Anis Rassoi Jr - Chagas Disease

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1388 www.thelancet.com Vol 375 April 17, 2010

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

Anis Rassi Jr, Anis Rassi, José Antonio Marin-Neto

Chagas disease is a chronic, systemic, parasitic infection caused by the protozoan Trypanosoma cruzi, and wasdiscovered in 1909. The disease affects about 8 million people in Latin America, of whom 30–40% either have or willdevelop cardiomyopathy, digestive megasyndromes, or both. In the past three decades, the control and managementof 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 widenedrange 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 healthproblem 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.

IntroductionRecognised by WHO as one of the world’s 13 most neglectedtropical diseases,1 Chagas disease has been a scourge tohumanity since antiquity, and continues to be a relevantsocial and economic problem in many Latin Americancountries.2,3 This lifelong infection, also known as Americantrypanosomiasis, is caused by the protozoan parasiteTrypanosoma cruzi, and was discovered in 1909 by theBrazilian physician Carlos Chagas (1879–1934). Chagas’original report4 is unique in the history of medicine, in thesense that a single scientist described in great detail boththe cycle of transmission (vector, hosts, and a novel in-fectious organism) and the acute clinical manifestations of the first human case. Findings from paleoparasitology

studies that recovered T cruzi DNA from human mummiesshowed that Chagas disease affl icted man as early as9000 years ago.5 Notably, the first reported case of Chagasdisease might have preceded Carlos Chagas’ discovery—Charles Darwin quite possibly contracted T cruzi infectionduring his expedition to South America in 1835, as sug-gested by his vivid description of contact with the kissingbug, triatomine, and by some of his symptoms in later life.6

AetiologyVector-borne transmissionChagas disease is transmitted to human beings and tomore than 150 species of domestic animals (eg, dogs,

cats, and guineapigs) and wild mammals (eg, rodents,marsupials, and armadillos) mainly by large, blood-sucking 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 arecompetent vectors for T cruzi.8,9

Triatoma infestans, Rhodnius prolixus, and Triatomadimidiata are the three most important vector species inthe transmission of T cruzi to man.10,11 Historically,T infestans has been by far the most important vector, andhas been the primary vector in sub-Amazonian endemicregions (southern South America). R prolixus is typicallyreported in northern South America and Central America,

and T dimidiata occupies a similar area, but also extendsfurther north into Mexico. Triatomines have five nymphalstages and adults of both sexes, all of which can harbourand transmit T cruzi. The probability that a triatomine isinfected with T cruzi increases in accordance with thenumber of bloodmeals taken, so that older instars andadults tend to have the highest infection rates.

Other mechanisms of transmissionChagas disease can be transmitted to man by non-vectorial mechanisms, such as blood transfusion andvertically from mother to infant. The risk of acquisitionof Chagas disease after transfusion of one unit of bloodfrom 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 componenttransfused, and, perhaps, the parasite strain.12,13 Thetransmission risk seems to be higher for transfusion of platelets than for other blood components. Congenitaltransmission occurs in 5% of pregnancies or more inchronically infected women in some regions of Bolivia,Chile, and Paraguay, and in 1–2% or less in most otherendemic countries.10,14,15 These differences might beattributable to the strain of the parasite, the immunologicalstatus of infected mothers, placental factors, and thedifferent methodologies used for detection of congenitalcases. Transfusion-based and congenital transmissions

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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are the main forms of infestation of human beings inurban zones and in non-endemic countries.

Transmission of infection from a chronically infecteddonor of a solid organ or bone marrow is also possibleand has been well documented in Latin America. In non-endemic regions, such as the USA and Canada, and manyparts of Europe, a few cases of infection mediated bytransfusion and transplantation have been documented,16–19 but the actual number of cases might be substantiallyhigher because of the large number of immigrants fromendemic areas of Latin America.

Rarely, Chagas disease can be contracted by ingestionof food or liquid contaminated with T cruzi, and fromaccidents in laboratories that deal with live parasites.Orally transmitted Chagas disease is usually responsible

for regional outbreaks of acute infection in areas devoidof domiciled insect vectors. Ingestion of contaminated

food such as sugar cane juice, açaí fruit juice, or rawmeat is generally associated with massive parasiticinfestation, resulting in more severe acute clinicalpresentation and high mortality.20

Life cycle of T cruziThe life cycle of T cruzi is complex, with severaldevelopmental stages in insect vectors and mammalianhosts; the insect vector seems to be unaffected byinfection with the parasite. Non-replicative bloodstreamtrypomastigotes and replicative intracellular amastigotesare the typical forms of the organism that are identifiedin mammalian hosts, whereas replicative epimastigotes

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, invad

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 intracellu

multiplication. Image of Romaña sign has been reproduced from Rassi and colleagues;21 copyright 2009 Editora Roca.

Rhodnius prolixus

Triatoma infestans

Triatoma dimidiata

Trypomastigotein blood smear

Triatomine insect

Infective metacyclic trypomastigotesreleased onto skin of a mammalianhost in faeces

Metacyclic trypomastigotes enter the hostthrough rubbing or scratching of the bitewound, or through permissive mucosal orconjunctival surfaces

Foregut

Trypomastigotes transform into

epimastigotes, and epimastigotesreplicate by binary fission (midgut)

Epimastigotes migrate to thehindgut and rectum, and differentiateinto metacyclic trypomastigotes thatare released by defecation

Signs of portal of entry*

Romaña signEscape fromvacuole†

Differentiationinto amastigotes

Myocardial cell full of amastigotes

Replication of amastigotes bybinary fission

Transformation of amastigotesinto trypomastigotes

Megaoesophagus Megacolon Cardiomyopathy

Cell lysis

After decades

Trypomastigotesin bloodstream

Infection of new cells

Trypomastigote inlysosome-derivedmembrane-boundvacuole

Skin or mucosaMammalian host

Recruitment and fusion of

lysosomes from the host cellare needed for trypomastigotesto penetrate local cells

Chagoma

Spread of infection‡

Bloodmeal

Chronic phase of Chagas disease Acute phase of Chagas disease



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and infective metacyclic trypomastigotes infect thetriatomine vector (figure 1).21–23

During the acute stage, all types of nucleated cells inthe human host are potential targets for infection.With development of the immune response, para-sitaemia reduces to a subpatent concentration and thenumber of parasites in the tissues declines substantially,signalling the end of the acute phase. However, since theparasite 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 cruziT cruzi belongs to a heterogeneous species consisting of apool of strains, stocks, or isolates that circulate amongmammalian hosts and insect vectors. The heterogeneity of the parasite has been extensively studied by biological,biochemical, and molecular methods, and could explainthe varying clinical manifestations of Chagas disease andthe geographical differences in morbidity and mortality.24,25 In 1999, a consensus regarding the strains of T cruzi wasreached 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 isassociated with human disease in all endemic countries

north of the Amazon basin. T cruzi II, which predominatesin the domestic environment throughout the Southern

Cone countries, seems to have increased resistance totrypanocidal drugs, and, at least in Brazil and Argentina,has been convincingly related to the tissue damage causedby Chagas disease.27,28 The T cruzi II lineage is furthersubdivided into five discrete typing units: IIa, IIb, IIc, IId,and IIe.29 In 2006, the existence of a T cruzi III lineage wasreported.30 However, no definite correlation betweendisease severity and parasite lineage has been established.Completion of the genome sequence of the T cruzi CLBrener strain31 (a member of unit IIe) opens prospects forthe development of novel therapeutic and diagnostictechniques, and could increase our understanding of themechanisms of disease.

EpidemiologyChagas disease was originally confined to poor, ruralareas of South and Central America, in which vector-borne transmission to man occurs. In the past 20 years,improved vector control programmes (such as theSouthern Cone Initiative to Control/Eliminate ChagasDisease, Andean Pact Initiative to Control/EliminateChagas Disease, and Central America Initiative toControl/Eliminate Chagas Disease), and compulsoryblood-bank screening have substantially reduced newcases of infection and decreased the burden of Chagasdisease in Latin America.32

In countrywide surveys done in the 1980s, 100 millionpeople (ie, 25% of all inhabitants of Latin America) were

estimated to be at risk of infection, and 17·4 million wereinfected in 18 endemic countries in 1980–85 (table 1).10 According to estimates by the Pan American HealthOrganization,34 20% of Latin America’s population wereat risk (109 million individuals) and nearly 7·7 millionindividuals were infected in 2005 (table 1).33,34 Moreover,transmission of T cruzi by the main domiciliary vectorspecies, T infestans, was halted in Uruguay in 1997, Chilein 1999, and Brazil in 2006. According to federallegislation, several endemic countries are now screeningfor T cruzi in virtually all blood donations,3 and thenumber of infected blood samples has decreasedsubstantially 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 peryear 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 immigrantsfrom countries endemic for disease has meant that Chagasdisease is becoming an important health issue in the USAand Canada and in many parts of Europe and the westernPacific, where an increasing number of infected individualshas been identified (figure 2).36–39 The most commondestination for migrants from Latin America is the USA,where an estimated 300 167 individuals (mainly fromMexico) are infected with T cruzi.37 Spain has the secondhighest number of infected immigrants, an estimated

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 900 000 (30·0%) 11% 436 000 (1·0%) 11%

Ecuador 30 000 (10·7%)* 41% 230 000 (1·7%) 47%

Peru 621 000 (9·8%) 39% 192 000 (0·7%) 12%

Venezuela 1 200 000 (3·0%) 72% 310 000 (1·2%) 18%

Central America Initiative (launched in 1997)Belize ·· ·· 2000 (0·7%) 50%

Costa Rica 130 000 (11·7%) 45% 23 000 (0·5%) 23%

El Salvador 900 000 (20·0%) 45% 232 000 (3·4%) 39%

Guatemala 1 100 000 (16·6%) 54% 250 000 (2·0%) 17%

Honduras 300 000 (15·2%) 47% 220 000 (3·1%) 49%

Nicaragua ·· ·· 58 600 (1·1%) 25%

Panama 200 000 (17·7%) 47% 21 000 (0·01%) 31%

Mexico ·· ·· 1 100 000 (1·0%) 28%

Total 17 395 000 (4·3%) 25% 7 694 500 (1·4%)† 20%

··=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



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

Phases, forms, and clinical evolutionThe initial phase of infection with T cruzi lasts for4–8 weeks, and the chronic phase persists for the host’s

lifespan.10,40,41

The acute phase is usually asymptomatic ormight present as a self-limiting febrile illness. Symptomsappear 1–2 weeks after exposure to infected triatominebugs, or up to a few months after transfusion of infectedblood. Treatment with an antiparasitic drug, such asbenznidazole, will usually cure acute infection42,43 andprevent chronic manifestations. Death occurs occasionallyin the acute phase (<5–10% of symptomatic cases) as aresult of severe myocarditis or meningoencephalitis, orboth (figure 3).

Manifestations of the acute disease resolve spon-taneously in about 90% of infected individuals even if theinfection is not treated with trypanocidal drugs. About60–70% of these patients will never develop clinically

apparent disease. These patients have the indeterminateform of chronic Chagas disease, which is characterised bypositivity for antibodies against T cruzi in serum, a normal12-lead electrocardiogram (ECG), and normal radiologicalexamination of the chest, oesophagus, and colon. Theremaining 30–40% of patients will subsequently develop adeterminate form of chronic disease—ie, cardiac, digestive(megaoesophagus and megacolon), or cardiodigestive—usually 10–30 years after the initial infection (figure 3).44 Adirect progression from the acute phase to a clinical formof Chagas disease has been recorded in a few patients(5–10%). Reactivation of Chagas disease can also occur inchronically infected patients who become immunologically

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

Pathogenesis and pathophysiologicalmechanismsOrgan and tissue damage during acute T cruzi infection

is caused by the parasite itself and by the host’s acuteimmunoinflammatory response, which is elicited by thepresence of the parasite.46 Findings from several studiesin experimental models of T cruzi infection have suggestedthat a strong T-helper-1 immune response with both CD4 and CD8 cells, and characterised by the production of some specific cytokines—such as interferon γ, tumournecrosis factor α, and interleukin 12—is important in thecontrol of parasitism.47–50 By comparison, production of interleukin 10 and transforming growth factor β is relatedto parasite replication by inhibition of macrophagetrypanocidal activity.51,52 The T-helper-1 immune responsehas a protective role mainly through the synthesis of nitricoxide, which exerts a potent trypanocidal action.53,54 During

chronic infection, the balance between immune-mediatedparasite containment and damaging inflammation of thehost tissues probably determines the course of disease. If the immunological response is ineffi cient, or paradoxicallyleads to tissue damage, both parasite load and immune-mediated inflammation increase. By contrast, a wellexecuted immune response, in which parasite burden islowered and inflammatory consequences are kept to aminimum, results in reduced tissue damage.55

Although the pathogenesis of chronic Chagas diseaseis not completely understood, a growing consensusindicates that parasite persistence is needed fordevelopment of disease.55–57 However, we do not yet know

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.

0–100100–500500–10001000–2000

3000–40004000–500047 000–67 000300 000Endemic countries*Data unavailable

Infected individuals

France Austria

Italy

Japan

Spain

Portugal

Belgium

Netherlands

Switzerland

Sweden

Denmark Norway

Germany

GreeceUSA

UKCanada

Australia

Guatemala

Belize

El SalvadorHonduras

Colombia

Venezuela

Brazil

Uruguay

Panama

Costa RicaNicaragua

Ecuador

Peru

Bolivia

Chile

Paraguay

Argentina

Mexico



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whether tissue damage is mostly caused by direct parasitefactors, or is indirectly triggered through parasite-drivenimmunopathology or even autoimmune mechanisms.58–60 Autoimmunity is seen in some patients and in animalmodels, and could arise from polyclonal activation, 61

molecular self-mimicry by parasite antigens,62

or crypticepitopes shared by the host and parasites.63 However, tomake a case for a predominant pathogenic role of autoimmunity in Chagas disease, we need to showunequivocally that transfer of antibodies or T cells fromanimals infected with T cruzi to naive recipients resultsin myocarditis, emulating the clinical course of chronicChagas heart disease. Conversely, the establishment of chronic T cruzi infection is related to a generaliseddepression of the T-cell response.64

In chronic Chagas heart disease, a low-intensity,slowly progressive but incessant myocarditis leads toimpairment of contractile function and dilatation of allfour chambers. A left ventricular apical aneurysm and

other segmental wall motion abnormalities, similar tothose seen in coronary heart disease, are common andusually appear at early stages.65 Histological examinationshows widespread destruction of myocardial cells,diffuse fibrosis, oedema, mononuclear cell infiltrationof the myocardium, and scarring of the conductionsystem.66 Such damage explains the frequent occurrenceof atrioventricular blocks, intraventricular blocks, andsinus node dysfunction in Chagas heart disease. Theprogressive destruction of cardiac fibres and the intensefibrosis from replacement of dead myocytes predisposesthe patient to heart failure and ventriculararrhythmias.67,68 Abnormalities in the coronary micro-

vasculature and focal hypoperfusion might contributeto the myocardial damage.69,70

Chronic Chagas gastrointestinal disease is caused bydestruction of intramural autonomic ganglia, whichpredominantly affects the oesophagus, colon, or both.71

Striking neuronal depopulation can also occur in theheart, and the so-called neurogenic theory for thepathogenesis of Chagas cardiomyopathy postulates thatthe deranged parasympathetic system allows unopposedsympathetic overactivity.71 However, this theory is flawedwith many conceptual and experimental obstacles, whichinclude the subtleness and variability of the intensity of cardiac denervation in patients with Chagas heart disease,the absence of correlation between parasympatheticdenervation and the extent of myocardial dysfunction,and the fact that sympathetic denervation (mainly at thesinus node and at the myocardium) also occurs duringthe early stages of disease.60

Clinical manifestationsAcute Chagas diseaseIn most individuals, irrespective of the mechanism of transmission, acute Chagas infection is usuallyasymptomatic, which is probably because the parasite loadis fairly small. When symptoms occur they include:prolonged fever; malaise; enlargement of the liver, spleen,and lymph nodes; subcutaneous oedema (localised orgeneralised); and, in the particular case of vector-bornetransmission, the signs of portal of entry of T cruzi throughthe skin (chagoma) or via the ocular mucous membranes(Romaña sign; figure 1, table 2). An ECG might showsinus tachycardia, first-degree atrioventricular block, low

Figure 3: Natural history of Chagas disease in man

Human exposure to T cruzi

(vectorial, via transfusion, congenital,

oral, via organ transplant, accidental)

No infection

Death from myocarditis ormeningoencephallitis

Cure (50–80%

of cases)

Cure (20–60%

of cases)

Cure (lower proportion

of cases than for theindeterminate form)

Immunosuppression

Reactivation

Permanentindeterminate form

Cardiac Cardiodigestive Digestive

Antiparasitic drug<5–10% of symptomatic cases

10–30 years laterAntiparasitic drug Antiparasitic drugChronic phase in

indeterminate form

Chronic phase in

determinate form

Acute Chagas infection(asymptomatic or symptomatic)



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QRS voltage, or primary T-wave changes; and a chestradiograph might show variable degrees of cardiomegaly.10,72 Repetition of the ECG and chest radiograph is crucial fordetection of these abnormalities. In congenitally infectedinfants, the most common symptoms, which might beapparent at birth or develop within weeks after delivery,are hypotonicity, fever, hepatosplenomegaly, and anaemia.

Other findings include prematurity, low birthweight, andlow Apgar score.73,74 In-utero infections are also associatedwith abortion and placentitis. Serious manifestations,including myocarditis, meningoencephalitis, andpneumonitis, are uncommon, but have a high risk of death (table 2).15 A woman infected with T cruzi, at anystage of disease, could give birth to an infected fetusduring any of her pregnancies.

Chronic Chagas diseaseThe clinical outcome of the chronic phase of Chagasdisease ranges from the absence of signs and symptomsof disease (indeterminate form) to severe illness andpremature death (table 3). Typical clinical manifestations

of this phase are related to the pathological involvementof heart, oesophagus, colon, or a combination, and aregrouped into three major forms: cardiac, digestive, andcardiodigestive.67,75,76

The digestive form is seen almost exclusively south of the Amazon basin (mainly in Argentina, Brazil, Chile, andBolivia), and is rare in northern South America, CentralAmerica, and Mexico. This geographical distribution isprobably due to differences in parasite strains.77,78 Gastrointestinal dysfunction (mainly megaoesophagus,megacolon, or both)79 develops in about 10–15% of chronically infected patients. The megaoesophagus causesdysphagia with odynophagia, combined with epigastric

pain, regurgitation, ptyalism, and malnutrition in severecases. Megacolon often affects the sigmoid segment,rectum, or descending colon, or a combination, andproduces prolonged obstipation, abdominal distension,and occasionally large bowel obstruction due to fecalomaor sigmoid volvulus. Patients with megaoesophagus havean increased prevalence of cancer of the oesophagus.80

Conversely, an increased frequency of colorectal cancer hasnot been reported in patients with chagasic megacolon.81

The cardiac form is the most serious and frequentmanifestation of chronic Chagas disease. It develops in20–30% of individuals and typically leads to abnormalitiesof the conduction system, bradyarrhythmias and tachyar-rhythmias, apical aneurysms, cardiac failure, thrombo-embolism, and sudden death.67,75,76 The most common ECGabnormalities are right bundle branch block, left anteriorfascicular block, ventricular premature beats, ST-T changes,abnormal Q waves, and low voltage of QRS. Thecombination of right bundle branch block and left anteriorfascicular block is very typical in Chagas heart disease.

Frequent, complex ventricular premature beats,

including couplets and runs of non-sustained ventriculartachycardia, are a common finding on Holter monitoringor stress testing. Ventricular premature beats correlatewith the severity of ventricular dysfunction, but can alsooccur in patients with quite well preserved ventricularfunction. Episodes of non-sustained ventricular tachycardiaare seen in about 40% of patients with mild wall motionabnormalities, and in virtually all patients with heartfailure, which is more frequent than in othercardiomyopathies. 82 Sustained ventricular tachycardia isanother hallmark of the disease. This life-threateningarrhythmia can be reproduced during programmedventricular stimulation in about 85% of patients and

Geographicaldistribution

Predominantpopulation

Incubationtime

Clinical presentation Diagnosis Mortality

Vectorial Endemiccountries

Children andadolescents

1–2 weeks Asymptomatic; fever, malaise, lymphadenopathy,hepatosplenomegaly, subcutaneous oedema; signs of portal of entry (Romaña sign, chagoma); myocarditis,

meningoencephalitis

Parasite detection by microscopy: fresh bloodspecimen; stained blood smears; buffy coatpreparation (microhaematocrit technique); or

serum precipitate (Strout technique)

Low (<5–10%)*

Transfusion-

based

Endemic and

non-endemiccountries

Adults 8–120 days Same as for vectorial but excluding signs of portal of entry Same as for vectorial Variable†

Congenital Endemic andnon-endemic

countries

Neonates andchildren younger

than 1 year

Up to a few

weeks

Asymptomatic; abortion, neonatal death, prematurity,

low birthweight, low Apgar score; hypotonicity, fever,

hepatosplenomegaly, respiratory distress, anaemia;myocarditis, meningoencephalitis, megaviscera, oedema

Microhaematocrit with cord blood or peripheral

blood from neonate; two or more samples in the

first month of life; IgG serology at 6–9 months of age if microhaematocrit negative or not done

Unknown

Oral Amazon

basin, and

regionaloutbreaks

Individuals of any

age from the same

family orcommunity

3–22 days Same as for transfusion-based plus headache, myalgia,

vomiting, abdominal pain, jaundice, diarrhoea, and

digestive haemorrhage

Same as for vectorial High (8–35%)

Reactivation-

based

Endemic and

non-endemic

countries

Patients with

associate immuno-

suppressive states

Variable Same as for transfusion-based plus panniculitis,

subcutaneous parasite-containing nodules, and skin ulcers

Same as for vectorial, and parasites can also be

detected in tissues by microscopy or PCR

Variable†

*Refers to symptomatic cases; since 95% of acute infections from vectorial transmission are asymptomatic and 5–10% of patients with acute symptoms die, estimated mortality in this phase of infection is

between one in 200 and one in 400. †Depends on the underlying disease and the patients’ clinical condition.

Table 2: Epidemiology, clinical manifestations, and diagnosis of acute or reactivated Chagas disease by mechanism of disease acquisition



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seems to result from an intramyocardial or subepicardialre-entry circuit that is usually located at the inferior-posterior-lateral wall of the left ventricle.83–85

Heart failure is often a late manifestation of Chagasheart disease. It is usually biventricular with apredominance of right-sided failure (peripheral oedema,hepatomegaly, and ascites more prominent thanpulmonary congestion) at advanced stages. Isolated leftheart failure can be present in the early stages of cardiacdecompensation.67,75,76 Heart failure of chagasic aetiologyis associated with higher mortality than is heart failurefrom other causes.86

Systemic and pulmonary embolisms arising frommural thrombi in the cardiac chambers are quitefrequent.87 Clinically, brain is by far the most frequentlyrecognised site of embolisms (followed by limbs andlungs), but at necropsy embolisms are found more

frequently in the lungs, kidneys, and spleen. Chagasdisease is an independent risk factor for stroke inendemic countries.88

Sudden death is the main cause of death in patientswith Chagas heart disease, accounting for nearly two-thirds of all deaths, followed by refractory heart failure(25–30%), and thromboembolism (10–15%).89 Suddencardiac death can occur even in patients who werepreviously asymptomatic. It is usually associated withventricular tachycardia and fibrillation or, more rarely,with complete atrioventricular block or sinus nodedysfunction. Leading causes of death vary dependent onthe stage of disease, with a clear predominance of sudden

death at early stages, and a slight predominance of deathfrom pump failure at advanced stages.

On the basis of our own experience and our review of

published reports, we propose a schematic classificationof Chagas heart disease into four stages to helpphysicians improve their understanding of the hetero-geneous clinical course (table 3). This classificationcould also be useful for epidemiological studies.Although other staging systems exists, such as Kuschnir,90 Los Andes,91 and the Brazilian Consensus,92 they arebased solely on functional capacity, ECG findings, andleft ventricular function or size.

The association of heart disease with megaoesophagusor megacolon, or both defines the cardiodigestive form of Chagas disease. In most countries the development of megaoesophagus usually precedes heart and colon disease,but the exact prevalence of the cardiodigestive form is not

known because of the scarcity of appropriate studies.Individuals with AIDS or receiving immuno-

suppressive treatment might experience an exacerbationof chronic infection, leading to increases in parasitaemiaand intracellular parasite replication (table 2). Fever,myocarditis, panniculitis, and skin lesions are commonin recipients of solid organ or bone marrowtransplants,93,94 whereas in patients with AIDS the mostcommon manifestations are meningoencephalitis andCNS lesions that resemble the lesions of cerebraltoxoplasmosis.95,96 Figure 4 summarises the commonclinical manifestations associated with the chronicphase of Chagas disease.

Cardiacsymptoms*

NYHAclass

ECG changes Chestradiograph

(cardiomegaly)

24-h Holter(complex

ventricular

arrhythmias†)

2D echocardiogram Thrombo-embolism

Sustainedventricular

tachycardia

Suddendeath

Left ventricular

wall motion

abnormalities

Left ventricular

apical aneurysm

Indeterminate Absent ·· Absent Absent Very rare Absent Absent Absent Absent Absent

Digestive‡ Absent ·· Absent Absent Rare Rare Very rare Absent Absent Absent

Cardiacstage I

Absent orminimal

·· Not specific§ Absent Rare Rare Very rare Very rare Rare Rare

Cardiac

stage II

Fairly

common

I or II Right bundle branch block with or

without left anterior fascicular block,

monomorphic ventricular prematurebeats, diffuse ST-T changes, first or

second degree atrioventricular block

Absent or mild Common Absent or

segmental

Common Fairly

common

Common Common

Cardiac

stage III

Common I, II,

or III

As for stage II plus Q waves,

polymorphic ventricular premature

beats, advanced atrioventricular block,severe bradycardia, low QRS voltage

Mild to

moderate

Very common Segmental or

diffuse (mild to

moderate)

Common Fairly

common

Common Common

Cardiac

stage IV

Common II, III,

or IV

As for stage III plus atrial flutter or

fibrillation

Moderate to

severe

Very common Diffuse (severe) Fairly common Common Fairly

common

Fairly

common

NHYA=New York Heart Association. ECG=electrocardiogram. ··=data not applicable. *Palpitations, presyncope, syncope, atypical chest pain, fatigue, and oedema. †Couplets or episodes of non-sustained

ventricular tachycardia, or both. ‡Megaoesophagus or megacolon, or both without apparent heart disease; the cardiodigestive form of chronic Chagas disease is not included in the table because several

combinations are possible. §Incomplete right bundle branch block, incomplete left anterior fascicular block, mild bradycardia, minor increase in PR interval, minor ST-T changes. ¶Minor interchanges in some

characteristics are possible across the different stages of cardiac disease.

Table 3: Rational clinical and functional classification of chronic Chagas disease¶



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Figure 4: Common findings in chronic Chagas disease

(A) Cardiac segmental form. (B) Cardiac global dilated form. *All findings shown for patients with the cardiac segmental form might also occur in patients with the global dilated form. LV=left

ventricle. RV=right ventricle. LA=left atrium. RA=right atrium. Parts of this figure have been reproduced from Rassi and colleagues;21 copyright 2009 Editora Roca.

++

++

++++

+

++

+++

Apical aneurysm

Thrombus(arrow)

Sinus nodedysfunction

Q waves

Ventricular premature beatsNon-sustained ventricular

tachycardiaVentricular tachycardia andventricular fibrillation

Right bundlebranch blockand left

anteriorfascicularblock

LV

LA

RV

RA

LV

LV

LA

LA

RV

RV

RA

RA

A*

Atrioventricularblock

V1

V5

D1 D2 V1

V5

aVL

V1 V2 V3 V5

Tricuspidregurgitation

Mitralregurgitation

B

Advanced cardiac disease

Cardiac disease

Digestive disease

Megaoesophagus (groups I, II, II and IV) Megacolon



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DiagnosisDiagnosis of acute infection is based on the microscopicdetection of trypomastigotes in blood (table 2).10,97 Micro-haematocrit is the method of choice to identify congenitalinfection because of its heightened sensitivity and thesmall amount of blood needed. Microscopic examinationof cord blood or peripheral blood of the neonate by thistechnique is strongly recommended during the first monthof life.73,74 If the results are repeatedly negative or if the test

is not done early in life, the infant should be tested foranti-T cruzi IgG antibodies at 6–9 months of age(preferentially at 9 months) when maternal antibodies areno longer present in the baby.92,97 In specialised centres,assays based on amplification of T cruzi DNA by PCRcould also be used for early diagnosis of congenitalinfection, since in this context the sensitivity of PCR seemsto be greater than that of microscopic examination.98–100

During the chronic phase, because parasitaemia isscarce, the presence of IgG antibodies against T cruzi antigens needs to be detected by at least two differentserological methods (usually enzyme-linked immuno-sorbent assay, indirect immunofluorescence, or indirect

haemagglutination) to confirm diagnosis.92,97 PCR is nothelpful in routine diagnosis because of the need for specificlaboratory facilities, poor standardisation, potential DNAcross-contamination, and variable results across labora-tories and countries. However, because of its heightenedsensitivity compared with other parasitological methods,PCR could be useful to confirm diagnosis in cases of inconclusive serology,92 and as an auxiliary method tomonitor treatment.101 PCR is useful to identify treatment

failure from positive detection of T cruzi DNA, but nottreatment success since even repeated negative PCRresults do not necessarily indicate parasitological cure. Atbest, such results are indicative of the absence of parasiteDNA at the time of the test.

Assessment of patients with suspected chronicChagas diseaseFigure 5 shows the steps necessary to assess patients withsuspected Chagas disease. After confirmation of thediagnosis, a thorough search for cardiovascular andgastrointestinal symptoms and a resting 12-lead ECG areneeded to define the clinical form of disease. Although

Figure 5: Assessment of patients with suspected chronic Trypanosoma cruzi infection

ELISA=enzyme-linked immunosorbent assay. ECG=electrocardiogram. *Dysphagia, odynophagia, regurgitation, aspiration, long-term and prolonged constipation.

High suspicion of Chagas disease because patient has potentially been exposed to disease

(contact with kissing bugs, endemic region, mother with Chagas disease, or previous blood

transfusion or organ transplant) or has a clinical syndrome compatible with disease

Two or more T cruzi-specific serological tests (ELISA, indirect immunofluorescence,

indirect haemagglutination)

Positive Negative

Chagas disease exceptionalChagas disease confirmed

12-lead ECG andgastrointestinal symptoms*

ECG normalNo gastrointestinal symptoms

ECG abnormalNo gastrointestinal symptoms

ECG abnormalGastrointestinal symptoms

ECG normalGastrointestinal symptoms

Digestive formCardiodigestive formCardiac formIndeterminate form

Undertake reassessment every1 or 2 years, and possibly treat withan antiparasitic drug

Confirm digestive form, decideabout the need for symptomatic

or surgical treatment, and possiblytreat with an antiparasitic drug

Complete cardiac assessment by chest radiography, echocardiography, 24 h-Holter

monitoring (combined with an exercise test when possible), and other tests as indicated

Chronic Chagas heart disease stages I, II, III, or IV (categorised as per table 4)

4: Consider the prognosis

5: Decide on antiparasitic and symptomatic treatment

3: Establish the stage of cardiac disease

2: Define the clinical form of chronic disease

1: Confirm the diagnosis



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barium swallow and enema are needed for final diagnosisof the digestive form, these tests are usually notrecommended as standard practice for patients withoutgastrointestinal symptoms. Asymptomatic patients with anormal ECG and no gastrointestinal tract or cardiovascularsymptoms have a favourable prognosis102,103 and should befollowed up every 12–24 months. Strictly, the indeterminateform is defined by the presence of normal findings from

radiological examination of the chest, oesophagus, andcolon, but in common clinical practice, these tests areusually not done on asymptomatic patients. Patients withECG changes consistent with Chagas heart disease104 should undergo a routine cardiac assessment to establishthe stage of disease. Ambulatory 24-h Holter monitoringis used to detect arrhythmias; and combined chestradiography and 2D echocardiography refine theassessment of cardiac size and function, and provideadditional prognostic information. From the results of these tests, clinicians can stratify individual patients byrisk and implement appropriate treatment.

Prognostic markers and risk stratification in

Chagas heart diseaseImproved understanding of prognostic factors in Chagasheart disease has helped clinicians to identify patients’risk, choose appropriate treatment, and direct patientcounselling. Some of us used a rigorous multivariateanalysis to develop a risk score for mortality prediction in424 outpatients from a regional Brazilian cohort,105 andthe score has been validated successfully in two externalcohorts.105,106 Several demographic, clinical, and non-invasive variables were tested, and six were identified asindependent predictors of mortality and were assignedpoints according to the strength of their statisticalassociation with the outcome. From addition of the points

to provide the risk score, patients can be classified intogroups of low, intermediate, and high risk (figure 6).

Subsequently, two systematic reviews integrated theresults of all previous studies in which multivariableregression models of prognosis were used and a clearlydefined outcome (all-cause mortality, sudden cardiacdeath, or cardiovascular death) was analysed.68,108 According to these reviews, the strongest and most

consistent predictors of mortality are New York HeartAssociation (NYHA) functional class III or IV,cardiomegaly on chest radiography, impaired leftventricular systolic function on echocardiogram orcineventriculography, and non-sustained ventriculartachycardia on 24-h Holter monitoring68,105,107,108 (figure 6). On the basis of these findings, we propose arisk-stratification model for mortality that can assisttreatment in patients with Chagas heart disease (table 4).

TreatmentThe aim of treatment is to eradicate the parasite andtarget the signs and symptoms of disease.

Antitrypanosomal treatmentAccording to recommendations in 200592 and 2007,109 anti-trypanosomal treatment is strongly recommended for allcases of acute, congenital, and reactivated infection, forall children with infection, and for patients up to 18 yearsof age with chronic disease. Drug treatment shouldgenerally be offered to adults aged 19–50 years withoutadvanced Chagas heart disease, and is optional for thoseolder than 50 years because benefit has not been provenin this population.109 By contrast, antitrypanosomaltreatment is contraindicated during pregnancy and inpatients with severe renal or hepatic insuffi ciency, andgenerally should not be offered to patients with advanced

Figure 6: Prognostic factors in Chagas heart disease

(A) Rassi score105 for prediction of total mortality. (B) Kaplan-Meier survival curves according to New York Heart Association (NYHA) functional class (reproduced from Rassi Jr and colleagues;105

copyright 2006 Massachusetts Medical Society). (C) Kaplan-Meier survival curves according to the presence (+) or absence (–) of non-sustained ventricular tachycardia (NSVT) on 24-h Holter monitori

and left ventricular systolic dysfunction (LVSD; segmental or global wall motion abnormality) on 2D echocardiogram (reproduced from Rassi Jr and colleagues;107 copyright 1999 John Wiley & Sons).

Survival curves in B and C were derived from the same cohort. ECG=electrocardiogram.

p<0·001

Follow-up (years)

1210 8 6

4

2

0

0 3 6 9 12 15

p<0·001

P r o b a b i l i t y o f s u r v i v a l ( % )

100

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0

Follow-up (years)

NSVT– and LVSD– (n=233)NSVT+ and LVSD– (n=89)

NSVT– and LVSD+ (n=55)NSVT+ and LVSD+ (n=67)

NYHA class I or II (n=380)NYHA class III or IV (n=44)

PointsRisk factor

NYHA class III or IV

Cardiomegaly (chest radiograph)Segmental or global wall motionabnormality (2D echocardiogram)

Non-sustained ventricular tachycardia(24-h Holter)Low QRS voltage (ECG)

Male sex

55

3

3

22

Total MortalityTotal points

2%18%

63%

10 years 5 years

10%44%

84%

0–67–11

12–20

Risk

LowIntermediate

High

Total mortality

A B C



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Chagas heart disease or megaoesophagus with substantialimpairment of swallowing.

Benznidazole and nifurtimox are the only drugs withproven effi cacy against Chagas disease.110–113 Benznidazolehas the best safety and effi cacy profile,114 and therefore isusually used for first-line treatment. Children should betreated with benznidazole (5–10 mg/kg daily) in two orthree divided doses for 60 days, or with nifurtimox(15 mg/kg daily) in three divided doses for 60–90 days,preferably after meals for both drugs. For adults, dailytreatment with 5 mg/kg benznidazole or 8–10 mg/kgnifurtimox is recommended for the same duration as for

children.92

Antitrypanosomal treatment in establishedmild to moderate Chagas heart disease is under scrutinyby the BENEFIT trial,115 which is comparing benznidazolewith placebo in 3000 patients (aged 18–75 years) fromseveral centres in Latin America.

Treatment of cardiac symptomsDespite a scarcity of evidence from randomised controlledtrials about treatment of rhythm disturbances, someobservational data suggest that amiodarone could improvesurvival in patients with Chagas heart disease who are athigh risk of death because of malignant arrhythmias.82,89,116 Thus, amiodarone is usually recommended as thetreatment of choice for all patients with sustained

ventricular tachycardia, and for those with non-sustainedventricular tachycardia and myocardial dysfunction.117

Patients with refractory or haemodynamically unstablesustained ventricular tachycardia, and those resuscitatedfrom sudden death have been treated with implantablecardioverter defibrillators (ICDs).118 However, trials havenot yet compared the effi cacy of ICDs with that of amiodarone in patients with Chagas heart disease andmalignant ventricular arrhythmias.119 The largest single-centre study of ICD treatment for secondary preventionenrolled 90 patients and showed very disappointingresults.120 Mortality in ICD recipients was 18%, 27%, 40%,50%, and 73% after follow-up of 1, 2, 3, 4, and 5 years,

respectively, with yearly mortality of 16·6%. Moreover, thisincreased mortality (never reported before for anypopulation with ICDs) occurred in patients who weremostly in NYHA class I at the time of device implantationand had fairly well preserved left ventricular function.Indirect comparison of these results with those frompublished reports in patients with sustained malignantventricular tachyarrhythmias who were treated withantiarrhythmic drugs (usually amiodarone) does notconfirm the predominant impression that ICDs aresuperior, and shows an urgent need for a randomisedcontrolled trial.119 Radiofrequency catheter ablation of

ventricular tachycardia has been attempted in a fewpatients but neither effi cacy nor effect on survival andrecurrence of arrhythmia has been adequately established.121 Severe bradyarrhythmias are treated with pacemakers, asin other cardiac conditions. The evidence for benefit of pacemaker implantation in patients with Chagas heartdisease is based mostly on case series reports.89

In the absence of a randomised controlled trial,treatment of patients with Chagas heart failure hastraditionally been extrapolated from guidelines developedfor the management of heart failure from other causes.122 However, the pathophysiology of Chagas heart disease hassome peculiarities that could have clinical relevance andtherapeutic implications. For example, increased doses of

diuretics are justified at advanced stages of disease becauseof the predominance of systemic congestive manifestationsover signs of pulmonary congestion. Patients with Chagasheart disease also have striking conduction disturbancesand tend to have symptomatic bradycardia that can beaggravated by the use of digoxin, amiodarone, and,especially, β blockers. Whether β blockers are able toreduce mortality, including in combination withamiodarone, is of particular interest, and remains to beestablished.123 Cardiac resynchronisation is another formof treatment for heart failure, and is mostly for patientswith left bundle branch block. However, remarkably fewdata support its use in patients with right bundle branch

Risk factor Treatment

NHYA class

III or IV

Left ventricular systolic dysfunction

(echocardiography) or cardiomegaly (chestradiography), or both

Non-sustained ventricular

tachycardia (24-h Holtermonitoring)

Very high Present* Present Present ACE inhibitor, spironolactone, amiodarone, diuretics,digitalis, β blocker†, cardiac transplant‡, possibly treat

with an implantable cardioverter defibrillator

High Absent Present Present ACE inhibitor, amiodarone, diuretic‡, β blocker†, possibly

treat with an implantable cardioverter defibrillator

Intermediate Absent Present Absent ACE inhibitor, β blocker, diuretic‡, possibly treat with an

antiparasitic drug

Intermediate Absent Absent Present Possibly treat with amiodarone and an antiparasitic drug

Low Absent Absent Absent Possibly treat with an antiparasitic drug

NYHA=New York Heart Association. ACE=angiotensin-converting enzyme. *Nearly all patients with Chagas heart disease in NYHA class III or IV also have left ventricular

systolic dysfunction on echocardiogram and non-sustained ventricular tachycardia on 24-h Holter monitoring. †If clinically tolerated. ‡For selected patients.

Table 4: Stratification of risk of death associated with Chagas heart disease and recommended treatment



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block, which is much more common in patients withChagas heart disease.

Palliative procedures, such as dynamic cardiomyoplastyand partial left ventriculectomy, are contraindicatedbecause of unsatisfactory results. Cardiac transplantationis an alternative for selected patients with end-stage heartfailure, and some findings suggest that survival of patientswith Chagas heart disease might be better than that of patients with transplants because of other types of cardiacdisease.124 During the immunosuppressive regimen neededto avoid transplant rejection, the patient groups that shouldreceive trypanocidal drugs—all those with transplants oronly those with reactivation of T cruzi infection—is not yetknown.125 The potential benefit of transplantation of bonemarrow cells for treatment of Chagas heart failure is beingassessed in a multicentre randomised controlled trial

sponsored by the Brazilian Health Ministry.126

Because of the high occurrence of thromboembolic phenomena, oralanticoagulants are recommended for patients with atrialfibrillation, previous embolism, and apical aneurysm withrecent thrombus, even in the absence of a randomisedcontrolled trial to prove their effi cacy.

Treatment of gastrointestinal symptomsTreatment of megaoesophagus is directed at palliation of symptoms with a focus on aiding the transit of food andliquids through the achalasic lower oesophageal sphincter.Sublingual nitrates and nifedipine induce lower-oesophageal-sphincter relaxation and could be used beforemeals as temporary treatment while waiting for definitive

management. Endoscopic botulin toxin injection in thesphincter region is rarely used because of its transitoryeffi cacy (months). The same is true for endoscopicpneumatic balloon dilatation, which is now reserved forselected cases. Non-advanced megaoesophagus is besttreated by laparoscopic Heller’s myotomy andfundoplication, a more definitive form of treatment. Inadvanced cases, different techniques of oesophagealresection have been used with variable results.127

The early stage of colonic dysfunction can be treatedwith a fibre-rich diet and abundant fluid intake, as well aslaxatives and occasional enema. Faecal impaction canoccur as the disease progresses requiring manualemptying under general anaesthesia. Patients with

megacolon who fail to respond to conservative measures,and those with frequent fecaloma or sigmoid volvulus,need to undergo surgical organ resection.128

Chagas disease prevention and future directionsIn the past 30 years, remarkable progress has been madein the prevention and control of Chagas disease. 3,129,130 Because no vaccine is available, the focus of primaryprevention has relied on vector control and prevention of transmission from non-vectorial mechanisms. Asubstantial decrease in the burden of Chagas disease hasbeen achieved with compulsory screening of blood donorsand continuous application of insecticides with residual

action in infested houses, which have been supported bycontinuous health education, community participation,

improved housing, and epidemiological surveillance.

32

However, this neglected disease is far from conquered.Future challenges include the continued risk of vector-borne transmission in several Latin American countries,the possibility of resurgence of vector-borne transmissionin regions once successfully controlled, the emergence of Chagas disease in regions previously considered free of disease (such as the Amazon basin), the spread of T cruzi infection by congenital transmission, or via bloodtransfusion or organ transplantation in non-endemic andendemic regions, and the outbreak of local microepidemics of orally transmitted disease.3,129,130

Control of Chagas disease also requires adequateantiparasitic treatment of chronically infected

individuals.130

New drugs with fewer side-effects andincreased trypanocidal activity are urgently needed.However, T cruzi elimination, or at least a reduced parasiteburden is feasible with available drugs (benznidazole andnifurtimox), and provides a unique opportunity to halt orreverse disease progression.112,113 Thus, health services anddisease control programmes should allocate suffi cientresources to ensure that comprehensive serologicalscreening and supervised treatment are readily availableto most patients with chronic T cruzi infection. Theinadequate and problematic supply of benznidazole andnifurtimox in many settings, and the absence of paediatricdrug formulations are additional barriers to targetedtreatment that need to be addressed in the short term. 130

Improved serological, parasitological, or molecular assays,especially rapid tests, are highly desirable for diagnosis of patients in both acute and chronic phases, and to confirmcure after treatment.131

Last, for patients with established chronic Chagas heartdisease, we need to make use of validated risk-stratificationmodels and potentially effective and life-saving treatments,such as drugs to prevent and treat heart failure,amiodarone, pacemakers, and heart transplantation. The clinical challenge is to identify the subset of patients whowill benefit most from one or a combination of thesetreatments and apply them consistently. Whether thedetection and quantification of early signs of heartinvolvement (eg, fibrosis) by novel myocardial imaging

technologies (eg, cardiac MRI) will provide additionalprognostic information and help to guide treatment is of great interest.132 Other priorities for future research includethe assessment of the safety and effi cacy of non-con-ventional treatments, such as cardiac resynchronisation,ICDs, and stem-cell therapy. Randomised controlled trialsare clearly warranted to answer these very importantquestions.

Contributors

AR Jr conceived the idea, searched for published work, was the mentor forall figures and tables, and wrote most of the report. AR and JAM-Ncontributed to writing, review, and editing of the report. All authors haveseen and approved the revised version.



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Conflicts of interest

We declare that we have no conflicts of interest.

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Anis Rassoi Jr - Chagas Disease

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