Nuclear medicine in the management of inflammatory and infectious diseases 9783642078712, 3642078710

Table of contents :
Inflammatory Bowel Diseases.- 1 The Gastroenterologist's Update on Inflammatory Bowel Diseases.- 2 Inflammatory Bowel Diseases: The Radiologist's Point of View.- 3 Inflammatory Bowel Diseases: The Use of Radiolabelled Cytokines for In Vivo Evaluation of Inflammatory Activity.- 4 Radiolabelled White Blood Cells in Inflammatory Bowel Diseases.- 5 The Use of Radiolabeled Monoclonal Antibodies in Inflammatory Bowel Diseases.- 6 First Round Table Discussion.- Orthopaedic Infections.- 7 Orthopaedic Infections: The Orthopaedic Surgeon's Update on Prosthesis Infection.- 8 Orthopaedic Infections: The Infectious Disease Specialist's Point of View.- 9 Painful Joint Prostheses: The Role of Nuclear Medicine.- 10 The Nuclear Medicine Point of View in Orthopaedic Infections: Imaging with Tc-99m-Ciprofloxacin, Infecton.- 11 Second Round Table Discussion.- Fever of Unknown Origin and Endocarditis.- 12 Fever of Unknown Origin and Endocarditis.- 13 Fever of Unknown Origin and Endocarditis: The Nuclear Medicine Point of View.- 14 Nuclear Medicine for the Delineation of Endocarditis.- 15 Third Round Table Discussion.- Vascular Prosthesis Infections.- 16 Vascular Prosthesis Infections: The Vascular Surgeon's Update.- 17 Infection of Vascular Prostheses: The Radiologist's Point of View.- 18 Nuclear Medicine Techniques in the Diagnosis of Vascular Prosthesis Infections: An Introduction.- 19 Imaging Vascular Prosthesis Infections: The Nuclear Medicine Point of View.- 20 99mTc-HMPAO-Labelled Leukocyte Scan and CT in the Diagnosis of Vascular Graft Infection.- 21 Fourth Round Table Discussion.- Rheumatoid Arthritis.- 22 The Rheumatologist's Update on Rheumatic Diseases.- 23 99mTc-Labelled Human Immunoglobulin Scintigraphy in Rheumatoid Arthritis.- 24 Rheumatoid Arthritis: The Use of Somatostatin Analogs. When and How?.- 25 Fifth Round Table Discussion.- Neurological Infections.- 26 White Blood Cell Scintigraphy in Neurosurgery Infections: The Neurosurgeon's Point of View.- 27 Infections of the Central Nervous System: The Neuroradiologist's Point of View.- 28 On the Role of Nuclear Medicine Imaging for Routine Assessment of Infectious Brain Pathology: A Questionnaire.- 29 Sixth Round Table Discussion.

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Nuclear Medicine in Infectious Diseases Alberto Signore Andor W. J. M. Glaudemans Editors

123

Nuclear Medicine in Infectious Diseases

Alberto Signore • Andor W. J. M. Glaudemans Editors

Nuclear Medicine in Infectious Diseases

Editors Alberto Signore Nuclear Medicine Sapienza University of Rome Rome Italy

Andor W. J. M. Glaudemans Nuclear Medicine and Molecular Imaging University of Groningen Groningen The Netherlands

ISBN 978-3-030-25493-3 ISBN 978-3-030-25494-0 https://doi.org/10.1007/978-3-030-25494-0

(eBook)

© Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Foreword

Infectious diseases have traditionally been an area of medicine, in which nuclear medicine technologies have provided pivotal imaging information for clinical decision-making and appropriate patient management. This textbook Nuclear Medicine in Infectious Diseases, edited by Dr. Andor Glaudemans and Prof. Alberto Signore, is a comprehensive overview on the traditional and more recently developed radiopharmaceuticals used for imaging infection, imaging methodology, and a large number of clinical applications. The textbook is divided into various etiologies and organ systems, addressed in detail by experts in the field. In the past decades, new radiopharmaceuticals and the introduction of hybrid scanners, integrating molecular imaging from SPECT and PET with anatomical information from CT and MRI have boosted the number of indications and procedures. With an abundance of available literature, Nuclear Medicine in Infectious Diseases guides the evidence-based choice of the optimal, imaging agents, matching the clinical condition of the patient. As imaging mostly relies on qualitative interpretation, the guidance provided for the acquisition of the scans and the subsequent recommendations for image interpretation are essential to get the best out of each procedure to which we submit our patients. The close links to information in current multidisciplinary guidelines make this textbook very practical for any healthcare professional involved in the treatment of patients with infectious diseases. It can also be recommended for students and residents, seeking comprehensive knowledge on the relevance and impact of nuclear medicine imaging in infections. Wim J. G. Oyen Diagnostic Imaging and Radiotherapy Humanitas University Milan, Italy Nuclear Medicine Radboud University Medical Center Nijmegen, The Netherlands

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Preface

Molecular imaging of infectious diseases has dramatically gained interest in the last decades due to an improvement in our understanding and knowledge of the pathophysiology in infections and recent developments in imaging modalities. Nuclear medicine imaging offers unique possibilities to distinguish infection-related processes from sterile inflammatory conditions or neoplasia, but has also an important added value in defining the extent of an infection, in selecting the best location for biopsy and, most certainly, in monitoring therapy efficacy. Furthermore, the recent development in hybrid multimodality imaging systems makes combination of pathophysiology and anatomy possible, and this synergism leads to better diagnostic accuracy. Nuclear medicine has positioned itself clearly as an important key player in the field of diagnosing and monitoring infections. Till recently, there was a lack of uniformity in the performance and interpretation of nuclear medicine techniques in the field of infection. Therefore, a major European program of education and standardization of techniques has started in the late 1990s allowing us to have guidelines with the correct acquisition protocols and image interpretation criteria for most infective diseases. This information is rapidly spreading worldwide and several European and National scientific societies are now accepting and integrating our techniques in clinical diagnostic flowcharts. Indeed, our nuclear medicine techniques are now part of many diagnostic flowcharts and guidelines recently published. The European Association of Nuclear Medicine (EANM), more particularly the Inflammation and Infection Committee of the EANM, took in many cases the initiative for these joint collaborations between several European societies. Thus, diagnostic flowcharts have been prepared for endocarditis, with the European Society of Cardiology (ESC) and the European Association of Cardiovascular Imaging (EACVI); for peripheral bone infection and prosthetic joint infection with the European Bone and Joint Infection Society (EBJIS), the European Society of Radiology (ESR), and the European Society for Clinical Microbiology and Infectious Diseases (ESCMID); for spine infections with the European Society of Neuroradiology (ESNR); for abdominal infections with the European Crohn’s and Colitis Organization (ECCO) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR). Soon, every clinician working with nuclear medicine imaging techniques and every nuclear medicine physician will stick to these guidelines, so we can build up expertise and share results to improve health care. vii

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The most up-to-date concepts of our techniques will be discussed in the beginning of this book. The first chapters also provide the reader with an overview of existing radiopharmaceuticals for SPECT and PET imaging. All of the most clinically relevant infectious diseases are described in separate chapters and the guidelines are explained and discussed. Sternal wound infections, vascular graft infections, and diabetic foot infections are also explained and discussed with several case examples, despite joint guidelines are not yet available. The remaining of the book is devoted to the nuclear medicine imaging of infections at different body sites as well as fever of unknown origin, fungal infections, and tuberculosis and AIDS-associated infections. This is not our first book in the field, but certainly we gained experience from previous work and we are now proud to edit an outstanding book. For this reason, we invited the most relevant international experts to prepare the different chapters with a common scheme that will help the reader to compare different chapters and have quick answers to their main clinical and practical questions. We are very happy that our book is produced by one of the premier publishers in the field. This guarantees a high quality of reproduction and allows for the inclusion of many color figures, which is essential in the field of nuclear medicine. We would like to thank Gesa Frese and Niveka Somasundaram from Springer Verlag for their help and support during the development of this book. Infections in general represent a real emergency globally, and early diagnosis and possibilities for therapy monitoring become more and more important but will continue to pose huge challenges. Therefore, this book is not only indicated for nuclear medicine physicians, but also for other specialists working in the field, such as infectiologists, medical microbiologists, trauma and orthopedic surgeons, and vascular surgeons, and in particular for medical students and registrars in nuclear medicine who want to get a 360° view on this highly interesting topic. Basically, for everyone working with patients with infectious diseases this book will be a superb asset. Rome, Italy Groningen, The Netherlands

Alberto Signore Andor W. J. M. Glaudemans

Contents

1

Infections: The Emergency of the New Millennium . . . . . . . . . . . . . . . Nicola Petrosillo

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Gamma Camera Imaging of Infectious Diseases . . . . . . . . . . . . . . . . . . Filippo Galli

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Radiopharmaceuticals for PET Imaging of Infection . . . . . . . . . . . . . . 19 Alfred O. Ankrah and Philip H. Elsinga

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Hybrid SPECT/CT and PET/CT Imaging in Infectious Diseases . . . . 37 Sveva Auletta, Thomas Q. Christensen, and Søren Hess

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Acquisition Protocols and Image Interpretation Criteria Nuclear Medicine Imaging of Infectious Diseases . . . . . . . . . . 61 Alberto Signore, Elena Lazzeri, and Chiara Lauri

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Nuclear Medicine Imaging of Soft Tissue Infections . . . . . . . . . . . . . . . 73 Elena Lazzeri

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Nuclear Medicine Imaging of Peripheral Bone Osteomyelitis and Sternal Wound Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Andor W. J. M. Glaudemans

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Imaging of Spine Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Lazzeri Elena

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Nuclear Medicine Imaging of Prosthetic Joint Infections . . . . . . . . . . . 119 Alberto Signore, Carmelo D’Arrigo, and Chiara Lauri

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Nuclear Medicine Imaging of Vascular Graft Infections . . . . . . . . . . . 133 Chiara Lauri, Maurizio Taurino, and Alberto Signore

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Nuclear Medicine Imaging of Diabetic Foot Infections . . . . . . . . . . . . . 145 Chiara Lauri, Luigi Uccioli, and Alberto Signore

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Nuclear Medicine Imaging of Cardiovascular Implantable Electronic Device Infection and Endocarditis . . . . . . . . . . . . . . . . . . . . 161 P. A. Erba, M. Sollini, R. Zanca, A. Marciano, S. Vitali, F. Bartoli, and E. Lazzeri ix

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Nuclear Medicine Imaging of Fever of Unknown Origin . . . . . . . . . . . 199 Ilse J. E. Kouijzer, Chantal P. Bleeker-Rovers, and Lioe-Fee de Geus-Oei

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Nuclear Medicine Imaging of Infection/Inflammation by PET/CT and PET/MR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Barbara Juarez Amorim, Benedikt Michael Schaarschmidt, Johannes Grueneisen, Shahein Tajmir, Lale Umutlu, Alberto Signore, and Onofrio Antonio Catalano

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Imaging Tuberculosis and AIDS Associated Infections . . . . . . . . . . . . . 237 Ismaheel O. Lawal and Mike M. Sathekge

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Imaging Fungal Infections and Therapy Follow-Up . . . . . . . . . . . . . . . 259 Andor W. J. M. Glaudemans

1

Infections: The Emergency of the New Millennium Nicola Petrosillo

“For all they knew, in that invisible micro-organic world there might be as many different kinds of germs as there are grains of sand on this beach. And also, in that same invisible world it might well be that new kinds of germs came to be. It might be there that life originated…” (Jack London. The Scarlet Plague. Mills & Boon, Limited, London 1916)

1.1

Introduction

At the beginning of 2015, the British Economist Jim O’Neill chaired a review of antimicrobial resistance, commissioned by the UK Government and the Wellcome Trust; on May 2016, he published a report titled “Tackling drug-resistant infections globally: final report and recommendations.” In this report, the estimate of the burden of antimicrobial resistance in the next decades was shocking. He estimated that “by 2050, 10 million lives a year and a cumulative 100 trillion USD of economic output are at risk due to the rise of drug-resistant infections if we do not find proactive solutions now to slow down the rise of drug resistance. Even today, 700,000 people die of resistant infections every year” [1]. In the same period, a devastating Ebola virus epidemic plagued part of West Africa and threatened developed countries. The Ebola epidemic in the period 2013– 2016 hit 28,616 suspected cases and caused 11,310 deaths [2]. The first two decades of the New Millennium are facing several problems in healthcare. Antimicrobial resistance is spreading worldwide due to antibiotic

N. Petrosillo (*) National Institute for Infectious Diseases “Lazzaro Spallanzani”, IRCCS, Rome, Italy e-mail: [email protected] © Springer Nature Switzerland AG 2020 A. Signore, A. W. J. M. Glaudemans (eds.), Nuclear Medicine in Infectious Diseases, https://doi.org/10.1007/978-3-030-25494-0_1

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overuse/misuse in the human and animal setting, and even environment is polluted with resistant organisms and antimicrobials. While the demand for health is growing all over the world, technology is advancing, surgical interventions are becoming more complex, the availability of drugs and diagnostic and therapeutic aids is increasingly extensive and modern, and the risk of infection acquired in health facilities is becoming too high, with its weight of morbidity, mortality, and costs for the community. If the risk factors and all the other socio-economical reasons for developing and spreading emerging infections will remain in the next years—and there is no reason why they will not—these infection will represent a challenge for the healthcare system in the New Millennium because hospital and community preparedness is widely insufficient, awareness among professionals and media raises only when an epidemic is ongoing, and prevention is lacking.

1.2

From Optimism to the Harsh Reality: The History of Infectious Diseases in the Past Century

The first half of the twentieth century was dominated by an optimistic feeling on the treatment, control, and prevention of infectious diseases. In 1931, Henry Sigerist wrote, “Most of the infectious diseases … have now yielded up their secrets…. Many illnesses … had been completely exterminated; others had … largely under control….” [3]. Up to 1960, antibiotics were extensively developed by pharmaceutical industries and immunization added to this optimism. All this contributed to the sentence, today ironically mentioned almost in every conference dealing with antimicrobial resistance and emerging infection, by the Surgeon General William H. Stewart to the US Congress that it was time to “close the book on infectious diseases” [4]. All this determined a drastical reduction of funding for the research against infectious diseases. Pharmaceutical companies shut down the development of new antibiotics and only few drops come out of the pipeline. In much of the developed world, the public had forgotten the impact of infectious diseases on previous generations and shared in the confidence that modern medicine and technology would prevail. In the late 1970s–early 1980s, this atmosphere of optimism was clouded by some dramatic epidemics that changed the feeling and opinion on the future of infectious diseases. Since 1976, an outbreak of Ebola virus disease was spreading in Zaire with a mortality rate up to 88%; however, the emergence of a new disease in United States, namely the Legionnaire disease outbreak at Philadelphia in 1976, was the first sign of something changing between humans and organisms, and of the susceptibility of people with comorbidities to emerging infectious agents. Finally, what completely changed the history of infectious diseases was the emergence of the first cases of pneumocistosis at S. Francisco in 1981, and the subsequent discovery of the human immunodeficiency virus (HIV) that caused opportunistic infections (AIDS) in infected individuals. Other emerging infections occurred worldwide later on, including Hantavirus epidemic in United States in 1993, H5N1 influenza in China in 1993, Diphtheria in Eastern Europe in 1997 after the fall of the barriers from West and East Europe, SARS in Asia in 2003, etc. [5].

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What Are Emerging Infectious Diseases (EIDs)?

EIDs are not only those infections that create social alarm when the media discover them, they include [6] • events caused by newly evolved organisms, such as multidrug-resistant tuberculosis, plasmid-mediated colistin resistance in Gram negatives, carbapenemresistant Enterobacteriaceae, etc. • infections caused by germs entering human population for the first time recently, such as HIV-1 infection in 1981, severe acute respiratory syndrome (SARS) coronavirus in 2003, Middle East respiratory syndrome caused by a novel coronavirus (Middle East respiratory syndrome coronavirus, or MERS-CoV) that was first identified in 2012 in Saudi Arabia • infections caused by pathogens that are historically present, but with a recent dramatic increase, such as Ebola virus disease in Democratic Republic of Congo in 2018 The main concern for EIDs is represented by their capability of spreading causing epidemic/pandemic and social alarm. Main causes of EID spread include (Fig. 1.1) – Poverty, famine, displacement, and war all represent conditions that are ruthlessly exploited by infectious diseases and emerging pathogens. Moreover, war events often stop or deteriorate ongoing infection prevention and control proMalaria, HIV, vaccine-preventable diseases

Poverty, famine, displacement and war

Healthcare-associated infections

Crowding, close contacts

Tourism, migration, asylum seekers, refugees and all conditions for mobility

TB, SARS Mers-CoV HIV, etc..

Emerging Infectious Diseases Globalization and centralization of food production and supply, and new food vehicles

Haemolytic uraemic syndrome, etc…

Environmental modifications, with change in vector distribution and susceptibility

Overuse/misuse of antimicrobials in human, animal and environmental fields

Zika, Dengue, Chikungunya West Nile

antimicrobial resistance

Fig. 1.1 Major drivers for emergence of threatening infections in the New Millennium

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N. Petrosillo

grams, both in the community and healthcare setting, including vaccination, medication supply, access to surgical and medical care, etc. [7]. Re-emergence of malaria by Plasmodium falciparum in Afghanistan, trypanosomiasis in Democratic Republic of Congo, AIDS, vaccine-preventable diseases such as measles, all are dramatically affected by war events [7]. Crowding: micro-organisms often require close contact for their direct or indirect transmission; this is valid both for community (SARS, MERS-CoV) and healthcare-associated infection. Crowding is a condition that can facilitate the transmission of potentially life-threatening infections because of the likelihood of reaching susceptible hosts and, as it is the case of patients in crowded healthcare facilities, for the easier probability to have limited/poor infection control measures and understaffing. Tourism, migration, asylum seekers, refugees, and all conditions for mobility. Travel can model infectious disease dynamics by introducing potential pathogens into susceptible populations or by modifying the rate of contacts and exposures between infected and susceptible individuals. Globalization and centralization of food production and supply, and new food vehicles: the case of hemolytic uremic syndrome (HUS) clusters of cases caused by Shiga toxin-producing Escherichia coli (STEC) O157 in Germany in 2016– 2017 likely associated with packaged minced meat consumption is emblematic. Environmental modifications, with change in vector distribution and susceptibility. The recent emergence of Zika, the spread of Dengue, Chikungunya, and West Nile fever in countries that was not present in the past clearly document an ecological change involving especially vectors. Overuse/misuse of antimicrobials in human, animal, and environmental fields [8].

1.4

The New Millennium: Infectious Disease Threats

At the beginning of the New Millennium, the severe acute respiratory syndrome (SARS) coronavirus (CoV) outbreak created social and political alarm because of the threat of transmission of the highly life-threatening virus through international traveling from Asia. The big economical expansion of Asian countries and their international trade seemed to be hampered by the fear of contagion. Luckily, the outbreak was limited and the alert quickly returned. However, this outbreak raised attention to the fact that emerging infections originate largely from animals (zoonosis). Indeed, SARS was introduced into humans from civet cats sold for consumption at markets, which had acquired infection from the original reservoir, horseshoe bats [9]. This was the first signal that new infections were under the corner. As a matter of concern, the source of EIDs is often from animals (zoonosis), that more commonly have a wildlife, as is the case of Nipah virus in Perak, Malaysia, and SARS in Guangdong Province, China. Indeed, zoonotic viral EIDs represent a major and increasing threat to global health.

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If viral emerging infections represent a concern mainly in the underdeveloped area of the world, the emergence of antimicrobial resistance is a growing problem worldwide but especially in developing and high income countries, where misuse and overuse of antibiotics among humans and in the veterinary setting, including animal feeding, artificially created the selection of resistant strains. Resistance to antimicrobials is a natural process that occurred before the discovery of antibiotics. In 1931, a sulfa drug, prontosil rubrum, was the first clinically useful antibacterial agent to be discovered. However, prontosil was not the first antibacterial agent to be invented, and humans were not the initial inventors. According to sophisticated genetic analysis, it is clear that bacteria invented antibiotics and consequently induced antibiotic resistance mechanisms somewhere between 2 and 2.5 billion years ago. Bacteria have been killing each other with these weapons, and using resistance mechanisms to protect themselves against these weapons, for 20 million times longer than we have even known that antibiotics exist [10]. This was surprisingly discovered in a deep cave explored in New Mexico in 2011, isolated from the surface of the planet for 4 million years, in which scientists cultured many different types of bacteria from the walls of the caves. Resistance to at least one modern antibiotic was found in many isolated organisms, and some of them were multidrug resistant, even to modern antibiotics [11]. However, nowadays the process for creating resistant organisms has been accelerated because overuse of antimicrobials has increased the rate at which resistance is developing and spreading. Indeed, currently the major drivers behind the occurrence and spread of antimicrobial resistance are represented by the use of antimicrobials in human and veterinary field, and by the transmission of resistant organisms between humans, animals, and environment. On the other side, we lack new drugs to challenge these new superbugs. This results in facing a growing enemy with a largely depleted armory. While antimicrobial overuse/misuse determines ecological pressure on bacteria and contributes to the emergence and selection of AMR, poor infection prevention, and control practices is the main cause for the further spread of these bacteria. From a microbiological point of view, over the past decades, bacteria with specific clones expressing resistant to several antimicrobials spread worldwide. This is the case of Enterobacteriaceae, mainly Klebsiella pneumoniae resistant to carbapenems with different resistance enzymes including KPC (Klebsiella pneumoniae carbapenemase), NDM-1 (New Delhi Metalloprotease), and other metallobetalactamases. More recent pan-resistant strains, expressing also resistance to polymixins, have been identified as cause of severe diseases; some colistin-resistant strains had a chromosomal resistance, likely induced by antibiotic pressure, but in other cases colistin resistance was linked to mobile elements, plasmids, like MCR-1 and others. This emerging resistance represents an important concern due to its potential for spreading among bacteria of different species; as evidenced recently in China, environment is one of the main sources of these mobile elements, likely due to the wide use of colistin in agriculture [12]. Antimicrobial resistance is commonly found in organisms that cause healthcareassociated infections, but it is not only a matter of hospitals and other healthcare facilities because it is widespread also in the community.

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The Healthcare-Associated Infections and Their Burden of Antimicrobial Resistance in the New Millennium

Healthcare-associated infections (HAI) can be acquired during home, outpatient, long term or hospital care; they represent one of the greatest challenges of modern medicine. In United States, according to the Institute of Medicine, nosocomial infections now concern 5–15 per 100 hospitalized patients and can lead to complications in 25–50% of those admitted to intensive care units [13]. From 2016 to 2017, a large point prevalence survey of HAI and antimicrobial use was conducted in the European Union and European Economic Area (EU/EEA) including 310,755 patients from 1209 acute care hospitals in 28 countries and 117,138 residents from 2221 long-term care facilities in 23 countries. The authors estimated that 6.5% (cumulative 95% confidence interval (cCI): 5.4–7.8%) patients in acute care hospitals and 3.9% (95% cCI: 2.4–6.0%) residents in longterm care facilities had at least one HAI. It means that in Europe, on any given day, more than 98,000 patients in acute care hospitals and around 130,000 residents in long-term care facilities had an HAI.  The burden of HAI is therefore alarming, with around 9 million infections yearly in acute care hospitals and 4.4 million in long-term care facilities. More than a quarter of HAIs were respiratory tract infections, mainly pneumonia, followed by urinary tract infections (18.9%), surgical site infections (18.4%), bloodstream infection (8.9%), and gastrointestinal infections (8.9%). Among the latter around half of them were Clostridioides difficile infections. In this survey, in acute care hospitals the 10 most commonly isolated organisms included E. coli (16.1%), S. aureus (11.6%), Klebsiella spp. (10.4%), Enterococcus spp. (9.7%), P. aeruginosa (8.0%), C. difficile (7.3%), Coagulase negative Staphylococci (7.1%), Candida spp. (5.2%), Enterobacter spp. (4.4%), and Proteus spp. (3.8%). Moreover, the prevalence survey assessed the rate of antimicrobial resistance in these infections that is 31.3% in acute care hospitals and 28% in long-term care facilities [14]. Rates of antimicrobial resistance in Europe are annually assessed by the European Centers for Disease Control (ECDC). In their last report [15], ECDC well describes the situation of antimicrobial resistance in Europe. For E. coli, more than half (58.2%) of the isolates reported to EARS-Net for 2017 were resistant to at least one of the antimicrobial groups under regular surveillance, i.e., aminopenicillins, fluoroquinolones, third-generation cephalosporins, aminoglycosides, and carbapenems. Resistance was the highest for aminopenicillins (58.7%) and lowest, fortunately, for carbapenems (less than 1%). K. pneumoniae is one of the biggest issues in Europe and worldwide. At the EU/ EEA level, more than a third (34.1%) of the isolates reported to EARS-Net for 2017 were resistant to at least one of the antimicrobial groups under regular surveillance, i.e., fluoroquinolones, third-generation cephalosporins, aminoglycosides, and

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carbapenems. Carbapenem resistance was on average 7.2%, but the range was extremely variable with highest rates, up to 65%, in Southern/Eastern Europe. Among Gram negatives, Pseudomonas aeruginosa remains one of the most threatening organisms. Less than one third of the isolates in Europe, according to EARS-Net were resistant to at least one of the antimicrobials historically used against these organisms, namely piperacillin/tazobactam, fluoroquinolones, ceftazidime, aminoglycosides, and carbapenems. The list of challenging Gram negatives is completed by Acinetobacter baumannii, non-fermenting organisms that in more than half of the isolates reported to ERAS-NET were resistant to at least one of the antimicrobials historically used against, namely fluoroquinolones, aminoglycosides, and carbapenems. In some European countries, resistance to carbapenems is up to 96%. However, the danger does not only come from Gram negatives. Staphylococcus aureus, the most known Gram-positive organism, responsible for sepsis, osteomyelitis, skin and soft tissue infections, surgical site infections, and pneumonia, carries a resistance to methicillin up to 44.4% in Europe.

1.6

Conclusions

Mobility, people traveling much more frequently and far greater distances than in the past, living in more densely populated areas, centralization of food production and supply and new food vehicles, war, famine and displacement, change in vector distribution and susceptibility, and more opportunities to come into closer contact with wild animals, all represent a potential for emerging infectious diseases, either caused by new or well-known viral agents or by antimicrobial-resistant bacteria to spread rapidly and cause outbreaks locally or globally. Whereas viral emerging infections are marginally a concern for developed countries, that are just lapped by them, antimicrobial resistance is importantly a matter of developed and developing countries, where this issue has become a top priority for global policy makers and public health authorities. New mechanisms of resistance continue to emerge and spread globally, threatening our ability to treat common infections. The overuse and misuse of antimicrobials both in the human and animal field, and their dispersion in the environment pose a risk for selection of mechanisms of resistance of germs. Some settings, like the healthcare facilities, where the use of antimicrobials is obviously intense and infection prevention and control can be poor, represent the reservoir for multidrug-resistant organisms and, sometimes, the melting pot for pan-resistant strains. The New Millennium opened with alarming data on infections and antimicrobial resistance. Healthcare workers, care givers, decision-makers, politicians, and media should raise public awareness that antimicrobials should be wisely prescribed and administered both in the human and animal field, avoiding self-prescription and overuse of these valuable tools against bacterial infections.

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References 1. O’Neill J. Tackling drug-resistant infections globally: final report and recommendations; 2016. 2. World Health Organization. http://apps.who.int/gho/data/view.ebola-sitrep.ebola-summarylatest?lang=en. Accessed 9 June 2016. 3. Sigerist HE. The Great Doctors, vol. 372. New York: Dover Publications; 1971. 4. Garrett L. In: Mann JM, Tarantola DJM, Netter TW, editors. AIDS in the World. Cambridge: Harvard University Press; 1992. p. 825–39. 5. Cohen ML. Changing patterns of infectious disease. Nature. 2000;406(6797):762–7. 6. Jones KE, Patel NG, Levy MA, Storeygard A, Balk D, Gittleman JL, Daszak P. Global trends in emerging infectious diseases. Nature. 2008;451(7181):990–3. 7. Conolly MA, Heymann DL.  Deadly comrades: war and infectious diseases. Lancet. 2002;360(Suppl):S23–4. 8. Petersen E, Petrosillo N, Koopmans M, ESCMID Emerging Infections Task Force Expert Panel. Emerging infections-an increasingly important topic: review by the Emerging Infections Task Force. Clin Microbiol Infect. 2018;24(4):369–75. 9. Smith KM, Anthony SJ, Switzer WM, Epstein JH, Seimon T, Jia H, et al. Zoonotic viruses associated with illegally imported wildlife products. PLoS One. 2012;7:e29505. 10. Spellberg B, Bartlett JG, Gilbert DN. The future of antibiotics and resistance. N Engl J Med. 2013;368(4):299–302. 11. Bhullar K, Waglechner N, Pawlowski A, Koteva K, Banks ED, Johnston MD, Barton HA, Wright GD.  Antibiotic resistance is prevalent in an isolated cave microbiome. PLoS One. 2012;7(4):e34953. 12. Zhou HW, Zhang T, Ma JH, Fang Y, Wang HY, Huang ZX, et al. Occurrence of plasmid and chromosome-encoded mcr-1 in water-borne Enterobacteriaceae in China. Antimicrob Agents Chemother. 2017;61(8) 13. Pittet D. Infection control and quality health care in the new millenium. Am J Infect Control. 2005;33:258–67. 14. Suetens C, Latour K, Kärki T, et al. Prevalence of healthcare-associated infections, estimated incidence and composite antimicrobial resistance index in acute care hospitals and longterm care facilities: results from two European point prevalence surveys, 2016 to 2017. Euro Surveill. 2018;23(46):1800516. 15. European Centre for Disease Prevention and Control. Surveillance of antimicrobial resistance in Europe—annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net) 2017. Stockholm: ECDC; 2017.

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Gamma Camera Imaging of Infectious Diseases Filippo Galli

Management of patients affected by infectious diseases is very challenging. Being able to distinguish an infectious focus from an inflammatory site can radically change the therapeutic approach, but often it is not sufficient. Other information like extent of the lesion or which pathogen is involved has great influence on timing and success rate of the therapy. Conventional radiological techniques like computed tomography (CT) or magnetic resonance imaging (MRI) are more suitable to identify anatomical changes that occur at late stage of disease [1]. However, this usually means that the disease is already in a chronic phase and therapy failure rate increases. That is why, in these patients, early diagnosis is crucial and nuclear medicine imaging can play an important role, given the possibility to identify functional and biochemical changes at very early stages. For this purpose, it is possible to use of specific radiopharmaceuticals that bind to key biomarkers or exploit pathophysiological processes. The need of a more and more personalized medicine led to the development of several new radiopharmaceuticals that try to answer different clinical questions. However, with regard to imaging infection, clinical availability is limited, and in some cases there is the need to apply specific acquisition protocols or more than one labelled compound to overcome the lack of specificity of some radiopharmaceuticals (i.e. radiolabelled white blood cells, WBCs) [2]. In this chapter, we will discuss the available radiopharmaceuticals for gamma camera imaging of infection describing the actual gold standard and promising compounds under development or trials. Pathogens, inflammatory cells and physiological processes offer plenty of biomarkers to be targeted by specific radiopharmaceuticals. Currently, radiolabelled white blood cells are the gold standard for imaging of infection, especially in

F. Galli (*) Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, “Sapienza” University of Rome, Rome, Italy © Springer Nature Switzerland AG 2020 A. Signore, A. W. J. M. Glaudemans (eds.), Nuclear Medicine in Infectious Diseases, https://doi.org/10.1007/978-3-030-25494-0_2

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orthopaedic and vascular prostheses [3]. This is particularly relevant in elder patients where an early diagnosis is crucial to choose the best therapeutic approach.

2.1

Clinically Validated and Commercially Available Radiopharmaceuticals

2.1.1

111

In-8-Hydroxyquinoline and 99mTc-Exametazime

Indium-111-labelled 8-hydroxyquinoline (111In-oxine) has been developed in the 1970s to radiolabel autologous WBCs for imaging of infection/inflammation [4]. The radioisotopes form a lipophilic complex with three molecules of 8-hydroxyquinoline, and it is able to diffuse through the plasma membrane of any blood cell [5]. Once inside, it binds to lactoferrin or other components of the cytoplasm that strongly chelate indium, whereas the free oxine is released. Physiological uptake in liver, spleen and bone marrow was observed in normal subjects with transient activity in the lungs. Blood half-life is between 5 and 10 h and clearance from liver and spleen is very low, resulting in very low excretion in faeces and urines. 111 In-oxine is supplied as a ready-to-use radiopharmaceutical. When radiolabelling total leucocytes purified from the patient, about 60–70% of the radioactivity is bound to granulocytes only and higher activity in the blood pool may be observed. The radiolabelling procedure is very well established and extensively described in the SNM or EANM guidelines [6, 7]. Briefly, a blood sample, 40–60 mL, should be collected from the patient and mixed with an anti-coagulant (ACD-A, citrate dextrose solution) and a sedimentation agent. Hydroxy-ethyl starch (HES) has been used for long, but in some countries it is now available anymore. Therefore, it can be replaced with gelofusine or similar compounds. After red cell sedimentation, the leukocyte-rich and platelet-rich plasma (LRPRP) can be centrifuged and washed to pellet down WBCs before resuspension with 111In-oxine. After incubation, the free 111In-oxine can be removed by another centrifugation step and quality controls can be performed before the injection. The labelling is stable, with an observed release of 111In-oxine from the cells of 3% after 1 h and up to 24% at 24 h due to cell damage during manipulation. In some countries, 111In-oxine has been almost replaced by 99mTc-exametazime (HMPAO), which is another 99mTc-chelating lipophilic complex able to freely penetrate into the cells [8]. Therefore, the radiolabelling procedure is almost identical to the one for 111In-oxine. However, 99mTcHMPAO transforms over time in a hydrophilic complex; therefore, the labelling should be performed within 20 min from its preparation. Once inside the cells, the hydrophilic 99mTc-HMPAO remains trapped or bound to cytoplasmic components. Contrarily to 111In-oxine, release of 99mTc-HMPAO has been observed in the gastrointestinal tract. For this reason, the former is preferred in patients with suspect of infection in the abdomen or pelvis. Administered activity range from 185 to 540 MBq and the organs that receive the highest radiation dose are spleen, large bowel and bladder due to WBCs physiological biodistribution and radiopharmaceutical metabolism. 99mTc-HMPAO requires shorter imaging times and showed a lower

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Table 2.1 Radiation dosimetry for 111In-oxine and 99mTc-HMPAO labelled leucocytes

Population In-oxine Adults Children (5 years old) 99m Tc-HMPAO Adults Children (5 years old)

Administered activity (MBq)

Organ receiving the largest radiation dose (Spleen) (mGy/ MBq)

Effective dose equivalent (mSv/ MBq)

10–18.5 0.15–0.25/kg

5.5 17.0

0.59 1.8

111

185–370 3.7–7.4/kg

0.15 0.48

0.011 0.034

International Commission on Radiological Protection. Annals of the ICRP, Publication 53, Radiation Dose to Patients from Radiopharmaceuticals. Pergamon, Elsevier Science, London; 1988, pp. 255–256 and Publication 80, Radiation Dose to Patients from Radiopharmaceuticals, Ed. J Valentin, Elsevier Science, Oxford, UK; 1999, p. 67

absorbed dose due to lower energy of technetium-99m. Also, in patients with prolonged lung blood pool activity due to renal failure or other pathologies 111In-oxine is a better option [9, 10]. Labelling efficiency of 111In-oxine is usually higher than 99mTc-HMPAO, with lower efflux of the radiopharmaceutical from the cell. Furthermore, if there is the need to perform a bone marrow scan at 24 h, 111In-oxine-labelled WBC does not interfere with imaging of 99mTc-nanocolloids, due to difference in the energy windows. When using 111In-oxine labelled WBCs, image resolution is quite poor due to the higher energy of indium-111 and requires longer acquisition times. Moreover, technetium-99m can be produced in-house given the availability of generators, whereas indium-111 should be purchased in advanced. Finally, radiation exposure of labelled cells, critical organs (spleen) and the whole body to 111In-oxine (Table  2.1), which is substantially higher than that from 99mTc-HMPAO.  WBCs radiolabelling requires a properly equipped laboratory and trained personnel as for any other procedure that involves patient’s blood manipulation. In the last years, risk of contamination has been minimized either by the establishment of dedicated courses for operators or by the development of specific devices like the Leukokit® [11]. This closed system acts as a mini-isolator and during the whole labelling procedure that blood of the patients does not get in contact with air. Therefore, it is possible to reduce the risk of contamination and speed the process up at little cost.

2.1.2

Gallium-67 Citrate

Gallium-67 citrate is a radiopharmaceutical that has been widely used to image solid tumours, inflammation and infection [12]. The radioisotope has a half-life of 78.26 h, and it can be produced by cyclotron with energy abundances of 93 keV (40%), 184 keV (20%), 300 keV (17%) or 393 keV (5%). In its Ga3+ form, it is able to bind to different molecules able to chelate iron. These include transferrin

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Fig. 2.1 Gallium-67 scintigraphy images revealing pericardial uptake (arrows) in a patient with pyrexia of unknown origin. Echocardiography and aspiration revealed tuberculosis (TB) pericarditis. The patient was subsequently treated with anti-TB medication. RT right; LT left

glycoproteins, lactoferrin, bacterial siderophore and many others. For this reason, it accumulates in inflammatory or fast proliferating sites and it found great application in imaging fever of unknown origin (FUO) due to very high sensitivity (Fig. 2.1). It has also been used in acute or chronic inflammation, despite its low specificity. It is characterized by high uptake in kidneys and liver where it is metabolized and excreted. Nowadays, the use of 67Ga-citrate is obsolete and has been replaced by [18F]FDG-PET/CT. However, it may still find application in FUO, sarcoidosis and spinal discitis or vertebral osteomyelitis in those centres lacking a PET-CT scanner. Given its long half-life, the possibility to replace it with gallium-68 for PET application has been explored, but this radiopharmaceutical surprisingly showed a different biodistribution and will be discussed in details in the next chapter [13].

2.1.3

99m

Tc-Besilesomab

To overcome limitations related to ex  vivo cell labelling, radiolabelled antigranulocyte monoclonal antibodies have been developed [14]. This way it is possible to label WBCs in vivo, without the need of any external manipulation, thus

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reducing costs, risks and time. This radiopharmaceutical is composed of a murine monoclonal antibody anti non-specific cross-reacting antigen (NCA-95), (or CD66b and CEACAM8 antibodies) that recognizes human mature granulocytes, myelocytes and promyelocytes. From 1992, this radiolabelled antibody called 99m Tc-besilesomab (Scintimun®) has been approved in several countries, as Hungary, Switzerland, Sweden, Czech Republic and Germany, allowing the diagnosis of osteomyelitis around 100,000, and from 2010 was admitted by the European Medicines Agency (EMEA) for patients with suspected osteomyelitis. The normal biodistribution of Scintimun® is characterized by a 10% of the activity that binds neutrophils, 40% accumulates in bone marrow and 20% remains in the blood pool. Considering this data, the physiological uptake from the bone marrow is the main limitation of this radiopharmaceutical, due to the possibility to obtain false-negative results in this region. It is also possible to have false positive results in myeloma, or uptake in bone metastasis [3, 15]. A phase III trial compared Scintimun® and 99mTc-HMPAO-labelled WBCs evaluating the sensitivity, the specificity and accuracy in the diagnosis of infection or sterile inflammation in 119 patients with suspected osteomyelitis. Eventually, Scintimun® showed a higher sensitivity and a slightly lower specificity if compared with 99mTc-HMPAO-labelled WBCs, but lower specificity [16].

2.2

Experimental Radiopharmaceuticals

A bacteria-specific radiopharmaceutical has not been developed yet and many efforts have been made to do so by labelling different compounds like peptides, monoclonal antibodies, antibiotics or antimicrobial peptides. In this paragraph, we will report the most studied radiopharmaceuticals in humans and that could find a place in the clinical practice. The theoretical advantages of a radiolabelled antibiotic over WBCs are represented by the lack of bone marrow uptake, so that a 99mTc-sulphur colloid scan can be avoided, and this is particularly relevant in patients affected by osteomyelitis. Furthermore, there would be no blood handling as the radiopharmaceutical could be prepared starting from a user-friendly kit. The examination could be easily performed also in leukopenic subjects.

2.2.1

99m

Tc-Ciprofloxacin

Ciprofloxacin is a second-generation fluoroquinolone approved for human use for a number of bacterial infections. It was the first 99mTc-radiolabelled antibiotic to be tested in human under the name of Infecton to image infections after extensive pre-clinical testing [17, 18]. The hypothesis was that if antibiotics are specific against bacteria, it could be possible to radiolabel them to be used as diagnostic radiopharmaceuticals. First studies with 99mTc-ciprofloxacin were promising, showing fast renal clearance with low hepatic, bone marrow or gastrointestinal

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uptake. However, despite a high sensitivity, different group obtained controversial results [19]. This variability, especially in terms of specificity, might have been depended on bacterial strain, ongoing antibiotic therapy and lack of standardization or interpretation criteria. Overall, it was tested in tuberculosis, FUO, osteomyelitis, hip and knee prosthesis, spinal, abdominal or gastrointestinal and orthopaedic infections. It was also proposed as the radiopharmaceutical of choice in immune-deficient patients with uncertain WBC scans. Comparative studies with radiolabelled WBCs were performed in patients affected by osteomyelitis (Fig. 2.2) [20]. In this study, authors reported a sensitivity, specificity and accuracy of infecton in musculoskeletal infection of 94%, 83% and 89%, respectively. However, the specificity was decreased due to some false-positive findings. Although 99mTcciprofloxacin was studied in many patients, it was not able to reach the clinical practice because of many concerns about its specificity. Indeed, like for many other antibiotics, resistant strains might not accumulate ciprofloxacin and in some cases, there is the lack of a specific target or receptor on the outer membrane or wall. After ciprofloxacin, many other antibiotics have been radiolabelled and studied, but all of them shared similar issues: poor specificity, lack of characterization of the radiolabelling method or unknown mechanism of binding. Some of them, including ciprofloxacin, have been radiolabelled with positron emitting isotopes to increase the resolution and allow quantitation in the hope of increasing their specificity. This will be discussed in the next chapter.

a

b

Fig. 2.2 (a) 99mTc-HMPAO-WBC images show focal tracer accumulation in distal tip of left hip endoprosthesis but no abnormal findings in right femora, where fixation nail is present, in a 77-year-old man who underwent orthopaedic surgery 1 year previously. (b) Infecton scans confirm abnormality in distal end of left hip prosthesis and also show pronounced focal accumulation of tracer in area of right femoral fixation nail. Biopsy results confirmed osteomyelitis on both sides

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Gamma Camera Imaging of Infectious Diseases

30 min

60 min

15

120 min

Fig. 2.3 Positive 99mTc-UBI 29–41 scintigraphy findings in patient with infection in medial aspect of right hand. Markedly greater focal tracer accumulation is seen on side with infection (arrows) than on normal contralateral side. Tracer uptake is maximal on image obtained at 30 min [22]

2.2.2

99m

Tc-Ubiquicidin 29-41

Antimicrobial peptides are part of our innate immunity against infection and are generally found in abundance in mammals and other eukaryotic organisms [21]. They are produced by phagocytes, epithelial and endothelial cells and other cell types providing protection against microbial attacks. Their expression is induced by contact with microorganisms or microbial products like lipopolysaccharides or proinflammatory cytokines like tumour necrosis factor-α, interferon-γ and interleukin1. Their action is directed against a broad spectrum of bacterial strains by binding to negative charges on their surface. They have many cationic domains and, because of electrostatic interactions upon binding, create pores on the bacterial membrane leading the cell to death. Ubiquicidin (UBI) 29–41 is a very well-characterized antimicrobial peptide (TGRAKRRMQYNRR, mw 1693  Da) fragment that has been labelled with technetium-99m. It is able to bind bacteria, but not eukaryotic cells because of the lack of negative charges on the outer of the plasma membrane. Given these characteristics, it has been proposed as a promising radiopharmaceutical to distinguish sterile inflammation from bacterial infection. In vivo it showed kidneys excretion with a 85% clearance of the injected dose after 24 h and accumulation in inflamed sites at 30 min from injection with a decrease of the radioactive signal over time (Fig. 2.3) [22]. Similarly to 99mTc-ciprofloxacin, 99mTc-UBI 29-41 specificity represents a major concern because despite the availability of pre-clinical and clinical reports it did not find its place in the diagnostic flowchart.

2.3

Future Perspectives and New Trends

The development of a radiopharmaceutical to be used as an alternative to radiolabelled WBCs would have huge impact in the management of patients affected by infectious diseases. However, till now, no radiopharmaceutical was able to compete with radiolabelled WBCs that despite a cumbersome procedure and high costs related to equipment and training still represents the gold standard for imaging of infection/inflammation in prostheses and other pathological conditions. Monoclonal

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radiolabelled antibodies seemed a valid alternative to be used in osteomyelitis, but the possibility to develop HAMAs is a great limitation that requires the use of humanized versions with high costs of production. A systematic review of the literature reported a very high number of antibiotics that has been tested in animal models, but all of them showed specificity issues. Another issue that emerged is the lack of standardization among the studies; therefore, drawing appropriate conclusions about their potential is very challenging. Moreover, many mechanisms of action or binding sites/targets are still unclear, and there is the chance that in most cases what we observe is just an unspecific accumulation of the radiopharmaceutical due to increased inflammation. The need of an early and specific diagnosis implies that we should be able to image infective foci when the number of bacteria is still very low. This is why there is the need of a highly specific radiopharmaceutical that accumulates with high target-to-background ratios. Since the biologic mechanism of antibiotics or anti-microbial peptides is not based on the recognition of a membrane bound antigen/receptor, there are many concerns about their use for imaging purposes.

References 1. Signore A, Anzola KL, Auletta S, Varani M, Petitti A, Pacilio M, Galli F, Lauri C. Current status of molecular imaging in inflammatory and autoimmune disorders. Curr Pharm Des. 2018;24:743–53. 2. Palestro CJ, Love C, Tronco GG, Tomas MB, Rini JN. Combined labeled leukocyte and technetium 99m sulfur colloid bone marrow imaging for diagnosing musculoskeletal infection. Radiographics. 2006;26:859–70. 3. Signore A, Jamar F, Israel O, Buscombe J, Martin-Comin J, Lazzeri E. Clinical indications, image acquisition and data interpretation for white blood cells and anti-granulocyte monoclonal antibody scintigraphy: an EANM procedural guideline. Eur J Nucl Med Mol Imaging. 2018;45:1816–31. 4. Ascher NL, Ahrenholz DH, Simmons RL, Weiblen B, Gomez L, Forstrom LA, Frick MP, Henke C, McCullough J. Indium 111 autologous tagged leukocytes in the diagnosis of intraperitoneal sepsis. Arch Surg. 1979;114:386–92. 5. Indium In 111 Oxyquinoline. Drugs and Lactation Database (LactMed) [Internet]. Bethesda: National Library of Medicine (US); 2006. 6. Roca M, de Vries EF, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with (111)In-oxine. Inflammation/Infection Taskgroup of the European Association of Nuclear Medicine. Eur J Nucl Med Mol Imaging. 2010;37:835–41. 7. Seabold JE, Forstrom LA, Schauwecker DS, Brown ML, Datz FL, McAfee JG, Palestro CJ, Royal HD.  Procedure guideline for indium-111-leukocyte scintigraphy for suspected infection/inflammation. Society of Nuclear Medicine. J Nucl Med. 1997;38:997–1001. 8. Peters AM, Danpure HJ, Osman S, Hawker RJ, Henderson BL, Hodgson HJ, Kelly JD, Neirinckx RD, Lavender JP.  Clinical experience with 99mTc-hexamethylpropyleneamineoxime for labelling leucocytes and imaging inflammation. Lancet. 1986;2:946–9. 9. de Vries EF, Roca M, Jamar F, Israel O, Signore A.  Guidelines for the labelling of leucocytes with (99m)Tc-HMPAO. Inflammation/Infection Taskgroup of the European Association of Nuclear Medicine. Eur J Nucl Med Mol Imaging. 2010;37:842–8. https://doi.org/10.1007/ s00259-010-1394-4. Erratum in: Eur J Nucl Med Mol Imaging. 2010;37:1235. 10. Datz FL, Seabold JE, Brown ML, Forstrom LA, Greenspan BS, McAfee JG, Palestro CJ, Schauwecker DS, Royal HD.  Procedure guideline for technetium-99m-HMPAO-labeled

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11. 12. 13. 14. 15. 16.

17. 18. 19. 20.

21. 22.

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leukocyte scintigraphy for suspected infection/inflammation. Society of Nuclear Medicine. J Nucl Med. 1997;38:987–90. Signore A, Glaudemans AWJM, Malviya G, Lazzeri E, Prandini N, Viglietti AL, et  al. Development and testing of a new disposable sterile device for labelling white blood cells. Q J Nucl Med Mol Imaging. 2012;56:400–8. Anghileri LJ. 67Ga-citrate accumulation by staphylococcal abscesses and by tumors. A common cause: changes in the alkaline-earths metabolism. Nucl Med (Stuttg). 1974;13:151–9. Vorster M, Buscombe J, Saad Z, Sathekge M. Past and future of Ga-citrate for infection and inflammation imaging. Curr Pharm Des. 2018;24:787–94. Bosslet K, Luben G, Schwarz A, Hundt E, Harthus HP, Seiler FR, et al. Immunohistochemical localization and molecular characteristics of three monoclonal antibody-defined epitopes detectable on carcinoembryonic antigen (CEA). Int J Cancer. 1985;36:75–84. Lazzeri E, Signore A, Erba PA, et al., editors. Radionuclide imaging of infection and inflammation: a pictorial case-based atlas. New York: Springer; 2013. Richter WS, Ivancevic V, Meller J, Lang O, Le Guludec D, Szilvazi I, Amthauer H, Chossat F, Dahmane A, Schwenke C, Signore A. 99mTc-besilesomab (Scintimun) in peripheral osteomyelitis: comparison with 99mTc-labelled white blood cells. Eur J Nucl Med Mol Imaging. 2011;38:899–910. Vinjamuri S, Hall AV, Solanki KK, et al. Comparison of 99mTc-1nfecton imaging with radiolabelled white-cell imaging in the evaluation of bacterial infection. Lancet. 1996;347:233–5. Hall AV, Solanki KK, Vinjamuri S, Britton KE, Das SS. Evaluation of the efficacy of 99mTcInfecton, a novel agent for detecting sites of infection. J Clin Pathol. 1998;51:215–9. Sarda L, Crémieux AC, Lebellec Y, Meulemans A, Lebtahi R, Hayem G, Génin R, Delahaye N, Huten D, Le Guludec D.  Inability of 99mTc-ciprofloxacin scintigraphy to discriminate between septic and sterile osteoarticular diseases. J Nucl Med. 2003;44(6):920–6. Sonmezoglu K, Sonmezoglu M, Halac M, Akgün I, Türkmen C, Önsel C, Kanmaz B, Solanki K, Britton KE, Uslu I.  Usefulness of 99mTc-ciprofloxacin (infecton) scan in diagnosis of chronic orthopedic infections: comparative study with 99mTc-HMPAO leukocyte scintigraphy. J Nucl Med. 2001;42:567–74. Ganz ME, Lehrer RI. Defensins and other endogenous peptide antibiotics of the vertebrates. J Leukoc Biol. 1995;58:128–36. Akhtar MS, Qaisar A, Irfanullah J, Iqbal J, Khan B, Jehangir M, Nadeem MA, Khan MA, Afzal MS, Ul-Haq I, Imran MB. Antimicrobial peptide 99mTc-ubiquicidin 29-41 as human infection-imaging agent: clinical trial. J Nucl Med. 2005;46:567–73.

3

Radiopharmaceuticals for PET Imaging of Infection Alfred O. Ankrah and Philip H. Elsinga

3.1

Introduction

Fluorine-18 fluorodeoxyglucose ([18F]FDG) is the most common PET tracer used in the evaluation of infection. [18F]FDG is used for evaluating bacterial, fungal, parasitic, and viral infections [1–3]. [18F]FDG is used for the assessment of site-specific infections such as spondylodiscitis, infection in specialized groups such as diabetic or neutropenic patients and patients with prosthetic devices [4]. However, [18F]FDG is nonspecific and other PET tracers have been used in an attempt to overcome this limitation of [18F]FDG by taking advantage of differences in microorganisms and mammalian biochemical processes [5]. [68Ga]Gallium citrate has also been tested in some infections but it is also a nonspecific tracer accumulating in non-infectious inflammation. Radiolabeled white blood cells (WBC) imaging is the method of choice in the evaluation of many infections in nuclear medicine imaging. SPECTbased radiolabeled WBC is the most commonly used in clinical practice. PET imaging affords better special resolution and better ability to quantify tracer uptake that is crucial for monitoring the treatment of infection. White blood cells have been labeled with PET radioisotopes and radiopharmaceuticals to take advantage of the properties of PET imaging. Some challenges in PET labeling of WBC have not allowed PET WBC to supplant SPECT WBC in the clinical evaluation of infection. Other compounds have been labeled with 18F for infection imaging. The use of the A. O. Ankrah Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Nuclear Medicine, University of Pretoria, Steve Biko Academic Hospital, Pretoria, South Africa P. H. Elsinga (*) Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands e-mail: [email protected] © Springer Nature Switzerland AG 2020 A. Signore, A. W. J. M. Glaudemans (eds.), Nuclear Medicine in Infectious Diseases, https://doi.org/10.1007/978-3-030-25494-0_3

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68

Ga-based radiopharmaceuticals has been gaining prominence in the last decade. Some 68Ga-based tracers have been used in infection imaging or have the potential to be used. Other PET radioisotopes such as 64Cu and 89Zr have been used in infection imaging especially in procedures where a longer half-life is desirable. In this chapter, we briefly review the various PET tracers that are used or can potentially be used in infection. Process Activated immune cells Infiltration of leucocytes Host defense Immune response Bacterial cell wall Bacterial biosynthesis

Host defense Bacterial metabolism

Target Energy consumption

Iron availability Iron scavenging Antimicrobial peptides Cell wall synthesis inhibition Folic acid synthesis inhibition Protein synthesis inhibition RNA synthesis inhibition DNA synthesis inhibition Bacterial antigens Carbohydrate metabolism Various other processes

Tracer example [18F]FDG

Stage Clinical

Radiolabeled white blood cells

Clinical

[68Ga]citrate [68Ga]siderophores Ubiquicidine peptides No PET tracers

Clinical Preclinical Clinical Preclinical

[18F]trimethoprim

Preclinical

[68Ga]puromycin

Preclinical

[11C]rifampicin [68Ga]ciprofloxacin 64 Cu and 89Zr-radiolabeled antibodies [18F]carbohydrates

Preclinical Preclinical Preclinical

[18F]FLT, PET-amino acids, etc.

Preclinical

Preclinical

3.2

Clinically Validated/Tested and Commercially Available Radiopharmaceuticals

3.2.1

[18F]FDG

During infection, the human body responds with the migration and activation of immune cells to the site of infection. These activated immune cells markedly increase their glucose uptake. The glucose transporters on the membrane of immune cells transport [18F]FDG, a glucose analog into the cell. Once [18F]FDG is inside the immune cell it is phosphorylated like glucose but is unable to continue along the biochemical pathway for glucose utilization and remains trapped in the immune cell. In addition to this, some microorganisms like bacteria have been found to contribute to the [18F]FDG signal by actively taking up [18F]FDG [6]. Compared to other methods used in infection imaging, the process of imaging with FDG is relatively fast with the study complete within a few hours. Unlike white cell labeling, [18F]FDG does not require direct handling of blood

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and laborious labeling procedures. [18F]FDG can be used in patients with neutropenia where anatomical-based imaging modalities or white cell imaging may be less helpful. [18F]FDG has some limitations including its non-specificity that is particularly a problem in the early postoperative period when inflammation at the site of operation limits the ability of [18F]FDG to detect infection. [18F]FDG does not image the microorganism themselves but rather the downstream immune activation.

3.2.1.1 [18F]FDG and Different Microorganisms [18F]FDG-PET has been used in the evaluation of different microorganisms. For viruses, [18F]FDG has been used to stage the infection and assess HIV-associated infections and malignancies [1, 7]. In bacterial imaging, [18F]FDG has been used to determine the site of infection when the site of infection is unknown or stage infection to determine the location of undiagnosed disease. In bacterial infections that require prolonged treatment like tuberculosis, [18F]FDG is useful in monitoring treatment of infection (Fig. 3.1) [8]. In fungal infections, [18F]FDG can be used to help diagnosis and guide therapy in a wide array of fungal infections [3, 9]. For parasitic infections, [18F]FDG has been used in the follow-up of treatment for alveolar echinococcosis [2]. 3.2.1.2 FDG Imaging of Some Site-Specific Infections Which Have Been Validated Osteomyelitis [18F]FDG is useful in the diagnosis of osteomyelitis, especially chronic osteomyelitis. A meta-analysis found the sensitivity and specificity of [18F]FDG-PET in chronic osteomyelitis to be 96% and 91%, respectively [10]. [18F]FDG-PET is particularly useful in multi-focal osteomyelitis. Spondylodiscitis [18F]FDG is used for imaging spondylodiscitis where other imaging modalities may be suboptimal [11–13]. Differentiating degenerative disease from infection is particularly challenging, and [18F]FDG-PET/CT is very useful for this purpose [12]. A meta-analysis found the pooled sensitivity and specificity of [18F]FDG-PET/CT in spondylodiscitis to be 97% and 88% [14]. Diabetic Foot FDG-PET is useful in diagnosing pedal osteomyelitis. One study found PET/CT had sensitivity and specificity of 81% and 93% in the diagnosis of pedal osteomyelitis in the diabetic foot [15]. Hip and Knee Prosthesis [18F]FDG-PET has been used in the evaluation of infected prosthesis of the hip and knee joints. Several studies found [18F]FDG-PET useful and also established interpretation criteria [16–20]. A meta-analysis of the diagnosis of infected knee and ankle prosthesis by [18F]FDG-PET found a pooled sensitivity of 87% and specificity of 87% [21].

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a

b

c

d

Fig. 3.1 18F-FDG-PET/CT scan before anti-TB treatment and 2 months after initiation of treatment for interim assessment of treatment response. (a) Maximum intensity projection (MIP) image before treatment (PET images only), showing extensive disease: pulmonary, cervical, axillary, mediastinal, abdominal, pelvic and inguinal lymph nodes, hepatic and skeletal metastasis to the lumbar spine and right humerus. (b) MIP image after 2 months of anti-TB treatment (PET images only): complete metabolic response of the pulmonary and right humeral lesions and the pelvic and inguinal lymph nodes. Good metabolic response in the mediastinal, cervical, and axillary nodes. Active disease is still present in the lumber spine with progression of the hepatic lesions. (c) Transverse scans showing axillary nodes before treatment (PET and integrated PET/CT images). (d) Transverse scans showing response of axillary nodes after 2 month of anti-TB therapy; nodal uptake diminished but still present

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Infected Vascular Graft Some studies have evaluated the role of [18F]FDG-PET in the evaluation of infected vascular graft. The sensitivity, specificity, and accuracy of [18F]FDG-PET in the diagnosis of infected vascular graft were 100%, 86%, and 97%%, respectively [22]. Infective Endocarditis [18F]FDG-PET/CT is used in the evaluation of infected prosthetic heart valves and is recommended by major international guidelines [23]. The sensitivity and specificity of [18F]FDG-PET/CT in prosthetic heart valves was found to be 71% and 95%, respectively, after confounder were removed the sensitivity and specificity improved to 91% and 95% [24]. [18F]FDG-PET/CT is not recommended in the assessment of native valve infective endocarditis; however, it is useful in detecting septic emboli from native valve endocarditis. Cardiac Implantable Electronic Device Infections [18F]FDG-PET/CT is a useful additive tool in patients with suspected cardiac implantable electronic device infections [25]. A meta-analysis found [18F]FDG-PET had a pooled sensitivity and specificity of 87% and 94% for infected implantable cardiac devices [26].

3.2.2

Labeled White Blood Cells

During infection, chemotactic agents attract leucocytes to the site of infection. Radiolabeled WBC provides a means of imaging infection. Leucocytes have been labeled with [18F]FDG [27, 28]. The sensitivity and specificity per lesion were found to be 91% and 85%, respectively, and 86% for both sensitivity and specificity per patient [27]. The labeling efficiency of [18F]FDG labeled white cells are lower than SPECT-based tracers, and the short half-life of 18F is not ideal for delayed imaging which is essential the diagnosis of infection by labeled WBCs. Leucocytes have also been labeled with 64Cu because the long half-life of 64Cu would permit delayed imaging to distinguish infection. The labeling efficiency and viability of the labeled leucocytes were higher than 111In-labeled leucocyte. However, there was higher leakage from 64Cu compared to SPECT-based labeled leucocytes [29]. The radiation exposure to the long-lived lymphocytes from PETbased radioisotope is a concern [30].

3.2.3

[68Ga]Citrate

[68Ga]citrate has been used to image osteomyelitis, tuberculosis, and soft-tissue infections in human studies [31–33]. Iron is utilized by both mammals and microorganism for their metabolism. Gallium mimics iron, and in infection, the uptake of gallium is due to transferrin-dependent and independent mechanisms. [68Ga]citrate like [18F]FDG lacks specificity and accumulates in sterile inflammatory process or malignancy [34]. The ease of preparation of the radiopharmaceutical and the availability of good manufacturing practice 68Ga-generators makes the use of [68Ga]

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citrate appealing. The sensitivity and specificity for osteomyelitis was 100% and 76%, respectively. Larger studies with [68Ga]citrate are required to validate its use in various clinical scenarios.

3.2.4

Peptides

AMPs are peptides produced by the immune system of the host against microorganisms. They have low toxicity and have activity against a wide range of microorganisms. Several AMPs have been labeled for imaging infection. For PET imaging, ubiquicidin fragments have been most widely investigated.

3.2.5

Ubiquicidin (UBI) Fragments

UBI, a 51 amino acid peptide that binds negatively charged moieties in the cell wall of bacteria has shown promising results for imaging infection. Several fragments of UBI have been labeled with 68Ga and 18F and tested in different animal models [35–39]. The [68Ga]UBI fragments were able to distinguish infection and inflammation and had good localization of infection (Fig.  3.2) [36]. [68Ga]UBI fragments (UBI29-41 and UBI31-38) have been used in humans with promising results [36, 37]. The UBI29-41 fragment was labeled with 18F but did not have as much success in imaging infection as the 68Ga-labeled counterpart due to significant defluorination and the lack of specific binding to Staphylococcus aureus in vivo. Larger studies with [68Ga]UBI would be necessary to validate the use of the tracer in different clinical situations.

a

b

c

Fig. 3.2 PET/CT images of healthy mouse (a), mouse with sterile inflammation (b), and mouse infected with S. aureus (c). Images were acquired 2 h after injection of 68Ga-NOTA-UBI-29-41 (1, coronal; 2, sagittal; and 3, axial). Images correspond to frame 2 of 4. Arrows indicate inflamed or infected muscle (Mónica Vilche et al. J Nucl Med 2016;57:622–627)

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3.3

Experimental Radiopharmaceuticals

3.3.1

Peptides

25

3.3.1.1 Depsipeptide Derivative A depsipeptide derivative was labeled with 68Ga by DOTA chelation and was used for in  vivo evaluation of Escherichia coli in a mouse model and Staphylococcus aureus and Mycobacterium tuberculosis in a rabbit model [40, 41]. The tracer detected these infections but was not able to differentiate infection-associated inflammation from bacteremia. 3.3.1.2 K-A9 Peptide K-A9 is a peptide that binds to Staphylococcus aureus that was selected and proposed as an imaging peptide [42]. The peptide was radiolabeled with 68Ga but was not found to be selective towards infection probably due to some factors including vascular leakiness, hyperemia, and the peptide-binding epitopes in dead bacteria [43].

3.3.2

Antibiotics

Antibiotics have been used extensively with SPECT tracers. A few have also been labeled with PET radionuclides.

3.3.2.1 Ciprofloxacin Radiolabeled ciprofloxacin is one of the earliest antibiotics used in imaging infections. The antibiotic or its conjugates have been labeled with 68Ga and 18F [44, 45]. [68Ga]ciprofloxacin conjugates were labeled by bifunctional DOTA and NOTA chelators [44]. The [68Ga]ciprofloxacin conjugates (Fig.  3.3) could discriminate between Staphylococcus aureus infected sites in rat muscle from inflammation. These tracers are yet to be tested in the clinic. Ciprofloxacin was also labeled by nucleophilic 18F-fluorination. However, the radioactivity was not retained in the infected tissue, and the clearance from infected tissue was similar to non-infected tissue [45]. 3.3.2.2 Trimethoprim Trimethoprim inhibits the synthesis of the nucleic acid thymidine in bacteria by inhibiting tetrahydrofolic acid. Trimethoprim has been labeled with 18F by nucleophilic fluorination and was found to show a very high uptake (>100-fold) in live bacteria but not in other pathologies such as cancer or sterile inflammation in a mouse model. The biodistribution of this tracer has been determined in a nonhuman primate but no human studies have been carried out [46].

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N

68Ga

N

N

O O O

O

O

F OH

O

N HN

H N

N

N

S

Fig. 3.3 Chemical structure of [68Ga]-Bz-SCN-ciprofloxacin

3.3.2.3 Puromycin Puromycin is an antibiotic that interrupts bacteria protein synthesis by terminating the translation of ribosomes. Puromycin has been labeled with 68Ga by DOTA chelation and showed promising results for uptake in Staphylococcus aureus foci compared to sterile inflammation [47]. Puromycin has also been labeled with 18F for imaging protein synthesis [48]. This labeled antibiotic has not yet been tested for infection imaging. 3.3.2.4 Rifampicin The anti-mycobacterial agent rifampicin was radiolabeled with 11C.  The SPECT equivalent of this radiolabeled antibiotic was evaluated as a tuberculosis imaging agent. The 11C-labelled antibiotic was used to determine the distribution of the agent but may play a role in imaging the infection. The short half-life of 11C however may limit its clinical application [49]. 3.3.2.5 Isoniazid The anti-mycobacterial drug isoniazid was radiolabeled with 18F by nucleophilic substitution [50]. The tracer was used to image mice infected with Mycobacterium tuberculosis and the tracer showed good uptake at infected sites. This tracer is yet to be translated to human studies. 3.3.2.6 Pyrazinamide Pyrazinamide, an anti-mycobacterial agent, was labeled with 18F by a fluoride exchange reaction. The biodistribution of the 5-[18F]pyrazinamide compound was

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assessed. The pyrazinamide analog did not show significant differences in infected tissue and uninfected mice model of tuberculosis. There was rapid and extensive defluorination of [18F]pyrazinamide. As a result of this, the fluorine analog of pyrazinamide may be limited as an infection imaging agent [51].

3.3.2.7 Fluconazole Fluconazole an antifungal agent has been radiolabeled with 99mTc and was found to be an excellent tracer for detecting Candida albicans in mice [52]. The agent was also labeled with 18F. The PET tracer, however, may not be as successful in imaging Candida infections as there was intense hepatic uptake due to the excretion of the [18F]fluconazole [53].

3.3.3

Antibody Labeling

3.3.3.1 Antibodies Against Gram-Negative Bacteria Polyclonal antibodies against the outer membrane protein of Yersinia enterocolitica, adhesion A, were labeled with 64Cu. The radiolabeling was achieved by chelation with 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA). The 64 Cu-labeled antibody was taken up in infected tissues in a dose-dependent manner. The 64Cu-labeled antibiotic was able to detect infection in spleens of mice with low dose infection in contrast to FDG [54]. 3.3.3.2 Antibodies Against Gram-Positive Bacteria Gram-positive bacteria surface molecule lipoteichoic acid (LTA) was imaged with the anti-LTA antibody SAC55 labeled with 89Zr after its conjugation with bifunctional chelate, p-SCN-Bn-DFO. The tracer was tested in a mouse model of prosthetic joint infection and was able to distinguish infection prosthetic joints from inflammation non-infected joint. The findings are yet to be translated to humans [55]. 3.3.3.3 Antibody Against Simian Immunodeficiency Virus Envelope Protein A monoclonal antibody against the glycoprotein Gp120 on the surface of Simian immunodeficiency virus has been labeled with 64Cu. The radiolabeling method was DOTA chelation of the modified antibiotic. The tracer was used to provide the location and quantification of in vivo viral replication in a nonhuman primate [56]. 3.3.3.4 Aspergillus Fumigatus-Specific Monoclonal Antibody JF5 The JF5 monoclonal antibody binds to an extracellular mannoprotein of Aspergillus fumigatus that is produced during growth of the fungi. The JF5 monoclonal body was radiolabeled with 64Cu by chelating with DOTA.  The tracer was tested in a neutrophil-depleted mouse model of invasive fungal infection. The tracer was able to distinguish the growth phase of Aspergillus fumigatus from other pathology including infection with other microorganisms [57].

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A. O. Ankrah and P. H. Elsinga

Imaging Targeted Molecules or Metabolism Specific to Microorganisms

3.3.4.1 Siderophores Siderophores are proteins used by microorganisms to scavenge iron in their microenvironment. 68Ga-Labeled siderophores have been used for imaging invasive pulmonary aspergillosis in an animal model. Two compounds triacetylfusarinine and ferrioxamine E were radiolabeled using the direct method. The 68Ga-labeled siderophores showed high sensitivity and selectivity for rat lungs infected with Aspergillus fumigatus [58, 59]. 3.3.4.2 Carbohydrate Metabolism Maltodextrins: Maltohexose was labeled with 18F by nucleophilic substitution. [18F] fluoromaltohexose is transported into the bacteria by a maltodextrin transporter which is unique to bacteria making it a promising agent. In an in vivo study involving a rat model of an implantable cardiac device, the tracer was found to be specific and sensitive for the detection of Staphylococcus aureus [60]. The tracer had earlier been shown to be sensitive and specific for the detection of Escherichia coli in in vitro studies [61]. The tracer was found to accumulate in as few as 105 colony forming units [62]. Maltotriose: Maltotriose is also utilized by bacteria but not mammalian cells. 6-[18F]fluoromaltotriose was radiolabeled by nucleophilic 18F-fluorination. In preliminary in  vivo studies in mice, the tracer was specifically taken up by viable Escherichia coli but not in sterile inflammation [63]. Sorbitol: Sorbitol is a substrate for Gram-negative bacteria, Enterobacteriaceae. The tracer [18F]fluorosorbitol ([18F]FDS). The tracer which can easily be synthesized from [18F]FDG (Fig.  3.4) was found to be promising as a bacteria-specific imaging agent some studies. [18F]FDS was found to be a better biomarker than [18F] FDG, in tracking bacterial lung infection using a mouse model [64]. In another study, [18F]FDS was found to accumulate in susceptible and carbapenem-resistant drug isolates [65]. [18F]FDS was evaluated in humans for safety and no adverse Fig. 3.4 Synthesis of [18F] FDS from clinical grade [18F]FDG via a reduction step

CHO

CH2OH

H

18F

HO

H

NaBH4

H

OH

45 ºC

H

OH CH2OH [18F]FDG

H

18F

HO

H

H

OH

H

OH CH2OH [18F]FDS

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effects were observed 24 h after administration of the tracer [66]. [18F]FDS was able to detect Enterobacteraceae in mixed infections, brain infections, and mice undergoing chemotherapy [67]. [18F]Fluorodeoxyglucose-phosphate (FDG-P): Bacteria can utilize FDG-P using universal hexose phosphate transporters which are not present in mammalian cells. Unlike FDS which targeted only Gram-negative bacteria, it was hoped that FDG-P would be useful in imaging Gram-positive bacteria with high sensitivity and bacteria selectivity. FDG-P uptake was higher in Staphylococcal-infected catheter implants in mice compared to uninfected implants [68]. D-mannitol: The ability of some bacteria to utilize D-mannitol as a source of energy has been exploited for potential bacterial imaging. The sugar was radiolabeled with 18F. The radiolabeled D-mannitol was rapidly taken up by Gram-positive and Gram-negative bacteria in a myositis model in mice. The tracer was taken up by both susceptible and resistant microorganisms [65]. Fluoroacetamide-D-glycopyranose (FAG): Amino sugars are important components of the bacterial cell wall. This makes them a good target for imaging bacteria. An analog of an amino sugar was radiolabeled by microwave irradiation to [18F] FAG. The radiolabeled tracer was able to distinguish infection with Escherichia coli and sterile inflammation in an animal model [69]. Trehalose analogs: Trehalose is a disaccharide sugar that is used by plants and microorganism for some functions like stress protection and energy storage. A modified 18F-labeled analog of trehalose has been produced by the chemoenzymatic conversion of FDG. The 18F-labeled analog of trehalose was shown to be metabolized by Mycobacterium smegmatis but not mammalian cell in cellular uptake experiments. There are no clinical studies available [70].

3.3.5

Other Metabolites

3.3.5.1 Fialuridine (FIAU) Fialuridine is a nucleoside analog that is a building block of the nucleic acid of microorganisms. Fialuridine is phosphorylated by thymidine kinase and remains trapped in the microorganism allowing imaging is tagged with a radioisotope. FIAU has been radiolabeled with 18F and 124I [68, 71, 72]. The [18F]FIAU was radiolabeled by nucleophilic substitution. The synthesis of [18F]FIAU is more complex and achieves lower yields than [124I]FIAU. When [124I]FIAU was used in the evaluation of prosthetic joint prosthesis the image quality and specificity was low [73]. 3.3.5.2 Para-Aminobenzoic acid (PABA) PABA is utilized by bacteria in the synthesis of folate. In mammals, folate is obtained from the diet and mammals cannot utilize PABA.  This makes PABA a good target to image infection. PABA has been labeled with 11C and 18F [74, 75]. In an animal model, the [11C]PABA was able to distinguish between infection and sterile inflammation. The [18F]PABA was tested in an animal model where it was found to be useful in imaging Staphylococcal aureus infection.

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3.3.5.3 D-Methionine d-Methionine was labeled with 11C and successfully used to image bacteria. D-amino acids are used solely by bacteria for building their cell walls. The [11C] methionine rapidly accumulated in Gram-positive and Gram-negative bacteria. No human study has been done on this PET tracer [76]. 3.3.5.4 Prothrombin Some Staphylococcus sp. produce staphylocoagulase which help bacteria evade detection by the immune system of their host by covering their antigen with clotted blood from the host. An analog of prothrombin was labeled with 64Cu by chelation with DOTA. This enabled the detection of Staphylococcus sp.-induced endocarditis in mice [77]. 3.3.5.5 Transferrin Transferrin is a protein involved in the transport of iron. Transferrin was labeled with 68Ga as [68Ga]apo-transferrin. The tracer was found to be able to detect Staphylococcus aureus infection in a rat model within an hour of injection [78].

3.3.6

Nonspecific Tracers Used in Infection to Discriminate Infection from Malignancy

3.3.6.1 [18F]fluorothymidine ([18F]FLT) Synthesis of DNA can be imaged by [18F]FLT. During an infection, microorganisms are constantly growing with actively synthesizing nucleic acids. The growth of Staphylococcus aureus in rabbit was imaged using [18F]FLT. However, nucleic acid formation is not limited to bacteria growth and makes the tracer just as nonspecific as [18F]FDG [79, 80]. In another study using a model with Yersinia enterocolitica, [18F]FLT was not useful in assessing bacterial proliferation [81]. Other clinically available PET tracers have been used in the evaluation of different aspects a particular infection. In tuberculosis, for example, [18F]NaF used to evaluate calcification of tuberculous granulomas in mice, the complex lipid covering was evaluated by [11C]choline or [18F]fluoroethylcholine. The use of these tracers is limited to the pathology of a particular infection and lacked specificity for the infection [8].

3.4

Conclusion and Future Perspective

PET imaging of infection has gained prominence over the last decade. [18F]FDG has been found useful in many site-specific infections. It is likely to be validated in more clinical situations in the future. The introduction of PET/MRI into clinical practice may open a new chapter in infection imaging, especially where soft-tissue definition is essential. The use microorganism-specific tracers are being explored and the presence of longer acting PET tracer such as 64Cu and 89Zr has increased the possibilities

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especially in the labeling of antibodies. A lot of the tracers are at the preclinical stage of development. A lot more research needed for the clinical application of these tracers. The search for an ideal PET tracer is still ongoing. The ideal tracer should be able to distinguish infection from inflammation, cheap, easy to prepare, and not require handling of blood products. A tracer should be able to detect both resistant and susceptible species. Another major clinical hurdle is biofilm formation making bacteria not sensitive to anti-bacterial agents as these agents are not able to penetrate into biofilm. Recent research on adaptive biofilm-targeted agents can trigger development of a completely new class of imaging agents in the future.

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33. Salomäki SP, Kemppainen J, Hohenthal U, Luoto P, Eskola O, Nuutila P, Seppänen M, Pirilä L, Oksi J, Roivainen A.  Head-to-head comparison of 68Ga-citrate and 18F-FDG PET/CT for detection of infectious foci in patients with Staphylococcus aureus bacteraemia. Contrast Media Mol Imaging. 2017;2017:3179607. 34. Vorster M, Maes A, Jacobs A, Malefahlo S, Pottel H, Van de Wiele C, Sathekge MM. Evaluating the possible role of 68Ga-citrate PET/CT in the characterization of indeterminate lung lesions. Ann Nucl Med. 2014;28(6):523–30. 35. Ebenhan T, Zeevaart JR, Venter JD, Govender T, Kruger GH, Jarvis NV, et al. Preclinical evaluation of 68Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-ubiquicidin as a radioligand for PET infection imaging. J Nucl Med. 2014;55(2):308–14. 36. Bhatt J, Mukherjee A, Shinto A, Karuppusamy KK, Korde A, Kumar M, et  al. Gallium-68 labeled Ubiquicidin derived octapeptide as a potential infection imaging agent. Nucl Med Biol. 2018;62–63:47–53. 37. Ebenhan T, Sathekge MM, Lengana T, Koole M, Gheysens O, Govender T, et al. 68Ga-NOTAfunctionalized Ubiquicidin: cytotoxicity, biodistribution, radiation dosimetry, and first-inhuman PET/CT imaging of infections. J Nucl Med. 2018;59(2):334–9. 38. Vilche M, Reyes AL, Vasilskis E, Oliver P, Balter H, Engler H. 68Ga-NOTA-UBI-29-41 as a PET tracer for detection of bacterial infection. J Nucl Med. 2016;57(4):622–7. 39. Salber D, Gunawan J, Langen KJ, Fricke E, Klauth P, Burchert W, et  al. Comparison of [99mTc]- and [18F]ubiquicidin autoradiography to anti-Staphylococcus aureus immunofluorescence in rat muscle abscesses. J Nucl Med. 2008;49(6):995–9. 40. Ebenhan T, Mokaleng BB, Venter JD, Kruger HG, Zeevaart JR, Sathekge M.  Preclinical assessment of a 68Ga-DOTA functionalized depsipeptide as a radiodiagnostic infection imaging agent. Molecules. 2017;22(9):E1403. 41. Mokaleng BB, Ebenhan T, Ramesh S, Govender T, Kruger HG, Parboosing R, et al. Synthesis, 68Ga-radiolabeling, and preliminary in vivo assessment of a depsipeptide-derived compound as a potential PET/CT infection imaging agent. Biomed Res Int. 2015;2015:284354. 42. Nielsen KM, Kyneb MH, Alstrup AK, Jensen JJ, Bender D, Schønheyder HC, et  al. (68) Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections: selection, radiolabelling and preliminary biological evaluation. Nucl Med Biol. 2016;43(10):593–605. 43. Nielsen KM, Jorgensen NP, Kyneb MH, Borghammer P, Meyer RL, Thomsen TR, et  al. Preclinical evaluation of potential infection-imaging probe [68Ga]Ga-DOTA-K-A9  in sterile and infectious inflammation. J Label Compd Radiopharm [Internet]. 2018 May [cited 2019. 02.26]. https://onlinelibrary.wiley.com/doi/full/10.1002/jlcr.3640. https://doi.org/10.1002/ jlcr.3640 44. Satpati D, Arjun C, Krishnamohan R, Samuel G, Banerjee S. 68Ga-labeled ciprofloxacin conjugates as radiotracers for targeting bacterial infection. Chem Biol Drug Des. 2016;87(5): 680–6. 45. Langer O, Brunner M, Zeitlinger M, Ziegler S, Muller U, Dobrozemsky G, et al. In vitro and in vivo evaluation of [18F]ciprofloxacin for the imaging of bacterial infections with PET. Eur J Nucl Med Mol Imaging. 2005;32(2):143–50. 46. Sellmyer MA, Lee I, Hou C, Weng CC, Li S, Lieberman BP, et  al. Bacterial infection imaging with [18F]fluoropropyl-trimethoprim. Proc Natl Acad Sci U S A. 2017;114(31): 8372–7. 47. Eigner S, Beckford Vera D, Lebeda O, Eigner Henke K. 68Ga-DOTA-puromycin: in  vivo imaging of bacterial infection. J Nucl Med. 2013;S54(2):1218. 48. Betts HM, Milicevic Sephton S, Tong C, Awais RO, Hill PJ, Perkins AC, et  al. Synthesis, in vitro evaluation, and radiolabeling of fluorinated puromycin analogues: potential candidates for PET imaging of protein synthesis. J Med Chem. 2016;59(20):9422–30. 49. DeMarco VP, Ordonez AA, Klunk M, Prideaux B, Wang H, Zhuo Z, et  al. Determination of [11C]rifampin pharmacokinetics within Mycobacterium tuberculosis-infected mice by using dynamic positron emission tomography bioimaging. Antimicrob Agents Chemother. 2015;59(9):5768–74.

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50. Weinstein EA, Liu L, Ordonez AA, Wang H, Hooker JM, Tonge PJ, Jain SK.  Noninvasive determination of 2-[18F]-fluoroisonicotinic acid hydrazide pharmacokinetics by positron emission tomography in mycobacterium tuberculosis-infected mice. Antimicrob Agents Chemother. 2012;57(12):6284–90. 51. Zhang Z, Ordonez AA, Smith-Jones P, Wang H, Gogarty KR, Daryaee F, et al. The biodistribution of 5-[18F]fluoropyrazinamide in Mycobacterium tuberculosis-infected mice determined by positron emission tomography. PLoS One. 2017;12(2):e0170871. 52. Lupetti A, Welling MM, Pauwels EK, Nibbering PH.  Detection of fungal infections using radiolabeled antifungal agents. Curr Drug Targets. 2005;6(8):945–54. 53. Livni E, Fischman AJ, Ray S, Sinclair I, Elmaleh DR, Alpert NM, et  al. Synthesis of 18F-labeled fluconazole and positron emission tomography studies in rabbits. Int J Rad Appl Instrum B. 1992;19(2):191–9. 54. Wiehr S, Warnke P, Rolle AM, Schutz M Oberhettinger P, Kohlhofer U, et al. New pathogenspecific immunoPET/MR tracer for molecular imaging of a systemic bacterial infection. Oncotarget. 2016;7(10):10990–1001. 55. Pickett JE, Thompson JM, Sadowska A, Tkaczyk C, Sellman BR, Minola A, et al. Molecularly specific detection of bacterial lipoteichoic acid for diagnosis of prosthetic joint infection of the bone. Bone Res. 2018;6:13. 56. Santangelo PJ, Rogers KA, Zurla C, Blanchard EL, Gumber S, Strait K, et al. Whole-body immunoPET reveals active SIV dynamics in viremic and antiretroviral therapy-treated macaques. Nat Methods. 2015;12(5):427–32. 57. Rolle AM, Hasenberg M, Thornton CR, Solouk-Saran D, Männ L, Weski J, et al. ImmunoPET/ MR imaging allows specific detection of Aspergillus fumigatus lung infection in vivo. Proc Natl Acad Sci U S A. 2016;113(8):E1026–33. 58. Petrik M, Franssen GM, Haas H, Laverman P, Hörtnagl C, et  al. Preclinical evaluation of two 68Ga-siderophores as potential radiopharmaceuticals for Aspergillus fumigatus infection imaging. Eur J Nucl Med Mol Imaging. 2012;39(7):1175–83. 59. Petrik M, Haas H, Laverman P, Schrettl M, Franssen GM, Blatzer M, et  al. 68Ga-triacetylfusarinine C and 68Ga-ferrioxamine E for Aspergillus infection imaging: uptake specificity in various microorganisms. Mol Imaging Biol. 2014;16(1):102–8. 60. Takemiya K, Ning X, Seo W, Wang X, Mohammad R, Joseph G, et al. Novel PET and near infrared imaging probes for the specific detection of bacterial infections associated with cardiac devices. JACC Cardiovasc Imaging. 2018. pii:S1936-878X(18)30207-9. 61. Ning X, Seo W, Lee S, Takemiya K, Rafi M, Feng X, Weiss D, Wang X, Williams L, Camp VM, et al. PET imaging of bacterial infections with fluorine-18 labeled maltohexaose. Angew Chem Int Ed Engl. 2014;53(51):14096–101. 62. Ning X, Lee S, Wang Z, Kim D, Stubblefield B, Gilbert E, et al. Maltodextrin-based imaging probes detect bacteria in  vivo with high sensitivity and specificity. Nat Mater. 2011;10(8): 602–7. 63. Gowrishankar G, Namavari M, Jouannot EB, Hoehne A, Reeves R, Hardy J, et al. Investigation of 6-[18F]-fluoromaltose as a novel PET tracer for imaging bacterial infection. PLoS One. 2014;9(9):e107951. 64. Li J, Zheng H, Fodah R, Warawa JM, Ng CK.  Validation of 2-18F-fluorodeoxysorbitol as a potential radiopharmaceutical for imaging bacterial infection in the lung. J Nucl Med. 2018;59(1):134–9. 65. Ordonez AA, Weinstein EA, Bambarger LE, Saini V, Chang YS, DeMarco VP, Klunk MH, Urbanowski ME, Moulton KL Murawski AM, et  al. A systematic approach for developing bacteria-specific imaging tracers. J Nucl Med. 2017;58(1):144–50. 66. Yao S, Xing H, Zhu W, Wu Z, Zhang Y, Ma Y, Liu Y, Zhu Z, Li Z, Fang L. Infection imaging with 18F-FDS and first-in-human evaluation. Nucl Med Biol. 2016;43:206–14. 67. Weinstein EA, Ordonez AA, DeMarco VP, Murawski AM, Pokkali S, MacDonald EM, et al. Imaging Enterobacteriaceae infection in vivo with 18F-fluorodeoxysorbitol positron emission tomography. Sci Transl Med. 2014;6(259):259ra146.

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68. Mills B, Awais RO, Luckett J Turton D, Williams P, Perkins AC, et  al. [18F]FDG-6-P as a novel in  vivo tool for imaging staphylococcal infections. EJNMMI Res. 2015; 5:13. 69. Martìnez ME, Kiyono Y, Noriki S, Inai K, Mandap KS, Kobayashi M, et al. New radiosynthesis of 2-deoxy-2-[18F]fluoroacetamido-D-glucopyranose and its evaluation as a bacterial infections imaging agent. Nucl Med Biol. 2011;38(6):807–17. 70. Peña-Zalbidea S, Huang AY, Kavunja HW, Salinas B, Desco M, Drake C, et al. Chemoenzymatic radiosynthesis of 2-deoxy-2-[18F]fluoro-d-trehalose ([18F]-2-FDTre): a PET radioprobe for in vivo tracing of trehalose metabolism. Carbohydr Res. 2019;472:16–22. 71. Rajamani S, Kuszpit K, Scarff JM, Lundh L, Khan M, Brown J, et  al. Bioengineering of bacterial pathogens for noninvasive imaging and in vivo evaluation of therapeutics. Sci Rep. 2018;8(1):12618. 72. Diaz LA, Foss CA, Thornton K, Nimmagadda S, Endras CJ, Uzuner O, et al. Imaging of musculoskeletal bacterial infections by [124I]FIAU-PET/CT. PLoS One. 2007;2(10):e1007. 73. Zhang XM, Zhang HH, McLeroth P, Berkowitz RD, Mont MA, Stabin MG, et al. [124I]FIAU: human dosimetry and infection imaging in patients with suspected prosthetic joint infection. Nucl Med Biol. 2016;43(5):273–9. 74. Mutch CA, Ordonez AA, Qui H, Parker M, Bambarger LE, Villanueva-Meyer JE, et al. [11C] Para-aminobenzoic acid: a positron emission tomography tracer targeting bacteria-specific metabolism. ACS Infect Dis. 2018;4(7):1067–72. 75. Zhang Z, Ordonez AA, Wang H, Li Y, Gogarty KR, Weinstein EA, et al. Positron emission tomography imaging with 2-[18F]F-p-aminobenzoic acid detects Staphylococcus aureus infections and monitors drug response. ACS Infect Dis. 2018;4(11):1635–44. 76. Neumann KD, Villanueva-Meyer JE, Mutch CA, Flavell RR, Blecha JE, Kwak T, et al. Imaging active infection in vivo using D-amino acid derived PET radiotracers. Sci Rep. 2017;7(1):7903. 77. Panizzi P, Nahrendorf M, Figueiredo JL, Panizzi J, Marinelli B, Iwamoto Y, et  al. In vivo detection of Staphylococcus aureus endocarditis by targeting pathogen-specific prothrombin activation. Nat Med. 2012;17(9):1142–6. 78. Kumar V, Boddeti DK, Evans SG, Roesch F, Howman-Giles R. Potential use of 68Ga-apotransferrin as a PET imaging agent for detecting Staphylococcus aureus infection. Nucl Med Biol. 2011;38(3):393–8. 79. Jang SJ, Lee YJ, Lim S, Kim KI, Lee KC, An GI, et  al. Imaging of a localized bacterial infection with endogenous thymidine kinase using radioisotope-labeled nucleosides. Int J Med Microbiol. 2012;302(2):101–7. 80. Tan Y, Liang J, Liu D, Zhu F, Wang G, Ding X, et al. 18F-FLT PET/CT imaging in a Wister rabbit inflammation model. Exp Ther Med. 2014;8(1):69–72. 81. Wiehr S, Rolle AM, Warnke P, Kohlhofer U, Quintanilla-Martinez L, Reischl G, et al. The positron emission tomography tracer 3′-deoxy-3′-[18F]Fluorothymidine ([18F]FLT) is not suitable to detect tissue proliferation induced by systemic yersinia enterocolitica infection in mice. PLoS One. 2016;11(10):e0164163.

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Hybrid SPECT/CT and PET/CT Imaging in Infectious Diseases Sveva Auletta, Thomas Q. Christensen, and Søren Hess

4.1

Introduction

Hybrid imaging with SPECT/CT and PET/CT has had a profound impact on diagnostic imaging in general and nuclear medicine in particular—fusion scanners combine the best of two worlds and generally improve assessment of patients, especially anatomically difficult regions, or in the assessment of small foci in liver, vertebra, or joints. Disadvantages compared to simple planar images or to stand-alone modalities include equipment prize, claustrophobia, acquisition time, and a multitude of novel artifacts and pitfalls to be aware of [1–4]. The aim of this chapter is to provide an overview of hybrid imaging in general and with special emphasis on infection imaging whenever possible as the literature within this domain is still relatively limited. Basically speaking, nuclear medicine and scintigraphic examinations provide information on physiology and pathophysiology but include only limited morphologic information. From the early days, the mainstay was two-dimensional planar images, initially regional static images, later whole-body scans and more advanced dynamic acquisition. On the other hand, radiology and radiographic examinations provide anatomic information, but only limited functional data, likewise initially with two-dimensional images. For decades, the two specialties developed separately alongside each other, but remained relatively segregated. However, the combined knowledge of anatomy and function was early recognized by clinicians in medical S. Auletta (*) Nuclear Medicine Unit, Department of Medical-Surgical Sciences and Translational Medicine, Faculty of Medicine and Psychology, University “Sapienza” of Rome, Rome, Italy T. Q. Christensen Department of Clinical Engineering, Region of Southern Denmark, Odense, Denmark S. Hess Department of Radiology and Nuclear Medicine, Hospital of Southwest Jutland, Esbjerg, Denmark © Springer Nature Switzerland AG 2020 A. Signore, A. W. J. M. Glaudemans (eds.), Nuclear Medicine in Infectious Diseases, https://doi.org/10.1007/978-3-030-25494-0_4

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practice, and with the advent of 3D imaging within both specialties, parallel assessment of functional and anatomical images have become the mainstay in diagnostic imaging. Pioneering developments in 3D tomographic technique include work by several individuals and groups, e.g., emission scans in the 1960s by David Kuhl and colleagues, CT in the 1970s by Godfrey Houndsfield’s and Allan Cormack’s groups, PET technology in the 1970s and 1980s by Michael Ter-Pogossian, Michael Phelps, and colleagues, and finally, hybrid systems like SPECT/CT introduced by Bruce Hasegawa’s group during the 1980s and 1990s (commercialized in 1999), and PET/ CT introduced in 1999 by David Townsend and colleagues (commercialized in 2001). Whenever patients undergo various imaging modalities, the overall correlation of anatomic and physiologic information is obvious, but the backdrop of hybrid system developments were the intrinsic challenges with stand-alone systems; sideby-side assessment and comparison were challenging due to differences in positioning caused by differences in scanner tables and in image size. Side-by-side comparison was best achieved in rigid structures, e.g., brain and bone, but difficult in interchangeable or deformable organs. Initial work on brain studies from the 1980s paved the way, but further developments and translation to thorax/abdomen proved more difficult, e.g., internal organ motion like the bowel, artifacts from respiratory movements, and generally difficult regions like head-and-neck, where arm or shoulder positioning may significantly impact image quality. All of these challenges become ever more pronounced the longer the time period between the separate examinations. With improved computer technology came also the potential for software-based image fusion that relied on alignment through anatomic markers, the so-called segmentation method. However, some of the challenges mentioned above regarding side-by-side interpretation also apply to segmentation fusion. Thus, “hardware fusion” became the mainstay with sequential co-registration and consequently better alignment, improved patient course and better health care logistics with only one visit instead of two or more. Today, it is difficult to imagine diagnostic imaging without hybrid scanners and 3D acquisitions—in general and in infection imaging.

4.2

SPECT/CT Characteristics

4.2.1

Basic Concepts

4.2.1.1 Planar Imaging The gamma camera (also known as the Anger scintillation camera after its inventor Hal Anger) works by detecting gamma photons emitted when the radionuclide in the radiopharmaceutical decays. As gamma rays are very high energetic electromagnetic waves, they are very difficult to detect with normal photon imaging detectors. Because of this, high-density crystals are used to absorb the gamma rays and reemit them at lower energies as visible or ultraviolet light, through the process

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known as scintillation, which can then be detected. These scintillation crystals are then optically coupled to very sensitive detectors to detect the relatively very few photons that are emitted from the small number of radionuclides. The most commonly used gamma camera design for many years was based on scintillation crystals of sodium iodide doped with thallium (NaI(Tl)) in combination with the sensitive detectors of photomultiplier tubes (PMTs). Detectors have also been developed based on semiconductor material of cadmium zinc telluride (CZT) without the need for combination with scintillation crystals, which offers better image quality but at a higher financial cost. In order to make sure that only counts are registered that originates from the detection of gamma photons emitted by the radionuclide used in the examination and to decrease noise an energy window is applied that narrowly encloses the expected energy of the emitted gamma photons. Only detections with energy within that window are registered as counts. With better energy resolution this energy window can be made smaller and increase image quality. This is also a factor in the better image quality of CZT detectors. Collimators are plates of lead with a lot of adjacent hexagon-shaped holes through it. These are put in front of the scintillation crystal and almost exclusively allow gamma photons from a specific angle to pass through and be detected. This creates projections where individual counts can be detected and summed to form a two-dimensional image of the radiopharmaceutical distribution. The lead walls between the adjacent holes are called septa and can be made thicker to decrease the penetration of gamma photons to another hole as the level of penetration increases with increasing energy of the incoming photons. The penetration of gamma photons to another hole will increase the noise in the image. On the other hand, thicker septa will decrease the sensitivity as fewer photons will be detected. By decreasing the diameter of the holes in the collimator and thereby having more and smaller holes, the spatial resolution will be increased by creating more projections in the same area, but this will also lead to a decrease in sensitivity. Thus, the choice of collimator is a compromise between all these aspects and depends very much on the isotopes used for the specific examination as the energy of the gamma photons they emit limits septa thickness. The combination of collimator, scintillation crystal, and PMTs constitute the image receptor of the gamma camera and is commonly known as the camera head. The size of the camera head will determine how much of the patient can be scanned at the same time, which is also known as the field-of-view (FOV). An image of the radiopharmaceutical distribution taken in this way is known as planar imaging or a scintigraphy (named after the scintillation crystal that makes imaging gamma rays possible). Gamma cameras are most commonly one-headed or two-headed, but are available in different configurations with a variety of camera heads depending on their intended use.

4.2.1.2 SPECT and SPECT/CT By rotating the gamma camera heads around the patient, the scanner is able to acquire projections from many different angles of the patient and by computer-based

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reconstructing with topographical techniques a set of three-dimensional images is created. This is the foundation of Single Photon Emission Computed Tomography (SPECT). In order to generate SPECT images at least an arc of 180° around the patient needs to be acquired although a full arc of 360° achieves better image quality. Because of this and in order to decrease examination time SPECT is most commonly performed with a two camera head system that only needs 180° rotation each to achieve a full circle arc. The images are most frequently acquired with the camera heads opposite each other and the patient in the middle. The images are then acquired in that position for a certain time before the camera heads are moved a few degrees and acquire another set of data. This is done until a full 180° arc is formed; the longer the time spent acquiring at each position and the fewer the degrees of angle between the positions, the better the quality of the acquired SPECT images, but at the expense of overall examination time. SPECT is most often combined with X-ray computed tomography (CT) forming the hybrid modality of SPECT/ CT. CT generates three-dimensional X-ray images from a collection of many X-ray transmission images in much the same way as SPECT generates three-dimensional emission images from planar emission images.

4.2.2

Improved Anatomical Location

The formation of three-dimensional images with SPECT offers a big advancement in diagnostics as the detected radiopharmaceutical distribution will no longer be overlapped as in planar imaging where no difference can be made between gamma rays coming from different depth layers in the patient. In this way, SPECT offers higher contrast and a reduction in noise that could otherwise lead to loss of structural information as the activity in an under- or overlying organ would be superimposed to the organ of interest. As SPECT consists of three-dimensional images, they can also be used together with the three-dimensional CT images. This is not possible in planar imaging as these images are only in spatial two-dimensions. The addition of CT with SPECT offers many advantages both in terms of correction techniques that can be applied to the SPECT images as well as the much-added diagnostic information that is provided by the addition of the high spatial resolution anatomical images of CT that leads to improved information about the anatomical location of the SPECT emission data. Although attenuation correction (AC; see below) may significantly impact image quality, also adversely if applied improperly, one of greatest clinical improvements and impact of image fusion of SPECT and CT over stand-alone SPECT and planar images are two-fold, i.e., improved anatomical location of foci leading to more precise reporting, and better differentiation between benign and malignant or simply between pathological and physiological uptake, leading to a higher degree of confidence in reporting. This is also of great importance in infection, where there is often a fine line between physiologic and pathologic uptake with both labelled leucocytes and FDG.

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Some of the issues from planar images that have been ameliorated with SPECT/ CT include higher detection rate, in general, in obese patients, and in anatomically difficult regions such as head and neck. Also, the ability to find profoundly located foci otherwise attenuated by especially abdominal organs, and better differentiation of foci in close relation to highly active areas such as physiologic bladder uptake. Several of these issues have been explored in sentinel node imaging, e.g., Khafif et al. who found that SPECT/CT improved the detection of sentinel nodes in 30% of patients with oral cavity cancer compared to planar lymphoscintigraphy [5]. Lerman et al. found additional sentinel nodes with SPECT/CT in 13% of patients with breast cancer, including several foci obscured by the high-intensity areas of injection. Furthermore, in a subgroup of overweight and obese patients, SPECT/CT missed sentinel nodes in significantly fewer patients than planar images (11% versus 28%), and also performed better than planar images in patients where blue-dye technique failed to identify sentinel nodes, i.e., 75% versus 48% of patients [6]. Better anatomic localization and fewer equivocal studies with SPECT/CT over planar or SPECT have also been corroborated by other several studies [7–9]. As mentioned in the introduction, there are only few studies specifically addressing SPECT/CT in infection imaging. Horger et al. evaluated SPECT/CT compared to SPECT in patients with chronic osteomyelitis examined with anti-granulocyte antibody scintigraphy and found similar sensitivity of 100% but significantly improved specificity from 78% to 89% and higher accuracy in differentiating soft tissue infections from bone involvement [10]. Other groups have reported similar results with the addition of SPECT and SPECT/CT to planar labelled white blood cell-scintigraphy in bone infections, i.e., improved specificity with better anatomic localization and better delineation of disease extent [11, 12]. One study found additionally a significant clinical contribution to final diagnosis in 35% [13]. Also, in a more heterogeneous population with fever of unknown origin or non-specified suspected infection, Bar-Shalom et al. found SPECT/CT to contribute with incremental information (improved diagnosis, localization, and definition of disease extent) compared to whole-body planar studies or SPECT in 48% of patients, i.e., 63% of patients who underwent labelled white blood cell-scintigraphy and 36% who underwent gallium scintigraphy [14].

4.2.3

Motion Correction and Iterative Reconstructions

Generally speaking, all medical diagnostic imaging procedures are prone to decreased image quality due to patient motion, voluntary or involuntary. This is especially true in imaging procedures that require long acquisition times as is the case with nuclear medicine examinations where imaging times are often more than 10  min. Long examination times allow the patient to move during the scan so regions with activity may be detectable in multiples locations. This will smear out the activity distribution and cause blurring of the lesions in the image. As multiple views are acquired at different times in SPECT when the camera heads rotate around the patient, motion that has happened between the views can be detected as phase

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shifts in the raw data (sinograms) and be corrected for to some degree, which is not a possibility in the static image acquisition of planar imaging. With increased computer processing power, iterative reconstruction algorithms were adopted for SPECT images. With iterative reconstructions, an initial guess of an image is applied, e.g., a uniform sphere of radioactivity distribution (although more advanced models are normally used for the initial guess image). The projections that would produce this initial guess image is then calculated and compared with the actually measured projections. The differences between the measured and guessed projections along with different corrections applied are then used to give an estimate of a new updated image of radioactivity distribution which calculated projections more resembles the actual measured ones. This method of calculated image projections with estimation and correction constitutes one iteration in the reconstruction process and with each additional iteration cycle the updated image will progressively converge towards the true image. However, each iteration has the disadvantage of adding more noise to the image because the already present noise and inaccuracies in the measured projections will be enhanced as well. Thus, a filter is used to decrease and control the noise and generate images that can be visually assessed. Another approach to limiting noise is to stop the reconstruction process after a certain number of iterations although at the expense of complete convergence to the true image. The use of iterative reconstructions has greatly increased the image quality in SPECT as many system limiting factors that decrease image quality can be modelled in the iterative reconstruction loop and applied as corrections to the estimated image. The improvement of iterative reconstruction algorithms has been an important area of research and development as more models of different system aspects have been incorporated in the iterative reconstructions and used for corrections. The future aspects of reconstruction developments might be the incorporation of artificial intelligence that can learn from a vast number of images and projection data and find correlations in these to know how the true image is supposed to be from the acquired projections and might further advance image quality.

4.2.4

Attenuation and Scatter Correction

The introduction of CT does not only increase the diagnostic value by adding an extra imaging modality with its own strengths but it is also used for corrections of the SPECT images with resulting better image quality. CT images are generated by sending X-rays through the patient and detecting the change in intensity on the other side of the patient. The X-ray beam intensity detected will be less than the emitted intensity as the beam will be attenuated along its path. The degree of attenuation varies depending on the amount and densities of the tissues that it has passed through as more tissue and higher density increases the attenuation. This is used to generate X-ray images of various intensity profiles where different organs of the body are variably projected depending on their ability to attenuate the X-ray beam intensity. By using a fast-rotating detector and X-ray tube design and continuous movement

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of the patient table enables short whole-body scan time. These acquired X-ray images are then tomographically reconstructed into three-dimensional CT images. The effect of attenuation of photons is also a factor when radionuclides emit gamma photons as some of these will be attenuated before reaching the detector. As the degree of attenuation will vary depending on where the radiopharmaceuticals are located so will the intensity of the detected signal. This will then lead to inaccurate interpretations of the radiopharmaceutical distribution as regions of low attenuation, for example, the lungs that consists mostly of air will seem to have a relatively higher concentration than regions of high attenuation, for example, the lower abdomen where a lot of denser tissue and bone are located even though this might not be the real case. To accommodate these differences in attenuation at various locations, the CT scan can be used to attenuation correction which will give a truer picture of the radiopharmaceutical distribution. The CT scan is essentially an attenuation map of the patient but needs to be adjusted for use of attenuation correction with SPECT. The X-ray beam in CT consists of a spectrum of photon energies with various attenuation coefficients which needs to be converted into one attenuation coefficient for the monochromatic, single energy, of gamma photons in nuclear medicine. The higher energy of gamma photons in nuclear medicine also leads to different interactions with the tissue that in higher degree depends on the elemental compositions of the tissues. This conversion from CT units to attenuation coefficients for the gamma photons in nuclear medicine can be solved by bilinear fitting. This way an attenuation map can be created from CT and used for attenuation correction of the SPECT images which is incorporated in the iterative reconstruction loop. When a photon is emitted from the radionuclide, its path can be altered by scattering in the surrounding media. After scattering, the photon might be detected by the system and give rise to an event being detected in another projection, which overall will lead to a reduction in image contrast. When photons are scattered, they lose some of their energy to the media. In order to correct for scatter, another energy window can be applied at lower energies where photons that have undergone several scattered events can be detected. Counts detected in this window can then be used to give an estimate of the amount of scattered events in the energy window for the radiopharmaceutical signal. This multiple energy windows method can be applied for both planar imaging and SPECT.  With the addition of CT, a more accurate method can be used to correct scatter by using the information given by the attenuation map. At the photon energies used in nuclear medicine, almost all interactions with surrounding tissue that leads to attenuation are by Compton scatter. Because of this, the attenuation map can give information about the probabilities of Compton scatter at different locations. This can be used to give a better model of the distribution of scatter and incorporated into the iterative reconstruction loop. The clinical value of correcting artifacts induced by attenuation (attenuation correction, AC) and scatter (scatter correction, SC) has been extensively explored in myocardial perfusion imaging since several specific factors influence image quality and diagnostic performance; the breast and abdomen may attenuate the anterior and inferior parts of the heart and induce artificial perfusion defects that may be

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misinterpreted as ischemic lesions especially in adipose patients. Much data support that AC significantly reduces such findings, improve reader confidence, and reduce observer variability, but the application of AC remains controversial as misalignment or AC itself may induce artifacts, especially in the apex [15, 16]. Several authors have reported a significant proportion of studies to harbor AC artifacts due to misalignment between emission data and transmission data; Fricke et al. found induced perfusion defects in 27 of 140 MPI after CT-based AC, but after optimized co-registration 6/27 became normal and in 15/27 the presence and severity of the defects were significantly reduced [17]. Similarly, Goetze et al. found misregistration errors in SPECT/CT data in 42% and quantified the spatial mismatch to be more than 1 pixel in 64% [18]. More generally applicable, also in infectious diseases, are the effects of AC on more deeply located lesions, e.g., in the abdomen or the mediastinum. The former was explored by Ruf et al. [19] and Steffen et al. [20] in somatostatin receptor scintigraphy; they found increased intensity and more clear contrast between foci and background, but the overall impact on sensitivity and patient management was limited or negligible. Similarly, Ruf et al. [21] found improved image contrast but limited impact on overall sensitivity with SPECT/CT in parathyroid scintigraphy. They did however find additional mediastinal foci.

4.2.5

Disadvantages

Although the implementation of SPECT/CT has improved the diagnostic quality of nuclear medicine procedures, there are disadvantages compared to planar imaging. The need for multiple camera heads and the incorporation of another imaging modality means that the financial cost of a SPECT/CT scanner is higher than that of a conventional gamma camera intended for planar imaging only, especially an increased demand for more advanced diagnostic CT scanners raises the prize substantially. Although CT offers many advantages, it may also lead to pitfalls and artifacts in the SPECT images caused by incorrect attenuation correction. This can be caused by misalignment between the SPECT and CT acquisitions due to patient movement, or by artifacts in the CT acquisition such as beam hardening, truncation of arms outside the CT FOV, streak-artifacts, or artifacts from CT contrast agents not present in the SPECT acquisition. Multiple disadvantages also arise as the camera heads need to rotate around the patient to generate the SPECT images. Because of this, longer acquisition times are needed to obtain one FOV compared to planar imaging. Thus, SPECT examination times are generally longer which decreases patient comfort and increases the change for patient movement during the scan, and this may cause additional artifacts as well. The increased examination time for SPECT/CT acquisitions also decreases the desire to do whole-body examinations as the whole procedure simply takes too long, whereas whole-body planar imaging can easily be accomplished within an appropriate time frame. The increased time to obtain usable images at all angles also

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means that the time resolution decreases which decreases the value of dynamic studies where the radiopharmaceutical distribution is followed over time, especially if the radiopharmaceutical has very rapid kinetics. The fact that the camera heads rotate around the patient may also cause artifacts if the mechanical movement of the camera heads are not aligned with each other as blurring or ring artifacts will then be introduced into the image. The spatial resolution of SPECT is also inherently lower than planar imaging as all parts of the camera heads will not be able to get as close to the patient as possible in all the angular views, and because of the design of the collimators, as an increase in distance from patient to camera head decreases spatial resolution. However, this effect can to some degree be countered with modeling in the iterative reconstruction loop and due to the increase in contrast and other advantages of SPECT.

4.2.6

Partial Volume Effects

In all imaging methods, partial volume effects (PVE) always plays a role. PVE is caused by the limitation in spatial resolution, which will always limit how perfect a point source can be imaged by the system. When a volume with a different intensity than its surroundings approaches the size of the spatial resolution of the system, then the system will not be able to image the exact boundary where the intensity change. This will lead to “spill-over” between the surroundings and the small volume as the intensities in the small volume is spread over a larger volume than is the actual size of the volume. These effects of intensity “spill-over” are known as PVE. PVE will lead to loss of contrast in the image and will be seen as blurring. If the small volume is the so-called hot spot, the intensity will be less than the true intensity and conversely if the small volume is a cold spot the intensity will be higher than the true intensity. The effects of PVE will become more severe the smaller the volume is or the worse the spatial resolution of the system is. Nuclear medicine is considered a quantitative discipline as the intensity values in the images can be computed into activity concentration units that can reflect uptake dynamics of the tissues. When doing quantitation PVE can be the predominant source of error in inaccurate estimates of uptake values. This is both due to the “spill-over” of intensity that will lead to wrong activity concentrations and also the more difficult delineation due to the lowered contrast and resulting blurring that will make it more difficult to define where the region of interest starts and stops. As PVE depends a lot on size, it is also important to keep PVE in mind when comparing regions of different sizes or follow-up studies where a lesion might change dimensions due to therapy or disease progression. If the true size of volume and system resolution is known, then PVE can easily be corrected for but this is though not often the case in clinical studies where organs and lesions come in great variety. In clinical settings, PVE can be corrected for with partial volume corrections that use the high-resolution anatomical structural information of other modalities such as CT and MRI to gain more information about the true size of the regions and correct for PVE.  However,

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these corrections are very sensitive to errors in misalignment and system resolution assumptions along with various errors in the data processing.

4.3

Spect Quantitation and Its Relevance for Imaging Infections

Since nuclear medicine techniques are quantitative, fully quantitative or semiquantitative parameters may be extracted and interpreted after image reconstruction and correction. The semi-quantitative analysis is considered essential to exactly identify the inflammatory lesion site (e.g., the distinction between soft and bone tissues in musculoskeletal infections). Depending on radiopharmaceutical used, numerous acquisition protocols have been described for planar images or SPECT/ CT, from whom the clinician is able to obtain image-derived parameters such as the Volume of Interest (VOI), the Region of Interest (ROI), the Target-to-Background (T/B) ratio as well as the Standardized Uptake Value (SUV). Generally, in infection imaging, planar acquisition is usually acceptable for the diagnosis, allowing both a visual assessment of radiopharmaceutical distribution and ROI measurement for the differential diagnosis between specific and nonspecific accumulation. Sometimes, SPECT/CT is strongly recommended or mandatory in selected pathological conditions, including endocarditis, diabetic foot, or vascular prosthesis as well as when planar images have a doubtful result. Indeed, SPECT/ CT allows not only the measuring of ROI, but also the VOI. The CT registers a set of images that permits to define the VOI that can be later used for SPECT images. In this way, it is possible to study the radiopharmaceutical uptake in the whole volume of lesion. Following the recent guidelines of European Society of Nuclear Medicine (EANM) [22], once acquired images time-corrected for isotope decay, the ROI can be drawn manually in the area with the highest concentration of radiopharmaceutical and, then, copied this area in the contralateral site as normal reference standard tissue. The mean counts per pixel in the ROIs are then used to calculate the T/B ratio, also called Lesion-to-Reference (L/R) ratio. The T/B ratios should be calculated whenever a scintigraphy is performed, whether with labelled autologous leukocytes (WBC), radiolabelled anti-granulocytes monoclonal antibodies (mAbs), or other approved/experimental radiopharmaceuticals. For example, WBC scintigraphy usually includes at least two acquisition time points after radiopharmaceutical injection, delayed (2–4 h) and late (20–24 h) by planar imaging, where the clinician can draw the ROI and measure the T/B ratio at each time point, obtaining the T/Blate and the T/Bdelayed ratios [23]. In this way, the evaluation of T/B ratios at different time points allow to assess the increase of radiopharmaceutical uptake in intensity and/or in size over time and classify a scan as positive, negative, or equivocal. In 2004, a study performed a qualitative and semi-quantitative analysis comparing early and late T/B ratios obtained by drawing circular ROI in 78 patients with suspected hip or knee prosthesis infection who underwent 99mTc-HMPAO-WBC scintigraphy twice. The study showed a change in ratios between early and late imaging, resulting in T/Blate > T/Bearly in the presence of infection. This suggested

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that the addition of semi-quantitative analysis led to an improvement of sensitivity, specificity, and accuracy on qualitative analysis, influencing the final diagnosis [24]. In 2012, T/B ratios were also found useful in predicting the response of intraarticular infliximab therapy in patients with refractory monoarthritis who underwent two sequential scintigraphies with 99mTc-infliximab. In this study, planar anterior and posterior images of joints were acquired at 6 and 20 h post injection; circular ROIs were drawn for infected joints, whereas the background rectangular ROI were drawn approximately 5 cm below the knee or above the ankle. The radioactivity in the ROI were normalized to the area and divided by the background counts to calculate T/B ratios. Results indicated that T/B ratios and their comparison pre- and post-therapy allowed a stratification of patients in responders, partial responders and non-responders and also significantly correlated with the arthritis score, swelling score, tenderness score, and ultrasonography score, proposing this semi-quantitative index as a predictive factor of infliximab therapy [25]. Recently, interleukin-2 radiolabelled with 99mTc (99mTc-HYNIC-IL-2) was used to perform planar and SPECT/CT imaging for the study of atherosclerotic plaques of carotid artery in ten patients. For planar imaging, the location of the plaque was established by drawing a marker on the skin on the basis of ultrasound scan, whereas for SPECT imaging the location was defined by CT. For semi-quantitative analysis, in the planar images the T/B ratios were calculated by drawing ROIs at the drawn skin and over the carotid artery below the bifurcation as background; in the SPECT/CT, a VOI was drawn on the region defined on CT and circular VOIs at an area close to carotid artery, bone marrow, and temporal muscle as reference standards. The maximum number of counts in the target VOI was divided by the maximum counts in the background areas to calculate the T/B ratios. Results demonstrated that both planar and SPECT T/B ratios are significantly higher in the infected atherosclerotic plaques than asymptomatic ones, due to a higher number of CD25+ T lymphocytes that infiltrate the symptomatic plaques. This suggests that T/B ratio is a valid method to monitor the inflammation and stability of atherosclerotic plaques in humans [26]. Conversely, a study showed how the atheroma imaging is a challenge on the basis of lesion localization (e.g., coronary artery) and thickness as well as the spatial resolution of SPECT and the current available radiopharmaceuticals, making the imaging very difficult, due to a non-high T/B ratio. In other words, for lesions with a size detectable by the imaging device a low T/B ratio is sufficient. However, as lesion decreases in size, the T/B ratio necessary for detection exponentially increases, not allowing the imaging of smaller atheroma [27]. Therefore, the ROI and T/B ratio as semi-quantitative parameters should be interpreted with caution in reference to the acquisition protocol, the radiopharmaceutical that has been used, the infection characteristics, including the type, the location and, especially, the extent. Another parameter that can be considered is the SUV, the activity concentration normalized by the injected activity and patient’s body weight, although it is more used in PET quantitation for oncological diseases. Different types of SUV can be measured depending on the activity concentration as calculated by the voxel with highest (SUVmax) or the average (SUVmean) value within the ROI.  Very recently, quantitative bone SPECT/CT imaging was performed in patients with knee

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osteoarthritis (OA) to select them for unicompartmental knee arthroplasty (UKA), using SUV as quantitative tool. Scintigraphic images were reconstructed using three different algorithms, applying attenuation and scatter correction for each one: – The reference ordered subset expectation maximization (OSEM) 3D iterative algorithm (FLASH3D, Siemens) (OSEM-3D), data set 1 – The ordered subset conjugate gradient minimization (OSCGM) xSPECT algorithm (Siemens), allowing to perform SUV quantification, thanks to the xSPECT Quant tool, data set 2 – The OSCGM-enhanced (OSCGM-e) xSPECTbone algorithm (Siemens), which uses CT data to constrain uptakes to bone structures, also allowing SUV quantification, thanks to the xSPECT Quant tool, data set 3 For each data set of each knee compartment (lateral, medial, and patellofemoral), SUVmax, SUVpeak (maximum average SUV within a 1 cm3 spherical volume), metabolic OA volume (MOAV, total volume of the voxels whose SUV was superior to 50% of the knee joint SUVmax), and metabolic OA burden (MOAB, product of the MOAV and the SUVmean) were calculated and correlated to clinical data and peroperative OA staging of International Cartilage Repair Society (ICRS) scale. Experimental data showed different performances between reconstruction algorithms, but SUVmax and SUVpeak well correlate with intraoperative evaluation of OA according to the ICRS scale, making the quantitative bone SPECT/CT a valid technique for patient selection before UKA surgery [28]. Furthermore, Hermes Medical Solution has developed a software solution (Hermes SUV SPECT®) that enables the SUV calculation and enhances SPECT/CT reconstruction. The software algorithms convert the recorded counts per voxel into activity per unit volume (Bq/cc), carry out the attenuation correction from hybrid imaging and Monte-Carlo model scatter correction, allowing the SUV calculation quantitatively and improving image quality by reducing dose and acquisition time [29].

4.4

PET/CT Characteristics

4.4.1

Basic Concepts

Positron emission tomography (PET) is designed to achieve the same task as SPECT in generating diagnostic three-dimensional images of patients although the underlying physics is fundamentally different; it takes advantage of the physical process that occurs when an emitted positron from the radioactive decay of a radionuclide interacts with an electron from the molecules in the human body in a process called annihilation. Annihilation occurs because the positron is the antiparticle or antimatter of the electron with the same quantum mechanical characteristics of the electron but with opposite (positive) charge (hence the name positron or antielectron). When a positron and an electron encounters in space and time, they cancel each other out in the electromagnetically quantum field and seize to exist as a result of their similar

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quantum mechanical characteristics but opposite charges—not unlike two identical opposing waves that collide and cancel each other out. As a result of annihilation, the positron and electron are transformed into two gamma photons emitted in opposite direction to conserve energy and momentum, each with an energy of exactly 511 keV which equals the rest masses of the particles in concordance with Einstein’s famous equation E = mc2. By detecting these two photons in coincidence, i.e., almost simultaneously within an appropriately time window and in opposing detectors, a line-of-response (LOR) between the two detectors can be created along which the annihilation event must have occurred and thereby the location of the positron-emitting radiopharmaceutical. With the detection of LORs in many different projections, a tomographic image can be reconstructed with three-dimensional information about the tracer distribution. Overall, this way of detecting the radiation from the radiopharmaceutical gives rise to all the advantages PET has to offer over SPECT.

4.4.1.1 Sensitivity Because information about the direction of the detected photons is inherently given by the coincidence detection method and LOR formation, there is no need for collimators as in SPECT or planar imaging. This increases the sensitivity dramatically since there is no loss of photons as there is in the lead septas of the collimators, thus, each detector element has a higher change of detecting photons emitted from the decay of the radiopharmaceutical. In SPECT, only around 0.01% of emitted photons are detected, whereas the same number for PET is around 1% [30]. The increased sensitivity leads to a higher count rate from the injected radiopharmaceutical which in turn leads to improved image quality as the signal-to-noise ratio is improved. At the same time, higher sensitivity may either reduce scan time or injected dose with unchanged image quality given the same decay rate. This reduction in scan time has been one of the key elements in allowing the whole-body scans that are often employed routinely in PET-examinations compared to SPECT or SPECT/CT. With special reference to infection/inflammation, the whole-body approach is important in patients suspected of fever or bacteremia of unknown origin, where the goal is to establish the focal point or origin of systemic infection or inflammation. On the other hand, the relative non-specificity of [18F]-FDG may result in falsepositive findings and lead to unnecessary or invasive confirmatory procedures, when a sensitive whole-body scan becomes the standard in search of unknown foci in heterogeneous populations [31]. 4.4.1.2 Spatial Resolution The lack of collimators in PET also considerably increases the spatial resolution compared to SPECT as this is not a limiting factor. One of the physical limitations to spatial resolution is the kinetic energy of the emitted positron as the probability to interact and annihilate with an electron increases at lower kinetic energies with a steep increase when the positron has lost almost all of its kinetic energy. As the

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positron is emitted, it will slowly lose its kinetic to the surroundings as it passes through and will annihilate with an electron when it is almost at a standstill and have lost almost all kinetic energy as this is where the probability is the highest for annihilation. Because the positrons must travel some distance to lose kinetic energy, the location of the annihilation event is often not the same as the location of the emitting radiopharmaceutical, and this decreases the achievable spatial resolution. All positron-emitting isotopes does so with a spectrum of kinetic energy with a given maximum, and using an isotope with a spectrum of low energies can help to minimize this spatial resolution degradation. This is one of the reasons why [18F] is at the center of PET imaging with an average kinetic energy of emitted positrons of 250  keV compared to the emitted positrons from another commonly used PETisotope [68Ga] with an average kinetic energy of 890  keV.  The spatial resolution degradation due to the positron range along with other spatial resolution degrading effects can be modelled and put into the iterative reconstruction loop to increase the spatial resolution of the reconstructed images. This is often termed point spread function modeling. There is always a possibility that the positron annihilates with an electron while still having some kinetic energy and in combination with the law of conservation of momentum the two annihilation gamma photons may not be emitted in exactly opposite directions but within a range of 180 ± 0.25°. This also degrades spatial resolution and sets a limiting physical factor of the spatial resolution of PET. With digital PET scanners, the change from the classic bulky analog PMT detectors to much smaller silicon-based digital detectors results in smaller detector parts, both crystal sizes and the detectors themselves, and this is one of the important contributing factors to the higher spatial resolution of digital PET scanners. With the much better spatial resolution in PET compared to SPECT, the effects due to PVE also decreases considerably, although not in any way to be negligible, which is one of the reasons why PET is considered a modality much more suitable for quantitative studies.

4.4.1.3 Scanner Design Since there is no need to change collimators between different PET isotopes and in order to maximize the advantages of the coincidence detection method of PET, the detector elements are arranged in a ring formation around the patient allowing simultaneous acquisition of all the projections that covers a part of the body. A PET detector ring typically consists of bigger blocks in which the scintillation crystals and detector elements are coupled together for easy replicability if only one detector element fails. The more detector rings that are put together the more of the axial FOV are covered. With increasing axial FOV, scan time or administered activity can be decreased as more of the patient is covered in one FOV although the increase in FOV also increases the amount of scattered events detected. As PET has simultaneous acquisition of all the projections in one axial FOV, there is no need to move the detectors around the patient in order to record enough projections. Thus, PET is a better technique for dynamic acquisitions as the change in distribution of the tracer over time can be followed more easily.

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With special reference to infection and inflammation, a short scan time is always desirable in severely ill patients, e.g., septicemia and especially in complex populations such as Intensive Care Unit (ICU) or cancer patients with febrile neutropenia and comorbidity like pain and dyspnea. Similarly, dose reduction is always a separate goal, but especially in children and adolescents e.g., fever of unknown origin (FUO) or inflammatory bowel disease (IBD).

4.4.1.4 Time-of-Flight Following the development of very fast scintillation crystals and electronics in modern PET scanners, a very high temporal resolution has been achieved which enables all newer scanners the ability to do Time-Of-Flight (TOF) PET.  With TOF PET, the time difference between the detection of two annihilation photons is determined which generates data on which of the photons that traveled the shortest distance from the annihilation site to the detector. In this way, a LOR is created that does not have an equal change of the location of the annihilation event but has regions of increasing probability. The signal-to-noise ratio (SNR) will increase because only events constrained within this smaller volume given by many projections with TOF LORs will be taken into account in the reconstruction of the PET images. The higher the time resolution of the PET scanner, the smaller the region of higher probabilities on a LOR will be and hence further increases the SNR. This is another reason for the emergence of the digital PET scanners as the silicon-based detectors provide a higher time resolution. Because the photons travel at the speed of light over a distance less than a meter, the time resolution has to be in the range of picoseconds (10−12 s). Typical time resolution of analog PET scanners is around 550 ps and digital PET scanners around 350 ps [32]. 4.4.1.5 Hybrid PET/CT The addition of a CT scan in the PET/CT hybrid modality has had a tremendous impact on the diagnostic quality of examinations, similar to what was experienced in the transition from SPECT to SPECT/CT; PET provides information on physiology and CT provides anatomical correlation. The need for CT scanners of diagnostic quality was recognized early with PET and has been the standard for a decade allowing for full diagnostic CT examinations with or without CT contrastenhancement comparable to scans made with stand-alone CT scanners in radiology departments. Unlike SPECT examinations, a PET scan is always accompanied with a CT scan, either diagnostic quality or a low-dose scan for anatomic correlation and AC. The added value of CT to PET has been explored in various settings including bone pathology; Metser et  al. found that stand-alone PET detected significantly more malignant lesions than CT alone in the spine, but interpretation with regard to lesion localization to specific levels was incorrect in almost one-fifth of patients with stand-alone PET compared to PET/CT including clinically highly relevant lesions in the soft tissue around the spine which were only detected on hybrid images [33]. Similarly, Nakamoto et  al. found 21% of alleged bone metastases

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actually located in soft tissues when applying CT correlation [34], and Taira et al. found positive predictive value for malignant bone lesions in PET, CT, PET/CT to be 61%, 17%, and 98%, respectively [35]. Also, specificity and the ability to differentiate benign from malignant bone lesions is also improved with PET/CT over stand-alone PET, e.g., 56% versus 88% [36]. Controversy remains towards the necessity of performing diagnostic quality CT with contrast-enhancement in infection and inflammation, but in suspected FUO or infections related to prostheses, heart valves, or other devices are suspected, some data suggests an added diagnostic value of full diagnostic CT over low-dose scans for anatomical correlation and AC [37]. On the other hand, CT-induced artifacts from foreign bodies are a potential source of flawed scans, and non-AC images should always be at hand for correlation in these settings. CT AC is more straightforward in PET as the coincidence detection method means that the photons traverse along the projection in the same manner as the X-ray photons from the CT and encounter the densities along it even though the energy of the photons in PET is much higher than that of the spectrum of photon energies in CT X-rays. Thus, CT scans can easily be made into transitions maps using similar techniques as with AC in SPECT/CT.

4.4.2

Disadvantages

As there are more detectors in PET scanners and scintillation crystals are more difficult to produce, they are more expensive than SPECT scanners. Depending on the specific characteristics of the SPECT and PET scanners, the price of a PET might be 1.5–3 times that of a SPECT scanner although this also depends very much on the quality of the CT-part of the scanner, a frequent limiting factor in acquiring a PET scanner.

4.4.2.1 Isotopes As most PET isotopes are cyclotron derived, a cyclotron must be close enough to overcome the inherent limitations of transportation time. With isotopes of very short half-life even a local cyclotron is needed. Gallium-based imaging used to be the gold standard for radionuclide infection and inflammation imaging with [67Ga], but is now widely considered obsolete due to poor image resolution, high radiation doses, and generally limited applicability. However, with the relative non-specificity of [18F]-FDG, it is not surprising that 68Ga-based PET imaging has been explored; beside the potentially better specificity, [68Ga] has the advantage of being generatorproduced and thus independent of cyclotron facilities [38, 39]. However, until now most results (albeit mainly from preclinical trials) have been less than encouraging. One must also keep in mind the aforementioned challenge related to kinetic energy, where [68Ga] was mentioned as an isotope with particularly high energy leading to reduced spatial resolution. A series of other non-18F-based radiopharmaceuticals are currently under investigation as more bacteria-specific tracers, which

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would be highly desirable and allow for better differentiation between septic infection and aseptic inflammation, but these results are also equivocal at best and hampered by a lack of standardization in study designs [40].

4.4.2.2 Random Coincidence A problem specific to PET that does not exist in SPECT imaging is random coincidence events (randoms) that can be detected and registered as true events. Randoms are caused by two photons that do not originate from the same annihilation event but is being registered within the same coincidence timing window creating an incorrect LOR.  The chance of randoms happening is approximately proportional to the amount of radioactivity in the patient. The amount of randoms can be decreased by having a smaller timing window while still large enough to accommodate the differences in arrival time that is useful for TOF information. Improvements in temporal resolution in the detectors allow for smaller time windows to be used. Although randoms cannot be distinguished from true coincidence events, they can be estimated and corrected for in the iterative reconstruction. This can be done either by having a delayed timing window on one of the detectors that are not influenced by true coincidences or modelled by the amount of individual counts on each detector. The information is then incorporated into the iterative reconstruction loop. 4.4.2.3 Scatter Scatter is as much of a problem in PET as it is in SPECT imaging as the scattered photons may change direction and be intersected in another detector forming a different LOR. Correction for this is similar to the techniques in SPECT but because a CT scan is always combined with PET the density map along the LOR can be used in model-based scatter correction and incorporated in the iterative reconstruction loop. Again, the choice of radiopharmaceutical should be kept in mind as some of the correction techniques, including point-spread-function and scatter correction is based on and established for [18F], and therefore not necessarily optimized for alternative isotopes like [68Ga]. 4.4.2.4 Misalignment Misalignment issues are also as challenging in PET as in SPECT due to patient motion between each scan and the involuntary motion by respiration and cardiac cycles. Gating of the cardiac cycle has been achievable through an ECG signal for many years, also in cardiac SPECT studies. However, solutions to handle the motion from respiration has been explored more extensively in PET, and now solutions exist for gating a respiratory signal by external devices that monitors the respiratory cycle of the patient. With the advancement of computer processing power and developments in computer algorithms, gating without an external device but by algorithms determining respiratory patterns directly in the PET raw data are becoming feasible and promising for easy incorporation in the standard clinical workflow. This data-driven gating method is slowly becoming available in clinical scanners and might become standard in future PET scanners.

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4.4.2.5 Radiation The radiation dose is generally a little higher in PET compared with SPECT radiopharmaceuticals as all of the positron energy is deposited in the patient and each decay is at least followed by two high energy gamma photons of 511 keV (some isotopes also emit more prompt gammas when decaying). On the other hand, the typically shorter half-lives of PET isotopes are more efficiently used for the examination as a large quantity of the radioactive isotopes has decayed during the time of the examination or shortly thereafter. This limits the amount of unnecessary radioactive exposure not used to generate diagnostic images given to the patient and surroundings.

4.5

Pet Quantitation and Its Relevance for Imaging Infections

For PET infection imaging, [18F]-FDG has been proposed as the main choice between PET radiopharmaceuticals because activated leukocytes, especially neutrophils and monocytes/macrophages, express high levels of glucose transporters (mainly GLUT1 and GLUT3) [41]. However, its application is still controversial in several aspects of infectious diseases imaging, despite its indication for sarcoidosis, peripheral bone osteomyelitis, fever of unknown origin (FUO), spondylodiscitis, and other infections that will be intensively discussed in the following chapters. As for SPECT/CT, PET images can be interpreted qualitatively and semiquantitatively. For the qualitative analysis, PET images are visually assessed for increased uptake of [18F]-FDG, taking into account the pattern (focal, linear, and diffuse), the intensity, and relationship to areas of physiological distribution. Surely, the functional information provided by PET are combined and fused with anatomical information provided by CT.  In the visual analysis, it is important to bear in mind the potential presence of false-negative scans caused by lesion size, low metabolic rate, drugs interfering with uptake, and hyperglycemia (although this seems to have less impact on diagnostic performance in infection and inflammation than in malignancies) [42, 43]. Conversely, false-positive scans such as injection artifacts, contamination, pathological uptake not related to infection must also be born in mind. For semi-quantitative analysis, the SUV is the main parameter and both SUVmax and SUVmean may be calculated as quantitative parameter, but it has not yet been validated as thoroughly in infection and inflammation as in malignancies, and therefore, it should be used carefully in clinical practice [44]. In 2002, Chin and colleagues compared the differences in SUV measurement (SUVmax and SUVmean) in [18F]-FDG PET/CT in patients with human immunodeficiency (HIV) infection by using iterative reconstruction with segmented attenuation correction (IR SAC) or filtered back-projection with measured attenuation correction (FBP MAC) as reconstruction techniques. Better results were observed for IR SAC with a significant increase in SUVmean and significant decrease in SUVmax in comparison to FBP MAC. Thus, IR SAC would have several advantages such as a reduction in acquisition time without compromising lesion detection as well as a lower noise propagation from the transmission scan to the emission scan, making IR

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SAC a potential technique for more accurate SUV values in clinical practice [45]. SUVmax was used as quantitative parameter for correlation to a newly developed visual qualitative analysis in patients with suspected spondylodiscitis. The classification system is based on [18F]-FDG uptake patterns according to disease severity, defining five scores (0–4): scores 0–1 were classified as normal or unspecific uptake, score 2 was classified as discitis, scores 3–4 were classified as spondylodiscitis. Results demonstrated a slight increase of SUVmax with the increasing of score, but with significant different values between physiological/unspecific uptake and discitis/spondylodiscitis, considering the qualitative and semi-quantitative analysis effective to predict or exclude spondylodiscitis [46]. T/B ratio was applied in [18F]-FDG PET/CT to derive uptake thresholds in patients with increased cardiovascular disease risk, with known cardiovascular disease and in healthy controls. [18F]-FDG uptake was evaluated in the carotids or in the aorta, whereas venous or remote arterial blood was used as background, from where ROI were drawn and SUV was calculated for each lesion/control site. Background corrections were performed to SUV, subtracting or dividing by background SUV, thus obtaining T/B ratio. Secondly, T/B ratiomax was defined as 90th percentile of T/B ratio values of segments above a pre-defined cutoff level, considering these sites as active, allowing the calculation of T/B ratioactive slices and the percentage of active slices (%active 18 slices). Results showed the efficacy of [ F]-FDG uptake thresholds for arterial wall inflammation for establishing a potential therapeutic window for anti-inflammatory therapies, suggesting the use of T/B ratio as quantitative method, but further studies are needed to confirm these findings [47]. Very recently, the added value of quantitative analysis by SUV to qualitative assessment was evaluated in a study that included patients with suspected fracture-related infections who underwent [18F]-FDG PET/ CT. SUVs were obtained by drawing a spherical VOI on the target area, contralateral side as corresponding anatomical reference and nearby muscle as background. For all VOIs, SUVmax and SUVpeak (average value in a high-uptake part of the VOI) were measured, from whose ratios between the suspected infectious area and the contralateral one was calculated (SUVmaxratio and SUVpeakratio). In addition, SUVmaxmuscleratio and SUVpeakmuscleratio were calculated correcting for background [18F]-FDG uptake, considering SUVs of the suspected infection site and SUVs of nearby muscles. Results reported how the quantitative analysis improves the diagnostic accuracy and the area under the curve (AUC) of receiver operating characteristic (ROC) curves in comparison to qualitative analysis alone [48]. Also, sporadic studies using SUVmax measurements for response evaluation has been presented, e.g., in spondylodiscitis and vascular graft infections: Nanni et al. found that the decrease in SUVmax between baseline scans and post-treatment scans (delta-SUVmax) correlated better with response than any other parameter including C-reactive protein [49]. Similarly, Husmann et al. have found PET/CT to impact decision-making and monitoring patients during conservative treatment for vascular graft infections [50, 51]. Thus, PET quantitation, mainly SUV, seems to be very useful and effective for infection imaging. However, the use of SUV-based parameters is prone to several pitfalls related to both technical issues and patient-related factors which may over or underestimate SUV values if not addressed properly and timely, e.g.,

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extravasation at injection site, time-delay and decay between activity measurements and injection, and patient body composition [52]. Furthermore, the absence of definitive consensus interpretation criteria must be kept in mind, so SUV in this field should be used with caution. Other quantification methods have been suggested amongst other to counteract the abovementioned pitfalls in SUV measurements, most promising is the concept of global disease score and metabolic burden which is based on the summation of PVE-corrected SUVmean values to a single number representing the overall disease burden throughout the body, a concept that may be particularly suited for the systemic diseases of infection and inflammation [52, 53]. However, these novel methods are still under investigation and further evaluation is needed prior to a more widespread implementation. In conclusion, hybrid imaging has revolutionized the diagnosis of infectious diseases, allowing the lesions’ localization as well as the quantitation of radiopharmaceutical uptake in the infective site compared to background signal. However, in infection imaging, the semi-quantitative analysis alone does not consider the extent of lesions and the activity pattern, thus combining it with the qualitative evaluation is essential for the diagnosis. Indeed, contrary to oncological diseases, for infections assessing the extent of tissues involved is much more important rather than radiopharmaceutical uptake in the affected area. Therefore, the semi-quantitative parameters described above should be used with caution in infectious diseases.

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9. Pfannenberg AC, Eschmann SM, Horger M, Lamberts R, Vonthein R, Claussen CD, et  al. Benefit of anatomical-functional image fusion in the diagnostic work-up of neuroendocrine neoplasms. Eur J Nucl Med Mol Imaging. 2003;30(6):835–43. https://doi.org/10.1007/ s00259-003-1160-y. 10. Horger M, Eschmann SM, Pfannenberg C, Storek D, Dammann F, Vonthein R, et al. The value of SPET/CT in chronic osteomyelitis. Eur J Nucl Med Mol Imaging. 2003;30(12):1665–73. https://doi.org/10.1007/s00259-003-1321-z. 11. Weon YC, Yang SO, Choi YY, Shin JW, Ryu JS, Shin MJ, et al. Use of Tc-99m HMPAO leukocyte scans to evaluate bone infection: incremental value of additional SPECT images. Clin Nucl Med. 2000;25(7):519–26. 12. Sanli Y, Ozkan ZG, Unal SN, Turkmen C, Kilicoglu O.  The additional value of Tc 99m HMPAO white blood cell SPECT in the evaluation of bone and soft tissue infections. Mol Imaging Radionuclide Ther. 2011;20(1):7–13. https://doi.org/10.4274/mirt.20.02. 13. Filippi L, Schillaci O. Usefulness of hybrid SPECT/CT in 99mTc-HMPAO-labeled leukocyte scintigraphy for bone and joint infections. J Nucl Med. 2006;47(12):1908–13. 14. Bar-Shalom R, Yefremov N, Guralnik L, Keidar Z, Engel A, Nitecki S, et  al. SPECT/CT using 67Ga and 111In-labeled leukocyte scintigraphy for diagnosis of infection. J Nucl Med. 2006;47(4):587–94. 15. Even-Sapir E, Keidar Z, Bar-Shalom R. Hybrid imaging (SPECT/CT and PET/CT)—improving the diagnostic accuracy of functional/metabolic and anatomic imaging. Semin Nucl Med. 2009;39(4):264–75. https://doi.org/10.1053/j.semnuclmed.2009.03.004. 16. Seo Y, Mari C, Hasegawa BH.  Technological development and advances in single-photon emission computed tomography/computed tomography. Semin Nucl Med. 2008;38(3):177– 98. https://doi.org/10.1053/j.semnuclmed.2008.01.001. 17. Fricke H, Fricke E, Weise R, Kammeier A, Lindner O, Burchert W.  A method to remove artifacts in attenuation-corrected myocardial perfusion SPECT Introduced by misalignment between emission scan and CT-derived attenuation maps. J Nucl Med. 2004;45(10):1619–25. 18. Goetze S, Wahl RL. Prevalence of misregistration between SPECT and CT for attenuationcorrected myocardial perfusion SPECT.  J Nucl Cardiol. 2007;14(2):200–6. https://doi. org/10.1016/j.nuclcard.2006.12.325. 19. Ruf J, Steffen I, Mehl S, Rosner C, Denecke T, Pape UF, et al. Influence of attenuation correction by integrated low-dose CT on somatostatin receptor SPECT.  Nucl Med Commun. 2007;28(10):782–8. https://doi.org/10.1097/MNM.0b013e3282efa1a9. 20. Steffen IG, Mehl S, Heuck F, Elgeti F, Furth C, Amthauer H, et al. Attenuation correction of somatostatin receptor SPECT by integrated low-dose CT: is there an impact on sensitivity? Clin Nucl Med. 2009;34(12):869–73. https://doi.org/10.1097/RLU.0b013e3181becfcb. 21. Ruf J, Seehofer D, Denecke T, Stelter L, Rayes N, Felix R, et al. Impact of image fusion and attenuation correction by SPECT-CT on the scintigraphic detection of parathyroid adenomas. Nuklearmedizin. 2007;46(1):15–21. 22. Signore A, Jamar F, Israel O, Buscombe J, Martin-Comin J, Lazzeri E. Clinical indications, image acquisition and data interpretation for white blood cells and anti-granulocyte monoclonal antibody scintigraphy: an EANM procedural guideline. Eur J Nucl Med Mol Imaging. 2018; https://doi.org/10.1007/s00259-018-4052-x. 23. Erba PA, Isreal O.  SPECT/CT in infection and inflammation. Clin Transl Imaging. 2014;2:519–35. 24. Pelosi E, Baiocco C, Pennone M, Migliaretti G, Varetto T, Maiello A, Bellò M, Bisi G. 99mTcHMPAO-leukocyte scintigraphy in patients with symptomatic total hip or knee arthroplasty: improved diagnostic accuracy by means of semiquantitative evaluation. J Nucl Med. 2004;45:438–44. 25. Conti F, Malviya G, Ceccarelli F, Priori R, Iagnocco A, Valesini G, Signore A. Role of scintigraphy with 99mTc-infliximab in predicting the response of intraarticular infliximab treatment in patients with refractory monoarthritis. Eur J Nucl Med Mol Imaging. 2012;39:1339–47. 26. Glaudemans AWJM, Bonanno E, Galli F, Zeebregts CJ, de Vries EFJ, Koole M, Luurtsema G, Boersma HH, Taurino M, Slart RHJA, Signore A. In vivo and in vitro evidence that 99mTc-

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46. Hungenbach S, Delank KS, Dietlein M, Eysel P, Drzezga A, Schmidt MC. 18F-fluorodeoxyglucose uptake pattern in patients with suspected spondylodiscitis. Nucl Med Commun. 2013;34:1068–74. 47. van der Valk FM, Verweij SL, Zwinderman KAH, Strang AC, et  al. Thresholds for arterial wall inflammation quantified by 18F-FDG PET imaging. JACC Cardiovasc Imaging. 2016;9:1198–207. 48. Lemans JVC, Hobbelink MGG, IJpma FFA, Plate JDT, van den Kieboom J, Bosch P, Leene LPH, Glaudemans AWJM, Govaert GAM. The diagnostic accuracy of 18F-FDG PET/CT in diagnosing fracture-related infections. Eur J Nucl Med Mol Imaging. 2019;46:999–1008. 49. Nanni C, Boriani L, Salvadori C, Zamparini E, Rorato G, Ambrosini V, et al. FDG PET/CT is useful for the interim evaluation of response to therapy in patients affected by haematogenous spondylodiscitis. Eur J Nucl Med Mol Imaging. 2012;39:1538–44. 50. Husmann L, Huellner MW, Ledergerber B, et al. Comparing diagnostic accuracy of 18F-FDGPET/CT, contrast enhanced CT and combined imaging in patients with suspected vascular graft infections. Eur J Nucl Med Mol Imaging. 2019;46:1359–68. 51. Husmann L, Sah BR, Scherrer A, Burger IA, Stolzmann P, Weber R, Rancic Z, Mayer D, Hasse B, Cohort VASGRA. ¹8F-FDG PET/CT for therapy control in vascular graft infections: a first feasibility study. J Nucl Med. 2015;56:1024–9. 52. Hess S, Hansson SH, Pedersen KT, Basu S, Høilund-Carlsen PF. FDG-PET/CT in infectious and inflammatory diseases. PET Clin. 2014;9:497–519. 53. Houshmand S, Salavati A, Hess S, Werner TJ, Alavi A, Zaidi H. An update on novel quantitative techniques in the context of evolving whole-body PET imaging. PET Clin. 2015;10:45–58.

5

Acquisition Protocols and Image Interpretation Criteria Nuclear Medicine Imaging of Infectious Diseases Alberto Signore, Elena Lazzeri, and Chiara Lauri

5.1

Introduction

In the past decades, nuclear medicine (NM) has developed enormously in the field of infections and inflammation and in many cases has become an indispensable diagnostic tool for clinicians. Several techniques and radiopharmaceuticals are available allowing to image cells involved in infective processes at a histological level, and tissue and function alterations induced by the infection/inflammatory process. Among all, radiolabeled white blood cells (WBCs) scintigraphy is able to specifically target the granulocytes thus representing a surrogate marker of neutrophilmediated infections [1]. The principal steps of this exam consist in a blood sample, the isolation of granulocytes from all the other blood cells for their labeling and the injection of radiolabeled autologous WBCs to the patient. The availability of a sterile disposable device, Leukokit, has provided an instrument to facilitate the whole WBC purification and labeling procedure, reducing time and assuring sterility. The utility and safety of Leukokit were reported in several studies that obtained high values of labeling efficiency comparable to the standard technique. Hence, Leukokit has been used for WBC labeling also using other chelating agents for 99mTc or other isotopes such as 111In, 18F-FDG, and 64CuCl [2]. This modality is nowadays the NM gold standard test for detection of infection allowing achieving a differentiation between an aseptic inflammation from an infection. Indeed in the first condition only an exiguous uptake of granulocytes is observed, on the contrary, the increased chemotaxis and vascular permeability in consequence of infective processes, result in an exalted recruitment of granulocytes in the site of A. Signore (*) · C. Lauri Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, “Sapienza” University of Rome, Rome, Italy e-mail: [email protected] E. Lazzeri Regional Center of Nuclear Medicine, Pisa University Hospital, Pisa, Italy © Springer Nature Switzerland AG 2020 A. Signore, A. W. J. M. Glaudemans (eds.), Nuclear Medicine in Infectious Diseases, https://doi.org/10.1007/978-3-030-25494-0_5

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infection. The ability to specifically image granulocytes migration through the infected site has no peers in the field of imaging techniques; therefore, radiolabeled WBCs scintigraphy has gained a more crescent interest in the last decades being nowadays the imaging modality of choice in several infective indications. In particular, they could be applied for the study of musculoskeletal infections as well as cardiovascular, gastro-intestinal, and central nervous systems infections [3–12]. However, the diagnostic accuracy of WBCs scintigraphy is strictly dependent on the modalities used for image acquisition, display, and interpretation. The use of monoclonal antibodies (MoAbs) or antibodies fragments (Fab) direct against specific antigens expressed by activated granulocytes has been proposed in order to overcome the problems of the in vivo labeling procedures of autologous leukocytes. Although their use could seem easier than compared with radiolabeled WBC, several limitations have to be taken into consideration. First of all, the entire antibodies have a high molecular weight that constitutes a limiting factor for their diffusion into the infective focus. They also have long plasma half-life and they present a reticulo-endothelial clearance that justifies the high uptake in liver and bone marrow. Moreover, their accumulation into inflamed sites is nonspecific mainly depending on the increased vascular permeability. Furthermore, MoAbs induce human murine antibodies (HAMA) in the host thus limiting their use at only one time in the life. With the use of Fab’ fragments some of these limitations can be escaped but the diagnostic accuracy is lower than MoAb [13–15]. Unfortunately, different centers through the world adopt different acquisition protocols and different interpretative criteria for radiolabeled WBCs and MoAbs thus leading to an heterogeneity in reported results. The Infection and Inflammation task group of the European Association of Nuclear Medicine (EANM), aiming at overcoming these discrepancies, provided specific guidelines for the labeling of WBCs with both 111In and 99mTc and for acquisition protocols and interpretation criteria of this examination [16–18].

5.2

Biodistribution of Radiolabeled WBCs in Infections and Inflammations

The active recruitment of granulocytes from the blood to the site of infection and inflammation is a dynamic process. The knowledge of this principle is pivotal when performing radiolabeled WBCs in order to faithfully reflect the physiopathology that underlies an infective or inflammatory process [19]. Figure 5.1 shows time-activity curves of radiolabeled WBCs. At time 0, immediately after the intravenous injection of radiolabeled WBCs, 100% of radioactivity is detectable in the blood. With the passing of the time, the granulocytes start to migrate into bone marrow (blue curve), where they accumulate within the first hour post injection and they remain stable with time. In parallel, they are also recruited in the sites of inflammations and infections. In particular, they progressively accumulate in sterile inflammations (yellow curve), where the radioactivity reaches a maximum within the first 2–4 h and then it starts to progressively decrease with time. Conversely, in acute, sub-acute, and chronic infections (green curves) the radioactivity always shows a progressive

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1st

2nd

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3rd

90 Blood

80 70 60

acute

50 Bone marrow

40 30

subacute

20 10

chronic

Lung

infl.

0 0

2

4

6

8

20

hours

Fig. 5.1 Time-activity curves of radiolabeled WBCs in blood, lungs, bone marrow, infections, and inflammations

increase with time, as a result of continuous recruitment of granulocytes from blood in the site of infection. Therefore, it is recommended to acquire at different time point in order to differentiate between an infection from a sterile inflammation. In particular, the first acquisition that should be performed within 30 min-1 h (early images) post injection (p.i.) reproduces bone marrow and vascular distribution, lung transit and liver/spleen ratio; the sites of infections are generally observed after 3–4  h (delayed images) and their uptake should be compared with the images acquired after 20–24  h (late images) p.i. in order to verify the real increase or decrease of radioactivity over time [18–21] thus confirming or ruling out an infection.

5.3

Acquisition Protocols for Radiolabeled WBCs

A large field-of-view camera with a low-energy high-resolution collimator is usually preferred for 99mTc (140 keV with a 15–20% energy window) and a mediumenergy collimator for 111In. In vivo quality controls of lungs, abdomen, and pelvis are strongly suggested in order to verify the correct biodistribution of radiolabeled leukocytes therefore, in addition to images of the region of interest, antero-posterior acquisition of lungs should be performed at 30  min (“early images”) post injection (p.i.) and wholebody images at 3–4 h (“delayed images”) and at 20–24 h (“late images”). Fixed counts or fixed time protocols of acquisition are both possible for radiolabeled WBCs but the images need to be interpreted with caution considering the possible interference of other organs and operator bias in imaging display. Therefore, EANM guidelines recommend acquiring images by using time corrected for isotope

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decay protocols (i.e., if early images are acquired for 100 s, delayed images, obtained 2.5  h post the first acquisition, should be acquired for 133  s and delayed images, obtained 20 h post the first acquisition, should be acquired for 1007 s) [18]. The acquisition time for images corrected for 99mTc and 111In decay are reported in Table 5.1. Since the radioactive decay is compensated by an extension of the acquisition time, delayed and late images can be directly comparable. Therefore, by using this method the images should be displayed, not as a percentage of maximum uptake, but all with the same range of activity in row counts, thus reducing operator interference in the final image interpretation. This approach also allows to detect a real increase in activity or in size, with time, in the suspected site and it makes quantitative analysis more accurate (Fig.  5.2). This method is derived from the results of recent multicenter European studies [20, 21] that underline the high accuracy of radiolabeled WBCs in detecting different kind of infections in particular in osteomyelitis (OM), prosthetic joint infections (PJI), diabetic foot OM, and some soft tissue infections. Table 5.1 Calculation of acquisition times for images corrected for 99mTc and 111In decay Min post 1st acq.

Hours post 1st acq.

Corrected acquisition time (s)

0 90 120 150 180 210 1170 1200 1230 1260 1290

0 1.5 2 2.5 3 3.5 19.5 20 20.5 21 21.5

100 119 126 133 141 150 951 1007 1067 1131 1198

150 178 189 200 212 225 1426 1511 1601 1696 1797

200 238 252 267 283 300 1902 2015 2135 2262 2396

250 297 315 334 354 375 2377 2519 2668 2827 2995

0 90 120 150 180 210 1170 1200 1230 1260 1290

0 1.5 2 2.5 3 3.5 19.5 20 20.5 21 21.5

100 102 102 103 103 104 122 123 124 124 125

150 152 153 154 155 156 184 184 185 186 187

200 203 204 205 206 207 245 246 247 249 250

250 254 255 257 258 259 306 307 309 311 312

99m

Tc Early images

Delayed images

Late images

111

In Early images

Delayed images

Late images

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a

b

c

d

e

f

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Fig. 5.2 Three different examples of acquisition protocols and images display. (a) images acquired with fixed counts (100,000) and displayed in % of maximum pixel; (b) images acquired with fixed counts (100,000) and displayed with same activity scale in counts; (c) images acquired with fixed times (300 s) and displayed in % of maximum pixel; (d) images acquired with fixed times (300 s) and displayed with same activity scale in counts; (e) images acquired with times corrected for 99mTc decay and displayed in % of maximum pixel; (f) images acquired with times corrected for 99mTc decay and displayed with same activity scale in counts. Only this last example of acquisition and image display allows to detect an increase/decrease of activity over time. In particular, this patient had an infected prosthesis in the right knee

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Sometimes, depending on the clinical indication, SPECT or SPECT/CT is required in addition to planar images. In some specific circumstances, for example, in vascular graft infections, diabetic foot, endocarditis, the appeal to planar images is mandatory in order to correctly localize the uptake. SPECT/CT acquisitions could also be used in order to perform precise semi-quantitative measurements evaluating the target to background (T/B) ratios over time; therefore in this case, they should be acquired in a 128 × 128 or 64 × 64 matrix using the same decay-corrected protocol (i.e., for 7 s/step 5 h p.i and 40/s step for late images). The protocols for SPECT and total-body acquisitions are reported in Tables 5.2 and 5.3. However, the diagnosis of infection is often obtained by planar images alone. SPECT/CT is useful only for a precise anatomic localization of WBC accumulation and therefore SPECT/CT may be performed only 20 h p.i. for 30–40 s/step. The SPECT acquisition at 3–5 h is often not necessary since radiolabeled WBC may have not migrated enough into the infection site. Despite three-time point acquisitions are generally suggested, the clinical indication should guide the choice of protocols. For example, the imaging of peripheral OM or PJI requires 30  min, 2–3  h, and 20–24  h acquisition, whereas for imaging of Table 5.2 Acquisition times for SPECT corrected for infection

Sites of infection Example 1 Example 2 Periphery and skull Thorax Abdomen

Time first SPECT (h) 3 4 5

Time second SPECT (h) 20 20 20

Time interval (h) 17 16 15

5 5

20 20

15 15

Sec per step first SPECT 10 5 7 6 5

99m

Tc decay according to the site of Total time first SPECT (s) 640 320 448

Sec per step second SPECT 68.6 31.5 40

384 320

34 28

Total time second SPECT (s) 43,904 2016 2560 2176 1792

Table 5.3 Speed and duration of total-body acquisitions considering times corrected for decay Example 1

Example 2

Example 3

Example 4

Time (h) 0 3 20 0 3 20 0 3 20 0 3 20

Length (cm) 140 140 140 120 120 120 100 100 100 80 80 80

Speed (cm/min) 20 9.9 1.4 20 9.9 1.4 20 9.9 1.4 20 14 2

99m

Total duration scan (s) 420 848 6045 360 727 5178 300 605 4312 240 339 2418

Tc

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vascular graft infection (VGI) a dynamic acquisition (one image every 5 s for 150 s p.i.) is helpful to visualize vascular structures and the eventual presence of aneurysms, then the standard acquisitions should be performed. In case of abdominal graft oblique projections are useful, in addition to standard antero-posterior views, in order to limit the possible interference of bowel activity and SPECT/CT is mandatory at 2–4 h p.i. In the assessment of VGI, late images do not seem mandatory but they can be useful in the inconclusive cases for the better visualization of the infective process [22]. The presence of bowel activity is also a limiting factor when using 99mTc for the study of inflammatory bowel disease (IBD); therefore, for this indication 30 min and 2–3 h images are generally suggested. When 111In is used, these pitfalls do not occur.

5.4

Interpretative Criteria for Radiolabeled WBCs

5.4.1

Qualitative Assessment

Once correctly acquired by using time corrected for isotope decay protocols, the images should be correctly displayed in order to achieve a correct interpretation. If we display images in % of maximum counts/pixels we need to adjust the intensity scale of each image to make bone marrow activity comparable thus introducing a bias [20, 21, 23]. The correct display is by using absolute counts and adjusting the intensity to all the images together. By comparing delayed and late images, the scan is classified as: – positive for infection: when an increase in uptake extent and/or intensity is observed in the region of interest – negative for infection: when there is no uptake or a decrease of activity over time – doubtful cases: for example, when the increase or decrease of the uptake is not so clear between delayed and late images or when we observe only a slight increase in size but not in activity or when bone marrow activity increases/ decreases thus not allowing a correct evaluation of region of interests In a large retrospective study conducted on 297 patients that performed radiolabeled WBC scans, Glaudemans et al. concluded that by using time corrected for decay acquisition protocol and the above-mentioned interpretative criteria, visual analysis led to a sensitivity of 85%, a specificity of 97%, a diagnostic accuracy of 94.5%, a positive predictive value of 88.8%, and a negative predictive value of 95.9% [20].

5.4.2

Semi-quantitative Assessment

In doubtful cases, the visual assessment should be completed by a semi-quantitative analysis in order to differentiate between a real infection from a sterile inflammation [20, 21, 24–26].

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T/B ratios analysis can be performed by drawing region of interests (ROIs) on the affected and unaffected sites, but the size and position of ROIs tissue are observer-dependent and the selection of reference could strongly influence the results of semi-quantitative analysis. Glaudemans et al. also investigated four different reference tissues for the measurement of background activity. They used contralateral tissue in 285 patients, ipsi-lateral bone marrow in 169 patients, contralateral bone marrow in 177 patients, and anterior superior iliac crest in 73 subjects. The best results were achieved when contralateral tissue was used providing a sensitivity of 91.9%, a specificity of 82.1%, a diagnostic accuracy of 84.2%, a positive predictive value of 58.7%, and a negative predictive value of 97.3%. However in patients with OM and osteosynthesis, the use of contralateral bone marrow as reference gave the highest sensitivity and specificity (100% and 85.7% and 100% and 93.3%, respectively) [20]. The mean counts per pixel in these ROIs have to be recorded both in delayed and late images (T/Bdelayed and T/Blate, respectively). By comparing T/B ratios of delayed and late images, the scan is classified as: – positive of infection: when the T/B ratio increases with time (T/Blate > T/Bdelayed) – negative for infection: when T/Blate is significantly decreased compared to T/ Bdelayed – equivocal: when the T/Blate is similar or slightly decreased compared to T/Bdelayed [20, 25] For our experience, an increase or decrease of more than 20% could be used as cut-off in order to define a positive or negative scan (Fig. 5.3). By using these strategies, it is possible to discriminate an infection from an aseptic inflammation reaching an accuracy around 90% that further increases when SPECT/CT is added to planar images [5, 27, 28] (Fig. 5.4).

Step 1

Step 2

Step 3

Decrease

Qualitative analysis

Doubtful

Soft tissue inf.

Semiquantitative analysis

Increase

Fig. 5.3 Suggested steps for images interpretation

Increase

_20%

Osteomyelitis

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T/B3h=2.4

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T/B20h=1.8

Fig. 5.4 An example of negative WBC scan in which both qualitative and semi-quantitative analysis showed a decreased activity between delayed and late images [21]

5.5

Conclusions

The application of correct and well-standardized acquisition protocols and interpretative criteria could exalt the accuracy of an imaging modality that is specific and accurate itself thus offering an undeniable tool for achieving a correct diagnosis. Uniformity in the diagnostic approach at infective and inflammatory diseases worldwide is desirable in order to warranty an appropriate treatment of patients.

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7. Martín Comín J, Rodríguez Gasén A, Van de Wiele C. Nuclear medicine imaging of infections and inflammatory diseases of the abdomen. In: Signore A, Quintero AM, editors. Diagnostic imaging of infections and inflammatory diseases: a multi-disciplinary approach. New York: Wiley; 2013. p. 216–40. 8. Signore A. Nuclear medicine imaging of abdominal infections and inflammation. In: Lazzeri E, Signore A, Erba PA, Prandini N, Versari A, D’Errico G, Mariani G, editors. Radionuclide imaging of infection and inflammation. A pictorial case-based atlas. Milan: Springer-Verlag; 2013. p. 229–52. 9. Lauri C, AWJM G, Signore A.  Leukocyte imaging of the diabetic foot. Curr Pharm Des. 2018;24(12):1270–6. 10. Lauri C, Tamminga M, Glaudemans AWJM, Juárez Orozco LE, Erba PA, Jutte PC, Lipsky BA, IJzerman MJ, Signore A, Slart RHJA. Detection of osteomyelitis in the diabetic foot by imaging techniques: a systematic review and meta-analysis comparing MRI, white blood cell scintigraphy, and FDG-PET. Diabetes Care. 2017;40(8):1111–20. 11. Glaudemans AWJM, Jutte PC, Cataldo MA, Cassar-Pullicino V, Gheysens O, Borens O, Trampuz A, Wörtler K, Petrosillo N, Winkler H, Signore A, Sconfienza LM. Consensus document for the diagnosis of peripheral bone infection in adults: a joint paper by the EANM, EBJIS, and ESR (with ESCMID endorsement). Eur J Nucl Med Mol Imaging. 2019;46(4):957–70. 12. Signore A, Sconfienza LM, Borens O, Glaudemans AWJM, Cassar-Pullicino V, Trampuz A, Winkler H, Gheysens O, Vanhoenacker FMHM, Petrosillo N, Jutte PC. Consensus document for the diagnosis of prosthetic joint infections: a joint paper by the EANM, EBJIS, and ESR (with ESCMID endorsement). Eur J Nucl Med Mol Imaging. 2019;46(4):971–88. 13. Locher JT, Seybold K, Andres RJ, Schubiger PA, Mach JP, Buchegger F. Imaging of inflammatory and infectious lesions after injection of radioiodinated monoclonal antigranulocyte antibodies. Nucl Med Commun. 1986;7:659–70. 14. Becker W, Bair J, Behr T, Repp R, Streckenbach H, Beck H, et al. Detection of soft-tissue infections and osteomyelitis using a technetium-99m-labeled anti-granulocyte monoclonal antibody fragment. J Nucl Med. 1994;35(9):1436–43. 15. Gratz S, Reize P, Kemke B, Kampen WU, Lusteri M, Hoffken H. Targeting of osteomyelitis with IgG and fab’ monoclonal antibodies labeled with [99mTc]: kinetic evaluations. Q J Nucl Med Mol Imaging. 2014;60:413–23. 16. Roca M, de Vries EF, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with (111)in-oxine. Inflammation/infection Taskgroup of the European Association of Nuclear Medicine. Eur J Nucl Med Mol Imaging. 2010;37(4):835–41. https://doi.org/10.1007/s00259010-1393-5. Erratum in: Eur J Nucl Med Mol Imaging. 2010 Jun;37(6):1234. 17. de Vries EF, Roca M, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with (99m)Tc-HMPAO.  Inflammation/infection Taskgroup of the European Association of Nuclear Medicine. Eur J Nucl Med Mol Imaging. 2010;37(4):842–8. https://doi.org/10.1007/ s00259-010-1394-4. Erratum in: Eur J Nucl Med Mol Imaging.2010 Jun;37(6):1235. PubMed PMID: 20198473; PubMed Central PMCID: PMC2844965. 18. Signore A, Jamar F, Israel O, Buscombe J, Martin-Comin J, Lazzeri E. Clinical indications, image acquisition and data interpretation for white blood cells and anti-granulocyte monoclonal antibody scintigraphy: an EANM procedural guideline. Eur J Nucl Med Mol Imaging. 2018;45(10):1816–31. 19. Signore A, Glaudemans AW. The molecular imaging approach to image infections and inflammation by nuclear medicine techniques. Ann Nucl Med. 2011;25(10):681–700. 20. Glaudemans AW, de Vries EF, Vermeulen LE, Slart RH, Dierckx RA, Signore A. A large retrospective single-centre study to define the best image acquisition protocols and interpretation criteria for white blood cell scintigraphy with 99mTc-HMPAO-labelled leucocytes in musculoskeletal infections. Eur J Nucl Med Mol Imaging. 2013;40(11):1760–9. 21. Erba PA, Glaudemans AW, Veltman NC, Sollini M, Pacilio M, Galli F, Dierckx RA, Signore A. Image acquisition and interpretation criteria for 99mTc-HMPAO-labelled white blood cell scintigraphy: results of a multicentre study. Eur J Nucl Med Mol Imaging. 2014;41(4):615–23.

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22. Erba PA, Leo G, Sollini M, Tascini C, Boni R, Berchiolli RN, Menichetti F, Ferrari M, Lazzeri E, Mariani G. Radiolabelled leucocyte scintigraphy versus conventional radiological imaging for the management of late, low-grade vascular prosthesis infections. Eur J Nucl Med Mol Imaging. 2014;41(2):357–68. 23. Signore A, Quintero AM.  Diagnostic imaging of infections and inflammatory diseases: a multi-disciplinary approach. New York: Wiley; 2013. 24. Grippaudo FR, Pacilio M, Di Girolamo M, Dierckx RA, Signore A. Radiolabelled white blood cell scintigraphy in the work-up of dermal filler complications. Eur J Nucl Med Mol Imaging. 2013;40(3):418–25. 25. Pelosi E, Baiocco C, Pennone M, Migliaretti G, Varetto T, Maiello A, et al. 99mTc-HMPAOleukocyte scintigraphy in patients with symptomatic total hip or knee arthroplasty: improved diagnostic accuracy by means of semiquantitative evaluation. J Nucl Med. 2004;45(3):438–44. 26. Wang SJ, Kao CH, Chen DU, Lin MS, Yeh SH, Lan JL. Quantitative 99mTc-HMPAO white blood cells and 67Ga scanning in rheumatoid arthritis. Nucl Med Commun. 1991;12(6):551–8. 27. Glaudemans AW, Galli F, Pacilio M, Signore A. Leukocyte and bacteria imaging in prosthetic joint infection. Eur Cell Mater. 2013;25:61–77. 28. Palestro C, Swyer A, Kim C, Goldsmith S. Infected knee prosthesis: diagnosis with in-111 leukocyte, Tc-99m sulfur colloid, and Tc-99m MDP imaging. Radiology. 1991;179(3):645–8.

6

Nuclear Medicine Imaging of Soft Tissue Infections Elena Lazzeri

6.1

Introduction

Infection of soft tissues may be acute or chronic and may be classified as primary or secondary according to the hematogenous spreading or local contamination by microorganisms. Superficial or deep skin layers can be the locations of soft tissue infections. Soft tissues infections frequently present with nonspecific signs and symptoms especially those of deep tissues. Soft tissues diagnosis and evaluation of extension may be tricky. The microorganism isolation, through multiple sampling or histology of biopsies, is currently the first diagnostic method to diagnose the presence of soft tissue infections. Diagnostic imaging is mandatory to evaluate the extension of infection disease, to evaluate the response to the antibiotic treatment, and to evaluate a relapse of disease. Radiologic and radionuclide imaging is often performed as part of a diagnostic work-up. It is essential that the choice of diagnostic procedure(s) performed is optimized for the clinical situation of the patient since every diagnostic test is not equally accurate in all clinical situations [1–3].

6.2

The Instrumental Diagnostic Tools

6.2.1

Radiologic Imaging

6.2.1.1 Ultrasound (US) US is widely available and can be easily and early performed (even in an emergency setting). US is the first diagnostic technique to assess the presence of soft tissue infection. It can evaluate fluid collections and facilitate the percutaneous fine needle ago biopsy (FNAB) to identify the pathogen microorganism. US imaging can be improved by Echo-color Doppler to characterize soft tissue collections and to E. Lazzeri (*) Regional Center of Nuclear Medicine, Pisa University Hospital, Pisa, Italy © Springer Nature Switzerland AG 2020 A. Signore, A. W. J. M. Glaudemans (eds.), Nuclear Medicine in Infectious Diseases, https://doi.org/10.1007/978-3-030-25494-0_6

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differentiate liquid from corpuscolate materials. US has however some disadvantages especially in some deep tissues and thorax evaluation [4, 5].

6.2.1.2 Computed Tomography (CT) CT is widely available and can be useful in uncertain situations to confirm the suspected diagnosis and to evaluate the extent of the disease. CT with high spatial and contrast resolution can provide detailed anatomic information of soft tissues infections. Image findings of soft tissue infections can be however nonspecific and can be tricky to differentiate infectious disease from non-infectious processes; for this reason, it is mandatory for radiologists to know well the clinical history and laboratory findings [6]. 6.2.1.3 Magnetic Resonance Imaging (MRI) Magnetic Resonance Imaging (MRI) is currently the first diagnostic imaging of choice for the evaluation of the anatomic changes of soft tissues caused by infectious processes. MRI can provide accurate informations on the infection extent and on the presence of an abscess, particularly in case of musculoskeletal infections. The use of MRI is however limited in patients with suspected post-surgical soft tissues infections since some image findings of inflammatory reactions are very similar to those of infection processes. [6, 7].

6.2.2

Nuclear Medicine Imaging

Nuclear medicine techniques enable to diagnose most of the soft tissues infections (skin, muscles, brain, abdominal and chest organs, etc.). Different radiopharmaceuticals can be chosen according to the etiology, pathophysiology, and clinical situation of patient with suspected soft tissue infection. The available radiopharmaceuticals for the diagnosis of soft tissue infection are 67 Gallium-citrate (Ga), 99mTc-Haesametyl-Propyl-Amino-Oxime-labelled autologous leukocytes scintigraphy (99mTc-HMPAO-WBC), and 18F-fluoro-deoxyglucose ([18F]FDG).

6.2.2.1 Diphosphonates Dynamic Bone Scan (Dynamic BS) Dynamic BS can be done with 99mTc-methyl diphosphonate (MDP) or 99mTc-hydroxi diphosphonate (HDP). Dynamic BS is composed by three phases; during the iv injection of radiopharmaceutical (first phase or vascular phase), the region of suspected infection is located under the Gamma-camera. 5 min later (second phase or blood pool phase) planar images were acquired in the same region. Three to four hours later (third or late phase) planar and total-body images were acquired. Dynamic BS can be useful when it is essential to evaluate the vascularization of a lesion and check or rule out the bone involvement. 6.2.2.2 67Ga-Citrate Ga-citrate has been successfully used for the study of soft tissues infections and abscesses [8]. Its use is limited to clinical indications such as FUO, chronic 67

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osteomyelitis of the spine and lung infections, especially in immune-compromised patients. 67Ga-citrate has a higher sensitivity for the identification of chronic infections [9]; however, long time for images acquisition (at least 2–3 days) and poor image quality have determined a progressive reduction of the use of 67Ga-citrate. Recent availability of 68Ga-citrate for PET/CT use could be a very useful radiopharmaceutical for the diagnosis of soft tissues infection.

6.2.2.3 Labelled Leukocytes Scintigraphy (WBC) 111 In-oxine or 99mTc-HMPAO-labeled WBC scintigraphy is currently the procedure of choice and represents the gold standard for an early diagnosis of soft tissues infection [10–12]. 111In-oxine presents higher stability and its half-life allows delayed imaging; however, the radiation burden and the photon energies of 111In are its limits. 99mTc-HMPAO shows a better quality imaging. Relative disadvantages are the urinary and fast cecum bowel excretion (from 2 h and 30 min after injection) [13]. Sensitivity and specificity of radiolabeled WBCs for the diagnosis of soft tissue infections ranges from 86% to 90%, the higher sensitivity is predominantly in acute infections explained by the increased neutrophil leukocytes response. Singlephoton emission-computed tomography (SPECT/CT) hybrid images can improve the diagnostic accuracy allowing the precise localization and extent of the disease. WBC scintigraphy is particularly useful in identifying neutrophil-mediated flogistic pathologies, such as bacterial infections [1–3]. 6.2.2.4 PET or PET/CT with [18F]FDG F-FDG can be used to detect infectious and inflammatory diseases [14–16] as fever of unknown origin (FUO), vasculitis, chronic granulomatous disease, infective endocarditis, sarcoidosis and thromboembolic disease [17, 18]. The main advantages of [18F]FDG-PET/CT are the short time acquisition (  10  mg/L and ESR  >  30 should advice the surgeon to perform joint aspiration in outpatient [8]. IL-6 represents a promising highly specific marker for joint infection but is not yet available broadly among laboratories. WBC counts represent a readily available, but highly non-specific, marker of infection and it has shown to be less consistent than CRP and ESR. In a patient with high suspicion index of PJI, joint aspiration and synovial fluid analysis should be performed. Knee aspiration is easily reproducible in outpatient setting, hip aspiration often requires expertise and it is recommended to be imaging guided [6]. WBC synovial fluid leukocyte count is routinely performed. Based on international consensus, recommended thresholds are 3000 WBCs, 80% PMN and 10,000 WBCs, 90% PMN, respectively, for chronic and acute PJI. Synovial fluid cultures remain the most effective method for organism identification; despite a high specificity, they have shown poor sensitivity: a negative culture does not exclude a PJI.  As a consequence of that, the surgeon should make every effort to try and improve the yield of cultures from synovial fluid analysis [8]. In recent years, alpha-defensin has been identified as a promising biomarker: it is an antimicrobial peptide that is naturally released from activated neutrophils: when infection is present, WBCs release the peptide that integrates into the pathogen’s membranes. Because of that, alpha-defensin maintains its high diagnostic accuracy for PJI even under antibiotic administration. It has been recently introduced commercially a novel Synovasure peri-prosthetic joint infection (PJI) lateral flow test device; it features easy use and quick results (10 min), that means it can be performed intra-operatively. Alpha-defensin from synovial fluid is highly reliable for predicting a diagnosis of PJI and it is precise in ruling out this diagnosis (highly sensitive). Several reports have proven the validity of this biomarker for the diagnosis of PJI as it showed a strong match with the results of the MSIS criteria, which still remain the gold standard for PJI diagnosis [9]. In the following paragraphs, we will explore the role of different NM modalities in this specific clinical setting examining their pros and cons (Table 9.1).

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Table 9.1 Statements on the diagnosis of PJI (adapted from the consensus document published by EANM, ESR, EBJIS and ESCMID [7]) Nr Statement 1 PJI should be suspected when one or more of the following symptoms and signs are present: Otherwise unexplained pain and/or fever, redness, swelling, scar inflammation, and movement limitations. These symptoms are (especially in the chronic phase) not specific and require other investigations 2 Sinus tract and purulent discharge are clear signs of prosthetic joint infection 3 CRP and ESR should always be performed in patients with suspected prosthetic joint infection. A normal value does not rule out PJI 4 In the case of fever, blood cultures should always be performed in patients suspected of having prosthetic joint infection in order to identify the causative bacteria 5 Conventional radiography is the first imaging modality to perform in patients with suspicion of PJI for diagnosis and follow-up 6 Ultrasound can detect complications around the prosthesis, but the capacity for detecting infection is controversial 7 Imaging may be useful for guiding joint aspiration or periprosthetic tissue biopsy 8 Leukocyte count and differential in synovial fluid has high diagnostic accuracy in detecting PJI 9 Bacterial culture from joint aspiration has high diagnostic accuracy in detecting prosthetic joint infection 10 Measurement of the synovial biomarkers alphadefensin, leukocyte esterase, interleukin-6, and C reactive protein is useful in the detection of prosthetic joint infection 11 Biopsy of periprosthetic tissue for histology and cultures can be performed for preoperative diagnosis in cases where ESR and/or CRP are positive and aspiration is inconclusive or impossible to test (dry tap) 12 Antibiotic therapy should be postponed or discontinued before pre- and intraoperative sampling 13 Antibiotic therapy should not be discontinued before white blood cell scintigraphy 14 Computed tomography can be effectively used to diagnose PJI 15 The diagnostic accuracy for three-phase bone scintigraphy in patients with suspected infection within the first 2 years after hip or knee prosthesis placement is low 16 In the case of negative three-phase bone scintigraphy, a diagnosis of prosthetic joint infection can be excluded 17 In the case of a positive three-phase bone scan, the addition of white blood cell scintigraphy leads to high diagnostic accuracy for PJI 18 In the case of negative white blood cell scintigraphy, the probability of prosthetic joint infection is low 19 18F-FDG-PET in patients with suspected prosthetic joint infection has high sensitivity but lower specificity than white blood cell scintigraphy or antigranulocyte antibody scintigraphy 20 Anti-granulocyte scintigraphy is a good alternative to white blood cell scintigraphy, with similar sensitivity and specificity 21 Hybrid SPECT/CT imaging can improve localization of infection (and diagnostic accuracy) 22 Semiquantitative analysis of WBC accumulation over time in WBC scan increases diagnostic accuracy for PJI

LoE 4

5 2 5

2 2 2 2 2 2

2

4 4 2 2

2 2 2 2

2 2 3

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Table 9.1 (continued) Nr Statement 23 Combining WBC scan with bone marrow scan increases diagnostic accuracy for PJI detection 24 MRI is wholly feasible in patients with suspected PJI 25 MRI demonstrates high diagnostic performance in detecting clinically suspected PJI, with no ionizing radiation

LoE 3 2 2

LoE level of evidence

9.3

Gamma-Camera Imaging

Different radiopharmaceuticals suitable for gamma camera imaging are available for imaging of PJI with high diagnostic accuracy allowing the detection of an infection even before the appearance of radiological signs detectable with radiological modalities (Table 9.2).

9.3.1

Three-Phase Bone Scan

It is a common practice, when a PJI is suspected, to perform a three-phase bone scintigraphy as a first screening modality. Although this examination is widely available, easy to perform and with low cost [10], the accumulation of diphosphonates is not specific being present in infection and in aseptic loosening as well. If the bone scan is positive, an infection can be suspected but it needs to be confirmed with a more specific test since a bone scintigraphy can be positive in several clinical conditions (fractures, bone remodelling, metabolic diseases…). Moreover, bone scintigraphy may be positive for a very long period after surgery (2 years after hip prosthesis and up to 5  years in knee prosthesis) [3]. In the first years from joint replacement surgery, indeed, a physiologic bone remodelling may occur, thus leading to false positive results at bone scan. Conversely, a negative three-phase bone scan can rule out the hypothesis of an infection. Concluding, this modality is recommended as initial assessment only in patients with low-test probability in order to definitively exclude the infection but in patients with high probability of infection, especially if performed within the first 5 years from surgery, it is better to directly perform more specific and accurate imaging modality, in particular white blood cells (WBCs) scintigraphy [6].

9.3.2

Radiolabelled White Blood Cells

Autologous radiolabelled WBCs scintigraphy with both 111-Indium (111In) and 99m -Technetium (99mTc) is nowadays a milestone for the diagnosis of infection.

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Table 9.2 Gamma-camera and PET/CT imaging of prosthetic joint infections Gammacamera imaging 99m Tc-HDP

99m

Tc WBC

99m Tc antigranulocyte monoclonal antibodies

Why Shows bone abnormalities

When In low probability cases, to exclude an infection

How 3-phase acquisition preferred

Pitfalls High uptake in bone metastases, fractures, Paget’s disease

Detection of granulocytes in soft tissues and bone

Limited use during antibiotic treatment

30–60 min, 2–3 h and 20–24 h p.i.

Detection of granulocytes in infected areas

Not during antibiotic treatment and not immediately after joint replacement due to false positivity because of acute edema

4–6 h and 24 h p.i.

Possible false positives in case of bone marrow expansion, requires combined 99m Tcnanocolloid scan Non-specific accumulation due to increased vascular permeability; induction of HAMA (for the entire antibody)

PET Imaging Why 18 FDetection of FDG inflammatory process associated to infections

When Not immediately after surgery

How Acquire images at 1 h p.i.

Pitfalls It does not discriminate between infection and aseptic loosening

Interpretation criteria When positive in all phases indicates an inflammation but not necessarily an infection If uptake increases with time, it is a sign of infection

If uptake increases with time, it is a sign of infection

Interpretation criteria The presence of any uptake area is suggestive of an infection

The diagnostic accuracy of this examination could be higher than other radiological and NM modalities especially if correct acquisition protocols and interpretative criteria are adopted [11–14]. The presence of an increased uptake over time, in terms of intensity and/or extension, in the affected joint compared to contralateral is suggestive for a PJI.  Conversely, a decreased uptake over time rules out the hypothesis of an infection since this modality has a very high negative predictive value (more than 90%–100% depending on the studies) [13, 15– 17] (Fig. 9.1).

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Fig. 9.1 A young patient with an infected left hip prosthesis and a subcutaneous abscess (top left). Abscess was drained and oral antibiotic therapy started. After 6 months, a pelvic NMR showed the persistence of a sinus tract from the femoral neck to the skin (top right images). The 99mTc-WBC scan showed a very mild increase of uptake over time in planar images (bottom left images); but semi-quantitative analysis over the femoral neck and peri-prosthetic soft tissue highlighted the presence of a mild infection mainly in the soft tissues that required further antibiotic therapy but not the removal of the prosthesis

When qualitative assessment is not diriment, a semi-quantitative analysis can be helpful in comparing target to background ratio (T/B) of delayed and late images (see also Chap. 6). Despite all these precautions, false positive results may occur in presence of bone marrow expansion as consequence of a physiologic accumulation of WBCs in reticulo-endothelial system and this is the reason why a bone marrow

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scintigraphy may be performed after WBCs scan [18, 19]. The diagnostic accuracy of combined WBCs and bone marrow scan ranges from 83% to 98% for both 111In and 99mTc [20–24]. Although well acquired, displayed and interpreted planar images have an important limitation, as they are not always able to localize the uptake into bone or soft tissue infection. This distinction is crucial in the optic of treatment. The added value of single photon emission computed tomography (SPECT)/computed tomography (CT) is indisputable in many other clinical settings and it is well known that it is able to improve the diagnostic accuracy of several scintigraphic scans. In the specific clinical setting of PJI, the appeal to SPECT/CT in addition to planar images allows a correct assessment of the extent of infective process into bone and/or soft tissues aiming to discriminate, with high specificity, between PJI and STI [25–27]. Kim et al. reported a sensitivity, specificity and diagnostic accuracy of planar images, respectively, of 82%, 88% and 84%. Adding SPECT/CT these values increased to 93.3%. CT component resulted more contributory in patients affected with hip prosthesis than for hip prosthesis [17]. In the series studied by Filippi et  al. in 2006, the accuracy of WBCs scintigraphy improved from 64% for SPECT alone, to 100% when SPECT/CT was applied [28]. van der Bruggen et al. performed 111In-labelled WBCs with SPECT and 99mTc-sulphur colloid reaching a diagnostic accuracy of 95% [29].

9.3.3

Anti-granulocyte Scintigraphy

Monoclonal antibodies (MoAbs) against specific receptors expressed on granulocytes’ surface represent an alternative option to the use of radiolabelled WBCs especially in the centres that are not equipped for the labelling procedure. Only two antibodies are commercially available: besilesomab (Scintimun®), a whole murine antibody, and sulesomab (Leukoscan®), a Fab fragment. Images acquisition and interpretation are the same of WBCs scan and have been recently published in a procedural guideline [14]. However also this imaging modality has some limitations: first of all besilesomab, being a murine-derived antibody, may induce human murine antibodies (HAMA) in the hosts, therefore this radiopharmaceutical cannot be used in the follow-up. From the few studies and meta-analysis available in literature directly comparing MoAbs and radiolabelled WBCs in patients with PJI, it emerges that MoAbs have a sensitivity of 83% and a specificity of 80% that is slightly lower than radiolabelled WBCs [30–33], therefore we can conclude that these two imaging approaches are comparable and that MoAbs can be used in alternative to radiolabelled WBCs [7].

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9.4

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PET Imaging

The role of FDG-PET/CT in the diagnosis of infections and inflammation is now well consolidated and largely defined in recent European guidelines [34]; however, it is well known the uptake of FDG is not specific, therefore a big caution must be used when interpreting a FGD scan. Moreover, the presence of metal devices can create artefacts at CT scan that can degrade images quality interfering on the exact localization of infective process. Several authors tried to define interpretative criteria for diagnosing a PJI using qualitative or semi-quantitative analysis but an unanimous consensus still does not exist [21, 35, 36]. According to the meta-analysis performed in 2008 by Kwee et al., the pooled sensitivity and specificity of FDG-PET for the diagnosis of hip or knee prosthesis infection were 82.1% and 86.6%, respectively [37]. Gemmel et al. reported 84% of both sensitivity and specificity concluding that [18F]FDG-PET/CT seems to be more accurate for hip than knee prosthesis [20]. In general, the diagnostic accuracy is influenced by the type and location of the prostheses and the type of reconstruction method performed for the PET scan. Reinartz and co-workers found, with [18F]FDG-PETCT, an accuracy of 95% in hip prosthesis [36]; in the series of Zhuang et al., the diagnostic accuracy was 89.5% for hip prosthesis and 77.8% for knee prosthesis [38]; Basu et al. found a sensitivity and specificity of 81.8% and 93.1% for hip prosthesis and 94.7% and 88.2% for knee arthroplasty [39]. The joint EANM/SNMMI guidelines for FDG use in inflammation and infection reported an overall sensitivity of 95% and a specificity of 98% for knee and hip prosthesis [34]. If we take in exam the few papers comparing FDG-PET and WBCs scintigraphy [21, 36, 39–41], the results are very discordant mainly due to the different acquisition protocols and interpretative criteria used. Love et al. found a higher diagnostic accuracy of combined WBC scan and bone marrow scintigraphy compared to FDGPET/CT [21]. On the contrary, Pill et al. [41] reported higher sensitivity and specificity for FDG-PET/CT (95% and 93%, respectively) compared to combined 111 In-labelled WBC and 99mTc-sulphur colloid (50% and of 95%, respectively). Whereas, in the study of Vanquickenborne et al. the two imaging modalities showed a similar sensitivity (88%), but WBC scan was more specific than FDG-PET (100% vs. 78%) [42].

9.5

Role of Hybrid Imaging

As stated before, hybrid imaging (SPECT/CT, PET/CT and PET/MRI) is revolutionizing the way of making imaging in several clinical settings through the combination of morphological and functional information [43]. These methods allow an

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accurate localization of suspected foci of uptake, thus allowing a precise evaluation of bone and soft tissues. The added value of SPECT/CT over planar images is indisputable and this modality should be an integral part of radiolabelled WBCs scan in order to correctly localize the uptake and to assess the extent of the infection, thus further improving the accuracy of this examination. The importance to integrate radiological and functional imaging is also confirmed by the fact that the most recent PET cameras are always integrated with a CT tomograph and that the use of PET stand-alone is nowadays outdated. In the last decades, many efforts are directed towards the creation of PET-MRI tomographs that combine the high-quality images provided by MRI with PET data, thus representing a real revolution in the diagnostic approach of several diseases.

9.6

Consensus Document for the Diagnosis of PJI

Recently, four European Societies (EANM, ESR, EBJIS and ESCMID) developed a joint evidence-based guideline for diagnosing of PJIs. Several statements were formulated for each topic aiming at defining an evidence-based diagnostic flow chart. Each statement was examined by using PICO methodology (Population/ Problem—Intervention/indicator—Comparator—Outcome) and a level of evidence was assigned to each statement in consensus with all delegates and societies according to the indications provided by OCEBM [44]. The resulting diagnostic flow charts for imaging of PJI is shown in Fig. 9.2. Table 9.1 summarizes all statements and their level of evidence (1 = highest level of evidence, 5 = lower level of evidence or expert opinion).

9.7

Future Perspectives and New Trends

Very few articles are emerging on the possible use of FDG-PET/CT labelled leukocytes in the diagnosis of several infective diseases [45–47] but the experience on the specific field of PJI is very limited. Preliminary data, however, seem to support the use of FDG-PET/CT labelled leukocytes since this modality is characterized by a higher sensitivity, specificity and diagnostic accuracy than FDG alone [47]. PET/MRI is emerging as a powerful imaging modality for the evaluation of several diseases. Given the possibility to study soft tissues and bone with very high quality images, we expect that, in near future, this modality will become a promising tool for the assessment of several musculoskeletal infections.

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Blood culture

CRP, ESR, WBC count

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Xray

If suspicion persists: Consider bone or soft tissue biopsy/ aspiration under imaging guidance

Advanced imaging tests

Nuclear medicine examinations (see Figure 2)

MRI

More than 2 years after prosthesis implant

within 2 years after prosthesis implant

3-phase bone scan or FDG-PET1

Negative

No infection

WBC scan (with or w/out bone-marrow scan2)

Positive

Suspicion of acute infection: WBC scan2 (or AGA scan2)

Suspicion of chronic infection: AGA scan2 (or WBC scan2)

Negative

Positive

Positive

Infection

Negative

No infection

Fig. 9.2 Diagnostic flow chart to follow in case of suspected PJI based on published evidence. The choice of an advanced imaging modality depends on costs, availability, radiation burden and operator experience. Initial stratification can be based on time after surgery and should include three-phase bone scan or FDG-PET/CT (both characterized by high sensitivity but less specificity) in order to exclude the infection in case of low probability of infection or radiolabelled WBCs, as first imaging modality, in patients with suspected PJI within 2 years from implant or with high probability of infection

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References 1. Kurtz SM, Lau E, Watson H, Schmier JK, Parvizi J. Economic burden of periprosthetic joint infection in the United States. J Arthroplasty. 2012;27:61–5. 2. Trampuz A, Zimmerli W. Prosthetic joint infections: update in diagnosis and treatment. Swiss Med Wkly. 2005;135(17–18):243–51. 3. Glaudemans AW, Galli F, Pacilio M, Signore A. Leukocyte and bacteria imaging in prosthetic joint infection. Eur Cell Mater. 2013;25:61–77. 4. Zimmerli W, Trampuz A, Ochsner PE.  Prosthetic-joint infections. N Engl J Med. 2004;351(16):1645–54. 5. Berbari EF, Hanssen AD, Duffy MC, Steckelberg JM, Ilstrup DM, Harmsen WS, et al. Risk factors for prosthetic joint infection: case-control study. Clin Infect Dis. 1998;27(5):1247–54. 6. Springer BD. The diagnosis of periprosthetic joint infection. J Arthroplasty. 2015;30(6):908–11. 7. Signore A, Sconfienza LM, Borens O, Glaudemans AWJM, Cassar-Pullicino V, Trampuz A, Winkler H, Gheysens O, Vanhoenacker FMHM, Petrosillo N, Jutte PC. Consensus document for the diagnosis of prosthetic joint infections: a joint paper by the EANM, EBJIS, and ESR (with ESCMID endorsement). Eur J Nucl Med Mol Imaging. 2019;46(4):971–88. 8. Yuan J, Yan Y, Zhang J, Wang B, Feng J. Diagnostic accuracy of alpha-defensin in periprosthetic joint infection: a systematic review and meta-analysis. Int Orthop. 2017;41(12):2447–55. 9. Parvizi J, Tan TL, Goswami K, Higuera C, Della Valle C, Chen AF, Shohat N.  The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria. J Arthroplasty. 2018;33(5):1309–1314.e2. 10. Prandini N, Lazzeri E, Rossi B, Erba P, Parisella MG, Signore A. Nuclear medicine imaging of bone infections. Nucl Med Commun. 2006;27:633–44. 11. Roca M, de Vries EF, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with (111)in-oxine. Inflammation/infection taskgroup of the European association of nuclear medicine. Eur J Nucl Med Mol Imaging. 2010;37(4):835–41. 12. de Vries EF, Roca M, Jamar F, Israel O, Signore A.  Guidelines for the labelling of leucocytes with (99m)Tc-HMPAO. Inflammation/infection taskgroup of the European association of nuclear medicine. Eur J Nucl Med Mol Imaging. 2010;37(4):842–8. 13. Erba PA, Glaudemans AW, Veltman NC, Sollini M, Pacilio M, Galli F, Dierckx RA, Signore A. Image acquisition and interpretation criteria for 99mTc-HMPAO-labelled white blood cell scintigraphy: results of a multicentre study. Eur J Nucl Med Mol Imaging. 2014;41(4):615–23. 14. Signore A, Jamar F, Israel O, Buscombe J, Martin-Comin J, Lazzeri E. Clinical indications, image acquisition and data interpretation for white blood cells and anti-granulocyte monoclonal antibody scintigraphy: an EANM procedural guideline. Eur J Nucl Med Mol Imaging. 2018;45(10):1816–31. 15. Glaudemans AW, de Vries EF, Vermeulen LE, Slart RH, Dierckx RA, Signore A. A large retrospective single-centre study to define the best image acquisition protocols and interpretation criteria for white blood cell scintigraphy with99mTc-HMPAO-labelled leucocytes in musculoskeletal infections. Eur J Nucl Med Mol Imaging. 2013;40(11):1760–9. 16. Sousa R, Massada M, Pereira A, Fontes F, Amorim I, Oliveira A. Diagnostic accuracy of combined 99mTc-sulesomab and 99mTcnanocolloid bone marrow imaging in detecting prosthetic joint infection. Nucl Med Commun. 2011;32(9):834–9. 17. Kim HO, Na SJ, Oh SJ, Jung BS, Lee SH, Chang JS, et al. Usefulness of adding SPECT/CT to 99mTc-hexamethylpropylene amine oxime (HMPAO)-labeled leukocyte imaging for diagnosing prosthetic joint infections. J Comput Assist Tomogr. 2014;38(2):313–9. 18. Palestro CJ, Roumanas P, Swyer AJ, Kim CK, Goldsmith SJ. Diagnosis of musculoskeletal infection using combined in-111 labeled leukocyte and Tc-99m SC marrow imaging. Clin Nucl Med. 1992;17(4):269–73. 19. Palestro CJ, Love C, Tronco GG, Tomas MB, Rini JN. Combined labeled leukocyte and technetium 99m sulfur colloid bone marrow imaging for diagnosing musculoskeletal infection. Radiographics. 2006;26(3):859–70.

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20. Gemmel F, Van den Wyngaert H, Love C, Welling MM, Gemmel P, Palestro CJ. Prosthetic joint infections: radionuclide state-of-the-art imaging. Eur J Nucl Med Mol Imaging. 2012;39(5):892–909. 21. Love C, Marwin SE, Tomas MB, Krauss ES, Tronco GG, Bhargava KK, Nichols KJ, Palestro CJ. Diagnosing infection in the failed joint replacement: a comparison of coincidence detection 18F-FDG and 111In-labeled leukocyte/99mTc-sulfur colloid marrow imaging. J Nucl Med. 2004;45(11):1864–71. 22. Simonsen L, Buhl A, Oersnes T, Duus B.  White blood cell scintigraphy for differentiation of infection and aseptic loosening: a retrospective study of 76 painful hip prostheses. Acta Orthop. 2007;78(5):640–7. 23. Mulamba L, Ferrant A, Leners N, de Nayer P, Rombouts JJ, Vincent A. Indium-111 leucocyte scanning in the evaluation of painful hip arthroplasty. Acta Orthop Scand. 1983;54(5):695–7. 24. Palestro CJ, Kim CK, Swyer AJ, Capozzi JD, Solomon RW, Goldsmith SJ. Total-hip arthroplasty: periprosthetic indium-111- labeled leukocyte activity and complementary technetium99msulfur colloid imaging in suspected infection. J Nucl Med. 1990;31(12):1950–5. 25. Thang SP, Tong AK, Lam WW, Ng DC.  SPECT/CT in musculoskeletal infections. Semin Musculoskelet Radiol. 2014;18(2):194–202. 26. Mariani G, Bruselli L, Kuwert T, Kim EE, Flotats A, Israel O, Dondi M, Watanabe N. A review on the clinical uses of SPECT/CT. Eur J Nucl Med Mol Imaging. 2010;37(10):1959–85. 27. Scharf S.  SPECT/CT imaging in general orthopedic practice. Semin Nucl Med. 2009;39(5):293–307. 28. Filippi L, Schillaci O. Usefulness of Tc-99m HMPAO-labeled leukocyte scintigraphy for bone and joint infections. J Nucl Med. 2006;47:1908–13. 29. van der Bruggen W, Bleeker-Rovers CP, Boerman OC, Gotthardt M, Oyen WJ.  PET and SPECT in osteomyelitis and prosthetic bone and joint infections: a systematic review. Semin Nucl Med. 2010;40:3–15. 30. Richter WS, Ivancevic V, Meller J, Lang O, Le Guludec D, Szilvazi I, et al. 99mTc-besilesomab (Scintimun) in peripheral osteomyelitis: comparison with 99mTc-labelled white blood cells. Eur J Nucl Med Mol Imaging. 2011;38(5):899–910. 31. Palestro CJ. Radionuclide imaging of osteomyelitis. Semin Nucl Med. 2015;45(1):32–46. 32. Pakos EE, Trikalinos TA, Fotopoulos AD, Ioannidis JP. Prosthesis infection: diagnosis after total joint arthroplasty with antigranulocyte scintigraphy with 99mTc-labeled monoclonal antibodies—a meta-analysis. Radiology. 2007;242(1):101–8. 33. Xing D, Ma X, Ma J, Wang J, Chen Y, Yang Y.  Use of antigranulocyte scintigraphy with 99mTc-labeled monoclonal antibodies for the diagnosis of periprosthetic infection in patients after total joint arthroplasty: a diagnostic meta-analysis. PLoS One. 2013;8(7):e69857. 34. Jamar F, Buscombe J, Chiti A, Christian PE, Delbeke D, Donohoe KJ, Israel O, Martin-Comin J, Signore A.  EANM/SNMMI guideline for 18F-FDG use in inflammation and infection. J Nucl Med. 2013;54(4):647–58. 35. Chacko TK, Zhuang H, Stevenson K, Moussavian B, Alavi A. The importance of the location of fluorodeoxyglucose uptake in periprosthetic infection in painful hip prostheses. Nucl Med Commun. 2002;23(9):851–5. 36. Reinartz P, Mumme T, Hermanns B, et  al. Radionuclide imaging of the painful hip arthroplasty: positron-emission tomography versus triple-phase bone scanning. J Bone Joint Surg Br. 2005;87:465–70. 37. Kwee TC, Kwee RM, Alavi A. FDG-PET for diagnosing prosthetic joint infection: systematic review and metaanalysis. Eur J Nucl Med Mol Imaging. 2008;35(11):2122–32. 38. Zhuang H, Duarte PS, Pourdehnad M, et al. The promising role of 18F-FDG PET in detecting infected lower limb prosthesis implants. J Nucl Med. 2001;42:44–8. 39. Basu S, Kwee TC, Saboury B, et  al. FDG PET for diagnosing infection in hip and knee prostheses: prospective study in 221 prostheses and subgroup comparison with combined 111In-labeled leukocyte/99mTc-sulfur colloid bone marrow imaging in 88 prostheses. Clin Nucl Med. 2014;39:609–15.

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40. Van Acker F, Nuyts J, Maes A, et al. FDG-PET, 99mtc-HMPAO white blood cell SPET and bone scintigraphy in the evaluation of painful total knee arthroplasties. Eur J Nucl Med. 2001;28:1496–504. 41. Pill SG, Parvizi J, Tang PH, Garino JP, Nelson C, Zhuang H, Alavi A. Comparison of fluorodeoxyglucose positron emission tomography and(111)indium-white blood cell imaging in the diagnosis of periprosthetic infectionof the hip. J Arthroplasty. 2006;21(6 Suppl 2):91–7. 42. Vanquickenborne B, Maes A, Nuyts J, Van Acker F, Stuyck J, Mulier M, Verbruggen A, Mortelmans L. The value of (18)FDG-PET for the detection of infected hip prosthesis. Eur J Nucl Med Mol Imaging. 2003;30(5):705–15. Epub 2003 Mar 4. 43. Glaudemans AW, Prandini N, DI Girolamo M, Argento G, Lauri C, Lazzeri E, Muto M, Sconfienza LM, Signore A. Hybrid imaging of musculoskeletal infections. Q J Nucl Med Mol Imaging. 2018;62(1):3–13. 44. OCEBM Levels of Evidence Working Group. The Oxford 2011 levels of evidence. Oxford center for evidence-based medicine. www.cebm.net/index.aspx?0=5653. Website; 2016. 45. Rini JN, Bhargava KK, Tronco GG, Singer C, Caprioli R, Marwin SE, et al. PET with FDGlabeled leukocytes versus scintigraphy with 111In-oxine-labeled leukocytes for detection of infection. Radiology. 2006;238(3):978–87. 46. Dumarey N, Egrise D, Blocklet D, Stallenberg B, Remmelink M, del Marmol V, et al. Imaging infection with 18F-FDG-labeled leukocyte PET/CT: initial experience in 21 patients. J Nucl Med. 2006;47:625–32. 47. Aksoy SY, Asa S, Ozhan M, Ocak M, Sager MS, Erkan ME, Halac M, Kabasakal L, Sönmezoglu K, Kanmaz B. FDG and FDG-labelled leucocyte PET/CT in the imaging of prosthetic joint infection. Eur J Nucl Med Mol Imaging. 2014;41(3):556–64.

Nuclear Medicine Imaging of Vascular Graft Infections

10

Chiara Lauri, Maurizio Taurino, and Alberto Signore

10.1

Introduction

Prosthetic graft replacement is nowadays a common practice for the treatment of aneurysms and vascular occlusive diseases. Although the complication rates of this procedure are low, the development of vascular graft infection (VGI) is associated to high morbidity and mortality rates [1]. The incidence of VGI ranges between 1 and 6% mainly depending on the location of the graft (0.5–1% for abdominal grafts, 1.5–2% for aorto-femoral and 6% for infra-inguinal grafts) [2–6]. The clinical presentation is characterized by two different features. In many instances, symptoms are not specific like weakness, weight loss, malaise, fever or abdominal or lumbar pain. An increase of inflammatory markers (erythrocytes sedimentation rate, C-reactive protein, leucocytosis, pro-calcitonin) is frequently observed. In other cases, non-specific symptomatology is present with haematemesis, rectal blood loss, septic embolism, graft thrombosis up to haemorrhagic shock [7]. The final diagnosis of VGI is confirmed by the microbiological cultures (Staphylococcus aureus 20–53%, Enterobacteriaceae 14–41%, Pseudomonas aeruginosa, Streptococcus, Enterococcus 10–15%). However, such definition is not possible in all the cases. So, during the course of the disease and the follow-up it is useful to keep under control several inflammatory markers. The prognosis is poor. After conservative treatment, cases of survival are anecdotal. Following surgical repair, by means of various techniques, early

C. Lauri (*) · A. Signore Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, “Sapienza” University of Rome, Rome, Italy e-mail: [email protected] M. Taurino Vascular Surgery Unit, Department of Clinical and Molecular Medicine, “Sapienza” University of Rome, Rome, Italy © Springer Nature Switzerland AG 2020 A. Signore, A. W. J. M. Glaudemans (eds.), Nuclear Medicine in Infectious Diseases, https://doi.org/10.1007/978-3-030-25494-0_10

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mortality is reported ranging from 7 to 38%, with amputation rate 10% and recurrence of infection up to 27% [8, 9]. Therefore, a correct and prompt identification of VGI is mandatory in order to ensure the best management for these kinds of patients.

10.2

The Clinical Questions

The main clinical question is to understand if the graft is infected or not because it really changes the therapeutic management of the patients but, unfortunately, despite several attempts of standardization were made [10] at present a unanimous consensus on which is the best diagnostic strategy able to answer to this clinical question still not exists so far. Early identification of site and extent of infection is not only challenging but also crucial for adequate treatment and prognostication of the patient. As always, a correct management of the patients derives from the collaboration between different specialists, in particular vascular surgeons, radiologists, nuclear medicine (NM) physicians and experts in infective diseases and from the combination of clinical, biochemical, microbiological findings and imaging modalities. Among them, computed tomography (CT), especially with contrast enhancement (CE), and magnetic resonance imaging (MRI), and in particular angio-MRI, provide a high-quality visualization of structural abnormalities associated to the infection; however, some typical anatomic alterations can appear in late stages of the disease, thus causing the progression of the infection. Moreover, these modalities are not able to differentiate an infection from a sterile inflammation, that is crucial aspect for therapy decision-making. Nuclear medicine imaging is commonly adopted as a powerful tool in the management of such infection, especially in the early phase, when the CT scan (still considered in clinical vascular surgery setting the “gold standard”) could be insufficient [11]. Functional imaging provided by NM modalities offers a wide armamentarium of radiopharmaceuticals, suitable for both gamma-camera and PET imaging, that are both sensitive and specific for detecting infections (Table 10.1).

10.3

Gamma-Camera Imaging

Different radiopharmaceuticals suitable for gamma-camera imaging are available for imaging of VGI with high diagnostic accuracy allowing detection of infection before the appearance of radiological signs detectable with radiological modalities.

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Table 10.1 Gamma-camera and PET/CT imaging of vascular graft infections Gammacamera imaging 99m Tc-WBC

99m Tc antigranulocyte monoclonal antibodies

PET/CT imaging 18 F-FDG

18

F-FDGWBC

Why Detection of granulocytes in infected grafts

When Not during antibiotic treatment

Detection of granulocytes in infected grafts

Not during antibiotic treatment

How Acquire dynamic images from injection to time 5′, then static AP and oblique images at 30′ and 90′ p.i. Imaging at 20 h could be useful in equivocal cases. SPECT/CT mandatory at 3 h Acquire static AP and oblique images at 30′ and 90′ p.i. Imaging at 20 h could be useful in equivocal cases. SPECT/CT mandatory at 3 h

Why Detection of inflammatory process associated to infected grafts

When Not before 1–3 months from surgery

How Acquire images at 1 h p.i.

Detection of granulocytes in infected grafts

In case of doubtful FDG-PET or 99m Tc-WBC scan

Acquire images at 1 h and 3 h p.i.

Pitfalls Bowel and spine activity could interfere with evaluation of abdominal grafts

Non-specific accumulation; Induction of HAMA (for the entire antibody)

Pitfalls It does not discriminate between infection and sterile inflammation Damaged cells may not migrate correctly to an infection site

Interpretation criteria If uptake increases with time, it is a sign of infection; SPECT/CT helps in identifying the region of WBC accumulation

If uptake increases with time, it is a sign of infection; SPECT/CT helps in identifying the region of WBC accumulation

Interpretation criteria Focal and intense uptake in the graft wall is suggestive of infection Focal and intense uptake in the graft wall is suggestive of infection

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In the following paragraphs, we will explore the role of different modalities in this specific clinical setting examining their pros and cons.

10.3.1

67

Gallium-Citrate

67

Gallium-citrate has been used in past for the evaluation of VGI and for the assessment of infection in general; however, the poor spatial resolution, the lack of anatomic landmarks and its high uptake in abdominal organs such as liver, colon and kidneys represent limiting factors to its application especially for the evaluation of abdominal or pelvic grafts [12], so this imaging modality was abandoned soon. The use of SPECT/CT could however overcome the limitations of planar images providing a better spatial resolution and a more precise localization [12].

10.3.2 Anti-granulocyte Scintigraphy Anti-granulocyte antibodies and radiolabelled immunoglobulins (HIG) have been proposed and used for imaging VGI in few series with a reported sensitivity of 92–100% and a specificity ranging from 62.5 to 100% [12–17]. The main advantage of the use of a murine anti-granulocyte antibody is related to the easier labelling procedure that is performed in  vivo and not in  vitro; however, the possibility to induce human anti-murine antibodies (HAMA) after the administration of these molecules represents a limiting factor for their use in follow-up. Moreover, data available in literature on the use of anti-granulocyte antibodies and radiolabelled HIG in the assessment of VGI are based only on small series without standardized protocols of acquisition and interpretation, so definitive conclusions and the superiority of these modalities over autologous leucocytes cannot be completely assessed.

10.3.3 Radiolabelled White Blood Cells Radiolabelled white blood cells (WBCs) scintigraphy is nowadays the NM gold standard imaging modality for the diagnosis of infections since the protocols for labelling of leucocytes, acquisition and images interpretation are well defined and standardized in several guidelines [18–21]. Granulocytes can be easily radiolabelled with both 111In and 99mTc. The first isotope has an excellent biodistribution and high target specificity; however, its physical characteristics and high radiation doses make it less suitable for single-photon emission computed tomography (SPECT), so the preferred agent is 99mTc. The advantages of 99mTc compared to 111In are related to the better physical characteristic, better image quality and lower radiation burden; however, the physiological bowel visualization could interfere with the evaluation of abdominal graft. In literature, a lot of differences regarding acquisition protocols exist among the studies, thus giving very discordant results. Moreover, given the relatively

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low incidence of this problem, the studies are mainly performed on small populations that could be misleading. Nevertheless, if we examine the few existing meta-analysis and reviews [2, 22] we can conclude that radiolabelled WBC scintigraphy is a reliable tool for the assessment of VGI. In a large meta-analysis conducted by Annovazzi et al. in 2005 [2] performed on 32 original papers and 5 reviews published between 1980 and 2003, the authors found higher diagnostic performance of 99mTc-WBC scan compared with 111In-WBC scan and CT in terms of sensitivity (97.7% vs 84.1% vs 75%), specificity (88.6% vs 79.4% vs 56.6%), diagnostic accuracy (94.6% vs 81.5% vs 78.6), positive predictive value (PPV) (90% vs 85% vs 100%) and negative predictive value (NPV) (100% vs 93.8% vs 82%). The analysis of literature performed by Khaja et al. in 2013 confirms that 99mTc-WBC has higher sensitivity, specificity and diagnostic accuracy than 111In-WBC (83.7%, 97.5% and 83.5% vs 83%, 87% and 81%, respectively) [22]. As concerns the acquisition protocols we have already underlined the importance of performing this examination following the standardized criteria proposed by EANM but, unfortunately, at this moment only these suggestions were applied only in one paper [23]. Erba et al. acquired a dynamic scan in the first 5 min (for the imaging of vascular tree and of the eventual presence of an aneurysm), early images (30 min to 1 h post injection) that reflect vascular distribution, and delayed images (2–4 h post injection) with SPECT/CT that generally detect and localize the site of infection. In the assessment of VGI, late images (24 h post injection) do not seem mandatory but they can be useful in the inconclusive cases for the better visualization of the infective process [23] (Fig.  10.1). Considering the physiologic bowel uptake showed by 99mTc-WBC that could interfere with the evaluation of abdominal grafts, it is fundamental to acquire also lateral and oblique projections but it could be more important to appeal SPECT/CT for a precise and correct localization of the uptake (Fig. 10.2). In the series of 55 patients with suspected late and low-grade VGI studied in 2014 by Erba et  al. with 99mTc-WBC scan, SPECT/CT showed a

Fig. 10.1 Antero-posterior images acquired 30′, 2 h and 20 h p.i. with times corrected for 99mTc decay in a patient with a suspicious of abdominal graft infection. Delayed images revealed mild accumulation of autologous leucocytes in abdomen (yellow arrow). In this case, late images were useful to visualize the increasing of uptake over time allowing the diagnosis of infection. The correct site of WBC accumulation was then confirmed by SPECT/CT that is mandatory for the correct localization of uptake and differential diagnosis between an infection and a bowel transit of radioactivity

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Fig. 10.2 Antero-posterior images acquired 30′, 1 h, 3 h and 20 h p.i. with times corrected for 99m Tc decay in a patient with a suspicious of abdominal graft infection. This series of images clearly show that early accumulation of radiolabelled WBC occurs within the first 3 h after administration i.v. into the infected graft and late images (20 h) are often masked by intestinal activity. The different kinetic pattern of labelled cells in infected vascular grafts from osteomyelitis may be due to slower migration of leucocytes in soft tissues and bones as compared to a vascular compartment in which they circulate

specificity and sensitivity of 100%, far superior to planar images, SPECT and ultrasounds, allowing the reduction of false positive results in 37% of patients [23]. The value of SPECT/CT, with both 111In-WBC and 67Gallium-citrate, was also explored in the study of Bar-Shalom and co-workers. In their population 111In-WBC SPECT/ CT improved diagnosis, localization and provided a better evaluation of extent of the disease in 67% of patients with suspected VGI [12]. The retrospective study performed in 2013 by Khaja and colleagues on 20 patients with suspected VGI comparing planar images of 111In-WBC, CT and SPECT/CT, gave similar conclusions. The use of SPECT/CT resulted in improved sensitivity, diagnostic accuracy and negative predictive value compared to the individual modalities alone [22]. Possible false positives results at WBC scan may occur up to 3 months from open surgery, thus representing a possible limitation of this modality in the early postoperative period [24]; however, in 2006 Liberatore et  al. explored the utility of 99m Tc-WBC scintigraphy within the first month after implantation on endovascular prosthesis. They found no false positive results in this period and they concluded that 99mTc-WBC scintigraphy is reliable to assess an infection in the earlier stages after endovascular surgery [25] (Table 10.2).

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Table 10.2 Results of published meta-analysis with data from 1980 to 2012 111

In-WBCa 111 In-WBCb 99m Tc-WBCa 99m Tc-WBCb 18 F-FDG-PET/CTb 18 F-FDG-PET/CTc 18 F-FDG-PET/CTd

Cases 397 341 434 293 163 189 173

Studies (range) 1980–2003 1985–2007 1980–2003 1989–1998 2005–2010 2005–2012 2005–2010

Sensitivity 84.1% 83% 97.7% 83.7% 93.7% 88.9% 88.8%

Specificity 79.4% 87% 88.6% 97.5% 75% 64.6% 79.5%

Accuracy 81.5% 81% 94.6% 83.5% 81% 74.5% 84%

a

Annovazzi A, et al. Nucl Med Commun. 2005;26:657 Khaja MS, et al. Clin Imaging. 2013;37:239 c Jamar F, et al. J Nucl Med. 2013;54:647 d Saleem BR, et al. Biomed Res Int. 2014;47:1971 b

Data in literature are still limited to small series and a lot of discrepancies in techniques, modality of acquisition and interpretation of the images between the studies still exist making a direct comparison very difficult to perform. However, the role WBC scan is nowadays well established for imaging infection and inflammation in general and it seem to be reliable also in this specific scenario.

10.4

PET/CT Imaging

[18F]-FDG-PET/CT has also recently gained a consolidated role in imaging infections and inflammation, but it is unclear if this imaging modality offers any significant advantage over radiolabelled WBC in the study of VGI [26]. [18F]-FDG-PET/CT has of course several advantages over labelled WBCs mainly related to the presence of a CT co-registration that does not imply any change in patient’s position and allows a more precise localization of the uptake and higher target-to-background ratio (TBR). Moreover, it also must be considered that this modality does not require blood manipulation and it is shorter than radiolabelled WBC (2–3 h vs 20 h), thus resulting in more comfortableness for the patient. In recent years, the introduction of 18F-FDG-PET/CT proved to be a useful tool for the confirmation of VGI.  Its more extensive application and improvement in accuracy could favourably influence the therapeutic decision both in the early phase and during the follow-up, considering that, in a very recent experience, reached a sensitivity, specificity and accuracy of 100%, 50% and 78.3%. The combination with the very high specificity of contrast-enhanced CT scan could be a pillar in the diagnosis of VGI [27]. Despite a great sensitivity, it is well known that this modality is burdened by high rate of false positive cases, especially in post-surgical period, since it cannot allow distinguishing the physiologic sterile inflammation from a real infection. The presence of a synthetic material may induce a foreign-body reaction characterized by a low-grade inflammation, thus resulting in an increased [18F]-FDG uptake that can be present for a long time, even years, after surgery depending on

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the material. In particular within the first 6–8 weeks, the risk of a false positive finding is very high [28, 29]. Some authors attempted to define [18F]-FDG patterns in low-grade infections by using three-point scale of evaluation for a qualitative analysis (none, inhomogeneous, intense) and drawing region of interests (ROIs) on the graft and on blood background, as reference. They conclude that the focal uptake represents a valid diagnostic test with very high values of specificity (92.7%) and PPV (93.5%). The presence of mild inhomogeneous uptake represents a challenge because it could be justified by the presence of both low-grade infection and sterile inflammation around the foreign body. They also evaluated morphological parameters on CT slices in particular the characteristics of graft boundaries (irregular vs smooth) and the presence of pseudo-aneurysms [28]. For a morphological point of view, the presence of irregular boundaries seems to be an independent predictor of VGI; if these irregularities are not present, the probability of VGI is very low. Combining qualitative analysis of pattern of FDG distribution on the graft device with morphological assessment of borders, they found that the presence of smooth borders without focal uptake was associated to a low probability of an infection (less than 5%), whereas in presence of irregular boundaries and intense and focal uptake the probability of infection was more than 96%. In the subgroup of patients with inhomogeneous uptake the presence of irregular graft boundaries provided a specificity, sensitivity, PPV and NPV for predicting VGI of 85.7%, 72.7%, 88.9% and 66.7%, respectively. In this specific group of patients, the presence of irregularity increases the probability of an infection to 78%; on the contrary, the absence of irregularity lowers the probability to 28%. Therefore they suggest performing CT scan analysis since it could be very useful, especially in ambiguous cases and when inhomogeneous uptake is present. No other parameters, for example semi-quantitative analysis using standardized uptake value (SUV) analysis, the presence of pseudoaneurysms or fluid collections, added significant information in this study [28]. With a similar purpose of previous study, Keidar et al. in 2014 evaluated [18F]-FDG uptake in patients with non-infected graft aiming to assess the incidence, the pattern and the changes over time and to analyse the relationship between [18F]-FDG avidity and graft materials [30]. [18F]-FDG uptake was recorded in 92% of non-infected graft underlying the lack of specificity of this radiopharmaceutical. Dacron showed higher uptake than Gore-Tex and native vein. Only native implanted vessels seem to show a reduced avidity of [18F]-FDG over time because the inflammation decreases with healing, whereas synthetic materials did not show any changes over time, thus reflecting a chronic foreign-body inflammation. Approximately two-third of patients with increased [18F]-FDG activity showed diffuse homogeneous uptake and it was more prevalent in Dacron material and no focal uptake was observed. Therefore, similarly to previous study, a diffuse [18F]-FDG uptake should be interpreted as noninfected, on the other hand, the presence of a focal uptake is associated with high probability of an infection [30] (Fig. 10.3). Some interpreting criteria have been also proposed for the diagnosis of VGI but they are not universally recognized. Some authors suggest four- or five-point

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Fig. 10.3 Sagittal, coronal and transaxial views of [18F]-FDG-PET/CT reveal a focal and nonhomogeneous uptake (SUVmax = 7.5) involving the abdominal graft and the surrounding tissue. The scan was suggestive for the presence of an infection

visual scale to diagnose VGI as follows: grade 0: FDG uptake similar to background; grade 1: FDG uptake similar to inactive muscles and fat (low FDG uptake); grade 2: FDG uptake higher than inactive muscles and fat (moderate FDG uptake); grade 3: FDG uptake less than physiologic uptake by bladder (strong FDG uptake); grade 4: FDG uptake comparable to the physiologic urinary uptake (very strong FDG uptake). Grades 3 and 4 are suggestive for the presence of an infection [31, 32]. Based on preliminary finding derived from the analysis of non-infected grafts, the real predictor of the presence of an infection seems to be represented by high intensity of uptake and the focal pattern [33]. The contribution of semi-quantitative measurements (SUV and T/B ratio) over the qualitative evaluation is still controversial. Some authors suggest a SUV >8 in the peri-graft area as cut-off value for distinguishing infected graft from noninfected (SUVmax average 5). The use of this cut-off was associated with 100% of specificity and 80% of sensitivity [29, 31]. T/B ratio is maybe more reproducible among the centres and some authors proposed cut-off of 5.9 ± 2.7 for infections (vs 4.1 ± 2.1 in non-infected grafts) [31]; however, all these findings need to be further confirmed by larger studies and they need to be validated and standardized. At the moment SUV and TBR analysis seem to have a limited value for the assessment of VGI. In general from different meta-analysis aiming to evaluate the possible role of [18F]-FDG-PET/CT in the work-up of VGI, the sensitivity of this modality ranges between 88.8% [34] and 96% [22], the specificity ranges between 64.6% [26] and 75% [22] and the diagnostic accuracy is calculated approximately of 74.5% [26] or 84% [34] depending on the studies [35] (Fig. 10.3). Concluding, [18F]-FDG-PET/CT has high sensitivity and moderate specificity for the detection of VGI but at present moment standardized interpretative criteria remain to be defined and the clinical usefulness of this modality should be validated through further large multicentre studies.

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Role of Hybrid Imaging

The possibility to appeal to functional imaging allows a praecox diagnosis of infection even before the appearance of morphological signs detectable with radiological methodologies; however, functional images are limited by the lack of anatomical landmarks that leads to the inability to define graft and peri-graft tissue. The relatively recent birth of hybrid imaging (SPECT/CT, PET/CT and PET/MRI) is revolutionizing the diagnostic panorama through the integration of morphological and functional information. These methods allow an accurate localization of suspected foci of uptake with a single imaging session and they can be very useful in the definition of difficult clinical scenarios for example in patients with multiple grafts. As we have already mentioned, the added value of SPECT/CT over planar images is undeniable, therefore the appeal to hybrid imaging should be mandatory in order to improve the accuracy of radiolabelled WBC.

10.6

Future Perspectives and New Trends

Recently, WBCs labelled with [18F]-FDG ([18F]-FDG WBCs) have been proposed as a radiopharmaceutical for imaging infections and inflammation. This modality combines the high specificity of radiolabelled WBCs with the advantages of PET imaging, thus resulting in a very advanced modality that could allow achieving an accurate diagnosis of infections overcoming the limitations of traditional labelling of WBCs. The feasibility of [18F]-FDG WBCs has been demonstrated in a preliminary study on 21 patients with different kind of infections providing high diagnostic performance for both per-patient and per-lesion basis [36], thus suggesting that this modality could be a diagnostic instrument for imaging infections but at the moment no data in literature are available supporting its usefulness in suspected VGI. In future new isotopes could be used for labelling WBC, such as 64Cu, allowing us to acquire images also at later time-points. Finally, PET/MRI will probably gain a role in this specific indication since this modality is emerging as a powerful diagnostic tool in other infective and inflammatory disease.

References 1. Swain TW III, Calligaro KD, Dougherty MD. Management of infected aortic prosthetic grafts. Vasc Endovascular Surg. 2004;38(1):75–82. 2. Annovazzi A, Bagni B, Burroni L, D’Alessandria C, Signore A. Nuclear medicine imaging of inflammatory/infective disorders of the abdomen. Nucl Med Commun. 2005;26(7):657–64. 3. Legout L, D’Elia PV, Sarraz-Bournet B, Haulon S, Meybeck A, Senneville E, Leroy O.  Diagnosis and management of prosthetic vascular graft infections. Med Mal Infect. 2012;42(3):102–9. 4. Seeger JM.  Management of patients with prosthetic vascular graft infection. Am Surg. 2000;66(2):166–77.

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5. FitzGerald SF, Kelly C, Humphreys H.  Diagnosis and treatment of prosthetic aortic graft infections: confusion and inconsistency in the absence of evidence or consensus. J Antimicrob Chemother. 2005;56(6):996–9. 6. Antonios VS, Noel AA, Steckelberg JM, et al. Prosthetic vascular graft infection: a risk factor analysis using a case-control study. J Infect. 2006;53(1):49–55. 7. Reilly LM, Stoney RJ, Goldstone J, Ehrenfeld WK.  Improved management of aortic graft infection: the influence of operation sequence and staging. J Vasc Surg. 1987;5(3):421–31. 8. Clagett GP, Valentine RJ, Hagino RT. Autogenous aortoiliac/femoral reconstruction from superficial femoral–popliteal veins: feasibility and durability. J. Vasc. Surg. 1997;25(2):255–70. 9. O’Hara PJ, Hertzer NR, Beven EG, Krajewski LP. Surgical management of infected abdominal aortic grafts: review of a 25-year experience. J. Vasc. Surg. 1996;3(5):725–31. 10. Lyons OTA, Baguneid M, Barwick TD, Bell RE, Foster N, Homer-Vanniasinkam S, Hopkins S, Hussain A, Katsanos K, Modarai B, Sandoe JAT, Thomas S, Price NM. Diagnosis of aortic graft infection: a case definition by the Management of Aortic Graft Infection Collaboration (MAGIC). Eur J Vasc Endovasc Surg. 2016;52(6):758–63. 11. Sood A, Bhattacharya A, Aggarwal P, Basher RK, Mittal BR. 18F-FDG-labeled autologous leukocyte PET-CT in a patient with aortic valve-tube graft infection after Bentall procedure. Clin Nucl Med. 2019;44(3):e161–2. 12. Bar-Shalom R, Yefremov N, Guralnik L, Keidar Z, Engel A, Nitecki S, Israel O. SPECT/CT using 67Ga and 111In-labeled leukocyte scintigraphy for diagnosis of infection. J Nucl Med. 2006;47(4):587–94. 13. Roll D, Hierholzer J, Cordes M, Hepp W, Langer M, Zwicker C, Felix R. Diagnostic evaluation of radioimmunoscintigraphy (RIS) using 123I-labeled monoclonal antibodies against human granulocytes (Mab-47) for the detection of prosthetic vascular graft infection. Int J Radiat Appl Instrum B Nucl Med Biol. 1991;18(1):135–40. 14. Cordes M, Hepp W, Langer R, Pannhorst J, Hierholzer J, Felix R. Vascular graft infection: detection by 123I-labeled antigranulocyte antibody (anti-NCA95) scintigraphy. Nucl Med. 1991;30:173–7. 15. Cordes M, Hepp W, Barzen G, Langer R.  Diagnostic evaluation of radioimmunoscintigraphy (RIS) with use of iodine 123-labeled antibodies against human granulocytes (123I-AntiNCA95) for the detection of prosthetic vascular graft infection. J Vasc Surg. 1991;14(5):703–4. 16. Venz S, Cordes M, Hepp W. (123I)-anti-NCA95 antibodies in diagnosis of bacterial wound infections after prosthetic vascular replacement. Comparison with computerized tomography. Vasa. 1994;23:138–44. 17. Tronco GG, Love C, Rini JN, Yu AK, Bhargava KK, Nichols KJ, Pugliese PV, Palestro CJ. Diagnosing prosthetic vascular graft infection with the antigranulocyte antibody 99mTcfanolesomab. Nucl Med Commun. 2007;28(4):297–300. 18. Roca M, de Vries EFJ, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with 111In-oxine. Eur J Nucl Med Mol Imaging. 2010;37(4):835–41. 19. de Vries EFJ, Roca M, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with 99mTc-HMPAO. Eur J Nucl Med Mol Imaging. 2010;37(4):842–8. 20. Erba PA, Glaudemans AWJM, Veltman NC, Sollini M, Pacilio M, Galli F, Dierckx RAJO, Signore A.  Image acquisition and interpretation criteria for 99mTc-HMPAO-labelled white blood cell scintigraphy: results of a multicentre study. Eur J Nucl Med Mol Imaging. 2014;41(4):615–23. 21. Signore A, Jamar F, Israel O, Buscombe J, Martin-Comin J, Lazzeri E. Clinical indications, image acquisition and data interpretation for white blood cells and anti-granulocyte monoclonal antibody scintigraphy: an EANM procedural guideline. Eur J Nucl Med Mol Imaging. 2018;45(10):1816–31. 22. Khaja MS, Sildiroglu O, Hagspiel K, Rehm PK, Cherry KJ, Turba UC. Prosthetic vascular graft infection imaging. Clin Imaging. 2013;37(2):239–44. 23. Erba PA, Leo G, Sollini M, Tascini C, Boni R, Berchiolli RN, Menichetti F, Ferrari M, Lazzeri E, Mariani G. Radiolabelled leucocyte scintigraphy versus conventional radiological imaging

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Nuclear Medicine Imaging of Diabetic Foot Infections

11

Chiara Lauri, Luigi Uccioli, and Alberto Signore

11.1

Introduction

Diabetic foot (DF) is a clinical entity characterized by hard-to-heal ulcers with a very high rate of relapses responsible for a very high risk of major amputation. DF involves patients with long-standing, often not well-controlled, diabetes complicated by peripheral and/or peripheral arterial diseases. These chronic complications are linked to several other comorbidities such as ischemic heart disease, heart failure and chronic kidney disease; therefore, DF is nowadays considered a syndrome more than a specific disorder, because patients with DF have a higher mortality rate than diabetic patients without DF. DF represents a major health burden worldwide, and considering the increasing life expectancy, the number of patients who develop such complications problems will grow further in the next years. Up to 15% of diabetic patients will develop foot ulcers and about 15–25% of these patients require amputation. Indeed diabetes is still the main cause of nontraumatic amputation, thus constituting a dramatic circumstance for the individuals and for social costs [1–3]. Foot ulcers represent the entryway of microorganism that initially colonize the soft tissues and then could spread to the deeper bone, thus causing osteomyelitis (OM) [4, 5].

C. Lauri (*) · A. Signore Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, “Sapienza” University of Rome, Rome, Italy e-mail: [email protected] L. Uccioli Diabetic Foot Unit, Department Systems Medicine, University of Rome Tor Vergata, Rome, Italy © Springer Nature Switzerland AG 2020 A. Signore, A. W. J. M. Glaudemans (eds.), Nuclear Medicine in Infectious Diseases, https://doi.org/10.1007/978-3-030-25494-0_11

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Fig. 11.1 Chronic Charcot with foot ulcer

Approximately more than 50% of DF wounds are infected at their presentation [6]. Therefore, prompt identification of infection is mandatory in order to avoid further complications such as amputation, bacteraemia/septicaemia and death [3]. In addition to this, 2.5% of diabetic patients develop Charcot osteoarthropaty, a progressive degenerative disease that usually interests tarsal and metatarsal joints causing deformities and loss of normal bony architecture [7] (Fig. 11.1). This condition and its management considerably differ from soft tissue infections (STI) and OM. A proper offloading and immobilization are generally the only

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treatment of Charcot foot, but in the presence of an infection, the therapeutic approach depends on its extent and whether it involves soft tissue or bone. Complicated DF could require a watchful waiting approach or re-vascularization and/or antibiotic therapy depending on the cases. In order to avoid amputation, a conservative surgery (debridement) may be necessary. To further complicate this scenario is the possibility that Charcot, OM and STI may coexist in the same patient, thus an accurate identification of the real nature of DF lesions is mandatory. The gold standard method for diagnosing an infection is the isolation of microorganisms on cultures deriving from bone biopsies and the presence of characteristic features on histopathological examination [6]. However biopsy is an invasive procedure that needs to be exactly targeted at the infected area and that could result in a contamination by microorganism present in soft tissue. More recently, the “probe-to-bone” test has emerged as a simple and effective tool for the diagnosis of OM. However, its sensitivity and specificity have never been systematically studied, only moderate reproducibility was found among clinicians with varying levels of experience [8], and the results have been highly dependent on the pretest probability of OM [9, 10]. Serum biomarkers of infections/inflammation, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), although always performed in the first steps, are completely non-specific, and they often fail to provide useful results. On the other hand, imaging offers a complementary and less invasive approach in the diagnosis of DF disorders, providing a wide panel of modalities that range from conventional plain X-ray to state-of-the-art techniques such as magnetic resonance imaging (MRI), 99mTc-HMPAO-labelled white blood cells (99mTcHMPAO-WBC) with single-photon emission computed tomography/computed tomography (SPECT/CT), 111In-oxine-labelled white blood cells (111In-oxineWBC) with SPECT/CT, [18F]Fluorodeoxyglucose positron emission tomography (FDG-PET)/CT or 99mTc-anti-granulocyte antibodies [11–17]. Radiological imaging techniques, and in particular CT and MRI, provide high-quality images, but the findings are often non-specific. Conversely, functional imaging provided by nuclear medicine (NM) modalities could overcome the lack of specificity of radiology especially with the appeal to hybrid imaging (SPECT/CT, PET/CT and PET/MRI). Nowadays, a wide panel of radiopharmaceuticals and different NM modalities are available to specifically image infection and inflammation (Table 11.1). As always the choice of the most appropriate advanced imaging modality should, of course, be based on the clinical presentation, the real indication and the analysis of previous examinations. Several other factors should also be considered, such as ongoing antibiotic therapy, presence of neuropathic joint, costs, availability of the modality, waiting time before imaging can take place, contraindications and even patient’s compliance.

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Table 11.1 Gamma-camera and PET imaging in diabetic foot Gammacamera imaging 99m Tc-HDP

Why Shows bone abnormalities

When In low probability cases, to exclude any bone defect

How Threephase acquisition preferred

Pitfalls High uptake in bone metastases, fractures, Charcot, Paget disease

99m

Detection of granulocytes in soft tissues and bone

Limited use during antibiotic treatment

30–60 min, 2–3 h and 20–24 h p.i.

99m Tc antigranulocyte monoclonal antibodies

Detection of granulocytes in infected areas

Not during antibiotic treatment and not immediately after foot surgery due to false positivity because of acute oedema

4–6 h and 24 h p.i.

Possible false positives in patients with Charcot, requires combined 99m Tcnanocolloid scan Non-specific accumulation due to increased vascular permeability; induction of HAMA (for the entire antibody)

Tc WBC

PET/CT imaging Why 18 FDetection of FDG inflammatory process associated to infections

11.2

When Not immediately after foot surgery

How Acquire images at 1 h p.i.

Pitfalls It does not discriminate between infection and sterile inflammation in Charcot foot

Interpretation criteria When positive in all phases, indicates inflammation but not necessarily an infection If uptake increases with time, it is a sign of infection and if mismatch with colloids

If uptake increases with time, it is a sign of infection

Interpretation criteria The presence of any uptake in the suspected area is suggestive of an infection. CT will guide for the location

The Clinical Questions

Difficult healing chronic ulcers are the most characteristic lesions of DF; however, some evaluations need to be done before to define an ulcer as a chronic non-healing ulcer: Offloading has been applied? Peripheral arterial perfusion is adequate? Debridement has been performed? Infection is present? Therefore, one important question we should answer to when we approach to a patient with DF disorders is if there is an infection or not. But it is also of the same importance to understand if the infection involves the soft tissues or the bone

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because it radically changes the management of the patient. Nevertheless, diagnosing DF complications is still a challenge since it is not always easy to achieve a precise discrimination between OM, STI and Charcot. The main problems in diagnosing DF infections are: 1. OM can occur in the presence of both infected and non-infected ulcers. 2. Possible microorganisms that colonize open wounds could contaminate bone specimens or cultures 3. The presence of peripheral neuropathy and vascular impairment may mimic or even reduce inflammatory findings at both soft tissues and bone, thus resulting in their less usefulness. 4. Anatomic changes in bone may be nonspecific and may appear in later stages of infection, thus causing a delay in diagnosis. 5. Different conditions may coexist in the same patient, thus further complicating both diagnostic and therapeutic approach. In the following paragraphs, we explore which of the principal NM modalities are able to overcome these problems, leading to a most accurate diagnosis of DF infections.

11.3

Gamma-Camera Imaging

Several radiopharmaceuticals suitable for gamma-camera imaging are available for imaging of DF able to identify some pathophysiological changes even before the detection of anatomic alterations. In the last decades, several efforts have been made in order to develop more specific radiopharmaceuticals for imaging infections, and a lot of work is constantly done aiming to standardize the procedures of acquisition and interpretation of NM scans.

11.3.1 Three-Phase Bone Scan One of the first modalities used for imaging infections and inflammations of different musculoskeletal districts is three-phase bone scan. This modality has a very high sensitivity, which is over 90% in the majority of studies, but the reported specificity is approximately around 50% depending on the studies [18–20]. Indeed, the presence of hyperperfusion, hyperaemia and increased bone matrix apposition are commonly observed in OM [11] as well as in a lot of different conditions (e.g. in the presence of fractures or neuropathic joint), thus making this modality not suitable for a precise diagnosis of OM. Three-phase bone scan has a very high negative predictive value so, if the scan is negative, the diagnosis of OM can be ruled out; therefore, this exam can be useful in the first diagnostic steps in order to exclude the presence of OM. Conversely, in the presence of a positive scintigraphy, other NM modalities have to be performed in order to detect the infection.

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11.3.2 Radiolabelled WBCs The NM gold standard for imaging infection is represented by radiolabelled WBCs using both 111In and 99mTc. This is nowadays a well-consolidated modality that specifically targets activated granulocytes, mainly neutrophils representing a surrogate marker of bacterial infections [21]. Several guidelines exist regarding labelling procedures, acquisition protocols and interpretative criteria [22–26], thus making this procedure well standardized and relatively easy to realize; however, not all the centres are able to perform because it requires qualified personnel, adequate laboratories and is a time-consuming procedure for the labelling and for acquisition as three time point acquisition are necessary after the reinjection of autologous cells (30 min, 3 h and 24 h post injection) in order to trace the physiologic dynamic process of migration of granulocytes. Early images (30 min to 1 h post injection) give a map of bone marrow activity, whereas by comparing the extent and/or the uptake of delayed (3 h p.i.) and late images (20 h p.i.), we can differentiate between STI (the uptake decreases or is stable over time) and OM (the uptake increases over time). In a recent meta-analysis and systematic review based on studies comparing WBC, [18F]-FDG PET/CT and MRI for the detection of DF osteomyelitis (DFO), the pooled sensitivity and specificity of radiolabelled WBC were respectively 91% and 92% for 99mTc hexamethylpropylene amine oxine (HMPAO) and 92% and 75% for 111In-oxine [27]. In particular, 99mTc-HMPAO WBC scintigraphy, followed by [18F]-FDG PET/CT, revealed to have higher specificity than other imaging modalities in the diagnosis of DFO, whereas the sensitivity was approximately 90% for all three imaging modalities. In literature data regarding the use of radiolabelled WBC scintigraphy in DF are very discordant. The sensitivity and specificity of this modality range from 75% [28] to 100% [29–31] and from 67% [31] to 100% [32], respectively, depending on the studies. The variation in labelling procedure, the different acquisitions protocols, planar images vs SPECT/CT and interpretative criteria adopted in these studies could explain these discrepancies, thus complicating a direct comparison between the studies. In particular, several papers adopted only one-time point images after 2 h [33], 3 h [34–37] or 4 h [38, 39] or 24 h [31, 40–43] p.i. Others adopted outdated protocols of acquisition using fixed times or fixed counts that are very far from what recommended in guidelines of European Association of Nuclear Medicine (EANM) [23]. Two large studies attempted to define the best imaging protocols and interpretative criteria for radiolabelled 99mTc-HMPAO WBC scintigraphy in musculoskeletal infections [44, 45], concluding that by using at least two time points acquisition (after 3 and 24  h p.i.) with times corrected for isotope decay, this will results in higher diagnostic accuracy of this modality. Therefore it is reasonable that the specificity and diagnostic accuracy of this modality would increase if correct protocols of acquisitions and interpretations would be applied. In the specific field of DF, only few studies applied the correct methodology suggested by EANM reported very high values of sensitivity and specificity [46, 47]. In particular Familiari et al. acquired early, delayed and late images with times corrected for 99mTc decay and displaying the images by using the same intensity colour

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scale. They performed both qualitative and semi-quantitative analysis drawing regions of interest (ROIs) on the area of increased uptake, for the target (T), and in contralateral side for the background (B). A T/B ratio greater than 2.0 after 20 h p.i. showing an increase over time were considered as diagnostic criteria for OM; T/B ratio greater than 2.0 after 20 h p.i. with a decrease over time were considered as diagnostic criteria for STI. Using these criteria, they reported a sensitivity of 86%, a specificity of 100%, a positive predictive value (PPV) of 100%, a negative predictive value (NPV) of 86% and an accuracy of 92% [46]. These results lead to an important consideration: DFO cannot be approached as a normal OM because the peripheral vascular insufficiency that characterizes diabetic patients may be responsible of the fact that soft tissues show a decreased uptake over time exactly as aseptic flogosis does, whereas OM shows an increased uptake over time being the bone generally well vascularized. Nevertheless the only strategy to observe this phenomenon is by using the correct acquisitions protocols. Some authors investigated the role of SPECT/CT.  Filippi et  al. [47] performed sequential planar images (30 min, 4 h and 24 h) acquiring for 10 min (at 30 min and 4 h) and for 15 min (24 h). However, the interpretation of exam was based only in comparison with contralateral background activity, so not considering the increasing activity over time. SPECT and SPECT/CT were performed at 6 h. SPECT/CT substantially changed the interpretation of planar and SPECT images in 52.6% of suspected lesions, confirming the bone infection at one site, excluding the diagnosis of osteomyelitis in six cases and better defining the extent of disease to bone or soft tissue in three cases. They concluded that SPECT/CT is a useful diagnostic tool in order to assess the presence of osteomyelitis and to evaluate its extension. Przybylski et al. retrospectively evaluated the reliability of SPECT/CT in a small group of patients with diabetic foot ulcers. Planar and SPECT/CT images were acquired 3 h post 99mTc WBC injection and they found a sensitivity, specificity and diagnostic accuracy of 87.50%, 71.43% and 80%, respectively [34]. Heiba et al. [40] compared the diagnostic value of dual isotope SPECT/CT of 111In WBC+ bone scintigraphy with the results of SPECT/CT of 111In WBC and SPECT/CT of bone scan stand-alone. The SPECT/CT of the combined protocol was superior to the others diagnostic approach in discriminating OM and STI and in defining the extent of the process. The accuracy of radiolabelled WBC in differentiating OM from STI also depends on the district of the foot [12]. Despite for forefoot disorders the previous considerations may be applied for a correct discrimination between these two conditions, in mid- and hind foot disorders the presence of Charcot osteoarthropaty may also be considered. In this situation radiolabelled WBC uptake could be related not only to an infection, but also to a physiological bone marrow expansion secondary to chronic inflammation, thus resulting in a lower specificity [48–50] (Fig. 11.2). In order to overcome this limitation, it is suggested to perform a bone marrow scintigraphy using nanocolloids in addition to radiolabelled WBC scan. Indeed, both the radiopharmaceuticals accumulate in bone marrow, but only WBC accumulate in infective foci so if the images of these two modalities are congruent (match), the diagnosis of Charcot is the most probable, conversely, in case of mismatch (positive at WBC and negative at colloids), it is probably OM (Fig. 11.3).

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Fig. 11.2 Anteroposterior views of 99mTC-HMPAO WBC scan acquired after 30 min, 3 h and 20 h p.i. in a patient with Charcot osteoarthropathy. Images show early and persistent activity in the mid-hind foot without an increase over time, a sign of inflamed joint (Charcot) without infection

Fore foot

WBC + mAb + FDG +

Mid/hind-foot

WBC – mAb – FDG +/–

WBC/Nanocol +/– FDG +

WBC/Nanocol –/– FDG +/–

OM

STI

WBC/Nanocol +/+ FDG +

Charcot

Fig. 11.3 Diagnostic flowchart for the correct use of nuclear medicine techniques and radiopharmaceuticals in the diagnosis in diabetic foot infection. In case of suspected fore foot infection, WBC, mAb and FDG can differentiate between osteomyelitis and soft tissue infection mainly because of the use of hybrid imaging. In case of suspected mid-hind foot infection, FDG cannot differentiate between an osteomyelitis and a Charcot neuroarthropathy, while WBC, in conjunction with bone-marrow scintigraphy with nanocolloids, can allow the differential diagnosis between osteomyelitis, soft tissue infection or Charcot neuroarthropathy

Another possible application of radiolabelled WBC is in therapy monitoring. Despite this specific aspect has not being extensively studied in DF, preliminary findings support the usefulness of WBC scintigraphy in the evaluation of antibiotic treatment [51, 52]. However, we should clarify that the role of nuclear medicine (either with labelled WBC or with FDG) for determining to stop antibiotic therapy has not yet been established. Indeed, the end of treatment should be evaluated clinically and with

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laboratory tests. After stopping the therapy, and in the suspicion of a recurrence of the infection, a new scan can be performed. This flowchart emphasizes the sensitivity and specificity of our procedures and WBC scan in particular. In case of persistent positivity of serological tests after long antibiotic treatment, a change in therapy should be attempted before performing a new scan, thus limiting to perform scans under antibiotic therapy to very selected cases. This applies to all osteomyelitis and soft tissue or prosthetic joint infections and not only to the DF.

11.3.3 Anti-Granulocyte Scintigraphy The use of monoclonal antibodies (MoAbs) or antibodies fragments (Fab’) direct against specific antigens expressed by activated granulocytes has been proposed in order to overcome the problems of the in vivo labelling procedures of autologous leukocytes. Although their use could seem easier than compared with radiolabelled WBC, several limitations have to be taken into consideration. First of all the entire antibodies have a high molecular weight that constitutes a limiting factor for their diffusion into the infective focus. They also have long plasma half-life, and they present a reticulo-endothelial clearance that justifies the high uptake in liver and bone marrow. Moreover their accumulation into inflamed sites is non-specific, mainly depending on the increased vascular permeability. Furthermore MoAbs induce human murine antibodies (HAMA) in the host, thus limiting their use at only one time in life. With the use of Fab’ fragments, some of these limitations can be escaped, but the diagnostic accuracy is lower than MoAb. The role of MoAbs or Fab’ fragments has not been extensively investigated in DF, and data in literature are mainly based on small groups of patients. Some authors explored the use of 99mTc-besilesomab (Scintimun®) in 25 diabetic patients reporting a sensitivity, specificity and accuracy of 93%, 78% and 84%, respectively [53]. Others compared 99mTc-fanolesomab with 111In WBC scan, reporting similar diagnostic performance between these two imaging modalities [54]. Delcourt and colleagues compared combined Fab’ (sulesomab)/bone scan with 67Ga/bone scan in patients with suspected DFO founding higher diagnostic performance with the use of sulesomab (Leukoscan®) [55]. Other few studies available on this specific topic confirm that the use of MoAbs or their fragments could be a valid alternative to radiolabelled WBC, but at the moment, there are no standardized protocols for acquisition and interpretation, and the few data in literature are not sufficient to conclude that MoAbs or their fragments have to be preferred to radiolabelled WBC in the assessment of DF disorders.

11.4

PET Imaging

The role of [18F]-FDG PET in the field of infection and inflammation is now wellconsolidated as recognized in guidelines published in 2013 by EANM and Society of Nuclear Medicine and molecular Imaging (SNMMI) [24].

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[18F]-FDG offers several advantages over conventional scintigraphy: firstly it avoids the manipulation of potentially infected blood, secondly the acquisition time is considerably shorter than radiolabelled WBC and thirdly image quality resolution is better than planar scintigraphy. Moreover in the presence of CT co-registration, it is possible to have a precise definition of the anatomical landmarks. Nevertheless, FDG is a non-specific radiopharmaceutical because it accumulates in infections, inflammations, malignancies, reparative processes and in all the other conditions in which glucose is metabolized as a source of energy [56]. In a meta-analysis published in 2013 that compared [18F]-FDG PET and PET/CT in patients with DFO, the per patient-based analysis revealed a pooled sensitivity of 74% and a specificity of 91% [57]. Nevertheless this meta-analysis was conducted only on four studies [46, 58–60]. In another more recent meta-analysis including six studies on 254 patients, the sensitivity and specificity of [18F]-FDG PET/CT were 89% and 92%, respectively. The diagnostic performance of this modality really depends on the presence of CT co-registration, which evaluates the extension of infection into bone and soft tissues, thus improving the accuracy of the exam [60, 61]. In a large cohort of 110 diabetic patients with clinical suspicious of pedal OM, Nawaz et al. [58] compared [18F]-FDG-PET and MRI. Although 18F-FDG was less sensitive (81% vs 91%), it showed higher specificity (93% vs 78%) and diagnostic accuracy (90% vs 81%). Diagnosis of osteomyelitis was based on the visual assessment of 18F-FDG uptake on bony structures without any semi-quantitative analysis of standardized uptake value (SUV). Furthermore, no CT co-registration was performed in this study maybe influencing the relative low sensitivity compared to MRI. Basu et al. [62] explored the role of [18F]-FDG-PET in 63 patients with DF disorders performing a semi-quantitative analysis with SUV. The authors found higher SUVmax values in patients with OM compared with patients with Charcot and uncomplicated DF (2.9–6.2 vs. 0.7–2.4 vs. 0.2–0.7), thus concluding that SUV could be a good parameter for differentiating these conditions. Although other authors found greater values of SUVmax in OM compared with Charcot [59, 63], at present there are not sufficient evidences that this parameter could be reliable for differentiating the different features that compose DF as that also emerge from the paper of Familiari et  al. [46] in which the authors did not find any correlation between SUVmax values and STI or OM or Charcot. They also concluded that 99mTcWBC scintigraphy is superior to [18F]-FDG PET/CT in detecting OM in terms of sensitivity, specificity and diagnostic accuracy (86%, 100% and 92% vs. 43%, 67% and 54%, respectively). Charcot foot is a chronic complication involving the foot of patients with peripheral neuropathy, characterized by an inflammatory involvement of foot bones, joints and soft tissues. Clinically it is characterized by inflammatory signs that involve the foot and allow a diagnosis before the foot bone fractures that are characteristic of this condition. RM is gold standard for diagnosis and offloading for treatment, but duration of treatment has been driven, until now, by the clinical evaluation of foot, mainly the normalization of foot temperature in comparison with the contralateral. In a recent paper, [18F]-FDG PET has been utilized to follow the time courses of foot inflammation in Charcot foot patients, and it has been highlighted that signs of

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Fig. 11.4 Transversal, sagittal and coronal views of FDG-PET/CT showing a diffuse and mild uptake of FDG surrounding bone and joint destruction in the right foot in a patient with Charcot foot. There is some uptake of FDG in joints and bones that does not allow to discriminate between a pan-inflammatory reaction and an infection. FDG is not indicated in patients with Charcot foot unless to quantify the inflammatory burden [64]

inflammation of the foot are still present when the patient is considered clinically recovered. Inflammatory signs monitored by [18F]-FDG PET may last long time; therefore, it has been hypothesized that Charcot foot relapses could not be real relapses but part of the same initial inflammatory process that never disappeared but considered extinguished only by clinical signs (Fig.  11.4). Driven by [18F]-FDG PET, offloading should last longer than before and allow a definitive recovery without relapses [64]. At present well-defined interpretative criteria (qualitative analysis vs SUVmax evaluation) for differentiating infection, inflammation, STI, OM and Charcot do not exist yet thus representing a great limiting factor in the study of DF. The presence of CT of course helps in localizing the uptake in bone rather than in soft tissue, but it does not solve the problem of discriminating between an infection from an inflammation/ degeneration [65]. In the attempt to develop a more specific radiopharmaceutical for PET imaging, WBC have also been labelled with FDG but at present the few studies available in literature do not focus on DF. The short half-life of 18F, indeed, represents a major limiting factor since delayed and late images cannot be performed. Concerning the use of FDG in patients with hyperglycaemia, it has been reported that the level of glycaemia does not interfere with PET sensitivity, and therefore, FDG can be used in diabetic patients regardless the value of blood glycaemia [61, 66].

11.5

Role of Hybrid Imaging

One of the most important limitations of functional imaging (in particular planar and SPECT images but also PET stand-alone) is the lack of anatomic localization, which is a great problem especially in the evaluation of DF considering the small size of bony structures that could result in an overlap of the uptake between bone

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and soft tissue, thus leading to a wrong interpretation of the scan and to a wrong therapeutic strategy [12, 67]. Therefore, when possible, the appeal to hybrid images that combine functional and anatomic information should be mandatory in order to improve the diagnostic accuracy of NM modalities. In the previous paragraphs the added value of CT co-registration for SPECT and PET modalities has already been discussed, and different papers exploring different radiopharmaceuticals for both gamma-camera and PET imaging, although by using very different acquisition protocols, conclude that hybrid imaging, when available, offers an undeniable tool especially for the correct localization of the uptake and the accurate evaluation of the extent of infective process (Table 11.1).

11.6

Future Perspectives and New Trends

In the last decades, several efforts have been made in order to develop hybrid camera systems able to combine MRI and PET imaging. The PET/MRI is emerging as a powerful diagnostic tool for several indications in the field of infection and inflammation. At present no studies exploring the utility of PET/MRI in DF disorders are available, but, considering the high-quality resolution of the images especially for the evaluation of soft tissues, in future this modality will gain a role also in this specific indication, thus allowing a differentiation between OM, STI and Charcot. Moreover new PET radiopharmaceuticals and imaging modalities are being developed, for example 64Cu-labelled WBC and 68Ga citrate PET/CT that could be a promising tool in future. In the era of molecular imaging and personalized therapy, many efforts are converging towards the development of new radiopharmaceuticals that specifically target active molecules, physiopathological processes and pathogens that could also be applied in the evaluation of DF disorders, thus providing the opportunity to exactly characterize the infective process.

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tion criteria for white blood cell scintigraphy with (99)mTc-HMPAO-labelled leucocytes in musculoskeletal infections. Eur J Nucl Med Mol Imaging. 2013;40:1760–9. Erba PA, Glaudemans AW, Veltman NC, Sollini M, Pacilio M, Galli F, et al. Image acquisition and interpretation criteria for 99mTc-HMPAO-labelled white blood cell scintigraphy: results of a multicenter study. Eur J Nucl Med Mol Imaging. 2014;41:615–23. Familiari D, Glaudemans AW, Vitale V, Prosperi D, Bagni O, Lenza A, Cavallini M, Scopinaro F, Signore A. Can sequential 18F-FDG PET/CT replace WBC imaging in the diabetic foot? J Nucl Med. 2011;52(7):1012–9. Filippi L, Uccioli L, Giurato L, Schillaci O. Diabetic foot infection: usefulness of SPECT/CT for 99mTc-HMPAO-labeled leukocyte imaging. J Nucl Med. 2009;50:1042–6. Palestro CJ, Mehta HH, Patel M, et al. Marrow versus infection in the Charcot joint: indium-111 leukocyte and technetium-99m sulphur colloid scintigraphy. J Nucl Med. 1998;39(2): 346–50. Palestro CJ, Roumanas P, Swyer AJ, Kim CK, Goldsmith SJ. Diagnosis of musculoskeletal infection using combined in-111 labeled leukocyte and Tc-99m SC marrow imaging. Clin Nucl Med. 1992;17(4):269–73. Tomas MB, Patel M, Marwin SE, Palestro CJ.  The diabetic foot. Br J Radiol. 2000;73(868):443–50. Vouillarmet J, Morelec I, Thivolet C.  Assessing diabetic foot osteomyelitis remission with white blood cell SPECT/CT imaging. Diabet Med. 2014;31(9):1093–9. Lazaga F, Van Asten SA, Nichols A, et  al. Hybrid imaging with 99mTc-WBC SPECT/CT to monitor the effect of therapy in diabetic foot osteomyelitis. Int Wound J. 2016;13(6): 1158–60. Dominguez-Gadea L, Martin-Curto LM, de la Calle H, Crespo A.  Diabetic foot infections: scintigraphic evaluation with 99mTc labelled anti-granulocyte antibodies. Nucl Med Commun. 1993;14(3):212–8. Palestro CJ, Caprioli R, Love C, et  al. Rapid diagnosis of pedal osteomyelitis in diabetics with a technetium-99m-labeled monoclonal antigranulocyte antibody. J Foot Ankle Surg. 2003;42(1):2–8. Delcourt A, Huglo D, Prangere T, et  al. Comparison between Leukoscan (Sulesomab) and Gallium-67 for the diagnosis of osteomyelitis in the diabetic foot. Diabetes Metab. 2005;31(2):125–33. Basu S, Chryssikos T, Moghadam-Kia S, Zhuang H, Torigian DA, Alavi A. Positron emission tomography as a diagnostic tool in infection: present role and future possibilities. Semin Nucl Med. 2009;39:36–51. Treglia G, Sadeghi R, Annunziata S, Zakavi SR, Caldarella C, Muoio B, Bertagna F, Ceriani L, Giovanella L. Diagnostic performance of Fluorine-18-Fluorodeoxyglucose positron emission tomography for the diagnosis of osteomyelitis related to diabetic foot: a systematic review and a meta-analysis. Foot (Edinb). 2013;23(4):140–8. Nawaz A, Torigian DA, Siegelman ES, Basu S, Chryssikos T, Alavi A. Diagnostic performance of FDG-PET, MRI, and plain film radiography (PFR) for the diagnosis of osteomyelitis in the diabetic foot. Mol Imaging Biol. 2010;12(3):335–42. Kagna O, Srour S, Melamed E, Militianu D, Keidar Z.  FDG PET/CT imaging in the diagnosis of osteomyelitis in the diabetic foot. Eur J Nucl Med Mol Imaging. 2012;39(10): 1545–50. Schwegler B, Stumpe KD, Weishaupt D, Strobel K, Spinas GA, von Schulthess GK, et  al. Unsuspected osteomyelitis is frequent in persistent diabetic foot ulcer and better diagnosed by MRI than by 18F-FDG PET or 99mTc-MOAB. J Intern Med. 2008;263:99–106. Keidar Z, Militianu D, Melamed E, Bar-Shalom R, Israel O.  The diabetic foot: initial experience with 18F-FDG PET/CT.  J Nucl Med. 2005;46(3):444–9. PubMed PMID: 15750157. Basu S, Chryssikos T, Houseni M, Scot Malay D, Shah J, Zhuang H, Alavi A. Potential role of FDG PET in the setting of diabetic neuro-osteoarthropathy: can it differentiate uncomplicated

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P. A. Erba, M. Sollini, R. Zanca, A. Marciano, S. Vitali, F. Bartoli, and E. Lazzeri

12.1

Introduction

Cardiovascular infections have been recognized as significant causes of cardiac diseases for many decades. The spectra of microorganisms causing cardiovascular infections are very broad and include all classes of microbes. They can cause diseases involving various components of the native structure of the heart—pericardium, muscle, endocardium, valves, autonomic nerves and the vessels—as well as implanted devices such as valve prosthesis (all types of prosthetic valves, annuloplasty rings, intracardiac patches and shunts), cardiovascular implantable electronic devices (CIED), left ventricular assist device (LVAD) catheters and vascular graft. The severity of cardiovascular infection depends upon several factors such as the involved microorganism, the location and the type of the biomaterial, and the host defence status. In addition, the maturity of the biofilm, a community of adherent microorganisms embedded within a self-produced matrix of extracellular polymeric substances, developed on the device plays a key role [1]. A common characteristic of cardiovascular infections is that matrix-embedded bacterial communities tolerate efficiently antibiotics and host phagocytic defences.

P. A. Erba (*) Department of Translational Research and Advanced Technologies in Medicine, Regional Center of Nuclear Medicine, University of Pisa, Pisa, Italy Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands e-mail: [email protected] M. Sollini Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy R. Zanca · A. Marciano · S. Vitali · F. Bartoli · E. Lazzeri Department of Translational Research and Advanced Technologies in Medicine, Regional Center of Nuclear Medicine, University of Pisa, Pisa, Italy © Springer Nature Switzerland AG 2020 A. Signore, A. W. J. M. Glaudemans (eds.), Nuclear Medicine in Infectious Diseases, https://doi.org/10.1007/978-3-030-25494-0_12

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Therefore, the only opportunity to eradicate effectively the infection is often their surgical treatment, consisting of the removal of the infected device. The diagnosis of cardiovascular infections is hardly based on a single symptom, sign or diagnostic test. Rather, it requires a clinical suspicion, most commonly triggered by systemic illness in a patient with risk factors and a careful evaluation performed according to a specific diagnostic flowchart. The heterogeneity of clinical presentations requires a multidisciplinary discussion in addition to the application of the diagnostic criteria. Microbiology and imaging are currently the benchmarks for a prompt and accurate diagnosis. The standard practice for the microbiological diagnosis includes routine microbiological sampling consisting of culturing, identification, and antibiotic susceptibility tests that is used also for treatment guidance. Blood culture is the most important initial laboratory test. If antibiotic therapy has been administered prior to the collection of blood cultures, the rate of positive cultures declines [2]. In cases of suspected culture-negative infection, other microbiological testing approaches may be useful. Echocardiography is the first-line imaging modality that plays a key role in both the diagnosis and management of IE/CIED infections. However, multimodality imaging, including molecular imaging techniques are nowadays widely used to integrate the traditional diagnostic criteria and therefore fill in such uncertainty gap with information on the biochemical burden of these infections.

12.2

Cardiovascular Implantable Electronic Device (CIED) Infections

12.2.1 Background and Epidemiology Over the last decades, there has been a substantial increase in the number of CIED implantations as a result of expanded indications and ageing of the population. Infection represents one of the most serious complications of CIED therapy associated with significant mortality, morbidity and financial healthcare burden. It is difficult to give a precise rate of device infections because of divergent definitions and the retrospective nature of available data. In the Danish registry including 46,299 consecutive patients who underwent pacemaker implantation between 1982 and 2007, the incidence of infection was 4.82/1000 device-years after a primary implantation and 12.12/1000 device-years after replacement [3]. The incidence of CIED infection in the USA has been found increasing from 1.53% in 2004 to 2.41% in 2008 [4]. However, more recent data from the PADIT trial have shown infection rates of 0.9%, and even in high-risk patients enrolled in the WRAP-IT trial, the infection rate was lower than earlier data [5, 6]. CIED infections occur via two major mechanisms. Most commonly, leads and pulse generator are contaminated during implantation or subsequent manipulation. Alternatively, device erosion late after pocket manipulation also leads to infection. In both cases contamination and subsequent bacterial colonization result in pocket infection which can spread along the intravascular parts of the

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leads and progress to systemic infection. A less common mechanism is involvement of the system by a bloodstream infection. Multiple factors play a role in the pathogenesis of CIED infections. Identifying risk factors for device infection is important because it may allow for preventive measures, such as avoiding temporary pacing and delaying implantation in case of fever, although many factors may not be modifiable. Risk factors may be divided into patient-related, procedure-related and device-related factors. Device-related factors are those affecting bacterial adherence to the generator or lead surfaces. Adherence is better on irregular device surfaces. A more hydrophobic surface also facilitate adherence [7]. Therefore, out of the commonly used polymers, polyvinylchloride and silicone allow better adherence than polytetrafluoroethylene, while polyurethane allows less adherence than polyethylene. Metals also differ in their propensity for bacterial adherence—e.g. stainless steel adheres microbes better than titanium. A meta-analysis which pooled data from 60 studies (21 prospective and 39 retrospective) with a total of 206,176 patients [8] identified the following related risk factors for CIED infection: – Patients’ related factors: age, male sex, diabetes, renal failure/ESRD, COPD, anticoagulants, steroids, CVC, history of device infection and implant site trauma – Procedure related factors: lack of antibiotic prophylaxis, device replacement/ revision, reintervention, number of prior device-related procedures, temporary pacing, procedure duration, operator experience, lead dislodgement and postoperative haematoma – Device-related factors: ICD device, CRT, dual-chamber system, number of leads, abdominal pocket and epicardial leads. Similar observations were reported from device registry data matched with Medicare fee-for-service claims data [8] and from a National Inpatient Sample database with 85,203 device-related infections, increasing from 1.45% to 3.41% (P 12 h apart; or (b) All of 3 or a majority of ≥4 separate cultures of blood (first and last samples drawn ≥1 h apart); or (c) Single positive blood culture for Coxiella burnetii or phase I IgG antibody titre > 1:800 Imaging positive for D. Echocardiogram (including ICE) positive for: (a) CIED infection: CIED infections and/ (i) Clinical pocket/generator infection or IE (ii) Lead-vegetation (b) Valve IE (i) Vegetations (ii) Abscess, pseudoaneurysm, intracardiac fistula (iii) Valvular perforation or aneurysm (iv) New partial dehiscence of prosthetic valve E. [18F]FDG PET/CT (caution should be taken in case of recent implants) or radiolabeled WBC SPECT/CT detection of abnormal activity at pocket/generator site, along leads or at valve site F. Definite paravalvular leakage by cardiac CT Minor criteria (a) Predisposition such as predisposing heart condition (for example new onset tricuspid valve regurgitation) or injection drug use (b) Fever (temperature >38 °C) (c) Vascular phenomena (including those detected only by imaging): major arterial emboli, septic pulmonary embolisms, infectious (mycotic) aneurysm, intracranial haemorrhage, conjunctival haemorrhages, and Janeway’s lesions (d) Microbiological evidence: positive blood culture which does not meet a major criterion as noted above or serological evidence of active infection with organism consistent with IE or pocket culture or leads culture (extracted by non infected pocket) CIED cardiac implantable electronic device, ICE Intracardiac echocardiography, IE infective endocarditis a Based on merging of the modified Duke- and ESC 2015 Guidelines criteria

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12.2.4 Echocardiography Echocardiography should be the first diagnostic tool in the assessment of patients with CIED in order to identify lead vegetations and tricuspid valve involvement [21]. Transthoracic (TTE) and transesophageal echocardiography (TOE) are both recommended in case of suspected CIED infections. While TTE better defines pericardial effusion, ventricular dysfunction and pulmonary vascular pressure, TOE is superior for the detection and sizing of vegetations [25] and can visualize lead vegetations in the right atrium-superior vena cava area and in regions less well visualized by TTE. In the absence of typical vegetations of measurable size, both TTE and TOE may be false negative in cardiac device-related infective endocarditis (CDRIE). Intracardiac echocardiography (ICE) is effective and has a high sensitivity for the detection of vegetations in cardiac devices [26]. In patients with CIED infections treated with percutaneous lead extraction, a TTE before hospital discharge is recommended to detect retained segments of the pacemaker lead and to assess tricuspid valve function, right ventricular function and pulmonary hypertension. A TOE should be considered after percutaneous lead extraction in order to detect residual infected material and potential tricuspid valve complications. However, a normal echocardiography does not rule out CDRIE.

12.2.5 Radiolabelled Leucocyte Scintigraphy, Fluorine-18-Fludeoxyglucose Positron Emission Tomography-Computerized Tomography and Computerized Tomography Radiolabelled leucocyte (WBC) scintigraphy and fluorine-18-fludeoxyglucose ([18F]FDG) positron emission tomography-computerized tomography (PET/CT) scanning are complementary tools for the diagnosis of cardiac device-related infective endocarditis (CDRIE) and related complications in complex cases. [18F]FDG PET/CT and WBC imaging provide additional diagnostic values, particularly in the subset of possible CDRIE, and may distinguish between early-onset superficial surgical site infection and a true generator pocket infection or differentiate between superficial and deep pocket infection. Patients with a suspected infection but without [18F]FDG uptake have a favourable outcome under antibiotic therapy [27]. At PET/CT the diagnosis of local infections is quite straightforward, with pooled specificity and sensitivity of 93% (95% CI, 84%–98%) and 98% (95% CI, 88%–100%), respectively, and AUC of 0.98 at ROC analysis [28, 29]. Figure 12.1 shows an example of [18F]FDG PET/CT in a patient with CIED infection. The largest study with WBC scintigraphy including single-photon emission tomography-computerized tomography (SPECT/CT) reported a 94% sensitivity and a 100% specificity [30]. In case of lead-related infective endocarditis, [18F]FDG PET/CT and WBC are very specific when tracer uptake is visualized (only if applied late after implantation), although a negative result does not completely exclude the presence of small vegetations with low metabolic activity (limited sensitivity and negative predictive value). Therefore, the diagnostic

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a

b

c

Fig. 12.1 Example of a [18F]FDG PET/CT in a patient with CIED infection. Man, 75 years with an ICD for 8 years and fever for several weeks with increased CRP and ESR. Echocardiography was negative. Antimicrobial treatment was initiated. PET/CT images (Discovery 710 PET/CT, GE Healthcare) show increased uptake of [18F]FDG at the atrioventricular-ventricular portion of the lead (a, coronal, sagittal and transaxial superimposed PET/CT images from left to right) associated with pericardial involvement (b, transaxial images, from left to right CT, emission and superimposed PET/CT) and lung embolism (c, transaxial images, from left to right CT, emission and superimposed PET/CT)

accuracy for lead infections is lower with overall pooled sensitivity of 65% (95% CI, 53%–76%), specificity of 88% (95% CI, 77%–94%) and AUC of 0.861 [28, 31]. Figure 12.2 shows an example of WBC imaging in patients with CIED infection. [18F]FDG PET/CT has the ability of whole body evaluation of abnormal focal uptake of [18F]FDG in a single scan with very high sensitivity. This capability has proven particularly useful for the identification of unexpected embolic localizations and metastatic infections [32, 33], including mycotic aneurysms, spleen and lung embolisms and spondylodiscitis (but unable to detect brain emboli), thereby impacting on Duke score, the diagnostic certainty and therapeutic management. In addition, the identification of the infection entry by [18F]FDG PET/CT and WBC imaging is critical for the prevention of infective endocarditis relapse. The primary infectious site may be indicated by the common biotope of the bacteria strain (digestive, skin and catheter) [34]. Figure 12.3 shows an example of the identification of the portal of entry (POE) by [18F]FDG PET/CT in a patient with CIED infection. In a series of patients with suspected pulmonary embolism or CIED infections, the addition of contrast-enhanced CT to the standard [18F]FDG PET/CT protocol

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Fig. 12.2 Tecnetium-99 m–hexamethyl propylene amine oxime-labelled autologous white blood cell (99mTc-HMPAO-WBC) scintigraphy in a patient with localized pocket infection (left panel, fused single-photon emission computed tomography [SPECT]/CT sections, transaxial slices) and also the intravascular portion of the lead (right panel, fused single-photon emission computed tomography [SPECT]/CT sections, transaxial slices). Obvious focal accumulation of radiolabelled WBCs is evident

Fig. 12.3 Example of [18F]FDG PET/CT showing the POE in a patient with CIED infection: intense radiopharmaceutical uptake is present at the site of a sacral decubitus ulcer (from left to right transaxial CT, emission and superimposed images), representing the POE of the recurrent CIED infection

results in a high rate of patients reclassified from “possible” infective endocarditis to “definite” endocarditis, improving the overall diagnostic accuracy with or without the Duke score. Though not recommended on a routine basis, contrast-enhanced CT combined with PET may prove useful in selected patients. Apart from being a complement to radionuclide imaging study, cardiac CT can visualize the coronary arteries prior to any surgical procedure, thereby avoiding preoperative invasive coronary angiography, which carries a risk for vegetation embolization during catheter manipulation in the aortic root [35]. CT angiography may add important remote information on vascular complications including mycotic aneurysm, arterial emboli and septic pulmonary infarcts, which add to the diagnostic criteria and affect the overall treatment strategy.

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Clinical suspicion of CIED infection - use 2019 International CIED Infection Criteria

Positive blood culture Pocket clinically negative

Pocket clinically positive TTE + TEE Optional/Consider: 1. [18F]FDG PET/CT or WBC SPECT/CT (extent disease, portal of entry, other source) 2. ICE 3. Imaging for embolic events

Negative blood culture* Pocket clinically negative, but high suspicion

1.TTE + TEE 2.[18F]FDG PET/CT or WBC SPECT/CT (extent disease, Portal of Entry, other source) 3. ICE 4. Imaging for embolic events

Pocket clinically positive

TTE + TEE

Removal / Extraction + Antibiotic therapy

Assess 2019 International CIED Infection Criteria Superficial incisional infection

Definite CIED infection

Possible CIED infection

Rejected CIED infection

Refer patient to a center with CIED infection/extraction expertise

Conservative treatment

Removal/Extraction + Antibiotic therapy

Repeat blood culture/echo Consider other imaging methods Within 2 weeks

Look for alternative diagnosis

Fig. 12.4 Proposed diagnostic algorithm in CIED infections. (From Blomström-Lundqvist et al. [23])

A wider use of contrast-enhanced CT is limited by the deleterious impact of contrast agents on kidney function particularly as the patients are exposed to nephrotoxic antibiotics. An extensive description of the technical aspects and the interpretation criteria for multimodality imaging has recently been published [29]. Multidisciplinary team (the endocarditis team) evaluations of imaging results are recommended and have been shown to significantly reduce the 1-year mortality [36], from 18.5 to 8.2%. Figure 12.4 shows the proposed diagnostic flowchart for the use of imaging in patients with suspected CIED infection.

12.2.6 Left Ventricular Assist Device-Associated Infections Implantable left ventricular assist device (LVAD) represents a major medical development for end-stage heart failure in selected patients [37]. This treatment is currently used as a bridge-to-transplantation, a bridge-to-recovery or a destination therapy as the last resort in patients with neither perspectives of recovery nor heart transplant. Implantable LVAD intended for long-term use rely on a percutaneous driveline, to carry electric signals and energy from the controller and batteries to the implanted pump. As with any other implantable foreign device, it is subject to LVAD-related infections. The presence of a driveline piercing the skin places the patient at continual risk of infection that can affect the exit site, the subcutaneous tunnel, the abdominal pocket (if present) and the implanted pump and that can disseminate through bloodstream infection. The transition from pulsatile to continuous flow LVAD significantly improved the clinical outcome [38] and decreased the risk of infectious complications. Nonetheless, LVAD-related infections are still common with a prevalence that ranges from 23 to 58%, being associated

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with a high mortality rate (15–44%) [39]. The major sites of infection comprise the mediastinum drivelines and device surface, identified as LVAD endocarditis [40]. The major pathogens involved in these emerging foreign device-related infectious diseases, where the ‘big five’ are—as could be expected—Staphylococcus aureus, Enterobacteriaceae, Pseudomonas aeruginosa, coagulase-negative Staphylococci, and Corynebacterium spp [41]. The management of LVAD infections, due to the few data currently available in literature and the lack of specific guidelines, is poorly standardized and is mainly derived from the available recommendation of other CIED infections, prosthetic valves or vascular prosthesis, although their characteristics significantly differ. The only available specific recommendation to assist therapeutic decisions (i.e. the use of antimicrobial treatment and surgery) in this challenging context is based on observational studies and expert opinion [42].

12.2.6.1 Diagnostic Workup The use of CT as main diagnostic imaging in these patients relies on the possibility to detect the presence of oedema as primary sign of infection, a finding that is often unspecific. The usefulness of WBS SPECT/CT and [18F]FDG PET/CT in the diagnosis of LVAD-related infection has been shown in small patient groups under routine clinical conditions. Molecular imaging allows precise anatomic location and accurate extent of a suspected infection [39] with sensitivity of 100% and a specificity of 94% in case of [18F]FDG PET/CT [43]. The use of the metabolic volume has been recently reported to be associated with increased diagnostic accuracy as compared to the SUVmax in a series of 48 patients. In particular, the NPV and sensitivity increased up to >95% by using the metabolic volume compared to 87.5% when using SUVmax [44].

12.3

Infective Endocarditis

12.3.1 Background and Epidemiology Infective endocarditis (IE) is a complex and deadly disease, which associates cardiac-located infection and multi-organ complications. Mortality rate of IE is approximately 10% at initial admission which might rise up to 20% in the first year [45–49]. Globally, in 2010, 1.58 million disability-adjusted life-years or years of healthy life lost as a result of death and nonfatal illness or impairment were associated with IE [50]. Therefore, prompt identification of patients at high risk of poor outcome is necessary and urgent in order to make accurate clinical decisions for improving patient prognosis. Although the overall disease incidence has remained stable ranging annually from 3 to 7 per 100,000 person-years in the most contemporary population surveys [51–58], during the last years the epidemiology of IE has become more complex and the epidemiological profile has changed substantially. Currently characteristics of IE patients have shifted towards an increased mean patient age, a higher proportion of prosthetic valves and other cardiac devices, and a decreasing proportion of rheumatic heart disease. At present, 25%–50% of the

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cases occur in patients older than 60 years [59], an age-related pattern that implies several diagnostic and therapeutic challenges: the usual patient population affected by IE is sicker and older, often with many comorbid conditions. The development of IE requires the simultaneous occurrence of several independent factors: alteration of the cardiac valve surface, bacteraemia and creation of the infected mass or ‘vegetation’. The alteration of the cardiac valve surface as a consequence of specific disease (such as rheumatic carditis), mechanical injury by catheters or electrodes or injury arising from repeated injections of solid particles in drug abusers facilitates bacterial attachment and colonization. Bacteraemia (the minimum magnitude of bacteraemia is still unknown) with an organism capable of attaching to and colonizing valve tissue lead to the creation of the infected mass or ‘vegetation’ by ‘burying’ of the proliferating organism within a protective matrix of serum molecules (e.g. fibrin) and platelets. In prosthetic valve endocarditis (PVE) and IE related to CIEDs, biofilm formation contributes directly to the evolution of device-associated vegetation propagation. In case of native valve endocarditis (NVE), the role of biofilm has not been yet established. As a systemic disease, IE results in characteristic pathological changes in multiple target organs [60]. Portions of the platelet–fibrin matrix of the vegetation may dislodge from the infected heart valve and travel with arterial blood until lodging in a vascular bed downstream from the heart. IE may present clinically as an acute, rapidly progressive infection or as a subacute or chronic disease with low-grade fever and non-specific symptoms which may thwart or confound initial assessment [61]. Therefore, patients may be referred to a variety of specialists who may consider a range of alternative diagnoses.

12.3.2 Microbiology Significant changes in the sustained microorganism has been demonstrated in IE with an increased incidence of Staphylococcus aureus sustained IE, underlying the increasing importance of the proportion of health care-associated infections. In PVE, staphylococcal and fungal infections are more frequent and streptococcal infection less frequent than in NVE. Staphylococci, fungi and Gram-negative bacilli are the main causes of early PVE, while the microbiology of late PVE mirrors that of NVE, with staphylococci, oral streptococci, S. bovis and enterococci being the most frequent organisms, more likely due to community-acquired infections. Staphyloccoci and Enteroccoci are the most common agents in prosthetic valve implantation endocarditis [62, 63]. The clinical history of IE is highly variable according to the causative microorganism, the presence or absence of pre-existing cardiac disease, the presence or absence of prosthetic valves or cardiac devices and the presentation.

12.3.3 Diagnosis Diagnosis of IE remains challenging and includes identification of the infective pathogen, detection of cardiac lesions and non-cardiac localizations of the disease.

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Evidence of valve or intracardiac material involvement is a major diagnosis criterion, with echocardiography as the first-line imaging method. However, it is well known that echocardiography has several limitations and other imaging modalities (computed tomography, magnetic resonance imaging and nuclear imaging) have progressively shown to be useful to demonstrate/depict both valve involvement and the presence of IE-related peripheral complications (metastatic infection and infectious embolism) as well as occult predisposing lesions that may be the source of infection. Pure anatomical imaging modality (multislice CT) or hybrid modalities such as PET/CT and SPECT/CT) have shown to be particularly useful in the presence of prosthetic material (valve prostheses or other intracardiac materials). Therefore, in the latest update of the European Society of Cardiology (ESC) Guideline for the management of IE, multimodality imaging has been integrated in the diagnostic algorithm of IE [21]. Along with blood cultures and echocardiography, which remains the first imaging test that plays a central role in both the diagnosis and the subsequent clinical management of patients with IE [21], other multimodality imaging techniques were introduced. Cardiac/whole body CT scan, cerebral MRI, [18F]FDG PET/CT and radiolabelled WBC SPECT/CT are positioned central of the diagnostic workup since they have been demonstrated to contribute to reach an early and accurate diagnosis [17]. The value of cardiac CT has also been underlined in the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines [64].

12.3.4 Echocardiography In the “Duke criteria” proposed by Durack et al. in 1994 [65] and modified by Li et al. in 2001 [66], the major criteria evidenced by echocardiography are vegetation, abscess and new dehiscence of prosthetic valve. The 2015 ESC Guidelines added the presence of perivalvular complications, i.e. pseudoaneurysm, intracardiac fistula and valve perforation or aneurysm, as new major echocardiographic criteria, since the presence of such lesion in the context of suspected IE is highly suggestive [21]. Both echocardiographic modalities, TTE and TEE, are used in clinical practice. During the last 20 years, TTE has been recognized as the first step of the imaging assessment in any patient with suspected IE [67]. This modality is useful to detect vegetation and assess the extent of valve damage but is limited by a relatively low sensitivity in several situations [68], such as prosthetic valve IE (sensitivity to detect vegetation of 68% in NVE vs. 27% in PVE, respectively) [69], in small vs. large vegetation (sensitivity of 25%, 70% and 100%, respectively, for vegetation length 11 mm) [70] and in presence of perivalvular abscess (sensitivity is low (28%), especially for the diagnosis of mitral vs. aortic abscesses (9% vs. 42%, respectively) [71]. In case of right-sided IE, TTE is accurate for the diagnosis of tricuspid valve lesion [72] but is clearly inferior to TEE in case of pulmonary valve location and CDRIE [73, 74]. Although TEE allows in the majority of cases a better evaluation than TTE [70], TTE remains the easiest accessible imaging technique for a rapid first screening of

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cardiac structure, excellent to rule out IE in patients with good ultrasound quality, normal valve anatomy and no valve disease or implantable intracardiac material [75]. TTE plays a key role to assess initially and monitor the hemodynamic consequences of the valve damage and is the preferred method after hospital discharge [21]. TEE must be performed in nearly all patients with suspected IE and systematically in patients with intracardiac implantable material (i.e. prosthetic valve, CIED) [21, 76, 77]. The sensitivity is higher to detect vegetations (40–63% and 90–100%, respectively, for TTE and TEE) [73], abscesses (sensitivity 87% and specificity 95%) [71], and overall perivalvular complications [78]. However in some patients, despite a high index of suspicion, both TTE and TEE initial examinations may be negative, especially when performed early in the infective process [79]. In this circumstance, TTE/TEE should be repeated within 1  week in case of high clinical probability of IE. Conversely, false diagnosis of IE may occur in other situations. For example, it may be difficult to differentiate in native valves between vegetations and thrombi, cusp prolapse, cardiac tumours, myxomatous changes, Lambl’s excrescences, strands or non-infective vegetations (marantic endocarditis). Similarly in prosthetic valves, differentiation between vegetation and pannus, valve thrombosis, or leaflet degeneration may be difficult in TTE [68, 80]. Echocardiography also plays a key role in both the short-term and the long-term prognostic assessments [81], for the decision to operate and for the choice of the optimal timing of surgery [82]. Several echocardiographic features have been associated with worse prognosis, including perivalvular complications, severe valve regurgitation or obstruction, low left ventricular ejection fraction and pulmonary hypertension [81]. The presence of vegetation, its size and its multivalvular location have been associated with worse prognosis. In a recent series [83], large vegetations (>15 mm length) were associated with a worse prognosis.

12.3.5 Computed Tomography For the first time in the setting of IE, CT was introduced in 2004 ESC guidelines as a tool to exclude cerebral haemorrhage before early cardiac surgery in patients with left-sided IE complicated by cerebral embolism [67]. At the same time, progress in the temporal and spatial resolution of the multislice CT scanners allowed the performance of non-invasive coronary angiography, CTA, to detect coronary disease in patients referred for conventional cardiac valve surgery [84]. Therefore, this appeared to be particularly useful to detect concomitant coronary disease before cardiac surgery in patients with large aortic vegetation, in order to avoid vegetation’s dislodgement during catheter-based coronary angiography [82]. CTA is an imaging modality able to assess both valve and perivalvular IE lesions [85]. Compared to surgical findings in left-sided valve IE, the sensitivity and specificity to detect perivalvular lesions (abscesses and pseudoaneuryms) are very high (>95%) [86], especially in aortic position [87]. Detection of valve lesions as vegetation, thickening, valve perforation or valve aneurysm is also feasible [85]. However, the sensitivity is lower for small vegetation (in aortic position, the sensitivity to

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detect vegetation with length 10 mm) [87]. When combined both imaging assessment by TEE and CTA in aortic prosthetic valve IE, the agreement with surgical findings (abscess, vegetation and dehiscence) is very good (kappa value of 0.88), and the diagnostic yield is better compared to individual TEE or CTA assessment (kappa values of 0.79 and 0.66, respectively) [88]. Hence, in some specific situations of left-sided IE where echocardiography is limited, CTA is a good complementary diagnostic technique: i.e. (1) in patients with suspected transcatheter valve IE in which echogenicity may be limited by the stent-frame, the obstructive pattern by leaflet thickening seems to be frequent and well visualized by CTA [89]; (2) in the setting of suspected paravalvular infection extension when the anatomy cannot be clearly delineated by echocardiography, especially in patients with prosthetic valves [76]; (3) before surgical treatment, to accurately assess the IE-related perivalvular lesions and for a better procedure planning [86, 90]. CTA is also useful after surgery, during the in-hospital period and the later follow-up, to assess the intervention results, especially when complex perivalvular lesions were present [90]. The main limitations of CT are the risk of nephrotoxicity associated with contrast agent injection and the radiation exposure. The use of MRI for the detection of central nervous system complications may partially avoid these risks. However, CT may be more accessible and feasible in most clinical conditions [21]. CTA has also technical limitations in septic patients with fast heart rates and enables to perform a breath hold. In this sense, a specific CT acquisitions protocol in left-sided IE may be useful to limit risks and improve cardiac images with: [85] (1) two different acquisition phases (a first arterial phase ECG-gated acquisition covering the cardiac structures and a second whole body venous phase acquisition performed around 60 s after iodine injection); (2) radiation dose reduction measures should always be addressed and (3) the use of intravenous beta-blockers is indicated in patients with a fast heart rate (>65 bpm) and no contraindications (septic and unstable patients).

12.3.6 Molecular Imaging Nuclear molecular imaging techniques are evolving as an important diagnostic method for patients with IE or device infection, and they have achieved three main contributions: 1. A significant improvement in the diagnosis of suspected IE/device infection, especially in patients with prosthetic materials where echocardiography interpretation may have several difficulties (possible IE or device infection cases). 2. Clarification of the perivalvular infection extension and complications, although a definite IE diagnosis has been already achieved. 3. Detection of extracardiac IE-related lesions, some of them relevant for decision-making.

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12.3.7 Fluorine-18-Fludeoxyglucose Positron Emission Tomography-Computerized Tomography [18F]FDG PET/CT detects activated inflammatory cells in infection and inflammation processes (leukocytes, monocyte macrophages and CD4+ T lymphocytes), which express a high density of glucose transporters and actively incorporate the tracer used [91–93]. Recent studies have reported promising results with the use of this technique in the diagnosis of prosthetic valve IE [33, 94] and cardiac device infection [95–100]. In a number of recent systematic reviews on the assessment of prosthetic valve IE, [18F]FDG PET/CT sensitivity and specificity have been reported 73–100% and 71–100%, respectively, with a 67–100% positive and 50–100% negative predictive values [101–104]. In particular, the overall pooled sensitivity of [18F]FDG PET/CT in IE is 61% [101], increasing to 73% when only prosthetic valve IE is considered and to 76% [104] or 81% with a overall accuracy with an AUC of 0.897 when including only studies reporting adequate cardiac preparation [102]. Thus, even in case of negative [18F]FDG PET/CT results (that includes also a whole-body evaluation for embolism detection), a thorough interpretation of the echocardiography and CT is essential. Pooled specificity of [18F]FDG PET/CT in patients with adequate cardiac preparation has been reported between 85 and 90% [102, 104]. Addition of [18F]FDG PET/CT to the modified Duke criteria increased sensitivity for a definite IE from 52–70% to 91–97% [103] by reducing the number of possible prosthetic valve IE cases. There is a considerable improvement in the diagnostic sensitivity (from ≈50 to ≈90%) when the Duke criteria and PET/CT are used in combination. By reclassifying most possible IE cases into a more conclusive group (definite or rejected), [18F] FDG PET/CT may have a major impact on the therapeutic strategies and the clinical outcomes in this population. Furthermore, the most recent [18F]FDG PET/CT systems can perform PET/CTA, combining the high sensitivity of [18F]FDG PET/CT to detect inflammation with the high spatial resolution of CTA to define structural damage. Thus, [18F]FDG PET/ CTA provides further important benefits over conventional PET/CT [33]. Current ESC guidelines have recently included CTA and PET/CT findings as a major criterion in the diagnostic algorithm of IE (Table 12.2) [21], specifically recommended to reach a prompt IE diagnosis in patients with a normal or doubtful echocardiography and a persistently high clinical suspicion of prosthetic valve IE (Fig. 12.5).

12.3.7.1

Prosthetic Valve Endocarditis

Radiolabelled Leucocyte Scintigraphy Sensitivity of WBC SPECT/CT has been reported overall 64–90% with 36–100% specificity, and 85–100% positive and 47–81% negative predictive values [105, 106]. In case of abscess formation WBC SPECT/CT presented 83–100% sensitivity, 78–87% specificity, and 43–71% positive and 93–100% negative predictive

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Table 12.2 The ESC 2015 modified criteria for diagnosis of IE Major criteria Blood cultures positive for IE Typical microorganisms consistent with IE from 2 separate blood cultures: Viridans streptococci, Streptococcus gallolyticus (S bovis), HACEK group, S. aureus; or Community-acquired enterococci, in the absence of a primary focus; or Microorganisms consistent with IE from persistently positive blood cultures: ≥2 positive blood cultures of blood samples drawn >12 h apart; or All of 3 or a majority of ≥4 separate cultures of blood (with first and last samples drawn ≥1 h apart); or Single positive blood culture for Coxiella burnetii or phase I IgG antibody titre > 1:800 Imaging positive for IE Echocardiogram positive for IE: Vegetation; Abscess, pseudoaneurysm, intracardiac fistula; Valvular perforation or aneurysm; New partial dehiscence of prosthetic valve Abnormal activity around the site of prosthetic valve implantation detected by [18F]FDG PET/CT (only if the prosthesis was implanted for >3 months) or radiolabelled WBC SPECT/CT Definite paravalvular lesions by cardiac CT Minor criteria 1. Predisposition such as predisposing heart condition, or injection drug use 2. Fever defined as temperature >38 °C 3. Vascular phenomena (including those detected only by imaging): major arterial emboli, septic pulmonary infarcts, infectious (mycotic) aneurysm, intracranial haemorrhage, conjunctival haemorrhages, and Janeway’s lesions 4. Immunological phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factor 5. Microbiological evidence: positive blood culture but does not meet a major criterion as noted above or serological evidence of active infection with organism consistent with IE Adapted from Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr, Ryan T, Bashore T, Corey GR. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30:633–8

values [107], even in the early post-intervention phase [105, 107]. As for [18F] FDGPET/CT, WBC SPECT/CT has an excellent positive predictive value for the detection of perivalvular infection and abscesses in patients with a suspicion of PVE. In addition, the intensity of WBC accumulation in the perivalvular area represents an interesting marker of local infectious activity: patients with a mild activity on the first exam disappearing on the second imaging evaluation seem to have a favourable outcome [107]. This opens the very interesting perspective of the use of molecular multimodality imaging for the assessment of antimicrobial treatment response. The most recent hybrid equipment allows to perform CTA also during a WBC SPECT/CT scan. However, this potential further development has not been yet evaluated.

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Clinical suspicion of IE

Modified Duke criteria (Li)

Definite IE

Possible/rejected IE but high suspicion

Native valve

1 - Repeat echo

Rejected IE Low suspicion

Prosthetic valve

1 - Repeat echo (TTE + TOE)/microbiology

(TTE + TOE)/microbiology

2 - 18F-FDG PET/CT or Leucocytes labeled SPECT/CT

2 - Imaging for embolic events a

3 - Cardiac CT

3 - Cardiac CT

4 - Imaging for embolic events a

ESC 2015 modified diagnostic criteriab

Definite IE

Possible IE

Rejected IE

Fig. 12.5 Proposed diagnostic algorithm for IE. From Habib et al. [21]. CT computed tomography, FDG fluorodeoxyglucose, IE infective endocarditis, PET positron emission tomography, SPECT single-photon emission computerized tomography, TOE transoesophageal echocardiography, TTE transthoracic echocardiography. aMay include cerebral MRI, whole body CT, and/or PET/CT. bSee Table 12.2

Figure 12.6 presents an example of WBC imaging in a complex patient with a possible endocarditis on an aortic and a mitral mechanical prosthesis. On the basis of the exam, IE was confirmed and a POE of the infection was also identified. [18F]FDG PET/CT In a recent systematic review on the assessment of PVE, [18F]FDG PET/CT sensitivity and specificity have been reported 73–100% and 71–100%, respectively, with a 67–100% positive and 50–100% negative predictive values (PPV and NPV, respectively). Addition of [18F]FDG PET/CT to the modified Duke criteria increased sensitivity for a definite IE from 52–70% to 91–97% [103] by reducing the number of possible PVE cases. This finding has been confirmed in several series [33, 94, 106, 108–111]. Figure 12.7 shows an example of [18F]FDG PET/CT in PVE. [18F]FDG PET/CT has been reported to have similar sensitivities for vegetations, perivalvular sequelae and prosthetic valve dehiscence compared with

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Fig. 12.6 Example of a WBC scan in a 74-year-old man with an aortic and mitral mechanical prosthesis positioned in 1995 and 1974, respectively. The patient presents fever, increased CRP and ESR, negative RF. Echocardiography, both TEE and TOE were negative. Positive urine culture with isolation of P. mirabilis and positive blood culture with isolation of Enterococcus faecalis were found. WBC scan was performed (a, whole body images; b, spot images of the chest, c, MIP and SPECT/CT). SPECT/CT shows a focal area of increased uptake the perivalvular aortic region, at the medial aspect (c from left to right MIP, transaxial, coronal and sagittal view and reconstructed 3D images, respectively). In this case, the add value of SPECT/CT images is clearly evident since planar images alone are not able to diagnose IE due to the activity of the sternum that cover the valvular uptake. In addition, at whole body images (a, anterior view at left and posterior view at right) a focal area of mild uptake is evident at the distal 1° right tooth, better evident at planar images (d, anterior view). Plain X-ray (d, middle panel) shows a corresponding area of osteolysis. This finding most likely represents to be the portal of entry of the infection. Treatment with antimicrobial was initiated and right tooth amputation performed. (From Sollini M et al. The “3 M” Approach to Cardiovascular Infections: Multimodality, Multitracers, and Multidisciplinary. Semin Nucl Med. 2018 May;48(3):199–22 [34])

Fig. 12.7 [18F]FDG PET/CT (Discovery 710 PET/CT, GE Healthcare) images in a 66-year-old man with aortic biological valve 4 years ago. The patient developed hyperpyrexia and underwent empiric antimicrobial treatment. ESR and CRP were increased, and blood culture was positive with the isolation of S. capitis. Echocardiography was negative. PET/CT was performed after 24 h of LCHF diet. Images show suppression of myocardial [18F]FDG uptake. An area of uptake was found mainly at the posterior aspect aortic valve prosthesis at the site of an abscess (a, transaxial view from left to right CT, emission and superimposed PET/CT)

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echocardiography [94]. When 18F-FDG-PET/CT is associated with CT-angiography ([18F]FDG PET/CTA), the diagnosis of infective endocarditis sensitivity and specificity increased to 91% with 93% PPV and 88% NPV [33, 112]. In association with the Duke criteria, [18F]FDG PET/CTA allowed reclassification of 90% of the cases initially classified as possible IE and provided a more conclusive diagnosis (definite/reject) in 95% of the patients. This combined multimodality procedure should be considered in all the patients where echocardiography presents significant limitations. In fact, its ability to provide relevant information on the local extent of the disease such as the presence of pseudo aneurysms, fistulas, thrombosis and coronary involvement is significant for the subsequent clinical and surgical decision-making. In addition, by adding CTA to PET/CT in IE patients, it is possible to assess the entire chest identifying septic pulmonary infarcts and abscesses and evaluate the aorta and the coronary arteries in prevision of surgery. Figure 12.7 presents an examples of [18F]FDG PET/CTA contribution in patients with suspected IE.

12.3.7.2 Native Valve Endocarditis In case of native valve, despite imaging interpretation might be more straightforward than in PVE, the diagnostic value of [18F]FDG PET/CT has not been well determined. In fact, most studies included mainly PVE or a mixed patient population with both native and prosthetic valves. A recent prospective study in patients with bacteraemia (Staphylococcus, Streptococcus spp and Enterococcus spp) and a very limited proportion of patients with prosthetic valve showed a limited accuracy (sensitivity 39%, specificity 93%) of [18F]FDG PET/CT for diagnosing IE [113]. Other smaller studies did not show better results [108, 114]. The low sensitivity of [18F]FDG PET/CT in NVE is likely to be mainly related to the location and the size of the lesions. In fact, in case of NVE the presence of a vegetation is the main finding, at least in the initial phase of the disease. Whereas in case of PVE infection, it generally spreads along the sewing ring or leads to abscess formation. It should also be noticed that this is a clinical setting where echocardiography presents a very high accuracy; therefore, the use of multimodality imaging is reserved to a limited number of patients, i.e. patients with severe valve calcific degeneration with suboptimal acoustic window. For example, in patients with S. aureus bacteraemia due to the high frequency of IE, TTE or TOE is always recommended [115].

12.3.8 PET/CT (PET/CTA If Available) in Prosthetic Valve IE Several studies suggested that the sensitivity of the modified Duke criteria could be significantly increased if [18F]FDG PET/CT [94] or [18F]FDG PET/CTA [33] results were put together with the clinical, microbiological and echocardiographic parameters. The main added value of using this technique is the significant reduction of the rate of misdiagnosed IE, classified in the possible IE category by using the Duke

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Fig. 12.8 Postoperative inflammation versus infective endocarditis in prosthetic aortic valves. (a) Fused [18F]FDG PET/CTA transverse view of the aortic valve in a 38-year-old man with aortic regurgitation who had undergone aortic valve replacement with a bileaflet mechanical prosthesis (21-mm Sorin Bicarbon with stitches on a 7-mm Teflon patch) 1 month previously. A normally inserted aortic prosthesis with mild, homogeneous valvular inflammatory reaction is evident (arrows). (b) [18F]FDG PET/CTA showing intense (SUVmax 13.33) heterogeneous periprosthetic [18F]FDG uptake and a poorly delimited perivalvular soft tissue lesion, findings consistent with a periprosthetic abscess (arrowheads) in a 56-year-old man with mechanical aortic valve infective endocarditis (valve implantation 3 years previously) with positive blood cultures for Staphylococcus aureus. (Adapted from Pizzi MN et  al. 18F-FDG-PET/CTA of Prosthetic Cardiac Valves and Valve-Tube Grafts: Infective Versus Inflammatory Patterns. JACC Cardiovasc Imaging. 2016 Oct;9(10):1224–7 [161])

criteria. Reclassification of most possible IE cases into a more conclusive diagnosis of definite or rejected IE leads to a significant increase in the diagnostic sensitivity (91–97%), which could have important impact on IE outcomes. Moreover, [18F] FDG PET/CTA has yielded additional benefits over [18F]FDG PET/CT in these patients: (1) identification of a larger number of anatomic lesions than non-gated [18F]FDG PET/CT; (2) additional reduction of doubtful studies on non-gated [18F] FDG PET/CT and (3) preoperative information about coronary artery disease in patients with an indication for surgery. Figure 12.8 shows an example of [18F]FDG PET/CTA in patients with IE.

12.3.9 Extracardiac Workup in Infective Endocarditis 12.3.9.1 Embolism Detection Extracardiac manifestations in IE (both NVE and PVE) are reported in 30–80% of patients. Most frequent are embolic stroke or septic embolization to bone, spleen or kidneys [84], although only some of these are symptomatic [52, 56, 116]. The majority of embolisms take place within the first 14 days after treatment initiation [117], and they might appear as the initial symptom leading to the diagnosis and frequently are recurrent [117]. The localization of the emboli

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and their cerebral/extracerebral proportion vary according to the studies, in particular according to the frequency and modalities of imaging, and the proportion of right-sided and left-sided IE. The search for asymptomatic embolic events through systematic extracardiac imaging has become a very important topic, due to the fact that the detection of asymptomatic embolic events is now considered a minor Duke criterion in the 2015 ESC criteria [21]. This represents another main difference between the ESC and the American Heart Association (AHA) recommendation in which only symptomatic extracardiac localizations of IE are considered as Duke classification minor criteria [64]. A panel of imaging modalities is used routinely to evaluate patients with extracardiac infective processes and includes dental radiography, abdominal ultrasound, CT scan of cerebrum, whole-body CT or MRI scan. Several factors have been associated with an increased risk of embolism [118] including age, diabetes, atrial fibrillation, embolism before antibiotics, vegetation length and Staphylococcus aureus infection [119]. Among them, the size and mobility of the vegetations at echocardiography are the most potent independent predictors of new embolic event in patients with IE [83, 117, 119–121]. Beyond cardiac assessment in left-sided IE, CT allows to screen extracardiac IE-related complications including (1) intra-abdominal lesions (splenic, renal and hepatic infarction or abscess, mesenteric ischaemia) [64] and (2) other metastatic locations of the infection (spondylodiscitis, vascular mycotic aneurysm and vasculitis) [122]. MRI is also highly sensitive and specific for the diagnosis of musculoskeletal lesions, as spondylodiscitis, osteomyelitis, septic arthritis and peripheral soft tissue infections [122]. CT can detect central nervous system lesions such as embolic stroke, intracranial haemorrhage, intracranial mycotic aneurysm and brain abscess. Although CT is easily available in most centres, concerning the detection of all these IE-related brain lesions, cerebral MRI has higher sensitivity than CT, and it is of particular interest in the management of patients with left-sided IE [123]. Different studies including systematic cerebral MRI during acute IE have consistently reported very frequent lesions, affecting up to 60–80% of patients [124]. Most abnormalities are ischaemic lesions (50–80%) with more frequent small lesions than larger territorial infarcts [125]. In patients without neurological symptoms, MRI can show cerebral lesions in at least half of patients, most often ischaemic lesions [126]. The impact of systematic cerebral MRI on IE diagnosis is marked in patients with non-definite IE and without neurological symptoms since it can add one minor Duke criterion, upgrading the diagnosis of IE in 25% of these patients, thereby leading to earlier diagnosis [123]. In patients with neurological symptoms, brain imaging must be urgently performed and are abnormal in the majority of cases. MRI has a higher sensitivity than CT in the diagnosis of the culprit lesion, in particular with regard to stroke, transient ischaemic attack and encephalopathy. Catheter-based cerebral angiography remains limited to cases with high suspicion of cerebral mycotic aneurysm.

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Fig. 12.9 Examples of different pattern of uptake in patients with IE and spleen embolisms at [18F]FDG PET/CT (Discovery 710 PET/CT GE Healthcare; (a) upper panel superimposed PET/ CT images, lower panel CT images) and radiolabelled WBC imaging (Infinia, GE Healthcare; (b) upper panel superimposed SPET/CT images, lower panel CT images). At PET/CT, spleen embolisms might present increased homogeneous [18F]FDG uptake (a, left upper panel) corresponding to a segmental wedge-shaped low-attenuation defect at TC (a, left lower panel) or a rim of high uptake surrounding a wide photopenic area as a consequence of colliquation (a, right upper panel), corresponding to a low-attenuation area at the CT images (a, right lower panel). At radiolabelled SPECT/CT imaging due to the physiological accumulation of the radiolabelled WBC in the spleen, the typical pattern of splenic embolism is a segmental wedge-shaped cold area (b, upper panel; lower panel the corresponding CT image). (From Sollini M et  al. The “3  M” Approach to Cardiovascular Infections: Multimodality, Multitracers, and Multidisciplinary. Semin Nucl Med. 2018 May;48(3):199–22 [34])

In right-sided IE, especially CDRIE, CT with contrast agent injection may reveal pulmonary embolisms, infarcts and abscesses. In this specific situation, nuclear imaging by ventilation-perfusion scintigraphy may be an alternative to CT in order to screen septic pulmonary embolism [97]. A noticeable advantage of [18F]FDG PET/CT and WBC SPECT/CT is the possibility to perform the extracardiac workup within a single imaging procedure and to reveal the concomitant presence of extracardiac infection sites as the consequence of both septic embolism and primary infective processes (Fig. 12.9). Early detection of embolic events have been reported using [18F]FDG PET/CT with a high sensitivity (87–100%) and specificity (80%) [103], at a reasonable cost-effectiveness, especially in patients with Gram-positive bacteraemia. Extracerebral peripheral localizations of IE were found in 24–74% among the definite IE population; most of these peripheral localizations were silent (50–71%) and revealed by [18F]FDG PET/ CT.  This has been shown particularly useful in the identification of unexpected embolic localizations such as in the case of mycotic aneurysms [127], a potential life-threatening complication requiring specific treatment. In a case–control study, [18F]FDG PET/CT detected peripheral localizations in 57.4% of IE patients, representing the only initially positive imaging technique in about half of the patients with embolic events [128]. Detection of metastatic infection by [18F]FDG PET/CT

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led to change of treatment in up to 35% of patients [114] and with a twofold reduction in the number of relapses [128]. 18F]FDG PET/CT has been demonstrated to determine a change in therapeutic plan in 28% of patients by leading to advance scheduled cardiac surgery or initiation of a specific antimicrobial regimen for the treatment of the embolic foci [129]. [18F]FDG PET/CT is very accurate in organs with low physiological uptake, therefore not applicable in ruling out the presence of brain embolism [130], where the use of CT/MRI remains fundamental. Performing additional planar and SPECT/CT spot images constitutes an invaluable aid for detecting septic embolism even in asymptomatic patients [30, 105]. WBC SPECT/CT has been used in a mixed population of PVE and NVE patients, showing that no cases were undiagnosed when either the echography or the blood cultures were positive [105]. However, a recent study from the East Danish Database on Endocarditis comparing the performances of [18F]FDG PET/CT scan and WBC SPECT/CT acquired within 1 week apart and within 14 days of IE treatment initiation showed [18F]FDG PET/CT to have a significantly higher clinical utility score than WBC SPECT/CT and to be potentially superior to WBC-SPECT/CT in the detection of extracardiac pathology in patients with IE [131]. It should be noted that in this study the protocol of WBC imaging acquisition used in the study is not the one recommended by the current EANM guideline; therefore, performance of the technique might have been underestimated.

12.3.9.2 Identification of the Infection POE in IE The identification of the infection POE at [18F]FDG PET/CT and subsequent eradication of the sources of infection is particularly important in IE to prevent recurrence either relapse and/or reinfection. The risk of recurrence amongst survivors of IE varies between 2.7 and 22.5% [50, 132–137]. Relapses are more often due to insufficient duration of original treatment, suboptimal choice of initial antibiotics, and a persistent focus of infection (e.g. periprosthetic abscess). In a large multicentre cohort of patients with IE, history of IE was an independent predictor of repeat IE [138], highlighting the importance of obtaining timely infection source control. The potential portal of entry of a new episode must be searched for in order to eradicate it and thus lower the risk for a new IE episode. This primary infectious site may be suspected based on the common biotope of the bacteria strain (digestive, skin and catheter). Yet published research on this topic is very limited. In a recent study, systematic search for the portal of entry identified the site of primary infection in 74% of patients, mainly cutaneous (40%), followed by oral or dental (29%) and gastrointestinal (23%) [139]. [18F]FDG-PET/CT has been demonstrated to be able to reveal the source of infection, including cases where the sustaining portal of entry was a neoplasia (colonic cancer) [33]. The link between some type of microorganism and colon cancer was first described in 1951 [140]. Previously categorized as a Lancefield group D streptococcus, an enterococcus or simply as ‘Streptococcus bovis group’, these bacteria have since been differentiated by deoxyribonucleic acid sequencing as Streptococcus gallolyticus and Streptococcus infantarius. Several studies support that the association between bacteraemia and IE is due to these pathogens and GI

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pathology: mostly colon cancer [141–144] but also adenomatous polyps [145], diverticulosis [142] and biliary lesions [142, 144]. Taken together, these evidence highlights the importance of searching for a culprit GI source in case of patients with S. bovis group microorganisms. Once the POE has been identified, risk modification can be attempted. This topic is of clinical importance, as it relates to our understanding of the sources of infection in patients with IE and also influences management of patients. Therefore, from a practical and clinical perspective, systematic search for multiple sites of primary infections can be considered as an add element for the prevention and treatment planning for IE recurrence and should be always be part of the standard report of a [18F]FDG PET/CT or WBC imaging.

12.4

Specific Technical Considerations: Patient Preparation, Radiopharmaceuticals Preparation and Acquisition Protocols, Imaging Post-processing and Imaging Reading/Interpretation

12.4.1 WBC SPECT/CT 12.4.1.1 Patient Preparation In case of CVS infection, the WBC scan procedure is very similar to the one used for any other infection. No specific patient preparation is required, besides the standard for WBC imaging. The general rules for the radiolabelling of WBC preparation are also applied. 12.4.1.2

Radiopharmaceutical: Preparation, Administered Activities and Special Considerations The WBC can be radiolabelled either with 99mTc-hexamethylpropyleneamine oxime ([99mTc]HMPAO, 370–555 MBq) or with [111In]oxine (10–18.5 MBq), as detailed in the specific guidelines from the European Association of Nuclear Medicine (EANM) [146, 147] and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) [148, 149]. It is important to be aware if the patient is under antibiotic treatment and consider its possible effect on WBC uptake when reading the images, but there is no evidence for discontinuation of treatment before the imaging session. 12.4.1.3 Image Acquisition Protocol and Post-processing An important aspect of WBC imaging in cardiovascular infections is the image acquisition protocol that should include planar acquisitions at 30 min (early images), 4–6  h (delayed images), and 20–24  h (late images) after reinjection of [99mTc] HMPAO/111In-oxine WBC with mandatory inclusion of SPECT/CT acquisition as part of the standard imaging protocol. The importance of including SPECT/CT acquisition is due to the failure of planar images alone to detect the site and the extension of infections in the cardiovascular system [105]. Therefore, in this context SPECT/CT images are used not only to confirm and localize findings at planar images consistent with infection (area or increased uptake intensity or size over

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time) but also to increase the diagnostic accuracy. If semi-quantitative evaluation of WBC is used to reach a diagnosis, it is very important that both the planar and SPECT/CT images are always acquired with a ‘time-corrected for isotope decay’ modality. SPECT/CT images should cover the thorax in case of IE and the thorax– upper abdominal area in case of CIEDs and LVAD infections, ensuring that all components of the device are included in the field of view, considering all the possible generator positions (i.e. abdomen). In case of vascular prosthesis, the whole anatomical region where the graft is positioned should be included in the field-of-view, including the region of the native vessels at the proximal and distal prosthetic sites. For abdominal vascular prosthesis, acquisition of dynamic images might help in differentiating persistent WBC accumulation from blood pool activity as well as images within the first 2  h p.i., to minimize the interference due to the HMPAO elimination via the hepatobiliary system. Late SPECT/CT acquisitions are particularly relevant in case of IE, CIEDs infections and thoracic aorta infections since background activity related to the blood pool spillover strongly hampers the detectability of lesions. In addition to this standard protocol, accurate extracardiac workup searching for septic emboli or for the portal of entry should always be performed. This might require additional SPECT/CT acquisitions. The images have to be reconstructed with and without attenuation correction to identify potential reconstruction artefacts. Image Reading and Imaging Interpretation When reading WBC imaging, some important issues should be taken into consideration. Rarely, false-positive findings have been described for WBC imaging in IE and CIED infections, even in case of very early infections. False-positive results are more frequent in case of VPI, in particular for those located in the abdominal area, but SPECT/CT has been shown to significantly decrease the false-positive rate [150]. On the other hand, false-negative scans have been observed in the presence of IE caused by some specific strains [105]. Embolisms at WBC imaging might appear either as area of increased uptake over time in the brain, lung and soft tissue or as cold spot when spleen embolism and spondylodiscitis occur. This latter appearance has to be considered non-specific for infectious embolisms since it might be present in other benign or malignant conditions, such as in the case of vertebral crush or metastasis. Therefore, despite these findings in patients with IE are highly suggestive for septic embolism, they should be confirmed by additional diagnostic imaging tests. Due to the limited spatial resolution, reduced sensitivity has been described in case of small embolism [105].

12.4.1.4 [18F]FDG PET/CT PET/CT technique has several clear advantages over WBC imaging such as the lack of blood handling, a shorter study time that allows the conclusion of the scan within 1–2 h after tracer administration and high target-to-background ratio. However, performing a [18F]FDG PET/CT for cardiovascular infections is more complex than a simple translation of the standard protocol used in oncology. Starting from patients’ preparation, some specific aspects of the imaging protocol and imaging reading

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should be considered. An extensive review of the main critical technical issues is provided in the ‘Recommendation on nuclear and multi-modality imaging in IE and CIED Infections’ released by the EANM [29]. Patient Preparation Patient preparation is very important to reduce the physiological uptake of [18F] FDG of the myocardium. This can be achieved by the application of a proper fatenriched diet, lacking carbohydrates followed by fasting. Additionally, the use of intravenous heparin approximately 15 min prior to [18F]FDG injection can be used [151]. There is a general agreement that high-fat, low-carbohydrate diet for at least two meals with a fast of at least 4 h is the minimum to obtain a suppression of physiologic myocardial glucose utilization. Table 12.1 summarized the possible protocols described in literature to prepare patients for [18F]FDG PET/CT in case of IE/ CIED infections. Since there is no evidence demonstrating that a specific patient preparation technique is superior to another, each institution should continuously evaluate its image quality data to ensure that more than 80% of the scans achieve an adequate physiological [18F]FDG myocardial suppression. Efforts should be made to decrease blood glucose to the lowest possible level, although hyperglycaemia does not represent an absolute contraindication for performing the study [93]. Indeed, in case of infection and inflammation neither diabetes nor hyperglycaemia at the time of the study has been demonstrated to increase PET/CT false-negative rate [152]. Radiopharmaceutical: Administered Activity and Special Considerations The [18F]FDG activity recommended in the joint EANM/SNMMI guidelines on PET imaging in inflammation/infection is of 2.5–5.0 MBq/kg (175–350 MBq in a 70 kg standard adult) [93]. Although antimicrobial treatment is expected to decrease the intensity of [18F] FDG accumulation [153], there is no evidence at this stage to routinely recommend treatment discontinuation before performing PET/CT. On the contrary, corticosteroid treatment should be discontinued or at least reduced to the lowest possible dose in the 24 h preceding the exam. Image Acquisition Protocol and Post-processing Image acquisition generally starts after an uptake time of 45–60 min, the emission time/bed position depends on the sensitivity of the scanner. The field of acquisition, as in oncology, generally includes from skull base to mid thighs (total body). Whole body images including the lower limbs, might be suggested to detect complications of IE such as mycotic aneurysms that may require specific treatment by embolization to prevent rupture [127]. An additional separate bed on the cardiac region is useful to record gated images. Diagnostic angio-CT (CTA) scan might be also performed, to maximize the diagnostic information provided by the exam. Despite delayed imaging have been proposed to increase specificity in diagnosing infection of cardiovascular implants [154, 155], recent data suggested that in IE delayed images are more prone to false-positive results [156].

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Also in case of [18F]FDG PET/CT, image reconstruction with and without attenuation correction is recommended to identify potential reconstruction artefacts. Metal artefact reduction techniques are useful to minimize overcorrection even if they do not always recover completely PET image quality. Image Reading and Interpretation PET/CT images have to be visually evaluated for increased [18F]FDG uptake, taking into consideration the pattern (focal, linear and diffuse), the intensity and the relationship to areas of physiologic distribution. PET information is compared with morphologic information obtained by CT and possible CTA. Analysis by the application of the standard uptake value (SUV) is possible. However, conversely to its application in oncology, SUV has not been validated in inflammation and infection. If SUV is used, all the factors influencing its quantification should be carefully considered, including those related to patient preparation (glycaemia, concurrent treatment, etc.), time of uptake and the use of positive contrast. Several physiological variants and pathological conditions that enter in the differential diagnosis with IE/CIED infection should be recognized to prevent misinterpretation of a positive scan. Therefore, specific training in the field should always be undertaken before the implementation of the technique in a new centre on a daily basis. Caution must be taken when interpreting [18F]FDG PET/CT (PET/CTA) images, since [18F]FDG uptake can be present in circumstances other than infection: (1) Non-infected prosthetic valves can frequently display mild homogeneous [18F]FDG uptake, which remains steady over time and limits [18F]FDG PET/CT (PET/CTA) specificity [157]. (2) A postoperative inflammatory response may result in nonspecific [18F]FDG uptake in the immediate postoperative period [158]. Indeed, one of the major findings that should be recognized is the presence of faint and homogeneous [18F]FDG uptake strictly limited to the valve annulus, very similar to the pattern observed in prosthetic vascular graft [159]. This pattern of uptake around the prosthetic valve is frequently visible and may have different causes, particularly early after surgery. It most likely results from the persistent host reaction against the biomaterial coating, the sewing ring of prosthetic valve. In this sense, [18F]FDG PET/CT is not recommended by guidelines until 3 months after surgery, although there is little available data on the morphologic and metabolic features following prosthetic valve or valve-tube graft surgeries and their short-term evolution. However, Mathieu et al. have recently shown that the mean amount of [18F]FDG uptake was not significantly different between patients scanned within 3  months [157]. This has been confirmed by a recent multicentre study on a large cohort of patients where recent valve implantation was not a significant predictor of falsepositive interpretations [160]. A recent experience by Pizzi et al. suggests that specific metabolic and anatomic patterns might help differentiate between inflammation and infection in these patients [161]. (3) There are also a number of normal (unsuccessful myocardial suppression, atrial wall uptake in patients with atrial fibrillation and lypomatous hypertrophy) [162] or pathological conditions that can mimic the pattern of focally increased [18F]FDG uptake typically observed in IE [163]. In fact,

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focally increased [18F]FDG uptake might be found in many other conditions such as active thrombi [164], soft atherosclerotic plaques [165], vasculitis [166], primary cardiac tumours [167] and cardiac metastasis [168], post-surgical inflammation [169] and foreign body reactions (such as BioGlue, a surgical adhesive used to repair the aortic root) [158] stitches and in case of Libman–Sacks endocarditis [170]. Therefore, it is necessary to adopt accurate patient selection and inclusion criteria as well as accurate imaging reading to maintain a high specificity for IE using [18F]FDG. Conversely, some circumstances in which the diagnostic sensitivity of [18F]FDG PET/CT (PET/CTA) is decreased should be considered as possible false-negative studies: (1) small lesions below the metabolic/spatial resolution of [18F]FDG PET/ CT (PET/CTA) and (2) use antimicrobial which affects the intensity of [18F]FDG uptake [153]; therefore, ongoing treatments should be always carefully considered when reporting the scan. The clinical discussion within the endocarditis team is in our experience the best way to overcome the above-mentioned limitations when they occurs, thus optimizing the imaging results for the subsequent patient management.

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116. Delahaye F, Goulet V, Lacassin F, Ecochard R, Selton-Suty C, Hoen B, et al. Characteristics of infective endocarditis in France in 1991. A 1-year survey. Eur Heart J. 1995;16(3):394–401. 117. Vilacosta I, Graupner C, San Roman JA, Sarria C, Ronderos R, Fernandez C, et  al. Risk of embolization after institution of antibiotic therapy for infective endocarditis. J Am Coll Cardiol. 2002;39(9):1489–95. 118. Habib G.  Embolic risk in subacute bacterial endocarditis: determinants and role of transesophageal echocardiography. Curr Cardiol Rep. 2003;5(2):129–36. 119. Hubert S, Thuny F, Resseguier N, Giorgi R, Tribouilloy C, Le Dolley Y, et al. Prediction of symptomatic embolism in infective endocarditis: construction and validation of a risk calculator in a multicenter cohort. J Am Coll Cardiol. 2013;62(15):1384–92. 120. Di Salvo G, Habib G, Pergola V, Avierinos JF, Philip E, Casalta JP, et al. Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol. 2001;37(4): 1069–76. 121. Steckelberg JM, Murphy JG, Ballard D, Bailey K, Tajik AJ, Taliercio CP, et  al. Emboli in infective endocarditis: the prognostic value of echocardiography. Ann Intern Med. 1991;114(8):635–40. 122. Colen TW, Gunn M, Cook E, Dubinsky T. Radiologic manifestations of extra-cardiac complications of infective endocarditis. Eur Radiol. 2008;18(11):2433–45. 123. Duval X, Iung B, Klein I, Brochet E, Thabut G, Arnoult F, et al. Effect of early cerebral magnetic resonance imaging on clinical decisions in infective endocarditis: a prospective study. Ann Intern Med. 2010;152(8):497–504, W175. 124. Snygg-Martin U, Gustafsson L, Rosengren L, Alsio A, Ackerholm P, Andersson R, et  al. Cerebrovascular complications in patients with left-sided infective endocarditis are common: a prospective study using magnetic resonance imaging and neurochemical brain damage markers. Clin Infect Dis. 2008;47(1):23–30. 125. Cooper HA, Thompson EC, Laureno R, Fuisz A, Mark AS, Lin M, et al. Subclinical brain embolization in left-sided infective endocarditis: results from the evaluation by MRI of the brains of patients with left-sided intracardiac solid masses (EMBOLISM) pilot study. Circulation. 2009;120(7):585–91. 126. Iung B, Tubiana S, Klein I, Messika-Zeitoun D, Brochet E, Lepage L, et al. Determinants of cerebral lesions in endocarditis on systematic cerebral magnetic resonance imaging: a prospective study. Stroke. 2013;44(11):3056–62. 127. Mikail N, Benali K, Ou P, Slama J, Hyafil F, Le Guludec D, et  al. Detection of mycotic aneurysms of lower limbs by whole-body (18)F-FDG-PET.  JACC Cardiovasc Imaging. 2015;8(7):859–62. 128. Kestler M, Munoz P, Rodriguez-Creixems M, Rotger A, Jimenez-Requena F, Mari A, et  al. Role of (18)F-FDG PET in patients with infectious endocarditis. J Nucl Med. 2014;55(7):1093–8. 129. Van Riet J, Hill EE, Gheysens O, Dymarkowski S, Herregods MC, Herijgers P, et al. (18) F-FDG PET/CT for early detection of embolism and metastatic infection in patients with infective endocarditis. Eur J Nucl Med Mol Imaging. 2010;37(6):1189–97. 130. Özcan C, Asmar A, Gill S, Thomassen A, Diederichsen AC. The value of FDG-PET/CT in the diagnostic work-up of extra cardiac infectious manifestations in infectious endocarditis. Int J Cardiovasc Imaging. 2013;29(7):1629–37. 131. Lauridsen TK, Iversen KK, Ihlemann N, Hasbak P, Loft A, Berthelsen AK, et al. Clinical utility of. Int J Cardiovasc Imaging. 2017;33(5):751–60. 132. Renzulli A, Carozza A, Romano G, De Feo M, Della Corte A, Gregorio R, et al. Recurrent infective endocarditis: a multivariate analysis of 21 years of experience. [email protected]. Ann Thorac Surg. 2001;72(1):39–43. 133. Alexiou C, Langley SM, Stafford H, Lowes JA, Livesey SA, Monro JL. Surgery for active culture-positive endocarditis: determinants of early and late outcome. Ann Thorac Surg. 2000;69(5):1448–54.

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134. Kaiser SP, Melby SJ, Zierer A, Schuessler RB, Moon MR, Moazami N, et  al. Long-term outcomes in valve replacement surgery for infective endocarditis. Ann Thorac Surg. 2007;83(1):30–5. 135. David TE, Gavra G, Feindel CM, Regesta T, Armstrong S, Maganti MD.  Surgical treatment of active infective endocarditis: a continued challenge. J Thorac Cardiovasc Surg. 2007;133(1):144–9. 136. Tornos MP, Permanyer-Miralda G, Olona M, Gil M, Galve E, Almirante B, et  al. Longterm complications of native valve infective endocarditis in non-addicts. A 15-year follow-up study. Ann Intern Med. 1992;117(7):567–72. 137. Mansur AJ, Dal Bó CM, Fukushima JT, Issa VS, Grinberg M, Pomerantzeff PM. Relapses, recurrences, valve replacements, and mortality during the long-term follow-up after infective endocarditis. Am Heart J. 2001;141(1):78–86. 138. Chu VH, Sexton DJ, Cabell CH, Reller LB, Pappas PA, Singh RK, et al. Repeat infective endocarditis: differentiating relapse from reinfection. Clin Infect Dis. 2005;41(3):406–9. 139. Delahaye F, M'Hammedi A, Guerpillon B, de Gevigney G, Boibieux A, Dauwalder O, et al. Systematic search for present and potential portals of entry for infective endocarditis. J Am Coll Cardiol. 2016;67(2):151–8. 140. McCoy WC, Mason JM.  Enterococcal endocarditis associated with carcinoma of the sigmoid; report of a case. J Med Assoc State Ala. 1951;21(6):162–6. 141. Galdy S, Nastasi G. Streptococcus bovis endocarditis and colon cancer: myth or reality? A case report and literature review. BMJ Case Rep. 2012;2012. 142. Lazarovitch T, Shango M, Levine M, Brusovansky R, Akins R, Hayakawa K, et al. The relationship between the new taxonomy of Streptococcus bovis and its clonality to colon cancer, endocarditis, and biliary disease. Infection. 2013;41(2):329–37. 143. Klein RS, Recco RA, Catalano MT, Edberg SC, Casey JI, Steigbigel NH.  Association of Streptococcus bovis with carcinoma of the colon. N Engl J Med. 1977;297(15):800–2. 144. Fernández-Ruiz M, Villar-Silva J, Llenas-García J, Caurcel-Díaz L, Vila-Santos J, Sanz-Sanz F, et al. Streptococcus bovis bacteraemia revisited: clinical and microbiological correlates in a contemporary series of 59 patients. J Infect. 2010;61(4):307–13. 145. Klein RS, Catalano MT, Edberg SC, Casey JI, Steigbigel NH. Streptococcus bovis septicemia and carcinoma of the colon. Ann Intern Med. 1979;91(4):560–2. 146. Roca M, de Vries EF, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with (111)in-oxine. Inflammation/infection taskgroup of the European association of nuclear medicine. Eur J Nucl Med Mol Imaging. 2010;37(4):835–41. 147. de Vries EF, Roca M, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with (99m)Tc-HMPAO.  Inflammation/infection taskgroup of the European association of nuclear medicine. Eur J Nucl Med Mol Imaging. 2010;37(4):842–8. 148. Palestro CJ.  Society of nuclear medicine procedure guideline for 99mTc-exametazime (HMPAO)-labeled leukocyte scintigraphy for suspected infection/inflammation; 2004. 149. Palestro CJ. Society of nuclear medicine procedure guideline for 111In-leukocyte scintigraphy for suspected infection/inflammation; 2004. 150. Erba PA, Leo G, Sollini M, Tascini C, Boni R, Berchiolli RN, et al. Radiolabelled leucocyte scintigraphy versus conventional radiological imaging for the management of late, low-grade vascular prosthesis infections. Eur J Nucl Med Mol Imaging. 2014;41(2):357–68. 151. Osborne MT, Hulten EA, Murthy VL, Skali H, Taqueti VR, Dorbala S, et al. Patient preparation for cardiac fluorine-18 fluorodeoxyglucose positron emission tomography imaging of inflammation. J Nucl Cardiol. 2017;24(1):86–99. 152. Rabkin Z, Israel O, Keidar Z. Do hyperglycemia and diabetes affect the incidence of falsenegative 18F-FDG PET/CT studies in patients evaluated for infection or inflammation and cancer? A comparative analysis. J Nucl Med. 2010;51(7):1015–20. 153. Scholtens AM, van Aarnhem EE, Budde RP. Effect of antibiotics on FDG-PET/CT imaging of prosthetic heart valve endocarditis. Eur Heart J Cardiovasc Imaging. 2015;16(11):1223.

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154. Caldarella C, Leccisotti L, Treglia G, Giordano A.  Which is the optimal acquisition time for FDG PET/CT imaging in patients with infective endocarditis? J Nucl Cardiol. 2013;20(2):307–9. 155. Leccisotti L, Perna F, Lago M, Leo M, Stefanelli A, Calcagni ML, et  al. Cardiovascular implantable electronic device infection: delayed vs standard FDG PET-CT imaging. J Nucl Cardiol. 2014;21(3):622–32. 156. Scholtens AM, Swart LE, Verberne HJ, Budde RPJ, Lam MGEH. Dual-time-point FDG PET/ CT imaging in prosthetic heart valve endocarditis. J Nucl Cardiol. 2018;25(6):1960–7. 157. Mathieu C, Mikail N, Benali K, Iung B, Duval X, Nataf P, et  al. Characterization of 18F-fluorodeoxyglucose uptake pattern in noninfected prosthetic heart valves. Circ Cardiovasc Imaging. 2017;10(3):e005585. 158. Schouten LR, Verberne HJ, Bouma BJ, van Eck-Smit BL, Mulder BJ. Surgical glue for repair of the aortic root as a possible explanation for increased F-18 FDG uptake. J Nucl Cardiol. 2008;15(1):146–7. 159. Keidar Z, Pirmisashvili N, Leiderman M, Nitecki S, Israel O. 18F-FDG uptake in noninfected prosthetic vascular grafts: incidence, patterns, and changes over time. J Nucl Med. 2014;55(3):392–5. 160. Swart LE, Gomes A, Scholtens AM, Sinha B, Tanis W, Lam MGEH, et al. Improving the diagnostic performance of. Circulation. 2018;138(14):1412–27. 161. Pizzi MN, Roque A, Cuellar-Calabria H, Fernandez-Hidalgo N, Ferreira-Gonzalez I, Gonzalez-Alujas MT, et al. 18F-FDG-PET/CTA of prosthetic cardiac valves and valve-tube grafts: infective versus inflammatory patterns. JACC Cardiovasc Imaging. 2016;9(10):1224–7. 162. Fan CM, Fischman AJ, Kwek BH, Abbara S, Aquino SL. Lipomatous hypertrophy of the interatrial septum: increased uptake on FDG PET. AJR Am J Roentgenol. 2005;184(1):339–42. 163. Scholtens AM, Swart LE, Verberne HJ, Tanis W, Lam MG, Budde RP. Confounders in FDGPET/CT imaging of suspected prosthetic valve endocarditis. JACC Cardiovasc Imaging. 2016;9(12):1462–5. 164. García JR, Simo M, Huguet M, Ysamat M, Lomeña F. Usefulness of 18-fluorodeoxyglucose positron emission tomography in the evaluation of tumor cardiac thrombus from renal cell carcinoma. Clin Transl Oncol. 2006;8(2):124–8. 165. Williams G, Kolodny GM. Retrospective study of coronary uptake of 18F-fluorodeoxyglucose in association with calcification and coronary artery disease: a preliminary study. Nucl Med Commun. 2009;30(4):287–91. 166. Kobayashi Y, Ishii K, Oda K, Nariai T, Tanaka Y, Ishiwata K, et al. Aortic wall inflammation due to Takayasu arteritis imaged with 18F-FDG PET coregistered with enhanced CT. J Nucl Med. 2005;46(6):917–22. 167. Rahbar K, Seifarth H, Schäfers M, Stegger L, Hoffmeier A, Spieker T, et al. Differentiation of malignant and benign cardiac tumors using 18F-FDG PET/CT.  J Nucl Med. 2012;53(6):856–63. 168. Kaderli AA, Baran I, Aydin O, Bicer M, Akpinar T, Ozkalemkas F, et al. Diffuse involvement of the heart and great vessels in primary cardiac lymphoma. Eur J Echocardiogr. 2010;11(1):74–6. 169. Abidov A, D'agnolo A, Hayes SW, Berman DS, Waxman AD. Uptake of FDG in the area of a recently implanted bioprosthetic mitral valve. Clin Nucl Med. 2004;29(12):848. 170. Dahl A, Schaadt BK, Santoni-Rugiu E, Bruun NE. Molecular imaging in libman-sacks endocarditis. Infect Dis (Lond). 2015;47(4):263–6.

Nuclear Medicine Imaging of Fever of Unknown Origin

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Ilse J. E. Kouijzer, Chantal P. Bleeker-Rovers, and Lioe-Fee de Geus-Oei

13.1

Introduction

Fever of unknown origin (FUO) refers to a prolonged febrile illness without an established etiology despite intensive evaluation and diagnostic testing. In 1961, FUO was defined by Petersdorf and Beeson as an illness of more than 3 weeks duration with fever higher than 38.3 °C (101 °F) on several occasions and diagnosis uncertain after 1 week of study in the hospital [1]. In 1992, this definition has been changed by removing the requirement that the evaluation must take place in a hospital and by excluding immunocompromised patients [2], because these patients need a different approach in diagnosis and therapy [3]. Later, the quantitative criterion of diagnosis uncertain after a period of time was changed to a qualitative criterion that requires a number of diagnostic investigations to be performed [4–6]. The current definition of FUO is: (1) temperature ≥38.3  °C (101  °F) on at least two occasions, (2) duration of illness ≥3 weeks or multiple febrile episodes in ≥3 weeks, (3) not immunocompromised (defined as neutropenia for at least 1  week in the 3  months prior to the start of the fever, known HIV infection, known hypogammaglobulinemia or use of 10 mg prednisone or equivalent for at least 2 weeks in the 3 months prior to the start of fever), and (4) uncertain diagnosis despite thorough history-taking, physical examination, and the following investigations: erythrocyte sedimentation rate or C-reactive protein, hemoglobin,

I. J. E. Kouijzer · C. P. Bleeker-Rovers (*) Division of Infectious Diseases, Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands e-mail: [email protected] L.-F. de Geus-Oei Division of Radiology, Leiden University Medical Center, Leiden, The Netherlands © Springer Nature Switzerland AG 2020 A. Signore, A. W. J. M. Glaudemans (eds.), Nuclear Medicine in Infectious Diseases, https://doi.org/10.1007/978-3-030-25494-0_13

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platelet count, leukocyte count and differentiation, electrolytes, creatinine, total serum protein, protein electrophoresis, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, ferritin, antinuclear antibodies, rheumatoid factor, microscopic urinalysis, three blood cultures, urine culture, chest X-ray, abdominal ultrasonography, and tuberculin skin test or interferon gamma release assay. FUO is closely related to inflammation of unknown origin (IUO) which is defined as increased inflammatory parameters without fever and no diagnosis after the abovementioned investigations. Causes and workup for both FUO and IUO are the same [7]. It is highly advised to use these definitions in future research, so that study results can be easily compared.

13.2

The Clinical Questions

FUO has an extensive differential diagnosis which can be subdivided in four categories: infections, malignancies, noninfectious inflammatory diseases (NIID), and miscellaneous causes [6, 8]. In Western countries, infections account for one-fifth of FUO cases, with next in frequency NIID and malignancies. In non-Western countries, infections (mostly tuberculosis) are a much more common cause of FUO (43% versus 17%) with similar cases due to NIID and malignancies [9]. NIID in FUO includes systemic rheumatologic and vasculitis diseases, granulomatous diseases (i.e., sarcoidosis and Crohn’s disease), and hereditary periodic fever syndromes. In most cases of FUO, the fever is caused by an uncommon presentation of a common disease, such as a large vessel vasculitis without the typical clinical signs and symptoms. Miscellaneous causes are drug fever, pulmonary embolisms, and factitious fever. For diagnosing FUO, it is very important to search for potentially diagnostic clues (PDCs) in a complete and repeated history-taking, physical examination, and the essential investigations. PDCs are defined as all localizing signs, symptoms, and abnormalities potentially indicating a certain diagnosis. A limited list of probable diagnoses based on these PDCs could then be drawn. Further diagnostic procedures should be limited to specific investigations to confirm or exclude these possible diseases, because most investigations are helpful only when performed in patients with PDCs for the diagnosis searched for. When PDCs are absent, whole-body imaging should be performed to guide additional diagnostic tests. Focal inflammatory and infectious processes can be detected by conventional radiologic imaging techniques, such as CT and MRI. However, inflammatory and infectious lesions can remain undetected, as substantial anatomic changes take time to develop and may be absent in an early phase. Distinction between active foci and residual changes due to cured processes or surgery is a limitation of these techniques. Scintigraphic imaging is a noninvasive method allowing delineation of both

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localization and number of infectious and inflammatory foci in all parts of the body, based on functional (physiological and/or biochemical) changes of tissues rather than anatomical changes.

13.3

Gamma Camera Imaging

13.3.1

67

Ga-Citrate Scintigraphy

The value of 67Ga-Citrate scintigraphy has been investigated in patients with FUO. Knockaert et al. investigated the diagnostic contribution of 67Ga-Citrate scintigraphy in 145 patients with FUO. In 99 out of 145 patients (68%), a final diagnosis was established. Of all 82 abnormal scans, 42 (29%) were considered as helpful in the diagnosis of FUO [10]. Habib et  al. retrospectively studied the value of 67 Ga-Citrate scintigraphy in 102 patients with FUO [11]. In this study, only 21% of scans contributed to the diagnosis, and in 2%, the contribution of 67Ga-Citrate scintigraphy was considered significant or crucial. Blockmans et al. performed a study on 67Ga-Citrate scintigraphy and 18F-FDG-PET in 40 patients with FUO [12]. 67 Ga-Citrate scintigraphy was helpful in 25% and 18F-FDG-PET was helpful in 35% of cases. Meller et al. prospectively compared 67Ga-Citrate SPECT to 18F-FDG-PET in 18 patients with FUO [13]. Sensitivity and specificity for 18F-FDG-PET were 81% and 86%, respectively. For 67Ga-Citrate SPECT, sensitivity was 67% and specificity was 78%. The authors concluded 18F-FDG-PET to be superior to 67Ga-Citrate SPECT in FUO, due to the superior tracer kinetics and better spatial resolution in 18 F-FDG-PET. General disadvantages of 67Ga-Citrate scintigraphy are its high radiation burden, long physical half-life (78 h) of 67Ga, and therefore delayed imaging up to 72 h after tracer injection. These unfavorable characteristics, the limited specificity, and the development of newer radiopharmaceuticals have resulted in the replacement of 67Ga-Citrate scintigraphy for many indications.

13.3.2 Leukocyte Scintigraphy Leukocyte scintigraphy with radioactive isotopes (111In or 99mTc) is widely used in many acute and several chronic infections and inflammatory diseases; however, it has not been extensively studied in patients with FUO.  Kjaer et  al. performed a retrospective study on 31 patients with FUO who underwent 111In-leukocyte scintigraphy which was helpful in 19% of all cases [14]. Sensitivity, specificity, negative predictive value, and positive predictive value were 75%, 83%, 60%, and 90%, respectively. CRP was elevated in all patients with positive scans and only in half of patients with true-negative scans. Kjaer et  al. also prospectively compared 111 In-leukocyte scintigraphy to 18F-FDG-PET in patients with FUO [15]. Nineteen patients with FUO underwent both 111In-leukocyte scintigraphy and 18F-FDG-PET

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within 1 week. For 111In-leukocyte scintigraphy, sensitivity was 71% and specificity was 92%. For 18F-FDG-PET, sensitivity was 50% and specificity was 46%. In this study, 18F-FDG-PET was performed without combined CT. 18F-FDG-PET results were often considered as false-positive when nonspecific 18F-FDG uptake was found in patients without a final FUO diagnosis. Results of some small studies performed in the 1980s cannot be directly extrapolated to current clinical practice, as the percentage of patients with FUO diagnosed with infectious diseases has decreased [6], and leukocyte scintigraphy is especially helpful in diagnosing infectious diseases. Labeled leukocytes only rarely accumulate in neoplastic diseases [16]. Although the number of patients with FUO who are diagnosed with neoplastic diseases may be small, the therapeutic and prognostic consequences of a delay in diagnosis of malignancies are clinically very important. High accuracy in diagnosing neoplastic disease should be an important characteristic of a nuclear imaging technique in these patients.

13.3.3 Immunoscintigraphy The value of immunoscintigraphy with 99mTc-labeled antigranulocyte antibody antiNCA-95 (BW 250/183, IgG1) was investigated in a retrospective study in 34 FUO patients [17]. In this study, an infectious cause for fever was found in 59% of patients. The sensitivity and specificity of immunoscintigraphy for infection were 40% and 92%, respectively. Another retrospective study on this imaging technique in 51 patients with FUO showed a helpfulness of 27% with scintigraphy positive in 12 out of 18 patients with infection and in 2 out of 4 patients with neoplastic disease [18]. The major drawback of radiolabeled anti-NCA-95, however, is the production of HAMA (human anti-mouse antibody) after the first injection.

13.4

PET Imaging

13.4.1

18

F-FDG-PET

Because 18F-FDG-PET provides whole-body imaging in a single session with a relatively low radiation exposure, it plays an important role in the diagnosis of patients with FUO in clinical practice. Many studies on the value of 18F-FDG-PET and 18F-FDG-PET/CT in the diagnosis of FUO have been published, often referring to the effectiveness of these imaging techniques in terms of sensitivity, specificity, and clinical helpfulness. However, calculating sensitivity and specificity in patients with FUO is difficult or even misleading due to the lack of a true gold standard. Also, in a relatively high number of patients, a final diagnosis cannot be established, and nonspecific 18F-FDG-uptake could lead to false-positive findings and to shortcomings in the follow-up of these findings. Therefore, in FUO it is more useful to investigate the clinical helpfulness of 18F-FDG-PET and 18F-FDG-PET/CT rather

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than sensitivities and specificities [19]. 18F-FDG-PET/CT is helpful when the F-FDG-PET/CT contributes to the final causal diagnosis of FUO. The value of 18F-FDG-PET (without combined CT) in FUO patients has been studied in several studies [15, 20–25]. Seshadri et al. [20] investigated the value of 18 F-FDG-PET scans in 23 patients with FUO. 18F-FDG-PET was helpful in 52% of patients with FUO. In a large Japanese multicenter retrospective survey, Kubota et al. [21] analyzed the diagnostic results of 18F-FDG-PET for FUO according to four groups of final diagnosis: infection; arthritis, vasculitis, or other autoimmune/collagen disease (A/V); tumor/granuloma (T/G); and other/unknown (O/U) diagnoses. Sensitivity was highest in the T/G group (100%, 7/7), followed by the infection group (89%, 24/27), the A/V group (65%, 11/17), and the O/U group (0%, 0/1). Overall helpfulness of 18F-FDG-PET was 51%. Bleeker-Rovers et al. [22] showed that 18F-FDG-PET was used to provide a final diagnosis in 35 (50%) patients of 70 included patients with FUO. 18F-FDG-PET was considered helpful in 66% of all patients with a final diagnosis and 18F-FDG-PET contributed to the ultimate diagnosis in 33% of all patients. Buysschaert et al. [23] performed a prospective study of 74 patients with FUO. Of all 18F-FDG-PET scans, 53 (72%) were abnormal, and a final diagnosis was established in 39 (53%). In those 39 patients with a final diagnosis, 49% of the scans were helpful. In the study of Kjaer et al. in 19 patients with FUO, helpfulness of 18F-FDG-PET was 16% [15]. In 35 patients with FUO, Bleeker-Rovers et al. [24] retrospectively studied the contribution of 18F-FDG-PET and observed that 18 F-FDG-PET was helpful in 37%. A small retrospective study of 16 patients with FUO showed that 18F-FDG-PET led to the final diagnosis in 11 patients (69%) [25]. Comparing these studies is difficult. The exact definition of FUO was different in most of the studies underlining the need to use the same definition when doing research on this subject. In some studies, the patient population is (highly) selected as not all patients with FUO referred to the hospital were recruited but only those patients referred to the Nuclear Medicine Department [21] or Department of Infectious Diseases [15]. In the retrospective study of Kubota et al. [21], a PET/CT scanner was used in some cases; unfortunately the exact number of patients who underwent PET/ CT was not mentioned. In general, 18F-FDG-PET was often performed without a structured diagnostic protocol and therefore at different stages of the diagnostic process of FUO. Bleeker-Rovers et al. [6] showed that using a structured diagnostic protocol, including 18F-FDG-PET, reduces the chance of selection bias. 18

13.5

Role of Hybrid Imaging

13.5.1

67

Ga-SPECT/CT

The only study on the value of SPECT/CT in patients with FUO is performed by Hung et al. [26]. In this study, 58 patients with FUO underwent both 18F-FDG-PET/ CT and 67Ga-SPECT/CT within 7  days from each other. 18F-FDG-PET/CT was helpful in 57% of patients versus 33% for 67Ga-SPECT/CT. In 67Ga-SPECT/CT, a

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high false-negative rate of 55% was observed. 18F-FDG-PET/CT scans depicted all 67 Ga-avide lesions.

13.5.2

18

F-FDG-PET/CT

For 18F-FDG-PET/CT, improved anatomical resolution by direct integration with CT has further boosted the accuracy of 18F-FDG-PET. 18F-FDG-PET/CT has some advantages compared to conventional techniques such as CT and MRI.  First, 18 F-FDG-PET/CT is more suitable as a screening method when clues for specific sites of infection are absent because it provides whole-body imaging in a single session without increasing radiation exposure. Second, it detects early metabolic activity rather than the relatively late anatomical changes as visualized by CT or MRI and does not rely on nonspecific signs such as edema or increased perfusion. Also, there are less artifacts due to metallic hardware, and there are no contrast-related reactions. In contrast to conventional nuclear imaging techniques, 18F-FDG-PET/CT has the advantages of higher resolution, higher sensitivity in chronic low-grade infections, and high accuracy in the central skeleton, as well as the short time period between injection of the radiopharmaceutical and the moment of image acquisition [27]. The value of 18F-FDG-PET/CT has been investigated in three prospective studies and in 15 retrospective studies in 1101 patients with FUO [26, 28–44]. Keidar et al. performed one study on the value of 18F-FDG-PET/CT in 48 patients with FUO [28]. In this study, 18F-FDG-PET/CT identified the underlying etiology of FUO in 22 patients (46%). In 90% of cases, 18F-FDG-PET/CT contributed clinically important information to the diagnosis by exclusion of a focal etiology. Schonau et al. performed a prospective study in 240 patients with both FUO and IUO [44]. 18 F-FDG-PET/CT was helpful in 56.7% of all patients and in 71.6% of patients with a final diagnosis. Absence of intermittent fever, higher age, and elevated CRP level increased the likelihood of a helpful 18F-FDG-PET/CT. Hung et al. [26] prospectively included 58 patients with FUO who underwent both 18F-FDG-PET/CT and 67 Ga-SPECT/CT within 7 days from each other. 18F-FDG-PET/CT was helpful in 57% of patients versus 33% for 67Ga-SPECT/CT. Balink et al. [29] retrospectively included 68 patients with FUO. 18F-FDG-PET/CT was helpful in 56% and in 93% of positive studies and 18F-FDG-PET/CT led to the causal source of FUO either by identifying the etiology of the FUO or by guiding further management. Federici et al. [30] investigated the value of 18F-FDG-PET/CT in ten patients with FUO and four patients with unexplained inflammatory syndrome without fever. In 50% of patients with FUO, 18F-FDG-PET/CT was helpful. Ferda et  al. [31] performed a retrospective study in 48 patients with FUO and 18F-FDG-PET/CT was concluded to be helpful in 54% of cases. The study of Kei et al. [32] in 12 patients with FUO showed 18F-FDG-PET/CT to be helpful in 42%. Sheng et  al. [33] included 48 patients with FUO, and 18F-FDG-PET/CT was helpful in 67% of the cases. In 36 patients (75%), a final diagnosis was established, and in 89% of these patients,

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18

F-FDG-PET/CT contributed to this diagnosis. The study of Pelosi et al. [34] in 24 patients with FUO showed 18F-FDG-PET/CT to be helpful in 46%. Pedersen et al. [35] retrospectively included 22 patients with FUO and 18F-FDG-PET/CT successfully identified the cause of FUO in 45%. Crouzet et al. [36] investigated the value of 18F-FDG-PET/CT in 79 patients with FUO. 18F-FDG-PET/CT was helpful in 57% of all patients. In all patients with a final diagnosis, 18F-FDG-PET/CT contributed to the final diagnosis in 74%. The study of Kim et al. [37] in 48 patients with FUO showed 18F-FDG-PET/CT to be helpful in 52%. Another study of Manohar et al. [42] in 103 patients with FUO investigated the role of 18F-FDG-PET/CT, and it was helpful in 60% of patients. Of all 63 patients with a final diagnosis, 18F-FDGPET/CT contributed to this diagnosis in 98% of these patients. Tokmak et al. [38] investigated 21 patients with FUO, and in these patients 18F-FDG-PET/CT was helpful in 60%. In the study of Buch-Olsen et al. [43], 18F-FDG-PET/CT was helpful in 53% of 57 FUO patients. Singh et al. [39] included 47 patients with FUO, and 18 F-FDG-PET/CT was helpful in 38% of patients. In this study, a final diagnosis could be established in 53% of patients. The largest retrospective study performed on the value of 18F-FDG-PET/CT in FUO is of Gafter-Gvili et al. [41]. In this study in 112 patients with FUO, 18F-FDG-PET/CT was helpful in 46% of patients. Pereira et  al. [40] investigated the role of 18F-FDG-PET/CT in 76 patients of FUO, and 18 F-FDG-PET/CT was helpful in 60% of patients. Comparing all studies on 18 F-FDG-PET/CT in patients with FUO is difficult. The definition of FUO was not further specified in seven studies [29, 31, 33, 34, 36, 37, 43]. In general, the exact definition of FUO varied in all studies. In the study of Pereira et al., immunocompromised patients were included [40] although these patients need a different approach and are difficult to compare with non-immunocompromised patients with FUO. In most of the studies no follow-up term was mentioned. Also, because the majority of these studies were retrospective studies, there may be inclusion bias as patients with negative findings on conventional imaging techniques are more likely to undergo 18F-FDG-PET/CT than patients with positive findings. The difference in timing of 18F-FDG-PET/CT as well as the selection of patients could have affected the calculation of clinical helpfulness.

13.5.3 Cost-Effectiveness of 18F-FDG-PET/CT in FUO One Spanish study has been published on the cost-effectiveness of 18F-FDG-PET/ CT in 20 patients with FUO [45]. The mean cost per patient of the diagnostic procedures preceding 18F-FDG-PET/CT was €11,167, including an average of 11 days of hospitalization and outpatient checks. If 18F-FDG-PET/CT had been performed earlier in the diagnostic process, €5471 per patient would have been saved on hospitalization days and diagnostic tests. Another study on cost-effectiveness of 18 F-FDG-PET/CT in 46 patients with IUO has been published [46]. In this retrospective study, all patients underwent 18F-FDG-PET/CT and were compared with

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46 patients with IUO without 18F-FDG-PET/CT being performed. In patients who underwent 18F-FDG-PET/CT, a final diagnosis was established in 32 patients (70%). Estimated mean cost per patient of all diagnostic procedures with 18F-FDG-PET/CT was €1821. When adding the cost of mean number of hospitalization days per patient (6.9 days, range 0–32 days), the mean cost increased to €5298 per patient. In patients without 18F-FDG-PET/CT being performed, a diagnosis was reached in 14 patients (30%). Estimated mean cost per patient of all diagnostic procedures without 18F-FDG-PET/CT was €2051. When adding the cost of mean number of hospitalization days per patient (21 days, range unknown), the mean cost increased to €12,614 per patient. So, 18F-FDG-PET/CT has the potential to become a costeffective routine imaging technique for further diagnostic decision-making by avoiding unnecessary, invasive, and expensive investigations and by reducing the duration of hospitalization.

13.5.4 Timing of 18F-FDG-PET/CT in FUO Bleeker-Rovers et al. showed that 18F-FDG-PET (without combined CT) did not contribute to the final diagnosis of FUO in case of normal C-reactive protein (CRP) and/ or erythrocyte sedimentation rate (ESR) [22]. In a large retrospective study in 498 patients with FUO and IUO, the predictive values of CRP and ESR to a positive 18 F-FDG-PET/CT result were determined [47]. In 331 of 498 patients, a final diagnosis was established. 18F-FDG-PET/CT had a diagnostic accuracy of 89%. Elevated CRP reflected the presence and degree of inflammation more truly compared to ESR. 18 F-FDG-PET/CT was 100% true negative only in patients with CRP less than 5 mg/L. The retrospective study by Okuyucu et al. investigating 76 patients with FUO found 18F-FDG-PET/CT to be helpful and contributory for the diagnosis of FUO when patients had higher levels of CRP and ESR [48]. A prospective study on 240 patients with FUO or IUO showed that elevated CRP level increased the likelihood for a diagnostic 18F-FDG-PET/CT [44]. A recent retrospective study on 104 patients with FUO or IUO showed that 18F-FDG-PET/CT was never contributive to the diagnosis when both inflammatory parameters and body temperature were normal [49].

13.6

Future Perspectives and New Trends

In patients with FUO, 18F-FDG-PET/CT is the imaging technique of choice when PDCs are absent to guide additional diagnostic tests. 18F-FDG-PET/CT has favorable characteristics with high resolution, relatively low radiation burden, imaging performed within 2  h, and no contrast-related reactions. 18F-FDG-PET/CT has been extensively studied in patients with FUO and has an overall clinical helpfulness of 55% [50], which is higher compared to other imaging techniques.

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Fig. 13.1 A 70-year-old woman presented with malaise, weight loss, and night sweats. Laboratory results showed increased ESR (100 mm/h) and anemia (Hb 6.4 mmol/L). Blood cultures were negative. 18F-FDG-PET/ CT showed increased 18F-FDG uptake of the large vessels. This patient was treated with corticosteroids for the diagnosis of large vessel vasculitis

18

F-FDG-PET/CT should therefore be the routine procedure in the workup of FUO when diagnostic clues are absent. 18F-FDG-PET/CT appears to be costeffective in FUO by avoiding unnecessary investigations and reducing duration of hospitalization. 18F-FDG-PET/CT should be performed when CRP levels are increased (Fig. 13.1). Hybrid PET/MR systems are more and more available for clinical use. No studies on the value of PET/MR in FUO have been performed. Advantages of combination of PET with MR are the excellent soft tissue contrast of MR compared to CT, the lack of ionizing radiation, and diffusion weighted imaging. PET/MR, as for PET/CT, could be used in FUO patients and could provide a better contrast in soft tissue and vertebrae. Of course, in children with FUO, PET/MR could be preferred because of the lack of radiation burden (Table 13.1).

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Table 13.1 Imaging modalities in diagnosis of fever of unknown origin Gamma-camera imaging 67 Ga-Citrate

Why Replaced by PET/CT imaging due to unfavorable characteristics

When Replaced by PET imaging due to unfavorable characteristics

How Delayed imaging 48 h and 72 h after injection

Pitfalls Limited specificity

111

In-leukocyte scintigraphy

Shows increased uptake in case of infection/ inflammation

Not in neutropenic patients

Imaging 3 h, 24 h, and 48 h after injection

Low sensitivity in neoplastic disease

99m

Tc-labeled antigranulocyte antibody

Shows increased uptake in case of infection/ inflammation

Not in neutropenic patients

Imaging 30 min, 3 h, and 24 h after injection

Low sensitivity in neoplastic disease

PET imaging 18 F-FDG-PET

Why Replaced by PET/CT imaging

When Replaced by PET/CT imaging

How Imaging 1 h after injection

Pitfalls Poor anatomical localization and limited spatial resolution

18

First-choice imaging technique in FUO

First-choice imaging technique in FUO

Imaging 1 h after injection

Limited spatial resolution

F-FDG-PET/ CT

Interpretation criteria Focal accumulation with intensity higher than surrounding tissue indicates inflammation Focal accumulation with intensity higher than surrounding tissue indicates inflammation Focal accumulation with intensity higher than surrounding tissue indicates inflammation Interpretation criteria Focal accumulation with intensity higher than surrounding tissue indicates inflammation Focal accumulation with intensity higher than surrounding tissue indicates inflammation

References 1. Petersdorf RG, Beeson PB.  Fever of unexplained origin: report on 100 cases. Medicine (Baltimore). 1961;40:1–30. 2. Petersdorf RG.  Fever of unknown origin. An old friend revisited. Arch Intern Med. 1992;152(1):21–2. 3. Durack DT, Street AC. Fever of unknown origin—reexamined and redefined. Curr Clin Top Infect Dis. 1991;11:35–51.

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4. de Kleijn EM, Vandenbroucke JP, van der Meer JW. Fever of unknown origin (FUO). I A. prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. The Netherlands FUO Study Group. Medicine. 1997;76(6):392–400. 5. de Kleijn EM, van Lier HJ, van der Meer JW. Fever of unknown origin (FUO). II. Diagnostic procedures in a prospective multicenter study of 167 patients. The Netherlands FUO Study Group. Medicine. 1997;76(6):401–14. 6. Bleeker-Rovers CP, Vos FJ, de Kleijn EM, Mudde AH, Dofferhoff TS, Richter C, et  al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine. 2007;86(1):26–38. 7. Vanderschueren S, Del Biondo E, Ruttens D, Van Boxelaer I, Wauters E, Knockaert DD. Inflammation of unknown origin versus fever of unknown origin: two of a kind. Eur J Intern Med. 2009;20(4):415–8. 8. Vanderschueren S, Knockaert D, Adriaenssens T, Demey W, Durnez A, Blockmans D, et al. From prolonged febrile illness to fever of unknown origin: the challenge continues. Arch Intern Med. 2003;163(9):1033–41. 9. Mulders-Manders C, Simon A, Bleeker-Rovers C. Fever of unknown origin. Clin Med (Lond). 2015;15(3):280–4. 10. Knockaert DC, Mortelmans LA, De Roo MC, Bobbaers HJ. Clinical value of gallium-67 scintigraphy in evaluation of fever of unknown origin. Clin Infect Dis. 1994;18(4):601–5. 11. Habib GS, Masri R, Ben-Haim S. The utility of gallium scintigraphy in the evaluation of fever of unknown origin. Isr Med Assoc J. 2004;6(8):463–6. 12. Blockmans D, Knockaert D, Maes A, De Caestecker J, Stroobants S, Bobbaers H, et  al. Clinical value of [(18)F]fluoro-deoxyglucose positron emission tomography for patients with fever of unknown origin. Clin Infect Dis. 2001;32(2):191–6. 13. Meller J, Altenvoerde G, Munzel U, Jauho A, Behe M, Gratz S, et al. Fever of unknown origin: prospective comparison of [18F]FDG imaging with a double-head coincidence camera and gallium-67 citrate SPET. Eur J Nucl Med. 2000;27(11):1617–25. 14. Kjaer A, Lebech AM. Diagnostic value of (111)In-granulocyte scintigraphy in patients with fever of unknown origin. J Nucl Med. 2002;43(2):140–4. 15. Kjaer A, Lebech AM, Eigtved A, Hojgaard L. Fever of unknown origin: prospective comparison of diagnostic value of 18F-FDG PET and 111In-granulocyte scintigraphy. Eur J Nucl Med Mol Imaging. 2004;31(5):622–6. 16. Schell-Frederick E, Fruhling J, Van der Auwera P, Van Laethem Y, Klastersky J. 111Indiumoxine-labeled leukocytes in the diagnosis of localized infection in patients with neoplastic disease. Cancer. 1984;54(5):817–24. 17. Becker W, Dolkemeyer U, Gramatzki M, Schneider MU, Scheele J, Wolf F.  Use of immunoscintigraphy in the diagnosis of fever of unknown origin. Eur J Nucl Med. 1993;20(11):1078–83. 18. Meller J, Ivancevic V, Conrad M, Gratz S, Munz DL, Becker W. Clinical value of immunoscintigraphy in patients with fever of unknown origin. J Nucl Med. 1998;39(7):1248–53. 19. Meller J, Sahlmann CO, Scheel AK. 18F-FDG PET and PET/CT in fever of unknown origin. J Nucl Med. 2007;48(1):35–45. 20. Seshadri N, Sonoda LI, Lever AM, Balan K.  Superiority of 18F-FDG PET compared to 111In-labelled leucocyte scintigraphy in the evaluation of fever of unknown origin. J Infect. 2012;65(1):71–9. 21. Kubota K, Nakamoto Y, Tamaki N, Kanegae K, Fukuda H, Kaneda T, et  al. FDG-PET for the diagnosis of fever of unknown origin: a Japanese multi-center study. Ann Nucl Med. 2011;25(5):355–64. 22. Bleeker-Rovers CP, Vos FJ, Mudde AH, Dofferhoff ASM, de Geus-Oei LF, Rijnders AJ, et al. A prospective multi-centre study of the value of FDG-PET as part of a structured diagnostic protocol in patients with fever of unknown origin. Eur J Nucl Med Mol Imaging. 2007;34(5):694–703. 23. Buysschaert I, Vanderschueren S, Blockmans D, Mortelmans L, Knockaert D. Contribution of (18)fluoro-deoxyglucose positron emission tomography to the work-up of patients with fever of unknown origin. Eur J Intern Med. 2004;15(3):151–6.

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24. Bleeker-Rovers CP, de Kleijn EM, Corstens FH, van der Meer JW, Oyen WJ. Clinical value of FDG PET in patients with fever of unknown origin and patients suspected of focal infection or inflammation. Eur J Nucl Med Mol Imaging. 2004;31(1):29–37. 25. Lorenzen J, Buchert R, Bohuslavizki KH. Value of FDG PET in patients with fever of unknown origin. Nucl Med Commun. 2001;22(7):779–83. 26. Hung BT, Wang PW, Su YJ, Huang WC, Chang YH, Huang SH, et al. The efficacy of 18FFDG PET/CT and 67Ga SPECT/CT in diagnosing fever of unknown origin. Int J Infect Dis. 2017;62:10–7. 27. Bleeker-Rovers CP, Boerman OC, Rennen HJ, Corstens FH, Oyen WJ. Radiolabeled compounds in diagnosis of infectious and inflammatory disease. Curr Pharm Des. 2004;10(24):2935–50. 28. Keidar Z, Gurman-Balbir A, Gaitini D, Israel O. Fever of unknown origin: the role of 18FFDG PET/CT. J Nucl Med. 2008;49(12):1980–5. 29. Balink H, Collins J, Bruyn GA, Gemmel F. F-18 FDG PET/CT in the diagnosis of fever of unknown origin. Clin Nucl Med. 2009;34(12):862–8. 30. Federici L, Blondet C, Imperiale A, Sibilia J, Pasquali JL, Pflumio F, et  al. Value of (18) F-FDG-PET/CT in patients with fever of unknown origin and unexplained prolonged inflammatory syndrome: a single centre analysis experience. Int J Clin Pract. 2010;64(1):55–60. 31. Ferda J, Ferdova E, Zahlava J, Matejovic M, Kreuzberg B. Fever of unknown origin: a value of (18)F-FDG-PET/CT with integrated full diagnostic isotropic CT imaging. Eur J Radiol. 2010;73(3):518–25. 32. Kei PL, Kok TY, Padhy AK, Ng DC, Goh AS. [18F] FDG PET/CT in patients with fever of unknown origin: a local experience. Nucl Med Commun. 2010;31(9):788–92. 33. Sheng JF, Sheng ZK, Shen XM, Bi S, Li JJ, Sheng GP, et al. Diagnostic value of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in patients with fever of unknown origin. Eur J Intern Med. 2011;22(1):112–6. 34. Pelosi E, Skanjeti A, Penna D, Arena V. Role of integrated PET/CT with [(1)(8)F]-FDG in the management of patients with fever of unknown origin: a single-centre experience. Radiol Med. 2011;116(5):809–20. 35. Pedersen TI, Roed C, Knudsen LS, Loft A, Skinhoj P, Nielsen SD.  Fever of unknown origin: a retrospective study of 52 cases with evaluation of the diagnostic utility of FDG-PET/ CT. Scand J Infect Dis. 2012;44(1):18–23. 36. Crouzet J, Boudousq V, Lechiche C, Pouget JP, Kotzki PO, Collombier L, et al. Place of (18) F-FDG-PET with computed tomography in the diagnostic algorithm of patients with fever of unknown origin. Eur J Clin Microbiol Infect Dis. 2012;31(8):1727–33. 37. Kim YJ, Kim SI, Hong KW, Kang MW. Diagnostic value of 18F-FDG PET/CT in patients with fever of unknown origin. Intern Med J. 2012;42(7):834–7. 38. Tokmak H, Ergonul O, Demirkol O, Cetiner M, Ferhanoglu B. Diagnostic contribution of (18) F-FDG-PET/CT in fever of unknown origin. Int J Infect Dis. 2014;19:53–8. 39. Singh N, Kumar R, Malhotra A, Bhalla AS, Kumar U, Sood R. Diagnostic utility of fluorodeoxyglucose positron emission tomography/computed tomography in pyrexia of unknown origin. Indian J Nucl Med. 2015;30(3):204–12. 40. Pereira AM, Husmann L, Sah BR, Battegay E, Franzen D. Determinants of diagnostic performance of 18F-FDG PET/CT in patients with fever of unknown origin. Nucl Med Commun. 2016;37(1):57–65. 41. Gafter-Gvili A, Raibman S, Grossman A, Avni T, Paul M, Leibovici L, et al. [18F]FDG-PET/ CT for the diagnosis of patients with fever of unknown origin. QJM. 2015;108(4):289–98. 42. Manohar K, Mittal BR, Jain S, Sharma A, Kalra N, Bhattacharya A, et al. F-18 FDG-PET/CT in evaluation of patients with fever of unknown origin. Jpn J Radiol. 2013;31(5):320–7. 43. Buch-Olsen KM, Andersen RV, Hess S, Braad PE, Schifter S. 18F-FDG-PET/CT in fever of unknown origin: clinical value. Nucl Med Commun. 2014;35(9):955–60. 44. Schonau V, Vogel K, Englbrecht M, Wacker J, Schmidt D, Manger B, et al. The value of (18) F-FDG-PET/CT in identifying the cause of fever of unknown origin (FUO) and inflammation of unknown origin (IUO): data from a prospective study. Ann Rheum Dis. 2018;77(1):70–7.

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45. Nakayo EMB, Vicente AMG, Castrejon AMS, Narvaez JAM, Rubio MPT, Garcia VMP, et al. Analysis of cost-effectiveness in the diagnosis of fever of unknown origin and the role of F-18-FDG PET-CT: a proposal of diagnostic algorithm. Rev Esp Med Nucl Imagen Mol. 2012;31(4):178–86. 46. Balink H, Tan SS, Veeger NJ, Holleman F, van Eck-Smit BL, Bennink RJ, et al. (1)(8)F-FDG PET/CT in inflammation of unknown origin: a cost-effectiveness pilot-study. Eur J Nucl Med Mol Imaging. 2015;42(9):1408–13. 47. Balink H, Veeger NJ, Bennink RJ, Slart RH, Holleman F, van Eck-Smit BL, et al. The predictive value of C-reactive protein and erythrocyte sedimentation rate for 18F-FDG PET/CT outcome in patients with fever and inflammation of unknown origin. Nucl Med Commun. 2015;36(6):604–9. 48. Okuyucu K, Alagoz E, Demirbas S, Ince S, Karakas A, Karacalioglu O, et al. Evaluation of predictor variables of diagnostic [18F] FDG-PET/CT in fever of unknown origin. Q J Nucl Med Mol Imaging. 2018;62(3):313–20. 49. Mulders-Manders CM, Kouijzer IJE, Janssen MJR, Oyen WJG, Simon A, Bleeker-Rovers CP.  Optimal use of [18F]FDG-PET/CT in patients with fever or inflammation of unknown origin. Q J Nucl Med Mol Imaging. 2019 [accepted for publication]. 50. Kouijzer IJE, Mulders-Manders CM, Bleeker-Rovers CP, Oyen WJG. Fever of unknown origin: the value of FDG-PET/CT. Semin Nucl Med. 2018;48(2):100–7.

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Barbara Juarez Amorim, Benedikt Michael Schaarschmidt, Johannes Grueneisen, Shahein Tajmir, Lale Umutlu, Alberto Signore, and Onofrio Antonio Catalano

14.1

General Introduction

Morphologic imaging, like ultrasound (US), computed tomography (CT), and magnetic resonance (MR) are first-line imaging modalities used to evaluate abdominopelvic pathologies. They are available on a large scale and are cost-effective, and, in the case of US and MR, they are also radiation-free. However, in some cases, reaching a diagnosis only on the basis of morphologic imaging might be challenging. B. J. Amorim Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Division of Nuclear Medicine, State University of Campinas (UNICAMP), Campinas, Brazil B. M. Schaarschmidt · J. Grueneisen · L. Umutlu Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Essen, Germany S. Tajmir Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA A. Signore Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, “Sapienza” University of Rome, Rome, Italy e-mail: [email protected] O. A. Catalano (*) Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Department of Radiology, Parthenope University, Naples, Italy e-mail: [email protected] © Springer Nature Switzerland AG 2020 A. Signore, A. W. J. M. Glaudemans (eds.), Nuclear Medicine in Infectious Diseases, https://doi.org/10.1007/978-3-030-25494-0_14

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Nuclear medicine, being able to evaluate lesion metabolism, can provide important additional information. Nowadays, 18F-FDG PET/CT plays a major role not only in oncologic imaging but also in infectious and inflammatory disease. Other radiopharmaceutical and nuclear medicine modalities, like gallium-67 citrate or radiolabeled white blood cells (WBC) scintigraphy, due to technical challenges, low availability on the territory, and poor resolution, are rarely used. On the other hand, 18 F-FDG PET/CT, due to its wide availability, high sensitivity, and technical standardization, has been used more and more often. It may allow an early diagnosis of infectious and inflammatory disease, may consequently prompt an earlier treatment, and also be used for treatment monitoring. More recently, PET/MR has emerged as a novel tool to image oncological, inflammatory, and infectious diseases. PET/MR has important advantages in the evaluation of abdominal inflammatory and infectious diseases: (1) simultaneous acquisition of PET and MR data allows an ideal co-registration and fusion of the metabolic and morphologic data of the entire abdomen and pelvis, including the bowel, which are subject to breathing-induced motion and peristalsis; (2) higher soft tissue delineation of PET/MR, when compared with PET/CT; (3) lower radiation exposure of PET/MR in relation to PET/CT; (4) complementarity of functional and metabolic investigation through the addition of diffusion weighted imaging (DWI), and in some cases of magnetic resonance perfusion (MRp), to the 18F-FDG PET-based investigation of glucose metabolism. Therefore, PET/MR has the potentiality to replace PET/CT in the infection/inflammatory scenario in the near future. In this chapter, we review the nuclear medicine tools currently employed in the case of abdominal inflammatory and infectious diseases, based on the most recent and relevant literature, as well as on our personal experience. This chapter encompasses from the conventional nuclear medicine imaging studies still used to the most innovative hybrid technologies.

14.2

Inflammatory Bowel Disease

14.2.1 Introduction Idiopathic inflammatory bowel disease (IBD) comprises two types of chronic intestinal disorders: Crohn’s disease and ulcerative colitis. Ulcerative colitis is a longterm condition that results in inflammation and ulcers of the colon and rectum with a continuous involvement of (sub)mucosal wall tissue of the large intestine, starting from the rectum and ascending throughout the colon. Meanwhile, Crohn’s disease is characterized by a chronic/relapsing course, the discontinuous involvement of the gastrointestinal tract with several skipped areas, the tendency to involve any segment of the gastrointestinal tract from the oral cavity to the rectum, and by asymmetric transmural inflammation of the bowel wall [1, 2]. IBD is a global disease with the highest prevalence in Europe and North America, reaching 505 cases per 100,000 habitants for ulcerative colitis and 322 cases per 100,000 habitants for Crohn’s disease. Although the incidence is essentially stable

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in the above regions, IBD incidence is increasing in newly industrialized countries that are adopting a western lifestyle [3].

14.2.2 The Clinical Questions Endoscopy is the gold standard for the evaluation of IBD; however, due to its invasiveness, noninvasive imaging has been extensively used in this setting. Imaging studies can help establish diagnosis, assess disease extent, determine activity, and detect and characterize complications, such as abscesses, fistulae, and strictures. Morphological imaging plays a major role in this evaluation as attested by a consensus of the European Crohn’s and Colitis Organization and European Society of Gastrointestinal and Abdominal Radiology (ECCO/ESGAR) [4]. However, nuclear medicine still plays an important role as detailed below. While abscess and fistulae can be easily evaluated by many imaging modalities, strictures are challenging. Strictures can be caused by acute transmural inflammation, chronic fibrosis, or both. The differentiation has relevant clinical implications since inflammatory strictures are treated with medical therapy, meanwhile fibrotic strictures are treated with surgical resection or dilatation [2, 4].

14.2.3 Gamma-Camera Imaging Gamma-camera imaging may still play a role in IBD, especially through scintigraphy with radiolabeled white blood cells (WBC scintigraphy), using 111In-oxine or 99m Tc-HMPAO (hexamethylpropyleneamine oxine) or with anti-granulocyte antibody (AGA) scintigraphy labeled with technicium-99m In IBD. WBC scintigraphy is useful in the diagnosis of the IBD, especially to evaluate disease extension and activity with a normal scan making the presence of activity disease very unlikely [4, 5]. The labeling with 99mTc-HMPAO is preferred since the use of technicium-99m allows a better quality of images, lower radiation exposure, and more availability. For IBD, usually images are performed in two sections: early images at 30 min to 1 h and delayed images performed up to 4 h. Later images are not indicated since after 4 h physiologic bowel activity will be observed and interfere in interpretation [6]. Although there are some disagreements about what is the best time to perform the late images, a good option can be obtaining images after 2 h as suggested by a study which performed images at three time points (1, 2, and 4 h) [7]. Uptake on early images, which increases over late images, usually linear, is suggestive of bowel inflammation. Shifting patterns of bowel activity on later images usually indicates physiological bowel activity or sometimes bleeding within the bowel lumen. The use of SPECT images has been reported to present with similar accuracy, but these images can allow better information about the disease extent. One advantage is its relatively low radiation exposure (2–4 mSv/exam). However, WBC scintigraphy has important limitations such as the long acquisition time, long preparation time, numerous technical challenges including those

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related to the necessity of blood handling, and the lack of anatomic definition. These limitations have restricted these studies to very few patients per year in few institutions, usually tertiary hospitals. Anti-granulocyte antibody (AGA) scintigraphy labeled with technicium-99m is a less complex and faster procedure. However, its accuracy is reported in literature to be significantly lower with a sensitivity of just 45% compared with 79% for WBC scintigraphy in a meta-analysis [8].

14.2.4 PET and PET/CT Imaging F-fluordesoxiglucose (18F-FDG) is the most available radiopharmaceutical for PET, usually performed for oncological purposes. However, the overexpression of glucose transporter 1 and 3 (GLUT-1 and GLUT-3) by inflammatory and autoimmune diseases allows its application for imaging of inflammatory and infectious processes, such as IBD [9]. Stand-alone PET imaging has been completely replaced by PET/CT imaging. The hybrid devices allow the investigation of disease metabolism and activity in conjunction with morphology, synergistically improving the evaluation of IBD. The former 18F-FDG PET published studies evaluated IBD with stand-alone PET scanners. In one study, the authors evaluated 25 pediatric patients with suspected IBD using PET; endoscopy and biopsy were used as standard of reference. The sensitivity and specificity of PET were 81% and 85%, respectively. In eight of ten patients in whom colonoscopy was limited, FDG-PET localized inflammatory areas in the nonvisualized proximal colon [10]. In another study in 45 pediatric patients, PET had sensitivity and specificity of 82% and 97%, respectively, on a segmentbased analysis. The authors believed that the radiation exposure of 3–7 mSv was justified in those children due to the accuracy of the diagnosis [11]. Another study in 23 children with IBD compared FDG-PET with colonoscopy and ultrasonography (US), using histology as reference. FDG-PET showed sensitivity, specificity, and accuracy of 98%, 68%, and 83%, respectively, as compared to colonoscopy (90%, 75%, and 82%) and US (56%, 92%, and 75%). For the small bowel, FDG-PET had higher values (100%, 86%, and 90%). These bowel segments were not accessible by endoscopy [12]. PET/CT technique in investigating infectious or inflammatory abdominal diseases is similar to the one used in oncologic imaging. Patients may be required to drink six glasses of water as a CT negative contrast. Intravenous contrast is not usually administered. Imaging interpretation can be performed with a simple visual approach comparing bowel activity to liver activity; this is adequate in the clinical settings. A bowel uptake equal or less than the liver is considered physiological. A potential pitfall can be an increased uptake due to the use of metformin [13]. One drawback of PET/CT is the radiation exposure, which is estimated to be around 10 mSv, and approximately half of this radiation comes from the CT scan. There are many studies addressing the utility of 18F-FDG PET/CT in inflammatory bowel disease. Two meta-analyses evaluated the role of FDG-PET and PET/CT 18

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performance in IBD. One meta-analysis compared the FDG-PET performance with WBC and AGA scintigraphy. They found that FDG-PET had a higher diagnostic performance compared with WBC scintigraphy on per-bowel-segment analysis; however, the diagnostic accuracy between FDG-PET and WBC scintigraphy was not statistically significant (pooled sensitivity of 84% and 79%, respectively, and pooled specificity of 86% for both). The authors concluded that WBC scintigraphy can be used with satisfactory diagnostic accuracy when PET scanners are not available [8]. Another meta-analysis found similarly good performance values for FDGPET with a pooled sensitivity and specificity of 85% and 87%, respectively [14]. One study with a total of 22 patients quantitatively evaluated IBD metabolism using SUVmax (the maximum standardized uptake value) and PVC-TLG (partial volume corrected—total lesion glycolysis). These metrics had a significant correlation with pathological and clinical disease activity markers and have been proposed as measurements of global disease activity and treatment response in IBD [15]. Other studies evaluated PET/CT performed in association with negative oral contrast media to induce bowel wall distention, also called PET/CT-enterography (PET/CT-E). One of them recruited 13 patients and revealed that in three patients (23.1%) PET/CT-E showed active inflammation not observed by CT-enterography alone. Overall, PET/CT performed better than CT in detecting and grading active inflammation [16]. In another one performed in 28 patients, the SUVmax from PET/ CT-E was significantly higher in abnormal versus normal bowel segments (5.0 vs. 2.1, respectively). Moreover, SUVmax was capable of differentiating different degrees of disease activity [17]. These data have also been confirmed by other groups [18]. Just few studies addressed the PET/CT capability for evaluating treatment response. One of them with eight Crohn’s disease patients treated with anti-tumor necrosis factor drugs demonstrated a decline in SUVratio (bowel SUV/liver SUV) in patients who achieved clinical response [19]. Another study also detected a decrease in a visual score uptake after treatment [20]. More recently, PET/MR has being applied in the evaluation of patients affected by benign conditions such as inflammatory diseases. This novel tool can offer multiple potential advantages compared to PET/CT, including reduction in radiation exposure, improved anatomic detail, higher soft tissue resolution, additional functional capabilities of MR, and co-acquisition. For equivalent injected activity, PET/ MR allows a 20% reduction in radiation exposure if only CT for attenuation correction is used and up to 60–73% when also diagnostic quality CT is acquired [21]. In the bowel evaluation, the co-acquisition is especially important since it allows better fusion of morphological and metabolic images, reducing the miss-registration, which frequently occur in the asynchronously acquired PET/CT due to bowel peristalsis. There are still very few but promising studies investigating PET/MR in IBD. These studies have been performed with enterography MR (PET/MR-E). In our practice we invite patients to start drinking a negative oral contrast solution, usually a diluted polyethylene-glycol solution, about 2  h before being scanned. Additionally, 5 min before scan, N-butilbromur of joscine (Buscopan®) or Glucagon

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Fig. 14.1 18F-FDG PET/MR in a patient with Crohn’s disease. (a) FDG-PET; (b) Fused PET/MR; (c) MR STIR. Notice the perfect fusion of PET and MR images showing an inflamed terminal ileum loop with wall thickening and marked FDG uptake

is injected intravenously. Images are acquired typically 60–80 min after FDG injection starting from the mid-thigh and moving upward to the diaphragm; co-acquired PET and MR sequences are obtained before and after gadolinium chelates intravenous injection. Figure 14.1 shows a PET/MR in a patient with Crohn’s disease. One study compared PET/MR-E, PET/CT, and MR-E alone in 35 patients with small bowel Crohn’s disease. All three methods were equally accurate in detecting inflammation sites. However, PET/MR was more accurate in detecting a fibrotic component compared to PET/CT and MR alone. Specifically, PET/CT accuracy was 28% versus 67% from PET/MR-E. The SUVmax analysis showed that the best SUVmax cutoff was 2.95 (82% sensitivity and 88% specificity) in identifying a fibrotic component with mild inflammation [22]. Another study, performed in 19 Crohn’s disease patients, evaluated PET/MR-E capability in discriminating inflammatory from fibrotic strictures. It analyzed several quantitative parameters and their combination: SUVmax, signal intensity on T2w images, and ADC values from diffusion MR images. The best discriminator between both entities was a combined PET/MR-E biomarker ADC × SUVmax [23]. In another recent study with 52 Crohn’s disease patients, PET/MR-E significantly improved specificity (93% vs. 71%) and diagnostic accuracy (92% vs. 73%) compared to conventional MR indices to detect both active inflammation and severe inflammation [24].

14.2.5 Future Perspectives and New Trends Currently, 18F-FDG PET/CT, due to its good accuracy, seems to be the nuclear medicine test of choice in the settings of IBD. It allows a noninvasive evaluation and quantification of bowel inflammation. WBC scintigraphy is the most classical study in IBD and has been performed for many years with a very good accuracy. Its indications have been precisely reported in the consensus of the European Crohn’s and Colitis Organization and European Society of Gastrointestinal and Abdominal Radiology (ECCO/ESGAR)

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Table 14.1 Inflammatory bowel disease Gammacamera imaging 99m TcHMPAO WBC scintigraphy

Why Shows inflammatory activity

PET imaging Why 18 Highest Faccuracy FDG PET/ CT FFDG PET/ MR 18

Lower radiation exposure, higher soft tissue resolution

When When PET or PET/CT not available

How Imaging within 4 h from injection is preferred

When As first choice to compliment anatomical imaging

How Similar to oncologic PET/CT

Still research study: discrimination of inflammatory from fibrotic strictures

PET/MR enterography

Pitfalls Shifting bowel activity on images obtained later than 4 h indicates physiological excretion Pitfalls Use of metformin increases bowel uptake Use of metformin increases bowel uptake

Interpretation criteria Uptake on early images (~30 min) which increases over late images (~2 h) Interpretation criteria Visual comparison with liver (>liver = positive)

Without an established consensus yet

[4]. However, due to its complexity and low availability compared to PET/CT, PET/CT has already largely replaced WBC scintigraphy in clinical practice for IBD. Moreover, PET/MR is emerging in the field of inflammation imaging and brings to the table many advantages that make it more appealing than PET/CT (Table 14.1).

14.3

Large Vessel Vasculitis

14.3.1 Introduction Vasculitis is an inflammatory blood vessel disorder classified according to the caliber and type of vessel predominantly involved. Large vessel vasculitis encompasses Takayasu arteritis and giant cell vasculitis. Early diagnosis is important since vasculitis can lead to arterial obstruction or aneurysms when untreated, which can lead even to rupture [25].

14.3.2 The Clinical Questions Vasculitis can have atypical presentation, and the biochemical flogistic indices have low specificity, which make the diagnosis very challenging. Moreover, during the management of these diseases, it is difficult to distinguish disease activity from

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damage induced by chronic, smoldering inflammation that is characteristic of these entities. Distinguishing disease activity from damage is important since active disease mandates treatment [26]. Imaging with CT angiography or MR angiography can help identifying active inflammation using parameters such as wall thickening or contrast uptake in the vessel wall. However, there is a paucity of scoring systems to quantify the extent of involvement [26].

14.3.3 PET and PET/CT Imaging F-FDG PET (FDG-PET) has been increasingly used in vasculitis evaluation. FDG-PET can be of value in diagnosis, disease activity monitoring, and evaluation of damage progression in large vessels vasculitis. A very recent meta-analysis investigating FDG-PET and PET/CT for the assessment of disease activity in large vessel vasculitis, which included a total of 298 patients, showed a pooled sensitivity and specificity of 88% and 81%, respectively [27]. Monitoring treatment response is a potential role for FDG-PET. However, there are few studies in literature with small patient cohorts. Despite that, these studies have showed that FDG-PET can demonstrate decrease in FDG uptake after treatment as shown in a prospective study with 35 patients [28]. Recently, an international procedure recommendation has been published in order to facilitate clinical studies and daily clinical applications [29]. The authors suggest that FDG-PET/CT protocol can be similar to the one used in oncologic imaging. However, patients need to withdraw or delay glucocorticoids therapy until FDG-PET/CT has been acquired, unless there is a risk of ischemic complications, such as in case of giant cell arteritis with temporal artery involvement. However, one study also included a carbohydrate-sparse meal the day before imaging [30]. For a clinical purpose, a visual analysis grading scale is employed: 0 = no uptake (≤mediastinum); 1  =  low-grade uptake (liver). Grade 2 is possibly indicative and grade 3 is considered positive for active large vessel vasculitis. Several quantification methods have been proposed, including SUV and target-to-background ratios (TBR). There is no consensus yet which quantification method is indicated; moreover, for clinical purpose they are not deemed necessary [29]. One of the major studies with FDG-PET/CT in large vessel vasculitis encompassed 170 scans including 56 patients and 59 controls evaluated prospectively and longitudinally. FDG-PET/CT was able to distinguish patients with clinically active disease with a sensitivity of 85% and a specificity of 83%. Moreover, FDG-PET/CT was interpreted as active vasculitis in 58% of patients considered clinically in remission, and clinical relapse was more common in patients with a higher visual FDG score [30]. PET/MR is starting to be investigated in this setting with one study analyzing 12 patients with large vessels vasculitis who performed an 18F-FDG PET/MR.  The authors analyzed different sets of images and found that the combination between 18

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Table 14.2 Large vessel vasculitis PET imaging Why 18 Highest Faccuracy FDG PET/ CT

When First choice to compliment anatomical imaging

How Similar to oncologic imaging

Pitfalls Use of glucocorticoids can lead to false negative

Interpretation criteria Visual comparison with liver (>liver = positive; equal to liver = possibly)

PET and MR analysis was stronger, rather than MR and PET alone. PET alone found 86 areas with increased FDG uptake, contrast-enhanced MR alone detected 49 regions with abnormalities, meanwhile PET/MR together found 95 vasculitis areas. Additionally, PET/MR had a strong and significant correlation with C-reactive protein [31].

14.3.4 Future Perspectives and New Trends FDG-PET/CT is an imaging modality that has been highly explored to diagnose and manage large vessel vasculitis. The perspective is that this application will increase in a near future with the introduction of more powerful PET/CT scanners. Moreover, the sophisticated molecular imaging assessment possible with PET/MR scanners, together with the development of new specific radiopharmaceuticals for inflammation, will probably improve the diagnosis and management of large vessel vasculitis (Table 14.2).

14.4

Other Abdominal Infections and Inflammatory Diseases

14.4.1 Retroperitoneal Fibrosis Retroperitoneal fibrosis is a rare disease characterized by the presence of a retroperitoneal tissue, consisting of chronic inflammation and marked fibrosis, which often entraps the ureters or other abdominal organs. More than two thirds of cases are idiopathic, but it can be secondary to drugs and neoplasms. In this last case, retroperitoneal fibrosis results from an exuberant desmoplastic response to retroperitoneal metastases such as prostate, breast, and colon cancers or to retroperitoneal primary tumors such as lymphomas and sarcomas. Moreover, additional fibrotic processes outside of the retroperitoneum are not uncommon and have been described in more than 15% of patients [32, 33]. PET images have been used to evaluate retroperitoneal fibrosis since 18F-FDG can highlight the metabolic activity, demonstrate the full extent of the vascular inflammatory involvement, detect occult neoplastic or infectious processes to which retroperitoneal fibrosis can be secondary or associated, and monitor therapy [32, 33]. In a recent systematic review about the applicability of FDG-PET/CT in

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retroperitoneal fibrosis, the authors analyzed nine studies. FDG-PET/CT was able to detect inflammatory activity with a sensitivity and specificity up to 95.5% and 90.9%, respectively. Additionally, PET/CT was able to predict the best time for stent removal and evaluate therapeutic improvements better than anatomical imaging such as CT. In one study with the highest cohort of patients (n = 78), the authors observed that the highest the FDG uptake, the better the therapeutic response with steroids. However, FGD-PET/CT was limited in differentiating benign from malignant lesions with a low positive predictive value of 50% but with a high negative predictive value of 100% [33]. The evaluation of the metabolic activity is usually performed by visual analysis with a four-point scale: 0 = no uptake; 1 = uptake less than liver; 2 = uptake similar to liver; 3 = uptake greater than liver. Scores above 1 are usually considered positive for active disease. Retroperitoneal fibrosis has also been evaluated with 18F-FDG PET/MR in a couple of studies. Twenty-two PET/MR scans were performed in 17 patients with untreated and treated retroperitoneal fibrosis. The authors found a higher and significant 18F-FDG uptake in the untreated patients. Additionally, they found restricted diffusion and hyperintense T2 signal more frequently in the untreated patients group. A strong correlation between ADC and SUVmax as well as between laboratory inflammatory markers, such as erythrocyte sedimentation rate and C-reactive protein, and SUVmax was reported [34]. In another study performed in 14 patients, FDG-PET/MR was superior to clinical and inflammatory parameters in the assessment of disease activity. PET/MR detected active disease even when other inflammatory parameters, such as C-reactive protein and erythrocyte sedimentation rate, were in the normal range. Additionally, they found associated large vessel vasculitis in 21% of patients [35]. In conclusion, FDG-PET/CT and FDG-PET/MR may have an important role in the evaluation of retroperitoneal fibrosis. The main indication is evaluation of disease activity, which can be difficulty with the traditional morphologic imaging. Inflammatory markers alone have limited correlation with PET parameters. PET/ MR has the advantage to require less radiation exposure and to provide higher quality of soft tissue images. However, further multicenter and prospective studies are necessary to determine the real role of hybrid imaging in this entity.

14.4.2 Renal Cyst Infections Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and is characterized by the development of numerous renal and hepatic cysts. In the ADPKD population, renal infection is a common problem and represents a diagnostic challenge due to lack of specific symptoms and limitations of conventional imaging [36]. Despite 18F-FDG is excreted by the kidney, some studies have found FDG-PET/ CT useful in these settings. In particular, a study, that evaluated FDG-PET/CT in a cohort of 31 patients with acute pyelonephritis, found that a focal FDG uptake, as opposed to a diffuse uptake, was associated with a higher frequency of abscess

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formation requiring drainage. FDG-PET/CT was also able of detecting extrarenal coinfections in seven patients [37]. Another study, that evaluated 30 patients with ADPKD and suspected cyst infection, found FDG-PET/CT 88.9% sensitive and 75% specific in diagnosis renal cyst infections. Additionally, in five cases, FDG-PET/CT was able to rule out renal cyst infection and instead demonstrated pneumonia, peritonitis, pancreatitis, colitis, and cholangitis as responsible for the infectious status of the patients. The authors concluded that FDG-PET/CT is a useful imaging modality for the evaluation of renal cyst infection in these patients [38]. These results are in line with another study performed in 24 ADPKD patients with suspected abdominal infection where PET/ CT detected cyst infection in 84.6% of patients, whereas CT contributed to the diagnosis only in one patient. Interestingly, in this study, infections usually affected liver cysts rather than renal cysts [36]. The diagnostic criteria used by the authors to call for a positive study were heterogeneous, focal, or multifocal uptake in the cyst walls higher than in the surrounding parenchyma, or diffuse accumulation within the cyst after having excluded intra-cystic hemorrhage by CT. White blood cells labeled with 18F-FDG have been explored in PET/CT (WBCPET/CT) in several infectious diseases. A prospective study in 17 ADPKD patients with suspected renal cyst infection found WBC-PET/CT advantageous over CT or MR, with a sensitivity of 85.7% and a specificity of 87.5% [39]. In conclusion, FDG-PET/CT can play a role in suspected renal cyst infection in ADPKD patients, especially when a definitive diagnosis cannot be achieved by morphologic imaging, such as US and CT, and/or when there is suspicious for coinfection in other sites. WBC-PET/CT is a promising tool, but its role is still to be defined.

14.4.3 Abscess, Infection, and Inflammation Mimicking Tumor on Abdomen Hybrid imaging, especially FDG-PET/CT, is mainly used for oncologic imaging. However, 18F-FDG has a deficient specificity due to its uptake in inflammatory and infectious tissues, which sometimes can be as intense as tumor lesions. Therefore, differentiating a neoplastic from an infectious or inflammatory entity might be challenging; this has been investigated by very few studies, predominantly case reports. One study analyzed the performance of FDG-PET/CT, contrast-enhanced CT and MR in differentiating tubo-ovarian abscess versus adnexal masses in 43 patients and found that MR with diffusion images had the highest accuracy (97.7%), followed by MR without diffusion weighted imaging (83.7%). Contrast-enhanced CT and FDG-PET/CT had a lower accuracy (74.4% and 81.4%, respectively) [40]. In our unpublished experience, based on PET/MR, we have observed that MR sequences add value to PET imaging and are often capable of differentiating inflammatory or infectious lesions from neoplastic lesions. Figures 14.2 and 14.3 show a PET/MR detecting an abscess and a tumor recurrence in a same patient. A study explored the performance of FDG-PET/MR in 31 patients with indeterminate

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Fig. 14.2 In a patient with a resected mucinous rectal cancer, infected pelvic collections, and increased CEA, CT and PET/CT were indeterminate to make the differential diagnosis between recurrence and infection. Same day FDG-PET/MR diagnosed a pelvic collection as abscesses. (a) PET showing increased FDG uptake; (b) T2w hyperintense lesion; (c) Fused PET and T2w; (d) T1w post contrast showing peripheral enhancement; (e, f) DWI and ADC with restricted diffusion. Features compatible with an abscess. These findings were confirmed by biopsy, and a proper treatment could be established for this patient (continue on Fig. 14.3)

Fig. 14.3 Same patient as Fig. 14.2. FDG-PET/MR also revealed a tumor recurrence below the abscess. (a) PET showing increased FDG uptake; (b) T2w with a hyperintense lesion; (c) Fused PET and T2w; (d) T1w post contrast showing lesion enhancement; (e, f) DWI and ADC with no diffusion restriction. Features compatible with mucinous tumor recurrence. These findings were confirmed by biopsy, and a proper treatment could be established for this patient

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findings on PET/CT. In 18 of 31 cases, PET/MR resulted in a more definitive interpretation. In the majority of cases (15/18), PET/MR was capable of distinguishing infection/inflammation from malignancy [41].

14.4.4 Acute Cholecystitis Acute cholecystitis is a common acute complication of cholelithiasis. The majority of cases are due to a stone obstruction in the cystic duct or gallbladder neck, which occurs in 85–95% of cases. However, acute acalculous cholecystitis can occur in 5–20% of cases. The modality of choice in the diagnosis of acute cholecystitis is US, which can demonstrate gallbladder distention, wall thickening, and positive Murphy sign. However, CT is sometimes performed, especially when the gallbladder cannot be assessed by US or in the case of nonspecific abdominal pain [42]. When US and CT have equivocal results, hepatobiliary scintigraphy with 99mTcHIDA (hepatoiminodiacetic acid) radiopharmaceuticals, usually 99mTc-mebrofenin, can be performed. HIDA scan outperforms US with sensitivity 91–92% for HIDA scan versus 26–73% for US, and specificity of 71–79% for HIDA scan versus 58–80% for US [42, 43]. To perform hepatobiliary scintigraphy, patients need to fast at least 3–4 h before radiopharmaceutical injection and no longer than 24 h. A shorter or too long fasting can cause a false-positive study. The images are performed dynamically over a 1-h period. Later images, if necessary, can be obtained for up to 4 h. The diagnose of acute cholecystitis is achieved when the gallbladder is not filled with the tracer within 4 h. In order to shorten the study, morphine can be injected if the gallbladder is still not visualized and the tracer is visualized on small bowels at 60-min acquisition. Acute cholecystitis is suspected if the gallbladder is still not visualized within 30 min from morphine injection [43]. Figure 14.4 shows a hepatobiliary scintigraphy with acute cholecystitis. FDG-PET/CT has no indication in the diagnosis of acute cholecystitis. However, 18 F-FDG presents uptake in cases of cholecystitis as well as in gallbladder cancer. In the literature, there are very few case reports describing uptake in acute as well as in chronic cholecystitis [44, 45].

Fig. 14.4 Hepatobiliary scintigraphy with 99mTc-mebrofenin. (a) Sixty minutes image after tracer injection. It is observed the presence of tracer in bowels without gallbladder filling. (b) Thirty minutes after morphine injection, the gallbladder is still not filled, compatible with cystic duct obstruction. (c) CECT showing gallbladder distention and wall thickening, peri-cholecystic fat stranding. Features compatible with acute cholecystitis

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14.4.5 Autoimmune Pancreatitis Autoimmune pancreatitis (AIP) accounts for about 2–11% of chronic pancreatitis cases and is classified into two types. Type 1 is part of the systemic immunoglobulin G4 (IgG4)-related disease. Contrast-enhanced CT and MR typically demonstrate a “sausage-like” enlargement of the pancreas with a “capsule-like” rim and variable degrees of narrowing of the main pancreatic duct. However, about 30% of patients present with atypical radiologic and laboratory findings such as focal pancreatic mass and dilated pancreatic duct, simulating neoplasm [46, 47]. Moreover, in around 30% of cases, other systems and organs are involved such as bile ducts, salivary and lachrymal glands, lymph nodes, and retroperitoneal tissue. Differently from conventional chronic pancreatitis, which usually does not present FDG uptake, FDG-PET usually shows diffuse uptake in AIP.  The uptake patterns in AIP are longitudinal shape, heterogeneous or diffuse, and multifocal. Concomitant FDG uptake by other organs can be indicative of systemic disease. FDG-PET can also be used to monitor therapy after corticosteroid administration [47]. A recent study evaluated FDG-PET/CT capability to differentiate AIP from pancreatic cancer; overall 53 patients with suspected AIP and 61 with pancreatic cancer were recruited. The authors were able to differentiate both entities with a sensitivity and a specificity of 90.6% and 84.0%, respectively. The majority of patients with AIP had at least one site of extra-pancreatic inflammation, and the main sites were mediastinal lymph nodes and salivary glands [46]. Recently, a case report also showed the value of FDG-PET/MR in AIP. The study demonstrated a diffuse and moderate FDG uptake in the pancreas. The MR portion showed delayed contrast enhancement and restricted diffusion [48].

14.5

PET/MR Imaging of Spondylodiscitis

14.5.1 Introduction The incidence of spondylodiscitis for hospitalization is considered 4.8 per 100,000 patients in the USA with an inpatient mortality of 2.2% and an increased risk for male patients, elderly patients, and patients with a high comorbidity [49]. Pyogenic spondylodiscitis is usually located in the lumbar spine [50]. Although most patients present with back pain and/or fever, a prompt diagnosis can be delayed by equivocal clinical findings [51]. The most common cause is hematogenous spread by septic embolism. As arterial intervertebral anastomoses regress in adolescents, pyogenic infections in adults usually start at the anterior endplate, progress to the posterior part of the vertebral body, and then lead to a secondary involvement of the avascular intervertebral disc [51]. Infectious foci can be more frequently observed in the posterior endplate in fungal and tuberculous spondylodiscitis. Thus, a possible route of infection via the venous lumbosacral plexus is discussed in the literature [52]. A further possible

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cause is iatrogenic inoculation, e.g., during spinal surgery or interventional pain treatment procedures [53]. Until now, there are no sufficient guidelines for the treatment of spondylodiscitis. In most cases of pyogenic spondylodiscitis, directed antimicrobial treatment is sufficient, necessitating radiographic or CT-guided sampling, although biopsies are only culture-positive in around 30% [53–55]. In larger fluid collections, additional CT-guided drainage placement can be helpful [53]. Surgical treatment, however, is necessary if spondylodiscitis is accompanied by an acute or progressive neurological deficit, an intraspinal infectious focus, instability of the vertebral column, or a failure to conservative therapy. Treatment options include surgical debridement, instrumentation, and intervertebral fusion as well as corpectomy and complex anteroposterior reconstruction including instrumentation [51].

14.5.2 The Clinical Questions As osseous changes mostly occur in the late stages of the disease, MRI is considered the most accurate modality in spondylodiscitis to image bone marrow and soft tissue changes. However, sensitivity and specificity of MRI can be impaired in selected cases or MRI might not be possible due to contraindications [50]. Here, nuclear medicine imaging can play an important role and decisively increase diagnostic certainty, especially in the four following scenarios: • In patients who cannot undergo MRI due to inlying foreign bodies that cannot be removed, such as shrapnels, implants, or medical devices such as pacemakers not suitable for MRI examinations. • In patients with metal implants, e.g., after dorsal instrumentation, diagnostic accuracy of morphological imaging techniques such as CT or MRI can be drastically impaired by artifacts. • If the clinical presentation of the patient is misleading, degenerative changes with acute edema, such as Modic I changes, can mimic spondylodiscitis in sole morphological MRI. • In morphological MRI, signal changes of the affected segment during therapy can be difficult to interpret as they are not correlated to the clinical status of the patient.

14.5.3 PET Imaging Due to its wide availability, 18F-fluorodeoxyglucose (18F-FDG) is considered the most important radiopharmaceutical for PET imaging of infectious diseases. Migration of inflammatory cells to inflamed foci, expressing a high amount of glucose transporters that lead to an increased FDG accumulation within these cells, makes this unspecific radiotracer suitable to image inflammatory and infectious processes [56].

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Nevertheless, MRI is still considered the modality of choice for spondylodiscitis imaging due to its wider availability [50]. Furthermore, it is more sensitive than PET/CT in the detection of epidural abscesses [57]. In selected cases, however, inlying foreign bodies can prohibit MRI examinations or seriously degrade image quality. Here, 18F-FDG PET/CT is a viable alternative. Studies by Skanjeti et al. and Smids et al. found comparable sensitivities and specificities between PET and MRI as well as between PET/CT and MRI, respectively [58, 59]. In a recent metaanalysis, Kim et al. reported a sensitivity and specificity rates of 95% and 88% for PET/CT and of 85% and 66% for PET/MRI, respectively [60]. Still, these results have to be interpreted with caution due to the low patient number of the analyzed studies. Furthermore, a study by Fuster et al. published in 2015 was included in this meta-analysis that was heavily criticized for its surprisingly low sensitivity and specificity values for MRI [60–62]. Additionally, studies using different modalities such as PET, PET/CT, and even PET/MRI were included in this meta-analysis [60]. Metal implants like spinal fusion hardware can cause significant impairments in MR imaging of the spine, limiting its diagnostic competence to detect potential spondylodiscitis. Despite the small number of studies and small patient cohorts, PET/CT showed promising results to close this diagnostic gap. Sensitivity and specificity rates of 100% and 81%, respectively, have been reported by Winter et al. in 2003 [63] and of 88% and 100%, respectively, by Hartmann et al. in 2007 [64]. In 2013, Bagrosky et  al. published a small retrospective study assessing 18F-FDG PET/CT for the evaluation of spinal fusion hardware infection in pediatric patients. Here, PET/CT correctly identified spinal fusion hardware infection in 6 out of 20 investigated patients [65]. However, no comparison between MRI and PET/CT was performed in these studies, and the results are based on small cohorts. Furthermore, new metal artifact reduction techniques might improve the diagnostic accuracy of MRI [66]. Therefore, further research is needed to elucidate the role of PET/CT in postoperative patients. However, PET/CT has to be considered an important adjunct to date if MR imaging findings are equivocal. Degenerative changes exhibiting edema in the vertebral endplates, so-called Modic I changes, can be difficult to distinguish from early spondylodiscitis. Especially in patients who undergo early MRI within 2 weeks after symptom onset, a definite diagnosis is difficult. Here, PET/CT is superior to MRI with sensitivity and specificity rates of 96% and 95% compared to 67% and 84%, respectively [59]. These data are supported by further preliminary studies. Stumpe et al. and Ohtori et al. considered 18F-FDG PET and 18F-FDG PET/CT as useful tools to differentiate between degenerative changes and spondylodiscitis although the results were based on small study cohorts. Thus, further validation of these results is necessary in larger cohorts for a definite recommendation [67, 68]. Although MRI is highly sensitive for the detection of spondylodiscitis, the assessment of treatment response can be problematic. In follow-up MRI, especially contrast enhancement can prevail or even increase despite symptom resolution [69– 71]. In a study published by Kowalski et  al., no imaging parameter in follow-up MRI correlated with the patient’s clinical status [72]. Here, a pilot study by Niccoli Asabella et al. showed promising results for 18F-FDG PET/CT in the early response

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assessment of antibiotic therapy in patients with spondylodiscitis [73]. Furthermore, PET/CT showed higher values for sensitivity and specificity in the detection of relapse after spondylodiscitis treatment in a pilot study by Dauchy et al. although no significant differences were observed between PET/CT and MRI due to the small size of the analyzed cohort [74]. However, these results still have to be validated in a bigger cohort. By combining the two most reliable techniques in spondylodiscitis imaging, MRI and PET, integrated PET/MRI holds strong potential in spondylodiscitis imaging (see Figs. 14.5 and 14.6) [75]. However, the diagnostic value of this new hybrid imaging technique has only been explored in a preliminary study by Fahnert et al. in 2016. Here, the authors reported a relevant increase in sensitivity and specificity in PET/MRI when compared to MRI [76]. A recently published pilot study by Hulsen et  al. on osteomyelitis imaging also shows promising results, supporting these findings [77]. Still, these results have to be considered as preliminary due to the small size of the analyzed cohorts, necessitating further research. Additionally, new radiotracers might strengthen the role of PET in spondylodiscitis imaging even further. A new option is 68Ga-Citrate, which is an advancement of 67Ga-Citrate. Clinical relevance of 67Ga is limited due to its high price and long examination times, as imaging has to be generally performed 18–72 h after injection [52].

a

b

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Fig. 14.5 A 64-year-old male patient undergoing PET/CT and MRI for fever of unknown origin. Morphological T2- (a) and contrast-enhanced T1-weighted images (b) are displayed as well as PET (c) and retrospectively fused PET/CT images (d). A hyperintense fluid collection in the intervertebral space of L5/S1 is indicative for spondylodiscitis although only weak contrast enhancement of the bordering endplates can be observed. Increased tracer uptake in PET confirms the diagnosis of an acute spondylodiscitis

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Fig. 14.6 A 79-year-old male patient suffering from spondylodiscitis without adequate response to antibiotic treatment. Morphological, fused, and PET images are displayed for 18F-FDG PET/ CT (a–c). Acute inflammation can be observed ranging from T4–T6 with near total destruction of the vertebral bodies

Furthermore, image quality was limited due to the low injectable activity (because of its long half-life) and the wide gamma spectrum. Due the shorter half-life of 68Ga, higher activities can be injected, thus increasing image quality and reducing acquisition times. Pilot studies show promising results; however, there is need for further validation in larger patient cohorts [78]. Another interesting approach is the use of radiolabeled antimicrobial peptides such as 68Ga-NOTA-Ubiquicidin. Although initial studies show promising results, these findings have to be considered as preliminary and further research is needed [79–81].

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Conclusions

Inflammatory and infectious diseases in the abdomen are important entities that can be assessed by nuclear medicine. WBC scintigraphy is an imaging study with a very high specificity in diagnosing infections. However, due to its procedure complexity, FDG-PET/CT has increasingly been used in this setting. Nevertheless, the lack of reimbursement for evaluating inflammatory and infectious diseases is an important limitation of usage of FDG-PET/CT for this indication. The use of PET/MR for inflammation and infection is an emerging and promising application. The literature is very limited yet with studies encompassing few patients. Moreover, there is a lack of studies comparing PET/MR with PET/ CT. However, PET/MR has important advantages in abdominal inflammatory and infectious diseases such as simultaneously acquisition allowing an ideal coregistration, higher soft tissue delineation, lower radiation exposure, and improved lesions characterization. Therefore, PET/MR has the potential to overcome PET/CT in the future in these settings.

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Imaging Tuberculosis and AIDS Associated Infections

15

Ismaheel O. Lawal and Mike M. Sathekge

15.1

Introduction

An estimated 1.7 billion individuals harbor the Mycobacterium tuberculosis (MTB), the causative agent of Tuberculosis (TB) [1]. About 3–10% of these individuals harboring MTB will develop symptomatic TB in their lifetime. Despite several efforts for prevention, early diagnosis, and effective treatment, TB remains one of the top ten causes of death and the leading cause of death from a single infectious agent [2]. In 2017, new TB occurred in 10.0 million people. In the same year, TB was responsible for deaths in an estimated 1.3 million people without human immunodeficiency virus (HIV) infection and 300 thousand deaths among people living with HIV infection (PLWHIV) [2]. HIV infection is associated with a suppressed function of the innate and acquired immunity. PLWHIV are therefore at increased risk of reactivation of latent TB as well as acquiring a new symptomatic infection. In addition to TB which represents the most important HIV-associated infection, PLWHIV are predisposed to other types of infectious conditions caused by bacteria, fungi, viral, protozoal, and other agents. Some of these infections occur in the circumstance of a very depressed immune function such as seen in HIV infection and have come to be described as acquired immunodeficiency syndrome (AIDS)defining conditions. There are more than a dozen infectious disorders that are AIDSdefining including bacterial (such as infections due MTB, Mycobacterium avium complex, salmonella species), viral (such as infections due to cytomegalovirus and herpes simplex virus), fungi (such as infections due to Pneumocystis jirovecii, Candida species, Histoplasma capsulatum, Cryptococcus species, Coccidioides

I. O. Lawal · M. M. Sathekge (*) Department of Nuclear Medicine, Steve Biko Academic Hospital and University of Pretoria, Pretoria, South Africa e-mail: [email protected] © Springer Nature Switzerland AG 2020 A. Signore, A. W. J. M. Glaudemans (eds.), Nuclear Medicine in Infectious Diseases, https://doi.org/10.1007/978-3-030-25494-0_15

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immitis), and parasitic (such as infections due to Isospora belli, Toxoplasma gondii) infections [3]. The incidence of these AIDS-defining conditions and their mortalities have reduced significantly due to widespread screening for HIV infection and the institution of anti-retroviral therapy (ART) at CD4 count levels above levels where these pathogens cause symptomatic diseases [4, 5]. In this chapter, we will present an updated knowledge of the radionuclide imaging of tuberculosis. PLWHIV are generally immunosuppressed predisposing to a wide variety of infectious conditions. The radionuclide approach to imaging these infectious conditions are mostly similar between PLWHIV and their HIV negative counterparts and have been described in details in other chapters of this book. We will provide a brief description of radionuclide imaging technique of infectious diseases with strong associations with HIV infection where sufficient published work exists in the literature.

15.2

The Clinical Questions

Microbial culture of sputum or biopsy specimen is the reference standard for the diagnosis and treatment response assessment of TB. Microbial culture with a liquid or solid medium is time-consuming (requiring weeks for a positive culture), prone to contamination, and is expensive [6, 7]. Xpert MTB/RIF is a sputum-based realtime PCR method recommended by the World Health Organization for rapid diagnosis of TB and for assessing microbial sensitivity to Rifampicin. Xpert MTB/RIF, which is based on nucleic acid amplification, is not able to differentiate life from dead bacteria reliably [8]. Smear microscopy for acid-fast bacilli offers a faster and cheap alternative to diagnosis but is poorly sensitive especially in paucibacillary situations, is operator-dependent, cannot differentiate live from dead bacteria or differentiate MTB from non-tuberculous mycobacterial species reliably [9–11]. IFN-γ released assays (IGRAs), a test of T-cell response to MTB antigen, is mostly positive in patients with TB but not sufficiently sensitive in PLWHIV [12]. Owing to the limitations associated with these diagnostic techniques, most patients are treated in endemic regions based on typical clinical presentation and supporting imaging findings, only 30% patients treated for TB were culture-positive in one series [13]. The clinical questions imaging seeks to answer in TB management include: Could imaging be used • as an ancillary tool for the diagnosis of TB? • to predict response to anti-tuberculous therapy (ATT)? • to evaluate extent of disease, i.e., pulmonary TB (PTB) versus extra-pulmonary TB (EPTB)? • for therapy response assessment with a view to shortening or lengthening treatment duration in the appropriate setting? • to distinguish latent TB infection (LTBI) from subclinical TB? • to predict relapse following completion of treatment? • to distinguish active from inactive TB? • to distinguish TB from other infectious conditions or sterile inflammation?

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PLWHIV are predisposed to a wide range of infections from different organisms. In addition to infectious diseases, the risk of malignancies is heightened among PLWHIV. Biopsy for microbial culture or histological examination is necessary to diagnose infection or malignancy prior management. Obtaining a biological specimen for a specific diagnosis may not be possible as in individuals with a fever of unknown origin (FUO) or may be too invasive and dangerous [14]. When feasible, biopsy may be fraught with sampling error [15]. It will, therefore, be interesting to have molecular probes targeted at different groups of microbial agents with excellent accuracy for in vivo diagnosis using radionuclide techniques. Also, an important question that must be answered when imaging is used for evaluating HIV-associated infection is differentiating infection from inflammatory noninfectious conditions and neoplastic diseases. Imaging for treatment response assessment will be of clinical value as it may help to guide treatment duration. This may be necessary for individuals with invasive fungal infections in whom treatment duration is not clearly defined and where drugs used for treatment are expensive and may be toxic to the patients [16, 17].

15.3

Gamma-Camera Imaging

15.3.1 Gamma-Camera Imaging of Tuberculosis In recent years, single photon emission tomographic (SPECT) probes have been successfully synthesized for preclinical and clinical imaging of TB. These probes target the mycobacterial bacilli with potential for improved specificity in the clinical diagnosis of TB. Foss et al. recently reported the successful synthesis of I-125 anti-C3d monoclonal antibody [18]. C3d is the terminal fragment of C3, a complement protein which is enzymatically cleaved via the alternate pathway. When produced in response to TB infection, C3d covalently binds to the cell membrane of MTB facilitating the bacterial phagocytosis by the host macrophages [19, 20]. In a mouse model of MTB, the tracer localized to the site of pulmonary tuberculosis on SPECT/CT imaging with physiologic tracer uptake seen in the thyroid and spleen at 24  h post tracer injection. Urinary excretion of metabolized radioiodine was seen in the kidney at 48 h [18]. Ethambutol is a first-line antimycobacterial agent that inhibits cell wall synthesis [21]. Radiolabeling of ethambutol to technetium-99m (Tc-99m) has been described [22, 23]. In a recent retrospective analysis of 168 patients evaluated for TB, Tc-99m ethambutol demonstrated a sensitivity and specificity, respectively, of 94.9% and 83.3% for detecting TB at any sites (PTB and EPTB) with microbial culture used as the standard of reference [24]. In 23 patients who had been on ethambutol-containing chemotherapy for less than 2 weeks (range: 7–12 days), positive Tc-99m ethambutol scintigraphy was obtained in all of them indicating that a short course of the agent is not a contraindication for obtaining the scan [24]. The clinical utility of Tc-99m ethambutol scintigraphy has also been demonstrated in a more selected

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group of patients with histologically confirmed spinal TB [25]. In this cohort, Tc-99m ethambutol had a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 90.91%, 71.43%, 93.75%, 62.5%, and 87.5%, respectively [25]. Tc-99m ethambutol scintigraphy shows physiologic uptake in liver and spleen with the urinary system being the major route of excretion. This suggests that TB involvement of any of these sites may not be accurately identified on Tc-99m ethambutol scintigraphy. Also, Tc-99m ethambutol has been reported to accumulate in normal lung parenchyma which may impair visualization of areas of subtle pathologic uptake [26]. Tc-99m ethambutol has minimal liver excretion into the bile which may also impair the assessment of abdominal TB [26]. These may account for the generally poor signal-to-noise ratio seen in most published images of Tc-99m ethambutol scintigraphy. Other first-line anti-TB agents have been labeled with Tc-99m for SPECT imaging of TB. Sigh et al. reported a successful radiolabeling of isoniazid (INH) with Tc-99m for bacterial-specific imaging of TB [27]. Tc-99m INH complex is highly protein bound leading to prolonged blood pool activity. This may be advantageous to ensure tracer penetration in poorly perfused TB lesions. The tracer was able to detect lesions in TB-infected rabbits [27]. Ciprofloxacin is an aminoglycoside that disrupts bacterial replication via the inhibition of DNA gyrase. Tc-99m ciprofloxacin has been synthesized and used for clinical imaging of non-tuberculous bacterial infections [28, 29]. Lee and colleagues prospectively enrolled normal volunteers (n = 5), patients with active PTB (n = 10) and patients with inactive tuberculosis (n = 6) [30]. Tc-99m ciprofloxacin was able to correctly identify eight of ten patients with active TB and ten out of 11 patients without active TB. The authors concluded that Tc-99m ciprofloxacin has the potential to differentiate between active and inactive TB [30] correctly. The potential of Tc-99m ciprofloxacin for therapy response assessment was shown in a study that prospectively recruited 25 patients with extraspinal osteoarticular tuberculosis [31]. The patients were imaged at baseline before the commencement of ATT, at 3 and 6 months after commencement of treatment. Tc-99m ciprofloxacin was positive in all patients at baseline. On the three-month scan, 4/25 patients had no residual uptake while the remaining 21/25 patients had complete resolution of all TB lesions on the six-month scan. The negative imaging finding on the six-month scan correlated with clinical and radiological findings as well [31]. Ciprofloxacin is not specific for MTB hence it cannot differentiate TB from other forms of infection [32]. Before the widespread availability of positron emission tomography as a clinical imaging tool, many nonspecific radiopharmaceuticals have been used for TB imaging including Gallium-67 citrate, Tc-99m Sestamibi, Tc-99m Tetrofosmin, and Thallium-201 chloride. Gallium-67 citrate (Ga-67 citrate) is perhaps the best studied agent among these lots. Ga-67 citrate has a ferric-like iron behavior with complex in vivo characteristics. Following intravenous administration, it is transported in the blood bound to transferrin. At the site of infection, increased vascular permeability enhances Gallium-transferrin complex leakage into the extravascular space. Gallium dissociates from transferrin and preferentially binds to lactoferrin and siderophores released by leucocytes and bacteria [33]. Ga-67 citrate is also believed to

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reach the site of infection by free transport in the blood and via circulating leucocytes. Siemsen et al., in a cohort of 575 patients with mixed pathologies including carcinoma of the lung, lymphoma, tuberculosis, sarcoidosis, etc., showed that Ga-67 citrate is not able to differentiate between the different pathologies. When the diagnosis is known, however, Ga-67 citrate can help define the degree of disease activity, treatment response, the spatial extent of the disease and the presence of unsuspected disease foci [34]. Siemsen and colleagues found that Ga-67 citrate could identify 192 of 197 patients with active TB. The scan was true negative in all 32 patients with inactive TB. The intensity of tracer avidity within TB lesions decreased with ATT [34]. Whole-body Ga-67 citrate may help detect extra-pulmonary involvement of TB [35]. This finding has therapy implication as the presence of disease at some extra-pulmonary sites such as bone may warrant a more extended treatment duration. The ability of Ga-67 citrate to differentiate between infection due to MTB from infection due to non-tuberculous mycobacterial (NTM) organisms has been reported [36]. MTB infection shows a higher avidity for tracer compared with NTM [36]. This results in lower sensitivity of Ga-67 citrate scintigraphy for NTM compared with MTB. There are several drawbacks to the use of Ga-67 citrate scintigraphy for clinical imaging of TB in current practice including its poor image resolution, high radiation burden to the patients, long duration required to complete the study (up to 96 h after tracer injection), variability in physiologic tracer distribution with the attendant risk of misdiagnosis, etc. The clinical use of Ga-67 citrate for TB imaging is now restricted to centers without PET camera. Macrophages are abundant in the tuberculous granuloma. Activated macrophages express translocator protein (TSPO) on their mitochondrial membrane utilized for lipid transport [37, 38]. DPA-713 is a synthetic ligand for TSPO.  Radioiodinated DPA-713 accumulates in activated phagocytic cells in Mycobacterium tuberculosis-induced inflammation. In a mouse model of MTB, I-125-DPA-713 SPECT showed a more discrete localization within TB lesions compared with a more diffuse pattern of uptake on F-18 FDG PET/CT [39]. Physiologic distribution of I-125-DPA-713 was reported in brown fat, thymus, adrenal glands, and liver with biliary excretion into the bowel. Excretion was mainly via the urinary system. Visualization of the thyroid was seen due to the uptake of free radioiodine [39]. In a follow-up study by the same group, I-125-DPA-713 SPECT imaging showed a good correlation between bacterial load and the level of tracer accumulation in tuberculous lesions of animals on different anti-tuberculous regimens [40]. Findings from these studies suggest that radioiodinated DPA-713 SPECT imaging holds promise for initial evaluation of TB and therapy response assessment via nonspecific targeting of host inflammatory response to MTB. Nonspecific imaging probes such as Thallium-201 chloride, Tc-99m sestamibi, Tc-99m Tetrofosmin, Tc-99m citrate, Tc-99m dimercaptosuccinic acid, and Tc-99m-EDDA-tricine-HYNIC-Tyr3-octretate have been used in the past for clinical TB imaging [41–45]. These agents are neither sufficiently sensitive nor specific for TB. The availability of newer molecular probes, especially for PET imaging, has made the use of these older agents fall out of favor. These agents will not be discussed any further.

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15.3.2 Gamma-Camera Imaging of HIV-Associated Infections Despite the wide availability and utilization of effective ART combinations, HIVassociation infections remain a significant cause of mortality among PLWHIV [46]. Pulmonary infections remain a significant contributor to opportunistic infections seen in people diagnosed with HIV infection. The type of infection an HIV-infected person is susceptible to is dependent on the CD4 count, level of HIV viremia, underlying risk factors, and the geographical location of the patient which influence the pathogens the individual is exposed to [46, 47]. The respiratory tract, being a sieve for the inspired air, carry an enormous burden of HIV-associated infections. Pneumocystis jirovecii pneumonia (PJP) is a leading opportunistic infection among PLWHIV. Radionuclide imaging is useful as an ancillary tool in the evaluation of HIVassociated infections. Ga-67 citrate scintigraphy is the most reported gammacamera imaging technique for HIV-associated infections. Negative Ga-67 citrate scintigraphy, in the appropriate setting, has an excellent negative predictive value. A combination of factors must be considered to improve its clinical utility [33]. Such factors must include recognizing a particular pattern representing a specific disease as well as the correlation of scintigraphic findings with findings from other imaging modalities, microbiology, serology, and biochemical findings. Diffuse lung uptake of Ga-67 citrate has a high sensitivity but poor specificity for PJP [48]. In a series of 71 HIV-infected patients evaluated with 86 Ga-67 citrate scans, 57/86 scans show abnormalities [48]. In 27 scans, chest X-ray was normal suggesting better sensitivity of Ga-67 citrate scintigraphy than a chest x-ray. In 40/57 abnormal scans, diffuse gallium-67 uptake was seen in both lungs with PJP responsible for this pattern in 29 scans. Other causes of diffuse Ga-67 citrate uptake in the lungs reported in the study included cytomegalovirus (CMV) infection, cryptococcal infection, histoplasmosis, bleomycin toxicity, and suspected toxoplasmosis. Pulmonary Kaposi sarcoma was the most cause of a negative scan in the series [48]. PJP is associated with an increased pulmonary membrane permeability due to the presence of alveolitis. Tc-99m DTPA given as an aerosol for inhalation has been used to measure the alveolar membrane permeability in the lungs. Faster lung clearance of Tc-99m DTPA is seen with PJP.  Combination of Ga-67 citrate scintigraphy and Tc-99m DTPA may be complementary especially in patients who have false negative Ga-67 citrate scan findings [49]. Despite the early institution of ART among PLWHIV, invasive fungal infection is still responsible for up to 47% of AIDS-related death [50]. Other than PJP, common types of invasive fungal infections among PLWHIV include cryptococcal meningitis, disseminated histoplasmosis, and chronic pulmonary aspergillosis complicating tuberculosis [50]. Imaging plays an essential role in the diagnosis and monitoring of fungal infections [16, 17]. Several radiolabeled antimicrobial peptides have been evaluated for in vivo imaging of invasive fungal infection. Welling and coworkers tested nine antimicrobial compounds for preclinical imaging of microbial infections including infection due to Candida albicans [51]. The compounds tested were ubiquicidine (UBI) peptides, lactoferrin peptides, ciprofloxacin, defensins, and human polyclonal IgG.  UBI is a positively charged

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antimicrobial peptide which is used for infection imaging on the basis of its attraction to the negatively charged microbial cell membrane [14, 52]. In the study by Welling et al., all antimicrobial compounds tested were labeled with Tc-99m and all localized to sites of C. albicans infection in mice with a high signal-to-noise ratio [51]. Chitinases are a group of enzymes that break down chitin, a cell wall component of fungi which is not seen in the mammalian cell membrane. Radioiodinated chitinase has been reported to accumulate significantly at the sight of an animal model of fungal infections due to C. albicans and Aspergillus fumigatus [53]. Accumulation of radioiodinated chitinase at sites of bacterial infection due to S. aureus and E. coli was much less. This study demonstrates the feasibility of exploiting a target that is unique to fungi agents for their in vivo imaging. Fluconazole is a frequently used antifungal agent which inhibits the biosynthesis of ergosterol, a component of the fungal cell wall. Tc-99m fluconazole has been successfully synthesized for invasive fungal infection imaging [54]. Tc-99m fluconazole accumulates at the site of C. albicans infection but not in sterile inflammation, bacterial infection, or infection due to A. fumigatus. The authors concluded that Tc-99m fluconazole could distinguish C. albicans from a bacterial infection or sterile inflammation [54]. In a more recent study, another group has tested a cyclic peptide labeled with Indium-111 (111In-DTPA-c[CGGRLGPPFC]-NH2) for in  vivo imaging of a murine model of invasive pulmonary aspergillosis [55]. The tracer binds to the surface of A. fumigatus hyphae, and the authors speculate that it may also bind hyphae of other Aspergillus species as well as other molds.

15.4

PET Imaging

15.4.1 PET Imaging of Tuberculosis Most of the recent advances in the radionuclide imaging of TB have been with the use of PET. PET is a more sensitive technique than SPECT imaging with a gammacamera. Also, and until recently, quantification is only possible with PET imaging allowing for an objective assessment of disease extent on follow-up in patients on treatment. The widespread availability of the PET system for clinical imaging has also made it an attractive technique for infection imaging. F-18 fluorodeoxyglucose (FDG) remains the most commonly used tracer for clinical TB imaging. Macrophages and lymphocytes are the most abundant cells in the TB granuloma. Both cell types increased their use of glucose to cope with the high energy demand during the inflammatory response mounted to curtail TB infection. Being an analog of glucose, the trapping of FDG is similarly accentuated by the inflammatory cells. Active TB lesion, therefore, show very intense FDG accumulation on PET imaging [56]. FDG PET imaging has been used as an important supportive tool in the clinical management of TB including in the pretreatment assessment of disease and its extent, to predict and monitor response to ATT, to assess for resolution of disease at completion of treatment, and to differentiate active from inactive TB [57, 58].

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In TB endemic region, patients are treated for TB based on typical symptoms and supporting imaging findings [13]. FDG has been shown to have several clinical utilities when obtained for pretreatment assessment of disease. In patients with signs and symptoms suggestive of TB, and in whom microbial culture is negative, FDG PET may guide biopsy for histological/microbiology confirmation of TB. Maximum standardized uptake value (SUVmax) is a commonly used metric to quantify the avidity of lesion on PET imaging. SUVmax has been shown to correlate with disease extent and can predict treatment duration [59]. Patients with high SUVmax tend to have extra-pulmonary disease involvement. Determination of extrapulmonary involvement is essential in TB management as it often impacts on treatment duration. While patients with pulmonary and lymph node disease caused by drug-sensitive MTB are generally treated with a standard regimen of ATT for 6 months, patients with extra-pulmonary involvement often require a much longer duration of treatment (Fig. 15.1). FDG PET images the whole-body making it possible to detect sites of extra-pulmonary involvement [60]. Several studies have shown FDG PET to be a useful modality for predicting and assessing response to treatment. Early works by Sathekge and colleagues in HIVinfected patients showed that FDG PET could reliably predict responders from nonresponders to ATT [61, 62]. Involvement of many lymph node groups (≥5) and a high SUVmax of the involved lymph nodes could reliably predict patients who may not respond to treatment. Many other workers have confirmed the utility of FDG PET for response assessment in TB management. FDG PET obtained as early as 1 month post initiation of treatment could separate responders from non-responders in a group of

Fig. 15.1 FDG PET/CT to assess for extra-pulmonary involvement. A 49-year-old HIV-infected female diagnosed with pulmonary tuberculosis. FDG PET/CT obtained to evaluate for extrapulmonary sites of involvement showed findings in favor of tuberculosis involvement in multiple lymph nodes, liver, spleen, and the peritoneum

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prospectively recruited patients with PTB and EPTB [63]. All responders showed a decline in SUVmax of lesions while two patients did not show a significant response. One of the two patients without a significant decline in SUVmax had repeat biopsy because treatment had been initiated without a positive culture. Repeat biopsy confirmed non-Hodgkin lymphoma. While patients may be commenced on ATT based on suggestive symptoms and supporting imaging findings, this clinical assessment may sometimes be wrong. FDG PET response assessment provides a useful tool that may guide further diagnostic exploration. In a group of patients with multidrug-resistant TB (MDR-TB), FDG PET obtained at 2 months following commencement of ATT outperformed microscopy and culture obtained at the same time in predicting treatment outcome [64]. This latter study, done in a clinical trial setting, shows how powerful a tool FDG PET is in predicting treatment outcome. This is even more important in the patients imaged in this study (MDR-TB) who require prolonged treatment (treatment is continued for 18–24  months after negative microbial culture) with expensive drugs that have severe side effects. Duraja and coworkers demonstrated the utility of serial FDG PET obtained at baseline, 6, 12, and 18 months after commencement of ATT for response assessment in patients with TB of the spine [65]. They showed a progressive decline in SUV of lesions which correlate with clinical symptoms up to 12 months after commencement of ATT. The decline in erythrocyte sedimentation rate (ESR), a commonly used biomarker of inflammation/infection, did not correlate with the decline in SUV at any time-point [65]. Negative end-of-treatment (EOT) FDG PET is an excellent predictor of a durable cure (Fig. 15.2). Imaging done at EOT, however, often show residual lesions even in patients declared cured bacteriologically. TB lesions are highly heterogeneous. Some lesions may respond to treatment while others may not, and new lesions may appear during ongoing treatment (Fig. 15.3). Jeong et al. reported FDG uptake in lesions considered as due old healed TB [66]. Residual lesions after completion of treatment may contain slowly replicating MTB which are not effectively eliminated by antimycobacterial chemotherapy [67]. These slowly replicating bacilli are metabolically active but are non-culturable hence microbial culture is always negative despite their

Fig. 15.2 Negative FDG PET/CT predicts durable response to treatment. FDG PET/CT scan obtained in a 40-year-old HIV-infected male at the completion of anti-tuberculous treatment show multiple bilateral lung cysts with no associated metabolic activity. No tuberculosis relapse was seen after 24 months of follow-up

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Fig. 15.3 FDG PET/CT for response assessment in tuberculosis. Baseline (right) and post treatment (left) FDG PET/CT images of a patient with tuberculosis. Post treatment images show resolution of the baseline lesions with appearance of new tuberculosis lesions

presence [68]. These persisting bacilli are responsible for TB relapse [67]. The presence of these persisting bacilli stimulates an inflammatory response that may result in FDG uptake in residual TB lesions. Persisting FDG uptake was recently reported in residual lung lesions of patients considered cured based on negative microbial culture [69]. MTB RNA was demonstrated in the broncho-alveolar large samples obtained from these patients. While bacterial DNA may be from live or dead bacteria, RNA is more specific for living bacteria indicating the presence of replicating MTB in these patients considered cured according to the current standard of care. Other factors that may cause persisting metabolic activity in a residual TB lesion include persisting cell wall of dead bacilli stimulating an inflammatory response and nonspecific inflammation especially in lymph nodes of HIV-infected individuals. Among the 1.7 billion people with latent TB across the world [1], a subset of these people has subclinical TB with a heightened risk for developing overt clinical TB. Patients with subclinical TB represents a group with actively replicating bacilli who can infect their close contacts. Esmail et al. screened 265 newly diagnosed HIVinfected patients before commencing ART [70]. They identified 35 patients with positive immunologic response to MTB antigen (suggestive of exposure to MTB),

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but with no clinical feature or chest X-ray finding suggestive of active TB and were imaged with FDG PET/CT. Of 35 patients imaged, ten patients showed metabolically active lung lesions categorized as subclinical TB while 25 patients had no evidence of subclinical TB (either normal lungs or metabolically inactive lung nodules). On follow-up, the patients with subclinical TB were significantly more likely to develop overt clinical TB while none of the patients without subclinical TB developed active disease [70]. These results show the potential of FDG PET to identify patients with subclinical TB requiring a full regimen of ATT versus patients without in whom prophylaxis with a single agent (isoniazid) is sufficient for TB prevention. Over the last decade or so, FDG has been found to be a useful tracer for TB imaging. The biodistribution of FDG is one of its limitation in clinical TB imaging. FDG accumulates intensely in the brain, myocardium and has a urinary route of excretion. TB involvement of these organs can, therefore, not be adequately evaluated with FDG PET. Gallium-68 citrate (Ga-68 citrate), a congener of Ga-67 citrate, is a PET tracer that is attracting a renewed interest due to the wide availability of Germanium-68/Gallium-68 generator in many PET centers across the world [71]. Ga-68 citrate does not accumulate in the brain to any significant extent and is useful in evaluating intracranial TB (Fig. 15.4). Vorster et al. showed that Ga-68 could differentiate active from inactive TB lesions and outperformed stand-alone CT in

Fig. 15.4 Comparison between Ga-68 citrate and FDG PET/CT for the evaluation of brain tuberculosis. Ga-68-citrate images (top row) show circumferential area of tracer uptake in tuberculous brain lesion. FDG PET/CT images (bottom row) was false negative—lesion appear photopaenic on PET image

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Fig. 15.5 Comparison between FDG PET/CT and Ga-68 citrate PET/CT in the evaluation of tuberculosis. A 25-year-old female with mono-resistant Mycobacterium tuberculosis infection. FDG PET/CT (top row) shows metabolically active cavitatory left lung lesions with multiple mediastinal lymph nodes involvement. Ga-68 citrate PET/CT demonstrates the left lung lesion but not the mediastinal lymph nodes

demonstrating the extent of EPTB [72]. Like Ga-67 citrate, Ga-68 citrate cannot reliably differentiate between infectious lesions such as TB from malignant lesions [73]. The signal-to-noise ratio on Ga-68 citrate PET images is less than optimum compared with FDG PET images. High blood pool activity contributes to this high background noise seen on Ga-68 citrate PET/CT hence lesions with subtle avidity for tracer may be missed (Fig. 15.5). Other probes that target the host response to tubercle bacilli have been explored in preclinical imaging of TB.  DPA-713 labeled with I-125 targeting mitochondrialexpressed TSPO was discussed earlier in this chapter for SPECT imaging of mouse model of TB [39]. I-125 decays with a half-life of about 60 days by emitting a gamma photon of 35 KeV.  It is therefore not suitable for clinical imaging. Ordonez and coworkers have labeled DPA-713 with I-124 for PET imaging of host response to the tubercle bacilli [40]. I-124 DPA-713 demonstrated excellent localization in the lungs of infected mice compared with non-infected mice. Depsipeptide is an antimicrobial peptide that has been functionalized and radiolabeled with Ga-68 using DOTA as a

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linker. Ebenhan and colleagues showed good tracer localization to TB myositis without significant accumulation at the site of infection due to E. coli [74]. The tracer could however not reliably different sterile inflammation from infection due to TB. Several other host responses to mycobacterial species have been targeted for radionuclide imaging in limited studies. Hypoxia within TB lesion, whether consolidation or cavity, has been demonstrated using F-18 labeled fluoromisonidazole (FMISO), a molecular probe that accumulates at the site of hypoxic and not in oxygen-rich milieu [75]. The hypoxia within the core of the TB lesion stimulates neovascularization in the periphery of the lesion. Neovascularization is an essential step in tumor growth. Ga-68 alfatide II, a molecular probe targeting new blood vessels show uptake in both TB lesions and lung cancer with lung cancer showing significantly more avidity for the tracer than TB lesions [76]. Prostate-specific membrane antigen (PSMA) is overexpressed on metastatic prostate carcinoma and is commonly targeted for prostate cancer imaging with SPECT and PET techniques. PSMA is also expressed in neovasculature of other tumors and infectious/inflammatory diseases including TB. Pyka et al. demonstrated Ga-68 PSMA uptake in two TB lesions in patients with metastatic prostate carcinoma [77]. Expression of PSMA in these lesions was confirmed on immunohistochemical staining. Cellular proliferation and increased trapping of lipids by inflammatory cells are two other processes occurring in TB lesions that have been targeted for radionuclide imaging. F-18 fluorothymidine, a marker of cellular proliferation and radiolabeled choline, a marker of increased lipid utilization during inflammation have been shown to accumulate in TB lesions. The most important lesson to be derived from these studies showing inflammation-induced trapping of tracers more commonly used for other indications lie in the importance of the knowledge that TB may be a confounder in the interpretation of these scans when imaging is done for indications other than TB. Non-specificity of tracers targeting host inflammatory response to mycobacterial agents has led to a new interest in developing bacterial-specific probes for PET imaging. Most of the early effort has been with the use of radiolabeled antimycobacterial chemotherapeutical agents for PET imaging. These chemotherapy agents act by binding to a component of the bacteria. The initial effort with the use of F-18 pyrazinamide, a first-line chemotherapy agent that act against MTB but not against non-tuberculous mycobacterial species, for TB imaging was met with a disappointing result due to defluorination of the tracer in the liver leading to images with poor signal-to-noise ratio and intense uptake of free F-18 in the bones [78]. Isoniazid and rifampicin are the backbones of the first-line regimen in the treatment of DS-TB. Both agents have been successfully labeled for in vivo study of the pharmacokinetics of these agents and for their abilities to localize to TB lesions [79–81]. Weinstein and colleagues showed good localization of F-18 labeled isoniazid in both diffuse and discrete lesions of mouse models of pulmonary TB. Background activity of F-18 isoniazid was seen in the heart, liver, kidneys, and urinary bladder [80]. In another work by the same group, the biokinetics of rifampicin was studied using C-11 rifampin. The concentration of C-11 rifampin was significantly lower in TB-infected lung tissues compared with uninfected lung tissues [81]. In a follow-up study, dynamic C-11 rifampin PET imaging showed a significant decline in rifampin

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penetration into the brain by 2 weeks after initiation of ATT in a rabbit model of tuberculous meningitis [82]. This decline in brain penetration may be related to repair in blood–brain barrier leakages that occur following initiation of treatment as well as induction of P-glycoprotein efflux pump [82]. The application of radiolabeled antimycobacterial agents is not limited to noninvasive imaging of TB but may find greater applicability in the bioimaging of in vivo drug kinetics. Pharmacokinetics studies are currently done using repeated blood sampling. Drug concentration in plasma may be significantly different from drug concentration at the sites of infection. Similarly, repeated blood sampling is limited in small animals such as mice. Dynamic PET imaging, therefore, presents an opportunity for real-time monitoring of drug distribution in the whole body.

15.4.2 PET Imaging of HIV-Associated Infections Fungal infections constitute a major category of opportunistic infections seen among PLWHIV. Detailed discussion on imaging of fungal infection and therapy response assessment is presented in another chapter of this book and will not be discussed any further in this chapter. Imaging plays a limited role in the management of viral and parasitic opportunistic infections in PLWHIV.  Opportunistic infections in PLWHIV may present with fever of unknown origin. Detailed discussion on radionuclide imaging of FUO is presented in another chapter of this book. FDG and Ga-68 citrate concentrate as sites of opportunistic infection and may provide a nonspecific technique for imaging. Since these techniques can only indicate the presence of infection but cannot identify the causative agent, microbiological assessment is still necessary for confirmation. Imaging may, therefore, guide biopsy to obtain a representative specimen for microbiological assessment. Radiolabeled antiviral agents have been explored in animal models of viral infection and may hold potential for clinical translation [83].

15.5

Role of Hybrid Imaging

Hybrid imaging techniques using functional imaging modalities such as SPECT and PET with morphological modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) is a significant advancement in clinical imaging. This combined metabolic and morphologic imaging technique offers complementary anatomic and physiologic information of the disease being imaged. In the clinical imaging of TB and opportunistic infections in PLWHIV, anatomic information presented by CT is useful for accurate localization of the site of infection, assessment of associated tissue damage, detection of infection spread between tissue compartments, and for image-guided biopsy. Some HIV-associated infections have a pathognomonic feature on anatomic imaging, e.g., CT halo sign associated with angioinvasive fungal pneumonias [84]. Interpreted with functional imaging data, these morphologic information helps to improve the specificity of functional

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imaging interpretation. CT data are used for attenuation correction which improves the quantitative and qualitative accuracy of functional imaging with PET or SPECT. PET/MR is making an inroad into the clinic. The excellent anatomic information, as well as additional functional data available on MRI imaging, may add to the sensitivity and specificity of infection imaging.

15.6

Future Perspectives and New Trends

Host inflammatory response to infection has been the target in infection imaging over the past decades. This method lacks specificity as it cannot differentiate between inflammation due to different microbial agents. In order to surmount this challenge, efforts are now being made in developing probes that target the microbial organism with a promise for high specificity in radionuclide imaging of infectious diseases. Radiolabeled antimicrobial agents not only hold promise for targeted microbial imaging but present an opportunity for the noninvasive study of in vivo pharmacokinetic studies which may find great applicability in drug development. Clinical application of PET/MRI for clinical imaging is gaining more acceptance by the day. The exquisite soft tissue resolution of MRI technique and the functional imaging that is derivable from it may in the future find more spread clinical application in infection imaging. Summary table showing characteristics of the tracers with sufficient clinical experience for imaging of tuberculosis and other HIV-associated infections Gammacamera imaging Tc-99m ethambutol

Tc-99m ciprofloxacin

Why Shows mycobacterial infection

When To increase specificity by differentiating mycobacterial infection from other infectious diseases and sterile inflammation

Shows microbial infection

To increase specificity by differentiating infection from sterile inflammation

How Planar images at 1 and 3 h p.i. Additional SPECT/CT imaging for improved contrast resolution and localization Acquire early planar and SPECT/CT images at 1–4 h p.i. Delayed planar imaging at 4–24 h may be indicated

Pitfalls High background activity in the lungs

Accumulates in different types of infection including pyogenic bacterial, TB and fungi infections

Interpretation criteria Tracer uptake above background activity indicates mycobacterial infection

Tracer accumulation indicates infection

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Gammacamera imaging Ga-67 citrate

Tc-99m UBI 29-41

Why Shows host inflammatory response to infection

When Reduced sensitivity in the setting of ongoing therapy

How Acquire images at 48 h p.i. Additional images at 72 h and 96 h p.i. if indicated

To distinguish sterile inflammation from infection

To increase specificity by differentiating infection from sterile inflammation

Planar images at 1 h p.i. Additional SPECT images improve contrast resolution and localization

PET imaging Why F-18 Shows host FDG inflammatory response to infection

When In TB to assess the extent of disease and monitor response to treatment. In other OI to detect the presence of infection and guide biopsy In case of suspected TB or OI in organs with high physiologic FDG uptake such as brain

How Acquire image 1 h p.i.

Pitfalls Cannot distinguish between different infections seen in HIV-infected patients. Accumulates in tumors and sterile inflammation Accumulates in different types of infection including bacterial and fungi infections

Pitfalls Not specific for TB or any OI. Uptake is seen in sterile inflammation and tumors

High blood pool activity may impair visualization of small lesions adjacent to blood vessels and heart. Not specific for infection. Accumulates in sterile inflammation and tumors TB tuberculosis, OI opportunistic infections, p.i. post injection Ga-68 citrate

To improve sensitivity for TBM and brain tuberculoma

Acquire images 1 h p.i.

Interpretation criteria Tracer uptake indicates inflammation but not necessarily infection

Tracer uptake indicates infection

Interpretation criteria Tracer uptake indicates inflammation but not necessarily infection

Tracer uptake indicates inflammation but not necessarily infection

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43. Raziel G, Masjedi MR, Fotouhi F, Asli NI, Shafiei B, Javadi H, et  al. The role of Tc-99m MIBI scintigraphy in the management of patients with pulmonary tuberculosis. Eur Rev Med Pharmacol Sci. 2012;16:622–9. 44. Degirmenci B, Kilinc O, Cirak KA, Capa G, Akpinar O, Halilcolar H, et al. Technetium-99mtetrofosmin scintigraphy in pulmonary tuberculosis. J Nucl Med. 1998;39:116–20. 45. Gulaldi NC, Bayhan H, Ercan MT, Kibar M, Oztürk B, Ogretensoy M, et al. The visualization of pulmonary tuberculosis with Tc-99m (V) DMSA and Tc-99m citrate in comparison to Ga-67 citrate. Clin Nucl Med. 1995;20:1012–4. 46. The Antiretroviral Therapy Cohort Collaboration. Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies. Clin Infect Dis. 2010;50:1387–96. 47. Lee CY, Tseng YT, Lin WR, Chen YH, Tsai JJ, Wang WH, et al. AIDS-related opportunistic illnesses and early initiation of HIV care remain critical in the contemporary HAART era: a retrospective cohort study in Taiwan. BMC Infect Dis. 2018;18:352. 48. Kramer EL, Sanger JJ, Garay SM, Greene JB, Tiu S, Banner H, et al. Gallium-67 scans of the chest in patients with acquired immunodeficiency syndrome. J Nucl Med. 1987;28:1107–14. 49. Rosso J, Guillon JM, Parrot A, Denis M, Akoun G, Mayaud C, et al. Technetium-99m-DTPA aerosol and Gallium-67 scanning in pulmonary complications of human immunodeficiency virus infection. J Nucl Med. 1992;33:81–7. 50. Denning DW. Minimizing fungal disease death will allow UNAIDS target of reducing annual AIDS deaths below 500 000 by 20202 to be realized. Philos Trans R Soc Lond B Biol Sci. 2016;371:20150468. 51. Welling MM, Lupetti A, Balter HS, Lazzeri S, Souto B, Rey AM, et al. 99mTc-Labeled antimicrobial peptides for detection of bacterial and Candida albicans infections. J Nucl Med. 2001;42:788–94. 52. Sathekge M, Garcia-Perez O, Paez D, El-Haj N, Kain-Godoy T, Lawal I, et  al. Molecular imaging in musculoskeletal infections with 99mTc-UBI 29-41 SPECT/CT.  Ann Nucl Med. 2018;32:54–9. 53. Siaens R, Eijsink VGH, Dierckx R, Slegers G. 123I-labeled chitinase as specific radioligand for in vivo detection of fungal infections in mice. J Nucl Med. 2004;45:1209–16. 54. Lupetti A, Welling MM, Mazzi U, Nibbering PH, Pauwels EKJ. Technetium-99m labeled fluconazole and antimicrobial peptides for imaging of Candida albicans and Aspergillus fumigatus infections. Eur J Nucl Med. 2002;29:674–9. 55. Yang Z, Kontoyiannis DP, Wen X, Xiong C, Zhang R, Albert ND, et al. Gamma scintigraphy imaging of murine invasive pulmonary aspergillosis with a 111In-labeled cyclic peptide. Nucl Med Biol. 2009;36:259–66. 56. Sathekge MM, Maes A, Pottel H, Stoltz A, van de Wiele C. Dual time-point FDG PET-CT for differentiating benign from malignant solitary pulmonary nodules in a TB endemic area. S Afr Med J. 2010;100:598–601. 57. Vorster M, Sathekge MM, Bomanji J. Advances in imaging of tuberculosis: the role of 18FFDG PET and PET/CT. Curr Opin Pulm Med. 2014;20:287–93. 58. Ankrah AO, Glaudemans AWJM, Maes A, van de Wiele C, Dierckx RAJO, Vorster M. Tuberculosis. Semin Nucl Med. 2018;48:108–30. 59. Lang D, Huber H, Kaiser B, Virgolini I, Lamprecht B, Gabriel M. SUV as a possible predictor of disease extent and therapy duration in complex tuberculosis. Clin Nucl Med. 2018;43:94–100. 60. Stelzmueller I, Huber H, Wunn R, Hodolic M, Mandi M, Lamprecht B, et al. 18F-FDG PET/ CT in the initial assessment and for follow-up in patients with tuberculosis. Clin Nucl Med. 2016;41:e187–94. 61. Sathekge M, Maes A, Kgomo M, Stoltz A, Van de Wiele C.  Use of 18F-FDG PET to predict response to first-line tuberculostatics in HIV-associated tuberculosis. J Nucl Med. 2011;52:880–5. 62. Sathekge M, Maes A, D’Asseler Y, Vorster M, Gongxeka H, Van de Wiele C.  Tuberculous lymphadenitis: FDG PET and CT findings in responsive and nonresponsive disease. Eur J Nucl Med Mol Imaging. 2012;39:1184–90.

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63. Martinez V, Castilla-Lievre MA, Guillet-Caruba C, Grenier G, Fior R, Desarnaud S, et  al. 18 F-FDG PET/CT in tuberculosis: an early non-invasive marker of therapeutic response. Int J Tuberc Lung Dis. 2012;16:1180–5. 64. Chen RY, Dodd LE, Lee M, Paripati P, Hammoud DA, Mountz JM, et  al. PET/CT and high resolution CT as potential imaging biomarkers associated with treatment outcomes in MDR-TB. Sci Transl Med. 2014;6:265ra166. 65. Dureja S, Sen IB, Acharya S. Potential role of F18 FDG PET-CT as an imaging biomarker for the noninvasive evaluation in uncomplicated skeletal tuberculosis: a prospective clinical observational study. Eur Spine J. 2014;23:2449–54. 66. Jeong YJ, Paeng JC, Nam HY, Lee JS, Lee SM, Yoo CG, et al. 18F-FDG positron-emission tomography/computed tomography findings of radiographic lesions suggesting old healed tuberculosis. J Korean Med Sci. 2014;29(3):386–91. 67. Sathekge MM, Ankrah AO, Lawal I, Vorster M. Monitoring response to therapy. Semin Nucl Med. 2017;48:166–81. 68. Hu Y, Mangan JA, Dhillon J, Sole KM, Mitchison DA, Butcher PD, et al. Detection of mRNA transcripts and active transcription in persistent Mycobacterium tuberculosis induced by exposure to rifampin or pyrazinamide. J Bacteriol. 2000;182:6358–65. 69. Malherbe ST, Shenai S, Ronacher K, Loxton AG, Dolganov G, Kriel M, et al. Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure. Nat Med. 2016;22(10):1094–100. 70. Esmail H, Lia RP, Lesosky M, Wilkinson KA, Graham CM, Coussens AK, et al. Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[18]fluoro-D-glucose positron emission and computed tomography. Nat Med. 2016;22:1090–3. 71. Vorster M, Maes A, van de Wiele C, Sathekge M. Gallium-68 PET: a powerful generator-based alternative to infection and inflammation imaging. Semin Nucl Med. 2016;46:436–47. 72. Vorster M, Maes A, van de Wiele C, Sathekge M. 68Ga-citrate PET/CT in tuberculosis: a pilot study. Q J Nucl Med Mol Imaging. 2019;63:48–55. 73. Vorster M, Jacobs A, Malefahlo S, Pottel H, van de Wiele C, Sathekge M. Evaluating the possible role of 68Ga-citrate PET/CT in the characterization of indeterminate lung lesions. Ann Nucl Med. 2014;28:523–30. 74. Ebenhan T, Mokaleng BB, Venter JD, Kruger HG, Zeevaart JR, Sathekge M.  Preclinical assessment of a 68Ga-DOTA-functionalized depsipeptide as radiodiagnostic infection imaging agent. Molecules. 2017;22:1403. 75. Belton M, Brilha S, Manavaki R, Mauri F, Nijran K, Hong YT, et  al. Hypoxia and tissue destruction in pulmonary TB. Thorax. 2016;71:1145–53. 76. Kang F, Wang S, Tian F, Zhao M, Zhang M, Wang Z, et al. Comparing the diagnostic potential of 68Ga-Alfatide II and 18F-FDG in differentiating between non-small cell lung cancer and tuberculosis. J Nucl Med. 2016;57:672–7. 77. Pyka T, Weirich G, Einspieler I, Maurer T, Theisen J, Hatzichristodoulou G, et al. 68Ga-PSMAHBED-CC PET for differential diagnosis of suggestive lung lesions in patients with prostate cancer. J Nucl Med. 2016;57:367–71. 78. Zhang Z, Ordonez AA, Smith-Jones P, Wang H, Gogarty KR, Daryaee F, et al. The biodistribution of 5-[18F] fluoropyrazinamide in Mycobacterium tuberculosis-infected mice determined by positron emission tomography. PLoS One. 2017;12:e0170871. 79. Liu L, Xu Y, Shea C, Fowler JS, Hooker JM, Tonge PJ.  Radiosynthesis and bioimaging of the tuberculosis chemotherapeutics isoniazid, rifampicin and pyrazinamide in baboons. J Med Chem. 2010;53:2882–91. 80. Weinstein EA, Liu L, Ordonez AA, Wang H, Hooker JM, Tonge PJ, et al. Noninvasive determination of 2-[18F]-fluoroisonicotinic acid hydrazide pharmacokinetics by positron emission tomography in Mycobacterium tuberculosis-infected mice. Antimicrob Agents Chemother. 2012;56:6284–90. 81. DeMarco VP, Ordonez AA, Klunk M, Prideaux B, Wang H, Zhuo Z, et  al. Determination of [11C] rifampin pharmacokinetics within Mycobacterium tuberculosis-infected mice by using dynamic positron emission tomography bioimaging. Antimicrob Agents Chemother. 2015;59:5768–74.

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Imaging Fungal Infections and Therapy Follow-Up

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Andor W. J. M. Glaudemans

16.1

Introduction

Fungal infections can be divided into superficial, mucous, or invasive. Superficial and mucous fungal infections can be recognized easily by clinical findings and/or microscopy and are easy accessible. In these infections, diagnostic imaging modalities are necessary. However, on the other hand, invasive fungal infections (IFIs) are often difficult to diagnose and to treat, cause high morbidity, and can even be life threatening. In these cases, a proper and fast diagnosis is essential and imaging techniques play an important role. True morbidity and mortality rates of IFIs are unknown because epidemiological data do not exist, but certainly there has been a significant increase in the incidence of IFIs in the past decades [1–3]. This is due to changes and improvements in medical care: there has been significant developments in the treatment of oncological diseases (growing use of intensive chemotherapy), an increase in number of patients with organ and stem cell transplantation, and an increase in the use of immunosuppressive drugs for all kind of diseases. IFIs tend to develop in this population: patients that are severely immunocompromised (because of the use of chemotherapy in solid tumors or hematological malignancies) or use immunosuppressive drugs (after transplantation or because of other diseases). Still, IFIs remain understudied and underdiagnosed in comparison to other infectious diseases [4]. Risk factors for the development of IFIs include (1) patients with underlying diseases such as malignancies, human immunodeficiency syndrome (HIV), bowel surgery leading to an alternation in normal bacteria and fungi in the body, end organ failure, (2) patients with medical therapies that cause immune suppression such as A. W. J. M. Glaudemans (*) Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands e-mail: [email protected] © Springer Nature Switzerland AG 2020 A. Signore, A. W. J. M. Glaudemans (eds.), Nuclear Medicine in Infectious Diseases, https://doi.org/10.1007/978-3-030-25494-0_16

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chemotherapy, transplantations, invasive and complex surgeries, (3) patients with long-lasting immune modulating therapies, (4) patients with severe burns, (5) patients in intensive care units with insertion of catheters or other foreign body material for a long time, (6) patients with prolonged use of antibiotics that change the normal flora, and (7) premature babies [5].

16.2

Pathogens Causing Fungal Infections

In general, IFIs are caused by innumerous different species of fungi. To make nomenclature easier, most of these species have been divided into yeasts (most common type Candida) and molds (most common type Aspergillus). Candida and Aspergillus together form almost 90% of the fungi that cause IFIs.

16.2.1 Candida Invasive infection with a Candida species is one of the most occurring blood stream infections in patients in intensive care units [6]. Candida albicans is the most predominant species, but in recent years, due to the introduction of antifungal prophylaxis, there has been a shift in the proportion of IFIs due to C. albicans towards IFIs caused by less common Candida species, such as Candida krusei, Candida parapsilosis, and Candida glabrata. These types vary in virulence and susceptibility to antifungal drugs. Incidence of the type involved depends on geography. C. glabrata can be seen in Northern Europe, the USA, and Canada, whereas C. parapsilosis is more frequent in Southern Europe, Asia, and South Africa [6]. The mortality rate of an IFI caused by Candida is between 20 and 40% [7]. Children with Candida IFI may have on the long-term neurological impairment, such as cerebral palsy, blindness, hearing problems, and cognitive deficits. IFIs caused by a Candida species usually presents with fever and sepsis, but occasionally it may also present as a blood culture negative syndrome in cases of hepatosplenic candidiasis with deep-seated involvement of other organs, usually occurring in patients with hematological malignancies [6]. In these cases, monitoring therapy is a challenging task, and imaging might be helpful [8].

16.2.2 Aspergillus IFIs caused by aspergillosis leads to high morbidity and mortality in severely immunocompromised patients with mortality rates reported between 50 and 90% [5]. Many different Aspergillus species exist, with Aspergillus fumigatus being the most common. IFIs caused by Aspergillus is frequently seen in patients with the typical risk factors and is increasingly diagnosed in patients who are treated on the ICU with burns or traumas [9].

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Invasive aspergillosis is rare in neonates, but occurs more frequently in children, with mortality rates as high as in adults and significantly contributing to the mortality rates in immunocompromised children [10].

16.2.3 Other Fungal Pathogens There are a number of other—rarer—types of fungi that may cause IFIs, such as Histoplasmosis, Cryptococcus, Zygomycocis, and Pneumocystis jeroveci. Cryptococcus and Pneumocystis are most often found in patients with HIV/ AIDS. Incidence of other species vary with geographic location, patient age, and virulence. Also the morbidity and mortality varies between the different fungus type and the initial load of fungi at the site of infection. In Cryptococcus, the mortality is high, mentioned rates vary between 20 and 70% [11]. Also the duration of therapy for the rarer causes of IFI is often longer and depends on expert opinion. In some patients, treatment duration is mentioned of more than 2 years [11, 12].

16.3

The Diagnostic Problem in Fungal Infections

Since IFIs lead to high morbidity and mortality, early and accurate diagnosis is essential to start therapy as soon as possible. Many diagnostic tools are available, including direct and indirect methods of detection. Despite this extensive armamentarium, no single test is perfect and it is almost always necessary to perform several diagnostic tests to achieve maximum accuracy. Direct methods include the detection of fungi in blood or body fluids by microscopy and cultures or from tissue by histopathology. This can only be achieved by biopsies via invasive procedures and may have significant risks. For example, in a sick child suffering from an oncological disease and having thrombocytopenia as a result of the chemotherapy, taking a lung biopsy because of suspicion of pulmonary aspergillosis may lead to complications, such as severe bleeding. Even when having cultures, the identification of the exact type and species of the fungi is a time-consuming process which delays the onset of therapy. Moreover, the yield is only 50–60% in cases where there is fungemia [13]. The results of histology may come faster, but only identifies fungi to a certain degree which may help in starting initial therapy faster but ultimately culture to define the exact type and species is necessary to define the best possible therapy. To overcome the limitations in time mentioned above, indirect methods were developed. Often, antifungal therapy was started empirically when there is a high suspicion. This leads, however, to exposure to antifungal drugs of patients who did not have IFIs but still had the risk of adverse reactions on the drugs. Therefore, guidelines for ICU patients were developed to define those patients with the highest risk of having an IFI. Several indirect methods play a role in these guidelines [14]

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and include commercially available assays against antigens in the fungal cell wall to detect galactomannan (GM) or β-1,3-d-glucan (BDG) for detection of Aspergillus and most fungal species, respectively [10].

16.3.1 Existing Diagnostic Guidelines The most recent guidelines regarding a standard set of definitions for the diagnosis of IFIs were published back in 2008 by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. These definitions provide criteria for proven and probable invasive fungal disease (see Tables 16.1 and 16.2) and were made to strengthen the consistency and reproducibility of studies in patients with IFIs [15]. The role of imaging modalities in these criteria is minor and consists only of radiological imaging modalities; nuclear medicine imaging techniques are not mentioned at all.

Table 16.1 Criteria for proven invasive fungal disease (adapted from [15] with imaging signs depicted in red) Analysis

M olds

Microscopic Histopathologic, cytopathologic, or analysis: sterile direct microscopic examination of a material specimen obtained by needle aspiration or biopsy in which hyphae or melanized yeast-like forms are seen accompanied by evidence of a ssociated tissue damage Culture: sterile material

Culture: blood

Serological analysis: CSF

Recovery of a mold or “black yeast” by culture of a specimen obtained by a sterile procedure from a normally sterile and clinically or radiologically abnormal site consistent with an infectious disease process, excluding bronchoalveolar lavage fluid, a cranial sinus cavity specimen, and urine Blood culture that yields a mold in the context of a compatible infectious disease process Not applicable

Yeasts Histopathologic, cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or biopsy from a normally sterile site showing yeast cells (Cryptococcus species indicated by encapsulated budding yeasts or Candida species showing pseudo-hyphae or true hyphae Recovery of a yeast by culture of a sample obtained by a sterile procedure (including a freshly places (< 24 h ago drain) from a norm ally sterile site showing a clinical or radiological abnormality consistent with an infectious disease process Blood culture that yields yeast or yea stlike fungi Cryptococcal antigen in CSF indicates disseminated cryptococcosis

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Table 16.2 Criteria for probably invasive fungal disease (adapted from [15] with imaging signs depicted in red) Host factors

-Recent history of neutropenia temporally related to the onset of fungal disease -Receipt of an allogeneic stem cell transplant -Prolonged use of corticosteroids at a mean minimum dose of 0.3 mg/kg/day or prednisone equivalent for >3 weeks -Treatment with recognized T cell immunosuppressants, such as cyclosporine, TNF-a blockers, specific monoclonal antibodies, or nucleoside analogues during the past 90 days -Inherited severe immunodeficiency

Clinical criteria 1. Lower respiratory tract fungal disease

Presence of 1 of the following 3 signs on CT: -Dense, well-circumscribed lesions with or without halo sign -Air-crescent sign -Cavity

2. Tracheobronchitis

Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopic analysis

3. Sinonasal infection

Imaging showings inusitis plus at least 1 of the following 3 signs: -Acute localized pain (including pain radiating to the eye) -Nasal ulcer with black eschar -Extension from the paranasal sinus across bony barriers

4. CNS infection

1 of the following 2 signs: -Focal lesions on imaging -Meningeal enhancement on MRI or CT

5. Disseminated candidiasis

At least 1 of the following 2 entities after an episode of candidemia within the previous 2 weeks: -Small, target-like abscesses in liver or spleen -Progressive retinal exudates on ophthalmologic examination

Mycological criteria 1. Direct test (cytology, direct microscopy, or culture)

Mold in sputum, bronchoalveolar lavage fluid, bronchial brush, or sinus aspirate samples, indicated by 1 of the following: -Presence of fungal elements indicating a mold -Recovery by culture of a mold

2. Indirect test (detection of antigen or cell-wall constituents)

Aspergillosis: -Galactomannan antigen detected in plasma, serum, bronchoalveolar lavage fluid, or CSF Invasive fungal disease other than cryptococcosis and zygomycoses: -β-D-glucan detected in serum

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Imaging Possibilities to Diagnose Fungal Infections

16.4.1 Anatomical Imaging In daily clinical practice, the above mentioned testing tests, such as biopsy, galactomannan test, and β-1,3-d-glucan (BDG) assay, together with imaging techniques constitute the diagnostic pathway to track and diagnose fungal infections. Plain radiographs (of the chest), ultrasound, computed tomography (CT), high-resolution computed tomography of the chest (HR-CT), and magnetic resonance imaging (MRI) all play a role in the diagnosis and management of IFIs, but also all have their limitations. In case of acute fungal sinusitis, MRI of the head and neck region can be useful to identify these local fungal infections [16]. CT is not useful in the acute setting of sinusitis but can be useful on the long term where it can evaluate changes in the bone. Ultrasound, CT, and MRI of the abdomen can be useful to diagnose spread of infection in the spleen, kidneys, and/or liver. The two most used anatomical imaging modalities in patients with IFIs are now discussed separately.

16.4.1.1 HR-CT of the Lungs HR-CT has been found very valuable in pulmonary IFIs, especially with the presence of a positive indirect test, and particularly for invasive pulmonary aspergillosis. Spores of the Aspergillus species usually enter the body through the sinuses or through the respiratory tract, thereby eventually invading the lungs, resulting in bronchopneumonia in the early stages which are often unrecognized on chest radiographs. In case of progression of disease, nodular appearance or patchy consolidations may appear. In general, around 70% of IFIs are believed to involve the lungs in the immunocompromised patient [10]. Two key signs exist on HR-CT which are suggestive for invasive pulmonary fungal infection: the halo sign and the air crescent sign. The halo sign is a ground glass opacity surrounding a pulmonary nodule or mass and represents hemorrhage. The air crescent sign described the crescent of air that can be seen in invasive aspergillosis. When having both the halo sign and the air crescent sign this is highly suggestive for invasive pulmonary fungal infections. However, both signs may be transient visible, may not be visible at all, and can also be present in other pulmonary diseases. A study by Green et  al., in 235 patients with invasive pulmonary aspergillosis, the halo sign was seen in 61% of the patients, and the air crescent sign only in 10% of the patients, indicating that these signs are clearly not visible in all patients with pulmonary IFIs [17]. The use of HR-CT in pulmonary candidiasis is much more limited. Pulmonary candidiasis usually gives small nodular lesions, which do not cavitate, and which can be missed completely [18]. The main limitation of the use of HR-CT of the lungs, despite the above mentioned significant findings of the halo sign and the air crescent sign, is that it only visualizes lesions of the lungs. And IFIs may occur everywhere, in all organs and tissues throughout the body.

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16.4.1.2 MRI of the Brain MRI of the brain is particularly useful to identify spread of infection in the brain [19]. Initially, a cerebritis is produced without abscess formation which is hard to recognize by MRI. In a later stage, clear abscesses are formed that are easy to recognize by post-gadolinium MRI as reduced diffusion due to high viscosity and cellularity of fungal pus with ring enhancement. Other signs that may be seen by MRI are the mycotic vasculitis-mediated septic infarction (predominantly at the gray-white junction or perforating arterioles) or enhanced uptake of the meninges and choroid plexus in case of cryptococcus or aspergillus. The latter one may be accompanied by hydrocephalus with or without white matter edema [19]. The main limitations of MRI of the brain in case of IFIs is (1) the non-specificity of the abscess formation (this can also be found in other infectious diseases), and (2) the visualization of the brain only, so other manifestations of IFIs throughout the body are missed.

16.4.2 Nuclear Medicine Imaging As mentioned above, anatomical imaging modalities such as HR-CT of the chest and MRI of the brain can be very useful to detect fungal infection sites. However, with these imaging techniques it is only possible to image a limited area of the body. Since IFIs may occur in all organs and/or tissues throughout the body, it is essential to have a specific and noninvasive whole-body imaging test. Nuclear medicine techniques such as positron emission tomography (PET) detect in vivo pathophysiological changes often before anatomical changes can be observed by CT or MRI. Modern hybrid imaging modalities such as PET/CT provide the unique opportunity to combine the good anatomical resolution of the CT with the metabolic information of the PET to diagnose, localize, and stage IFIs at an early stage [20].

16.4.2.1 FDG-PET/CT 18 F-fluorodeoxyglucose (FDG) is the most commonly used tracer for PET/CT imaging in patients with suspected IFIs. FDG-PET/CT is a whole-body imaging technique: it is not limited to only one region of the body, so it can provide information of the whole body in one imaging session (which is also very convenient for the often critically ill patients) and is able to pick up infectious foci which may not yet have become clinically apparent by providing information about the increased metabolic uptake of FDG in the fungal infection sites. A recently published paper by Ankrah et al. provides a nice overview of available literature studies aiming at the detection and staging of IFIs, both in pulmonary IFIs as in extrapulmonary IFIs, ranged by the site of infection (liver, spleen, kidneys, bone and joints, adrenal glands, central nervous system, sinuses, aorta, and lymph node involvement [10]. Mainly case reports and only some small patient studies were found.

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The overall agreement between the studies is that FDG-PET/CT (1) is able to detect infectious foci which are not detected by other imaging techniques, (2) is helpful to know the extent of infection and the organs involved, (3) is able to define the site of most active infection for biopsy, and (4) shows a typical heart-shape pattern of aspergillus lesions with a central area of decreased metabolism. For the referring clinician, it is extremely helpful, to know the extent and dissemination of the infection and which organs are involved, to decide the best therapy strategy. As we all know, FDG-PET is a nonspecific imaging technique; it is not able to differentiate between infection and malignancy, and it is not able to tell exactly which bacteria or fungus is involved. Therefore, histological confirmation is always necessary for a final diagnosis. FDG-PET/CT may help to define the best biopsy site by showing not only the best accessible lesion but also by showing which lesion shows the highest metabolic activity which may provide the highest chance of a positive biopsy result. The best evidence for the use of FDG-PET for the detection of IFIs is from a study of Hot et al., including 30 consecutive patients with probable or proven IFI involving a wide range of fungi. FDG-PET showed uptake in all areas noted by conventional imaging, but also detected more lesions in the liver and spleen in some cases of hepatosplenic candidiasis, probably due to the early stage of disease where the anatomical changes associated with infection were not visible yet. Another important finding was that in a patient with aspergillosis where HR-CT has made an impact on early diagnosis, FDG-PET not only detected these active lesions, but was also able to correctly differentiate inactive noninvasive aspergilloma from active disease [21]. For staging, there are more studies available with the overall agreement that FDG-PET/CT is useful especially because of the whole-body imaging possibility, thereby able to detect dissemination of infection which was not detected by other imaging techniques [20–22]. Before choosing the correct therapeutic regimen, it is helpful to know the extent of infection and the organs involved. Recently, a study was published by Douglas et al., involving 45 patients with 48 separate IFI episodes. Proven IFI referred to the confirmed identification of fungal infection in a sterile site by culture, cryptococcal antigen detection or histopathology, or evidence of fungal tissue invasion on histopathology from needle aspiration or biopsy. Probable infection referred to the isolation of fungus or galactomannan at a site in conjunction with host predisposition and clinical features. FDG-PET/CT was classified as contributing to management if it localized infection, revealed a clinically occult site of infection or detected dissemination. FDG-PET/CT located clinically occult infection or dissemination to another organ in 40 and 38% of patients, respectively. Of 40 patients who had both FDG-PET/CT and conventional CT, sites of IFI dissemination were detected in 35% with FDG-PET/CT and only in 5% with conventional CT only. In this study, FDG-PET/CT was able to localize clinically occult infection and dissemination in a majority of patients [23]. Despite the aspecificity of FDG-PET, and the fact that histological confirmation is always necessary, there are some FDG uptake patterns that may point

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towards IFI.  High bilateral uptake in the adrenal glands in an immunocompromised patient must raise the suspicion of a fungal infection. Multiple round lesions widely spread throughout the body or in liver or spleen in a patient with risk factors for IFI may lead to suspected Candida infection. The FDG uptake in these round lesions is usually not very intense and the lesions are often small. Involvement of the esophagus (esophageal candidiasis) with increased FDG uptake further strengthens the diagnosis Candida infection. In fungal infections caused by an Aspergillus species, the lesions are usually bigger and show intense uptake, often with a central area of decreased metabolism (heart-shaped lesion), most likely due to the angio-invasive nature of the fungi causing necrosis due to an infective thrombotic vasculitis.

16.5

The Therapeutic Problem in Fungal Infections

Definite microbiological proof of a fungal infection is of invaluable importance to start targeted antifungal therapy as soon as possible. A delay in the start of therapy (or starting with the wrong therapy) is associated with increased mortality [24, 25]. Different antifungal strategies have been studied for the prevention of IFIs in nonneutropenic critically ill patients, the so-called untargeted antifungal treatment. For example, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) provided three definitions of different treatment strategies in candida diseases: prophylactic, pre-emptive, and empiric. Prophylaxis was defined as the administration of fungal agents without proven or suspected IFI but with risk factors for its development. Pre-emptive treatment was defined as treatment triggered by imaging (probable IFI) or without (possible IFI) microbiological evidence of fungal infection. Empiric treatment was defined as antifungal treatment triggered by signs and symptoms of infection in patients at risk for IFI, in the absence of microbiological and imaging evidence of infection at the moment of therapy start [26]. FDGPET/CT was not mentioned as one of the imaging possibilities, but would be a helpful tool for the early diagnosis, especially in the pre-emptive and the empiric group. Besides this challenge of a correct and early diagnosis to start the targeted therapy as soon as possible, there is also another treatment challenge. As IFIs often occur in severely ill and immunocompromised patients with often other life-threatening diseases, these patients are often treated with antifungal drugs for a long time period. This could last for 6  months to even a couple of years depending on the type of fungal infections. However, these drugs also cause side effects and are also very expensive. At this moment, there is no imaging modality that is able to define the time period of the therapy. Lesions on HR-CT or MRI may persist for a long time due to fibrosis, even after successful treatment. Also for therapy evaluation, there is an absolute need for a noninvasive whole-body imaging technique that tells the treating clinician how long the antifungal drugs should be given.

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16.5.1 Existing Classes of Antifungal Drugs Antifungal drugs can be divided into four classes [10, 27]: – The fluoropyrimidine group: Synthetic analogues of DNA, with 5-fluorocytosine as antifungal agent in use. This is a prodrug processing no antifungal properties on its own but converted to 5-fluorouracil, by a cytosine deaminase enzyme in fungi and not in humans, it exerts its antifungal effects. Diffuses rapidly throughout the body after oral administration. Generally safe but may cause hepatotoxicity and bone marrow suppression. Broad-spectrum activity particularly potent with Candida and other yeasts, though its action against Aspergillus and other molds is more limited. Use is declining because of resistance development. Mostly used in combination with other antifungal agents [10, 28]. – The polyene group: Amphiphilic organic compounds known as macrolides that target ergosterol, the main component of fungal membranes. Amphotericin B is one of the drugs belonging to this class. Broad spectrum covering most fungi. They also possess an affinity for human cholesterol, leading to their toxicity. Toxicity is mainly hepatic and renal. Liposomal or lipid complexes minimize these side effects. Resistance is reported but as a rare clinical effect. Major limitation is its toxicity [10, 29]. – The azole group: Most commonly used antifungal drugs in clinical practice. Involves fluconazole, itraconazole, and the more recent new generation drugs voriconazole and posaconazole. Target is a key enzyme in the ergosterol biosynthesis. Broadspectrum activity but resistance has been mentioned. Fluconazole has oral and intravenous formulations, diffuses throughout the body, even to the cerebrospinal fluid. Beware of specific drug interactions with some antineoplastic and HIV drugs. Resistance of Candida species against fluconazole has developed due to over-prescription. Newer generation drugs have wide range of activity and are more effective against Candida and Aspergillus. Side effects and drug interactions are similar to older azoles, but higher antifungal plasma levels can be reached [10, 30, 31]. – The echinocandin group: New class in antifungal agents. Inhibits enzymes responsible for the synthesis of the cell wall. Includes micafungin, caspofungin, and anidulafungin. Low toxicity profile, interaction with other drugs is rare. Broad activity range against both Candida and Aspergillus. Some fungi show resistance. Absence of oral formulation. Especially used when other antifungal drugs are ineffective. Anidulafungin can be used in patients with hepatic and renal impairment. Combination with other antifungal agents has a synergistic or at least an additive effect [10, 32, 33].

16.6

Imaging Possibilities in Therapy Guidance and Therapy Evaluation

In general, there is an absolute need for a noninvasive whole-body diagnostic test that tells the clinician if the followed treatment regimen is successful and for how long this strategy should be followed.

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Anatomic imaging modalities are often not able to help in therapy guidance since lesions on CT or MRI may persist for a long time, even after successful treatment due to, e.g., fibrosis. On the other hand, FDG-PET/CT could fill these gaps by telling to the referring clinician and the patient: – There is no metabolic active infection anymore (complete metabolic response), treatment can be stopped – There is progression of metabolic uptake, so progression of infection (metabolic progression), treatment should be modified – There is decrease in metabolic uptake, but no normalization (partial metabolic response), treatment should be continued The earlier mentioned recent review by Ankrah et al. [10] also summarized the available evidence on the use of FDG-PET for therapy evaluation in patients with IFIs. Almost all published papers are case reports, but the general agreement between all these cases is that FDG-PET/CT (1) may serve as a valuable tool for monitoring treatment response, (2) led to a change in antifungal therapy regimen in cases of poor metabolic response, (3) may help to determine sites of surgery when antifungal agents may not effectively reach the site of fungal infection, (4) helped in therapy decision-making to continue antifungal therapy in cases with still disease activity, even after 120  days, (5) helped in therapy decision-making by stopping antifungal therapy in cases with inactive disease at a time point when other imaging modalities had not completely resolved, and (6) helped in deciding the best time point for autologous stem cell transplantation by showing a complete metabolic response on the therapy. IFIs in immunocompromised patients are life threatening, and especially in cases where there is no fungemia, the duration of therapy is not known. In cases if patients are being evaluated for stem cell transplantation, huge decisions depend on whether there is still active fungal disease or not. FDG-PET/CT could help in this decision-making. Recently, two studies with FDG-PET for therapy evaluation in IFIs in larger patient cohorts were published in 2019; the first one by Ankrah et  al. [34]. This study included 28 patients with, in total, 98 FDG-PET/CT scans. Patients with a definite diagnosis of IFI (n = 18) had fungi cultured at the beginning or during the course of their treatment. Patients who were diagnosed as clinical IFI (n = 10) had a clinical suspicion of IFI with or without positive serological markers for IFIs, and showed improvement on antifungal treatment and clinical follow-up. Eighteen patients were diagnosed with Aspergillus (8 without specified species), 9 with Candida (2 with unspecified species), and 1 with Hormographiella aspergillata. The baseline FDG-PET/CT was defined as a scan performed before or within 2 weeks of the initiation of antifungal therapy. For treatment evaluation, FDG-PET/ CT was performed when the treating clinician felt the need to evaluate the IFI with imaging, so not on an exact time point. The responses of IFIs to treatment were classified into three groups based on FDG-PET/CT findings on the final scan: (1) patients with a complete metabolic response (CMR, complete resolution of FDG uptake), (2) with a partial response

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(PR, any reduction in FDG uptake not reaching complete normalization), and (3) with progression of the infection (progressive disease, PD, appearance of new lesions or an increase in size or intensity of existing lesions due to IFI). When FDGPET/CT led to a cessation or change in antifungal drugs or resulted in surgery, it was defined as alternation of therapy and having added value. When FDG-PET/CT led to a prolongation of therapy (because of PR), it was considered as having added value. In this study, in 28 patients with a mean age of 43 years (±22) FDG-PET/CT altered management in 14 out of the 28 patients (50%). At the final FDG-PET/CT scan, 19 (68%) had a CMR, seven a PR, and two patients were defined as having PD. FDG-PET/CT resulted in a prolongation of therapy in 18 patients (68%), and to a change in therapy in 8 patients (28%). In total, FDG-PET/CT added value to treatment in 26 out of the 28 patients (93%) [33]. The second recently published study with FDG-PET/CT for therapy evaluation was already mentioned in the diagnosis part [23]. Eighteen of the included 45 patients, also had both FDG-PET/CT and conventional CT follow-up imaging, at a median of 2.5 months after initial FDG-PET/CT. Of the 18 patients, the findings were discordant in 11 (61%), where the normalization of FDG avidity of a lesion suggested that the active infection had resolved, yet the CT scan showed a persisting infection. The authors concluded that FDG-PET/CT was particularly helpful in demonstrating response to antifungal therapy [23].

16.7

Clinical Questions

In daily clinical practice, the referring physician/infectiologist has the following questions for the medical imaging specialist when asking for a FDG-PET/CT for the detection or staging of IFI: – In a patient with risk factors or an immunocompromised patients: Are there signs of a fungal infection? – In a patient with high suspicion of an IFI: What is the extent of the fungal infection? Which organs are involved? – In a patient with high suspicion of an IFI, to prove the diagnosis, to detect the exact type of fungus involved, to start the adequate treatment: What is best accessible site showing high metabolic uptake for biopsy? When having a baseline FDG-PET/CT, the treating physician/infectiologist may have the following questions regarding the follow-up scans in patients with proven or possible IFI: – Is there complete metabolic response? Can I stop the treatment? Can I perform stem cell transplantation is this patient? – Is there progressive disease? Do I have to modify the treatment? – Is there partial metabolic response? Do I have to continue the treatment?

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271

Cases

Case 1 Fifty-eight year-old male patient, known with hairy cell leukemia and neutropenia. Diagnosed by bronchoalveolar lavage with invasive fungal infection with Hormographiella aspergillata (definite IFI, very aggressive sort). Figure 16.1 shows the baseline FDG-PET (several intrapulmonary lesions, several active lymph nodes in het mediastinum and hili, and a large lesion in the abdomen between liver and spleen) and three follow-up scans (the second one on an inferior camera system). The lung lesions show partial metabolic response (decrease of FDG uptake in time, but no complete normalization). However, the sagittal view of the second scan now shows two lesions in the abdomen (progressive disease). This patient went to surgery and two encapsulated fungal infection sites were found between the liver and the spleen, the antifungal drugs could not

Fig. 16.1 FDG-PET scans, MIP images of the patient of case 1. Upper row: coronal MIP views, lower row: sagittal MIP views

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Stop treatment

Fig. 16.2 FDG-PET scans, MIP images of the patient of case 1

reach these lesions). On scan 3 and 4 no pathological lesions in the abdomen were found. Because of the incomplete metabolic response, several times the antifungal drug regimen was adapted. In total, the patient underwent 26 months of antifungal therapy: ambisone, flucytosine, voriconazole, caspofungin, and posaconazole. In total, 11 follow-up FDG-PET/CT scans were performed. Figure  16.2 shows again the baseline FDG-PET and the three last follow-up scans. Scan 9 (second image of the left) showed complete metabolic response but the treating physician still wanted to prolong the treatment for another 3 months. After scan 10 (third image of the left, again complete metabolic response, the uptake at the right scapula was because of a fracture after a trauma) the decision was taken to stop the treatment. The last scan (scan 11, right image) was performed to check 3 months after the treatment stop to see if there was still complete metabolic response, which was the case. Case 2 Sixty-year-old female patient, known with acute myeloid leukemia, treatment with chemotherapy. X-ray of the chest suspected for pneumonia (Fig.  16.3, image A), however after 3  weeks no reaction on antibiotics. FDG-PET/CT (Fig. 16.3, image B and C) with high resolution CT (Fig. 16.3, image D) was performed and showed a metabolic active lesion in the upper lobe of the right lung with a typical halo sign and an air crescent sign on the HR-CT, typical for pulmonary aspergillosis. Follow-up FDG-PET/CT (Fig. 16.4, image A) after 6 weeks showed complete metabolic response, while the low dose CT scan and the X-ray of the chest at the same day (Fig. 16.4, image B) still showed an anatomical substrate, probably due to fibrosis.

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Fig. 16.3 Baseline scans of the patient of case 2. (a) X-ray chest, (b) FDG-PET MIP image, (c) fused FDG-PET/low dose CT image, (d) HR-CT image

Fig. 16.4 Follow-up scans of the patient of case 2. (a) Fused FDG-PET/low dose CT image, (b) X-ray chest

Case 3 Twenty-year-old female patient, known with acute lymphatic leukemia, chemotherapy, neutropenic, fever. Baseline FDG-PET (Fig. 16.5, left image) shows involvement of the lungs and the kidneys. Follow-up scan (Fig. 16.5, second image) showed

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Fig. 16.5 Baseline FDG-PET and three follow-up scans of the patient of case 3

progressive disease with involvement of both lungs, both kidneys, and the spleen). Therapy was modified. Next follow-up scan (third image) showed partial metabolic response, still uptake visible in spleen and kidneys. Therapy was continued. Last follow-up scan (right image) showed complete metabolic response, therapy was stopped. Case 4 Thirty-eight-year-old male, known with acute lymphatic leukemia and neutropenia. Diagnoses with fever and bacteremia, treated for several weeks with meropenem, but still persistent fever. Figure  16.6 shows the baseline FDG-PET/CT showing several lesions with increased FDG uptake throughout the body, HR-CT showed multiple intrapulmonary lesions with halo sign. Biopsy of lung lesions showed aspergillosus. Figure 16.7 shows the baseline FDG-PET and three follow-up scans. The first follow-up scan (second image) showed decrease of the lung lesions but increase of lesions in the lever. Therapy was prolonged. The second follow-up scan (third image) showed progressive disease with also multiple intense lymph nodes. Therapy was modified. The last follow-up scan (right image) showed complete metabolic response. Case 5 Sixty-three-year-old female patient, known with acute myeloid leukemia, chemotherapy, fever, and increasing infection parameters. FDG-PET was performed to see if there was an active infection and showed (Fig. 16.8) high metabolically active lesions in several organs and in subcutaneous and muscular tissue. Biopsy revealed invasive candida infection.

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Fig. 16.6 Baseline FDG-PET MIP image (left) and HR-CT scan of the chest (right) of the patient of case 4

Switch treatment

Fig. 16.7 Baseline FDG-PET image and three follow-up scans of the patient of case 4

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Fig. 16.8 FDG-PET MIP image of the patient of case 5

16.9

Conclusions

Invasive fungal infections occur mostly in immunosuppressed patients and can be life-threatening. In these patients there is both a diagnostic problem and a therapeutic problem. Diagnosis of the exact fungus involved is difficult and no diagnostic test is perfect. Therefore, it is often necessary to perform several diagnostic tests to achieve maximum accuracy. The indications and added value of the most often used imaging tests are depicted in Table 16.3. FDG-PET/CT can play a major role in this diagnostic pathway since it is a whole-body imaging technique, detects pathophysiological changes before anatomical changes, may pick up infectious foci which are not yet clinically apparent, and may provide the best location of biopsy. With regards to the therapeutic problem, antifungal drugs are often used for a long time period, the duration of treatment regimens differ, the drugs are expensive and may cause severe side effects. Lesions on CT on MRI may persist for a long time even after successful treatment due to, e.g., fibrosis. FDG-PET/CT may also close this gap since this whole-body imaging test can tell the treating clinician that there is (1) no active infection anymore, you can stop the treatment, (2) progression of the infection, you have to modify the treatment, or (3) response on the treatment, but no complete remission, you have to continue the treatment.

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Table 16.3 Value of imaging techniques in patients with invasive fungal infections Imaging modality High resolution CT

Indications – Pulmonary IFIs, particularly for invasive pulmonary aspergillosis

MRI

– Spread of infection/abscesses in the brain – Spread of infection/primary IFI location in the facial sinuses

FDG-PET/ CT

– Whole-body imaging of all infectious foci in the body – Best location for biopsy – Involvement of which organs/tissues – Therapy decision-making and therapy evaluation

Advantages and limitations Advantages: – Both halo sign and air crescent sign present is highly suggestive for invasive pulmonary fungal infection Limitations: – However, both signs may be transient visible, not visible at all, and can also be present in other pulmonary disease – Use much more limited in pulmonary candidiasis – Only visualizes lung lesions Advantages: – Typical MRI sings – Also easy recognition of involvement of meninges, choroid plexus Limitations: – Only visualizes brain lesions Advantages diagnosis and staging: – Defines sites of most active infection for biopsy – Detects infectious foci that are not yet clinically apparent and not detected by other imaging techniques – Helpful to determine extent of infections – May help to differentiate based on pattern between aspergillosus and candidiasis Advantages therapy evaluation: – Helps in therapy decision-making and therapy guiding (stop, modify, or continue treatment) – Helps to determine when agents do not effectively reach the infection site, and when surgery is recommended – Helps to determine best time point of organ or stem cell transplantation when infection has resolved Limitations: – Aspecificity, always biopsy needed for confirmation

So in general, although literature evidence is scarce, FDG-PET/CT has been underutilized in the management of IFIs and can really be useful for the diagnosis, the staging, and particularly for therapy evaluation. Prospective randomized studies with large patient numbers are needed for the exact validation of FDG-PET/CT in IFIs. Furthermore, more emphasis should be given to the development of specific antifungal tracers for an even better possibility to diagnose IFI as soon as possible and to start adequate treatment at an early time point.

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