Case Studies in Infectious Disease: Trypanosoma Spp 9781136985362, 9780815341420, 0203854101, 0815341423, 1136985360

Table of contents :
Book Cover......Page 1
Title......Page 2
Copyright......Page 3
Preface to Case Studies in Infectious Disease......Page 4
Table of Contents......Page 5
Trypanosoma spp.......Page 8
Answers to Multiple Choice Questions......Page 20

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Trypanosoma spp.

Peter M. Lydyard Michael F. Cole John Holton William L. Irving Nino Porakishvili Pradhib Venkatesan Katherine N. Ward

This edition published in the Taylor & Francis e-Library, 2009. To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.

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©2010 by Garland Science, Taylor & Francis Group, LLC

This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. All rights reserved. No part of this book covered by the copyright heron may be reproduced or used in any format in any form or by any means—graphic, electronic, or mechanical, including photocopying, recording, taping, or information storage and retrieval systems—without permission of the publisher.

The publisher makes no representation, express or implied, that the drug doses in this book are correct. Readers must check up to date product information and clinical procedures with the manufacturers, current codes of conduct, and current safety regulations. ISBN 978-0-8153-4142-0 Library of Congress Cataloging-in-Publication Data Case studies in infectious disease / Peter M Lydyard ... [et al.]. p. ; cm. Includes bibliographical references. SBN 978-0-8153-4142-0 1. Communicable diseases--Case studies. I. Lydyard, Peter M. [DNLM: 1. Communicable Diseases--Case Reports. 2. Bacterial Infections--Case Reports. 3. Mycoses--Case Reports. 4. Parasitic Diseases-Case Reports. 5. Virus Diseases--Case Reports. WC 100 C337 2009] RC112.C37 2009 616.9--dc22 2009004968

Published by Garland Science, Taylor & Francis Group, LLC, an informa business 270 Madison Avenue, New York NY 10016, USA, and 2 Park Square, Milton Park, Abingdon, OX14 4RN, UK. Visit our web site at http://www.garlandscience.com ISBN 0-203-85410-1 Master e-book ISBN

Peter M. Lydyard, Emeritus Professor of Immunology, University College Medical School, London, UK and Honorary Professor of Immunology, School of Biosciences, University of Westminster, London, UK. Michael F. Cole, Professor of Microbiology & Immunology, Georgetown University School of Medicine, Washington, DC, USA. John Holton, Reader and Honorary Consultant in Clinical Microbiology, Windeyer Institute of Medical Sciences, University College London and University College London Hospital Foundation Trust, London, UK. William L. Irving, Professor and Honorary Consultant in Virology, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK. Nino Porakishvili, Senior Lecturer, School of Biosciences, University of Westminster, London, UK and Honorary Professor, Javakhishvili Tbilisi State University, Tbilisi, Georgia. Pradhib Venkatesan, Consultant in Infectious Diseases, Nottingham University Hospitals NHS Trust, Nottingham, UK. Katherine N. Ward, Consultant Virologist and Honorary Senior Lecturer, University College Medical School, London, UK and Honorary Consultant, Health Protection Agency, UK.

Preface to Case Studies in Infectious Disease The idea for this book came from a successful course in a medical school setting. Each of the forty cases has been selected by the authors as being those that cause the most morbidity and mortality worldwide. The cases themselves follow the natural history of infection from point of entry of the pathogen through pathogenesis, clinical presentation, diagnosis, and treatment. We believe that this approach provides the reader with a logical basis for understanding these diverse medically-important organisms. Following the description of a case history, the same five sets of core questions are asked to encourage the student to think about infections in a common sequence. The initial set concerns the nature of the infectious agent, how it gains access to the body, what cells are infected, and how the organism spreads; the second set asks about host defense mechanisms against the agent and how disease is caused; the third set enquires about the clinical manifestations of the infection and the complications that can occur; the fourth set is related to how the infection is diagnosed, and what is the differential diagnosis, and the final set asks how the infection is managed, and what preventative measures can be taken to avoid the infection. In order to facilitate the learning process, each case includes summary bullet points, a reference list, a further reading list and some relevant reliable websites. Some of the websites contain images that are referred to in the text. Each chapter concludes with multiple-choice questions for self-testing with the answers given in the back of the book. In the contents section, diseases are listed alphabetically under the causative agent. A separate table categorizes the pathogens as bacterial, viral, protozoal/worm/fungal and acts as a guide to the relative involvement of each body system affected. Finally, there is a comprehensive glossary to allow rapid access to microbiology and medical terms highlighted in bold in the text. All figures are available in JPEG and PowerPoint® format at www.garlandscience.com/gs_textbooks.asp We believe that this book would be an excellent textbook for any course in microbiology and in particular for medical students who need instant access to key information about specific infections. Happy learning!!

The authors March, 2009

Table of Contents The glossary for Case Studies in Infectious Disease can be found at http://www.garlandscience.com/textbooks/0815341423.asp Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Case 9 Case 10 Case 11 Case 12 Case 13 Case 14 Case 15 Case 16 Case 17 Case 18 Case 19 Case 20 Case 21 Case 22 Case 23 Case 24 Case 25 Case 26 Case 27 Case 28 Case 29 Case 30 Case 31 Case 32 Case 33 Case 34 Case 35 Case 36 Case 37 Case 38 Case 39 Case 40

Aspergillus fumigatus Borellia burgdorferi and related species Campylobacter jejuni Chlamydia trachomatis Clostridium difficile Coxiella burnetti Coxsackie B virus Echinococcus spp. Epstein-Barr virus Escherichia coli Giardia lamblia Helicobacter pylori Hepatitis B virus Herpes simplex virus 1 Herpes simplex virus 2 Histoplasma capsulatum Human immunodeficiency virus Influenza virus Leishmania spp. Leptospira spp. Listeria monocytogenes Mycobacterium leprae Mycobacterium tuberculosis Neisseria gonorrhoeae Neisseria meningitidis Norovirus Parvovirus Plasmodium spp. Respiratory syncytial virus Rickettsia spp. Salmonella typhi Schistosoma spp. Staphylococcus aureus Streptococcus mitis Streptococcus pneumoniae Streptococcus pyogenes Toxoplasma gondii Trypanosoma spp. Varicella-zoster virus Wuchereia bancrofti

Guide to the relative involvement of each body system affected by the infectious organisms described in this book: the organisms are categorized into bacteria, viruses, and protozoa/fungi/worms

Organism

Resp

MS

GI

H/B

GU

CNS

CV

Skin

Syst

1+

1+

L/H

Bacteria Borrelia burgdorferi

4+

Campylobacter jejuni

4+

Chlamydia trachomatis

2+ 2+

Clostridium difficile

4+

4+

Coxiella burnetti

4+

Escherichia coli

4+

4+

Helicobacter pylori

4+

4+

4+

4+

4+

Listeria monocytogenes

2+

4+

Mycobacterium leprae

4+ 4+

4+

2+ 4+

Neisseria meningitidis

2+ 4+

Rickettsia spp.

4+ 4+

Salmonella typhi

4+

4+ 1+

1+

2+

1+ 1+

4+

Streptococcus pyogenes

4+ 4+

Streptococcus mitis Streptococcus pneumoniae

2+

2+

Neisseria gonorrhoeae

Staphylococcus aureus

4+

4+

Leptospira spp.

Mycobacterium tuberculosis

2+

4+

1+

4+

3+

4+

4+ 3+

Viruses Coxsackie B virus

1+

1+

4+

1+

Epstein-Barr virus Hepatitis B virus

4+

2+

4+

4+

Herpes simplex virus 1

2+

4+

4+

Herpes simplex virus 2

4+

2+

4+

2+

Human immunodeficiency virus

Influenza virus

2+

4+

1+

Norovirus

1+

4+

Parvovirus

2+

Respiratory syncytial virus

4+

Varicella-zoster virus

2+

3+

4+ 2+

4+

2+

Protozoa/Fungi/Worms Aspergillus fumigatus

4+

Echinococcus spp.

2+

Giardia lamblia Histoplasma capsulatum

1+ 4+ 4+

3+

1+

Leishmania spp.

4+

4+ 4+

4+

4+ 4+

Toxoplasma gondii Trypanosoma spp.

4+ 4+

Plasmodium spp. Schistosoma spp.

2+

2+ 4+

Wuchereria bancrofti

4+

4+ 4+ 4+

The rating system (+4 the strongest, +1 the weakest) indicates the greater to lesser involvement of the body system. KEY: Resp = Respiratory: MS = Musculoskeletal: GI = Gastrointestinal H/B = Hepatobiliary: GU = Genitourinary: CNS = Central Nervous System Skin = Dermatological: Syst = Systemic: L/H = Lymphatic-Hematological

Trypanosoma spp.

A 32-year-old female from Brazil presented to her local hospital with a sudden onset of left leg, arm, and facial weakness. She was able to speak and reported being in good health in the past except that she got short of breath running after her 4-year-old son. She grew up as a child in Brazil but came to the UK in her early twenties. A CT scan of her brain showed an acute stroke. The ECG tracing of her heart was abnormal with broadened QRS complexes. A chest X-ray showed enlargement of the heart (Figure 1). An ECHO scan of the heart showed a dilated left ventricle with an apical aneurysm, in which there was a small thrombus. An ELISA test for Trypanosoma cruzi antibodies was performed because of her Brazilian origin and proved positive. She was diagnosed with Chagas’ disease with cardiomyopathy and an embolic stroke. She was treated with intensive rehabilitation, anticoagulated, and commenced on ACE inhibitors. For her infection she was treated with benznidazole.

Figure 1. A chest X-ray showing enlargement of the heart due to Chagas' disease.

1. What is the causative agent, how does it enter the body and how does it spread a) within the body and b) from person to person? Causative agent Trypanosomes are flagellated protozoan parasites. In Africa the species of Trypanosoma brucei has two subspecies that infect humans (Figure 2). In Central and West Africa this is T. brucei gambiense and in East and Southern Africa it is T. brucei rhodesiense. The species in South America is Trypanosoma cruzi (Figure 3). It is estimated that in the course of evolution T. brucei and T. cruzi diverged from each other about 100 million years ago. The life cycle and clinical features arising from these two species differ. Entry and spread within the body When T. brucei is inoculated into a new human host by tsetse flies local multiplication occurs under the skin. There is spread to lymph nodes and then entry into the bloodstream. Multiplication occurs in blood. Within a few weeks T. brucei rhodesiense passes from the bloodstream, probably through the choroid plexus, into the central nervous system (CNS). This CNS invasion takes several months with T. brucei gambiense.

Figure 2. Trypanosoma brucei spp. in a blood film. The trypanosomes are slender with an undulating membrane leading to the flagellum.

2

TRYPANOSOMA

Figure 3. Trypanosoma cruzi in a blood film. It often appears as a 'C' shape.

Figure 4. Triatoma infestans, which transmits Trypanosoma cruzi.

Figure 5. Tsetse fly, Glossina morsitans, the vector for African trypanosomiasis.

T. cruzi is transmitted by triatomine bugs (Figure 4). Local inflammation occurs at the site of inoculation. Again there is spread to local lymph nodes and then entry into the bloodstream. Various tissues may be invaded but key targets are the heart and the gastrointestinal tract. Multiplication occurs in the tissues. The intracellular life form is the amastigote, which lacks a flagellum. Replication of the amastigote produces a pseudocyst within a cell. The extracellular life form is the trypomastigote. T. cruzi emerges from infected cells and passes onto other cells.

Person to person spread African trypanosomiasis is spread by tsetse flies belonging to the genus Glossina (Figure 5). The geographical distribution of African trypanosomiasis is determined by the ecological requirements of tsetse flies. This is patchy in countries between the sub-Saharan region and the Kalahari and Namib deserts. Infection of humans can be person to person but also a zoonosis with tsetse flies transmitting trypanosomes from a reservoir of ungulates (see below). Glossina morsitans morsitans usually transmits T. brucei rhodesiense and G. palpalis usually transmits T. brucei gambiense. Trypanosomes ingested from an animal host pass through the mid-gut of the tsetse fly, undergo developmental changes and reach the salivary glands. Here they are referred to as metacyclic trypomastigotes. When tsetse flies bite humans their saliva passes into the bites bearing these trypomastigotes. This is called salivarian transmission. The life cycle of African trypanosomiasis is shown in Figure 6. In South America various animals can serve as a reservoir, examples include the armadillo and the opossum. Triatomine bugs ingest trypanosomes when biting infected animals. The trypanosomes remain within the intestine of the bug. If they next feed on humans they bite the skin and defecate at the same time. Humans reflexly scratching in the vicinity of the bite rub feces bearing metacyclic trypomastigotes into the open wound. This is called stercorarian transmission, the Latin root sterco referring to feces. The life cycle of South American trypanosomiasis is shown in Figure 7. Regrettably another form of transmission of trypanosomiasis is through blood transfusion. In resource-poor settings blood screening may not be

TRYPANOSOMA

tsetse fly stages

human stages

2 injected metacyclic trypomastigotes transform into bloodstream trypomastigotes, which are carried to other sites

1 tsetse fly takes a blood meal (injects metacyclic trypomastigotes)

8 epimastigotes multiply in salivary gland, they transform into metacyclic trypomastigotes

3

i

3 amastigotes multiply by binary fission in various body fluids, e.g. blood, lymph, and spinal fluid es leave l 7 procyclic trypomastigotes sfor for into the mid-gut and transform epimastigotes

d

6 bloodstream trypomastigotes transform into procyclic trypomastigotes in tsetse fly’s mid-gut, procyclic trypomastigotes multiply by binary fission i infective stage d diagnostic stage

4 trypomastigotes in blood 5 tsetse fly takes a blood meal (bloodstream trypomastigotes ingested)

Figure 6. Life cycle of African trypanosomiasis. Tsetse flies inoculate humans with metacyclic trypomastigotes when they take a blood meal (1). Trypomastigotes multiply in tissue fluid, then in lymph nodes, and then enter the bloodstream (2). In the bloodstream they continue multiplying with antigenic variation

to avoid the host response. Eventually they enter the central nervous system (3). Circulating parasite may be engulfed by tsetse flies when they take a blood meal (4). There is then development within the mid-gut of the tsetse fly before migration to the salivary glands (6–8).

feasible. However, transfusion-related transmission has been described in the USA from blood donated by South American immigrants. Understandably antibody screening of blood is not routine in nonendemic countries.

Epidemiology Despite control efforts WHO estimated in 2004 that African trypanosomiasis has a prevalence of about 0.5 million and accounts for 48000 deaths per annum, while complicated Chagas’ disease afflicts about 5 million in South America and is responsible for about 14 000 deaths per annum. These are very likely to be underestimates as there are no robust mechanisms for reporting cases. African trypanosomiasis is present in 36 countries and South American trypanosomiasis is present in 18 countries.

4

TRYPANOSOMA

triatomine bug stages

human stages

2 metacyclic trypomastigotes penetrate various cells at bite wound site, inside cells they transform into amastigotes

1 triatomine bug takes a blood meal (passes metacyclic trypomastigotes in feces, trypomastigotes enter bite wound or mucosal membranes, such as the conjunctiva)

8 metacyclic trypomastigotes in hind-gut

i

trypomastigotes can infect other cells and transform into amastigotes in new infection sites, clinical manifestations can result from this infective cycle

7 multiply in mid-gut

3 amastigotes multiply by binary fission in cells of infected tissues

d

6 epimastigotes in mid-gut

infective stage d diagnostic stage i

5 triatomine bug takes a blood meal

4 intracellular amastigotes transform into trypomastigotes, then burst out of the cell and enter the bloodstream

(trypomastigotes ingested)

Figure 7. Life cycle of South American trypanosomiasis. Humans are infected by stercorarian transmission from triatomine bugs (1). At the site of infection metacyclic trypomastigotes enter cells (2), transform into amastigotes and multiply (3). Trypomastigotes arise from infected cells, enter the

bloodstream and infect other cells in the body (4). Any circulating parasite may be engulfed by triatomine bugs when they take a blood meal (5). Further development occurs in the mid-gut of the bugs (6-8).

2. What is the host response to the infection and what is the disease pathogenesis? There are innate and adaptive host responses to trypanosomal infection. Humans may be exposed to nonpathogenic species of trypanosomes. However, in normal human serum, apolipoprotein L-1 binds to the trypanosome surface and is endocytosed. Within the trypanosomal cytoplasm, apoliprotein L-1 reaches and forms pores in lysosomes. Release of lysosomal contents causes trypanosomal killing. Species of trypanosomes that are usually nonpathogenic may only cause infection in humans with apolipoprotein L-1 deficiency. The pathogenic species T. brucei rhodesiense possesses a serum resistance-associated protein (SRA), which strongly binds to apolipoprotein L-1, inhibiting its toxic action. The other pathogenic species, T. brucei gambiense, does not possess SRA and how it might resist the action of apolipoprotein L-1 is not clear.

TRYPANOSOMA

5

T. brucei remains extracellular in the bloodstream and is exposed to the host immune response. Specific antibodies appear against the surface glycoprotein and lyse the trypanosomes through activation of complement. However, in T. brucei rhodesiense there are an estimated one thousand different variants of the surface glycoprotein. T. brucei switches the gene from one variant to another (antigenic variation). Each new antibody response is met with a gene switch and the escaping, new variants of trypanosomes multiply in successive waves (Figure 8). The variant specific glycoproteins (VSG) stimulate B lymphocytes to produce IgM in a T-cell independent manner. Eventually host serum has an excess of polyclonal IgM antibodies. The polyclonal activation of B cells compromises their ability to respond to other pathogens (another escape mechanism, like the antigenic variation to fool the host immune system). Other trypanosomal antigens pass through antigen-presenting cells and stimulate CD4+ lymphocytes to mount a T-cell-dependent antibody response. Trypanosomes directly release factors that stimulate CD8+ T lymphocytes and macrophages. Through this cellular activation various a (TNF-a a) cytokines and mediators appear. Tumor necrosis factor-a contributes to the weight loss of chronic infection. It seems to inhibit trypanosomal growth, but conversely interferon-gg (IFN-gg) seems to help trypanosomal proliferation. Dysregulated antibody production leads to the appearance of autoantibodies. Immune complexes damage vascular endothelium and on binding to the surface of red blood cells cause hemolysis. Chronic infection suppresses bone marrow function, probably through cytokine effects. This, added to hemolysis, causes anemia. Equally, platelet numbers may fall and disturbance of clotting may lead to hemorrhage or conversely thrombosis. Inflammation occurs in tissues containing T. brucei. This ranges from the skin at the site of local inoculation, to lymph nodes, to organs seeded from

1 2 3 4

.....1000

1 2 3 4

.....1000

1 2 3 4

.....1000

genes

parasitemia

1

2

antibody response to coat 1 Ag helps to clear first wave of parasites

3

antibody response to coat 2 Ag helps to clear second wave of parasites

no effect on parasites by antibody to coat 1 Ag 2

time after infection (weeks)

Figure 8. Antigenic variation of T. brucei. An antigen-specific response is made against the surface coat antigen, which gradually removes the parasites from the bloodstream (coat 1). During this time some of the parasites escape by switching their surface coat gene and the antibody response has to start from scratch. Antibodies to the second coat antigen (coat 2) are made, which remove these new parasites from the circulation. Some of the parasite will then escape again by switching their gene usage to coat 3 and so on. In T. brucei rhodesiense it is estimated that there are a thousand different variants of the glycoprotein that makes up the surface coat. (For simplicity, individual genes are depicted in a linear sequence whereas they are actually scattered about in the genome of the organism.)

6

TRYPANOSOMA

the bloodstream such as the heart, the kidneys, and eventually the CNS. Within the CNS there is progressive inflammation of the leptomeninges. The inflammatory response, immune complexes, local cytokines, and prostaglandins all contribute to CNS pathology, which eventually involves disruption of the choroid plexus and the blood–brain barrier. While T. brucei is extracellular T. cruzi is principally intracellular. The pseudocysts within tissues do not excite an inflammatory response. This only occurs once they rupture from cells and release antigens. T. cruzi is coated with a mucin-type glycoprotein that is anchored to the surface by a glycosylphosphatidylinositol (GPI). There are several hundred surface mucin genes, but antigenic variation in T. cruzi has not been established. GPI is well recognized as a potent macrophage activator and is thereby pro-inflammatory. Cell-mediated immune responses occur in infected tissue. In mice, CD8+ lymphocytes are essential for survival during the early stages of experimental infection. There is a polyclonal activation of B cells and it is conceivable that autoantibodies arise through dysregulation. Various T. cruzi antigens are also cross-reactive with host antigens found in vascular endothelium, muscle interstitium, and cardiac and nervous tissue. Autoimmune pathology is possible as passive transfer of serum or lymphocytes can cause pathology in recipients. However, it is not clear whether chronic pathology is caused by long-term infection-stimulated tissue inflammation or an autoimmune process or both.

3. What is the typical clinical presentation and what complications can occur? In African trypanosomiasis local inflammation at the site of tsetse fly inoculation is sometimes apparent and referred to as a trypanosomal chancre. This may occur in half of T. brucei rhodesiense infections but is rare with T. brucei gambiense. It appears after 1–2 weeks, may last for 2–3 weeks, and may reach a diameter of 3–5 cm. There may be regional lymphadenopathy. Symptoms occur once trypanosomes multiply and circulate in the bloodstream. These commence about 1–3 weeks after infection. There are fevers, headache, malaise, and loss of appetite. The fevers follow a cyclical pattern as the VSGs change. More generalized lymphadenopathy, hepatomegaly, and splenomegaly appear. There may be skin rashes. Invasion of the CNS represents the second stage of infection. There is progressive mental deterioration culminating in coma and death, with a variety of intervening CNS manifestations. There is disturbance of motor function, co-ordination, behavior, and sleep. African trypanosomiasis is called sleeping sickness. Patients may sleep in the daytime and be awake at night. T. brucei rhodesiense infection progresses more rapidly, with death within 9 months, while T. brucei gambiense may take a few years.

Figure 9. Romana’s sign in a boy. There is swelling by the right eyebrow. The boy will have been infected in that region by a triatomine bug.

In South American trypanosomiasis inflammation at the site of inoculation is called a chagoma. The disease was originally described by Carlos Chagas in Brazil in 1907 and the disease is also called Chagas’ disease. Sometimes the inflammation occurs around the eyelid and the local swelling is called Romana’s sign (Figure 9). Regional lymphadenopathy is followed by fever,

TRYPANOSOMA

headache, malaise, hepatomegaly, splenomegaly, and rash. In the acute phase, inflammation in seeded organs results in myocarditis, diarrhea, and vomiting or meningoencephalitis. The clinical features of the acute phase last 1–2 months and features may not return despite continued infection. Up to a third of patients suffer chronic complications after one or two decades. These principally affect the heart and the gastrointestinal tract. Cardiac muscle weakens and thins. Impaired cardiac function results in heart failure. Aneurysms can develop, typically at the apex of the left ventricle. Clots formed within the aneurysm can embolize. Cardiac conduction is altered with ECG abnormalities. Dysrhythmias or complete heart block may cause sudden death. In Brazil, more than elsewhere, gastrointestinal involvement results in dilatation and loss of peristalsis. This results in megaesophagus and megacolon, with accompanying dysphagia and constipation (Figure 10). The inability to eat causes cachexia and death.

4. How is the disease diagnosed and what is the differential diagnosis? Unfortunately many individuals suffer from trypanosomiasis distant from diagnostic facilities. Clinical features are nonspecific. In Chagas’ disease Romana’s sign and local lymphadenopathy are suggestive. In African trypanosomiasis the simplest test is the Card Agglutination Test for Trypanosomiasis (CATT). A drop of heparinized whole blood is placed on a card containing antigen and the presence of agglutination is observed over 5 minutes. This test has high sensitivity but false positive results can occur. Direct visualization of parasite may be observed in lymph node aspirates, blood films, and cerebrospinal fluid (CSF). If present in reasonable numbers the motile trypanosomes are easily observed. However, the level of parasitemia may be low in later stages of infection making parasitological diagnosis difficult. Examination of the CSF is essential for staging infection. In Chagas’ disease trypanosomes may be seen in a blood film during the acute phase. The main diagnostic test is serology, which may employ an ELISA. Once there are organ complications, ECGs or ECHOs of the heart reveal structural abnormalities and imaging of the esophagus and colon reveal dilatation.

Differential diagnosis Mega syndromes do not have alternative explanations of note. The differential diagnosis for the cardiac complications includes other cardiomyopathies. Otherwise the systemic febrile phase of early Chagas’ disease and African trypanosomiasis has a long differential diagnosis. In Africa the CNS phase may have to be distinguished from encephalitis, cerebral tuberculosis, HIV-related neurological disease, and cerebral tumors.

Figure 10. A plain abdominal X ray. There is marked dilatation of the colon, megacolon, which is easily apparent on the X ray.

7

8

TRYPANOSOMA

5. How is the disease managed and prevented? Management The treatments available for African trypanosomiasis are shown in Table 1. The year in which these agents were first developed is shown in brackets. The drugs are toxic and need to be bettered. Melarsoprol is an arsenical drug and causes a reactive encephalopathy in 20% on treatment and mortality in 2–12%. Drugs for Chagas’ disease include nifurtimox and benznidazole. Again they are both toxic and it is uncertain whether they should be used in the

Table 1. Drugs used to treat trypanosomiasis Pathogen

Drugs and comments

T. brucei gambiense

Early stage Pentamidine (1940) Intravenous or intramuscular Can cause drop in blood pressure, and changes in renal and hepatic function and blood glucose levels Late stage Melarsoprol (1949) Intravenous Can cause encephalopathy, with convulsions and coma, headache, thrombophlebitis, rash Eflornithine (1990) Intravenous Can cause bone marrow suppression and gastrointestinal upset Alternative to melarsoprol if available

T. brucei rhodesiense

Early stage Suramin (1920) Intravenous Can cause reversible nephrotoxicity, bone marrow suppression, and rash Late stage Melarsoprol (see above)

T. cruzi

Benznidazole Oral Can cause gastrointestinal upset, headache, joint pains, itch, and rash Nifurtimox Oral Can cause gastrointestinal upset, headache, joint and muscle pains

TRYPANOSOMA

9

asymptomatic phase of infection before complications arise. Potentially individuals will die with, rather than from, T. cruzi infection. Toxicity seems to be less in children than in adults. There are now studies of benznidazole in children showing that a 60-day course is reasonably well tolerated with disappearance of T. cruzi antibodies in almost 60%.

Prevention The control of trypanosomiasis is hampered by its rural occurrence. When possible it is important to actively diagnose cases and offer treatment for or before complications. Otherwise vector control is the key strategy employed. Insecticide sprays are used to kill tsetse flies. Insecticideimpregnated traps are positioned in key locations (Figure 11). Tsetse populations have been reduced in some localities by the release of sterilized male flies. While tsetse flies are principally outdoors the triatomine bugs of South America live within cracks in walls or in thatched roofs. Improved housing is important in reducing bug populations. Insecticide spraying has also been very successful in eliminating transmission in many areas. In South America universal blood screening is also important. Figure 11. Tsetse fly traps in rural Africa.

SUMMARY 1. What is the causative agent, how does it enter the body and how does it spread a) within the body and b) from person to person?

2. What is the host response to the infection and what is the disease pathogenesis? ●

South American trypanosomiasis is caused by Trypanosoma cruzi.

Nonpathogenic trypanosomes are killed by normal human serum through the action of apolipoprotein L-1. Pathogenic trypanosomes neutralize this through a serum resistanceassociated protein (SRA).

●

●

Tsetse flies transmit infection in Africa from other humans or an animal, ungulate reservoir.

In the bloodstream T. brucei species are killed by the action of antibody and complement.

●

●

Triatomine bugs transmit infection in South America from an animal reservoir.

T. brucei species undergo antigenic variation and evade the antibody response.

●

●

After an insect bite trypanosomes spread from local tissue to lymph nodes, then enter the bloodstream, and finally invade tissues.

Antigenic stimulation by T. brucei causes polyclonal antibody production by B cells.

●

●

In African trypanosomiasis invasion of the central nervous system occurs after weeks to several months.

Trypanosome-derived lymphocyte triggering factor (TLTF) and trypanosomal macrophage activating factor (TMAF) stimulate CD8+ T cells and macrophages, respectively.

In South American trypanosomiasis an aflagellate, intracellular life form, the amastigote, forms a pseudocyst within cells.

●

●

In African trypanosomiasis various cytokines are produced, and among these TNF-a can cause weight loss.

●

Trypanosomes are flagellated protozoan parasites.

●

African trypanosomiasis is caused by Trypanosoma brucei rhodesiense or T. brucei gambiense.

●

10

TRYPANOSOMA

●

Invasion of the central nervous system and leptomeningeal inflammation cause a ‘sleeping sickness.’

●

T. cruzi sheds glycosylphosphatidylinositol (GPI), which is a potent macrophage activator.

●

Inflammation occurs in T. cruzi-infected tissue and this may lead to long-term pathology, particularly of cardiac muscle and gastrointestinal smooth muscle.

●

Autoantibodies also appear in T. cruzi infection but their relative contribution to pathology is unclear.

3. What is the typical clinical presentation and what complications can occur?

●

Weakening of intestinal smooth muscle leads to dilatation and megaesophagus or megacolon.

4. How is the disease diagnosed, and what is the differential diagnosis? ●

The simplest test for African trypanosomiasis is a card agglutination test for antigen.

●

Trypanosomes may be seen on a blood film or in a tissue sample.

●

South American trypanosomiasis may be diagnosed by a serological test.

5. How is the disease managed and prevented? ●

Drugs for trypanosomes are toxic.

●

Melarsoprol is used for late stage African trypanosomiasis but can cause a fatal encephalopathy.

●

Swelling may occur at the site of the insect bite.

●

As trypanosomes enter the bloodstream there are fevers, headache, malaise, and loss of appetite.

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Once the central nervous system is invaded in African trypanosomiasis there is progression to coma and death with a variety of intervening neurological problems.

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For chronic South American trypanosomiasis treatment with benznidazole is probably beneficial in children but of uncertain value in adults.

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After clinical features from acute T. cruzi infection up to a third of patients suffer complications in the heart or gastrointestinal tract.

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Tsetse fly numbers can be reduced by outdoor insecticide-impregnated traps.

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Improving housing conditions reduces the population of triatomine bugs, which would otherwise live in cracks in walls or thatched roofs.

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Cardiac muscle can become weak and aneurysmal.

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FURTHER READING Burri C, Brun R. Human African trypanosomiasis. In: Cook GC, Zumla AI. Manson’s Tropical Diseases, 21st edition. Elsevier, Edinburgh, 2003, 1303–1323.

Murphy K, Travers P, Walport M. Janeway’s Immunobiology, 7th edition. Garland Science, New York, 2008.

Miles MA. American trypanosomiasis (Chagas disease). In: Cook GC, Zumla AI. Manson’s Tropical Diseases, 21st edition. Elsevier, Edinburgh, 2003, 1325–1337.

REFERENCES Barrett MP, Burchmore RJS, Stich A, et al. The trypanosomiases. Lancet, 2003, 362: 1469–1480.

Pentreath VW. Trypanosomiasis and the nervous system. Trans R Soc Trop Med Hyg, 1995, 89: 9–15.

De Andrade ALSS, Zicker F, de Oliviera RM, et al. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet, 1996, 348: 1407–1413.

Vanhollebeke B, Truc P, Poelvoorde P, et al. Human Trypanosoma evansi infection linked to a lack of apolipoprotein L-1. N Engl J Med, 2006, 355: 2752–2756.

WEB SITES Center for Disease Control, Atlanta, GA, USA: www.cdc.gov/

World Health Organization: www.who.int

Health Protection Agency: www.hpa.org.uk

MULTIPLE CHOICE QUESTIONS The questions should be answered either by selecting True (T) or False (F) for each answer statement, or by selecting the answer statements which best answer the question. Answers can be found in the back of the book.

C. T. cruzi is inoculated into a new human host through saliva from the biting vector. D. Trypanosomiasis can be transmitted by blood transfusion. E. Infections never pass from human to human.

1. Which of the following are true about Trypanosoma? A. They are flagellated protozoan parasites. B. T. cruzi is responsible for African trypanosomiasis.

3. Which of the following are true about the spread of trypanosomes?

C. They have animal reservoirs.

A. They are inoculated directly into the bloodstream.

D. T. brucei species cause infections in Asia.

B. Invasion of the central nervous system occurs in the first few days.

E. T. cruzi remains extracellular. 2. Which of the following are true about the life cycle of trypanosomiasis? A. T. brucei species are transmitted by sandflies. B. T. cruzi is transmitted by triatomine bugs.

C. A key target for T. cruzi is the reticuloendothelial system including the liver, spleen, and bone marrow. D. T. cruzi invades tissues and multiplies between cells rather than within cells. E. T. brucei gambiense invades the heart tissue.

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MULTIPLE CHOICE QUESTIONS (continued) 4. Which of the following are true of the host response to Trypanosoma brucei? A. Antibody and complement lyse T. brucei species. B. CD4+ T lymphocytes help B lymphocytes to produce anti-trypanosomal antibodies. C. Tumour necrosis factor-a inhibits trypanosomal growth.

D. Infection of the heart results in thickening of heart muscle. E. Weakening of the gastrointestinal smooth muscle occurs with infection in all geographical areas. 8. Which of the following are true of the diagnosis of trypanosomiasis?

D. T. brucei species must inhibit apolipoprotein L-1 to avoid lysosomal killing.

A. South American trypanosomiasis, Chagas’ disease, can always be diagnosed by characteristic clinical features.

E. T. brucei rhodesiense evades host antibody responses by switching between about 100 variant surface glycoproteins.

B. The card agglutination test for African trypanosomiasis tests for trypanosomal antigen in the bloodstream.

5. Which of the following are true of the host response to Trypanosoma cruzi?

C. The card agglutination test for trypanosomiasis has a low sensitivity, but a high specificity.

A. Autoantibodies appear in the course of infection.

D. For African trypanosomiasis diagnosis may be based on microscopy of blood or cerebrospinal fluid.

B. Antigenic variation is a clearly established immune evasion mechanism.

E. A serological test for antibody is available for Chagas’ disease.

C. Tissue pseudocysts excite a tissue inflammatory reaction. D. CD8+ T lymphocytes can kill cells bearing T. cruzi antigen. E. Macrophages are suppressed by T. cruzi. 6. Which of the following statements are true about the clinical features of African trypanosomiasis? A. A trypanosomal chancre may be seen in up to half of T. brucei rhodesiense infections. B. Lymphadenopathy is not observed in T. brucei gambiense infection. C. Fevers commence within a month of infection. D. Death follows invasion by trypanosomes of the central nervous system. E. Progression to death is more rapid with T. brucei gambiense than with T. brucei rhodesiense. 7. Which of the following are true of the clinical features of South American trypanosomiasis? A. Inflammation at the site of inoculation is called a chagoma. B. In the acute phase of infection the liver and spleen may be enlarged. C. Long-term complications occur in all those infected.

9. Which of the following are true for the treatment of trypanosomiasis? A. The use of melarsoprol for African trypanosomiasis is associated with encephalopathy in about 20%. B. Benznidazole is better tolerated by children than adults with T. cruzi infection. C. All individuals with T. cruzi infection should be treated to prevent complications. D. Pentamidine is used in the early stage of T. brucei gambiense infection. E. Late stage African trypanosomiasis is treated with benznidazole. 10. Which of the following are true of the control of trypanosomiasis? A. A vaccine is available. B. Treatment of infected individuals is a key part in eliminating the reservoir of infection. C. Insecticide-treated traps are used to control tsetse fly populations. D. Corrugated roofs are preferable to thatched roofs to limit triatomine bug populations. E. Screening of blood before transfusion is ineffective in preventing transmission.

Answers to Multiple Choice Questions 1. Which of the following are true about Trypanosoma? A. They are flagellated protozoan parasites. TRUE. B. T. cruzi is responsible for African trypanosomiasis. FALSE: T. cruzi is responsible for South American trypanosomiasis. C. They have animal reservoirs. TRUE. D. T. brucei species cause infections in Asia. FALSE: trypanosomes pathogenic to humans are found in Africa and South America. E. T. cruzi remains extracellular. FALSE: T. cruzi has a prolonged intracellular life stage. 2. Which of the following are true about the life cycle of trypanosomiasis? A. T. brucei species are transmitted by sandflies. FALSE: this species is transmitted by tsetse flies. Sandflies transmit leishmaniasis. B. T. cruzi is transmitted by triatomine bugs. TRUE. C. T. cruzi is inoculated into a new human host through saliva from the biting vector. FALSE: this is how tsetse flies transmit African trypanosomiasis. T. cruzi is excreted in the feces of biting triatomine bugs, and the feces are then rubbed into the bite wound by the host. D. Trypanosomiasis can be transmitted by blood transfusion. TRUE. E. Infections never pass from human to human. FALSE. 3. Which of the following are true about the spread of trypanosomes? A. They are inoculated directly into the bloodstream. FALSE: from local tissue they pass to lymph nodes and then enter the bloodstream. B. Invasion of the central nervous system occurs in the first few days. FALSE: for T. brucei species this takes a few weeks for T. brucei rhodesiense and several months for T. brucei gambiense. C. A key target for T. cruzi is the reticuloendothelial system including the liver, spleen, and bone marrow. FALSE: key targets are the heart and gastrointestinal tract. D. T. cruzi invades tissues and multiplies between cells rather than within cells. FALSE: multiplication is intracellular. E. T. brucei gambiense invades the heart tissue. FALSE: this species invades the central nervous system.

4. Which of the following are true of the host response to Trypanosoma brucei? A. Antibody and complement lyse T. brucei species. TRUE. B. CD4+ T lymphocytes help B lymphocytes to produce anti-trypanosomal antibodies. TRUE. C. Tumor necrosis factor-a inhibits trypanosomal growth. TRUE. D. T. brucei species must inhibit apolipoprotein L-1 to avoid lysosomal killing. TRUE. E. T. brucei rhodesiense evades host antibody responses by switching between about 100 variant surface glycoproteins. FALSE: in fact the number is about 1000. 5. Which of the following are true of the host response to Trypanosoma cruzi? A. Autoantibodies appear in the course of infection. TRUE. B. Antigenic variation is a clearly established immune evasion mechanism. FALSE: although it may happen, it is not established as an immune evasion mechanism. C. Tissue pseudocysts excite a tissue inflammatory reaction. FALSE: this only occurs when the cyst ruptures. D. CD8+ T lymphocytes can kill cells bearing T. cruzi antigen. TRUE. E. Macrophages are suppressed by T. cruzi. FALSE: macrophages are stimulated by T. cruzi-derived glycosylphosphatidylinositol (GPI). 6. Which of the following statements are true about the clinical features of African trypanosomiasis? A. A trypanosomal chancre may be seen in up to half of T. brucei rhodesiense infections. TRUE. B. Lymphadenopathy is not observed in T. brucei gambiense infection. FALSE. C. Fevers commence within a month of infection. TRUE. D. Death follows invasion of the central nervous system by trypanosomes. TRUE. E. Progression to death is more rapid with T. brucei gambiense than with T. brucei rhodesiense. FALSE.

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7. Which of the following are true of the clinical features of South American trypanosomiasis? A. Inflammation at the site of inoculation is called a chagoma. TRUE. B. In the acute phase of infection the liver and spleen may be enlarged. TRUE. C. Long-term complications occur in all those infected. FALSE: they occur in about one-third. D. Infection of the heart results in thickening of heart muscle. FALSE: infection weakens and thins the muscle, which may become aneurysmal. E. Weakening of the gastrointestinal smooth muscle occurs with infection in all geographical areas. FALSE: this feature is mainly seen in Brazil. 8. Which of the following are true of the diagnosis of trypanosomiasis? A. South American trypanosomiasis, Chagas’ disease, can always be diagnosed by characteristic clinical features. FALSE: although late features may be characteristic and highly suggestive, some infections remain subclinical. B. The card agglutination test for African trypanosomiasis tests for trypanosomal antigen in the bloodstream. FALSE: the card contains antigen to which antibody in the blood binds. C. The card agglutination test for trypanosomiasis has a low sensitivity, but a high specificity. FALSE: the converse is true, it has a high sensitivity but low specificity. D. For African trypanosomiasis diagnosis may be based on microscopy of blood or cerebrospinal fluid. TRUE. E. A serological test for antibody is available for Chagas’ disease. TRUE.

9. Which of the following are true for the treatment of trypanosomiasis? A. The use of melarsoprol for African trypanosomiasis is associated with encephalopathy in about 20%. TRUE. B. Benznidazole is better tolerated by children than adults with T. cruzi infection. TRUE. C. All individuals with T. cruzi infection should be treated to prevent complications. FALSE: as some will not develop complications treatment may be more toxic than beneficial. D. Pentamidine is used in the early stage of T. brucei gambiense infection. TRUE. E. Late stage African trypanosomiasis is treated with benznidazole. FALSE: this drug is used for South American trypanosomiasis. 10.Which of the following are true of the control of trypanosomiasis? A. A vaccine is available. FALSE. B. Treatment of infected individuals is a key part in eliminating the reservoir of infection. FALSE: there is also an animal reservoir. C. Insecticide-treated traps are used to control tsetse fly populations. TRUE. D. Corrugated roofs are preferable to thatched roofs to limit triatomine bug populations. TRUE. E. Screening of blood before transfusion is ineffective in preventing transmission. FALSE: this is important and practiced in South America.

Figure Acknowledgements Figure 1. Reprint permission kindly given by the World Health Organization, Special Programme for Research and Training in Tropical Diseases, http://www.who.int/tdr/index.html image #9905349. Additional photographic credit is given to Andy Crump who took the photograph in 1999 in Argentina. Figure 2. Reprint permission kindly given by the Centers for Disease Control & Prevention, Atlanta, Georgia. Image is found in the Public Health Image Library #613. Additional photographic credit is given to Dr. Myron G. Schultz who took the photo in 1970. Figure 3. Reprint permission kindly given by the Centers for Disease Control & Prevention, Atlanta, Georgia. Image is found in the Public Health Image Library #543. Figure 4. Reprint permission kindly given by the Centers for Disease Control & Prevention, Atlanta, Georgia. Image is found in the Public Health Image Library #613. Additional photographic credit notes that the images was donated by the World Health Organization, Geneva, Switzerland, in 1976. Figure 5. Reprint permission kindly granted by Science Photo Library (Image Z340/031). Additional photographic credit attributed to Martin Dohrn. Figure 6. Adapted with kind permission from the Centers for Disease Control & Prevention, Atlanta, Georgia. Image is found in the Public Health Image Library #3418. Additional photographic

credit is given to Alexander J. da Silva, PhD, and Melanie Moser who created the image in 2003. Figure 7. Adapted with kind permission from the Centers for Disease Control & Prevention, Atlanta, Georgia. Image is found in the Public Health Image Library #3384. Additional photographic credit is given to Alexander J. da Silva, PhD, and Melanie Moser who created the image in 2002. Figure 8. This figure was produced specifically for this publication. Figure 9. Reprint permission kindly given by the Centers for Disease Control & Prevention, Atlanta, Georgia. Image is found in the Public Health Image Library #2617. Additional photographic credit notes that the photo was taken by Dr. Mae Melvin in 1962. Figure 10. Reprint permission kindly given by the World Health Organization, Special Programme for Research and Training in Tropical Diseases, http://www.who.int/tdr/index.html image #9105027. Additional photographic notes indicate the image was taken in Brazil in 1990. Figure 11. Reprint permission kindly given by the World Health Organization, Special Programme for Research and Training in Tropical Diseases, http://www.who.int/tdr/index.html image #9604658. Additional photographic credit is given to Andy Crump who took the photograph in 1996 in Uganda.