Seminar

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

Lancet 2010; 375: 1388–402 Chagas disease is a chronic, systemic, parasitic infection caused by the protozoan Trypanosoma cruzi, and was
Division of Cardiology, Anis discovered in 1909. The disease affects about 8 million people in Latin America, of whom 30–40% either have or will
Rassi Hospital, Goiânia, GO, develop cardiomyopathy, digestive megasyndromes, or both. In the past three decades, the control and management
Brazil (A Rassi Jr MD,
of Chagas disease has undergone several improvements. Large-scale vector control programmes and screening of
Prof A Rassi MD); and Division
of Cardiology, Department of blood donors have reduced disease incidence and prevalence. Although more effective trypanocidal drugs are needed,
Internal Medicine, Medical treatment with benznidazole (or nifurtimox) is reasonably safe and effective, and is now recommended for a widened
School of Ribeirão Preto, range of patients. Improved models for risk stratification are available, and certain guided treatments could halt or
University of São Paulo,
reverse disease progression. By contrast, some challenges remain: Chagas disease is becoming an emerging health
Ribeirão Preto, SP, Brazil
(Prof J A Marin-Neto MD) problem in non-endemic areas because of growing population movements; early detection and treatment of
Correspondence to: asymptomatic individuals are underused; and the potential benefits of novel therapies (eg, implantable cardioverter
Dr Anis Rassi Jr, Anis Rassi defibrillators) need assessment in prospective randomised trials.
Hospital, Avenida José Alves 453,
Setor Oeste, Goiânia GO, Brazil,
CEP 74110-020
Introduction cats, and guineapigs) and wild mammals (eg, rodents,
arassijr@terra.com.br Recognised by WHO as one of the world’s 13 most neglected marsupials, and armadillos) mainly by large, blood-
tropical diseases,1 Chagas disease has been a scourge to sucking reduviid bugs of the subfamily Triatominae,
humanity since antiquity, and continues to be a relevant within three overlapping cycles: domestic, peridomestic,
social and economic problem in many Latin American and sylvatic.7 Although more than 130 species of
countries.2,3 This lifelong infection, also known as American triatomine bugs have been identified, only a handful are
trypanosomiasis, is caused by the protozoan parasite competent vectors for T cruzi.8,9
Trypanosoma cruzi, and was discovered in 1909 by the Triatoma infestans, Rhodnius prolixus, and Triatoma
Brazilian physician Carlos Chagas (1879–1934). Chagas’ dimidiata are the three most important vector species in
original report4 is unique in the history of medicine, in the the transmission of T cruzi to man.10,11 Historically,
sense that a single scientist described in great detail both T infestans has been by far the most important vector, and
the cycle of transmission (vector, hosts, and a novel in- has been the primary vector in sub-Amazonian endemic
fectious organism) and the acute clinical manifestations of regions (southern South America). R prolixus is typically
the first human case. Findings from paleoparasitology reported in northern South America and Central America,
studies that recovered T cruzi DNA from human mummies and T dimidiata occupies a similar area, but also extends
showed that Chagas disease afflicted man as early as further north into Mexico. Triatomines have five nymphal
9000 years ago.5 Notably, the first reported case of Chagas stages and adults of both sexes, all of which can harbour
disease might have preceded Carlos Chagas’ discovery— and transmit T cruzi. The probability that a triatomine is
Charles Darwin quite possibly contracted T cruzi infection infected with T cruzi increases in accordance with the
during his expedition to South America in 1835, as sug- number of bloodmeals taken, so that older instars and
gested by his vivid description of contact with the kissing adults tend to have the highest infection rates.
bug, triatomine, and by some of his symptoms in later life.6
Other mechanisms of transmission
Aetiology Chagas disease can be transmitted to man by non-
Vector-borne transmission vectorial mechanisms, such as blood transfusion and
Chagas disease is transmitted to human beings and to vertically from mother to infant. The risk of acquisition
more than 150 species of domestic animals (eg, dogs, 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
Search strategy and selection criteria parasites in the donor’s blood, the blood component
We searched PubMed for reports published between January, 1999, and September, transfused, and, perhaps, the parasite strain.12,13 The
2009, using the terms “Chagas disease”, “American trypanosomiasis”, “Trypanosoma transmission risk seems to be higher for transfusion of
cruzi”, and other specific terms when needed. No language restriction was placed on platelets than for other blood components. Congenital
searches and we included some frequently referenced and older seminal papers, review transmission occurs in 5% of pregnancies or more in
articles, and book chapters. We completed the search with our personal database of chronically infected women in some regions of Bolivia,
references, and with a manual search of references from selected reports. We also Chile, and Paraguay, and in 1–2% or less in most other
reviewed abstracts from pertinent scientific meetings, and publications from WHO, TDR endemic countries.10,14,15 These differences might be
(WHO’s Special Programme for Research and Training in Tropical Diseases), and the Pan attributable to the strain of the parasite, the immunological
American Health Organization. Some further references were added in response to status of infected mothers, placental factors, and the
suggestions from referees. different methodologies used for detection of congenital
cases. Transfusion-based and congenital transmissions

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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
Foregut into metacyclic trypomastigotes that
are released by defecation
Infective metacyclic trypomastigotes
Rhodnius prolixus released onto skin of a mammalian
host in faeces
Metacyclic trypomastigotes enter the host
through rubbing or scratching of the bite
Bloodmeal Triatomine insect wound, or through permissive mucosal or
Triatoma dimidiata
conjunctival surfaces
Mammalian host Skin or mucosa

Signs of portal of entry*

Trypomastigote
in blood smear Recruitment and fusion of
Trypomastigotes lysosomes from the host cell
in bloodstream are needed for trypomastigotes
Infection of to penetrate local cells
new cells
Cell lysis
Trypomastigote in
lysosome-derived
membrane-bound
vacuole
Spread of infection‡ Escape from
Romaña sign
vacuole†
Transformation of Differentiation
Replication of
amastigotes into amastigotes
amastigotes by
After decades into trypomastigotes
binary fission

Myocardial cell full of amastigotes

Megaoesophagus Megacolon Cardiomyopathy Chagoma
Chronic phase of Chagas disease 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 non-
endemic 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
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

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north of the Amazon basin. T cruzi II, which predominates

1980–85 2005
in the domestic environment throughout the Southern
Infected individuals Individuals at Infected individuals Individuals at Cone countries, seems to have increased resistance to
risk of infection risk of infection
trypanocidal drugs, and, at least in Brazil and Argentina,
Southern Cone Initiative (launched in 1991) has been convincingly related to the tissue damage caused
Argentina 2 640 000 (10·0%) 23% 1 600 000 (4·1%) 19% by Chagas disease.27,28 The T cruzi II lineage is further
Bolivia 1 300 000 (24·0%) 32% 620 000 (6·8%) 35% subdivided into five discrete typing units: IIa, IIb, IIc, IId,
Brazil 6 180 000 (4·2%) 32% 1 900 000 (1·0%) 12% and IIe.29 In 2006, the existence of a T cruzi III lineage was
Chile 1 460 000 (16·9%) 63% 160 200 (1·0%) 5% reported.30 However, no definite correlation between
Paraguay 397 000 (21·4%) 31% 150 000 (2·5%) 58% disease severity and parasite lineage has been established.
Uruguay 37 000 (3·4%) 33% 21 700 (0·7%) 19% Completion of the genome sequence of the T cruzi CL
Andean Pact Initiative (launched in 1997) Brener strain31 (a member of unit IIe) opens prospects for
Colombia 900 000 (30·0%) 11% 436 000 (1·0%) 11% the development of novel therapeutic and diagnostic
Ecuador 30 000 (10·7%)* 41% 230 000 (1·7%) 47% techniques, and could increase our understanding of the
Peru 621 000 (9·8%) 39% 192 000 (0·7%) 12% mechanisms of disease.
Venezuela 1 200 000 (3·0%) 72% 310 000 (1·2%) 18%
Central America Initiative (launched in 1997) Epidemiology
Belize ·· ·· 2000 (0·7%) 50% Chagas disease was originally confined to poor, rural
Costa Rica 130 000 (11·7%) 45% 23 000 (0·5%) 23% areas of South and Central America, in which vector-
El Salvador 900 000 (20·0%) 45% 232 000 (3·4%) 39% borne transmission to man occurs. In the past 20 years,
Guatemala 1 100 000 (16·6%) 54% 250 000 (2·0%) 17% improved vector control programmes (such as the
Honduras 300 000 (15·2%) 47% 220 000 (3·1%) 49% Southern Cone Initiative to Control/Eliminate Chagas
Nicaragua ·· ·· 58 600 (1·1%) 25% Disease, Andean Pact Initiative to Control/Eliminate
Panama 200 000 (17·7%) 47% 21 000 (0·01%) 31% Chagas Disease, and Central America Initiative to
Mexico ·· ·· 1 100 000 (1·0%) 28% Control/Eliminate Chagas Disease), and compulsory
Total 17 395 000 (4·3%) 25% 7 694 500 (1·4%)† 20% blood-bank screening have substantially reduced new
cases of infection and decreased the burden of Chagas
··=data not available. *Prevalence of infected individuals was underestimated.33 †Includes about 150 000 infected disease in Latin America.32
individuals living in the USA and 18 000 in the Guianas, but data for these regions are not shown in the table.
In countrywide surveys done in the 1980s, 100 million
Table 1: Prevalence of Trypanosoma cruzi infection in Latin American countries in 1980–8510 and 2005,34 people (ie, 25% of all inhabitants of Latin America) were
and effect of initiatives to control or eliminate Chagas disease estimated to be at risk of infection, and 17·4 million were
infected in 18 endemic countries in 1980–85 (table 1).10
and infective metacyclic trypomastigotes infect the According to estimates by the Pan American Health
triatomine vector (figure 1).21–23 Organization,34 20% of Latin America’s population were
During the acute stage, all types of nucleated cells in at risk (109 million individuals) and nearly 7·7 million
the human host are potential targets for infection. individuals were infected in 2005 (table 1).33,34 Moreover,
With development of the immune response, para- transmission of T cruzi by the main domiciliary vector
sitaemia reduces to a subpatent concentration and the species, T infestans, was halted in Uruguay in 1997, Chile
number of parasites in the tissues declines substantially, in 1999, and Brazil in 2006. According to federal
signalling the end of the acute phase. However, since the legislation, several endemic countries are now screening
parasite is not completely eliminated, infection of for T cruzi in virtually all blood donations,3 and the
specific tissues, such as muscle or enteric ganglia, number of infected blood samples has decreased
persists indefinitely for the life of the host. substantially in all Latin American countries.10,34,35
Other important achievements were the reductions in
Genetic diversity of T cruzi the incidence of new cases of Chagas disease (700 000 per
T cruzi belongs to a heterogeneous species consisting of a year in 1990 vs 41 200 per year in 2006) and the number of
pool of strains, stocks, or isolates that circulate among deaths from Chagas disease (about 50 000 per year vs
mammalian hosts and insect vectors. The heterogeneity of 12 500 per year).3 However, the recent influx of immigrants
the parasite has been extensively studied by biological, from countries endemic for disease has meant that Chagas
biochemical, and molecular methods, and could explain disease is becoming an important health issue in the USA
the varying clinical manifestations of Chagas disease and and Canada and in many parts of Europe and the western
the geographical differences in morbidity and mortality.24,25 Pacific, where an increasing number of infected individuals
In 1999, a consensus regarding the strains of T cruzi was has been identified (figure 2).36–39 The most common
reached and two major lineages were described.26 T cruzi I, destination for migrants from Latin America is the USA,
which predominates in the sylvatic transmission cycle, where an estimated 300 167 individuals (mainly from
seems to be less resistant to trypanocidal drugs, and is Mexico) are infected with T cruzi.37 Spain has the second
associated with human disease in all endemic countries highest number of infected immigrants, an estimated

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Canada
USA
Belize
Mexico Nicaragua
Costa Rica
Guatemala
Panama
Honduras Venezuela
El Salvador
Colombia
Infected individuals Ecuador
0–100
Peru
100–500
500–1000
1000–2000 Bolivia
3000–4000 Paraguay
4000–5000
47 000–67 000 Chile
300 000
Endemic countries*
Data unavailable
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
Phases, forms, and clinical evolution
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 (<5–10% of symptomatic cases) as a
result of severe myocarditis or meningoencephalitis, or
both (figure 3).
Manifestations of the acute disease resolve spon-
taneously in about 90% of infected individuals even if the
infection is not treated with trypanocidal drugs. About
60–70% of these patients will never develop clinically
apparent disease. These patients have the indeterminate
form of chronic Chagas disease, which is characterised by
positivity for antibodies against T cruzi in serum, a normal
12-lead electrocardiogram (ECG), and normal radiological
examination of the chest, oesophagus, and colon. The
remaining 30–40% of patients will subsequently develop a
determinate form of chronic disease—ie, cardiac, digestive
(megaoesophagus and megacolon), or cardiodigestive—
usually 10–30 years after the initial infection (figure 3).44 A
direct progression from the acute phase to a clinical form
of Chagas disease has been recorded in a few patients
(5–10%). Reactivation of Chagas disease can also occur in
chronically infected patients who become immunologically
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Denmark Norway
Netherlands
Sweden
UK
Belgium Germany
France Austria
Spain Italy
Portugal Greece
Switzerland Japan
Brazil
Australia
Uruguay
Argentina
compromised, such as those who are co-infected with HIV
or those who are receiving immunosuppressive drugs.45
Pathogenesis and pathophysiological
mechanisms
Organ and tissue damage during acute T cruzi infection
is caused by the parasite itself and by the host’s acute
immunoinflammatory response, which is elicited by the
presence of the parasite.46 Findings from several studies
in experimental models of T cruzi infection have suggested
that 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, tumour
necrosis factor α, and interleukin 12—is important in the
control of parasitism.47–50 By comparison, production of
interleukin 10 and transforming growth factor β is related
to parasite replication by inhibition of macrophage
trypanocidal activity.51,52 The T-helper-1 immune response
has a protective role mainly through the synthesis of nitric
oxide, which exerts a potent trypanocidal action.53,54 During
chronic infection, the balance between immune-mediated
parasite containment and damaging inflammation of the
host tissues probably determines the course of disease. If
the immunological response is inefficient, or paradoxically
leads to tissue damage, both parasite load and immune-
mediated inflammation increase. By contrast, a well
executed immune response, in which parasite burden is
lowered and inflammatory consequences are kept to a
minimum, results in reduced tissue damage.55
Although the pathogenesis of chronic Chagas disease
is not completely understood, a growing consensus
indicates that parasite persistence is needed for
development of disease.55–57 However, we do not yet know
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Human exposure to T cruzi
(vectorial, via transfusion, congenital,
oral, via organ transplant, accidental)
Cure (50–80% Antiparasitic drug
of cases)
Antiparasitic drug
Cure (20–60% Chronic phase in
of cases) indeterminate form
Permanent
indeterminate form
Figure 3: Natural history of Chagas disease in man
whether tissue damage is mostly caused by direct parasite
factors, or is indirectly triggered through parasite-driven
immunopathology or even autoimmune mechanisms.58–60
Autoimmunity is seen in some patients and in animal
models, and could arise from polyclonal activation,61
molecular self-mimicry by parasite antigens,62 or cryptic
epitopes shared by the host and parasites.63 However, to
make a case for a predominant pathogenic role of
autoimmunity in Chagas disease, we need to show
unequivocally that transfer of antibodies or T cells from
animals infected with T cruzi to naive recipients results
in myocarditis, emulating the clinical course of chronic
Chagas heart disease. Conversely, the establishment of
chronic T cruzi infection is related to a generalised
depression of the T-cell response.64
In chronic Chagas heart disease, a low-intensity,
slowly progressive but incessant myocarditis leads to
impairment of contractile function and dilatation of all
four chambers. A left ventricular apical aneurysm and
other segmental wall motion abnormalities, similar to
those seen in coronary heart disease, are common and
usually appear at early stages.65 Histological examination
shows widespread destruction of myocardial cells,
diffuse fibrosis, oedema, mononuclear cell infiltration
of the myocardium, and scarring of the conduction
system.66 Such damage explains the frequent occurrence
of atrioventricular blocks, intraventricular blocks, and
sinus node dysfunction in Chagas heart disease. The
progressive destruction of cardiac fibres and the intense
fibrosis from replacement of dead myocytes predisposes
the patient to heart failure and ventricular
arrhythmias.67,68 Abnormalities in the coronary micro-
1392
No infection
<5–10% of
Acute Chagas infection symptomatic cases Death from myocarditis or
(asymptomatic or symptomatic) meningoencephallitis
10–30 years later Antiparasitic drug Cure (lower proportion
Chronic phase in
of cases than for the
determinate form
indeterminate form)
Immunosuppression
Reactivation
Cardiac Cardiodigestive Digestive
vasculature and focal hypoperfusion might contribute
to the myocardial damage.69,70
Chronic Chagas gastrointestinal disease is caused by
destruction of intramural autonomic ganglia, which
predominantly affects the oesophagus, colon, or both.71
Striking neuronal depopulation can also occur in the
heart, and the so-called neurogenic theory for the
pathogenesis of Chagas cardiomyopathy postulates that
the deranged parasympathetic system allows unopposed
sympathetic overactivity.71 However, this theory is flawed
with many conceptual and experimental obstacles, which
include the subtleness and variability of the intensity of
cardiac denervation in patients with Chagas heart disease,
the absence of correlation between parasympathetic
denervation and the extent of myocardial dysfunction,
and the fact that sympathetic denervation (mainly at the
sinus node and at the myocardium) also occurs during
the early stages of disease.60
Clinical manifestations
Acute Chagas disease
In most individuals, irrespective of the mechanism of
transmission, acute Chagas infection is usually
asymptomatic, which is probably because the parasite load
is fairly small. When symptoms occur they include:
prolonged fever; malaise; enlargement of the liver, spleen,
and lymph nodes; subcutaneous oedema (localised or
generalised); and, in the particular case of vector-borne
transmission, the signs of portal of entry of T cruzi through
the skin (chagoma) or via the ocular mucous membranes
(Romaña sign; figure 1, table 2). An ECG might show
sinus tachycardia, first-degree atrioventricular block, low
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Geographical Predominant Incubation Clinical presentation Diagnosis Mortality

distribution population time
Vectorial Endemic Children and 1–2 weeks Asymptomatic; fever, malaise, lymphadenopathy, Parasite detection by microscopy: fresh blood Low (<5–10%)*
countries adolescents hepatosplenomegaly, subcutaneous oedema; signs of specimen; stained blood smears; buffy coat
portal of entry (Romaña sign, chagoma); myocarditis, preparation (microhaematocrit technique); or
meningoencephalitis serum precipitate (Strout technique)
Transfusion- Endemic and Adults 8–120 days Same as for vectorial but excluding signs of portal of entry Same as for vectorial Variable†
based non-endemic
countries
Congenital Endemic and Neonates and Up to a few Asymptomatic; abortion, neonatal death, prematurity, Microhaematocrit with cord blood or peripheral Unknown
non-endemic children younger weeks low birthweight, low Apgar score; hypotonicity, fever, blood from neonate; two or more samples in the
countries than 1 year hepatosplenomegaly, respiratory distress, anaemia; first month of life; IgG serology at 6–9 months of
myocarditis, meningoencephalitis, megaviscera, oedema age if microhaematocrit negative or not done
Oral Amazon Individuals of any 3–22 days Same as for transfusion-based plus headache, myalgia, Same as for vectorial High (8–35%)
basin, and age from the same vomiting, abdominal pain, jaundice, diarrhoea, and
regional family or digestive haemorrhage
outbreaks community
Reactivation- Endemic and Patients with Variable Same as for transfusion-based plus panniculitis, Same as for vectorial, and parasites can also be Variable†
based non-endemic associate immuno- subcutaneous parasite-containing nodules, and skin ulcers detected in tissues by microscopy or PCR
countries suppressive states

*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

QRS voltage, or primary T-wave changes; and a chest
radiograph might show variable degrees of cardiomegaly.10,72
Repetition of the ECG and chest radiograph is crucial for
detection of these abnormalities. In congenitally infected
infants, the most common symptoms, which might be
apparent at birth or develop within weeks after delivery,
are hypotonicity, fever, hepatosplenomegaly, and anaemia.
Other findings include prematurity, low birthweight, and
low Apgar score.73,74 In-utero infections are also associated
with abortion and placentitis. Serious manifestations,
including myocarditis, meningoencephalitis, and
pneumonitis, are uncommon, but have a high risk of
death (table 2).15 A woman infected with T cruzi, at any
stage of disease, could give birth to an infected fetus
during any of her pregnancies.
Chronic Chagas disease
The clinical outcome of the chronic phase of Chagas
disease ranges from the absence of signs and symptoms
of disease (indeterminate form) to severe illness and
premature death (table 3). Typical clinical manifestations
of this phase are related to the pathological involvement
of heart, oesophagus, colon, or a combination, and are
grouped into three major forms: cardiac, digestive, and
cardiodigestive.67,75,76
The digestive form is seen almost exclusively south of
the Amazon basin (mainly in Argentina, Brazil, Chile, and
Bolivia), and is rare in northern South America, Central
America, and Mexico. This geographical distribution is
probably 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 causes
dysphagia with odynophagia, combined with epigastric
pain, regurgitation, ptyalism, and malnutrition in severe
cases. Megacolon often affects the sigmoid segment,
rectum, or descending colon, or a combination, and
produces prolonged obstipation, abdominal distension,
and occasionally large bowel obstruction due to fecaloma
or sigmoid volvulus. Patients with megaoesophagus have
an increased prevalence of cancer of the oesophagus.80
Conversely, an increased frequency of colorectal cancer has
not been reported in patients with chagasic megacolon.81
The cardiac form is the most serious and frequent
manifestation of chronic Chagas disease. It develops in
20–30% of individuals and typically leads to abnormalities
of the conduction system, bradyarrhythmias and tachyar-
rhythmias, apical aneurysms, cardiac failure, thrombo-
embolism, and sudden death.67,75,76 The most common ECG
abnormalities are right bundle branch block, left anterior
fascicular block, ventricular premature beats, ST-T changes,
abnormal Q waves, and low voltage of QRS. The
combination of right bundle branch block and left anterior
fascicular block is very typical in Chagas heart disease.
Frequent, complex ventricular premature beats,
including couplets and runs of non-sustained ventricular
tachycardia, are a common finding on Holter monitoring
or stress testing. Ventricular premature beats correlate
with the severity of ventricular dysfunction, but can also
occur in patients with quite well preserved ventricular
function. Episodes of non-sustained ventricular tachycardia
are seen in about 40% of patients with mild wall motion
abnormalities, and in virtually all patients with heart
failure, which is more frequent than in other
cardiomyopathies.82 Sustained ventricular tachycardia is
another hallmark of the disease. This life-threatening
arrhythmia can be reproduced during programmed
ventricular stimulation in about 85% of patients and

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Cardiac NYHA ECG changes Chest 24-h Holter 2D echocardiogram Thrombo- Sustained Sudden
symptoms* class radiograph (complex embolism ventricular death
(cardiomegaly) ventricular tachycardia
arrhythmias†)
Left ventricular Left ventricular
wall motion apical aneurysm
abnormalities
Indeterminate Absent ·· Absent Absent Very rare Absent Absent Absent Absent Absent
Digestive‡ Absent ·· Absent Absent Rare Rare Very rare Absent Absent Absent
Cardiac Absent or ·· Not specific§ Absent Rare Rare Very rare Very rare Rare Rare
stage I minimal
Cardiac Fairly I or II Right bundle branch block with or Absent or mild Common Absent or Common Fairly Common Common
stage II common without left anterior fascicular block, segmental common
monomorphic ventricular premature
beats, diffuse ST-T changes, first or
second degree atrioventricular block
Cardiac Common I, II, As for stage II plus Q waves, Mild to Very common Segmental or Common Fairly Common Common
stage III or III polymorphic ventricular premature moderate diffuse (mild to common
beats, advanced atrioventricular block, moderate)
severe bradycardia, low QRS voltage
Cardiac Common II, III, As for stage III plus atrial flutter or Moderate to Very common Diffuse (severe) Fairly common Common Fairly Fairly
stage IV or IV fibrillation severe common 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¶

seems to result from an intramyocardial or subepicardial
re-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 Chagas
heart disease. It is usually biventricular with a
predominance of right-sided failure (peripheral oedema,
hepatomegaly, and ascites more prominent than
pulmonary congestion) at advanced stages. Isolated left
heart failure can be present in the early stages of cardiac
decompensation.67,75,76 Heart failure of chagasic aetiology
is associated with higher mortality than is heart failure
from other causes.86
Systemic and pulmonary embolisms arising from
mural thrombi in the cardiac chambers are quite
frequent.87 Clinically, brain is by far the most frequently
recognised site of embolisms (followed by limbs and
lungs), but at necropsy embolisms are found more
frequently in the lungs, kidneys, and spleen. Chagas
disease is an independent risk factor for stroke in
endemic countries.88
Sudden death is the main cause of death in patients
with Chagas heart disease, accounting for nearly two-
thirds of all deaths, followed by refractory heart failure
(25–30%), and thromboembolism (10–15%).89 Sudden
cardiac death can occur even in patients who were
previously asymptomatic. It is usually associated with
ventricular tachycardia and fibrillation or, more rarely,
with complete atrioventricular block or sinus node
dysfunction. Leading causes of death vary dependent on
the stage of disease, with a clear predominance of sudden
death at early stages, and a slight predominance of death
from pump failure at advanced stages.
On the basis of our own experience and our review of
published reports, we propose a schematic classification
of Chagas heart disease into four stages to help
physicians improve their understanding of the hetero-
geneous clinical course (table 3). This classification
could also be useful for epidemiological studies.
Although other staging systems exists, such as Kuschnir,90
Los Andes,91 and the Brazilian Consensus,92 they are
based solely on functional capacity, ECG findings, and
left ventricular function or size.
The association of heart disease with megaoesophagus
or 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 exacerbation
of chronic infection, leading to increases in parasitaemia
and intracellular parasite replication (table 2). Fever,
myocarditis, panniculitis, and skin lesions are common
in recipients of solid organ or bone marrow
transplants,93,94 whereas in patients with AIDS the most
common manifestations are meningoencephalitis and
CNS lesions that resemble the lesions of cerebral
toxoplasmosis.95,96 Figure 4 summarises the common
clinical manifestations associated with the chronic
phase of Chagas disease.

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Cardiac disease
Sinus node Ventricular premature beats
V1 dysfunction Non-sustained ventricular V5
tachycardia
Atrioventricular Ventricular tachycardia and
block ventricular fibrillation
V5
aVL
+ A*
Right bundle ++
++ Q waves
branch block
D1 D2 V1 and left V1 V2 V3 V5
anterior +
fascicular ++ +
+
block +++
+

LV
RV
Thrombus
(arrow)

Apical aneurysm LA RA

Mitral
regurgitation
B LV
Tricuspid
regurgitation
RV

LA RA

Advanced cardiac disease

LV

RV

LA RA

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

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.

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 Seminar

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,

1: Confirm the diagnosis
indirect haemagglutination)

Positive Negative

Chagas disease exceptional

Chagas disease confirmed

12-lead ECG and

2: Define the clinical form of chronic disease
gastrointestinal symptoms*

ECG normal ECG abnormal ECG abnormal ECG normal

No gastrointestinal symptoms No gastrointestinal symptoms Gastrointestinal symptoms Gastrointestinal symptoms

Indeterminate form Cardiac form Cardiodigestive form Digestive form

Undertake reassessment every Confirm digestive form, decide

1 or 2 years, and possibly treat with
an antiparasitic drug
3: Establish the stage of cardiac disease
about the need for symptomatic
or surgical treatment, and possibly
treat 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

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.

Diagnosis haemagglutination) to confirm diagnosis.92,97 PCR is not

Diagnosis of acute infection is based on the microscopic
detection of trypomastigotes in blood (table 2).10,97 Micro-
haematocrit is the method of choice to identify congenital
infection because of its heightened sensitivity and the
small amount of blood needed. Microscopic examination
of cord blood or peripheral blood of the neonate by this
technique is strongly recommended during the first month
of life.73,74 If the results are repeatedly negative or if the test
is not done early in life, the infant should be tested for
anti-T cruzi IgG antibodies at 6–9 months of age
(preferentially at 9 months) when maternal antibodies are
no longer present in the baby.92,97 In specialised centres,
assays based on amplification of T cruzi DNA by PCR
could also be used for early diagnosis of congenital
infection, since in this context the sensitivity of PCR seems
to be greater than that of microscopic examination.98–100
During the chronic phase, because parasitaemia is
scarce, the presence of IgG antibodies against T cruzi
antigens needs to be detected by at least two different
serological methods (usually enzyme-linked immuno-
sorbent assay, indirect immunofluorescence, or indirect
helpful in routine diagnosis because of the need for specific
laboratory facilities, poor standardisation, potential DNA
cross-contamination, and variable results across labora-
tories and countries. However, because of its heightened
sensitivity compared with other parasitological methods,
PCR could be useful to confirm diagnosis in cases of
inconclusive serology,92 and as an auxiliary method to
monitor treatment.101 PCR is useful to identify treatment
failure from positive detection of T cruzi DNA, but not
treatment success since even repeated negative PCR
results do not necessarily indicate parasitological cure. At
best, such results are indicative of the absence of parasite
DNA at the time of the test.
Assessment of patients with suspected chronic
Chagas disease
Figure 5 shows the steps necessary to assess patients with
suspected Chagas disease. After confirmation of the
diagnosis, a thorough search for cardiovascular and
gastrointestinal symptoms and a resting 12-lead ECG are
needed to define the clinical form of disease. Although

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 Seminar

A B NYHA class I or II (n=380)

C
p<0·001
100 NYHA class III or IV (n=44) 100
Risk factor Points
90 90
NYHA class III or IV 5
Cardiomegaly (chest radiograph) 5 80 80
Segmental or global wall motion 3

Probability of survival (%)

abnormality (2D echocardiogram) 70 70
Non-sustained ventricular tachycardia 3
60 60
(24-h Holter)
Low QRS voltage (ECG) 2
50 50
Male sex 2
40 40
Total points TotalRisk
Total mortality Mortality 30 30
5 years 10 years
20 20 NSVT– and LVSD– (n=233)
0–6 2% 10% Low NSVT+ and LVSD– (n=89)
p<0·001
7–11 18% 44% Intermediate 10 10 NSVT– and LVSD+ (n=55)
12–20 63% 84% High NSVT+ and LVSD+ (n=67)
0 0
0 2 4 6 8 10 12 0 3 6 9 12 15
Follow-up (years) Follow-up (years)

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 monitoring
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.

barium swallow and enema are needed for final diagnosis
of the digestive form, these tests are usually not
recommended as standard practice for patients without
gastrointestinal symptoms. Asymptomatic patients with a
normal ECG and no gastrointestinal tract or cardiovascular
symptoms have a favourable prognosis102,103 and should be
followed up every 12–24 months. Strictly, the indeterminate
form is defined by the presence of normal findings from
radiological examination of the chest, oesophagus, and
colon, but in common clinical practice, these tests are
usually not done on asymptomatic patients. Patients with
ECG changes consistent with Chagas heart disease104
should undergo a routine cardiac assessment to establish
the stage of disease. Ambulatory 24-h Holter monitoring
is used to detect arrhythmias; and combined chest
radiography and 2D echocardiography refine the
assessment of cardiac size and function, and provide
additional prognostic information. From the results of
these tests, clinicians can stratify individual patients by
risk and implement appropriate treatment.
Prognostic markers and risk stratification in
Chagas heart disease
Improved understanding of prognostic factors in Chagas
heart disease has helped clinicians to identify patients’
risk, choose appropriate treatment, and direct patient
counselling. Some of us used a rigorous multivariate
analysis to develop a risk score for mortality prediction in
424 outpatients from a regional Brazilian cohort,105 and
the score has been validated successfully in two external
cohorts.105,106 Several demographic, clinical, and non-
invasive variables were tested, and six were identified as
independent predictors of mortality and were assigned
points according to the strength of their statistical
association with the outcome. From addition of the points
to provide the risk score, patients can be classified into
groups of low, intermediate, and high risk (figure 6).
Subsequently, two systematic reviews integrated the
results of all previous studies in which multivariable
regression models of prognosis were used and a clearly
defined outcome (all-cause mortality, sudden cardiac
death, or cardiovascular death) was analysed.68,108
According to these reviews, the strongest and most
consistent predictors of mortality are New York Heart
Association (NYHA) functional class III or IV,
cardiomegaly on chest radiography, impaired left
ventricular systolic function on echocardiogram or
cineventriculography, and non-sustained ventricular
tachycardia on 24-h Holter monitoring68,105,107,108
(figure 6). On the basis of these findings, we propose a
risk-stratification model for mortality that can assist
treatment in patients with Chagas heart disease (table 4).
Treatment
The aim of treatment is to eradicate the parasite and
target the signs and symptoms of disease.
Antitrypanosomal treatment
According to recommendations in 200592 and 2007,109 anti-
trypanosomal treatment is strongly recommended for all
cases of acute, congenital, and reactivated infection, for
all children with infection, and for patients up to 18 years
of age with chronic disease. Drug treatment should
generally be offered to adults aged 19–50 years without
advanced Chagas heart disease, and is optional for those
older than 50 years because benefit has not been proven
in this population.109 By contrast, antitrypanosomal
treatment is contraindicated during pregnancy and in
patients with severe renal or hepatic insufficiency, and
generally should not be offered to patients with advanced

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Risk factor
NHYA class Left ventricular systolic dysfunction
III or IV (echocardiography) or cardiomegaly (chest
radiography), or both
Very high Present* Present
High Absent Present
Intermediate Absent Present
Intermediate Absent Absent
Low Absent Absent
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
Chagas heart disease or megaoesophagus with substantial
impairment of swallowing.
Benznidazole and nifurtimox are the only drugs with
proven efficacy against Chagas disease.110–113 Benznidazole
has the best safety and efficacy profile,114 and therefore is
usually used for first-line treatment. Children should be
treated with benznidazole (5–10 mg/kg daily) in two or
three 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, daily
treatment with 5 mg/kg benznidazole or 8–10 mg/kg
nifurtimox is recommended for the same duration as for
children.92 Antitrypanosomal treatment in established
mild to moderate Chagas heart disease is under scrutiny
by the BENEFIT trial,115 which is comparing benznidazole
with placebo in 3000 patients (aged 18–75 years) from
several centres in Latin America.
Treatment of cardiac symptoms
Despite a scarcity of evidence from randomised controlled
trials about treatment of rhythm disturbances, some
observational data suggest that amiodarone could improve
survival in patients with Chagas heart disease who are at
high risk of death because of malignant arrhythmias.82,89,116
Thus, amiodarone is usually recommended as the
treatment of choice for all patients with sustained
ventricular tachycardia, and for those with non-sustained
ventricular tachycardia and myocardial dysfunction.117
Patients with refractory or haemodynamically unstable
sustained ventricular tachycardia, and those resuscitated
from sudden death have been treated with implantable
cardioverter defibrillators (ICDs).118 However, trials have
not yet compared the efficacy of ICDs with that of
amiodarone in patients with Chagas heart disease and
malignant ventricular arrhythmias.119 The largest single-
centre study of ICD treatment for secondary prevention
enrolled 90 patients and showed very disappointing
results.120 Mortality in ICD recipients was 18%, 27%, 40%,
50%, and 73% after follow-up of 1, 2, 3, 4, and 5 years,
1398
Treatment
Non-sustained ventricular
tachycardia (24-h Holter
monitoring)
Present ACE inhibitor, spironolactone, amiodarone, diuretics,
digitalis, β blocker†, cardiac transplant‡, possibly treat
with an implantable cardioverter defibrillator
Present ACE inhibitor, amiodarone, diuretic‡, β blocker†, possibly
treat with an implantable cardioverter defibrillator
Absent ACE inhibitor, β blocker, diuretic‡, possibly treat with an
antiparasitic drug
Present Possibly treat with amiodarone and an antiparasitic drug
Absent Possibly treat with an antiparasitic drug
respectively, with yearly mortality of 16·6%. Moreover, this
increased mortality (never reported before for any
population with ICDs) occurred in patients who were
mostly in NYHA class I at the time of device implantation
and had fairly well preserved left ventricular function.
Indirect comparison of these results with those from
published reports in patients with sustained malignant
ventricular tachyarrhythmias who were treated with
antiarrhythmic drugs (usually amiodarone) does not
confirm the predominant impression that ICDs are
superior, and shows an urgent need for a randomised
controlled trial.119 Radiofrequency catheter ablation of
ventricular tachycardia has been attempted in a few
patients but neither efficacy nor effect on survival and
recurrence of arrhythmia has been adequately established.121
Severe bradyarrhythmias are treated with pacemakers, as
in other cardiac conditions. The evidence for benefit of
pacemaker implantation in patients with Chagas heart
disease is based mostly on case series reports.89
In the absence of a randomised controlled trial,
treatment of patients with Chagas heart failure has
traditionally been extrapolated from guidelines developed
for the management of heart failure from other causes.122
However, the pathophysiology of Chagas heart disease has
some peculiarities that could have clinical relevance and
therapeutic implications. For example, increased doses of
diuretics are justified at advanced stages of disease because
of the predominance of systemic congestive manifestations
over signs of pulmonary congestion. Patients with Chagas
heart disease also have striking conduction disturbances
and tend to have symptomatic bradycardia that can be
aggravated by the use of digoxin, amiodarone, and,
especially, β blockers. Whether β blockers are able to
reduce mortality, including in combination with
amiodarone, is of particular interest, and remains to be
established.123 Cardiac resynchronisation is another form
of treatment for heart failure, and is mostly for patients
with left bundle branch block. However, remarkably few
data support its use in patients with right bundle branch
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block, which is much more common in patients with
Chagas heart disease.
Palliative procedures, such as dynamic cardiomyoplasty
and partial left ventriculectomy, are contraindicated
because of unsatisfactory results. Cardiac transplantation
is an alternative for selected patients with end-stage heart
failure, and some findings suggest that survival of patients
with Chagas heart disease might be better than that of
patients with transplants because of other types of cardiac
disease.124 During the immunosuppressive regimen needed
to avoid transplant rejection, the patient groups that should
receive trypanocidal drugs—all those with transplants or
only those with reactivation of T cruzi infection—is not yet
known.125 The potential benefit of transplantation of bone
marrow cells for treatment of Chagas heart failure is being
assessed in a multicentre randomised controlled trial
sponsored by the Brazilian Health Ministry.126 Because of
the high occurrence of thromboembolic phenomena, oral
anticoagulants are recommended for patients with atrial
fibrillation, previous embolism, and apical aneurysm with
recent thrombus, even in the absence of a randomised
controlled trial to prove their efficacy.
Treatment of gastrointestinal symptoms
Treatment of megaoesophagus is directed at palliation of
symptoms with a focus on aiding the transit of food and
liquids through the achalasic lower oesophageal sphincter.
Sublingual nitrates and nifedipine induce lower-
oesophageal-sphincter relaxation and could be used before
meals as temporary treatment while waiting for definitive
management. Endoscopic botulin toxin injection in the
sphincter region is rarely used because of its transitory
efficacy (months). The same is true for endoscopic
pneumatic balloon dilatation, which is now reserved for
selected cases. Non-advanced megaoesophagus is best
treated by laparoscopic Heller’s myotomy and
fundoplication, a more definitive form of treatment. In
advanced cases, different techniques of oesophageal
resection have been used with variable results.127
The early stage of colonic dysfunction can be treated
with a fibre-rich diet and abundant fluid intake, as well as
laxatives and occasional enema. Faecal impaction can
occur as the disease progresses requiring manual
emptying 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 directions
In the past 30 years, remarkable progress has been made
in the prevention and control of Chagas disease.3,129,130
Because no vaccine is available, the focus of primary
prevention has relied on vector control and prevention of
transmission from non-vectorial mechanisms. A
substantial decrease in the burden of Chagas disease has
been achieved with compulsory screening of blood donors
and continuous application of insecticides with residual
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Seminar
action in infested houses, which have been supported by
continuous 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 transmission
in 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 blood
transfusion or organ transplantation in non-endemic and
endemic regions, and the outbreak of local micro
epidemics of orally transmitted disease.3,129,130
Control of Chagas disease also requires adequate
antiparasitic treatment of chronically infected
individuals.130 New drugs with fewer side-effects and
increased trypanocidal activity are urgently needed.
However, T cruzi elimination, or at least a reduced parasite
burden is feasible with available drugs (benznidazole and
nifurtimox), and provides a unique opportunity to halt or
reverse disease progression.112,113 Thus, health services and
disease control programmes should allocate sufficient
resources to ensure that comprehensive serological
screening and supervised treatment are readily available
to most patients with chronic T cruzi infection. The
inadequate and problematic supply of benznidazole and
nifurtimox in many settings, and the absence of paediatric
drug formulations are additional barriers to targeted
treatment 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 confirm
cure after treatment.131
Last, for patients with established chronic Chagas heart
disease, we need to make use of validated risk-stratification
models 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 who
will benefit most from one or a combination of these
treatments and apply them consistently. Whether the
detection and quantification of early signs of heart
involvement (eg, fibrosis) by novel myocardial imaging
technologies (eg, cardiac MRI) will provide additional
prognostic information and help to guide treatment is of
great interest.132 Other priorities for future research include
the assessment of the safety and efficacy of non-con-
ventional treatments, such as cardiac resynchronisation,
ICDs, and stem-cell therapy. Randomised controlled trials
are clearly warranted to answer these very important
questions.
Contributors
AR Jr conceived the idea, searched for published work, was the mentor for
all figures and tables, and wrote most of the report. AR and JAM-N
contributed to writing, review, and editing of the report. All authors have
seen and approved the revised version.
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Conflicts of interest 24 Macedo AM, Machado CR, Oliveira RP, Pena SD. Trypanosoma
We declare that we have no conflicts of interest. cruzi: genetic structure of populations and relevance of genetic
variability to the pathogenesis of Chagas disease.
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