Chagas disease

Seminar

Chagas disease Anis Rassi Jr, Anis Rassi, José Antonio Marin-Neto Lancet 2010; 375: 1388–402 Division of Cardiology, Anis Rassi Hospital, Goiânia, GO, Brazil (A Rassi Jr MD, Prof A Rassi MD); and Division of Cardiology, Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil (Prof J A Marin-Neto MD) Correspondence to: Dr Anis Rassi Jr, Anis Rassi Hospital, Avenida José Alves 453, Setor Oeste, Goiânia GO, Brazil, CEP 74110-020 [email protected]

Chagas disease is a chronic, systemic, parasitic infection caused by the protozoan Trypanosoma cruzi, and was discovered in 1909. The disease affects about 8 million people in Latin America, of whom 30–40% either have or will develop cardiomyopathy, digestive megasyndromes, or both. In the past three decades, the control and management of Chagas disease has undergone several improvements. Large-scale vector control programmes and screening of blood donors have reduced disease incidence and prevalence. Although more effective trypanocidal drugs are needed, treatment with benznidazole (or nifurtimox) is reasonably safe and effective, and is now recommended for a widened range of patients. Improved models for risk stratification are available, and certain guided treatments could halt or reverse disease progression. By contrast, some challenges remain: Chagas disease is becoming an emerging health problem in non-endemic areas because of growing population movements; early detection and treatment of asymptomatic individuals are underused; and the potential benefits of novel therapies (eg, implantable cardioverter defibrillators) need assessment in prospective randomised trials.

Introduction Recognised by WHO as one of the world’s 13 most neglected tropical diseases,1 Chagas disease has been a scourge to humanity since antiquity, and continues to be a relevant social and economic problem in many Latin American countries.2,3 This lifelong infection, also known as American trypanosomiasis, is caused by the protozoan parasite Trypanosoma cruzi, and was discovered in 1909 by the Brazilian physician Carlos Chagas (1879–1934). Chagas’ original report4 is unique in the history of medicine, in the sense that a single scientist described in great detail both the cycle of transmission (vector, hosts, and a novel infectious organism) and the acute clinical manifestations of the first human case. Findings from paleoparasitology studies that recovered T cruzi DNA from human mummies showed that Chagas disease afflicted man as early as 9000 years ago.5 Notably, the first reported case of Chagas disease might have preceded Carlos Chagas’ discovery— Charles Darwin quite possibly contracted T cruzi infection during his expedition to South America in 1835, as suggested by his vivid description of contact with the kissing bug, triatomine, and by some of his symptoms in later life.6

cats, and guineapigs) and wild mammals (eg, rodents, marsupials, and armadillos) mainly by large, bloodsucking reduviid bugs of the subfamily Triatominae, within three overlapping cycles: domestic, peridomestic, and sylvatic.7 Although more than 130 species of triatomine bugs have been identified, only a handful are competent vectors for T cruzi.8,9 Triatoma infestans, Rhodnius prolixus, and Triatoma dimidiata are the three most important vector species in the transmission of T cruzi to man.10,11 Historically, T infestans has been by far the most important vector, and has been the primary vector in sub-Amazonian endemic regions (southern South America). R prolixus is typically reported in northern South America and Central America, and T dimidiata occupies a similar area, but also extends further north into Mexico. Triatomines have five nymphal stages and adults of both sexes, all of which can harbour and transmit T cruzi. The probability that a triatomine is infected with T cruzi increases in accordance with the number of bloodmeals taken, so that older instars and adults tend to have the highest infection rates.

Other mechanisms of transmission

Aetiology Vector-borne transmission Chagas disease is transmitted to human beings and to more than 150 species of domestic animals (eg, dogs,

Search strategy and selection criteria We searched PubMed for reports published between January, 1999, and September, 2009, using the terms “Chagas disease”, “American trypanosomiasis”, “Trypanosoma cruzi”, and other specific terms when needed. No language restriction was placed on searches and we included some frequently referenced and older seminal papers, review articles, and book chapters. We completed the search with our personal database of references, and with a manual search of references from selected reports. We also reviewed abstracts from pertinent scientific meetings, and publications from WHO, TDR (WHO’s Special Programme for Research and Training in Tropical Diseases), and the Pan American Health Organization. Some further references were added in response to suggestions from referees.

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Chagas disease can be transmitted to man by nonvectorial mechanisms, such as blood transfusion and vertically from mother to infant. The risk of acquisition of Chagas disease after transfusion of one unit of blood from an infected donor is less than 10–20%, and depends on several factors, including the concentration of parasites in the donor’s blood, the blood component transfused, and, perhaps, the parasite strain.12,13 The transmission risk seems to be higher for transfusion of platelets than for other blood components. Congenital transmission occurs in 5% of pregnancies or more in chronically infected women in some regions of Bolivia, Chile, and Paraguay, and in 1–2% or less in most other endemic countries.10,14,15 These differences might be attributable to the strain of the parasite, the immunological status of infected mothers, placental factors, and the different methodologies used for detection of congenital cases. Transfusion-based and congenital transmissions www.thelancet.com Vol 375 April 17, 2010

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Trypomastigotes transform into epimastigotes, and epimastigotes replicate by binary fission (midgut) Triatoma infestans

Epimastigotes migrate to the hindgut and rectum, and differentiate into metacyclic trypomastigotes that are released by defecation Infective metacyclic trypomastigotes released onto skin of a mammalian host in faeces

Foregut Rhodnius prolixus

Triatoma dimidiata

Bloodmeal

Metacyclic trypomastigotes enter the host through rubbing or scratching of the bite wound, or through permissive mucosal or conjunctival surfaces

Triatomine insect Mammalian host

Signs of portal of entry*

Trypomastigote in blood smear

Trypomastigotes in bloodstream Infection of new cells

Recruitment and fusion of lysosomes from the host cell are needed for trypomastigotes to penetrate local cells

Cell lysis

Trypomastigote in lysosome-derived membrane-bound vacuole

Spread of infection‡

After decades

Skin or mucosa

Escape from vacuole† Transformation of amastigotes into trypomastigotes

Replication of amastigotes by binary fission

Romaña sign

Differentiation into amastigotes

Myocardial cell full of amastigotes Megaoesophagus

Megacolon Chronic phase of Chagas disease

Cardiomyopathy

Chagoma Acute phase of Chagas disease

Figure 1: Vector-borne transmission and life cycle of Trypanosoma cruzi *Penetration of the intact mucous membrane of the eye by infective trypomastigotes leads to a painless reaction of the conjunctiva, with unilateral oedema of both eyelids and lymphadenitis of the preauricular ganglia (Romaña sign); a bite in any other part of the skin can lead to a reaction in the subcutaneous tissue with local oedema and induration, vascular congestion, and cellular infiltration (chagoma). †Trypomastigotes in the host cell escape from the parasitophorous vacuole and are released into the cytoplasm by an unusual mechanism: trypomastigotes transform into spherical amastigotes that begin replication, and when the local cell is swollen with amastigotes, they transform back into trypomastigotes with growth of flagellae. ‡Trypomastigotes lyse infected cells, invade adjacent tissues, and spread via the lymphatics and bloodstream to distant sites, mainly muscle cells (cardiac, smooth, and skeletal) and ganglion cells, where they undergo further cycles of intracellular multiplication. Image of Romaña sign has been reproduced from Rassi and colleagues;21 copyright 2009 Editora Roca.

are the main forms of infestation of human beings in urban zones and in non-endemic countries. Transmission of infection from a chronically infected donor of a solid organ or bone marrow is also possible and has been well documented in Latin America. In nonendemic regions, such as the USA and Canada, and many parts of Europe, a few cases of infection mediated by transfusion and transplantation have been documented,16–19 but the actual number of cases might be substantially higher because of the large number of immigrants from endemic areas of Latin America. Rarely, Chagas disease can be contracted by ingestion of food or liquid contaminated with T cruzi, and from accidents in laboratories that deal with live parasites. Orally transmitted Chagas disease is usually responsible www.thelancet.com Vol 375 April 17, 2010

for regional outbreaks of acute infection in areas devoid of domiciled insect vectors. Ingestion of contaminated food such as sugar cane juice, açaí fruit juice, or raw meat is generally associated with massive parasitic infestation, resulting in more severe acute clinical presentation and high mortality.20

Life cycle of T cruzi The life cycle of T cruzi is complex, with several developmental stages in insect vectors and mammalian hosts; the insect vector seems to be unaffected by infection with the parasite. Non-replicative bloodstream trypomastigotes and replicative intracellular amastigotes are the typical forms of the organism that are identified in mammalian hosts, whereas replicative epimastigotes 1389

Seminar

1980–85

2005

Infected individuals

Individuals at risk of infection

Infected individuals Individuals at risk of infection

Southern Cone Initiative (launched in 1991) Argentina

2 640 000 (10·0%)

23%

1 600 000 (4·1%)

19%

Bolivia

1 300 000 (24·0%)

32%

620 000 (6·8%)

35%

Brazil

6 180 000 (4·2%)

32%

1 900 000 (1·0%)

12%

Chile

1 460 000 (16·9%)

63%

160 200 (1·0%)

5%

Paraguay

397 000 (21·4%)

31%

150 000 (2·5%)

58%

Uruguay

37 000 (3·4%)

33%

21 700 (0·7%)

19%

Andean Pact Initiative (launched in 1997) Colombia Ecuador Peru Venezuela

900 000 (30·0%)

11%

436 000 (1·0%)

11%

41%

230 000 (1·7%)

47%

621 000 (9·8%)

39%

192 000 (0·7%)

12%

1 200 000 (3·0%)

72%

310 000 (1·2%)

18%

30 000 (10·7%)*

Epidemiology

Central America Initiative (launched in 1997) Belize Costa Rica

··

··

2000 (0·7%)

50%

130 000 (11·7%)

45%

23 000 (0·5%)

23% 39%

El Salvador

900 000 (20·0%)

45%

232 000 (3·4%)

Guatemala

1 100 000 (16·6%)

54%

250 000 (2·0%)

17%

Honduras

300 000 (15·2%)

47%

220 000 (3·1%)

49%

58 600 (1·1%)

25%

Nicaragua Panama Mexico Total

··

··

200 000 (17·7%)

47%

··

··

1 100 000 (1·0%)

28%

25%

7 694 500 (1·4%)†

20%

17 395 000 (4·3%)

21 000 (0·01%)

31%

··=data not available. *Prevalence of infected individuals was underestimated.33 †Includes about 150 000 infected individuals living in the USA and 18 000 in the Guianas, but data for these regions are not shown in the table.

Table 1: Prevalence of Trypanosoma cruzi infection in Latin American countries in 1980–8510 and 2005,34 and effect of initiatives to control or eliminate Chagas disease

and infective metacyclic trypomastigotes infect the triatomine vector (figure 1).21–23 During the acute stage, all types of nucleated cells in the human host are potential targets for infection. With development of the immune response, parasitaemia reduces to a subpatent concentration and the number of parasites in the tissues declines substantially, signalling the end of the acute phase. However, since the parasite is not completely eliminated, infection of specific tissues, such as muscle or enteric ganglia, persists indefinitely for the life of the host.

Genetic diversity of T cruzi T cruzi belongs to a heterogeneous species consisting of a pool of strains, stocks, or isolates that circulate among mammalian hosts and insect vectors. The heterogeneity of the parasite has been extensively studied by biological, biochemical, and molecular methods, and could explain the varying clinical manifestations of Chagas disease and the geographical differences in morbidity and mortality.24,25 In 1999, a consensus regarding the strains of T cruzi was reached and two major lineages were described.26 T cruzi I, which predominates in the sylvatic transmission cycle, seems to be less resistant to trypanocidal drugs, and is associated with human disease in all endemic countries 1390

north of the Amazon basin. T cruzi II, which predominates in the domestic environment throughout the Southern Cone countries, seems to have increased resistance to trypanocidal drugs, and, at least in Brazil and Argentina, has been convincingly related to the tissue damage caused by Chagas disease.27,28 The T cruzi II lineage is further subdivided into five discrete typing units: IIa, IIb, IIc, IId, and IIe.29 In 2006, the existence of a T cruzi III lineage was reported.30 However, no definite correlation between disease severity and parasite lineage has been established. Completion of the genome sequence of the T cruzi CL Brener strain31 (a member of unit IIe) opens prospects for the development of novel therapeutic and diagnostic techniques, and could increase our understanding of the mechanisms of disease.

Chagas disease was originally confined to poor, rural areas of South and Central America, in which vectorborne transmission to man occurs. In the past 20 years, improved vector control programmes (such as the Southern Cone Initiative to Control/Eliminate Chagas Disease, Andean Pact Initiative to Control/Eliminate Chagas Disease, and Central America Initiative to Control/Eliminate Chagas Disease), and compulsory blood-bank screening have substantially reduced new cases of infection and decreased the burden of Chagas disease in Latin America.32 In countrywide surveys done in the 1980s, 100 million people (ie, 25% of all inhabitants of Latin America) were estimated to be at risk of infection, and 17·4 million were infected in 18 endemic countries in 1980–85 (table 1).10 According to estimates by the Pan American Health Organization,34 20% of Latin America’s population were at risk (109 million individuals) and nearly 7·7 million individuals were infected in 2005 (table 1).33,34 Moreover, transmission of T cruzi by the main domiciliary vector species, T infestans, was halted in Uruguay in 1997, Chile in 1999, and Brazil in 2006. According to federal legislation, several endemic countries are now screening for T cruzi in virtually all blood donations,3 and the number of infected blood samples has decreased substantially in all Latin American countries.10,34,35 Other important achievements were the reductions in the incidence of new cases of Chagas disease (700 000 per year in 1990 vs 41 200 per year in 2006) and the number of deaths from Chagas disease (about 50 000 per year vs 12 500 per year).3 However, the recent influx of immigrants from countries endemic for disease has meant that Chagas disease is becoming an important health issue in the USA and Canada and in many parts of Europe and the western Pacific, where an increasing number of infected individuals has been identified (figure 2).36–39 The most common destination for migrants from Latin America is the USA, where an estimated 300 167 individuals (mainly from Mexico) are infected with T cruzi.37 Spain has the second highest number of infected immigrants, an estimated www.thelancet.com Vol 375 April 17, 2010

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Denmark Norway Netherlands UK Belgium France Spain

Canada

USA

Portugal

Sweden Germany Austria Italy Greece

Switzerland

Japan

Belize Nicaragua Costa Rica

Mexico Guatemala Honduras El Salvador

Panama

Colombia Infected individuals Ecuador 0–100 Peru 100–500 500–1000 Bolivia 1000–2000 3000–4000 Paraguay 4000–5000 Chile 47 000–67 000 300 000 Endemic countries* Data unavailable

Venezuela Brazil

Australia Uruguay Argentina

Figure 2: Estimated number of immigrants with Trypanosoma cruzi infection living in non-endemic countries Data are supplied for Canada, Australia, and Japan in 2006;36 the USA in 2005;37 Spain in 2008;38 and other European countries in 2004–06.39 *Prevelance of T cruzi infection is shown in table 1.

47 738–67 423, with most originating from Ecuador, Argentina, Bolivia, and Peru.38

compromised, such as those who are co-infected with HIV or those who are receiving immunosuppressive drugs.45

Phases, forms, and clinical evolution

Pathogenesis and pathophysiological mechanisms

The initial phase of infection with T cruzi lasts for 4–8 weeks, and the chronic phase persists for the host’s lifespan.10,40,41 The acute phase is usually asymptomatic or might present as a self-limiting febrile illness. Symptoms appear 1–2 weeks after exposure to infected triatomine bugs, or up to a few months after transfusion of infected blood. Treatment with an antiparasitic drug, such as benznidazole, will usually cure acute infection42,43 and prevent chronic manifestations. Death occurs occasionally in the acute phase (