Tutorial 08

Objetivos Estudar a Doena de Chagas

Doena de Chagas
Trypanosoma cruzi is endemic in South, Central and parts of North America
(also Mexico and possibly South Texas). T. cruzi infection occurred mainly in rural
areas where humans live in poorly constructed dwellings and in close contact with
potential vectors. However, rural-to-urban and international migrations have changed
the epidemiology of CD affecting peri-urban, urban, endemic and non-endemic areas
alike.
The prevalence and incidence of the disease are decreasing. Eradicating
transmission of T. cruzi by the main domiciliary vector species, Triatoma infestans,
from three endemic countries (Uruguay in 1997; Chile in 1999; and Brazil in 2006)
According to the most recent estimates, there are currently 7.6 million people
infected with T. cruzi in Latin America.
Pathogenesis and Pathology

Tissue damage appears to be caused both by direct parasite effects and

secondary to the hosts immune response. Cross-reactivity between T. cruzi antigens
and auto-antigens, and an imbalance between CD4+ and CD8+ T lymphocyte responses
leading to excessive production of inflammatory cytokines may have roles in immunemediated tissue damage.
During the acute phase of infection (usually corresponding to the first 23 months
after infection), all types of nucleated cells may be infected and inflammatory
changes are especially marked close to ruptured infected cells. Lesions reveal

localized inflammatory reactions, acute diffuse myocarditis with myocyte necrosis,

interstitial edema and inflammatory cell infiltrates. Inflammatory lesions may also be
found in the smooth muscle of the esophagus and colon, and the central and peripheral
nervous systems. In nearly all infected individuals, an effective host immune response,
involving T helper-1, CD4+ and CD8+ lymphocytes and the production of
interferon-, tumor necrosis factor- and interleukin-12, develops within 60 days
of infection which controls the parasitemia. However, in the absence of effective
treatment, tissue infection persists for the life of the host. In the indeterminate form of
the chronic phase, isolated inflammatory foci may be found in tissues.
Sensitive methods of parasite detection, such as immunohistochemistry and polymerase
chain reaction (PCR).
Evidence exists for multiple hypotheses to explain the aetiology of chronic cardiac
lesions implicating the parasite directly, the immune reaction to the parasite and
autoimmunity elicited either directly by the parasite (mimicry) or indirectly (bystander
activation).7,8 The end-product of these lesions is varying degrees of necrosis, neuronal
damage, microvascular damage and fibrosis.
There is evidence of both functional and anatomical parasympathetic neuronal
damage. Patients with CD lack the tonic inhibitory parasympathetic action on the sinus
node and thus the chronotropic mechanism to respond to changes in blood pressure or
venous return. Neuronal loss is occur during the acute stage of the disease; the extent
of neuronal damage however, does not correlate with disease stage. Therefore, despite
possible contributions of parasympathetic impairment to the impact of CHD cardiac
dysautonomia is unlikely to explain the main pathogenic mechanism underlying CHD.
Microcirculatory changes leading to ischaemia also were implicated in the pathogenesis
of chronic CHD. Diffuse collapse of intramyocardial arterioles has been observed in the
hearts of chronically infected patients. Occlusive platelet thrombi in small epicardial
and intramural coronary arteries and increased production of cytokines and mediators
that promote vasospasm and platelet aggregation have been demonstrated in
experimental models of CD.
The inflammatory infiltrate in chronic Chagasic cardiomyopathy has a predominance of
macrophages, CD8+ and CD4+ lymphocytes (in a 2 : 1 ratio) and in some instances has
been shown to correlate with more advanced stages of the disease. Persistence of
parasites and antigens is thought to be involved in recruitment of T. cruzi-specific CD8+
T lymphocytes which predominate in the myocardial infiltrate of chronic myocarditis.
The cytokine profile associated with this myocarditis is also shifted toward Th1
cytokines so that elevated INF- levels and decreased IL-10 levels may potentially
perpetuate an existent, ongoing inflammatory process. However, the exact mechanism
responsible for the turning point from immunoprotection to immune-mediated
aggression leading to irreversible tissue damage remains elusive: not only is parasite
persistence true for both symptomatic and asymptomatic patients, but presence of the
parasite in heart tissue does not always correlate with inflammation.
Autoimmunity has also been postulated as a plausible aetiology for the chronic
myocarditis observed in T. cruzi-infected patients. Several T. cruzi antigens that cross-

react with cardiac and non-cardiac host components have been identified, but only some
have been shown to have functional activity. Among these, attention has focused on
antibodies that cross-react with cardiac myosin and the immunodominant T. cruzi
antigen B13 initially because they were detected in 100% of patients with chronic
Chagasic cardiomyopathy in contrast to 14% of asymptomatic infected individuals, and
later because T-cell clones derived from lesions of chronic CHD were found to be
simultaneously reactive to cardiac myosin heavy chain and the B13 T. cruzi protein.
Opponents to the molecular mimicry theory with specific relevance to anti B13cardiac myosin crossreactive antibodies and derived cellular autoimmunity contend that
these antibodies do not bind to intact myocytes, are not unique to T. cruzi infection,
Are present in asymptomatic patients without heart lesions, and that myosin
autoimmunity is not essential for cardiac inflammation in experimental models.
Arguing against autoimmunity developing as a result of parasite-specific immune
responses, antigen exposure after tissue damage may also sensitize autoreactive T cells
to selfantigens given a proinflammatory environment. The question, therefore, is not
whether autoimmunity is present, but whether it is a primary cause or merely a
contributing factor to the pathogenesis of chronic myocarditis. Further evidence is
required from experiments to prove an association between the development of similar
cardiac lesions with transfer of autoantibodies and/or autoreactive cells to susceptible
hosts.
Although the effects of both autonomic and microvascular disturbances in CHD
may play an important role in potentiating and perpetuating cardiac muscle damage,
persistent inflammation in the setting of continuous antigenic stimulation is
perhaps the common pathway for tissue damage.
Multiple mechanisms seem to explain this chronic inflammation (including antiparasite immunity and possibly autoimmunity), which are not necessarily mutually
exclusive. The course to progression to chronic CHD and other forms of the disease has
been suggested to be related to genetic properties of both host and parasite. However,
the molecular mechanisms underlying tissue tropism and the initial trigger or
determinant of the course of chronic disease are not yet known.
Clinical Features
ACUTE CHAGAS DISEASE

ACUTE TRYPANOSOMA CRUZI INFECTION

The incubation period is 12 weeks, after which the acute phase of infection
begins. The acute phase lasts 812 weeks and is characterized by circulating

trypomastigotes detectable by microscopy of fresh blood. Most patients are

asymptomatic or have mild, nonspecific symptoms, such as fever,
lymphadenopathy and/or hepatosplenomegaly, and do not come to clinical
attention during the acute phase. In some patients, acute infection is associated with
inflammation and swelling at the site of inoculation, known as a chagoma. Chagomas
typically occur on the face or extremities, and parasites may be demonstrable in an
aspirate of the lesion. Inoculation via the conjunctiva leads to the characteristic
unilateral swelling of the upper and lower eyelid known as the Romaa sign. Severe
acute disease occurs in less than 1% of patients; manifestations include acute
myocarditis pericardial effusion, and/or meningoencephalitis. Acute Chagas disease
carries an estimated risk of mortality in the range of 1 in 200 to 1 in 400 cases. Orallytransmitted T. cruzi infection appears to be associated with more severe acute
morbidity and higher mortality than vector-borne infection.
CHRONIC TRYPANOSOMA CRUZI INFECTION
Eight to 12 weeks after infection, parasitemia levels become undetectable by
microscopy and, in the absence of effective anti-trypanosomal treatment, the individual
passes into the chronic phase. Persons with chronic T. cruzi infection can transmit the
parasite to the vector and directly to other humans through blood components, organ
donation and congenitally. Persons with chronic T. cruzi infection, but without signs or
symptoms of Chagas disease, are considered to have the indeterminate or asymptomatic
form. An estimated 2030% of people who initially have the indeterminate form of
Chagas disease progress over a period of years (to decades) to clinically-evident cardiac
and/or gastrointestinal disease.
CHRONIC CHAGAS HEART DISEASE
Cardiac involvement is the most frequent and most severe manifestation of chronic CD.
Transition from the indeterminate form to the cardiac form of chronic CD is usually
manifested by the appearance of ECG changes such as incomplete or complete right
bundle branch block (RBBB), left anterior fascicular block (LAFB), minimal ST-T
changes, and monomorphic premature ventricular contractions (PVCs) mostly in
asymptomatic or oligosymptomatic patients. As the disease advances, associated
intraventricular conduction defects (usually RBBB with LAFB), polymorphic PVCs,
bradyarrhythmias, high-grade atrioventricular blocks, q-waves, nonsustained or
sustained ventricular tachycardia and ultimately atrial flutter or fibrillation may ensue.
Symptoms such as palpitations, atypical chest pain, presyncope, syncope,
dyspnoea on exertion and oedema are usually observed throughout the course of
CHD. Findings on physical examination vary according to the stage of the disease and
the presence of conduction system abnormalities. They include: cardiac rhythm
irregularities; displaced point of maximal impulse; gallop rhythms; a loud second
heart sound implying pulmonary hypertension; mitral or tricuspid regurgitation
murmurs; an increase in the systemic venous pressure with liver enlargement and
oedema; and borderline low systolic blood pressure with a reduced radial pulse
implying systolic dysfunction.
The clinical course of CHD is diverse and difficult to predict, with some patients
remaining
asymptomatic
lifelong,
despite
electrocardiographic
and/or

echocardiographic evidence of the disease; some presenting with signs, symptoms and
complications of progressive heart failure or advanced cardiac arrhythmias; and others
dying unexpectedly without prior symptoms.
Currently, several staging systems of CHD are available. They can help to
identify patients at different degrees of risk, facilitate choices among treatment
alternatives and aid patient counselling. Most systems classify patients into four or five
stages, based on their functional capacity, ECG findings and the presence or
absence of heart enlargement and/or systolic dysfunction on echocardiogram.
Systemic and pulmonary embolism arising from mural thrombi in the cardiac
chambers is relatively frequent. Although the brain is by far the most common clinically
recognized site of embolisms (followed by limbs and lungs), at necropsy, embolisms are
found more frequently in the lungs, kidneys and spleen. CD is an independent risk
factor for stroke in endemic areas. Mortality in CHD is due to sudden cardiac arrest in
5565% of patients, congestive heart failure in 2530% of patients and thromboembolic
phenomena in 1015%.

Chronic Gastrointestinal Chagas Disease (Megadisease)

Dysfunction of the GI tract is the second most common consequence of chronic T. cruzi
infection.89,90 As in the case of chagasic cardiopathy, GI Chagas disease usually
occurs years or even decades after infection with T. cruzi is acquired. Dysfunction
related to megaesophagus (Fig. 99.7) is the most typical clinical manifestation, but
symptoms due to megacolon are also frequent. The process underlying megadisease is a
loss of neurons in the gut.91 Quantitative assessments of this degenerative process have
shown that in severely affected patients as many as 85% of the neurons in the esophagus
and 50% of those in the colon may be lost. The factors that determine the rate and
pattern of the neuronal destruction are not known.
Pathologic examination of esophageal specimens obtained surgically or at autopsy
from patients with megaesophagus have shown dilatation and varying degrees of
thickening of the muscular wall. As in the case of cardiac tissue, microscopic

examination shows mononuclear cell infiltration and fibrosis, but finding parasites is
unusual. The most common symptom associated with chagasic megaesophagus is
dysphagia. Many patients experiencing this sense the accumulation of swallowed food
in the esophagus and take in water or more food, or even eat in a standing position, to
facilitate its passage into the stomach. Pain, typically starting in the lower substernal
area and spreading upward, is also a frequent symptom in patients with megaesophagus.
In patients with severe degrees of megaesophagus, regurgitation can become a problem,
and if the underlying problem is not treated, it can lead to intermittent aspiration with
associated chronic cough, bronchitis, and pneumonia.
As in the case of chagasic megaesophagus, colonic disease is manifested by dilatation
and typically the sigmoid colon is the most affected segment. As the disease progresses,
the colon can become markedly enlarged in both length and diameter, and the
thickening of the wall can become less pronounced. The pathologic changes evident on
microscopic examination of affected colonic tissue are similar to those found in the
esophagus. The cardinal symptom associated with Chagas disease of the colon is
constipation. Pain is also a common symptom, resulting from accumulation of feces and
flatus, as well as ineffective and recurrent colonic contractions.
Other GI and urinary viscera can be affected in persons with chronic Chagas disease,
but this is much less common.92 The most frequent occurrence is hypertrophy of the
parotid glands, which is present in as many as 25% of patients with chagasic
megaesophagus. The stomach may also be affected, and hypoperistalsis, hypotonia,
decreased acid secretion, and delayed emptying of the stomach have been documented
in patients with megaesophagus, but dilatation of the stomach is not found frequently.93
The pathogenesis of the cardiac and GI lesions of chronic Chagas disease has been
debated for decades. Recently, convincing evidence has accumulated supporting the
concept that the low-level presence of parasites in chronically affected cardiac tissue,
detectable by molecular methods, stimulates a chronic inflammatory response that over
time leads to the pathologic changes observed microscopically.
OTHER CLINICAL MANIFESTATIONS
Among some immunosuppressed hosts such as HIV-infected individuals and transplant
recipients, reactivation of infection and de novo infection (including transmission with
transplanted organs among transplant patients) have been reported.1,12 With
reactivation in HIV-positive patients, myocarditis has been reported in up to 45% of
cases.12 Reactivation of CD among heart transplant patients has been estimated to
occur in approximately 30% of cases. However, not all these cases are accompanied by
florid symptoms or diagnosed by endomyocardial biopsy and therefore, the true
incidence of myocarditis with reactivation is difficult to estimate. Acute T. cruzi
infection can also result as a consequence of donor-related transmission, which has been
reported after kidney, heart, liver and multi-organ transplants. Involvement in this
setting can range from asymptomatic parasitaemia that easily responds to treatment
without further complications to severe, fulminant disease despite therapy (including
death directly attributable to Chagasic myocarditis). Approximately 1 in 20 T. cruzi
infections in pregnant women is passed vertically to the unborn fetus.1 In congenitally
infected infants, the most common symptoms, which may be apparent at birth or
develop within weeks after delivery, are hypotonicity, fever, hepatosplenomegaly and
anemia. Other findings include prematurity and low birth weight. In utero infections are

also associated with abortion and placentitis. Serious manifestations, including

myocarditis,
meningoencephalitis and pneumonitis, are uncommon, but carry a high risk of death.1,5
Finally, reactivation of latent CD may present with dermatological manifestations
including indurated erythematous plaques with necrosis, erythematous papules and
nodules, panniculitis or skin ulcers.13 Some of these lesions may resemble erythema
migrans due to Lyme disease borreliosis.

Diagnosis
Diagnosis of acute and early congenital T. cruzi infection requires demonstration of the
parasite in blood by microscopy, PCR or hemoculture. Diagnosis of chronic infection
relies on serologic tests (e.g. ELISA) to detect IgG antibodies to T. cruzi
DIAGNOSIS
Appropriate diagnostic testing for T. cruzi infection varies depending on the phase of the
disease and the status of the patient
DIAGNOSIS OF ACUTE TRYPANOSOMA CRUZI INFECTION
Because the parasitemia level is high during the acute phase, motile trypomastigotes can
be detected by microscopy of fresh preparations of anti-coagulated blood or buffy coat
[3]. Parasites may also be visualized by microscopy of blood smears stained by Giemsa
or other standard stains. Even without treatment, the parasitemia level decreases within
90 days of infection and is undetectable by microscopy in the chronic phase. PCR is a
sensitive diagnostic tool in the acute phase of Chagas disease and to monitor for acute
T. cruzi infection in the recipient of an infected organ, or after accidental exposure .
DIAGNOSIS OF CONGENITAL TRYPANOSOMA CRUZI INFECTION
In the first months of life, congenital Chagas disease is an acute T. cruzi infection and
similar diagnostic methods are employed.
Concentration methods give better sensitivity than direct examination of whole blood.
The most widely used technique in Latin American health facilities is the
microhematocrit method. In this technique, cord or neonatal blood is collected and
sealed in 46 heparinized microhematocrit tubes, centrifuged and the buffy coat layer

examined by microscopy. Repeated sampling on several occasions during the first

months of life increases sensitivity, but may not be acceptable to the parents of a
neonate. Hemoculture can increase sensitivity, but the technique is not widely available,
and results are not available for
3060 days. Molecular techniques have higher sensitivity and detect congenital
infections earlier in life compared with the microhematocrit method [29]. Transient
detection of parasite DNA has occasionally
been reported in specimens from infants who subsequently are found to be uninfected
[4]. For this reason, positive PCR results on two samples drawn on separate occasions
are sometimes required for confirmation of congenital infection. PCR is increasingly
used for the early diagnosis of congenital Chagas disease in Latin America and is the
method of choice in industrialized countries. For infants not diagnosed at birth,
conventional IgG serology (as outlined below for chronic T. cruzi infection) is
recommended after nine months of age, when transferred maternal antibody has
disappeared and the congenital infection has passed into the chronic phase.
DIAGNOSIS OF CHRONIC TRYPANOSOMA CRUZI INFECTION
Diagnosis of chronic infection relies on tests to detect IgG antibodies to T. cruzi, most
commonly the ELISA and immunofluorescent antibody assay (IFA). No single serologic
assay has sufficient sensitivity and specificity to be relied on alone; two tests based on
different antigens (e.g. whole parasite lysate and recombinant antigens) and/ or
techniques (e.g. ELISA, IFA, immunoblot) are used in parallel to increase the accuracy
of the diagnosis [3]. Published data suggest that the sensitivity of serologic assays varies
by geographical location, possibly because of T. cruzi strain differences and resulting
antibody responses [30, 31]. Inevitably, a proportion of individuals tested by two assays
will have discordant serologic results and need further testing to resolve their infection
status. The status of some individuals remains difficult to resolve, even after a third test,
because there is no true gold standard assay for chronic T. cruzi infection [32]. Assays
such as the radioimmune precipitation assay (RIPA) and trypomastigote excretedsecreted antigen immunoblot (TESA-blot) are promoted as reference tests but even
these do not have perfect sensitivity and specificity, and may not be capable of resolving
the diagnosis.
UTILITY OF PCR FOR DIAGNOSIS OR MONITORING
Molecular techniques currently provide the most sensitive tools to diagnose acute phase
and early congenital Chagas disease and to monitor for acute T. cruzi infection in the
recipient of an infected organ or after accidental exposure (Table 98-3). PCR assays
usually show positive results days to weeks before circulating trypomastigotes are
visible by microscopy of peripheral blood [29]. In chronic T. cruzi infection, PCR is
used as a research tool, but is not generally a useful diagnostic test. Although PCR
results will be positive for a proportion of patients, the sensitivity is highly variable
depending on characteristics of the population tested, as well as the PCR primers and
methods used. Quantitative PCR assays (e.g. real-time PCR) are useful for monitoring
for reactivation in immunosuppressed patients with chronic T. cruzi infection, such as an
organ recipient or HIV-coinfected patient. In these patients, a positive result on
conventional PCR does not prove reactivation, but quantitative PCR assays showing
rising parasite numbers over time provide the earliest and most sensitive indicator of
reactivation [33]. The Centers for Disease Control (CDC) currently performs several

conventional and real-time PCR assays with primers targeting kinetoplast and nuclear
DNA.
PATIENT EVALUATION
The initial evaluation of a patient diagnosed with T. cruzi infection should begin with
the complete medical history and physical examination.
Details on family history, potential exposure to the vector and history of blood
transfusion in endemic areas should be recorded. A detailed review of systems should
focus on cardiovascular and gastrointestinal symptoms. Screening should be offered to
other family members, including children of seropositive mothers, and the patient
should be advised regarding possible transmission routes (such as blood and organ
donation). An HIV test and/or evaluation for other causes of immunosuppression should
be considered, as management of Chagas disease in these patients merits special
attention.
Every patient should have a resting 12-lead ECG with a 30-second rhythm strip; other
tests should be ordered if warranted by signs and symptoms elicited during the history
and examination. In the strict sense, the indeterminate form is defined by positive antiT. cruzi serology in an asymptomatic person with a normal physical examination, a
normal 12-lead ECG and normal radiologic examination of the chest, esophagus and
colon. However, patients with a normal ECG and no cardiovascular and gastrointestinal
symptoms have a favorable prognosis and yearly follow-up may be sufficient without
having to perform any additional tests.
Patients with cardiovascular symptoms and/or ECG abnormalities suggestive of Chagas
cardiac disease (Tables 98-1 and 98-4) should undergo further evaluation, including
two-dimensional (2-D) ECG, exercise testing and 24-hour ambulatory ECG monitoring.
The need for additional cardiac studies should be assessed on an individual basis. A
barium swallow or enema should be performed in patients with upper or lower
gastrointestinal symptoms respectively. Esophageal manometry may be of use for
patients with suggestive symptoms in whom the barium swallow is inconclusive.
Patients with megaesophagus may be at increased risk for esophageal cancer and an
upper gastrointestinal endoscopy may be indicated, especially in patients with new, or
progressive, symptoms. An increased risk of colorectal cancer has not been found in
patients with megacolon.
Additional procedures may have a role in patient evaluation in the future. Segmental
cardiac wall motion abnormalities detected by 2-D ECG and areas of myocardial
fibrosis demonstrated by delayedenhancement magnetic resonance imaging (MRI) have
been found in patients with normal ECGs; research studies suggest that minor
abnormalities of ventricular contractility may be predictive of future deterioration in
function. Diastolic dysfunction and elevated blood levels of brain natriuretic peptide
(BNP) appear to correlate with prognosis in patients with cardiomyopathy owing to a
variety of etiologies, including Chagas disease [41]. 2-D echo and 24-hour ambulatory
ECG monitoring results are used to assess risk in some prognostic scores for Chagas
disease
Management and Treatment

Indication for anti-parasitic therapy depends on the phase of the disease and the clinical
status and age of the patient. There are currently only two available drugs: benznidazole
and nifurtimox
ANTITRYPANOSOMAL THERAPY
SPECIFIC ANTI-PARASITIC DRUGS
Nifurtimox, a nitrofuran compound, acts through production of nitrogenated free
radicals (e.g. superoxide, hydrogen peroxide) for which parasites have much lower
detoxification capacity than vertebrates [42]. Benznidazole, a nitroimidazole derivative,
is thought to act through the mechanism of reductive stress by covalent binding of
nitroreduction intermediates to parasite molecules [42]. Both drugs are rapidly absorbed
from the gastrointestinal tract (plasma levels peak at 1 hour after a single oral dose); the
average biological half-life is 12 hours. Nifurtimox is rapidly and extensively
metabolized in the liver using cytochrome P-450 and P-450 reductase. Interindividual
variability suggests that metabolism of nifurtimox may be under genetic control.
Elimination of both drugs is predominantly renal. Hepatic or renal function impairment
increase blood concentrations of the medication, increasing the risk of side effects.
Concurrent alcohol intake may enhance the occurrence of side effects. In tissue other
than the liver (testicles, ovaries, adrenal glands, colon, esophagus), the reducing activity
is variable. Both drugs are mutagenic and have been reported to increase the risk of
lymphomas in experimental animals but no increase in incidence of human lymphoma
has been reported among treated populations. The drugs are known to be teratogenic in
experimental animals and their use in pregnant women is contraindicated. Risk for
significant infant exposure to drugs through breast milk seems small and below the level
of exposure of infants with Chagas disease receiving nifurtimox treatment. This
potential degree of exposure may not justify discontinuation of breastfeeding.
Recent trials have all used benznidazole and this drug is usually better tolerated than
nifurtimox; for these reasons benznidazole is viewed by most experts as the first line
treatment. Nevertheless, individual tolerance variesif one drug must be discontinued,
the other can be used as an alternative. Nifurtimox is indicated for a patient in the acute
phase with documented benznidazole treatment failure.
Indications
Treatment has been recommended for all cases of acute and congenital infection,
reactivated infection, and in early chronic CD (particularly children/adolescents <18
years), based on evidence of shortening of the diseases clinical course, cure of infection
or reduction of parasites. For infected adults without advanced cardiomyopathy up to
age 50 years, aetiological treatment should generally also be offered.2,5,18 The
rationale for these recommendations stems from evidence of slowing of the progression
of cardiomyopathy. In a recent observational trial, 566 chronically infected adults (30
50 years of age) without heart failure were assigned, in alternating sequence, to
benznidazole or no treatment.16 After a median follow-up of 9.8 years, fewer treated
patients had progression of disease or developed
ECG abnormalities. Negative seroconversion was more frequent in treated patients.
Another recently published controlled study including 111 patients (1746 years of age)
with chronic CD and a normal electrocardiogram, showed similar favourable results
with benznidazole over a mean follow-up of

21 years.16 For those over the age of 50 years, aetiological treatment is considered
optional, because of the lack of any available data. A multi-centre, randomized, placebocontrolled trial of benznidazole enrolling 3000 patients with mild to moderate CHD and
1875 years of age is currently underway, and should help clarify treatment decisions in
this population. In contrast, aetiological treatment is contraindicated during
pregnancy and in patients with severe renal or hepatic insufficiency, and it should
generally not be offered to patients with advanced Chagasic cardiomyopathy or
megaoesophagus with significant impairment of swallowing.15,16 A more controversial
issue is prophylactic treatment for transplant patients: some authors have recommended
it for patients with Chagasic cardiomyopathy who undergo cardiac transplantation to
prevent disease reactivation, while others recommend it for all infected donors pretransplant and for their respective recipients posttransplant. For chronic CD, cure is
documented when previously positive serologic tests turn negative, usually years or
decades after treatment.
Only two drugs, benznidazole and nifurtimox, are recommended for treatment of CD.
Of the two, benznidazole (a nitroimidazole derivative) has been more extensively
investigated in clinical studies and is better tolerated overall.15,16 Adverse reactions
such as generalized or, sometimes, localized allergic dermatitis occurs in approximately
2030% of patients and consists of pruritic and non-bullous polymorphous
erythematous rashes, often followed by desquamation. Severe exfoliative dermatitis can
occur and should lead to prompt discontinuation of treatment. Another adverse effect,
which occurs in approximately 510% of patients, most commonly late in the treatment
course, is a dose-dependent peripheral sensitive neuropathy, affecting mainly the distal
parts of the lower limbs; it also should prompt cessation of treatment. Rare serious
adverse events include leukopaenia with granulocytopaenia or agranulocytosis
(sometimes followed by fever and tonsillitis), and thrombocytopenic purpura.
Additional reported side effects include nausea, vomiting, anorexia, weight loss,
insomnia, loss of taste and onycholysis. Nifurtimox, a nitrofuran compound, can be
associated with gastrointestinal side effects in 3070% of patients as well as central and
peripheral nervous system toxicity. Both compounds are better tolerated by children
allowing for increased dosage regimens. Individuals younger than 12 years of age
should be treated with benznidazole orally at a dose of 10 mg/kg per day in 2 divided
doses for 60 days; nifurtimox is an alternative in those younger than 10 years, at a dose
of 1520 mg/kg per day orally in 34 divided doses for 90 days or at a dose of 12.515
mg/kg per day orally in 34 divided doses for 90 days among those 1116 years of age.
Individuals 12 years of age and older should be treated with benznidazole at a dose of
57 mg/kg per day in 2 divided doses for 60 days. Nifurtimox is recommended at a dose
of 810 mg/kg per day in 34 divided doses for 90 days. Both drugs are contraindicated
in
pregnancy.2,18
MEDICAL TREATMENT
Treatment of heart failure in patients with CHD should follow specific treatment
targeted at each stage, according to current guidelines for heart failure of other
aetiologies.9 An important exception is the use of beta-blockers, which should be used
with caution in CHD due to a higher incidence of atrioventricular conduction defects
and associated bradyarrhythmias. Cardiac transplantation has been performed with good

results for patients with advanced CHD but may not be available or accessible in all
countries where this disease is endemic. Although not tested in randomized controlled
clinical trials, amiodarone has been associated with a survival advantage in casecontrol
studies among patients with ventricular tachycardia and has therefore been proposed for
management of patients with sustained and non-sustained ventricular tachycardia.1
However, treatment with amiodarone has been associated with pulmonary, cardiac,
thyroid, liver, ocular, skin, central nervous system and genitourinary toxicities so that
treatment needs to be individualized. Pacemaker implantation is the recommended
treatment for severe bradyarrhythmias and advanced conduction abnormalities. The role
of cardioverter-defibrillator implantation and cardiac resynchronization, however, are
not well established in CHD. Finally, anticoagulation has been advocated for patients
with atrial fibrillation, previous thromboembolic phenomena or an LV aneurysm with
thrombus
There is no evidence that antiparasitic treatment affects the progression of
gastrointestinal CD.11,18 Decisions to treat a patient with gastrointestinal dysfunction
should be guided on evidence of cardiac disease, to prevent its progression.
Antiparasitic treatment may be cumbersome to administer to patients if they have a
digestive megasyndrome such as in the case of megaoesophagus due to dysphagia or
decreased intestinal absorption. Surgical management of megasyndromes is crucial for
improving quality of life, and in the case of megaoesophagus to enable the ability to
provide oral antiparasitic treatment and other medications if indicated to decrease
progression of heart disease.18
Prevention
Most T. cruzi infections can be prevented by decreasing vectorial transmission,
improving blood product screening and detecting and treating transplacental
transmission. Multinational programmes involving the endemic countries have achieved
enormous success in decreasing both the prevalence and incidence of CD by following
several operational stages. The tools for interrupting transmission are based on
implementation of vector control activities such as insecticide spraying, housing
improvements and education as well as strengthening implementation of policy for use
and screening of blood products for transfusion.3 All initially reactive donations are retested in duplicate using the same screening test; donations testing repeatedly reactive
have confirmatory testing by the radioimmunoprecipitation assay (RIPA).6 Continued
surveillance is also important to consolidate and maintain the success
achieved. For individuals travelling to endemic areas, compliance with general food and
water precautions is advised to prevent the extremely rare occurrence of food-borne CD.
More importantly,
travellers should avoid sleeping in poorly constructed houses or consider sleeping in
insecticide-impregnated bed nets. However, the protective efficacy of insecticide-treated
materials in reducing CD transmission and eliminating the vector population has yet to
be demonstrated. Finally, no vaccine for CD is currently available. However, the Slim
Initiative for Antipoverty Vaccine Development, a privatepublic partnership has
recently gathered a group of experts and key players in Latin America to develop
preventive and therapeutic vaccines against T. cruzi infection.