indication. The generally accepted end points for an efficacy trial are the cure rate at the end of treatment and the relapse rate during a two-year post-treatment follow-up. There is thus a genuine need for surrogate markers for these parameters, such as early bactericidal activity (130) as well as two-month sputum culture conversion rate (131) and its possible molecular marker[s] (132). Expansion of the knowledge in mycobacterial genomics has offered great potential in drug target discovery and birth of new antimycobacterial agents (133). In addition, the development of combinatorial chemistry and robotic screening brings promise in the introduction of an era of rational discovery of new antituberculosis drugs (92). DOSAGES AND ADVERSE REACTIONS OF ANTITUBERCULOSIS DRUGS The usual dosages of the drugs used in conventional SCC and therapy of MDR-TB are shown in Table 52.2. The reader is referred to the chapter “Evolution of chemotherapeutic regimens in the treatment of tuberculosis and their scientific rationale” [Chapter 51] regarding the definitions of adverse drug reactions and related events. The important adverse reactions to these antituberculosis drugs are listed in Table 52.3.

760

Tuberculosis Table 52.2: Usual dosages of antituberculosis drugs

Drug

Daily dosage Adults and children*† [mg/kg]

Intermittent dosage Adults

Weight [kg]

Adults and children [mg/kg]

Dosage

Adults Weight [kg]

Dosage

Drugs commonly used in conventional therapy Isoniazid

5

–

300 mg

Rifampicin‡

10

Streptomycin

12-15

Pyrazinamide

20-30

< 50 > 50 < 50 > 50 < 50 > 50

450 mg 600 mg 500-750 mg 750 mg 1.0-1.5 g 1.5-2.0 g

10 three times/week 15 twice/week 10-12 three times/week 10-12 twice/week 12-15 thrice or twice/week 30-40 three times/week 40-60 twice/week

Ethambutol

15

–

Thioacetazone

2.5

–

30 three times/week 45 twice/week –

150 mg

– – – – < 50 > 50 < 50 > 50 < 50 > 50 –

– – 600 mg 600-900 mg 500-750 mg 750 mg 1.5-2.0 g 2.0-2.5 g 2.5-3.0 g 3.0-3.5 g –

–

–

Drugs commonly used in therapy for multidrug-resistant tuberculosis Amikacin Kanamycin Capreomycin Ofloxacin Levofloxacin Ciprofloxacin Ethionamide Prothionamide Cycloserine Para-aminosalicylic acid

15 15 15

15 [adults] 15 [adults] 2 g/10 kg

< 50 > 50 < 50 > 50 < 50 > 50

750 mg 750 mg 750 mg 600-800 mg 500-600 mg 750-1500 mg 500 mg 750 mg 500 mg 750 mg 8-10 g 10-12 g

three to five times/week

* Some authorities recommend higher dosages of isoniazid, rifampicin, and streptomycin for children † Drugs for treatment of multidrug-resistant tuberculosis may require split dosing to meet tolerance ‡ Dosage of rifampicin > 600 mg twice per week is associated with higher risk of “flu” syndrome

Although more than 25 per cent of study patients on antituberculosis treatment reported at least one type of reaction (18,19,44), most of these were mild and required no modification of treatment regimens. Less than 10 per cent of patients required termination or prolonged suspension of drug[s]. The most common reactions were gastrointestinal or cutaneous in nature (18,19). Adverse reactions mostly occur within the first three months of the treatment. Peripheral neuropathy caused by isoniazid can be prevented by an adequate supplement of pyridoxine [vitamin B6] in the at-risk groups. Arthralgia can occur during pyrazinamide administration. It is less likely to occur during intermittent than daily

administration, and is usually mild and self-limited. It usually responds well to symptomatic treatment. If a serious reaction such as haematological, circulatory or renal in type occurs after administration of rifampicin, the drug should be withdrawn and never given again. The initial recommended approach in managing gastrointestinal intolerance, not associated with hepatic toxicity, is to change the time of drug administration and/or to administer the drugs with food (22). The former approach often refers to altering the timing of drug administration closer to mealtime. If bedtime administration is eventually desired, self-administered therapy has to be given. As for drug administration with

Treatment of Tuberculosis 761 Table 52.3: Adverse reactions to antituberculosis drugs Drug

Reactions Common

Uncommon

Rare

Fever Giddiness Convulsion Optic neuritis Mental symptoms Haemolytic anaemia Aplastic anaemia Lupoid reactions Arthralgia Gynaecomastia Shortness of breath Shock Haemolytic anaemia Acute renal failure Thrombotic thrombocytopenic purpura Sideroblastic anaemia Gout

Drugs commonly used in conventional therapy Isoniazid

Asymptomatic elevation of serum hepatic enzymes

Hepatitis Cutaneous hypersensitivity Peripheral neuropathy

Rifampicin

Pruritus

Pyrazinamide

Anorexia Nausea Flushing Photosensitization

Hepatitis Cutaneous hypersensitivity Gastrointestinal reactions Thrombocytopenia Febrile reaction “Flu syndrome” Hepatitis Vomiting Arthralgia Cutaneous reactions Retrobulbar neuritis Cutaneous reactions Arthralgia Vertigo Ataxia Deafness

Ethambutol

Streptomycin

Thioacetazone

Cutaneous hypersensitivity Giddiness Numbness Tinnitus Gastrointestinal reactions Cutaneous hypersensitivity Vertigo Conjunctivitis

Hepatitis Erythema multiforme Exfoliative dermatitis Haemolytic anaemia

Peripheral neuropathy

Clinical renal failure Aplastic anaemia

Agranulocytosis

Drugs commonly used in therapy for multidrug-resistant tuberculosis Amikacin Kanamycin Capreomycin

Hearing damage, vestibular disturbance Deranged renal function tests

Clinical renal failure

Ofloxacin Ciprofloxacin

Gastrointestinal reactions Insomnia

Anxiety Dizziness Headache Paraesthesia Tremor

Convulsion Cutaneous hypersensitivity

Ethionamide Prothionamide

Gastrointestinal reactions

Hepatitis Peripheral neuropathy

Convulsion Depression Alopecia Hypothyroidism Impotence Gynaecomastia -Contd-

762

Tuberculosis

-ContdReactions Drug Common

Uncommon

Rare

Cycloserine

Dizziness Headache Depression Memory loss

Psychosis Convulsion

Sideroblastic anaemia

Para-aminosalicylic acid

Gastrointestinal reactions

Hepatitis Drug fever

Hypothyroidism Haematological reactions Generalized hypersensitivity Malabsorption

food, one caveat would be impaired bioavailability of medications in some patients (134,135). When a significant cutaneous reaction resulting from drug hypersensitivity [allergy] occurs, all drugs must be stopped until the reaction has subsided. Reintroduction of drugs may follow the suggested protocol [Table 52.4]. The rationale of drug challenge is to identify the drug responsible for the reaction. The purpose of starting with a small challenge dose is that if a reaction indeed occurs, it will not be as severe as to a full dose. The dose is gradually increased over three days. There is no evidence that this challenge process leads to the development of drug resistance. If the initial cutaneous reactions were rather severe, a smaller initial challenge dose [approximately one-tenth of the dose shown for day 1] should be given. If a reaction occurs with the first challenge dose, it is known that the patient is hypersensitive to that drug. When starting to desensitise, it is usually safe to begin with one-tenth of the normal dose. Then the dose is increased by one-tenth each day. If the patient has a mild reaction to a dose, the same dose [instead of a higher dose] is given next day. If there is no reaction, the dose is to be increased again by one-tenth each day. If the reaction is severe [which is unusual], a lower dose is used and the dose then increased more gradually. If a reaction occurs with the second challenge dose as shown in Table 52.4, desensitization can be started with the first challenge dose and then the dose is increased by the amount equal to the first challenge dose each day. Some patients may need antihistamine or steroid to control the severe reaction. For very severe drug reactions requiring highdose corticosteroid therapy, desensitization should not be attempted. Desensitization is a tedious process and should be performed in specialized centres. Desensitiza-

Table 52.4: A suggested protocol for reintroducing antituberculosis drugs after “disappearance” of cutaneous reaction Order of reintroduction

Challenge doses Day 1

Day 2

Day 3

Isoniazid

50 mg

300 mg

300 mg

Rifampicin

75 mg

300 mg

Full dose*

Pyrazinamide

250 mg

1g

Full dose*

Ethambutol

100 mg

500 mg

Full dose*

Streptomycin

125 mg

500 mg

Full dose*

* as described in Table 52.2

tion process can be associated with the risk of development of drug resistance. If other effective drugs are available, it is easier to substitute another drug for the one that has caused the reaction except when the disease is severe and the incriminated drug[s] being the most potent and crucial one(s). Desensitization can be dangerous for HIV infected patients and is not recommended (17). Second-line [reserve] drug regimens on the whole are more toxic and can be poorly tolerated by patients. In a study in Hong Kong (57), about 40 per cent of patients experienced adverse reactions of varying severity. However, only half of these patients required modification of their drug regimens (57). In a study undertaken in Peru (136), young patients with little co-morbid disease could have these adverse effects largely managed on outpatient basis. Suspension of an agent only occurred in 11.7 per cent of patients and discontinuation of therapy was never required (136). Transient changes in serum bilirubin and alanine transaminase levels are rather common during antituber-

Treatment of Tuberculosis 763 culosis treatment and may not signify true hepatotoxicity (10,18). However, drug-induced hepatotoxicity during administration of SCC has been well documented, and deaths due to fulminant hepatic necrosis, while rare, have been reported (137). Patients with underlying liver diseases, especially those related to alcohol (138), hepatitis B (139), hepatitis C (140), and HIV (140), appear to be more prone to develop drug-induced hepatic dysfunction or toxicity. Other possible predisposing factors include old age and malnutrition (138). Hepatitis B (141) and hepatitis C (142) are prevalent in Asia, and HIV infection (143) is also surging therein. The populations in some Asian countries are also ageing. While rifampicin and isoniazid co-administration exhibit additive risk for hepatotoxicity (144), the contribution of pyrazinamide to hepatotoxic potential in SCC, though not yet totally clear, is increasingly being recognized (145-147). In the face of extensive disease when delay in therapy might be detrimental to the patient’s health, the fluoroquinolone, ofloxacin, can be used with streptomycin and ethambutol as a relatively safe and efficacious interim regimen for treatment (148). Indeed, one randomized clinical trial has also demonstrated the safety of an ofloxacin-based regimen in patients with chronic liver disease (149). The hepatotoxic potential of a combination of isoniazid and rifampicin was found to be greater than that of isoniazid, ofloxacin and pyrazinamide used together. More work should be done to unravel the potential utility of ofloxacin in this important setting. The reader is also referred to the chapter “Antituberculosis treatment induced hepatotoxicity [Chapter 54] for more details. The development of antituberculosis therapy related renal impairment necessitates the withdrawal of the incriminated drugs, commonly streptomycin [and other aminoglycosides] or rifampicin. Clinically significant interactions during antituberculosis treatment principally involve rifampicin (150,151), isoniazid (150,152) and the fluoroquinolones (150). Interactions between these antituberculosis agents and the co-administered drugs constitute the majority of such interactions. The consequences can be therapeutic failure or drug toxicity. Most interactions are pharmacokinetic rather than pharmacodynamic in nature. The cytochrome P450 isoform enzymes being a superfamily of more than 30 related enzymes are responsible for many drug interactions [especially those involving rifampicin and

isoniazid] (150-152) during drug biotransformation [metabolism] in the liver or intestine. Generally speaking, rifampicin acts as an enzyme inducer (150) and isoniazid an inhibitor (152). The agents interacting significantly with rifampicin include anticoagulants, anticonvulsants, antiinfectives, cardiovascular therapeutics, oral contraceptives, glucocorticoids, immunosuppressants, psychotropics, sulphonylureas, and theophylline (150). Table 52.5 shows some examples of such drugs involved in clinically significant interactions with rifampicin. Isoniazid interacts principally with anticonvulsants, benzodiazepines, theophylline, paracetamol and some food (152). Induction effect with rifampicin can occur between under five to fourteen days (150). Similarly, some time is required after withdrawal of the rifampicin for the induced enzyme system to return to its baseline activity (151). For inhibition effect, its onset and disappearance are generally rapid upon institution and cessation respectively of the inhibitor (150). These phenomena are of great relevance in the management of drug interactions during antituberculosis treatment. Fluoroquinolones can have disturbance of their absorption by a variety of agents especially metal cations (150). Important interactions of fluoroquinolones usually result from their enzyme inhibiting potential or pharmacodynamic mechanisms (150). The geriatric and immunocompromised patient populations are particularly at risk of drug interactions during treatment of their TB. One common denominator being significant comorbidities and concomitant polypharmacy. TREATMENT OF EXTRA-PULMONARY TUBERCULOSIS AND OTHER SPECIFIC SETTINGS In general, extra-pulmonary TB accounts for about 20 per cent of all reported cases (17). Lymphatic, pleural, bone or joint disease are the most common, and pericardial, meningeal and miliary forms are more likely to result in a fatal outcome (17). Treatment recommendations are compromised by the paucity of data from controlled clinical trials. Many experts now agree that most extrapulmonary TB can be treated with the standard six-month short-course regimen (17,22,46). Some authorities recommend nine months of treatment for disseminated [miliary] TB and some cases of bone and joint TB (22). In addition, some experts favour the use for nine to twelve months of treatment for TB meningitis (22,46).

764

Tuberculosis Table 52.5: Clinically significant drug interactions with rifampicin

Analgesics Alfentanil Codeine Methadone Anticoagulants Phenprocoumon Warfarin Antidiabetics Glibenclamide Glimepiride Glipizide Antiepileptics Hexobarbitone Phenytoin Sodium valproate Antimicrobials Clarithromycin Delavirdine Doxycycline Indinavir Itraconazole Ketoconazole Nelfinavir Nevirapine Saquinavir

Cardiovascular drugs Digitoxin Digoxin Diltiazem Enalapril Losartan Metoprolol Mexiletine Propanolol Quinidine Verapamil Immunosuppressants Corticosteroids Cyclosporine Tacrolimus Psychotropics Diazepam Haloperidol Midazolam Nortriptyline Zolpidem Zopiclone Sundry others Levothyroxine Oral contraceptives Tamoxifen Theophylline

Patients with silicosis are at risk of developing active pulmonary TB, and are more difficult to treat because of impaired local host defence as well as impeded penetration of drugs into the fibrotic disease sites. In Hong Kong, a study (153) on such patients showed that with a regimen of H3R3Z3S3, ethambutol being added in the first three months if there was a history of previous chemotherapy, treatment for six months proved inadequate. A relapse rate of 22 per cent during three years and 33 per cent during five years occurred, compared with only seven per cent during three years in patients treated for eight months. The study also showed slower conversion of sputum bacteriology in the silicotic patients than in the non-silicotic ones even when the same four- or fivedrug regimens were given. Only 80 per cent of the studied group had negative sputum culture at two months after treatment. One additional problem is that about 20 per cent of patients experienced adverse reactions to this intensive regimen, with intolerance largely to strepto-

mycin and pyrazinamide. A prospective study (154) for silicotuberculosis undertaken in Taiwan showed that a nine-month regimen [HRZS for two months followed by HR for seven months] yielded a success rate of 95 per cent and relapse rate of five per cent after 18 to 40 months of follow-up. This latter regimen was better tolerated in comparison with the Hong Kong regimen. For HIV infected patients with drug-susceptible TB, the standard six-month regimen can result in good sputum bacteriological conversion and low rate of treatment failure. But the relapse rate of TB is generally higher than that in HIV negative patients. Prolongation of therapy to 12 months can result in lower relapse rate but no significant impact on survival (155). The most recent guidelines of the CDC (156), in USA recommend the minimum duration of treatment to be six months, but that if the clinical or bacteriological response is slow, treatment should be offered for a total period of nine months, or for at least four months after achievement of culture negativity. Combination regimens of highly active antiretroviral drugs have improved the prognosis of HIV infected patients, but have also complicated the management of those with concomitant TB. Rifampicin is a stronger enzyme inducer than rifabutin. The HIV protease inhibitors and some non-nucleoside reverse transcriptase inhibitors are significant enzyme inhibitors. Interactions between rifamycins with HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors are complex and adjustment of drug dosages is very often required (157). Otherwise, loss of therapeutic efficacy and development of drug toxicity may ensue. To circumvent this, the CDC also lists, a non-rifamycin containing regimen as a possible alternative, namely the administration of isoniazid, pyrazinamide and streptomycin for nine months with ethambutol also for the first two months (156). However, there are a number of concerns with this latter strategy especially regarding its inferior efficacy and the need to utilize prolonged duration of parenteral therapy. The reader is also referred to the chapter “Tuberculosis and human immunodeficiency virus infection” [Chapter 40] for more details. SURGICAL TREATMENT OF MULTIDRUGRESISTANT PULMONARY TUBERCULOSIS The most important indication of surgery in the management of TB today is centred on the MDR-TB setting.

Treatment of Tuberculosis 765 Basically, there are three selection criteria for adjunctive surgery in patients with such disease (158). First, profound drug resistance in vitro is present, leading to a high probability of failure or relapse with medical treatment alone. Secondly, the disease is sufficiently localized so that its great preponderance could be resected with expectation of still adequate postoperative cardiopulmonary capacity. Thirdly, there is sufficient drug activity to suppress the mycobacterial burden to facilitate healing of the bronchial stump. Patients must receive antituberculosis treatment prior to surgery for a minimum duration of three months (159). If possible, patients should achieve culture conversion to negativity before surgery (159,160). Unfortunately, this cannot always occur (160). In some reports, sputum culture conversion only occurred after surgery together with prolonged duration of drug therapy afterwards. Ventilation/perfusion scan, pulmonary function test, and computed tomography [CT] of the chest are important investigations for pre-operative assessment (159). In patients with suspected pulmonary arterial hypertension, right heart catheterization may be needed. Bronchoscopy should be done in patients with suspected bronchostenosis. The nutritional status of the patient should be optimized for improving outcome. In experienced hands, the outcome could be rewarding [operative mortality: 0% to 3.3%] (159,160). Complications included respiratory failure, bronchopleural fistulae, infections and other problems of the wound, bleeding, pneumonia, and recurrent laryngeal nerve injury. The cure rate was noted to reach 90 per cent or more when combined medical and surgical modalities were applied in treating selected MDR-TB patients (159,160). The reader is also referred to the chapter “Surgery for pleuropulmonary tuberculosis” [Chapter 55] for more details. IMMUNOTHERAPY OF PULMONARY TUBERCULOSIS Cell-mediated protective immunological response in TB is largely based on macrophage activation and granuloma formation that require cytokines especially interferon-γ [IFN-γ] and tumour necrosis factor-α [TNF-α] (106). Lymphocyte-macrophage interaction in the immunopathogenesis of TB is depicted schematically in Figure 52.2. The IFN-γ has been shown to have efficacy in lowering bacillary load in MDR-TB and nontuberculous mycobacteriosis in anecdotal reports (161,162). Adjunctive

Figure 52.2: Activation of macrophage and T-lymphocytes in tuberculosis APC = antigen presenting cell; Th0 = T-helper type-null lymphocyte; Th 1 = T-helper type-1 lymphocyte; Th2 = T-helper type-2 lymphocyte; IL = interleukin; IFN-γ = Interferon-gamma

immunotherapy with low-dose recombinant human interleukin-2 was also found to stimulate immune activation and might enhance the antimicrobial response in MDR-TB (163). However, this cytokine did not enhance bacillary clearance or improvement in symptoms in HIVseronegative adults with drug-susceptible TB (164). In a study, aerosolized interferon-alpha [IFN-α] treatment was found to reduce the sputum mycobacteria colony counts in patients with MDR-TB (165). Interleukin-12 [IL-12], a cytokine amplifying lymphocyte-macrophage activation, may also contribute to the host protective immunity against Mycobacterium tuberculosis (166-168). Preliminary data concerning the use of heat-killed Mycobacterium vaccae [NCTC 11659] in patients with MDR-TB in several centres have suggested possible efficacy (169). A randomized clinical trial of this form of immunotherapy in MDR-TB patients appears warranted. On the other hand, the efficacy of immunotherapy with Mycobacterium vaccae in African patients with newly diagnosed pulmonary TB appears somewhat conflicting (170,171). Another potential use of immunotherapy in TB is to down-regulate the host inflammatory response. When given to patients with advanced TB and acquired immunodeficiency syndrome [AIDS], thalidomide, a potent TNF-α inhibitor, caused weight gain and decreased viral replication (172). In HIVpositive patients with TB, pentoxifylline, which can suppress TNF-α in cell cultures, resulted in decreased plasma HIV ribonucleic acid and improved performance scores (173).

766

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Preliminary data (174,175) are available suggesting that adjuvant therapy with Mycobacterium w vaccination along with antituberculosis drugs is well-tolerated and facilitates early sputum conversion. Two large-scale multicentre trials that are already underway (176,177) are expected to provide definitive evidence regarding this treatment modality in Category II [treatment failure, treatment after interruption, relapse] and Category I [new pulmonary TB] patients. It is clear that the current data on the role of immunotherapy in MDR-TB are limited. Further evaluation of this modality of therapy is required (178). CORTICOSTEROIDS AS ADJUNCTIVE TREATMENT IN TUBERCULOSIS Aside from replacement therapy in Addison’s disease [TB-induced adrenal insufficiency] (179), corticosteroids have been found useful as adjunctive therapy for TB in certain clinical settings (180). Two controlled trials using prednisolone have demonstrated benefit in fibrinoeffusive tuberculous pericarditis in terms of survival, resolution of clinical symptoms and need for repeat pericardiocentesis (181,182). In a double-blind, randomized, placebo-controlled trial of adjunctive prednisolone in the treatment of effusive TB pericarditis in HIVseropositive patients, a significant reduction of mortality was observed (183). Data obtained from trials of varying degrees of rigour have shown that adjunctive corticosteroids offered an advantage over antituberculosis chemotherapy alone in the management of Stages II and III TB meningitis for survival and/or frequency of neurological sequelae (184-186). However, change in intracranial pressure or incidence of basal ganglia infarction was not significantly affected (186). More controlled studies can elucidate the utility of steroids further. The definitive usefulness of adjunctive corticosteroid in the management of TB pleuritis has not been thoroughly established (187,188). The efficacy of adjunctive corticosteroid in endobronchial TB in adults has been equivocal (189,190). There has been some interesting but anecdotal data on the use of local steroids in the management of this condition (191). Preliminary retrospective analysis has suggested that corticosteroid administration in combination with antituberculosis treatment could reduce morbidity and mortality in peritoneal TB (192). Two clinical studies (193,194), including one randomized controlled trial, have shown

that adjunctive corticosteroid therapy could be beneficial in causing defervescence, improvement in serum albumin, gain in body weight and radiographic improvement more rapidly in TB patients with toxic [immunological] reactions. Paradoxical response to antituberculosis treatment has been found to improve with corticosteroid treatment (195,196). Such response, presumably due to immunological awakening, has been reported to be more common among HIV infected patients with TB especially following upon initiation of highly active antiretroviral therapy (188,189,197,198). Furthermore, corticosteroid treatment was reported to result in a favourable response in some HIV-infected patients with disseminated TB (199). More experience needs to be accumulated. THERAPEUTIC DRUG MONITORING IN ANTITUBERCULOSIS TREATMENT Therapeutic drug monitoring [TDM] represents an arena of multidisciplinary service where clinicians, clinical pharmacologists and laboratory specialists collaborate in optimizing therapy for patients (200). Serum concentrations of drugs are assessed from blood samples drawn by direct venipuncture or by an indwelling intravenous catheter. The crucial and practical pieces of information conducive to successful TDM are the actual times of drug-dose administration and blood sampling (200). As the peak serum concentration may be more important for most drugs, a twohour post-dose sample can be collected for the purpose (201). For a few drugs, like ethambutol and rifabutin, a three-hour time point may approximate the peak better (201). For cases with suspected delay in absorption, a second sample typically six-hour post-dose, enables assessment of information on the rate and completeness of absorption (201). Blood samples obtained should be promptly centrifuged and the serum harvested and frozen at -20 °C to -70 °C, depending on the duration of storage prior to analysis. The drug assay technology applied should be specific for the drug of interest. The generally preferred techniques include high-performance liquid chromatography and gas chromatography (201). Therapeutic drug monitoring in antituberculosis treatment, however, is still not yet well developed. The areas of potential usefulness of TDM in TB (200) are: [i] optimization of therapy to ensure and improve success in specific clinical settings; [ii] management of pharmaco-

Treatment of Tuberculosis 767 kinetic drug interactions; [iii] management of drugdisease interactions; [iv] evaluation of new drug formulations; [v] study of influence of dietary contents and antiulcer therapy on bioavailability of drugs; and [vi] monitoring of drug adherence. The conventional antituberculosis drugs, namely isoniazid, rifampicin, pyrazinamide, and ethambutol have relatively predictable pharmacokinetics and are generally highly efficacious when given in standard doses under DOT settings. The usual values of their pharmacokinetic parameters are shown in Table 52.6. On the other hand, second-line [reserve] agents have narrower therapeutic indices [toxic: therapeutic ratios]. The consequences of treatment failure of drug-resistant TB may prove difficult to manage. So are some toxicities related to treatment for such disease. Examples of the first potentially useful setting (22,200,201) include patients with unsatisfactory treatment response not explained by poor adherence or drug resistance, malabsorption of antituberculosis drugs in HIV-seropositive subjects and other settings, scheduling administration and dosing of second-line [reserve] drugs in some patients with MDR-TB, and perhaps optimizing dosing in selected patients with TB empyema and TB meningitis. There are still many questions to be answered in terms of clinical applicability in the use of TDM in the treatment of TB. The most important limitation is the current lack of sufficient data to formulate clinically validated ranges for antituberculosis agents (22). One proposed solution is to employ the distribution of concentrations of a drug achieved in healthy volunteers as the therapeutic range (22,201). However, in practice this approach can still be problematic. One important example is concerned with HIV infected patients. Notwithstanding the serum

concentrations of drugs are frequently low among HIV infected patients with active TB compared with healthy volunteers (202,203), HIV-related TB responds well to conventional antituberculosis regimens (204). Recurrence of TB in patients was also not found to be significantly associated with antituberculosis drug levels or HIV status (205). Examples of the second setting mainly include study and management of pharmacokinetic interactions of rifampicin (150,200) [and other rifamycins], as well as isoniazid (150) to a lesser extent. If an interaction is suspected to have occurred, one should check the clinical situation compatibility especially regarding the time course. In addition to data retrieval from literature, TDM can be used to confirm the pharmacokinetic interactions. The clinical or pharmacodynamic consequence is then assessed largely in the perspectives of change in efficacy or production of toxicity. The TDM can also help to guide implementation of new treatment strategy. Examples of the third setting largely focus on renal impairment. Streptomycin, ethambutol, ofloxacin and cycloserine are drugs that are clearly dependent on the renal route of clearance (200,201), and TDM for these antituberculosis drugs in the face of renal dysfunction can be of significant relevance in guiding therapy to achieve optimum response and to avoid inadvertent toxicity. The role of TDM in managing patients with TB in the face of hepatic dysfunction requires further delineation (200). The most important example of the fourth setting can be found in association with fixed-dose combination formulations, where bioequivalence studies are germane to recommending utility of these compounds for treatment (35).

Table 52.6: Usual pharmacokinetics of conventional antituberculosis drugs Drug

Dose

Serum Cmax

Serum tmax

Serum t½

Isoniazid

300 mg

3-5 mg/l

0.75-2 h

1.5-4 h

Rifampicin

600 mg

7-20 mg/l

2h

3h

Pyrazinamide

25 mg/kg

20-50 mg/l

2h

9h

Ethambutol

15 mg/kg

2-5 mg/l

2-3 h

Biphasic: 2-4 h, 12-14 h

Streptomycin

15 mg/kg

35-45 mg/l

0.5-1.5 h [intramuscular]

3h

Cmax = peak serum drug concentration; tmax = time to peak concentration; t½ = serum half-life

768

Tuberculosis

The shortcomings of TDM principally include the time necessary for both patients and health care providers to obtain and transport blood samples, and the relatively high cost resulting from the demand for specialized technology and expertise in measuring serum drug concentrations. Furthermore, it must be stressed that TDM taken in isolation is of limited value, therefore, correlation with clinical and bacteriological data is mandatory (201). In conclusion, TDM of antituberculosis agents apparently provides a new opportunity in the clinical management of selected patients with TB, with a goal to improve their outcome. It is likely that TDM will furnish a new paradigm of care for some patients with TB (200,201). In the coming decade, with further advancement in knowledge, technology and expertise, new horizons and expanding indications of TDM may be attained.

10.

11.

12.

13.

14.

15.

REFERENCES 1. Medical Research Council. A Medical Research Council Investigation. Streptomycin treatment of pulmonary tuberculosis. BMJ 1948;2:769-82. 2. Medical Research Council. A Medical Research Council Investigation. Treatment of pulmonary tuberculosis with streptomycin and para-aminosalicylic acid. BMJ 1950;2:107385. 3. Medical Research Council. Various combinations of isoniazid with streptomycin or with PAS in the treatment of pulmonary tuberculosis; seventh report to the Medical Research Council by their Tuberculosis Chemotherapy Trials Committee. BMJ 1955;1:434-45. 4. Bayer R, Wilkinson D. Directly observed therapy for tuberculosis: history of an idea. Lancet 1995;345:1545-8. 5. Mitchison DA. Basic mechanisms of chemotherapy. Chest 1979;76[Suppl]:771-81. 6. British Thoracic Society. A controlled trial of 6-months’ chemotherapy in pulmonary tuberculosis. Final report: results during the 36-months after the end of chemotherapy and beyond. Br J Dis Chest 1984;78:330-6. 7. Singapore Tuberculosis Service/British Medical Research Council. Five year follow up of a clinical trial of three 6-month regimens of chemotherapy given intermittently in the continuation phase in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1988;137:1147-50. 8. China Tuberculosis Control Collaboration. Results of directly observed short-course chemotherapy in 112,842 Chinese patients with smear-positive tuberculosis. Lancet 1996;347: 358-62. 9. Tam CM, Chan SL, Lam CW, Leung CC, Kam KM, Morris JS, et al. Rifapentine and isoniazid in the continuation phase of

16.

17.

18.

19.

20.

21.

treating pulmonary tuberculosis. Initial report. Am J Respir Crit Care Med 1998;157:1726-33. Cohn DL, Catlin BJ, Peterson KL, Judson FN, Sbarbaro JA. A 62-dose, 6-month therapy for pulmonary and extrapulmonary tuberculosis. A twice-weekly, directly observed and cost effective regimen. Ann Intern Med 1990;112:407-15. Snider DE, Graczyk J, Bek E, Rogowski J. Supervised sixmonth treatment of newly diagnosed pulmonary tuberculosis using isoniazid, rifampin, and pyrazinamide with and without streptomycin. Am Rev Respir Dis 1984;130:1091-4. Third East African / British Medical Research Council Study. Controlled clinical trial of four short-course regimens of chemotherapy for two durations in the treatment of pulmonary tuberculosis. Second report. Tubercle 1980;61:59-69. Hong Kong Chest Service/British Medical Research Council Study. Controlled trial of 6-month and 8-month regimens in the treatment of pulmonary tuberculosis: the results up to 24 months. Tubercle 1979;60:201-10. British Thoracic and Tuberculosis Association. Short-course chemotherapy in pulmonary tuberculosis. A controlled trial by the British Thoracic and Tuberculosis Association. Lancet 1976;2:1102-4. Slutkin G, Schecter GF, Hopewell PC. The results of 9-month isoniazid-rifampin therapy for pulmonary tuberculosis under program condition in San Francisco. Am Rev Respir Dis 1988;138:1622-4. Combs D, O’Brien R, Geiter LJ. USPHS tuberculosis shortcourse chemotherapy trial 21: effectiveness, toxicity and acceptability. The report of final results. Ann Intern Med 1990;112:397-406. World Health Organization. Treatment of tuberculosis: Guidelines for national programmes. Third edition. WHO/ CDS/TB/2003.313. Geneva: World Health Organization; 2003. Hong Kong Chest Service/British Medical Research Council. Controlled trial of four three-times-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. Second report: the results up to 24 months. Tubercle 1982;63:89-98. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 2, 4 and 6 months of pyrazinamide in 6month, three-times-weekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampicin and pyrazinamide. Results at 30 months. Am Rev Respir Dis 1991;143:700-6. Tam CM, Chan SL, Kam KM, Goodall RL, Mitchison DA. Rifapentine and isoniazid in the continuation phase of a 6month regimen. Final report at 5 years: prognostic value of various measures. Int J Tuberc Lung Dis 2002;6:3-10. Benator D, Bhattacharya M, Bozeman L, Burman W, Cantazaro A, Chaisson R, et al. The Tuberculosis Trials Consortium. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drugsusceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet 2002;360:528-34.

Treatment of Tuberculosis 769 22. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603-62. 23. Van Gorkom J, Kibuga DK. Cost-effectiveness and total costs of three alternative strategies for the prevention and management of severe skin reactions attributable to thiacetazone in the treatment of human immunodeficiency virus positive patients with tuberculosis in Kenya. Tuber Lung Dis 1996;77:30-6. 24. Sbarbaro J, Blomberg B, Chaulet P. Fixed-dose combination formulations for tuberculosis treatment. Int J Tuberc Lung Dis 1999;3[Suppl]:S286-8. 25. Moulding T, Dutt AK, Reichman LB. Fixed-dose combinations of antituberculosis medications to prevent drug resistance. Ann Intern Med 1995;122:951-4. 26. Mitchison DA. How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis. Int J Tuberc Lung Dis 1998;2:10-5. 27. Fox W. Drug combinations and the bioavailability of rifampicin. Tubercle 1990;71:241-5. 28. Ellard GA, Fourie PB. Rifampicin bioavailability: a review of its pharmacology and the chemotherapeutic necessity for ensuring optimal absorption. Int J Tuberc Lung Dis 1999;3[Suppl]:S301-8. 29. The promise and reality of fixed dose combinations with rifampicin. A joint statement of the International Union Against Tuberculosis and Lung Disease/World Health Organization. Tuber Lung Dis 1994;75:180-1. 30. Panchagnula R, Agrawal S, Kaur KJ, Singh I, Kaur CL. Evaluation of rifampicin bioequivalence in fixed-dose combinations using the WHO/IUATLD recommended protocol. Int J Tuberc Lung Dis 2000;4:1169-72. 31. Agrawal S, Singh I, Kaur KJ, Bhade SR, Kaul CL, Panchagnula R. Bioequivalence assessment of rifampicin, isoniazid and pyrazinamide in a fixed dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol vs separate formulations. Int J Clin Pharmacol Ther 2002;40:474-81. 32. Tuberculosis management in Europe. Recommendations of a task force of the European Respiratory Society, the World Health Organization and the International Union Against Tuberculosis and Lung Disease Europe Region. Eur Respir J 1999;14:978-92. 33. Teo SK. Assessment of a combined preparation of isoniazid, rifampicin and pyrazinamide [Rifater] in the initial phase of chemotherapy in three 6-month regimens for smear positive pulmonary tuberculosis: a five-year follow-up report. Int J Tuberc Lung Dis 1999;3:126-32. 34. Blomberg B, Spinaci S, Fourie B, Laing R. The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis. Bull World Health Organ 2001;79:61-8. 35. Blomberg B, Fourie B. Fixed-dose combination drugs for tuberculosis: application in standardised treatment regimens. Drugs 2003;63:535-53. 36. Yew WW. Directly observed therapy, short-course: the best way to prevent multidrug-resistant tuberculosis. Chemotherapy 1999;45[Suppl]:S26-33.

37. Sumartojo E. When tuberculosis treatment fails. A social behavioral account of patient adherence. Am Rev Respir Dis 1993;147:1311-20. 38. World Health Organization Global Tuberculosis Programme. Global tuberculosis control. WHO/GTB/97.225. Geneva: World Health Organization; 1997. 39. Kochi A. Tuberculosis control–Is DOTS the health breakthrough of the 1990s? World Health Forum 1997;18:22532. 40. Zwarenstein M, Schoeman JH, Vundule C, Lombard CJ, Tatley M. Randomised controlled trial of self-supervised and directly observed treatment of tuberculosis. Lancet 1998;352:1340-3. 41. Walley JD, Khan MA, Newell JN, Khan MH. Effectiveness of the direct observation component of DOTS for tuberculosis: a randomised control trial in Pakistan. Lancet 2001;357:6649. 42. Espinal MA, Laszlo A, Simonsen L, Boulahbal F, Kim SJ, Reniero A, et al. Global trends in resistance to antituberculosis drugs. World Health Organization – International Union Against Tuberculosis and Lung Disease Working Group on Anti-tuberculosis Drug Resistance Surveillance. N Engl J Med 2001;344:1294-303. 43. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. A controlled trial of 2-month, 3-month and 12-month regimens of chemotherapy for sputum-smear-negative pulmonary tuberculosis. Results at 60 months. Am Rev Respir Dis 1984;130:23-8. 44. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. A controlled trial of 3-month, 4-month and 6-month regimens of chemotherapy for sputum-smear-negative pulmonary tuberculosis. Results at 5 years. Am Rev Respir Dis 1989;139:871-6. 45. Davidson PT. Drug resistance and the selection of therapy for tuberculosis. Am Rev Respir Dis 1987;136:255-7. 46. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 1998;53:536-48. 47. Hong Kong Chest Service/British Medical Research Council. Five-year follow up of a controlled trial of five 6-month regimens of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1987;136:1339-42. 48. Babu Swai O, Aluoch JA, Githui WA, Thiong’O R, Edwards EA, Darbyshire JH, et al. Controlled clinical trial of a regimen of two durations for the treatment of isoniazid resistant pulmonary tuberculosis. Tubercle 1988;69:5-14. 49. Barnes PF, Block AB, Davidson PT, Snider DE Jr. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1991;324:1644-50. 50. Becerra MC, Freeman J, Bayona J, Shin SS, Kim JY, Furin JJ, et al. Using treatment failure under effective directly observed short-course chemotherapy programs to identify patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2000;4:108-14. 51. Espinal MA, Kim SJ, Suarez PG, Kam KM, Khomenko AG, Migliori GB, et al. Standard short-course chemotherapy for

770

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

Tuberculosis drug-resistant tuberculosis: treatment outcome in 6 countries. JAMA 2000;283:2537-45. Migliori GB, Espinal M, Danilova ID, Punga VV, Grzemska M, Raviglione MC. Frequency of recurrence among MDRTB cases ‘successfully’ treated with standardised short-course chemotherapy. Int J Tuberc Lung Dis 2002;6:858-64. Yew WW, Kwan SY, Ma WK, Khin MA, Chau PY. In-vitro activity of ofloxacin against Mycobacterium tuberculosis and its clinical efficacy in multiply resistant pulmonary tuberculosis. J Antimicrob Chemother 1990;26:227-36. Goble M, Iseman MD, Madsen LA, Waite D, Ackerson L, Horsburgh CR. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993;328:527-32. Telzak EE, Sepkowitz K, Alpert P, Mannheimer S, Medard F, El-Sadr W, et al. Multidrug-resistant tuberculosis in patients without HIV infection. N Engl J Med 1995;333:907-11. Park SK, Kim CT, Song SD. Outcome of chemotherapy in 107 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. Int J Tuberc Lung Dis 1998;2:877-84. Yew WW, Chan CK, Chau CH, Tam CM, Leung CC, Wong PC, et al. Outcomes of patients with multidrug-resistant pulmonary tuberculosis treated with ofloxacin/levofloxacincontaining regimens. Chest 2000;117:744-51. Dye C, Williams BG, Espinal MA, Raviglione MC. Erasing the world’s slow stain: strategies to beat multidrug-resistant tuberculosis. Science 2002;295:2042-6. Suarez PG, Floyd K, Portocarrero J, Alarcon E, Rapiti E, Ramos G, et al. Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 2002;359: 1980-9. Farmer P, Kim JY. Community based approaches to the control of multidrug resistant tuberculosis: introducing “DOTS-plus”. BMJ 1998;317:671-4. Park MM, Davis AL, Schluger NW, Cohen H, Rom WN. Outcome of MDR-TB patients 1983-1993. Prolonged survival with appropriate therapy. Am J Respir Crit Care Med 1996;153:317-24. Heifets LB, Cangelosi GA. Drug susceptibility testing of Mycobacterium tuberculosis: a neglected problem at the turn of the century. Int J Tuberc Lung Dis 1999;3:564-81. World Health Organization. Guidelines for drug susceptibility testing for second-line anti-tuberculosis drugs for DOTS-Plus. WHO/CDS/TB/2001.288. Geneva: World Health Organization; 2001. Telzak EE, Chirgwin KD, Nelson ET, Matts JP, Sepkowitz KA, Benson CA, et al. Predictors for multidrug-resistant tuberculosis among HIV-infected patients and response to specific drug regimens. Int J Tuberc Lung Dis 1999;3:337-43. Yew WW, Chan CK, Leung CC, Chau CH, Tam CM, Lee J, et al. Comparative roles of levofloxacin and ofloxacin in the treatment of multidrug-resistant tuberculosis: preliminary results of a retrospective study from Hong Kong. Chest 2003; 124:1476-81. Kennedy N, Fox R, Kisyombe GM, Saruni AO, Uiso LO, Ramsay AR, et al. Early bactericidal and sterilising activities

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

of ciprofloxacin in pulmonary tuberculosis. Am Rev Respir Dis 1993;148:1547-51. Kennedy N, Berger L, Curram J, Fox R, Gutmann J, Kisyombe GM, et al. Randomised controlled trial of a drug regimen that includes ciprofloxacin for the treatment of pulmonary tuberculosis. Clin Infect Dis 1996;22:827-33. Berning SE, Madsen L, Iseman MD, Peloquin CA. Long-term safety of ofloxacin and ciprofloxacin in the treatment of mycobacterial infections. Am J Respir Crit Care Med 1995;151:2006-9. Kennedy N, Fox R, Uiso L, Ngowi FI, Gillespie SH. Safety profile of ciprofloxacin during long-term therapy for pulmonary tuberculosis. J Antimicrob Chemother 1993;32:897-902. Yew WW, Wong CF, Wong PC, Lee J, Chau CH. Adverse neurological reactions in patients with multidrug-resistant tuberculosis after co-administration of cycloserine and ofloxacin. Clin Infect Dis 1993;17:288-9. Rastogi N, Goh KS. In vitro activity of the new difluorinated quinolone sparfloxacin [AT-4140] against Mycobacterium tuberculosis compared with activities of ofloxacin and ciprofloxacin. Antimicrob Agents Chemother 1991;35:19336. Yew WW, Piddock LJ, Li MS, Lyon D, Chan CY, Cheng AF. In vitro activity of quinolones and macrolides against mycobacteria. J Antimicrob Chemother 1994;34:343-51. Jaillon P, Morganroth J, Brumpt I, Talbot G. Overview of electrocardiographic and cardiovascular safety data for sparfloxacin. Sparfloxacin Safety Group. J Antimicrob Chemother 1996;37[SupplA]:161-7. Lubasch A, Erbes R, Mauch H, Lode H. Sparfloxacin in the treatment of drug resistant tuberculosis or intolerance of first line therapy. Eur Respir J 2001;17:641-6. Ji B, Lounis N, Maslo C, Truffot-Pernot C, Bonna P, Grosset J. In vitro and in vivo activities of moxifloxacin and clinafloxacin against Mycobacterium tuberculosis. Antimicrob Agents Chemother 1998;42:2066-9. Miyazaki E, Miyazaki M, Chan JM, Chaisson RE, Bishai WR. Moxifloxacin [BAY12-8039], a new 8-methoxyquinolone, is active in a mouse model of tuberculosis. Antimicrob Agents Chemother 1999;43:85-9. Yoshimatsu T, Nuermberger E, Tyagi S, Chaisson R, Bishai W, Grosset J. Bactericidal activity of increasing daily and weekly doses of moxifloxacin in murine tuberculosis. Antimicrob Agents Chemother 2002;46:1875-9. Saito H, Tomioka H, Sato K, Dekio S. In vitro and in vivo antimycobacterial activities of a new quinolone DU 6859a. Antimicrob Agents Chemother 1994;38:2877-82. Fung-Tomc J, Minassian B, Kolek B, Washo T, Huczko E, Bonner D. In vitro antibacterial spectrum of a new broadspectrum 8-methoxy fluoroquinolone, gatifloxacin. J Antimicrob Chemother 2000;45:437-46. Alvirez-Freites EJ, Carter JL, Cynamon MH. In vitro and in vivo activities of gatifloxacin against Mycobacterium tuberculosis. Antimicrob Agents Chemother 2002;46:1022-5. Balfour JA, Lamb HM. Moxifloxacin: a review of its clinical potential in the management of community-acquired respiratory tract infections. Drugs 2000;59:115-39.

Treatment of Tuberculosis 771 82. Lounis N, Bentoucha A, Truffot-Pernot C, Ji B, O’Brien RJ, Vernon A, et al. Effectiveness of once-weekly rifapentine and moxifloxacin regimens against Mycobacterium tuberculosis in mice. Antimicrob Agents Chemother 2001;45:3482-6. 83. Hu Y, Coates AR, Mitchison DA. Sterilising activities of fluoroquinolones against rifampin-tolerant populations of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2003;47:653-7. 84. American Health Consultants. ‘Drug of Dreams’ preps for first large-scale trial: study to begin this year. TB Monitor 2002;9:73-5. 85. Valerio G, Bracciale P, Manisco V, Quitadamo M, Legari G, Bellanova S. Long-term tolerance and effectiveness of moxifloxacin therapy for tuberculosis: preliminary results. J Chemother 2003;15:66-70. 86. Nuermberger EL, Yoshimatsu T, Tyagi S, Williams K, Rosenthal I, O’Brien RJ, et al. Moxifloxacin-containing regimens of reduced duration produce a stable cure in murine tuberculosis. Am J Respir Crit Care Med 2004;170:1131-4. 87. Takahata M, Mitsuyama J, Yamashiro Y, Yonezawa M, Araki H, Todo Y, et al. In vitro and in vivo antimicrobial activities of T-3811 ME, a novel des-F [6]-quinolone. Antimicrob Agents Chemother 1999;43:1077-84. 88. Zhao BY, Pine R, Domagala J, Drlica K. Fluoroquinolone action against clinical isolates of Mycobacterium tuberculosis: effects of a C-8 methoxyl group on survival in liquid media and in human macrophages. Antimicrob Agents Chemother 1999;43:661-6. 89. Sullivan EA, Kreiswirth BN, Palumbo L, Kapur V, Musser JM, Ebrahimzadeh A, et al. Emergence of fluoroquinoloneresistant tuberculosis in New York City. Lancet 1995;345:114850. 90. Perlman DC, El Sadr WM, Heifets LB, Nelson ET, Matts JP, Chirgwin K, et al. Susceptibility to levofloxacin of Mycobacterium tuberculosis isolates from patients with HIVrelated tuberculosis and characterization of a strain with levofloxacin monoresistance. Community Programs for Clinical Research on AIDS 019 and the AIDS Clinical Trials Group 222 Protocol Team. AIDS 1997;11:1473-8. 91. Yew WW, Chan E, Chan CY, Cheng AF. Genotypic and phenotypic resistance of Mycobacterium tuberculosis to rifamycins and fluoroquinolones. Int J Tuberc Lung Dis 2002;6:936-7. 92. O’Brien RJ, Nunn PP. The need for new drugs against tuberculosis. Obstacles, opportunities, and next steps. Am J Respir Crit Care Med 2001;163:1055-8. 93. Yew WW, Chau CH, Wong PC, Lee J, Wong CF, Cheung SW, et al. Ciprofloxacin in the management of pulmonary tuberculosis in the face of hepatic dysfunction. Drugs Exp Clin Res 1995;21:79-83. 94. Berning SE. The role of fluoroquinolones in tuberculosis today. Drugs 2001;61:9-18. 95. Uzun M, Erturan Z, Ang O. Investigation of cross-resistance between rifampin and rifabutin in Mycobacterium tuberculosis complex strains. Int J Tuberc Lung Dis 2002;6:164-5.

96. Hong Kong Chest Service/British Medical Research Council. A controlled study of rifabutin and an uncontrolled study of ofloxacin in the retreatment of patients with pulmonary tuberculosis resistant to isoniazid, streptomycin, and rifampicin. Tuber Lung Dis 1992;73:59-67. 97. Pretet S, Lebeaut A, Parrot R, Truffot C, Grosset J, Dinh-Xuan AT. Combined chemotherapy including rifabutin for rifampicin and isoniazid resistant pulmonary tuberculosis. GETIM [Group for the study and treatment of resistant mycobacterial infection]. Eur Respir J 1992;5:680-4. 98. Hirata T, Saito H, Tomioka H, Sato K, Jidoi J, Hosoe K, et al. In vitro and in vivo activities of the benzoxazinorifamycin KRM-1648 against Mycobacterium tuberculosis. Antimicrob Agents Chemother 1995;39:2295-303. 99. Shoen CM, Chase SE, Destefano MS, Harpster TS, Chmielewski AJ, Cynamon MH. Evaluation of rifalazil in long-term treatment regimens for tuberculosis in mice. Antimicrob Agents Chemother 2000;44:1458-62. 100. Dietze R, Teixeira L, Rocha LM, Palaci M, Johnson JL, Wells C, et al. Safety and bactericidal activity of rifalazil in patients with pulmonary tuberculosis. Antimicrob Agents Chemother 2001;45:1972-6. 101. Bock NN, Sterling TR, Hamilton CD, Palhucki C, Wang YC, Conwell DS, et al. Tuberculosis Trials Consortium, Centers for Disease Control and Prevention, Atlanta, Georgia. A prospective, randomised, double-blind study of the tolerability of rifapentine 600, 900, and 1200 mg plus isoniazid in the continuation phase of tuberculosis treatment. Am J Respir Crit Care Med 2002;165:1526-30. 102. Vernon AA, Burman W, Benator D, Khan A, Bozeman L. Acquired rifamycin monoresistance in patients with HIVrelated tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials Consortium. Lancet 1999; 353:1843-7. 103. Potkar C, Gogtay N, Gokhale P, Kshirsagar NA, Ajay S, Cooverji ND, et al. Phase I pharmacokinetic study of a new 3-azinomethyl-rifamycin [rifametane] as compared to rifampicin. Chemotherapy 1999;45:147-53. 104. Kanyok TP, Reddy MV, Chinnaswamy J, Danziger LH, Gangadharam PRJ. In vivo activity of paromomycin against susceptible and multidrug-resistant Mycobacterium tuberculosis and M. avium complex strains. Antimicrob Agents Chemother 1994;38:170-3. 105. Donald PR, Sirgel FA, Kanyok TP, Danziger LH, Venter A, Botha FJ, et al. Early bactericidal activity of paromomycin [aminosidine] in patients with smear-positive pulmonary tuberculosis. Antimicrob Agents Chemother 2000;44:3285-7. 106. Schraufnagel DE. Tuberculosis treatment for the beginning of the next century. Int J Tuberc Lung Dis 1999;3:651-62. 107. Truffot-Pernot C, Lounis N, Grosset JH, Ji B. Clarithromycin is inactive against Mycobacterium tuberculosis. Antimicrob Agents Chemother 1995;39:2827-8. 108. Wong CS, Palmer GS, Cynamon MH. In vitro susceptibility of Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium kansasii to amoxicillin and ticarcillin in

772

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121. 122.

Tuberculosis combination with clavulanic acid. J Antimicrob Chemother 1988;22:863-6. Donald PR, Sirgel FA, Venter A, Parkin DP, Van de Wal BW, Barendse A, et al. Early bactericidal activity of amoxicillin in combination with clavulanic acid in patients with sputum smear-positive pulmonary tuberculosis. Scand J Infect Dis 2001;33:466-9. Nadler JP, Berger J, Nord JA, Cofsky R, Saxena M. Amoxicillin-clavulanic acid for treating drug-resistant Mycobacterium tuberculosis. Chest 1991;99:1025-6. Yew WW, Wong CF, Lee J, Wong PC, Chau CH. Do betalactam-beta-lactamase inhibitor combinations have a place in the treatment of multidrug-resistant tuberculosis? Tuber Lung Dis 1995;76:90-2. Jagannath C, Reddy MV, Kailasam S, O’Sullivan JF, Gangadharam PR. Chemotherapeutic activity of clofazimine and its analogues against Mycobacterium tuberculosis. In vitro, intracellular and in vivo studies. Am J Respir Crit Care Med 1995;151:1083-6. Barbachyn MR, Hutchison DK, Brickner SJ, Cynamon MH, Kilburn JO, Klemens SP, et al. Identification of a novel oxazolidinone [U-100480] with potent antimycobacterial activity. J Med Chem 1996;39:680-5. Cynamon MH, Klemens SP, Sharpe CA, Chase S. Activities of several novel oxazolidinones against Mycobacterium tuberculosis in a murine model. Antimicrob Agents Chemother 1999;43:1189-91. Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 2000;405:962-6. Oleksijew A, Meulbroek J, Ewing P, Jarvis K, Mitten M, Paige L, et al. In vivo efficacy of ABT-255 against drug-sensitive and -resistant Mycobacterium tuberculosis strains. Antimicrob Agents Chemother 1998;42:2674-7. Brown-Elliott BA, Wallace RJ Jr, Blinkhorn R, Crist CJ, Mann LB. Successful treatment of disseminated Mycobacterium chelonae infection with linezolid. Clin Infect Dis 2001;33:14334. Ashtekar DR, Costa-Perira R, Nagrajan K, Vishvanathan N, Bhatt AD, Rittel W. In vitro and in vivo activities of nitroimidazole CGI 17341 against Mycobacterium tuberculosis. Antimicrob Agents Chemother 1993;37:183-6. Andries K, Verhasselt P, Guillemont J, Göhlmann HW, Neefs JM, Winkler H, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005;307:223-7. McNeeley D. Open Forum II on Key Issues in TB Drug Development, London, 11 December 2006. Available at URL: http://www.kaisernetwork.org/health _cast/uploaded_ files/ McNeeley_David (12-12) TMC207.pdf. Accessed on September 4, 2008. Arora S. International Union Against Tuberculosis and Lung Disease, New Drugs Symposium. Paris, 31 October 2004. Nacy C. Open Forum II on Key Issues in TB Drug Development, London, 11 December 2006. Available at URL: http://

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

www.kaisernetwork.org/health _cast/uploaded_files/ Nacy,_Carol_(12-12)_SQ109.pdf. Accessed on September 4, 2008. Hittel N. Open Forum II on Key Issues in TB Drug Development, London, 11 December 2006. Available at URL: http://www.kaisernetwork.org/health_cast/uploaded_ files/Hittel,_Norbert_(12-12)_OPC_67683.pdf . Accessed on September 4, 2008. Mckinney JD, Honer ZU, Bentrup K, Munoz-Elias EJ, Miczak A, Chen B, et al. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 2000;406:735-8. Slayden RA, Lee RE, Armour JW, Cooper AM, Orme IM, Brennan PJ, et al. Antimycobacterial action of thiolactomycin: an inhibitor of fatty acid and mycolic acid synthesis. Antimicrob Agents Chemother 1996;40:2813-9. Schroeder EK, de Souza N, Santos DS, Blanchard JS, Basso LA. Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis. Curr Pharm Biotechnol 2002;3:197-225. Parrish NM, Houston T, Jones PB, Townsend C, Dick JD. In vitro activity of a novel antimycobacterial compound Noctanesufonylacetamide, and its effects on lipid and mycolic acid synthesis. Antimicrob Agents Chemother 2001;45:114350. Suarez S, O’Hara P, Kazantseva M, Newcomer CE, Hopfer R, McMurray DN, et al. Airways delivery of rifampicin microparticles for the treatment of tuberculosis. J Antimicrob Chemother 2001;48:431-4. Romano G, Michell P, Pacilio C, Giordano A. Latest development in gene transfer technology: achievements, perspectives and controversies over therapeutic applications. Stem Cells 2000;18:19-39. Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 1980;121:939-49. Mitchison DA. Assessment of new sterilising drugs for treating pulmonary tuberculosis by culture at 2 months. Am Rev Respir Dis 1993;147:1062-3. Desjardin LE, Perkins MD, Wolski K, Haun S, Teixeira L, Chen Y, et al. Measurement of sputum Mycobacterium tuberculosis messenger RNA as a surrogate for response to chemotherapy. Am J Respir Crit Care Med 1999;160:203-10. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998;393: 537-44. Peloquin CA, Namdar R, Dodge AA, Nix DE. Pharmacokinetics of isoniazid under fasting conditions, with food, and with antacids. Int J Tuberc Lung Dis 1999;3:703-10. Peloquin CA, Namdar R, Singleton MD, Nix DE. Pharmacokinetics of rifampin under fasting conditions, with food and with antacids. Chest 1999;115:12-8. Furin JJ, Mitnick CD, Shin SS, Bayona J, Becerra MC, Singler JM, et al. Occurrence of serious adverse effects in patients receiving community-based therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2001;5:648-55.

Treatment of Tuberculosis 773 137. Whittington RM. Fatal hepatotoxicity of antitubercular chemotherapy. Lancet 1991;338:1083-4. 138. Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax 1996;51:132-6. 139. Wong WM, Wu PC, Yuen MF, Cheng CC, Yew WW, Wong PC, et al. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology 2000;31:201-6. 140. Ungo JR, Jones D, Ashkin D, Hollender ES, Bernstein D, Albanese AP, et al. Antituberculosis drug-induced hepatotoxicity. The role of Hepatitis C virus and the human immunodeficiency virus. Am J Respir Crit Care Med 1998;157:1871-6. 141. Chen CJ, Wang LY, Yu MW. Epidemiology of hepatitis B virus infection in the Asia-Pacific region. J Gastroenterol Hepatol 2000;15[Suppl]:E3-6. 142. Songsivilai S, Jinathongthai S, Wongsena W, Tiangpitayakorn C, Dharakul T. High prevalence of hepatitis C infection among blood donors in northeastern Thailand. Am J Trop Med Hyg 1997;57:66-9. 143. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence and mortality by country: WHO Global Surveillance and Monitoring Project. JAMA 1999;282:677-86. 144. Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 1991;99:465-71. 145. Parthasarathy R, Sarma GR, Janardhanam B, Ramachandran P, Santha T, Sivasubramanian S, et al. Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide. Tubercle 1986;67:99-108. 146. Tahaoglu K, Ataç G, Sevim T, Tarun T, Yazicioglu O, Horzum G, et al. The management of anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberc Lung Dis 2001;5:65-9. 147. Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003;167:1472-7. 148. Yew WW, Lee J, Wong PC, Kwan SY. Tolerance of ofloxacin in the treatment of pulmonary tuberculosis in presence of hepatic dysfunction. Int J Clin Pharmcol Res 1992;12:173-8. 149. Saigal S, Agarwal SR, Nandeesh HP, Sarin SK. Safety of an ofloxacin-based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver disease: a preliminary report. J Gastroenterol Hepatol 2001;16:102832. 150. Yew WW. Clinically significant interactions with drugs used in the treatment of tuberculosis. Drug Saf 2002;25:111-33. 151. Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivisto KT. Pharmacokinetic interactions with rifampicin: clinical relevance. Clin Pharmacokinet 2003;42:819-50. 152. Self TH, Chrisman CR, Baciewicz AM, Bronze MS. Isoniazid drug and food interactions. Am J Med Sci 1999;317:304-11. 153. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. A controlled

154.

155.

156.

157.

158.

159.

160.

161.

162.

163.

164.

165.

166.

167.

clinical comparison of 6 and 8 months of antituberculosis chemotherapy in the treatment of patients with silicotuberculosis in Hong Kong. Am Rev Respir Dis 1991;143:262-7. Lin TP, Suo J, Lee CN, Lee JJ, Yang SP. Short-course chemotherapy of pulmonary tuberculosis in pneumoconiotic patients. Am Rev Respir Dis 1987;136:808-10. Perriens JH, St Louis ME, Mukadi YB, Brown C, Prignot J, Pouthier F, et al. Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled trial of treatment for either 6 or 12 months. N Engl J Med 1995;332:779-84. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR Morb Mortal Wkly Rep 1998;47[RR-20]:1-58. Centers for Disease Control and Prevention. Updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIVinfected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR Morb Mortal Wkly Rep 2000;49:185-9. Iseman MD, Madsen L, Goble M, Pomerantz M. Surgical intervention in the treatment of pulmonary disease caused by drug-resistant Mycobacterium tuberculosis. Am Rev Respir Dis 1990;141:623-5. Pomerantz BJ, Cleveland JC Jr, Olson HK, Pomerantz M. Pulmonary resection for multi-drug resistant tuberculosis. J Thorac Cardiovasc Surg 2001;121:448-53. Park SK, Lee CM, Heu JP, Song SD. A retrospective study for the outcome of pulmonary resection in 49 patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2002;6:143-9. Condos R, Rom WN, Schluger NW. Treatment of multidrugresistant pulmonary tuberculosis with interferon-gamma via aerosol. Lancet 1997;349:1513-5. Holland SM, Eisenstein EM, Kuhns DB, Turner ML, Fleisher TA, Strober W, et al. Treatment of refractory disseminated nontuberculous mycobacterial infection with interferon gamma: a preliminary report. N Engl J Med 1994;330:1348-55. Johnson BJ, Bekker LG, Rickman R, Brown S, Lesser M, Ress S, et al. rhuIL-2 adjunctive therapy in multidrug resistant tuberculosis: a comparison of two treatment regimens and placebo. Tuber Lung Dis 1997;78:195-203. Johnson JL, Ssekasanvu E, Okwera A, Mayanja H, Hirsch CS, Nakibali JG, et al. Randomized trial of adjunctive interleukin-2 in adults with pulmonary tuberculosis. Am J Respir Crit Care Med 2003;168:185-91. Giosue S, Casarini M, Ameglio F, Zangrilli P, Palla M, Altieri AM, et al. Aerosolized interferon-alpha treatment in patients with multi-drug-resistant pulmonary tuberculosis. Eur Cytokine Netw 2000;11:99-104. Flynn JL, Goldstein MM, Triebold KJ, Sypek J, Wolf S, Bloom BR. IL-12 increases resistance of BALB/c mice to Mycobacterium tuberculosis infection. J Immunol 1995;155:2515-24. Cooper AM, Magram J, Ferrante J, Orme IM. Interleukin-12 [IL-12] is crucial to the development of protective immunity

774

168.

169.

170.

171.

172.

173.

174.

175.

176.

177.

178.

179. 180.

181.

Tuberculosis in mice intravenously infected with Mycobacterium tuberculosis. J Exp Med 1997;186:39-45. Denis M. Interleukin-12 [IL-12] augments cytolytic activity of natural killer cells toward Mycobacterium tuberculosis infected human monocytes. Cell Immunol 1994;156:529-36. Stanford JL, Stanford CA, Grange JM, Lan NN, Etemadi A. Does immunotherapy with heat-killed Mycobacterium vaccae offer hope for the treatment of multidrug-resistant pulmonary tuberculosis? Respir Med 2001;95:444-7. Durban Immunotherapy Trial Group. Immunotherapy with Mycobacterium vaccae in patients with newly diagnosed pulmonary tuberculosis: a randomised controlled trial. Lancet 1999;354:116-9. Johnson JL, Kamya RM, Okwera A, Loughlin AM, Nyole S, Hom DL, et al. Randomised controlled trial of Mycobacterium vaccae immunotherapy in non-human immunodeficiency virus-infected Ugandan adults with newly diagnosed pulmonary tuberculosis. The Uganda-Case Western Reserve University Research Collaboration. J Infect Dis 2000;181:130412. Klausner JD, Makonkawkeyoon S, Akarasewi P, Nakata K, Kasinrerk W, Corral L, et al. The effect of thalidomide on the pathogenesis of human immunodeficiency virus type 1 and M. tuberculosis infection. J Acquir Immune Defic Syndr Hum Retrovirol 1996;11:247-57. Wallis RS, Nsubuga P, Whalen C, Mugerwa RD, Okwera A, Oette D, et al. Pentoxifylline therapy in human immunodeficiency virus-seropositive persons with tuberculosis: a randomised controlled trial. J Infect Dis 1996;174:727-33. Patel N, Deshpande MM, Shah M. Effect of an immunomodulator containing Mycobacterium w on sputum conversion in pulmonary tuberculosis. J Indian Med Assoc 2002;100:191-3. Patel N, Trapathi SB. Improved cure rates in pulmonary tuberculosis category II [retreatment] with Mycobacterium w. J Indian Med Assoc 2003;101:680,682. Efficacy and safety study of immunomodulator as an adjunct therapy in pulmonary tuberculosis [TB] retreatment patients. Available at URL: http://www.clinicaltrials.gov/ ct/show/ NCT00265226?order_1. Accessed on September 5, 2008. Efficacy and safety of immunomodulator as an adjunct therapy in new pulmonary tuberculosis [Category I] patients. Available at URL: http://clinicaltrials.gov/ct2/show/ NCT00341328. Accessed on October 20, 2008. Barnes PF. Immunotherapy for tuberculosis: wave of the future or tilting at windmills? Am J Respir Crit Care Med 2003;168:142-3. Dedon JF, Courtney DL, Holmes FF. Addison’s disease from tuberculosis in a centenarian. J Am Geriatr Soc 1992;40:618-9. Dooley DP, Carpenter JL, Rademacher S. Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 1997;25:872-87. Strang JI, Kakaza HH, Gibson DG, Girling DJ, Nunn AJ, Fox W. Controlled trial of prednisolone as adjuvant in treatment of tuberculous constrictive pericarditis in Transkei. Lancet 1987;2:1418-22.

182. Strang JI, Kakaza HH, Gibson DG, Allen BW, Mitchison DA, Evans DJ, et al. Controlled clinical trial of complete open surgical drainage and of prednisolone in treatment of tuberculous pericardial effusion in Transkei. Lancet 1988;2:759-63. 183. Hakim JG, Ternouth I, Mushangi E, Siziya S, Robertson V, Malin A. Double blind randomised placebo controlled trial of adjunctive prednisolone in the treatment of effusive tuberculous pericarditis in HIV seropositive patients. Heart 2000;84:183-8. 184. Girgis NI, Farid Z, Kilpatrick ME, Sultan Y, Mikhail IA. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991;10:179-83. 185. Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT, Nguyen TC, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351:1741-51. 186. Schoeman JF, Van Zyl LE, Laubscher JA, Donald PR. Effect of corticosteroids on intracranial pressure, computed tomographic findings and clinical outcome in young children with tuberculous meningitis. Pediatrics 1997;99:226-31. 187. Lee CH, Wang WJ, Lan RS, Tsai YH, Chiang YH. Corticosteroids in the treatment of tuberculous pleurisy. A double-blind, placebo-controlled, randomized study. Chest 1988;94:1256-9. 188. Galarza I, Canete C, Granados A, Estopa R, Manresa F. Randomised trial of corticosteroids in the treatment of tuberculous pleurisy. Thorax 1995;50:1305-7. 189. Ip MS, So SY, Lam WK, Mok CK. Endobronchial tuberculosis revisited. Chest 1986;89:727-30. 190. Chan HS, Sun A, Hoheisel GB. Endobronchial tuberculosis: is corticosteroid treatment useful? A report of 8 cases and review of the literature. Postgrad Med J 1990;66:822-6. 191. Verhaeghe W, Noppen M, Meysman M, Monsieur I, Vincken W. Rapid healing of endobronchial tuberculosis by local endoscopic injection of corticosteroids. Monaldi Arch Chest Dis 1996;51:391-3. 192. Alrajhi AA, Halim MA, al-Hokrail A, Alrabiah F, al-Omran K. Corticosteroid treatment of peritoneal tuberculosis. Clin Infect Dis 1998;27:52-6. 193. Muthuswamy P, Hu TC, Carasso B, Antonio M, Dandamudi N. Prednisone as adjunctive therapy in the management of pulmonary tuberculosis: report of 12 cases and review of the literature. Chest 1995;107:1621-30. 194. Bilaceroglu S, Perim K, Buyuksirin M, Celikten E. Prednisolone: a beneficial and safe adjunct to antituberculosis treatment? A randomised controlled trial. Int J Tuberc Lung Dis 1999;3:47-54. 195. Abdul Jabbar M. Paradoxical response to chemotherapy for intracranial tuberculoma: two case reports from Saudi Arabia. J Trop Med Hyg 1991;94:374-6. 196. Cheng VC, Ho PL, Lee RA, Chan KS, Chan KK, Woo PC, et al. Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients. Eur J Clin Microbiol Infect Dis 2002;21:803-9. 197. Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical worsening of tuberculosis following antiretroviral therapy

Treatment of Tuberculosis 775

198. 199.

200.

201. 202.

in patients with AIDS. Am J Respir Crit Care Med 1998;158:157-61. Orlovic D, Smego RA Jr. Paradoxical tuberculous reactions in HIV-infected patients. Int J Tuberc Lung Dis 2001;5:370-5. Masud T, Kemp E. Corticosteroid in treatment of disseminated tuberculosis in patient with HIV infection. BMJ 1988;296:464-5. Yew WW. Therapeutic drug monitoring in antituberculosis chemotherapy: clinical perspectives. Clin Chim Acta 2001;313:31-6. Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs 2002;62:2169-83. Peloquin CA, Nitta AT, Burman WJ, Brudney KF, MirandaMassari JR, McGuiness ME, et al. Low antituberculosis drug

concentrations in patients with AIDS. Ann Pharmacother 1996;30:919-25. 203. Sahai J, Gallicano K, Swick L, Tailor S, Garber G, Seguin I, et al. Reduced plasma concentrations of antituberculous drugs in patients with HIV infection. Ann Intern Med 1997;127:28993. 204. Perlman DC, El-Helou P, Salomon N. Tuberculosis in patients with human immunodeficiency virus infection. Semin Respir Infect 1999;14:344-52. 205. Narita M, Hisada M, Thimmappa B, Stambaugh J, Ibrahim E, Hollender E, et al. Tuberculosis recurrence: multivariate analysis of serum levels of tuberculosis drugs, human immunodeficiency virus status, and other risk factors. Clin Infect Dis 2001;32:515-7.

776

Tuberculosis

Treatment of Latent Tuberculosis Infection

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DS Maru, CB Ogbunugafor, S Basu

INTRODUCTION The huge global reservoir of latent tuberculosis infection [LTBI] presents a persistent challenge to the global control of the disease. It is estimated that the global prevalence of LTBI is over 30 per cent, infecting two billion individuals, the vast majority of whom live in resource-poor, highly endemic countries. Estimated prevalence in these countries can reach over 80 per cent (1). It has long been argued that, in highly endemic, poor countries, scarce antituberculosis resources should be saved for treatment of active cases. Indeed, DOTS is and should remain the focus of public health programmes. In addition to DOTS, however, it is important to consider strategies to reduce the huge prevalence of LTBI. The strategy that many industrialized countries have taken to reduce LTBI has been targeted screening and treatment of high-risk populations. This strategy has largely been ignored in poor countries. Delivery of a preventive strategy to asymptomatic individuals that requires up to one year of daily dosing in poor places with low health infrastructure and medication delivery methods is problematic. Furthermore, defining LTBI is complicated by as much as 60 per cent reactivity to the tuberculin skin test [TST], which is commonly used in rich countries to define LTBI cases. In countries the size of India or China, the prospects of providing treatment over six or nine months to 60 per cent of the population would seem completely unfeasible and non-productive. Despite these major obstacles, treatment of LTBI may be an important strategy in certain patient populations. The spectre of human immunodeficiency virus [HIV] and multidrug-resistant tuberculosis [MDR-TB] require that

a more proactive approach to tuberculosis [TB] control be undertaken. As new diagnostic tests develop, as shorter treatment regimens become available, and as the health infrastructure further develops, LTBI treatment for some even low-to-medium risk patients might be more feasible. Successes in the treatment of LTBI among HIV-seropositive individuals suggest that targeted treatment in poor countries may be possible. Targeted treatment of recent LTBI is a feasible strategy that has yet to be explored fully. Finally, both national and international finances for TB have been mobilized like never before, which may provide the resources necessary to implement an LTBI treatment programme. This chapter seeks to provide a framework for clinicians and public health officials to address these issues among the patient populations with whom they work. The chapter also focusses on issues concerning treating LTBI in resource-poor countries whose annual TB incidence exceeds 100 per 100 000 individuals. DIAGNOSTIC TESTS The paucity of tools available for the diagnosis of LTBI is a central barrier to the implementation of effective treatment of LTBI. Given the toxicity and cost associated with antituberculosis chemotherapy, it is crucial that a diagnostic test be sufficiently specific while at the same time preserving the sensitivity necessary for an effective screening programme. The most widely used test, the century-old TST, is inadequate on both accounts. This has hampered research in LTBI diagnosis for years; given the limits of TST as the gold standard, it has been difficult to adequately assess new diagnostic strategies. The

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The reader is referred to the chapter “Tuberculin skin test” [Chapter 11] for more details.

The fundamental statistical consideration on utility of these tests as tools for determining LTBI is the positive predictive value [PPV] in a given population. Since environmental mycobacteria are so common in areas where TB is endemic (2), specificity is low for the TST, decreasing the PPV. On the other hand, a high prevalence of LTBI improves the PPV. Perhaps of greater clinical relevance than one carrying LTBI is that of risk of developing active TB. This risk is highly dependent upon age, history of active TB contacts, and whether the TST was a recent conversion [Table 53.2] (3,4). Immunosuppressive therapy and HIV infection also confer as much as 10 times greater risk of activation (3). Physicians need to take these issues into account when they consider particular patients for testing for LTBI.

Interferon-gamma Release Assays

TREATMENT REGIMENS

The reader is referred to the chapter “Diagnosis of latent tuberculosis infection: recent advances and future directions” [Chapter 10] for more details.

Even as diagnosis is hampered by a lack of sensitivity and specificity, LTBI treatment is hampered by long, potentially toxic regimens that are difficult to administer among asymptomatic individuals. Treatment regimens for LTBI are listed in Table 53.3. Among HIV-seronegative subjects, the effectiveness of isoniazid treatment, measured by the decrease in TB has been found to range from 25 to 92 percent; when adherence was high, the protective efficacy was observed to be close to 90 per cent (4). Recently, Churchyard et al (5) computed that, in HIV infected adults with no previous history of TB, the combined efficacy of all TB preventive therapy regimens [regardless of TST status], was a 36 per cent reduction in the TB incidence compared with placebo. The greatest reduction in the TB incidence [62%] was observed among individuals with a positive TST result. Isoniazid alone, given for six to twelve months, reduced the TB incidence by 33 per cent overall and by 64 per cent among individuals with positive TST results (5). All the trials evaluating preventive treatment for LTBI have included individuals with no previous history of TB. Published evidence also suggests that TB preventive therapy for HIV infected individuals previously treated for TB [secondary preventive therapy] is also effective in reducing TB recurrence (5). However, currently published international guidelines (4) do not endorse the use of secondary preventive therapy. This issue also merits evaluation in future studies.

interferon-gamma release assays that have recently become available, have broadened the possibilities of LTBI detection. Performance Characteristics of Latent Tuberculosis Infection Diagnostic Tests In the absence of a gold standard test for LTBI, approximations are made in determining the performance characteristics of these tests [Table 53.1]. Tuberculin Skin Test

Table 53.1: Methods to approximate performance characteristics of latent tuberculosis infection diagnostic tests Sensitivity Response among culture-positive TB cases Actually determines sensitivity for disease not infection May overestimate sensitivity if immune response is weak in paucibacillary cases May under-estimate sensitivity if immune response is weak owing to TB disease Long-term risk for developing active TB among subjects with various levels of test reactivity Does determine the most relevant measure for public health programming: risk Requires long period of follow-up and significant epidemiological resources Specificity Response among low-risk populations May underestimate specificity if certain members of the population have been exposed May overestimate specificity if low-risk populations are also at lower risk of acquiring environmental mycobacteria Long-term risk for developing active TB among subjects with various levels of test reactivity Does determine the most relevant measure for public health programming: risk Requires long period of follow-up and significant epidemiological resources TB = tuberculosis

Isoniazid Since the 1950s, randomized, controlled trials have evaluated isoniazid regimens in more than 20 trials,

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Tuberculosis Table 53.2: Annual risk of developing active tuberculosis* Age group [years] 0 to 5 [%]

6 to 15 [%]

16 to 35 [%]

36 to 55 [%]

Over 56 [%]

6 19 24

4 8 14

12 15 19

7 10 12

7 10 12

29 37 54

6 12 12

30 37 56

23 28 42

12 15 17

Non-conversion positive result 5 to 9 mm 10 to 14 mm > 15 mm Recent conversion or contact with active tuberculosis case 5 to 9 mm 10 to 14 mm > 15 mm

* Based on data from studies carried out in the United States of America Adapted from reference: 3

Table 53.3: Treatment regimens for latent tuberculosis infection Isoniazid 5 mg/kg [300 mg max] daily for 9 months Isoniazid 15 mg/kg [900 mg max] twice weekly for 9 months given as DOT Isoniazid 300 mg daily for 6 months Isoniazid 300 mg twice weekly for 6 months given as DOT Rifampicin 10 mg/kg [600 mg max] with pyrazinamide 15-20 mg/kg [2000 mg max] for 2 months Rifampicin 10 mg/kg [600 mg max] with pyrazinamide 50 mg/kg [4000 mg max] twice weekly for 2 months given as DOT Rifampicin 10 mg/kg [600 mg max] daily for 4 months Note: In paediatric populations, doses are: isoniazid 10-20 mg/ kg [300 mg max] daily, 20-40 mg/kg [900 mg max] twice weekly; no adjustments for rifampicin necessary DOT = directly observed treatment Source: reference 4

totaling more than 100 000 patients. These observations show a clear impact of isoniazid on the development of active TB, with effectiveness [1–relative risk] ranging from 25 to 90 per cent (6). The high variability in results is largely due to differences in adherence and baseline risk rates. The standard remains a nine-month, isoniazidbased regimen. Variation in efficacy may also be due to variability in hepatic metabolism. This was suggested to be the cause for the null result in one Japanese study (7); however, other Japanese studies have shown positive impacts similar to those from other countries (8). The regimen suggested by the American Thoracic Society

[ATS] and Centers for Disease Control and Prevention [CDC] guidelines (4) is nine months, based on extrapolations from controlled studies of six-month and twelve-month regimens. These studies have shown improved effectiveness of approximately 10 per cent, during the course of the 12-month regimen. Noncontrolled sub-group analyses, however, have suggested equivalency of the nine-month and twelve-month regimens (4). Transient elevation of liver function tests can be expected in as many as of 10 to 22 per cent of patients. Clinical hepatitis, however, develops at a rate of approximately one to two per cent in younger individuals with no risk factors, but increases with age, alcohol abuse, chronic viral hepatitis, and HIV to as high as 10 per cent. The recent commercialization of rapid, point-of-care liver enzyme assays, providing costs decline, could make such monitoring easier in rural areas where laboratory facilities may be lacking. The reader is referred to the chapter “Antituberculosis treatment induced hepatotoxicity” [Chapter 54] for more details. Rifamycin-based Regimens Since adherence and retention have been limited with otherwise effective isoniazid regimens, the development of shorter regimens is a priority. These have typically been rifamycin-based regimens. The well-studied is a two-month regimen consisting of pyrazinamide and rifampicin. Owing to concerns over hepatotoxicity, this

Treatment of Latent Tuberculosis Infection combination has not been evaluated in a randomized, controlled trial among HIV-seronegative patients. Among HIV-seropositive patients, in whom risk is elevated, the benefits have outweighed these costs. For both ethical and scientific reasons, these regimens must be compared with standard isoniazid regimens as opposed to placebo. Four randomized controlled trials involving over 5000 patients have shown statistical equivalence to isoniazid regimens (9-12). Following these successes, the rifampicin and pyrazinamide regimen was piloted in seronegative patients. However, severe liver injury including deaths were reported among 5.8 per cent of 1311 patients treated with this regimen (13-17). Revised guidelines (18) recommended that rifampicin and pyrazinamide regimen should not generally be offered to patients with LTBI and the clinicians should choose from the alternative regimens available. The rifampicin and pyrazinamide regimen definitely should not be used in persons with underlying liver disease, history of alcoholism, or isoniazidassociated liver injury (18). If the potential benefits of this regimen outweigh the risk of hepatotoxicity, it should be very carefully employed in selected situations only by the experts. At the moment, these regimens have been understudied in paediatric populations, though some uncontrolled data suggest their effectiveness. As such, these are definitely second-line agents among paediatric populations, except in the case of contact with a known case of isoniazid-resistant TB. Rifabutin, like rifampicin, works by inhibiting the enzyme bacterial deoxyribonucleic acid-dependent ribonucleic acid polymerase. The most important use of rifabutin is among HIV-positive patients at risk for isoniazid-resistant TB. Rifabutin may interact less with protease inhibitors and non-nucleoside reverse transcriptase inhibitors than does rifampicin. On the Horizon: Moxifloxacin-based Regimens The increased prevalence of MDR-TB has engendered an even greater urgency to explore new classes for potential treatments of LTBI. Among the fluoroquinolones, moxifloxacin shows the greatest promise to date in the treatment of LTBI. The drug has strong in vitro (19-20) and in vivo activity in non-human models (21), and in the treatment of active TB in humans, it has bactericidal activity comparable to first-line agents

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(22,23). Additionally, in vitro studies of moxifloxacin and other fluoroquinolones have shown that there appears to be no indication of cross-resistance between fluoroquinolone resistance and resistance to other antituberculosis drugs (24). Finally, in a murine model of LTBI, moxifloxacin was highly effective as part of various combination treatment regimens, including shorter duration ones (25). Widespread use of fluoroquinolones in general practice for other disease indications even though patients are actually infected with Mycobacterium tuberculosis, especially inadvertant treatment of smearnegative pulmonary TB with fluoroquinolones due to a misdiagnosis of community acquired pneumonia can actually result in monotherapy for TB (26,27). These factors may facilitate the emergence of moxifloxacin resistance. It is necessary to safeguard the use of moxifloxacin, as it is a valuable addition to the armamentarium of antituberculosis drugs (26,27). PROGRAMMATIC ISSUES IN LATENT TUBERCULOSIS INFECTION TREATMENT: THE CASE OF INDIA India constitutes one-fifth of the global burden of TB, and approximately 40 per cent of the population is estimated to have LTBI. The annual risk of developing LTBI is 1.5 per cent (28-30). The economic losses of TB are enormous. In India, three to four months of work is lost if an adult develops active TB, resulting in the loss of 20 to 30 per cent of annual household income. If the patient dies as a result of TB, 15 years of productivity are lost. India was the site of discovery and implementation of key chemotherapy regimens, including DOTS, in the control of TB. This, along with a relatively well-funded higher medical education system that attracts top students in medical research and practice, provides the experience necessary to deliver and evaluate such a programme. Furthermore, India is home to the most advanced generic drug manufacturing industry in the developing world, which can help to ensure a steady supply of cheap medicines. For these reasons, India appears well situated to be a global leader in LTBI control. There are several major barriers to implement the widespread LTBI treatment, however, which have been highlighted by some as arguments against such programmes.

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Tuberculosis is too Endemic to Treat Latent Tuberculosis Infection The real question is not whether LTBI is too endemic but rather whether false-positive rates for LTBI diagnostics are too high. If, in a given country 40 per cent of the citizens are in fact true LTBI cases, and they can be detected with a specific assay, then they should be treated. The enormity of these numbers should not be a deterrent as sub-populations for several diseases that have massive prevalence rates are routinely treated. Examples include prevalence rates of 30 per cent for HIV in some African communities (31,32), of 50 per cent for diabetes in some American Indian populations (33,34), of 40 per cent for hepatitis C virus (35,36) among some prison populations in the United States. Where there is an epidemic, the public health system must treat all patients affected. However, that largely moral argument may take a secondary role to the very real problem of limited resources. This has been the argument with regard to DOTS that limited resources must focus on smearpositive pulmonary TB, because that is where the major chain of transmission is located. While that is in large part true, very rarely in public health is funding a zerosum game. That is to say, LTBI treatment, if appropriately marketed, would not drain resources from other areas because the problem of resources is largely one of political will as opposed to absolute finances. This is especially true as huge, wealthy multinational donors, led by the Bill and Melinda Gates Foundation, continue to enter into the global public health financing arena. Furthermore, it remains to be seen whether an LTBI programme can be cost-effective, as has been demonstrated in wealthier countries. Given the huge economic burden of TB, efforts aimed at prevention could prove highly cost-effective. Now, for example, if 60 per cent of the citizens are TST-positive, but only 20 per cent of these are true LTBI cases, then certainly there is an argument against treating all TST-positive cases. This is why there is clearly a need for new diagnostic tests. However, this does not mean that no TST-positive patients should be treated. The most obvious subpopulation are high-risk patients who show recent TST conversion. These are patients that have not reacted to previous BCG vaccination, the most common reason for a false-positive TST. Although these patients could represent conversion due to nontuberculous

mycobacteria [NTM] infection, the epidemiological evidence suggests that the bulk of them would represent true LTBI. While these may represent a small reservoir of LTBI, there is a wealth of data suggesting they should be treated; indeed, any foreigner who comes to India and subsequently converts will be given treatment. At the very least, then, for that 40 per cent of the population that is not reactive at any given moment, it may be prudent to serially, perhaps annually, test them for conversion. Massive Campaigns to Treat Latent Tuberculosis Infection will only Lead to Drug-resistance It has been hypothesized (37) that community-wide isoniazid preventive therapy for HIV-TB co-infected individuals will reduce the incidence of TB in the shortterm but may also speed the emergence of drug-resistant TB. A recent review (38) highlighted the paucity of data and did not exclude the possibility of an increased risk for isoniazid-resistant TB following isoniazid preventive therapy. It also emphasized the importance of exclusion of active TB prior to isoniazid preventive therapy and continued surveillance for isoniazid resistance. Emergence of drug-resistance is a major concern, but should not be a barrier provided appropriate control measures are put into place to prevent this phenomenon. There are three major reasons why an LTBI campaign would lead to the development of drug resistance. The major reason, as with any infection, is improper dosing or administration. These issues are tied to a lack of preventative medicine culture that finds origin in sociopolitical will rather than clinical capability. The key here is rigorous education, monitoring, and follow-up. It will also be important to discover once-weekly and shortcourse treatment regimens, which would make adherence and follow-up more likely, as well as even opening the possibility of directly observed therapy. The next problem would be the development of resistance due to partially treating active TB. This should be avoided by taking a rigorous history and review of symptoms, as well as assessing a chest radiograph prior to starting treatment. In any case, all studies employing treatment should have in place sound mechanisms of follow-up so that any patient who develops active TB should submit samples for drug resistance testing. This will ensure that the patient is placed on an appropriate regimen and that the treatment programme is appropriately evaluated.

Treatment of Latent Tuberculosis Infection However, the lack of a ‘gold standard’ for the diagnosis of LTBI, costs involved in getting mycobacterial culture and sensitivity tested in a reliable, periodically accredited laboratory and the enormity of the task of following up millions of persons for prolonged periods, all seem to be insurmountable hurdles for implementing massive LTBI treatment campaigns in resource-limited settings. Rural Health Care Facilities and Personnel are Extremely Lacking The provision of adequate rural health care facilities and personnel is among India’s greatest public health failures, and represents a huge barrier to successful implementation of any public health programmes. Again, however, the success of several vaccination campaigns, of nutrient supplementation, and of DOTS suggests that, in spite of this, some strides in preventive public health can be made even in rural areas with poor health facilities. DECIDING WHEN TO TREAT LATENT TUBERCULOSIS INFECTION IN HIGH-PREVALENCE SETTINGS Clearly, there is not enough evidence to start rolling out LTBI screening and treatment for the general population. For the clinician working in endemic areas, however, there are several options for detecting and treating LTBI. It is prudent, even in the absence of contact tracing by public health authorities, for individual clinicians to encourage the family and personal contacts of active TB patients to at least be screened using the TST. If the TST is reactive, the patient is asymptomatic and chest radiograph is negative, patients can be counselled as to which treatment regimen, if any, would be most appropriate for them. Whichever regimen is started, it is then the duty of the clinician and the health care team to ensure that treatment is appropriately adhered to. REFERENCES 1. Dye C, Bassili A, Bierrenbach A, Broekmans J, Chadha V, Glaziou P, et al. Measuring tuberculosis burden, trends, and the impact of control programmes. Lancet Infect Dis 2008;8:233-43. Epub 2008 Jan 16. 2. Radhakrishna S, Frieden TR, Subramani R, Narayanan PR. Value of dual testing for identifying tuberculous infection. Tuberculosis [Edinb] 2006;86:47-53. 3. Horsburgh CR Jr. Priorities for the treatment of latent tuberculosis infection in the United States. N Engl J Med 2004;350:2060-7.

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4. Joint Statement of the American Thoracic Society [ATS] and the Centers for Disease Control and Prevention [CDC]. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S22147. 5. Churchyard GJ, Scano F, Grant AD, Chaisson RE. Tuberculosis preventive therapy in the era of HIV infection: overview and research priorities. J Infect Dis 2007;196[Suppl 1]:S52-62. 6. Dooley KE, Sterling TR. Treatment of latent tuberculosis infection: challenges and prospects. Clin Chest Med 2005;26:313-26. 7. Bush OB Jr, Sugimoto M, Fujii Y, Brown FA Jr. Isoniazid prophylaxis in contacts of persons with known tuberculosis. Second report. Am Rev Respir Dis 1965;92:732-40. 8. Chiba Y, Takahara T, Kondo K, Nagashima A. Chemoprophylaxis of tuberculosis for adults in Japan. Bull Int Union Tuberc 1964;35:91-3. 9. Quigley MA, Mwinga A, Hosp M, Lisse I, Fuchs D, Porter JDH, et al. Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults. AIDS 2001;15:215-22. 10. Mwinga A, Hosp M, Godfrey-Faussett P, Quigley M, Mwaba P, Mugala BN, et al. Twice weekly tuberculosis preventive therapy in HIV infection in Zambia. AIDS 1998;12:2447-57. 11. Gordin F. Short-term tuberculosis prophylaxis is effective in persons with HIV. Am Fam Physician 1998;58:948. 12. Halsey NA, Coberly JS, Desormeaux J, Losikoff P, Atkinson J, Moulton LH, et al. Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection. Lancet 1998;351:786-92. 13. Centers for Disease Control and Prevention [CDC]; American Thoracic Society. Update: fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations: United States, 2001. Am J Respir Crit Care Med 2001;164:1319–20. 14. Stout JE, Engemann JJ, Cheng AC, Fortenberry ER, Hamilton CD. Safety of 2 months of rifampin and pyrazinamide for treatment of latent tuberculosis. Am J Respir Crit Care Med 2003;167:824–7. 15. Jasmer RM, Saukkonen JJ, Blumberg HM, Daley CL, Bernardo J, Vittinghoff E, et al. Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial. Ann Intern Med 2002;137:640-7. 16. Bock NN, Rogers T, Tapia JR, Heron GD, DeVoe B, Geiter LJ. Acceptability of short-course rifampin and pyrazinamide treatment of latent tuberculosis infection among jail inmates. Chest 2001;119:833-7. 17. McNeill L, Allen M, Estrada C, Cook P. Reduction in incidence of severe hepatotoxicity by frequent monitoring of liver enzymes in patients receiving pyrazinamide and rifampin for treatment of latent tuberculosis. Chest 2003;123:102-6. 18. Centers for Disease Control and Prevention [CDC]; American Thoracic Society. Update: adverse event data and revised

782

19.

20.

21.

22.

23.

24.

25.

26. 27.

Tuberculosis American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection-United States, 2003. MMWR Morb Mortal Wkly Rep 2003;52:735-9. Rodriguez JC, Ruiz M, Climent A, Royo G. In vitro activity of four fluoroquinolones against Mycobacterium tuberculosis. Int J Antimicrob Agents 2001;17:229-31. Rodriguez JC, Ruiz M, Lopez M, Royo G. In vitro activity of moxifloxacin, levofloxacin, gatifloxacin and linezolid against Mycobacterium tuberculosis. Int J Antimicrob Agents 2002;20:464-7. Alvirez-Freites EJ, Carter JL, Cynamon MH. In vitro and in vivo activities of gatifloxacin against Mycobacterium tuberculosis. Antimicrob Agents Chemother 2002;46:1022-5. Gosling RD, Uiso LO, Sam NE, Bongard E, Kanduma EG, Nyindo M, et al. The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis. Am J Respir Crit Care Med 2003;168:1342-5. Pletz MW, De Roux A, Roth A, Neumann KH, Mauch H, Lode H, et al. Early bactericidal activity of moxifloxacin in treatment of pulmonary tuberculosis: a prospective, randomized study. Antimicrob Agents Chemother 2004;48:780-2. Fattorini L, Tan D, Iona E, Mattei M, Giannoni F, Brunori L, et al. Activities of moxifloxacin alone and in combination with other antimicrobial agents against multidrug-resistant Mycobacterium tuberculosis infection in BALB/c mice. Antimicrob Agents Chemother 2003;47:360-2. Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH, et al. Rifapentine, moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. Am J Respir Crit Care Med 2005;172:452-6. Drlica K, Zhao X, Kreiswirth B. Minimising moxifloxacin resistance with tuberculosis. Lancet Infect Dis 2008;8:273-5. Wang JY, Hsueh PR, Jan IS, Lee LN, Liaw YS, Yang PC, et al. Empirical treatment with a fluoroquinolone delays the treatment for tuberculosis and is associated with a poor

28. 29.

30. 31.

32. 33.

34.

35.

36.

37.

38.

prognosis in endemic areas. Thorax 2006;61:903-8. Epub 2006 Jun 29. Chadha VK. Tuberculosis epidemiology in India: a review. Int J Tuberc Lung Dis 2005;9:1072-82. Chadha VK, Kumar P, Jagannatha PS, Vaidyanathan PS, Unnikrishnan KP. Average annual risk of tuberculous infection in India. Int J Tuberc Lung Dis 2005;9:116-8. Khatri GR, Frieden TR. Controlling tuberculosis in India. N Engl J Med 2002;347:1420-5. Johnson L, Bradshaw D, Dorrington R. South African Comparative Risk Assessment Collaborating Group. The burden of disease attributable to sexually transmitted infections in South Africa in 2000. S Afr Med J 2007;97:65862. Mbirimtengerenji ND. Is HIV/AIDS epidemic outcome of poverty in sub-saharan Africa? Croat Med J 2007;48:605-17. Diamant AL, Babey SH, Hastert TA, Brown ER. Diabetes: the growing epidemic. Policy Brief UCLA Cent Health Policy Res 2007;[PB2007-9]:1-12. Pohar SL, Johnson JA. Health care utilization and costs in Saskatchewan’s registered Indian population with diabetes. BMC Health Serv Res 2007;7:126. Aceijas C, Rhodes T. Global estimates of prevalence of HCV infection among injecting drug users. Int J Drug Policy 2007;18:352-8. Epub 2007 Aug 7. Weinbaum CM, Sabin KM, Santibanez SS. Hepatitis B, hepatitis C, and HIV in correctional populations: a review of epidemiology and prevention. AIDS 2005;19[Suppl 3]:S41-6. Cohen T, Lipsitch M, Walensky RP, Murray M. Beneficial and perverse effects of isoniazid preventive therapy for latent tuberculosis infection in HIV-tuberculosis coinfected populations. Proc Natl Acad Sci U S A 2006;103:7042-7. Epub 2006 Apr 21. Balcells ME, Thomas SL, Godfrey-Faussett P, Grant AD.Isoniazid preventive therapy and risk for resistant tuberculosis. Emerg Infect Dis 2006;12:744-51.

Antituberculosis Treatment Induced Hepatotoxicity

Antituberculosis Treatment Induced Hepatotoxicity

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54 PK Garg, RK Tandon

INTRODUCTION In the present era, short-course antituberculosis treatment with standard first-line drugs, namely, isoniazid, rifampicin, pyrazinamide, ethambutol or streptomycin is the norm and these drugs constitute the essential components of the DOTS strategy for control of tuberculosis [TB] endorsed by the World Health Organization [WHO] (1). Antituberculosis treatment may result in adverse effects involving almost all systems in the body including the gastrointestinal tract, liver, skin, nervous system, otovestibular apparatus and the eyes. Of these, drug-induced hepatotoxicity [DIH] is an important and commonly encountered adverse effect (2-8). Antituberculosis DIH usually has a benign course, but may result in serious morbidity and even mortality (2-8). EFFECT OF ANTITUBERCULOSIS DRUGS ON THE LIVER Isoniazid Isoniazid was introduced for the treatment of TB in the 1960s. Initially the hepatotoxic potential of isoniazid was not recognized. In 1969, however, Scharer and Smith (9) reported that 10.3 per cent of patients receiving isoniazid developed liver function abnormalities. In a large study (10) of 2321 patients who were on isoniazid prophylaxis, clinical hepatitis was reported to occur in 19 [0.8%] cases and overt jaundice in 13 [0.6%] cases with one death (10). In a randomized, double-blind study (11) the incidence of hepatotoxicity due to isoniazid chemo-

prophylaxis was evaluated. In this study (11), 20 836 subjects were administered isoniazid in a dosage of 300 mg/day as chemoprophylaxis while 6991 control subjects received a placebo. The relative risk of developing hepatotoxicity in patients receiving isoniazid chemoprophylaxis for less than one year was found to be 5.2/1000 irrespective of age (11). After these early reports, the United States Public Health Service [USPHS] conducted a large multicentre prospective study (12) in patients receiving isoniazid for chemoprophylaxis to find out the incidence and course of isoniazid-induced hepatotoxicity (12). In 13 838 patients, the overall incidence of isoniazid-induced hepatotoxicity was found to be one per cent with a mortality rate of 0.06 per cent. This high mortality rate resulted in the termination of the study (13). In addition to patients developing clinical hepatitis, a large proportion of patients had developed asymptomatic elevation of transaminases (14). Usually, isoniazid-induced hepatitis gradually resolves within one to four weeks after stopping isoniazid. However, if the drug is continued, patients may develop severe hepatitis including fulminant hepatic failure (15). Snider and Caras (16) after reviewing the articles published from 1965 through 1989, identified 177 deaths from isoniazid-induced hepatitis among persons taking isoniazid alone for chemoprophylaxis in the United States. They (16) also found that: [i] deaths from isoniazid hepatitis are less frequent now than in 1970s; [ii] increasing proportion of deaths occur with increasing age; and [iii] women may be at an increased risk of death.

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Pathogenesis The pathogenesis of isoniazid induced hepatotoxicity is not well-understood. Both dose related toxicity and hypersensitivity reaction have been considered. The histopathological picture resembles that of viral hepatitis and shows hepatocyte necrosis, ballooning degeneration and inflammatory infiltrate (17). These findings may suggest dose related toxicity. Hypersensitivity is considered unlikely because of the delayed onset of isoniazidinduced hepatotoxicity, absence of symptoms usually associated with hypersensitivity such as rash, fever, arthralgia and eosinophilia, and no hepatotoxicity on rechallenge in most cases (18,19). However, in some patients there is a circumstantial evidence of hypersensitivity to the drug. In these patients, eosinophils are prominent on liver biopsy and hepatotoxicity recurs on re-challenge (19). In addition, lack of direct correlation between serum drug levels and hepatotoxicity argues against a direct toxic effect (20). Rifampicin The major adverse effect of rifampicin therapy is hepatotoxicity. Abnormalities in the liver function tests are common in patients receiving rifampicin and these resolve even while the drug continues to be used. Elevation of bilirubin and alkaline phosphatase levels are characteristic with rifampicin treatment. In several published studies (21-24), the reported incidence of transaminase elevation and overt clinical hepatitis during rifampicin therapy in the absence of isoniazid varied from 0.6 to 2.7 per cent. On meta-analysis, the mean incidence of hepatitis in 1264 patients on rifampicin therapy without isoniazid was computed to be 1.1 per cent, significantly lower than the 2.6 per cent observed with isoniazid and rifampicin combination (25). Pathogenesis Rifampicin-induced hepatotoxicity occurs earlier compared to isoniazid and produces a patchy cellular abnormality with marked periportal inflammation (26). Rifampicin-induced hepatitis has been postulated to occur as a part of systemic allergic reaction and due to unconjugated hyperbilirubinaemia as a result of competition with bilirubin for uptake at hepatocyte plasma membrane (26).

HEPATOTOXICITY DUE TO COMBINATION TREATMENT OF ACTIVE TUBERCULOSIS DISEASE WITH ISONIAZID, RIFAMPICIN AND PYRAZINAMIDE Isoniazid and Rifampicin There is evidence to suggest that DIH occurs with greater frequency and may be more severe when isoniazid and rifampicin are administered in combination than when either drug is given alone (2,25). Some reports (27,28) have suggested that hepatitis appeared sooner with isoniazid and rifampicin combination therapy than with isoniazid therapy alone, with significant elevation of transaminase levels and hypoprothrombinaemia occurring in some patients. More than a decade ago, Steele et al (25) undertook a meta-analysis to estimate the incidence of antituberculosis treatment induced hepatotoxicity. A total of 34 clinical studies [22 involving adults and 12 involving children] published between 1966 and 1989 were analysed. They found that the incidence of clinical hepatitis in adults with isoniazid alone was 0.6 per cent, with multidrug isoniazid regimens without rifampicin 1.6 per cent and with regimens containing rifampicin and not isoniazid 1.1 per cent. The incidence of clinical hepatitis in 6 105 patients taking isoniazid and rifampicin combination was 2.6 per cent which was significantly higher than the incidence in patients taking multiple drugs containing isoniazid without rifampicin and those taking multiple drugs containing rifampicin without isoniazid. Children receiving isoniazid and rifampicin combination had a significantly higher incidence of hepatitis [6.9%] compared to those receiving multiple drug isoniazid containing regimens without rifampicin [1.6%]. The authors concluded that isoniazid and rifampicin combination caused more hepatotoxicity than either of the drugs administered alone and the hepatotoxic effects of these two drugs given together was additive rather than synergistic. In a retrospective study (29), five of the thirteen orthotopic liver transplant recipients developed hepatotoxicity. All of them were receiving isoniazid and rifampicin as a part of a multidrug regimen for the treatment of TB. In this study (29) patients receiving isoniazid alone, or, isoniazid along with ethambutol for chemoprophylaxis did not develop hepatotoxicity.

Antituberculosis Treatment Induced Hepatotoxicity Pathogenesis It is not clear as to why is there an increased risk of hepatotoxicity with isoniazid and rifampicin combination. The answer probably lies in the interaction between isoniazid and rifampicin metabolism [Figure 54.1]. The metabolism of isoniazid is influenced by both genetic and intercurrent factors. The principal metabolite of isoniazid, acetyl isoniazid, is converted to monoacetyl hydrazine. This in turn is metabolized by microsomal p-450 enzymes to other compounds causing hepatotoxicity and this effect may be enhanced by rifampicininduced enzyme induction. Because acetyl isoniazid formation occurs in larger amounts in rapid rather than slow acetylators, it was suggested that rapid acetylators are more prone to hepatotoxicity (19). However, subsequent studies questioned this hypothesis as it was shown that monoacetyl hydrazine formed was rapidly converted into the less toxic diacetyl hydrazine which was excreted rapidly (30). Both rapid and slow acetylators excreted similar proportions of monoacetyl hydrazine suggesting that the more rapid formation of monoacetyl hydrazine is compensated by its more rapid conversion to diacetyl hydrazine and its excretion in rapid acetylators (31).

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Other studies (32-36) have suggested that products of hydrolysis rather than acetylation are the critical toxic metabolites of isoniazid hydrolase. Ellard and Gammon (32) showed that a small portion of isoniazid is directly hydrolyzed by isoniazid. They (32) also showed that the proportion of drug metabolized through this direct pathway is greater in slow acetylators than in rapid acetylators. Sarma and colleague (33) showed that the hepatotoxic action of metabolites of isoniazid is not so much due to monoacetyl hydrazine but due to the hydrazine formed from isoniazid. Rifampicin induces the metabolism of isoniazid by isoniazid hydrolase resulting in the formation of isonicotinic acid and hydrazine (34). It has been suggested that concomitant administration of rifampicin and isoniazid could result in increasing levels of hydrazine and this could provoke hepatotoxicity especially in slow acetylators (33). This hypothesis is supported by the finding of increased hepatotoxicity in slow acetylators (35,36). There is a considerable debate with regard to whether the hepatotoxicity is due to the additive effect of isoniazid and rifampicin or synergistic direct toxic effect of drugs or is a hypersensitivity phenomenon. The first human case of a proven hepatotoxic interaction between

Figure 54.1: Pathways of isoniazid metabolism * Oxidation induced by alcohol and cytochrome P450 2E1 NAT = N-acetyl transferase; GSTM = glutathione S-transferase M

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isoniazid and rifampicin has been reported by Askgaard et al (37). A 35-year-old black Somalian patient with miliary TB developed hepatotoxicity after a few days of treatment with isoniazid, rifampicin, pyrazinamide and ethambutol. On withdrawing all the drugs, the liver profile normalized and remained so after isoniazid challenge. Hepatotoxicity recurred when isoniazid was added but it was well-tolerated when rifampicin was reintroduced without isoniazid. In a study from Chandigarh (38), the role of oxidative stress as a mechanism of hepatotoxicity caused by isoniazid and rifampicin was investigated in young growing rats. Altered profile of antioxidant enzymes with increased lipid peroxidation indicated that isoniazid and rifampicin induced hepatotoxicity appeared to be mediated through oxidative stress. It has also been shown that rifampicin and isoniazid resulted in an increase in acetaminophen and isoniazid-induced cytotoxicity in human HepG2 hepatoma cells (39). Rifampicin, Isoniazid and Pyrazinamide Hepatotoxicity is the most serious side effect of pyrazinamide treatment. Earlier pyrazinamide was employed in a dosage of 40 to 50 mg/kg/day for prolonged periods and hepatotoxicity developed in about 15 per cent of the cases leading to the abandonment of pyrazinamide as a first-line drug (40). However, pyrazinamide is presently administered in a dosage of 25 to 35 mg/kg/day. The contribution of pyrazinamide to the development of hepatotoxicity at this dosage has been controversial. In a large Indian study (41) on hepatic toxicity with shortcourse regimens containing rifampicin, isoniazid and pyrazinamide, there was no indication that pyrazinamide contributed to the development of hepatotoxicity. However, in some studies (42-45), pyrazinamide was found to significantly contribute to the development hepatotoxicity when given along with isoniazid and rifampicin. Pathogenesis The exact pathogenetic mechanism of pyrazinamide induced hepatic damage has not been clarified as yet. In patients receiving a combination of isoniazid, rifampicin and pyrazinamide, two patterns of fulminant liver injury have been observed. Late increases in serum transaminases [usually after 1 month] occur during

pyrazinamide-induced hepatotoxicity, whereas, early increases in serum transaminases [usually within first 15 days] are likely to be caused by rifampicin-induced isoniazid hepatotoxicity (45). HEPATOTOXICITY DUE TO TREATMENT OF LATENT TUBERCULOSIS INFECTION Earlier, the terms “preventive therapy” and “chemoprophylaxis” have been used to refer to the use of a simple regimen using isoniazid to prevent the development of active TB disease in persons known or likely to be infected with Mycobacterium tuberculosis. As these terms were confusing, the term “treatment of latent tuberculosis infection [LTBI]” has replaced these terms in the statement of the American Thoracic Society [ATS] and the Centers for disease Control and Prevention [CDC] (46). Though uncommon in India, targeted tuberculin testing and treatment of LTBI is often practiced in developed countries, like the USA, as per these guidelines using isoniazid alone for six or nine months, or rifampicin alone for four months or the combination of rifampicin and pyrazinamide for two months. Because of cost-effectiveness, the National Institute for Health and Clinical Excellence [NICE] guidelines (47) recommend a two-step approach, with an initial tuberculin skin test [TST], followed by an interferon-gamma release assay test to confirm positivity. Six month course of isoniazid or rifampicin or a three-month course comprising of rifampicin and isoniazid is recommended for the treatment of LTBI (47). In the late 1960s, and the early 1970s, it was observed that a large proportion of the subjects who were treated for LTBI with isoniazid developed asymptomatic elevation of hepatic transaminases and one per cent to ten per cent developed clinically evident hepatotoxicity (9-13). More recent evidence suggests that less than one per cent of persons receiving clinically monitored isoniazid prophylaxis developed DIH (48). Though the rifampicin and pyrazinamide regimen was well tolerated in human immunodeficiency virus [HIV]-seropositive patients, after the publication of the ATS guidelines (46), severe liver injury including deaths were reported among 5.8 per cent of 1311 patients treated with the rifampicin and pyrazinamide regimen (49-51). Pyrazinamide has often been implicated as the agent chiefly responsible for this (52). A meta-analysis

Antituberculosis Treatment Induced Hepatotoxicity (53) compared rifampicin plus pyrazinamide versus isoniazid for treatment of LTBI and concluded that the former treatment regimen increases the risk of hepatotoxicity especially in non-HIV infected persons. Revised guidelines (47,52) recommended that rifampicun and pyrazinamide regimen should generally not be offered to patients with LTBI and the clinicians should choose from the alternative regimens available. This regimen definitely should not be used in persons with underlying liver disease, history of alcoholism, or isoniazid-associated liver injury (52). If the potential benefits of this regimen outweigh the risk of DIH, it should be very carefully employed in selected situations only by experts. Curiously, the hepatotoxicity rate is higher among the HIV-seronegative subjects than in HIVseropositive subjects. Furthermore, rates of DIH that have been observed with this two-drug regimen are higher than those observed among patients with active TB who are treated with three potentially hepatotoxic drugs [isoniazid in addition to rifampicin and pyrazinamide] during the initial intensive phase of two months (54). These issues merit further study. FACTORS IMPLICATED IN THE DEVELOPMENT OF ANTITUBERCULOSIS TREATMENT INDUCED HEPATOTOXICITY The fact that antituberculosis drugs cause hepatotoxicity only in a small proportion of patients raises the question about some predisposing factors for the development of antituberculosis treatment induced hepatotoxicity. Certain putative factors have been implicated in the development of antituberculosis treatment induced hepatotoxicity [Table 54.1]. These are discussed below. Age Isoniazid-induced hepatotoxicity has been correlated with age. The incidence of serious hepatotoxicity is rare below 20 years of age. It was found to be 0.3 per cent in the age group of 20 to 34 years, 1.2 per cent in 35 to 39 years age group and in patients above the age of 50 years, the risk increased to 2.3 per cent (55). Riska (11) found that the relative risk of hepatotoxicity due to isoniazid prophylaxis was 2.8/1000 in patients younger than 35 years while it was 7.7/1000 in those more than 50 years of age. In a case-control study, Pande et al (56) observed that antituberculosis treatment induced hepatotoxicity

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Table 54.1: Risk factors for the development of antituberculosis treatment induced hepatotoxicity Advanced age Female sex Moderately/far advanced/extensive disease [pulmonary tuberculosis] Hypoalbuminaemia, malnutrition Alcoholism Underlying liver disease Hepatitis B virus infection Hepatitis C virus infection Human immunodeficiency virus infection Acetylator phenotype N-acetyltransferase activity Glutathione S-transferase activity

was more frequent in older patients. However, in another Indian study (57), it was observed that age had no relation with antituberculosis treatment induced hepatotoxicity. Sex In some studies (42,44,56,58), elderly females have been reported to be at a higher risk to develop antituberculosis treatment induced hepatotoxicity. However, some workers believe that the incidence of DIH due to antituberculosis drugs is not influenced by the gender of the patients (55). Ethnic and Racial Variation In Indian patients, a higher risk of DIH due to antituberculosis drugs has been reported (41,57,59,60) than in their Western counterparts (61-63). The risk of DIH, based on data derived from four prospective studies from India (25) was 11.5 per cent, compared with 4.3 per cent in 14 published studies from the West (56). Genetic Factors Though several risk factors have been suggested for the development of DIH due to antituberculosis treatment, the role of genetic factors has not been fully evaluated (63). Sharma et al (64) recently reported the major histocompatibility complex [MHC] class II alleles and clinical risk factors for the development of DIH in 346 north Indian patients with TB receiving

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antituberculosis treatment. Of these, 56 patients [16%] developed DIH, whereas the remaining 290 patients did not. Multivariate logistic regression analysis revealed that, older age, moderately or far advanced disease, serum albumin less than 3.5 g/dl, absence of human leucocyte antigen [HLA]-DQA1*0102, and presence of HLA-DQB1*0201 were independent risk factors for the development of DIH (64). Acetylator Status and Hepatotoxicity There is considerable confusion in the literature regarding acetylator phenotype status and the development of hepatotoxicity. Rapid acetylators have been shown to be more susceptible to isoniazid-induced toxic hepatitis (23). On the other hand, in patients receiving regimens containing isoniazid and rifampicin, the incidence of DIH was found to be higher in slow acetylators than in rapid acetylators (41,56). However, Gurumurthy et al (65) in a study of 3000 south Indian patients receiving various isoniazid containing regimens demonstrated no relationship between the acetylator phenotype and the incidence of hepatotoxicity. Singh et al (66) also did not find any correlation between the acetylator status and the development of antituberculosis treatment induced hepatotoxicity. Drug-Metabolizing Enzyme Polymorphisms and Predisposition to Antituberculosis Treatment Induced Hepatotoxicity N-acetyl Transferase and Cytochrome P450 2E1 N-acetyl transferase [NAT] activity, one of the earliest pharmacogenetic traits to be recognized, was first identified as the genetically controlled step for the inactivation of isoniazid. Molecular genetic studies of NAT in humans revealed the presence of three loci, two of which encode distinct enzymes with similar action and the third is a pseudogene (67). Human NAT1 is found in liver, gut and almost all tissues. It acetylates para-aminosalicylate and para-aminobenzoic acid. In contrast, humans NAT2, found primarily in the liver and intestinal epithelium, acetylates substrates, such as isoniazid, dapsone and arylamine carcinogens. Gene mapping studies in humans have demonstrated that the NAT genes are located between 170 and 360 kb at 8p22. The coding region for both NAT1 and NAT2 is 870 bp and is intron less (5,67). Both NAT1 and NAT2 loci are highly polymorphic. The

genotype-phenotype correlation study for human NAT2 has revealed alleles associated with rapid and slow acetylation. Isoniazid is metabolized to hepatotoxic intermediates by the isoenzyme NAT2 and cytochrome P450 2E1 [CYP2E1]. However, the association of polymorphic NAT acetylator status and hepatotoxicity induced by isoniazid is not clear (5). Huang et al (68) reported that NAT2 slow-acetylator status and age were the only independent risk factors for DIH due to antituberculosis treatment. Additionally, it was also observed that slow acetylators were prone to develop more severe hepatotoxicity than rapid acetylators (68,69). Ohno et al (70) also reported that NAT2 slow acetylator genotype significantly affected the development of DIH due to isoinazid and rifampicin. In another report (71), even after adjustment for acetylator status and age, the CYP2E1 c1/c1 genotype remained an independent risk factor for hepatotoxicity suggesting that CYP2E1 genetic polymorphism may be associated with susceptibility to DIH caused by antituberculosis treatment. While no association was found between NAT2 polymorphism and DIH due to isoniazid in the treatment of LTBI, genotyping of CYP2E1 polymorphisms was found to be a useful predictive tool for predicting isoniazid-induced hepatic toxicity (72). Glutathione S-transferase In a case-control study (73) of polymorphisms at the glutathione S-transferase [GST] loci [GSTM1 and GSTT1] and their relation to the development of DIH due to antituberculosis treatment, the frequencies of mutations at GSTT1 and NAT2 genes were not significantly different between cases and controls. However, frequency of homozygous ‘null’ mutation at the GSTM1 gene was significantly higher among cases suggesting that these mutations could predispose to the development of DIH due to antituberculosis treatment (73). A recent metaanalysis (74) concluded that NAT2mt, CYP2E1*1A and GSTM1 null have a modest effect on genetic susceptibility to antituberculosis treatment induced hepatotoxicity. Underlying Chronic Liver Disease Even though there are reports that patients with known liver disease can be treated with isoniazid and rifampicin containing regimens without undue risk, many workers have reported that patients with underlying liver disease

Antituberculosis Treatment Induced Hepatotoxicity and alcoholics are more prone to develop DIH due to antituberculosis treatment. Gronhagen-Riska et al (58) studied predisposing factors in hepatitis due to combined isoniazid and rifampicin treatment and reported that one half of the patients who developed large increases in transaminases [> 150 units/l] were either alcoholics or had a history of previous liver or biliary disease. The peak transaminase and bilirubin levels were higher in patients who were hepatitis B virus [HBV] carriers than in those who were not (58). Other studies (11,13) also suggested that concurrent and previous biliary disorders and alcoholism were risk factors for DIH caused by isoniazid. Hepatitis and the Human Immunodeficiency Viruses In a study (75) involving 43 HBV carriers and 276 noncarriers who received antituberculosis treatment, and 86 HBV carriers who did not receive antituberculosis treatment, the incidence of DIH was significantly higher in HBV carriers [34.9%] when compared to non-carriers [9.4%] and HBV carriers not given antituberculosis drugs [8.1%]. For patients given antituberculosis drugs, HBV carriers who developed liver dysfunction were younger and had more severe liver injury compared with noncarriers. By multiple logistic regression analysis, age and HBV infection were found to be risk factors for DIH caused by antituberculosis treatment (75). Sparse literature is available regarding the role of hepatitis C virus [HCV] and the HIV in the genesis of DIH caused by antituberculosis treatment. Ungo et al (76) reported that the relative risk of developing DIH if the patient was HCV or HIV positive was five-fold and fourfold, respectively. If a patient was co-infected with both HCV and HIV, the relative risk of developing DIH was increased by 14.4-fold (77). In another recent study from Korea (77), DIH developed more frequently in HCVseropositive patients with TB [7 of 54 patients, 13%] than in control subjects [4 of 97 patients, 4%]. These issues merit further study. Malnutrition Mehta et al (78) have shown that drug metabolizing processes in the liver including acetylation pathways are deranged in states of protein energy malnutrition. A significant decrease in isoniazid metabolism has been demonstrated in kwashiorkar (79). In India, a higher incidence of rifampicin-and isoniazid-induced hepato-

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toxicity has been reported in patients with malnutrition (80). In another study (81) from India, it has been observed that mild degree of malnutrition in children does not predispose to hepatotoxicity. Singh et al (42) reported that malnutrition predisposed to the development of antituberculosis treatment induced hepatotoxicity. They also reported that malnourished patients had received higher than normal dosage of antituberculosis drugs per kilogram body weight and suggested that this could be one of the reasons for the development of hepatotoxicity in them. ANTITUBERCULOSIS TREATMENT INDUCED HEPATOTOXICITY AND TYPE OF TUBERCULOSIS Patients with severe forms of TB have been reported to be at a higher risk of developing DIH than those with mild disease (82). Patients with TB meningitis have been observed to have a higher incidence of DIH compared to those with milder disease (83). Similar findings have been reported in studies from India (56). Development of DIH has been attributed to multiple factors including hepatic involvement by primary disease, malnutrition, more frequent hospitalization and parenteral therapy (41,84). Close biochemical monitoring revealed that the diagnosis of antituberculosis treatment induced hepatotoxicity was made frequently in these patients (41,84). CLINICAL COURSE OF ANTITUBERCULOSIS TREATMENT INDUCED HEPATOTOXICITY While most of the patients with antituberculosis treatment induced hepatotoxicity have only asymptomatic elevation of transaminases, few develop overt icteric hepatitis. The onset of hepatitis usually resembles viral hepatitis. In fact, it was emphasized that not all cases of presumed antituberculosis treatment induced hepatotoxicity were due to antituberculosis drugs but many of these cases were acutally due to viral hepatitis (84,85). Majority of the cases with antituberculosis induced hepatitis resolve spontaneously following withdrawal of the offending drugs. However, in a substantial proportion of patients severe liver damage may occur leading to acute or subacute liver failure with subsequent mortality. The development of antituberculosis treatment induced acute liver failure has been reported (86) and such cases mark the rapidity, severity and the importance of antituberculosis treatment induced hepatotoxicity. In

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the study reported by Singh et al (86), overall mortality in patients with antituberculosis treatment induced hepatotoxicity was 12 per cent while it was 75 per cent in patients who developed acute and subacute liver failure due to antituberculosis treatment. MANAGEMENT OF ANTITUBERCULOSIS TREATMENT INDUCED HEPATOTOXICITY Diagnosis When DIH is suspected, the patient receiving antituberculosis treatment should be systematically investigated for other causes, such as viral hepatitis. Due consideration must be given to the drug interactions between the antituberculosis drugs and other drugs administered for co-morbid illnesses which can result in hepatic dysfunction. Isoniazid when administered alone enhances the toxicity of drugs with hepatotoxic potential such as phenytoin, carbamazepine, valproate, acetaminophen due to inhibition of several cytochrome P450 enzymes. When isoniazid is co-administered with rifampicin, the inductive capability of rifampicin exceeds the inhibitory effect of isoniazid and results in decreased levels of phenytoin. Other clinically important drug interactions include decrease in the serum concentrations of HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors, corticosteroids and oral contraceptive pill containing ethinyl oestradiol and norethindrone induced by rifampicin (87). In these situations, therapeutic drug monitoring may be useful. The criteria for the diagnosis of DIH in patients receiving antituberculosis treatment according to some of the published international guidelines are listed in Table 54.2 (87-89). According to WHO classification (90), severity of hepatotoxicity is defined as follows: grade 1, for any serum ALT level of 51 to 125 IU/l, or 1.25 to 2.5 times normal; grade 2, for any serum ALT level of 126 to 250 IU/l, or 2.6 to 5.0 times normal; grade 3, for any serum ALT level of 251 to 500 IU/l, or 5.1 to 10.0 times normal; and grade 4, for any serum ALT level greater than 500 IU/l, or greater than 10 times normal, or greater than 250 IU/l if accompanied by compatible symptoms. Ideally, antituberculosis treatment should be individualized according to the body weight and co-morbid illnesses. Whenever feasible, baseline liver function testing must be done. Consensus guidelines for the management of patients with antituberculosis treatment induced hepatotoxicity are yet to be evolved. The recent

Table 54.2: Diagnosis of antituberculosis drug-induced hepatotoxicity Guidelines (reference)

Elevation of transaminases

Elevation of serum bilirubin

ATS/CDC/IDSA Three-fold increase Any increase (2,87) in ALT over the upper normal limit in patients reporting jaundice and/or hepatitis symptoms such as nausea, vomiting, abdominal pain, unex-plained fatigue] Five-fold increase in ALT over the upper normal limit in the absence of symptoms ERS/WHO/ Five-fold increase in Any increase IUATLD (88) ALT over the upper normal limit HKTBS (3,89) Three-fold progressive Two-fold persistent escalating increase in increase ALT over the upper normal limit ATS = American Thoracic Society; CDC = Centers for Disease Control and Prevention; IDSA = Infectious Diseases Society of America; ALT = alanine aminotransferase; ERS = European Respiratory Society; WHO = World Health Organization; IUATLD = International Union Against Tuberculosis and Lung Disease; AST = aspartate aminotransferase; HKTBS = Hong Kong Tuberculosis Service

guidelines published by the American Thoracic Society [ATS], CDC and the Infectious Diseases Society of America [IDSA] (2,87) form the basis for the diagnosis and management principles listed below. Guidelines for Monitoring Patients Receiving Treatment for Active Tuberculosis Disease Screening for Viral Hepatitis The guidelines (2) specifically recommend screening for viral hepatitis in a certain group of patients [Table 54.3]. This is especially important in developing nations (85). Monitoring of Liver Functions There is no consensus protocol for monitoring of liver functions in patients receiving antituberculosis treatment for active TB disease. be repeated if fever, malaise, vomiting, jaundice, or unexplained deterioration occur.

Antituberculosis Treatment Induced Hepatotoxicity Table 54.3: Patient groups receiving treatment for active tuberculosis disease in whom screening for viral hepatitis is indicated Individuals who inject drugs Persons born in endemic areas of Asia, Africa, the Pacific Islands, Eastern Europe, or the Amazon Basin Human immunodeficiency virus infected patients Persons who may have had sexual or household contact with chronically infected individuals Subjects who may have had occupational exposure to infected blood Chronic haemodialysis patients Recipients of clotting factors before 1987; blood or solid organ transplants prior to 1992

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Guidelines for Monitoring Patients Receiving Treatment for Latent Tuberculosis Infection The guidelines (2,87) also recommend that individuals over the age of 35 years who are treated for LTBI with isoniazid alone, or isoniazid with rifampicin should have baseline measurement and scheduled monitoring of ALT every other month; or at one, three, and six months in those taking a nine-month regimen, depending on the perceived hepatotoxicity risk, effectiveness of patient education, and the stability of ALT. The WHO and IUATLD recommend only clinical monitoring for hepatotoxicity in patients with TB in low-income countries (46,91,92).

Patients with undiagnosed liver disease Infants born to infected mothers Source: reference 2

These guidelines (2,87) do not recommend baseline liver function monitoring for healthy patients, but recommend monitoring of serum ALT and bilirubin in patients with a possible liver disorder, those with a history of chronic liver disease [e.g., chronic hepatitis B and C, alcoholic hepatitis, and cirrhosis], patients with chronic use of alcohol, those with HIV infection treated with highly active antiretroviral therapy [HAART], pregnant women, and those who are up to three months post-partum, for patients receiving other medications and for those with chronic medical conditions. The guidelines (2,87) also advocate measuring serum transaminases and bilirubin concentrations every two to four weeks for the first two to three months, and then as necessary. These (2,87) suggest that ALT is preferred for detecting and tracking hepatocellular injury in those who develop symptoms of DIH; estimation of AST, serum bilirubin, and alkaline phosphatase are adjunctive for monitoring chronic liver disease, cholestasis, or severe hepatocellular injury. The upper limits of normal used should be that of the laboratory performing the assay and the reference limits for enzymes should be adjusted for age in children and in adults older than 60 years, and for gender in adults, if available. These guidelines also advocate the use of international normalized ratio periodically as well in patients with severe hepatic impairment.

Treatment of Tuberculosis in Patients with Antituberculosis Drug Induced Hepatotoxicity Once the diagnosis of DIH is established, it is essential to first stop all potentially hepatotoxic drugs till complete clinical and biochemical resolution of hepatotoxicity occurs. In the interim period, at least three nonhepatotoxic drugs such as ethambutol, streptomycin and quinolones [moxifloxacin or ofloxacin] can be used after appropriate checks on renal function and visual acuity. After complete resolution of transaminitis, most antituberculosis drugs can be safely restarted in a phased manner. Regarding the safety and wisdom of re-starting the same hepatotoxic drugs which caused hepatitis, the clinical experience has shown that these drugs can be given safely. The re-introduction of antituberculosis drugs has seldom been systematically studied and a great deal of controversy exists regarding sequence in which the drugs are to be reintroduced, whether the re-introduction should be done in full dosage or in gradually escalating dosage. Recommendations for Re-introduction of Treatment in Patients with Antituberculosis Drug-Induced Hepatotoxicity According to the guidelines (2,87), suspected antituberculosis drugs can be started one at a time once the transaminase levels return to less than two times the upper normal. Rifampicin is to be restarted first. If the liver functions remain normal after one week, isoniazid can be added to the regimen. If the liver functions remain

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normal after one week, then pyrazinamide is added. If there is recurrence of symptoms or deterioration of liver functions, the last added drug should be stopped. Depending on the number of doses taken, bacteriological status and the severity of the disease, the treatment may have to be individualized and extended. In a recent study (93) in TB patients with serious liver injury, a 12-month regimen of ethambutol, and ofloxacin, including streptomycin for the first three months, followed by ethambutol and ofloxacin for the subsequent nine months was well tolerated, and it was effective in 85 per cent of patients.

confirmed in studies with a large sample size. In a study from Copenhagen (96), 61 of the 752 [8%] patients with TB [8%] developed DIH. Recurrence of DIH was observed in 16 of these 61 patients [26.2%] on re-introduction of antituberculosis treatment and they required a modified regimen. In a recent case-control study from New Delhi (97), four of the 45 patients [9%] had recurrence of DIH after re-introduction of antituberculosis drugs. There was no statistically significant difference in recurrence of DIH in three regimens used for reintroduction. Low serum albumin was a significant risk factor for recurrence of DIH (97).

Recurrence of Drug-Induced Hepatotoxicity on Re-treatment

Liver Transplantation

Review of published literature suggests that the recurrence rate of DIH when antituberculosis drugs are re-introduced ranges from 6.3 to 26.2 per cent (2,87,89,9496). In a study from New Delhi (86), after resolution of DIH, re-introduction of isoniazid and rifampicin was possible in 41 of 44 patients suggesting that the recurrence rate of DIH on re-introduction was 6.8 per cent. In another study (94), 55 of the cohort of 1036 patients [5.3%] developed DIH. Treatment was re-introduced in 48 patients and successfully completed in 45 patients indicating that the recurrence rate of DIH on reintroduction of antituberculosis treatment was 6.3 per cent. In a randomized prospective study from Turkey (95) patients who developed DIH on antituberculosis treatment [n = 45] were re-treated with a drug regimen consisting of isoniazid, rifampicin, ethambutol and streptomycin administered by gradually increasing the number and dosage of the drugs [group I, n= 20]. The remaining patients [group II, n = 25] were re-treated with the same regimen [isoniazid, rifampicin, pyrazinamide and ethambutol] in the same dosages throughout. While none of the patients in group I developed recurrence of DIH, in 24% of the patients group II developed recurrence of DIH. The patients who developed recurrence of DIH while receiving group II regimen were then treated with the regimen used for group I patients and it was observed that all the patients recovered. The observations from this study suggest that recurrence rate of DIH is higher when the full-dose regimen including pyrazinamide is used compared with gradual re-introduction of rifampicin and isoniazid in a regimen that does not contain pyrazinamide. These observations need to be

Occasionally, liver transplantation may be required for seriously ill patients with antituberculosis drug induced acute liver failure (98). However, published literature on this topic is sparse. ISSUES TO BE RESOLVED Consensus guidelines for the management of patients with antituberculosis treatment induced hepatotoxicity are yet to be evolved (5-8). The re-introduction of antituberculosis drugs has seldom been systematically studied and a great deal of controversy exists regarding sequence in which the drugs are to be re-introduced, whether the re-introduction should be done using all drugs at once, in full dosage or sequentially, in gradually escalating dosage (5-8). Since there is no consensus on these issues, large multicentre studies are required to provide answers to these questions. REFERENCES 1. Maher D, Chaulet P, Spinaci A, Harries A. Treatment of tuberculosis: guidelines for National Programmes. Geneva: World Health Organization; 1997. 2. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al. ATS [American Thoracic Society] hepatotoxicity of antituberculosis therapy subcommittee. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935-52. 3. Yew WW, Leung CC. Antituberculosis drugs and hepatotoxicity. Respirology 2006;11:699-707. 4. Tostmann A, Boeree MJ, Aarnoutse RE, de Lange WC, van der Ven AJ, Dekhuijzen R. Antituberculosis drug-induced hepatotoxicity: concise up-to-date review. J Gastroenterol Hepatol 2008;23:192-202. Epub 2007 Nov 6.

Antituberculosis Treatment Induced Hepatotoxicity 5. Sharma SK. Antituberculosis drugs and hepatotoxicity. Infect Genet Evol 2004;4:167-70. 6. Sharma SK, Mohan A. Antituberculosis treatment induced hepatotoxicity. In: Venkataraman GS, editor. Medicine update. Mumbai: Association of Physicians of India; 2004;14:298-306. 7. Sharma SK, Mohan A. Antituberculosis treatment induced hepatotoxicity: from bench to bed-side. In: Gupta SB, editor. Medicine update. Mumbai: Association of Physicians of India; 2005;15:479-84. 8. Mohan A, Sharma SK. Side effects of antituberculosis drugs. Am J Respir Crit Care Med 2004;169:882-3. 9. Scharer L, Smith JP. Serum transaminase elevations and other hepatic abnormalities in patients receiving isoniazid. Ann Intern Med 1969;71:113-20. 10. Garibaldi RA, Drusin RE, Ferebee SH, Gregg MB. Isoniazid associated hepatitis: report of an outbreak. Am Rev Respir Dis 1972;106:357-65. 11. Riska N. Hepatitis cases in isoniazid treated groups and in a control group. Bull Int Union Tuberc 1976;51:203. 12. Kopanoff DE, Snider DE, Caras GH. Isoniazid-related hepatitis–US Public Health Service Cooperative Surveillance Study. Am Rev Respir Dis 1978;117:991-1001. 13. Levin ML, Moodie AS. Isoniazid prophylaxis and deaths in Baltimore. Maryland State Med J 1974;24:64-7. 14. Brummer DL. Isoniazid and liver disease. Ann Intern Med 1971;75:643. 15. Cohen R, Kalser MH, Thomson RV. Fatal hepatic necrosis secondary to isoniazid therapy. JAMA 1961;176:877-9. 16. Snider DE Jr, Caras GJ. Isoniazid associated hepatitis deaths. A review of available information. Am Rev Respir Dis 1992;145:494-7. 17. Black M, Mitchell JR, Zimmerman HJ, Ishak KG, Epler GR. Isoniazid-associated hepatitis in 114 patients. Gastroenterology 1975;69:289-302. 18. Meddrey WC, Boitmott JK. Isoniazid hepatitis. Ann Intern Med 1973;70:1-12. 19. Mitchell JR, Thorgeirsson UP, Black M, Timbrell JA, Snodgrass WR, Potter WZ, et al. Increased incidence of isoniazid hepatitis in rapid acetylators, possible relation to hydrazine metabolites. Clin Pharmacol Ther 1975;18:70-9. 20. Mitchell JR, Long MWW, Thorgeirsson UP, Jollow DJ. Acetylation rates and monthly liver function tests during one year of isoniazid preventive therapy. Chest 1975;68:181-90. 21. Thompson JE. The effect of rifampicin on liver morphology in tuberculous alcoholics. Aust NZ J Med 1976;6:111-6. 22. Lees AW, Allan GW, Smith J. Toxicity from rifampin plus isoniazid and rifampicin plus ethambutol therapy. Tubercle 1971;52:182-90. 23. Raleigh JW. Rifampin in treatment of advanced pulmonary tuberculosis. Am Rev Respir Dis 1973;105:397-409. 24. Hong Kong Tuberculosis Treatment Service/Brompton Hospital/British Medical Research Council. A controlled trial of daily and intermittent rifampicin plus ethambutol in the treatment of patients with pulmonary tuberculosis: results up to 30 months. Tubercle 1975;56:179-89.

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25. Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampicin. A meta-analysis. Chest 1991;99:46571. 26. Kenwright S, Levi AJ. Sites for competition in selective hepatic uptake of rifampicin SV, flavaspidic acid, bilirubin and bromsulphthalein. Gut 1974;15:220-6. 27. Tsagaropoulon-Stinga H, Mataki-Emmanouilidon T, KaridaKa-Valioti S, Manios S. Hepatotoxic reactions in children with severe tuberculosis treated with isoniazid-rifampin. Pediatr Infect Dis 1985;4:270-3. 28. Pessayre D, Bentata M, Degott C, Nonel O, Miguet JP, Rueff B, et al. Isoniazid-rifampin fulminant hepatitis. A possible consequence of the enchancement of isoniazid hepatotoxicity in enzyme induction. Gastroenterology 1977;72:284-9. 29. Schluger LK, Sheiner PA, Jonas M, Guarrera JV, Fiel IM, Mergers B, et al. Isoniazid hepatotoxicity after orthotopic liver transplantation. Mt Sinai Med J 1996;63:64-9. 30. Ellard GA, Mitchison DA, Girling DJ, Nunn AJ, Fox W. The hepatic toxicity of isoniazid among rapid and slow acetylators of the drug. Am Rev Respir Dis 1978;118:628-9. 31. Lauterburg BH, Smith CV, Todd EL, Mitchell JR. Pharmacokinetics of the toxic hydrazine metabolites formed from isoniazid in human. Pharmacol Exp Ther 1985;235:566-70. 32. Ellard GA, Gammon PT. Pharmacokinetics of isoniazid metabolism in man. J Pharmacokinet Biopharm 1976;4:83113. 33. Sarma GR, Immanuel C, Kailasam S, Narayana AL, Ventakatesan P. Rifampin-induced release of hydrazine from isonizaid. A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin. Am Rev Respir Dis 1986;133:1072-1105. 34. Blair IA, Mansilla Tinoco R, Brodie MJ, Clare RA, Dollery CT, Timbrell JA, et al. Plasma hydrazine concentrations in man after isoniazid and hydralazine administration. Hum Toxicol 1985;4:195-202. 35. Dickinson DS, Bailey WC, Hirschowitz BI, Soong SJ, Eidus L, Hodgkin HM. Risk factors for isoniazid [INH]-induced liver dysfunction. J Clin Gastroenterol 1981;3:271-9. 36. Wiber WW, Hein DW, Litwin A, Lower GM Jr. Relationship of acetylator status to isoniazid toxicity, lupus erythematosus, and bladder cancer. Feb Proc 1983;42:3086-90. 37. Askgaard DS, Wilcke T, Dossing M. Hepatotoxicity caused by the combined treatment action of isoniazid and rifampicin. Thorax 1996;50:213-4. 38. Sodhi CP, Rana SV, Mehta SK, Vaiphei K, Attari S, Mehta S. Study of oxidative-stress in isoniazid-rifampicin induced hepatic injury in young rats. Drug Chem Toxicol 1997;20: 255-69. 39. Nicod L, Viollon C, Regnier A, Jacqueson A, Richert L. Rifampicin and isoniazid cytotoxicity in human HepG2 hepatoma cells. Hum Exp Toxicol 1997;16:28-34. 40. Girling DJ. The hepatic toxicity of antituberculous regimens containing isoniazid, rifampicin, and pyrazinamide. Tubercle 1978;59:13-32.

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41. Parthasathy R, Sarma GR, Janardhanam B, Ramachandran R, Santha T, Sivasubramanian S, et al. Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide. Tubercle 1986;67:99-108. 42. Singh J, Arora A, Garg PK, Thakur VS, Pande JN, Tandon RK. Antituberculosis treatment induced hepatotoxicity: role of predictive factors. Postgrad Med J 1995;71:359-62. 43. Chang KC, Leung CC, Yew WW, Lau TY, Tam CM. Hepatotoxicity of pyrazinamide: cohort and case-control analyses. Am J Respir Crit Care Med 2008;177:1391-6. Epub 2008 Apr 3. 44. Schberg T, Rebhan K, Lode H. Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. Eur Respir J 1996;10:2026-30. 45. Durand F, Jebrak G, Pessayre D, Fournier M, Bernuau J. Hepatotoxicity of antitubercular treatments. Rationale for monitoring liver status. Drug Saf 1996;15:394-405. 46. Joint Statement of the American Thoracic Society [ATS] and the Centers for Disease Control and Prevention [CDC]. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161;S221-47. 47. National Institute for Health and Clinical Excellence, National Collaborating Centre for Chronic Conditions. Management of non-respiratory tuberculosis. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London: Royal College of Physicians; 2006.p.63-76. 48. Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999;281:10148. 49. Centers for Disease Control and Prevention [CDC]; American Thoracic Society. Update: fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations: United States, 2001. Am J Respir Crit Care Med 2001;164:1319-20. 50. Stout JE, Engemann JJ, Cheng AC, Fortenberry ER, Hamilton CD. Safety of 2 months of rifampin and pyrazinamide for treatment of latent tuberculosis. Am J Respir Crit Care Med 2003;167:824-7. 51. Jasmer RM, Saukkonen JJ, Blumberg HM, Daley CL, Bernardo J, Vittinghoff E, et al. Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial. Ann Intern Med 2002;137:640-7. 52. Centers for Disease Control and Prevention [CDC], American Thoracic Society. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection-United States, 2003. MMWR Morb Mortal Wkly Rep 2003;52:735-9. 53. Gao XF, Wang L, Liu GJ, Wen J, Sun X, Xie Y, Li YP. Rifampicin plus pyrazinamide versus isoniazid for treating latent tuberculosis infection: a meta-analysis. Int J Tuberc Lung Dis 2006;10:1080-90.

54. Jasmer RM, Daley CL. Rifampin and pyrazinamide for treatment of latent tuberculosis infection: is it safe? Am J Respir Crit Care Med 2003;167:809-10. 55. Centers for Disease Control. National Consensus Conference on Tuberculosis. Preventive treatment of tuberculosis. Chest 1985;87[Suppl2]:128-32. 56. Pande JN, Singh SPN, Khilnani GC, Khilnani S, Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax 1996;51:132-6. 57. Taneja DP, Dalip K. Study of hepatotoxicity and other side effects of antitubercular drugs. J Indian Med Assoc 1990; 88:278-9. 58. Gronhagen-Riska C, Hellstrom PE, Froseth B. Predisposing factors in hepatitis induced by isoniazid rifampin treatment of tuberculosis. Am Rev Respir Dis 1978;118:461-6. 59. Purohit SD, Gupta PR, Sharma TN, Gupta DN, Chawla MP. Rifampicin and hepatic toxicity. Indian J Tuberc 1983;30: 107-9. 60. Mehta S. Malnutrition and drugs: clinical implications. Dev Pharmacol Ther 1990;15:159-65. 61. Dutt AK, Moers D, Stead WW. Short-course chemotherapy for tuberculosis with mainly twice-weekly isoniazid and rifampin. Community physicians’ seven-year experience with mainly outpatients. Am J Med 1984;77:233-42. 62. Anonymous. Short-course chemotherapy in pulmonary tuberculosis. A controlled trial by the British Thoracic and Tuberculosis Association. Lancet 1975;1:119-24. 63. Bothamley GH. Treatment, tuberculosis, and human leukocyte antigen [editorial]. Am J Respir Crit Care Med 2002;166:907-8. 64. Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 2002;166:916-9. 65. Gurumurthy P, Krishnamurthy MS, Nazareth O, Parthsarathy R, Sarma GR, Somasundaram PR, et al. Lack of relationship between hepatic toxicity and acetylator phenotype in three thousand South Indian patients during treatment with isoniazid for tuberculosis. Am Rev Respir Dis 1984;129:58-61. 66. Singh J, Garg PK, Thakur VS, Tandon RK. Antitubercular treatment induced hepatotoxicity: does acetylator status matter? Indian J Physiol Pharmacol 1995;35:43-6. 67. Sim E, Payton M, Noble M, Minchin R. An update on genetic, structural and functional studies of arylamine Nacetyltransferases in eucaryotes and procaryotes. Hum Mol Genet 2000;9:2435-41. 68. Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 2003;37:924-30. 69. Cho HJ, Koh WJ, Ryu YJ, Ki CS, Nam MH, Kim JW, et al. Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis [Edinb] 2007;87:551-6.

Antituberculosis Treatment Induced Hepatotoxicity 70. Ohno M, Yamaguchi I, Yamamoto I, Fukuda T, Yokota S, Maekura R, et al. Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity. Int J Tuberc Lung Dis 2000;4:256-61. 71. Huang YS, Chern HD, Su WJ, Wu JC, Lai SL, Yang SY, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology 2002;35:883-9. 72. Vuilleumier N, Rossier MF, Chiappe A, Degoumois F, Dayer P, Mermillod B, et al. CYP2E1 genotype and isoniazidinduced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol 2006;62:423-9. 73. Roy B, Chowdhury A, Kundu S, Santra A, Dey B, Chakraborty M, et al. Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 ‘null’ mutation. J Gastroenterol Hepatol 2001;16:1033-7. 74. Sun F, Chen Y, Xiang Y, Zhan S. Drug-metabolising enzyme polymorphisms and predisposition to antituberculosis druginduced liver injury: a meta-analysis. Int J Tuberc Lung Dis 2008;12:994-1002. 75. Wong WM, Wu PC, Yuen MF, Cheng CC, Yew WW, Wong PC, et al. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology 2000;31:201-6. 76. Ungo JR, Jones D, Ashkin D, Hollender ES, Bernstein D, Albanese AP, et al. Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus. Am J Respir Crit Care Med 1998;157:1871-6. 77. Kwon YS, Koh WJ, Suh GY, Chung MP, Kim H, Kwon OJ. Hepatitis C virus infection and hepatotoxicity during antituberculosis chemotherapy. Chest 2007;131:803-8. 78. Mehta S, Nain CK, Sharma B, Mathur VS. Metabolism of sulfadiazine in children with protein-calorie malnutrition. Pharmacology 1980;21:369-74. 79. Buchanan N, Eyberg C, Davis MD. Isoniazid pharmacokinetics in kwashiorkor. S Afr Med J 1979;56:299-300. 80. Rugmini PS, Mehta S. Hepatotoxicity of isoniazid and rifampicin in children. Indian Pediatrics 1984;21:119-24. 81. Seth V, Beotra A. Hepatic function in relation to acetylator phenotype in children treated with antitubercular drugs. Indian J Med Res 1989;89:306-9. 82. O’Brien RJ, Long MV, Floy SC, Lyle MA, Snider DE Jr. Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis. Pediatrics 1983;72:491-9. 83. Visudhiphan P, Chiemchanya S. Evaluation of rifampicin in the treatment of tuberculous meningitis in children. J Pediatr 1975;87:983. 84. Kumar A, Misra PK, Mehotra R, Govil YC, Rana GS. Hepatotoxicity of rifampin and isoniazid. Is it all drug induced hepatitis? Am Rev Respir Dis 1991;143:1350-2. 85. Sarda P, Sharma SK, Mohan A, Makharia G, Jayaswal A, Pandey RM, et al. Acute viral hepatitis confounds

86.

87.

88.

89.

90. 91.

92.

93.

94.

95.

96.

97.

98.

795

antituberculosis treatment induced hepatotoxicity in developing countries. Indian J Med Res 2008 [in press]. Singh J, Garg PK, Tandon RK. Hepatotoxicity due to antituberculosis therapy. Clinical profile and reintroduction of therapy. J Clin Gastroenterol 1996;22:211-4. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al. American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603-62. Migliori GB, Raviglione MC, Schaberg T, Davies PD, Zellweger JP, Grzemska M, et al. Tuberculosis management in Europe. Task Force of the European Respiratory Society [ERS], the World Health Organization [WHO] and the International Union Against Tuberculosis and Lung Disease [IUATLD] Europe Region. Eur Respir J 1999;14:978-92. Chang KC, Leung CC, Yew WW, Tam CM. Standard antituberculosis treatment and hepatotoxicity: do dosing schedules matter? Eur Respir J 2007;29:347-51. Epub 2006 Sep 27. World Health Organization. Adverse drug reaction terminology. Geneva: World Health Organization; 1979 World Health Organization, Stop TB Department. Treatment of tuberculosis: guidelines for national programmes. Third edition. Geneva: World Health Organization;2003. Enarson DA, Rieder HL, Arnadottir T, Trébucq A. Management of tuberculosis. A guide for low income countries. Fifth edition. Paris: International Union Against Tuberculosis and Lung Disease; 2000. Szklo A, Mello FC, Guerra RL, Dorman SE, Muzy-de-Souza GR, Conde MB. Alternative anti-tuberculosis regimen including ofloxacin for the treatment of patients with hepatic injury. Int J Tuberc Lung Dis 2007;11:775-80. Teleman MD, Chee CB, Earnest A, Wang YT. Hepatotoxicity of tuberculosis chemotherapy under general programme conditions in Singapore. Int J Tuberc Lung Dis 2002;6:699705. Tahaoglu K, Atac G, Sevim T, Tarun T, Yazicioglu O, Horzum G, et al. The management of anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberc Lung Dis 2001;5:65-9. Dossing M, Wilcke JT, Askgaard DS, Nybo B. Liver injury during antituberculosis treatment: an 11-year study. Tuber Lung Dis 1996;77:335-40. Sarda P. Reintroduction of antituberculosis drugs in anti-TB drugs induced hepatitis. MD Thesis. New Delhi: All India Institute of Medical Sciences; 2006. Durand F, Bernuau J, Pessayre D, Samuel D, Belaiche J, Degott C, et al. Deleterious influence of pyrazinamide on the outcome of patients with fulminant and subfulminant liver failure during anti-tuberculosis treatment including isoniazid. Hepatology 1995;21:929-32.

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Surgery for Pleuropulmonary Tuberculosis

55

Arvind Kumar, D Dilip, Abha Chandra

INTRODUCTION Till the time effective antituberculosis treatment was available in the middle of the twentieth century, surgery was the only therapeutic option for pulmonary tuberculosis [TB]. Several operations were devised and practiced with the aim of controlling spread of the disease and promoting healing of the lesions. With the advent of effective antituberculosis treatment, there has been a gradual decline in the need for surgical intervention in patients with pulmonary and pleural TB. The human immunodeficiency virus [HIV] infection and acquired immunodeficiency syndrome [AIDS] pandemic has resulted in the resurgence of TB worldwide. Furthermore, multidrug-resistant TB [MDR-TB] is a major public health problem in several parts of the world. Because of all these factors, there has been renewed interest in surgery. Presently, there has been an increase in the number of patients with pulmonary and pleural TB requiring surgical intervention for diagnostic or therapeutic purposes. This chapter deals with the role of surgery in the management of pleuropulmonary TB. Although the emphasis will be on the operative methods used currently, the history of development of various surgical procedures for TB has also been described. Tuberculosis of the vertebra and the oesophagus belongs to the domain of orthopaedics and gastrointestinal surgery and will not be discussed here. The reader is referred to the chapters “Skeletal tuberculosis” [Chapter 23] and “Abdominal tuberculosis” [Chapter 19] for more details.

SURGERY IN THE DIAGNOSIS OF TUBERCULOSIS Inspite of the advances in modern methods of imaging and diagnosis, a definitive diagnosis of pleural and pulmonary TB is not possible in several patients. In this setting, surgery is often performed to obtain tissue specimen to confirm the diagnosis and exclude underlying malignancy. In the series reported by Ishida et al (1), 36 patients who presented with a solitary pulmonary nodule on the chest radiograph underwent surgery for the confirmation of diagnosis. Pre-operatively, lung cancer was initially suspected in 21 [58%] of these patients. The histopathological diagnosis revealed pulmonary tuberculoma in these patients. In another retrospective study (2) where thoracotomy was performed to ascertain the aetiological diagnosis and rule out malignancy, 24 of 31 patients [77%] were found to have pulmonary TB. At the Sri Venkateswara Institute of Medical Sciences [SVIMS], Tirupati, during the period 1996 to 2000, 23 patients with a solitary lung lesion in whom TB was suspected preoperatively but diagnostic work-up did not reveal an aetiological clue underwent thoracotomy for the confirmation of diagnosis. Of these patients, 15 [65%] were found to have TB, five were found to have bronchogenic carcinoma and three were found to have a fungal ball [aspergilloma] and definitive treatment could be instituted in all these patients. Video-assisted Thoracoscopic Surgery In a study reported from the All India Institute of Medical Sciences [AIIMS], New Delhi (3), video-assisted thoracoscopic surgery [VATS] was helpful in confirming the

Surgery for Pleuropulmonary Tuberculosis 797 diagnosis of TB in five of the 18 patients with pulmonary pathology, three of the eight patients with mediastinal pathology and one of the five patients with pleural pathology. Importantly, VATS was helpful in providing a definitive diagnosis in all 18 patients with lung pathology, seven of the eight patients with mediastinal lesions and five of the six patients with pleural pathology who would have otherwise undergone diagnostic thoracotomy (3). In another study from Switzerland (4), VATS was useful in confirming TB as the aetiological diagnosis in 10 of the 96 patients [10.4%] in whom the pre-operative diagnoses were lung cancer [n = 4], empyema [n = 2], Pancoast tumour, pericardial effusion, pleural mesothelioma, and mediastinal lymphoma [one patient each]. Similar observations were also reported from Japan (5). Thus, VATS, a minimally invasive procedure has been found to be of great assistance in confirming the diagnosis of TB in recent times. SURGERY IN THE TREATMENT OF ACTIVE PULMONARY TUBERCULOSIS Several surgical procedures have been used for the treatment of active pulmonary TB in the era before the advent of effective antituberculosis treatment. It is likely that several of these so called “historical” procedures may have relevance in the current scenario as well. The Cavernostomy Era During the eighteenth century and the first-half of the nineteenth century, following the Hippocratic principles of laying the abscess cavity open, large TB cavities in the lungs were opened through the thoracic wall [cavernostomy]. The earliest mention of cavernostomy dates back to 1726 (6). Hastings and Stork (7) reported similar procedures with success in 1844. Thereafter, no reports of surgical treatment of pulmonary TB appeared in the literature for the next 40 years. The procedure of cavernostomy was revived in 1938 by Monaldi (8) who introduced a trocar and a cannula into the lung cavity through the chest wall, inserted a catheter and applied suction. Others performed “open cavernostomy” in a staged manner. At first, rib resection was performed and a pack was placed against the parietal pleura for 10 to 14 days to ensure formation of adhesions. In the second stage, the cavity was entered and a large drainage tube was inserted. This procedure invariably caused TB

broncho-pleuro-cutaneous fistula, which would drain indefinitely. These procedures are seldom employed in the current era. The Collapse Therapy Era The period between the eighth decade of the nineteenth century and the fourth decade of the twentieth century marked the era of “bed rest” and “collapse therapy”. Bed rest was introduced by Dettweitter in Germany and Turban in Switzerland around 1880 (9). By decreasing the functional residual capacity of the lung, bed rest therapy was thought to decrease the static tension on the walls of the TB cavities. Bed rest also resulted in a decrease in the dynamic traction on the cavity walls by decreasing the ventilation and increasing blood flow to the apices of the lung. This caused the cavities to collapse and facilitated healing. Good treatment consisted of bed rest round the clock, at least during the first few months of treatment. Exercise was gradually increased as and when the pulmonary lesion began to come under control. Even under the most favourable circumstances, a year of sanatorium treatment was the rule. During this period, an artificial pneumothorax was extensively used by the internists as a treatment for pulmonary TB. The surgeons also became involved later to help in the lysis of intrapleural adhesions so as to enhance the efficacy of pneumothorax (10). The other procedures developed and practiced during this period included thoracoplasty (11-13), phrenic nerve interruption (14), pneumonolysis with plombage and later with pneumothorax (15,16), and minor pulmonary resections and decortication (17). Several patients are living today because they underwent collapse therapy in one or another form in this pre-chemotherapy era. Although most collapse therapy procedures have been abandoned today, some are still in use. The surgeons involved in the treatment of TB patients today should at least be aware of the older procedures and what they had to offer. Collapse therapy was used in about 70 per cent of the sanatorium patients. Only patients with very minimal lesions or those with bilateral extensive lesions that were too advanced for this treatment did not receive collapse therapy. The purpose of collapse therapy was relaxation of the diseased lung, so as to allow the scar tissue produced by the natural healing process a better chance to contract.

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Phrenic Nerve Paralysis The purpose of phrenic nerve paralysis was to relax the lung and also to “rest” it. Following phrenic nerve paralysis, a rise of the ipsilateral hemidiaphragm occurs, reducing the distance between the apex of the lung and its base, and thus, relaxing the diseased portion. Since the excursions of the diaphragm on the paralysed side are reduced, the lung receives more rest. Although numerous enthusiastic reports had appeared at that time, but, it is difficult to evaluate the benefits of phrenic nerve palsy in retrospect (14). Cavities at the base of the lung were thought to have responded more favourably than at any other locations. In the 1930s, this was amongst the commonest operations and many thousand procedures of phrenic nerve paralysis were performed. Pneumothorax The use of an artificial pneumothorax in the treatment of pulmonary TB began in the late nineteenth century and came into wide use between 1920 and 1940. In this procedure, a needle was introduced into the chest cavity and air was slowly introduced into the chest to collapse the lung using a specially designed pneumothorax apparatus. The procedure was repeated at regular intervals until the desired amount of collapse was achieved. If there were no intrapleural adhesions, the pneumothorax relaxed the lung effectively, contraction of scar tissue was promoted and the cavity walls could approximate. The collapse interfered surprisingly little with pulmonary function, even when bilateral pneumothoraces were produced. Once a satisfactory collapse by pneumothorax had been obtained, it was usually continued for two years or sometimes even longer, on an ambulatory basis. When the chest radiographs suggested healing of the TB lesion, refilling of pneumothorax was stopped, and the lung re-expanded. The normal portions of the lung became overinflated to compensate for the contracted disease portions. If all went well, pneumothorax yielded good results but this was true only in a small percentage of patients. In many cases pleural adhesions prevented the induction of pneumothorax leading to its failure. For such cases, division of these adhesions [intrapleural pneumonolysis] was done to help achieve total collapse of the lung. This could be done by performing a thoracotomy or by the closed method by using a thoracoscope as populari-

sed by Jacobeus (10). This method was useful only for thin adhesions which contain only fibrous tissue. Thick adhesions which could contain lung tissue or even an extension of a cavity posed a problem as their division would result in a bronchopleural fistula [BPF] and empyema. The safety of intrapleural pneumonolysis rested largely on the judgement of the surgeon. In case adhesions appeared to be too thick for safe division, it was far better to abandon the attempt at artificial pneumothorax and proceed to perform some other collapse therapy procedure. Recently, there has been renewed interest in the usefulness of artificial pneumothorax in the management of pulmonary TB. In a recent report (18), use of additional artificial pneumothorax was found to be useful in achieving culture negativity in all the new cases with cavitary pulmonary TB [n = 56] compared with 80 per cent observed in the control group [n = 55] who received antituberculosis treatment alone. Similarly, among re-treatment cases, artificial pneumothorax resulted in culture-negativity in 81 per cent patients [n = 53] compared with 40 per cent observed in the control group [n = 50]. The authors concluded that artificial pneumothorax was a useful addition in managing certain patients with cavitary disease, especially those with drug-resistant TB. Pneumoperitoneum For sometime the pneumoperitoneum was used as a method of achieving collapse therapy. With pneumoperitoneum both hemidiaphragms were elevated to some extent contributing to collapse of the lung. The results of pneumoperitoneum alone were unpredictable, and therefore, on several occasions it was combined with phrenic nerve paralysis to achieve a rise of the hemidiaphragm twice as great as could be obtained with either of the procedures alone. The combined procedures were often effective in the closure of a basal cavity. Extrapleural Pneumonolysis When dense intrapleural adhesions prevented the induction of pneumothorax, and thoracoplasty did not seem to be applicable or desirable, an extrapleural pneumonolysis was performed (19). For this procedure a small piece of rib was resected under local anaesthesia between the scapula and the spine. The parietal pleura was exposed and dissected away from the chest wall by

Surgery for Pleuropulmonary Tuberculosis 799 blunt dissection, creating a space between the apex of the lung, covered by both visceral and parietal pleura and the chest wall. The space, thus, created was filled with some material in order to maintain the collapse of the lung so produced. The most common method of maintaining the space was to fill it up with lumps of paraffin. The paraffin eventually became encapsulated with the scar tissue and remained in place permanently without causing any problem. Sometimes the wall of a TB cavity would slough off because of disruption of its blood supply from pleura during extrapleural dissection, creating a BPF and ultimately an empyema. Occasionally, the sloughing of the wall of the TB cavity would lead to the paraffin going into the cavity leading to expectoration of slivers of paraffin, a condition very difficult to treat. The other method of maintaining the lung collapse after an extrapleural pneumonolysis included keeping up air refills in which case the procedure was known as extrapleural pneumothorax (19). This procedure provided more extensive collapse than was possible with paraffin. Like intrapleural pneumonolysis, TB empyema was a problem in extrapleural pneumonolysis also. Sometimes the air in an extrapleural pneumothorax was replaced with sterile mineral oil thus creating an “oleothorax” (19,20). The oil became encapsulated by a thick fibrous capsule. Sometimes there was exudation of lot of fluid into the space, raising its pressure very high and leading to BPF and aspiration of this oil into both the lungs with unfortunate results. Thoracoplasty Thoracoplasty was initially used in the treatment of empyemas in the 1880s (21). In 1885, de Cerenville (22), removed anterior portions of the second and third ribs in an attempt to collapse underlying TB cavities. Other variations of thoracoplasty were also tried but none was sufficiently extensive to achieve collapse of the underlying TB cavities. Brauer (23), is credited to be the first to have advocated extensive rib resections sufficient to collapse the diseased lung. Other workers (23,24), attempted resection of the second through the ninth ribs along with their periosteum and intercostal muscles. However, postoperatively, paradoxical respiration with respiratory insufficiency was a major problem. The mortality rate of this operation was 30 per cent. Brauer (23) recommended staging the procedure and hypothesised that preserving the periosteum and intercostal

muscles would stabilize the chest wall. He also recommended “positive pressure breathing” during the post-operative period to control paradoxical movement of the chest wall and the mediastinum (23,24). In paravertebral thoracoplasty procedure, ribs were resected posteriorly from the angle back to the transverse process (25). This less extensive procedure had much lower mortality than Brauer’s and Friederich’s procedure and was more effective than de Cerenville’s technique (23-25). Alexander is considered to be the father of thoracoplasty in the USA. During his early career, he himself had contracted pulmonary TB, for which he was hospitalized and was advised bed rest. During the hospitalization, he wrote the first English text on the surgical treatment of TB (26). During the subsequent years, he perfected the technique of staged posterior lateral thoracoplasty with an operative mortality of less than two per cent and cavity closure and sputum conversion in over 80 per cent cases (27). Standard thoracoplasty The extent of thoracoplasty will depend on the extent of the disease. An average thoracoplasty may consist of extraperiosteal resection of seven ribs in three stages at two to three weeks intervals [Figure 55.1]. There is some deformity with thoracoplasty but not as much as might be imagined [Figure 55.2]. Since the clavicles hold the shoulder girdles in place, the shoulders remain at the same level. Scoliosis tends to occur with thoracoplasty, the convexity of the curve being towards the thoracoplasty side. However, with proper physical therapy, scoliosis can be minimized and normal arm movement retained. The results of thoracoplasty in the closure of TB pulmonary cavities were good on the whole. In properly selected patients cavity closure and sputum conversion occurred in 80 to 90 per cent of the patients. The use of thoracoplasty for obliteration of the TB empyemas occupying the entire hemithorax usually requires resection of nine or ten ribs. Thoracoplasty is an effective method for obliteration of empyema. Alternative procedures include pleuro-pneumonectomy or decortication. Plombage thoracoplasty During the 1940s it was realized that an excellent collapse of lung could be obtained by stripping the periosteum off the ribs and letting the lung, with parietal pleura, periosteal beds, and intercostal muscles and bundles, fall away from the chest wall. The advantage of this type of collapse over

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Figure 55.1: Thoracoplasty incision [upper panel centre]. Periosteum of the third, fourth and fifth ribs being peeled off [middle panel left]. Third, fourth and fifth ribs being excised [middle panel right, lower panel left]. The third, fourth and fifth ribs have been removed and the chest wall has fallen into the cavity obliterating the pleural space [lower panel right]

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Figure 55.2: Chest radiograph [postero-anterior view] showing thoracoplasty on the left side

extrapleural pneumonolysis is that a more extensive collapse can be obtained, if desired, and reduction in pulmonary function is less, thus, making it suitable for patients who could not tolerate standard thoracoplasty or resection because of age, emphysema, or extensive disease (19). Substances used to maintain the collapse [plombe] included Lucite spheres, Ivalon sponges, pingpong balls, polythene spheres and sheets, and paraffin. The spheres had to be large enough so that they would not slip between the denuded ribs and the moulded paraffin had to be introduced in one mass to fit the extraperiosteal space. The ribs could then be easily spread for the introduction of these materials. The advantage of this procedure over a standard thoracoplasty was that much more collapse could be achieved in one stage procedure. On the other hand, the collapse was not as satisfactory as with standard thoracoplasty, especially for large or medially located cavities. Infection in the extraperiosteal space could occur, and migration of the introduced foreign bodies was often reported. Pressure necrosis of various adjacent structures by Lucite spheres has sometimes produced rather dramatic complications. Experience with paraffin and polythene spheres has been rather good, better than with Lucite spheres or Ivalon sponges. For instance, if the paraffin mass migrates, its

removal and unroofing of the residual space by resecting the original ribs was done. By this time regeneration of ribs from the displaced periosteum would have taken place and would maintain the collapse. Because of the possibility of infection or other complications, some surgeons made it a practice to remove the plombe routinely after several months. Most others removed the plombe only if and when the plombage material migrated. Some others were inclined to remove the plombe electively only in young patients. A major disadvantage of an extraperiosteal plombage was that the subsequent pulmonary resection beneath it, when necessary, was technically, extremely difficult more so than with standard thoracoplasty (19). Recently, a new modality of collapse therapy which uses percutaneous tissue expanders [the Perthese tissue expander] has been described (28). Compared with the classical extrapleural thoracoplasty, long-term complications such as erosion of major vessels, infection, and migration are likely to be less with this technique (28). The Modern Era From 1950s onwards availability of predictably effective antituberculosis treatment coupled with significant advances in the fields of anaesthesiology and intensive care, blood transfusion, and the availability of potent antibiotics opened the way for much wider applications of surgical methods in the treatment of TB. The main operations during this era became resections (24,29,30). Previously proposed operations were improved and modified. It was possible to greatly expand indications for various operations and markedly improve their results. Numerous pulmonary resections and other operations performed to treat TB during the 1950s provided a powerful impetus to the development of thoracic surgery including cardiac surgery. Although fundamentally, no “new” operations were proposed during this period, the previously described operations were improved upon, refined and the surgical outcome improved dramatically making them more acceptable in the treatment algorithms of various patients. Current Status of Surgery Antituberculosis treatment sometimes proves ineffective or of little benefit in controlling the disease. This lack of response may vary from as low as five per cent of all

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patients to as high as 40 to 55 per cent patients (29). This happens in patients with resistant forms of infection or in the treatment of certain forms of TB and its complications or sequelae which are associated with irreversible morphological changes in organs and tissues. Surgery is indispensable in such patients. In combination with chemotherapy, surgery can ensure sufficiently radical removal of localized lesions and save the patients life, halt progression of the disease, create better conditions for reparative processes, restore organ functions and promote complete recovery (29,30). Although, there are conflicting views regarding the exact role of surgery in the overall management of patients with pulmonary TB, most physicians, however, consider the use of surgical methods appropriate in the situations outlined in Table 55.1 (31-35). The presence of a cavitary disease in itself is not an indication for surgery unless it is associated with one of these complications. The relative indications for resection are listed in Table 55.2. Table 55.1: Definite indications for surgery in patients with pleuropulmonary tuberculosis To procure tissue material for confirmation of diagnosis of tuberculosis Multidrug-resistant tuberculosis Complications of tuberculosis Haemorrhage Bronchopleural fistula Empyema Bronchiectasis Tracheal or bronchial stenosis Broncholiths Pulmonary aspergilloma Table 55.2: Relative indications for surgery in patients with pleuropulmonary tuberculosis Destroyed lobe or lung distal to an irreversibly damaged bronchus and subject to repeated tuberculosis or, pyogenic infection An open negative cavity of significant size [> 2 to 3 cm] in a young person A cavity in an immunocompromised host Demonstrable nontuberculous mycobacteria multidrug-resistant organisms in a cavitary disease that can be resected clearly by lobectomy Recurrent sputum positive infection in a given segment or lobe, even though no macroscopic cavity can be demonstrated Asymptomatic peripheral nodule

Preoperative Work-up The patients to be taken up for surgery for chest TB should have reasonably localized disease amenable to surgical resection and they should have adequate cardiopulmonary reserve to undergo the operation safely. The preoperative work-up apart from a chest radiograph includes computed tomography [CT] of the chest, pulmonary function tests and if possible, arterial blood gas analysis. It has been suggested that ventilation perfusion scan should also be done on all these patients as it is useful in determining the extent and the type of resection to be performed. The primary role of the ventilation perfusion scan is to confirm that the regions to be resected are physiologically inert and contributed minimally to the patient’s respiratory capacity. In addition, sometimes, an area which appears normal on chest radiograph and CT may actually have no function on ventilation scan and is best removed than left inside. These patients should also have frequent sputum analysis for smear and culture of mycobacteria. The patients should be reviewed jointly by the physician and the surgeon and they should be started on an intensive drug regimen to achieve sputum negativity or at least reduce the bacterial load to the minimum possible extent before surgery. Ideally, surgery should be performed when the smears and culture have become negative as it has a direct bearing on the incidence of bronchial stump related complications after surgery. Pomerantz et al (31) have reported 65 per cent success in achieving sputum conversion after an average of two and a half months of intensive chemotherapy. Treasure et al (35) also used intensive preoperative chemotherapeutic regimen but reported success in turning sputum negative in much higher number of patients [17 of 19 patients; 90 per cent]. They reported that patients with persistent cavities, or disease affecting multiple segments or a lobe or with total lung destruction were candidates who benefited from surgery. Surgical removal of destroyed lung tissue harbouring a large number of bacilli protected from antibiotics by poor blood supply assists in converting the sputum negative and helps prevent relapse. It is also recommended that bronchoscopy be performed at or before operation to exclude the presence of endobronchial disease at the proposed bronchial resection margin, as its presence will greatly increase the risk of bronchopleural fistula after resection (24).

Surgery for Pleuropulmonary Tuberculosis 803 Preoperative Preparation Nutritional Build up Most of the patients with chest TB would have been ill for a long time and are in a chronically debilitated condition with poor nutritional status. Before taking up for surgery, it is important to build up nutrition of these patients. When possible this should be achieved by enteral means by encouraging high protein and calorie diet. Sometimes, patients may need hyperalimentation. The value of nutritional build up needs to be emphasized as it has a direct bearing on the outcome and the complications after surgery. Patients with anaemia and hypoproteinaemia have uniformly poor outcome after surgery. Incentive Spirometry The outcome after surgery can be improved and the incidence of complications reduced by pre-operative chest exercises in the form of deep breathing and breathholding exercises and incentive spirometry. It is important to explain the value of these simple looking exercises in improving the postoperative outcome to the patient in detail in order to achieve their maximum cooperation and compliance. Several days of such “chest training” helps tremendously in improving the outcome after surgery. Principles of Surgery Double lumen endotracheal tube should be used for anaesthesia in these patients to avoid cross-contamination of the contralateral lung. Patients with TB often have extensive, dense adhesions between pleura and the lung and it may be impossible to find a plane between the pleura and the lung. Additionally, dissecting through the infected material present in the pleural cavity increases the risk of postoperative empyema several folds. Due to these reasons, an extrapleural approach for pneumonectomy has been suggested (36) which decreases the morbidity as well as mortality of this operation. Dehiscence of the bronchial stump leading to BPF and empyema is the most feared and the most common complication after resectional lung surgery for TB with a reported incidence of 25 to 40 per cent (2) in the past. Reinforcement of the bronchial stump by a vascularised tissue like intercostal muscle, pedicled

extrathoracic skeletal muscle [myocutaneous flap using latissimus dorsi or serratus anterior] or omentum has been shown to significantly decrease the incidence of this complication (2,29,34). These should be used in all cases of resectional lung surgery for TB. The aim of surgery in TB is to remove all the diseasebearing lung tissue at the same time preserving as much of normal lung tissue as possible. Sometimes the amount of lung tissue remaining after a resection may not be adequate to fill the entire pleural cavity and may lead to space problems post-operatively. In such cases, a concomitant tailoring thoracoplasty is recommended to reduce the chances of post-operative space problems (29). The exact procedure to be performed may vary from segmental or wedge resection to lobectomy, pneumonectomy or pleuropneumonectomy with or without myoplasty. Multidrug-Resistant Tuberculosis Patients infected with Mycobacterium tuberculosis resistant to rifampicin and isoniazid with or without resistance to other antituberculosis drugs have MDR-TB. Indications for surgery in patients with MDR-TB are listed in Table 55.3. Various procedures performed for patients with MDR-TB have ranged from segmental resection to pleuropneumonectomy. Pomerantz et al (31) in a series of 42 patients with MDR-TB reported one postoperative death secondary to acute respiratory distress syndrome. There were six late deaths, from two months to four years postoperatively, two of which were related to the resistant Mycobacterium tuberculosis infection. Only three patients had persistently positive sputum after surgery and the postoperative sputum smear conversion rate Table 55.3: Indications for surgery in patients with multidrug-resistant tuberculosis Drug resistance so extensive that there is a high probability of failure or relapse Disease sufficiently localized so that the great preponderance of radiographically visible disease could be resected with the expectation of adequate cardiopulmonary reserve after surgery and sufficient drug activity to diminish the mycobacterial burden enough to facilitate probable healing of the bronchial stump after surgery Adapted from reference 29

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was over 90 per cent. There was one late death each due to renal failure, myocardial infarction, drug overdosage and respiratory failure. The major complications were seen in eight patients. Three had wound infection, two had respiratory failure, one patient each had recurrent laryngeal nerve palsy and Horner’s syndrome and one patient had re-exploration for bleeding. Only one patient who underwent completion pneumonectomy developed BPF and remained sputum positive. In the past this subject had undergone lobectomy. As compared to this, in the group of patients with infection due to drugresistant non tuberculous mycobacteria [NTM], eight of the thirty-eight patients operated developed BPF signifying a much higher complication rate in this group. They (31) also reported that among patients with MDRTB requiring pneumonectomy, it was the left side which was affected in over 85 per cent cases [left lung syndrome], whereas in cases with NTM infection, there was an even distribution between right and the left sides. Similar was the experience reported by Ashour et al (37). The exact reason for this preferential destruction of left lung is not known. Whether this is due to the smaller size, more horizontal course of the left main bronchus, more limited peribronchial space, or, other causes is not clear. In a study reported by Jouveshomme et al (38), seven patients underwent collapse therapy with polystyrene sphere plombage for pulmonary MDR-TB. Four patients were infected with multidrug-resistant strains of Mycobacterium tuberculosis, two with Mycobacterium xenopi, one with Mycobacterium avium. All patients were adequately treated before surgery, had extensive, bilateral cavitary disease and were considered unsuitable for resection because of extensive disease or functional respiratory impairment. Six patients had active disease at the time of surgery. Collapse therapy with insertion of six to eighteen spheres resulted in longstanding bacteriological conversion in six patients. Collapse therapy was unilateral in six and bilateral in one. No immediate postoperative complication or death was observed. Hospital stay was short [mean 12 days]. The authors concluded that collapse therapy is a conservative alternative therapy in patients with pulmonary disease caused by multidrug-resistant mycobacteria at high risk of treatment failure and considered unsuitable for pulmonary resection. Kir et al (39) evaluated the results of resectional surgery as an adjuvant therapy in 27 HIV-negative

patients with MDR-TB. The lesions were bilateral in 16 cases, with a preponderance of cavities on one side. Out of 27 cases, five patients had unilaterally destroyed lung; 20 patients underwent pneumonectomy [left side 15, right side 5]. Lobectomy operations included bilobectomy superior [n = 1], right lower lobectomy [n = 2], right upper lobectomy [n = 3], and left upper lobectomy with superior segmentectomy [n = 1]. Because of haemorrhage, two cases who underwent a right and left pneumonectomy, respectively, required revision on the first day. Bronchopleural fistula developed in two patients who underwent left pneumonectomy. Apical residual space was left in one of the three patients who underwent right upper lobectomy. Retreatment protocols resulted in negative cultures and smears in all patients with an average duration of four months [1 to 6 months]. A total of four patients [16%] completed a retreatment period of 18 to 24 months with negative cultures. Only one patient [3.7%] developed relapse in the 17th month of retreatment. In 22 patients, sputum culture became negative and at the time of reporting of this study, they were still on re-treatment. The authors concluded that judicious use of surgery in conjunction with antituberculosis treatment was useful in the treatment of MDRTB. In a retrospective study (40), the role of pulmonary resection as an adjunct in the treatment of MDR-TB was evaluated. Sixty-two patients with MDR-TB were studied, postoperative complications were observed in 16 patients [23%]. There was one postoperative death. Eighteen of 24 patients [75%] who were persistently sputum positive at the time of operation immediately converted to a negative sputum smear and culture status. For all patients who were sputum negative after operation, 80 per cent remained relapse-free by actuarial analysis. In another study (35), 19 of the 59 patients who underwent surgery, were operated for MDR-TB. There were two late deaths: one with progressive disease and massive haemoptysis and the other due to a relapse of MDR-TB. Of the patients operated on as part of their therapeutic regimen for MDR-TB, 17 [89%] of the 19 patients remained culture negative. In a study from South Africa (41) [n = 23] lung resection [pneumonectomy in 17 patients and lobectomy in 6] as an adjunct to antituberculosis treatment was found to be useful in curing 95.6 per cent of patients with MDR-TB. In a study

Surgery for Pleuropulmonary Tuberculosis 805 evaluating the role of adjunctive surgery in patients with MDR-TB in resource-limited setting, such as Lima, Peru [n = 121] (42), sustained culture-negative status was achieved in 74.8 per cent of the survivors and 63 per cent of those followed-up for at least six months after surgery were either cured or probably cured. Similarly, surgical resection [n = 23] was found to be useful in achieving negative sputum smear conversion in all the patients with MDR-TB; one patient had a relapse at one year, in another study (43). Based on the experience reported in the literature about surgery for MDR-TB, it can be concluded that the operation can be performed with a low mortality [below 3%]. However, the complication rates are high with BPF and empyema being the major complications. Sputum positivity at the time of surgery, previous chest irradiation, prior pulmonary resection and extensive lung destruction with polymicrobial parenchymal contamination are the major factors affecting morbidity and mortality. Over 90 per cent of the patients achieve sputum negative status postoperatively. Although operation related mortality is less than three per cent, total deaths due to all causes occur in about 14 per cent patients, which also compares favourably with over 22 per cent mortality due to TB in a similar group of patients treated medically (31). More liberal use of muscle flaps to reinforce the bronchial stump and fill the residual space has helped significantly in reducing the rates of BPF, air leaks and residual space problems. These must be used in patients with positive sputum, when residual post-lobectomy space is anticipated, when BPF already exists pre-operatively or when extensive polymicrobial contamination is present. In patients with NTM infection, the outcome is poorer as compared to patients with resistant Mycobacterium tuberculosis infection. However, these patients should also be operated before the disease causes extensive destruction of the lung or polymicrobial infection, when the incidence of complications becomes very high. Thus, surgery is currently recommended for patients with MDR-TB whose prognosis with medical treatment is poor. It should be performed after minimum of three months of intensive chemotherapeutic regimen, achieving sputum negative status, if possible. The operative risks are acceptable and the long-term survival is much improved than that with continued medical treatment alone. However, for this to be achieved, the

chemotherapeutic regimen needs to continue for prolonged periods after surgery also, probably for well over a year, otherwise recrudescence of the disease with poor survival is a real possibility. SURGERY FOR THE COMPLICATIONS OF TUBERCULOSIS Bronchopleural Fistula Bronchopleural fistula may develop in TB patients following lung resections or spontaneously in association with lung lesions or empyema. Although the incidence of post-resection fistula in patients with TB has come down from as high as 28 per cent, two or three decades ago, to three per cent or less in recent years (41-43), it nevertheless, remains an important problem for the thoracic surgeon. Also, the non-surgical, spontaneously occurring BPF continues to be a problem, responsible for up to 27 per cent of all TB related BPF in one series (45). Spontaneous BPF develops due to liquefaction necrosis and rupture of a sub-pleural TB focus. If the fistula is small and effective chemotherapy is instituted, the leak may close spontaneously and the lung re-expands as the pleural air is absorbed. Unfortunately, such is usually not the case and the leak persists with pneumothorax leading to collapse of the underlying lung and ultimately development of an empyema. It is generally believed that every patient with active pulmonary TB who develops pneumothorax has a BPF. Bronchopleural fistula is a serious condition with a reported mortality of 23.1 per cent, mostly due to aspiration and its complications (44,45). In post-resection BPF, the incidence of this complication is highest during the first three months after surgery, although it can occur at any time even several years after surgery (46,47). The risk of aspiration pneumonia is highest during these first three months and its incidence decreases dramatically if BPF occurs later than three months after surgery (37). Adequate dependent surgical drainage is the basic principle in the treatment of BPF. Drainage alone may result in closure of the fistula in some patients. In patients with non-surgical, spontaneously occurring BPF associated with pulmonary TB, intercostal tube drainage should be complemented with intensive chemotherapy as all of these patients have active, severe, often sputum positive TB infection. The pulmonary disease may vary in severity from an isolated focus to extensive disease

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with cavities or even bilateral disease. Continuous suction should always be applied to the tube thoracostomy and intensive antituberculosis chemotherapy continued. These patients, apart from TB infection, have associated secondary pyogenic infection also which is often polymicrobial and needs antibiotics based on the culture reports. Ihm et al (48) analysed 52 patients with spontaneous BPF of TB aetiology. Of these, 38 patients were treated with intercostal tube drainage with chemotherapy and the lung re-expanded in 28. On analyzing the factors affecting the success or failure of intercostal tube drainage, they found that the size of the BPF that gave rise to pneumothorax was the most important factor. This in turn was influenced by the extent of TB disease in the lung. Patients with extensive parenchymal disease, poorly controlled by drugs, had large fistulae, early development of a restrictive peel on the lung and poor outcome following tube drainage. The initial degree of collapse of the lung had no bearing on the outcome. A short time interval between the onset of pneumothorax and chest tube insertion was a favourable factor, but not dramatically so, and a long interval did not preclude success (48). In patients failing to re-expand the lung following tube drainage, suction and chemotherapy, thoracotomy and decortication, with or without lobectomy or pneumonectomy or pleuropneumonectomy may be required depending upon the findings at surgery. The timing of this procedure is crucial. It is vital to recognize the point at which no further headway is being made with tube thoracostomy and chemotherapy and schedule the patient for definitive surgery straightaway. In the post-resection BPF, tube drainage alone may close the fistula in up to 20 per cent patients (49), otherwise definitive surgical procedure is required. For patients with post-lobectomy or post-pneumonectomy fistula, this may involve dissection down to the lung or the mediastinum to identify the fistula site and its suture ligation. Suture ligation alone has a high failure rate. Use of pedicle muscle flaps has been recommended to fill up the empyema cavity and buttress the suture closure of the fistula site. This has been reported successful in over 75 per cent patients (44). However, it is important that the muscle flap completely fills the empyema cavity. The muscles that have been used include intercostals, pectoralis major, serratus anterior, latissimus, dorsi and sacrospinalis. Indications for myoplasty in the treatment

Table 55.4: Indications for myoplasty in the treatment of bronchopleural fistula A persistent bronchopleural fistula despite an adequate drainage and thoracoplasty When thoracoplasty alone is not considered to be sufficient to close the fistula [due to a large residual cavity] In a situation where myoplasty is likely to obviate the need for a thoracoplasty altogether

of BPF are listed in Table 55.4. For post-pneumonectomy fistulae, reamputation of a long bronchial stump may sometimes affect the closure especially if the BPF has been diagnosed early (49,50). Further resection of the residual lung [site of BPF] or thoracoplasty of various types have also been recommended for treating resistant postresectional BPF but these have the disadvantage of further compromizing the already compensated cardiopulmonary reserve of these patients. On the other hand, myoplasty, can close the fistula without excision of additional lung tissue and with the removal of few, if any, additional ribs. Using the myoplasty techniques, a high rate of BPF closure with a low mortality has been reported (49-51). Tuberculosis Empyema The term “tuberculosis empyema” has been an all inclusive one ranging in meaning from asymptomatic pleural effusion to massive, frankly purulent involvement of the pleura with BPF and trapping of the lung. Simple TB pleural effusion with or without associated parenchymal disease responds rapidly to antituberculosis treatment. Thoracocentesis may be used to confirm the diagnosis or relieve symptoms of dyspnoea due to lung compression. Unfortunately, some patients develop a restricting pleural peel with or without secondary pyogenic infection of the pleural fluid. It is suggested that in these patients, antituberculosis treatment along with antimicrobial therapy [according to culture if possible] should be continued till maximum resolution of the parenchymal disease and associated sepsis is achieved. At that point, an anatomical evaluation of the disease status by a CT scan should be done. In case of a residual cavity with collapsed lung, surgical intervention is indicated and decortication should be performed [Figures 55.3A and 55.3B]. If the underlying lung is grossly diseased or destroyed or fails to expand following

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Figure 55.3A: Chest radiograph [postero-anterior view] showing hydropneumothorax on the right side

Figure 55.3B: Chest radiograph [postero-anterior view] of the same patient after decortication on the right side

decortication, pulmonary resection may also be needed. In these situations also, muscle flaps should be liberally used to obliterate the residual spaces and buttress the bronchial stump to prevent the development of postresection BPF. The use of myoplasty reduces the need for thoracoplasty in many situations or at least reduces the number of ribs that need to be resected in the thoracoplasty.

the dependent position. Once stabilization is accomplished, diagnostic and therapeutic interventions should be promptly performed because recurrent bleeding occurs unpredictably. Early bronchoscopy, preferably during active bleeding, should be performed with three goals in mind: to lateralise the bleeding side, localise the specific site, and identify the cause of the bleeding. In those patients with lateralized or localized persistent bleeding, immediate control of the airway may be obtained during the procedure with topical therapy, endobronchial tamponade, or unilateral intubation of the non-bleeding lung. If bleeding continues but the site of origin is uncertain, lung isolation or use of a doublelumen tube is reasonable, provided that the staff is skilled in this procedure. If the bleeding cannot be localized because the rate of haemorrhage makes it impossible to visualize the airway, emergent rigid bronchoscopy or urgent arteriography is indicated. Numerous reports in the recent past have outlined the value of arteriography and embolization in the management of haemoptysis (5462). Arteriography and embolization should be used emergently for both diagnosis and therapy in patients who continue to bleed despite endobronchial therapy. Mani et al (54) in a series of 37 patients presenting with massive or recurrent haemoptysis of TB aetiology, were able to successfully control the bleeding in all the

Haemoptysis Haemoptysis is a frequent complaint in patients with pulmonary TB. Sometimes, the bleeding may be sudden and large in amount, threatening life of the patient. This topic has been dealt with in the chapter “Complications of tuberculosis” [Chapter 35]. The treatment of massive or life threatening haemoptysis has to be immediate and quick. Medical or expectant treatment is associated with an unacceptably high mortality (52,53). The first priority in treating patients with massive haemoptysis is to maintain the airway, optimize oxygenation, and stabilize the haemodynamic status. The major question to be answered is whether or not the patient should be intubated for better gas exchange, suctioning, and protection from sudden cardiorespiratory arrest. If the bleeding site is known, the patient should be placed with the bleeding lung in

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33 patients where embolization with gelfoam could be performed. In two patients the bronchial artery could not be cannulated and in the remaining two embolization was not performed because the anterior spinal artery was seen to be arising from the bronchial artery trunk. During six months of follow-up, four of these 33 patients had relapse of haemoptysis. Three were treated by reembolization of the abnormal bleeding vessels while one died due to aspiration. They concluded that the bronchial artery embolization is an effective method of treatment for immediate control of life-threatening haemoptysis. Similar experience has been reported by others (55,57,59). Sharma et al (57) have reported the use of an indigenous coil embolization for controlling recurrent, massive haemoptysis secondary to post-TB bronchiectasis. This method is extremely cheap and highly effective. In patients with life-threatening haemoptysis, early operation is considered when bleeding has been localized to one side and embolization is not available or not feasible when bleeding continues despite embolization or it is associated with persistent haemodynamic and respiratory compromise. However, before surgery it should be ensured that the lesion is sufficiently localized to be resectable and the patient’s general condition [cardiopulmonary status] does not contraindicate thoracotomy and pulmonary resection (52,53). For patients in whom bleeding has ceased or decreased, emergent intervention may not be necessary. Surgery is the most definitive form of therapy for patients with haemoptysis because it removes the source of bleeding. Whether to proceed with elective surgery in patients with a major bleed that has stopped or one that is controlled angiographically is a difficult decision. Limited data are available to assist in this decision, even for specific diseases, such as bronchiectasis. Similarly, the long-term course of patients treated with endobronchial tamponade or topical therapy is unknown. For patients with inoperable disease, limited cardiopulmonary reserve or bilateral progressive disease, embolization is the mainstay of treatment and should be pursued vigorously, even repeating it, if necessary. It frequently controls bleeding for prolonged periods. Majority of patients with lifethreatening haemoptysis due to TB have bilateral disease, often with cavitation. Localization of the side and the lobe from which the bleeding is originating is of paramount importance for therapy. Bronchoscopy performed during bleeding is able to localize it in most of the cases. However, it needs to be performed quickly when the patient is actively bleeding.

Foci of Residual Disease With the many effective combinations of antituberculosis agents available presently, there is little, if any, medical indication for removing lung tissue, previously affected by TB as a prophylactic measure. However, sociological and psychological factors may also play an important role in the treatment of TB. There is an evidence to indicate that this type of involvement not only constitutes a continuing threat to the patient but that resection of the affected tissue eliminates this threat, reduces hospitalization and duration of treatment, and is associated with excellent long-term control of disease (52,53). For various reasons, both individual and societal, certain patients are unable to effectively and diligently maintain the drug treatment regimen. The association of antituberculosis drug treatment failure and alcoholism is widely recognized. It is estimated that as many as 40 to 60 per cent of the population of TB sanatoria are alcoholic (52,53). The problem of alcoholism along with its consequences is magnified in the non-hospital environment. Similarly, patients with psychological disorders ranging from psychosis to simple denial of a physical disease state to mental incompetence may be unable to maintain an adequate drug regimen. Resection of TB foci with the potential to recur if the long-term requirements of drug therapy are not met is the logical course if such treatment alleviates or reduces the need for prolonged therapy. Tracheal or Bronchial Stenosis, Broncholiths and Bronchiectasis Tuberculosis is a necrotizing infection, and certain patients, although cured of the infectious process, carry in their lungs the residuum of this destruction. Patients with a destroyed lobe or lung, bronchial stenosis with distal recurrent secondary infection and atelectasis, bronchiectasis with chronic infection and its consequences, and other similar residua may be candidates for operative intervention. These abnormalities are doubtful indications, however, unless associated with significant symptoms that cannot be controlled by current medical modalities. Pulmonary Aspergilloma Pulmonary aspergilloma is often produced in residual cavities of TB origin. This topic has been covered in the

Surgery for Pleuropulmonary Tuberculosis 809 chapter “Complications of tuberculosis” [Chapter 35]. The surgical treatment of aspergilloma is a much debated matter. On the basis of having described its spontaneous lysis in five to fifteen per cent of cases (63), some authors advise an expectant attitude for uncomplicated, asymptomatic cases of aspergilloma while others advise that it is preferable to treat all aspergillus lesions with respect to the future risk of complications (64). If there are accompanying clinical symptoms, and if the patient meets the conditions of operability, it is preferable to undertake surgical resection taking into account the condition of the affected lung. Lobectomy is preferred, although there may also be indications for segmental resection or pneumonectomy depending on the size of the lesion (6466). Another surgical technique used, although only in patients with high operative risk, is simple cavernostomy and extraction of the aspergilloma as well as myoplasty in the treated zone (67). A surgical alternative in cases that precludes operation is intracavitary instillation of antifungal agents (64). In patients with massive haemoptysis, embolization of the bronchial arteries is indicated as a primary recourse before planned surgery. Surgical treatment for aspergilloma demands individual, careful validation because it is a complex pathology with high incidence of post-resection complications. Cold Abscess of the Chest Wall Cold abscesses of the chest wall, though uncommonly encountered in industrialized countries, are common problems in areas where TB is highly endemic (68). Because fine needle aspiration remains an inaccurate diagnostic tool and antituberculosis treatment is not always efficient, chest wall TB cold abscesses remain in most patients a surgical entity. Faure et al (69) described the surgical management of 18 patients with one or more cold abscesses of the chest wall. Before operation, the diagnosis was confirmed by needle aspiration of the abscess only in four patients and presumed in four others. One patient did not undergo operation after a favourable response to medical treatment. In the other patients, an operation was indicated because of lack of response [n = 5] and the absence of diagnosis [n = 12]. Management included adequate debridement and a postoperative antituberculosis treatment regimen with prevention of recurrence in the mind. Follow-up details were available in 11 of the 17 patients undergoing operation. The only patient who required a second operation because of

recurrence at the same location was the one who had refused the antituberculosis treatment after the first surgical procedure. Surgery for Complications Caused by Enlarged Mediastinal Lymph Node Tuberculosis in Children Sometimes, surgical intervention may be required in children with mediastinal lymph node TB for the management of complications caused by the enlarged lymph nodes. Freixinet et al (70) treated six children, aged two months to three years, who required an invasive procedure for the management of complications caused by enlarged mediastinal lymph nodes secondary to TB. Radiological and endoscopic studies revealed bronchial involvement by lymph nodes, with endobronchial granulomas and lobar or pulmonary obstruction in four patients and marked tracheal and oesophageal stenosis produced by extrinsic compression in the remaining two. Histopathological study of the lymph node or bronchial samples from the six patients disclosed granulomas with caseous necrosis and Langhans’ giant cells. All children were treated with a standard six-month drug regimen consisting of isoniazid, rifampicin, and pyrazinamide. Five of the patients underwent thoracotomy for the purpose of nodal curettage or excision. In one, right upper lobectomy and bronchoplasty were necessary. The sixth patient was treated by the endoscopic resection of the granulomas. There was no postoperative morbidity, and radiologic and endoscopic evidence of resolution of the lesions was observed in all the patients. The authors (70) felt that, surgical treatment, when performed as an adjuvant treatment for tracheobronchial complications stemming from mediastinal TB lymphadenitis, results in the resolution of the lesions and has no related morbidity. Surgery for Complications of Previous Surgery Sometimes, plombage therapy can result in long-term postoperative complications. The management of these late complications is challenging and frequently requires surgical intervention. Thomas et al (71) reported an infected axillary sinus tract that discharged balls made of an acrylic resin consisting essentially of polymerized methyl methacrylate [lucite] 45 years following performance of an extraperiosteal pneumonolysis and Lucite ball plombage for collapse therapy of right upper lobe cavitary TB.

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Surgical extraction of the balls was performed, followed by a partial decortication of the lung and intrathoracic transposition of a pectoralis major muscle flap to fill the residual pleural space. Primary healing was attained, and the patient was well 18 months after surgery. Nell et al (72) reported a patient who received a plombage in 1947. The patient was admitted to hospital with hoarseness of voice. A CT of the chest revealed transthoracic penetration of the paraffin plombage with intrusion into the overlying soft tissue. The patient underwent excision and debridement of the paraffin wax mass followed by thoracoplasty. The patient then developed septicaemia and died due to multiple organ failure 23 days after the surgical intervention. Early ablation of plombage should be considered in order to prevent late complications. SURGERY FOR TUBERCULOSIS: INDIAN EXPERIENCE Indian experience regarding the role of surgery in the treatment of TB is summarized in Table 55.5 (73,74). A retrospective analysis of the surgical procedures in 1655

patients in 20 years in a university hospital for thoracic TB revealed that surgery was necessary in 2.2 per cent of all TB patients seen at that centre (73). The most common indications included TB empyema with or without BPF [Table 55.4]. All procedures were performed under the cover of antituberculosis treatment and supportive treatment with the aim of resolution of process, obliteration of the empyema space, control of sepsis and improvement of activity performance. The morbidity was extensive and mortality was high in major procedures. Good results could be obtained in over 92 per cent cases and only 66.2 per cent on major surgery cases. After the advent of drug treatment for pulmonary TB, the operation of thoracoplasty became rare in the developed countries. However, this was not the case in developing countries like India. Dewan et al (75) reported results of thoracoplasty in 139 patients. Indications of surgery were TB empyema [n = 84], pyogenic empyema [n = 33], post-operative empyema with BPF [n = 8], drugresistant pulmonary TB [n = 2] and recurrent haemoptysis [n = 2]. Successful outcome in the form of control of sepsis, closure of BPF, sputum conversion and control of

Table 55.5: Indications for surgery in pleuropulmonary tuberculosis: Indian experience Variable

Tuberculosis empyema with or without bronchopleural fistula ICT drainage Thoracostoma Decortication Thoracoplasty Continuous short tube drainage† Complicated pulmonary tuberculosis Pneumonectomy Lobectomy Segmental wedge resection Thoracoplasty Bullectomy Cold abscess in the chest wall Osteomyelitis of ribs, or sternum Aspergilloma

Lahiri et al (73) [1970-1990] [n = 1655] No. [%]

SVIMS, Tirupati (74)* [1993-2007] [n = 355] No. [%]

1507 [91.0]

206 [58.0]

1507 [91.0] 56 [3.4] 45 [2.7] 6 [0.4] 17 [1.1] 78 [4.7] 35 [2.1] 30 [1.8] 3 [0.2] 10 [0.6] 0 [0] 54 [3.3] 16 [1.0] 0 [0]

206 [58.0] 2 [0.6] 120 [33.8] 5 [1.4] 22 [6.2] 149 [42.0] 40 [11.3] 71 [20.0] 3 [0.8] 2 [0.6] 7 [2.0] 2 [0.6] 7 [2.0] 17 [4.8]

Some patients underwent more than one procedure * Data updated from reference 74 † The intercostal tube was cut short, fixed with a safety pin and left open to atmosphere. This procedure was used in patients who were either unfit, or could not afford major surgery ICT = intercostal tube; SVIMS = Sri Venkateswara Institute of Medical Sciences

Surgery for Pleuropulmonary Tuberculosis 811 haemoptysis was achieved in most cases. There were four deaths in the entire series. The authors concluded that with the persisting problem of pulmonary TB in the developing countries, thoracoplasty is still an operation of continued relevance. Pratap et al (76) described the immediate and long-term results of resectional surgery in patients with pulmonary aspergilloma. In this series (75), morbidity due to complications was 29 per cent and the mortality was under three per cent. REFERENCES 1. Ishida T, Yokoyama H, Kaneko S, Sugio K, Sugimachi K, Hara N. Pulmonary tuberculoma and indications for surgery: radiographic and clinicopathological analysis. Respir Med 1992;86:431-6. 2. Whyte RI, Deegan SP, Kaplan DK, Evans CC, Donnelly RJ. Recent surgical experience for pulmonary tuberculosis. Respir Med 1989;83:357-61. 3. Kumar A, Mohan A, Sharma SK, Kaul V, Parsad R, Chattopadhyay TK, et al. Video assisted thoracoscopic surgery [VATS] in the diagnosis of intrathoracic pathology: initial experience. Indian J Chest Dis Allied Sci 1999;41:5-13. 4. Beshay M, Dorn P, Kuester JR, Carboni GL, Gugger M, Schmid RA. Video thoracoscopic surgery used to manage tuberculosis in thoracic surgery. Surg Endosc 2005;19:13414. Epub 2005 Jun 23. 5. Hosaka N, Kameko M, Nishimura H, Hosaka S. Prevalence of tuberculosis in small pulmonary nodules obtained by video-assisted thoracoscopic surgery. Respir Med 2006;100:238-43. Epub 2005 Jun 16. 6. Barry E. A treatise on a consumption of the lungs. Dublin;1726. 7. Hastings J, Stork R. A case of tuberculous excavation of the left lung treated by perforation of the cavity through the walls of the chest. Med Gaz 1844;5:378. 8. Monaldi V. Tentativi di aspirazione endocavitaria nelle caverne tubercolari del polmone. Lotta Tuberc 1938;9:910. 9. Pratt JH. The evolution of rest treatment of pulmonary tuberculosis. Am Rev Tuberc 1944;50:185-201. 10. Jacobeus C. Ueber laparound thoracoscopy. Beitr Klin Tuberk 1912;25:185. 11. Forlanini C. Zur behandlung der lungenschwind uddurch kunstlich erzeugten pneumothorax. Dtsch Med Wochenschr 1906;32:1401-6. 12. Spengler C. Chirurgische und klimatische behandleung der lungen-schwindtsucht. Vesh Natur forsch [Bremen];1890. 13. Friedrich P. Weitere fragestellungen und winke fur brustwand-tungen mobilisierung. Dtsch Z Chir 1909;100:181. 14. Sauerbruch F. Die chirurgische behandlung der tungentuberkulose. Munch Med Wochenschr 1921;9:261. 15. Stuertz C. Kunstliche zwerchfellaehmung bei swchweren chronischen einseitigen lungenerkrankungen. Dtsch Med Wochenschr 1911;37:2224.

16. Schkabgem G. Kongress der Deutschen Gesellschaft fur Chirurgie zu Berkub. Int Zbl Tuberk Forsch 1907;2:38. 17. Tuffier TL. De la resection du sommet du poumon. Semin Med 1891;11:202. 18. Motus IY, Skorniakov SN, Sokolov VA, Egorov EA, Kildyusheva EI, Savel’ev AV, et al. Reviving an old idea: can artificial pneumothorax play a role in the modern management of tuberculosis? Int J Tuberc Lung Dis 2006;10:571-7. 19. Steele JD. The surgical treatment of pulmonary tuberculosis. Ann Thorac Surg 1968;6:484-502. 20. Graf W. Ueber die thoracoplastische totalausschaltung des spitzentherfeldbereichs der lunge und die klinische auswertung desextrapleuralen Selektivpneumothorax und Oleothorax. Dtsch Med Wochenschr 1936;62:632. 21. Schede M. Die behandlung der empyema. Verhandl Cong Innere Med 1890;9:41-141. 22. de Cerenville. De intervention operatoire dnas les maladies poumon. Rev Med Suisse Rom 1885;5:441-67. 23. Brauer L. Erfahrungen und uberlegungen zur lungen kollapstherapie. Beitr Klin Tuberk 1909;12:49-154. 24. Boyd AD, Crawford BK, Glassman L. Surgical therapy for tuberculosis. In: Rom WN, Garay SM. Textbook of tuberculosis. Boston: Little, Brown and Company; 1996. 25. Wilms M. Die pfeilerresektion der rippen zur verengerung des thorax bei lungentuberkulose. Therap Gegenw 1913;54: 17-24. 26. Alexander J. The surgery of pulmonary tuberculosis. Philadelphia: Lea and Febiger;1925. 27. Alexander J. The collapse therapy of pulmonary tuberculosis. Springfield: Charles C. Thomas;1937. 28. Bertin F, Labrousse L, Gazaille V, Vincent F, Guerlin A, Laskar M. New modality of collapse therapy for pulmonary tuberculosis sequels: tissue expander. Ann Thorac Surg 2007;84:1023-5. 29. Perelman MI, Strelzov VP. Surgery for pulmonary tuberculosis. World J Surg 1997;21:457-67. 30. Olcmen A, Gunluoglu MZ, Demir A, Akin H, Kara HV, Dincer SI. Role and outcome of surgery for pulmonary tuberculosis. Asian Cardiovasc Thorac Ann 2006;14:363-6. 31. Pomerantz M, Madsen L, Goble M, Iseman M. Surgical management of resistant mycobacterial tuberculosis and other mycobacterial pulmonary infections. Ann Thorac Surg 1991;52:1108-12. 32. Pomerantz M, Brown J. The surgical management of tuberculosis. Semin Thorac Cardiovasc Surg 1995;7:108-11. 33. Reed CE, Parker EF, Crawford FA. Surgical resection for complications of pulmonary tuberculosis. Ann Thorac Surg 1989;48:165. 34. Rizzi A, Rocco G, Robustellini M, Rossi G, Della-Pona S, Massera F. Results of surgical management of tuberculosis: experience in 206 patients undergoing operation. Ann Thorac Surg 1995;59:896-900. 35. Treasure RL, Seaworth BJ. Current role of surgery in Mycobacterium tuberculosis. Ann Thorac Surg 1995;59:14059.

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36. Brown J, Pomerantz M. Extra-pleural pneumonectomy for tuberculosis chest. Surg Clin North Am 1995;5:289-96. 37. Ashour M, Pandya L, Mezraqji A, Qutashat W, Desouki M, al-Sharif N, et al. Unilateral post-tuberculous lung destruction: the left bronchus syndrome. Thorax 1990;45:210-2. 38. Jouveshomme S, Dautzenberg B, Bakdach H, Derenne JP. Preliminary results of collapse therapy with plombage for pulmonary disease caused by multidrug-resistant mycobacteria. Am J Respir Crit Care Med 1998;157:1609-15. 39. Kir A, Tahaoglu K, Okur E, Hatipoglu T. Role of surgery in multidrug-resistant tuberculosis: results of 27 cases. Eur J Cardiothorac Surg 1997;12:531-4. 40. van Leuven M, De Groot M, Shean KP, von Oppell UO, Willcox PA. Pulmonary resection as an adjunct in the treatment of multiple drug-resistant tuberculosis. Ann Thorac Surg 1997;63:1368-73. 41. Naidoo R, Reddi A. Lung resection for multidrug-resistant tuberculosis. Asian Cardiovasc Thorac Ann 2005;13:172-4. 42. Somocurcio JG, Sotomayor A, Shin S, Portilla S, Valcarcel M, Guerra D, et al. Surgery for patients with drug-resistant tuberculosis: report of 121 cases receiving community-based treatment in Lima, Peru. Thorax 2007;62:416-21. Epub 2006 Aug 23. 43. Mohsen T, Zeid AA, Haj-Yahia S. Lobectomy or pneumonectomy for multidrug-resistant pulmonary tuberculosis can be performed with acceptable morbidity and mortality: a seven-year review of a single institution’s experience. J Thorac Cardiovasc Surg 2007;134:194-8. 44. Floyd RD, Hollister WF, Sealy WC. Complications in 430 consecutive resections for tuberculosis. Surg Gynecol Obstet 1959;109:467. 45. Kirsh MM, Rotman H, Behrendt DM, Orringer MB, Sloan H. Complications of pulmonary resection. Ann Thorac Surg 1975;20:215-36. 46. Malave G, Foster ED, Wilson JA, Munro DD. Bronchopleural fistula-present-day study of an old problem. A review of 52 cases. Ann Thorac Surg 1971;11:1-10. 47. Hollaus PH, Lax F, el-Nashef BB, Hauck HH, Lucciarini P, Pridun NS. Natural history of bronchopleural fistula after pneumonectomy: a review of 96 cases. Ann Thorac Surg 1997;63:1391-7. 48. Ihm HJ, Hankins JR, Miller JE, McLaughlin JS. Pneumothorax associated with pulmonary tuberculosis. J Thorac Cardiovasc Surg 1972;64:211-9. 49. Ali SM, Siddiqui AA, McLaughlin JS. Open drainage of massive tuberculous empyema with progressive re-expansion of the lung: an old concept revisited. Ann Thorac Surg 1996;62:218-24. 50. Hankins JR, Miller JE, Mclaughlim JS. The use of chest wall muscle flaps to close broncho-pleural fistulas: experience with 21 patients. Ann Thorac Surg 1978;25:491-9. 51. Thourani VH, Lancaster RT, Mansour KA, Miller JI Jr. Twenty-six years of experience with the modified eloesser flap. Ann Thorac Surg 2003;76:401-5; discussion 405-6. 52. Erdogan A, Yegin A, Gurses G, Demircan A. Surgical management of tuberculosis-related hemoptysis. Ann Thorac Surg 2005;79:299-302.

53. Jougon J, Ballester M, Delcambre F, Mac Bride T, Valat P, Gomez F, et al. Massive hemoptysis: what place for medical and surgical treatment. Eur J Cardiothorac Surg 2002;22:34551. 54. Mani S, Mayekar R, Rananavare R, Maniar D, Matthews Joseph J, Doshi A. Control of tubercular haemoptysis by bronchial artery embolization. Trop Doct 1997;27:149-50. 55. Ramakantan R, Bandekar VG, Gandhi MS, Aulakh BG, Deshmukh HL. Massive haemoptysis due to pulmonary tuberculosis: control with bronchial artery embolization. Radiology 1996;200:691-4. 56. Marshall TJ, Flower CD, Jackson JE. The role of radiology in the investigation and management of patients with haemoptysis. Clin Radiol 1996;51:391-400. 57. Sharma S, Kothari SS, Bhargava AD, Dey J, Wali JP, Wasir HS. Transcatheter indigeneous coil embolization in recurrent massive hemoptysis secondary to post-tubercular bronchiectasis. J Assoc Physicians India 1995;43:127-9. 58. Wong KP, Young N, Marksen G. Bronchial artery embolization to control haemoptysis. Australasian Radiol 1994;38:2569. 59. Sharma S, Kothari SS, Rajani M, Venugopal P. Life threatening arterial haemorrhage: results of treatment by transcatheter embolization using home-made steel coils. Clin Radiol 1994;49:252-5. 60. Fartoukh M, Khalil A, Louis L, Carette MF, Bazelly B, Cadranel J, et al. An integrated approach to diagnosis and management of severe haemoptysis in patients admitted to the intensive care unit: a case series from a referral centre. Respir Res 2007;8:11. 61. Lampmann LE, Tjan TG. Embolization therapy in haemoptysis. Eur J Radiol 1994;18:15-9. 62. Bin Sarwar Zubairi A, Tanveer-ul-Haq, Fatima K, Azeemuddin M, Zubairi MA, Irfan M. Bronchial artery embolization in the treatment of massive hemoptysis. Saudi Med J 2007;28:1076-9. 63. Wex P, Utta E, Drozdz W. Surgical treatment of pulmonary and pleuro-pulmonary Aspergillus disease. Thorac Cardiovasc Surg 1993;41:64-70. 64. Torres-Melero J, Torres AJ, Hernando F, Remezal M, Balibrea JL. Surgical treatment of pulmonary aspergilloma. Arch Bronconeumol 1995;31:68-72. 64. Zmeili OS, Soubani AO. Pulmonary aspergillosis: a clinical update. QJM 2007;100:317-34. 65. Freixinet J. Surgical indications for treatment of pulmonary tuberculosis. World J Surg 1997;21:475-9. 66. Lee KS, Kim HT, Kim YH, Choe KO. Treatment of hemoptysis in patients with cavitary aspergilloma of the lung: value of percutaneous instillation of amphotericin B. AJR Am J Roentgenol 1993;161:727-31. 67. Rao RS, Curzon PG, Muers MF, Watson DA. Cavernoscopic evacuation of aspergilloma: an alternative method of palliation for haemoptysis in high risk patients. Thorax 1984;39:394-6. 68. Kuzucu A, Soysal O, Gunen H. The role of surgery in chest wall tuberculosis. Interact Cardiovasc Thorac Surg 2004;3:99103.

Surgery for Pleuropulmonary Tuberculosis 813 69. Faure E, Souilamas R, Riquet M, Chehab A, Le PimpecBarthes F, Manac’h D, et al. Cold abscess of the chest wall: a surgical entity? Ann Thorac Surg 1998;66:1174-8. 70. Freixinet J, Varela A, Lopez Rivero L, Caminero JA, Rodriguez de Castro F, Serrano A. Surgical treatment of childhood mediastinal tuberculous lymphadenitis. Ann Thorac Surg 1995;59:644-6. 71. Thomas GE, Chandrasekhar B, Grannis FW Jr. Surgical treatment of complications 45 years after extraperiosteal pneumonolysis and plombage using acrylic resin balls for cavitary pulmonary tuberculosis. Chest 1995;108:1163-4. 72. Nell H, Buxbaum A, Czedron A, Vetter N. Fatal complication of paraffin plombage after half a century. Wien Klin Wochenschr 1998;110:729-31.

73. Lahiri TK, Agrawal D, Gupta R, Kumar S. Analysis of status of surgery in thoracic tuberculosis. Indian J Chest Dis Allied Sci 1998;40:99-108. 74. Kumar A, Dilip D, Chandra A. Surgery for pleuropulmonary tuberculosis. In: Sharma SK, editor. Tuberculosis. First edition. New Delhi: Jaypee Brothers Medical Publishers; 2001.p.514-9. 75. Dewan RK, Singh S, Kumar A, Meena BK. Thoracoplasty: an obsolete procedure? Indian J Chest Dis Allied Sci 1999;41:838. 76. Pratap H, Dewan RK, Singh L, Gill S, Vaddadi S. Surgical treatment of pulmonary aspergilloma: a series of 72 cases. Indian J Chest Dis Allied Sci 2007;49:23-7.

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DOTS: The Strategy that Ensures Cure of Tuberculosis Patients

56

Thomas R Frieden

INTRODUCTION On March 24, 1997, the Director-General of the World Health Organization [WHO], declared that, “The DOTS strategy represents the most important public health breakthrough of the decade, in terms of lives which will be saved” (1). Yet DOTS is nothing new. In fact, the essential principles of DOTS were first discovered in India at the Tuberculosis Research Centre [TRC] in Chennai [earlier known as Madras] and the National Tuberculosis Institute [NTI], Bengaluru [earlier known as Bangalore], in the 1950s and 1960s. The determination that tuberculosis [TB] patients need not be hospitalized was first proven in Chennai and changed care of TB patients worldwide (2). Use of supervised treatment, now known as directly observed treatment [DOT], in which patients are observed to take their antituberculosis medications, was shown to be essential in India (3). The efficacy of intermittent treatment, with medications given two or three times a week, was also first shown to be effective in India (4). The efficacy of case finding by microscopy among patients attending health services was also demonstrated in India (5,6). By 2002, India had the largest DOTS programme in the world, in terms of number of patients treated annually (7). The five fundamental principles of the WHO-recommended DOTS strategy are: [i] Political will; [ii] Casefinding primarily by microscopic examination of sputa of patients presenting to health facilities; [iii] Shortcourse chemotherapy given under direct observation; [iv] Adequate drug supply; and [v] Systematic

monitoring and accountability for every patient diagnosed (8). In this chapter, the principles, scientific basis, and experience with implementation of DOTS will be reviewed. In addition, the relevance of DOTS in the context of the human immunodeficiency virus [HIV] epidemic, multidrug-resistance and recent epidemiological findings will also be reviewed. Since 1993, India has adapted and pilot-tested the DOTS strategy as the Revised National Tuberculosis Control Programme [RNTCP]. POLITICAL WILL By any measure, the burden of suffering caused by TB in India and elsewhere is staggering. Globally, there are more than nine million cases and 1.7 million deaths from TB in 2006, and nearly 100 million people died of TB in the twentieth century (9,10). In India, 1000 people die from TB every day. Tuberculosis affects young adults disproportionately, and it therefore, leaves more orphans than any other infectious disease, impoverishes families, and undermines economic development (11). Tuberculosis causes nearly one-third of female infertility in India (12), and kills more women of reproductive age than all causes of maternal mortality combined (9). India accounts for nearly 20 per cent of all TB cases in the world and cases may increase in India as the population grows and the HIV epidemic progresses (13). Despite the heavy burden of disease, in many countries TB control efforts are poorly funded and supported. Shortages of drugs and equipment are common and key posts within the TB control programme

DOTS: The Strategy that Ensures Cure of Tuberculosis Patients 815 are often vacant or suffer from low prestige and high staff turnover. It is the responsibility of physicians, as leaders in their communities, to ensure that effective TB control programmes exist, and to support and coordinate their own efforts with those of TB control programmes. Although TB control is a core government function, it cannot be accomplished by any one individual or sector, but requires communication and collaboration between local health authorities, the primary health care system, hospitals, medical schools, private physicians, nongovernmental organizations and others. DIAGNOSIS BY SPUTUM MICROSCOPY OF PATIENTS ATTENDING HEALTH FACILITIES Two important concepts are combined in this aspect of the DOTS strategy. First, that diagnosis should be based primarily on microscopy rather than chest radiograph, clinical examination, or culture, and, second, that casefinding should be done primarily among patients attending health facilities, and not by active case-finding in the community. Figure 56.1 presents the diagnostic algorithm

recommended by WHO (14). Sputum microscopy is a highly specific test and should be the primary tool for diagnosis. In contrast, the unreliability of chest radiograph is well-documented; 30 per cent or more of patients classified as having “active” TB on the basis of chest radiograph, even by experts, are found not to have TB (15-17). Culture, even where available, has a limited role in diagnosis: a decision taken on the basis of the algorithm presented in Figure 56.1 will often be more rapid than one based on culture (18). The technical and logistic requirements for culture make it unsuitable as a primary diagnostic tool in developing countries. In addition to being a specific diagnostic tool, the acid-fast bacilli [AFB] smear correlates with severity of disease, mortality, and infectiousness (19,20). Furthermore, it is a low-cost, appropriate technology which can be done reliably even in remote areas (21). Current technology for serological and amplification tests on sputum samples is more expensive and less informative than the AFB smear and is not of proven utility in TB control. Future developments in this field may facilitate diagnosis, particularly of smear-negative and extra-pulmonary TB cases, and

Figure 56.1: Diagnosis algorithms: standardized management plan for patients with tuberculosis 1 Screening: cough more than 2 to 3 weeks. Diagnosis: clinical signs, symptoms, normal chest radiography 2 Consider other diagnosis TB = tuberculosis; AFB = acid-fast bacilli

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there are circumstances where culture and sensitivity testing can be useful (22). The second component of this aspect of the DOTS strategy is the approach to case-finding. All too often, there are efforts to do massive case-finding for TB. These efforts result in low cure rates (17,19). This is because most patients with active TB seek care, and the few who do not are less likely to complete treatment (18). This was well-documented in India more than 30 years ago: “Even with the present extremely limited and inadequate facilities available for the diagnosis and treatment of the disease, over half of the sputum-positive persons have actually sought assistance at government medical institutions, motivated by their symptoms” (6). Dr Karel Styblo, who developed the DOTS strategy based in large part on the principles discovered in India, wrote about this phenomenon: “Well-organized outpatient chemotherapy, especially if provided free of charge, will attract symptomatic cases from far and wide” (19). Experience with the RNTCP in India demonstrates the validity of both aspects of this diagnostic approach. In the RNTCP, half of all patients with pulmonary TB are diagnosed on the basis of positive sputum smears, as opposed to less than one out of four in the previous programme. Furthermore, in areas where the programme has been successfully operating for several years,

case detection rates have increased steadily as patients learn that effective services are available and seek care at government centres (7). SHORT-COURSE CHEMOTHERAPY GIVEN IN A PROGRAMME OF DIRECTLY OBSERVED TREATMENT This principle also has two aspects, both of which are crucial. The efficacy of short-course, intermittent treatment has been conclusively demonstrated in controlled clinical trials in India and elsewhere (23-33). Short-course treatment has also been documented to be effective for extra-pulmonary TB (34,35). The first series of trials showed that with isoniazid and rifampicin, with or without other drugs, a nine-month course of treatment could be given. The next trials showed that, with addition of pyrazinamide for the first two months, treatment duration could be reduced to six months, but giving pyrazinamide for a longer period of time did not give additional benefit (36). Trials attempting to reduce the length of treatment to below six months have failed, indicating that with the currently available medications no practical regimen of less than six months duration is acceptable for patients with smear-positive TB (37,38). Treatment regimens which are recommended by WHO are presented in Table 56.1 (39). As noted above,

Table 56.1: World Health Organization-recommended treatment regimens Tuberculosis treatment

Tuberculosis patients

Initial phase

Continuation phase

Category I

New smear-positive pulmonary TB; New smear-negative pulmonary TB with extensive parenchymal involvement; concomitant HIV or new cases of severe forms of extra-pulmonary TB Sputum smear-positive relapse; treatment failure; treatment after interruption New smear-negative pulmonary TB [other than in Category I]; new less severe forms of extra-pulmonary TB Chronic [still sputum-positive after supervised re-treatment]; proven or suspected MDR-TB cases

2HRZE [2HRZS] 2H3R3Z3E3 [2H3R3Z3S3]

6HE 4HR 4H3R3

2SHRZE/1HRZE 2S3H3R3Z3E3 /1 H3R3Z3E3 2HRZE 2H3R3Z3E3*

5H3R3E3 5HRE 6HE 4HR 4H3R3*

Category II Category III

Category IV

Specially designed standardized or individualized regimens

The number before the letters refers to the number of months of treatment. The subscript refers to the number of doses per week * Under the Revised National Tuberculosis Control Programme of the Government of India, Category III regimen 2H3R3Z3/4H3R3 has been used with an apparently low failure rate TB = tuberculosis; HIV = human immunodeficiency virus; H = isonaizid; R = rifampicin; Z = pyrazinamide; E = ethambutol; S = streptomycin; MDR-TB = multidrug-resistant tuberculosis Source: reference 39

DOTS: The Strategy that Ensures Cure of Tuberculosis Patients 817 it is now well-documented that intermittent treatment given twice or thrice weekly is as effective as daily therapy. This should not be surprising, since the doubling time of Mycobacterium tuberculosis is 18 to 24 hours, compared with 12 to 20 minutes for most bacteria (40). In fact, in one animal model, intermittent treatment was more effective than daily treatment (41). The recent study of Chaisson et al (30) is of particular note since the regimen which was used is identical to that of the RNTCP of India for new smear-positive patients, i.e., two months of thrice weekly isoniazid, rifampicin, pyrazinamide, and ethambutol, followed by four months of isoniazid and rifampicin thrice weekly. Cure rates were 87 and 81 per cent for HIV uninfected and HIV infected patients, respectively. The lower cure rate in HIV infected patients was a result of deaths from non-TB-associated causes. The authors concluded that, “thrice-weekly, supervised, short-course therapy for TB was highly effective in patients with and without HIV infection. Intermittent therapy was extremely well-tolerated.” However, intermittent treatment should only be given in a programme of direct observation of treatment (42). Drugs can only be effective if they are taken (42,43). Virtually all clinical studies of short-course chemotherapy were conducted using supervised therapy. It can, therefore, be argued that use of unsupervised rifampicincontaining regimens is experimental and potentially dangerous. The DOT is becoming the standard of care for TB (44-46). A large body of evidence has conclusively demonstrated that a large proportion of patients [at least 30%] do not take medications regularly as prescribed, and that it is not possible to predict which patients will not adhere to treatment (42,43,47-49). This observation was first made in TB in India (50). Studies from the TRC, Chennai demonstrated that non-adherence was not related to side effects, dosage, or prior receipt of one year of supervised treatment. Non-adherence was as high with placebo as with active drug. Surprise home visits revealed a much greater degree of non-adherence than pill counts or urine tests. The experience was summarized as follows: “Every effort was made to obtain and keep the patient’s co-operation and much time was spent during several interviews explaining both to the patient and to the family the seriousness of the disease and the necessity for a long-course of chemotherapy. The infectious nature of the disease and the radiographic lesion was demonstrated to the whole family. The patient was warned that he would feel much better after a few

weeks of treatment and that he might be tempted to stop taking his medicine, but that to do so might have very serious consequences. Such instruction was repeated at every monthly examination, and at other visits to the clinic as well as in the patient’s home, by the doctors, by the public health nurses, and by the health visitors. Further, an attempt was always made to get another member of the family to watch the patient swallow the medicine. The explanation was always given in simple language. “Despite this approach, ensuring self-administration was a major problem” (3). Directly observed therapy is the most difficult and the most controversial aspect of the DOTS strategy. It should be clarified that DOTS is the comprehensive fivepoint strategy outlined above, whereas DOT is one essential component of that strategy. Observation must be done by a person who is accessible and acceptable to the patient and who is accountable to the health system (14). In some countries [Tanzania, Cambodia], DOT is given in hospital for the first two months (51,52). In various countries, health staff [Nicaragua (53), China (54), New York City (55)], community volunteers [South Africa (56,57)], members of non-governmental organizations [Bangladesh (58)], religious leaders [Philippines (59)] or others have given DOT. Each community has strengths, and the challenge in implementing this aspect of the DOTS strategy is to identify and enlist the support of these strengths. Even in the unstable environment of a refugee camp, DOT has been shown to be feasible (60). In India, health staff including multi-purpose workers and pharmacists have given DOT, as have Anganwadi workers, Dais, community volunteers, tea vendors, and others (7). Directly observed therapy means more than the mere mechanical procedure of watching patients as they take medications, an approach that it likely to fail. Rather, direct observation succeeds through the building of human bonds between patients and health care workers or community volunteers, and by transmitting recognition of the value of treatment success for patients and their communities. It also implies recognition of the responsibility of the programme and of the community for successful treatment, which is accomplished by providing treatment with respect for the patient, at convenient times, and in appropriate facilities (61). It may be impossible to arrange DOT for some patients. In a well-functioning programme, this should occur in less than 10 per cent of the cases. In these cases,

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the patient may need to be given self-administered treatment which a family member may be able to assist the patient in taking. However, assistance by a family member, as indicated in the study cited above from the TRC, is unreliable. There are no examples of successful large-scale DOTS programmes in which immediate family members have been utilized as the primary DOT providers. Organising DOTS may not be simple, but it is only method which, on a programme basis, can ensure a high cure rate. ADEQUATE SUPPLY OF GOOD QUALITY DRUGS Obviously, for treatment to succeed there must be enough drugs for patients to complete prescribed treatment. In addition, it is important that drugs should be of good quality, with adequate bioavailability. Particular concerns are for the bioavailability of rifampicin in combination tablets, particularly when rifampicin and pyrazinamide are combined, and the stability of ethambutol, which may be compromised by poor quality packaging or excessive humidity during storage. Combination tablets of proven bioavailability have the theoretical advantage of preventing monotherapy. Fixed-dose combination [FDC] tablets incorporate two or more medications into the same tablet and prevent providers and patients from using a single antituberculosis drug. This should reduce the likelihood of development of drug resistance, and should also reduce the likelihood of physician prescription error and patient medication error. The FDCs can also simplify treatment for patients and logistics for programme managers. However, FDCs of low bioavailability could result in treatment failure and drug resistance, and FDCs increase the cost of antituberculosis drugs (14). The benefits of FDCs on a programme basis are difficult to document and, of course, FDCs do not ensure that the drugs will be taken. In India, drugs in the RNTCP are being supplied in blister packs in patient-wise boxes containing the entire course of treatment. In this way, the patient is assured of having drugs available until cure, and no patient can be begun on treatment unless a full supply of drugs is present. SYSTEMATIC MONITORING AND ACCOUNTABILITY Although record-keeping is often seen as unimportant, an effective system of registering patients is the heart of

the DOTS strategy because it ensures accountability. The information system designed by Dr Styblo of the International Union Against Tuberculosis and Lung Disease and recommended by WHO is simple but remarkably robust. This system allows effective programme management as well as operational research (62). At each microscopy centre, a good quality microscope and reagents are supplied, and the laboratory technician is trained, supervised, and included in a quality control network. Every patient whose sputum is examined is recorded in the Laboratory Register. Every patient whose sputum is found to be positive for AFB and started on treatment is recorded in the TB Register, and the outcome of every such patient is recorded. Quarterly reporting of diagnosed cases allows simple but revealing analysis of the descriptive epidemiology of TB. Smear-positive patients are monitored for sputum conversion to negative at the end of the intensive phase of treatment, and the sputum conversion rate is monitored as an early indicator of programme effectiveness. Finally, the outcome of treatment is systematically recorded in one of six categories, which are all strictly defined [Table 56.2]. The global target for cure of new smear-positive patients is 85 per cent or more (8). Information in TB Laboratory Register and the TB Register can be easily checked for internal consistency and consistency between records, and can also be externally verified by reviewing sputum slides, interviewing patients and health workers, and by monitoring consumption of drugs and supplies. RESULTS OF DOTS The DOTS strategy has been implemented successfully in a wide variety of countries and contexts. In the United States, Baltimore demonstrated a marked reduction in case rates despite a high rate of HIV infection with use of DOTS (63). And in New York City, by 1991 half of TB patients were HIV infected and one in five had multidrug-resistant tuberculosis [MDR-TB] (64), but DOTS resulted in a rapid decrease in both TB and in multidrugresistance (65). Murray et al (51) reviewed experience in Malawi, Mozambique and Tanzania, documenting cure rates of 86 to 90 per cent. Effective programmes have been established and have continued to function well even in the context of civil war [Mozambique (51) and Nicaragua (53)]. Application of universal DOT and subsequent adoption of short-course chemotherapy were

DOTS: The Strategy that Ensures Cure of Tuberculosis Patients 819 Table 56.2: World Health Organization-recommended case definitions New case A patient who has never had treatment for TB or who has taken antituberculosis drugs for less than 1 month Relapse A patient previously treated for TB for whom treatment has been successful [i.e., who has been declared cured or who has completed treatment but does not meet the criteria to be classified as cured or as having treatment failure], and is diagnosed with bacteriologically positive [smear or culture] TB Treatment after failure A patient who is started on a re-treatment regimen after having failed previous treatment Treatment after default A patient who returns to treatment, positive bacteriologically, following interruption of treatment for 2 months or more Transfer in A patient who has been transferred from another TB register to continue treatment Multidrug-resistant TB A patient who has active TB with bacilli resistant at least to both rifampicin and isoniazid Chronic case A patient who is sputum-positive at the end of a standard re-treatment regimen Other All cases that do not fit the above definitions Smear-positive pulmonary TB Either: a patient with at least two or more initial sputum smear examinations positive for AFB; or: a patient with at least one sputum smear examination positive for AFB plus radiographic abnormalities consistent with active pulmonary TB as determined by a clinician; or: a patient with at least one sputum smear positive for AFB plus sputum culture positive for Mycobacterium tuberculosis Smear-negative pulmonary tuberculosis A patient with pulmonary TB that does not meet the above definition for smear-positive TB. This group includes cases without smear result, which should be exceptional in adults but are relatively more frequent in children. Treatment outcomes Cure: Patient who is sputum smear-negative in the last month of treatment and on at least one previous occasion Treatment completed: Patient who has completed treatment but who does not meet the criteria to be classified as cured or as having treatment failure Treatment success: Patient who has either been cured or who has completed treatment Treatment failure: Patient who is sputum smear-positive at 5 months or later during treatment. Also a patient who was initially smearnegative before starting treatment and became smear-positive after completing the initial phase of treatment Died: Patient who dies for any reason during the course of treatment Default: Patient whose treatment was interrupted for 2 consecutive months or more Transfer out: Patient who has been transferred to another recording and reporting unit and for whom the treatment outcome is not known TB = tuberculosis; AFB = acid-fast bacilli

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Tuberculosis

associated with a substantial decline in TB in Cuba, to a level below that of many industrialized countries (66). In Beijing, DOT was implemented in 1978, and shortcourse chemotherapy was introduced in 1988. Prevalence of smear-positive TB in Beijing decreased from 127 per 100 000 in 1979 to 16 per 100 000 in 1990, a decrease of 17 per cent annually (54). More recently, a World Bankassisted project in China has had considerable success. New patients were treated with 2[HRZS]3 4[HR]3, and retreatment cases with 2[HRZSE]3 6[HRE]3 (66). More than three million patients have undergone sputum examinations, and by the end of 2002 more than 1.5 million smear-positive patients had been treated, with a cure rate of more than 90 per cent. The failure rate in previously treated patients fell progressively from eighteen to six per cent in the first year of the programme. The programme in China currently covers a population of 700 million (67,68). In the South-east Asia Region, Bangladesh has had good success in DOTS implementation, with coverage of the entire country and a cure rate above 80 per cent (69). In India the RNTCP has obtained overall cure rates of 85 per cent, with some areas consistently achieving cure rates above 90 per cent (70). In addition, DOTS has been shown to be highly costeffective (51,71). MULTIDRUG-RESISTANT AND EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS The emergence of drug resistance is a symptom of ineffective TB control (72). If patients are prescribed appropriate antituberculosis treatment and take this treatment, development of resistance is extremely rare. In contrast, in situations where prescribing practices or case holding or both are poor, drug resistance can emerge. Effective treatment programmes can prevent drug resistance (73,74) and can even result in a decrease in drug resistance if it has emerged; this has been documented in Edinburgh [Scotland] (75), Libya (76), Korea (77), Burkina Faso (78), Beijing (79), Texas [USA] (80), South Africa (81), and New York City [USA] (65). Treatment of MDR-TB is difficult, expensive, often unsuccessful, and should only be undertaken with the appropriate expertise and resources (72). Prevention of the development of drug-resistant TB by ensuring cure of new smear-positive patients is a much higher public health priority than treatment of MDR-TB. This is because a low cure rate among new cases will result in the creation

of drug-resistant cases at a faster rate than these cases can be cured, even if unlimited resources are available. Although treatment of MDR-TB is difficult and expensive, it may be important for TB control in some contexts. For disease control, if multi-drug-resistance is present in congregate facilities [e.g., prisons, hospitals] where immunosuppressed [e.g., HIV infected or malnourished] people are present, it is essential to promptly diagnose and treat patients with MDR-TB or there can be rapid spread of the disease. For patient care, in contexts where resources permit [e.g., targets for case detection and treatment success met and resources in place to continue DOTS implementation], treatment of MDR-TB can be lifesaving and can prevent the further spread of disease. The reader is referred to the chapters “Drug-resistant tuberculosis” [Chapter 49] and “Antituberculosis drugresistance surveillance” [Chapter 50] for details regarding extensively drug-resistant tuberculosis [XDR-TB]. HUMAN IMMUNODEFICIENCY VIRUS Infection with the HIV is the most potent known risk factor for progression to active TB among adults (82). Individuals who are not HIV infected and who become infected with Mycobacterium tuberculosis have approximately a 10 per cent lifetime risk of developing active TB, compared with a risk of 60 per cent or more in persons infected with both HIV and Mycobacterium tuberculosis (83). Among persons with acquired immunodeficiency syndrome [AIDS] who become infected with Mycobacterium tuberculosis, the risk of progression to active TB is very high, and the rate is very fast. In outbreaks of TB in wards for AIDS patients in the United States, the median time from TB exposure to disease was three months, and in some outbreaks more than one-third of exposed patients developed TB (84). The HIV epidemic is a stress test for TB control programmes, and can relentlessly reveal programme weaknesses. Cantwell and Binkin (85) reviewed experience in 20 countries in sub-Saharan Africa representing half of the population and 85 per cent of the reported cases of the region. They (85) found that from 1975 until 1985, case rates decreased by an average of 1.6 per cent per year. After 1985, with an increase in rates of HIV infection, case rates increased by an average of 7.7 per cent per year. Case rates increased approximately twice as fast in countries with high rates of HIV-seropositivity. The increase in case rates after 1985 was much lower in

DOTS: The Strategy that Ensures Cure of Tuberculosis Patients 821 countries with good quality TB control services. The authors (85) concluded that improving quality of national TB programmes “is essential to mitigate the resurgence of TB in the HIV era.” One lesson learned from the unfortunate experience in the United States and elsewhere is that MDR-TB can spread very rapidly among HIV-infected persons who are hospitalized (86-90). This experience has recently been documented in Argentina (91), Italy (92), South Africa (93), Spain (94), and Russia (95). Tuberculosis in HIV infected persons, particularly in patients with advanced HIV-related disease and low CD4+ T-cell lymphocyte counts, tends to be smear-negative, extrapulmonary, and with atypical presentation on chest radiograph and a high [15% to 25%] case fatality rate (96-98). Nevertheless, patients with HIV respond well to appropriate antituberculosis treatment (99,100). Patients with HIV infection and TB disease survive longer if they are given short-course chemotherapy [SCC] with rifampicin-containing regimens compared with patients given conventional treatment (101), and longer still if SCC is given in a programme of DOT (102,103). Tuberculosis appears to hasten the development of AIDS in HIV-infected persons (104,105,106). Use of intermittent treatment for patients with advanced HIV disease and low CD4+ cell counts appears to be associated with an elevated rate of development of rifampin resistance if the patient relapses (107). However, even among severely immunosuppressed HIV infected patients, relapse and development of resistance occurs in fewer than five per cent of patients. The reader is referred to chapters “Drugresistant tuberculosis” [Chapter 49], and “Tuberculosis and human immunodeficiency virus infection” [Chapter 40] for more details. PREVENTION OF NOSOCOMIAL SPREAD OF TUBERCULOSIS AMONG HUMAN IMMUNODEFICENCY VIRUS INFECTED PATIENTS Recommendations on the prevention of nosocomial spread of TB have been published by the US Centers for Disease Control and Prevention (108), but some of these recommendations may be impractical for developing countries. The basic principles of TB infection control, however, are clear and generalizable. In order to prevent nosocomial spread of TB, hospitals located in areas with a high prevalence of both HIV and TB should: [i] develop a plan for TB care and infection control, and assign staff

clear roles and responsibilities for implementing this plan. This plan must include a clear and practical protocol for ensuring that patients who are discharged continue on treatment and complete the course so that they are not admitted again with infectious, possibly drug-resistant TB; [ii] ensure prompt diagnosis; most TB is spread in hospitals by patients whose TB has not been diagnosed and who, therefore, have not begun treatment. Since the radiographic appearance of TB in HIV infected persons is often atypical, in areas of high HIV prevalence, all patients who have chest symptoms should undergo three sputum examinations for AFB which must be performed accurately and reported promptly; [iii] ensure that effective antituberculosis drugs are used, and that the health staff directly observe the patient to ingest every dose. This also means ensuring that a proper history is taken from patients and that patients who have been treated for TB in the past are treated with a more intensive regimen; [iv] keep TB patients in separate wards from HIV infected patients who do not have TB, with separate air supply [e.g., in different wings or buildings rather than on adjacent floors of the same building]. Whenever possible, TB should be diagnosed and treated on an outpatient basis; [v] ensure that TB patients who fail to respond to directly observed antituberculosis treatment are not in proximity to HIV infected persons, including staff and patients with and without TB. This is important because patients who are responding poorly to treatment may harbour drug-resistant strains of Mycobacterium tuberculosis which may spread rapidly among HIVinfected persons; and [vi] take steps to reduce the concentration of airborne Mycobacterium tuberculosis. Risk to patients and staff may be reduced by ensuring that patients cover their mouths when they cough or sneeze, increasing natural sunlight [because the ultraviolet rays in direct sunlight kill aerosolized bacilli], increasing ventilation [e.g., by placing window exhaust fans in rooms where TB patients will be treated], and, possibly, by careful use of upper-room ultraviolet irradiation. Sputum collection should be done outside and away from other people. Tanzania and Malawi have had programmes of DOTS for more than 10 years. Despite high rates of HIV infection, which is present in up to one-third of TB patients, there has been no evidence of an increased rate of relapse among HIV infected patients, and rates of drug resistance remain low (73,74). Avoiding the creation of drug-resistant TB is the best way to prevent the spread of such strains.

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MOLECULAR EPIDEMIOLOGY Molecular tools are being applied to the study of the epidemiology of TB, sometimes with surprising results. One such technology is restriction length polymorphism analysis [RFLP] using IS6110. The RFLP analysis has revealed that in some areas one-third to one-half of TB cases may result from transmission of infection within the previous two years (109-112). This is a much larger proportion than was expected. There are still important unknowns about both the technology of RFLP (113) and about the molecular epidemiology of TB in developing countries. In some developing countries the proportion of cases which result from recent transmission has also been found to be higher than expected (114-116). If this is confirmed, then the potential for rapidly reversing the TB epidemic may also be greater than expected (117). GLOBAL EXPANSION OF DOTS: CURRENT STATUS The reader is referred to the chapter “Epidemiology: global perspective” [Chapter 4] for more details. LESSONS LEARNT The technology to control TB has been known for decades, and much of this technology was first established in India. A systematic approach, referred to as the DOTS strategy and being implemented under the RNTCP in India, can double cure rates. Successful implementation of the RNTCP in India could save lives. Success will require active communication, collaboration, and participation on the part of governmental and nongovernmental sectors (118,119). REFERENCES 1. World Health Organization. WHO calls for immediate use of new tuberculosis breakthrough [press release]. WHO/ 24;1997:1-2. Geneva: World Health Organization; 1997. 2. Tuberculosis Chemotherapy Centre, Madras. A concurrent comparison of home and sanatorium treatment of pulmonary tuberculosis in South India. Bull World Health Organ 1959;21:51-144. 3. Fox W. Self-administration of medicaments. A review of published work and a study of the problems. Bull Int Union Tuberc 1961;31:307-31. 4. Tuberculosis Chemotherapy Centre, Madras. A concurrent comparison of intermittent [twice-weekly] isoniazid plus streptomycin and daily isoniazid plus PAS in the domiciliary treatment of pulmonary tuberculosis. Bull World Health Organ 1964;31:247-71.

5. Banerji D, Anderson S. A sociological study of awareness of symptoms among persons with pulmonary tuberculosis. Bull World Health Organ 1963;29:665-83. 6. Baily GVJ, Savic D, Gothi GD, Naidu VB, Nair SS. Potential yield of pulmonary tuberculosis cases by direct microscopy of sputum in a district of South India. Bull World Health Organ 1967;37:875-92. 7. Khatri GR, Frieden TR. Controlling tuberculosis in India. N Engl J Med 2002;347:1420-5. 8. World Health Organization. Framework for effective tuberculosis control. WHO/TB/94.179. Geneva: World Health Organization; 1994. 9. World Health Organization. Global tuberculosis control : surveillance, planning, financing: WHO report 2008. WHO/ HTM/TB/2008.393. Geneva: World Health Organization; 2008. 10. World Health Organization. TB deaths reach historic levels [press release]. WHO/96/22. Geneva: World Health Organization; 1996. 11. World Health Organization. Groups at risk: report on the tuberculosis epidemic, 1996. WHO/TB/96. Geneva: World Health Organization; 1996. 12. Parikh FR, Naik N, Nadkarni SG, Soonawala SB, Kamat SA, Parikh RM. Genital tuberculosis a major pelvic factor causing infertility in Indian women. Fertil Steril 1997;67:497-500. 13. World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO Report 2002. WHO/ CDS/TB/2002.295. Geneva: World Health Organization; 2002. 14. World Health Organization. Treatment of tuberculosis. Guidelines for national programmes. Third Edition. WHO/ CDS/TB/2003.313. Geneva: World Health Organization; 1997. 15. Newell RR, Chamberlain WE, Rigler L. Descriptive classification of pulmonary shadows. A revelation of unreliability in the roentgenographic diagnosis of tuberculosis. Am Rev Tuberc 1954;69:566-84. 16. Garland LH. Studies on the accuracy of diagnostic procedures. Am J Roentgenol Radiol Nucl Med 1959;82:2538. 17. Toman K. Tuberculosis case-finding and chemotherapy. Geneva: World Health Organization; 1979. 18. Urbanczik R. Present position of microscopy and of culture in diagnostic mycobacteriology. Zbl Bakt Hyg 1985;A260:817. 19. Styblo K. Epidemiology of tuberculosis. VEB Gustav Fischer Verlag Jena: 1984. 20. Rouillon A, Perdrizet S, Parrot R. Transmission of tubercle bacilli: the effects of chemotherapy. Tubercle 1976;57:275-99. 21. Shimao T. Tuberculosis case-finding. WHO/TB/82.131. Geneva: World Health Organization; 1982. 22. American Thoracic Society. Rapid diagnostic tests for tuberculosis: what is the appropriate use? Am J Respir Crit Care Med 1997;155:1804-14. 23. Fox W. Whither short-course chemotherapy? Br J Dis Chest 1981;75:331-55.

DOTS: The Strategy that Ensures Cure of Tuberculosis Patients 823 24. Mitchison DA, Nunn AJ. Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986;133:423-30. 25. Hong Kong Chest Service/British Medical Research Council. Five-year follow-up of a controlled trial of five 6-month regimens of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1987;136:1339-42. 26. Tuberculosis Chemotherapy Centre, Madras. Controlled comparison of oral twice-weekly and oral daily isoniazid plus PAS in newly diagnosed pulmonary tuberculosis. Br Med J 1973;2:7-11. 27. Singapore Tuberculosis Service/British Medical Research Council. Five-year follow-up of a clinical trial of three 6month regimens of chemotherapy given intermittently in the continuation phase in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1988;137:1147-50. 28. Cohn LD, Catlin BJ, Peterson KL, Judson FN, Sbarbaro JA. A 62-dose, 6-month therapy for pulmonary and extrapulmonary tuberculosis. Ann Intern Med 1990;112:407-15. 29. Iseman MD, Sbarbaro JA. Short-course chemotherapy of tuberculosis. Hail Britannia [and friends]. Am Rev Respir Dis 1991;143:697-8. 30. Chaisson RE, Clermont HC, Holt EA, Cantave M, Johnson MP, Atkinson J, et al. Six-month supervised intermittent tuberculosis therapy in Haitian patients with and without HIV infection. Am J Respir Crit Care Med 1996;154:1034-8. 31. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 6- and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong: the results up to 30 months. Am Rev Respir Dis 1977;115:727-32. 32. East African/British Medical Research Council Study. Results at 5 years of a controlled comparison of a 6-month and a standard 18-month regimen of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1977;115:3-8. 33. Third East African/British Medical Research Council Study. Controlled clinical trial of four short-course regimens of chemotherapy for two durations in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1978:118:39-48. 34. Balasubramanian R, Ramachandran R. Management of nonpulmonary forms of tuberculosis: review of TRC studies over two decades. Indian J Pediatr 2000;67[Suppl 2]:S34-40. 35. Yuen AP, Wong SH, Tam CM, Chan SL, Wei WI, Lau SK. Prospective randomized study of thrice weekly six-month and nine-month chemotherapy for cervical tuberculous lymphadenopathy. Otolaryngol Head Neck Surg 1997;116:189-92. 36. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 2, 4, and 6 months of pyrazinamide in 6month, three-times-weekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin, and pyrazinamide: results at 30 months. Am Rev Respir Dis 1991;143:700-6. 37. Balasubramanian R, Sivasubramanian S, Vijayan K, Ramachandran R, Jawahar MD, Paramasivan CN, et al. Five-

38.

39.

40.

41. 42.

43.

44.

45. 46.

47. 48.

49.

50.

51.

52.

year results of a 3-month and two 5-month regimens for the treatment of sputum-positive pulmonary tuberculosis in South India. Tubercle 1990;71:253-8. Singapore Tuberculosis Service/British Medical Research Council. Clinical trial of 6-month and 4-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1979;119:579-85. World Health Organization. Treatment of tuberculosis. Guidelines for national programmes. Third edition. Revised June 2004. WHO/CDS/TB/2003.313. Available at URL: http://whqlibdoc.who.int/hq/ 2003/ WHO_CDS_TB_2003. 313_eng.pdf. Accessed on September 25, 2008. North RJ, Izzo AA. Mycobacterial virulence. Virulent strains of Mycobacterium tuberculosis have faster in vivo doubling times and are better equipped to resist growth-inhibiting functions of macrophages in the presence and absence of specific immunity. J Exp Med 1993;177:1723-33. Mitchison DA, Dickinson JM. Laboratory aspects of intermittent drug therapy. Postgrad Med J 1971;47;737-41. Datta M, Radhmani MP, Selvaraj R, Paramasivan CN, Gopalan BN, Sudeendran CR, et al. Critical assessment of smear-positive pulmonary tuberculosis patients after chemotherapy under the district tuberculosis programme. Tuber Lung Dis 1993;74:180-6. Grzybowski S. Drugs are not enough: failure of short-course chemotherapy in a district in India. Tuber Lung Dis 1993;74:145-6. Centers for Disease Control. Initial therapy for tuberculosis in the era of multidrug resistance. Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Morb Mortal Wkly Rep 1993;42[RR7]:1-8. Bayer R, Wilkinson D. Directly observed therapy for tuberculosis: history of an idea. Lancet 1995;345:1545-8. Iseman MD, Cohn DL, Sbarbaro JA. Directly observed treatment of tuberculosis–we can’t afford not to try it. N Engl J Med 1993;338:576-8. Sbarbaro JA. The patient-physician relationship: compliance revisited. Annals of Allergy 1990;64:326-32. Haynes RB, McKibbon KA, Kanai R. Systematic review of randomized trials of interventions to assist patients to follow prescriptions for medications. Lancet 1996;348:383-6. Pablos-Mendez A, Knirsch C, Barr GR, Lerner BH, Frieden TR. Nonadherence in tuberculosis treatment: predictors and consequences in New York City. Am J Med 1997;102:164-70. Fox W. The problem of self-administration of drugs with particular reference to pulmonary tuberculosis. Tubercle 1958;39:269-74. Murray CJL, DeJonghe E, Chum HJ, Nyangulu DS, Salomao A, Styblo K. Cost-effectiveness of chemotherapy for pulmonary tuberculosis in three sub-Saharan African countries. Lancet 1991;338:1305-8. Sovann N. DOTS strategy implementation in a country reestablishing its health infrastructure [abstract]. 19th Eastern Region Conference of the International Union Against Tuberculosis and Lung Disease, Singapore, 5-8 September, 1997.

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Tuberculosis

53. Heldal E, Cruz JR, Arnadottir T, Tardencilla A, Enarson DA. Successful management of a national tuberculosis programme under conditions of war. Int J Tuber Lung Dis 1997;1: 16-24. 54. Zhang LX, Kan GQ. Tuberculosis control programme in Beijing. Tuber Lung Dis 1992;73:162-6. 55. Fujiwara PI, Larkin C, Frieden TR. Directly observed therapy in New York City: history, implementation, results, and challenges. Clin Chest Med 1997;18:135-48. 56. Wilkinson D. High-compliance tuberculosis treatment programme in a rural community. Lancet 1994;343:647-8. 57. Wilkinson D, Davies GR. Coping with Africa’s increasing tuberculosis burden: are community supervisors an essential component of the DOT strategy? Trop Med Internat Health 1997;2:700-4. 58. Chowdhury AMR, Chowdhury S, Islam MN, Islam A, Vaughan JP. Control of tuberculosis by community health workers in Bangladesh. Lancet 1997;350:169-72. 59. Manalo F, Tan F, Sbarbaro JA, Iseman MD. Community-based short-course treatment of pulmonary tuberculosis in a developing nation. Initial report of an eight-month, largely intermittent regimen in a population with a high prevalence of drug resistance. Am Rev Respir Dis 1990;142:1301-5. 60. Miles SH, Maat RB. A successful supervised outpatient shortcourse tuberculosis treatment program in an open refugee camp on the Thai-Cambodian border. Am Rev Respir Dis 1984;130:827-30. 61. Frieden TR, Driver CR. Tuberculosis control: past 10 years and future progress. Tuberculosis 2003;83:82-5. 62. Reider HL, Arnadottir T, Tardencilla Gutierrez AA, Kasalika AC, Salaniponi FL, Ba F, et al. Evaluation of a standardized recording tool for sputum smear microscopy for acid-fast bacilli under routine conditions in low income countries. Int J Tuberc Lung Dis 1997;1:339-45. 63. Chaulk CP, Moore-Rice K, Rizzo R, Chaisson RE. Eleven years of community-based directly observed therapy for tuberculosis. JAMA 1995;274:945-51. 64. Frieden TR, Sterling T, Pablos-Mendez A, Kilburn JO, Cauthen GM, Dooley SW. The emergence of drug resistant tuberculosis in New York City. N Engl J Med 1993;328:521-6. 65. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City - turning the tide. N Engl J Med 1995;333:229-33. 66. Gonzalez E, Armas L, Alonso A. Tuberculosis in the Republic of Cuba: its possible elimination. Tuber Lung Dis 1994;75:18894. 67. China Tuberculosis Control Collaboration. Results of directly observed short-course chemotherapy by 112,842 Chinese patients with smear-positive tuberculosis. Lancet 1996;347:358-62. 68. Dai ZC, Duanmu HJ. Directly Observed Treatment, ShortCourse [DOTS] in China [abstract]. 19th Eastern Region Conference of the International Union Against Tuberculosis and Lung Disease, Singapore, 5-8 September, 1997. 69. Abul KM, Ahsan A. DOTS implementation by Government in Bangladesh [abstract]. 19th Eastern Region Conference of International Union Against Tuberculosis and Lung Disease, Singapore, 5-8 September, 1997.

70. Revised National Tuberculosis Control Programme. RNTCP performance report, India: first quarter, 2003. New Delhi: Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare; 2003. 71. Sawert H, Kongsin S, Payanandana V, Akarasewi P, Nunn PP, Raviglione MC. Costs and benefits of improving tuberculosis control: the case of Thailand. Soc Sci Med 1997;44:180516. 72. Crofton J, Chaulet, Maher D. Guidelines for the management of drug-resistant tuberculosis. WHO/TB/96.210. Geneva: World Health Organization; 1996. 73. Chum HJ, O’Brien RJ, Chonde TM, Graf P, Rieder HL. An epidemiological study of tuberculosis and HIV infection in Tanzania, 1991-1993. AIDS 1996;10:299-309. 74. Glynn JR, Jenkins PA, Fine PEM, Ponnighaus JM, Sterne JA, Mkandwire PK, et al. Patterns of initial and acquired antituberculosis drug resistance in Karonga District, Malawi. Lancet 1995;345:907-10. 75. Crofton J. The contribution of chemotherapy to the control of tuberculosis as a community disease. Thorax 1971;20:49-54. 76. Khalil A, Sathianathan S. Impact of anti-tuberculosis legislation in Libya on the prevalence of primary and acquired resistance to the three main drugs at a major tuberculosis centre. Tubercle 1978;59:1-12. 77. Kim SJ, Bai GH, Hong YP. Drug-resistant tuberculosis in Korea, 1994. Int J Tuberc Lung Dis 1997;1:302-8. 78. Ledru S, Cauchoix B, Yameogo M, Zoubaga A, LamandeChiron J, Portaels F, et al. Impact of short-course therapy on tuberculosis drug resistance in South-West Burkina Faso. Tuber Lung Dis 1996;77:429-36. 79. Zhang LX, Kan GQ, Tu DH, Li JS, Liu XX. Trend of initial drug resistance of tubercle bacilli isolated from new patients with pulmonary tuberculosis and its correlation with the tuberculosis programme in Beijing. Tuber Lung Dis 1995;76:100-3. 80. Weis DE, Slocum PC, Blais FX, King B, Nunn M, Matney GB, et al. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994;330:1179-84. 81. Weyer K, Kleeberg HH. Primary and acquired drug resistance in adult black patients with tuberculosis in South Africa: results of a continuous national drug resistance surveillance programme involvement. Tuber Lung Dis 1992;73:106-12. 82. Selwyn PA, Hartel D, Lewis VA, Schoenbaum EE, Vermund SH, Klein RS, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989;320:545-50. 83. Telzak EE. Tuberculosis and human immunodeficiency virus infection. Med Clin North Am 1997;81:345-60. 84. Dooley SW, Villareno ME, Lawrence M, Salinas L, Anil S, Rullan JV, et al. Nosocomial transmission of tuberculosis in a hospital unit for HIV-infected patients. JAMA 1992;267:2632-4. 85. Cantwell MF, Binkin NJ. Tuberculosis in sub-Saharan Africa: a regional assessment of the impact of the human immunodeficiency virus and national tuberculosis control program quality. Tuber Lung Dis 1996;77:220-6.

DOTS: The Strategy that Ensures Cure of Tuberculosis Patients 825 86. Pearson ML, Jereb JA, Frieden TR, Crawford JT, Davis BJ, Dooley SW, et al. Nosocomial transmission of multidrugresistant Mycobacterium tuberculosis. A risk to patients and health care workers. Ann Intern Med 1992;117:191-6. 87. Centers for Disease Control. Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons Florida and New York, 1988-1991. MMWR Morb Mortal Wkly Rep 1991;40:585-91. 88. Coronado VG, Beck-Sague CM, Hutton MD, Davis BJ, Nicholas P, Villareal C, et al. Transmission of multidrugresistant Mycobacterium tuberculosis among persons with human immunodeficiency virus infection in an urban hospital: epidemiologic and restriction fragment length polymorphism analysis. J Infect Dis 1993;168:1052-5. 89. Small PM, Shafer RW, Hopewell PC, Singh SP, Murphy MJ, Desmond E, et al. Exogenous reinfection with multidrugresistant Mycobacterium tuberculosis in patients with advanced HIV infection. N Engl J Med 1993;328:1137-44. 90. Frieden, TR, Sherman LF, Maw KL, Fujiwara PI, Crawford JT, Nivin B, et al. A multi-institutional outbreak of highly drug-resistant tuberculosis: epidemiology and clinical outcomes. JAMA 1996;276:1229-35. 91. Ritacco V, Di Lonardo M, Reniero A, Ambroggi M, Barrerra L, Dambrosi A, et al. Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires. J Infect Dis 1997;176:637-42. 92. Moro ML, Gori A, Errante I, Infuso A, Franzetti F, Sodano L, et al. An outbreak of multidrug-resistant tuberculosis involving HIV-infected patients of two hospitals in Milan, Italy. Italian Multidrug-Resistant Tuberculosis Outbreak Study Group. AIDS 1998;12:1095-1102. 93. Sacks LV, Pendle S, Orlovic D, Blumberg L, Constantinou C. A comparison of outbreak- and nonoutbreak-related multidrug-resistant tuberculosis among human immunodeficiency virus-infected patients in a South African hospital. Clin Infect Dis 1999;29:96-101. 94. Centers for Disease Control and Prevention. Multidrugresistant tuberculosis outbreak on an HIV ward–Madrid, Spain, 1991-1995. MMWR Morb Mortal Wkly Rep 1996;45:330-3. 95. Drobniewski F, Balabanova Y, Ruddy M, Weldon L, Jeltkova K, Brown T, et al. Rifampin- and multidrug-resistant tuberculosis in Russian civilians and prison inmates: dominance of the Beijing strain family. Emerg Infect Dis 2002;8:1320-6. 96. Perlman DC, el-Sadr WM, Nelson ET, Matts JP, Telzak EE, Salomon N, et al. Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. The Terry Beirn Community Programs for Clinical Research on AIDS [CPCRA]. The AIDS Clinical Trials Group [ATCG]. Clin Infect Dis 1997;25:242-6. 97. Elliot AM, Namaambo K, Allen BW, Luo N, Hayes RJ, Pobce JO, et al. Negative sputum smear results in HIV-positive patients with pulmonary tuberculosis in Lusaka, Zambia. Tuber Lung Dis 1993;74:191-4.

98. Mukadi YD, Wiktor S, Coulibaly IM, Coulibaly D, Mbengue A, Folquet AM, et al. Impact of HIV infection on the development, clinical presentation, and outcome of tuberculosis among children in Abidjan, Cote d’Ivoire. AIDS 1997;11:11518. 99. Small PM, Schecter GF, Goodman PC, Sande MA, Chaisson RE, Hopewell PC. Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection. N Engl J Med 1991;324:289-94. 100. Perriens JH, St. Louis ME, Mukadi YB, Brown C, Prignot J, Pouthier F, et al. Pulmonary tuberculosis in HIV-infected patients in Zaire. N Engl J Med 1995;332:779-84. 101. Okwera A, Whalen C, Byekwaso F, Vjecha M, Johnson J, Huebner R, et al. Randomized trial of thiacetazone and rifampicin-containing regimens for pulmonary tuberculosis in HIV-infected Ugandans. The Makerere University-Case Western University Research Collaboration. Lancet 1994;344: 1323-8. 102. Alwood K, Keruly J, Moore-Rice K, Stanton DL, Chaulk CP, Chaisson RE. Effectiveness of supervised, intermittent therapy for tuberculosis in HIV-infected patients. AIDS 1994;8:1103-8. 103. Alpert PL, Munsiff SS, Gourevitch MN, et al. A prospective study of tuberculosis and human immunodeficiency virus infection: clinical manifestations and factors associated with survival. Clin Infect Dis 1997;24:661-8. 104. Leroy V, Salmi LR, Dupon M, Sentilhes A, Texier-Maugein J, Dequae L, et al. Progression of human immunodeficiency virus infection in patients with tuberculosis disease. A cohort study in Bordeaux, France, 1988-1994. The Groupe d1 Epidemiologie Clinique du Sida en Aquitaine [GESCA]. Am J Epidemiol 1997;145:293-300. 105. Whalen C, Horsburgh CR, Hom D, Lahart C, Simberkoff M, Ellner J. Accelerated course of human immunodeficiency virus infection after tuberculosis. Am J Respir Crit Care Med 1995;151:129-35. 106. Collins KR, Quinones-Mateu ME, Toossi Z, Arts EJ. Impact of tuberculosis on HIV-1 replication, diversity, and disease progression. AIDS Rev 2002;4:165-76. 107. Centers for Disease Control and Prevention. Acquired rifamycin resistance in persons with advanced HIV disease being treated for active tuberculosis with intermittent rifamycin-based regimens. MMWR Morb Mortal Wkly Rep 2002;5:214-5. 108. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities. MMWR Morb Mort Wkly Rep 1994;43[RR-13]:1-132. 109. Small PM, Hopewell PC, Singh SP, Paz A, Personnet J, Rustom DC, et al. The epidemiology of tuberculosis in San Francisco. A population based study using conventional and molecular methods. N Engl J Med 1994;330:1703-9. 110. Alland D, Kalkut GE, Moss AR, McAdam RA, Hahn JA, Bosworth W, et al. Transmission of tuberculosis in New York City. An analysis by DNA fingerprinting and conventional epidemiologic methods. N Engl J Med 1994;330:1710-6.

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111. Frieden TR, Woodley CL, Crawford JT, Lew D, Dooley SW. The molecular epidemiology of tuberculosis in New York City: the importance of nosocomial transmission and laboratory error. Tuber Lung Dis 1996;77:407-13. 112. Strassle A, Putnik J, Weber R, Fehr-Merhof A, Wust J, Pfyffer GE. Molecular epidemiology of Mycobacterium tuberculosis strains isolated from patients in a human immunodeficiency virus cohort in Switzerland. J Clin Microbiol 1997;35:374-8. 113. Fang Z, Forbes KJ. A Mycobacterium tuberculosis IS6110 preferential locus (ipl) for insertion into the genome. J Clin Microbiol 1997;35:479-81. 114. Gilks CF, Godfrey-Faussett P, Batchelor BI, Ojoo JC, Ojoo SJ, Brindle RJ, et al. Recent transmission of tuberculosis in a cohort of HIV-1-infected female sex workers in Nairobi, Kenya. AIDS 1997;11:911-8. 115. Wilkinson D, Pillay M, Crump J, Lombard C, Davies GR,

116.

117. 118.

119.

Sturm AW. Molecular epidemiology and transmission dynamics of Mycobacterium tuberculosis in rural Africa. Trop Med Int Health 1997;2:747-53. Palittapongarnpim P, Luangsook P, Tansuphaswadikul, Chuchottaworn C, Prachaktam R, Sathapatayavongs B. Restriction fragment length polymorphism study of Mycobacterium tuberculosis in Thailand using IS6110 as probe. Int J Tuberc Lung Dis 1997;1:370-6. Kaye K, Frieden TR. The modern epidemiology of tuberculosis. Epidemiol Rev 1996;18:52-63. Frieden TR, Munsiff SS. The DOTS strategy for controlling the global tuberculosis epidemic. Clin Chest Med 2005;26:197205. Frieden TR, Sbarbaro JA. Promoting adherence to treatment for tuberculosis: the importance of direct observation. Bull World Health Organ 2007;85:407-9.

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Directly Observed Therapy

57 Ian Smith

INTRODUCTION Detecting people with active tuberculosis [TB] and achieving high cure rates in these patients is the primary strategy for interrupting transmission of this devastating disease, and is more effective than other control interventions such as bacille Calmette-Guérin [BCG] vaccination and preventive therapy (1). In 2006, TB caused 1.7 million TB, deaths worldwide of which 98 per cent occurred in developing countries (2). Although the incidence of TB is falling in most regions of the world, the total number of new TB cases registered slow increase largely due to the human immunodeficiency virus [HIV] pandemic in Africa, where TB incidence rates are highest (2,3). Results of model programmes in Africa have demonstrated that the introduction of short-course chemotherapy [SCC] is one of the most cost-effective interventions available in primary health care (3-5). Based on these experiences, the World Health Organization [WHO] now advocates DOTS as an essential strategy for TB control, with an emphasis on improving health service performance in the delivery of care to people with TB, rather than blaming the patient for poor compliance. Unfortunately, few National Tuberculosis Programmes [NTPs] in developing countries have been able to achieve and sustain the global TB control targets first promoted by WHO in 1991 (6): detecting at least 70 per cent of sputum smear-positive cases and achieving a cure rate of at least 85 per cent among those cases. These targets were subsequently re-affirmed at the 53rd World Health Assembly in 2000 (6). By 2006, DOTS has been implemented in 184 countries. Case detection rates followed;

from 11 per cent in 1995 to over 61 per cent by 2006 (2,3). The global treatment success rate had reached 84.7 per cent by 2005 (2,3). There is clearly a need to rapidly expand DOTS. WHAT IS DIRECTLY OBSERVED THERAPY? Directly Observed Therapy [DOT] has been widely advocated as a tool for achieving compliance with treatment for patients with TB for many years. Although definitions of DOT vary, in essence, it refers to the act of a responsible observer holding the drugs and observing each administration (7). Morse (8) further defines the observer as a health care worker or a trained lay person. Use of the terms DOT and DOTS interchangeably has led to some confusion. For the purpose of this discussion, and in general, the term DOT refers to the specific activity of directly observing therapy, i.e., watching the patient taking his or her treatment. On the other hand, DOTS is a “brand name” for effective TB control and incorporates the five essential elements promoted by WHO (9): [i] political commitment; [ii] passive case-finding by sputum smear examination; [iii] standardized regimens of SCC with a priority for infectious cases, given under direct observation; [iv] a continuous and uninterrupted supply of medicines; and [v] a cohort reporting system to monitor the outcome of treatment. These have been further simplified to funding, microscopes, observers, medicines, and reporting books (10). COMPLIANCE, ADHERENCE OR CONCORDANCE? With the emphasis on a high case-detection and cure rates as the main objectives of TB control, and awareness that

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low cure rates can lead to an increased prevalence of drug-resistant TB and may increase the overall incidence of TB, it is not surprising that investigations of compliance feature prominently in sociological studies relating to TB. Numerous studies over the years have documented the poor treatment success rates achieved in many TB programmes all over the world, including India (11-13). Although compliance is frequently thought of in terms of the patient, Wallace Fox (14,15) identified doctor compliance as an issue to be considered. He showed that treatment failure was commonly attributable to the failure of physicians to adhere to agreed policies and principles of therapy, such as duration of therapy, treatment regimen, and hospitalization. Banerji (16) echoes the concern that compliance is all too frequently a form of ‘victim blaming’, with patient as victim. He identifies health workers and managers as the main culprits, because of their failure to appropriately diagnose patients with TB, their inability to implement and maintain effective TB programmes, and their dogmatic and aggressive attitudes towards patients who discontinue treatment. A clear example of poor doctor compliance is provided by Uplekar and Rangan (17) who reported a study of 102 private practitioners in Mumbai. These doctors (17) used 10 different drug combinations in 80 different regimens of varying duration. This example becomes more salient when combined with the fact that India accounts for 20 per cent of the world’s estimated incident TB burden (2) and nearly half of India’s TB patients seek care in the private sector (18). This form of poor compliance is not only reflected in the treatment of patients, but also in the lack of ability to gather standard monitoring and evaluation data from the private sector (19). A third level of compliance is illustrated by Grange and Festenstein (20), who describe national non-compliance. This lack of political commitment is demonstrated by countries failing to adopt or adequately fund effective TB control measures. Compliance must, therefore, be considered in terms of the social, cultural and economic context of the community, and is influenced by political stability, favourable health strategies, standardized control policies, a healthy infrastructure, trained and supervised staff, public education and community participation. Sumartojo (21) finds compliance a pejorative expression, carrying the unfortunate connotation of a docile and passive patient, yielding, submissive and subservient to

the will of the provider. She (21) suggests “adherence” as an alternative term, reflecting the active role of the patient in the management of their illness. More recently, the term “concordance” has been suggested, to reflect a relationship between the patient and prescriber, based on exchange of information, negotiation and co-operation, and expressing agreement and harmony (22). In that spirit, this chapter will henceforth use the term concordance. Default is an equally unpopular word–also implying a moral judgement. Rouillon (23) points out that to default is a natural phenomenon, and “the normal sensible person is the one who defaults”. It is the abnormal, perhaps obsessive, individual who continues to take medication for months after he or she feels better! She (23) defines default as “an omission on the part of the patient or services, an omission which necessitates a corrective intervention, in the interests of the patient and/or in those of the community”. All too often the term is used for the patient rather than the services! Fortunately, there are those who continue to remind us that the patient is not the main culprit; Banerji (16) uses his definition of defaulter: “anyone whose conduct with regard to treatment is contrary to his own good, or to that of society, or to both”, to mark out health administrators as the main problem. The factors that influence concordance with treatment are diverse [Table 57.1]. Some are patient characteristics, including health beliefs, demographic factors, and cultural influences. Others relate to the nature of the health services, for example, accessibility and appropriateness of health facilities, treatment regimens, and attitudes of health workers. Factors in the make up of society, can also be of importance, for example the socio-economic status of the community, and political stability. Finally, environmental factors may adversely affect treatment concordance; mountains, rivers, monsoons, poor roads and snow can all seriously interrupt treatment supplies, and prevent patients from reaching health services. Although many studies have tended to focus on demographic factors, it is clear that health beliefs and quality of services are two, perhaps more important, determinants. An in-depth study from Wardha district in Maharashtra State, India, demonstrated the influence of health motivation, perceived severity of disease, presence of social support, and satisfaction with the health care provider on treatment concordance (24).

Directly Observed Therapy 829 Table 57.1: Factors influencing concordance with treatment The patient Demographic Age Marital status Ethnic group Cognitive/Affective Knowledge about tuberculosis and treatment Previous experience of taking medicines Feeling better/feeling worse/feeling no better Perceived severity of symptoms Cultural Health beliefs Decision making power Family and social support Adverse events [e.g., death in the family] Contrary advice Others Substance abuse Disease [e.g., HIV/AIDS] Pregnancy The heath service National treatment policy Quality of health service Attitudes of health workers Adverse effects of drugs Availability of drugs Delivery of drugs to patients Follow-up of late patients Availability of alternative sources of treatment Society Socio-economic status of the community Migration Educational opportunities Social and political stability The environment Distance Season Methods of transport HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome

Any assessment of causes of default must take into account the influence of bias. Many published reports on treatment outcome come from programmes of operational research, which tend to achieve good results. Studies of concordance from such programmes achieving

80 per cent treatment success or higher must be interpreted with caution, as the factors influencing concordance in the small proportion of patients defaulting from treatment may be quite different from programmes achieving poor cure rates. It might be assumed that in programmes achieving high cure rates, the proportion of patients defaulting due to social problems is high. In contrast, the main factor influencing treatment concordance in programmes with poor cure rates is probably the quality of the health services. IS DIRECTLY OBSERVED THERAPY THE ONLY STRATEGY FOR IMPROVING TREATMENT CONCORDANCE? The DOT is not the only method used for improving concordance with treatment. Many other interventions have been promoted, and are summarized in Table 57.2. However, few of these have been rigorously evaluated, and a systematic review of different approaches to promote adherence to TB treatment was only able to find evidence for following methods; reminder cards, monetary incentives, health education, and intensive supervision of staff (25). The many different approaches to improving treatment concordance can also be categorized as policing, manipulating, exhorting and empowering. Policing methods include enforced hospitalization (26) and involuntary detention. Some methods are highly manipulative and ethically questionable, for instance notifying community leaders, particularly in a culture where TB carries a stigma. Exhortation, including health education for patients (27) and supervision of health workers (28) is of value, but these approaches alone generally do not achieve satisfactory cure rates. Empowering strategies, such as providing a flexible and responsive service, developing support groups and social networks, providing education and economic assistance, are less easy to develop within the framework of the existing health services, but provide the key to enabling greater concordance with treatment. Depending on the attitude of the personnel providing DOT, and the extent DOT is adapted to the needs of the patient, this strategy can be a policing or an empowering approach to improving treatment concordance. The relationship between all the factors involved in promoting concordance can be summarized in the form of a simple diagram, known as the “Hold Chain” [Figure 57.1]. Drawing on the model of the “Cold Chain”

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Table 57.2: Interventions designed to improve treatment concordance Treatment Standardized regimens of short-course chemotherapy Intermittent chemotherapy Fixed-dose combination tablets Blister packaging Calender packaging Education Patient counselling Family counselling Mass media health education Incentives Financial rewards to patients Gifts in kind; lottery tickets, meal tickets, bus tickets Loans and economic aid Bond and deposits Prepayment schemes Financial rewards to health workers Micro-credit schemes Operational Directly observed therapy High quality health services; accessible, acceptable and appropriate to needs of individual patients and the local culture Rapid follow up of late patients by health worker or letter Doorstep delivery of medicines Involuntary detention Frequent supervision of health services Community approaches Ex-tuberculosis patients motivating new patients Community volunteers supervising treatment Education of community leaders Social incentives Treatment contracts [verbal or written] Family involvement Support groups, self help groups, and social networks Notification of late patients to community leaders Certificate of treatment completion

promoted by the Extended Programme of Immunization to maintain vaccines at the correct temperature from manufacture to the child, the Hold Chain is visualized as a series of factors which are inextricably linked. The first essential component is a quality health service, which patients trust and use. Low utilization of government health services is common in many developing countries, as patients prefer to use traditional healers or the private sector, both of which may be more accessible

and “user-friendly”. The next key element is an effective regimen, to rapidly and permanently render patients non-infectious, and relieve their symptoms without creating adverse effects. The third link in the chain is DOT, to ensure that patients take treatment until they are cured. However, good drugs can be misused if health workers have not been trained how to use them appropriately, the fourth link, and will be totally useless if the distribution system fails to procure and deliver them in a timely fashion to treatment centres–the fifth link in the chain. The final link is education-a high quality service, good drugs, treatment observers, skilled health workers, and an efficient logistics system will be of little benefit if patients don’t know that medicines for TB are effective and available, and must be taken for a full course of treatment. Such knowledge will spread by word of mouth as patients are treated and cured, but can also be promoted by a programme of health education. Failure to ensure the integrity of any single link will result in a break in the chain, and loss of treatment concordance. The term “Hold” refers not to holding the patient on treatment, but to holding the health services together! Therefore, DOT is one essential link within a combination of factors which together ensure that patients are given the maximum opportunity to achieve a successful outcome of treatment. HISTORY OF DIRECTLY OBSERVED THERAPY The history of DOT presents us with a remarkable global journey, which begins in Europe, and takes us through Asia, America, and Africa, before finally emerging as a truly international approach to improving treatment concordance. Grange (29) suggests that the earliest documented example of DOT for patients with TB comes from the eleventh century, when King Edward, the Confessor would lay hands on the afflicted person and declare “The king toucheth thee, but God healeth thee”. A more conventional form of supervised treatment was introduced in the 1840s, with the establishment of the sanatorium movement in Europe (30). Patients who were admitted to these mountain sanatoria were isolated for long periods of time, and subjected to diverse and disciplined regimens of treatment. An early advocate of supervised therapy and support to the patient wrote in 1904, “In the solution of the TB programme a plan of supervised home relief must play a chief part” (31).

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Figure 57.1: The Hold Chain

The discovery of effective drugs in the 1940’s transformed the management of people with TB. Perhaps because of the long history of sanatorium treatment, the first patients to be treated with streptomycin, and later para-aminosalicylic acid [PAS], were all hospitalized for the full course of treatment (32). The importance of doctor compliance and of mutual support was emphasized even at this early stage in the development of TB treatment; a footnote to the overview of the first three studies of combined chemotherapy praised the participating clinicians thus; “Only by their constant adherence to a centrally devised scheme, and by a most remarkable team spirit on a large scale have these investigations been possible” (32). In the late 1950s the focus shifted to Asia, and Bayer and Wilkinson (33) take the story up from here in their history of DOT. The British Medical Research Council [BMRC] studies conducted by Wallace Fox (34) in Madras demonstrated that hospitalization was not necessary to prevent transmission of disease. These findings led to a shift to ambulatory chemotherapy for people with TB in most parts of the world. However, in an earlier article, Fox (35) had identified the problems of poor compliance with treatment, which later led him to conclude that supervised treatment was essential and feasible (36),

observations that influenced the development of a programme of supervised ambulatory care in Hong Kong (37). The studies from India therefore, provide the earliest example of modern conventional DOT utilising effective treatment to ensure high cure rates in people with TB. However, the evidence that patients taking treatment for TB do not pose a threat to their families and communities was the primary message that came across from the Indian studies, and ambulatory treatment that was rapidly adopted around the developing world was often unsupervised. From Asia we return to Europe, where the principle of supervised treatment was adopted by Stradling and Poole (38,39) in London, and then travel further westwards to America, where the call for supervised treatment was taken up by Sbarbaro (40), which he termed “directly administered” treatment. However, these were lone voices, and the few others who practised supervised treatment usually reserved it for a selected group of patients whom they regarded as most likely to default. This was despite awareness of the difficulties in predicting treatment concordance (41), a finding which was confirmed 30 years later in New York (42). Those who argued for “selective” DOT won through (43), despite repeated calls for universal DOT (44). Even

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though the United States of America [USA] adopted DOT as the standard of care for all people with TB (45), arguments over selective and universal DOT have continued (44,46,47), and consequently has yet to achieve the global targets for TB control. The developed world still has much to learn from developing countries! We return to the 1970s to take up the story of DOT in the developing world. In 1974 WHO published the 9th report of the Expert Committee on Tuberculosis (48), which proposed the use of a supervised regimen of intermittent streptomycin and isoniazid, as a means for ensuring patient compliance. However, the next major step forward in the history of DOT was the development of SCC regimens given under direct supervision in the International Union Against Tuberculosis and Lung Disease [IUATLD] supported programme in Tanzania, which was subsequently expanded to a further six countries in Africa, and to Nicaragua (49). The Tanzania model, developed by Dr Karel Styblo, was based on hospitalization of TB patients for the intensive phase of treatment. The reasons for doing so were significantly different from the early days; the emphasis was now on supervision of therapy, and continuation of treatment until the patient was cured. Over the last two decades, universal hospitalization of patients has been largely abandoned due to a massive increase in the incidence of TB resulting from the acquired immunodeficiency syndrome [AIDS] pandemic, and the inability of the health services to cope with the large number of patients. The principle that has been established is, therefore, not hospitalization, but supervision of drug-taking. The role of Dr Karel Styblo in the development of these innovative programmes cannot be understated. The principles which evolved here were later adapted and promoted by WHO as DOTS, and adopted in places as diverse as China (50), Nepal (51), New York (52), and India (53) as the Revised National Tuberculosis Control Programme [RNTCP] from the early 1990s. We have, therefore, come full circle. The principles of modern TB control first developed in India in the late 1950s have travelled around the world, and finally returned home nearly 40 years later, as DOTS. HOW DOES DIRECTLY OBSERVED THERAPY WORK? It is well recognised that many patients [perhaps 50 per cent] do not take their medication as intended by the

prescribing health worker (54). However, the simple act of observing treatment is clearly not the only factor promoting a positive outcome of treatment. Simply having someone to help and encourage you can be of considerable benefit in promoting treatment concordance. Thomas Frieden, originally working in New York and later with the RNTCP in India, has described the value of the “human bond” between patient and health worker, emphasizing the value of the social support provided by a treatment observer. Parallel studies in the field of maternity care have demonstrated the benefits of a birth attendant to support the mother during labour (55). A more appropriate definition of DOT is, therefore, a strategy to improve treatment concordance, in which a responsible person who is accountable to the health service observes the patient taking medication correctly, and provides the support and encouragement needed to complete a full course of treatment. This relationship between observer and patient helps to explain why the effect of DOT extends beyond the initial period of supervision. In poor treatment programmes, about half of the episodes of default occur in the first two months of treatment. For example, 54 per cent of defaulting patients attending a rural hospital in Sind, Pakistan, did so in the first two months of treatment (56)–a result which led the authors to call for a programme of supervised treatment. Programmes which have implemented DOTS have been able to demonstrate that treatment concordance is maintained through the continuation phase, even if the frequency of contact with the health worker is reduced to as little as once every three months (57). Countries which have introduced DOT have demonstrated a profound and sustained increase in their treatment success rates. Cure rates in China were 52 to 58 per cent before the introduction of DOT, and rose to 89.7 per cent in newly diagnosed patients following the establishment of a new project of DOTS (50). The beneficial effects of DOT extend beyond a simple increase in the cure rate, and positively impact on rates of drug resistance and relapse. In a retrospective study (58) comparing 407 unsupervised treatment episodes from 1980 to 1986 with 581 treatment courses of DOT from 1986 to 1992 in Texas, USA, the proportion of patients with primary drug resistance fell from 13 to 6.7 per cent, acquired drug resistance dropped from 14 to 2.1 per cent, and the frequency of relapse declined from 20.9 to

Directly Observed Therapy 833 5.5 per cent. The failure rate in previously treated patients fell to 6.2 from 17.6 per cent, following the introduction of DOT in China (50). The cost-effectiveness of ambulatory DOT has also been shown. A study from the Hlabisa Health District in South Africa (59), compared hospitalization with ambulatory DOT, and demonstrated that the latter was 2.4 to 4.2 times more cost-effective. A study by Moore and colleagues from Baltimore (60) compared three different treatment strategies; DOT, unsupervised fixeddose combination [FDC] tablets, and unsupervised individual tablets. Again, DOT proved to be the most cost-effective approach. WHO OBSERVES TREATMENT? Five different methods of delivering DOT have been described, which fit neatly into a hierarchy of supervision [Figure 57.2]. These are hospitalization; ambulatory DOT at a health facility; DOT by a field level health worker; DOT by a community member; and DOT by a relative. Those at the top offer a high level of accountability to the health service but are relatively inaccessible for the patient; the reverse is true at the bottom. Hospitalization of TB patients was widely practised up to the 1960s and then abandoned in favour of ambulatory treatment. It is usually restricted to patients with smear-positive TB, and is often limited to the first two months of therapy, or, until the patient becomes smear-negative. Ambulatory health facility-based DOT, as recommended in the WHO training materials “Managing

Figure 57.2: The hierarchy of DOT

Tuberculosis at the District Level” (61), is practised in several countries, for example, Botswana (62), China (50,63) and is the main method adopted in India, Bangladesh and Nepal. Patients attend the health post or treatment centre daily [or two to three times a week if taking an intermittent regimen] and a nominated treatment supervisor at the health facility supplies the medicines and watches them take the medication correctly. Completion rates of 83 per cent have been achieved in India (53), and as high as 92 per cent in Botswana before the advent of the HIV pandemic (62). China has achieved remarkably high cure rates of 89.7 per cent (50). Field-based health workers, such as Village Health Workers and Community Health Volunteers are utilized as treatment supervisors in some programmes, for example, the TB control programme organized by BRAC, a non-governmental organization [NGO] in Bangladesh (64). A female health volunteer receives a full course of treatment for the patient, and either takes the medicines to the patient each day, or the patient comes to the health worker. An alternative methodology utilizes specially designated mobile treatment supervisors who observe treatment at each patient’s home or work place. This method has produced excellent results in several cities of North America, such as New York (52) and Baltimore (65) where treatment supervisors provide a home delivery service of DOT for patients who are unable to attend a health facility. Few developing countries will be able to adopt this method, for the obvious reason of cost. Community leaders have also been advocated as treatment supervisors. A programme in KwaZulu utilizing a variety of different supervisors, including health workers, storekeepers, teachers and other lay people, has been extensively reported, with treatment completion rates of over 80 per cent (66-68). An attractive alternative to observation by health workers is observation of treatment by family members. This approach has been utilized in various programmes in Asia, including Thailand and Nepal, but concerns that family DOT could easily degenerate into unsupervised treatment, have led some to call this sloppy DOTS! A study carried out in several hill districts of Nepal compared health facility-based daily DOT with family or community-based DOT and no DOT (69). In the first group, all patients had daily DOT supervised by treatment centre staff during the intensive phase. In the

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second group of treatment centres, 75 per cent of supervisors nominated by patients were family or community members and 13 per cent of patients had no supervisor. In the third group, 93 per cent of patients were unsupervised and received a monthly supply of medicines. Treatment outcomes demonstrated a profound difference; cure rates for smear-positive patients were 91 per cent in the first group, 57 per cent in the family or community-based DOT group, and 34 per cent in the unsupervised group. It would appear that the role of a family-based system should be to supplement DOT by a method which provides more accountability, such as DOT at a health facility. IS DIRECTLY OBSERVED THERAPY ESSENTIAL? The DOT is perhaps the most contentious aspect of DOTS, and arguments continue over the relative value of the different components of an effective TB control programme (7). Can a programme achieve acceptable cure rates without DOT? Although many developed countries in America and Europe, and several rapidly developing countries in Asia have been able to demonstrate a decline in the incidence and transmission of TB without using DOT, the following statement from the WHO (70) still holds true “The only proven way of ensuring adherence and achieving WHO global targets is through direct observation of treatment. In some settings in some countries, other ways of closely supervising treatment have been tried. No developing country has so far demonstrated country-wide application of ways of supervising self-administered treatment under programme conditions, with success rates equalling those when treatment is directly observed”. In Nepal, unsupervised SCC has been used extensively since the early 1990s. Results from NGO supported districts have been excellent, with treatment success rates approaching or exceeding 85 per cent, even in remote and hilly situations. However, these districts have received additional manpower and other resources that could not be provided in routine programme conditions by the NTP. Where unsupervised SCC has been used in programme conditions in Nepal, the WHO targets have not been achieved (71). Four districts which initially piloted DOT under programme conditions achieved the WHO target of 85 per cent cure rate (72), and subsequently DOTS was expanded across the whole country.

CHOOSING A DIRECTLY OBSERVED THERAPY METHOD Does each of these approaches work the same? Are all equally effective? Assessment of the relative value of a DOT strategy must be based on the outcome of treatment, with sputum conversion after two months of treatment for early evaluation, and cure rates as the final outcome measure. Other factors, such as cost, replicability and sustainability may also be important secondary indicators. In the absence of randomized controlled trials [RCTs] of different DOT strategies, it is difficult to generalize, but it would appear that the more accountable approaches achieve higher cure rates. However, such studies are difficult to interpret, as other confounding factors may be playing a part, such as pre-existing quality of health services, level of health worker supervision and support from NGOs. In contrasting studies of the effectiveness of community health volunteers in South Africa, Dick et al (73) showed no additional benefit of volunteers in improving the treatment concordance of adults, whereas Wilkinson and Davies (68) have reported superior results from volunteers compared with health workers. Health workers who are opposed to DOT frequently argue that this improvement in cure rates is at the cost of case-finding, and suggest that DOT will push people into taking unsupervised treatment in the private sector. In fact the reverse is usually true, and case-finding often initially increases following the introduction of DOT. The choice of a particular DOT method depends on several factors, including the local socio-cultural environment, and the capacity of the health service infrastructure (70). Economic considerations are clearly important, and the ability to pay incentives to health workers who diagnose and treat patients until they are cured, such as in China (50), may be an important factor in encouraging high rates of treatment concordance. A well-developed health service with a high hospital bed to population ratio may allow for hospitalization of patients, though it is unlikely that many developing countries will be able to provide this service for all patients, particularly if the incidence of TB rises with HIV infection and AIDS. The burden of disease clearly influences the choice of a DOT strategy, and is related to the total number of TB cases, and the proportion attributable to HIV. In areas of high

Directly Observed Therapy 835 HIV endemicity, where community-based care systems involving family members, NGOs, and volunteers are active in providing care for people with AIDS, selection of a DOT strategy should take into account these existing support structures. The NGOs are generally good at facilitating community participation, though problems remain in ensuring it is maintained, and in replicating this involvement over larger areas. Cultural factors may be significant, particularly where TB related stigma is common. In these areas a familybased system may be the most acceptable to the patient and community, and other options that draw attention to the patient’s disease status may be less successful. In cultures in which family members already play an important role in providing health care, involvement of the family in providing support to the patient may be an appropriate way of building on existing cultural norms and values, such as providing DOT in the continuation phase of treatment. CONTROVERSIES SURROUNDING DIRECTLY OBSERVED THERAPY Critics of DOT have claimed that it is paternalistic, and denies patients the right to consume their medicines in private (74,75). In contrast, Sbarbaro (40) has argued that the public health rights of the community override the rights of the individual, and the responsibility of public health authorities to protect citizens from infectious diseases is clearly laid down in law. Milburn and Cochrane (22) further argue that patients who selectively take some medicines and not others, or erratically take their treatment, are at risk of developing and spreading drug-resistant TB. As DOT has clearly been shown to produce higher cure rates than unsupervised treatment, it is possible that patients who do not receive DOT could sue their doctor for malpractice in societies where litigation is common! Arguments against DOT must take into account the consequences of not implementing DOT, and require discussions between experts in ethics, law, and public health, and include patient groups. The second argument against DOT is that it is unproven, i.e., there has been no RCT to demonstrate the efficacy of DOT (74). Although strictly true, it is hard to accept this as a valid criticism in light of the cumulative evidence of success with DOT in so many countries around the world. It is hard to see what additional evidence an RCT would provide. As most of the efficacy

studies of antituberculosis treatment regimens were conducted under conditions of direct observation of patients, unsupervised rifampicin containing regimens are, in effect, experimental! It will also be difficult to conduct an RCT of DOT, the results of which can be generalized to other populations. The DOT is a management tool not a drug. It is not a uniform, standardized procedure which can be tested easily–there are many ways of doing DOT. A third concern that has been expressed is that the excellent results obtained in pilot projects may not be maintained as DOT expands throughout the country (76). Evidence from other developing countries, particularly the IUATLD-supported countries, and large countries such as China (50) and India (53), have demonstrated that this is not the case. With good planning and management, DOT can be expanded to cover national populations without compromising cure rates. WHAT IS THE FUTURE OF DIRECTLY OBSERVED THERAPY? Success with the rapid global expansion of DOT provides us with hope that the epidemic of TB can at last be contained and eventually reversed. However, many challenges lie ahead. Where does the future of DOT lie as NTPs endeavour to find more effective ways of controlling this disease? First, the concept of DOT is expanding to include treatment observers other than salaried health workers in the government public health system. Health sector reform, community-based care and rapidly growing private health care services create opportunities for other categories of people to be involved in supervising treatment. The rapidly growing HIV epidemic in Asia is leading to changes in delivery of health services, and development of community-based support systems for people with HIV and TB. The challenge will be to maintain the level of accountability required to ensure that patients are cured of their disease. Second, DOT is being further extended to ‘hard to reach’ populations. These are populations with limited access to health services, often because of geographical isolation, social isolation, or civil unrest. Innovative ways of ensuring DOT for people living in mountainous regions, island communities, and areas affected by snows and monsoons will have to be developed (77). Finding ways of implementing DOT in prisons (78,79), refugee

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communities (80), and for homeless or nomadic communities also present different challenges. Third, the impact of successful DOTS programmes will be compromised considerably if the majority of patients with TB continue to receive their treatment in the private sector. Ways of encouraging private doctors and pharmacies to introduce DOT are being developed, and may require supportive legislation. Fourth, DOT is becoming more efficient, and less time-consuming for the patient and the health care worker. This is being achieved by utilizing FDC tablets blister packs, and patient kits, such as those promoted by the Global Drug Facility (81). Regimens are also changing, to make them easier to supervise (82,83). Fifth, the principles of DOT are expanding to other disease control programmes. Leprosy Control Programmes have introduced monthly observed treatment as part of multi-drug therapy [MDT], and calls have been made for DOT to be introduced for people taking anti-viral treatment for HIV (84,85). A similar case could be made for malaria treatment (86). Finally, we must remind ourselves of the problems that necessitate DOT. Without support and encouragement, people will not continue to comply indefinitely with a prescribed behaviour. This is as true for patients, doctors, and managers as it is for patients. The DOT has been of great benefit in increasing treatment concordance, but the principles of observation and support need to be expanded further to other aspects of TB control. We need Directly Observed Training, Directly Observed Supervision, Directly Observed Microscopy, and Directly Observed Logistics. As Olle-Goig (87) has suggested, we need DOD–Directly Observed Doctors!

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REFERENCES 1. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009-21. 2. World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008. 3. Dye C, Hosseini M, Watt C. Did we reach the 2005 targets for tuberculosis control? Bull World Health Organ 2007;85:3649. 4. Murray CJL, DeJonghe E, Chum HJ, Nyangulu DS, Salomao A, Styblo K. Cost effectiveness of chemotherapy for pulmo-

19.

20. 21.

22. 23.

nary tuberculosis in three sub-Saharan African countries. Lancet 1991;338:1305-8. DeJonghe E, Murray C, Chuan H, Nyangulu D, Salomao A, Styblo K. Cost-effectiveness of chemotherapy for sputum smear-positive pulmonary tuberculosis in Malawi, Mozambique and Tanzania. Int J Health Plann Manage 1994:9;151-81. Kochi A. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle 1991;72:1-6. Squire SB, Wilkinson D. Strengthening “DOTS” through community care for tuberculosis. BMJ 1997;315:1395-6. Morse DI. DOT for tuberculosis. BMJ 1996;312:719-20. World Health Organization. An expanded DOTS framework for effective tuberculosis control. WHO/CDS/TB/2002.297. Geneva: World Health Organization; 2002. World Health Organization. WHO report on the tuberculosis epidemic 1997. WHO/TB/97.224. Geneva: World Health Organization; 1997. Andersen S, Banerji D. A sociological enquiry into an urban tuberculosis control programme in India. Bull World Health Organ 1963;29:685-700. Reed JB, McCausland R, Elwood JM. Default in the outpatient treatment of tuberculosis in two hospitals in Northern India. J Epidemiol Commun Health 1990;44:20-3. Datta M, Radhmani MP, Selvaraj R, Paramasivan CN, Gopalan BN, Sudeendra CR, et al. Critical assessment of smear-positive pulmonary tuberculosis patients after chemotherapy under the district tuberculosis programme. Tuber Lung Dis 1993;74:180-6. Fox W. Compliance of patients and physicians: experiences and lessons from tuberculosis I. BMJ 1983;287:33-5. Fox W. Compliance of patients and physicians: experiences and lessons from tuberculosis II. BMJ 1983;287:101-5. Banerji D. A social science approach to strengthening India’s National Tuberculosis Programme. Indian J Tuberc 1993;40:61-82. Uplekar MW, Rangan S. Private doctors and tuberculosis control in India. Tuber Lung Dis 1993;74:332-7. Panthania V, Almeida J, Kochi A. TB patients and for-profit health care providers in India. WHO/TB/97.223. Geneva: World Health Organization;1997. Uplekar M, Panthania V, Raviglione M. Private practitioners and public health: weak links in tuberculosis control. Lancet 2001;358:912-6. Grange JM, Festenstein F. The human dimension of tuberculosis control. Tuber Lung Dis 1993;74:219-22. Sumartojo E. When tuberculosis treatment fails: a social behavioural account of patient adherence. Am Rev Respir Dis 1993;147:1311-20. Milburn HJ, Cochrane GM. Treating the patient as a decision maker is not always appropriate. BMJ 1997;314:1906. Rouillon A. Problems in organising effective ambulatory treatment of tuberculosis patients. Bull Int Union Tuberc 1972;47:68-83.

Directly Observed Therapy 837 24. Barnhoorn F, Adriaanse H. In search of factors responsible for noncompliance among tuberculosis patients in Wardha district, India. Soc Sci Med 1992;34:291-306. 25. Volmink J, Garner P. Systematic review of randomized controlled trials of strategies to promote adherence to tuberculosis treatment. BMJ 1997;315:1403-6. 26. Curtis R, Friedman SR, Neaigus A, Jose B, Goldstein M, Des Jarlais DC. Implications of DOT in tuberculosis control measures among IDUs. Public Health Rep 1994;109:319-27. 27. Malla P, Gadtaula RP, Bam DS. Impact of repeated health education on treatment outcome in patients with smearpositive tuberculosis. Tuber Lung Dis 1996;77:S97. 28. Jin BW, Kim SC, Mori T, Shimao T. The impact of intensified supervisory activities on tuberculosis treatment. Tuber Lung Dis 1993;74:267-72. 29. Grange JM. DOTS and beyond: towards a holistic approach to the conquest of tuberculosis. Int J Tuberc Lung Dis 1997;1:293-6. 30. Davies PDO. Clinical tuberculosis. London: Chapman and Hall; 1994. 31. Philip RW. The organization of the home treatment of pulmonary tuberculosis. BMJ 1904:1357-60. 32. Medical Research Council. The prevention of streptomycin resistance by combined chemotherapy. BMJ 1952:1157-62. 33. Bayer R, Wilkinson D. DOT for tuberculosis: history of an idea. Lancet 1995;345:1545-8. 34. Tuberculosis Chemotherapy Centre, Madras. A concurrent comparison of home and sanatorium treatment of pulmonary tuberculosis in South India. Bull World Health Organ 1959;21:51-144. 35. Fox W. The problem of self-administration of drugs; with particular reference to pulmonary tuberculosis. Tubercle 1958;39:269-74. 36. Fox W. Self-administration of medicaments: a review of published work, and a study of the problems. Bull Int Union Tuberc 1961;31:307-31. 37. Moodie AS. Mass ambulatory chemotherapy in the treatment of tuberculosis in a predominantly urban community. Am Rev Respir Dis 1967;95:384-97. 38. Stradling P, Poole G. Towards foolproof chemotherapy for tuberculosis. Tubercle 1963;44:71-5. 39. Poole G, Stradling P. Intermittent chemotherapy for pulmonary TB in an urban community. Br Med J 1969;1:82-4. 40. Sbarbaro JA. Compliance: inducements and enforcements. Chest 1979;76:750-6. 41. Davis MS. Predicting non-compliant behaviour. J Health Soc Behav 1967;8:265-71. 42. Pablos-Mendez A, Knirsch CA, Barr RG, Lerner BH, Frieden TR. Nonadherence in tuberculosis treatment: predictors and consequences in New York City. Am J Med 1997;102:164-70. 43. American Thoracic Society. Guidelines for short-course tuberculosis chemotherapy. Am Rev Respir Dis 1980;212:6114. 44. Sbarbaro JA. All patients should receive DOT in tuberculosis. Am Rev Respir Dis 1988;138:1075-6.

45. Advisory Council for the Elimination of Tuberculosis. Initial therapy for tuberculosis in the era of multi-drug resistance: recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Mortal Morb Wkly Rep 1993.42RR/7. 46. Weis SE. Universal directly observed therapy. A treatment strategy for tuberculosis. Clin Chest Med 1997;18:155-63. 47. Volmink J, Matchaba P, Garner P. DOT and treatment adherence. Lancet 2000;355:1345-50. 48. World Health Organization. WHO Technical Report No 552. Ninth Report of Expert Committee on Tuberculosis. Geneva: World Health Organization; 1974. 49. Enarson DA. The International Union Against Tuberculosis and Lung Disease model National Tuberculosis Programmes. Tuber Lung Dis 1995;76:85-9. 50. China Tuberculosis Collaboration. Results of directly observed short course chemotherapy in 112,842 Chinese patients with smear-positive tuberculosis. Lancet 1996;347:358-62. 51. Neher A, Breyer G, Shrestha B, Feldmann K. Directly observed intermittent SCC in the Kathmandu valley. Tuber Lung Dis 1996;77:302-7. 52. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City–turning the tide. N Engl J Med 1995;333:229. 53. Khatri GR, Frieden TR. Controlling tuberculosis in India. N Engl J Med 2002;347:1420-5. 54. Sackett DL, Snow JC. The magnitude of compliance and non compliance. In: Haynes RB, Taylor WD, Sackett DL, editors. Compliance in health care. Baltimore: Johns Hopkins Press;1979. 55. Zhang J, Bernasko JW, Leybovich E, Fahs M, Hatch MC. Continuous labor support from labor attendant for primiparous women: a meta-analysis. Obstet Gynecol 1996;88:739-44. 56. Sloan JP, Sloan MC. An assessment of default and noncompliance in tuberculosis control in Pakistan. Trans Royal Soc Trop Med Hyg 1981;75:717-8. 57. Gninanfon M, Anangonou S, Kinde-Gazard D, Taw L, Shang H, Lambregts K, et al. Simplified drug delivery during the continuation phase of treatment. Int J Tuberc Lung Dis 1997;5:S86. 58. Weis SE, Slocum PHC, Blais FX, King B, Nunn M, Matney GB, et al. The effect of DOT on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994;330:1179-84. 59. Floyd K, Wilkinson D, Gilks C. Comparison of cost- effectiveness of directly observed treatment [DOT] and conventionally delivered treatment for tuberculosis: experience from rural South Africa. BMJ 1997;315:1407-11. 60. Moore RD, Chaulk CP, Griffiths R, Cavalcante S, Chaisson RE. Cost-effectiveness of directly observed versus selfadministered therapy for tuberculosis. Am J Respir Crit Care Med 1996;54:1013-9. 61. World Health Organization. Managing tuberculosis at the district level: a training course. Geneva: World Health Organization; 1994.

838

Tuberculosis

62. Kumaresan JA, Manganu ET. Case holding in patients with tuberculosis in Botswana. BMJ 1992;305:340-1. 63. Zhang L-X, Kan G-Q. Tuberculosis control programme in Beijing. Tuber Lung Dis 1992;73:162-6. 64. Chowdhury AMR, Chowdhury S, Islam MN, Islam A, Vaughan JP. Control of tuberculosis by community health workers in Bangladesh. Lancet 1997;350:169-72. 65. Chaulk CP, Moore-Rice K, Rizzo R, Chaisson RE. Eleven years of community-based DOT for tuberculosis. JAMA 1995;274:945-51. 66. Wilkinson D. High-compliance tuberculosis treatment programme in a rural community. Lancet 1994;343:647-8. 67. Wilkinson D, Davies GR, Connolly C. DOT for tuberculosis in rural South Africa 1991 through 1994. Am J Public Health 1996;86:1094-7. 68. Wilkinson D, Davies GR. Coping with Africa’s increasing tuberculosis burden: are community supervisors an essential component of the DOT strategy? Trop Med Int Health 1997;2:700-4. 69. Mathema B, Pande SB, Jochem K, Houston RA, Smith I, Bam DS, et al. Tuberculosis treatment in Nepal: a rapid assessment of government centers using different types of patient supervision. Int J Tuberc Lung Dis 2001;5:912-9. 70. World Health Organization. Treatment of tuberculosis: Guidelines for National Programmes. WHO/TB/97.227. Geneva: World Health Organization; 1997. 71. Onozaki I, Shakya TM. Feasibility study of a district tuberculosis programme with an 8-month SCC regimen utilizing the integrated health service network under field conditions in Nepal. Tuber Lung Dis 1995;76:65-71. 72. Malla P, Bam DS, Sharma NR. Preliminary report of four national demonstration DOTS treatment centres in Nepal. Int J Tuber Lung Dis 1997;1:S69. 73. Dick J, Schoeman JH, Mohammed A, Lombard C. Tuberculosis in the community: 1. Evaluation of a volunteer health worker programme to enhance adherence to anti-tuberculosis treatment. Tuber Lung Dis 1996;77:274-9.

74. Annas GJ. Control of tuberculosis–the law and the public’s health. N Engl J Med 1993;328:585-8. 75. Volmink J, Garner P. Directly observed therapy. Lancet 1997;349:1399-1400. 76. Subramaniam A. Raising hopes of a new cure. India Today. October 15 1995. 77. Bam DS. Tuberculosis services for hard to reach populations in Nepal. Int J Tuberc Lung Dis 1997;1:S10. 78. Reyes H, Coninx R. Pitfalls of tuberculosis programmes in prisons. BMJ 1997;315:1447-50. 79. Drobniewski F. Tuberculosis in prisons–forgotten plague. Lancet 1995;346:948-9. 80. Porter J, Kessler C. Tuberculosis in refugees: a neglected dimension of the ‘global epidemic of tuberculosis’. Trans Royal Soc Trop Med Hyg 1995;89:241-2. 81. Kumaresan J, Smith I, Arnold V, Evans P. The Global TB Drug Facility: innovative global procurement. Int J Tuberc Lung Dis 2004;8:130-8. 82. De Cock KM, Wilkinson D. Tuberculosis control in resourcepoor countries: alternative approaches in the era of HIV. Lancet 1995;346:675-7. 83. Wilkinson D, Anderson E, Davies GR, Sturm AW, McAdam KP. Efficacy of twice weekly treatment for tuberculosis given under direct observation in Africa. Trans Royal Soc Trop Med Hyg 1997;1:87-9. 84. Woodward WC. Should DOT be considered for treatment of HIV? JAMA 1996;276:1956. 85. Laurence J. Ethical concerns in international HIV clinical trials. The AIDS Reader 1997;7:147-54. 86. Phillips EJ, Keystone JS, Kain KC. Failure of combined chloroquine and high-dose primaquine therapy for Plasmodium vivax malaria acquired in Guyana, South America. Clin Infect Dis 1996;23:1171-3. 87. Olle-Goig JE. Non-compliance with tuberculosis treatment: patients and physicians. Tuber Lung Dis 1995;76:277-8.

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The Role of Medical Colleges in Tuberculosis Control

58

Jai P Narain, E Cooreman, LM Nath

INTRODUCTION Tuberculosis [TB] continues to remain a major public health problem, particularly in South and South-East Asia and sub-Saharan Africa. National Tuberculosis Programmes [NTPs] have made a major progress in recent years, but still there are many challenges that need to be addressed (1). Tuberculosis is a curable infectious disease. Control of this communicable disease is possible through a policy package branded under the name “DOTS”. While DOTS was initially an abbreviation for Directly Observed Treatment, Short-course, “DOTS” the acronym has now become synonymous with the entire strategy. Additional elements, necessary for the management and control of multidrugresistant tuberculosis [MDR-TB], are part of a broadened strategy, known as “DOTS-Plus”. Implementation of these strategies implies an organizational framework for effective utilization of the existing tools for diagnosis [sputum microscopy to identify the most important group of patients, the sputum smear-positive pulmonary TB cases; and culture and drug susceptibility testing to identify drug-resistant cases], treatment [standardized short-course chemotherapy] and treatment delivery through directly observed treatment [DOT] (2). The DOTS has been recognized as one of the most cost-effective health interventions available today (1-3). Many countries have included the delivery of DOTS services as a component of essential services packages to be made available as a part of primary health care. All countries in South-East Asia which have adopted this World Health Organization [WHO] recommended TB control strategy, are showing improving trends in

detection of infectious cases as well as high cure and success rates (4). The DOTS coverage is almost worldwide, compared to only 10 per cent in 1998 (5). This success is possible through the emerging partnerships in countries in the development of policies, strategies and plans, in the delivery of services, in advocacy, communication and social mobilization. The NTPs are reaching out to other public and private health care providers in order to improve accessibility and increase the reach of the DOTS services. Implementation of DOTS needs to be further widened, without compromising on the quality (1). Further acceleration in DOTS expansion and enhancing TB control requires all sectors including medical colleges to play their roles,. ROLE OF MEDICAL COLLEGES Medical colleges play a specific, but important role in health care including TB control. Their role is focussed in four major areas: advocacy, education, service delivery and research (6-8). In spite of the available knowledge and tools for diagnosis and treatment, TB is still not diagnosed and treated properly in many parts of the world (9). There are many reasons for this situation. In several instances, doctors are to be blamed for poor diagnosis [e.g., inappropriate use of radiology, inadequate use of sputum microscopy] and treatment [e.g., prescription of ineffective and inadequate regimens]. Incorrect doses and drug regimens are sometimes prescribed and the treatment is given for an inadequate period. Patients are not monitored during the treatment. Neither patients nor their families are informed about the disease, its

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transmission or treatment. Contacts of smear-positive cases are often not checked. Although the situation is improving, these weaknesses are still common particularly in the non-DOTS areas, both public and private (9,10). As a result of this, an enormous amount of resources may be wasted on misdiagnosed or mismanaged patients. The inadequate use of antituberculosis drugs is increasingly leading to the emergence of multidrug resistance. It is therefore essential to improve the knowledge of medical graduates about TB and to train them to acquire the skills necessary for the proper diagnosis and management of TB in an individual patient and in the community (11,12). The expanded DOTS strategy will not succeed unless medical practitioners can be trained to manage TB properly. The active participation of doctors in TB control will lead to a change in the attitude of other health care providers and their involvement will be more easily obtained (13-15). Medical colleges must adapt and use their potential to contribute proactively to shaping the health system. By introducing changes in the medical education, research and delivery of care for TB control, medical faculties have the unique opportunity to demonstrate their social accountability. Advocacy Involvement of medical colleges to support the implementation of the expanded DOTS strategy aims in the first place at creating an additional constituency of support. The senior teaching staff in medical colleges are generally very influential and respected in the community. They can support TB control from different angles. As captains of health, they facilitate political, legal and social change for better treatment of TB patients; as opinion makers among medical professionals, they are in a position to effect attitudinal changes. Through acting as role model for medical and paramedical students, they impart a “zeal” among them. And finally, as resource persons with access to the latest information, they continuously update themselves, disseminate correct information and lead the media. Medical Education The doctors of the future should possess the following five aptitudes and should take up their responsibilities as a:

“Care provider”, who considers the patient holistically, as an individual, as part of a family and as part of the wider community; and who provides high quality continuing care within a doctor-patient relationship based on mutual respect and trust; “Decision maker”, who chooses which technologies to apply in enhancing care in an ethical and cost-effective fashion. “Communicator”, who is able to promote a healthy lifestyle by effective explanation and advocacy appropriate to the cultural and economic context, thereby empowering individuals and groups to improve and protect their health. “Community leader”, who having gained local respect and trust, can reconcile individual and community health requirements and initiate action on behalf of the community. “Manager”, who can work efficiently and harmoniously with individuals and organizations inside and outside the health care system to meet the needs of patients and communities. To fulfil these roles, the medical colleges should provide every medical graduate with the knowledge, skills and attitudes essential to the management of TB in the patient and in the community as a whole. The medical college should have an effective educational strategy to provide such ability. The results of the educational process should be adequately assessed and evaluated before the medical student is allowed to graduate as a doctor. Specific and essential knowledge, skills and attitudes that must be imparted to doctors before they leave the medical college are listed in the Table 58.1. The implementation of TB control services is witnessing a shift from vertical set ups to partially or fully integrated general health services. Similarly, with regard to health professional, a shift is taking place from the traditional view of human resources development [HRD] as the organization of a few basic training courses, seldom taking into account educational principles, towards a clearer understanding of HRD more broadly in the context of health systems and the subsequent need to work on the quality aspects of HRD for TB control. Different types of training can be distinguished: preand in-service training. Pre-service training includes the training usually provided by medical, nursing or

The Role of Medical Colleges in Tuberculosis Control 841 Table 58.1: Specific and essential knowledge, skills and attitudes to be imparted to medical students Basic science of TB Transmission of the TB bacillus in humans and the immune response TB bacteriology TB histology

available resources, the arrangement of how, when and where should be determined by the best possible learning process: students should in optimal conditions and circumstances acquire all required competencies as efficiently as possible. In the case of TB, how, when and where are interdependent. Three educational options can be chosen: sequential, fully or partially integrated.

TB in the individual patient Pulmonary TB in adults Extra-pulmonary TB Specific aspects of childhood TB TB and HIV infection Treatment Prevention TB as it affects the community Epidemiology of TB National TB programme principles Organization of treatment Organization of case-finding Prevention of TB disease and infection Evaluation of national TB programmes TB = tuberculosis; HIV= human immunodeficiency virus

laboratory colleges. In-service training can be in the form of initial training [for staff that were not trained in the particular subject before]; advanced training [for selected staff with higher responsibilities]; retraining [for staff already trained and based on identified needs] and training on new interventions such as MDR-TB, TB and human immunodeficiency virus [HIV] co-infection. Medical colleges will focus in the first place on preservice training, i.e., they train the future doctors, after which they will graduate and start working as medical practitioners. Medical colleges get increasingly involved in in-service training, where the NTPs makes use of the faculty and training facilities of medical colleges or specialized TB institutes for offering advanced or refresher training for NTP selected staff or as part of a continuous medical education programme. Distant education programmes are also being developed, with courses being offered in tailored modules. EDUCATIONAL STRATEGY Having defined the required knowledge, skills and attitudes necessary for the twenty-first century medical professional in TB control, it must be defined how, when and where that education should take place. Within the

Sequential This has been and is the most widely used form in different medical colleges in India, with basic scientific and biological aspects taught in the earlier part of the curriculum. Traditionally, clinical training comes later. Public health training is often offered at a separate time, early, middle or late. Whilst sequential training is easiest for the teachers, it can leave the student with disjointed knowledge and skills, unless substantial time is devoted towards putting together several elements in a “revision course”. Fully Integrated In this option, modular training is provided in a fully integrated manner. The biomedical and scientific elements can be integrated with clinical and public health training, either as part of a module devoted entirely to TB or as part of a module devoted to respiratory diseases, in general. Although modular training is optimal for the student, considerable reorganization and institutional change is likely to be necessary to implement such training. There is a trend that more and more subjects are taught in a modular way. Partially Integrated Some medical colleges provide integrated modular training in the fundamental biomedical subjects early in the curriculum and follow this in later years with integrated clinical and public health modules for TB. This should be considered as a transitional compromise, the optimal eventual aim being fully integrated modular training. Within each option, different approaches can be considered, such as plenary ex-cathedra lectures in the classroom or lecture theatre; lectures in smaller groups, problem-solving exercises, simulation or role play exercises, practical work, projects, reading of reference works, text books or specially prepared materials, use of

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audio-visual techniques, among others. Whenever possible, the approaches which favour the active participation of a maximum number of learners should be preferred. The sites of learning can and should vary. The precinct of the medical college is obviously a major site but teaching about TB should also be provided within chest or general hospitals, usually but not exclusively at the bedside. Students should also experience and learn about TB at sites in the community. These could include rural and urban practice area clinics, primary care sites and private health facilities in collaboration with selected general practitioners. Distant learning includes that the students study at their own pace, usually at their own place. A tutor is assigned who will guide the student from a distance and get feedback through correspondence. Site visits can be included in distant learning packages. Appropriate assessment of students is important for the following three reasons. It is essential to make sure that medical students at the time of graduation have achieved the objectives of the particular course, in this case related to the management of TB in all its manifestations including when associated with HIV. Assessments will motivate students and encourage them to work harder. Assessments can also guide the teachers and the students about which part of the course has been successful and which part needs to be improved. Traditionally, the assessment has been by conducting an examination, which is mainly centred on the theoretical knowledge. The examination can be in the form of multiple-choice questions or essay type questions. However, this does not lead itself to the assessment of practical skills. There is a need to assess the attitudes and the ability of young graduates to handle persons who suffer from the intense trauma of being diagnosed with a stigmatizing, but curable disease. As it is envisaged that different departments and disciplines in the medical faculty will be involved in teaching a wide variety of essential elements identified, it is inevitable that a range of student assessment methods will have to be used. The selection of the most appropriate method of assessment will depend on validity, reliability, quality and feasibility. The objective structured clinical examination [OSCE] and the objective structured practical examination [OSPE] have many features that will help teachers to determine students’ competencies, skills and attitudes. However, there may be practical difficulties, such as the

number of students and pressure of work in the hospital which may make clinical examination as a part of final examinations difficult in some situations. Also possible are the assessment of managing patient problems in the practical settings, including assessment of training in the community which should form part of the final examination. Another valid and much favoured method is a constant day-to-day evaluation, with appropriate feedback, of students as they face real and contrived experiences during the course of their training. Such continuous assessment could be best used as a method of formative assessment to promote students learning. Finally, it is necessary to bear in mind that no assessment method is perfect. Each has advantages and disadvantages. Therefore, it is always necessary to use a variety of methods. The selection of method should be based on the objectives of the course, economy of time and expense, reliability and validity of the instruments and the value as a learning tool for the students. Variety is inevitable in view of the diverse topics being tested and because it is envisaged that many different departments of the faculty will be involved. The overall objective of producing a doctor competent and confident to handle the diagnosis, therapy and overall management of the patient, family and community will be the collective responsibility of the medical college and not of any single department. However, the brunt of the responsibilities in TB control will lie with the departments of microbiology, medicine and other clinical specialties and community medicine. SERVICE DELIVERY Major tertiary hospitals are linked to medical colleges. In addition to their referral function for a large area, they may also cater as primary health care facility for people living in the immediate catchment area. These referral centres tend to see a more diverse spectrum of pathology, making it more straightforward for students to come in contact with different forms of TB in a relatively short time. While the routine TB cases are diagnosed and managed in the more peripheral health facilities, difficult diagnostic cases and in particular pulmonary smearnegative and extra-pulmonary cases, patients co-infected with HIV and childhood TB are relatively over-represented in the setting of a medical college hospital.

The Role of Medical Colleges in Tuberculosis Control 843 In recent years, NTPs in South and South-East Asia have set up TB management units or “DOTS corners” (16,17). While diagnosis and clinical care is provided through the clinician, the DOTS corner provides the management of the TB patient: patient registration, classification, follow up, drug supply, referral to a peripheral health facility and maintenance of records. This DOTS corner, usually reporting to the district TB officer, thus, provides the vital link between the public health TB control programme and the individual clinical care provided by the hospital in- or out-patient departments. The availability of a “demonstration centre” within the precinct of a medical college hospital allows an immediate exposure to one model of delivering NTP services. The medical faculty is a primary resource for providing technical support for the implementation of DOTS services within the medical college hospital. Other hospitals, affiliated to or working in close collaboration with medical college hospitals, will also directly benefit from this technical support. The medical college and its hospital serves as training and referral centre. Through its network with other hospitals, it can assist in ensuring quality of services, including laboratory services. They can contribute to the development of guidelines, policies and strategies, tailored to the needs of the programme and the character of a tertiary hospital. They can provide assistance with planning, monitoring and reviewing of TB control efforts. They can also play a role in disease and drug resistance surveillance. In the context of increasing spread of HIV, medical colleges can play a crucial role in developing a holistic approach to address the issue of HIV-TB co-infection [Table 58.2] (18,19). Building a supportive environment starting from the setting of the hospital may have a much wider impact. Reducing transmission of HIV and TB within health facilities should be part of the general infectious control measures applied in large hospitals. Both the in- and out-patient departments will provide TB curative services. The involvement of the community health department may also foster community-based treatment and care for people living with HIV and TB. RESEARCH Medical colleges traditionally play an important role in research. Their academic nature implies conducting both fundamental and operational research in many fields, including TB. Several operational research projects have

Table 58.2: Involvement of medical colleges in the Revised National Tuberculosis Control Programme in India In order to streamline the activities of the medical colleges, a National Task Force, five Zonal Task Forces and several State Task Forces were set up. A core committee has been set up in each medical college with representatives from the faculty and the RNTCP The Central TB Division is piloting a “referral for treatment” mechanism aimed at developing a seamless RNTCP service between medical colleges and general health services. The RNTCP provides the human resources and logistic support needed to implement and coordinate activities in medical college hospitals. Laboratory consumables and drugs as well as funds for facility upgradation are being made available. Medical colleges provide the necessary space, designate faculty members for supervision, and avail of staff sensitization programme. By the 2nd quarter of 2008, 263 of the 277 medical colleges have been involved. Medical colleges contribute 15% to 20% of the overall number of cases RNTCP = revised national tuberculosis control programme; TB = tuberculosis

been undertaken or are underway through the involvement of medical faculties in the WHO South-East Asia region, especially in India. Results from locally undertaken research activities will contribute to the global body of evidence in a relevant way. Through research, evidence is generated which will provide the basis for making new policies or updating strategies and guidelines. The WHO, NTPs and other stakeholders [including medical colleges] are setting the research agenda that will lead to the best use of currently available diagnostic and treatment tools as well as the development of new diagnostics, drugs and vaccines. The NTPs in many countries are now seeking partnerships with prominent national and international agencies. Operational research contributes to an improved performance of the TB programme, as well as strengthening of the health structure. Laboratory quality assurance, integrated care for AIDS patients suffering from TB, drug management and surveillance are some examples that will benefit the health system as a whole. MANAGING MEDICAL EDUCATION AND PRACTICE Tuberculosis Task Force To respond to the urgent need for students to be properly trained in TB, a “TB Task Force” should be set up in each

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medical to plan a proper curriculum and teaching strategy. The Task Force should ensure that: [i] essential knowledge and skills are covered by every teacher in their respective fields of TB teaching or training; [ii] evaluation covers essential knowledge, skills and attitudes; [iii] progress is made towards the ideal of integrated modules, which move from integrated teaching to integrated learning; and [iv] the content of the curriculum and the systems of evaluation are updated according to priorities in the NTPs (20,21). The composition of the Task Force should be decided locally. It should, however, include a bacteriologist, histopathologist, chest physician, radiologist, infectious disease physician, a public health physician or official as well as a representative of the students. The Task Force, through consensus, should agree to a proposal regarding changes and improvements requirements. It should then strive to obtain consensus within the medical college, and particularly the curriculum development committee or analogue body.

Implementation of Tuberculosis Control in Medical Colleges: Indian Experience Medical colleges have been actively involved in the implementation of the Revised National Tuberculosis Control Programme [RNTCP] of the Government of India since 2001. This unique experiment has generated a tremendous response and the medical colleges have contributed to nearly 15 to 20 per cent of the overall number of TB cases diagnosed and treated with DOTS (22-24). They have shown their involvement in treatment of HIV-TB co-infection. In the future, their continued involvement by adopting the DOTS-Plus strategy, will help in prevention and management of MDR-TB and XDR-TB (25). In the scenario of developing countries, teaching hospitals attached to medical colleges and tertiary care medical institutes appear to be excellent places for education of medical students and conducting operational research relevant to the NTPs (22-24). REFERENCES

Guidelines Development In providing good undergraduate training and evaluation in TB, the medical college already contributes to practice guidelines, but its contribution should not stop there. Together with NTP managers, it should work actively with medical professional organizations, both in the public and private sector, and with national and international organizations [e.g., WHO] to formulate and evaluate guidelines for best practice in TB. Research activities conducted through medical colleges should be consistent with the short, medium and long-term needs of national TB programmes. Continuing Education Medical colleges offer facilities for continuing education, e.g. through postgraduate courses, seminars and diplomas. National TB programmes as well as non-governmental and international organizations also offer or provide opportunities to attend job-oriented trainings. The TB Task Force should enlist the cooperation of medical practitioners in developing a programme of continuing medical education in TB in their district, province or country. It is crucial that doctors, whose profession is considered the backbone of health care, are striving to keep up-to-date and well informed.

1. Sharma SK, Liu JJ. Progress of DOTS in global tuberculosis control. Lancet 2006;367:951-2. 2. Nair N, Narain JP. Good progress with DOTS in the SouthEast Asia Region. J Indian Med Assoc 2003;101:140-1,147. 3. Sharma SK, Mohan A. Scientific basis of directly observed treatment, short-course [DOTS]. J Indian Med Assoc 2003;101:157-8,166. 4. TB India 2008. RNTCP status report. New Delhi: Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India; 2008. 5. Enarson DA, Billo NE. Critical evaluation of the Global DOTS Expansion Plan. Bull World Health Organ 2007;85:395-8; discussion 399-403. 6. World Health Organization. Tuberculosis control and medical schools. Report of a WHO workshop, Rome, Italy 29-31 October1997. Available at URL: http://whqlibdoc. who.int/hq/1998/WHO_TB_98.236.pdf. Accessed on September 28, 2008. 7. Mohan A, Sharma SK. Medical schools and tuberculosis control: bridging the discordance between what is preached and what is practiced. Indian J Chest Dis Allied Sci 2004;46:57. 8. Narain JP, Nath LM. The role of medical schools in tuberculosis control. In: Sharma SK, Mohan A, editors. Tuberculosis. First edition. New Delhi: Jaypee Brothers Medical Publishers; 2001.p.597-600. 9. Hopewell PC, Pai M, Maher D, Uplekar M, Raviglione MC. International standards for tuberculosis care. Lancet Infect Dis 2006;6:710-25.

The Role of Medical Colleges in Tuberculosis Control 845 10. Narain JP. Tuberculosis. Epidemiology and control. SEA-TB248. New Delhi: World Health Organization Regional Office for South-East Asia; 2002. 11. Ait-Khaled N, Enarson DA. Tuberculosis. A manual for medical students. Geneva: World Health Organization; 2003. Available at URL: http://whqlibdoc.who.int/hq/2003/ WHO_CDS_TB_99.272.pdf. Accessed on September 28, 2008. 12. AIIMS-WHO Meeting on the Involvement of Medical Schools in TB and STI/HIV Control. Report on an Informal Consultation on 28-30 November 2001 and Follow-up meeting on 29 April 2002. 13. Tonsing J, Mandal PP. Medical colleges’ involvement in the RNTCP: current status. J Indian Med Assoc 2003;101:164-6. 14. Granich R, Chauhan LS. Status report of the Revised National Tuberculosis Control Programme: January 2003. J Indian Med Assoc 2003;101:150-1. 15. Chauhan LS. Challenges for the RNTCP in India. J Indian Med Assoc 2003;101:152-3. 16. World Health Organization Regional Office for South-East Asia. Joint Tuberculosis Programme Review, India. WHOSEA-TB-265. New Delhi: World Health Organization Regional Office for South-East Asia; 2003. 17. Joint Tuberculosis Programme Review, India, 2006. 3-17 October 2006. SE-TB-299. New Delhi: World Health Organization Regional Office for South-East Asia; 2007. Availabe at URL: http://www.tbcindia.org/Pdfs/JMM2006%20Report.pdf. Accessed on October 24, 2008.

18. World Health Organization. TB/HIV research priorities in resource-limited settings. Report of an expert consultation 14 -15 February 2005, Geneva, Switzerland. WHO/HTM/ TB/2005.355. Available at URL: http://whqlibdoc.who.int/ hq/2005/WHO_HTM_TB_2005.355.pdf. Accessed on September 28, 2008. 19. Narain JP, Lo YR.Epidemiology of HIV-TB in Asia. Indian J Med Res 2004;120:277-89. 20. Atienza MA, Roa CC, Sana EA. Development of a core curriculum on tuberculosis control for philippine medical schools. Ann Acad Med Singapore 2007;36:930-7. 21. Harrity S, Jackson M, Hoffman H, Catanzaro A. The National Tuberculosis Curriculum Consortium: a model of multidisciplinary educational collaboration. Int J Tuberc Lung Dis 2007;11:270-4. 22. Sharma SK, Lawaniya S, Lal H, Singh UB, Sinha PK. DOTS centre at a tertiary care teaching hospital: lessons learned and future directions. Indian J Chest Dis Allied Sci 2004;46:251-6. 23. Tahir M, Sharma SK, Rohrberg DS, Gupta D, Singh UB, Sinha PK. DOTS at a tertiary care center in northern India: successes, challenges and the next steps in tuberculosis control. Indian J Med Res 2006;123:702-6. 24. Chauhan LS. RNTCP 2007: looking ahead to future challenges. J Indian Med Assoc 2007;105:192,194,196. 25. Recommendations of the 7th National Task Force meeting for involvement of Medical Colleges in the RNTCP, New Delhi 22-24 October, 2008.

Public-Private Mix for Tuberculosis Control

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Mukund Uplekar, Knut Lonnroth

THE DIVERSE MIX OF HEALTH CARE PROVIDERS In most countries with a significant burden of tuberculosis [TB], DOTS implementation for TB control has been limited largely to public sector services under National Tuberculosis Programmes [NTPs]. In reality, however, many patients with symptoms of TB, including the very poor, do seek and receive care from a wide variety of health care providers outside the network of NTP services (1). Studies in India, for example, have shown that in urban and rural areas alike, 50 to 88 per cent of TB patients’ first contact was a private provider (2,3). Various factors such as gender, stigma, convenient location, indirect costs such as loss of wages, transport costs, etc., and patient perception of the NTP care played a major role in determining the patient’s decision to first visit a non-NTP provider (4). The NTP services were not preferred due to inconvenient opening hours, long waiting times, lack of information and patient perceptions of poor quality of care at government hospitals and DOTS centres (2). The magnitude and the role of non-NTP providers, both private and public, vary greatly from country to country. Some countries have a large private medical sector that provides services to all segments of population, rich and poor. Private providers also include practitioners who may not be formally qualified, such as traditional healers in rural areas and informally trained practitioners in urban slums. Civic groups working with disadvantaged communities and non-governmental organizations [NGOs] provide TB care in many countries. Urban areas in most countries have a mix of public sector providers, which include medical college hospitals,

speciality centres, such as chest clinics and general public hospitals. In spite of being a part of the public sector, these providers do not always coordinate with NTP or apply DOTS. Many countries have networks of health services for their specific worker populations, such as those run by social insurance organizations or public sector undertakings like military, railways or mines. Private industries may also offer health services for employees. Provision of diagnosis and treatment by these private and public providers, who manage sizeable proportions of TB patients, are often non-standardized and lack an evidence-based approach. Thus, the TB patients they serve are not only deprived of the benefits of DOTS but are also subject to mismanagement which could contribute to a growing incidence of multidrugresistant-TB [MDR-TB] or extensively drug-resistant TB [XDR-TB] (5) and undoing the TB control efforts of NTPs. Since the introduction of DOTS in the early 1990s, a great deal of progress has been made in global TB control. However, the global TB targets-detecting at least 70 per cent of the infectious cases and curing 85 per cent of them were missed twice, first in the year 2000 and then in 2005, signalling that TB control efforts, although impressive, were not sufficient. It became clear that the Stop TB Partnership targets and the TB related Millennium Development Goals [MDG] of halving the prevalence and mortality of the disease by 2015 would not to be met if current efforts were not intensified. This led to the development of the new Stop TB Strategy of the World Health Organization [WHO]. Systematic involvement of all relevant health care providers in delivering effective TB services to all segments of the population is among the essential components of the Stop TB Strategy (6,7).

Public-Private Mix for Tuberculosis Control PUBLIC-PRIVATE MIX In order to address this apparent weakness of exclusion of a large proportion of health care providers from efforts to control TB, WHO and partners embarked the PublicPrivate Mix [PPM] for DOTS [PPM DOTS] initiative in the mid 1990s. The term ‘PPM DOTS’ represents a comprehensive approach to engage all relevant health care providers in DOTS implementation. It encompasses all forms of public-private [between NTP and the private sector], public-public [between NTP and other public sector care providers] and private-private [e.g., between an NGO or a private hospital and the neighbourhood private providers] collaboration for the common purpose of ensuring provision of standard TB care in a community. In 2001, the global DOTS Expansion Working Group [DEWG] of the Stop TB Partnership established a subgroup on PPM for DOTS Expansion [PPM Subgroup] with its secretariat based in WHO, Geneva. The subgroup has helped develop practical tools for PPM (8). It has also enabled the development of new PPM initiatives in several settings, reviewed and discussed barriers to scale up PPM, helped conduct systematic documentation and evaluation of processes and outcomes of PPM projects to provide evidence for the feasibility, effectiveness and cost effectiveness of PPM (9-11). Originally, PPM was a strategy for DOTS expansion. However, PPM is also relevant for improving management and control of MDR-TB including XDR-TB as well as for expanding TB and human immunodeficiency virus [HIV] collaborative activities. To reflect this, the PPM subgroup has re-labelled PPM DOTS to “PPM for TB care and control”. “Engaging all care providers” is one of the new and essential components of WHO’s Stop TB Strategy launched in 2006 (6). It is also a prominent element of the Global Plan to Stop TB 2006-2015 developed by the Stop TB Partnership (12). Many countries are now scaling up PPM in line with the Stop TB Strategy and the Global Plan. Addressing and expanding PPM for TB care and control should get a further boost by the recently developed International Standards for Tuberculosis Care [ISTC] (13). These standards address the basic elements of diagnosis and treatment of TB with a series of straightforward statements that are backed by evidence. ISTC could be used to secure a broad base of endorsements

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from NTPs, professional medical and nursing societies, academic institutions, NGOs, HIV-focussed organizations, and to create peer pressure for providers to conform to the principles of PPM as well as to serve as the basis for pre-service and in-service training. Professional societies and associations in many countries including India have endorsed ISTC and are working with the NTPs to put them in practice (Philip Hopewell, personal communication). THE PUBLIC-PRIVATE MIX EVIDENCE BASE A considerable amount of knowledge and field experience on how to undertake PPM for TB care and control now exists. The WHO conducted a global assessment of the role of private providers in TB control in 1999-2000 (5). The assessment helped to both underscore the need and identify possible approaches for NTPs to work with the private sector to initiate and sustain productive collaboration. As a second step, WHO helped to set up or formalize local PPM initiatives at diverse sites in Asia and Africa during 2000-2002. A systematic documentation of processes and outcomes of these and other projects provided evidence for their feasibility and effectiveness (8,14-17). World Health Organization and the partners of the PPM subgroup have since continued to conduct operational research on a large number of PPM projects. To date, over 50 PPM initiatives have been implemented in 14 countries, of which over 30 have been evaluated, these include diverse projects linking NTPs to various care providers, like non-qualified village doctors, informal and formal private practitioners, private general practitioners, specialist chest physicians, public and private hospitals, and NGOs. Treatment outcomes have been evaluated for over 20000 TB patients in 15 initiatives. Treatment success rates in the projects that provided drugs free of charge to patients were between 75 and 90 per cent. The impact on case detection has also been evaluated in several PPM initiatives. All these initiatives have shown an increase in case detection ranging from 10 to 60 per cent (18). Cost and cost-effectiveness analyses undertaken for three well-established initiatives in India showed that DOTS delivered through a variety of public and private providers was at least as cost-effective as DOTS delivered exclusively by the public health sector, and that the

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approach was much more cost-effective as compared with TB treatment provided in the conventional nonDOTS private health sector. Moreover, PPM significantly reduced the financial burden on TB patients [mainly by providing drugs free of charge] and facilitated their access to quality TB care (14,15). Data from Bangladesh, India and Myanmar indicate that PPM helps to reach the poor when providers used by them are also involved (19-21). In conclusion, evidence emerging from the field shows that PPM for TB care and control is a feasible, productive and a cost-effective approach to improve case detection and treatment outcomes as well as to foster equity in access to care and financial protection for the poor. IMPLEMENTING PUBLIC-PRIVATE MIX World Health Organization with the help of the PPM subgroup has developed a guiding document to help countries develop national PPM strategies and operational plans (18). The document, the essence of which is summarized below, does not provide a blueprint for implementing PPM, but sets out the essential steps required to develop national PPM strategy and operational guidelines. Country adaptation is essential to identify the most suitable model. The standard country level PPM approach, therefore, involves three major steps: [i] conduct a situation assessment; [ii] develop operational guidelines; and [iii] implement. National Situation Assessment The steps involved in a situation assessment includes to: [i] make a list of all health care provider groups including, for example, public, voluntary, academia, privatequalified, private non-qualified, etc.; [ii] determine if they are presently linked with NTP and, if so, what is their current role in TB control; [iii] assess what potential contribution the providers can make; and [iv] identify input required to optimize their contribution. It is essential to map out all relevant public and private health care providers in a given setting and identifying suitable roles for different providers in TB control. Table 59.1 lists possible providers types to map out. Figure 59.1 provides an example of options for task mix and role division for different types of providers. The scheme depicted in this figure is only a suggestion, and the suitable task mix will vary across and within

Table 59.1: Some categories of health care providers who manage tuberculosis symptomatics and patients Public health care providers General hospitals Speciality hospitals and academic institutions Health institutions under state insurance schemes Health facilities under government corporations and ministries Prison health services Army health services Private health care providers Private hospitals and clinics Corporate health services Non-governmental organization hospitals and clinics Individual private physicians, nurses, midwives, clinical officers, etc. Pharmacies and drug shops Practitioners of traditional medical systems Informal, non-qualified practitioners

countries depending on nature of the provider mix, their willingness to take on different tasks, the status of NTP, patient preferences, and the health regulatory framework. To illustrate, an NTP should be in a position to carry out all the tasks; a medical college or a public, voluntary or private institution may also be able to undertake most clinical and public health tasks. Individual providers including pharmacists and non-physicians may be able to refer suspects and, at times, supervise treatment while trained physicians could diagnose and categorize patients as well as initiate treatment. The NTP would be expected to fill the gaps and weaknesses by supporting or taking on the tasks those other providers are unwilling or unable to carry out. In all settings, it is essential that NTP is responsible for covering the main part of the cost of diagnosis and treatment. As a minimum, NTP should provide anti-TB drugs free of charge to providers who should dispense them free of charge to patients. The NTP should also develop and maintain strong stewardship capacity to guide and oversee the newly joined private and public providers. The generic PPM model [Figure 59.2] entails that the government-run NTP assumes the responsibility of funding, regulating and monitoring, while the day-to-day collaborative implementation may be carried out by the local unit of NTP itself or by relevant non-NTP providers. In order to ensure that all relevant stakeholders are involved in developing a national strategy for PPM, the

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Figure 59.1: Indicative task mix for different provider categories. Shaded cells correspond to tasks that could be taken up by respective provider type TB = Tuberculosis

NTP should constitute a task force, coalition or coordination committee with broad representation of various groups as indicated in Table 59.2. This body can act as an interface between NTP and other providers. It may also advise NTP in carrying out various tasks, such as advocacy, sensitization, training, supervision, quality control, monitoring and evaluation. In some settings, the issue of diagnosis of smear-negative and culture-negative forms of TB has been effectively addressed by establishing diagnostic committees comprising relevant local experts.

Developing Operational Guidelines National policy and operational guidelines on PPM should be developed and implemented as an iterative process: policy leading to preparation of operational guidelines to help phased implementation and results of implementation feeding back into policy for any revision required. Developing and using draft policies and guidelines first may facilitate rapid implementation. Based on experience and evidence gathered, subsequent revisions may be undertaken.

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Tuberculosis Defining the Task Mix for Different Providers Building on the situation assessment discussed above [Figure 59.1], roles and responsibilities for different providers need to be clearly defined, while providing different options so that the guidelines provide sufficient flexibility for local adaptation. Developing Practical Tools to Help Implementation The examples of practical tools include laboratory request form, referral-for-treatment form, feedback or backreferral form, transfer form, laboratory register, TB register and the TB treatment card. Most of the tools could be adaptations of those used routinely by NTP.

Figure 59.2: Generic PPM model. A generic PPM structure emerging from PPM DOTS field projects. The national government formulates a PPM policy in consultation with the stakeholders. A co-ordination mechanism helps to bring the public and the private sectors together, agree on implementation schemes and maintain dialogue. A local DOTS agency-public, private or voluntaryimplements DOTS through a network of willing health care providers in an area PPM = public-private mix; PP = private provider; MoU = memorandum of understanding Table 59.2: Public-Private Mix, DOTS: stakeholders at national, provincial and local levels Ministry of Health, its departments and sub-national counterparts Other ministries such as Ministries of Labour, Interior, Defence, etc. Health insurance organization Drug regulatory authority Academic institutions Social welfare programme for the poor and marginalized Professional organizations Hospital associations, Pharmacy associations etc. National and international NGOs involved in TB service delivery Drug industry Consumer organizations NGOs = non-governmental organizations; TB = tuberculosis

There are seven essential elements of operational guidelines for PPM. These are described below. Formulating Objectives These may include: [i] increase in case detection; [ii] improved treatment outcomes; [iii] improved access for the poor; and [iv] reduced financial burden for patients.

Develop a Training Strategy The training strategy should be based on the defined task mix, and target NTP staff as well as various provider types to be involved. Developing Standards for Certification of Providers While the criteria for certification and de-certification should be related to the specific task options for respective providers, these criteria should be similar for the public and private sectors. The certification may be informal initially and may gradually evolve into a formal, standardized procedure. Developing Incentives and Enablers Financial compensation may be necessary for providers who manage a large number of TB suspects and cases. However, evidence shows that individual private practitioners who have few TB patients at any time, and voluntary organizations providing TB care may find inkind, non-monetary incentives sufficient to enter into collaboration with NTP (22). Some examples of effective non-monetary incentives include: access to free TB drugs; an opportunity to serve society through free care for the poor; access to free training and continuing education; free microscopy services, opportunity to deliver high quality services; recognition due to formal association with a government programme; and potential to expand business as a result thereof. Monitoring and Evaluation Plan It is important to monitor the process of PPM in relation to defined objectives and evaluate the process in order

Public-Private Mix for Tuberculosis Control to fine-tune PPM strategies and implementation plans in a stepwise manner. Implementation Proper As discussed above, the national guidelines need to be flexible enough to allow for local adaptation, the logical steps of which are: [i] preparation; [ii] mapping and first contact with providers; [iii] selection of providers; [iv] implementation proper; and [v] advocacy and communication. Preparation A clear, written message from the top NTP management on the importance and priority of PPM is the first prerequisite before local implementation begins. Operational guidelines, including guidance on local implementation, should preferably be made available. Draft sensitization and training materials should be ready for use. The implementation tools, including any new formats and adapted NTP registers and reports, should be handy. Most importantly, NTP staff must be oriented about PPM; their tasks and responsibilities should be defined and a plan of implementation should be available according to locally defined objectives for PPM. A local task force, equivalent to national task force, may be established to engage all relevant partners in planning and implementation at local level. Such a local task force might also be given operational responsibilities towards sensitization, training, supervision and quality control. Mapping on Local Level and First Contact with Provider The local NTP unit should have a map of its area to enable marking of all public and non-public providers on it. In many settings and in large urban areas, such maps may have to be prepared with a physical listing and verification of all types of health care providers. Other public health and development programmes and NGOs working in the local area may be able to assist in this task. In dealing with private providers, using a neutral interface such as a local NGO or a civil society institution has been found to expedite both provider enrolment and programme implementation. Depending on the local context and resources, mapping, making the first contact with the provider and sensitization may or may not be combined. While mapping will provide a general idea

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of the nature of individual and institutional providers, a first contact with the providers will be required to understand their current and potential contribution to TB control. During these visits, relevant NTP staff should also provide general information about the local TB programme and convey the desire to begin collaboration. Information obtained on different providers during the prioritization of providers for active collaboration and their training are important steps that require serious thought in local implementation. Some common principles should be given consideration. Institutional providers are likely to give a higher yield of cases but will also require greater time and attention on the part of senior NTP staff. These may include medical colleges, general public hospitals, corporate health care institutions, institutions under health insurance organizations, among others. Private practitioners may not be handling a large number of cases individually but it may be possible to identify and target first the ones handling a large number of suspects and cases. Chest physicians with large practices may belong to this category. Since private practitioners may be the first port of call for most people, involving them will have additional benefits like reducing diagnostic delay and cost of care for patients. The poor are likely to first approach NGOs operating in poor areas, non-physicians like pharmacists, nonqualified providers and traditional healers. Approaching these types of providers might help in providing the poor with better access. In some communities, female patients may prefer female care providers. Involving female care providers may help to address gender differentials in case detection. Involving other public sector institutions within and outside the Ministry of Health may require a parallel process of getting approvals and directives from their top regional or national management. After initial mapping, first contact and sensitization, it should be possible to identify tough-to-tackle providers. It is worthwhile making a beginning with willing providers before spending energies on those reluctant to collaborate. Implementation Proper The method of launching PPM locally will vary from setting to setting. A proper launch with fanfare may be inspiring to both NTP staff and other care providers and may boost their initial commitment. In the beginning,

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PPM should be seen by both public and private counterparts as a ‘learning- by-doing’ exercise. A key requirement, therefore, for NTP staff in particular, would be to give a fair amount of time and input patiently before expecting great outcomes. It is important that NTP staff stick to their commitment and diligently follow whatever is mutually agreed upon. The referral routines should be adhered to and proper records maintained. Any irregularity on the part of collaborating providers with regard to adherence to guidelines, providing quality care and maintaining proper records, if found, must be brought to their notice immediately but gently, and corrective measures taken to avoid recurrence. Also, in early stages, some form of documentation of the process should be maintained. Notes of problems that may arise and are locally identified should be made and forwarded to senior NTP management. This could help in better understanding the process of collaboration and also contribute towards any future revision of operational guidelines. Continuous dialogue between involved partners is necessary to address identified problems and potential tensions. Proper use of the practical tools and process and outcome indicators referred to above will help monitor the progress and evaluate the outcome of PPM. Advocacy and Communications A good NTP is self-advocating, both for patients and for other care providers. It has been observed that as the services improve, more and more patients get attracted to them. This also helps in improving the image of the programme among other care providers. A successful and strong NTP is in a better position to elicit collaboration from other care providers. To generate and sustain interest in PPM, advocacy should be directed both at NTP managers and staff and their counterparts among other private and public provider groups. Improvements in communications are required at two levels-inter-provider communication and patient-provider communication. The NTP staff may need input to learn to communicate effectively with diverse provider groups and all care providers would benefit from lessons in improving their communication and interaction with TB suspects and cases. Providing information to patients on the availability of TB services in the public and private sectors and the charges they may or may not need to pay for different services offered would help make the

collaboration open and transparent and may also help minimize the possibilities of misuse and malpractice. The NGOs with expertise in communication and social mobilization may provide useful assistance in communicating with both providers and patients. Locally appropriate advocacy and communication methods and materials should be used giving due consideration to the social stigma attached to the disease and to those suffering from it. In conclusion, in different country settings, different types of private as well as public providers operate outside NTPs. They include informal village doctors, private general practitioners, large public hospitals, specialist physicians, NGOs, medical colleges, corporate health services, etc. Since WHO is embarking on the global PPM project, several initiatives in different countries have successfully engaged diverse health care providers in TB care and control. Evidence from such initiatives shows that the diversity of settings and provider types regardless, there are some common steps required to set up productive collaborations with the wide array of public and private care providers, steps that have been outlined in brief in this chapter. Evidence also indicates that once PPM is successfully implemented, it can contribute not only to increased case detection and cure rates for NTPs, but also to improved access to quality TB care and to cost savings for patients. National Tuberculosis Programme is primarily responsible for planning and implementing a PPM strategy. However, PPM can never happen without the involvement and commitment by the providers that constitute the PPM in health care. Furthermore, experience has shown that individual private or NGO sector institutions can play an igniting role for PPM, and take the lead even before NTP has started to plan for PPM. Even individual physicians, especially chest specialists who are local opinion leaders, can take the lead and catalyse further action from NTP. The ISTC is a tool designed primarily for practitioners who are operating outside the public health domain. It is foreseen that the standards will be an important tool for clinicians to start become actively involved in national TB control efforts, and take the lead when necessary and appropriate. The reader is referred to the chapter “The International Standards for Tuberculosis Care” [Chapter 67] for more details.

Public-Private Mix for Tuberculosis Control ACKNOWLEDGEMENT The authors acknowledge the assistance provided by Hannah Monica Yesudian in the preparation of this manuscript.

REFERENCES 1. Uplekar M, Pathania V, Raviglione M. Private practitioners and public health: weak links in tuberculosis control. Lancet 2001;358:912-6. 2. World Health Organization. The behaviour and interaction of TB patients and private for profit health care providers in India: a review. WHO/TB/97.223. Geneva: World Health Organization; 1997. 3. Uplekar M, Juvekar S, Morankar S, Rangan S, Nunn P. Tuberculosis patients and practitioners in private clinics in India. Int J Tuberc Lung Dis 1998;2:324-9. 4. Dandona R, Dandona L, Mishra A, Dhingra S, Venkatagopalakrishna K, Chauhan LS. Utilisation of and barriers to public sector tuberculosis services in India. Natl Med J India 2004;17:292-9. 5. World Health Organization. Involving private practitioners in tuberculosis control: issues, interventions, and emerging policy framework. WHO/CDS/TB/2001.285. Geneva: World Health Organization; 2001. 6. World Health Organization. The stop TB strategy: Building on and enhancing DOTS to meet the TB-related millennium development goals. WHO/HTM/TB/2006.368. Geneva: World Health Organization; 2006. 7. Raviglione M, Uplekar M. WHO’s new Stop TB Strategy. Lancet 2006;367:952-5. 8. Lönnroth K, Uplekar M, Arora VK, Juvekar S, Lan NT, Mwaniki D, et al. Public-private mix for DOTS implementation – what makes it work? Bull World Health Organ 2004;82:580-6. 9. World Health Organization. Public-private mix for DOTS: towards scaling up. Report from the 3rd meeting of the PPM subgroup for DOTS expansion. WHO/HTM/TB/2005.356. Geneva: World Health Organization; 2005. 10. World Health Organization. Report of the first meeting of the public-private mix subgroup for DOTS expansion. WHO/CDS/TB/2003.317. Geneva: World Health Organization; 2003. 11. World Health Organization. Public-private mix for DOTS. Global progress. Report of the second meeting of the public-

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

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private mix subgroup for DOTS expansion. WHO/HTM/ TB/2004.338. Geneva: World Health Organization; 2004. World Health Organization. Stop TB Partnership. The Global Plan to Stop TB, 2006-2015. Actions for life: towards a world free of tuberculosis. WHO/HTM/STB/2006.35 Geneva: World Health Organization; 2006. Hopewell PC, Pai M, Maher D, Uplekar M, Raviglione MC. International standards for tuberculosis care. Lancet Infect Dis 2006;6:710-25. World Health Organization. Cost and cost-effectiveness of public-private mix DOTS: evidence from two pilot projects in India. WHO/HTM/TB/2004.337. Geneva: World Health Organization; 2004. Floyd K, Arora VK, Murthy KJ, Lönnroth K, Singla N, Akbar Y, et al. Cost and cost-effectiveness of PPM-DOTS for tuberculosis control: evidence from India. Bull World Health Organ 2006;84:437-45. Dewan PK, Lal SS, Lönnroth K, Wares F, Uplekar M, Sahu S, et al. Improving tuberculosis control through public-private collaboration in India: literature review. BMJ 2006;332:574-8. Ambe G, Lönnroth K, Dholakia Y, Copreaux J, Zignol M, Borremans N, et al. Every provider counts: effect of a comprehensive public-private mix approach for TB control in a large metropolitan area in India. Int J Tuberc Lung Dis 2005;9:5628. World Health Organization. Engaging all health care providers in TB control. WHO/HTM/TB/2006.360. Geneva: World Health Organization; 2006. Hamid Salim MA, Uplekar M, Daru P, Aung M, Declercq E, Lönnroth K. Turning liabilities into resources: the informal village doctors and TB control in Bangladesh. Bull World Health Organ 2006;84:479-84. Lönnroth K, Aung T, Maung W, Kluge H, Uplekar M. Social franchising of TB care through private GPs in Myanmar: an assessment of treatment result, access, equity and financial protection. Health Policy Plan 2007;22:156-66. Pantoja A, Lal SS, Lönnroth K, LS Chauhan, Uplekar M, Padma MR, et al. Cost and cost-effectiveness of scaled up and intensive PPM DOTS in Bangalore. Int J Tuberc Lung Dis 2006;10:S281. Lönnroth K, Uplekar M, Blanc L. Hard gains through soft contracts: productive engagement of private providers in tuberculosis control. Bull World Health Organ 2006;84:87683.

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Building Partnerships for Tuberculosis Control

60 Nani Nair, J Kumaresan

INTRODUCTION In the mid 1980s and into the 1990s, the world saw a 20 per cent increase in global notification rates for tuberculosis [TB], spurred in part by rising human immunodeficiency virus [HIV] infection and acquired immunodeficiency syndrome [AIDS] prevalence in many parts of the world including the South-East Asia [SEA] Region (1-4). Tuberculosis was and continues to be the leading cause of death due to infectious diseases globally today (5). This led the Forty-fourth World Health Assembly in 1991 to adopt a resolution [WHA 44.8] that urged member countries to intensify TB control as an integral part of primary health care and called for the establishment of global targets for TB control (6). The targets set were to cure at least 85 per cent of all sputum smear-positive cases detected annually and detect at least 70 per cent of all cases estimated to occur annually, by the year 2000. The principle on which these targets was based was that early detection of infectious cases and effective treatment leading to cure would reduce the prevalence of TB by half over the next five years thereby reducing transmission, and thus, the incidence of new infections (7). At that time less than 20 countries globally had effective control programmes in place (8). In India, for example, a programme review in 1992 showed that only 30 per cent of patients with TB were being diagnosed; of these, only about one-third were being cured (9). Recognizing that decades of neglect, combined with deficiencies in national control programmes was contributing to the increasing morbidity and mortality due to TB around the world. The World Health Organization [WHO] in 1993, therefore, took the unprecedented step of declaring TB a global emergency (10). At the same time

WHO began to promote an approach (11) that combined key elements from early work carried out at the Tuberculosis Research Centre [TRC], Chennai [then called Madras] (12) and the National Tuberculosis Institute [NTI] Bengaluru [then called Bangalore] (13) in India, with practical tools for field implementation that had been developed and successfully implemented by Dr Karel Styblo of the International Union Against TB and Lung Disease [IUATLD] in Malawi and Tanzania (14,15). The elements of the approach were outlined in the “Framework for effective tuberculosis control” launched by WHO in 1994 (16) and these elements, in 1995 were packaged together as the DOTS strategy (17). During the next few years, the strategy, actively promoted worldwide by the WHO and the IUATLD and hailed by the World Bank as one of the most cost-effective of health interventions began to be increasingly adopted by more countries (18). By 2007, 202 out of 212 countries and territories had adopted and were implementing DOTS (19). A GLOBAL PARTNERSHIP FOR TUBERCULOSIS CONTROL Despite good progress in DOTS expansion and increased funding for TB control, the first global monitoring report on progress with DOTS published by the WHO in 1997 (20) showed clearly that the targets for TB control were not going to be achieved by 2000. While treatment success rates were close to 80 per cent, the percentage of infectious cases being detected lagged behind at 11 per cent of all estimated cases. In 1998 the WHO, therefore, convened an “adhoc committee on the TB epidemic” to analyse the reasons

Building Partnerships for Tuberculosis Control 855 for slow progress towards targets and make recommendations to the global community to accelerate progress (21). Among the recommendations made by the adhoc committee were the creation of a global charter among all key partners and countries with the highest burdens of disease [22 countries account for 80 per cent of global TB burden], involvement of the private sector and communities in national TB control efforts and the creation of a global drug facility. Later that year, Dr Gro Harlem Brundtland, then Director-General of the WHO, launched the Stop TB Initiative founded on the principle of a global partnership to address the lacunae pointed out by the adhoc committee and to accelerate action against TB control (22). As a result of the efforts of the newly launched Stop TB Initiative (23), several events with far reaching implications on global TB control followed in rapid succession in 2000 and 2001. A ministerial conference on TB and sustainable health involving several global partners and ministers of health, finance and planning from countries with the highest TB burden, was held in Amsterdam in March 2000 leading to the landmark “Amsterdam Declaration” to stop TB. In May 2000, the World Health Assembly endorsed the formation of a global partnership for TB control and, at the same time, considering that most countries had not reached the targets set in 1991, postponed these targets to 2005 (24). In 2001 a structure for a global Stop TB partnership was developed [Figure 62.4] and this was endorsed at first meeting of the Stop TB Partners forum in Washington in October 2001 (25). At this first forum of the partnership, then comprising of 80 partners and high-burden countries endorsed the Washington Commitment to Stop TB, committing themselves to the 2005 targets and to specific actions as outlined in the global plan to stop TB (26). Also in 2001, the G-8 at their 26th summit in Okinawa (27), committed to reducing TB deaths and prevalence by half by 2010 and in the same year, the United Nations at its Millennium Assembly, adopted the Millennium Development Goals which included under one of its targets, the halting and reversal of the incidence of TB by 2015 (28). In January 2002, the Global Fund to Fight AIDS, TB and Malaria [GFATM] was set up as a financial instrument to resource activities aimed at control of these three diseases (29). TB control was now firmly established on the global health agenda.

The Global Partnership to Stop TB today comprises of a membership of over 300 institutions and individuals and is a result of a paradigm shift in global thinking on TB as being purely a concern for public health, to thinking of TB as a health concern with political, social and economic dimensions. The partnership is also a result of a recognition that different partners, not all of whom are necessarily directly involved in health of TB control bring different strengths to conquering the multidimensional challenges posed by TB (30). The Global Partnership to Stop TB through the Global Plan to stop TB, based on the Stop TB strategy launched by WHO in 2006, aims to eliminate TB as a public health problem, a goal that has eluded the world despite there being effective means to control it since the 1950s. Its mission is to ensure that every TB patient has access to effective diagnosis, treatment and cure; to stop the transmission of TB worldwide; to reduce the inequitable social and economic burden of the disease; and to develop and implement new preventive, diagnostic and therapeutic tools and strategies to eliminate TB. In the nearer term, it aims to meet the World Health Assembly’s targets for 2005 and the G-8 targets for 2010, which are incorporated into the United Nations’ Millennium Development Goals for 2015. Seven technical working groups advance the work of the Stop TB Partnership in the following areas: DOTS expansion; DOTS-Plus for the treatment of the patients with multidrug-resistant tuberculosis [MDR-TB]; TB and HIV; new TB drug development [Global Alliance for TB Drug Development]; new TB diagnostics development, and new TB vaccine development [TB Vaccine Development Coalition] and advocacy communication and social mobilization [ACSM]. Different coalitions of partners are contributing to these different areas of work. The WHO plays a lead role in the DOTS Expansion Working Group and guides the 22 High Burden Countries in making detailed national plans for DOTS implementation. The Working Group on DOTS-Plus for MDR-TB aims to develop an affordable, effective and evidence based response to MDR-TB in resource-poor settings. It has succeeded in reducing the price of second-line TB drugs by up to 90 per cent through the use of competitive, pooled procurement. The Working Group on TB/HIV has the mandate of reducing the burden of TB in population with high prevalence of HIV.

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The three research and development Working Groups are making substantial progress. The Global Alliance on TB Drug Development is an independent public-private partnership that aims to accelerate the discovery and development of new TB drugs that shorten and improve treatment, and are affordable by lowincome countries. The Global TB Drug Facility [GDF] is another vital arm of the partnership (31). It aims to supply quality TB drugs to allow for continued DOTS expansion in many of the high burden countries that still lack resources to procure these. The working group on Advocacy and Communications and social mobilization and task force on Finance and Resource Mobilization provide common support for the various activities of the Stop TB Partnership. TUBERCULOSIS IN THE SOUTH-EAST ASIA REGION The SEA Region of WHO bears the highest burden of TB globally, with 38 per cent of the world’s TB cases being in this Region [Figure 4.3A]. Five of the 22 countries with the highest TB burden globally namely, Bangladesh, India, Indonesia, Myanmar and Thailand belong to this Region and together, account for 95 per cent of the three million new cases of TB and the nearly half a million deaths that occur every year in the Region. The incidence of disease is the highest in the economically productive age groups between 15 to 54 years, with 80 per cent of all new smear-positive cases being reported among people in this age group (32,33). This poses significant threat not only to health; but also to social and economic development in the Region.

Figure 60.1: Case detection and treatment success rates, SouthEast Asia Region, 1997-2006 Source: “Annual report on TB in the SEA Region, WHO/SEA, 2007 (reference 34)”

services have been consistently higher than 85 per cent, while case detection rates continued to rise steadily in most member countries. The current case detection rate, i.e., the percentage of cases being registered under DOTS

Progress with Tuberculosis Control The Region, however, has made remarkable progress with DOTS since the strategy was introduced in Member Countries in the early 1990s. National TB Control Programmes [NTPs] in the eleven countries of the WHO SEA Region and particularly the five high burden countries, Bangladesh, India, Indonesia, Myanmar and Thailand have rapidly expanded DOTS to ensure that good diagnostic and microscopy services were made available to the entire population of the people in the region by 2006. Treatment success rates in areas and programmes offering DOTS diagnostic and treatment

Figure 60.2: Case detection and treatment success rates achieved by member countries in South-East Asia Region in 2007 BAN = Bangladesh; DPRK = Democratic People’s Republic of Korea; IND = India; INO = Indonesia; MAV = Maldives; MMR = Myanmar; NEP = Nepal; SRL = Sri Lanka; THA = Thailand; TLS = Timor-Leste; SEAR = South-East Asia Region Source: “Annual report on TB control, National TB Programmes SEA Region member countries, December 2007 (reference 36)”

Building Partnerships for Tuberculosis Control 857 against the total number of new smear-positive cases estimated to occur annually is above 68 per cent [Figure 60.1] (34). Much of the progress in case detection in the Region is attributable to increasing case detection in India, which alone contributed to 67 per cent of the global increase in case detection in 2002 (35). Figure 60.2 (36) shows the treatment success rates being achieved by national programmes under DOTS in the countries of the SEA Region.

International Developmental Partners in the Region Countries in the SEA Region are fortunate to have strong vibrant ties with several international development partners and donors who are funding and technically supporting countries in the Region, some with the highest burdens of disease and the least ability to pay. Figure 60.3 shows the major donors and partner agencies providing technical and financial support for TB control in countries in the SEA Region.

Figure 60.3: Major donors and partners supporting tuberculosis control in South-East Asia Region ADB = Asia Development Bank; AusAID = Australian Government Overseas Aid Programme; BNMT = Britain Nepal Medical Trust; BRAC = Bangladesh Rural Advancement Committee; CDC = Centres for Disease Control and Prevention, Atlanta, USA; CIDA = Canadian International Development Agency; DFB = Damien Foundation Belgium; DFID = UK Department for International Development; EBF = Eugene Bell Foundation; GDF = Global Drug Facility; GFATM = Global Fund to fight AIDS, TB and Malaria; Gorgas = Gorgas TB Initiative; INF = International Nepal Fellowship; JICA = Japan International Cooperation; Agency; KNCV = Royal Netherlands Tuberculosis Association; LEPRA = a medical development charity that evolved from the British Empire Leprosy Relief Association; LHL = Norwegian Association of Heart and Lung Patients; MSH = Management Sciences for Health; NORAD = Norwegian Agency for International Development; NLR = Netherlands; PATH = Programme for Appropriate Technology in Health; PSI = Population Services International; RIT = Research Institute for Tuberculosis [Japan]; SAARC = South Asian Association for Regional Cooperation; TBCTA = Tuberculosis Coalition for Technical Assistance; IUALTD= International Union Against TB and Lung Disease; USAID = United States Agency for International Development; WB = World Bank; WHO = World Health Organization; 3DF = 3 Diseases Fund

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National Partnerships for Tuberculosis Control in the South-East Asia Region It had long been recognized in the Region that public health systems alone could not deliver health care to all. Health systems in the Region were already overstretched. Countries in the Region did not have sufficient sustainable resources to meet the basic health needs of their populations (37). Many were undergoing a difficult process of health sector reform in order to address this and increase access to primary health care services including DOTS to those who were least able to pay for services (38). NON-GOVERNMENTAL ORGANIZATIONS AND TUBERCULOSIS CONTROL The role of non-governmental organizations [NGOs], for example, in leprosy elimination (39), rehabilitation of the physically handicapped and more recently in the prevention and care of the HIV-affected (40) have strengthened both government and community beliefs that NGOs can indeed deliver and what is more, deliver most effectively. Their role in TB prevention and control has been no less significant (41). The DOTS strategy itself, considered the most cost-effective strategy to combat TB today was first developed by a NGOs, the IUATLD. Traditionally, provision of TB treatment services has been the most common area for collaboration. However, with the advent of DOTS, national government organizations participation in stopping TB has taken on even greater importance. Being closer to the communities they serve, being more credible, dependable and more integrated in the services they provide, NGOs have a distinct edge over Government workers in convincing TB suspects to undergo diagnostic tests, take their medicines regularly and report for the prescribed follow ups to ensure complete cure. They have a comparative advantage over the public sector in flexibility, commitment, drive, and a sense of urgency for change. Among the multitudinal ways in which NGOs can partner national programmes effectively in stopping TB, there is, however, one that stands out most prominently. The NGOs have a major role to play in advocacy and mobilizing government and community support to stop TB. Through building a powerful lobby, NGOs can wield their power to influence the future of TB. The role of NGOs has increased significantly over the past two

decades. Strong presence at international forums has led to increasing recognition of the influence they can wield and their potential to contribute. The Bangladesh Rural Advancement Corporation, Bangladesh An outstanding example of a successful government and NGO collaboration to stop TB is in Bangladesh. The Bangladesh Rural Advancement Committee [BRAC] (42) and the Damien Foundation, Bangladesh, together with seven major NGOs in the country are providing DOTS services to over 90 per cent of the population. Their responsibilities in TB control include dissemination of TB information to communities; identifying and diagnosing TB suspects; providing DOTS and following up TB patients during and after treatment completion. The nucleus of the BRAC TB Control Programme is the utilization of community-based voluntary health workers, called Shastho Shebikas. These are local women, averaging 25 to 35 years of age, most having no formal education but trained by BRAC on essential health activities including TB control. Their responsibilities in relation to TB control are: [i]to disseminate information about TB to the community; [ii] to identify suspected patients and refer them to diagnostic centres for a sputum smear examination; to ensure directly observed treatment; [iii] to dispense medication during the initial and continuation phases; and [iv]to follow up on TB patients during and after treatment completion. An individual who is diagnosed with TB signs a contract with BRAC, witnessed by two community members including Shastho Shebikas, and pays a bond of takas 200 [US$5], to ensure that he or she completes the treatment. This amount is returned to the patients if they complete their prescribed treatment regimen and they pay takas 125 to the Shastho Shebikas for her work in identifying patients and ensuring that the patients take their medication daily. Treatment outcomes in the areas covered by BRAC, are very impressive. The cure rate has been over 85 per cent since 1995 and as high as 91.7 per cent in some areas. Case detection rates have also been high at close to 60 per cent in these areas with the proportion of women among the total number of cases diagnosed as well as the proportion of sputum-positive cases to the total cases being higher in the case of this community-based TB programme.

Building Partnerships for Tuberculosis Control 859 The reader is also referred to the chapter “Nongovernmental organizations and tuberculosis control” [Chapter 61] for more details. THE PRIVATE HEALTH SECTOR AND TUBERCULOSIS CONTROL In many high TB-burden countries, there is evidence that a substantial proportion of TB suspects and patients seek care from private and non-government providers (43-49). Most of these providers used unstandardized diagnostic and treatment protocols resulting in incorrect diagnosis, and poor treatment outcomes, with the risk of developing drug-resistant TB (44). Furthermore, in the absence of any legislation to notify these cases, most patients were not being reported. There were serious gaps in the perceptions and practice of private providers (45). Developing partnerships with health providers outside the government health system, and especially with private health providers was, therefore, critical to progress with DOTS. The reader is referred to the chapter “Public-private mix for tuberculosis control” [Chapter 59] for more details. Examples of ongoing Public-Private Initiatives in Tuberculosis Control in the Region Mahavir Trust Hospital, Hyderabad, India In a joint effort between the Government and the private sector, a charitable specialty trust hospital, Mahavir Hospital in Hyderabad, India undertook a project involving individual private practitioners in the DOTS programme (50). This project, initiated in 1995, currently covers a population of 500 000 in the city. Following a basic situation analysis where it was found that up to 80 per cent of patients sought treatment in the private sector and that most private facilities were not following national guidelines for either diagnosis or treatment, an intervention, first to sensitize private practitioners to the programme, and then to develop a model for collaboration, was developed with the charitable trust hospital functioning as an inter-phase between the government and individual private practitioners. A campaign was launched to inform local physicians about DOTS and to create a mechanism for referral of TB patients with the assurance that the private practitioner would continue to be the patient’s primary careprovider. A referral card was developed, and following

initial diagnosis, counselling and treatment of TB patients at the Mahavir Hospital, patients were referred back to identified DOTS centres within easy walking distance of their homes. Flexible timings were also ensured. The results of this programme have been outstanding. Nearly two-thirds of the patients were referred by the private practitioners in the project area and women accounted for nearly half of all smear-positive cases. National goals of 75 per cent case finding and a cure rate of more than 92 per cent among new smear-positive patients have been achieved. This experience shows that a strategy of collaboration between the public and private sectors is feasible and cost-effective. Kathmandu Valley, Nepal The NTP in Nepal had extended the DOTS strategy to 75 per cent of the country by end 2000. With cure rates well over 85 per cent, it was appropriate to focus on the private sector before the HIV epidemic and the development of multi-drug resistance became major concerns. Indirect evidence had shown that case detection in the public sector was around 50 per cent, with nearly 70 per cent of antituberculosis drug inputs being accounted for by the private sector. Private-public collaboration was considered especially important in urban areas in view of rapid population growth, high burden of disease, weaker public health services with a rapidly expanding private sector and the availability of over-the-counter antituberculosis drugs. A model for service linkage with private practitioners was, therefore, developed in one municipal ward, Lalitpur, in the Kathmandu valley (51). The Lalitpur Municipality has a population of 200 000 and was selected since it was close to Kathmandu. One hundred private practitioners were involved in this project. Following needs assessment and interviews with private practitioners, a working group as well as local DOTS committees consisting of all stakeholders were created. Standard case management protocols were developed and private practitioners were trained. Service providers [microscopy centres, treatment centres and sub-centres] were identified. These included five urban DOTS treatment centres and four diagnostic centres. Health workers, volunteers and social workers were trained to implement DOTS and late patient tracing mechanisms were developed with NGO support. Feedback to private practitioners was arranged through periodic private practitioner clinic visits. An informal

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Coalition Against Tuberculosis [CAT] involving the District Health Office, NGOs, the local municipality and members from the community was formed. Private practitioner referrals have contributed significantly to case-finding for the NTP. Presently, nearly a fifth of new registered cases by the NTP in Lalitpur are referred by the private practitioners. Treatment success rates in the project area rose to over 90 per cent showing that by sensitizing the private practitioners and providing appropriate information, it is possible to build on the strengths of local health services. These examples prove that it is possible to induct private health care providers into public health programmes with an intermediary organization coordinating between NTPs and private providers. The NTP fulfils a stewardship role ensuring technical support, training, quality microscopy services and antituberculosis drugs. A strong referral and feedback system coupled with regular supervision to offer support [rather than exercise control] remains at the heart of a sustainable collaboration. Long-term sustainability can be ensured by maintaining motivation among private practitioners, leaving the “ownership” of their patients with them, and allowing some degree of autonomy within the DOTS framework. Building then on the strengths of the private providers emerges as a successful and replicable proposition. Some common determinants of success that emerged from a detailed cross-site analysis of public-private mix [PPM] DOTS projects are: [i] government commitment to PPM is the sine qua non of the partnership; the government should finance and provide stewardship to PPM operations, in particular, it should subsidize drug costs; [ii] it is important to invest time for dialogue between all stakeholders in order to build trust and to achieve a high level of agreement on common goals for PPM; when conflicts of interest exist, they need to be identified early and discussed openly; [iii] using an NGO, or a medical association or some such intermediary ground may facilitate collaboration, especially when there is an initial distrust between government sector, NTP and private providers; [iv] improvement in referral and information systems through simple practical tools is an essential component both for the effective operationalization and evaluation of PPM; [v] training is crucial; it is as important to assure that NTP staff members are sensitized to the PPM philosophy, as they

are to sensitize private providers to the DOTS philosophy; [vi] sufficient supervision monitoring of private providers is required; this is ultimately the responsibility of the government sector; and [vii] providing drugs free of charge to patients improves treatment outcome, promotes equity and is also a tool for steering private providers through formal or informal “drugs for performance contracts”. These initial pilots are now spurring the formulation of national policy on public-private partnership for NTPs around the Region. India is among the first countries in the Region to frame a national policy and develop guidelines for the involvement of private providers in DOTS (52). At the present time, however, the scale of publicprivate collaboration is insufficient to show a demonstrable impact on national case finding and treatment outcomes. Efforts need to be directed at scaling-up successful initiatives without diluting the benefits accrued from the small-scale projects. The corporate sector could play an important role and has a tremendous potential to mobilize additional resources. Its involvement in health care delivery, research and development of new drugs and diagnostics and human resource development could be very promising. MEDICAL COLLEGES AND THEIR ROLE IN THE FUTURE OF TUBERCULOSIS CONTROL The NTPs did not initially attempt to reach out to medical schools and provide them with the necessary information to make a useful contribution in DOTS implementation. The medical academia on their part perceived national programme practice as having been simplified to the point of being ineffective, and therefore, preferred individualized treatment regimens over the broad-based approach advocated by the NTPs. As a result, the strengths of the DOTS strategy as practised by the NTPs in the use of microscopy for diagnosis, standardized treatment regimens, ensuring follow-up and accountability through recording and reporting, were introduced in very few medical colleges. An attitudinal change was needed to bridge the gap between internationallyaccepted national programme strategies and medical teaching and practice (53,54). The reader is referred to the chapter “The role of medical colleges in tuberculosis control” [Chapter 58] for details.

Building Partnerships for Tuberculosis Control 861 DOTS AT WORKPLACES Tuberculosis affects people of all ages, but the hardest hit are those between 20 and 45 years of age, men and women who are at work during the most economically productive years of their lives. Out of 2.5 billion people in employment worldwide, over 50 per cent are at risk of developing active TB in their lifetime. The business sector, therefore, has a large stake in controlling TB. The illness imposes great costs on employers with disruption of work, reduced productivity, high treatment costs, and in addition, significant indirect costs that are expended for replacement and retraining of workers. On the other hand, business and industry can actively contribute by identifying TB suspects within their workforce, referring them for diagnosis, and helping affected employees to be treated in order to prevent the spread of TB both at the workplace and by extension, in communities. A workplace may be more of a community, than even the neighbourhood in which people reside. Most workers spend a significant proportion of their waking hours in their places of work. In some situations, the workplace may also be where workers live. The dire need to introduce TB control services in workplaces may be stronger than in any other. Employers must, therefore, help provide access to information and support sick workers and link TB control with other workplace issues, such as HIV/AIDS, elimination of other occupational health hazards, like silicosis. Employers and their organizations can play a vital role in promoting and implementing TB control activities. Workers and their organizations can collaborate in these activities and advocate for the needs of employees, including access to health care and observance of ethical aspects of employment. Strategies are needed to ensure maximum ‘buy-in’ by various partners in workplace TB control. Experiences from workplaces in a number of settings in Asia and elsewhere have demonstrated that implementing DOTS has been both successful and costeffective. The DOTS programme can easily be built on the existing health services being offered to workers and sustained through supervision and monitoring of all TB cases through management systems which are in place at workplaces (55-56). The introduction of TB control practices into the workplace, therefore, offers several benefits, like a healthier workforce, reduced medical costs, higher work morale, higher productivity, an enhanced image in

society through a credible demonstration of corporate social responsibility and an improved image in relation to customers, potential buyers etc. DOTS at Workplaces – An Example From Bangladesh Bangladesh: Tuberculosis Control in the Chittagong Export Processing Zone Chittagong is the largest industrial city in Bangladesh, and therefore, attracts a large number of people seeking work. There are over 600 garment factories in the city in addition to industries in the Chittagong Export Processing Zone [CEPZ]. These garment factories alone employ 1.8 million workers, 80 per cent of whom are females, between the ages of 15 to 35 years. Recognizing that health facilities at individual factory premises were inadequate, the Bangladesh garment manufacturers and exporters established two health centres with one doctor and one nurse at each. Forty-three DOTS treatment centres, seven of which function also as diagnostic centres, were also established. These centres were established through collaboration between the NTP, the city corporation, local NGOs and the National Anti-TB Association of Bangladesh, [NATAB]. Tuberculosis cases identified at the health centres are referred to nearest NTP centre. Within the CEPZ, operated by Bangladesh Export Processing Zone Authority [BEPZA], there are 117 industries, employing 83589 workers, mostly young women. The Youngone Group in Bangladesh, which produces and exports sportswear including garments, shoes, nylon fabrics, quilting and luggage, operates within the CEPZ. It employs 24000 employees of which 80 per cent are females in age group between 18 to 30 years, coming from many different districts in Bangladesh. Tuberculosis was found to be common among these factory workers. The medical staff also recognized that most workers concealed their illness for fear of loosing their jobs. Those with TB in the CEPZ either had to attend the CEPZ hospital, or the nearest NTP centre - as a result, most workers suffering from TB preferred to consult private practitioners. This resulted in most being treated incompletely. Recognizing that these workers were among the most vulnerable to TB on account of close regular contact with affected workers, the management of Youngone Industries decided to establish a DOTS centre at Youngone Industry in the

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CEPZ. So far the Youngone Industries have registered 186 cases of TB among its workers, of whom a third were smear-positive cases. As a result of this initiative, the company enjoys the economic benefit accruing from increased work efficiency and better morale among its workers, national and

international recognition, and a better corporate image. There is growing interest at the CEPZ hospital in establishing DOTS centre under NTP, due to the initiative by the Youngone Group. Youngone is also interested in establishing a wider partnership to address TB-HIV coinfection (57).

Table 60.1: Community-based care in delivery of DOTS services Year

Setting

Coverage

Community involved Components of care provided

Effectiveness

1982

Tribal hamlets in Tamil Nadu, India

Hamlets = 62 Population: 96000

Literate tribal youth

Identification of symptomatics; sputum collection and drug dispensing; transportation

Increase in casefinding by 20%

1987

Rural villages in Tamil Nadu, India

Villages = 44

Dais [Traditional birth attendants]

Identification of symptomatics; collection and transportation of sputum samples; distribution of drugs; monitoring drug consumption.

600 symptomatics identified in 5 years [sputum positive cases 2.8%] cure rate = 85%

1990

Urban and Rural settings, Philippines

Lay and church group volunteers

Observation of treatment

Cure rate in rural areas = 90% cure rate in urban areas = 80%

1991

Rural Thanas in Bangladesh

Community health workers

Identification of symptoImprovement in casematics; referral and finding; cure rate = 66.3% follow-up drug distribution and monitoring of drug consumption; default retrieval; health education

1992

Hill districts in Nepal

Traditional healers

Identification of symptomatics

Improvement of outpatient attendance in PHIs One-third of diagnosed patients are referred by healers

1996

Rural and urban provinces

Through-out the country

Village doctors

Direct observation treatment

Cure rate among new sputum positive patients = 90% cure rate among previously treated patients = 81%

1997

Slum areas in Madurai city in Tamil Nadu, India

46000

Student volunteers

Drug dispensing; chasing of defaulters

Treatment completion rate = 83% Default retrieval successful on 57% occasions

1997

Rural community National Demonstration Centres, Nepal

Social workers and community workers

Direct observation of treatment and default retrieval

Cure rate = 85%

PHIs = Peripheral health institutes Source: reference 58

Building Partnerships for Tuberculosis Control 863 THE MEDIA AND TUBERCULOSIS CONTROL The NTPs in the SEA Region recognize that the media has a very significant role in stopping TB. Through advocacy, publications, broadcasts and social mobilization activities, the media does not merely heighten public awareness about TB and mobilize a demand for TB services, but also carries out the critical advocacy effort needed to build the political will necessary for governments to sustain effective TB control. Forging partnerships with the media is easier today than ever before. The media has changed its image. It no longer remains a passive observer, merely feeding facts to apathetic audiences. With rising health literacy, the media is beginning to respond to the peoples’ demand for more and more information on health matters. It is beginning to look more critically at the multi-dimensional determinants of health in the world today. TB is undeniably one of the major health concerns in the region. The NTPs need to provide the media with factual information to make TB more visible in the eyes of the government and the people, to caution on the dangers of ignoring the worsening epidemic and to highlight the efforts being made and successes with the DOTS strategy in beginning to overcome one of the biggest public health challenges of today. DOTS promises high cure rates for those afflicted with TB. The media offers some of the most cost-effective ways to inform people of the signs and symptoms of TB, to avail themselves of the free TB diagnostic and treatment services and to create a demand for these services. “PANOS” is a media agency with an interest in highlighting health issues (59). The agency held two regional workshops for the print media from SEA Region. International and regional experts on TB and its control explained various aspects of the disease to the participating journalists. These efforts of PANOS resulted in a spate of articles in national dailies and weeklies in many Asian countries during subsequent years and in a book, “Stopping A Killer”. COMMUNITY CONTRIBUTION TO TUBERCULOSIS CONTROL Partnerships for disease control also implies looking for new opportunities to work closely with communities. Each community’s problems are best understood by them and solutions, therefore, also lie with them. Scaling up

services at the community level through greater community involvement and indeed active participation in delivering DOTS services are essential for future sustainability. Community-based care in a number of settings has been demonstrated to be very cost-effective. Table 60.1 (58) shows the key features of nine studies undertaken between 1978 and 1997 in several Asian countries. The studies reveal that community TB services have been explored in various socio-cultural settings and that a range of communities have been involved with different means. All these projects point out the acceptability of services and record that the effectiveness is better than that of programmes operating only through public health institutions. The NTPs need to involve communities on a wider scale, ensuring first that quality services are in place within the public health system. A new vision, based on partnerships is clearly essential to build national capacities to deliver health for all and to deal with the many different but interconnected forces involved in delivering health services, including DOTS. These needed to encompass all the requirements for delivering effective health services including human resources, financing and service infrastructure. In order to increase the reach of DOTS to all, several initiatives have been taken around the world and in the SEA Region to build partnerships with other sectors—the private health sector, NGOs, business and industry, medical schools, the media and with civil society have all being involved to widen the resource base, reach and utilization of DOTS. These partnerships have helped to integrate the strengths of individual partners into national and local programmes, initiated pilots that have then been developed into regular programmes and enhanced national capacities to deliver primary health care. Wider and more inclusive partnerships need to be forged to meet the manifold challenges posed by TB, both globally and in the SEA Region. REFERENCES 1. World Health Organization. WHO report 2008. Global Tuberculosis Control: surveillance, planning, financing. WHO/HTM/TB/8.393. Geneva: World Health Organization; 2008. 2. Cegielski JP, Chin DP, Espinal MA, Frieden TR, Rodriquez Cruz R, Talbot EA, et al. The global tuberculosis situation.

864

3.

4.

5.

6.

7.

8. 9.

10. 11.

12.

13. 14. 15.

16.

17.

18. 19.

20.

Tuberculosis Progress and problems for the 20th century, prospects for the 21st century. Infect Dis Clin North Am 2002;16:1-58. Narain JP, Raviglione MC, Kochi A. HIV-associated tuberculosis in developing countries: epidemiology and strategies for prevention. Tuber Lung Dis 1992;73:311-21. Yanai H, Uthaivovravit W, Panich V, Sawanpanyalert P, Chaimanee B, Akarasewi P, et al. Rapid increase in HIVrelated tuberculosis, Chiang Rai, Thailand, 1990-94. AIDS 1996;10:527-31. Sudre P, ten Dam G, Kochi A. Tuberculosis: a global overview of the situation today. Bull World Health Organ 1992;70:14959. World Health Organization. Forty-fourth World Health Assembly. Resolutions and decisions. Resolutions WHA 44.8/WHA 44/1991/REC/1. Geneva: World Health Organization; 1991. Styblo K, Bumgarner JR. Tuberculosis can be controlled with existing technologies: evidence. Tuberculosis Surveillance Res Unit Progress Rep 1991;2:60-72. Raviglione MC. The TB epidemic from 1992 to 2002. Tuberculosis 2003;83:4-14. World Health Organization /South-East Asia Regional Office. Tuberculosis Programme Review, India. WHO/TB/95.186. New Delhi: World Health Organization; 1992. Nakajima H. Tuberculosis: a global emergency. World Health 1993;46:3. Kochi A. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle 1991;72:1-6. Tuberculosis Chemotherapy Centre. A concurrent comparison of home and sanitorium treatment of pulmonary tuberculosis in south India. Bull World Health Organ 1959;21:51-144. Nagpaul DR, Savic DM, Rao KP, Baily GV. Case-finding by microscopy. Bull Int Union Tuberc 1968;41:48-158. Styblo K. Epidemiology of tuberculosis. The Hague: Royal Netherlands Tuberculosis Association; 1991. Rouillon A. The mutual assistance programme of the IUATLD. Development, contribution and significance. Bull Int Union Tuberc Lung Dis 1991;66:159-72. World Health Organization. Global Tuberculosis Programme. Framework for effective tuberculosis control. WHO/TB/ 94.179. Geneva: World Health Organization; 1994. World Health Organization. What is DOTS – A Guide to understanding the WHO-recommended TB control strategy known as DOTS. WHO/CDS/TB/99.270. Geneva: World Health Organization; 1999. World Bank. World Development Report 1993. Investing in Health. New York: Oxford University Press; 1993. World Health Organization. WHO report 2007. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2007.376. Geneva: World Health Organization; 2007. Raviglione MC, Dye C, Schmidt S, Kochi A. Assessment of worldwide tuberculosis control. WHO Global Surveillance and Monitoring Project. Lancet 1997;350:624-9.

21. World Health Organization. Global Tuberculosis Programme. Report of the ad-hoc Committee on the Tuberculosis Epidemic. WHO/TB/98.245. Geneva: World Health Organization; 1998. 22. Stop TB Initiative. Tuberculosis and sustainable development. Report of a conference. WHO/CDS/STB/2000.6. Geneva: World Health Organization; 2000. 23. Stop TB Initiative. Amsterdam Declaration to Stop TB: a call for accelerated action against tuberculosis. Geneva: World Health Organization; 2000. 24. WHO. Fifty-third World Health Assembly. Resolution WHA 53.1. WHA 53/2000/REC. Geneva: World Health Organization; 2000. 25. Global Partnership to Stop TB. Washington Commitment to Stop TB. WHO/CDS/STB/2001.14a. Geneva: World Health Organization; 2001. 26. Global Partnership to Stop TB. Global Plan to Stop TB. WHO/ CDS/STB/2001.16. Geneva: World Health Organization; 2001. 27. G-8 Communiqué Okinawa 2000. Available at URL: http://www.stoptb.ca/Okinawa.html. Accessed on September 3, 2008. 28. Millennium Development Goals. Available at URL: http://www.development goals.org/about_the_goals.html. Accessed on September 3, 2008. 29. The Global Fund to Fight AIDS, TB and Malaria. Available at URL: http://www.theglobalfund.org. Accessed on September 3, 2008. 30. Kumaresan J, Heitkamp P, Smith I, Billo N. Global Partnership to Stop TB: a model of an effective public health partnership. Int J Tuberc Lung Dis 2004;8:120-9. 31. World Health Organization. Global TB Drug Facility. A Global mechanism to ensure uninterrupted access to quality TB Drugs for DOTS implementation. WHO/CDS/TB/ 2000.10A. Geneva: World Health Organization; 2001. 32. World Health Organization South-East Asia Regional Office. Tuberculosis control in the South-East Asia Region. The Regional Report 2003. SEA/TB/260. New Delhi: World Health Organization Regional Office for South-East Asia; 2003. 33. UNAIDS/WHO. Joint United Nations Programme on HIV/ AIDS. UNAIDS/03/39E. UNAIDS: Geneva; 2003. 34. Annual report on TB in the SEA Region, WHO/SEA, 2007. 35. World Health Organization South-East Asia Regional Office. Joint Tuberculosis Programme Review. SEA/TB/265. New Delhi: World Health Organization Regional Office for SouthEast Asia; 2003. 36. Annual report on TB control, National TB Programmes SEA Region member countries, December 2007. 37. Commission on health research for development. Health research: essential link to equity in development. New York: Oxford University Press; 1990. 38. World Health Organization. Expanding DOTS in the context of a changing health system. WHO/CDS/TB/2003.318. Geneva: World Health Organization; 2003.

Building Partnerships for Tuberculosis Control 865 39. Murthy KJ, Almeida JA, Ramana GV, Ishwesiah B. Publicprivate mix – a new approach to DOTS. Int J Tuberc Lung Dis 1998;2:52. 40. Marshall P, Hunt J. Non-Government Organizations: imperatives and pitfalls. In: Ling G, Porter D, editors. No place for borders: the HIV/AIDS epidemic and development in Asia and the pacific. New York: St. Martin’s Press; 1997. p.124-35. 41. World Health Organization Regional Office for South-east Asia. NGOs and TB control: principles and examples for organizations joining the fight against TB. SEA/TB/213. New Delhi: World Health Organization Regional Office for SouthEast Asia; 1999. 42. Chowdhury AM, Chowdhury S, Islam MN, Islam A, Vaughan JP. Control of tuberculosis by community health workers in Bangladesh. Lancet 1997;350:169-72. 43. Newell J. The implications for TB control of the growth in numbers of private practitioners in developing countries. Bull World Health Organ 2002;80:836-7. 44. Uplekar M, Pathania V, Raviglione M. Private practitioners and public health: weak links in tuberculosis control. Lancet 2001;358:912-6. 45. Vyas RM, Small PM, DeRiemer K. The private-public divide: impact of conflicting perceptions between the private and public health care sectors in India. Int J Tuberc Lung Dis 2003;7:543-9. 46. World Health Organization. Involving private practitioners in tuberculosis control: issues, interventions and emerging policy framework. WHO/CDS/TB/2001.285. Geneva: World Health Organization; 2001. 47. Kumar MK, Nair PK, Dewan PK, Frieden TR, Sahu S, Wares F, et al. A Public–private sector collaboration to improve tuberculosis case-detection and treatment, Kannur District, India, 2001-2002. Int J Tuberc Lung Dis 2005;9:870-6. 48. World Health Organization South-East Asia Regional Office. Report of the 1st meeting of the South-East Asia Stop TB Partners Forum. SEA/TB/268. New Delhi: World Health Organization Regional Office for South-East Asia; 2004. 49. World Health Organization. Cost and cost-effectiveness of public-private mix DOTS: evidence from two pilot projects

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

in India. WHO/HTM/TB/2004.337. Geneva: World Health Organization; 2004. Murthy KJ, Frieden TR, Yazdani A, Hreshikesh P. Publicprivate partnership in tuberculosis: experience in Hyderabad, India. Int J Tuberc Lung Dis 2001;5:354-9. World Health Organization South-East Asia Regional Office. Involving private practitioners in TB and STI control. Report of an Informal Consultation, Bangkok, 20-22 February 2001. SEA/TB/235 and SEA/STD/40. New Delhi: World Health Organization Regional Office for South-East Asia. 2001. Central TB Division, Directorate General of Health Services. Involvement of private practitioners in the Revised National Tuberculosis Control Programme. New Delhi: Ministry of Health and Family Welfare; 2002. World Health Organization South-East Asia Regional Office. Enhancing the role of medical schools in STI/HIV and TB control. SEA/AIDS/118, SEA/TB/228. New Delhi: World Health Organization Regional Office for South-East Asia; 2000. Central TB Division, Directorate General of Health Services. TB India 2004. RNTCP Status Report. New Delhi: Central TB Division; 2004. World Health Organization, International Labour Organization. Guidelines for workplace TB control activities. The contribution of workplace TB control activities to TB control in the community. WHO/CDS/TB/2003.312. Geneva: World Health Organization; 2003. World Economic Forum. Global Health Initiative: private sector intervention case example. Available at URL: http// www. weforum.org/globalhealth. Accessed on September 04, 2008. World Health Organization South-East Asia Regional Office. Report of DOTS in the workplace. New Delhi: World Health Organization Regional Office for South-East Asia; 2004. World Health Organization. Community contributions to TB Care: practice and policy. Review of experience of community contribution to TB care and recommendations to national TB programmes. WHO/CDS/TB/2003.312. Geneva: World Health Organization; 2003. Chowdhary A, Griffiths E, Susha B, editors. Stopping a killer. Kathmandu: PANOS Institute South Asia; 2002.

Non-governmental Organizations and Tuberculosis Control

61 Ian Smith

INTRODUCTION We live in a changing world. Relationships and roles are being redefined, as barriers are broken down, and organizations discover new ways of working together. Vocabulary is changing to reflect these developments, and words and phrases like “...networking ...cross-cutting issues ...multisectoral ...coalitions ...partnership ...collaboration ...” occur with increasing frequency in documents and discussions. These are not simply cliches born of the latest trends in health development fashion but they reflect the vision and action of organizations striving to find ways of increasing efficiency and effectiveness. These organizations understand that vertical approaches to service delivery are inefficient, that selfish competitiveness must be replaced by a rational and equitable distribution of resources, and that collaboration creates synergism, i.e. multiplying the positive impact of endeavours. Previous distinctions separating government and non-government, public and private, are disappearing as organizations learn to work together, and value the contributions of each other. This is seen clearly in the partnerships that have developed between government and non-governmental organizations [NGOs] to fight communicable diseases. Within the South-East Asia Region, NGOs make a vital contribution to disease control that is increasingly recognized by governments and international development partners. Tuberculosis [TB] control provides an excellent illustration of the value of these partnerships. Tuberculosis is a devastating disease, killing over a million people a year in the region, and infecting over a third of the population.

Across the region, NGOs and governments have developed a diverse array of innovative approaches to implement DOTS, the World Health Organization [WHO] recommended control strategy for TB, in response to the TB epidemic. The Revised National Tuberculosis Control Programme [RNTCP], Government of India reported that 2946 NGOs were participating in the programme in 2008 (1). International NGOs directly support TB control activities in 46 of the 75 districts of Nepal, and the Nepal Antituberculosis Association [NAA], one of the oldest national NGOs in the country, has activities in 28 districts. In Bangladesh, NGOs provide services in the majority of thanas, under contractual agreements between the Government of Bangladesh [GoB], the Bangladesh Rural Advancement Corporation [BRAC], an indigenous NGO in Bangladesh and the Leprosy Co-ordinating Committee [LCC], and provide treatment to over 70 per cent of patients registered in the country. National antituberculosis associations have played an important role in the history of TB control and continue to be active in many countries of the region, such as Bangladesh, India, Nepal and Sri Lanka. Roles have changed through, and many national and international NGOs are moving from their traditional roles of education and service provision, supported by voluntary contributions, to community, development and advocacy, with grant aid from funding agencies, including governments (2,3). Formal partnerships between governments and NGOs are developing rapidly. The Global Partnership to Stop TB, established in 2000, now comprises 450 partner organizations, the majority of which are NGOs (4). Stop TB is also promoting the development of national

Non-governmental Organizations and Tuberculosis Control partnerships, and has produced several tools to facilitate this process (5). In large countries, particularly those with a federal government system, partnerships at the state or district level may be more effective in ensuring collaboration, and evidence of the strengths and weaknesses of such coordination mechanisms is increasingly becoming available, for example from Pune and Mumbai in Maharashtra, India (6,7). A major catalyst to the development of national coordination mechanisms involving NGOs has been the Global Fund to Fight AIDS, Tuberculosis and Malaria [GFATM] (8). It was established in 2001, as an innovative approach to increase funds to tackle these three diseases. A key element in the grant-making process of the GFATM is the endorsement of funding proposals by the Country Coordination Mechanism [CCM], which also oversees implementation of the grant. The rules require that CCMs incorporate representatives from civil society, including local NGOs, and people living with the diseases (9). The effectiveness of CCMs is being watched closely, with particular attention being given to the role and involvement of NGOs (10). WHY SHOULD NON-GOVERNMENTAL ORGANIZATIONS BE CONCERNED ABOUT TUBERCULOSIS? Several factors have led to recognition by many NGOs that they need to play an important role in the fight against TB. Tuberculosis Causes a Huge Burden of Disease, Suffering and Death Many NGOs have a mandate to address health problems, and TB is one of the most serious threats to the health of people of South-East Asia, with more than three million people developing the disease in the region every year (11). DOTS is Cost-Effective Tuberculosis control tops the list of interventions in primary health care. Effective TB treatment costs only $3 to $7 [about Rs 135 to Rs 315] for every health year of life gained (12).

867

Tuberculosis is a Human Rights Issue The effect of TB is disproportionately great on people who have been deprived of some of their basic rights, such as prisoners and refugees (13). Tuberculosis is a Gender Issue Fewer women are registered for TB treatment than men (14). One contributing factor is that women have less access to health care services. Tuberculosis is the single biggest killer of young women. Tuberculosis in men also has a profound effect, on the well-being of women and families. Tuberculosis is a Child Health Issue Children get TB, but also suffer when their parents fall ill and die from TB. Tuberculosis is a Development Issue The effects of TB are felt most seriously by the poor and the poor get TB more than the rich. The DOTS can contribute to economic development. A study (15) from South-East Asia showed that every dollar invested in TB control gives a ’return’ of $55 [about Rs. 2475] to the community over a 20-year period. Specific initiatives are needed to ensure that the poor are not excluded from effective TB control services (16). DOTS is a Means to Improving the Overall Quality of Health Services The DOTS is an integrated approach to TB control at the district level of the health service. Introducing DOTS is a means to improvements in laboratory services, logistics, health management information systems, training and supervision. The Government Alone Cannot Defeat Tuberculosis Besides the government health services, other sectors such as NGOs and the private sector have a vital role in the national effort to control TB. In many countries, less than 50 per cent of TB patients are diagnosed and treated in government health services.

868 Tuberculosis The NGOs make a unique contribution at the community level. The NGOs are well-suited to participate in the national effort because of their credibility, access to communities, access to vulnerable populations, and greater flexibility of work. HOW CAN NON-GOVERNMENTAL ORGANIZATIONS BE INVOLVED IN TUBERCULOSIS CONTROL? Three basic principles govern the role of NGOs in TB control. These concern responsibilities roles, and approaches [Table 61.1]. First, governments retain the primary responsibility for maintaining and improving public health. Effective TB control demands a co-ordinated approach with standardized diagnostic, treatment, and information systems. The government must, therefore, take a lead in developing and maintaining these systems. The NGOs, along with the government and other agencies, become part of the national tuberculosis programmes [NTPs], and follow the same policies. Secondly, the role and nature of many NGOs has changed in recent years. Organizations have recognized that their primary role is to facilitate and support and to help build capacity of individuals, communities and governments (17). This is particularly important in TB control. Tuberculosis will not be eradicated in the shortterm, it will probably take at least 50 years. Few NGOs can be committed to provide services for that period of time, and recognize they must support and help communities and governments develop and maintain the services that are essential for TB control. This is true of most health and development problems, and illustrates the need for long-term commitment to sustainable TB control. Thirdly, greatest success is achieved when organizations select and approach that builds on their existing strengths. There is no ideal model for NGO involvement in TB control, but many alternative approaches, and the most suitable one will depend on the nature of the NGO. Organizations will be most successful if they build on

their existing skills and experience. For example, an NGO running hospitals or clinics would probably want to develop effective TB diagnosis and treatment services. On the other hand, organization involved in communitybased care for people with human immunodeficiency virus [HIV] infection and acquired immunodeficiency syndrome [AIDS], would probably want to incorporate community DOTS. EXAMPLES OF NON-GOVERNMENTAL ORGANIZATION APPROACHES TO TUBERCULOSIS CONTROL The diversity of approaches adopted by NGOs working in TB control is reflected in the following section, which attempts to categorize and describe the characteristics of different strategies. All of these complement the TB control activities of the government, and can make a major contribution to preventing transmission of TB, strengthening health services, and supporting communities and people with TB. These different approaches are not mutually exclusive, and a combination will often be required. Service Delivery The traditional model for NGO involvement in TB control has been service delivery through TB clinics and hospitals. Many NGOs in South-East Asia are still involved in this way and continue to make important contributions to TB care (18). In a service delivery approach, the NGO is responsible for diagnosing and treating people with TB. Treatment services may be specifically for TB patients, for example a TB clinic or a tuberculosis hospital. Alternatively, services may be provided as part of general health services, for example, in a hospital or health centre. The NGO health services are often of a high quality, and popular with patients. However, a service delivery approach requires long-term commitment, and has several other disadvantages [Table 61.2]. Health Service Management Support

Table 61.1: Principles of non-governmental organizations involvement in tuberculosis: strengths Facilitate and support community action Building on existing strengths Integrating DOTS in ongoing programme activities

Some NGOs prefer to avoid service delivery, and choose to support the development of effective government health services. They recognize that successful TB control programmes depend on good management, particularly for laboratory services, logistics and monitoring. These

Non-governmental Organizations and Tuberculosis Control Table 61.2: Disadvantages of non-governmental organizations health services General hospitals often have few or no community-based staff and cannot do defaulter tracing. Cure rates in general hospitals are often poor Service delivery is expensive because of the need to employ large numbers of staff Many hospitals charge fees for services, for example smear microscopy, whereas most National Tuberculosis Programmes have a policy of free diagnosis and treatment for tuberculosis patients Strong NGO health services sometimes may impede the development of the capacity of government health services Service delivery is unpopular with donors and may be difficult to sustain NGO = non-governmental organization; NTPs = National Tuberculosis Programmes; TB = tuberculosis

organizations help government staff carry out the management aspects of TB control, for example, needs assessment, planning, training, supervision, drug supply, quality assurance of sputum smear examination, and reporting. This support is in the form of skills development for government staff, and systems development to improve the efficiency and effectiveness of government services. It is less costly than a service delivery approach, does not require a long-term commitment, and involves capacity building; enabling government health workers to improve the quality of their work. Success relies on development of a close working relationship with government health services based on mutual trust and support. A weak health service infrastructure, frequent transfer of government health workers, and a wide gap between the salaries and incentives of NGO workers and government staff may hamper the development of this relationship. Community Participation and Community-based Care It is communities that are most affected by the TB epidemic, and it is communities that have most to gain from effective TB control measures. Involvement of the community is a key principle of TB control, because communities are most aware of local needs and circumstances, and most able to identify effective ways of delivering DOTS. Communities can identify local solutions to local problems, such as means of organizing observation of treatment. The NGOs can make an important contribution by facilitating links

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between government health services and local communities. Some countries have established district DOTS committees, to facilitate the introduction and local supervision of DOTS. Tuberculosis control can also be linked with other community development activities, such as community-based care, income generation, literacy and micro-credit. Many NGOs are committed to a communitybased approach, in which members of the community themselves take responsibility for identifying their own needs, planning interventions, implementing activities, and monitoring and evaluating outcomes. People with TB live in families and communities. These communities, in villages, towns, cities, slums, and factories provide valuable social support to the members of the community. Community-based care of people with chronic illness has become popular, as communities recognize that health services provided by institutions, such as health posts and hospitals, are limited in their capacity to provide adequate support within the home or local community. Relatives and neighbours already provide the majority of care; community-based care is a means of facilitating this existing system, and providing support to care givers. A basic principle of TB control is provision of care as close as possible to the patient’s home, often in the community to which the patient belongs. Community volunteers, local leaders, civil service organizations, colleagues in the work place, religious leaders, shopkeepers, teachers and many others can be actively and usefully involved in helping cure TB (19,20). There are two types of community-based care. The first type is care by outreach workers from the health services, or from NGOs. These are often salaried health workers or social workers, and may have been recruited from within the community. The second method is by volunteers from within the community [often as part of an NGO initiative]. Community-based care workers provide support, observation of treatment, nursing care, and education. Experience from Bangladesh (21) has demonstrated the cost-effectiveness of this approach, which achieved similar cure rates at one-third less the cost than through a health facility based approach (21). Community-based care has become popular in recent years as a result of the HIV epidemic. Many people with AIDS also have TB, and NGOs working in communitybased care for people with AIDS have discovered that they need to know as much about TB as HIV infection and AIDS. Tuberculosis is a treatable condition, and treating an AIDS patient for TB can make a very significant contribution to the quality and duration of life.

870 Tuberculosis Education Health education, information and communication [HEIC] is an important strategy in TB control. Many people with TB lack awareness of the basic symptoms of TB. Even if they do know about symptoms, they may not know that diagnosis and treatment is freely available through government or NGO health services or that TB can be cured. However, education of the community about TB treatment may have a negative impact, if treatment services are not widely available or are of poor quality. Provision of DOTS must go hand in hand with an education programme. There are many different ways of communicating messages about TB, for example, mass media [television and radio], printed materials [posters and pamphlets], and drama [puppet shows, street theatre]. One of the most important ways is by word of mouth. Health workers can play an important role in sharing information about TB during conversations with patients and people in the community. Advocacy The main role of advocacy in TB control is to draw the attention of policy makers, donors and the media to the magnitude of the TB epidemic, and to the benefits of DOTS. Many organizations have been most effective in advocating on behalf of groups in society who are disadvantaged due to social status, disease, gender, age, race, etc. Recently, these organizations have recognized that people affected by TB are often the most disadvantaged in society, and that advocacy on their behalf is vital in order to develop and maintain effective TB control programmes. World Tuberculosis Day [March 24th] provides a global opportunity to advocate for and with patients and programmes to raise awareness and increase commitment to DOTS. Around the world, organizations and individuals organize events to commemorate the anniversary of the discovery of Mycobacterium tuberculosis by Robert Koch in 1882. Patient’s Organizations There has been a rapid growth in self-help groups and patients’ organizations in the last few years, particularly for people with HIV infection and AIDS and other chronic illnesses. Such groups have many benefits, providing a social network for patients and their families, information and education about specific conditions, and advocacy

on behalf of people affected by a disease of disability. However, organizations specifically for TB patients are rare. The reasons are shown in Table 61.3. The potential for involving people with TB in existing self-help groups is great. These include micro-credit groups, adult literacy groups, and organizations for people affected by HIV infection and AIDS. Table 61.3: Reasons for the rarity of organizations for tuberculosis patients Tuberculosis is no longer a chronic disease; so most patients do not identify themselves as belonging to a group of long-term sufferers, with the exception of those with HIV-related TB, and those with MDR-TB Stigma may discourage people from identifying themselves as having TB Relatively few people with active tuberculosis live in the same geographical location [except in urban areas] Disadvantaged groups in society often have less experience in advocating on behalf of themselves TB = tuberculosis; MDR-TB = multidrug-resistant tuberculosis; HIV = human immunodeficiency virus

Research The principles underlying the DOTS strategy were first developed by an international NGO—the International Union Against Tuberculosis and Lung Disease [IUATLD] (22). Commitment to research has enabled many NTPs around the world to develop excellent TB control programmes in their own countries, NGOs with resources and a capacity for innovation and flexibility have the opportunity to conduct research. However, there is often a conflict between the need for standardization to ensure that everyone follows national policies and the need for innovation to improve the way TB control services are organized. Any deviation from NTP policy is only acceptable if it is agreed beforehand with the national authorities, and if it is part of a well-run research, designed to find solutions to important problems in the TB programmes. Research must be relevant to the needs of the NTP and must be scientifically rigorous. It must not hamper programmes by deviating attention and resources away from the primary purpose of introducing and maintaining excellent TB control services. Tuberculosis research does not have to be expensive. Important information can be gained simply and quickly by

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analyzing information in the routine recording and reporting system.

private practitioners, and act as the interface between the public and private sectors.

Partnerships with the Private Sector

Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome Organizations and Tuberculosis Control

In many countries of South-East Asia, the majority of people with TB are initially diagnosed and treated by doctors working in the private sector (23). This can cause serious problems for the NTPs, as poorly treated patients are a source of infection in the community, and may develop multidrug-resistant tuberculosis. Characteristics of poor management of TB patients in the private sector are shown in Table 61.4. Governments have three alternatives for improving the care of patients in the private sector. These are: education, Table 61.4: Characteristics of poor management of tuberculosis patients in the private sector Diagnosis by chest radiograph, without smear examination, leading to over-diagnosis of smear-negative TB and under diagnosis of smear-positive TB. Over-use of unnecessary and expensive tests Under-treatment; too few drugs, short duration, inadequate doses Over-treatment; prolonged duration No supervision of treatment No follow-up of late patients Inappropriate monitoring of treatment by chest radiograph Inadequate treatment records No reporting TB = tuberculosis

collaboration and legislation. The NGOs have an important role to play in establishing links between the public and private sectors in the first two of these approaches (2). The NGOs can educate private practitioners to adopt NTP diagnostic and treatment policies, and encourage them to refer patients for DOTS. In addition, NGOs may be able to provide diagnostic and treatment services to which private practitioners can refer patients. The NGOs can also provide outreach workers in the community for follow-up of late patients, and may be able to assist with recording and reporting of patients managed in the private sector. Links with national and local branches of medical associations, with chest physicians, para-medical workers, pharmacists and other associations may be possible. The NGOs can also help to facilitate the development of networks of

Tuberculosis is closely linked to HIV infection. People who are co-infected with TB and HIV have a very high risk of developing active TB, up to about 10 per cent a year. In many countries of South-East Asia, over 50 per cent of people with AIDS have active TB. There is also a strong link between TB control and prevention of AIDS. Treating people with TB and HIV infection prolongs their life, reduces suffering, and prevents the spread of TB to other people. The reverse is also true; if HIV increases, then the number of people with TB also rises. So preventing the spread of HIV is good for TB control. Organizations involved in HIV/AIDS prevention and care may not be fully aware of the close links between TB and HIV, and may not have experience in supporting people with TB (24). However, the close relationship between the two infections means it is important that HIV/AIDS organizations take urgent steps to learn about TB [and vice-versa], and find ways of integrating TB control activities into their work. Both programmes can serve as identification points for the two diseases and formally link with cross-referral of patients. Organizations involved in prevention of spread of HIV infection can develop educational approaches to help increase awareness of the links between HIV and TB. However, it is important that such educational approaches do not use fear to influence people. Creating fear may have a limited effect in the shortterm, but in the long-term can create stigma, and make life even harder for people with HIV and TB. SUCCESSFUL PARTNERSHIPS The NGOs involved in TB control do not exist in isolation, they form part of the NTP, which includes the community, the government, the private sector, and other NGOs. Successful participation in the NTP is facilitated by information, collaboration and coordination. Information A successful programme relies on a steady flow of information. The successful programme will generate

872 Tuberculosis information that it can share with others. Equally, a good programme needs information to ensure that it is up to date with current developments in TB control. Sources of information include newsletters, journals, books, conferences, meetings, training courses, and the World Wide Web.

Table 61.5: Key to successful networking Shared ownership Consensus Openness Transparency Communication

Collaboration There are many existing and potential partners working in TB control. Collaboration, working together, is an effective way of strengthening partnerships, reducing costs, sharing resources and skills, and maximizing the value of the contributions of different agencies. Co-ordination Co-ordination, keeping each other informed, is important to avoid duplication of effort. Networks are groups of individuals and organizations that meet and communicate together, and facilitate effective co-ordination. Most networks have formed to share information, co-ordinate activities, and advocate for action. Learning organizations are always keen to listen to others, to find out what works, and to share failures as well as successes. The rapid increase in the number of NGOs working in TB control, and the growth of information technology, has resulted in a profound change in the way information is shared. Many local and national TB networks have developed in recent years, such as the Tuberculosis Control Network [TBCN] in Nepal and the LCC in Bangladesh. Networks are needed at each level. In the community, networks of patients in self-help groups can offer mutual support to one another. At the district level, groups of NGOs can co-ordinate activities. At the national level, networks can share information and resources, and co-ordinate research, education and advocacy activities. There are some basic principles for successful networking [Table 61.5]. Shared ownership is important to prevent one organization dominating, or setting the agenda for the other organizations. A written constitution defining the structure, organization and ground rules of the network may help to prevent this. Rotating the chairperson and secretary and changing the venue of meetings can also help to prevent the emergence of dominant organizations or factions, which can be destructive. Because most networks exist to co-ordinate and share, decision making is usually by consensus,

though voting may be needed at times. Networks also have to define the membership. This will usually be open, with few restrictions or pro-qualifications, other than interest or involvement in TB control. Prior agreement on the scope of discussions within the network will help to prevent meetings from deviating from the main purpose. Appointment of a secretary responsible for arranging meetings, preparing and distributing the agenda, and keeping minutes of discussions, will help to increase the effectiveness of meetings. “Turf wars”, in which organizations compete for resources or areas of work, can be very destructive. These can be avoided by frequent communication and maintaining a commitment to openness and transparency in dealing with government and donors. The potential and need for NGO involvement in TB control is even greater than ever. The challenge of the TB epidemic, the recognized relationships between TB and poverty, human rights, women’s health, and child health, together with the added threats of HIV infection and AIDS and drug resistance, demand urgent attention from organizations committed to health and development. Opportunities for involvement are many, and most organizations will be able to find an approach that builds on their existing skills and experience. Community participation and co-ordination with the government and other NGOs are key principles that will ensure success (25). REFERENCES 1. Central TB Division. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. TB India 2008. RNTCP status report. New Delhi: Central TB Division. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India; 2008. 2. Nagpaul DR. NGOs as partners in National Tuberculosis Programme: Indian urban experience. Indian J Tuberc 1994;41:111-6. 3. Gellert GA. Non-governmental organizations in international health: past successes, future challenges. Int J Health Plan Manage 1996;11:19-31.

Non-governmental Organizations and Tuberculosis Control 4. Stop TB Partnership. Available at URL: http:// www.stoptb.org. Accessed on September 29, 2008. 5. Global Partnership to Stop TB. The power of partnership WHO/HTM/STB/2003.24. Geneva: World Health Organization; 2003. 6. Rangan SG, Juvekar SK, Rasalpurkar SB, Morankar SN, Joshi AN, Porter JD. Tuberculosis control in rural India: lessons from public-private collaboration. Int J Tuberc Lung Dis 2004;8:552-9. 7. Rangan S, Ambe G, Borremans N, Zallocco D, Porter J. The Mumbai experience in building field level partnerships for DOTS implementation. Tuberculosis [Edinb] 2003;83:165-72. 8. Investing in our future. The Global Fund to Fight AIDS, Tuberculosis and Malaria. Available at URL: http:// www.theglobalfund.org. Accessed on September 29, 2008. 9. The Global Fund to Fight AIDS, Tuberculosis and Malaria Country coordinating mechanisms. Guidelines for country coordinating mechanisms. Available at URL: http:// www.theglobalfund.org/en/apply/mechanisms/guidelines/ . Accessed on September 29, 2008. 10. Brugha R, Donoghue M, Starling M, Ndubani P, Sengooba F, Fernandes B, et al. The Global Fund: managing great expectations. Lancet 2004;364:95-100. 11. World Health Organization. Global tuberculosis control: surveillance, planning, financing: WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008. 12. World Bank. 1993. Investing in health: World development report. Oxford: Oxford University Press; 1993. 13. Global Partnership to Stop TB. Guidelines on social mobilization: a human rights approach to tuberculosis WHO/ CDS/STB/2001.9. Geneva: World Health Organization; 2001. 14. Holmes CB, Hausler H, Nunn P. A review of sex differences in the epidemiology of tuberculosis. Int J Tuberc Lung Dis 1998;2:96-104. 15. Sawert H, Kongsin S, Payanandana V, Akarasewi P, Nunn P, Raviglione MC. Costs and benefits of improving tuberculosis control: the case of Thailand. Soc Sci Med 1997; 44:1805-16.

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16. World Health Organization. Addressing poverty in TB control. Options for National TB Control Programmes. WHO/HTM/ TB/2005.352. Geneva: World Health Organization; 2005. 17. Broekmans JF. The point of view of a low prevalence country: The Netherlands. Bull Int Union Tuberc Lung Dis 1991;66:17983. 18. Neher A, Breyer G, Shrestha B, Feldmann K. Directly observed intermittent short-course chemotherapy in the Kathmandu valley. Tuber Lung Dis 1996;77:302-7. 19. Chowdhury AM, Chowdhury S, Islam MN, Islam A, Vaughan JP. Control of tuberculosis by community health workers in Bangladesh. Lancet 1997;350:169-72. 20. Wilkinson D, Davies GR. Coping with Africa’s increasing tuberculosis burden: are community supervisors an essential component of the DOT strategy? Trop Med Int Health 1997;2:700-4. 21. Islam MA, Wakai S, Ishikawa N, Chowdhury AM, Vaughan JP. Cost-effectiveness of community health workers in tuberculosis control in Bangladesh. Bull World Health Organ 2002;80:445-50. 22. Enarson DA. The International Union Against Tuberculosis and Lung Disease model National Tuberculosis Programmes. Tuber Lung Dis 1995;76:95-9. 23. Uplekar MW, Rangan S. Private doctors and tuberculosis control in India. Tuber Lung Dis 1993;74:332-7. 24. Maher D, Hausler HP, Raviglione MC, Kaleeba N, Aisu T, Fourie B, et al. Tuberculosis care in community care organizations in sub-Saharan Africa: practice and potential. Int J Tuberc Lung Dis 1997;1:276-83. 25. World Health Organization. Regional Office for South-east Asia. NGOs and TB Control. Principles and examples of organizations joining the fight against TB. New Delhi: World Health Organization. Regional Office for South-east Asia; 1999.

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Global Tuberculosis Control: The Future Prospects

62 D. Fraser Wares

“At the midpoint of the 20 th century, tuberculosis was recognized by all as the “White Plague”, undeniably the most dreaded enemy of the human race by any measure. Whether measured by prevalence, cost, social consequences, sheer misery or any yardstick, I believe that any observer of the time would consider the bacillus of tuberculosis as the enemy number one of the human race. None of us – myself included – believed that its control could be attained by medical means within this 20th century.” Professor H. Corwin Hinshaw Pioneer tuberculosis researcher at the Mayo Clinic, USA in the 1950-60s [quote from the introduction to his unfinished book titled “Conquest of a Plague”] INTRODUCTION Pre-1992 In 1960, the eminent figure in the field of tuberculosis [TB] Sir John Crofton, felt confident during a lecture at the Royal College of Physicians of London to state that: “I believe that we now have the weapons to defeat TB finally and completely,….”(1). In the same year as Sir Crofton delivered his lecture in London, the World Health Organization [WHO] at its seventh meeting stressed that “tuberculosis was the most important specific communicable disease in the world as a whole, and its control should receive priority and emphasis by the WHO and governments” (2). Important discoveries of drugs to treat TB, namely streptomycin, isoniazid and para-aminosalicylic acid [PAS], had been made in the two decades prior to Sir Crofton’s statement. Work by Crofton and colleagues in Edinburgh, Scotland (1), had

shown that by using multi-drug chemotherapy virtually all TB patients could be cured. In 1956, the Tuberculosis Chemotherapy Centre [TCC], now called Tuberculosis Research Centre [TRC], was opened in Madras [now called Chennai], India under the joint auspices of the Indian Council of Medical Research, the Madras State Government, the WHO and the British Medical Research Council. Through pioneering studies in the 1950s and 1960s, the TCC demonstrated the safety and efficacy of ambulatory TB treatment, the effectiveness of intermittent chemotherapy, and the feasibility and necessity of directly observed treatment (3,4). In the 1960s, the National Tuberculosis Institute [NTI] in Bengaluru [earlier known as Bangalore], India documented the importance of TB detection through sputum smear microscopy in primary health centres (5). During the 1960s, rifampicin, pyrazinamide and ethambutol were added to list of drugs effective against TB. Slowly over the next two decades, the threat of TB faded from the every day concerns of people in the developed world. Work in the 1970s and 1980s led by doctors such as Karel Styblo and Annik Rouillon of the International Union Against TB and Lung Disease [IUATLD], had begun to show that the principles laid out by the ground-breaking research of the previous two decades could also be implemented in developing countries, such as Tanzania (6). Yet in 1990 and 1991, reports were being published drawing attention to the fact that during the previous five years, there had been an ominous resurgence of TB, especially in sub-Saharan Africa (7). Between the mid 1980s and 1990, global notification rates had risen by

Global Tuberculosis Control: The Future Prospects 875 20 per cent (8). In October 1990, at a meeting of representatives of TB control programmes from all over the world convened by the WHO, Africa was described as “lost” to the epidemic of co-infection of human immunodeficiency virus [HIV] and TB (9). In an article in the Lancet that took its title, “Is Africa lost?”, from the WHO’s experts’ comments, the prominent authors stated “In conclusion, we are facing one of the greatest public-health disasters since the bubonic plague” (9). The HIV was stated to have “caused the greatest deterioration in the [TB] epidemiological situation in the last 100 years” (10). In India, where a National TB Programme had been initiated in 1962 and into which short-course chemotherapy [SCC] had been introduced since 1983, a study from south India showed mortality and failure rates of 28 per cent and 31 per cent, respectively amongst a cohort of patients during 1986-88 (11). Only 40 per cent of patients completed treatment, with this non-completion of treatment resulting in over a four-fold increase in mortality and two-fold increase in the failure rate when compared with patients who had completed treatment. In 1990, the Commission on Health Research for Development stated that “The magnitude of the TB problem is matched only by its relative neglect by the international community” (12). The next year, in an important global overview WHO repeated this message when it stated that “This report confirms the staggering global magnitude of the TB problem and the urgent need to revive antituberculosis control programmes throughout the world” (13). It was estimated that in 1990, nearly 8 million new cases of TB and 2.9 million deaths due to TB occurred worldwide, making TB then the leading infectious cause of death in the world. The TB notification rates in the 1990s had doubled or tripled in some African countries, such as Malawi, Tanzania and Zimbabwe, in as short a period as 10 years. In another important paper published in 1991, it was estimated that 1.7 billion people, i.e. a third of the human population, were infected with the tubercle bacillus (14). Over 95 per cent of the estimated eight million new cases and 2.9 million deaths were occurring in the developing world. At the same time, less than 15 countries worldwide were capable of reporting on treatment outcomes, less than half of TB cases were covered by proper treatment services, and less than half of the cases treated were cured (15). In 1992, the Government of India, together with WHO and the Swedish International

Development Agency, reviewed the National TB Programme. The Programme review showed that only 30 per cent of patients were diagnosed, out of which only 30 per cent were treated successfully (16). It had already been pointed out that such poor results of chemotherapy may slow down the natural decline of TB, worsen the epidemiological situation by keeping infectious cases alive to continue to transmit infection, and may lead to an increase in the prevalence of drug resistance (17). How had this situation arisen given the optimism of the previous decades? There were a number of factors to explain the resurgence of TB, or at least its halting decline, over the preceding two decades. Crucially, TB had come to be neglected as a public health issue by many countries and the international health community. In industrialized countries, advances in TB treatment had led to a relatively quick disappearance of the disease as a public health problem. The fact that the disease still had a huge impact on the poor in developing countries had slipped out of sight of the international health community. Many of these countries were in addition struggling to provide basic public services such as health services, due to the deterioration in their socio-economic conditions, increasing poverty, mounting debt and an ever growing population whose needs had to be met. Tuberculosis as a priority issue became less visible because of both WHO taking a strong step towards integration of programme functions and as a consequence of the health sector reform movement (18). In 1989, just before the establishment of a new TB Unit at the WHO, only two staff were responsible for WHO work on TB control worldwide (18). International funding for TB control work was minimal, and little, if any, important research was being conducted into new drugs, diagnostics or vaccines for TB. The spread of HIV and acquired immunodeficiency syndrome [AIDS], especially in sub-Saharan Africa, was playing an important role in further increasing TB morbidity and mortality [Figure 62.1] (19-22). Social and economic deterioration in countries of the former Soviet Union, with a resultant collapse of their public health services, had led to a dramatic rise in TB morbidity and mortality [Figure 62.1] (23). In the USA, the rise in TB notifications in the mid-1980s prompted the awakening of public health and TB experts in that country [Figure 62.2] (24,25). Identified reasons for the increase in the USA were growing urban poverty, TB control being given low priority with resultant deterioration of the TB control

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Figure 62.1: Trends in TB case notification rates, 1980-2000 in Africa and former Soviet Union HIV = human immunodeficiency virus; TB = tuberculosis Source: reference 22

THE RESPONSE: THE DOTS STRATEGY

Figure 62.2: Reported tuberculosis cases United States, 1979-1999 Reproduced with permission from “Schneider E, Castro KG. Tuberculosis trends in the United States, 1992-2001. Tuberculosis 2003;83:21-9 (reference 25)” Copyright [2003] Elsevier

programme infrastructure and poor TB control practices, and the burgeoning HIV epidemic (25). However, it soon became clear that a growing percentage of cases notified annually in the USA were among recent immigrants from low income and high TB burden countries HBCs, a direct consequence of the worldwide neglect of TB control (26,27). Many other industrialized countries were also seeing an increase in TB cases and driven by the similar factors of increased urban poverty, increase of TB cases seen amongst immigrants from HBCs and HIV (28). The finding that in industrialized countries, an increasing percentage of TB cases were amongst immigrants from HBCs, began to generate awareness that no sustainable TB control could be reached in the USA and many Western European countries without properly addressing the global TB epidemic.

Understanding the natural history of TB disease is key to the development of effective control strategies for the disease. In the absence of effective treatment, case fatality of TB was extremely high, around 50 per cent (29,30). An untreated smear-positive pulmonary TB individual remains, on an average, infectious for approximately two years, and then dies or recovers (31). In those two years, a single patient infects on an average 20 contacts (32). Of these infected contacts, on average two persons eventually break down with active disease, of which one will have smear-positive pulmonary TB (33). In this way, the chain of transmission of TB essentially remains steady, reflecting, in itself, a well-adjusted host-parasite relationship between man and Mycobacterium tuberculosis. Early detection of infectious cases and effective treatment leading to cure reduces the infectious period considerably, and thus, reduces transmission, thereby reducing the incidence of new infections. The failure to introduce effective treatment programmes in developing countries, by application of ambulatory therapy using standard chemotherapy regimens for smear-positive TB cases, had meant that the chain of transmission had continued unchanged in these countries. This despite an international consensus on the overall control strategy as expressed in the WHO Expert Reports on TB in 1964 and 1974 (34,35). The most important reason had been the failure to cure the sources of infection that were identified.

Global Tuberculosis Control: The Future Prospects 877 In an article in 1991, Dr Arata Kochi, the newly appointed head of WHO’s TB programme, highlighted three major programmatic deficiencies that had to be overcome: inadequate treatment services, high rates of failure to complete treatment, and the worldwide absence of adequate governmental surveillance and monitoring systems (14). It was also recognized that bacille CalmetteGuérin [BCG] did not have a significant impact on reducing transmission of infection and that renewed emphasis had to be given to the treatment of infectious cases, especially those whose sputum was smear positive. The WHO began to promote an approach that had been successfully implemented by Karel Styblo of the IUATLD in some of the poorest African countries, like Malawi and Tanzania. The approach was based on the concepts expressed in the 9th Report of the WHO Expert Committee on TB from 1974 (35). The prime objective of TB control programmes was to be the improvement of the cure rate of all patients under treatment, but most importantly of the smear-positive cases. During field implementation of these theoretical concepts in Tanzania, Styblo added the practical tools necessary to evaluate programme performance. The results showed that, even in a very poor country, it was possible to achieve high cure rates (6,36). Inspired by these observations, WHO requested all countries to focus on cure rates and achieve at least 85 per cent cure rates, and, later, expand TB services to detect more cases once the cure rates were permanently high (14). In May 1991, the 44th World Health Assembly met in Geneva and adopted a resolution [WHA 44.8] which: [i] urged member States to intensify TB control as an integral part of primary care using the new WHO strategy elaborated on the basis of the IUATLD approach; [ii] encouraged international partners to continue to help control TB by collaborating with National Programmes; and [iii] requested the establishment of global targets (37). The targets set were to cure 85 per cent of sputum smearpositive patients under treatment, and detect 70 per cent of such cases by the year 2000. If these targets were met, it was calculated that the result would be a 40 per cent decrease in infected contacts. This would lead to a rapid decrease in the prevalence of TB, which in turn would lead to a decrease in the incidence of the disease (38). In 1992, less than 20 countries were implementing a sound TB control strategy that would later be called the DOTS strategy. These included the countries assisted by the IUATLD and the Royal Netherlands Antituberculosis

Association [KNCV], such as Benin, Malawi, Mozambique, Nicaragua and Vietnam. They also included countries with a long history of adequate control, such as Algeria, Chile, Cuba and Uruguay. Finally there were two countries, China and Peru, in the initial phase of implementation of programmes that would become successful models later in the decade (39). A major boost to global TB control efforts was the publication of the World Bank’s 1993 Development Report, in which TB chemotherapy was called “one of the most cost-effective of all health interventions” (40). This official endorsement by the World Bank of the importance of investing in TB control influenced financial policies in many countries. Also in the same year, WHO declared TB a global emergency, an unprecedented step in public health and WHO’s own history (41). Soon afterwards in 1994, launched the “Framework for Effective Tuberculosis Control” which laid out the five essential elements of a TB control policy package (42). These five elements were: [i] government commitment to sustainable TB control; [ii] diagnosis through sputumsmear microscopy mainly among symptomatic patients self-referring to health services; [iii] standardized SCC provided under proper case management conditions, including direct observation of treatment [DOT]; [iv] a functioning drug supply system ensuring a regular, uninterrupted supply of all essential antituberculosis drugs; and [v] a recording and reporting system allowing assessment of treatment results from all patients registered. A year later, in 1995, this package was branded under the name “DOTS” – the Directly Observed Treatment, Short-course strategy for TB control. PROGRESS SINCE 1992 During the mid-1990s, there was rapid progress in global TB control. The DOTS strategy was aggressively marketed, and soon became widely adopted by international agencies and countries themselves and one of the most well-known brands in health (43). The number of WHO member countries adopting the DOTS strategy continued to grow throughout the 1990s (44). Countries were encouraged to adopt the strategy by the demonstration that it was effective at achieving high cure rates and by an increasing media interest in TB (45). At the same time, available external funding for TB control increased from $16 million in 1990 to $50 million in 1996, and up to $190 million in 2000 (18).

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However, despite the rapid adoption of DOTS and the increased finances available, following the establishment of a global surveillance and monitoring system and the publication of the first monitoring report by the WHO in 1997, it became apparent that the targets set for the year 2000 were not going to be reached (46). The report showed that only 11 per cent of all estimated cases were being treated under DOTS programmes, leaving nearly nine out of ten either untreated or managed through other TB control practices. The cure rate among those cases treated under DOTS in 1995 was 78 per cent (46). That the targets were not going to be met were largely as a result to the very slow pace of DOTS expansion in the 22 HBCs, who are home to 80 per cent of the global incident cases. In view of the slow pace of DOTS implementation, in early 1998 WHO convened an “Ad-hoc Committee on the TB Epidemic” to discuss the TB situation in countries with respect to the Year 2000 targets and to make recommendations for rapid control. The Committee highlighted six major issues which in their view were impeding global TB control efforts, namely: insufficient political will and commitment; lack of financing or ineffective use of financial resources; lack of trained human resources; lack of good management at programme level in many countries; problem in quality and/ or supply of antituberculosis drugs; and weakness of information systems (47). Also HIV-associated TB and multidrug-resistant TB [MDR-TB] were recognized by the Committee as two key epidemiological challenges that needed to be tackled urgently with effective interventions. In response to the issues highlighted, the Committee made a number of specific as well as general

recommendations which included: creation of a “global charter” among all key partners and the endemic countries to co-ordinate efforts more effectively; a proper balance between integration of TB control services and specificity, and between decentralization and centralized functions; involvement of private sector and communities in TB control activities; creation of a “global drug facility”, and strengthening of health information systems related to TB control activities. In November 1998, the new WHO Director-General launched the Stop TB Initiative [Table 62.1] with founding members comprising the American Lung Association ALA, the American Thoracic Society ATS, the IUATLD, the KNCV, the United States’ Centers for Disease Control and the WHO. Other organizations soon joined. A clarion call in the fight against TB, its purpose is to support partners in fulfillment of the vision and mission of the global movement. Mission of the Stop TB Initiative The mission of the Stop TB initiative is: [i] to ensure that every TB patient has access to effective diagnosis, treatment and cure; [ii] to stop the transmission of TB; [iii] to reduce the inequitable social and economic toll of TB; and [iv] to develop and implement new preventive, diagnostic and therapeutic tools and strategies to stop TB. Much has happened in the years since the launch of the Stop TB Initiative in 1998. As a result of the Initiative’s cultivation of high level support for accelerated action against TB in the HBCs, a Ministerial Conference on Tuberculosis and Sustainable Development was convened in Amsterdam in March 2000. On World TB

Table 62.1: Excerpt from the remarks of World Health Organization Director-General Brundtland at the Global Congress on Lung Health and the 29th International Union Against Tuberculosis and Lung Disease World Conference, Bangkok, November 1998 “Today I invite you to participate in a new Stop TB Initiative led by WHO. This initiative is at its very beginning. It is founded on partnership. Only with your and others’ participation will we be able to address the real problems of TB in Asia and the rest of the world. We need to reach out to the TB community but also beyond it – to the UN family, to the private sector and civil society. Tuberculosis is relevant to organizations that deal with human rights, women’s rights, poverty, prisoners and labour markets The initiative will develop a global action plan for TB control which identifies the role for different partners. It will focus on a global charter to secure commitments to improve TB control from Heads of State of endemic countries, international organizations, and donors. It will develop mechanisms to ensure global access to quality, fixed dose combination TB drugs Urgent action focussed on high burden countries, the emerging drug resistance problem and management of TB control in settings of high HIV prevalence is also planned. The initiative will support a balanced agenda for global TB research focussing on short- and longterm results” TB = tuberculosis; WHO = World Health Organization; UN = United Nations; HIV = human immunodeficiency virus

Global Tuberculosis Control: The Future Prospects 879 Day 2000 [24 March] ministers from 20 of the world’s 22 HBCs, adopted the landmark Amsterdam Declaration to Stop TB [Figure 62.3]. Along with the members of the Stop TB Initiative, the delegates from the 20 HBCs pledged to “develop and implement a global partnership agreement” through which “individuals, governments, private organizations and industry” could all contribute to efforts against TB (48,49). “Recognizing the enormity of the task ahead and the huge amount of resources required….” the conference participants – ministers and high level representatives of the Organization for Economic Co-operation and Development [OECD] governments, international development organizations, non-governmental organizations [NGOs] and bilateral donors – made the following commitments to meet the targets for global TB control by 2005: [i] to develop and/ or strengthen the TB component of national development plans; [ii] to ensure universal access to TB drugs through improved procurement and distribution; [iii] to accelerate Research and Development, and delivery of new tools and incentives for the development of TB diagnostics, drugs and vaccines; and [iv] to establish a Global Fund for TB. In May 2000, the World Health Assembly endorsed the idea of a Partnership, calling upon organizations of

Figure 62.3: Amsterdam Declaration to Stop TB, 24 March 2000

all types “to support and to participate in the global partnership to stop TB by which all parties co-ordinate activities and are united by common goals, technical strategies, and agreed-upon principles of action” (50). At the same World Health Assembly, the global TB targets set for 2000 were reconsidered. As most countries had failed to meet the targets set in 1991, the World Health Assembly under resolution WHA 53.1, postponed the targets to 2005. The momentum of the Amsterdam Declaration led to the establishment of a Global DOTS Expansion Plan [GDEP] in May 2001 (51). The GDEP promotes national inter-agency co-ordination committees and formulation of five-year DOTS expansion plans in line with global targets. It provided a template to mobilize the human and financial resources required to achieve the global TB control targets, working through strengthened national health systems. At the first GDEP meeting in November 2000, only nine countries had comprehensive plans, while three others were under preparation. By 2001, 20 of the 22 HBCs had comprehensive national plans, with the last two to be finalized in January 2002. Within the GDEP, an assessment of global financial needs for TB control had been conducted, and this was estimated at $1.2 billion per year. It was further estimated that there was a funding gap of at least $300 million that needed to be mobilized (52). Also in March 2001, the Global TB Drug Facility [GDF] was launched. The main goal of the GDF is to supply the high quality antituberculosis drugs needed to rapidly expand DOTS coverage in many HBCs that lack the resources or mechanisms to procure such drugs. It aimed to provide drugs to treat at least 10 million patients by 2005, thereby assisting countries to reach the global targets by 2005. A structure for the Stop TB Partnership was soon devised [Figure 62.4] and was endorsed at the First Global Partners’ Forum held in Washington in October 2001 [Figure 62.5]. In addition to the Stop TB Co-ordinationg Board and Partnership Secretariat, six Working Groups were set up to advance the work in vital technical areas, namely DOTS Expansion; DOTS-Plus for MDR-TB; TB and HIV; New TB Drug Development [Global Alliance for TB Drug Development]; New TB Diagnostics Development; and New TB Vaccine Development [TB Vaccine Development Coalition]. A Task Force on Advocacy and Communications and a parallel body on

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Figure 62.4: Structure of the Stop TB Partnership TB = tuberculosis; WHO = World Health Organization; HIV = human immunodeficiency virus; MDR-TB = multidrug-resistant tuberculosis; R & D = research and development

Figure 62.5: First global Stop TB Partners’ Forum, Washington 2001

Finance/Resource Mobilization provide common support for the various areas of the Global Partnership (53). At the Forum, the Partnership also unveiled the Global Plan to Stop TB 2001-2005, a budgeted, consensus based five-year business plan (54). It estimated that $9.1 billion would be necessary between 2001 and 2005 to expand DOTS, adapt it to the challenges of HIV and MDR-TB, develop new tools, and strengthen the global

movement to Stop TB. Also at the Forum, the Partners and the HBCs – some 80 countries and organizations – endorsed the Washington Commitment to Stop TB, committing themselves to the 2005 targets of 70 per cent case detection and 85 per cent treatment success under DOTS, and pledging specific actions to reach these targets (55). As TB became more visible on the international agenda and gained momentum, additional sets of targets were developed. At the 26th G8 Summit in Okinawa, Japan, in June 2000, the eight major industrialized countries discussed health related issues and committed themselves to reducing TB deaths and TB prevalence by 50 per cent by 2010 compared with levels in the year 2000 (56). In the same year, member states of the United Nations reaffirmed their commitment to sustaining development and eliminating poverty at the Millennium Assembly of the United Nations. The Millennium Development Goals were adopted and included to “combat HIV/AIDS, malaria and other diseases” (57). More specifically, TB was to be halted and the incidence of TB reversed by 2015. The Global Partnership to Stop TB now has over 250 organizations participating in it. The DOTS Expansion Working Group [DEWG] has published the Global Expansion Plan, assisted all 22 HBCs to prepare detailed national plans for DOTS Expansion and gives support to the countries as they implement these plans, and has assisted in the establishment and functioning of InterAgency Co-ordinating Committees in HBCs. By 2005, DOTS has been implemented in 187 countries covering nearly 89% of the world’s population (58-62). Subsequently, the new Stop TB strategy 2006, and the Global Plan to Stop TB, 2006-2015 (63) have been announced. The reader is referred to the chapter “Epidemiology: global perspective” [Chapter 4] for more details regarding these topics. Through the WHO/IUATLD Global Drug Resistance Surveillance Project, surveys in 72 countries have shown that MDR-TB is present globally and represents a major constraint to TB control, especially in a few settings named “hot spots” (64,65). These “hot spots” included the Baltic Republics of Estonia and Latvia, parts of the Russian Federation and China, Iran and the Dominican Republic. After much debate, in 1999 the international community established the Global Working Group on DOTS-Plus for MDR-TB, which was responsible for identifying solutions to the control of MDR-TB (66,67).

Global Tuberculosis Control: The Future Prospects 881 The establishment of good TB control by standard “DOTS” strategy is now seen as the sine-qua-non for DOTS-Plus. Much work has been done since 1999, in exploring whether programmes can effectively introduce expensive second-line drugs into their routine activities under “DOTS-Plus” projects and guidelines for establishing DOTS-Plus projects were published by WHO in 2000 (68). Currently, projects are implemented in Peru, Latvia, Estonia, the Philippines and three oblasts [provinces] in the Russian Federation. The results of a country-wide project in Peru are promising and suggest that MDR-TB can be effectively managed under routine conditions, using long regimens with second-line drugs with reasonable adherence and cure rates (69). The establishment of the DOTS-Plus Working Group has succeeded in placing second-line antituberculosis drugs on the WHO Essential Drug List [EDL]. This listing on the WHO EDL and through the use of competitive, pooled procurement under the Green Light Committee [GLC], a committee appointed from amongst the Working Group members, has resulted in a reduction of the price of second-line drugs by up to 90 per cent (70). In addition as the Working Group aims to develop an affordable, effective and evidence-based response to MDR-TB in resource-poor settings, the GLC has been tasked to control global access to the reduced cost secondline drugs via an application process from potential DOTS-Plus project sites, with the purpose of ensuring that misuse does not create further resistance (71). The GLC has now been subsumed under the GDF which has now taken on this additional function. The reader is also referred to the chapters “Antituberculosis drug resistance surveillance” [Chapter 50], “Drug-resistant tuberculosis” [Chapter 49] for more details. The Working Group on TB/HIV has developed a new strategic framework to reduce the burden of TB/HIV (72). Working Group members are now assisting countries to put the framework into practice and promote collaborative activities between TB and HIV/AIDS programmes. The three research and development Working Groups [Global Alliance for TB Drug Development, New TB Diagnostics Initiative and New TB Vaccine Initiative] are making substantial progress in their work on the medium- and long-range solutions to the TB problem. In its first two years of operations, the GDF completed six rounds of grant applications, 69 applications for grants of TB drugs were reviewed, with 46 applications and over

1.9 million patient treatment courses, worth over $23 million, approved. Twenty-seven countries had to date received the grants of TB drugs from the GDF. Through centralized, pooled procurement, the prices of antituberculosis drugs have been reduced by approximately a third with the average drug cost per patient for a full six-month regimen now standing at around $12 (73). In January 2002, the Global Fund to Fight AIDS, Tuberculosis and Malaria [GFATM] was set up as a financial instrument, complementary to existing programmes addressing these three diseases. The purpose of the Global Fund is to attract, manage and disburse additional resources through a new public-private partnership that will make a sustainable and significant contribution to the reduction of infections, illness and death, thereby mitigating the impact caused by HIV/ AIDS, TB and malaria in countries in need, and contributing to poverty reduction as part of the Millennium Development Goals. By January 2004, US$2.1 billion had been committed from the three rounds of Global Fund financing, of which over US$350 million [17%] had been approved for TB control activities. These funds will be disbursed to the respective countries over the next two years (74). The funding situation of TB control activities significantly improved in the year 2002. The total budget requirement for 2003 in the 22 HBCs was calculated at $481 million, of which $52 million [11%] was not available at the time of the publication of the Seventh WHO Annual Report on Global TB Control (44). The anticipated funding gap for 2003 was lower than that reported for 2002, and the approval of applications to the GFATM from a number of HBCs to fund TB control activities would have further reduced the funding gap. In 2002, WHO issued “An Expanded DOTS Framework for Effective TB Control” (75). The original framework dated from 1994 (42), and since then many challenges had been identified which had impeded sustainable implementation and expansion of TB control activities. Many of these stem from a weak political will failing to elicit the required health system and societal response to control TB. General public health services needed to enhance their capacity to sustain and expand DOTS implementation without compromising the quality of case detection and treatment. Community involvement in TB care and a patient-centred approach

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is needed, emphasizing and promoting to improve both access to and utilization of health services. Collaboration and synergy among the public, private and voluntary sectors are seen as essential to ensure accessible and quality-assured TB diagnosis and treatment. The increasing impact of HIV on the incidence of TB, especially in sub-Saharan Africa, called for new partnerships and approaches. A surge of drug-resistant forms of TB in the former Soviet Union and several other parts of the world, required effective implementation of the DOTS strategy to prevent the development of new MDR-TB cases in addition to measures to cure existing MDR-TB cases, i.e., DOTS-Plus activities. Sustaining DOTS programmes will also entail their integration into primary health care and adaptation to ongoing reforms within health sectors around the world. Recognition had been made that it was now necessary to widen the scope of the DOTS strategy and make it a comprehensive support strategy – support to all providers, patients and people to tackle the problem of TB. It laid equal emphasis on technical, managerial, social and political dimensions of DOTS. It acknowledged access to TB care as a human right and recognized TB control as a social good with large benefits to society. Cost savings for DOTS countries can be substantial, as indeed for the community – a study in Thailand found that for every US $1 invested by the government in TB control, the community gained US $50 over a 20-year period (76,77). Per capita costs of implementing DOTS may be as low as US $0.05 in some low-income countries (78). These, and the findings of others, underscored the contribution TB control makes to poverty alleviation by reducing the great socio-economic burden that the disease inflicts on the poor (79-81). The expanded framework reinforced the five essential elements of the original DOTS strategy, and applied to HIV-related and drug-resistant forms of TB as well. The five elements of the expanded framework were: [i] sustained political commitment to increase human and financial resources and make TB control a nation-wide activity, integral to the respective national health system; [ii] access to quality-assured TB sputum microscopy for case detection among persons presenting with, or found through screening to have, symptoms of TB [most importantly prolonged cough]. Special attention is necessary for case detection among HIV infected people and other high-risk groups, e.g., people in institutions;

[iii] standardized SCC to all cases of TB under proper case-management conditions including direct observation of treatment. Proper case management conditions imply technically sound and socially supportive treatment services; [iv] uninterrupted supply of quality-assured drugs with reliable drug procurement and distribution systems; and [v] recording and reporting system enabling outcome assessment of each and every patient and assessment of the overall programme performance. The expanded framework also contained some additional areas of key operations. These included: information, education, communication and social mobilization; involving private and voluntary health care providers; economic and financial planning; and operational research. In 2003, WHO also published the third edition of the Guidelines for National Programmes (82). Reflecting the new challenges facing TB control, the third edition included separate chapters on the management of chronic and multidrug-resistant cases, TB and HIV infection, and TB in children. CURRENT SITUATION After the unprecedented activity of the last decade directed towards the goal of global TB control, where do we stand today? Tremendous progress has been made and remarkable successes have occurred. The reader is referred to the chapter “Epidemiology: global perspective” [Chapter 4] for details regarding the expansion of DOTS worldwide, and its current status. Death rates under DOTS programmes are often dramatically lower than non-DOTS programmes, and DOTS has saved more than one million lives in the last 10 years (83). Significant declines in TB have been seen in a number of countries that have been implementing DOTS for some years. Mathematical modelling estimates that where TB incidence is stable and HIV absent, a control programme which reaches the WHO targets of 70 per cent case detection and 85 per cent cure would reduce the incidence rate by 11 per cent per year [range 8% to 12%/ year] and the death rate by 12 per cent per year [9% to 13%/year] (84,85). At a seven per cent annual decrease, incidence would be halved in 10 years. Reaching WHO targets by the year 2010 would save 23 per cent [15% to 30%] or 48 million cases by the year 2020 (84). As stated

Global Tuberculosis Control: The Future Prospects 883 by Dye et al (84) “The potential impact of chemotherapy [delivered as DOTS] on TB is greater in many developing countries now than it was in industrialized countries 50 years ago. To exploit this potential, case detection and cure rates urgently need to be improved in the principal endemic countries of the world”. The predictions of the mathematical model are now borne out by practical experience in Peru, which had implemented a DOTSbased programme in 1990 and has achieved high rates of case detection and cure. The incidence of pulmonary TB has been seen to be decreasing by at least six per cent a year and the number of deaths during the 1990s were cut by more than half [Figures 62.6 and 62.7] (86). China has also experienced dramatic declines in case prevalence as DOTS coverage and treatment success reached very high levels [Figure 62.8] (87,88). Deaths in those counties of China that are implementing the DOTS strategy have prevented at least 46 per cent of the TB deaths that would otherwise have occurred (89). India, the country with the largest TB problem in the world (44), has made tremendous progress in TB control through the implementation of the Revised National Tuberculosis Control Programme [RNTCP] – an adaptation of the DOTS strategy to local conditions (90,91). Starting in late 1993 with five pilots sites covering a population of 2.35 million, by the year 2006 the RNTCP covered the whole country, the fastest expansion of any programme in the history of DOTS (90,92-94). The reader is referred to the chapter “Revised National Tuberculosis Control Programme” [Chapter 63] for the more details regarding the achievements of the RNTCP.

Figure 62.6: Decline in tuberculosis incidence, Peru 1980-2000 Source: reference 86

Figure 62.7: Decline in tuberculosis deaths, Peru 1987 to 1999 Source : reference 86

Figure 62.8: Reduction of tuberculosis prevalence in DOTS areas, China 1990-2000 Source: reference 88

Since 2001, annually India has treated more patients under DOTS than any other country in the world, and has been the largest contributor to the global case load (43). Treatment outcomes have been maintained at a high level since the inception of the RNTCP, with a cure rate of between 84 to 86 per cent in those patients treated from the start of 2001 onwards. The mortality in the RNTCP has reduced to four per cent as compared to 20 to 30 per cent in the earlier National TB Programme (11,95). However, the estimates of the global situation suggest that in 2000 there were 8.3 million new TB cases (44,96). Incidence rates in sub-Saharan African countries average about 300 per 100 000 population, but in absolute terms, 60 per cent of all cases were in Asia. Nine percent of all

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new TB cases in adults were attributable to HIV infection, but in sub-Saharan Africa, this proportion was 31 per cent. Twelve percent of the TB deaths were attributable to HIV, with TB being the cause of death of 11 per cent of all adult AIDS deaths. It had already been estimated earlier that without more intensified TB control activity globally, the annual TB incidence was expected to increase by 41 per cent [21% to 61%] between 1998 and 2020, from 7.4 million to 10.6 million cases per year (84). The increase in geographical coverage of DOTS programmes does not seem to have translated directly into gains in case detection. More precisely, overall case detection from DOTS and non-DOTS areas has remained at around 40 to 50 per cent since 1980. The progression in case detection under DOTS has mainly been associated with gains in cases in DOTS areas from cases previously from non-DOTS areas, and not solely recruiting patients who were never detected and/or notified i.e., most patients recruited by DOTS programmes are those that would have been detected and treated anyway in the public health system (44,97-98). Case detection under DOTS has progressed in a linear fashion over the past years, with an average of 130 000 additional cases being enrolled annually, and at the current rate of progression, the 70 per cent case detection target will not be attained until after 2010 [Figure 62.9] (22). Some have suggested that even after 2010 the target is not likely to have been reached as the DOTS programmes expand to the harder-to reach groups (100). There is the possibility that the case detection rates may even plateau at 40 to 50 per cent, if additional strategies to detect and notify new cases are not widely implemented urgently. However, this global analyses did not take into consideration the recent rapid progress in DOTS expansion such as that made by India in the Years 2002 to 2003, which has led to an acceleration in global case detection [Figure 62.10]. The low case detection rates seen could, however, be due to either the denominator [estimated annual number of new smear-positive cases in a given country] being too high or from the numerator [number of smearpositive case notifications] being too low. The number of TB cases has been estimated on several occasions, with the results being similar and consistent (7,13,96,101,102). Hence it is unlikely that the low case detection is due to problems with the denominator at a global level.

Figure 62.9: Progress towards 70 per cent case detection, 1994-2003 Open circles mark the number of smear-positive cases notified under DOTS 1995 to 2003, expressed as a percentage of estimated new cases in each year. Closed circles show the total number of smear-positive cases notified [DOTS and non-DOTS] as a percentage of estimated cases WHO = World Health Organization Source: reference 44

If the low case detection is due to a problem with the numerator, where are the missing cases? First, they may just simply be in the community and not presenting to any health facility, if DOTS programmes and hence the TB services, are not easily accessible to the population [Figure 62.11]. DOTS geographical coverage refers to the percentage of national population that lives in an administrative area, such as a district or province, where DOTS services are provided. Full DOTS coverage in any given country does not mean that all care providers in this country follow the DOTS strategy, but only that governmental health services can provide it. Not all governmental health service facilities may, however, provide DOTS services. For example in some countries, only specialized TB clinics actually provide DOTS services, excluding a range of facilities including both out-patient and hospital primary health-care services. A whole range of factors, including geographical or financial, may mean that the population does not have access to services. Secondly, cases may be missed within DOTS Programmes if staff do not suspect or diagnose cases correctly. Thirdly, cases may be missed as they remain unreported, if DOTS programmes do not notify all cases

Global Tuberculosis Control: The Future Prospects 885

Figure 62.10: Case detection increasing within DOTS areas in India Source: reference 88

diagnosed. Furthermore, in some settings there may be a reluctance to register all cases, especially those deemed by the staff to have a high risk of not completing treatment. Fourthly, if not all the public health services and systems are fully linked, cases may be missed. For example, prevalence rates are often high amongst prisoners, but usually the prisons’ medical services are the responsibility of the Ministry of Justice and rarely are they linked efficiently with the general health services in the community under the Ministry of Health. Cases

Figure 62.11: Why may tuberculosis cases be “undetected”? TB = tuberculosis

are thus often not reported and a substantial proportion of TB cases may be missed (103). Fifthly, if all the public health systems are not implementing the DOTS programme, cases may be missed. For example in China, the hospital system, which diagnoses a large number of TB cases, remains largely separate from the DOTS programme, resulting in a lower than expected case detection rate [Figure 62.12] (87,104). In addition, patients may be simply being seen and treated under a non-DOTS TB control programme. Finally, the patient may seek advice and treatment from the private health sector, ranging from pharmacies, quacks, private practitioner’s clinics or private hospitals. Many developing countries, especially in Asia, are seeing a rapid expansion of the private health sector. For example it is estimated that 80 per cent of households in India choose the private sector for care of minor illnesses and 75 per cent for major ones (105). Hence many people with TB symptoms and disease seek treatment from the private sector, which may provide poor quality diagnosis and treatment (106). In general, there is little co-ordination between the public and private sectors in many low income HBCs and cases managed in the private sector usually go unreported to the national TB programmes. Serious differences in perception are seen between those practitioners in the public and private sectors, and coordination of activities, especially those related to public health activities, is rare (107,108). If the private sector is not involved in TB control activities by national TB programmes, a significant proportion of cases may be missed.

Figure 62.12: Improving case detection in China TB = tuberculosis Source: reference 104

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Priorities for Action Financial gaps are progressively decreasing, but in many settings, weaknesses of the general health systems, rather than of specific TB activities, are emerging as major constraints. Four major constraints to DOTS expansion were identified at the DEWG meeting held in late 2002, namely: inadequate human resources, in terms of number of staff and especially qualified staff; lack of a strategy to cope with decentralization of the health system; non-compliance of the private sector with the DOTS strategy; and inadequate or weak health infrastructures (22). The lack of collaborative activities between the HIV and TB programmes was also highlighted in countries with a high prevalence of HIV. Top priority for action remains geographical DOTS expansion within governmental health structures [Table 62.2]. Access to all public health services should be ensured during this process. However, there is an urgent need to address the limited capacity within health systems. Regardless of the increases in funding now available to TB control programmes, the lack of human resources is likely to become a key issue to controlling TB. As TB control is essentially a management problem, TB control programmes need more than anything else, good managers. Trained supervisory staff is crucial as effective, independent supervision at all levels is also key to success. Governments in the 22 HBCs must address the human resources crises that many of them face. This may, however, be doubly difficult as many countries are undertaking health sector reforms, during which there are many risks to TB control activities as well as a number of opportunities (109). Technical considerations are a primary consideration of national and international TB control programmes; the DOTS strategy requires strict technical rigour in order to achieve its goals and it must not compromise on its core principles, especially in the face of rapid health sector reform. To support governments in this, the DEWG has performed a survey on human resources in all HBCs, and in 2004-2005 organized a series of workshops for country level human resource focal persons. Guidelines on human resource development and expanding DOTS in the context of a changing health system, have recently been published by WHO (110,111). The above activities must be coupled with innovative approaches to increase case finding whilst maintaining

Table 62.2: Priorities for action that were listed to achieve 2005 global targets Improve, monitor and maintain quality of DOTS 100 per cent geographical coverage, involvement of all MoH care providers Comprehensive budgets, with increased utilization of those resources being made available Identification of non-financial constraints Widen access to DOTS Quality governmental health services accessible to all Patients’ constraints identified and solutions provided [IEC, enablers, incentives etc.] Collaboration with partners Non-MOH governmental systems and services Non-governmental sector: private practitioners, NGOs, academia, etc. Increase community/user awareness MoH = Ministry of Health; IEC = Information, Education and Communication; NGOs = Non-governmental organizations

high cure rates [Table 62.2]. These include engagement of communities, social mobilization, strengthening of primary care services, co-ordination with other care delivery systems and involvement of the private sector. A framework to involve private practitioners in TB control activities has been developed by WHO, and describes the strategy known as “public-private mix [PPM] DOTS” (112). The guiding principle is that all patients should have easy access to DOTS, including free antituberculosis drugs, regardless of the provider that they seek care from. The national TB programme should provide free drugs and quality microscopy services, public or private, and expect adherence to agreed standard practices in return from the private providers. A number of HBC countries, notably India and the Philippines, have already developed policy documents and have PPM projects up and running (113,114). Results from a number of PPM projects in India have shown overall positive results, although some weaknesses persist but appear manageable [Figure 62.13] (115-117). Recently, the International Standards for Tuberculosis Care have been published where the desired standards for care of patients with TB outside the National Tuberculosis programmes, especially in the private sector, have been published. The reader is referred to the chapter “International Standards for Tuberculosis Care” [Chapter 67] for more details.

Global Tuberculosis Control: The Future Prospects 887 Scaling up of services at the community level and greater involvement of the community are essential for future success (79). Community-based TB care in a number of settings has been demonstrated to be highly cost-effective and may generate demand for TB services and care by the community in addition to providing support to patients (118,119). Generating community awareness about TB is important and has traditionally been approached through information, education and communication [IEC] activities. However, translating information into a change of behaviour is the ideal goal. A framework for social mobilization, known as Communication for Behavioural Impact [COMBI] has been developed to achieve this goal. The COMBI is a strategic approach to social mobilization that uses a blend of communication strategies based on situational market analysis, all directed at the achievement of a specific behavioural goal. It has been successfully used in Zanzibar to prevent lymphatic filariasis (120). The COMBI activities for TB control are currently being conducted in Kenya and one state [Kerala] in India, with the aim of prompting people with a persistent cough to visit health centres for TB diagnosis, and thereby help increase case detection. The threat of MDR-TB is much better quantified today than a few years ago, with a sound international surveillance system for drug resistance prevalence having been established. Prices of second-line drugs have been drastically reduced, and pilot DOTS-Plus projects have shown that programmes can adequately introduce and manage these drugs under routine conditions cost-

Figure 62.13: Case detection rates, all cases and new smear positive, Kannur district, Kerala, India 2000-02 Tot = total; Sm+ = smear-positive; q = quarter Source: reference 115

effectively and with reasonable outcomes. There is, however, a continued need to bring new resources in for TB control in general, including for MDR-TB treatment. Multidrug-resistant TB and extensively drug-resistant TB [XDR-TB] can be a useful advocacy tool as a means of bringing in previously untapped public and private resources to TB control (66). This then needs to be translated into the wider implementation of the DOTSPlus management strategy, but with continued strict adherence to the guidelines laid out for such projects. Recently, XDR-TB has emerged as a new threat for global attempts at TB control and efforts are underway in several countries across the globe to tackle this new emerging threat (121). The HIV pandemic, with the biological and epidemiological interactions between TB and HIV, today presents a major challenge to TB control in high HIV-prevalence settings. Where the prevalence of HIV infection is high, it is unlikely that TB treatment alone will be able to reverse the rise in incidence of TB seen and will require more than simply implementing the DOTS strategy widely (96,122,123). To reduce the number of TB cases in a community, there is an urgent need to implement a strategy extended from the standard DOTS one which combines intensified case-finding and treatment to cure in order to reduce the transmission of TB, coupled with comprehensive, effective HIV prevention with widescale implementation and availability of integrated counselling and testing centres [ICTC], and care including the wider availability of antiretroviral therapies in low-income countries in order to reduce transmission of HIV. Enhanced TB case-finding could be considered in specific groups among whom rates of TB are higher than the general population, such as attendees at ICTC or household members of HIV-seropositive TB patients (124,125). In order to reduce reactivation of latent TB infection, current WHO recommendations are that in settings with a high prevalence of dual HIV/TB infection, TB preventive therapy should be offered to HIV co-infected individuals if they can undergo adequate screening to rule out active TB disease in order to avoid its use in such cases (126). However, due to the lack of ICTC, and the difficulties in excluding people who already have active TB disease, the use of preventive therapy is not routine in any HBCs. Furthermore, the durability of the

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efficacy of TB preventive therapy is unresolved, with studies in areas of high transmission showing that protection may not extend for more than two to three years beyond the end of the treatment, and there is at most a short prolongation of life (127-129). However, for the individual living with HIV, it is one of the few interventions proven to reduce morbidity in the absence of antiretroviral therapy. A number of studies have also shown efficacy of secondary preventive therapy i.e., preventive therapy in individuals who have a history of previous TB disease, in HIV infected individuals in communities with a high incidence of TB (130,131). Longterm isoniazid might therefore serve as chemoprophylaxis, as well as treating latent infection, but the efficacy of such an approach has not yet been documented. Use of antiretroviral drugs will also be beneficial in reducing reactivation of TB in individuals, with studies in Brazil and South Africa showing reductions in TB incidence (132-134). Any strategy that successfully reduces HIV transmission will benefit TB control. In the context of the combined epidemics of TB and HIV, the two most important strategies are ICTC, and implementation of anti-retroviral drugs. Studies have shown that people who accepted HIV counselling and testing were more likely to change their sexual behaviour in ways predicted to reduce HIV transmission compared to those who received health information alone (135). Economic evaluations suggest that this intervention should be one of the main pillars of any HIV prevention programme (136-138). Voluntary HIV testing identifies HIV-seropositive individuals who are a target for both enhanced TB case-finding and for TB preventive therapy. As discussed above, the implementation of anti-retroviral therapy [ART] will have direct effects on TB. In addition, as ART can dramatically reduce plasma levels of HIV, which correlate closely with infectivity, individuals taking ART are therefore likely to be less infectious in regard to transmission of HIV. How to deliver ART to those individuals infected with HIV in low-income countries who need them, is a major challenge. To address this challenge, WHO in 2003 launched the ‘3 by 5 Initiative’ with the aim of getting three million people on ART by the end of 2005 (139). However, this aim could not be eventually achieved (140). Co-ordination at country level between HIV and TB programmes is essential, as are specific interventions to tackle TB and HIV. The ProTEST project is one example

of the operationalization of combined TB/HIV reduction activities. The ProTEST uses enhanced integrated counselling and tesing as an entry point for a series of activities that aim to reduce HIV transmission and TB incidence. Evidence-based information for TB/HIV collaborative interventions has been collected through the ProTEST projects in Malawi, South Africa and Zambia (141).The lessons learnt from these sites have informed the expansion and implementation of similar TB/HIV activities, and collaborative TB/HIV activities are now being expanded in many countries (72). With further collaboration, TB and HIV control programmes are accentuating their own strengths and are learning from each other. Evidence is now beginning to appear that although overall incidence rates of TB are extremely difficult to contain, good TB control programmes may still be able to maintain stable incidence rates of TB among HIV-seronegative individuals living in populations with high prevalence of HIV (142). This may also imply that TB transmission rates can be kept constant, with important implications for the control of TB in the coming decades. Preventing TB disease and deaths, among HIV infected individuals, however, will require the implementation of additional interventions to increase access to HIV-testing, antituberculosis preventive therapy, and anti-retroviral drugs. According to the recently published update, the revised global estimate of people living with HIV/AIDS has been downsized to 33.2 million, a reduction of 16 per cent compared with the estimate of 39.5 million in 2006 (143,144) . While this is good news, it should not result in complacency, and all efforts at HIV-TB control must be continued. The reader is also referred to the chapter “Tuberculosis and human immunodeficiency virus infection” [Chapter 40] for more details. Finally, as primary care is often too poorly supported to guarantee adequate diagnosis and treatment of a variety of respiratory illnesses, including TB, the WHOsponsored Practical Approach to Lung Health [PAL] strategy aims to assist in the delivery of standardized syndromic management of common respiratory diseases (145). The strategy leads to improved diagnostic capacity and ensures correct, cost effective treatment of priority respiratory diseases (146). As a consequence, the strategy is likely to increase the detection of TB cases. The strategy targets multi-purpose health workers in lower-middle and middle-income countries, and is being implemented

Global Tuberculosis Control: The Future Prospects 889 in Chile, Morocco and some provinces in South Africa (147). This may be the natural evolution of well structured DOTS programmes towards supporting primary care in countries with good health services, such as Chile and Morocco. Global TB control is complex. However, we must not forget how far we have come in the last decade - today TB is fully curable, the means to deliver an effective cure is available through the DOTS strategy, and each cure means reduced transmission. Tuberculosis can be controlled – if appropriate policies are followed, effective clinical and public health management is ensured, and there are committed and co-ordinate efforts for its control from within and outside of the health sector (148). Rapid expansion of effective TB control services is urgently needed, both to avert the continued high burden of morbidity and mortality from TB, and because of the HIV epidemic. As anticipated (149), targets for global TB control could not be achieved by 2005. The TB community in collaboration and co-ordination with other sectors in and beyond health, must work to recognize and address the constraints to TB control (149). As Kumaresan et al (53) commented recently “TB is now clearly seen as a problem with political, social and economic dimensions, and current challenges require solutions and action in all of these areas, including human resources for health, poverty reduction, primary care services, sustainable finances, rigorous awareness raising and social mobilization for health, private and corporate sector involvement. More specifically, it requires commitment, dialogue and expertise and entities outside of the established TB community. Stopping TB presents a collection of challenges, but more fundamentally, a challenge to our collective will and commitment” (53). The answer to the challenge lies in our hands. As stated at the end of the nineteenth century by Dr Hermann Biggs, who as Head of the New York City Health Department implemented a range of innovative control activities against TB which at the time was a leading cause of death in the city, - “Public health is purchasable. Within natural limitations, a community can determine its own death rate” (150). Reaching the global targets is not an aim in itself, but a milestone in controlling TB. Tuberculosis control programmes, and the new approaches, will all need to be sustainable for decades after the targets have been reached in order to have a lasting impact on TB epidemio-

logy in the community. The primary task of global TB control over the next five to ten years is to dramatically reduce TB deaths, shorten the duration of illness and decrease the incidence of disease – in that order. By 2010, the International Development Target is to reduce TB deaths and TB prevalence by 50 per cent, and by 2015 the incidence of TB is to be reversed (56,57). Further progress will require the continued rigorous and dedicated application of current technology by all partners committed to the fight to stop TB. To achieve the longer term goals, will, however, require newer diagnostic techniques, drugs and vaccines which can be utilized in those areas where TB remains a public health problem (151-153). REFERENCES 1. Crofton J. Tuberculosis undefeated. BMJ 1960;2:679-87. 2. Keers RY. Tuberculosis: A journey down the centuries. London: Balliere Tindal; 1978.p.4-15 3. Fox W. Self-administration of medicaments: a review of published work and a study of the problems. Bull Int Union Tuberc 1962;32:307-31. 4. Tuberculosis Chemotherapy Centre. A concurrent comparison of home and sanitorium treatment of pulmonary tuberculosis in south India. Bull World Health Organ 1959;21:51144. 5. Nagpaul DR, Savic DM, Rao KP, Baily GV. Case-finding by microscopy. Bull Int Union Tuberc 1968;41:148-158. 6. Styblo K. Overview and epidemiologic assessment of the current global tuberculosis situation with an emphasis on control in developing countries. Rev Infect Dis 1989;II [Suppl 2]:S339-46. 7. Murray CJ, Styblo K, Rouillon A. Tuberculosis in developing countries: burden, intervention, and cost. Bull Int Union Tuberc Lung Dis 1990;65:6-24. 8. Cegielski JP, Chin DP, Espinal MA, Frieden TR, Rodriquez Cruz R, Talbot EA, et al. The global tuberculosis situation: progress and problems for the 20th century, prospects for the 21st century. Infect Dis Clin North Am 2002;16:1-58. 9. Stanford JL, Grange JM, Pozniak A. Is Africa lost? Lancet 1991;338:557-8. 10. Styblo K, Enarson DA. The impact of infection with human immunodeficiency virus on tuberculosis. In: Mitchel DA, editor. Recent advances in respiratory medicine. No. 5. Edinburgh: Churchill Livingstone; 1991. 11. Dutta M, Radhamani MP, Selvaraj R, Paramasivan CN, Gopalan BN, Sudeendra CR, et al. Critical assessment of smear-positive pulmonary tuberculosis patients after chemotherapy under the district tuberculosis programme. Tuberc Lung Dis 1993;74:180-6. 12. Commission on Health Research for Development. Health research: essential link to equity in development. New York: Oxford University Press; 1990.

890

Tuberculosis

13. Sudre P, ten Dam G, Kochi A. Tuberculosis: a global overview of the situation today. Bull World Health Organ 1992;70:14959. 14. Kochi A. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle 1991;72:1-6. 15. World Health Organization. Case studies for evaluation of tuberculosis control in various primary health care settings. Sturbridge: Mass, USA 25-28 May 1990. WHO/TUB Unit; 1990. 16. World Health Organization. Tuberculosis Programme Review, India, September 1992. WHO/TB/95.186. New Delhi: WHO; 1992. 17. Gryzbowski S. Tuberculosis: a look at the World situation. Chest 1983;84:756-61. 18. Raviglione MC, Pio A. Evolution of WHO policies for tuberculosis control, 1948-2001. Lancet 2002;359:775-80. 19. Narain JP, Raviglione MC, Kochi A. HIV-associated tuberculosis in developing countries: epidemiology and strategies for prevention. Tuber Lung Dis 1992;73:311-21. 20. De Cock KM, Soro B, Coulibaly IM, Lucas SB. Tuberculosis and HIV infection in sub-Saharan Africa. JAMA 1992;268:1581-7. 21. Yanai H, Uthaivovravit W, Panich V, Sawanpanyalert P, Chaimanee B, Akarasewi P, et al. Rapid increase in HIVrelated tuberculosis, Chiang Rai, Thailand, 1990-94. AIDS 1996;10:527-31. 22. World Health Organization. WHO Report 2003. Global tuberculosis control: surveillance, planning, financing. WHO/CDS/TB/2003.316. Geneva: World Health Organization; 2003. 23. Raviglione MC, Rieder HL, Styblo K, Khomenko AG, Esteves K, Kochi A. Tuberculosis trends in Eastern Europe and the former USSR. Tuber Lung Dis 1994;75:400-16. 24. Reichman LB. Editorial: The U-shaped curve of concern. Am Rev Respir Dis 1991;144:741-2. 25. Schneider E, Castro KG. Tuberculosis trends in the United States, 1992-2001. Tuberculosis 2003;83:21-9. 26. Rieder HL, Cauthen GM, Comstock GW, Snider Jr DE. Epidemiology of tuberculosis in the United States. Epidemiol Rev 1989;11:79-98. 27. Cantwell MF, Snider DE Jr, Cauthen GM, Onorato IM. The epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA 1994;332:1071-6. 28. Raviglione MC, Sudre P, Rieder HL, Spinaci S, Kochi A. Secular trends of tuberculosis in western Europe. Bull World Health Organ 1993;71:297-306. 29. Drolet GJ. Present trend of case fatality rates in tuberculosis. Am Rev Tuberc 1938;37:125-51. 30. National Tuberculosis Institute, Bangalore. Tuberculosis in a rural population of South India: a five-year epidemiological study. Bull World Health Organ 1974;51:473-88. 31. Holm J. Our enemy. The tubercle bacillus. International Tuberculosis Digest, no. 5. Paris: IUAT; 1970. 32. Styblo K. State of the art. I. Epidemiology of tuberculosis. Bull Int Union Tuberc 1978;53:141-52.

33. Styblo K. Volume 24, Selected papers. Epidemiology of tuberculosis. The Hague: Royal Netherlands Tuberculosis Association; 1991. 34. World Health Organization Expert Committee on Tuberculosis. Eighth Report. Technical Reports Series No.260. Geneva: World Health Organization; 1964. 35. World Health Organization Expert Committee on Tuberculosis. Ninth Report. Technical Reports Series No.552. Geneva: World Health Organization; 1974. 36. Rouillon A. The mutual assistance programme of the IUATLD. Development, contribution and significance. Bull Int Union Tuberc Lung Dis 1991;66:159-72. 37. World Health Organization. Forty-fourth World Health Assembly. Resolutions and decisions. Resolution WHA 44.8. WHA44/1991/REC/1. Geneva: World Health Organization; 1991. 38. Styblo K, Bumgarner JR. Tuberculosis can be controlled with existing technologies: evidence. Tuberculosis Surveillance and Research Unit Progress Report 1991;2:60-72. 39. Raviglione MC. The TB epidemic from 1992 to 2002. Tuberculosis 2003;83:4-14. 40. World Bank. World Development Report 1993. Investing in Health. New York: Oxford University Press;1993 [box 3.3, p.63]. 41. Nakajima H. Tuberculosis: a global emergency. World Health No. 4. Geneva: World Health Organization; 1993. 42. World Health Organization Global Tuberculosis Programme. Framework for effective tuberculosis control. WHO/TB/ 94.179. Geneva: World Health Organization; 1994. 43. Klaudt K. The political causes, solutions, of the current tuberculosis epidemic. In: Whitman J, editor. The politics of emerging and resurgent infectious diseases. London: MacMillan Press; 2000.p.223. 44. World Health Organization. WHO Report 2005. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2005.349. Geneva: World Health Organization; 2005. 45. China Tuberculosis Control Collaboration. Results of directly observed short-course chemotherapy in 112,842 Chinese patients with smear-positive tuberculosis. Lancet 1996;347:358-62. 46. Raviglione MC, Dye C, Schmidt S, Kochi A. Assessment of worldwide tuberculosis control. Lancet 1997;350:624-9. 47. World Health Organization. Global Tuberculosis Programme. Report of the ad-hoc Committee on the Tuberculosis Epidemic. WHO/TB/98.245. Geneva: World Health Organization; 1998. 48. Stop TB Initiative. Amsterdam 22-24 March 2000. Tuberculosis and Sustainable Development. Report of a conference. WHO/CDS/STB/2000.6. Geneva: World Health Organization; 2000. 49. Stop TB Initiative. Amsterdam Declaration to Stop TB: a call for accelerated action against tuberculosis. Geneva: World Health Organization; 2000. 50. World Health Organization. Fifty-third World Health Assembly. Resolution WHA 53.1. WHA53/2000/REC/. Geneva: World Health Organization; 2000.

Global Tuberculosis Control: The Future Prospects 891 51. World Health Organization. Global DOTS Expansion Plan – Progress in TB control in high burden countries 2001 One year after the Amsterdam Ministerial Conference. WHO/ CDS/STB/2001.11. Geneva: World Health Organization; 2001. 52. Floyd K, Blanc L, Raviglione M, Lee JW. Resources required for global tuberculosis control. Science 2002;295:2040-1. 53. Kumaresan J, Heitkamp P, Smith I, Billo N. Global Partnership to Stop TB: a model of an effective public health partnership. Int J Tuberc Lung Dis 2004;8:120-9. 54. Global Partnership to Stop TB. Global Plan to Stop TB. WHO/ CDS/STB/2001.16. Geneva: World Health Organization; 2001. 55. Global Partnership to Stop TB. Washington Commitment to Stop TB. WHO/CDS/STB/2001. 14a.Geneva: World Health Organization; 2001. 56. G8 Communique Okinawa 2000. Available at URL: http:// www.stoptb.ca/okinawa.html. Accessed on September 30, 2008. 57. Millennium Development Goals. Available at URL: http:// www.developmentgoals.org/About the_goals.htm. Accessed on September 30, 2008. 58. World Health Organization. WHO report 2007. Global tuberculosis control : surveillance, planning, financing. WHO/HTM/TB/2007.376. Geneva: World Health Organization; 2007. 59. Sharma SK, Liu JJ. Progress of DOTS in global tuberculosis control. Lancet 2006;367:951-2. 60. Maher D, Dye C, Floyd K, Pantoja A, Lonnroth K, Reid A, et al. Planning to improve global health: the next decade of tuberculosis control. Bull World Health Organ 2007;85:3417. 61. Dye C, Bassili A, Bierrenbach A, Broekmans J, Chadha V, Glaziou P. Measuring tuberculosis burden, trends, and the impact of control programmes. Lancet Infect Dis 2008;8:23343. Epub 2008 Jan 16. 62. Cox HS, Morrow M, Deutschmann PW. Long term efficacy of DOTS regimens for tuberculosis: systematic review. BMJ 2008;336:484-7. Epub 2008 Feb 4. 63. Raviglione MC, Uplekar MW. WHO’s new Stop TB Strategy. Lancet 2006;367:952-5. 64. Pablos-Mendez A, Raviglione MC, Laszlo A, Binkin N, Rieder HL, Bustreo F, et al. World Health Organization-International Union Against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. Global surveillance for antituberculosis-drug resistance, 19941997. N Engl J Med 1998;338:1641-9. 65. Espinal MA, Laszlo A, Simonsen L, Boulahbal F, Kim SJ, Reniero A, et al. Global trends in resistance to antituberculosis drugs. N Eng J Med 2001; 344:1294-303. 66. Farmer PE, Bayona J, Becerra M, Furin J, Henry C, Hiatt H, et al. The dilemma of MDR TB in the global era. Int J Tuberc Lung Dis 1998;2:869-76. 67. Espinal MA, Dye C, Raviglione MC, Kochi A. Rational ‘DOTS Plus’ for the control of MDR-TB. Int J Tuberc Lung Dis 1999;3:561-3. 68. World Health Organization. Guidelines for establishing DOTS-Plus projects. Projects for the management of

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83. 84.

85.

multidrug-resistant tuberculosis [MDR-TB]. WHO/CDS/ TB/2000.279. Geneva: World Health Organization; 2000. Suarez PG, Floyd K, Portcarrero J, Alarcon E, Rapitie, Famos G, et al. Feasibility and cost-effectiveness of standardized second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 2002;359:1980-9. Gupta R, Kim JY, Espinal MA, Candran JM, Pecoul B, Farmer PE, et al. Responding to market failures in tuberculosis control. Science 2001;293:1049-51. World Health Organization. Instructions for applying to the Green Light Committee for access to second-line antituberculosis drugs. WHO/CDS/TB/2001.286. Geneva: World Health Organization; 2001. World Health Organization. Strategic framework to decrease the burden of TB/HIV. WHO/ CDS/ TB/2002.296. WHO/ HIV_AIDS/2002.2. Geneva: World Health Organization; 2002. Kumaresan J, Smith I, Arnold V, Evans P. The Global TB Drug Facility: innovative global procurement. Int J Tuberc Lung Dis 2004;8:130-8. The Global Fund to Fight AIDS, TB and Malaria. Available at URL: http://theglobalfund.org. Accessed on September 30, 2008. World Health Organization. An expanded DOTS framework for effective tuberculosis control. WHO/CDS/TB/ 2002.297. Geneva: World Health Organization; 2002. Dholakia R, Almeida J. The potential economic benefits of the DOTS strategy against TB in India. WHO/TB/96.218. Geneva: World Health Organization; 1997. Sawert H, Kongsin S, Payanandana V, Akarasewi P, Nunn PP, Raviglione MC. Costs and benefits of improving tuberculosis control: the case of Thailand. Soc Sci Med 1997;44:1805-16. World Health Organization. Joint programme review: India. WHO/SEA/TB/2000.224. New Delhi: World Health Organization; 2000. World Health Organization. Macroeconomics and health: investing in health for economic development. Report of the Commission on Macroeconomic and Health. Geneva: World Health Organization; 2001. Kamolratanakul P, Sawert H, Kongsin S, Lertmaharit S, Sriwongsa J, Na-Songkhla S, et al. Economic impact of tuberculosis at the household level. Int J Tuberc Lung Dis 1999;3:596-602. Rajeshwari R, Balasubramanian R, Muniyandi M, Geetharamani S, Thresa X, Venkatatesan P, et al. Socioeconomic impact of TB on patients and families in India. Int J Tuberc Lung Dis 1999;3:869-77. World Health Organization. Treatment of tuberculosis. Guidelines for National Programmes. WHO/CDS/TB 2003.313. Geneva: World Health Organization; 2003. Frieden TR, Driver CR. Tuberculosis control: past 10 years and future progress. Tuberculosis 2003;83:82-5. Dye C, Garnett GP, Sleeman K, Williams BG. Prospects for worldwide tuberculosis control under the WHO DOTS strategy. Lancet 1998;352:1886-91. Dye C. Tuberculosis 2000-2010: control, but not elimination. Int J Tuberc Lung Dis 2000;4:S146-52.

892

Tuberculosis

86. Suarez PG, Watt CJ, Alarcon E, Portocarrero J, Zavala D, Canales R, et al. The dynamics of tuberculosis in response to 10 years of intensive control effort in Peru. J Infect Dis 2001;184:473-8. 87. Chen X, Zhao F, Duanmu H, Wan L, Du X, Chin D. The DOTS strategy in China: results and lessons after 10 years. Bull World Health Organ 2002;80:430-6. 88. Dye C. Presentation to DEWG meeting. The Hague. October 2003. World Health Organization, Geneva. 89. Dye C, Zhao F, Scheele S, Williams B. Evaluating the impact of tuberculosis control: number of deaths prevented by shortcourse chemotherapy in China. Int J Epid emiol 2000;29:55864. 90. Drazen JM. A milestone in tuberculosis control. N Eng J Med 2002;347:1444. 91. Khatri GR. DOTS progress in India: 1995-2002. Tuberculosis 2003;83:30-4. 92. Government of India and World Health Organization. Review Mission lauds India for achieving the fastest expansion of quality TB control programme in the world. Press Release, World Health Organization; Delhi 26 September 2003. 93. Revised National Tuberculosis Control Programme of India. Available at URL: http://www.tbcindia.org. Accessed on September 30, 2008. 94. Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. Revised National TB Control Programme Annual status report, 2006. New Delhi: Central TB Division; 2006. 95. Khatri GR, Frieden TR. Controlling tuberculosis in India. N Eng J Med 2002;347:1420-5. 96. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, et al. The growing burden of tuberculosis. Global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009-21. 97. World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO Report 2002. WHO/ TB/2002.295. Geneva: World Health Organization; 2002. 98. Dye C, Watt CJ, Bleed D. Low access to a highly effective therapy: a challenge for international tuberculosis control. Bull World Health Organ 2002;80:437-44. 99. Dye C, Watt CJ, Bleed D, Williams BG. What is the limit to case detection under the DOTS strategy for tuberculosis control. Tuberculosis 2003;83:35-43. 100. Blower SM, Daley CL. Problems and solutions for the Stop TB partnership. Lancet Infect Dis 2002;2:374-6. 101. Dolin P, Raviglione MC, Kochi A. Global tuberculosis incidence and mortality during 1990-2000. Bull World Health Organ 1994;72:213-20. 102. Dye C, Scheele S, Dolin P, Pathania V, Raviglione M. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. JAMA 1999;282:677-86. 103. Connix R, Maher D, Reyes H, Grzemska M. Tuberculosis in prisons in countries with high prevalence. BMJ 2000;320:4402. 104. Ministry of Health of the People’s Republic of China. Report on nationwide random survey for the epidemiology of

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

tuberculosis in 2000. Beijing: Ministry of Health of the People’s Republic of China; 2000. National Council of Applied Economic Research [NCAER]. Working Paper No. 53. Household survey of health care utilisation and expenditure. New Delhi: National Council of Applied Economic Research; 1995. Newell J. The implications for TB control of the growth in numbers of private practitioners in developing countries. Bull World Health Organ 2002;80:836-7. Uplekar M, Vikram P, Raviglione M. Private practitioners and public health: weak links in tuberculosis control. Lancet 2001;358:912-6. Vyas RM, Small PM, DeRiemer K. The private-public divide: impact of conflicting perceptions between the private and public health care sectors in India. Int J Tuberc Lung Dis 2003;7:543-9. Miller B. Health Sector Reform: scourge or salvation for TB control in developing countries? Int J Tuberc Lung Dis 2000;4:593-4. World Health Organization. Training for better TB control. Human resource development for TB control. A strategic approach within country support. WHO/CDS/TB 2002.301. Geneva: World Health Organization; 2002. World Health Organization. Expanding DOTS in the context of a changing health system. WHO/CDS/TB/2003.318. Geneva: World Health Organization; 2003. World Health Organization. Involving private practitioners in tuberculosis control: issues, interventions and emerging policy framework. WHO/CDS/TB/2001.285. Geneva: World Health Organization; 2001. Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. Involvement of Non-Governmental Organizations in the Revised National TB Control Programme. New Delhi: Central TB Division; 2001. Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. Involvement of Private Practitioners in the Revised National TB Control Programme. New Delhi: Central TB Division; 2002. Murthy KJ, Frieden TR, Yazdani A, Hreshikesh P. Publicprivate partnership in tuberculosis: experience in Hyderabad, India. Int J Tuberc Lung Dis 2001;5:354-9. Arora VK, Sarin R, Lonroth K. Feasibility and effectiveness of a public-private mix project for improved TB control in Delhi, India. Int J Tuberc Lung Dis 2003;7:1131-8. Kumar MK, Nair PK, Frieden TR, Sahu S, Wares F, Laseron K, et al. Improved tuberculosis case-detection through publicprivate partnership and laboratory-based surveillance, Kannur District, Kerala, India, 2001-2002. Int J Tuberc Lung Dis 2005;79:870-6. Maher D, van Gorkom JL, Gondrie PC, Raviglione M. Community contribution to tuberculosis care in countries with high tuberculosis prevalence : past, present and future. Int J Tuberc Lung Dis 1999;3:762-8. World Health Organization. Community contributions to TB care: practice and policy. Review of experience of community

Global Tuberculosis Control: The Future Prospects 893

120.

121. 122.

123. 124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

contribution to TB care and recommendations to national TB programmes. WHO/CDS/TB/2003.312. Geneva: World Health Organization; 2003. World Health Organization. The global elimination of lymphatic filariasis. The story of Zanzibar. WHO/CDS/ SMT/2002.15. Geneva: World Health Organization 2002. Chauhan LS. Drug resistant TB – RNTCP response. Indian J Tuberc 2008;55:5-8. DeCock KM, Chaisson RE. Will DOTS do it? A reappraisal of tuberculosis control in countries with high rates of HIV infection. Int J Tuberc Lung Dis 1999;3:457-65. Godfrey-Faussett P, Ayles H. Can we control tuberculosis in high HIV prevalence settings? Tuberculosis 2003;83:68-76. Ayles HM, Chikwampu D, Mwale A, Halumamba V, Mitimingi P, Godfrey-Faussett P. Routes to combined HIV/ TB care: VCT vs. Household. In: XIV International AIDS Conference, Barcelona; 2002. Elliott AM, Hayes RJ, Halwiindi B, Luo N, Tembo G, Pobee JO, et al. The impact of HIV on infectiousness of pulmonary tuberculosis: a community study in Zambia. AIDS 1993;7:9817. World Health Organization. Preventive therapy against tuberculosis in people living with HIV. Weekly Epidemiol Records 1999;74:385-400. Wilkinson D, Squire SB, Garner P. Effect of preventive treatment for tuberculosis in adults infected with HIV: systematic review of randomized placebo-controlled trials. BMJ 1998;317:625-9. Johnson JL, Okwera A, Hom DL, Mayanja H, Mutuluuza Kityo C, Nsubuga P, et al. Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults. AIDS 2001;15:2137-47. Quigley MA, Mwinga A, Hosp M, Lisse I, Fuchs D, Porter JDH, et al. Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults. AIDS 2001;15:215-22. Fitzgerald DW, Desvarieux M, Severe P, Joseph P, Johnson WD Jr, Pape JW. Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1 infected individuals: a randomized trial. Lancet 2000;356:1470-4. Churchyard GJ, Fielding K, Charalambous S, Day JH, Corbett EL, Hayes RJ, et al. Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans: time to change policy? AIDS 2003;17:2063-70. Jone JL, Hanson DL, Dworkin MS, De Cock KM. HIVassociated tuberculosis in the era of highly active antiretroviral therapy. Int J Tuberc Lung Dis 2000;4:1026-31. Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet 2002;359:2059-64. Boix V, Merino E, Portilla J. Highly active antiretroviral therapy for patients with tuberculosis: the solution or the problem? AIDS 2002;16:1436-7. The Voluntary HIV-1 Counselling and Testing Efficacy Study Group. Efficacy of voluntary HIV-1 counselling and testing

136.

137.

138.

139.

140.

141.

142.

143. 144. 145.

146. 147.

148. 149.

150.

151. 152. 153.

in individuals and couples in Kenya, Tanzania, and Trinidad: a randomized trial. Lancet 2000;356:103-12. Sweat M, Gregorich S, Sangiwa G, Furlonge C, Balmer D, Kamenga C, et al. Cost-effectiveness of voluntary HIV-1 counselling and testing in reducing sexual transmission of HIV-1 in Kenya and Tanzania. Lancet 2000;356:113-21. Creese A, Floyd K, Alban A, Guinness L. Cost-effectiveness of HIV/AIDS interventions in Africa: a systematic review of the evidence. Lancet 2002;359:1635-43. Merson MH, Dayton JM, O’Reilly K. Effectiveness of HIV prevention interventions in developing countries. AIDS 2000;14[Suppl 2]:68-84. World Health Organization. 3 by 5 Initiative. Available at URL: http://www.who.int/3by5/en. Accessed on September 30, 2008. Kerouedan D. 1986-2006: 20 years of failed international policy to control AIDS in Africa. Med Trop [Mars] 2007;67:515-28. Godfrey-Faussett P, Maher D, Makedi YD, Nunn P, Perriens J, Raviglione M . How human immunodeficiency virus voluntary testing can contribute to tuberculosis control. Bull World Health Organ 2002;80:939-45. Corbett EL, Charalambous S, Fielding K, Clayton T, Hayes RJ, De Cock KM, et al . Stable incidence rates of tuberculosis among human immunodeficiency virus negative South African miners during a decade of epidemic HIV-associated TB. J Infect Dis 2003;188:1156-63. Dandona L, Dandona R. Drop of HIV estimate for India to less than half. Lancet 2007;370:1811-3. Steinbrook R. HIV in India – a downsized epidemic. N Engl J Med 2008; 358: 107-9. World Health Organization. Report Adult Lung Health Initiative: recommendations of the Consultation, Geneva, 414 May 1998. WHO/TB/98.257. Geneva: World Health Organization; 1998. Chaulet P. After health sector reform, whither lung health? Int J Tuberc Lung Dis 1998;2:349-59. World Health Organization. Guide pratique pour la prise en charge des maladies ayant des symptoms respiratoires dans le formations saniataires de base au Maroc. WHO/CDS/TB/ 2002.298 [a,b,c]. Geneva: World Health Organization; 2002. Frieden TR. Can tuberculosis be controlled? Int J Epidemiol 2002;31:894-9. Veron LJ, Blanc LJ, Suchi M, Raviglione MC. DOTS expansion: will we reach the 2005 targets? Int J Tuberc Lung Dis 2004;8:139-46. Frieden TR, Lerner BH, Rutherford BR. Lessons from the 1800s: tuberculosis control in the new millennium. Lancet 2000;355:1085-92. Drobniewski FA, Caws M, Gibson A, Young D. Modern laboratory diagnosis of tuberculosis. Infect Dis 2003;3:141-7. Duncan K. Progress in TB drug development and what is still needed. Tuberculosis 2003;83:201-7. Reed SG, Alderson MR, Dalemans W, Lobet Y, Skeiky YAW. Prospects for a better vaccine against tuberculosis. Tuberculosis 2003;83:213-9.

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The Revised National Tuberculosis Control Programme [RNTCP]

63

Reuben Granich, LS Chauhan

EPIDEMIOLOGY Tuberculosis [TB] remains a serious public health problem in India, accounting for nearly one fifth of the global burden (1). India has more people with active TB than any other country in the world. Each year, there are approximately 1.8 million new cases of TB disease, of which nearly 800 000 are highly infectious [smearpositive] TB; two persons die from TB in India every three minutes – more than 1000 every day, and approximately 370 000 people each year (1). The socioe-conomic impact of TB in India is devastating and more women die of TB in India than from all causes of maternal mortality combined (1,2). Most TB patients are in the economically productive age group. India continues to incur huge costs due to TB amounting to nearly US$ three billion and 300 million in indirect and direct costs respectively. Over 300 000 children annually have to leave school as a result of their parents’ TB and more than 100 000 women are rejected every year by their families on account of their having TB (1,2). According to the recent estimates of TB burden by the World Health Organization [WHO] (3), the incidence of smear-positive TB is 75 and all forms of TB is 168 per 100 000 population, prevalence of all forms of TB in India is 299 per 100 000 population. India’s TB problem is further compounded by an estimated 2.5 million people infected with human immunodeficiency virus [HIV], TB being the most common opportunistic infection amongst HIV-infected individuals (4,5). Ironically, TB persists as a major health problem in spite of the fact that many of the basic scientific precepts of the WHO recommended DOTS strategy were discovered in India.

BRIEF HISTORY OF TUBERCULOSIS CONTROL IN INDIA A number of significant scientific and public health discoveries at the Tuberculosis Research Centre [TRC] in Chennai [earlier called Madras] and the National Tuberculosis Institute [NTI] in Bengaluru [earlier called Bangalore] in the 1950s and 1960s respectively laid much of the foundation for DOTS which is the international modern-day standard care for TB control. Tuberculosis control in India has a long and illustrious past (6). In the early 1900s TB was recognized as a serious problem and the first open-air sanitarium for treatment and isolation of TB patients was founded in 1906 in Tiluania, near Ajmer, followed by one in Almora two years later (3). In 1912, magnitude of the problem was recognized through a resolution regarding TB at the All India Sanitary Conference in Madras (7). Although it was recognized that TB prevalence was alarmingly high in various parts of the country, understanding of the extent of the problem was limited by a lack of reliable surveillance data. The introduction of tuberculin skin testing helped to clarify the situation and surveys carried out in Assam, Bengal, Bihar and Madras showed tuberculin positivity ranging from 11 to 33 per cent in persons aged below 15 years and 70 per cent in those aged over 15 years (6). Longitudinal surveys carried out in 1939 in south India also provided insight about the magnitude of TB problem (8). In 1946 the Bhore committee estimated that about 2.5 million patients required treatment in the country while only 6000 beds were available (8). Countrywide bacille Calmette-Guerin [BCG] campaigns in the 1940s revealed that TB infection

The Revised National Tuberculosis Control Programme [RNTCP] was widespread and also helped to increase the level of awareness among public health authorities and the general public. Without effective treatment, progress in TB control was minimal and despite an active sanatorium movement, millions of TB patients remained largely untreated. Lack of effective antituberculosis chemotherapy meant that the main line of treatment relied on good food, open air and dry climate. Under these conditions, treatment took a second place to diagnosis. By 1920, public opinion gained a momentum for effective measures for control of TB. India became a member of the International Union Against Tuberculosis [IUAT] in 1929 and the antituberculosis movement grew with support from the government. The Tuberculosis Association of India [TAI] was established in 1939 and the Directorate General of Health Services established a TB division in 1946. In 1939, the TAI recommended the Organized Home Treatment Scheme as the best compromise under the prevailing circumstances. Additionally, TB control was included in the government’s five-year plans. Work with BCG started in India as a pilot project in two centres in 1948 and in 1949 it was extended to cover schools in almost all states of India. A BCG Vaccine Production Centre in Guindy, Chennai was set up in 1948 and WHO and United Nations Children’s Fund [UNICEF] provided assistance for introducing mass BCG vaccination. The Government of India also established clinical, domiciliary and after care services, TB training, demonstration and research centres, and provided beds for isolation and treatment. Research and training, received new support in 1955 with the establishment of the Tuberculosis Chemotherapy Centre, Madras, now called the TRC, Chennai, and in 1959, the NTI, Bengaluru. In the 1940s, streptomycin and para-aminosalicylic acid [PAS] were introduced in the developed countries, followed by thioacetazone and isoniazid in the 1950s. This gave a global impetus to Tuberculosis treatment and control. In 1951, these drugs were tried out on a small number of patients at the New Delhi TB Centre, and subsequently followed by others. The monumental National Sample Survey [NSS] on TB carried out by Indian Council of Medical Research [ICMR] between 1955 and 1958 revealed that TB was equally distributed in the urban and rural populations (9).

895

In the 1950s and 1960s, research at the TRC in Chennai demonstrated that domiciliary treatment was as effective and less costly than in-patient treatment for TB (10). Additionally, use of directly observed treatment [DOT], in which patients are observed taking their medications, was shown to be essential (11). These seminal findings led to a radical change in thinking regarding TB care worldwide (12). Indian researchers also pioneered the efficacy of intermittent treatment where medications were successfully given two to three times a week (13). Improved case-finding using microscopy among patients attending health services was also demonstrated in India (14-15). In 1962, these and other path-breaking sociological and epidemiological studies led to the establishment of the National Tuberculosis Control Programme [NTP] in 1962. The NTP was implemented nationwide in a phased manner through the establishment of District TB Centres, urban chest clinics and in-patient beds. The NTP developed a substantial infrastructure and significantly raising awareness about TB. However, after implementation for two decades, it was observed that the drug adherence levels were not satisfactory. Short-course chemotherapy was introduced in 1985. Despite this intervention, ensuring drug supply and adherence continued to be a problem and programme goals to control TB were not achieved. In 1992, a comprehensive joint review of the TB programme in India by members of several organizations including the Government of India, WHO and Swedish International Development Agency [SIDA] found that less than half the patients with TB received an accurate diagnosis and that less than half of those were effectively treated (16). Laboratory services were under-utilized, treatment regimens were unnecessarily complicated, drug shortages were common, and completion of treatment was not systematically assessed. Importantly, the NTP had not made significant epidemiological impact on the prevalence of TB. Therefore, the Revised National Tuberculosis Control Programme [RNTCP], based on the WHO-recommended DOTS strategy, was started in 1993. TECHNICAL FOUNDATION The goal of RNTCP is to cure at least 85 per cent of new smear-positive cases of TB and to detect at least 70 per cent of such patients, after the desired cure rate has been

896

Tuberculosis

achieved (3). The RNTCP encompasses the five principles of the DOTS strategy and builds on the significant infrastructure under the NTP including a network of 446 District TB Centres, 330 TB Clinics and more than 47 600 TB beds. Community-based care is emphasized and infrastructure and management established by the NTP are strengthened under RNTCP by identifying a subdistrict supervisory unit known as TB Unit [TU] and adding a supervisory team consisting of the treatment supervisor and laboratory supervisor called as Senior Treatment Supervisor [STS] and Senior TB Laboratory Supervisor [STLS] respectively. Additionally, a medical officer is allocated for TB control activities in addition to his/her other functions. These three individuals at the sub-district management unit [i.e., TU] oversee operations for approximately 500 000 population which on an average includes five Designated Microscopy Centres [DMC]. Supervisory staff can be augmented in difficult, remote, hilly and tribal areas. A district as per its population may have one or more TUs which are supervised by a District TB Officer [DTO]. Sub-centres covering a population of 5000 are staffed by health care workers who can provide TB treatment under direct observation. Observation of treatment by a family member is not acceptable under the programme. However, RNTCP is flexible in identifying the DOT providers who are accessible and acceptable to the patient and accountable to the system. The DOT provider can be a medical or a para-medical personnel or a community volunteer or someone from the non-governmental organizations [NGOs] and private sector facility involved in the programme. In urban areas with limited infrastructure special arrangements have been made by including one treatment observer [TB Health Visitor] per 100 000 population on contract. Necessary transport facility is provided to the districts for regular supervision and effective logistic management. Proper supervision, modular training, and regular cross-checking of work plays a key role in maintaining quality services. The RNTCP has placed an emphasis on assuring high cure rates and carefully expanding case detection activities after achieving the acceptable cure rates i.e., 85 per cent among new smear-positive patients initiated on treatment. Basic RNTCP principles are: [i] political commitment to ensure adequate funds, staff, and other key inputs; [ii] diagnosis primarily by sputum smear microscopy of patients presenting to health facilities; [iii] regular and uninterrupted supply of

antituberculosis drugs including the use of a patient-wise boxes which contains a full course of medication for an individual which serves to preclude interruption of therapy for patients; [iv] use of intermittent [thrice weekly] regimens ensuring direct observation of every dose of treatment in the intensive phase and at least the first dose of the week in the continuation phase; and [v] systematic monitoring, supervision and cohort analysis. Health care providers are trained to ask all patients attending health care facilities if they have had a cough for three weeks or more [Figure 63.1]. These TB suspects then have three sputum smears [spot, morning, spot sputum smears] examined over a two-day period. If two of the three smears are positive for acid-fast bacilli [AFB],

Figure 63.1: Patient categorization under the Revised National Tuberculosis Control Programme* * The algorithm is expected to be revised in future. As per the proposed changes, any person with cough for 2 weeks or more [in place of “3 weeks or more”] will be considered as a “TB suspect”; 2 sputum specimens, 1 of them being an early morning specimen [in place of “3 sputum smears”] will be required for diagnosis; 1 of the 2 sputum specimens positive will be considered as “smear-positive TB” [in place of “2 or 3 positive”]; and specimens with scanty bacilli will be considered positive. Emphasis has been given to a quality assured laboratory. The reader can check http://www.tbcindia.org for the latest details

TB = tuberculosis

The Revised National Tuberculosis Control Programme [RNTCP] then treatment is started. If all three smears are negative, then a course of antibiotics is offered for one to two weeks and then a repeat sputum smear examination is done followed by a chest radiograph if the repeat sputum smear is found to be negative. If only one smear is positive or symptoms persist after the antibiotics, then also, a chest radiograph is obtained. A standardized system of categorization and treatment regimens are used to manage patients under RNTCP [Table 63.1]. All regimens are given as thrice weekly intermittent regimens. Although the emphasis is on treating infectious smear-positive patients, if three smears are negative and there is no response to one to two weeks of antibiotics, then a chest radiograph is taken after a repeat sputum examination. If the chest radiograph is consistent with TB, the patient is started on treatment for TB [Figure 63.1]. One of the greatest strengths of the RNTCP is the recording and reporting system. Based on the patient treatment card, the laboratory register and the TB register, this simple but robust system ensures accountability for each and every patient initiated on treatment. Quarterly Cohort reports on case-finding, sputum conversion and treatment outcome are compiled from the TB register at TU and district level which are analysed and sent to the state and central levels. Remarkably, around 95 per cent of quarterly reports from

897

districts are submitted via the internet and a quarterly surveillance report at the national level is generated within two months of the close of the quarter. Districts are encouraged to perform TU specific analyses to highlight good performance and areas that need attention [e.g., case detection, default, etc.,]. Likewise, the yearly report is compiled and disseminated to programme staff and others in a time bound manner. A central staff team reviews the quarterly reports and provides feedback directly to the states and districts. The RNTCP is planning to start a web-based surveillance system that should facilitate better data management, provide timely and useful feedback for end users, and an increased access to data for states and DTOs. Through training, direct supervision and internal evaluations, RNTCP emphasizes the importance of meticulous record keeping and accuracy. It also encourages a transparent analysis of the data at all levels and actively uses the information to make programme and policy decisions. Large-scale implementation of the RNTCP began in 1998 with a ‘soft’ loan of US$ 142 million from the World Bank (17). The five-year credit period starting May 1997 was later extended until September 2005. In addition, the RNTCP is supported by bilateral donors including the UK Department for International Development [DFID], Canadian International Development Agency

Table 63.1: Revised National Tuberculosis Control Programme treatment regimens Category of treatment

Type of patient

Regimen*

Category I

New sputum smear-positive Seriously ill† new sputum smear-negative Seriously ill† new extra-pulmonary

2H3R3Z3E3 + 4H3R3

Category II

Sputum smear-positive relapse Sputum smear-positive treatment failure Sputum smear-positive treatment after default Others‡

2H3R3Z3E3S3 + 1H3R3Z3E + 5H3R3

Category III

New sputum smear-negative, not seriously ill New extra-pulmonary, not seriously ill

2H3R3Z3 + 4H3R3

* The number before the letters refers to the number of months of treatment. The subscript after the letters refers to the number of doses per week † Seriously ill also includes any patient, pulmonary or extra-pulmonary TB who is HIV-seropositive and declares his/her sero-status to the categorizing/treating Medical Officer. For the purpose of categorization, HIV testing should not be done ‡ In rare and exceptional cases, patients who are sputum smear-negative or who have extra-pulmonary TB can have relapse or treatment failure. This diagnosis in all such cases should always be made by a Medical Officer and should be supported by culture or histopathological evidence of current, active TB. In these cases, the patient should be categorized as ‘Others’ and given Category II treatment The dosage strengths are as follows: H = isoniazid [600 mg]; R = rifampicin [450 mg]; Z = pyrazinamide [1500 mg]; E = ethambutol [1200 mg]; S = streptomycin [750 mg]. Patients who weigh 60 kg or more receive additional rifampicin [150 mg]. Patients who are more than 50 years old receive streptomycin [500 mg]. Patients who weigh less than 30 kg receive drugs as per body weight Patients in Categories I and II who have a positive sputum smear at the end of the initial intensive phase receive an additional one month of intensive phase treatment Source: reference 14

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Tuberculosis

[CIDA], Global Drug Facility [GDF], Global Fund to fight AIDS, TB and Malaria [GFATM], and United States Agency for International Development [USAID]. Technical support is provided by WHO, with a network of consultants deployed at the national, state and district levels to provide technical support and assistance in monitoring the programme. The second phase of RNTCP is in progress since October, 2005. As per analysis of the Joint TB Programme Review of 2003, RNTCP is highly economical, costing on an average less than two rupees [5 US cents] per capita per year (18). Policy direction, supervision, surveillance, drugs and microscopes are provided by the Central Government. States receive funds for further distribution to Districts for carrying out day-to-day activities. Additionally, higher level state staff receives training from the Centre. They are also provided guidelines and modular training materials to train staff in the field [Table 63.2]. The RNTCP has invested heavily and has also made significant strides in maintaining and improving the delivery of quality DOTS [Table 63.3]. Regular reviews of the programme at the state and district level are a key component of the process. In addition to the routine supervision and monitoring by the programme staff, each state conducts internal evaluation of two districts in a quarter. Central evaluations are conducted by the team from the Central TB Division to evaluate one or two

districts each month. Technical support is provided from three central institutes including Lala Ram Sarup [LRS] Institute of Tuberculosis and Respiratory Diseases, New Delhi, NTI, Bengaluru and the TRC, Chennai. These institutes work in close liaison with RNTCP and play a key role in setting national priorities, training, carrying out operational research [OR] and also in assisting the Programme in its monitoring and evaluation activities. The RNTCP actively collaborates and contributes to Global DOTS expansion efforts through dissemination of its training manuals, scientific research and participation in key working groups and international meetings. Finally, it works closely on technical matters with the WHO, Centers for Disease Control and Prevention [CDC], Atlanta, Royal Netherlands Tuberculosis Association [KNCV] and the International Union Against Tuberculosis and Lung Disease [IUATLD]. DRUG PROCUREMENT AND MANAGEMENT A strong drug procurement and management system is critical to the success of RNTCP. Medicines or packaging materials that lack effectiveness or appear to be of poor quality can seriously undermine confidence in the Programme. Every link in the supply chain, from manufacturer to patient must be quality assured. Over

Table 63.2: Number of staff trained under Revised National Tuberculosis Control Programme in the year 2006 Category of staff

Second MO-DTC MO-TC [TU] MO [at BPHC/PHC/CHC/Others]

Sanctioned

In Place

In place and trained in RNTCP

% Trained in RNTCP

511

392

337

86

2365

2238

1918

86

76556

64191

49112

77

STS

2415

2351

2231

95

STLS

2448

2373

2254

95

All LTs [including DMCs]

25582

21829

16921

78

LT/Microscopist of DMC

12134

11689

11006

94

1302

1114

975

88

Pharmacist

35759

30458

19997

66

MPHS

47194

37784

28523

75

MPHW

245370

217997

173746

80

2383

2104

1889

90

TO

TBHV

RNTCP = Revised National Tuberculosis Control Programme; MO = Medical Officer; DTC = District TB Centre; MOTC = Medical Officer TB Centre; TU = TB Unit; DMC = Designated Microscopy Centre; STS = Senior Treatment Supervisor; STLS = Senior Tuberculosis Laboratory Supervisor; LT = Laboratory Technician; TO = Treatment Organizer; BPHC = Block Primary Health Centre; CHC = Community Health;Centre; PHC = Primary Health Centre; MPHS = Multipurpose Health Supervisor; MPHW = Multipurpose Health Worker, TBHV = TB Health Visitor

13611

339

Kerala

22

Nagaland

Puducherry

11

395

10

Mizoram

Orissa

25

1383

49285

3079

2177

4857

4885

26

Manipur

Meghalaya

80410 142792

680

15

24397

67630

36133

1055

Madhya Pradesh

Maharashtra

1

568

Karnataka

Lakshadweep

296

Jharkhand

12392

65 120

Jammu and Kashmir

Himacha Pradesh

35591

234

80399

556

2104

49058

Haryana

16

337

390

27504

2411

79619

36766

Gujarat

166

Goa

2

Daman and Diu

Delhi

3

D and N Haveli

10 233

Chhattisgarh

923

Chandigarh

295

Bihar

2746

111304

813 12

775

131

125

143

225

194

188

135

118

22

72

119

122

103

210

152

145

133

296

184

153

118

232

86

125

232

137

193

Total Annual patients total registered case for detection treatment† rate

4

State population [in 100 000] covered by RNTCP*

Assam

Arunachal Pradesh

Andhra Pradesh

Andaman and Nicobar

State

636

21689

1193

689

1447

1064

55571

30424

6

10915

25956

16164

4932

4978

13116

34856

645

13695

98

127

10598

736

30834

16324

890

49099

256

New smearpositive patients registered for treatment

60

55

55

71

58

41

53

45

9

32

46

55

41

77

56

63

41

83

54

50

46

71

33

55

75

60

64

No.

80

65

74

95

77

55

66

56

12

64

61

73

43

81

59

78

51

87

67

62

57

75

45

74

100

81

85

%

Annual new smearpositive case detection rate

76

63

59

57

57

36

60

55

55

70

62

58

66

66

63

75

53

60

51

61

49

60

52

61

55

60

51

% New sputum positive out of total new pulmonary cases

201

12831

846

513

1097

1893

37461

25122

5

4694

15884

11774

2538

2621

7607

11699

574

9047

95

82

11092

489

28034

10536

732

32563

248

80

81

89

91

81

85

85

82

71

81

76

85

85

88

84

87

72

85

87

82

84

86

75

85

86

85

86

-Contd-

81

86

90

91

82

85

86

85

71

83

78

89

87

89

85

87

73

86

92

82

87

86

83

86

87

87

86

No. of new Cure rate Treatment smear-negative of new success cases registered smearrate of for treatment postive new smearpatients positive patients

Table 63.3: Performance of Revised National Tuberculosis Control Programme: case detection [2007], smear conversion [4th quarter 2006 and 1st to 3rd quarter 2007] and treatment outcomes [2006]

The Revised National Tuberculosis Control Programme [RNTCP] 899

1475587

13406 107226

245106

2573

86113

1538

111700

35875

130

143 123

131

74

131

262

176

136

Total Annual patients total registered case for detection treatment† rate

592635

5398 50133

99606

1460

33359

493

41155

14093

New smearpositive patients registered for treatment

52

58 58

53

42

51

84

65

54

No.

70

61 77

56

56

68

112

81

56

%

Annual new smearpositive case detection rate

60

62 69

56

76

58

64

55

65

% New sputum positive out of total new pulmonary cases

398865

3356 22539

77060

466

24075

279

33095

7717

84

88 86

83

86

82

86

87

83

86

89 87

86

90

83

86

89

85

No. of new Cure rate Treatment smear-negative of new success cases registered smearrate of for treatment postive new smearpatients positive patients

The Central TB Division, Government of India updates these data annually. The reader can access the updated information from the “TB India” report of the current year available at the URL: http://www.tbcindia.org

Values for shaded cells are not expected

Estimated new smear-positive cases/100 000 population based on annual risk of tuberculosis infection [ARI] data for North Zone [Chandigarh, Delhi, Haryana, Himachal Pradesh, Jammu and Kashmir, Punjab, Uttar Pradesh, Uttarakhand] = 95; East Zone [Andaman & Nicobar, Arunachal Pradesh, Assam, Bihar, Jharkhand, Manipur, Meghalaya, Mizoram, Nagaland, Sikkim, Tripura, West Bengal] = 75; South Zone [Andhra Pradesh, Karnataka, Lakshadweep, Puducherry, Tamil Nadu] = 75; West Zone [Chhattisgarh, Dadra & Nagar Haveli, Daman & Diu, Goa, Gujarat, Madhya Pradesh, Maharashtra, Rajasthan] = 80; Orissa = 85; Kerala = 50

* Projected population based on census population of 2001 is used for calculation of case-detection rate † Total patients registered for treatment includes new sputum smear-positive cases, new smear-negative cases, new extra-pulmonary cases, smear-positive re-treatment cases and ‘others’

11310

94 868

Uttarakhand West Bengal

Grand total

1874

35

658

Uttar Pradesh

Tripura

Tamil Nadu

6

635

Sikkim

263

Rajasthan

State population [in 100 000] covered by RNTCP*

Punjab

State

Table 63.3 -Contd-

900 Tuberculosis

The Revised National Tuberculosis Control Programme [RNTCP] the last few years, significant improvements in packaging, inspection, supply, storage and quality control practices and procedures have been achieved. Due to significant improvement in the information systems and tracking, procurement according to World Bank specified guidelines, an uninterrupted supply of quality antituberculosis medicines is maintained by the programme. Drug stock tracks the best possible utilization estimate and drug procurement plans are prepared to ensure a 12-month buffer stock at the national level. Improved blister pack designs in patientwise boxes have also been introduced and have proven to be extremely effective. The availability of drugs in patient-wise boxes ensures availability of full treatment course for every patient who is started on treatment. The innovative development and use of patient-wise boxes have enhanced patients’ confidence in the public health system and has simplified drug procurement and management. The RNTCP drugs are procured from an agency selected through International Competitive Bidding [ICB] process. Presently, procurements are being handled by United Nations Office for Project Services [UNOPS]. The Central TB Division [CTD], Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, calculates requirements, delivery schedule, technical specifications and consignee details. Tender is floated by procurement agents following ICB procedures. For long-term sustainability of RNTCP, antituberculosis drugs logistic management has been decentralized with capacity building of states and districts by establishing state, district and TU level drug stores and training of staff in drug logistic management. State Drug Stores [SDS] serve to facilitate drug distribution by reducing lead-time and greatly reduce the risk of stockout and expiry. Drugs are issued to the districts from the SDS on the basis of Quarterly Programme Management Reports which are tallied with the District’s Case-Finding Report. The PWBs of defaulters, treatment failure or dead patients are re-constituted so that the drugs from these patients are not wasted. A three-month buffer stock is maintained at each district by a system of projections of future utilization and supply needs of districts. Drugs are issued to SDSs from Government Medical Store Depots [GMSDs] by the CTD on the basis of Programme Management Report [PMR] of the state. In addition, drug

901

stocks at each GMSD and SDS are monitored through receipt of monthly statements regarding the quantities issued during the month, stock in hand and stock of expiry dates. Drug quality is assured in a number of ways including: [i] samples from each drug batch are taken and quality of drugs is tested prior to their clearance for dispatch by the manufacturers; [ii] checking of random samples from state and central government store houses; [iii] Central and State Drugs Inspectors intermittently take samples from districts, in addition to when they receive specific complaints; and [iv] use of an independent laboratory for quality assurance of antituberculosis drugs. Drug supply system and quality are the backbones of a strong national TB programme. The RNTCP takes several measures to assure that patients receive an uninterrupted supply of quality antituberculosis drugs. A web-based drug logistics management system is under development to increase efficiency of the current paperbased reporting system. Additionally, an independent laboratory hired under the programme for testing random and requested samples is serving as an important link in the quality control chain. DOTS EXPANSION The RNTCP began operations in 1993 in five pilot sites in Delhi, Gujarat, Kerala, Maharashtra and West Bengal, covering a population of 2.35 million. Piloting allowed for further refinement of the inputs [e.g., training modules, logistics, staffing, infrastructure, supervision, recording and reporting ] needed to establish a successful programme under field conditions. The Programme then progressively, but slowly, expanded to cover 13.9 million in 1995 and 20 million in 1996. Large scale expansion of DOTS services in India began in 1997 after a successful pilot, which established the technical and operational feasibility of the strategy. Thereafter, the RNTCP expanded rapidly, covering 50 per cent of the population in 2002; full nation-wide coverage [covering over 1.1 billion population] was achieved in March 2006 [Figures 63.2 and 63.3]. Presently more than 1 600 000 patients had been placed on treatment. The reader can access http://www.tbcindia.org for the latest figures on this topic. This remarkable expansion of RNTCP is the fastest expansion in the history of DOTS.

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Figure 63.2: Population in India covered under DOTS and total tuberculosis patients put on treatment each quarter Qtr = quarter

Quality of services was the main focus of RNTCP while expansion of DOTS was taking place in several states. Therefore, systematic appraisal of each district was done prior to start of service delivery. The appraisal process ensured that each district maintains a minimum standard before starting RNTCP service delivery [Figure 63.4]. PROGRAMME PERFORMANCE The RNTCP has made a significant contribution to public health capacity-expansion by training more than 500 000 health personnel of various cadres using a modular approach and the purchase of over 12 000 binocular microscopes. Since its inception in 1997, the programme has initiated more than eight million TB patients on treatment and prevented over 1.4 million TB deaths. Every month more than 120 000 patients are initiated on treatment. The programme has evaluated more than 36 million people with suspected TB. The RNTCP results over the years have consistently met the international benchmark of a treatment success rate of more than 85 per cent among new smear-positive pulmonary TB cases. Case detection rates are close to the global targets of 70 per cent [Figure 63.5]. During 2007, more than 6.48 million symptomatic persons were screened for TB free of charge and more than 1.47 million patients were initiated on treatment [Figure 63.6].

In participating institutions, roughly two to three per cent of out-patients are screened for TB. Smear microscopy, a much more reliable method of identifying persons with TB [chest radiographs are non-specific for TB], now forms the basis for diagnosis. The proportion of chest symptomatics who are smear-positive largely depends on referral practices. Although significant progress has been made in the area of case detection, RNTCP has a number of initiatives [e.g., collaboration with the private and corporate sectors, medical college task forces, community-based DOT providers, urban DOTS, etc.,] designed to increase DOTS delivery to persons suffering from TB. The RNTCP has made additional efforts to reach marginalized communities and internal and cross-border migratory populations. LABORATORY NETWORK AND QUALITY ASSURANCE Under the RNTCP, a DMC has been established to cater the need for approximately 100 000 population [50 000 for tribal, difficult and mountainous areas]. Each DMC is staffed by a RNTCP trained laboratory technician (2). The Programme provides assistance to improve laboratory facilities e.g., supply of a binocular microscope and essential laboratory consumables. By the end of 2007, there were more than 12 500 DMCs working under

The Revised National Tuberculosis Control Programme [RNTCP]

Figure 63.2: DOTS Implementation Status in India by District, 2007

Figure 63.3: The Revised National Tuberculosis Control Programme laboratory network NRL = National Reference Laboratory; IRL = Intermediate Reference Laboratory; TU =TB Unit; MC = medical college; DMC = Designated Microscopy Centre; EQA = external quality assurance; DTO = District Tuberculosis Officer; STLS = Senior TB Laboratory Supervisor

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Tuberculosis

Figure 63.5: Annualized new smear-positive case detection rate and treatment success rate in DOTS areas, India, 1999 to 2008. Population projected from 2001 census. Estimated number of new smear-positive cases = 75/100 000 population per year Qtr = quarter

Figure 63.6: New smear positive and total patients treated under the Revised National Tuberculosis Control Programe 1998-2007

The Revised National Tuberculosis Control Programme [RNTCP] RNTCP. Within respective districts, quality of the sputum smear microscopy work is ensured by the STLS based at the TB Unit level and at the district level by the DTO and at the state level by the Intermediate Reference Laboratory [IRL] staff. The STLS is expected to visit all [usually 5 DMCs per STLS] within their respective TU area at least once in a month. The laboratory network in the respective state is overseen by the State TB Cell [STC] headed by the State TB Officer, and staff from the State TB Training and Demonstration Centres [STDC]/IRL. Sanctioned staff posts at the STDCs and IRL include a microbiologist, epidemiologist, statistician and laboratory technicians. The STDCs are increasingly involved in training activities and assisting the STC in supervision, monitoring and evaluation of the RNTCP, including quality assurance of the laboratory services provided by RNTCP. At the national level, the CTD is assisted by the NTI, Bengaluru and the TRC, Chennai, LRS Institute of Tuberculosis and Respiratory Diseases, New Delhi and National JALMA Institute of Leprosy and Other Mycobacterial Diseases, Agra [the acronym JALMA stands for ‘Japanese Leprosy Mission for Asia’, a Tokyo based voluntary organization that originally managed this centre], and all these serve as National Reference Laboratories [NRLs]. The NRLs provide training and supervision of the laboratory-related activities performed by the STDCs in their role as intermediate level laboratories at the state level. Laboratory Quality Assurance Although many practitioners in India still rely on clinical examination and/or non-specific chest radiographs to establish a diagnosis of TB, under RNTCP, the core of the DOTS strategy relies on a bacteriological diagnosis and follow-up of cases by sputum smear microscopy. As the laboratory provides the foundation for the programme and ensures quality of the sputum smear microscopy services, it is a high priority for the RNTCP. Following the recommendation from the programme review of 2000, RNTCP developed a quality assurance protocol which included on-site supervision, panel testing, and random blinded rechecking [RBRC] of routine slides. On-site supervision is routine and districts also participate in a RBRC process. On the basis of the new international guidelines in 2002 (19) for the external quality assessment [EQA] of

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sputum smear microscopy services, a review of the existing RNTCP quality assurance protocol was done in 2003 with the technical input from NTI, TRC, LRS Institute and WHO. This review culminated in a national level consensus meeting held in August 2003, with the specific objectives of developing an updated RNTCP protocol for EQA of sputum smear microscopy services. The meeting also addressed the issue of capacity building to do population-based drug resistance surveillance in a number of states. A comprehensive sputum smear microscopy quality assurance protocol that includes on site evaluation, RBRC and panel testing has been developed and more than 90 per cent of the districts are implementing the quality assurance protocol [Figure 63.4 ] INFORMATION, EDUCATION AND COMMUNICATION Information, education and communication [IEC] and advocacy communication for social mobilization [ACSM] are important and crucial components of RNTCP. During RNTCP I, the focus was on local initiatives, as entire country was not covered under RNTCP. From 2000, when more than 50 per cent of the population was covered under DOTS, the programme focussed on large scale media activities for awareness generation. The RNTCP II aims to widen the scope for providing standardized, good quality treatment and diagnostic services to all TB patients in a patient-friendly environment, in whichever health care facility they seek treatment. The IEC approach has an important role in popularising this aspect. An effective RNTCP ACSM strategy is in place, in order to maintain high visibility of TB and RNTCP amongst policy makers, opinion leaders and community, and hence sustained long-term political and administrative commitment and greater community involvement to RNTCP. Advocacy and communication are central and integral part of the Phase II TB Project. The focus of IEC in RNTCP is on three main areas, i.e., awareness generation, advocacy, and patient-provider communication and counselling [Table 63.4]. Goals of ACSM include supporting TB efforts by : [i] improving case detection and treatment adherence; [ii] combating stigma and discrimination, [iii] empowering people affected by TB; and [iv] mobilizing political commitment and resources for TB.

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The programme has clearly defined communication strategy identifying objectives [communication needs]; target groups [communication players], and media options to reach target groups [communication tools]. The emphasis is on decentralized planning at the state and districts level in order to have need based locally relevant communication initiatives. To support states and also to maintain synergy and uniformity of messages, the Centre has developed prototype communication material which can be adapted in the field. The RNTCP is probably the first disease control programme in the country to have a web-based IEC resource centre on the official RNTCP website to house more than 300 types of material. Designated staff has also been provided in the states and at the district level. At the Central level. Advocacy and IEC Unit draws supports from an expert group known as IEC Advisory Group. This ‘think tank” has members from Centres of excellence, the fields of communication, social development and research and media. Similar arrangement has been recommended for the states by the programme. The programme has identified areas that need attention. The IEC baseline document has been developed which has information on knowledge, attitudes and practices among different target audiences and also has baseline information on capacity of states and districts in planning and implementation of IEC activities; it also identifies areas that need to be strengthened. The programme is drawing plans to address these issues. There is also plan to develop standardized training modules for training of IEC Officers, Communication facilitators, involve members of IEC Advisory Group in Table 63.4: The focus of information, education and communication in the Revised National Tuberculosis Control Programme Awareness raising to increase understanding about TB amongst The public so that they make use of RNTCP services Practitioners across the country so that they know about correct TB diagnosis and treatment and they refer patients to DOTS services, or become DOT providers themselves Advocacy to develop political, administrative and community-level commitment to TB control in India Patient-provider communication and counselling to assist patient compliance with the treatment regimen, to enhance the reputation of a patient-friendly service, and to encourage patients and their families to become advocates for the programme TB = tuberculosis; DOT = directly observed treatment; RNTCP = Revised National Tuberculosis Control Programme

Central Internal Evaluations [CIE], to prioritize linking the IEC activities to the programme objectives and issues in the districts and developing a mechanism to review and monitor this component. TUBERCULOSIS AND HUMAN IMMUNODEFICIENCY VIRUS India is among the world’s 22 high TB burden countries and with an estimated 2.5 million people living with HIV/infection, acquired immunodeficiency syndrome [AIDS] has the third highest estimated number of HIV infected people in the world (5). Approximately 40 per cent of people living with HIV/AIDS [PLHIV] in India are also infected with Mycobacterium tuberculosis. As HIV is the most powerful risk factor for progression from infection with Mycobacterium tuberculosis to active TB disease (20), the dual epidemic of HIV and TB results in increased TB related morbidity and mortality. The RNTCP services have expanded rapidly across India and in the absence of the HIV epidemic, it might have been expected to reduce the incidence of TB by five per cent a year or more at least for the first few years after full coverage was achieved, and possibly slow down after that as the epidemic ages. Even though the prevalence of HIV in India is an order of magnitude less than it is in East and southern Africa, it is likely that without improvements in TB control associated with the RNTCP programme, HIV would have given rise to an additional five million TB cases and 2.5 million AIDS deaths between the years 1990 and 2010. Analyses from a recent WHO-RNTCP-National AIDS Control Organization [NACO] modelling exercise indicate that RNTCP may be able to contain the impact of AIDS in terms of TB control and maintain the overall incidence of death rates due to TB at the current level over the next 10 years (21). As a direct result of the RNTCP programme it is likely that the number of TB cases will in fact decrease by about two million while the number of deaths will decrease by about 100 thousand during this period, even with the AIDS epidemic. Without HIV/AIDS, the RNTCP would have reduced these numbers by about 4.5 million and 1.4 million, respectively. When combined effect of HIV epidemic and impact of RNTCP is considered together, modelling suggests that RNTCP would compensate for the impact of HIV on TB over the longterm (21). Collaboration between TB and HIV programmes is essential to mitigate the high morbidity and mortality

The Revised National Tuberculosis Control Programme [RNTCP] from TB among PLHIV and dampen the potential negative impact that the HIV epidemic will have on TB control in India. Standard regimens of RNTCP, particularly if supervised properly, are as effective in HIV-seropositive as in HIV-seronegative patients (22). Treatment with DOTS can significantly prolong the life of HIV-infected persons (23), prevent drug resistance, and by quickly rendering a person with TB disease noninfectious, blunt transmission and the concomitant increase in TB cases. Providing treatment under DOTS for patients with TB and HIV may be the most important medical intervention widely available for most patients in India. Curing TB in HIV/AIDS patients will both improve their quality of life and reduce the spread of TB. Increasing access to care and antiretroviral therapy [ART] for eligible TB patients with HIV infection is also a priority for the NACO and RNTCP. Recognizing this, the Government of India has already taken important steps to strengthen the coordination between RNTCP and the NACO across the country with special focus to states with the highest burden of HIV in the general population. The key areas of focus are: [i] sensitization of the key state and district policy makers to highlight the importance of HIV-TB coinfection; [ii] development of training modules on HIVTB for different level of health functionaries of both programmes; [iii] joint training programmes on HIV-TB for different categories of programme and field staff; [iv] referral linkages between the service delivery sites of National AIDS and TB control programmes; [v] establishment of state and district co-ordination committees to monitor the progress of collaborative activities; [vi] development of IEC material on HIV/TB at the national level; [vii] cross-involvement of NGOs participating in the National AIDS Control Programme [NACP] and the RNTCP. To further strengthen this collaboration and improve the access to care for co-infected patients, OR on TB/ HIV has been prioritized. A number of OR projects have been undertaken. This includes the establishment and evaluation of decentralized delivery of cotrimoxazole preventive therapy [CPT] for HIV positive TB patients, establishment of referral linkages between decentralized RNTCP services and ART centres. MANAGEMENT OF PAEDIATRIC TUBERCULOSIS The actual global disease burden of childhood TB is not known, but it has been assumed that 10 per cent of the

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actual total TB case load is to be found amongst children. As per the WHO report 1996 (24), globally 1.5 million new cases and 130 000 deaths due to TB per year amongst children have been estimated. However, these figures may underestimate the true size of the problem. Childhood TB prevalence reflects the community prevalence of sputum smear-positive pulmonary TB, the age-related prevalence of sputum smear-positive pulmonary TB, the prevalence of childhood risk factors for disease and the stage of the TB epidemic. Proper identification and treatment of infectious cases will prevent childhood TB. However, often childhood TB is afforded a low priority by National TB Control programmes since there are diagnostic difficulties, cases are rarely infectious, resources are limited, there is often a misplaced faith in BCG and a lack of data on treatment. However, this rationale disregards the impact of TB on childhood morbidity and mortality. Children can present with TB at any age, but the majority of cases present between the ages of one and four years. The disease usually develops within one year of infection. Active TB disease is likely to be disseminated in children who develop the disease early. In children, the pulmonary to extra-pulmonary TB ratio is 1:3 and pulmonary TB is usually smear-negative. The prevalence of pulmonary TB is normally low between the ages of five and twelve years. Thereafter, the prevalence increases in adolescence in whom the presentation of pulmonary TB resembles that seen in adults (25). Reliable data on the burden of all forms of TB amongst children in India are not available and most surveys that have been conducted have focussed on pulmonary TB. Additionally, no significant population based studies on paediatric extrazpulmonary TB are available. In 2006, of the 1.4 million total patients registered for treatment under RNTCP, 64 697 were paediatric cases. Procurement and distribution of paediatric drug boxes for improved care of paediatric cases had been initiated in early 2007 and are now being used for treating paediatric patients in all states and union territories. To seek consensus on improved case detection and improved treatment outcomes for all diagnosed paediatric TB cases, a workshop of national and international paediatricians with expertise in childhood TB and TB control programme managers on the “Formulation of guidelines for diagnosis and treatment of paediatric TB cases under RNTCP” was held in New Delhi in 2003 (3). As a result of the workshop the “Consensus Statement

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on Management of Paediatrict TB” (26) was formulated and the same is being followed all over the country. Diagnosis Children presenting with fever and/or cough for more than three weeks, with or without weight loss or no weight gain; and history of contact with a suspected or diagnosed case of active TB disease within the last two years will be considered to be “suspect cases with pulmonary TB”. Diagnosis of pulmonary TB will be based on a combination of suggestive clinical presentation, sputum examination wherever possible, chest radiograph [postero-anterior view], tuberculin skin test [Mantoux test] using 1 tuberculin unit [TU] purified protein derivative [PPD] RT23 with Tween 80, considered to be positive if induration is greater than 10 mm after 48 to 72 hours; and history of contact as described in the diagnostic algorithm. Diagnosis of TB in children should be made by a medical officer. Where diagnostic difficulties are faced, referral of the child should be made to a paediatrician for further management. The existing RNTCP case definitions will be used for all cases diagnosed. The use of scoring systems is not recommended for use in diagnosis of pediatric TB patients currently.

given in Tables 63.5A and 63.5B. Intermittent shortcourse chemotherapy given under direct observation, as advocated in the RNTCP, should be used in children. To assist in calculating required dosages and administration of antituberculosis drugs for children, the medications are now made available in the form of combipacks in patient wise-boxes, linked to the child’s body weight. In patients with TBM on Category I treatment, the four drugs used during the intensive phase should be isoniazid, rifampicin, pyrazinamide, and streptomycin. Continuation phase of treatment in TBM and spinal TB with neurological complications should be given for six to seven months, extending the total duration of treatment to eight to nine months. Corticosteroids should be used initially to reduce inflammation in hospitalized cases with TBM and TB pericardiitis and tapered gradually over six to eight weeks. Any child who is to be started on category II treatment should be examined by a paediatrician or a TB expert. Treatment of Latent Tuberculosis Infection Asymptomatic children under six years of age, exposed to an adult with infectious [smear-positive] TB, are given six months treatment with isoniazid [5 mg/kg body weight].

Treatment of Paediatric Tuberculosis The DOTS is the recommended strategy for treatment of TB and all paediatric TB patients should be registered under RNTCP. Recommended treatment regimens are

PRIVATE SECTOR In India, with one of the largest private health care sectors in the world and almost one third of the global burden

Table 63.5A: Revised National Tuberculosis Control Programme treatment regimens for paediatric patients Treatment category

Type of patient

Regimen*

Category I

New smear positive; seriously ill smear negative; seriously ill extra-pulmonary

2H3R3Z3E3/4H3R3

Category II

Previously treated smear positive [relapse, treatment failure, treatment after default]

2H3R3Z3E3/1H3R3Z3E3/5H3R3E3

Category III

New smear negative and extra-pulmonary, not seriously ill

2H3R3Z3/4H3R3

* The number before the letters refers to the number of months of treatment. The subscript after the letters refers to the number of doses per week In children, seriously ill sputum smear-negative pulmonary TB includes all forms of sputum smear negative pulmonary TB other than primary complex. Seriously ill extra-pulmonary TB includes TB meningitis, disseminated TB, TB pericarditis, TB peritonitis and intestinal TB, bilateral extensive pleurisy, spinal TB with or without neurological complications, genitourinary TB, and bone and joint TB Not seriously ill sputum smear negative pulmonary TB includes primary complex. Not seriously ill extra-pulmonary TB includes lymph node TB and unilateral pleural effusion H = isoniazid; R = rifampicin; Z = pyrazinamide; E = ethambutol; S = streptomycin; TB = tuberculosis

The Revised National Tuberculosis Control Programme [RNTCP]

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Table 63.5B: Guidelines for use of paediatric patient wise boxes under the Revised National Tuberculosis Control Programme Product Code

Product Description

Strength

Unit

Product Code-13

Treatment box for paediatric category [6-10 Kg]. Each treatment box contains 24 combipacks of Schedule-5 in one pouch and 18 multi-blister calendar combi-pack of Schedule-6 in another pouch

Each combi-pack of Schedule-5, containing 1 tablet of rifampicin [75 mg]; 1 tablet of isoniazid [75 mg]; 1 tablet of ethambutol [200mg]; and 1 tablet of pyrazinamide [250mg]

Each multi-blister calender Treatment box combi-pack of Schedule-6 containing 3 tablets of rifampicin [75 mg each]; 3 tablets of isoniazid [75 mg each]; and 4 tablets of pyridoxine [5 mg each]

Product Code-14

Treatment box for paediatric category [11-17 Kg]. Each treatment box contains 24 combipacks of Schedule-7 in one pouch and 18 mult i-blister calendar combi-pack of Schedule-8 in another pouch

Each combi-pack of Schedule-7, containing: 1 tablet of rifampicin [150mg]; 1 tablet of isoniazid [150mg]; 1 tablet of ethambutol [400mg ]; and 1 tablet of pyrazinamide [500mg]

Each multi-blister calender Treatment box combi-pack of Schedule-8, containing 3 tablets of rifampicin [150 mg each]; 3 tablets of isoniazid [150mg each]; and 4 tablets of pyridoxine [5 mg each]

Product Code-15

Treatment box for prolongation of intensive phase of paediatric cases [6-10 kg, 18-25 kg]. Each box containing 5 pouches and each pouch containing 12 blister combi-packs of Schedule-5

Each combi-pack of Schedule-5, containing 1 tablet of rifampicin [75 mg]; 1 tablet of isoniazid [75 mg]; 1 tablet of ethambutol [200mg]; and 1 tablet of pyrazinamide [250mg]

Treatment box

Product Code-16

Treatment box for prolongation of intensive phase of paediatric cases [11-17, 18-25 kg and 26-30 kg]. Each box contains 5 pouches and each pouch contains 12 blister combi-packs of Schedule-7

Each combi-pack of Schedule-7 containing 1 tablet of rifampicin [150mg]; 1 tablet of isoniazid [150mg]; 1 tablet of ethambutol [400mg]; and 1 tablet of pyrazinamide [500mg]

Treatment box

The formulations used in RNTCP are rifampicin [75/150 mg]; isoniazid [75/150 mg]; ethambutol [200/400 mg]; pyrazinamide [250/ 500 mg] For the purpose of treatment, the paediatric population is divided into four weight bands: 6-10 kg; 11-17 kg; 18-25 kg; and 26-30 kg The antituberculosis drugs for paediatric patients are available in the form of generic patient wise boxes i.e., Product Code-13 and Product Code-14. Product Code-15 and Product Code-16 would be available for the prolongation of the intensive phase, if required and also to facilitate conversion of the boxes into Category II and for reconstitution, if required The generic patient wise boxes, would be used for the paediatric patients in the following manner: a child weighing 6-10 kg would require one box of Product Code-13; a child weighing 11-17 kg would require one box of Product Code-14; a child weighing 18-25 kg would require one box of Product Code-13 and one box of Product Code-14; a child weighing 26-30 kg would require two boxes of Product Code-14 In case, any patient is to be placed on Category II or III, the following steps will have to be taken to convert the generic boxes into a Category II or III box. For children to be placed on Category II, prolongation pouches would be added for prolongation of the intensive phase. For the extra one month of continuation phase, a prolongation pouch would be added after removing the pyrazinamide tablets from the prolongation pouch. For the other four months of continuation phase blisters, ethambutol tablets will need to be added which can be used from the supplies of loose drugs under the programme. Streptomycin injection [750 mg] supplied under the programme shall be used for such patients and the dosage would be as per body weight. For children who are to be put on Category III, the ethambutol tablets will be removed from the intensive phase blisters

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of TB, most patients with chest symptoms first consult private practitioners [PPs] (27,28). Unfortunately, TB is often inaccurately diagnosed and ineffectively treated in the private sector (28-33). This can result in diagnostic delay, prolonged infectiousness, drug resistance, poor treatment outcomes, and higher relapse rates. Although often sharing a common patient with similar objectives, there are often considerable misunderstandings between the private and public sectors regarding TB management (34). Consequently, the RNTCP has made efforts to develop partnerships with health providers outside the government health system, and in particular with the private health sector and NGOs. The goal is to raise the standard of care and provide a seamless more effective TB control environment for patients by improving access to quality TB care in either the public or private sector. In 2001, the RNTCP has developed official policy guidelines for involvement of NGOs and PPs in the programme. The policy guidelines for NGOs and PPs involvement provide a menu for collaboration on different levels of service delivery including referral, IEC, DOT provision alone, and operating a DMC with or without provision of DOT. To improve collaborations with the private sector, the RNTCP has started a number of initiatives including the provision of CMEs, seminars, workshops, lectures and conferences on RNTCP and the DOTS strategy. A national conference, was held at the All India Institute of Medical Studies [AIIMS], New Delhi in 2001 to share experiences and discuss modalities for private sector involvement in the RNTCP. District and State TB Control Societies are encouraged to include representatives from NGOs and PPs as members of the respective society. State/district action plans for implementation of the RNTCP include plans for NGO involvement. Finally, RNTCP is engaged with the Indian Medical Association [IMA] and the Indian Association of Paediatrics [IAP] and has co-edited a number of articles discussing RNTCP in the Journal of the Indian Medical Association (35-48). Thousands of NGOs, PPs, and RNTCP staff have recognized the potential benefit of RNTCP for their patients and have developed formal and informal collaborations. To date, about 2 400 NGOs and more than 17 000 PPs are officially providing RNTCP services. Evaluation and documentation of some of these programmes have shown that case detection and notification can increase significantly and that patients’ outcomes are similar between the public and privately managed

RNTCP TB cases. The corporate sector has also begun to collaborate and over 120 corporate sector units are involved in RNTCP including sugar mills in Uttar Pradesh, the tea gardens in North-East and West Bengal, Coal India in West Bengal and some of the other major houses of industry. Additionally, the Indian Business Alliance is a coalition recently formed by the Global Health Initiative of the World Economic Forum. The objective is to bring together these companies to work with Government of India to improve TB control. Members include Reliance, Larsen and Tourbo [L & T], Aditya Birla, Confederation of Indian Industry [CII], Tata, Hindustan Lever Limited [HLL], and other corporate houses. As part of this effort to expand collaborations, Government of India has started a publicprivate mix initiative in 14 large urban areas with the support of the CIDA and technical assistance from WHO. This ground-breaking initiative includes technical consultants who are dedicated to establish and improve public-private sector collaborations and is expected to significantly strengthen the partnership between the private health sector and TB control activities in India. The CTD conducted a three-day Consultation on Revision of NGO/PP Guidelines in January 2008 in Delhi to improve the collaboration with private sector in all aspects of RNTCP implementation. Subsequently, in August 2008, the CTD brought out the RNTCP Revised Schemes for NGOs and Private Providers [Table 63.6] (49) to meet the challenges of the present day programme implementation. These guidelines have been implemented with effect from October 1, 2008. ACADEMIC SECTOR India has over 277 medical colleges and over 18 000 new doctors graduate annually. Through research, academic work and practical training, medical colleges play a major role in establishing the standard of care for managing TB. Additionally, as referral centres of excellence, medical colleges treat a significant number of TB cases. The RNTCP recognizes the challenge and importance of introducing DOTS principles as the standard of care into both the training and clinical care practices of medical professionals. In order to further integrate medical colleges into the national effort to control TB, the RNTCP has made it a priority to involve medical colleges and their hospitals in the RNTCP. Under RNTCP, the District Health Society is authorized to provide a medical officer,

The Revised National Tuberculosis Control Programme [RNTCP]

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Table 63.6: Revised schemes for the involvement of non-governmental organizations and private providers in the Revised

National Tuberculosis Control Programme ACSM Scheme: TB advocacy, communication, and social mobilization SC Scheme: sputum collection centre/s Transport Scheme: sputum pick-up and transport service DMC Scheme: Designated Microscopy Cum Treatment Centre [A & B] A. Designated Microscopy and Treatment Centre for a NGO/Private lab B. Designated Microscopy Centre [microscopy only] LT Scheme: strengthening RNTCP diagnostic services Culture and DST Scheme: providing quality assured culture and drug susceptibility testing services Adherence scheme: Promoting treatment adherence Slum Scheme: Improving TB control in urban slums Tuberculosis Unit Model TB-HIV Scheme: delivering TB-HIV interventions to high HIV risk groups TB = tuberculosis; ACSM = advocacy, communication, and social mobilization; SC = sputum collection; NGO = non-governmental organization; LT = Laboratory Technician; DST = drug susceptibility testing; HIV = human immunodeficiency virus Detailed description of these schemes can be accessed at “Central TB Division. Revised Schemes for NGOs and Private Providers. Available at URL: http://www.tbcindia.org/pdfs/New%20Schemes%20NGO-PP%20140808.pdf. Accessed on October 12, 2008 (reference 49)”

a laboratory technician and a TB health visitor to the participating medical college with a DMC and a DOT centre. In addition, RNTCP supplies laboratory consumables and supplies, binocular microscopes [for government medical colleges], drugs for patients and funds for civil works for improving the laboratory facilities in medical colleges. In 1997 a national consensus conference on TB was held in Delhi and following this initiative the RNTCP organized a series of sensitization seminars, and national level workshops at Central TB Institutes for the training of medical college faculty staff. In 2002, the AIIMS hosted national-level meetings and seven premier medical colleges in different zones of the country were identified as nodal centres to take the lead in establishing academic sector for nation-wide participation in RNTCP (41,50). A national task force, five zonal task forces and several state-level medical college task forces were formed. Core activities include: [i] training and teaching RNTCP as part of CME courses to undergraduates, medical students, faculty, paramedical staff ; [ii] implementing RNTCP in the medical college including establishing DMC and DOTS centres, strengthening laboratory infrastructure, involvement in quality assurance and the management of difficult cases; [iii] advocacy regarding RNTCP through sensitization of professional bodies including the IMA; [iv] design and implementation of OR that is focussed on answering key issues facing RNTCP efforts to control TB [e.g., increasing case detection, providing

patient friendly services, improving provision of DOT, etc.]. Currently, 263 of the 277 medical colleges are involved in the RNTCP and all have established a Core Committee to oversee the functioning of a DMC and DOT centre within the medical college. To further integrate the services, RNTCP has started a “referral for treatment” mechanism to develop seamless communications between the medical colleges and the general health services so that all TB patients diagnosed at medical college receive RNTCP services [e.g., DOTS] at the most convenient location to the patient. Although establishing meaningful participation in RNTCP by the academic sector requires additional efforts by all involved, there is now a growing professional consensus in India regarding the efficacy of RNTCP’s DOTS-based strategy. RESEARCH The RNTCP is founded on basic scientific principles largely discovered in India and TB research plays an important role in determining the future direction of its TB control efforts (37). Although an impressive amount of research is published each year from India on TB, a relatively small proportion addresses practical difficulties of TB control in India. To fill up this gap, the RNTCP has established an OR agenda [Table 63.7] and a funding mechanism for OR proposals from interested researchers (3). Proposals are screened by a committee consisting of

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Tuberculosis Table 63.7: Priority operational research agenda for Revised National Tuberculosis Control Programme

Improving DOTS Implementation Prospective, community-based long-term cohort study of patients registered and treated under RNTCP, evaluating multiple key treatmentrelated questions Risk factors for death, default, and failure under RNTCP Evaluation of the impact of migration on treatment outcomes Treatment outcomes among patients with co-morbidities [e.g., diabetes mellitus, HIV infection] Treatment outcomes among patients with drug-resistant TB [other than MDR-TB] Prevalence of recurrent TB due to either relapse or re-infection Risk factors for recurrent TB, including relapse [i.e., reactivation] and reinfection Health seeking behaviour and reasons for delay in diagnosis among TB patients in vulnerable populations, including tribals and urban slum dwellers Pilot test of “2+2” [2 weeks cough and 2 sputum specimens] for TB suspect identification and initial evaluation in high and low workload settings Rapid retrospective evaluation of risk factors for Category II treatment default A cluster of randomized controlled trials of innovative and cost-effective programme interventions to reduce treatment default Evaluation of family-DOT in paediatric TB patients using paediatric patient-wise boxes Rapid retrospective evaluation of the impact of treatment interruptions on treatment outcomes Improving DOT: what modifiable factors are associated with higher quality of DOT in different settings? Evaluation of patient reasons for initial default, and the effectiveness of programme interventions to prevent initial default MDR-TB Prevalence of MDR TB in Category I failures, Category II entry, and Category II patients who are smear-positive at 3 months, and association of MDR-TB with past history of antituberculosis treatment [including whether it was DOTS or self administered non-DOTS treatment] Evaluation of innovative methods of community-based DOT provision for the delivery of RNTCP Category IV treatment TB-HIV Evaluation of the optimum screening modality for intensified case finding for TB disease in Antiretroviral Treatment and Care and Support Centres Reasons for loss of TB suspects referred from integrated counselling and testing centres [ICTCs] to designated microscopy centres [DMCs] ACSM Health marketing to private providers – what messages change behaviour? PPM Quality of TB diagnosis and care among private sector physicians RNTCP = Revised National Tuberculosis Control Programme; TB = tuberculosis; OR = operational research; DOT = directly observed treatment; HIV = human immunodeficiency virus; PPs = private practitioners; ACSM = advocacy communication for social mobilization; PPM = public-private mix; MDR-TB = multidrug-resistant tuberculosis

internal and external experts. Funds have also been made available to states for inviting proposals and funding research activities in their respective states. Completed research projects include annual risk of TB infection [ARI] studies, drug-resistance surveys, baseline studies on the accessibility and utilization of RNTCP services by various marginalized sectors [e.g., scheduled castes/scheduled tribes, women, people living with HIV/AIDS], and a

study of the RNTCP infrastructure and implementation mechanism (3). Measuring Epidemiological Impact The ARI estimates in India are available from studies conducted in smaller geographical areas over the last 30 years. Recently, the NTI, Bengaluru in collaboration with the TRC, Chennai completed a countrywide cross-

The Revised National Tuberculosis Control Programme [RNTCP] sectional survey, which for the first time provides current national and regional estimates of the ARI in India. National estimate of ARI prior to 2000 was 1.7 per cent and estimate based on National ARI survey [2001 to 2003] is 1.5 per cent (51,52). The ARI in urban areas [2.1] was higher than rural areas [1.2 to 1.3]. The zonal estimates are applied to the states that constitute the zone for calculating the incidence estimates used for monitoring case detection. Finally, to monitor trends and impact of RNTCP on the TB burden, a repeat survey using a zonal sampling approach will be undertaken in approximately five years. National ARI survey to estimate incidence has been initiated during the period 2007 to 2009. These data can then be used with corroboration from community-based prevalence studies and notification data to estimate the RNTCP’s impact on TB epidemiology in India. Drug Resistance Surveillance Monitoring population-based levels of drug resistance among TB patients can help a programme to better understand whether it is being effective since programmatic lapses [e.g., interrupted drug supply, inappropriate regimens, poor adherence to DOT] can lead to increased levels of resistance (53-55). Rifampicin resistance and multidrug-resistance [defined as resistance to both rifampicin and isoniazid with or without resistance to other antituberculosis drugs] among new patients started to appear in the 1980s, and has been less than three per cent in most studies (56). The TRC, Chennai in collaboration with the NTI, Bengaluru using the WHO/ IUATLD guidelines conducted a number of populationbased studies in districts across India which has provided valuable information about primary drug resistance (56,57). The reader is referred to the chapter “Antituberculosis drug resistance surveillance” [Chapter 50] for further details on this topic. A major challenge for the programme in achieving the goal of TB control is multidrug-resistant TB [MDRTB] and the emerging threat of extensively drug-resistant TB [XDR-TB]. Although the community based Drug resistance surveillance [DRS] conducted in Gujarat and Maharashtra recently estimated the prevalence of MDRTB to be around three percent amongst new cases, in terms of absolute numbers the burden is quite significant. The most effective means of preventing further develop-

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ment of MDR-TB and subsequent XDR-TB is through maintaining and improving quality of the RNTCP DOTS and more importantly promote the rational use of firstand second-line antituberculosis drugs amongst all health care providers. The national programme has initiated the DOTS-Plus services for management of MDR-TB in Gujarat and Maharashtra in August 2007 and in Andhra Pradesh in October 2008. These services will be introduced in other states across the country in a phased manner by 2009 to2010. Joint Monitoring Missions External reviews by national and international authorities have played an important role in monitoring and evaluating RNTCP’s progress. As a follow-up to the 1992 review that prompted the revised programme, a review conducted in February 2000 found the RNTCP implementation to be a success, with a striking increase in the proportion of patients cured (17). The 2000 review recommended rapid expansion of quality RNTCP services to cover the entire country by 2005 in order to make a significant impact on the TB epidemic. A followup review to assess progress, technical policies and performance was jointly organized by the Government of India and the WHO in September, 2003. A team of 20 national experts [from IMA, National Institute of Health and Family Welfare, leading medical colleges, central TB institutes, NGOs and programme staff from state and district level] and 22 international TB experts from CIDA, CDC, DANIDA, DFID, GDF, GFATM, IUATLD, KNCV, USAID and WHO conducted this review. From five states selected, three districts were randomly selected and one district was conveniently selected adding up to a total of 20 districts. Two DMCs were randomly selected from each of the 20 districts. At the time of 2003 review, a population of 740 million had access to DOTS and nearly 2.4 million patients had been placed on treatment with over 85 per cent treatment success. The review appreciated the extraordinary rapid expansion while maintaining high levels of treatment success, and noted that it was highly economical. The RNTCP has expanded faster than any other effective TB control programme in the history of DOTS, and its visibility has increased both nationally and internationally. Good infrastructure and management systems for TB control have been established and more than 500 000 staff have been trained. As a result, case detection rates are

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increasing and cure rates remain high. The teams found that overall the recording and reporting is excellent and that the published data at the central level reflect the programme activities in the field, including diagnosis of cases and outcomes of treatment. The RNTCP provides treatment that is free, intermittent and directly observed. Significant initiatives at central, state and local levels have resulted in greater involvement of NGOs, PPs and medical colleges. The Joint Monitoring Mission held in September 2003 provided valuable guidance for the RNTCP over the past four years. The third Joint Monitoring Mission was undertaken in 2006 that was jointly organized by the Government of India and WHO in October 2006, consisting of a team of 24 national experts. The team observed that the programme service delivery is well integrated into the health system, there is a well established effective drug logistic management system, quality assured drugs are available throughout the country free of charge, EQA has been implemented in the microscopy network, coordination between RNTCP and TB-HIV is evidenced in a joint action plan and a plan to address MDR-TB is prepared. THRUST AREAS The following topics are considered as ‘thrust areas’ for the RNTCP which is facing significant challenges in its efforts to control TB in India. Planning for the provision of quality TB services to a population of over one billion is a daunting task. To maintain and improve the existing standards of care involves a significant number of activities. Specifically, this means assuring that quality DOTS is being provided which will include screening several million people each year, performing almost 100 000 smear examinations every day and providing an uninterrupted supply of quality antituberculosis drugs under supervision to more than 1.4 million cases each year. The RNTCP has consistently shown treatment success rates of around 85 per cent, whilst case detection rates have gradually increased to 70 per cent in 2007. India has demonstrated that with the right combination of political commitment, adherence to technical standards, managerial capacity and partnership, rapid large-scale expansion of services with good results are possible in TB control. However, establishing that the patient is the “VIP” of the

programme which should strive to ensure that all patients have access to care remains a challenge and many patients still face significant economic and social barriers to access care. Combining maintenance and improvement of already existing DOTS services to difficult and hard to reach areas will require considerable planning, monitoring and supervision. Another challenge is ensuring that adequate resources are in place to sustain the Programme activities. Adequate resources have been ensured till 2011 in RNTCP II. However, long-term sustainability to achieve the ultimate goal of TB control will require careful planning. One of the thrust areas for RNTCP is filling up the vacancies of key staff arising from time to time. The costeffectiveness of DOTS and benefits of the Programme are clear and warrant further investment of resources. The significant direct and indirect costs to patients due to TB further supports the argument for strengthening the public health sector services. For example, sputum smear microscopy has a pivotal role to play in diagnosis and follow-up of TB patients and full-time trained laboratory technicians are essential for all RNTCP DMCs. Though the CTD is directly supporting appointments of an important proportion of these staff, the states also need to take the initiative in making staff appointments, as eventually they will need to manage and support the programme. The framework of National Rural Health Mission [NRHM] calls for convergence and integration which is a positive development for RNTCP and can improve equitable access and convenience of services. Another thrust area is to successfully decentralize some of the core managerial responsibility for running the programme to the states while maintaining quality. To ensure effective administration, accountability and sustainability of the programme, the states will need to increasingly shoulder responsibility for running the programme. As a step towards decentralization of programme management, the capacity of the states has been developed for technical and financial monitoring. The State TB Officers and accountants at the respective STCs have been trained in financial management and procurement in addition to the routine STO training curriculum under RNTCP. Capacity at state level to plan, supervise and monitor TB control requires more attention. Increased supervision is required at all levels to ensure proper programme functioning. Although recording and reporting is a strong component of the

The Revised National Tuberculosis Control Programme [RNTCP] programme, the capacity to analyse, interpret and improve performance based on findings is limited. Another challenge for RNTCP is to increase case detection and improve the standard of care through collaboration with other key partners including other governmental public health providers, the corporate sector, academia, PPs, NGOs, large para-statal organizations such as the Railways, Employees State Insurance Service [ESIS], and TB hospitals. The largely unregulated private sector is sizeable and provides a substantial proportion of outpatient care, and this care is of inconsistent quality (31). Although there has been progress in involving large and growing private sector, their involvement is not yet sufficient to provide maximal benefit to patients. A number of key partnerships are emerging including the significant involvement of the medical colleges, some parts of the corporate sector, ESIS and Railways, NGOs and PPs. The sixth thrust area is advocacy, communication and social mobilization in order to maintain high visibility of TB and RNTCP amongst policy makers, opinion leaders and community and hence, sustain long-term political and administrative commitment and greater community involvement in RNTCP. The goal of ACSM is to support TB efforts by [i] improving case detection and treatment adherence; [ii] combating stigma and discrimination; [iii] empowering people affected by TB; and [iv] mobilizing political commitment and resources for TB. By doing so, it aims to widen the scope for providing standardized, good quality treatment and diagnostic services to all TB patients in a patient-friendly environment Another area of thrust is the TB-HIV co-infection. Addressing this issue requires close coordination between the TB and HIV/AIDS programmes and steps have been taken to ensure a joint action plan. Cross-referral linkages between service delivery sites TB and AIDS control programme have been established across the country. A large number of HIV infected TB patients are being routinely identified and initiated on DOTS. However, providing optimal access to HIV care including antiretroviral therapy, to these TB patients co-infected with HIV, remains a challenge as HIV care is relatively centralized. Another area of thrust for TB/HIV collaborative activities is addressing needs of marginalized populations with high risk for HIV, such as commercial sex workers, men who have sex with men, etc. Due to various social factors reaching out to these populations remains a challenge, requiring a distinct approach

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Management of MDR-TB is also an important challenge. Although the overall proportion of patients with MDR-TB is relatively low when compared with other “hot spots”, there are a significant number of patients with MDR-TB in India. Effective implementation of RNTCP is the most effective means of preventing development of MDR-TB. The RNTCP recognizes that indiscriminate use of second-line drugs under non-DOTS conditions is widespread and is actively planning its national strategy regarding the issue of drug resistance. Plans include bolstering state capacity to perform drug resistance testing, widening drug resistance surveillance efforts, and making arrangements to provide second-line drugs. Establishment of the planned accredited network of IRLs for quality controlled culture and drug susceptibility testing [DST] to diagnose MDR-TB is a challenge to the programme. India is a large country with varied populations, cultures, beliefs and socio-economic status across the country. TB as a disease and its management is often viewed differently depending on the various sociocultural-economic conditions prevailing in India today. Despite the major challenges inherent in providing care across the diversity of modern India, the RNTCP and its partners have made significant advances in establishing a quality DOTS-based programme. For millions of patients the RNTCP has delivered on its promise of free and effective care for TB. However, the RNTCP is entering a new and challenging phase to improve patient management and treatment outcomes by further decentralizing DOT and making treatment observation more convenient to patients, particularly in slum and tribal areas. What is also required by the programme is to improve the capacity of the supervisors at all levels to evaluate and use programme data for action to improve the performance. An effective DOTS programme in Peru has been documented to result in a seven per cent decrease in TB incidence per year (58). However, this rate of decline is dependent on a number of factors including the presence of HIV/AIDS and the contribution of recent transmission. Although the impact of RNTCP on disease incidence will be known once ARI results will be available in 20092010, there is a high likelihood that with the active support of patients, the community, health authorities, providers, and policy makers, RNTCP should be able to achieve its goal of controlling TB to the extent that it is no longer a major public health problem in India.

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ACKNOWLEDGMENTS The authors wish to thank Mr Avijit Choudhary, Mr Santosh Kumar, WHO TB technical team, TB patients and health care workers across India who have markedly improved TB control in India.

REFERENCES 1. Central TB Division. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. TB India 2008. RNTCP status report. New Delhi: Central TB Division. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India; 2008. 2. Central TB Division. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. About RNTCP. Available at URL: http://www.tbcindia.org/ RNTCP.asp. Accessed on October 11, 2008. 3. World Health Organization. WHO report 2008. Global tuberculosis control: surveillance, planning, financing. WHO/HTM/TB/2007.8.393. Geneva: World Health Organization; 2008. 4. Steinbrook R. HIV in India – a downsized epidemic. N Engl J Med 2008;358:107-9. 5. Joint United Nations Programme on HIV/AIDS [UNAIDS] and World Health Organization. 07 AIDS epidemic update: December 2007. UNAIDS/07.27E / JC1322E. Geneva: Joint United Nations Programme on HIV/AIDS [UNAIDS] and World Health Organization; 2007. 6. Mahadev B, Kumar P. History of tuberculosis control in India. J Indian Med Assoc 2003;101:142-3. 7. Tuberculosis Association of India. India’s fight against tuberculosis; New Delhi: Tuberculosis Association of India;1956.p.7. 8. Bhore J. Report of the Health Survey and Development Committee. New Delhi: Ministry of Health, Government of India; 1946.p.157-67. 9. Indian Council of Medical Research. Tuberculosis in India: a national sample survey 1955-58. ICMR technical report series. New Delhi: Indian Council of Medical Research; 1959.p.112. 10. Tuberculosis Chemotherapy Centre. A concurrent comparison of home and sanitorium treatment of pulmonary tuberculosis in south India. Bull World Health Organ 1959;21:51-144. 11. Fox W. Self-administration of medicaments. A review of published work and a study of the problems. Bull Int Union Tuberc 1961;31:307-31. 12. Tuberculosis Research Centre, Madras. Ten year report. New Delhi: Indian Council of Medical Research; 1966.p.5-8. 13. Tuberculosis Research Centre, Madras. A concurrent comparison of intermittent [twice-weekly] isoniazid plus streptomycin and daily isoniazid plus PAS in the domiciliary treatment of pulmonary tuberculosis. Bull World Health Organ 1964;31:247-71.

14. Banerji D, Anderson S. A sociological study of awareness of symptoms among persons with pulmonary tuberculosis. Bull World Health Organ 1963;29:665-83. 15. Baily GV, Savic D, Gothi GD, Naidu VB, Nair SS. Potential yield of pulmonary tuberculosis cases by direct microscopy of sputum in a district in South India. Bull World Health Organ 1967;37:875-92. 16. Khatri GR, Frieden TR. Controlling Tuberculosis in India. N Engl J Med 2002;347:1420-5. 17. World Bank and tuberculosis [TB] control. Available at URL: http://web.worldbank.org/WBSITE/EXTERNAL/ TOPICS/EXTHEALTHNUTRITIONANDPOPULATION/ EXTTC/0,,menuPK:384147~pagePK:162100~ piPK:159310~ theSitePK:384139,00.html. Accessed on October 11, 2008. 18. World Health Organization. Joint tuberculosis programme review: India. WHO/SEA/TB/265/. New Delhi: World Health Organization Regional Office for South-East Asia. 2003. 19. Association of Public Health Laboratories. External quality assessment for AFB smear microscopy. Available at URL: http://www.aphl.org/programs/infectious_diseases/ Pages/eqa.aspx. Accessed on October 11, 2008. 20. Swaminathan S, Ramachandran R, Baskaran G, Parmasivan CN, Ramanathan U, Vankatesan P, et al. Risk of development of TB in HIV-infected patients, Int J Tuberc Lung Dis 2000;4:839-44. 21. Williams BG, Granich R, Chauhan LS, Dharmshaktu NS, Dye C. The impact of HIV/AIDS on the control of tuberculosis in India. Proc Natl Acad Sci USA 2005;102:9619-24. Epub 2005 Jun 23. 22. Alwood K, Keruly J, Moore-Rice K, Stanton DL, Chaulk CP, Chaisson RE Effectiveness of supervised, intermittent therapy for tuberculosis in HIV-infected patients. AIDS 1994;8:11038. 23. Perriens JH, St Louis ME, Mukadi YB Brown C, Prignot J, Pouthier F, et al. Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled trial of treatment for either 6 or 12 months. N Engl J Med 1995;332:779-84. 24. Kochi A.. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle 1991;72:1-6 . 25. World Health Organization. Treatment of tuberculosis. Guidelines for National Programmes. WHO/CDS/TB 2003.313. Geneva: World Health Organization;2003. 26. Guidelines for use of Pediatric Patient Wise boxes under the Revised National Tuberculosis Control Programme. Available at URL: http://www.tbcindia.org/pdfs/ PediatricGuidelinesFinal.pdf. Accessed on October 11, 2008. 27. The behaviour and interaction of TB patients and private forprofit health care providers in India: a review. WHO/TB/ 97.223. Geneva: World Health Organization; 1997. 28. Uplekar M, Juvekar S, Morankar S, Rangan S, Nunn P. Tuberculosis patients and practitioners in private clinics in India. Int J Tuberc Lung Dis 1998;2:324-9.

The Revised National Tuberculosis Control Programme [RNTCP] 29. Rajeswari R, Chandrasekaran V, Suhadev M, Sivasubramaniam S, Sudha G, Renu G. Factors associated with patient and health system delays in the diagnosis of tuberculosis in South India. Int J Tuberc Lung Dis 2002;6:789-95. 30. Uplekar M, Pathania V, Raviglione M. Private practitioners and public health: weak links in tuberculosis control. Lancet 2001;358:912-6. 31. Uplekar MW, Rangan S. Private doctors and tuberculosis control in India. Tuber Lung Dis 1993;74:332-7. 32. Uplekar MW, Shepard DS. Treatment of tuberculosis by private general practitioners in India. Tubercle 1991;72:28490. 33. Prasad R, Nautiyal RG, Mukherji PK, Jain A, Singh K, Ahuja RC. Treatment of new pulmonary tuberculosis patients: what do allopathic doctors do in India? Int J Tuberc Lung Dis 2002;6:895-902. 34. Vyas RM, Small PM, DeRiemer K. The private-public divide: impact of conflicting perceptions between the private and public health care sectors in India. Int J Tuberc Lung Dis 2003;7:543-9. 35. Chauhan LS, Granich R. TB control–the government and the private sector alliance. J Indian Med Assoc 2003;101:137. 36. Nair N, Narain JP. Good progress with DOTS in the SouthEast Asia Region. J Indian Med Assoc 2003;101:140-1, 147. 37. Granich R, Chauhan LS. Status report of the Revised National Tuberculosis Control Programme: January 2003. J Indian Med Assoc 2003;101:150-1, 156. 38. Chauhan LS. Challenges for the RNTCP in India. J Indian Med Assoc 2003;101:152-3. 39. Mandal PP, Bhatia V. Involvement of private practitioners in RNTCP. J Indian Med Assoc 2003;101:159-60. 40. Rangan S. The public-private mix in India’s Revised National Tuberculosis Control Programme–an update. J Indian Med Assoc 2003;101:161-3. 41. Tonsing J, Mandal PP. Medical colleges’ involvement in the RNTCP: current status. J Indian Med Assoc 2003;101:164-6. 42. Tonsing J, Ram T. Involvement of non-governmental organisations in the RNTCP. J Indian Med Assoc 2003;101:167-8, 170. 43. Singh A, Parasher D, Shekhawat GS, Garg V. Role of community volunteers in the RNTCP. J Indian Med Assoc 2003;101:171-2. 44. Selvakumar N. Role of laboratory in RNTCP. J Indian Med Assoc 2003;101:173-4.

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45. Salhotra VS. Drug procurement and management. J Indian Med Assoc 2003;101:175-6. 46. Wares DF, Chauhan LS. Health policy, systems and services research and the Revised National Tuberculosis Control Programme. J Indian Med Assoc 2003;101:177-9. 47. Sahu S, Granich R, Chauhan LS. Role of WHO recruited consultants in successful implementation and expansion of the DOTS programme in India. J Indian Med Assoc 2003;101:182-3. 48. Bhatia V, Chauhan LS. TB and human rights. J Indian Med Assoc 2003;101:180-1. 49. Central TB Division. Revised Schemes for NGOs and Private Providers. Available at URL: http://www.tbcindia.org/ pdfs/New%20Schemes%20NGO-PP%20140808.pdf. Accessed on October 12, 2008. 50. Mohan A, Sharma SK. Medical schools and tuberculosis control: bridging the discordance between what is preached and what is practiced. Indian J Chest Dis Allied Sci 2004;46:57. 51. Chadha VK, Kumar P, Jagannatha PS, Vaidyanathan PS, Unnikrishnan KP. Average annual risk of tuberculous infection in India. Int J Tuberc Lung Dis 2005;9:116-8. 52. Chadha VK, Agarwal SP, Kumar P, Chauhan LS, Kollapan C, Jaganath PS, et al. Annual risk of tuberculous infection in four defined zones of India: a comparative picture. Int J Tuberc Lung Dis 2005;9:569-75. 53. Narayanan PR, Garg R, Santha T, Kumaran PP. Shifting the focus of tuberculosis research in India. Tuberculosis [Edinb] 2003;83:135-42. 54. Pablos-Mendez A, Raviglione MC, Laszlo A, Binkin N, Rieder HL, Bustreo F, et al. Anti-tuberculosis drug resistance in the world. WHO/TB/97.229. Geneva: World Health Organization Global Tuberculosis Programme; 1997. 55. Chaulet, P, Boulahbal F, Grosset J. Surveillance of drug resistance for tuberculosis control: why and how? Tuber Lung Dis 1995;76:487-92. 56. Paramasivan CN. Status of drug resistance in tuberculosis after the introduction of rifampicin in India. J Indian Med Assoc 2003;101:154-6. 57. Paramasivan CN, Venkataraman P. Drug resistance in tuberculosis in India. Indian J Med Res 2004;120:377-86. 58. Suarez P, Watt CJ, Alarcon E, Portocarrero J, Zavala D, Canales R, et al. The dynamics of tuberculosis in response to 10 years of intensive control effort in Peru. J Infect Dis 2001;184:473-8.

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Tuberculosis Vaccine Development: Current Status and Future Expectations

64

Anil K Tyagi, Bappaditya Dey, Ruchi Jain

INTRODUCTION Tuberculosis [TB] is one of the most fatal infectious diseases, which continues to be a major global health problem. Despite all the available drugs and regimens, there is a general perception that in the absence of an effective TB vaccine, the real control of TB on a worldwide basis is unlikely. Although a vaccine represents one of the most efficacious and potent defenses against infectious diseases, a perfect vaccine against TB that would be most effective in the control of this disease has eluded us all the time. Unfortunately, bacille CalmetteGuérin [BCG], the currently used vaccine that was developed more than 80 years ago, has generated little protection and a great deal of controversy. THE BACILLE CALMETTE-GUERIN VACCINE HISTORY: SCIENTIFIC FABLE AND THE LESSONS LEARNED The BCG, the only available and widely used vaccine against TB, was developed by Calmette and Guerin between 1908 and 1921, from a Mycobacterium bovis strain by serial weekly passages for 13 years (1). Based on the encouraging results in infants during the next four years, BCG was distributed around the world and its use as a preventive vaccine against TB was encouraged. By 1948 more than 10 million immunizations were carried out and in the First International BCG Congress held in the same year in Paris, it was concluded that BCG vaccination was effective in preventing TB. In 1974, BCG vaccination was included in the expanded immunization programme of the World Health Organization [WHO] to strengthen

the fight against this infectious disease in children in developing countries (2). In India, the BCG vaccine laboratory was established in Chennai, Tamil Nadu, in 1948 to aid BCG immunization programme in the country and to supply BCG to some neighbouring countries. Though Pasteur strain remains the international reference strain of BCG (3), owing to the variations in production and preservation methodologies in different countries, BCG strains with genotypic and phenotypic differences have emerged. Variations in these strains have been observed with respect to tuberculin conversion rate, frequency of adverse reactions and even vaccine efficacy ranging from 0 to 80 per cent (4-6). Nevertheless, more than three billion children all over the world have been vaccinated with BCG. Although several studies have been carried out with different doses of BCG, in diverse age groups and populations and through various routes such as oral, per-rectal, parenteral, subcutaneous, and conjunctival route, these studies have yielded different results (7-11) and the intradermal route for vaccination with BCG still remains the standard international protocol. Considering the importance of lung immunity in TB, many investigators (12-16) have also employed intranasal route for BCG vaccination and have reported either an equivalent or a better protection than the intradermal route in various animal models. Despite the global use of BCG, skepticism about its efficacy and safety has persisted. A major setback occurred in 1929 in Lubeck Germany, where 72 out of 251 BCG vaccinated children died of TB, though later it was revealed that the particular BCG vaccine preparation was contaminated with the virulent Mycobacterium

Tuberculosis Vaccine Development: Current Status and Future Expectations tuberculosis ‘keil’ strain (17). Other than the most frequent and mild side effect of BCG vaccination like local indurations and regional suppurative adenitis (18), the only serious complication observed is disseminated BCG disease, seen in some children with human immunodeficiency virus [HIV] infection (19). However, the most persistent controversy remains its variable efficacy in different human populations. Till date, a number of controlled BCG efficacy trials and one controlled trial with BCG re-vaccination have been carried out. The results of these major trials have been extensively reviewed by Bloom and Fine (20), Colditz et al (21) and Comstock (10); and several reasons for the variable efficacy of BCG have been proposed, such as variations in strains, defects in preparation, environmental influences [exposure to sunlight, poor maintenance of cold chain], genetic or nutritional differences among the populations studied or exposure to environmental mycobacteria and methodological differences among the major trials (22). Based on the published data, a quantitative meta-analysis of BCG efficacy revealed that it reduces the risk of TB by 50 per cent among the vaccinated group (21). A recent meta-analysis (23) of effect of BCG vaccination on childhood TB, meningitis and miliary TB worldwide, found BCG vaccination to be a highly cost-effective intervention against severe childhood TB, and it was recommended that it should be retained in high-incidence countries as a strategy to supplement the chemotherapy of active TB. Although, repeated BCG vaccination is a common practice in many countries [those in Eastern Europe] for prevention of TB and leprosy, its effectiveness is yet to be evaluated (20). A trial at Malawi comparing single, repeated and a combination of BCG and killed Mycobacterium leprae vaccine, concluded that a single BCG vaccination confers 50 per cent or more protection against leprosy, but not against TB; a second vaccination added appreciably to the protection against leprosy, without providing any protection against TB (24). The inadequate and variable protective efficacy imparted by BCG in different populations poses a difficult question about the optimum effectiveness of new vaccines, thus, demanding their testing in diverse populations (25). UNIQUE FEATURES OF THE PATHOGEN Tubercle bacillus, the most virulent and pathogenic species of its kind, belongs to the genus Mycobacterium, which contains at least 100 different species (26); a

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majority of these are saprophytic water or soil-borne organisms. Mycobacterium tuberculosis is described as a slow growing, strictly aerobic, lipid rich, hydrophobic, acid-fast bacilli [AFB], which exhibits true cording. Mycobacterium tuberculosis is a strict aerobe and requires special enriched media for its growth in vitro. Multifactorial reasons for its slow growth include, the relative impermeability of the cell envelope, aberrations in nucleic acid synthesis, presence of weak promoter signals and a single ribosomal ribonucleic acid [rRNA] operon. In addition, several other factors such as the genomic organization with 41 per cent of the genes being transcribed in the direction opposite to that of replication (27), may also contribute to its slow growing nature. There is a compelling evidence to suggest that in addition to the innate virulence of the bacilli, the host responses play an important role in determining the clinical manifestation and ultimate outcome of infection. The availability of genome sequence of Mycobacterium tuberculosis [4 411 526 bp], which encodes nearly 4000 putative open reading frames [ORFs], has brought a paradigm shift in the approaches employed for cellular, biochemical and immunological dissection of this pathogen. However, in spite of the rapid progress made during the last two decades, towards understanding the molecular nature of Mycobacterium tuberculosis several important questions still need to be answered before a rational approach for the development of a TB vaccine can be anticipated. IMMUNOLOGY OF TUBERCULOSIS The reader is referred to the chapter “Immunology” [Chapter 7] for more details. COMPLICATIONS ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND ACQUIRED IMMUNODEFICIENCY SYNDROME The prevalence of childhood TB is relatively low even in highly endemic areas. However, with increasing incidences of HIV infection in children, it has become a matter of serious concern whether to immunize these infected children with BCG or not, which may accelerate the course of HIV infection (28-32) and may cause severe disseminated mycobacteriosis (33). Along with local adverse reactions, various forms of lymphadenopathy were reported in patients with severe immunocompro-

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mised condition, and in almost all of the cases adverse effect of BCG appeared only after the manifestation of clinical symptoms of HIV infection (33). The BCG vaccination is known to protect individuals from developing extra-pulmonary TB, such as meningitis and miliary TB (34). By contrast, HIV infection has been observed to reduce the efficacy of BCG against the development of extra-pulmonary TB (35). Thus, due to lack of sufficient studies to understand the effect of BCG vaccination in HIV-seropositive and -seronegative children and inadequate understanding of BCG and HIV interdependence, WHO has recommended to discontinue BCG vaccination in HIV infected children (36). Immunodeficiency caused by HIV infection considerably increases the risk of developing TB. During HIV infection, the progressive decline in CD4+ T-lymphocyte count, especially of the Th1 subtype with a shift towards Th2, results in failure to control most of the invading opportunistic organisms; Mycobacterium tuberculosis being the robust of all is often the earliest to break the host defense (37). Besides the potentiating effect of HIV on progression of TB, generation of cytokines like tumour necrosis factor-α [TNF-α] during control of TB infection may act as a potent enhancer of HIV replication resulting in an increased viral burden (38). Furthermore, the immune response generated during active TB has been shown to prime peripheral blood cells and enhance their susceptibility to HIV infection (39).

understanding of TB. Each animal model has its strengths and weaknesses with a varying degree of extrapolation of their research findings in humans. Nevertheless, all these animal models resemble the some important facets of the human TB in one-way or the other. First, animals can be easily infected by pulmonary route depositing a few virulent tubercle bacilli directly in to the alveolar spaces, which precisely epitomizes the way humans acquire infection. Secondly, various stages of disease progression in TB, such as, granuloma formation, liquefaction, cavity formation and haematogenous spread can be easily studied in some of the animal models, especially in guinea pigs, rabbits and non-human primates. Various features of TB such as fever, weight loss, respiratory distress and radiological abnormalities, can also be observed in these animal models. If left untreated, infected animals may eventually die of pulmonary insufficiency, a fate typical of human TB patients. The strong T-cell mediated immune responses as evident by a delayed type hypersensitivity [DTH] in guinea pigs further substantiate the fact that animal models have a significant similarity to humans. Due to analogy of animal models and humans in terms of their susceptibility and resistance to TB, the disease process and the consequences, the former can be successfully used for screening new antituberculosis vaccine as well as chemotherapeutic agents. Mouse Model of Tuberculosis

CONTRIBUTION OF VARIOUS ANIMAL MODELS IN THE UNDERSTANDING OF TUBERCULOSIS IMMUNOLOGY AND DEVELOPMENT OF VACCINES Animal models have played a great role in the field of vaccine development. They provide invaluable insights into the human system owing to the striking similarities between human and animal physiology. Unlike any other disease, contribution of different animal models to TB research has a long-standing history that can be traced back to the time of Robert Koch. Moreover, TB being an extremely complex disease with diverse clinical outcomes, it requires adequate animal models that can mimic the disease process in humans. This would help in understanding the pathogenesis of TB, mechanism of host defense and would aid in evaluating prospective prophylactic and therapeutic TB vaccines and drugs. The animal models, such as mouse, guinea pig, rabbit, and non-human primate have vastly contributed to our

Amongst various animal models of TB, mouse model is the most popular and has particularly stood the test of time. Inbred mouse strains have undoubtedly provided a huge wealth of information regarding the basic mechanisms of immune responses, which have subsequently been shown to draw a significant similarity with humans. The evidence for involvement of lymphocytes in mediating immunity to TB was successfully shown by the ability of whole blood and spleen homogenates [from an infected mice] to transfer DTH to a naive mice (40). It was also observed that CD4+ cells, when adoptively transferred, conferred immunity to TB (41) and a population of CD4+ memory cells also remains in the system after clearance of the infection by chemotherapy (42). Further, a seminal work in mouse model by Cooper and Flynn (43) and Flynn et al (44) firmly established the importance of Th1 pathway in the expression of protective immunity. The mouse data have also shown

Tuberculosis Vaccine Development: Current Status and Future Expectations a potential role for CD8+ (45), CD4-/CD8- (46) and γ/δ T-cells (47) in generating immune response to TB vaccines. In fact, there are several instances, where findings originally obtained in the mice model have later been verified in humans. For example, knock out mice deficient in interferon-γ [IFN-γ] and interleukin-12 [IL12] genes were found to be highly susceptible to Mycobacterium tuberculosis infection akin to patients with hereditary deficiency in IFN-γ and IL-12 signalling. Mice with deficient TNF-α signalling exhibited similarity with rheumatoid arthritis patients who developed reactivation TB on treatment with anti-TNF-a monoclonal antibodies. The most evident similarity is observed with dramatically increased incidence of primary and secondary TB in knock-out mice devoid of CD4+ T-cells, thus, mimicking HIV infection (48). The usefulness of the mouse model has grown tremendously over the last two decades due to availability of a vast database of reagents, like monoclonal antibodies to T-cell surface markers, primers and probes for the growing array of cytokines and chemokines. Moreover, advancement in the field of transgenic expression, gene knock-out, gene knock-in [both constitutive and conditional] technologies, along with the availability of large variety of mouse mutants with defined immune deficiencies have immensely helped the scientific investigations dissecting the precise nature of immune response to Mycobacterium tuberculosis infection. The mouse genome sequence has further helped in designing genome-based experiments to pin-point the importance of key genes involved in innate and adaptive immunity against TB and understanding the role of downstream signalling pathways. Although mouse model provides a huge advantage in terms of cost effectiveness, it fails to completely mimic the entire spectrum of human TB. The granulomatous pathology induced in mice in response to TB infection is very different to that observed in humans and other naturally susceptible hosts as mice are innately resistant to TB and generate a strong cellular immune response against TB infection, which controls bacterial growth and disease progression. Mice develop granuloma with the aggregation of lymphocytes towards the centre, which is in striking contrast to humans and guinea pigs wherein lymphocytes form a peripheral ring with arrangements of macrophages towards the centre (49-54). Thus, despite its definite advantages in the study of immunological

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aspects of TB, mice model has only been recommended for the first-order screening of vaccine candidates, due to differences in its pathology in comparison to humans. Hence, as the protection in mouse model does not guarantee its reproducibility in humans, the efficacy of new vaccines needs to be validated in other models of experimental TB. Guinea Pig Model of Tuberculosis Guinea pig model of low-dose, airborne infection with virulent Mycobacterium tuberculosis has been used for decades to elucidate events in the pathogenesis of pulmonary TB and mechanism of vaccine induced resistance. Guinea pig is currently one of the most useful models of human TB for evaluation of new vaccines. The primary reason for this preference stems from the ability of guinea pigs to initially develop strong immunity, which eventually results in considerable tissue damage, leading to the formation of granulomas as seen in humans. These granulomas then undergo an extensive caseation necrosis eventually killing the animal. Moreover, guinea pigs are sensitive to tuberculin skin testing and can be used to determine vaccination induced DTH reaction. On infection of lungs with Mycobacterium tuberculosis, a considerable host tissue remodelling occurs to thwart off the infection by permitting the correct influx of lymphocytes and macrophages. But this necessary lung tissue consolidation results in the death of the infected animals due to pulmonary insufficiency. Thus, a shortterm reduction in bacillary load may not be the most important criterion and a long-term survival and improved pathology in the guinea pig model may provide a better picture of efficacy of a vaccine. Further, in contrast to mice model, guinea pigs like humans have a group of CD1+ molecules that are responsible for the presentation of mycobacterial glycolipids to a specialized T-cell population. These CD1+ molecules have been shown to present mycolic acids, lipoarabinomanan and other components of the mycobacterial cell wall to human T-cells in vitro. Thus, guinea pigs can be employed to investigate the role of these glycolipids in protection and pathology. The guinea pig model has also been employed to study the effect of malnutrition on TB, which is known to induce a state of immunodeficiency. The precise mechanism of interference with the immune responses and compromised antimicrobial resistance that results

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from malnutrition has also been elucidated by using guinea pig model. McMurray and colleagues (54) have documented a series of immunological abnormalities associated with protein deficiency in guinea pigs, which, when viewed in a clinical context, mimic the situation, where malnutrition in humans results in an increased susceptibility to TB. Malnutrition is known to impair several aspects of mycobacterial antigen-specific peripheral T-cell function including lymphocyte proliferation (53), interleukin-2 [IL-2] production (54), expression of the CD2+ marker (55), and the ability to mount a DTH response (56). These immunological alterations, which seem to be associated with the loss of vaccine induced and naturally acquired resistance to pulmonary TB in the guinea pigs, can serve as suitable surrogate markers for protection. However, sufficient evidence to substantiate their utility is lacking at present. The only way to correlate the immunological readouts with protective efficacy [as measured by bacillary load and effect on survival of guinea pigs following infection] is to carry out a mass screening of vaccines with varying efficacy in the guinea pig model, followed by a statistical regression analysis. This would help in identification of immune responses required for protection. Furthermore, to screen new TB vaccine candidates, an ideal animal model would be one in which BCG efficacy is suboptimal, thus, providing room for improvement. Though, several genetically engineered mice strains are available, these are probably too impaired immunologically to provide an optimal window for efficacy evaluation. Thus, a moderately protein-deficient guinea pig has been proposed as an ideal animal model for testing the efficacy of new vaccines. Most of the vaccine candidates are first screened in mice model of TB and only promising candidates are taken up for screening in guinea pigs. But this strategy of prioritizing any vaccine candidate should be analysed very carefully as there are chances of loosing those candidates, which though may not be efficacious in mice but may have tremendous potential in guinea pigs which resembles humans more closely. But despite several advantages, guinea pig model of TB suffers from few disadvantages that have precluded its use as a first-orderscreening model. These include [i] high cost and requirement of extensive biosafety level III [BSL III] animal facility; and [ii] paucity of immunological reagents required to track down the immune responses and

contribution of various cell populations in mediating protection against the disease. Non-human Primate Model of Tuberculosis On comparative assessment of all the existing models of TB, non-human primates like Rhesus monkey, Cynomolgus monkey, etc., were found to mimic several aspects of human TB (57). Apart from the susceptibility to natural infection with a range of mycobacterial species, non-human primates are very similar to humans in terms of granuloma architecture and various stages of disease progression (58-61). These similarities are based on the presence of several common molecules in non-human primates and humans. For example, non-human primates [Rhesus monkey] and humans share the presence of functional major histocompatibility complex [MHC] molecules, which bind specifically to mycobacterial peptides (62,63). Further, both humans and nonhuman primates have CD1+ molecules in common that are required for presenting several non-peptide mycobacterial products to the T-cells (64-66). Besides, in primates the course of infection can be easily followed up by chest radiograph, weight loss, as well as by performing a variety of immunological assays, which provide a detailed insight into the disease progression. It has also been further developed to study HIV and TB co-infection (67,68), which would help understanding the disease pathogenesis and treatment of HIV-related TB (69,70). However, several critical disadvantages have reserved this model only for the final stage of vaccine evaluation. The disadvantages, such as, high cost, requirement of extensive biohazard containment facility, difficulty in handling and maintenance of disease-free colonies of these primates, which are extremely susceptible to mycobacterial infections, have resulted in the testing of only a few candidate vaccines in primates till date. Langermans and colleagues (71) using the Macaque model showed that protection against a high dose of Mycobacterium tuberculosis infection could be achieved in Cynomolgus monkeys with BCG vaccination, although no such protection was observed in case of Rhesus monkeys. Though Rhesus and Cynomolgus monkeys are closely related species they differ markedly in their susceptibility to Mycobacterium tuberculosis infection and BCG induced protection; these two species, thus, represent the two extremes of the degree of protection

Tuberculosis Vaccine Development: Current Status and Future Expectations induced by BCG in humans. Since most of the vaccines need to be compared to BCG, Cynomolgus can be very useful for evaluation of subunit and deoxyribonucleic acid [DNA] vaccines, whereas live attenuated vaccines [like recombinant BCG] may show a clear improvement over BCG in Rhesus monkeys (71). Recently, haemagglutinating virus of Japan-liposome encapsulating a combination of DNA vaccines expressing heat shock protein 65 [HSP65] and IL-12 has been tested in Cynomolgus monkeys. In the same study, a recombinant BCG harbouring the 72f fusion gene [r72f BCG] when used in Cynomolgus monkeys exerted a significant prophylactic effect against Mycobacterium tuberculosis infection (72). A vaccine based on the 72f fusion protein has entered Phase I clinical trial after evaluation in Cynomolgus monkeys (73). Another subunit vaccine, which is now in Phase I clinical trial is a fusion protein of 85B and early secreted antigen 6 [ESAT-6] which, when tested in non-human primate model using dimethyl dioctadecylammonium bromide/monophosphoryl lipid A [DDA/MPL] and in adjuvant system no. 02A [AS02A] of Glaxo SmithKline as adjuvants, induced a strong protective immune response. Both the formulations resulted in substantial reduction in bacillary load in lungs and significantly improved lung pathology. Furthermore, a very good correlation was observed between the disease severity and weight loss with elevated levels of immunoglobulin M [IgM] and immunoglobulin G [IgG] responses to several mycobacterial antigens, such as culture filtrate protein 10 [CFP 10], HSP-X [alpha crystalline] and MPT83. Along with higher levels of T-cell activation, an increased level of ESAT-6 specific IFN-γ was detected during infection (74). Though the studies in Macaque model have tremendously helped gaining an insight into the immune responses and pathogenesis associated with human TB, it suffers from some key limitations like inclusion of only a small number of animals in the study and difficulty of maintenance, etc., for long-term experiments. With the availability of more BSL III containment facilities, it should gradually become feasible to include a larger number of animals with longer experimental schedules in future studies. As primate model can reproduce several important aspects of human TB, improvement in this model will help in deciphering the disease pattern, immune responses, and pathology associated with different phases

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of the disease. Hence, it may be advisable to first test promising vaccine candidates in this model to generate sufficient data before including them for human trials. Deciphering the Mystery Behind an Array of Immune Responses to Vaccination and Infection Numerous meta-analyses based on several BCG efficacy trials in humans have resulted in some important observations concerning the susceptibility to infection and elicitation of immune responses. Different human populations respond differently to immunization as well as Mycobacterium tuberculosis infection. Various host factors, variability in the BCG strains, and differences in the virulence of Mycobacterium tuberculosis strains represent some of the multifactorial reasons for the apparent variability in the protective efficacy of BCG. The role of host factors is well exemplified by the fact that only 10 per cent of the exposed individuals actually develop the disease and rest 90 per cent are efficiently able to control the infection, which may remain latent for many years (75). Though till date there is no strong evidence in favour of the genetic bias for susceptibility to TB in humans, some epidemiological investigations suggest that susceptibility to TB may be under some genetic control (76). For example, although complete inability of BCG to provide protection in Chingleput trial (77) could suggest an underlying genetic bias for these results, a case-control study on immigrant Asian community in UK revealed far greater protection in immigrant Asians in UK than those in Chingleput, South India. Thus, genetic bias might not really have been at least the primary reason for the observations in Chingleput trial where BCG exhibited zero per cent efficacy (77,78). Indeed the contribution of other factors, like age, nutritional status, co-existence of other diseases, immune status, etc. may play an important role in determining the risk of developing TB. Besides, in specific subpopulations, like infants or persons with immunodeficiency, the occurrence of TB was found to be much higher than those in the general population (79-82). Apart from HIV co-infection, infections like, schistosomiasis and hookworm infection have been found to adversely affect the progression of TB. Co-infection with these parasites modulates the immune system of the host by down- regulating the T-cell responses against mycobacterial antigens, thereby resulting in a reduced protection by BCG immunization against TB (83-85).

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Apart from the host genetic factors and differences in BCG strains, which result in an enormous variability, there is an emerging evidence that various Mycobacterium tuberculosis strains may vary in their genetic composition as well as phenotype and, thus, may substantially affect the evaluation of vaccine candidates. The Beijing strain of Mycobacterium tuberculosis, for example, which is one of the most prevalent strains in Asian countries, has been implicated in TB outbreaks in BCG vaccinated populations and has been found to be frequently associated with drug resistance (86). This strain has also been found to be much more virulent in mice than the laboratory strain Mycobacterium tuberculosis H37Rv, which is normally used in the guinea pig and mouse models of Mycobacterium tuberculosis infection. Thus, evaluation of new vaccines against the challenge of Beijing strain requires serious consideration. Recently, Castanon-Arreola and colleagues (87) have reported that a recombinant BCG strain over-expressing the 38kDa antigen of Mycobacterium tuberculosis [an otherwise under-expressed antigen in conventional BCG strains] was able to provide better protection against a Beijing strain of Mycobacterium tuberculosis than BCG. The enhanced protective efficacy of recombinant BCG was not apparent when Mycobacterium tuberculosis H37Rv was employed as the challenge organism (87). The mechanism of influence of various strains of Mycobacterium tuberculosis on the final outcome of the TB pathogenesis is not yet known. But, with the rapid development of the molecular genetic tools such as restriction fragment length polymorphism [RFLP], random amplification of polymorphic DNA [RAPD] fingerprinting and microarray techniques, characterization of virulence determinants in the various strains of Mycobacterium tuberculosis should be possible in the near future. Various strains of BCG that have been used all over the world for immunization have also been implicated as a major cause of the heterogeneity observed in the protective efficacy of BCG. Support for this hypothesis has accumulated from several direct evidences; for example, a significant difference between the protective efficacies of the Paris and Japanese BCG strains was revealed in the studies carried out in Hong Kong (88,89). The Tice BCG strain imparted 75 per cent protection in a trial involving high-risk infants in Chicago, although in several other studies carried out in the United States, it failed to show any significant protection (90). Hence, it

would be highly beneficial, if the number of variables arising from the host, pathogen and the vaccine is minimized in order to obtain uniform results. IDENTIFICATION OF VACCINE TARGETS IN THE POST-GENOMIC ERA The publication of the genome sequence of Mycobacterium tuberculosis H37Rv in 1998 was a giant leap in understanding the biology of the tubercle bacilli in particular and Mycobacteria in general (27). The application of functional genomics to the vaccine development programme has tremendously accelerated the process of defining the complete set of immunodominant antigens and has provided the means for their discovery, production and manipulation. Further, sequencing of the genomes of six Mycobacterium species has opened several new vistas and has significantly helped the process of identification of vaccine candidate by inter-species comparison of the genome sequences (91-93). Moreover, it has also helped to understand the source of antigenic variation among different strains of Mycobacterium tuberculosis. In a recent finding, Pro-Glu [PE] and ProPro-Glu [PPE] proteins have been proposed as the source of antigenic variation, which may most likely affect the interaction of the bacilli with the host cell. Application of microarray technology has revealed a repertoire of new stage specific antigens of Mycobacterium tuberculosis, which are expressed in different phases of infection. Specifically, the identification of deleted regions from the genome of Mycobacterium bovis that are absent in the currently used vaccine strain, will allow identification of antigens responsible for pathogenicity and persistence (94). Unlike the conventional targeted gene knock-out methodology, application of techniques like transposon mutagenesis and signature tagged mutagenesis has made it possible to screen a large number of mutants to simultaneously screen for their in vivo growth and virulence in experimental animal models (95-99). This has lead to identification of virulence genes, which can be further assessed for their vaccine efficacy in a suitable animal model. Two other areas, namely subunit and nucleic acid vaccines have also been significantly benefited from the genome sequencing of Mycobacterium tuberculosis. For example, several secreted or surface exposed proteins, which are widely used as vaccine candidates were discovered based on the presence of specific sequences or motifs. This in silico analysis to

Tuberculosis Vaccine Development: Current Status and Future Expectations identify new vaccine candidates, which is termed as ‘reverse vaccinology’, has tremendously boosted the entire vaccine development programme. It has also provided access to the entire repertoire of Mycobacterium tuberculosis antigens. With the application of advanced immunoinformatic tools, several antigenic secretory proteins and their potent T-cell epitopes have been identified for the development of novel protein, peptide or epitope based vaccines. While the identification of new antigens as prospective vaccine candidates is an essential primary step in vaccine designing, this will have to be followed by understanding the role of these antigens in mycobacterial infection, disease process and resolution.

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humans, these animals were given a very high dose of infection (101,102). It clearly indicates that at this high dose of infection, the amount of antigen available to the immune system was enough to generate immune responses necessary for protection against reinfection. Thus, to out-perform Mycobacterium tuberculosis, a vaccine should induce a more potent immune response than the natural infection. Figure 64.1 depicts various stages of the disease progression, where specific intervention strategies like drugs and vaccines can be used. The various vaccination strategies that have emerged in the last two decades are listed in Table 64.1. Recombinant bacille Calmette-Guérin

VARIOUS STRATEGIES FOR THE DEVELOPMENT OF TUBERCULOSIS VACCINES Despite the lack of a perfect understanding about protective immunity and effector mechanisms involved in TB, there are several reasons to believe that a better TB vaccine is biologically possible. Less than 10 per cent of the two billion individuals infected with Mycobacterium tuberculosis develop the disease, which in many cases is promoted by immunodeficiency, such as a concurrent HIV infection (100). This strongly supports the argument that the immunocompetent host is well equipped to keep the pathogen in check. However, reactivation of persistent tubercle bacilli in asymptomatic individuals suggests that natural infection with Mycobacterium tuberculosis does not provide complete sterility or protection against reinfection. Possibly, during natural exposure, humans are infected with a very few Mycobacterium tuberculosis bacilli. Hence, in an immunocompetent host the immune response generated against the infection is sufficient enough to clear the system of this small number of bacilli. However, it does not provide complete sterilization, leaving behind very few bacilli in dormant state. In these conditions, only a negligible amount of antigen is available to the immune system resulting in depletion of the memory pool of lymphocytes, which require a continuous contact with the antigen for their maintenance in an activated or primed state (101). As a result, during reinfection, the immune system is not able to generate appropriate immune response to kill the infecting bacilli. However, under identical conditions primary infection with Mycobacterium tuberculosis did provide protection against reinfection in mice. But, unlike the natural infection in

It is well acclaimed that BCG protects children against childhood TB. Hence, instead of replacing BCG with another vaccine, it would be wise to improve the current vaccine by expressing in it the immunodominant antigens involved in pathogenesis, persistence and immunomodulation. Alternatively, BCG can be employed in a prime boost strategy. Thus, without hampering the childhood immunization programme, a recombinant BCG vaccine would help in improving the protective efficacy against adult pulmonary TB. Along with its potent immunoadjuvant property, high degree of safety for human use and the availability of expression systems that provide enhanced and stable expression of genes in mycobacteria, BCG became a very attractive vehicle for the development of new recombinant BCG vaccines. In addition, several ways have been devised to enhance the expression or secretion of a protein in to the extracellular milieu (103-112). Apart form the restoration of the lost genes, like ESAT-6 and MPB-64, which are absent from BCG, several other antigens like major secretory 30-32 kDa protein, 38 kDa lipoprotein etc. have been expressed in BCG and analysed for their protective efficacy in mice and guinea pig models of TB (113,114). However, such an approach should be employed cautiously as over-expression of the genes involved in pathogenesis might result in a BCG strain with enhanced virulence. For example, re-introduction of the complete region of difference 1 [RD1] locus, although resulted in a better protection in immunocompetent mice, it was found to be virulent in immunocompromised mice. Also, over-expression of antigens like 19kDa lipoprotein in BCG have resulted in an overall change in the immunomodulatory nature of BCG, resulting in loss of

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Figure 64.1: Different stages of Mycobacterium tuberculosis infection and intervention strategies. The figure illustrates the heterogeneity in terms of the outcome of infection in different individuals and various stages of the disease progression, where specific intervention strategies like drugs and vaccines can be used TB = tuberculosis; HIV = human immunodeficiency virus; MDR-TB = multidrug-resistant tuberculosis

Tuberculosis Vaccine Development: Current Status and Future Expectations Table 64.1: Various vaccination strategies that emerged in the last two decades Recombinant BCG Live attenuated mutants and auxotrophs of Mycobacteirum tuberculosis Nontuberculous mycobacterial vaccines Subunit vaccines DNA vaccines Epitope based vaccines Prime boost immunization strategy BCG = bacille Calmette-Guerin; DNA = deoxyribonucleic acid

protective immune responses induced by BCG alone (115,116). An efficient antituberculosis immunity relies upon a Th1 immune response which has led to the development of rBCG vaccines expressing human Th1 cytokines like IFN-γ, interferon-α-2β [IFN-α-2β], IL-2, IL-12, interleukin18 [IL-18] and granulocyte-macrophage colonystimulating factor [GM-CSF] (117-121). In most of these studies, though the recombinant strains showed improved Th1 response, their protective efficacy is yet to be assessed in an appropriate animal model. Though BCG is known to induce a detectable cytolytic Tlymphocyte [CTL] response (122), its inability to access class I antigen-processing pathway significantly has necessitated procedures to augment CD8+ T-cell response. Recently, an rBCG strain expressing listeriolysin of Listeria monocytogenes, which forms pores in the phagolysosomal membrane, has been reported to escape to the cytoplasm, thereby promoting antigen processing by class I pathway resulting in a greater cytotoxic T-cell response and a better protection against Mycobacterium tuberculosis infection (123). This vaccine is now undergoing Phase I clinical trial for its protective efficacy against TB. Live Attenuated Mutants and Auxotrophs of Mycobacterium tuberculosis The development of Mycobacterium tuberculosis mutants as vaccine candidates primarily relies upon the assumption that the vaccine strain should be antigenically as identical as possible to the disease-causing organism (124). By comparative genomics, it has been revealed that in comparison to Mycobacterium tuberculosis 16 defined regions [RD1-RD16] are deleted from the currently used

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BCG strains. These regions encode 129 ORFs including several regulatory genes as well as some of the highly immunodominant antigens (94,125). This has provided a rationale for the development of live vaccines using a Mycobacterium tuberculosis background rather than Mycobacterium bovis BCG background. Such strains can be developed by either: [i] producing auxotrophic mutants of Mycobacterium tuberculosis with limited replication capacity in immunocompromised subjects; or [ii] by disrupting virulence genes necessary for hostpathogen interaction (126). A number of auxotrophic Mycobacterium tuberculosis mutant strains developed by random transposonmutagenesis, signature tagged mutagenesis, illegitimate recombination and allelic exchange-homologous recombination have been assessed for their protective efficacy in experimental animal models (124,127-131). For example, a leucine auxotroph of Mycobacterium tuberculosis that was severely attenuated in severe combined immunodeficiency syndrome [SCID] mice was completely cleared from mouse organs within a few weeks of immunization. However, at least two doses were required to elicit significant protection in immunocompetent C57BL/6 mice. Due to its excellent safety in immunocompromised mice, this appears to be an excellent candidate vaccine for its use in immunodeficient individuals (132). The methionone, tryptophan and proline auxotrophs of Mycobacterium tuberculosis have been found to be highly attenuated and confer protection equivalent [proline] to or better [tryptophan] than BCG against Mycobacterium tuberculosis infection in DBA/2 mice (129). Similarly, a double auxotroph of Mycobacterium tuberculosis [leucine and pantothenate] has also been shown to provide a significant protection against Mycobacterium tuberculosis infection (124). The panCD mutant of Mycobacterium tuberculosis [genes required for de novo biosynthesis of pantothenate] was observed to be highly attenuated in immunocompromised SCID and IFN-γ deficient mice and has proven to be much safer than BCG. The mutant provided significant protection against Mycobacterium tuberculosis with a single immunization eliciting significant memory response as evident from the fact that the protection persisted even seven months after immunization (133). For the development of an ideal auxotrophic mutant, at least two or more unlinked genes should be deleted to reduce the probability of reversion. However, such mutants should

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be able to survive inside the host for sufficient time to generate an efficient immune response. Such auxotrophic mutants that are antigenically indistinguishable from the wild type Mycobacterium tuberculosis would target the appropriate antigen presenting cells during their residence in the host (20). A second approach relies on attenuation of Mycobacterium tuberculosis genes required for virulence. Till date several virulence genes have been identified, knocked out and the mutants assessed for their growth in vitro and in vivo (134-139). These knockout strains were found to have differences in their virulence and growth characteristics. For example, Mycobacterium tuberculosis mutants deficient in dormancy associated genes replicate in mice lungs in an unconstrained manner early after infection, but cease to grow at later stages due to their impaired dormancy gene programme (134). Some knockout strains have been shown to induce much less pathology in guinea pigs in comparison to the parental strain despite a growth rate that was comparable with the parental strain (135). Due to its highly pathogenic nature, development of attenuated strains of Mycobacterium tuberculosis requires careful consideration of two important aspects. As far as possible, the original strain should contain a complete repertoire of antigens and attenuation should result in a fine balance between attenuation and immunogenicity, as over-attenuated bacilli may be devoid of key antigens necessary for protective immunity. Nontuberculous Mycobacterial Vaccines Nontuberculous mycobacteria [NTM] that are closely related to Mycobacterium tuberculosis have been evaluated for their vaccine efficacy in various animal models and human trials. The close phylogenetic relationship of these organisms with Mycobacterium tuberculosis renders them antigenically similar to the pathogen. Apart from having the adjuvant-like property, these NTM are non-pathogenic even in immunocompromised individuals. Mycobacterium microti when used in a prophylactic mode conferred 77 per cent protection [equivalent to BCG] against TB infection in infants (140,141). Several studies have also been carried out with killed/live or recombinant Mycobacterium vaccae in both prophylactic and immunotherapeutic modes resulting in protective efficacy comparable to BCG (142-146). In a separate study, Mycobacterium habana exhibited improved

protection as compared to BCG in the mouse model (147,148). In another approach, killed Mycobacterium w [Mw] caused reduction in the bacillary load in mice and prevented formation of granulomatous lesions in guinea pigs (149,150). A study from north India revealed protective efficacy of Mw against leprosy. The follow-up studies in the same population showed that Mw also reduced the incidence of TB in this population by 61.5 per cent (151). Furthermore, with the advent of comparative genomics, sequencing of these NTM would aid in the development of these viable or killed NTM as a vaccine against TB. Subunit Vaccines Subunit vaccines represent one of the most popular approaches for vaccine development. Subunit vaccines against Mycobacterium tuberculosis mainly comprise of secretory [culture filtrate proteins] and non-secretory proteins or lipids and carbohydrate antigens derived from Mycobacterium tuberculosis cell wall but also includes vaccines based on non-mycobacterial vectors, like attenuated pox virus and adenovirus. Most of the vaccines included in this class have been identified by screening purified fractions or 2-D gels with antiserum collected from TB patients or by analysing T-cell response against these antigens and are expected to be inherently safe. However, these traditional ways of antigen discovery are now being replaced by new techniques, such as comparative genome and proteome analysis, which has tremendously accelerated the process of new antigen discovery. For example, a recent screen has identified 34 antigens that are expressed in Mycobacterium tuberculosis but not in BCG. Further testing of these antigens as DNA vaccines identified an antigen, which alone conferred as much protection against Mycobacterium tuberculosis infection as BCG. Lately, some new bioinformatic tools like MHC-I antigenic peptide processing prediction [MAPPP], Epimatrix etc., have enabled MHC-I epitope identification. These advances are likely to pave the way for the development of more specific epitope based subunit vaccines (152). Mycobacterium tuberculosis changes its antigenic repertoire when it shifts from an active state to a dormant non-replicating state. Thus, it can be advocated that for a prophylactic vaccine, the candidate antigens should comprise of proteins that are rapidly secreted during early infection. On the other hand, the proteins associated

Tuberculosis Vaccine Development: Current Status and Future Expectations with dormancy-induced genes would serve better for a post-exposure vaccine. Indeed a vaccine that includes antigens from both the classes is most likely to protect individuals from various populations with different age groups and exposure levels. The widespread use of BCG in neonates and its apparent efficacy against paediatric TB has made it difficult to replace BCG with a new vaccine. Thus recently, the focus of TB vaccine research has shifted towards using these subunit vaccine candidates as a boosting agent in populations that have already been immunized with BCG. The apparent inability of the subunit vaccines to mount a strong T-cell response has accelerated the process of adjuvant discovery required to induce a potent Th1 response by these subunit vaccines and new adjuvants like DDA, MPL-A and AS02A of Glaxo Smith Kline], which are potent modulators of T-cell responses, have now been shown to better enhance the immunogenicity and protective efficacy of several subunit vaccines than traditional adjuvants (153,154). In a recent report, ESAT-6 by itself failed to stimulate the adaptive arm of immune response, but stimulated protective immune responses equivalent to BCG when injected along with a mixture of DDA and MPL-A (155). These two adjuvants have already been declared safe for human use (156). The fusion protein 72f when used along with an adjuvant containing a saponin derivative from Quillaja saponaria [QS21] mixed with MPL-A exhibited very promising results in several animal models and now represents the first subunit vaccine to enter a clinical trial. Another recombinant protein resulting from the fusion of antigen 85B and ESAT-6 has also entered clinical trials in the year 2006. DNA Vaccines The DNA vaccines, the latest entry in the field of vaccine development, have quickly emerged as one of the most promising advancements in the field of vaccine discovery. The surprising observation that immunization with naked DNA could direct the immune system towards stronger and persistent cellular and humoral immune responses attracted many scientists towards this area (157-159). Intramuscular injection of a mammalian expression vector encoding a desired gene, results in the expression of corresponding protein, which subsequently induces a potent cellular immune response against the encoded antigen. This is especially advantageous in the

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context of TB, as the protective immunity against Mycobacterium tuberculosis is primarily dependent on the cellular fraction of the immune system (48). The DNA vaccine allows continuous expression of a particular antigen, thereby exposing the immune system to the antigen for a prolonged time. The usefulness of DNA vaccines has led to the development of a variety of methods for their delivery to a desired site in the host. Direct injection, electroporation or gene-gun based delivery into muscles, delivery to the respiratory mucosa using liposome encapsulated DNA vaccines etc., are in common use for delivery of DNA vaccines these days. Expression of antigens by DNA vaccines and their subsequent processing and presentation along with the MHC class I molecules mimics the antigen-processing pathway followed by an intracellular pathogen. Several DNA vaccines have been developed in the last decade and have been evaluated for their efficacy against TB in various animal models. The DNA vaccination with genes encoding the members of Ag85 complex of Mycobacterium tuberculosis and 65 kDa heat shock protein of Mycobacterium leprae conferred protection equal to BCG (160,161). A significant protection [equivalent to BCG] was also observed in case of ESAT-6, MPTP64 (162), PstS (163), a PPE protein (164), immunogenic protein [MPT70] (165) and 19kDa antigen (166) when used as DNA vaccines in mouse model of experimental TB. The advancements in the field of recombinant DNA technology have facilitated simultaneous expression of more than one gene using a mammalian expression vector. The DNA vaccines based on fusion of antigen Ag85B with either ESAT-6 or MPT64 gene conferred protection better or equivalent to BCG (167,168). Moreover, co-expression of co-stimulatory molecules, such as different cytokines and chemokines, inclusion of CpG motifs in the DNA vaccine backbone has helped in enhancing immunogenicity of DNA vaccines. Modifications in the mode of delivery would further improve the transfection ability of DNA vaccines, thereby enhancing the expression levels and consequently immunogenicity of the associated antigen (169). For example, elicitation of improved immunogenicity has been reported with the coating of DNA plasmid with gold particles and their delivery by a gene gun (170,171). Epitope Based Vaccines Immunodominant T-cell epitopes play a crucial role in a naturally occurring immune response. Recently,

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strategies for exclusive delivery of immunodominant T-cell epitopes of a single or multiple proteins have emerged. One of the potential advantages of this epitopebased approach includes higher safety, as it helps in getting rid of the unwanted, toxic or immunosuppressive regions from a protein. This also provides the opportunity to appropriately engineer epitopes to elicit a desired immune response. However, such epitopes need to be identified by employing either the new tools of bioinformatics or by screening the T-cells derived from TB patients at various stages of disease progression by in vitro assays employing different overlapping peptides of a protein (172,173). Moreover, comparative genomics and new bioinformatic tools have helped identification of conserved epitopes across various pathogenic organisms, which can be incorporated along with the Mycobacterium tuberculosis epitopes to generate a multipurpose vaccine. This approach can prove to be extremely beneficial, if the specificity of T-cells isolated from exposed but asymptomatic individuals is characterized against a vast array of peptides isolated from Mycobacterium tuberculosis proteome. These peptides can be further assessed for their immunogenicity in the form of a multivalent epitope-based vaccine (174). At present, several investigators are using the bioinformatic ‘genome mining’ tools for identification of putative secretory proteins and immunodominant peptides from Mycobacterium tuberculosis genome and assessing their immunomodulatory potential in vitro (174-176). Till date, many immunodominant proteins like 38 kDa (177,178), 30-32 kDa antigens (179-181), 19 kDa lipoprotein (182), ESAT-6 family (183), HSP65 (184), MPB70 (185,186), 28 kDa haemolysin (187), 24 kDa LppX (188), MPT51 (189), 16 kDa protein (190) and PE and PPE family of proteins (191) of Mycobacterium tuberculosis have been screened for immunodominant T-cell epitopes and some of them have also been assessed for immunogenicity in vitro and in animal models, but protective efficacy of these epitopebased vaccines is yet to be confirmed. After the availability of an effective delivery system, a multi-epitopebased vaccine could have the potential of being the safest means of immunization. Prime Boost Immunization Strategies The concept of ‘boosting’ the immune responses traces its history back to the era of Louis Pasteur. The fact that the immune system once primed with an antigen elicits

a heightened response to the secondary exposure of the antigen has been utilized to develop effective prime boost vaccination strategies against TB. Repeated administration with the same vaccine [called homologous boosting] has proved to be relatively inefficient at boosting cellular immunity, instead it generates a very strong humoral response. This has been especially observed in case of BCG, which, when administered repeatedly offered little benefit in humans as well as in various animal models. Besides, these studies (192-195) demonstrated that the mycobacterial sensitization dramatically lowers the efficacy of BCG with little protection. Prior sensitization to environmental mycobacteria and consequent immunity to BCG might be responsible for an early clearance of BCG, before it is able to mount a sufficient immune response. In order to circumvent this problem, ‘heterologous boosting’ came into being, which involves sequential administration of vaccines with appropriate intervals using different antigen-delivery system such that the immune system is primed to the antigen using one vector and is then boosted with the same antigen delivered through a different vector. The key strength of this strategy lies in the greater level of immunity it induces in comparison to single vaccination or homologous boosting. With the emergence of new strategies involving adenovirus and poxvirus in heterologous prime boost vaccination schemes, synergistic effects can be achieved instead of an additive effect generally observed in case of homologous boosting (196-198). This synergistic enhancement of immunity to the target antigen is reflected by an increased number of antigen-specific T-cells and selective enrichment of high avidity T-cells. Moreover, it also induces an elevated level of both CD4+ and CD8+T-cell response (196). The tremendous power of prime-boost was recently highlighted in a murine model, wherein, intranasal vaccination of mice with BCG followed by a booster of a recombinant Vaccinia virus expressing antigen 85A resulted in a nearly 300-fold reduction in bacillary load in the lungs following aerosol infection with Mycobacterium tuberculosis (199). This would mimic the situation where a gradually declining immunity of BCG can be enhanced by boosting with a candidate antigen specifically recognized by memory immunity. Amongst different strategies involving various antigens and delivery approaches, the prime boost strategy described above represented the only

Tuberculosis Vaccine Development: Current Status and Future Expectations successful immunization, significantly prolonging the survival of guinea pigs in comparison to BCG immunization (200). The protective efficacy of this vaccination strategy is currently being evaluated for its efficacy in Cynomolgus monkeys. With these encouraging results, this vaccine became the first of the new generation TB vaccines to enter the human trials (201). Moreover, it has been found to be innocuous and immunogenic in mycobacterially naive healthy volunteers and is now being tested in BCG vaccinated populations. Apart from the viral vectors, which have been highly recommended as boosting agents, subunit vaccines including both recombinant proteins and DNA vaccines are now being used to boost the immunity imparted by BCG. Brooks and colleagues (202) observed that with increasing age, mice vaccinated with BCG gradually lose their capacity to resist an aerosol infection with Mycobacterium tuberculosis. However, if these mice are boosted with the Ag85A protein [with MPLA as an adjuvant] in midlife, it restored back the resistance in elderly mice to levels equivalent to young ones; with reduced pathological damage and bacillary load in the lung. Recently, a comparative assessment of Mycobacterium tuberculosis and Mycobacterium bovis BCG genome and proteome, revealed an interesting pattern; wherein, homologue of Rv3407 of Mycobacterium tuberculosis was although present in the BCG genome, the encoded protein was present exclusively in Mycobacterium tuberculosis proteome (203). The DNA vaccine encoding Rv3407, when evaluated for its efficacy in mouse model as a boosting agent after BCG vaccination, improved the protection offered by BCG along with prolonged survival of Mycobacterium tuberculosis infected guinea pigs over two years. Besides the use of BCG as the priming agent, several efforts to develop other heterologous prime boost immunization strategies are underway. Immunization with DNA vaccine encoding ESAT-6 as a priming agent along with a booster of recombinant ESAT-6 protein significantly improved the immunogenicity of DNA vaccine inducing an enhanced antigen specific Th1 response (204). Though these vaccination protocols need to be evaluated for conferring protective efficacy in various animal models, the promising subunit vaccines would definitely find their use in the immunocompromised individuals, where live vaccines based on viral or bacterial vectors pose problems.

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The BCG dose not perform satisfactorily against adult TB. A possible reason for this may stem from the fact that the antimycobacterial memory response generated by BCG immunization during childhood may be rendered ineffective by continuous exposure to environmental mycobacteria resulting in the development of either immune tolerance or a diversion of the immunity towards Th2 or Treg arms. In these adults, any attempt to stimulate the previously generated immune responses would be ineffective. Thus, it would be a better option to generate a new primary response followed by a booster to elicit an adequate anti-mycobacterial immunity (205). Although, detailed studies need to be carried out, success of these heterologous prime boost immunization strategies has generated optimism for the development of effective antituberculosis vaccines in future. IMMUNOTHERAPEUTIC APPROACH TO COMBAT TUBERCULOSIS Current strategies for TB control are based on transmission reduction by treatment of active cases and prevention of disease by prophylactic vaccination. The available chemotherapy comprises of a very lengthy treatment schedule [6 to 9 months] with a combination of four drugs isoniazid, pyrazinamide, rifampicin and ethambutol. This therapy, although successful per se, often fails due to lengthy treatment regimens, which are difficult to follow in most of the developing countries, where TB is a major public health problem. Moreover, such non-compliance can often lead to relapse and emergence of drug resistance. Thus, a significant reduction in treatment schedule is likely to provide many fold advantages; such as, cost effectiveness, reduced incidence of drug resistance and latent infections. However, unless a difficult goal of a shorter chemotherapeutic regimen is achieved, use of immunotherapy to boost the immune system of infected patients as an adjunct to chemotherapy can provide a significant relief. It may not only reduce the prolonged chemotherapy period but may also eliminate dormant bacilli and consequently prevent reactivation. Additionally, a reduction in the conversion of reinfection into active disease may be another possible spin off (206). Immunotherapy can also be used to down-regulate a highly exaggerated immune response in patients with severe disease. An exaggerated pathological damage in active pulmonary TB, which stems from a localized and

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a systemic production of high levels of Th1 cytokines like IFN-γ or TNF-α, can be reduced by a targeted suppression of these cytokines by using neutralizing antibodies. Besides, the use of systemic immunosuppressing agents, like corticosteroids etc. can also produce similar effects. However, in the use of these immunomodulators an extreme care should be taken to avoid an increased suppression of the immune system, which may have unfavourable consequences (207). With growing evidence for the role of various Th1 cytokines, like IFN-γ, IL-2, IL-12, and IL-18 etc., in protective immunity against TB, several immunotherapeutic strategies using Th1 cytokines have been developed. For example, an aerosol delivery of IFN-γ was found to produce clinically encouraging response in treating multidrug-resistant TB [MDR-TB], although the effect was transient (208,209). In other studies (210,211), treatment with GM-CSF along with IFN-γ successfully treated patients with refractory central nervous system MDR-TB. Recently, a cocktail of six recombinant proteins [6 antigens: 85B, 38kDa, ESAT6, CFP21, Mtb8.4, and 16kDa] along with IFN-γ and Ribi adjuvant [monophosphoryl lipid A-trehalose dicorynomycolate {MPLA-TD}] conferred a significant protection against Mycobacterium tuberculosis infection in mice model (211). Besides, IL-2 immunotherapy in MDR-TB patients resulted in a significant immune activation and reduced bacillary burden (212). However, in a separate study (213), no significant reduction in the clinical symptoms was observed when IL-2 was used as an immunotherapeutic agent in adults suffering from drug-susceptible TB. Recently, immunotherapy with a combination of two DNA vaccines [Ag85A and PstS-3] in mice model along with chemotherapy was found to prevent exogenous reinfection as well as endogenous reactivation (214). In a separate study (215), supplementing the chemotherapy with DNA vaccine encoding the Mycobacterium leprae HSP60 resulted in a significantly reduced duration of treatment. In an alternative approach, the use of the NTM Mycobacterium vaccae as an immunotherapeutic agent successfully enhanced the Th1 response. However, the expected improvement in the treatment of HIV infected adults with pulmonary TB was not observed (216-218). Although adjunctive immunotherapy is reasonably effective, it still poses serious problems, such as, high cost, occasional occurrence of adverse and serious adverse events and induction of tolerance during long-

term application of immune adjunctive agents. Apart from characterization of the immune responses involved in protection against TB, identification of newer immunotherapeutic agents, their delivery mode and dosage will definitely help in shortening the prolonged chemotherapy period and an effective management of the disease in future. ROLE OF DIAGNOSTICS IN THE DEVELOPMENT AND ASSESSMENT OF NEW VACCINES Tuberculosis being a very complex disease with a diverse range of pathological and bacteriological outcomes, an ideal diagnostic test for TB should be able to precisely distinguish between various stages of the diseases. However, none of the currently available diagnostic tests fulfils these criteria. Apart from the need to develop robust diagnostic assays for an early detection of TB infection, a focussed and a coordinated effort is also required to develop tests for evaluating the efficacy of promising vaccine candidates undergoing pre-clinical trials. At present, in most of the TB vaccine trials, vaccine efficacy has been evaluated by differentiating between protected and unprotected subjects on the basis of various surrogate immunological markers and clinical and radiological features. The diagnosis of TB is primarily based on clinical symptoms like, cough for more than two to three weeks, haemoptysis, fever, weight loss and loss of appetite, chest radiographic features and a DTH response to tuberculin skin test [TST] (219,220). The confirmatory tests comprise of identification of AFB in the sputum and in other body fluids by direct smear and conventional culture methods. These techniques suffer from serious limitations of low sensitivity and specificity apart from being time consuming. The development of new diagnostic techniques based on lipid profiling (221), hybridization with specific gene probes (222-227), polymerase chain reaction [PCR] RFLP based methods (228-232) and new immunological assays involving both cellular and humoral responses, have overcome these limitations to some extent. As purified protein derivative [PPD] is comprised of many proteins present in Mycobacterium tuberculosis, Mycobacterium bovis BCG and other NTM, infection with Mycobacterium tuberculosis, exposure to environmental mycobacteria and vaccination with BCG can all cause positive TST. In addition to this, TST cannot distinguish between latent infection and active disease. Thus, it has

Tuberculosis Vaccine Development: Current Status and Future Expectations proved to be of limited value in evaluation of the efficacy of vaccine candidates especially those based on BCG, attenuated Mycobacterium tuberculosis, or other attenuated or killed mycobacterial species. These limitations of PPD can be circumvented by developing new reagents for skin test, which will help in specifically measuring the DTH response elicited exclusively by Mycobacterium tuberculosis infection. Several efforts have been made till date to identify Mycobacterium tuberculosis specific antigens that elicit DTH responses to develop an effective skin test based diagnostics (233,234). Apart from TST, assays based on cellular [T-cell] and humoral immune responses are showing promising results. For example, measurement of IFN-γ secreting T-cells specific for Mycobacterium tuberculosis antigens like ESAT-6 and CFP10, when used together, successfully detected Mycobacterium tuberculosis infected patients with remarkable specificity (235,236). The reader is referred to the chapter “Diagnosis of latent tuberculosis infection: recent advances and future directions” [Chapter 12] for more details. Staining for AFB, the most widely used method provides a simple and a fast means for detection of active TB but its sensitivity is too low and limited to the presence of at least 104 bacilli per ml of sputum (224,225). Also, any pathogenic and saprophytic mycobacterium, which shows acid-fast staining, may interfere with an accurate detection of Mycobacterium tuberculosis. Hence, enormous efforts are underway for the development of diagnostic procedures that can detect Mycobacterium tuberculosis directly in the clinical specimens in a minimum possible time with greater specificity and efficacy. Several PCR and hybridization based methods utilizing Mycobacterium tuberculosis specific nucleic acid probes have been developed in the last few years and are now available commercially. The examples include, MTD test [GenProbe, San Diego, CA], Amplicor test [Roche Molecular System] and Probe tech Direct TB-a strand displacement amplification [SDA] test [Becton and Dickinson], among others (237). With the availability of genome sequence of Mycobacterium tuberculosis, oligonucleotide probes specific for various clinically relevant mycobacteria have been developed which are now been regularly used for the identification of various clinical isolates (223,227). Although, these new methods are rapid, procedural complexity and requirement of a huge infrastructure and technical support may not encourage their use in the

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developing countries with limited resources. Thus, serious efforts are required to develop improved costeffective diagnostic methods for an early detection and treatment of infected individuals as well as to shorten the necessary follow-up phase of TB vaccine trials. KEY ISSUES SURROUNDING NEW TUBERCULOSIS VACCINES Expectations from a New Vaccine Last decade has clearly witnessed a sudden resurgence in the field of TB vaccine research; nearly 200 new vaccine candidates have already been evaluated for their efficacy in various animal models and five most promising candidates have entered the Phase I clinical trials. These vaccine candidates have shown encouraging results in various animal models including the non-human primate model. However, success in various animal models does not always guarantee effectiveness of a vaccine in human trials. Moreover, TB being a chronic disease with diverse clinical and pathological outcomes in different individuals, it may be unwise to expect a single vaccine to work efficiently in all these different situations (238). Hence, in order to test these vaccine candidates, target populations have to be carefully chosen, which may involve focussing in areas with a high prevalence of TB. A geographically endemic area or an epidemiological group at greater risk of infection may represent an appropriate choice for such trials. Several criteria that should be satisfied by a TB vaccine recommended for human use are listed in Table 64.2. Groundwork for Human Trials Since evaluation of a candidate vaccine in human trials requires an elaborate infrastructure, human resources, substantial funding and is time consuming, prior evaluation of candidate vaccines in animal models requires stringent criteria so that only promising candidates are taken up for human trials. Mass screening of large number of vaccine candidates in a single programme using a standardized protocol for the identification of promising vaccine candidates has been a long cherished dream. The National Institutes of Health [NIH]–pre clinical TB vaccine screening programme and the European Union [EU] TB vaccine integrated project, which are working towards this goal, have already tested more than 150 vaccine formulations

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Tuberculosis Table 64.2: Essential criteria for human tuberculosis vaccine

It should be able to induce a long-lasting and a heightened protective immune response against infection with virulent tubercle bacillus Apart from preventing the primary infection, a vaccine should also block the reactivation of dormant or latent TB infection As the infection with Mycobacterium tuberculosis itself does not generate a sufficient protective immunity against reinfection, a new TB vaccine is therefore expected to generate an immune response, which is qualitatively and quantitatively very different from the natural infection. A new vaccine meant to be used as a post-exposure vaccine is expected either to clear the bacilli without generating any occult signs of disease due to vaccine induced inflammation in the background of ongoing TB infection or it should be able to modulate the immune response in such a way that it aids in clearing bacillary load in lungs of patients undergoing antituberculosis treatment The new vaccines should be innocuous enough to safely immunize the neonates as well as the immunocompromised individuals, as these represent a population, which is highly susceptible to mycobacterial infections Since the uniform success of BCG against childhood TB would make its replacement in the immunization programme almost impossible, the new vaccine strategies should either be based on BCG or be evaluated in the background of a pre-existing BCG induced immunity The resource crunch and inadequate technical support faced by developing countries, which indeed would consume the major proportion of the new vaccine, would necessitate that a new vaccine should be inexpensive, easy to store and transport, and should have a long shelf life with an ease of administration TB = tuberculosis; BCG = bacille Calmette-Guerin

for their protective efficacy. However, the basic protocols followed by the two programmes differ in several aspects. The NIH pre-clinical screening programme uses a low dose aerosol mouse and guinea pig model. In mouse model, efficacy of the vaccine candidates is assessed on the basis of their ability to reduce the bacillary load in lungs after a specified period of Mycobacterium tuberculosis infection. The guinea pig model on the other hand employs an open-ended survival based assay extending up to a period of more than two years. Indeed, in addition to the survival time, reduction in lung pathology represents an important selection criterion for a promising vaccine. In contrast to NIH protocol, EU-TB vaccine cluster programme employs a high-dose guinea pig infection model. Since, BCG vaccination protects guinea pigs against low dose infection, a greater stringency is required to compare the efficacy of various vaccines, which is met by extending the time point of euthanasia up to 26 weeks post-infection. In these conditions, as BCG vaccinated animals are overwhelmed by the high dose of infection, vaccines that outperform BCG are chosen for human trials (239,240). Figure 64.2 depicts the protocol used for screening of vaccine candidates. Human Trials: New Challenges In planning the human trial of a candidate vaccine, several regulatory and operational issues need to be addressed to ensure completion of the trial within a short

period of time with a greater degree of accuracy and confidence (241). In order to efficiently translate the basic research findings into the clinical assessment, it would require: [i] focussed and coordinated effort of multidisciplinary expertise or networks, like mycobacteriologists, epidemiologists, clinical trial specialists, vaccine biologists, etc.; [ii] an appropriate trial site along with availability of a detailed knowledge of TB epidemiology of the trial site; [iii] availability of volunteers with negative TST and with no history of BCG vaccination. However, the criteria for volunteers in the endemic areas may require different considerations based on the available epidemiological knowledge; [iv] cost-effective and easy to perform robust diagnostic assays, expertise in data compilation and interpretation would also be required for a precise data analysis; and [v] appropriate financial resources, support from governmental and nongovernmental organizations. VACCINES IN PHASE I CLINICAL TRIAL At present nine most promising vaccine candidates have passed the regulatory hurdles and entered the Phase I clinical trials with encouraging results. These include: [i] MVA85A, a modified vaccinia virus based vaccine overexpressing Ag85A [University of Oxford/Emergent Biosolutions] (242); [ii] rBCG30, a recombinant BCG expressing Ag85B [UCLA School of Medicine/Aeras] (114); rBCGΔureC:Hly + , a urease C deficient and listeriolysin O secreting BCG [Max Planck Institute for

Tuberculosis Vaccine Development: Current Status and Future Expectations

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Figure 64.2: Variables involved in the screening of vaccine candidates. The figure depicts the protocol used for screening of vaccine candidates in a prophylactic mode against infection with Mycobacterium tuberculosis and the different parameters that are used as a measure of immunogenicity and protective efficacy i.d. = intradermal; s.c. = subcutaneous; i.m. = intramuscular; i.v. = intravenous; IFN-γ = interferon-γ; IL = interleukin; TGF-β = transforming growth factor-β

Infection Biology/Vakzine Project Management] (243); [iv] Mtb72f, a fusion protein of two proteins encoded by Rv1196 and Rv0125 from Mycobacterium tuberculosis [GlaxoSmithKline] (244); [v, vi] Ag85B-ESAT6, a fusion protein of ESAT6 and antigen 85B in adjuvant system H1/IC31 [Statens Serum Institut/Sanofi Pasteur] and LTK 63 [Statens Serum Institut/Novartis] respectively (245,246); [vii] Advac expressing Ag85A, Ag85B and TB10.4 [Aeras] (247); [viii] HyVac4/IC31, a fusion protein of Ag85B and TB10.4 [Statens Serum Institut, Sanofi Pasteur and Aeras] (248); and [ix] rBCG [Aeras] overexpressing Ag85A, Ag85B and TB10.4 [Aeras] (248). Modified vaccinia virus [MVA85A], based vaccine overexpressing Ag85A of Mycobacterium. tuberculosis, was

the first candidate TB vaccine to enter clinical trial. For this, based on IFN-γ ELISPOT test, volunteers without prior exposure to mycobacteria were included in the study. Safety and immunogenicity data emerging from these studies are quite encouraging. Besides, a prime boost vaccination strategy involving BCG as the priming agent and MVA85A as a booster was also used to assess safety and immunogenicity of this heterologous primeboost immunization regimen. In addition, a parallel trial is also being conducted in a TB endemic area in West Africa. For the first Phase I trial of rBCG30, 30 subjects were enrolled at two sites, and at both sites the vaccine was found to be safe and well tolerated by the volunteers.

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Phase I trial of both the fusion protein based vaccines is near completion. IMPACT OF ZOONOSIS ON TUBERCULOSIS VACCINE DEVELOPMENT Zoonotic diseases in humans include all the diseases that are acquired from or transmitted to any other vertebrate animal. Among the various zoonotic diseases, TB represents one of the most common diseases transmitted to humans. Although, Mycobacterium tuberculosis is the causative agent of human TB, a significant proportion of human infections are caused by Mycobacterium bovis – the aetiological agent of bovine TB. The pulmonary TB caused by both Mycobacterium tuberculosis and Mycobacterium bovis are clinically indistinguishable with similar radiographic and pathological features (249). Extra-pulmonary disease due to Mycobacterium bovis is mainly caused by drinking and handling of contaminated milk, which results in cervical lymphadenopathy and chronic intestinal and skin lesions. In many African and Asian countries, where cattle are an integral part of social life, close physical contact between humans and infected animals leads to a significant proportion of human TB of bovine origin. In the past, several incidences of human TB caused by Mycobacterium bovis were reported from South Africa (250-253), Latin America (254,255) and some of the Asian countries. The proportion of human TB in UK due to Mycobacterium bovis was estimated to be 3.1 per cent of all the forms of TB (256). Similarly in Latin America, two per cent of the total pulmonary cases and eight per cent of extra-pulmonary TB cases were reported to be caused by Mycobacterium bovis (257). In a recent study from India (258), analysis of cerebrospinal fluid from patients suffering form TB meningitis revealed that in comparison to Mycobacterium tuberculosis [2.8%], 17 per cent of the samples were found to be positive for Mycobacterium bovis of TB due to Mycobacterium bovis infection has also been reported in HIV -seropositive TB patients. For example, in France, 1.6 per cent of TB cases in HIV-seropositive patients were due to Mycobacterium bovis based infection (259). On the other hand, cases of Mycobacterium tuberculosis infection in cattle have also been reported from India as well as some of the European countries, though the incidence rate was not very high (260,261). As the performance of BCG in preventing bovine TB is doubtful, devising an effective vaccination strategy

against bovine TB would be a viable option in controlling Mycobacterium bovis based human infections in addition to reducing the burden of bovine TB. Several recombinant BCG strains, subunit vaccines and DNA vaccines expressing Mycobacterium tuberculosis antigens have also been assessed for their efficacy in bovine model against Mycobacterium bovis infection. Prime boost vaccination strategies using DNA vaccines encoding HSP65, HSP70 and Apa as priming agent followed by a booster of BCG have provided a substantial evidence that this regimen can provide better protection in calves than either of the vaccine when used alone (252). In another strategy, Vordermeier et al (263) reported substantial protection in cattle immunized with BCG followed by a booster of modified MVA85A and attenuated fowl pox strain FP9 [FP85A], expressing Ag85A. Furthermore, a combination of DNA vaccines encoding Ag85B, MPT64 and MPT83 when tested for their efficacy using DDA as an adjuvant, was found to be highly effective in controlling bovine TB (264). Apart from developing vaccines against both human and bovine forms of TB, control of zoonotic TB in India and other developing countries needs coordination between the human and bovine TB vaccine development programmes along with strict regulatory measures. In some industrialized and developed countries, animal TB control and eradication programme, together with milk pasteurization have drastically lowered the incidence of TB caused by Mycobacterium bovis in both animal and human population (265,266). However, a developing country like India, which has the largest livestock population in the world, has no effective control and eradication programmes for bovine TB. In addition to development of effective vaccines against both human and bovine TB, specific identification strategies for different species of Mycobacterium, will aid in detection of TB cases of diverse origin, which would help in developing effective treatment strategies. As the degree of cattle movement in a country also enhances the incidence of TB and other zoonotic diseases, strict surveillance of animal migration may help in bringing down incidence rate (267). In conclusion, despite the lack of a perfect understanding about protective immunity and effector mechanisms involved in TB, there are sufficient reasons to believe that a better vaccine is really possible. Although several key questions related to TB still need to be answered, and hence, a rational approach for the

Tuberculosis Vaccine Development: Current Status and Future Expectations development of a TB vaccine is not in place as yet, a great deal of hope has emerged due to rapid increase in our understanding of cellular immunity, knowledge of entire genome of several mycobacterial species and advent of new and improved approaches for studying global gene regulatory patterns. Besides, development in the area of proteomics and metabolomics will definitely facilitate identification and characterization of virulent determinants and immunodominant antigens, which would aid in developing effective intervention strategies. Along with a better understanding of the immunological correlates of protection, understanding the mystery behind the latent phase of TB will also facilitate rational designing of pre-exposure as well as post-exposure vaccines to eliminate the reservoir pool of Mycobacterium tuberculosis. In addition to a strict regional surveillance and international cooperation, if all the necessary resources are committed for the development of TB vaccines, we might be able to go a long way in our fight against this enormous global health problem. ACKNOWLEDGEMENTS A part of the work included in this chapter was supported by a financial grant-in-aid from the Department of Biotechnology, Government of India. BD and RJ are thankful to CSIR for research fellowships. Sumeet and Ram Niwas are acknowledged for help with the library work and bibliography. Ramandeep Singh is acknowledged for his help in providing several scientific research papers. Prof. H. K. Prasad, AIIMS is acknowledged for critical reading of the manuscript and suggestions. Rajiv Chawla is acknowledged for the efficient preparation of the manuscript.

REFERENCES 1. Calmette A, Guérin C. Nouvelles recherches experimentales sur la vaccination der bovides contre la tuberculose. Ann Inst Pasteur 1920;34:553-60. 2. Lugosi L. Theoretical and methodological aspects of BCG vaccine from the discovery of Calmette and Guérin to molecular biology. Tuber Lung Dis 1992;73:252-61. 3. Milstien JB, Gibson JJ. Quality control of BCG vaccine by WHO: a review of factors that may influence vaccine effectiveness and safety. Bull World Health Organ 1990;68:93108. 4. Hyge TV. The efficacy of BCG-vaccination: epidemic of tuberculosis in a State School, with an observation period of 12 years. Acta Tuberc Scand 1956;32:89-107. 5. Ponnighaus JM, Fine PE, Sterne JA, Wilson RJ, Msosa E, Gruer PJ, et al. Efficacy of BCG vaccine against leprosy and tuberculosis in northern Malawi. Lancet 1992;339:636-9.

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6. Brosch R, Behr MA. Comparative genomics and evolution of Mycobacterium bovis BCG. In: Cole ST, Eisenach KD, McMurray DN, Jacobs WR Jr, editors. Tuberculosis and the tubercle bacillus. Washington DC: ASM Press; 2005.p.49-69. 7. Tacquet A, Gaudier B, Gernez-Rieux C. Experimental study on the vitality of BCG during gastrointestinal passage in nonallergic infants vaccinated by the oral method. Med Exp Int J Exp Med 1962;6:373-81. 8. ten Dam HG, Hitze KL. Does BCG vaccination protect the newborn and young infants? Bull World Health Organ 1980;58:37-41. 9. Griffin JF, Mackintosh CG, Slobbe L, Thomson AJ, Buchan GS. Vaccine protocols to optimise the protective efficacy of BCG. Tuber Lung Dis 1999;79:135-43. 10. Comstock GW. Simple, practical ways to assess the protective efficacy of a new tuberculosis vaccine. Clin Infect Dis 2000;3[Suppl]:S250-3. 11. Corner LA, Buddle BM. Conjunctival vaccination of the brushtail possum [Trichosurus vulpecula] with bacille Calmette-Guérin. N Z Vet J 2005;53:133-6. 12. Cohn ML, Davis CL, Middlebrook G. Airborne immunisations against tuberculosis. Science 1958;128:1282-3. 13. Middlebrook G. Immunological aspects of airborne infection: reactions to inhaled antigens. Bacteriol Rev 1961;25:331-46. 14. Falero-Diaz G, Challacombe S, Banerjee D, Douce G, Boyd A, Ivanyi J. Intranasal vaccination of mice against infection with Mycobacterium tuberculosis. Vaccine 2000;18:3223-9. 15. Lyadova IV, Vordemeier HM, Eruslanov EB, Khhaidukov SV, Apt AS, Hewinson RG. Intranasal BCG vaccinations protect BALB/c mice against virulent Mycobacterium bovis and accelerates production of IFN-gamma in their lungs. Clin Exp Immunol 2001;126:274-9. 16. Chen L, Wang J, Zganiacz A, Xing Z. Single intranasal mucosal Mycobacterium bovis BCG vaccination confers improved protection compared to subcutaneous vaccination against pulmonary tuberculosis. Infect Immun 2004;72:23846. 17. Wilson H. A tuberculosis survey in a closed community. Med J Aust 1967;2:431-3. 18. Lotte A, Wasz-Hockert O, Poisson N, Dumitrescu N, Verron M, Couvet E. BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv Tuberc Res 1984;21:107-93. 19. von Reyn CF, Clements CJ, Mann JM. Human immunodeficiency virus infection and routine childhood immunisation. Lancet 1987;2:669-72. 20. Bloom BR, Fine PEM. The BCG experience: implications for future vaccines against tuberculosis. In: Bloom BR, editor. Tuberculosis: pathogenesis, protection and control. Washington DC: ASM Press; 1994.p.531-58. 21. Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, et al. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA 1994;271:698-702. 22. Clemens JD, Chuong JJ, Feinstein AR. The BCG controversy. A methodological and statistical reappraisal. JAMA 1983;249:2362-9.

938

Tuberculosis

23. Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of costeffectiveness. Lancet 2006;367:1173-80. 24. Karonga Prevention Trial Group. Randomised controlled trial of single BCG, repeated BCG or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi. Lancet 1996;348:17-24. 25. Fine PEM. The BCG story: lessons from the past and implications for the future. Rev Infect Dis 1989;11[Suppl 2]:S353-9. 26. Alphabetic strain list. Available at the URL: http:// rdna2.ridom.de/ridom2/servlet/link?page=list . Accessed on 12 October, 2008. 27. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998;393:53744. 28. World Health Organization. WHO report 2007. Global tuberculosis control: surveillance, planning, financing. Geneva: World Health Organization; 2007. 29. Quinn TC. Interactions of the human immunodeficiency virus and tuberculosis and the implications for BCG vaccination. Rev Infect Dis 1989;2[Suppl 2]:S379-84. 30. Centers for Disease Control and Prevention. Disseminated Mycobacterium bovis infection from BCG vaccination of a patient with acquired immunodeficiency syndrome. MMWR 1985;34:227-8. 31. Ninane J, Grymonprez A, Burtonboy G, Francois A, Cornu G. Disseminated BCG in HIV infection. Arch Dis Child 1988;63:1268-9. 32. Quinn TC, Piot P, McCormick JB, Feinsod FM, Taelman H, Kapita B, et al. Serologic and immunologic studies in patients with AIDS in North America and Africa. The potential role of infectious agents as cofactors in human immunodeficiency virus infection. JAMA 1987;257:2617-21. 33. Clements CJ, von Reyn CF, Mann JM. HIV infection and routine childhood immunisation: a review. Bull World Health Organ 1987;65:905-11. 34. Rodrigues LC, Diwan VK, Wheeler JG. Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis. Int J Epidemiol 1993;22:1154-8. 35. Arbelaez MP, Nelson KE, Munoz A. BCG vaccine effectiveness in preventing tuberculosis and its interaction with human immunodeficiency virus infection. Int J Epidemiol 2000;29:1085-91. 36. Global programme for vaccines and immunisation. Immunisation Policy. Geneva: World Health Organization.; 1996.p.1-51. 37. Clerici, Shrearer GM. A TH1→TH2 switch is a critical step in the etiology of HIV infection. Immunol Today 1993;14:10711. 38. Del Amo J, Malin AS, Pozniak A, De Cock KM. Does tuberculosis accelerate the progression of HIV disease? Evidence from basic science and epidemiology. AIDS 1999;913:1151-8. 39. Toossi Z, Sierra-Madero JG, Blinkhorn RA, Mettler MA, Rich EA. Enhanced susceptibility of blood monocytes from

40. 41.

42.

43.

44.

45. 46.

47.

48. 49. 50.

51.

52. 53.

54.

55.

56.

patients with pulmonary tuberculosis to productive infection with human immunodeficiency virus type 1. J Exp Med 1993;177:1511-6. Orme IM, Andersen P, Boom WH. T cell response to Mycobacterium tuberculosis. J Infect Dis 1993;167:1481-97. Orme IM. The dynamics of infection following BCG and Mycobacterium tuberculosis challenge in T-cell-deficient mice. Tubercle 1987;68:277-83. Orme IM. Characteristics and specificity of acquired immunologic memory to Mycobacterium tuberculosis infection. J Immunol 1988;140:3589-93. Cooper AM, Flynn JL. The protective immune response to Mycobacterium tuberculosis. Curr Opin Immunol 1995;7: 512-6. Flynn JL, Chan J, Triebold KJ, Dalton DK, Steward TA, Bloom BR. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med 1993;178: 2249-54. Kaufmann SH. CD8+ T lymphocytes in intracellular microbial infections. Immunol Today 1988;9:168-74. Schaible UE, Kaufmann SH. CD1 molecules and CD1dependent T cells in bacterial infections: a link from innate to acquired immunity? Semin Immunol 2000;12:527-35. Janis EM, Kaufmann SH, Schwartz RH, Pardoll DM. Activation of gamma delta T cells in the primary immune response to Mycobacterium tuberculosis. Science 1989;244: 713-6. Flynn JL, Chan J. Immunology of tuberculosis. Annu Rev Immunol 2001;19:93-129. Ulrichs T, Kaufmann SH. New insights into the function of granulomas in human tuberculosis. J Pathol 2006;208:261-9. Turner OC, Basaraba RJ, Orme IM. Immunopathogenesis of pulmonary granulomas in the guinea pig after infection with Mycobacterium tuberculosis. Infect Immun 2003;71:864-71. Kaplan G, Post FA, Moreira AL, Wainwright H, Kreiswirth BN, Tanverdi M, et al. Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity. Infect Immun 2003;71:7099-108. Lenzini L, Rottoli P, Rottoli L. The spectrum of human tuberculosis. Clin Exp Immunol 1977;27:230-7. Cohen MK, Bartow RA, Mintzer CL, McMurray DN. Effects of diet and genetics on Mycobacterium bovis BCG vaccine efficacy in inbred guinea pigs. Infect Immun 1987;55:314-9. McMurray DN, Mintzer CL, Bartow RA, Parr RL. Dietary protein deficiency and Mycobacterium bovis BCG affect interleukin-2 activity in experimental pulmonary tuberculosis. Infect Immun 1989;57:2606-11. Bartow RA, McMurray DN. Erythrocyte receptor [CD2]bearing T lymphocytes are affected by diet in experimental pulmonary tuberculosis. Infect Immun 1990;58:1843-7. McMurray DN, Carlomagno MA, Mintzer CL, Tetzlaff CL. Mycobacterium bovis BCG vaccine fails to protect proteindeficient guinea pigs against respiratory challenge with virulent Mycobacterium tuberculosis. Infect Immun 1985; 50:555-9.

Tuberculosis Vaccine Development: Current Status and Future Expectations 57. Walsh GP, Tan EV, dela Cruz EC, Abalos RM, Villahermosa LG, Young LJ, et al. The Philippine cynomolgus monkey [Macaca fasicularis] provides a new nonhuman primate model of tuberculosis that resembles human disease. Nat Med 1996;2:430-6. 58. Thoen CO, Richards WD, Jarnagin JL. Mycobacteria isolated from exotic animals. J Am Vet Med Assoc 1977;170:987-90. 59. Thorel MF. Isolation of Mycobacterium africanum from monkeys. Tubercle 1980;61:101-4. 60. West CS, Vainisi SJ, Vygantas CM, Beluhan FZ. Intraocular granulomas associated with tuberculosis in primates. J Am Vet Med Assoc 1981;179:1240-4. 61. Fourie PB, Odendaal MW. Mycobacterium tuberculosis in a closed colony of baboons [Papio ursinus]. Lab Anim 1983;17:125-8. 62. Bontrop RE, Otting N, de Groot NG, Doxiadis GG. Major histocompatibility complex class II polymorphisms in primates. Immunol Rev 1999;167:339-50. 63. Geluk A, Elferink DG, Slierendregt BL, van Meijgaarden KE, de Vries RR, Ottenhoff TH, et al. Evolutionary conservation of major histocompatibility complex-DR/peptide/T cell interactions in primates. J Exp Med 1993;177:979-87. 64. Porcelli S, Morita CT, Brenner MB. CD1b restricts the response of human CD4-8- T lymphocytes to a microbial antigen. Nature 1992;360:593-7. 65. Shinkai K, Locksley RM. CD1, tuberculosis, and the evolution of major histocompatibility complex molecules. J Exp Med 2000;191:907-14. 66. Behar SM, Dascher CC, Grusby MJ, Wang CR, Brenner MB. Susceptibility of mice deficient in CD1D or TAP1 to infection with Mycobacterium tuberculosis. J Exp Med 1999;189:197380. 67. Desrosiers RC. The simian immunodeficiency viruses. Annu Rev Immunol 1990;8:557-78. 68. Letvin NL. Animal models for AIDS. Immunol Today 1990;11:322-6. 69. Shen Y, Zhou D, Chalifoux L, Shen L, Simon M, Zeng X, et al. Induction of an AIDS virus-related tuberculosis-like disease in macaques: a model of simian immunodeficiency virusmycobacterium coinfection. Infect Immun 2002;70:869-77. 70. Flynn JL, Capuano SV, Croix D, Pawar S, Myers A, Zinovik A, et al. Non-human primates: a model for tuberculosis research. Tuberculosis [Edinb] 2003;83:116-8. 71. Langermans JA, Andersen P, van Soolingen D, Vervenne RA, Frost PA, van der Laan T, et al. Divergent effect of bacillus Calmette-Guerin [BCG] vaccination on Mycobacterium tuberculosis infection in highly related macaque species: implications for primate models in tuberculosis vaccine research. Proc Natl Acad Sci USA 2001;98:11497-502. 72. Kita Y, Tanaka T, Yoshida S, Ohara N, Kaneda Y, Kuwayama S, et al. Novel recombinant BCG and DNA-vaccination against tuberculosis in a cynomolgus monkey model. Vaccine 2005;23:2132-5. 73. Okada M, Tanaka T, Inoue Y, et al. New [DNA-rBCG-and Subunit-] vaccination against tuberculosis. In: Thirty-sixth [US–JAPAN] tuberculosis and leprosy research conference; 2001.p.127–32.

939

74. Langermans JA, Doherty TM, Vervenne RA, van der Laan T, Lyashchenko K, Greenwald R, et al. Protection of macaques against Mycobacterium tuberculosis infection by a subunit vaccine based on a fusion protein of antigen 85B and ESAT6. Vaccine 2005;23:2740-50. 75. Comstock GW. Epidemiology of tuberculosis. Am Rev Respir Dis 1982;125:8-15. 76. Skamene E. Genetic control of resistance to mycobacterial infection. Curr Top Microbiol Immunol 1986;124:49-66. 77. Baily GV. Tuberculosis prevention Trial, Madras. Indian J Med Res 1980;[72 Suppl]: 1-74. 78. Rodrigues LC, Noel Gill O, Smith PG. BCG vaccination in the first year of life protects children of Indian subcontinent ethnic origin against tuberculosis in England. J Epidemiol Community Health 1991;45:78-80. 79. Allen S, Batungwanayo J, Kerlikowske K, Lifson AR, Wolf W, Granich R, et al. Two-year incidence of tuberculosis in cohorts of HIV-infected and uninfected urban Rwandan women. Am Rev Respir Dis 1992;146:1439-44. 80. Markowitz N, Hansen NI, Hopewell PC, Glassroth J, Kvale PA, Mangura BT, et al. Incidence of tuberculosis in the United States among HIV-infected persons. Ann Intern Med 1997;126:123-32. 81. Selwyn PA, Sckell BM, Alcabes P, Friedland GH, Klein RS, Schoenbaum EE. High risk of active tuberculosis in HIVinfected drug users with cutaneous anergy. JAMA 1992;268:504-9. Erratum in: JAMA 1992;268:3434. 82. Philip CH, Robert MJ. Overview of clinical tuberculosis. In: Cole ST, Eisenach KD, McMurray DN, Jacobs WR Jr, editors. Tuberculosis and the tubercle bacillus. Wsahington DC: AMS Press; 2005.p.15-31. 83. Hotez PJ, Molyneux DH, Fenwick A, Ottesen E, Ehrlich Sachs S, Sachs JD. Incorporating a rapid-impact package for neglected tropical diseases with programmmes for HIV/ AIDS, tuberculosis and malaria. PLoS Med 2006;3:e102. 84. Borkow G, Weisman Z, Leng Q, Stein M, Kalinkovich A, Wolday D, et al. Helminths, human immunodeficiency virus and tuberculosis. Scand J Infect Dis 2001;33:568-71. 85. Elias D, Akuffo H, Pawlowski A, Haile M, Schon T, Britton S. Schistosoma mansoni infection reduces the protective efficacy of BCG vaccination against virulent Mycobacterium tuberculosis. Vaccine 2005;23:1326-34. 86. Kremer K, Glynn JR, Lillebaek T, Niemann S, Kurepina NE, Kreiswirth BN, et al. Definition of the Beijing/W lineage of Mycobacterium tuberculosis on the basis of genetic markers. J Clin Microbiol 2004;42:4040-9. 87. Castanon-Arreola M, Lopez-Vidal Y, Espitia-Pinzon C, Hernandez-Pando R. A new vaccine against tuberculosis shows greater protection in a mouse model with progressive pulmonary tuberculosis. Tuberculosis [Edinb] 2005;85:11526. 88. Comstock GW. Identification of an effective vaccine against tuberculosis. Am Rev Respir Dis 1988;138:479-80. 89. ten dam HG. BCG vaccination. In: Reichman LB, Hershfield ES, editors. Tuberculosis: a comprehensive international approach. New York: Marcel Dekker; 1993.p.251-69.

940

Tuberculosis

90. Rosenthal SR, Loewinsohn E, Graham ML, Liveright D, Thorne MG, Johnson V, et al. BCG vaccination against tuberculosis in Chicago: a twenty-year study statistically analysed. Pediatrics 1961;28:622-41. 91. Fleischmann RD, Alland D, Eisen JA, Carpenter L, White O, Peterson J, et al. Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. J Bacteriol 2002;184:5479-90. 92. Li L, Bannantine JP, Zhang Q, Amonsin A, May BJ, Alt D, et al. The complete genome sequence of Mycobacterium avium subspecies paratuberculosis. Proc Natl Acad Sci U S A 2005;102:12344-9. 93. Pathogen genomics. Available at the URL: http:// www.sanger.ac.uk/Projects/Pathogens/. Accessed on October 13, 2008. 94. Behr MA, Wilson MA, Gill WP, Salamon H, Schoolnik GK, Rane S, et al. Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 1999;284:1520-3. 95. Camacho LR, Ensergueix D, Perez E, Gicquel B, Guilhot C. Identification of a virulence gene cluster of Mycobacterium tuberculosis by signature-tagged transposon mutagenesis. Mol Microbiol 1999;34:257-67. 96. Cox JS, Chen B, McNeil M, Jacobs WR Jr. Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice. Nature 1999;402:79-83. 97. McKinney JD, Honer zu Bentrup K, Munoz-Elias EJ, Miczak A, Chen B, Chan WT, et al. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 2000;406:735-8. 98. Wards BJ, de Lisle GW, Collins DM. An esat6 knockout mutant of Mycobacterium bovis produced by homologous recombination will contribute to the development of a live tuberculosis vaccine. Tuber Lung Dis 2000;80:185-9. 99. Sassetti CM, Boyd DH, Rubin EJ. Comprehensive identification of conditionally essential genes in mycobacteria. Proc Natl Acad Sci USA 2001;98:12712-7. 100. Smith E, Thybo S, Bennedsen J. Infection with Mycobacterium bovis in a patient with AIDS: a late complication of BCG vaccination. Scand J Infect Dis 1992;24:109-10. 101. Andersen P, Smedegaard B. CD4+ T-Cell subsets that mediate immunological memory to Mycobacterium tuberculosis infection in mice. Infect Immun 2000;68:621-9. 102. Andersen P, Andersen AB, Sorensen AL, Nagai S. Recall of long-lived immunity to Mycobacterium tuberculosis infection in mice. J Immunol 1995;154:3359-72. 103. Ohara N, Yamada T. Recombinant BCG vaccines. Vaccine 2001;19:4089-98. 104. DasGupta SK, Jain S, Kaushal D, Tyagi AK. Expression systems for study of mycobacterial gene regulation and development of recombinant BCG vaccines. Biochem Biophys Res Commun 1998;246:797-804. 105. Jain S, Kaushal D, DasGupta SK, Tyagi AK. Construction of shuttle vectors for genetic manipulation and molecular analysis of mycobacteria. Gene 1997;190:37-44.

106. Stover CK, de la Cruz VF, Bansal GP, Hanson MS, Fuerst TR, Jacobs WR Jr, et al. Use of recombinant BCG as a vaccine delivery vehicle. Adv Exp Med Biol 1992;327:175-82. 107. Jacobs WR Jr, Tuckman M, Bloom BR. Introduction of foreign DNA into mycobacteria using a shuttle plasmid. Nature 1987;327:532-5. 108. Snapper SB, Lugosi L, Jekkel A, Melton RE, Kieser T, Bloom BR, et al. Lysogeny and transformation in mycobacteria: stable expression of foreign genes. Proc Natl Acad Sci USA 1988;85:6987-91. 109. Dhar N, Rao V, Tyagi AK. Recombinant BCG approach for development of vaccines: cloning and expression of immunodominant antigens of M. tuberculosis. FEMS Microbiol Lett 2000;190:309-16. 110. Matsuo K, Yamaguchi R, Yamazaki A, Tasaka H, Terasaka K, Totsuka M, et al. Establishment of a foreign antigen secretion system in mycobacteria. Infect Immun 1990;58:4049-54. 111. Stover CK, Bansal GP, Hanson MS, Burlein JE, Palaszynski SR, Young JF, et al. Protective immunity elicited by recombinant bacille Calmette-Guerin [BCG] expressing outer surface protein A [OspA] lipoprotein: a candidate Lyme disease vaccine. J Exp Med 1993;178:197-209. 112. Fennelly GJ, Flynn JL, ter Meulen V, Liebert UG, Bloom BR. Recombinant bacille Calmette-Guerin priming against measles. J Infect Dis 1995;172:698-705. 113. Harboe M, Wiker HG. Searching for secreted proteins of Mycobacterium leprae. Indian J Lepr 1999;71:19-35. 114. Horwitz MA, Harth G, Dillon BJ, Maslesa-Galic’ S. Recombinant bacillus Calmette-Guerin [BCG] vaccines expressing the Mycobacterium tuberculosis 30-kDa major secretory protein induce greater protective immunity against tuberculosis than conventional BCG vaccines in a highly susceptible animal model. Proc Natl Acad Sci USA 2000;97:13853-8. 115. Rao V, Dhar N, Shakila H, Singh R, Khera A, Jain R, et al. Increased expression of Mycobacterium tuberculosis 19 kDa lipoprotein obliterates the protective efficacy of BCG by polarising host immune responses to the Th2 subtype. Scand J Immunol 2005;61:410-7. 116. Pym AS, Brodin P, Brosch R, Huerre M, Cole ST. Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines Mycobacterium bovis BCG and Mycobacterium microti. Mol Microbiol 2002;46:709-17. 117. Kong D, Kunimoto DY. Secretion of human interleukin 2 by recombinant Mycobacterium bovis BCG. Infect Immun 1995;63:799-803. 118. O’Donnell MA, Aldovini A, Duda RB, Yang H, Szilvasi A, Young RA, et al. Recombinant Mycobacterium bovis BCG secreting functional interleukin-2 enhances gamma interferon production by splenocytes. Infect Immun 1994;62:2508-14. 119. Murray PJ, Aldovini A, Young RA. Manipulation and potentiation of antimycobacterial immunity using recombinant bacille Calmette-Guerin strains that secrete cytokines. Proc Natl Acad Sci USA 1996;93:934-9.

Tuberculosis Vaccine Development: Current Status and Future Expectations 120. Wangoo A, Brown IN, Marshall BG, Cook HT, Young DB, Shaw RJ. Bacille Calmette-Guerin [BCG]-associated inflammation and fibrosis: modulation by recombinant BCG expressing interferon-gamma [IFN-gamma]. Clin Exp Immunol 2000;119:92-8. 121. Luo Y, Chen X, Han R, O’Donnell MA. Recombinant bacille Calmette-Guerin [BCG] expressing human interferon-alpha 2B demonstrates enhanced immunogenicity. Clin Exp Immunol 2001;123:264-70. 122. Stover CK, de la Cruz VF, Fuerst TR, Burlein JE, Benson LA, Bennett LT, et al. New use of BCG for recombinant vaccines. Nature 1991;351:456-60. 123. Hess J, Miko D, Catic A, Lehmensiek V, Russell DG, Kaufmann SH. Mycobacterium bovis bacille Calmette-Guerin strains secreting listeriolysin of Listeria monocytogenes. Proc Natl Acad Sci USA 1998;95:5299-304. 124. Sampson SL, Dascher CC, Sambandamurthy VK, Russell RG, Jacobs WR Jr, Bloom BR, et al. Protection elicited by a double leucine and pantothenate auxotroph of Mycobacterium tuberculosis in guinea pigs. Infect Immun 2004;72:3031-7. 125. Mahairas GG, Sabo PJ, Hickey MJ, Singh DC, Stover CK. Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M. bovis. J Bacteriol 1996;178:1274-82. 126. Sambandamurthy VK, Jacobs WR Jr. Live attenuated mutants of Mycobacterium tuberculosis as candidate vaccines against tuberculosis. Microbes Infect 2005;7:955-61. 127. Collins DM, Kawakami RP, de Lisle GW, Pascopella L, Bloom BR, Jacobs WR Jr. Mutation of the principal sigma factor causes loss of virulence in a strain of the Mycobacterium tuberculosis complex. Proc Natl Acad Sci USA 1995;92:803640. 128. Jackson M, Phalen SW, Lagranderie M, Ensergueix D, Chavarot P, Marchal G, et al. Persistence and protective efficacy of a Mycobacterium tuberculosis auxotroph vaccine. Infect Immun 1999;67:2867-73. 129. Smith DA, Parish T, Stoker NG, Bancroft GJ. Characterization of auxotrophic mutants of Mycobacterium tuberculosis and their potential as vaccine candidates. Infect Immun 2001;69:142-50. 130. Chambers MA, Williams A, Gavier-Widén D, Whelan A, Hall G, Marsh PD, et al. Identification of a Mycobacterium bovis BCG auxotrophic mutant that protects guinea pigs against M. bovis and hematogenous spread of Mycobacterium tuberculosis without sensitization to tuberculin. Infect Immun 2000;68:7094-9. 131. Hondalus MK, Bardarov S, Russell R, Chan J, Jacobs WR Jr, Bloom BR. Attenuation of and protection induced by a leucine auxotroph of Mycobacterium tuberculosis. Infect Immun 2000;68:2888-98. 132. Pavelka MS, Chen B, Kelley CL, Collins FM, Jacobs WR Jr. Vaccine efficacy of a lysine auxotroph of Mycobacterium tuberculosis. Infect Immun 2003;71:4190-2. 133. Sambandamurthy VK, Derrick SC, Jalapathy KV, Chen B, Russell RG, Morris SL, et al. Long-term protection against

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144. 145.

146.

941

tuberculosis following vaccination with a severely attenuated double lysine and pantothenate auxotroph of Mycobacterium tuberculosis. Infect Immun 2005;73:1196-203. McKinney JD, Honer zu Bentrup K, Munoz-Elias EJ, Miczak A, Chen B, Chan WT, et al. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 2000;406:735-8. Pethe K, Alonso S, Biet F, Delogu G, Brennan MJ, Locht C, et al. The heparin-binding haemagglutinin of M. tuberculosis is required for extrapulmonary dissemination. Nature 2001;412:190-4. Collins DM, Kawakami RP, de Lisle GW, Pascopella L, Bloom BR, Jacobs WR Jr. Mutation of the principal sigma factor causes loss of virulence in a strain of the Mycobacterium tuberculosis complex. Proc Natl Acad Sci USA 1995;92:803640. Berthet FX, Lagranderie M, Gounon P, Laurent-Winter C, Ensergueix D, Chavarot P, et al. Attenuation of virulence by disruption of the Mycobacterium tuberculosis erp gene. Science1998;282:759-62. Singh R, Rao V, Shakila H, Gupta R, Khera A, Dhar N, et al. Disruption of mptpB impairs the ability of Mycobacterium tuberculosis to survive in guinea pigs. Mol Microbiol 2003;50:751-62. Singh A, Gupta R, Vishwakarma RA, Narayanan PR, Paramasivan CN, Ramanathan VD, et al. Requirement of the mymA operon for appropriate cell wall ultrastructure and persistence of Mycobacterium tuberculosis in the spleens of guinea pigs. J Bacteriol 2005;187:4173-86. Hart PD, Sutherland I. BCG and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early adult life. Br Med J 1977;2:293-5. Manabe YC, Scott CP, Bishai WR. Naturally attenuated, orally administered Mycobacterium microti as a tuberculosis vaccine is better than subcutaneous Mycobacterium bovis BCG. Infect Immun 2002;70:1566-70. Stanford JL, Bahr GM, Bypass P, Corrah T, Dowlati Y, Lucas S, et al. A modern approach to the immunotherapy of tuberculosis. Bull Int Union Tuberc Lung Dis 1990;65:27-9. Onyebujoh PC, Abdulmumini T, Robinson S, Rook GA, Stanford JL. Immunotherapy with Mycobacterium vaccae as an addition to chemotherapy for the treatment of pulmonary tuberculosis under difficult conditions in Africa. Respir Med 1995;89:199-207. Stanford JL, Grange JM. The promise of immunotherapy for tuberculosis. Respir Med 1994;88:3-7. Skinner MA, Yuan S, Prestidge R, Chuk D, Watson JD, Tan PL. Immunisation with heat-killed Mycobacterium vaccae stimulates CD8+ cytotoxic T-cells specific for macrophages infected with Mycobacterium tuberculosis. Infect Immun 1997;65:4525-30. Abou-Zeid C, Gares MP, Inwald J, Janssen R, Zhang Y, Young DB, et al. Induction of a type 1 immune response to a recombinant antigen from Mycobacterium tuberculosis expressed in Mycobacterium vaccae. Infect Immun 1997;65: 1856-62.

942

Tuberculosis

147. Chaturvedi V, Srivastava A, Gupta HP, Srivastava BS. Protective antigens of Mycobacterium habana are distributed between peripheral and integral compartments of plasma membrane: a study in experimental tuberculosis of mouse. Vaccine 1999;17:2882-7. 148. Prem Raj P, Srivastava S, Jain SK, Srivastava BS, Srivastava R. Protection by live Mycobacterium habana vaccine against Mycobacterium tuberculosis H37Rv challenge in mice. Indian J Med Res 2003;117:139-45. 149. Singh IG, Mukherjee R, Talwar GP. Resistance to intravenous inoculation of Mycobacterium tuberculosis H37Rv in mice of different inbred strains following immunisation with a leprosy vaccine based on Mycobacterium w. Vaccine 1991;9:10-4. 150. Talwar GP. An immunotherapeutic vaccine for multibacillary leprosy. Int Rev Immunol 1999;18:229-49. 151. Katoch K, Katoch VM, Natrajan M, Sreevatsa, Gupta UD, Sharma VD, et al. 10-12 years follow-up of highly bacillated BL/LL leprosy patients on combined chemotherapy and immunotherapy. Vaccine 2004;22:3649-57. 152. Hakenberg J, Nussbaum AK, Schild H, Rammensee HG, Kuttler C, Holzhutter HG, et al. MAPPP: MHC class I antigenic peptide processing prediction. Appl Bioinformatics 2003;2:155-8. 153. Doherty TM, Andersen P. Vaccines for tuberculosis: novel concepts and recent progress. Clin Microbiol Rev 2005;18:687702. 154. Doherty TM, Demissie A, Olobo J, Wolday D, Britton S, Eguale T, et al. Immune responses to the Mycobacterium tuberculosis-specific antigen ESAT-6 signal subclinical infection among contacts of tuberculosis patients. J Clin Microbiol 2002;40:704-6. 155. Brandt L, Elhay M, Rosenkrands I, Lindblad EB, Andersen P. ESAT-6 subunit vaccination against Mycobacterium tuberculosis. Infect Immun 2000;68:791-5. 156. Ulrich JT, Myers KR. Monophosphoryl lipid A as an adjuvant. Past experiences and new directions. Pharm Biotechnol 1995;6:495-524. 157. Fynan EF, Webster RG, Fuller DH, Haynes JR, Santoro JC, Robinson HL. DNA vaccines: protective immunisations by parenteral, mucosal, and gene-gun inoculations. Proc Natl Acad Sci U S A 1993;90:11478-82. 158. Raz E, Watanabe A, Baird SM, Eisenberg RA, Parr TB, Lotz M, et al. Systemic immunological effects of cytokine genes injected into skeletal muscle. Proc Natl Acad Sci USA 1993;90:4523-7. 159. Ulmer JB, Donnelly JJ, Parker SE, Rhodes GH, Felgner PL, Dwarki VJ, et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 1993;259:1745-9. 160. Lozes E, Huygen K, Content J, Denis O, Montgomery DL, Yawman AM, et al. Immunogenicity and efficacy of a tuberculosis DNA vaccine encoding the components of the secreted antigen 85 complex.Vaccine 1997;15:830-3.

161. Tascon RE, Colston MJ, Ragno S, Stavropoulos E, Gregory D, Lowrie DB. Vaccination against tuberculosis by DNA injection. Nat Med 1996;2:888-92. 162. Kamath AT, Feng CG, Macdonald M, Briscoe H, Britton WJ. Differential protective efficacy of DNA vaccines expressing secreted proteins of Mycobacterium tuberculosis. Infect Immun 1999;67:1702-7. 163. Tanghe A, Lefevre P, Denis O, D’Souza S, Braibant M, Lozes E, et al. Immunogenicity and protective efficacy of tuberculosis DNA vaccines encoding putative phosphate transport receptors. J Immunol 1999;162:1113-9. 164. Vipond J, Vipond R, Allen-Vercoe E, Clark SO, Hatch GJ, Gooch KE, et al. Selection of novel TB vaccine candidates and their evaluation as DNA vaccines against aerosol challenge. Vaccine 2006;24:6340-50. 165. Lowrie DB, Tascon RE, Bonato VL, Lima VM, Faccioli LH, Stavropoulos E, et al. Therapy of tuberculosis in mice by DNA vaccination. Nature 1999;400:269-71. 166. Erb KJ, Kirman J, Woodfield L, Wilson T, Collins DM, Watson JD, et al. Identification of potential CD8+ T-cell epitopes of the 19 kDa and AhpC proteins from Mycobacterium tuberculosis. No evidence for CD8+ T-cell priming against the identified peptides after DNA-vaccination of mice. Vaccine 1998;16:692-7. 167. Derrick SC, Yang AL, Morris SL. A polyvalent DNA vaccine expressing an ESAT6-Ag85B fusion protein protects mice against a primary infection with Mycobacterium tuberculosis and boosts BCG-induced protective immunity. Vaccine 2004;23:780-8. 168. Luo XD, Zhu DY, Chen Q, Jiang Y, Jiang S, Yang C. A study of the protective effect of the DNA vaccine encoding tubercle antigen 85B with MPT64 in mice challenged with Mycobacterium tuberculosis. Zhonghua Jie He He Hu Xi Za Zhi 2004;27:611-6. 169. van Drunen Littel-van den Hurk S, Babiuk SL, Babiuk LA. Strategies for improved formulation and delivery of DNA vaccines to veterinary target species. Immunol Rev 2004;199: 113-25. 170. Roy MJ, Wu MS, Barr LJ, Fuller JT, Tussey LG, Speller S, et al. Induction of antigen-specific CD8+ T cells, T helper cells, and protective levels of antibody in humans by particlemediated administration of a hepatitis B virus DNA vaccine. Vaccine 2000;19:764-78. 171. Denis O, Tanghe A, Palfliet K, Jurion F, van den Berg TP, Vanonckelen A, et al. Vaccination with plasmid DNA encoding mycobacterial antigen 85A stimulates a CD4+ and CD8+ T-cell epitopic repertoire broader than that stimulated by Mycobacterium tuberculosis H37Rv infection. Infect Immun 1998;66:1527-33. 172. Boesen H, Jensen BN, Wilcke T, Andersen P. Human T-cell responses to secreted antigen fractions of Mycobacterium tuberculosis. Infect Immun 1995;63:1491-7. 173. Vordermeier HM, Harris DP, Friscia G, Roman E, Surcel HM, Moreno C, et al. T-cell repertoire in tuberculosis: selective anergy to an immunodominant epitope of the 38-kDa antigen in patients with active disease. Eur J Immunol 1992;22: 2631-7.

Tuberculosis Vaccine Development: Current Status and Future Expectations 174. McMurry J, Sbai H, Gennaro ML, Carter EJ, Martin W, De Groot AS. Analyzing Mycobacterium tuberculosis proteomes for candidate vaccine epitopes. Tuberculosis 2005;85:95-105. 175. De Groot AS, McMurry J, Marcon L, Franco J, Rivera D, Kutzler M, et al. Developing an epitope-driven tuberculosis [TB] vaccine. Vaccine 2005;23:2121-31. 176. Caccamo N, Meraviglia S, La Mendola C, Bosze S, Hudecz F, Ivanyi J, et al. Characterization of HLA-DR- and TCR-binding residues of an immunodominant and genetically permissive peptide of the 16-kDa protein of Mycobacterium tuberculosis. Eur J Immunol 2004;34:2220-9. 177. Vordemeier HM, Harris DP, Roman E, Lathigra R, Moreno C, Ivanyi J. Identification of T cell stimulatory peptides from the 38-kDa protein of Mycobacterium tuberculosis. J Immunol 1991;147:1023-9. 178. da Fonseca DP, Joosten D, van der Zee R, Jue DL, Singh M, Vordermeier HM, et al. Identification of new cytotoxic T-cell epitopes on the 38-kilodalton lipoglycoprotein of Mycobacterium tuberculosis by using lipopeptides. Infect Immun 1998;66:3190-7. 179. Silver RF, Wallis RS, Ellner JJ. Mapping of T cell epitopes of the 30-kDa alpha antigen of Mycobacterium bovis strain bacillus Calmette-Guerin in purified protein derivative [PPD]-positive individuals. J Immunol 1995;154:4665-74. 180. Lee BY, Horwitz MA. T-cell epitope mapping of the three most abundant extracellular proteins of Mycobacterium tuberculosis in outbred guinea pigs. Infect Immun 1999;67:2665-70. 181. D’Souza S, Rosseels V, Romano M, Tanghe A, Denis O, Jurion F, et al. Mapping of murine Th1 helper T-Cell epitopes of mycolyl transferases Ag85A, Ag85B, and Ag85C from Mycobacterium tuberculosis. Infect Immun 2003;71:483-93. 182. Mohagheghpour N, Gammon D, Kawamura LM, van Vollenhoven A, Benike CJ, Engleman EG. CTL response to Mycobacterium tuberculosis: identification of an immunogenic epitope in the 19-kDa lipoprotein. J Immunol 1998;161:2400-6. 183. Olsen AW, Hansen PR, Holm A, Andersen P. Efficient protection against Mycobacterium tuberculosis by vaccination with a single subdominant epitope from the ESAT-6 antigen. Eur J Immunol 2000;30:1724-32. 184. Charo J, Geluk A, Sundback M, Mirzai B, Diehl AD, Malmberg KJ, et al. The identification of a common pathogenspecific HLA class I A0201-restricted cytotoxic T cell epitope encoded within the heat shock protein 65. Eur J Immunol 2001;31:3602-11. 185. Tollefsen S, Pollock JM, Lea T, Harboe M, Wiker HG. T- and B-cell epitopes in the secreted Mycobacterium bovis antigen MPB70 in mice. Scand J Immunol 2003;57:151-61. 186. Al-Attiyah R, Shaban FA, Wiker HG, Oftung F, Mustafa AS. Synthetic peptides identify promiscuous human Th1 cell epitopes of the secreted mycobacterial antigen MPB70. Infect Immun 2003;71:1953-60. 187. Shams H, Barnes PF, Weis SE, Klucar P, Wizel B. Human CD8+ T cells recognize epitopes of the 28-kDa hemolysin and

188.

189.

190.

191.

192.

193.

194.

195.

196. 197.

198. 199.

200.

943

the 38-kDa antigen of Mycobacterium tuberculosis. J Leukoc Biol 2003;74:1008-14. Al-Attiyah R, Mustafa AS. Computer-assisted prediction of HLA-DR binding and experimental analysis for human promiscuous Th1-cell peptides in the 24 kDa secreted lipoprotein [LppX] of Mycobacterium tuberculosis. Scand J Immunol 2004;59:16-24. Suzuki M, Aoshi T, Nagata T, Koide Y. Identification of murine H2-Dd- and H2-Ab-restricted T-cell epitopes on a novel protective antigen, MPT51, of Mycobacterium tuberculosis. Infect Immun 2004;72:3829-37. Caccamo N, Meraviglia S, Dieli F, Romano A, Titone L, Salerno A. Th0 to Th1 switch of CD4 T cell clones specific from the 16-kDa antigen of Mycobacterium tuberculosis after successful therapy: lack of involvement of epitope repertoire and HLA-DR. Immunol Lett 2005;98:253-8. Chaitra MG, Hariharaputran S, Chandra NR, Shaila MS, Nayak R. Defining putative T cell epitopes from PE and PPE families of proteins of Mycobacterium tuberculosis with vaccine potential. Vaccine 2005;23:1265-72. Tala-Heikkila MM, Tuominen JE, Tala EO. Bacillus CalmetteGuerin revaccination questionable with low tuberculosis incidence. Am J Respir Crit Care Med 1998;157:1324-7. Leung CC, Tam CM, Chan SL, Chan-Yeung M, Chan CK, Chang KC. Efficacy of the BCG revaccination programme in a cohort given BCG vaccination at birth in Hong Kong. Int J Tuberc Lung Dis 2001;5:717-23. Buddle BM, Wedlock DN, Parlane NA, Corner LA, De Lisle GW, Skinner MA. Revaccination of neonatal calves with Mycobacterium bovis BCG reduces the level of protection against bovine tuberculosis induced by a single vaccination. Infect Immun 2003;71:6411-9. Basaraba RJ, Izzo AA, Brandt L, Orme IM. Decreased survival of guinea pigs infected with Mycobacterium tuberculosis after multiple BCG vaccinations. Vaccine 2006;24:280-6. McShane H. Prime-boost immunisation strategies for infectious diseases. Curr Opin Mol Ther 2002;4:23-7.. Estcourt MJ, Ramsay AJ, Brooks A, Thomson SA, Medveckzy CJ, Ramshaw IA. Prime-boost immunisation generates a high frequency, high-avidity CD8[+] cytotoxic T lymphocyte population. Int Immunol 2002;14:31–7. Woodland DL. Jump-starting the immune system: primeboosting comes of age. Trends Immunol 2004;25:98-104. Goonetilleke NP, McShane H, Hannan CM, Anderson RJ, Brookes RH, Hill AV. Enhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette-Guerin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus Ankara. J Immunol 20031;171:1602-9. Williams A, Goonetilleke NP, McShane H, Clark SO, Hatch G, Gilbert SC, et al. Boosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigs. Infect Immun 2005;73:3814-6.

944

Tuberculosis

201. McShane H, Pathan AA, Sander CR, Goonetilleke NP, Fletcher HA, Hill AV. Boosting BCG with MVA85A: the first candidate subunit vaccine for tuberculosis in clinical trials. Tuberculosis [Edinb] 2005;85:47-52. 202. Brooks JV, Frank AA, Keen MA, Bellisle JT, Orme IM. Boosting vaccine for tuberculosis. Infect Immun 2001;69:2714-7. 203. Mollenkopf HJ, Grode L, Mattow J, Stein M, Mann P, Knapp B, et al. Application of mycobacterial proteomics to vaccine design: improved protection by Mycobacterium bovis BCG prime-Rv3407 DNA boost vaccination against tuberculosis. Infect Immun 2004;72:6471-9. 204. Wang QM, Sun SH, Hu ZL, Yin M, Xiao CJ, Zhang JC. Improved immunogenicity of a tuberculosis DNA vaccine encoding ESAT6 by DNA priming and protein boosting. Vaccine 2004;22:3622-7. 205. Brandt L, Feino CJ, Weinreich OA, Chilima B, Hirsch P, Appelberg R, et al. Failure of the Mycobacterium bovis BCG vaccine: some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis. Infect Immun 2002;70:672-8. 206. Barnes PF, Cave MD. Molecular epidemiology of tuberculosis. N Engl J Med 2003;349:1149-56. 207. Tomioka H. Adjunctive immunotherapy of mycobacterial infections. Curr Pharm 2004;10:3297-312. 208. Condos R, Rom WN, Schluger NW. Treatment of multidrugresistant pulmonary tuberculosis with interferon-gamma via aerosol. Lancet 1997;349:1513-5. 209. Giosue S, Casarini M, Ameglio F, Zangrilli P, Palla M, Altieri AM, et al. Aerosolized interferon-alpha treatment in patients with multi-drug-resistant pulmonary tuberculosis. Eur Cytokine Netw 2000;11:99-104. 210. Raad I, Hachem R, Leeds N, Sawaya R, Salem Z, Atweh S. Use of adjunctive treatment with interferon-gamma in an immunocompromised patient who had refractory multidrugresistant tuberculosis of the brain. Clin Infect Dis 1996;22: 572-4. 211. Hovav AH, Fishman Y, Bercovier H. Gamma interferon and monophosphoryl lipid A-trehalose dicorynomycolate are efficient adjuvants for Mycobacterium tuberculosis multivalent acellular vaccine. Infect Immun 2005;73:250-7. 212. Johnson BJ, Bekker LG, Rickman R, Brown S, Lesser M, Ress S, et al. rhuIL-2 adjunctive therapy in multidrug resistant tuberculosis: a comparison of two treatment regimens and placebo. Tuber Lung Dis 1997;78:195-203. 213. Johnson JL, Ssekasanvu E, Okwera A, Mayanja H, Hirsch CS, Nakibali JG, et al. Randomized trial of adjunctive interleukin2 in adults with pulmonary tuberculosis. Am J Respir Crit Care Med 2003;168:185-91. 214. Ha SJ, Jeon BY, Youn JI, Kim SC, Cho SN, Sung YC. Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis. Gene Ther 2005;12:634-8. 215. Silva CL, Bonato VL, Coelho-Castelo AA, De Souza AO, Santos SA, Lima KM, et al. Immunotherapy with plasmid DNA encoding mycobacterial hsp65 in association with

216.

217. 218.

219. 220.

221.

222.

223.

224.

225.

226.

227.

228.

chemotherapy is a more rapid and efficient form of treatment for tuberculosis in mice. Gene Ther 2005;12:281-7. Mwinga A, Nunn A, Ngwira B, Chintu C, Warndorff D, Fine P, et al. Mycobacterium vaccae [SRL172] immunotherapy as an adjunct to standard antituberculosis treatment in HIVinfected adults with pulmonary tuberculosis: a randomized placebo-controlled trial. Lancet 2002;360:1050-5. Etemadi A, Farid R, Stanford JL. Immunotherapy for drugresistant tuberculosis. Lancet 1992;340:1360-1. Johnson JL, Nunn AJ, Fourie PB, Ormerod LP, Mugerwa RD, Mwinga A, et al. Effect of Mycobacterium vaccae [SRL172] immunotherapy on radiographic healing in tuberculosis. Int J Tuberc Lung Dis 2004;8:1348-54. Huebner RE, Schein MF, Bass JB Jr.. The tuberculin skin test. [Review]. Clin Infect Dis 1993;17:968-75. Al Zahrani K, Al Jahdali H, Menzies D. Does size matter? Utility of size of tuberculin reactions for the diagnosis of mycobacterial disease. Am J Respir Crit Care Med 2000;162: 1419-22. Duffey PS, Guthertz LS, Evans GC. Improved rapid identification of mycobacteria by combining solid-phase extraction with high-performance liquid chromatography analysis of BACTEC cultures. J Clin Microbiol 1996;34:1939-43. McFadden JJ, Kunje Z, Seechum P. DNA probes for detection and identification. In: McFaden J, editor. Molecular biology of the mycobacteria. UK: Surrey University Press 1990.p.13972. Katoch VM, Kanujia GV, Shivannavar CT, Katoch K, Sharma VD, Patil MA, et al. Progress in developing ribosomal RNA and rRNA gene[s] based probes for diagnosis and epidemiology of infectious diesase specially leprosy. In: Kumar S, Sen AK, Dutta GP, Sharma RN, editors. Tropical diseases: molecular biology and control strategies. New Delhi: Council for Scientific and Industrial Research; 1994.p.581-7. Kaminski DA, Hardy DJ. Selective utilisation of DNA probes for identification of Mycobacterium species on the basis of cord formation in primary BACTEC 12B cultures. J Clin Microbiol 1995;33:1548-50. Sharma RK, Katoch K, Shivannavar CT, Sharma VD, Patil MA, Natarajan M, et al. Comparisons of sensitivity of probes targeting RNA vs DNA in leprosy cases. Indian J Med Microbiol 1996;14:99-104. Suffys PN, da Silva Rocha A, de Oliveira M, Campos CE, Barreto AM, Portaels F, et al. Rapid identification of Mycobacteria to the species level using INNO-LiPA Mycobacteria, a reverse hybridization assay. J Clin Microbiol 2001;39:447782. Ruiz P, Gutierrez J, Zerolo FJ, Casal M. GenoType mycobacterium assay for identification of mycobacterial species isolated from human clinical samples by using liquid medium. J Clin Microbiol2002;40:3076-8. Telenti A, Imboden P, Marchesi F, Schmidheini T, Bodmer T. Direct, automated detection of rifampin-resistant Mycobacterium tuberculosis by polymerase chain reaction and single-strand conformation polymorphism analysis. Antimicrob Agents Chemother 1993;37:2054-8.

Tuberculosis Vaccine Development: Current Status and Future Expectations 229. Goyal M, Ormerod LP, Shaw RJ. Epidemiology of an outbreak of drug-resistant tuberculosis in the U.K. using restriction fragment length polymorphism. Clin Sci [Lond] 1994;86:749-51. 230. Dobner P, Feldmann K, Rifai M, Loscher T, Rinder H. Rapid identification of mycobacterial species by PCR amplification of hypervariable 16S rRNA gene promoter region. J Clin Microbiol 1996;34:866-9. 231. Roth A, Reischl U, Streubel A, Naumann L, Kroppenstedt RM, Habicht M, et al. Novel diagnostic algorithm for identification of mycobacteria using genus-specific amplification of the 16S-23S rRNA gene spacer and restriction endonucleases. J Clin Microbiol 2000;38:1094-104. 232. Rogall T, Flohr T, Bottger EC. Differentiation of Mycobacterium species by direct sequencing of amplified DNA. J Gen Microbiol 1990;136:1915-20. 233. Lyashchenko K, Manca C, Colangeli R, Heijbel A, Williams A, Gennaro ML. Use of Mycobacterium tuberculosis complex-specific antigen cocktails for a skin test specific for tuberculosis. Infect Immun 1998;66:3606-10. 234. Campos-Neto A, Rodrigues-Junior V, Pedral-Sampaio DB, Netto EM, Ovendale PJ, Coler RN, et al. Evaluation of DPPD, a single recombinant Mycobacterium tuberculosis protein as an alternative antigen for the Mantoux test. Tuberculosis [Edinb] 2001;81:353-8. 235. Lalvani A, Nagvenkar P, Udwadia Z, Pathan AA, Wilkinson KA, Shastri JS, et al. Enumeration of T cells specific for RD1encoded antigens suggests a high prevalence of latent Mycobacterium tuberculosis infection in healthy urban Indians. J Infect Dis 2001;183:469-77. 236. Liu XQ, Dosanjh D, Varia H, Ewer K, Cockle P, Pasvol G, et al. Evaluation of T-cell responses to novel RD1- and RD2encoded Mycobacterium tuberculosis gene products for specific detection of human tuberculosis infection. Infect Immun 2004;72:2574-81. 237. Heifets L, Desmond E. Clinical mycobacteriology [tuberculosis] laboratory: services and methods. In: Cole S T, Eisenach KD, McMurray DN, Jacobs WR Jr, editors. Tuberculosis and the tubercle bacillus. Washington:ASM Press; 2005.p.49-69. 238. Kaufmann SH, McMichael AJ. Annulling a dangerous liaison: vaccination strategies against AIDS and tuberculosis. Nat Med 2005;11[4 suppl]:S33-44. 239. Izzo A, Brandt L, Lasco T, Kipnis AP, Orme I. NIH pre-clinical screening programme: overview and current status. Tuberculosis 2005;85:25-8. 240. Williams A, Hatch GJ, Clark SO, Gooch KE, Hatch KA, Hall GA, et al. Evaluation of vaccines in the EU TB Vaccine Cluster using a guinea pig aerosol infection model of tuberculosis. Tuberculosis 2005;85:29-38. 241. Researchers create blueprint for tuberculosis vaccine development. Available at the URL: http://www3.niaid.nih.gov/ news/newsreleases/2000/tbblueprint.htm. Accessed on October 13, 2008. 242. McShane H, Pathan AA, Sander CR, Keating SM, Gilbert SC, Huygen K, et al. Recombinant modified vaccinia virus Ankara

243.

244.

245.

246.

247.

248.

249.

250.

251.

252.

253.

254.

255.

945

expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nat Med 2004;10:1240-4. Grode L, Seiler P, Baumann S, Hess J, Brinkmann V, Nasser Eddine A, et al. Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille CalmetteGuerin mutants that secrete listeriolysin. J Clin Invest 2005;115:2472-9. Skeiky YA, Alderson MR, Ovendale PJ, Guderian JA, Brandt L, Dillon DC, et al. Differential immune responses and protective efficacy induced by components of a tuberculosis polyprotein vaccine, Mtb72F, delivered as naked DNA or recombinant protein. J Immunol 2004;172:7618-28. Agger EM, Rosenkrands I, Olsen AW, Hatch G, Williams A, Kritsch C, et al. Protective immunity to tuberculosis with Ag85B-ESAT-6 in a synthetic cationic adjuvant system IC31. Vaccine 2006;24:5452-60. Epub 2006 Apr 17. Langermans JA, Doherty TM, Vervenne RA, van der Laan T, Lyashchenko K, Greenwald R, et al. Protection of macaques against Mycobacterium tuberculosis infection by a subunit vaccine based on a fusion protein of antigen 85B and ESAT6. Vaccine 2005;23:2740-50. Santosuosso M, McCormick S, Zhang X, Zganiacz A, Xing Z. Intranasal boosting with an adenovirus-vectored vaccine markedly enhances protection by parenteral Mycobacterium bovis BCG immunization against pulmonary tuberculosis. Infect Immun 2006;74:4634-43. Aeras Global TB Vaccine Foundation. Our portfolio of vaccine candidates. Available at URL: http://www.aeras.org/ourapproach/vaccine-development.php. Accessed on October 12, 2008. O’Reilly LM, Daborn CJ. The epidemiology of Mycobacterium bovis infections in animals and man: a review. Tuber Lung Dis 1995;76[Suppl1]:1-46. Elasabban MS, Lofty O, Awad WM, Soufi HS, Mikhail DG, Hamman HM, et al. Bovine tuberculosis and its extent of spread as a source of infection to man and animals in the Arab Republic of Egypt. International Union Against Tuberculosis and Lung Disease–Conferencia sobre Tuberculosis Animal en África y el Medio Este, Cairo, Egipto,1992;p198211. Nafeh MA, Medhat A, Abdul-Hameed AG, Ahmad YA, Rashwan NM, Strickland GT. Tuberculous peritonitis in Egypt: the value of laparoscopy in diagnosis. Am J Trop Med Hyg 1992;47:470-7. Idigbe EO, Anyiwo CE, Onwujekwe DI. Human pulmonary infections with bovine and atypical mycobacteria in Lagos, Nigeria. J Trop Med Hyg 1986;89:143-8. Idrisu A, Schnurrenberger P. Public health significance of bovine tuberculosis in four northern states of Nigeria: a mycobacteriologic study. Nige Med J 1977;7:384-7. Barrera L, de Kantor IN. Nontuberculous mycobacteria and Mycobacterium bovis as a cause of human disease in Argentina. Trop Geogr Med 1987;39:222-7. Ritacco V, de Kantor IN. Zoonotic tuberculosis in Latin America. J Clin Microbiol. 1992;30:12:3299-3300.

946

Tuberculosis

256. Gervois M, Vaillant JM, Fontaine JF, Laroche G, Dubois G. Epidemiology of the human infection due to Mycobacterium bovis. Arch Monaldi 1972;27:294-317. 257. Cosivi O, Grange JM, Daborn CJ, Raviglione MC, Fujikura T, Cousins D, et al. Zoonotic tuberculosis due to Mycobacterium bovis in developing countries. Emerg Infect Dis 1998;4: 59-70. 258. Shah NP, Singhal A, Jain A, Kumar P, Uppal SS, Srivatsava MV, et al. Occurrence of overlooked zoonotic tuberculosis: detection of Mycobacterium bovis in human cerebrospinal fluid. J Clin Microbiol 2006;44:1352-8. 259. Dupon M, Ragnaud JM. Tuberculosis in patients infected with human immunodeficiency virus 1. A retrospective multicentre study of 123 cases in France. Q J Med 1992;306:719-30. 260. Mishra A, Singhal A, Chauhan DS, Katoch VM, Srivastava K, Thakral SS, et al. Direct detection and identification of Mycobacterium tuberculosis and Mycobacterium bovis in bovine samples by a novel nested PCR assay: correlation with conventional techniques. J Clin Microbiol 2005;43:5670-78. 261. Pavlik I, Ayele WY, Parmova I, Melicharek I, Hanzlikova M, Körmendy B, et al. Mycobacterium tuberculosis in animal and human populations in six Central European countries during 1990-1999. Veterinarni Medicina 2003;48:83-9.

262. Margot AS, Bryce MB, Neil WD, Denise K, Geoffrey WL, Ricardo ET, et al. A DNA Prime-Mycobacterium bovis BCG boost vaccination strategy for cattle induces protection against bovine tuberculosis. Infect Immun 2003;71:4901-7. 263. Vordermeier HM, Rhodes SG, Dean G, Goonetilleke N, Huygen K, Hill AV, et al. Cellular immune responses induced in cattle by heterologous prime-boost vaccination using recombinant viruses and bacille Calmette-Guérin. Immunology 2004;112:461-70. 264. Cai H, Tian X, Hu XD, Li SX, Yu DH, Zhu YX. Combined DNA vaccines formulated either in DDA or in saline protect cattle from Mycobacterium bovis infection. Vaccine 2005; 23:3887-95. 265. Walshe MJ, Grindle J, Nell A, Bachmann M. Dairy development in sub-Saharan Africa. African Technical Department Series. World Bank Technical Paper No. 135. Washington: World Bank; 1991; 266. Barrera L, De Kantor IN. Nontuberculous mycobacteria and Mycobacterium bovis as a cause of human disease in Argentina. Trop Geogr Med 1987;39:222-27. 267. Gilbert M, Mitchell A, Bourn D, Mawdsley J, Clifton-Hadley R, Wint W. Cattle movements and bovine tuberculosis in Great Britain. Nature 2005;435:491.

Ethical and Legal Issues in Tuberculosis Control 947

Ethical and Legal Issues in Tuberculosis Control

65 John Porter

Scientific thought succumbed because it violated the first law of culture, which says that the more man controls anything, the more uncontrollable both become Tyler SA (1) INTRODUCTION In the early years of the twenty-first century, increasing links are being made between communities, countries and continents. There are more opportunities for us to witness life in other places and to view and review our own structures and perceptions of the way we live and to learn from people of different cultures and religions. This new ‘internationalism’ brings with it increasing ‘complexity’ and an added importance for each of us to review our own beliefs and perceptions in order to allow increasing co-operation and understanding. In the field of public health, there are discussions aimed at widening the scope of health care beyond the treatment of diseases, like tuberculosis [TB], to a broader concept of ‘the creation of health’; that health is an entity that communities and societies have the opportunity of developing (2). This broader perception uses biomedical health care concepts and systems, but adds to them by including other disciplines, like anthropology, environmental sciences, ethics and human rights. It is anticipated that the result of this fusion, created through interdisciplinary work, will be a change in biomedicine’s perception of health and health care. Now, those of us working in TB control have an opportunity to view our control measures from different perspectives. Perhaps it is time to take note of the quotation at the beginning of the chapter and to consider whether the current control

methods for TB are violating the first law of culture, and therefore, making TB more uncontrollable. Is this why we have an increasing international problem with multidrug-resistant TB [MDR-TB] and extensively drugresistant TB [XDR-TB]? The field of ethics, because it is to do with questions about ‘how we ought to live’ (3), provides a framework which is included in the other disciplines which address health care issues and is also a useful tool for creating a framework with which to untangle the dilemmas that occur around the treatment and ‘control’ of people with TB. The morality of the individual is intimately connected with the ethics of the medical and public health fraternity and both of these entities also link with the legal profession and the law [Figure 65.1]. The law and the legal

Figure 65.1: Ethics and the law

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system provide a framework within a society to ‘assist and protect people’ (4); protecting the rights of individuals but at the same time protecting the rights of institutions and organizations, like professional medical bodies. The basic function of the law is to establish legal rights, and the basic purpose of the legal system is to define and enforce these rights (5). Ethics is not separate from the law, it is an integral part of the legal system and how laws are made and enforced. This chapter looks at TB control from the perspectives of ethics and law. It begins with an introduction to the two disciplines and then applies them to the current international strategy for TB control. The ‘ethical’ issues of TB are addressed through highlighting the potential problems for a TB patient who is seeking care through the health care system [relationship with the health care worker and interaction with the health care system etc.,]. The legal issues concentrate on groups of people at high risk for TB [e.g., alcoholics, prisoners, etc.,] to try to untangle the legal problems. Examples from India, the United States and the United Kingdom are used to provide the context for the discussion. BACKGROUND Public Health and Tuberculosis The control of infectious diseases is an important part of public health policy. In most countries, TB control is the responsibility of public health departments. Public health is ‘the science and art of preventing disease, prolonging life and promoting health through the organized efforts of society’ (6). A more succinct definition comes from the Institute of Medicine in the United States, which says that public health is ‘what we, as a society, do to assure the conditions for people to be healthy’ (7). Both definitions imply an imperative to balance the needs of the individual with the needs of the population in the control of infectious diseases. Inherent in this, as in all balances, is a tension, and this tension often engenders debate and even conflict between decision makers. The framework of ethics can assist in developing a course of action to resolve these conflicts by providing clarification of the questions and a system for weighing alternatives through ethical debate (8). During the past one hundred and fifty years, scientific structure and discourse have framed the development of technological medicine which has produced

sophisticated treatments and medications to treat illnesses, like TB. From the time that, Koch discovered the tubercle bacillus in 1882, there has been an understanding that TB is caused by Mycobacterium tuberculosis and that destroying the bacillus with drugs would provide an appropriate treatment. With the development of streptomycin and the subsequent development of other antituberculosis drugs, shortcourse chemotherapy [SCC] was developed; a solution for controlling TB worldwide had been found (9). However, by the early 1990s, there were signs of increasing TB cases in all countries associated with the movement of people from high to low TB prevalence countries, the increasing spectre of human immunodeficiency virus [HIV] infection and acquired immunodeficiency syndrome [AIDS], and decreasing funds to support public health infrastructures to control TB (9). In the early 1990s, the World Health Organization [WHO] developed the DOTS strategy to try to improve the uptake of TB control measures around the world, particularly in order to combat the increasing problem of MDR-TB. The strategy includes: government commitment to a national programme; case detection through ‘passive’ case-finding [sputum smear microscopy for pulmonary TB suspects]; SCC for all smearpositive pulmonary TB cases [under direct observation for at least the initial phase of treatment]; regular, uninterrupted supply of all essential antituberculosis drugs; and a monitoring system for programme supervision and evaluation (10,11). The international strategy for controlling TB, has been developed from a science base and has been created from many disciplines including medicine, epidemiology and the basic science. Now, however, with several new TB drug and vaccine candidates, which are in various stages of trials and testing, the health care fraternity is having to look at the basic human behavioural issues in TB control. The issues of how individual patients interact with health care systems, and in particular, how they interact with health care workers (12,13). For a person to complete their six months of antituberculosis treatment, they need to be supported and cared for and this requires strong health systems. This is a basic function of health care provision but one which has been increasingly neglected with the rise of the rapid technological approaches to treating disease. Are the current TB control methods consistent with the broad public health agenda

Ethical and Legal Issues in Tuberculosis Control 949 of preventing disease and promoting health? Is there sufficient emphasis on the care of TB patients in order to promote or create health? All of these questions become increasingly difficult and complex with the increase in prevalence of HIV in communities and its link with TB (14). Infectious Disease Control and Tuberculosis Methods for the control of infectious diseases have been developed principally through the study of epidemiology. The perspectives of biomedical scientists have dominated thinking in this area, and the control methods currently used reflect this focus. Epidemiologists look at the interaction between the agent, host and environment, and the main strategies for control are to attack the source [e.g., the treatment or isolation of cases and carriers]; to interrupt transmission [e.g., environmental and personal hygiene, vector control]; or to protect the susceptible population [e.g., immunization, chemoprophylaxis] [Table 65.1] (15). The categories, attacking the source and protecting the susceptible population, both relate to the treatment of patients. Attacking the source refers to the treatment of a case of disease: the patient is treated [a benefit to him or her] and the population is protected from being infected by him [a benefit to the population]. A person with infectious pulmonary TB needs to be treated not only for his or her benefit but also for the benefit of the public health, to prevent further transmission of Mycobacterium tuberculosis to others. Protecting the Table 65.1: Main strategies for control of infectious disease Attack source

Interrupt transmission

Protect susceptible people

Treatment of cases and carriers

Environmental hygiene

Immunization

Isolation of cases

Personal hygiene

Chemoprophylaxis

Surveillance of suspects

Vector control

Personal protection

Control of animal reservoir

Disinfection and sterilization

Better nutrition

Notification of cases

Restrict population movements

Adapted from reference 12

–

susceptible population requires the use of medication to prevent the development of a disease [treatment of latent TB infection]. The four principle methods for controlling TB are stated to be: the improvement of socio-economic conditions, case-finding and treatment, chemoprophylaxis and bacille Calmette-Guérin [BCG] vaccination (16). Although the improvement of socio-economic conditions undoubtedly has a major impact on TB (17), in public health terms TB control focusses on finding infectious cases [sputum positive] and treating them so that they are no longer infectious to others. This is the method for disrupting transmission, it concentrates on the individual with the aim of treating the person and protecting the community from further infection and disease. As has already been mentioned, the current international TB control strategy is DOTS. Part of the strategy is direct observation of treatment [DOT] which has been established to prevent the development of drug-resistant strains of TB. The ‘direct observation’ component of the strategy introduces ethical issues around the right to ‘control’ individuals with TB, in order to protect the majority [community]. But is case finding and treatment sufficient? Although it makes scientific and logical sense to concentrate on infectious TB cases, are there not other social, environmental and economic issues that need to be considered? What about structural interventions for example? Structural factors within the field of human immunodeficiency virus [HIV] infection have been broadly defined as physical, social, cultural, organizational, community, economic, legal or policy aspects of the environment that impede or facilitate persons’ efforts to avoid infection (18). With the increasing complexity of health care, the requests for a broad perception of health, and with the increasing inter-disciplinary nature of public health work, there is an opportunity to re-evaluate the current control measures. Are these control measures for TB appropriate? Are they sensitive to the needs of people with TB? Can they be improved to ensure the rights and dignity of all patients? ETHICS When one speaks of ethics, one might be speaking from one or a combination of three mutually interconnected perspectives: [i] the study of ethics; [ii] the adherence to ethical guidelines laid down by governments and professional bodies; and [iii] the application of ethical

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principles in daily life (19). The ethical process is not a once-and-for-all, nor a once-in-a while pursuit. On the contrary it forms part of our day-to-day interactions and is an integral part of our public health interventions (19). In the study of ethics, philosophers develop theories about the interaction between moral values and the ways in which societies operate. Morals—the values and norms that frame societies’ ideas about ‘right’ and ‘wrong’— are inherently cultural constructions. All cultures and societies have moral codes, but because these are culturally and historically contingent, they shift and change over time. The work of moral philosophers both reflects and to some extent informs this process. With the increasing co-operation and collaboration between countries in public health research, this cultural and historical contingency is important to understand. People’s perceptions and understanding of TB, ethics and the law, are framed by the cultural values and historical background of the society in which they live. The moral construct used in some societies is seen as ‘absolute’; for example, certain religious texts dictate the ‘way the community ought to live’, whereas in others, moral values are seen as ‘relative’ and more flexible, being seen to be different according to the context of the situation in which the ethical dilemma arises. Each community needs to be understood in terms of its history and cultural values. Ethics in the West In the western industrialized world, there has been a shift in moral thinking from absolute to relative values: from a deonotological model of ethics to a utilitarian model. The utilitarian theories suggest that answers to moral questions on right and wrong depend solely on the nature of the consequences of those actions or proposed actions, whereas deontology relates to moral rules not related to consequences, from the Greek word deon meaning duty (20). Although to some extent framed within the Judaic Christian religious traditions, the ethical theories and models developed in the west attempt to be ahistorical, abstract and formal. It has been argued that the ‘utilitarian’ structure has emerged with the growth of technology in the North (21). If one accepts Bell’s definition of technology as ‘the effort to transform nature for utilitarian purposes’ (21,22), one may then step back for a moment and look at the profound social and moral dilemmas inherent in this

phenomenon. When applied to health one consequence of the ‘utilitarian’ approach is the generation of interventions which are geared towards maximising majority over individual benefit (19). Ethics in the East It is difficult to locate the Eastern tradition in the historical, abstract and formal theories of ethics that have been developed in the West. Ethics in the East is framed by the religions of Islam, Hinduism and Buddhism as well as many others. In the Brahmanical-Hindu and Jaina traditions for example, it is recognized that ethics is the ‘soul’ of the complex spiritual and moral aspirations of the people, co-mingled with social and political structures forged over a vast period of time. This accounts for the cultures profuse literature in wisdom, legends, epics, liturgical texts, legal and political treatises. There are a variety of ethical systems within the Hindu tradition, but the tradition itself contains within it a diverse collection of social, cultural, religious and philosophical systems (23). The highest good is identified with the total harmony of the cosmic or natural order, characterized as rita: this is the creative purpose that circumscribes human behaviour. The social and moral order is, thus, seen as a correlate of the natural order. This is the ordered course of things, the truth of being or reality [sat] and hence the ‘Law’ (24). The convergence of the cosmic and the moral orders is universally commended in the all-embracing category of dharma, which becomes more or less the Indian analogue for ethics (23). What counts as ‘ethics’ then although in appearance naturalistic, is largely normative; the justification usually is that this is the ‘divined’ ordering of things, and hence, there is a tendency also to view the moral law as absolute. Ethics Principles and Tasks In the development of international guidelines for the control of infectious diseases like TB, the western philosophical model tends to dominate the process. There is, however, continuing research to try to develop an appropriate set of international ethical principles (25). In 1994 at the 38th Council for International Organizations of Medical Sciences [CIOMS] Conference in Ixtapa, a declaration was issued describing the emergence of bioethics as a global and multilayered enterprise and ‘the need to continue to work towards an ethics of health

Ethical and Legal Issues in Tuberculosis Control 951 which calls on us to consider the interconnections among all of our choices and actions that affect the health status of people anywhere’ [CIOMS, Declaration of Ixtapa] (26,27). There have been suggestions as to how ethics can be used in practice to assist with ethical dilemmas in medicine and public health. Beaufort and Dupuis (28) have suggested that the ethical process might be used to: [i] clarify concepts, [ii] analyse and structure arguments, [iii] weigh alternatives; and [iv] provide advice on an “appropriate” course of action. Another way of looking at ethical argument is that it can assist us to identify the obstacles that prevent us from acting “morally”. Once these obstacles have been identified, it is easier to find ways of overcoming them. As human beings we are moral agents: we interact daily with our family, friends, colleagues and acquaintances, and these interactions are framed by the values and norms that prevail in our society. By going to our jobs, taking care of our families and talking to our neighbours, we are acting as engaged participants in our moral community. As health care workers we are moral agents, too. In this we do not stop engaging with our moral community, but we expand the boundaries of that community: at this level we also interact with our professional ethics and with the legal system of the wider society (29). The four principles which currently dominate international bio-ethical debate are: respect for autonomy, beneficence, non-maleficence and justice (30). These principles-plus attention to their scope [i.e., how and to whom they apply] provide the basis for a rigorous consideration and resolution of ethical dilemmas. Although they do not provide “rules”, these principles can help public health workers make decisions when moral issues arise. In effect they make a common set of moral commitments, a common moral language, and a common set of moral issues (20) more visible and more accessible. These principles are considered to be prima facie: they are binding unless they conflict with other moral principles. They are outlined briefly below. Autonomy Autonomy, “self-rule”, although perceived differently in different cultures, is an attribute of all moral agents. Autonomy gives one the ability to make decisions on the basis of deliberation. Autonomy is also reciprocal: we

have a moral obligation to respect the autonomy of others as long as it is compatible with equal respect for the autonomy of all those potentially affected. According to the Western philosopher Kant, respect for autonomy means ‘treating others as ends in themselves and never merely as means’ to some [externally defined] end (20). The person with TB is an autonomous individual, a decision maker, and the decisions that they make about their treatment should be respected not only by the health care worker with whom they are interacting but also by the health care system that is providing the treatment. The quality of the relationship between the patient and the health care provider is a key to the provision of appropriate TB treatment. Beneficence and Non-maleficence There is always a need to balance the effort to help and the risk of causing harm. The traditional Hippocratic moral obligation of medicine is to provide beneficence with non-maleficence: net medical benefit to patients with minimal harm. Once again, the relationship between the health care provider and the patient determines whether there is a net benefit to the TB patient. It is also important to remember, however, that the health care provider will be more able to provide support and be beneficent to the person with TB if they are appropriately supported in their job by the organization or system that employs them. So, although the relationship between health care worker and the patient is important, the relationship of the health care worker with their employer is also part of the process of ensuring beneficent and non-maleficent care. Justice Justice refers to the moral obligation to act on the basis of fair adjudication between competing claims. Equality is at the heart of justice, but as Aristotle argued, justice is more than mere equality—people can be treated unjustly even if they are treated equally (31). Equity entails treating no portion of the population in a disproportionate manner. Inequity, then, is a descriptive term used to denote existing differences between groups or individuals in the distribution of or access to resources. However, inequity also denotes the reasons behind and responsibilities for underlying conditions of inequality. As such, it is inherently a statement of justice (32).

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People with TB need to be treated fairly and justly. If a community wishes to prevent the spread of TB, patients need to have access to a health care structure that provides them with treatment and care. This access needs to be available to all TB patients equally. The Application of Ethics in Public Health Little has been written in regard to moral issues in public health (33) or the application of ethics to public health decision making. In 1980, Shindell (34) suggested that a public health intervention should: [i] relate to a wellunderstood disease aetiology; [ii] be feasible; and [iii] entail only an appropriate trade-off of the rights of the individual against the benefits that accrue to the population. It is the third point that leads to moral debate and a tension between public health and civil liberties. In infectious disease control, interventions usually relate to diseases with a well-understood aetiology. The feasibility of a particular intervention will depend on the details of the disease outbreak [location, numbers, demographic character of people involved, etc.,] and the possibility of using standard control measures to intervene. In TB control, the aetiology of the disease is fairly well understood, the intervention [case finding and treatment] is feasible and there is an accepted [taken for granted] trade-off between the rights of the individual and the benefits of the population. Public health interventions tend to embody an imbalance of power and capacity between the implementers and the recipients. Public health professionals decide when and where to intervene, and normally what the intervention will consist of. It is presumed that whatever “harm” the intervention may impose on individuals is out-weighed by the “good” it will bring to the population as a whole. This form of practice does not exemplify respect for the autonomy of the people at the receiving end of the intervention (35,36). Hall (36) has argued that although individuals surrender some degree of personal freedom in exchange for membership of a society, ‘individual autonomy remains to some degree’. He (36) states that this residual autonomy is not addressed within public health and suggests that the utilitarian support for the practice of public health must be subordinated to the deontological rights of the individual. Within liberal democracies it is generally accepted that the state may intervene when the exercise of one

person’s freedom may result in harm to another (8). This is known as the ‘harm principle.’ The nineteenth century philosopher John Stuart Mill defined this principle in the following way: ‘The only purpose for which power can be rightfully exercised over any member of a civilized community, against his will, is to prevent harm to others. His own good, either physical or moral, is not a sufficient warrant’ (37). This principle provides the ethical and legal foundation for establishing public health programmes designed to require those with communicable diseases to behave in ways that are likely to reduce the risk of transmission. THE LAW What is It and What does It do? The values that are contained within a community help to define the legal statutes that are created. Ethics and the law are intimately connected [Figure 65.1]. The legal system in every country is unique, although it may use certain structures or processes, like ‘common law’, as a foundation (5). It is useful to have a working definition of the law to assist with the legal issues that pertain to TB control. Wing (5), from the United States, states that the law is ‘the sum or set or conglomerate of all of the laws in all of the jurisdictions: the constitutions, the statutes and the regulations that interpret them, the traditional principles known as common law, and the judicial opinions that apply and interpret all these legal rules and principles’. Wing (5) argues that the law is also the legal profession and the legal process – legislatures and their politics and finally ‘the law is what it is interpreted to be’. The basic function of the law is to establish legal rights, and the basic purpose of the legal system is to define and enforce those rights. Legal rights are the relationships that establish privileges and responsibilities among those governed by the legal system. Finally, some rights are protected, not by statute or regulation, but by an understanding and application of the prevailing ethics in an area. In general, ethics are regulated through whatever sanctions are imposed against censured behaviour by peers or colleagues. These statements underlie the essential link between ethics and the law, but, ‘it is normally accepted that ethics are something more than the law’ (38).

Ethical and Legal Issues in Tuberculosis Control 953 Legislation for Infectious Disease Control in the United States and United Kingdom Surveillance of infectious diseases began in the United States in 1874 in Massachusetts, when the State Board of Health instituted the first state-wide voluntary plan for weekly reporting of the prevalence of diseases by physicians. By the turn of the century, the forerunners of the Public Health Service had been established, and laws in all states required that certain communicable diseases be reported to local authorities (39). During the period 1940 to 1970, states added many diseases to their mandatory lists. Even in states that did not enact legislation to require additional reporting, surveillance and reporting efforts were broadened during this period through state regulation or directives from the state health commissioners (40). In the United Kingdom, the Infectious Disease Notification Act of 1988 amended the Infectious Disease [Notification] Extension Act of 1899 which required compulsory nation-wide notification of certain infectious diseases [but not TB]. In England and Wales, this list was re-enacted with modifications on a number of occasions and the current ‘notifiable diseases’ are contained in section 10 of the Public Health [Control of Disease] Act of 1984. Notification of TB is contained in Schedule 1 of the 1988 Regulations. The law for infectious diseases has two parts: surveillance and control; with control being further subdivided into control of the environment [in its widest sense to include premises and articles] and control of people. The control of actions by people is contained in both the 1984 Act and the 1988 Regulations, and the powers are wide ranging, from exclusion to incarceration. Section 10 of the 1984 Act allows the proper officer of any district to request any person to discontinue work ‘with a view to preventing the spread’ of TB and if they fail to do so, this may be an offence under section 19 of the 1984 Act. Under the powers contained in section 32[1][a] a person can be requested to leave his or her residence and under section 32[1][b] compulsory removal can be effected, under a court order, to alternative accommodation when any infectious disease occurs in a house. In addition, provisions are included in the 1984 Act to allow compulsory removal to and incarceration in a hospital if the person is considered a serious risk (41).

Legislation for the control of diseases like TB can have a range of ‘control’ measures, from ‘an order to complete treatment’, to ‘an order for detention while infectious’ (42). In New York City in 1993, the health code was revised to permit ‘compulsory actions to protect the public health’ in relation to TB (42). The types of regulatory action included: order for examination for suspected TB as out-patient or in detention; order to complete treatment; order for DOT; written warning of possible detention; order for detention while infectious; order for detention while non-infectious; discharge from detention before cure [for non-infectious patient] (43). Legislation in India In India, health regulation is a responsibility of each state. The central government has some authority but the laws are created through the state legislature; each state can make and enforce its own laws. Central government can also develop health legislation but has to depend solely on each state to enforce it. Just before independence in 1948, the Bhore committee (44) produced recommendations on health laws including statements on the control of infectious diseases. While showing great concern for the measures required to prevent and combat the spread of diseases between provinces, it made recommendations for giving the central government some legal powers in line with those existing in the United States at the time. Public Health Acts were recommended for the central as well as state governments to bring together existing legal provisions relating to health, to modify sections of the laws which required change in the interest of promoting efficient administration and to incorporate new provisions necessary for the health programmes recommended by the Bhore Committee. However, in keeping with the government policy of doing as little legislation in the field of health as possible, such a consolidated act was never adopted (38). TUBERCULOSIS CONTROL - ETHICAL ISSUES The following section looks at the ethical issues and dilemmas within the treatment and control of a person with TB. It focusses on the interaction between the patient and the health care provider, the interaction of the patient with the health care system, and on the separate stages of TB treatment from the problems of access to the

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systems established for monitoring and follow-up. Many of the ethical questions that arise in the control of TB are to do with relationship, particularly the relationship between the patient and the health care provider whether that person be a nurse, physician, community worker or manager; but also the broader interaction of the patient with the overall health structure. In public health decision making, there is always the issue of balancing the rights of the individual versus the rights of the population. Each of us is inextricably linked to the community in which we live and what happens to us affects the wider community. Our individual morality is interlinked with the ethics of the public health system [in this case the TB control programme] and with the laws of the state [Figure 65.2]. In the case of TB control, the biomedical model has established that a person with sputum positive TB is infectious to others, and is therefore, capable of transmitting the infection with the risk of the development of TB disease. However, it is important to remember that the determinants of risk for TB are personal, societal and programmatic [Figure 65.3]. The main ethical issue, therefore, in TB control is the perspective on this balance between the individual, and the community in which she or he lives; the balance between accepting the autonomy of the individual versus the process of justice and equity. The official process of justice in a society is provided through the legal system which through the law courts provides a structure for people to be heard and also develops the laws to govern and protect the

Figure 65.3: Determinants of risk of tuberculosis

society. ‘The law is there to assist and protect people’ (4). It can be argued that in the case of TB, the rights of the individual are justifiably sacrificed for the overall good of the population (45). As stated above, however, ethics demands a balance: while infected people have a right to be treated with dignity, worth, value and respect, they have a duty not to spread the infection to others (46). Relationship of a Tuberculosis Patient with the Health Care Provider A patient with TB wants both to understand what is wrong with them and to receive treatment. A person with a persistent cough will seek advice from members of their community who they know to have knowledge of health and disease. In some places this person will be the local traditional healer, in others it will be a physician practising in the private or government health system. The relationship that is developed with this person and with the health care system to which they belong will dictate how the person is treated and whether they are treated with dignity and respect. The whole ‘context’ of where a person comes from, their socio-economic conditions and level of education is essential for the health care worker to understand. Without an attempt to understand the patient’s perspective, health care providers will be unable to provide an appropriate service. How far does the person have to travel to come to the health facility? Can they afford to come? What is their job and how is it being affected by their illness? How can the health care worker provide a relationship of trust? Compliance and Adherence

Figure 65.2: Ethics of tuberculosis control programme, law and morality

Compliance can be defined as the extent to which a person’s health related behaviour coincides with medical

Ethical and Legal Issues in Tuberculosis Control 955 advice (47). When seeking care patients carry out their own “cost-benefit analyses”, balancing out their understandings of the severity of the illness, its impacts on their family members and their ability to obtain access to treatment, against the other conflicting priorities and demands of daily life. Patients with acute TB tend to comply with treatment because of the desire to get well and to be free from troubling symptoms of fever, cough and night sweats. Compliance after the initial phase of treatment, when the patient feels well, is more difficult to ensure. The balance of benefits and priorities has shifted from an immediate benefit to the patient to a more abstract [from the patient’s perspective] benefit to the community. From the patient’s point of view the “costs” of staying on treatment once symptoms have disappeared may well out-weigh the benefits, which must be difficult to assess. Thus, while the “failure” of patients to comply with maintenance therapy may appear to be irrational from the physicians’ or health care workers’ perspective, it is intelligible when seen from the patient’s point of view (48). Ethically, compliance relates to the interaction between the autonomy of the TB patient and the beneficence of the health care worker. Although health care workers may be trying to ‘do good’ and to avoid harm to the patient, however, they have difficulty acting as independent moral agents because they are participants in a health structure, and are therefore, bound to uphold the ethics of that structure [Figure 65.2]. As members of professional organizations and players in TB programmes, they are expected to conduct themselves in a particular manner, to follow the regulations of the programme, and to encourage patients to take and complete their treatment until cured. Cure is the goal, the outcome measure, which health care worker are obliged to bring about. But there is a danger inherent in this process. At some stage the health care worker’s compliance to the system may lead to coercion of patients: the end [cure] may come to justify any means taken to reach it, even if those means transgress against respect for the autonomy of patients. If patients are treated autonomously, then it must be accepted that they may choose not to follow the ‘orders’ of the system. The relationship between the health care worker and the patient, the trust and respect between them and the success of their communication are vital for ensuring an ethical approach to TB treatment (12,13).

Improved adherence to TB therapy will depend on an improved understanding of the social epidemiology of TB. Wherever it occurs TB is a disease of poverty. There is a strong evidence that the poorest compliance occurs in the poorest communities (49). It is, therefore, essential that the social and economic factors involved in noncompliance are understood and appreciated. Compliance will only be improved if these factors are taken into account. As Farmer (50) has noted, “those least likely to comply are those least able to comply” with treatment. In the United States and other industrialized nations TB is concentrated among the elderly and people from minority ethnic groups, many of whom are poor and have compromised access [social, physical and economic] to care (14,51). The main TB burden, however, occurs in the developing world where TB cases occur across a wide spectrum of society (52,53). Direct Observation of Treatment As has already been mentioned in the background to this chapter, DOT is part of the international DOTS strategy for TB control (10). But, DOT has potential difficult ethical questions relating to coercion and control, an imbalance between the autonomy of the individual patient and the control exerted by the health care worker in the system. It can be argued that ‘if a person’s health related behaviour does not coincide with medical advice, then it is appropriate to ensure that it does’ (19). The ethical, legal and Constitutional principles that justify efforts to control TB in the United States are broad enough to justify efforts to ensure that all patients with TB are treated until cured. Legal commentators have endorsed the goal of treatment to cure (44,54,55). There has been controversy, however, over the nature of the public health interventions that might be employed to achieve this goal and the extent to which the legal and ethical principles that guide medical and public health practice should constrain those interventions (8). In the United States, DOT has proven effective in increasing rates of treatment completion (56,57) and in decreasing the prevalence of drug resistance and relapse in communities in which it is used (58). It was initially recommended for persons with poor records of treatment adherence and for those whose demographic or psychological profile suggested a high risk of failure. Now, however, DOT has emerged as a standard of care (57). This change has come about because of the rise of drug resistance in the United States.

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In the United States, it has been argued that because DOT is standardized [is the same for all patients], the initial treatment decisions should not violate the principle of justice, and should thus preclude acts of discrimination (59). The fact that all patients start their post-hospitalized treatment under a common programme of supervision should help to reduce the stigma of being under treatment and create an effective public health plan for the control of TB. Yet is it reasonable to assume that such a programme will be equally appropriate in all settings, no matter how socially or economically diverse? Does DOT respect the autonomy of individuals everywhere in the same way? Indeed universal DOT has been challenged as an unethical intrusion on autonomy, as ‘gratuitously annoying’ (60), as a violation of the Constitutional requirement that the least restrictive measure be used, and as contrary to the requirements of the Americans With Disabilities Act [That decisions involving restrictions on those with disabilities be based on an individualized assessment] (61). The DOT has also been criticized on the basis that it is resource and manpower intensive, and so may be wasteful of scarce resources (59,62). It has been argued that the discourse of direct observation is one of domination and control of the health care worker over the patient (63). In ethical terms, it can be argued that the approach fails to respect the autonomy of the person with TB. The ‘care relationship’ between patients and providers should, in ethical terms, be characterized by a balance between the autonomy of the TB patients and the beneficence or non-maleficence of the health care worker and should lead to net benefit with minimal harm. If the health care worker attempts to force the patient into a type of treatment which they do not understand or agree with, then the relationship becomes coercive. A person goes to a medical practitioner because he is sick and wants to get well. The practitioner has access to technology and knowledge that the patient needs. It is an inherently unequal relationship. Yet this relationship is also the key relationship in health care. In TB control, the discipline of ethics helps to frame this relationship in order to ensure that this inequality is not abused. Indeed codes of conduct are an important part of ethics in medicine. The stronger this relationship the more appropriate the care provided. This relationship is destroyed if power is abused.

Those opposing direct observation may feel that it threatens this very important relationship. It is not that DOT is wrong. In fact, the DOT is a rational approach to the delivery of TB drugs. The problem comes, however, with the abuse of power that is potentially inherent in a relationship between a powerful medical worker and a sick vulnerable patient (19). Interaction and Relationship of a Tuberculosis Patient with the Health Care Structure [Official and Unofficial] In every country there is a health care structure whether official or unofficial. In some, it is organized and controlled by the government [regulated system], and in others it is a system established through traditional systems of medicine and health care [unregulated system]. Increasingly, the health care systems in many countries are being administered through a mixture of public and private providers. The Health Care Structure For a health care system to work and to provide appropriate care for people, it must be consistent with the underlying health beliefs and social norms of the community (64). If the government does not provide appropriate health care for communities, they will establish their own systems. The rise of the private sector in countries in Asia is an example. The ethical issues that relate to health care structures are to do with the rights of individuals to have a system of health care provided for them by government. In western industrialized countries, governments are considered to have a duty to provide systems of health care for the population and individuals consider that it is their right to be provided with a service. Access While it is important for health care to be consonant with patient belief systems, it must also be accessible to them in physical, geographic and economic terms (50,65). Not all people have equal access to health care structures and it is usually the most vulnerable groups [e.g., displaced populations, the poor, the unemployed, etc.,] that find it most difficult to use the health care services (66). In terms of ethics, it is important to look at the relative autonomy of people with TB within their community, the balance

Ethical and Legal Issues in Tuberculosis Control 957 between beneficence and non-maleficence, the net gain for being enrolled in TB treatment [the DOTS strategy, for example], and finally whether they are treated justly.

enable the development of solutions which meet the needs of the system as well as the needs of the patients and the communities in which they live.

Social and Cultural Burden

Treatment and Drugs

How people use the health care system [‘treatment seeking’] relates to cultural as well as social and economic factors. While the burden of TB has been well defined from the epidemiological perspective, there have been surprisingly few attempts to define the social and economic burden of TB (52). Similarly, there are only a limited number of studies on the actual costs or economic consequences of TB borne by families, communities, and economies in the developing world (67). Nevertheless, it is apparent that not all people are equally able to access health care structures (50). This is a question of equity. Ethical processes are critical in promoting equity. ‘Equitypromoting action in the health sector must put the needs and interests of the poorest and most vulnerable at their heart, as the relatively worse health outcomes of this group in comparison with other groups are most often a function of circumstances beyond their control’ (68).

Once the patient has accessed the system and been diagnosed with TB, she or he needs to be provided with a regular supply of antituberculosis drugs. This requires a system to have been developed to ensure that there is a regular drug supply. For this to be achieved, questions need to be asked about the type of health care system established in a country. It asks governments to be committed to dealing with TB and to ensuring an appropriate management and distribution system for TB drugs. It is not simply the uninterrupted supply of drugs that is important, however, it is also the access to those drugs by the people who need them.

Stigma Another issue which needs to be highlighted when considering a patient’s interaction with the health care structure as well as the ethics of the ‘passive case-finding’ approach [The health care system waits ‘passively’ for patients to present with TB rather than ‘actively’ looking for patients] advocated in TB control strategies is stigma. TB carries a social stigma. It is also a disease which affects the most marginalized, most poor and most vulnerable groups in communities, the very groups who tend to have the least autonomy. Although it is clear that the effects of stigma on passive case-finding needs to be better understood, there is evidence which indicates that it will have an effect on delaying treatment-seeking and that it may substantially constrain the ability of young people and women in particular to seek and obtain care (67). Passive case-finding is the method of waiting for people with TB to present to health facilities rather than actively going out to find cases. Passive case-finding may well be sound in public health terms, and even in macro-economic terms, but the ethical implications need to be taken into consideration as well. Considered and well-informed debate should

Monitoring Monitoring and evaluation of the TB system is obviously essential and can either promote equity and efficiency or seriously detract from it (10,11). It is important, for example, that health care workers are able to perform the tasks and achieve the targets they are being evaluated on: the criteria for evaluation need to be realistic and appropriate for particular contexts and given the real constraints faced on the ground. Recent operations research in India, for example, indicate that targets set at the national and international level may be placing stresses on health care workers that do not promote the care of patients (12,13,69). Ethical questions that need to be asked in relation to monitoring and evaluation include: Is the system just and equitable? Does the system respect both the TB patients and the health care workers that care for them? Does the system encourage health care workers to identify problems or does it penalize them for ‘not doing it right?’ Problems need to be identified and dealt with positively. This is the art of making difficult problems soluble, a process which Medawar called the ‘art of the soluble’ (70). After all it is through tackling problems that we find a process of engagement and integration between people with TB, their communities, districts, states, government and the international community (71). The international DOTS strategy makes sense scientifically, but if the emphasis is only on targets rather

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than the process developed to achieve these targets, then health care workers and patients may be used as ‘means’ to achieving a particular ‘end’: they may be abused. A system needs to be established in which both patients and providers are respected. The health service is, after all, there to provide a service for patients. A danger of having inappropriate targets for the health care worker is that they will focus on attaining these targets rather than on caring for the patient. This may lead to coercion by the health care worker of the patient, or to the exclusion of the patient from the system. Targets need to be adapted to the local community situation and made appropriate to them. As noted above, ethics requires people to treat each other as ends in themselves and not merely as the means to achieving a particular outcome ‘end’ (72). Concentrating on the moral and social aspects of a monitoring system will help to ensure that this is achieved, that people are respected and TB patients are not abused in the process. ‘The provision of social services has a strong person element: the quality of service depends heavily on the attitudes of the people undertaking it, and it is hard to monitor. Service provisioning, furthermore, often involves a position of power over users. Hence the importance of professional ethics’ (73). TUBERCULOSIS CONTROL - LEGAL ISSUES The next section focusses on some legal issues contained within the current TB control strategy. The examples used are from a western legal perspective. In the industrialized world the legal cases that are reported in the literature tend to relate to the loss of civil liberties. For example, in order to protect ‘the majority’, the legal system is used to ‘control’ people with TB who fail to follow public health recommendations and regulations to prevent the spread of Mycobacterium tuberculosis (8). These people are a minority of cases but affect certain groups who are themselves ‘minorities’; for example, the homeless, ethnic minorities, drug users and alcoholics (19). It can be argued that these people are the ‘outliers’ of a community, people who live on the fringes of society and who are not seen as part of the majority i.e. they are different from ‘the norm’. If ‘equality’ is the only aspect of justice that is important, then it could be argued that this situation is appropriate. However, the question of equity is also important. In the section on

‘ethics, principles and tasks’ it has already been stated that inequity denotes the reasons behind and responsibilities for underlying conditions of inequality, and it is therefore, inherently a statement of justice (32). Ethical processes are critical in promoting equity (29,68). Legal Processes Affect the Minority of Tuberculosis Patients A study conducted in New York City and published in 1999 indicates that between 1992 and 1997, legal action was required only for a minority of patients with TB (42). In 1993, because of the increasing rates of TB and cases of MDR-TB, the New York City Department of Health updated its Health Code to permit compulsory action to protect the public health. From this date, the Commissioner of Health could issue orders compelling a person to be examined for suspected TB, to complete treatment, to receive treatment under direct observation, or to be detained for treatment (43). The types of regulatory action ranged from ‘an order for examination for suspected TB’ to ‘an order for detention while infectious’. The study by Gasner et al (42) evaluated legal actions in TB control and showed that regulatory orders were issued for less than four per cent of the 8000 TB patients treated between 1993 and 1995. The paper strikingly highlights the social and demographic characteristics of those who were detained [‘the outliers’]; of the 304 patients who required regulatory action, 211 [69%] were black, 68 [22%] were Hispanic, 21 [7%] were white and 4 [1%] were Asian. Human immunodeficiency virus infection was documented in 147 cases [48%]. One hundred and fifty-two [50%] had a history of homelessness, 128 [42%] had used injection drugs, 183 [60%] had used ‘crack’ cocaine, 191 [63%] had a history of alcohol abuse and 145 [48%] had a history of incarceration (42). High Risk Groups In ethics there is a dictum which states ‘ought implies can’ (8). It can be argued, therefore, that a person cannot be held ethically accountable for failing to adhere to moral or legal standards [e.g., TB treatment], if he or she cannot do so, or if he or she faces insuperable obstacles to adherence. This statement highlights the plight of the most vulnerable groups in our communities (52). Ethically it is important to consider the duties of the

Ethical and Legal Issues in Tuberculosis Control 959 community to support these groups of vulnerable people to ensure that they are appropriately treated for TB, but perhaps more importantly, to find ways of preventing them from acquiring TB. This ethical principle of ‘ought implies can’ compels us to recognize that the elimination of impediments that impinge on the capacity of an individual to cooperate in his or her own care for TB is essential and we need to look for appropriate structural interventions (18). For example, homeless persons cannot reasonably be expected to comply with their treatment unless they are provided with a secure residence, and in many cases with other social supports (8). This is echoed in social science research which indicates that those with strong community or familial support are more likely to adhere to a full course of TB therapy (64,67,74,75). The New York City Tuberculosis Working Group (61) has argued that ‘the government that fails to provide adequate social supports for the most vulnerable loses the legal, as well as the moral, authority to threaten with a deprivation of liberty those whose behaviour poses a health risk’. Thus, the laws we develop in our communities and societies are a reflection of how we see the world, of the values we use to frame our legal system; and in the case of TB control, how we perceive and deal with these vulnerable groups of TB patients. Is it not easier to develop a law which confines high risk groups to ensure that they do not spread the disease to the larger population than to address the difficult, some may say impossible, social questions of homelessness? Is there not also the moral responsibility of the society to try to find ways of supporting these groups of people to prevent them from acquiring TB without resorting to coercion and control? Indeed if we are to believe Tyler’s statement (1) at the beginning of the chapter, our efforts to control TB patients in this way may be making the TB situation worse. Prisons Incarceration is the final legal action that can be taken to ensure that a person with TB takes their medication. However, prison itself is an important site for the transmission of TB as demonstrated by recent outbreaks of MDR-TB in prisons in the United States, Spain and Russia (76,77). These outbreaks have called for ‘international efforts to ensure effective global initiatives to control TB in these settings; strategies to screen, diagnose,

and treat frequently neglected populations residing in jails and prisons throughout the developing world’ (78). Prisoners have been confined to prison through the legal system in a particular country, but it is the responsibility of the government system which manages the prisons to ensure that prisoners are treated and cared for appropriately [duties]. In the case of TB, this means both ‘establishing the conditions in which people can be healthy’ in prisons [i.e., no overcrowding, poor nutrition etc.,] as well as providing appropriate treatment of TB cases when they arise. In many countries, the primary reason for the higher prevalence of Mycobacterium tuberculosis infection and increased incidence of TB disease within prisons is the disproportionate number of inmates who are otherwise at high risk for acquiring infection and developing active disease (78). The discussion of ethical and philosophical matters in health care is not new. Over two thousand years ago the writings of Hippocrates debated the duties of doctors towards their patients and the community. However, the last three decades of the twentieth century and the start of the twenty-first have seen a dramatic transformation in medical ethics. What has been limited in the past to codes of professional conduct became in the 1960s the new academic discipline called biomedical ethics or bioethics (27). By the 1980s bioethics had included the societal debate encompassing discussions about priority setting and health care reforms. Now, in the 1990s, a new phase is evolving which transcends health care matters, encompassing the full range of health determinants. This phase has moved towards the ‘bioethics of population health’ with a focus on the broader ethical issues in public health such as social justice, equity, sustainable health, sustainable living, globalization and environmentalism (79). As was stated in the introduction, the 1990s and early 2000 is witnessing increasing ‘internationalism’ and ‘complexity’ and the increasing need to address crosscultural ethical issues as well as the theoretical and practical convergence of public health and human rights (80). This is highlighted in the spectre of the HIV pandemic and the research being conducted in this area, which is driving an international agenda that is forcing individuals and governments to address broad ethical concerns about research and control. At the 38th CIOMS Conference in 1994, a Declaration was issued describing the emergence of bioethics as a global and multi-layered enterprise. The following

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statement from that conference sums up the contemporary importance of ethics to public health: “It is time to move beyond medical ethics, beyond bioethics, beyond an ethics of health care of health policy, towards an ethics of health which calls on us to consider the interconnections among all of our choices and actions that affect the health status of people anywhere. In doing so, we should acknowledge the equal moral worth of all people, and should recognize that the human condition is inherently a condition of vulnerability” (26). Ethical and legal debates provide an important focus for TB control activity. For too long, public health has been operating in an ‘ethical vacuum’. It is important to ensure that the autonomy and freedom of individuals is not being inappropriately jeopardized by the government, the legal system or the public health profession. It is important to protect the population from infectious disease epidemics, but it is equally important to ensure that the rights of the infected individual are not being violated, and that these individuals are supported by their communities and by their legal systems. If we agree that ‘the human condition is inherently a condition of vunerability’ but that some are more vulnerable than others, then the most vulnerable groups in our populations need to be protected and supported. It can even be argued in TB control strategies that if the socially vulnerable are targeted and their issues are addressed, then the problems of the remainder [the majority] of TB patients will also be covered (81). With increasing globalization, it continues to be important to remember that individuals as well as communities need to be respected and treated with the dignity they deserve. Tuberculosis control methods developed for one country may not be appropriate for another. If the ethical principles discussed in this chapter were to become part of the public health process, notions of autonomy, empowerment and justice would feature in public health decision-making at all levels. International, national and local decision-makers would be compelled to engage in a debate which problematized the taken-for-granted assumptions behind the principle of non-harming. Public health paternalism could no longer prevent control programmes from achieving the success they promise, and individuals and communities might come to enjoy the freedom to obtain care, and cure, for TB without having to compromise their autonomy (19).

REFERENCES 1. Tyler SA. Post-modern ethnography: from document of the occult to occult document. In: Clifford J, Marcus GE, editors. Writing culture: the poetics and politics of ethnography. Berkeley: University of California Press; 1986.p.122-40. 2. Kickbusch A. New players for a new era: responding to the global public health challenges. J Public Health Med 1997;19:171-8. 3. Rachels J. The elements of moral philosophy. New York: McGraw-Hill; 1997.p.1. 4. Lerner BH. Temporarily detained: tuberculous alcoholics in Seattle, 1949 through 1960. Am J Public Health 1996;86:25765. 5. Wing KR. The law and the public’s health. Ann Arbor: Health Administration Press; 1990.p.1-50. 6. Acheson Report. Public health in England: The report of the committee of inquiry into the future development of the public health function. London: HMSO; 1988. 7. Institute of Medicine. Future of public health. Washington DC: National Academy Press; 1988.p.1-7. 8. Bayer R, Dupuis LJ. Tuberculosis, public health and civil liberties. Annu Rev Public Health 1995;16:307-26. 9. Snider DE. Tuberculosis: the world situation. History of the disease and efforts to combat it. In: Porter JDH, McAdam KPWJ, editors. Tuberculosis-back to the future. London: John Wiley and Sons; 1994. 10. World Health Organization. WHO TB Programme. Framework for effective TB control. WHO/TB/94.179. Geneva: World Health Organization; 1994. 11. Harries AD, Mayer D. TB/HIV: a clinical manual. WHO/ TB/96.200. Geneva: World Health Organization; 1996. 12. Singh V, Jaiswal A, Porter JD, Ogden JA, Sarin R, Sharma PP, et al. TB control, poverty and vulnerability in Delhi, India. Trop Med Int Health 2002;7:693-700. 13. Jaiswal A, Singh V, Ogden JA, Porter JD, Sarin R, Sharma PP, et al. Adherence to tuberculosis treatment: lessons from the urban setting of Delhi, India. Trop Med Int Health 2003;8:625-33. 14. Brudney K, Dobkin J. Resurgent tuberculosis in New York City: human immunodeficiency virus, homelessness and the decline of tuberculosis control programs. Am Rev Respir Dis 1991;144:745-9. 15. Vaughan JP, Morrow RH. Manual of epidemiology for district health management. Geneva: World Health Organization; 1989. 16. Rodrigues LC, Smith PG. Tuberculosis in developing countries and methods for control. Trans Royal Soc Trop Med 1990;84:739-44. 17. McKeown T. The role of medicine: dream, mirage or nemesis? Princeton: Princeton University Press; 1979.p.45-65,92-96. 18. Sumartojo E. Structural factors in HIV prevention: concepts, examples, and implications for research. AIDS 2000;14[Suppl 1]:S3-10. 19. Porter JD, Ogden JA. Ethics of directly observed therapy for the control of infectious diseases. Bull Inst Pasteur 1997;95: 117-27.

Ethical and Legal Issues in Tuberculosis Control 961 20. Gillon R. Medical ethics: four principles plus attention to scope. BMJ 1994;309:184-8. 21. Hill P. The cultural and philosophical foundations of normative medical ethics. Soc Sci Med 1994;39:1149-54. 22. Bell D. Technology, nature and society. In: The winding passage: essays and sociological journeys 1960-1980. Cambridge: Abt Books; 1980. 23. Bilimoria P. Indian ethics. In: Singer PA, editor. A companion to ethics. Blackwell Companions to Philosophy. Oxford: Blackwell; 1991. 24. Rigveda. The hymns [Translation: Menen A]. New York: Scriber’s; 1954. 25. Stanley JM. The four principles in practice: facilitating international medical ethics. In: Gillon R, editor. Principles of health care ethics. London: John Wiley and Sons; 1994. 26. Declaration of Ixtapa. In: Bankowski Z, Bryant JH, Gallagher J. Ethics, equity and health for all 1994. Geneva: Council for International Organizations of Medical Sciences; 1997. 27. Wikler D. Bioethics, Human rights and the renewal of health for all: an overview. Geneva: Council for International Organizations of Medical Sciences; 1997.p.23-4. 28. Beaufort ID, Dupuis HM. Handboek gezondheidsethiek. Assen/Maastricht: Van Gorcum; 1988. 29. Porter JD, Ogden JA. Public health, ethics and tuberculosis. Indian J Tuberc 1999;46:3-10. 30. Beauchamp TL, Childress JF. Principles of biomedical ethics. Second edition. New York: Oxford University Press; 1983. 31. Aristotle. Nichomachean ethics. In: McKeon R. The basic works of Aristotle. Book 5. New York: Random House; 1941. 32. Stephens C. Environment, health and development: addressing complexity in the priority setting process. Geneva: World Health Oraganization Office of Global and Integrated Environmental Health; 1997. 33. Cole P. The moral bases for public health interventions. Epidemiology 1995;6:78-83. 34. Shindell S. Legal and ethical aspects of public health. In: Last JM, Maxcy-Rosenau, editors. Public health and preventive medicine. Eleventh edition. New York: Appleton Century Crofts; 1980.p.1834-45. 35. Skrabanek P. Why is preventative medicine exempted from ethical constraints? J Med Ethics 1990;16:187-90. 36. Hall SA. Symposium on ethics and public health: should public health respect autonomy? J Med Ethics 1992;18:97-201. 37. Mill JS. On Liberty. In: Wishy B, editor. Prefaces to liberty: selected writings of John Stuart Mill. Lanham: University Press of America; 1959. 38. Jesani A, Iyer A, Desai M, Adenwala M. Laws and health care providers. A study of legislation and legal aspects of health care delivery. Mumbai: Research Centre of Anusandhan Trust; 1996. 39. Thacker SB, Berkelman RL. Public health surveillance in the United states. Epidemiol Rev 1988;10:165. 40. Hogue LL. Public health and the law: issues and trends. Rockville: Aspen Systems Corporation; 1980.p.10. 41. Painter M, Button J. Legal aspects of communicable disease control. In: Noah N, O’Mahony M, editors. Communicable

42.

43. 44.

45.

46.

47.

48. 49. 50. 51. 52.

53.

54.

55.

56.

57.

58.

59.

disease epidemiology and control. London: Wiley and Sons; 1988. Gasner MR, Maw KL, Feldman GE, Fujiwara PI, Frieden TR. The use of legal action in New York City to ensure treatment of tuberculosis. N Engl J Med 1999:340:359-66. New York City Health Code. 1994. 11.47[d]. Bhore Committee. Report of the health survey and development committee 1946. Volume I: Survey, Volume II: Recommendations, Volume III: Appendices. New Delhi: Government of India, Manager of Publications; 1946. Gittler J. Controlling resurgent tuberculosis: public health agencies, public policy, and law. J Health Polit Policy Law 1994;19:107-47. Westaway MS, Wolmarans L. Cognitive and affective reactions of black urban South Africans towards tuberculosis. Tuber Lung Dis 1994;75:447-53. Snider DE. General view of problems with compliance in programme for the treatment of tuberculosis. Bull Int Union Tuberc 1982;57:255-60. Donovan JL, Blake DR. Patient non-compliance: deviance or reasoned decision-making? Soc Sci Med 1992;34:507-13. Yach D. Tuberculosis in the Western Cape health region of South Africa. Soc Sci Med 1988;27:683-9. Farmer P. Social scientists and the new tuberculosis. Soc Sci Med 1997;44:347-58. Selwyn PA. Tuberculosis and AIDS: epidemiological, clinical and social dimensions. J Law Med Ethics 1993;21:279-88. Rangan S, Uplekar M, Ogden J, Porter J, Brugha R, Zwi A, et al. Shifting the paradigm in tuberculosis control: a state of the art review. Int J Tuberc Lung Dis 1999;3:855-61. Porter JDH, Ogden JA. Social inequalities in the emergence of infectious disease. In: Strickland SS, Shetty PS, editors. Human biology and social inequality. Cambridge: Cambridge University Press; 1998.p.96-113. Gostin LO. Controlling the resurgent tuberculosis epidemic: a 50-state survey of TB statutes and proposals for reform. JAMA 1993;269:255-61. Reilly RG. Combating the tuberculosis epidemic: the legality of coercive treatment measures. Columbia J Law Social Prob 1993;27:101-49. Centers for Disease Control and Prevention. Approaches to improving adherence to antituberculosis therapy-South Carolina, and New York, 1986-1991. MMWR Morb Mortal Wkly Rep 1993;42:74-75, 81. Centers for Disease Control and Prevention. Initial therapy for tuberculosis in the era of multidrug resistance: recommendations of the Advisory Council for the elimination of tuberculosis. MMWR Morb Mortal Wkly Rep 1993;42:1-8. Weis SE, Slocum PC, Blais FX, King B, Nunn M, Matney GB, et al. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994;330:1179-84. Dubler NN, Bayer R, Landesman S; New York City Tuberculosis Working Group. Tuberculosis in the 1990’s: ethical, legal and public policy issues in screening, treatment and the protection of those in congregate facilities. A report

962

60. 61.

62. 63.

64.

65.

66.

67. 68.

69.

Tuberculosis from the working group on TB and HIV. In: The tuberculosis revival: individual rights and societal obligations in a time of AIDS. New York: United Hospital Funds of New York; 1992.p.1-42. Annas GJ. Control of tuberculosis - the law and the public’s health. N Engl J Med 1993;328:585-8. New York Working Group. Developing a system for tuberculosis prevention and care in New York City. In: The tuberculosis revival: individual rights and societal obligations in a time of AIDS. New York: United Hospital Fund of New York; 1992.p.51-8. Hansel A. The TB and HIV epidemics: history learned and unlearned. J Law Med Ethics 1993;21:376-81. Ogden JA. Compliance versus adherence: just a matter of language? The politics and poetics of public health. In: Porter JDH, Grange JM, editors. Tuberculosis - an interdisiplinary perspective. London: Imperial College Press; 1999.p.213-34. Barnhoorn F, Adriaanse H. In search of factors responsible for non-compliance among tuberculosis patients in Wardha District, India. Soc Sci Med 1992;34:291-306. Kimerling ME, Petri L. Tracing as part of tuberculosis control in a rural Cambodian district during 1992. Tuber Lung Dis 1995;76:156-9. Parker RG. Empowerment, community mobilization and social change in the face of HIV/AIDS. AIDS 1996;10[Suppl 3]:S27-31. Uplekar M, Rangan S. Tackling TB: the search for solutions. Bombay: FRCH; 1996. Gilson L. Re-addressing equity: the search for the holy grail? The importance of ethics processes. In: Mills A, editor. Reforming health sectors. London: Wiley and Sons; 1998. Lala Ram Swarup Institute of Tuberculosis and Allied Diseases. Final Report of the Operations Research to assess needs and perspectives of TB patients and providers of

70. 71.

72. 73. 74.

75. 76. 77.

78. 79.

80. 81.

tuberculosis care in Nehru Nagar and Moti Nagar chest clinic areas of Delhi. Delhi: DFID Health and Population Office; 1998. Medawar P. Plato’s republic incorporating the ‘art of the soluble’. London: Oxford University Press; 1984. Pronyk P, Porter JD. Public health and human rights: the ethics of international public health interventions for tuberculosis. In: Porter JD, Grange JM, editors. Tuberculosis-an interdisiplinary perspective. London: Imperial College Press; 1999.p.99-120. Gillon R. Deontological foundations for medical ethics? Chichester: John Wiley and Sons; 1994.p.14. Mackintosh M. Competition and contracting in selective social provisioning. Eur J Dev Res 1995;7:26-52. Sumartojo E. When tuberculosis treatment fails. A social behavioural account of patient adherence. Am Rev Respir Dis 1993;147:1311-20. Rubel AJ, Garro LC. Social and cultural factors in the successful control of tuberculosis. Public Health Rep 1992;107:626-36. Drobniewski F. Tuberculosis in prisons: forgotten plague. Lancet 1995;346:948-9. Bureau of Justice. Prisoners in 1996, Bureau of Justice Statistics. Washington DC: US Department of Justice, Office of Justice Program; 1997. Kendig N. Tuberculosis control in prisons. Int J Tuberc Lung Dis 1998;2:S57-63. Lerer LB, Lopez A, Kjellstrom T, Yach D. Health for all: analyzing health status and determinants. World Health Stat Q 1998;51:7-20. Mann J. Human rights and the new public health. Health and Human Rights 1994;1:229-33. Porter JDH, Ogden JA, Pronyk P. The way forward: an integrated approach to tuberculosis control. In: Porter JDH, Grange JM, editors. Tuberculosis-an interdisiplinary perspective. London: Imperial College Press; 1999.p.359-78.

Tuberculosis: Some Web-based Resources on the Internet 963

Tuberculosis: Some Web-based Resources on the Internet

66

Anju Sharma, NC Jain

INTRODUCTION Internet is the newest and fastest growing medium for information flows. Internet growth is ever accelerating, which indicates that the Internet is still in its expansion phase. It provides information and data from all over the world in a few seconds. It is a worldwide, publicly accessible series of interconnected computer networks that transmit data by using the standard Internet Protocol [IP]. It is also known as a “network of networks” that consists of millions of smaller domestic, academic, business, and government networks, which together carry various information and services. Most information these days in fact, is available online and an increasing number of people worldwide now have access to the Internet (1). Internet and the World Wide Web [www] are not synonymous. The Internet is a collection of interconnected computer networks, linked by copper wires, fiber-optic cables, and wireless connections. In contrast, the World Wide Web is a collection of interconnected documents and other resources, linked by hyperlinks and Uniform Resource Locators [URLs]. The World Wide Web is one of the services accessible via the Internet, along with many others including e-mail, file sharing and others (2). If one takes into account all web accessible information, there are about 550 billion web connected documents and 95 per cent of this information is available publicly as in 2007. As of June 30, 2008, 1.463 billion people were using the Internet according to Internet World Stats. Of these, 578 millions [39.5%] Internet users were in Asia, followed by 384 millions [26.3%] in Europe and

17 millions [248%] in North America. Africa had only 51 million [3.5%] users. The World Wide Web is very expensive in most of the developing countries including India. In India, less than per cent population has access to World Wide Web and most of them live in States and Union Territories like Delhi, Karnataka, Maharashtra, Tamil Nadu and a few metropolitan cities. If one looks at Internet penetration rates [% population] in the world North America tops the tally with 73.6 per cent penetration followed by Australia/Oceania [59.5%] and Europe [48.1%]. Asia has only 15.3 per cent penetration rate while Africa has the least of 5.3 per cent only. As per one estimate the World Wide Web contains about 170 terabytes [1 000 000 000 000 bytes or 1012 bytes] of information on its surface (3). How much new information is actually created each year? More that 90 per cent of new information is stored on magnetic media, primarily hard disks. Film represents seven per cent of the total, paper 0.01 per cent, and optical media 0.002 per cent. The amount of new information stored on paper, film, magnetic, and optical media has been increasing every year. This is what is called information explosion. Despite this development, the amount of information printed on paper is still increasing, but the vast majority of original information on paper is produced by individuals in office documents and postal mail, not in formally published titles such as books, newspapers and journals. English language is the dominant language if one looks at the distribution of web sites. Currently, only 50 per cent of all Internet users are native English speakers, though English web sites continue to dominate with

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approximately 78 per cent of all web sites and 96 per cent of e-commerce web sites being in English. It is not possible to estimate what percentage of web sites have their origins in the English speaking countries or others (2). The Internet has now become an essential infrastructure in the health environment. It provides an abundance of resources such as communication services including electronic mail and discussion groups; direct access to scientific and health-related information resources, including digital libraries. There are enumerable number of web sites available these days providing information, both authentic and otherwise, to public, researchers, clinicians, experts and whosoever is interested to know about health related issues, policies, new infections, emerging and re-emerging infections, diseases and medical research currently being done globally. There was a time when there were no means for general public to know about the etiology, pathogenesis, treatment, preventive measures of tuberculosis [TB], the white plague, as it was known as. Now with a burst of all kinds of information on the Internet it has become

possible for a lay person, a patient or otherwise, to know about the diseases like TB (4) , acquired immunodeficiency syndrome [AIDS] (5) , and various other resources (6) with just a click of mouse. Here are some of the sources on the Internet which provide information about tuberculosis. This is a compilation based on information available on PubMed [http://www.ncbi.nlm.gov/enterez/query.fcgi], Google [http://www.google.com], Google Scholar [http:// scholar.google.com/], Scirus – for scientific information only [http://www.scirus. com/], IndMed [http:// indmed.nic.in/], medIND [http://medind.nic.in/], and various published and other internet resources. This collection is not based on any guidelines or criteria but mainly our experience in the area of biomedical communications. The list can never be complete, the deletions as well as additions will be a continuous process. There may be problems about authenticity of information at certain sites though we have tried to include only the authentic web sites. Some important and useful web resources on TB are listed below:

Books Tuberculosis 2007 – From Basic Science to Patient Care, J C Palomino, S C Leao, V Retacco [Editors], [http://tuberculosistextbook.com] ebooks Opportunistic infections – Treatment and prophylaxis. Totowa: Humana Press; 2003 Schlossberg D. Tuberculosis and nontuberculosis mycobacterial infections. 5th edition, Philadelphia: The McGrawHill Co.,Inc; 2006 Reports Anti-tuberculosis drug resistance in the world WHO report [http://www.who.int/tb/publications/who_htm_tb_ 2004_343/] A research agenda for childhood tuberculosis. Improving the management of childhood tuberculosis within national tuberculosis programmes: research priorities based on a literature review WHO/HTM/TB/2007.381. [http:// whqlibdoc.who.int/hq/2007/WHO_HTM_TB_2007.381_eng.pdf] Communicable Disease Report CDR Weekly [http://www.hpa.org.uk/cdr/] Global tuberculosis control - surveillance, planning, financing, WHO Report 2007/WHO/HTM/TB/2007.376 [http:// www.who.int/tb/publications/global_report/2007/en/index.html] Clinical Trials/ Registers ATM Clinical Trials Registry [http://www.atmregistry. org/] Australian New Zealand Clinical Trials registry [ANZCTR] [http://www.anzctr.org.au/]

Tuberculosis: Some Web-based Resources on the Internet 965 Clinical Trials Registry – India [http://www.ctri.in/] ClinicalTrials.gov, A service from US National Institutes of Health [http://clinicaltrials.gov/] Current Controlled Trials [http://www.controlled-trials.com/] metaRegister of Controlled Trials [mRCT] [http://www.controlled-trials.com/mrct/] PhRMA Clinical Study Results Database [http://www.clinicalstudyresults.org/] The Cochrane Central Register of Controlled Trials [http://www.mrw.interscience.wiley.com/cochrane/ cochrane_clcentral_articles_fs.html] UNIM Clinical Trials Registry [UNIM – CTR] [http://www.umin.ac.jp/ctr/] WHO International Clinical Trials Registry Platform, ICTRP [http://www.who.int/ictrp/en/] Drug Development, Vaccines and Diagnostics AERAS Global TB Vaccine Foundation [AERAS] [http://www.AERAS.org ] Aeras Global TB Vaccine Foundation, Developing New Tuberculosis Vaccines for the World [http://www.aeras.org/]. Bill and Melinda Gates Foundation [BMGF] [http://www.gatesfoundation.org/GlobalHealth] European Commission TB Vaccine Cluster [http://www.pasteur.fr/recherche/EC_TBvaccine/] Foundation for Innovative New Diagnostics [FIND], Geneva, switzerland [http://www.finddiagnostics. org/] Global Alliance for TB Drug Development [http://www.tballiance.org/about/mission.php] KNCV Tuberculosis Foundation [KNCV] [http://www.kncvtbc.nl/] South African Tuberculosis Vaccine Initiative [http://www.satvi.uct.ac.za/] TBVAC - TBVAC is a cluster for tuberculosis vaccine developments composed of academic teams and industrial partners possessing complementary expertise. The major objective of the TBVAC project is to identify, develop and evaluate in pre-clinical and clinical Phase I trials new and improved vaccines [http://www.tb-vac.org] TB Vaccine Testing and Research Materials Contract, Colorado State University [www.cvmbs.colostate.edu/ microbiology/tb/top.htm] Tuberculosis Statistics Indiana State Department of Health, Indiana Tuberculosis Reports [http://www.in.gov/isdh/dataandstats/ tuberculosis/tb_index.htm] Minnesota Department of Health, TB Statistics [http://www.health.state.mn.us/divs/idepc/diseases/tb/stats.html] Morbidity and mortality statistics regarding tuberculosis in India [http://openmed.nic.in/787/]. Texas Department of State Health services Tuberculosis Statistics [http://www.dshs.state.tx.us/idcu/disease/tb/ statistics/] Tuberculosis and HIV: Statistics and Demographics , The Body The Complete HIV/AIDS Resource [http:// www.thebody.com/index/treat/tubercul_stats.html] Tuberculosis Data and Statistics, Department of Health, New York State [http://www.health. state.ny.us/statistics/ diseases/communicable/tuberculosis/]

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Tuberculosis- India [http://www.indiastat.com/india/ShowData.asp?secid=17800andptid=77 andlevel=3] Tuberculosis Statistics in the United States [http://tuberculosis.emedtv.com/tuberculosis/tuberculosis-statisticsin-the-united-states.html] Tuberculosis Statistics, Communicable Disease Service Tuberculosis Control Program New Jersey [http:// www.state.nj.us/health/cd/tbstats/] Professional Associations/Organizations American Lung Association [ http://www.lungusa.org/site/pp.asp?c=dvLUK9O0Eandb=22542] American Lung Association of California [http://www.californialung.org/] American Thoracic Society [http://www.thoracic. org/] California Tuberculosis Controllers Association, CTCA [ http://www.ctca.org/] Centers for Disease Control and Prevention, Atlanta, USA [http://www.cdc.gov/] Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, Nirman Bhawan, New Delhi, India [http://www.tbcindia.org] Foundation for Innovative New Diagnostics [FIND], Geneva, Switzerland [http://www.finddiagnostics. org/] Francis J. Curry National Tuberculosis Center [www.nationaltbcenter.edu/] Indian Council of Medical Research, New Delhi, India [http://www.icmr.nic.in] International Union against Tuberculosis and Lung Diseases [IUATLD] [http://www.iuatld.org/], IUATLD – Official publications; contains abstracts and some full-text articles for free Japan Anti-TB Association Research Institute of Tuberculosis [http://www.jata.or.jp/eindex.htm] John Hopkins Center for Tuberculosis Research, USA [http://www.jhsph.edu/dept/IH/Centers/TB_Research.html] National Institute of Allergy and Infectious Diseases [NIAID], Tuberculosis [http://niaid.nih.gov/publications/ tb.htm] , NIAID, Fact sheet and brochures about TB research and training opportunities National Institutes of Health, USA [http://www.nih.gov/] National Prevention Information Network NPIN, CDC, USA [http://www.cdcnpin.org/scripts/index.asp] National Tuberculosis Controllers Association, USA [http://www.ntca-tb.org/] National Tuberculosis Institute, Bangalore, India [http://ntiindia.kar.nic.in/] New Jersey Medical School Global Tuberculosis Institute [http://www.umdnj.edu/globaltb/home.htm] SAARC Tuberculosis and HIV/AIDS Centre [http://www.saarctb.com.np/tuberculosis.php] Stanford Center for Tuberculosis Research, USA [http://www.stanford.edu/group/molepi/] TBC India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. [http://www.tbcindia.org/] The Sanger Center [http://www.sanger.ac.uk/] The Tuberculosis Association of India, New Delhi, India http://tbassindia. org

Tuberculosis: Some Web-based Resources on the Internet 967 Tuberculosis Research Centre [ICMR], Chennai, India [http://trc-chennai.org] Permanent Institute of the Indian Council of Medical Research, WHO Collaborating Centre for Tuberculosis Control – Institution that conducts randomized controlled clinical trials to evaluate principles of chemotherapy World Health Organization, Geneva, Switzerland [http://www.who.int/en/] Newsletters/Magazines Division of Tuberculosis Elimination - DTBE Newsletters [http://www.cdc.gov/tb/newsletters.htm] FIND Newsletters [http://www.finddiagnostics.org/news/newsletters/] Hartland National TB Center Newsletters [http://www.heartlandntbc.org/newsletters.asp] Stop TB Partnership Newsletters [http://www.stoptb.org/resource_center/communique_and_newsletters.asp] TB Alliance Newsletters [http://72.3.224.152/newscenter/newsletters/] Glossaries/Dictionaries Division of Tuberculosis Elimination [DTBE], CDC, USA – Questions and Answers Glossary [http://www.cdc.gov/ tb/faqs/qa_glossary.htm] Health Glossary – Tuberculosis [http://www.singhealth.com.sg/HealthMatters/HealthGlossary/Tuberculosis.htm] TB Dictionary /A-Z [http://www.tbalert.org/tuberculosis/TBDictionary.php] Advocacy California Department of Public Health TB Advocacy and Partners [http://www.cdph.ca.gov/programs/tb/Pages/ AdvocacyandPartnersTBCB.aspx] Stop TB Parternership Advocacy, Communication and Social Mobilization Working Group [http://www.stoptb.org/ wg/advocacy_communication/default.asp?AM=ACSM] Tuberculosis Advocacy Report, WHO/CDS/TB/2003.321 [http://www.who.int/tb/publications/ advocacy_report_2003/en/index.html] Scientific Literature on Tuberculosis Community contribution to TB care: practice and policy. Geneva, World Health Organization, 2003 [WHO/CDS/ TB/2003.312] [http://www.wqlibdoc.who.int/hq/2003/WHO_CDS_TB_2003.312.pdf] Current TB News [http://www.hopkins-tb.org/news/index.shtml#top], Summaries prepared by the Centers for Disease Control and Prevention [CDC] and presented by Johns Hopkins Center for Tuberculosis Research – Weekly summaries of scientific articles and lay media reports Division of Tuberculosis Elimination, CDC [http://www.cdc.gov/nchstp/tb/pubs/pem.htm], CDC – Access to articles, fact sheets, guidelines and other publications The Connections [http://www.cdcnpin.org/connect/start.htm], CDC National Prevention Information Network – Access to information about the relationship between TB and HIV and sexually transmitted diseases The Global Plan to Stop TB, 2006–2015: methods used to assess costs, funding and funding gaps. Geneva, Stop TB Partnership and World Health Organization, 2006 [WHO/HTM/STB/2006.38] [http://www.stoptb.org/globalplan/ assets/documents/GlobalPlanFinal.pdf] Tuberculosis literature from the World Heath Organization http://www.int/gtb/publications/index.html] – Access to WHO documents, books, articles and other publications

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Search Tools Med Help International [http://www.medhelp.org] Medline Plus [http://www.nlm.nih.gov/medlineplus/] Medind [http://medind.nic.in] Medscape [http://www.medscape.com/], Search tool to access peer-reviewed information from articles, conference summaries and other publications. National Library of Medicine Gateway [http://gateway.nlm.nih.gov/gw/Cmd] PubMed [http://www.ncbinlm.nih.gov/entrez/query.fcgi], National Center for Biotechnology Information at the National Library of Medicine. National Institutes of Health [NIH] – Search tool to access literature citations and links to full-text journals Google [http://www.google.co.in/] Yahoo [http://www.yahoo.com/] Scopus [http://www.scopus.com/scopus/home.url] Epidemiological Data Global Tuberculosis Control Report [http://www.who.int/gtb/publicaions/globrep00], WHO – Epidemiologic and TB control data from different countries; data since 1998 available Global tuberculosis control: surveillance, planning and financing. Geneva, World Health Organization, 2008 [WHO/ HTM/TB/2008.393] [http://www.who.int/tb/publications/global_report/2008/en/index.html] Morbidity and Mortality Weekly Report [MMWR], [http://www.cdc.gov/mmwr/distrnds.html], CDC – Epidemiologic data based on weekly reports form the health departments WHO: Antituberculosis Drug Resistance in the World [http://www.who.int/gtb/publications/dritw/index.htm], WHO – Drug resistance surveillance data, obtained by WHO and IUATLD Literature for Lay People Frequently asked questions [FAQ] [http://www.cdc.gov/nchstp/tb/faqs/qa.htm], CDC – FAQ; also contains a glossary of terms Columbia University – Summary of TB pathogenesis and management; has a Spanish language version. [http:// www.cpmc.columbia.edu/resources/tbcpp/abouttb.html] Tuberculosis [http://www.lungusa.org/diseases/lungtb.html], American Lung Association – FAQ. What You Need to Know about Tuberculosis Management of Tuberculosis [Recommendations, Guidelines and Decision-making Algorithms] ATS-CDC-IDSA Guidelines for treatment of tuberculosis [http://www.thoracic.org/sections/publications/ statements/pages/mtpi/rr5211.html] A guide to monitoring and evaluation for collaborative TB/HIV activities. Geneva, World Health Organization, 2004 [WHO/HTM/TB/2004.342 and WHO/HIV/2004.09]. [http://whqlibdoc.who. int/hq/2004/WHO_ HTM_TB_2004.342.pdf]

Tuberculosis: Some Web-based Resources on the Internet 969 CDC. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings 2005, Morbidity and Mortality Weekly Report [MMWR] 54/RR-17 . Atlanta, GA , USA : Department of Health and Human Services, Centers for Disease Control and Prevention ; 2005.p.147. [http://www.cdc.gov/mmwr/PDF/rr/rr5417.pdf] CDC-NCHSTP-Division of TB Elimination : Major TB Guidelines [http://www.cdc.gov/nchstp/tb/default.htm] – Technical articles on tuberculosis CDHS/CTCA JOINT GUIDELINES. Targeted Testing and Treatment of Latent Tuberculosis Infection in Adults and Children [http://www.ctca.org/guidelines/index.html] CDHS/CTCA JOINT GUIDELINES. Guidelines for the Treatment of Active Tuberculosis Disease, 2003 [http:// www.ctca.org/guidelines/IIA1treatmentactivetb.pdf] CDHS/CTCA JOINT GUIDELINES, 1999. Guidelines for the Follow-Up and Assessment of Persons with Class B1/ B2 Tuberculosis [http://www.ctca.org/guidelines/IIA7bnotification.pdf] Diagnosis Standards and Classification of Tuberculosis in Adults and Children [http://www.cdc.gov/nchstp/tb/ pubs/tbfactsheets/1376.pdf], American Thoracic Society [ATS] and CDC – Diagnostic strategies in various risk populations and classification of TB based on pathogenesis Guidelines for the Prevention of Tuberculosis in Health Care Centers for Resource-Limited Settings [http:// www.who.int/gtb/publications/healthcare/index.htm] WHO –Infection control guidelines designed to reduce the risk of nosocomial Mycobacterium tuberculosis transmission within health care facilities in resource-limited settings Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization, 2006 WHO/HTM/TB/2006.361 [http://whqlibdoc.who.int/publications/2006/9241546956_eng.pdf] Improving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among adults and adolescents, Recommendations for HIV-prevalent and resource-constrained settings. WHO/HTM/TB/ 2007.379 and WHO/HIV/2007.1 [http://whqlibdoc.who.int/hq/2007 WHO_HTM_TB_2007.379_eng.pdf] Interim Policy on Collaborative TB/HIV Activities, Geneva, WHO, 2004. WHO/HTM/TB/2004.330; WHO/HTM/ HIV/2004.1 [http://whqlibdoc.who.int/hq/2004/WHO_HTM_TB_2004.330.pdf] Major Tuberculosis Guidelines [http://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/maj_guide.htm], CDC – Updated CDC guidelines for TB management in different settings National Institute for Health and Clinical Excellence, Clinical Guideline 33, Tuberculosis, clinical diagnosis and management of tuberculosis, and measures for its preventionand control, March 2006 [http://www.nice.org.uk/ nicemedial/pdf/CG033niceguideline.pdf] New technologies for TB control: a framework for their adoption, introduction and implementation WHO/HTM/STB/2007.40 [http://whqlibdoc.who.int/publications/2007/9789241595520_eng.pdf] Prevention and Treatment of Tuberculosis among Patients with HIV [http://aepo-xdv-www.epo.cdc.gov/wonder/ prevguid/m0055357/m0055357.asp], CDC – Guidelines for the diagnosis, treatment and prevention of TB among adults and children coinfected with HIV Recommendations for Prevention and Control of Tuberculosis among Foreign-Born Persons [http://www.cdc.gov/ epo/mmwr/preview/mmwrhtml/00054855.htm], CDC –Recommendations for preventive therapy, diagnosis, and management for TB in the foreign-born Role of BCG vaccine in the Prevention and Control of Tuberculosis in the United States [http://www.cdc.gov/epo/ mmwr/preview/mmwrhtml/00041047.htm], CDC – Considerations and recommendations regarding the use of BCG vaccine in the United States

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Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection [http://www.cdc.gov/epo/mmwr/ preview/mmwrhtml/rr4906a1.htm], CDC – Recommendations for tuberculin testing and treatment of latent infection The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. Anti-tuberculosis drug resistance in the world. Third global report. Geneva, World Health Organization, 2003 [WHO/HTM/TB/2004.343; more information about the project can be found at: http://www.who.int/tb/dots/dotsplus/surveillance/en/ index.html] TB Treatment Guidelines in PDA Format, Division of Tuberculosis Ellimination, National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention, CDC, Atalanta [http://www.cdc.gov/tb/pubs/PDA_TBGuidelines/ default.htm] Treatment of Tuberculosis : guidelines for national programmes, 3rd edition, 2003,WHO/CDS/TB/2003.313, Geneva, [http://www.who.int/tb/publications/cds_tb_2003_313/en/index.html] WHO Tuberculosis and Air Travel: Guidelines for prevention and control [second edition, 2006] – WHO Global Tuberculosis Programme, Geneva [http://www.who.int/entity/tb/publications/2006/who_htm_tb_2006_363.pdf] Updated Guidelines for the Use of Rifabutin or Rifampin among HIVInfected Patients Taking Protease Inhibitors or Nonnucleoside reverse transcriptase inhibitors [NNRTIs] [http://www.cdc.gov/epo/mmwr/preview/mmwrhtml/ mm4909a4.htm], CDC – Updated data about drug-drug interactions between anti-TB drugs and antiretroviral agents Research Databases BioHealthBase – Mycobacterium – Pathogen – Genome Database [http://www.biohealthbase.org/GSearch/ statsAutomation.do?decorator=Mycobacterium] BioTech Science – Mycobacterium Genomic Resources [http://biotech.icmb.utexas.edu/pages/science/ mycobacterium.html] Entrez-PubMed [http://www.ncbi.nlm.nih.gov/Entrez/index.html], National Center for Biotechnology Information] NCBI – Integrated access to biomedical literature, nucleotide and protein sequences, along with 3-dimensional protein structures, complete genomes, and population study data sets Sequence of Mycobacterium tuberculosis CDC1551 [http://www.tigr.org/tigr-scripts/CMR2/ GenomePage3.spl?database=gmt], The Institute for Genome Research [TIGR] – Sequence and annotation of CDC1551, a clinical isolate from Kentucky/Tennessee region Sequence of Mycobacterium tuberculosis H37Rv [http://www.sanger.ac.uk/Projects/M_tuberculosis/], Sanger Center – Sequence and annotation of H37Rv [laboratory strain] TubercuList [http://genolist.pasteur.fr/TubercuList/] Pasteur Institute – Data of DNA and protein sequences derived from H37Rv, linked to annotations and functional assignments EuroTB: Surveillance of tuberculosis in Europe [http://www.eurotb.org/] Research Groups Interested in Tuberculosis Action TB [http://www.uct.ac.za/depts/mmi/lsteyn/glaxo.html], Department of Medical Microbiology, University of Cape Town and Groote Schuur Hospital – Multinational research initiative to develop new effective, anti-TB drugs NIAID’s Tuberculosis Antimicrobial Acquisition and Coordinating Facility [TAACF] [http://www.taacf.org/], NIAID TB programme – Organization that screens compounds in high quality in vitro and in vivo assays, provided at no cost to the compound supplier

Tuberculosis: Some Web-based Resources on the Internet 971 Policy Research and Development [http://www.who.int/gtb/policyrd/index.htm], WHO –WHO research agenda Sequella Global Tuberculosis Foundation [http://www.sequellafoundation.org/index.asp], Sequella Foundation – Foundation focused on applied research to develop tools to control TB; currently interested in vaccine development Stanford Center for Tuberculosis Research [http://molepi.stanford.edu/], Stanford University – Research group focused on molecular epidemiology studies of TB; the Web site also includes software for analyzing DNA fingerprinting and DNA microarray data. The Atlanta Tuberculosis Prevention Coalition [http://www.emory.edu/MED_INF/ATPC/atpc.html], The Atlanta Tuberculosis Prevention Coalition – Organization interested in operational research in the management of TB The Global Research Tuberculosis Initiative [http://www.globalforumhealth.ch/docs/forum3doc391.htm], Global Forum for Health Research – Organization that promotes health policy research Trudeau Institute [http://www.trudeauinstitute.org/], Trudeau Institute – Independent research institute interested in human immune response against TB Resources for Research, Teaching and Training Francis J. Curry National Tuberculosis Center [http://www.nationaltbcenter.edu/ National Tuberculosis Center [CDC] – Tuberculosis Control Program Training Center GrantsNet [http://www.grantsnet.org/], Supported by Howard Hughes Medical Institute and American Association for the Advancement of Science [AAAS] – Search tool to find funds for training and grants in biomedical sciences; also contains grant-writing tools and tips IUATLD [http://www.iuatld.org/], IUATLD – Information about conferences and courses Upcoming events in TB [http://www.cdc.gov/nchstp/tb/calendar.htm], CDC – Calendar with TB-related events National Institutes of Health [NIH] [http://grants.nih.gov/grants/], NIH – NIH guide for grant writing, research contracts, and research training National Tuberculosis Center [http://www.umdnj.edu/ntbcweb/], New Jersey Medical School – Calendar of courses and conferences, and general information about TB and Direct Observed Therapy [DOT] strategy Self-Study Modules of Tuberculosis [http://www.cdc.gov/phtn/tbmodules], CDC –Training material and selfevaluation, teaching material Tuberculosis Academic Awards [http://www.nhlbi.nih.gov/funding/training/ tbaa/], National Heart, Lung and Blood Institute [NHLBI] – Information about awards to stimulate development and improvement in the quality of TB-related medical curricula, and education for health care workers Tuberculosis Research Activities, NIAID [http://www.niaid.nih.gov/dmid/tuberculosis/], NIAID – Information about research goals, resources, blueprints, meeting information, and links Tuberculosis.Net [http://tuberculosis.net/], Montefore Medical Center – Didactic teaching material Wellcome Trust Grants [http://www.wellcome.ac.uk/en/1/gra.html], Wellcome Trust Foundation – Organization that offers grants for research in biomedical topics Information about Regulatory Action State Tuberculosis Control Offices [http://www.cdc.gov/nchstp/tb/tboffices.htm], CDC –List of contact information of state TB control programs in United States State Tuberculosis Control Programs [http://www.cdc.gov/nchstp/tb/tbwebsites.htm], CDC – State TB control programs, including regional epidemiological and surveillance data

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Tuberculosis Handbook [http://www.who.int/gtb/publications/tbhandbook/index.htm], WHO – Synthesis of the general principles and practical approaches for TB control developed by the WHO Global Tuberculosis Program Tuberculosis Respiratory Protection Program in Health Care Facilities [http://www.cdc.gov/niosh/99-143.html], NIOSH – Practical guide to initiating and running a TB respiratory protection program in health care facilities What is DOTS? [http://www.who.int/gtb/publications/whatisdots/index.htm], WHO –Guide to understand the WHO recommended TB control strategy known as DOTS General Tuberculosis Web Sites American Lung Association: TB [http://www.lungusa.org/diseases/lungtb.html] – General TB factsheet Ask NOAH About: Tuberculosis, Bureau of Tuberculosis Control, New York City Department of Health [http:// www.noah-health.org/english/illness/tb/nycdoh/nycdohtb1.html] – Tuberculosis questions and answers BCG Vaccine [http://www.drgreene.com/960520.html] – Dr. Greene discusses the effectiveness of the BCG vaccine Brown University TB/HIV Research Laboratory [www.brown.edu/Research/TB-HIV_Lab/] Centers for Disease Control and Prevention - Division of Tuberculosis Elimination [http://www.cdc.gov/nchstp/ tb/] Columbia-Presbyterian Medical Center: TB Resources [http://www.cpmc.columbia.edu/resources/tbcpp/] – Basic factsheets and articles on tuberculosis including TB : Getting Cured and Skin Test Contact Investigation in a Worksite Toolbox [http://www.nationaltbcenter.edu/catalogue/epub/index.cfm? tableName=ciTBox] – This toolbox compiles instruments and resources for use during a worksite contact investigation. Using these materials, TB control staff will be able to follow step-by-step instructions for contact, implementation, and follow up; develop protocols for inclusion of a worksite in an investigation; and adapt standard templates for local use. The toolbox provides letters, forms, policies, and referenced materials EuroTB [www.eurotb.org/] – Programme aims to collect, analyse and publish epidemiological information on tuberculosis in Europe, with the aim of improving tuberculosis control Francis J. Curry National Tuberculosis Center [http://www.nationaltbcenter.edu/] –The Online Learning section includes knowledgable factsheets on testing and treatment of TB in a Question and Answer format. Pediatric Tuberculosis is an excellent QandA on TB testing in children, including BCG and testing recommendations General Information on TB [http://www.heartscreen.com/tb.html] International adoptions pose extra TB problems, on Dr. Ellen Aronson’s website [http://members.aol.com/ jaronmink/tb2.htm] Medical Library of the American Medical Association [AMA] [http://www.medem.com/search/ article_display.cfm?path=n:andmstr=/ZZZH7LZK1AC.htmlandsoc=AMAandsrch_typ=NAV_SERCH] – Good introduction to TB and symtoms in children MEDLINEplus Tuberculosis [http://www.nlm.nih.gov/medlineplus/tuberculosis.html] – The world’s largest medical library, the National Library of Medicine at the National Institutes of Health Merck Manual Home Edition [http://www.merck.com/pubs/mmanual_home/sec17/181.htm] – Diagnosis, treatment and prevention MMWR [USA] - Disease trends [http://www.cdc.gov/mmwr/distrnds.html] New Jersey Medical School Global Tuberculosis Institute [http://www.umdnj.edu/globaltb/home.htm]

Tuberculosis: Some Web-based Resources on the Internet 973 Questions and Answers about Tuberculosis [http://www.cdc.gov/tb] – This material discusses TB transmission, differentiates between latent TB infection and active TB disease, and describes how multidrug-resistant TB develops [http://www.cdc.gov/nchstp/tb/faqs/pdfs/qa.pdf] Sanger Center [http://www.sanger.ac.uk/Projects/M_tuberculosis/] – Sequence and annotation of H37Rv, [laboratory strain] Self-Study Modules on Tuberculosis: Modules 6-9 [Module 6: Contact Investigations for Tuberculosis] [www.cdc.gov/ nchstp/tb/pubs/ssmodules/module6/ss6contents.htm] – This instructional packet [and web-based course] includes a series of four print-based modules addressing TB contact investigation, case management, and confidentiality. Module 6 focuses on contact investigations. [http://www.cdc.gov/nchstp/tb/pubs/ssmodules/pdfs/6.pdf] Shelters and TB: What Staff Need to Know [http://www.nationaltbcenter.edu] – This videotape and guide are designed for shelter staff about how to prevent the spread of TB. This video describes what TB is, how it is spread, what to do when staff suspects someone with TB, how to develop and implement a TB infection control policy, and how shelters and health departments can work together to create a healthy and safe environment for staff and clients Stanford Center for Tuberculosis Research [http://www.stanford.edu/group/molepi/index.html] – Summary of research, list of publications, and information about international tuberculosis research Stop TB [http://www.stoptb.org/] – A global movement to accelerate social and political action to stop the unnecessary spread of tuberculosis around the world StopTB Partnership [http://www.stoptb.org] Target Tuberculosis [http://www.targettuberculosis.org.uk] – A UK charity targeting the causes and effects of tuberculosis overseas TB - General Information [fact sheet] [http://www.cdc.gov/nchstp/tb/pubs/tbfactsheets/250010.htm] – This tuberculosis fact sheet provides basic information about tuberculosis for patients and the general public. [http:// www.cdc.gov/nchstp/tb/pubs/tbfactsheets/250010.pdf] TB Alert [http://www.tbalert.org/] – A charity designed to increase awareness of tuberculosis and provide resources for service work and research for tuberculosis in developing countries TB in cattle - Department for Environment, Food and Rural Affairs [http://www.defra.gov.uk/animalh/tb/ index.htm] TB in Homeless Shelters: Reducing the Risk through Ventilation, Filters, and UV [http://www.nationaltbcenter.edu] – This guideline provides directors and facility managers of homeless shelters and other shelter workers with information on reducing the risk of TB transmission through ventilation, filters, and use of ultraviolet germicidal irradiation. [http://www.nationaltbcenter.edu/catalogue/downloads/tbhomelessshelters.pdf] The Acid Fast Club [http://www.nibsc.ac.uk/afc/] – Provides opportunities for people doing research on the pathology and bacteriology of tuberculosis to meet and discuss their work The British Lung Foundation [http://www.britishlungfoundation.org/] – The only charity in the UK that funds research into the prevention, diagnosis, treatment and cure of all lung diseases The Immunisation website [http://www.immunisation.org.uk/article.php?id=43] – It contains information on immunisation and vaccines, and is published by the Department of Health and for the NHS The Institute of Genome Research [TIGR] [http://www.tigr.org/tigr-scripts/CMR2GenomePage3.spl?database=gmt] – Sequence and annotation of CDC1551, a clinical isolate from Kentucky/Tennessee region

974

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The International Union Against Tuberculosis and Lung Disease [http://www.iuatld.org/] – A non-profit, nongovernmental voluntary organisation founded in 1920. Its members, organisations and individuals throughout the world are dedicated to the prevention and control of tuberculosis and lung disease, to disseminating information about the hazards of smoking and to the promotion of overall community health The Public Health Research Institute [PHRI] Tuberculosis Center [http://www.phri.org/programs/ program_tbcenter.asp] Think TB [http://www.cdc.gov/nchstp/tb/pubs/Posters/ThinkTB.htm] – This poster, available in English and Spanish, lists the symptoms of TB. [http://www.cdc.gov/nchstp/tb/pubs/Posters/images/NTEngPage.pdf] TubercuList World-Wide Web Server [http://genolist.pasteur.fr/TubercuList/] – Provided by Institut Pasteur Tuberculosis Control – INDIA [http://www.tbcindia.org/] Tuberculosis Education and the Congregate Setting Contact Investigation: A Resource for the Public Health Worker [http://www.umdnj.edu/ntbcweb/tbsplash.html] – This resource was developed for use by public health workers who provide TB education in congregate setting contact investigations. In addition to explaining how to effectively plan and conduct a successful TB education session, it contains: [1] a PowerPoint presentation on the basics of TB; [2] a list of TB-related terms, defined appropriately for lay audiences; [3] frequently-asked-questions [FAQ] sheet specific to contact investigations; [4] a pull-out TB fact sheet; and [5] an evaluation to assess the effectiveness of the TB education session. [http://www.umdnj.edu/ntbcweb/docs/congregate/CongregateSetting.pdf] Tuberculosis- Get the Facts! [http://www.cdc.gov/nchstp/tb/pubs/pamphlets/getthefacts_eng.htm] – This pamphlet, in English and Spanish, provides basic facts about TB transmission, infection, and the tuberculin skin test for patients and the general public. [http://www.cdc.gov/nchstp/tb/pubs/pamphlets/TBgtfctsEng.pdf] Tuberculosis Contact Investigations in Congregate Settings: A Resource for Evaluation [http://www.umdnj.edu/ ntbcweb/tbcontact.htm] – This resource is designed for use in the evaluation of tuberculosis [TB] contact investigations in congregate settings. It provides explanatory text and tools for assessing health care worker performance and skills as well as programmatic outcomes of contact investigations in congregate settings. [http://www.umdnj.edu/ ntbcweb/docs/Contact%20Investigations.pdf] What is DOTS? - Guide to the WHO recommended TB control strategy [http://www.who.int/docstore/gtb/ publications/whatisdots/] WHO Global Tuberculosis Control Report [http://www.who.int/tb/publications/global_report/] WHO Regional Office for Europe centralized information system for infectious diseases [CISID] [http:// www.data.euro.who.int/cisid/] World Health Organization [WHO] Tuberculosis Site [http://www.who.int/gtb/index.htm] – An international overview forTB detection and treatment World Health Organization Tuberculosis - Stop TB Department [http://www.who.int/tb/en/], World Health Organization Health topics – Tuberculosis [http://www.who.int/topics/tuberculosis/en/] Peer-reviewed Journals Abdominal Imaging. [http://www.mghabdimaging.org/] AIDS Care [http://aids-clinical-care.jwatch.org] AIDS Clinical Care [http://aids-clinical-care.jwatch.org/] AIDS Clinical Review [http://www.aegis.com/pubs/books/2001/BK011076.html]

Tuberculosis: Some Web-based Resources on the Internet 975 AIDS Reviews [http://atoz.ebsco.com/titles.asp?id=7510andsid=48071724andbid=109andlang=spaandTabID=2] American Journal of Respiratory and Critical Care Medicine [http://ajrccm.atsjournals.org], American Thoracic Society – Official publication; contains abstracts and some full text articles for free Annals of Medicine [http://www.annals.org/] Annual Review of Microbiology [http://arjournals.annualreviews.org/loi/micro?cookieSet=1] Antibiotics and Chemotherapy [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=showproductsand ProduktNr=223879andsearchWhat=bookseries] Antimicrobial Agents and Chemotherapy [http://aac.asm.org/] Archives in Internal Medicine [http://archinte.ama-assn.org] Basic and Clinical Pharmacology and Toxicology [www.blackwellpublishing.com/journal.asp?ref=1742-7835] BMC Medicine [Electronic Resource] [http://www.biomedcentral.com/bmcmed/] BMC Microbiology [Electronic Resource] [http://www.biomedcentral.com/bmcmicrobiol] BMC Pulmonary Medicine [Electronic Resource] [http://www.biomedcentral.com/bmcpulmmed] BMJ [Clinical Research Ed. ] [http://www.bmj.com] British Journal of Clinical Pharmacology [http://www.bjcp-journal.com/] British Medical Bulletin [http://bmb.oxfordjournals.org/] Bulletin of the World Health Organization [http://www.who.int/bulletin/en/index.html] Canadian Respiratory Journal: Journal of the Canadian Thoracic Society [http://www.csrt.com] Chest [http://www.chestnet.org] Clinical and Experimental Medicine [http://www.springer.com/west/home/medicine?SGWID=4-10054-701167875-0] Clinical Imaging [http://www.elsevier.com/locate/clinimag] Clinical Medicine and Research [http://www.clinmedres.org/] Clinical Microbiology Reviews [http://cmr.asm.org/] Clinical Pharmacology and Therapeutics. [http://www.nature.com/clpt/index.html] Clinical Trials [London, England] [http://clinicaltrials.gov/show/NCT00081029] Clinics in Chest Medicine. [http://www.elsevier.com/wps/find/journaldescription.cws_home/623356/ description#description] CMAJ: Canadian Medical Association Journal [http://www.cmaj.ca/] Critical Reviews in Microbiology [http://www.tandf.co.uk/journals/titles/1040841x.asp] Critical Reviews in Therapeutic Drug Carrier Systems [www.begellhouse.com/journals/3667c4ae6e8fd136.html] Croatian Medical Journal [http://www.cmj.hr/] Current Drug Targets. Infectious Disorders [www.bentham.org/cdtid/index.htm] Current Drug Targets [http://www.bentham.org/cdt/]

976

Tuberculosis

Current Microbiology [http://www.springer.com/284] Current Opinion in Drug Discovery and Development [http://www.biomedcentral.com/curropindrug discovdevel/] Current Opinion in Microbiology [http://www.current-opinion.com/jmcr/about.htm] Current Opinion in Pulmonary Medicine [http://www.co-pulmonarymedicine.com/] Current Topics in Microbiology and Immunology [http://www.trdrp.org/fundedresearch/ Views/ Periodical_Page.asp?periodical_id=194] Diagnostic Microbiology and Infectious Disease [http://www.elsevier.com/wps/product/cws_home/505759] Drug and Therapeutics Bulletin [http://dtb.bmj.com/dtb/do/home] Drug Metabolism and Drug Interactions [http://www.freundpublishing.com/Drug_ Metabolism_ Drug_Interactions/DRUGASc.htm] European Journal of Clinical Investigation [http://www.blackwellpublishing.com/journal.asp?ref=0014-2972] European Journal of Clinical Microbiology and Infectious Diseases: Official Publication of the European Society of Clinical Microbiology [http://ejournals.ebsco.com/direct.asp?JournalID=101941] European Journal of Medical Research [http://www.eurojournals.com/EJSR.htm] Expert Opinion On Drug Safety [http://www.expertopin.com/loi/eds] FEMS Immunology and Medical Microbiology [http://www.blackwellpublishing.com/journal.asp?ref=0928-8244] FEMS Microbiology Letters [http://www.fems-microbiology.org/website/nl/default.asp] FEMS Microbiology Reviews [http://www.fems-microbiology.org/website/nl/page22.asp] Health Policy and Planning [http://ejournals.ebsco.com/direct.asp?JournalID=101525] HIV Clinical Trials [http://www.aidsinfo.nih.gov/ClinicalTrials/Default.aspx] Indian Journal of Medical Microbiology [http://www.ijmm.org/] Indian Journal of Medical Sciences [http://www.indianjmedsci.org/] Indian Journal of Pathology and Microbiology [http://www.iapm.net/journal.htm] Indian Journal of Tuberculosis [http://lrsitbrd.nic.in/indian_journal_of_tuberculosis.htm] International Journal of Clinical Pharmacology and Therapeutics [http://www.clinnephrol.com/] International Journal of Clinical Pharmacology and Therapeutics [http://www.clinnephrol.com/index.php?id=93] International Journal of Clinical Practice [http://www.blackwellpublishing.com/ijcp_enhanced/] International Journal of Leprosy and Other Mycobacterial Diseases: Official Organ of the International Leprosy Association [http://www.leprosy-ila.org/leprosyjournal/html/71-1/71-1.php] International Journal of Medical Microbiology [http://www.sciencedirect.com/science/journal/14384221] International Journal of Tuberculosis and Lung Disease [http://www.ingenta.com/journals/browse/iuatld/ijtld] Irish Journal of Medical Science [http://www.ijms.ie/] JAMA: the Journal of the American Medical Association. [http://jama.ama-assn.org/]

Tuberculosis: Some Web-based Resources on the Internet 977 Journal of Acquired Immune Deficiency Syndromes [http://www.jaids.com/] Journal of Applied Microbiology [http://www.ingenta.com/journals/browse/bsc/jam] Journal of the Association of Physicians of India [http://www.JAPI.org] Journal of Clinical Microbiology [http://www.wt-group.com/jcm2008.html] Journal of HIV Therapy [http://www.ccspublishing.com/j_aids.htm] Journal of Infectious Diseases [http://ucp.uchicago.edu/JID/home.html] Journal of Medical Microbiology [http://jmm.sgmjournals.org/] Journal of Postgraduate Medicine [www.jpgmonline.com/] Journal of the Indian Medical Association [http://www.jimaonline.org.in] Journal of the Royal Society of Medicine [http://www.jrsm.org/] Journal of Thoracic Imaging [http://www.thoracicimaging.com/] Lancet Infectious Diseases [http://www.thelancet.com/journals/laninf ] Magnetic Resonance Imaging Clinics of North America. [http://www.mri.theclinics.com] Medical Microbiology and Immunology [http://www.springer.com/journal/430] Microbial Drug Resistance [Larchmont, N. Y.] [www.liebertpub.com/publication.aspx?pub_id=44] Microbial Pathogenesis [http://www.elsevier.com/wps/product/cws_home/622915] Microbiological Research [http://www.sciencedirect.com/science/journal/09445013] Minerva Medica [http://www.minervamedica.it/journals2.t] MMWR. Morbidity and Mortality Weekly Report [http://www.cdc.gov/mmwr/] MMWR. Recommendations and Reports [http://www.cdc.gov/mmwr/mmwr_rr.html] MMWR. Surveillance Summaries: Morbidity and Mortality Weekly Report. Surveillance Summaries/CDC [www.cdc.gov/mmwr/mmwr_ss.html] Molecular Microbiology [http://molmic35.biol.rug.nl/] Morbidity and Mortality Weekly Report [http://www.cdc.gov/mmwr/] Nature Medicine [http://www.nature.com/nm/] Nature Reviews Drug Discovery [www.nature.com/nrd/] Nature Reviews Microbiology [www.nature.com/nrmicro/] Nigerian Journal of Medicine: Journal of the National Association of Resident Doctors of Nigeria [http:// www.nigerjmed.com/] Nippon Rinsho. Japanese Journal of Clinical Medicine [http://www.nippon-rinsho.co.jp/] Paediatric Respiratory Reviews [http://www.elsevier.com/wps/product/cws_home/623066] Papua and New Guinea Medical Journal [http://www.pngimr.org.pg/png_medical_journals.htm] Pharmacology and Therapeutics [http://www.elsevier.com/locate/pharmthera]

978

Tuberculosis

PLoS Medicine [http://medicine.plosjournals.org] Postgraduate Medical Journal [http://pmj.bmj.com/] Postgraduate Medicine [http://www.postgradmed.com/journal.htm] Preventive Medicine [http://www.elsevier.com/locate/issn/0091-7435] Proceedings of the American Thoracic Society [http://www.thoracic.org/publications/pats/pats.asp] Pulmonary Pharmacology and Therapeutics [http://www.elsevier.com/wps/product/cws_home/622936] QJM: Monthly Journal of the Association of Physicians [http://qjmed.oxfordjournals.org/] Respiratory Care [http://www.rcjournal.com/] Respiratory Medicine [http://intl.elsevierhealth.com/journals/rmed/] Saudi Medical Journal [http://www.smj.org.sa/] Singapore Medical Journal [http://smj.sma.org.sg/smjcurrent.html] South African Medical Journal [http://www.ajol.info/journal_index.php?jid=76] Southern Medical Journal [http://www.sma.org/smj/] The American Journal of Medicine [http://www.amjmed.com/] The Ceylon Medical Journal [http://www.infolanka.com/CMJhome/] The European Respiratory Journal: Official Journal of the European Society For Clinical Respiratory Physiology [http://erj.ersjournals.com/] The Indian Journal of Chest Diseases and Allied Sciences [http://medind.nic.in/iae/iaem.shtml] The Indian Journal of Medical Research [http://www.icmr.nic.in/ijmr/ijmr.htm] The International Journal of Tuberculosis and Lung Disease: the Official Journal of the International Union Against Tuberculosis and Lung Disease [http://www.iuatld.org/full_picture/ en/educ_materials/ijtld/ijtld.phtml] The Journal of Antimicrobial Chemotherapy [http://jac.oxfordjournals.org/] The Journal of Clinical Investigation [http://www.jci.org/contents-by-date.0.shtml] The Journal of Experimental Medicine [http://www.jem.org/] The Journal of General and Applied Microbiology [http://www.iam.u-tokyo.ac.jp/JGAM/general.htm] The Journal of International Medical Research [http://www.jimronline.net/] The Journal of Laboratory and Clinical Medicine [http://www.elsevier.com/wps/product/cws_home/623309] The Journal of Pharmacology and Experimental Therapeutics [http://jpet.aspetjournals.org/] The Journal of the Association of Physicians of India [http://www.japi.org/previous_issue.asp] The Medical Clinics of North America [http://www.medical.theclinics.com/] The Lancet [http://www.thelancet.com/] The Medical Journal of Australia [http://www.mja.com.au/] The National Medical Journal of India [http://www.nmji.in/the%20Journal/the_journal.htm]

Tuberculosis: Some Web-based Resources on the Internet 979 The New England Journal of Medicine [http://www.nejm.org/JHome.htm] The New Zealand Medical Journal [http://www.nzma.org.nz/journal/] The Nigerian Postgraduate Medical Journal [http://www.galenicom.com/ca/medline/journal/ 1117-1936/] The Practitioner [http://www.practitioner.com] The West Indian Medical Journal [http://www.mona.uwi.edu/fms/wimj/] The Yale Journal of Biology and Medicine [http://www.med.yale.edu/yjbm/] Thorax [http://thorax.bmj.com/] Transactions of the Royal Society of Tropical Medicine and Hygiene [http://www.rstmh.org/] Trends in Microbiology [http://www.trends.com/tim/default.htm] Tropical Medicine and International Health: TM and IH [http://www.blackwellpublishing.com/ journal.asp?ref=1360-2276] Tuberculosis [Edinburgh, Scotland] [http://www.galenicom.com/en/medline/journal/1472-9792/Tuberculosis+ [Edinburgh,+Scotland]] Tuberkuloz Ve Toraks [http://www.tubtoraks.org/] Conference Reports/ Proceedings Amsterdam Report, Amsterdam, 22-24 March 2000 ”Tuberculosis and Sustainable Development”, [http:// www.stoptb.org/stop_tb_initiative/amsterdam_conference/] Proceedings of the National Consensus Conference on Tuberculosis, December 3-5, 1997, Canada Communicable Disease Report [http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/98vol24/24s2/index.html] Because of the ephemeral nature of the web sites, web based references may sometimes be elusive (7) as the content may be of permanent-unchanging, permanentstable, permanent-dynamic, or permanence not guaranteed type (8). While every effort has been made to verify the links cited in this chapter, the discerning reader should be aware of this possibility and should attempt further refined search to locate the URL if the listed link does not provide access to the web site cited. REFERENCES 1. Wikipedia – the free encyclopedia. Available URL: http:// en.wikipedia. org/wiki/Main_Page. Accessed on October 4, 2007.

2. Domain Statistics, Available URL: http://www. domainstats.com. Accessed on October 4, 2008. 3. Internet World Stats. Available URL: http://www. internetworldstats.com/stats.htm. Accessed on October 4, 2008. 4. Kato-Maeda M, Small PM. User’s guide to tuberculosis resources on the Internet. Clin Infect Dis 2001;32: 1580-8. 5. Sharma A, Jain NC. Some web-based resources for HIV/ AIDS. Indian J Med Res 2005;121: 611-9. 6. Jain NC. Some important medical resources available on the Internet. Curr Sci 2003;84:1170-1. 7. Crichlow R, Davies S, Winbush N. Accessibility and accuracy of web page references in 5 major medical journals. JAMA 2004;292:2723-4. 8. National Library of Medicine. Developing Permanence Levels and the Archives for NLM’s Permanent Web Documents. Available at URL: http://www.nlm.nih.gov/psd/pcm/ devpermanence.html. Accessed October 4, 2008.

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International Standards for Tuberculosis Care (ISTC)

67

Reproduced with kind permission of Dr PC Hopewell from URL://http://www.who.int/tb/publications/2006/istc_report.pdf. Accessed on October 20, 2008

International Standards for Tuberculosis Care [ISTC]

981

982

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

983

984

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

985

986

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

987

988

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

989

990

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

991

992

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

993

994

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

995

996

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

997

998

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

999

1000

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1001

1002

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1003

1004

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1005

1006

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1007

1008

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1009

1010

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1011

1012

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1013

1014

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1015

1016

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1017

1018

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1019

1020

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1021

1022

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1023

1024

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1025

1026

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1027

1028

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1029

1030

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1031

1032

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1033

1034

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1035

1036

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1037

1038

Tuberculosis

International Standards for Tuberculosis Care [ISTC]

1039

Index Note: “T” indicates table. For example, “T21.1” would be Table 1 in chapter 21

A Abdominal tuberculosis anal tuberculosis 281 bile duct tuberculosis 295 classification 274, T19.1 diagnosis ADA estimation 286,288 ascitic fluid examination 286, 288 barium studies 283 colonoscopy 289 computed tomography, and 285-287 fine needle aspiration cytology 289 interferon-gamma estimation 288 inverted umbrella sign [Fleischner’s sign] 283 laparoscopy 289 peritoneal biopsy 289 polymerase chain reaction 288 positron emission tomography 288 scintigraphy 288 serodiagnosis 288 Stierlin’s sign 284 string sign 284 ultrasonography 285 duodenal tuberculosis 280-281 gall bladder tuberculosis 297 gastric tuberculosis 280 gastrointestinal tuberculosis epidemiology 276-277 pathogenesis 276 hepatobiliary tuberculosis 296, T20.4 in children clinical manifestations 617 role of surgery 617-618 in HIV/AIDS 282 oesophageal tuberculosis 279-280 pancreatic tuberculosis 281 pathology 85-90 peritoneal tuberculosis acute 276 chronic 276 clinical features 275-276, T19.2 epidemiology 275 pathogenesis 275

pathology 88 treatment antituberculosis treatment 290 surgery 290 tuberculosis of appendix 281 tuberculosis of mesentery and its contents 276 tuberculosis of small bowel and colon clinical features 278-279, T19.3, T19.4 diffuse colitis 278 hypertrophic 277 pathology 84-87, 277-278 sclerotic 278 ulcerative 277 ulcerohypertrophic 278 Acetylator status 788 Acid-fast bacilli [AFB], demonstration by staining methods 162-164 Acute lung injury [ALI] in tuberculosis after initiation of antituberculosis treatment 537 definition 532 diagnosis 538 imaging findings 539 in cavitary pulmonary tuberculosis 537 in miliary tuberculosis 535 in tuberculosis pneumonia 535-536 incidence 535 management antituberculosis treatment 539 corticosteroids 539-540 mechanical ventilation 539 oxygen therapy 539 prognosis 540 pathogenesis 532-534 predisposing factors 535 Addison’s disease 553-554 Adenosine deaminase, estimation of in ascitic fluid 171, 286 in cerebrospinal fluid 310 in pericardial fluid 334 in pleural fluid 171, 250, 252-253, T17.1 Adjuvant BCG treatment of urinary bladder cancer, and arthritis 379

Adrenocortical reserve in tuberculosis effect of malnutrition 554 effect of rifampicin on corticosteroids 554 estimation of 554-558 in HIV-TB co-infection 558-559 Amikacin 737, 760, T51.2A, T51.2B, T52.2 Antiretroviral drugs 579-583 co-administration of HAART and antituberculosis treatment 582583, T40.7 highly active antiretroviral therapy [HAART] 579-583 non-nucleoside reverse transcriptase inhibitors [NNRTIs] 580-581, T40.5 efavirenz [EFV] 580-581, T40.5 nevirapine [NVP] 580-581, T40.5 nucleoside reverse transcriptase inhibitors [NRTIs] 580-581, T40.4 lamivudine [3TC] 580 stavudine [d4T] 580 zidovudine [ZDV] 589 nucleotide reverse transcriptase inhibitors [NtRTIs] 583-584, T40.7 protease inhibitors [PIs] amprenavir 583, T40.7 atazanavir 583, T40.7 fosamprenavir 583, T40.7 indinavir 583, T40.7 lopinavir 582-583, T40.7 nelfinavir 583, T40.7 ritonavir 582-583, T40.7 saquinavir 582-583, T40.7 therapy for individuals co-infected with HIV and tuberculosis 581582, T40.6, T40.7 rifabutin based regimens 582-583, T40.7 rifampicin based regimens 582-583, T40.7 Antituberculosis drugs adverse drug reactions, due to 761-773 T52.3 monitoring 742-743

1042

Tuberculosis

reintroduction following resolution of cutaneous reactions 762, T52.4 hepatotoxicity 791-792 capreomycin 760, T52.2 resistance, and tlyA gene 696, T49.1 classification of 737, T51.2A, T51.2B contraception and 446-447 current recommendations for standard regimens continuation phase 736-737 intensive phase 735-736 development of new drugs 757-759 dosages 759-760, T52.2 ethambutol 692-693, 760, T49.1, T52.2 resistance, and arabinosyl transferase genes 693 fixed-dose combinations 743-744 cutaneous reaction, protocol for reintroduction after 762, T52.4 fluoroquinolones 693-694, 760, T49.1, T52.2 hepatotoxicity, and see under “Hepatotoxicity due to antituberculosis treatment” intermittent treatment scientific basis of 737-738 short-course chemotherapy regimens 739-740 standard regimens 738-739 isoniazid 688-691, 777-779, 783-786, T49.1, T52.2 resistance, and ahpC gene 688-691 kasA gene 689-691 katG gene 688-691 oxyR gene 689-691 moxifloxacin for treatment of latent MDR-TB infection 779 resistance, and gyrA gene 694 newer drugs 705, T49.10 ocular toxicity, and 429 pyrazinamide 693, T49.1, T52.2 resistance, and pncA gene 693 rifabutin resistance 688 rifampicin 685-688, 760, 777-779, 783786 T49.1, T52.2 drug interactions 743, 764, T52.5 reasons to protect 745 resistance, and rpoB gene 685-688 short-course chemotherapy regimens basis of 751-752 evolution of 739-740

for extra-pulmonary tuberculosis 741-742 for pulmonary tuberculosis 740741 of less than six months 740 terminology of 740 streptomycin 691-692, T49.1, T52.2 resistance and rpsL gene 691 resistance and rrs gene 691 also see under individual drugs Annual risk of infection [ARI] 22-24, 30-31, 43 Assman foci 81 Atypical mycobacteria see under “Nontuberculous mycobacteria” Azithromycin 737, T51.2A

B BCG test 182 BCG vaccination history of 918-919 malnutrition, and 649 skin lesions, due to 392, T25.2 Bed rest therapy 10 Bhowali, King Edward Sanatorium 12 Blood groups, and susceptibility to tuberculosis 127 Bone and joint tuberculois see under “Skeletal tuberculosis” Breast tuberculosis classification of 436, T29.2 clinical features 435-436 differentiation from carcinoma breast 438 epidemiology 434 investigations 436-437 computed tomography 437 fine needle aspiration cytology 437 magnetic resonance imaging 438 mammography 436 open biopsy 438 ultrasonography 437 mode of infection 434-435 treatment 438 Broadbent’s sign 333 Bronchoalveolar lavage in lower lung field tuberculosis 230 in miliary tuberculosis 505-508 in pulmonary tuberculosis 222-223 Broncholith 520 Bronchopleural fistula 522, 805-806

C Cavernolith 520

Calmette, Albert 10 Candidate genes in tuberculosis 137-138, T8.5 Capreomycin 696, 737, 759-760, T49.1, T51.2A, T51.2B, T52.2 Case definitions for MDR-TB 698, T49.5 WHO recommended, for tuberculosis 819, T56.2 Categorization of patients under RNTCP 896, T63.1, T63.5A Cavernostomy 797 Choroidal tubercles 420, 423, 496 Choroidal tuberculosis 423-425 Chronic meningitis aetiology 315 definition 315 clinical evaluation 315-316 diagnostic studies neuroimaging studies 316 meningeal biopsy 316-317 management 317 Ciprofloxacin see under “Fluoroquinolones” Clarithromycin 737, T51.2A Clofazimine 737, T51.2A Compound palmar ganglion 370 Computed tomography in abdominal tuberculosis 285-287 breast tuberculosis 437 chronic meningitis 316 female genital tuberculosis 458 genitourinary tuberculosis 471 intracranial tuberculomas 318 miliary tuberculosis 501 pulmonary tuberculosis 201-207 radiculomyelitis 324 single, small, enhancing lesions [SSEL] 320 spinal tuberculosis 346-348 tuberculosis meningitis 308 Congenital tuberculosis 79, 218, 296, 598-599 Conjunctival tuberculosis 421-422 Corneal tuberculosis 422 Consumption 11 Crohn’s disease, differentiation from tuberculosis 88, T5.8 Cryptic miliary tuberculosis 497 Culture filtrate protein-10 [CFP-10] 189192, 606-607 Cutaneous tuberculosis BCG vaccination, skin lesions due to 400 clinical features acute miliary tuberculosis of the skin 385

Index 1043 apple jelly nodules 385, 421 lupus vulgaris 385-387, 421 scrofuloderma 387-388 tuberculosis chancre 385 tuberculosis cutis orificialis 388-389 tuberculosis gumma 388 tuberculosis verrucosa cutis 387 diagnosis 391-392 epidemiology 384 in immunocompromised hosts 391 treatment 393 tuberculids criteria for diagnosis 389 erythema induratum 390 erythema nodosum 390 lichen scrofulosorum 389 multiple episodes of Sweet’s syndrome 391 papulonecrotic tuberculids 390 Cycloserine 737, 760, T51.2A, T51.2B, T52.2

D Direct repeats [DR] 661-662, 683 Directly observed therapy adherence 827-829 basic concept 827 choice of method 834-835 compliance 827-829 concordance 827-830 factors improving 829, T 57.1 interventions for improving 830, T57.2 controversies surrounding 835 future 835-836 history of 830-832 hold chain 831 observation of treatment 833-834 Disseminated tuberculosis see under “miliary tuberculosis” DOTS Strategy746, 876-877 and improving the overall quality of health services 867 and MDR-TB 820 and XDR-TB 820 at work places 861-862 cost-effectiveness 867 fundamental principles adequate supply of good quality drugs 818 diagnosis by sputum microscopy 815-816 political will 814-815 short-course chemotherapy given under direct observation 816818

systematic monitoring and accountability 818 global expansion, current status 58, 60, 901 HIV co-infection, and 820-822 results of 818-820 DOTS-Plus Strategy 699-700, 728-730 Drug induced hepatotoxicity see under “Hepatotoxicity, due to antituberculosis treatment” Drug induced liver injury see under “Hepatotoxicity, due to antituberculosis treatment” Drug-resistant tuberculosis acquired resistance see under “resistance among previously treated cases” drug efflux pumps, and development of 695-696 drugs used in the treatment of 700, T49.6 global experience in the management of 702-704, T49.9A global prevalence 715-721 management DOTS-Plus strategy 699-700 monitoring response to treatment 702 nutritional enhancement 705 principles 697-699 regimens for drug-resistant tuberculosis, other than MDRTB 701, T49.8A regimens for MDR-TB 701, T49.8A treatment of latent MDR-TB infection 706 molecular basis of development of resistance to 685-696 capreomycin 696, T49.1 ethambutol 692-693, T49.1 fluoroquinolones 693-694, T49.1 isoniazid 688-691, T49.1 pyrazinamide 693, T49.1 rifampicin 685-688, T49.1 rifabutin 688 streptomycin 691-692, T49.1 molecular epidemiology 682-684 potential causes 696, T49.2, T49.3 primary resistance see under “resistance among new cases” prognostic markers 704, T49.9B resistance among new cases 714-715 resistance among previously treated cases 714-715

standardized definitions 697-698, T49.5 Drug susceptibility testing direct methods 169 E-test 170 indirect methods absolute concentration method [MIC method] 170 MBBacT system 170 proportion method 170 resistance ratio method 170 microscopic-observation drugsusceptibility assay [MODS] 170, 311

E E-test 170 Early secreted antigen-6 [ESAT-6] 109, 188-191, 196, 606-607 Echocardiography 335 Empyema thoracis 806-807 Endobronchial tuberculosis bronchography 238 bronchoscopic appearances 236-238 clinical course 234 epidemiology 232 in HIV infection 238 in lower lung field tuberculosis 238 Indian experience 239 investigations 234-238 microscopic appearance 233 NTM, and 239 pathophysiology macroscopic appearance 233 mechanisms of endobronchial infection 232-233 treatment 239-240 Endometrial tuberculosis 451 Enterobacterial repetitive intergenic consensus [ERIC] sequences 683 Epidemiology drug-resistant tuberculosis in India 721-728 MDR-TB 715-720, 725-728 XDR-TB 717-721 prevalence in newly diagnosed cases 721-724 prevalence in previously treated cases 725 epidemic prediction see under “mathematical modelling” epidemiological load evidence from animal models 18-19 force of infection 22

1044

Tuberculosis

global scenario current status 58, T4.1A, T4.1B historical trajectory 57-58 global targets 63-64 goals of intervention 25-28 HIV co-infection, and 60-62 India annual risk of infection [ARI] 30-31, 43 current status 43, 894 distribution area-wise 33-34 distribution as per socio-economic criteria 37-38 epidemiological trends 40-44 incidence, age-wise 34-36 mathematical modelling 44 prevalence, age-wise 34-36 prevalence, gender-wise 36-37 prevalence of pulmonary tuberculosis 31-38 Indian studies Madanapalle study 27 National Sample Survey 16-17, 28 New Delhi study 30 Studies in Bengaluru area 29 Tuberculosis Prevention Trial 2930 indices and definitions annual risk of infection [ARI] 22-24 death 21-23 incidence of disease 21-23 incidence of infection 21-23 prevalence of disease 21-23 prevalence of infection 21-23 issues in measurement active case detection 55-56 case notification 55 geographical heterogeneity 56 mathematical modelling 44,56-57 passive case detection 55 progress of infection 19 tuberculosis epidemic, course of 19-21 Epituberculosis 79, 218 Erythema nodosum 390 Ethambutol 692-693, 737, 760, T49.1, T51.2A, T51.2B, T52.2 Ethionamide 737, 760, T51.2A, T51.2B Extensively drug-resistant tuberculosis see under “XDR-TB”

F Faber’s test 368 Fall and rise phenomenon 744

Female genital tuberculosis clinical presentation 452-453 epidemiology 449-450 pathogenesis computed tomography 458 diagnosis 453-459 endometrial biopsy 454 endometrial tuberculosis 451 fallopian tube tuberculosis 450 hysterosalpingography 455-456 hysteroscopy 456-458 laparoscopy 456-458 magnetic resonance imaging 459 mycobacterial isolation 454-455 ovarian tuberculosis 451-452 polymerase chain reaction 459 serodiagnosis 458-459 tuberculosis of Bartholin gland 452 tuberculosis of the cervix 452 tuberculosis of the vulva and vagina 452 ultrasonography 458 pregnancy following treatment, of 460 in vitro fertilization 460 tuboplasty 460 treatment 459-460 Fleischner’s sign 283 Fluorescent amplified fragment length polymorphism [FAFLP] 683 Fluoroquinolones 693-694, 737, 760 T49.1, T51.2A, T51.2B, T52.2 Friedrich’s sign 332

G Gaenslen’s test 368 Gatifloxacin see under “Fluoroquinolones” Genetic susceptibility to tuberculosis ABO blood groups, and 127 racial differences 127 twin studies 127 Genitourinary tuberculosis clinical presentation 465-467, T32.2 diagnosis arteriography 470 computed tomography 471 cystoscopy 471 intravenous urography 469 magnetic resonance urography 470 microbiological methods 468 percutaneous antegrade pyelography 470 plain radiograph 468-469 polymerase chain reaction 468 retrograde pyelography 470

retrograde urethrography 471 ultrasonography 471 urine examination 467 voiding cystourethrogram 470 epidemiology 463 in children clinical presentation 614-615 role of surgery 615 in females see under “Female genital tuberculosis” in males tuberculosis of the epididymis 466-467 tuberculosis of the kidney 465-466 tuberculosis of the penis 467 tuberculosis of the prostate 467 tuberculosis of the testis 466 tuberculosis of the urethra 467 pathogenesis 463-465 tuberculosis of the ureter 466 tuberculosis of the urinary bladder 466 treatment antituberculosis treatment 471-472 surgery 472-477, T32.3 Ghon’s complex see under “primay complex” Giant cells foreign body Langhans’ 67, 69, 76, 83, 95 Global plan to stop TB 63,64 Granuloma 67-68, 116-117 also see under “granulomatous inflammation” Granulomatous hepatitis aetiology 294-295, T20.1 clinical presentation 295 differential diagnosis 296-298 idiopathic 301 laboratory abnormalities 295-296 pathological types 295 prognosis 302 treatment 301-303 Granulomatous inflammation 68-70 Guérin, Camille 10

H Haematological manifestations AIDS, and 548-549 anaemia 542-544 bone marrow changes 546-547, T37.3 coagulation abnormalities 545 drug-induced 547-548 leucocyte changes 544

Index 1045 NTM infection, and 547 pancytopenia 545 platelet abnormalities 543-545 Health care workers and tuberculosis controlling 637-641, T45.2 early diagnosis and treatment 637639 preventive strategies 639-641 factors influencing nosocomial transmission 635-637, T45.1 HEPA filters and individual protection 640- 641 IGRAs and detection of LTBI 635 infection control measures 639-641 occupational hazard 634 PAPR filters and individual protection 640-641 recognition of transmission interferon-gamma release assays 635 tuberculin skin test, and 634-635 risk assessment 637 risk of infection 635 treatment of latent tuberculosis infection 642 ultra-violet [UV] radiation, use of 641 Health education 747 Hepatotoxicity, due to antituberculosis treatment clinical course 789-790 due to isoniazid and rifampicin 784786 due to isoniazid, rifampicin and pyrazinamide 786 due to treatment of latent tuberculosis infection 786-787 effect of antituberculosis drugs on the liver 783-784 liver transplantation, and 792 management diagnosis 790, T54.2 guidelines for monitoring 790-791 recommendations for re-introduction of treatment 791-792 treatment of tuberculosis in patients who developed hepatotoxicity 791 recurrence of 792 risk factors for development acetylator status 788 age 787 ethnic and racial variation 787 genetic factors 787 glutathione S-transferase 788 hepatitis viruses 789 HIV 789 malnutrition 789

N-acetyl transferase and cytochrome P450 2E1 788 sex 787 type of tuberculosis 789 underlying chronic liver disease 788-789 Hippocratic succusion 220 HIV/AIDS and complications 919-920 and tuberculosis see under “Tuberculosis and HIV infection” Hold chain 831 Home sanatorium study 13 Huebschmann foci 78 Human immunodeficiency virus infection imaging 213-214 Human leucocyte antigen biological functions 131 disease associations 131-132 Hysterosalpingography 455-456

I Immunogenetics of tuberculosis family studies 135 HLA class I association studies 133-135, T8.3 HLA-DR2 in mycobacterial diseases 135-137 non-HLA genes 137 population studies HLA class I association studies 132-133, T8.2 Immune reconstitution inflammatory syndrome [IRIS] 406-407, 497, 583-584 also see under “IRIS” Immune response genes 127-128 Innate immunity interferon-gamma 112 interleukin-1 beta 112 interleukin-4 112 interleukin-6 111 interleukin-10 112 interleukin-12 112 interleukin-18 112 transforming growth factor-beta 113 tumour necrosis factor-alpha 110-111 Interferon-gamma, estimation of in ascitic fluid 171, 288 in pericardial fluid 334 in pleural fluid 171, 253 Interferon-gamma release assays and detection of LTBI 191-192, 635, 776-777 biology 188

commercially available assays, characteristics QuantiFERON®-TB Gold® 190 T-SPOT.TB® test 190 guidelines for use 192 implications for resource-limited settings 195 International standards for tuberculosis care [ISTC] 980-1038 Intracranial tuberculosis diagnosis 318 epidemiology 317-318 imaging studies 318 management 318,320 magentic resonance spectroscopy 319 pathology 317 prognosis and outcome 322-323 sequelae 323 Iron metabolism 542-543, 548 IS6110 659-662, 683-685, 697 Isoniazid 688-691, 737, 760, 777-779, 783-786, T49.1, T51.2A, T51.2B, T52.2

J Johne’s disease 107 also see under “Mycobacterium avium sub-species paratuberculosis”

K Kanamycin 737, 760, T51.2A, T51.2B, T52.2B Kasauli , Lady Linlithgow Sanatorium 12 Kinyoun’s method 162 Koch’s lymph 10 Koch’s phenomenon 105 Koch, Robert 9-10 Koenig’s syndrome 85 Kussmaul’s sign 333

L Laboratory diagnosis of tuberculosis animal inoculation 167 collection and transportation of clinical specimens bronchoscopic secretions 161 cerebrospinal fluid 161 serous fluids 161 sputum 160-161 tissue 161-162 urine 161 direct demonstration of mycobacteria in extra-pulmonary specimens 163-164

1046

Tuberculosis

fluorescent staining 163 Kinyoun’s method 162 Petroff’s method 163 with Gabett’s solution 162 Ziehl-Neelsen stain 164 Genotype assays GenoType Mycobacteria Assay 169 GenoType MTBDR Assay 169 immunodiagnosis 167-169 antibody detection tests 167 antigen detection 168 flow-through filter tests 168 lipoarabinomannan [LAM] in urine test 168 isolation of mycobacteria by culture BACTEC radiometric system 165 colony characteristics 165 culture characteristics 165 culture media 165, T10.3 mycobacteria growth indicator tube [MGIT] 165 mycobacteriophage-based detection tests 166 nucleic acid amplification tests amplified Mycobacterium tuberculosis direct test 168 ligase chain reaction [LCR] 168 loop mediated isothermal amplification [LAMP] 168 nucleic acid probes 168 polymerase chain reaction [PCR] 168 polymerase chain reaction sequencing 169 rapid liquid tuberculosis culture see under “mycobacteria growth inhibitor tube” Septi Chek Acid-fast Bacilli 165 Langhans Theodore 67 Latent tuberculosis infection interferon-gamma release assays [IGRAs], and detection of 191192, 635, 776-777 programmatic issues, India and 779782 regimens for treatment of 777-779, T53.3 treatment in high prevalence settings 781 treatment of latent MDR-TB infection 779 tuberculin skin test , and diagnosis of 186-188, 776-777 Levofloxacin see under “Fluoroquinolones”

Lower lung field tuberculosis bronchoscopy, and 229-230 clinical features 228 investigations 229-230 management 230 prevalence 227-228, T15.1 terminology of 227 Lymph node tuberculosis clinical features 398-399 in patients with HIV infection 399 epidemiology 397-398 diagnosis cytopathology 403-404 histopathology 403-404 imaging 401 molecular and other methods 404 diffrential diagnosis 401 in children 618 pathogenesis 398 treatment 405-407 IRIS, and 406-407

M Manget, John Jacob 493 Madanapalle, Union Mission Tuberculosis Sanatorium 12 Magnetic resonance imaging in breast tuberculosis 438 chronic meningitis 316 female genital tuberculosis 459 intracranial tuberculomas 318 miliary tuberculosis 501 radiculomyelitis 324 single, small, enhancing lesions [SSEL] 320 spinal tuberculosis 346-348 tuberculosis meningitis 308 Major histocompatibility complex central genes see under “class III genes” class I genes 128-129 class II genes 130 class III genes 130-131 Major polymorphic tandem repeats [MPTR] 683 Microscopic-observation drug susceptibility assay [MODS] 170, 311 Miliary tuberculosis atypical manifestations 497, T34.4 bronchoalveolar lavage 505-508 cardiopulmonary exercise testing 505 clinical presentation 494-497 complications 513 cryptic miliary tuberculosis 497, T34.5 diagnosis 508-511 epidemiology 493

gas exchange, and 502-504 imaging findinsgs chest radiograph 499-500 computed tomogrpahy 501 magnetic resonance imaging 501 ultrasonography 501 immune reconstitution inflammatory syndrome [IRIS] 497 immunological abnormalitites 505-508 in HIV infection and AIDS 497 in immunosuppressed patients 497 laboratory findings haematology 498 serum biochemistry 498 miliary pattern on chest radiograph 513, T34.11 prognosis 512-514 pulmonary functions, and 502-504 rare manifestations 497 treatment 511-513 corticosteroids, and 513 Moxifloxacin see under “Fluoroquinolones” Multidrug-resistant tuberculosis case definitions 698, T49.5 drugs used in the treatment of 700, T49.6 factors implicated in the causation 696, T49.2 global prevalence 715-721 in the immunocompromised 696-697 management DOTS-Plus strategy 699-700 global experience in the management of 702-704, T49.9A immunotherpay 765-766 monitoring response to treatment 702 nutritional enhancement 705 principles of treatment 697-699, 755-757 regimens for treatment 701, T49.8A surgery, for 764-765, 803-805 prevalence, in India 725-728 prevention, in India’s RNTCP 729-730 prognostic markers 704, T49.9B standardized definitions 697-698, T49.5 treatment of latent MDR-TB infection 706, 779 treatment outcome 728 also see under “MDR-TB” Musculoskeletal manifestations of tuberculosis arthralgias, antituberculosis treatment induced 379

Index 1047 changing clincal pattern 376 clinical setting for suspecting 374-376 diagnosis 379-380 indications for synovial biopsy 379-380 epidemiology 374 imaging 379 nontuberculous mycobacterial infections, and 378-379 panniculitis associated with tuberculosis 377-378 Poncet’s disease 376-377 reactive para-infectious arthritis see under “Poncet’s disease” rheumatic syndromes 374, T24.2 treatment 380 unusual presentations, of 378 Myocardial tuberculosis 339 Mycobacteria biochemical properties arylsulphatase test 166 catalase at room temperature 166 catalase at 68 oC 166 neutral red test 166 niacin test 166 nicotinamidase activity 167 nitrate reduction 166 peroxidase test 167 pyrazinamidase activity 167 susceptibility to p-nitrobenzoate 167 susceptibility to pyrazinamide 167 susceptibility to TCH 167 classification of 102, T6.1 culture media Dubos’ medium 164 liquid media 164 Loeffler serum slope 164 Lowenstein-Jensen medium 164 Middlebrook’s medium 164 Pawlowsky’s medium [potato medium] 164 solid media 164 Sula’s medium 164 Sutton’s medium 164 Tarshis medium [blood medium] 164 high performance liquid chromatography [HPLC], and identification of 169 saprophytic 107 Tween 80 degradation 166 Tween hydrolysis 166 Mycobacteria growth indicator tube [MGIT] 165 Mycobacterium abscessus 393, 666

Mycobacterium bovis 102-103 Mycobacterium arupense 666, 670 Mycobacterium aubaganense 666, 670 Mycobacterium avium intracellulare 393, 407, 666-668 Mycobacterium avium sub-species paratuberculosis 107, 666 Mycobacterium bohemicum 666, 670 Mycobacterium bolletti 666, 670 Mycobacterium canariasense 666, 670 Mycobacterium celatum 666, 669 Mycobacterium conspicuum 666, 669 Mycobacterium diernhoferi 666, 670 Mycobacterium elephantis 666, 670 Mycobacterium fortuitum-Mycobacterium chelonae complex 666, 669 Mycobacterium chelonae 394, 666 Mycobacterium fortuitum 394, 666 Mycobacterium fortuitum, third biovariant complex 666, 670 Mycobacterium boenickei 666, 670 Mycobacterium brisbanense 666, 670 Mycobacterium houstonense 666, 670 Mycobacterium neworleansese 666, 670 Mycobacterium parascrofulaceum 666, 670 Mycobacterium porcinum 666, 670 Mycobacterium genavense 666, 669 Mycobacterium goodii 666, 670 Mycobacterium gordonae 393, 666, Mycobacterium haemophilium 393, 666, 669 Mycobacterium heckeshornense 666, 670 Mycobacterium interjectum 666, 668 Mycobacterium kansasii 394, 666, 668 Mycobacterium malmoense 666, 669 Mycobacterium marinum 106-107, 392, 666, 669 fish tank granuloma 392, 666 swimming pool granuloma 392, 666, Mycobacterium neoaurum 666, 669 Mycobacterium palustre 666, 670 Mycobacterium paratuberculosis 106, 666, 668 Mycobacterium parmense 666, 670 Mycobacterium phocaicum 666, 670 Mycobacterium pseudoshottsi 666, 670 Mycobacterium scrofulaceum 393, 668, 666 Mycobacterium septicum 666, 670 Mycobacterium shottsi 666, 670 Mycobacterium simiae 666, 668 Mycobacterium smegmatis 107, 666, 669, 670 Mycobacterium szulgai 394, 666, 668 Mycobacterium terrae complex 666, 669 Mycobacterium nonchromogenicum 666, 669

Mycobacterium terrae 666, 669 Mycobacterium triviale 666, 669 Mycobacterium thermoresistible 666, 669 Mycobacterium tuberculosis antigenic structure 104 bacteriocins 105 biochemical properties 104 cell wall 103 culture characteristics 103-104 host immune response 124-125 morphology 102-103 mycobacteriophages 105 pathogenesis 105 postgenomics efforts and 705-706 susceptibility to physical and chemical agents 104 virulence in animals 104 Mycobacterium ulcerans 106, 392, 668 Buruli ulcer disease 392 Mycobacterium vaccae 669, 670 Mycobacterium w 107, 928 Mycobacterium woliniskyi 666, 670 Mycobacterium xenopi 666, 668

N National Task Force [NTF] 639, 902, 911 National Tuberculosis Institute, Bengaluru 13-14 Natural resistance associated macropahge protein [Nramp1] see under SLC11A1 Neelsen, Freidrich 71 Nitrate reduction test 166 Neurological tuberculosis classification 304, T21.1 role of surgery, in children 622-623 New Delhi Tuberculosis Centre 12 New Stop TB Strategy 63 Night cries 344, 351 Nonphotochromogens 103 Nontuberculous mycobacteria classification 103, T6.2 clinical manifestations 670 cutaneous lesions due to 393 diagnosis 670-674 culture methods 672 histopathology 672 identification of isolates 672-674 monitoring for toxicity 675 treatment 676, T48.6 distribution in the environment 665-667 lymphadenitis, due to 399-401, 407, T26.6 in children 618-620 prevention 676, T48.5

1048

Tuberculosis

pulmonary disease 671 species 666, T48.1A causing infection in humans 666, T48.1B Nutrition and tuberculosis adjuvant immunotherapy 651-652 clinical implications and interventions diagnosis 649-650 malnutrition and BCG vaccine 649 cycle of hunger and disease 652-653 impact of nutrition clinical evidence 647-648 evidence from animal models 646-647 impact of tuberculosis on nutrition 648-649 isonaizid and vitamin B6 deficiency 650 monitoring nutritional status 652 natural history of tuberculosis in malnourished patients 650 nutritional interventions in active tuberculosis 650-651

O Ocular tuberculosis choroidal tuberculosis 423-425 conjunctival tuberculosis 421-422 corneal tuberculosis 422 diagnosis 427-428 eye lid tuberculosis 421 in HIV infected patients 427 iritis and iridocyclitis 425 endophthalmitis 425 panophthalmitis 425 orbital tuberculosis 422-423 primary 420 secondary 420 scleral tuberculosis 422 treatment 428-429 tuberculosis of the lacrimal system 422 tuberculosis of the uveal tract 423 Oesophageal tuberculosis 279-280 Open-negative syndrome 525 Orthotopic neobladder 473, 475-476 Ofloxacin see under “Fluoroquinolones”

P Para-aminosalicylic acid 737, 760, T51.2A, T51.2B, T52.2 Parotid gland tuberculosis 414 Parrot’s law 72 Pott’s paraplegia see under “spinal tuberculosis”

People living with HIV/AIDS [PLHIV] 574, 579, 586 also see under “Tuberculosis and HIV infection” Photochromogens 103 Polymorphic GC-rich sequences [PGRS] 683 Primary complex 72, 217 Primary tuberculosis 72-78 T5.6 at rare sites eye 74 skin 74 gastrointestinal tract 74-75 genitourinary tract 75 liver 74-75 head and neck 75 Prosector’s warts 217 Prothionamide 737, 760, T51.2A, T51.2B, T52.2 Pulmonary tuberculosis complications amyloidosis 529 aspergilloma 521-522 chronic respiratory failure 527-528 cor-pulmonale 528 endobronchitis 524 enteritis 525 fungus ball 521-522 haemoptysis 519 in HIV-seropositive patients 523 laryngitis 525 open-negative syndrome 525 post-tuberculosis bronchiectasis 524 pulmonary artery hypertension 528-529 pulmonary function changes 527 Rasmussen’s aneurysm 519-520 scar carcinoma 527 spontaneous pneumothorax 525 tracheitis 524-525 diagnosis 220-222 fibreoptic bronchoscopy, and 222223 differential diagnosis 223-225, T14.1 natural history 217-219 physical signs 220- 221 cracked pot sound 220 Hippocratic succussion 220 myotactic irritability 220 post-tussive suction 220 post-primary 81-85, 218-219 imaging in 207-212 symptoms 218-220 primary 78-79, 81, 217-218 epituberculosis 79, 218 imaging in 201-207 in adults 80

progression 78-80 role of surgery in children 620-622, T43.3 Psoas abscess 344, 345-347 Pyrazinamide 693, 737, 760, T49.1, T51.2A, T51.2B, T52.2

R Rajayakshma 7 Ranke complex 72 Rapid growers 103 Reactivation and reinfection tuberculosis clinical presentation 657-658 distinguishing treatment failure and exogenous reinfection 661-663 molecular epidemiology 659-661 natural history of tuberculosis infection 656-657 pathogenesis 658 Reactive nitrogen intermediates [RNIs] 114 Reactive oxygen intermediates [ROIs] 113 Restriction fragment length polymorphisms [RFLP] 661-662, 683 Revised National Tuberculosis Control Programme [RNTCP] academic sector, and 910-911 advocacy communication for social mobilization [ACSM] 905-906 categorization of patients under RNTCP 896, T63.1, T63.5A DOTS expansion, and 901-902 drug procurement and management system 898-901 HIV-TB co-infection, and 906-907 information, education and communication [IEC] 905-906 laboratory network and quality assurance 902-905 medical colleges, and 910-911 management treatment of adult tuberculosis 897, T63.1 treatment of paediatric tuberculosis 907-908, T63.5A, T63.5B performance of 902, 899-900, T63.3 private sector, and 908, 910 quality assurance 902-905 research, and drug resistance surveillance 913 Joint Monitoring Missions 913-914 measuring epidemiological impact 912-913 priority areas 912, T63.7 thrust areas 914-915

Index 1049 staff trained in 898, T63.2 technical foundation 895-898 Rice bodies 369 Rich focus 95 Rifabutin 688, 737, T51.2A Rifampicin 685-688, 737, 760, 777-779, 783-786 T49.1, T51.2A, T51.2B, T52.2 drug interactions 743, 764, T52.5 “flu syndrome” 760 reasons to protect 745 resistance, and rpoB gene 685-688 Rifapentene 737, T51.2A Roentgen, Wilhelm Conrad 10 Runyon classification 103

S Salivary gland tuberculosis 414 Scotochromogens 103 Scrofula 7, 397 Silicotuberculosis clinical features 271 diagnosis 271-272 epidemiology 269-270 pathogenesis 270-271 prevention 272 radiographic findings 269 silicosis accelerated 269 acute 268-269 bronchoalveolar lavage 269 chronic 268 complications 269 treatment 272 Simon foci 78 Single, small, enhancing brain lesions on CT, and seizures aetiology 320 definition 320 management 321 neuroimaging 321 Skeletal tuberculosis at rare sites acromioclavicular joint 368 clavicle 369 ilium, ischium and ischiopubic ramus 369 scapula 369 sternoclavicular joint 368 sternum and ribs 369 symphysis pubis 369 prognosis 343 types osseous exudative [caseating] type 342-343

osseous granular type 342 synovial exudative [caseous] type 343 synovial granular type 343 tuberculosis of the ankle joint and foot clinical features 360 management 361 pathology 359-360 radiological features 361-362 tuberculosis bursitis 370 tuberculosis of the elbow joint clinical features 364 management 364-366 pathology 364 radiological features 364 tuberculosis of the hip joint clinical features 351-352 stage of advanced arthritis 352 stage of early arthritis 352 stage of synovitis 351-352 management 354-355 pathology 351 radiological features 352-354 tuberculosis of the knee joint clinical features 356-357 management 358-359 pathology 355 radiological features 357-358 tuberculosis of the sacroiliac joint clinical features 367-368 management 368 pathology 367 radiological features 368 tuberculosis of the prosthetic joint 371 tuberculosis of the shoulder joint clinical features 362 management 363-364 pathology 362 radiological features 362-363 tuberculosis of the spine see under “Spinal tuberculosis” tuberculosis of the wrist joint clinical features 366 management 367 pathology 366 radiological features 366 SLC11A1 145-146, 151, 543 Spinal tuberculosis cervical spine involvement, and 410-411 clinical features 344-345 differential diagnosis 348 18FDG-PET scan 371 formation of cold abscess 343 grading of paraplegia 345 imaging diagnosis

infection of bone 343 management antituberculosis treatment 349 surgery, indications for 349, T23.3 paraplegia in extension 345 paraplegia in flexion 345 paraplegia [Pott’s paraplegia] 344 pathology 343-344 radiological features 345-348 Spleen, tuberculosis of 76, 281-282 Sputum smear microscopy 162-163 grading 163 T10.1, T10.2 Stierlin’s sign 284 Streptomycin 691-692, 737, 760, T49.1, T51.2A, T51.2B, T52.2 resistance and rpsL gene 691 resistance and rrs gene 691 String sign 284 Surgery for active pulmonary tuberculosis current status 801-802 extrapleural pneumonolysis 798 phrenic nerve paralysis 798 pneumoperitoneum 798 pneumothorax 798 preoperative work-up 802-803 the cavernostomy era 797 the collapse therapy era 797 thoracoplasty 799-801 for complications of pulmonary tuberculosis aspergilloma 808-809 bronchial stenosis 808 bronchiectasis 808 broncholiths 808 caused by mediastinal lymphadenopathy 809 cold abscess of chest wall 809 foci of residual disease 808 for complications of previous surgery 809-810 haemoptysis 807-808 Indian experience 810-811 tracheal stenosis 808 for confirmation of diagnosis of tuberculosis 796 video-assisted thoracoscopic surgery 796-797 for MDR-TB 803-805 bronchopleural fistula, and 805-806 for tuberculosis empyema 806-807 Susceptibility to tuberculosis candidate genes interferon-gamma 150 interleukin-12/interleukin-23/ interferon-gamma pathway 150

1050

Tuberculosis

linkage studies 152-153 major histocompatibility complex 152 mannose binding lectins 152 SLC11A1 151, 543 vitamin D receptor 151-152 genetic studies in human populations Mendelian susceptibility to mycobacterial disease [OMIM 209950] 149-151 host-pathogen interplay 144 mouse models 145 adhesion molecules 148 cellular immunity 146 chemokines 147 cytokines 146-147 major histocompatibility complex 150 mouse knock-out models 146 pattern recognition receptors 148 qualitative trait locus analysis 148-149 SLC11A1 studies 145-146 pathogenesis 144 population variability 143 Syndrome of inappropriate antidiuretic hormome secretion [SIADH] 497, 562

T Tabes mesenterica 86 Takayasu arteritis 339 T-cell subsets with an immunoregulatory role gamma-delta T-cells 117 natural killer T-cells 117-118 Treg-cells 118 Terizidone 737, T51.2B Thioacetazone 737, 760, T51.2A, T51.2B, T52.2 Thyroid gland tuberculosis 563-564 Tobacco smoking and tuberculosis 72 Toll-like receptors, and innate immunity 110-111 “Tree-in-bud-appearance” 210, 234-235 Treatment of tuberculosis adjunctive corticosteroid treatment 766 aims of 752 categorization of patients under RNTCP 896, T63.1, T63.5A DOTS, and 754 extrapulmonary tuberculosis 763-764 history of 751 in patients who developed hepatotoxicity 791 monodrug-resistant tuberculosis 755

multidrug-resistant tuberculosis 755757, 764-766 RNTCP regimens for adult tuberculosis 897, T63.1 RNTCP regimens for paediatric tuberculosis 907-908, T63.5A, T63.5B smear-negative pulmonary tuberculosis 754-755 smear-positive pulmonary tuberculosis 752-754 therpeutic drug monitoring 766-768, T52.6 WHO regimens 816, T56.1 Tuberculin skin test administration 186-187 adverse effects 176 bacille Calmette-Guerin vaccination, and 177 booster phenomenon 181 conversion 181 dosage 175 epidemiological uses 182 false-positive and false-negative reactions 179 Heaf test 173 historical background 174 immunological basis 174 in HIV-seropositive persons 179 infection with environmental mycobacteria, and 176-177 interpretation 179-180 Mantoux test 173 newer tuberculins 182 old tuberculin 171 reading of the test 176 reversion 181 sarcoidosis, and 182 skin changes 175 standard tuberculin skin test, administration of 175 Tine test 173 tuberculins 174 Tuberculosis acquired T-cell mediated immune mechanisms 114-115 altered water and electrolyte metabolism, and 562-563 and diabetes mellitus 568 case definitions, for 819, T56.2 CD4+ and CD8+ T-cells, and 115-116 classification 66-67, T5.1 diabetes mellitus, and 566-568 generalized 76-77 infection, events during 109

hypercalcaemia 564-565 hypothalamus involvement, and 516 immune effector mechanisms against 113-114 immunoevasion 119 immunomodulators in 119-121 immunopathogenesis 108-109 in arts and literature 10-11 in the Vedas 7-8, 10 innate immunity 109-113 laboratory related safety issues 171 non-genetic factors influencing the incidence 126-127 perinatal 73-74 pituitary involvement, and 516 placental transmission of 442-443 primary 72-78, T5.6 tobacco smoking, and 72 treatment, scientific basis of 734-735 vitamin D deficiency, and 565-566 well known victims of 11-12, T2.1 Tuberculosis and HIV infection clinical presentation 576-578 drug-resistant tuberculosis, and 584-585 extensively drug-resistant tuberculosis [XDR-TB], and 585 in children 578 diagnosis 578 epidemiology 574-576 management of HIV-TB co-infection 579-584 antituberculosis treatment 580-581 BCG vaccination, and 585 controlling tuberculosis transmission 585 highly active anti-retroviral treatment [HAART], and 579-580 IRIS, and 583-584 prevention 585-587 repsonse to treatment 582-583 Tuberculosis Association of India 12 Tuberculosis control community contribution to 863 ethics adherence 954 application in public health 952 autonomy 951 beneficence 951 compliance 954 direct observation of treatment 955 in the east 950 in the west 950 justice 951

Index 1051 non-maleficence 951 principles and tasks 950-951 relationship of a patient with the health care provider 954 relationship of a patient with the health care structure 956-958 global partnership for 854-856 global tuberculosis control current situation 882-885 DOTS strategy, and 876-877 pre-1992 874-876 priorities or action 886-889 progress since 1992 877-878 Stop TB Initiative, mission of the 878-882 HIV/AIDS organizations, and 871 in India history of 11-12, 894-895 infectious disease control and tuberculosis 949 legal issues high risk groups 958-959 prisons 959-960 legislation for infectious disease control 953 media, and 863 medical colleges, and 839-841, 860 advocacy 840 continuing education 844 educational strategy 841-842 guidelines development 844 Indian experience 844 medical education 840 research 843 service delivery 842-843 Tuberculosis Task Force 843-844 Non-governmental organizations [NGOs], and advocacy 870 child health issue 867 co-ordination 872 collaboration 872 community care 869 community participation 869 development issue 867 education 870 examples of NGO approaches 868-871 gender issue 867 health service management support 868 human rights issue 867 information 871-872 patients’ organizations 870 research 870

service delivery 868 successful networking 872, T61.5 The Bangladesh Rural Advancement Corporation 858 private health sector, and 859, 871 progress in South-East Asia region 856-858 National parternships 858 public health and tuberculosis 948-949 public-private mix, and diverse mix of health care providers 846 evidencce base 847-848 examples of ongoing publicprivate initiatives Kathmandu Valley, Nepal 859860 Mahavir Trust Hospital, Hyderabad, India 859 implementing details, regarding 851-852 developing operational guidelines 849-851 national situation assessment 848-849 PPM DOTS 847, T59.2 Tuberculosis in children clinical features extrathoracic tuberculosis 593-594 intrathoracic tuberculosis 592-593 diagnosis interferon-gamma release assays 606-607 laboratory tests 594-596 novel culture systems and detection methods 608-609 nucleic acid amplification tests 609-611 radiology 594 scoring systems, and 596 screening for disease 603 serological diagnosis 606 traditional methods 607-608 drug-resistant tuberculosis, and 596-597 epidemiology 591 natural history 592 transmission 591-592 treatment 597-600 corticosteroids, and 598 monitoring of therapy 599-600 of a child in contact with an adult with tuberculosis 599 of infants born to a mother with tuberculosis 598

Tuberculosis in chronic renal failure clinical presentation during haemodialysis 480-482, T33.1 diagnosis 484 following renal transplantation 482484, T33.2 magnitude of the problem 480 management 484 antituberculosis drug dosage, and 485-486, T33.4 prognosis 489 treatment of active tuberculosis in patients on dialysis treatment 486 treatment of active tuberculosis in renal transplant recipients 488 treatment of LTBI in patients on dialysis treatment 487-488 treatment of LTBI in renal transplant recipients 488 nontuberculous mycobacterial infection, and 489 pathogenesis 479 Tuberculosis in head and neck region diagnosis 416 imaging, and 416 impact of HIV infection 417 indications for surgery, in 418,T27.2 tuberculosis of larynx clinical features 413-414 diagnosis 416 epidemiology 413 pathogenesis 412, 525 pathology 413 tuberculosis of nasal cavity 416 tuberculosis of oral cavity 412 tuberculosis of pharynx 414 tuberculosis of the ear clinical manifestations 415 pathogenesis 415 primary infection 414 tuberculosis of the nasopharynx 415 tuberculosis of the paranasal sinuses 415 turban epiglottis 413 tuberculosis of the salivary glands 414 treatment 417-418 Tuberculosis in pregnancy breast feeding, and 446 clinical presentation 441-442 diagnosis 444-445 effect of pregnancy on tuberculosis 442-443 effect of tuberculosis on pregnancy 443-444

1052

Tuberculosis

epidemiology 441 management of infants born to a mother with tuberculosis 446, 598 treatment of active tuberculosis 445446 treatment of latent tuberculosis infection 446 Tuberculosis in the elderly clinical features 627-630 extra-pulmonary tuberculosis 629 generalized tuberculosis 629 HIV infection, and 630 pulmonary tuberculosis 627-628 diagnosis 630 epidemiology 625-626 latent tuberculosis infection 626-627 reactivation and reinfection 626 treatment 630-632 adverse effects, of 631 of HIV-TB co-infection 631 of LTBI 631-632 treatment ex-juvantibus [trial treatment] 631 Tuberculosis meningitis clinical features 306-307 clinical staging system 307, T 21.4 complications 314-315 corticosteroids, and 313 CSF examination 308-311 diagnosis 307-311 differential diagnosis 307, T21.5 HIV infection, and 307 pathogenesis 305 pathology 305-306 treatment 311-314 Tuberculosis osteomyelitis 370-371 Tuberculosis pericarditis clinical features ascites precox 333 Broadbent’s sign 333 chronic constrictive pericarditis 332 Friedrich’s sign 332 Kussmaul’s sign 333 pericardial effusion 331 subacute effusive-constrictive pericarditis 331-332

diagnosis cardiac catheterization 336 chest radiograph 333 echocardiography 335 electrocardiogram 333 imaging 336 pericardial biopsy 334-335 pericardial fluid ADA estimation 334 pericardial fluid analysis 333-334 pericardial fluid IFN-gamma estimation 334 differential diagnosis 333 pathogensis 330-331 treatment antituberculosis treatment 336 corticosteroid treatment 337 pericardiocentesis and pericardiectomy 337 Tuberculosis radiculomyelitis clinical features 323 CSF examination 323 imaging studies 324-325 management 325 pathology 323 Tuberculosis Research Centre, Chennai 12-13 Tuberculosis tenosynovitis 369-370 TUNEL immunostaining 114

U Ultrasonography in abdominal tuberculosis 284 female genital tuberculosis 458 genitourinary tuberculosis 471 miliary tuberculosis 501 United Nations Millennium Development Goals 63,64 Urethra, tuberculosis of

V Vaccine development , animal models, and guinea pig model 921-922 mouse model 920-921 non-human primate model 922

development, impact of zoonoses on 936-937 DNA vaccines 929 epitope based vaccines 929-930 expectations from a new vaccine 933 human trials groundwork for 933 new challenges 934 identification of vaccine targets 924925 immune responses to vaccination 923-924 immunotherapeutic approach 932 live attenuated mutants and auxotrophs of Mycobacterium tuberculosis 927-928 nontuberculous mycobacterial vaccines 928-929 prime boost immunization strategies 930-931 recombinant BCG vaccine 925-927 role of diagnostics 932-933 strategies for development 925, T64.1 Vaccines in phase I clinical trial 934-936 Vagina, tuberculosis of 452 Variable number of tandem DNA repeats [VNTRs] 660 Viomycin 737, T51.2A, T51.2B Vulva, tuberculosis of 452

W Waksman, Selman 10 Web-based resources tuberculosis 963-979 World Tuberculosis Day 10

X XDR-TB 697, 717-22 global experience in the management of 702-704, T49.9A

Z Ziehl, Franz 71 Ziehl-Neelsen stain 164