Chagas’ Disease

Patricia Cristofaro, M.D.

Basic Information

Definition

Chagas’ disease is an infection caused by the protozoan parasite Trypanosoma cruzi. This is a vector-borne disease transmitted by reduviid bugs from multiple wild and domesticated animal reservoirs. The disease is characterized by an acute nonspecific febrile illness that may be followed, after a variable latency period, by chronic cardiac, GI, and neurologic sequelae. Globally, Chagas’ disease affects 8 to 11 million persons; vector-borne disease (as opposed to congenital infection) occurs only in the Americas.

Synonyms

American trypanosomiasis

Epidemiology & Demographics

Incidence (In U.S.)

•

Seven cases of autochthonous transmission in California, Texas, Tennessee, and Louisiana.
•

In the past 2 decades, six cases of laboratory-acquired infection, three cases of transfusion-associated transmission, and nine cases of imported disease reported to the CDC (none of the imported cases involved returning tourists).
•

Infection has been transmitted by organ transplantation.
•

Infection has been transmitted congenitally from mother to fetus over more than one generation.
•

Stercorarian transmission (i.e., transmission through the feces of an infected vector) is relatively inefficient; the incidence of T. cruzi infection is generally estimated to be less than 1% per year. The highest incidence is 4% per year in the hyperendemic Bolivian Chaco (Bern C: NJEM 373:456-466, 2015).

Prevalence (In U.S.)

Based on regional seroprevalence studies in Hispanic blood donors, it is estimated that between 300,000 and 300,500 persons infected with T. cruzi are currently residing in the U.S.

In the Americas, 8 to 10 million people are believed to be infected.

Predominant Sex

Male = female

Predominant Age

•

In highly endemic areas, mean age of acute infection: approximately 4 yr.
•

Variable age distribution for both types of chronic disease, depending on geography.
•

Mean age of onset of chronic disease: usually between 35 and 45 yr.

Peak Incidence

Unknown

Genetics

Congenital infection: Congenital transmission has been documented with attendant high fetal mortality and morbidity in surviving infants.

Neonatal infection: In rural areas, within substandard housing, transmission is likely to occur.

Physical Findings & Clinical Presentation

•
Inflammatory lesion that develops about 1 wk after contamination of a break in the skin with infected insect feces (chagoma)
1. 1.
  
  Area of induration and erythema
2. 2.
  
  Usually accompanied by local lymphadenopathy
•

Presence of Romaña’s sign, which consists of unilateral painless palpebral and periocular edema, when conjunctiva is portal of entry
•

Constitutional symptoms of fever, fatigue, and anorexia, along with edema of the face and lower extremities, generalized lymphadenopathy, and mild hepatosplenomegaly after the appearance of local signs of disease
•

Myocarditis in a small portion of patients, sometimes with resultant CHF
•

Uncommonly, CNS disease, such as meningoencephalitis, which carries a poor prognosis
•

Symptoms and signs of disease persisting for weeks to months followed by spontaneous resolution of the acute illness; patient then in the indeterminate phase of the disease (asymptomatic with attendant subpatent parasitemia and reactive antibodies to T. cruzi antigens)
•
Chronic disease may become manifest years to decades after the initial infection:
1. 1.
  Most common organ involved: heart followed by GI tract and to a much lesser extent the CNS
  1. a.
    
    Cardiac involvement takes the form of arrhythmias or cardiomyopathy but rarely both.
  2. b.
    
    Cardiomyopathy is bilateral but predominantly affects the right ventricle and is often accompanied by apical aneurysms and mural thrombi.
  3. c.
    
    Arrhythmias are a consequence of involvement of the bundle of His and have been implicated as the leading cause of sudden death in adults in highly endemic areas.
  4. d.
    
    Right-sided heart failure, thromboembolism, and rhythm disturbances associated with symptoms of dizziness and syncope are characteristic.
2. 2.
  
  Patients with megaesophagus: dysphagia, odynophagia, chronic cough, and regurgitation, frequently resulting in aspiration pneumonitis
3. 3.
  
  Megacolon: abdominal pain and chronic constipation, which, when severe, may lead to obstruction and perforation
4. 4.
  
  CNS symptoms: most often secondary to embolization from the heart
5. 5.
  
  Varying degrees of peripheral neuropathy

Etiology

•
T. cruzi
1. 1.
  
  Found only in the Americas, ranging from the southern U.S. to southern Argentina (Fig. E1)
2. 2.
  
  Transmitted to humans by various species of bloodsucking reduviid (“kissing”) insects, primarily those of the genera Triatoma, Panstrongylus, and Rhodnius
3. 3.
  
  Usually found in burrows and trees where infected insects transmit the parasite to natural reservoirs (e.g., opossums and armadillos)
4. 4.
  
  Intrusion into enzootic areas for farmland, allowing insects to take up residence in rural dwellings, thus including humans and domestic animals in the cycle of transmission
5. 5.
  
  Initial infection of insects by ingesting blood from animals or humans that have circulating flagellated trypanosomes (trypomastigotes)
6. 6.
  
  Multiplication in the insect midgut as epimastigotes, then differentiation into metacyclic trypomastigotes discharged with the feces during subsequent blood meals (Fig. E2)
7. 7.
  
  Transmission to the second mammalian host through contamination of mucous membranes, conjunctivae, or wounds with insect feces containing infectious forms
•
In the vertebrate host
1. 1.
  
  Movement of parasites into various cell types, intracellular transformation into amastigotes, and thereafter differentiation into trypomastigotes
2. 2.
  
  Following rupture of the cell membrane, parasitic invasion of local tissues or hematogenous spread to distant sites, maintaining a parasitemia infective for vectors
•

In addition to insect vectors, T. cruzi is transmitted through blood transfusions, transplacentally, and, occasionally, secondary to laboratory accidents or ingestion (including breast milk).
•

In 2007, voluntary screening was initiated in the U.S. blood supply; it is estimated to cover 75% to 90% of the blood supply.
•

Platelet transfusions appear to be more infective than packed red blood cells.

FIG.E1

Distribution of Chagas’ disease. Human infection is endemic in parts of Central and South America from the Andes to the Atlantic coast and as far south as the latitude of the River Plate (Río de la Plata, shown in *green*). Two major intergovernmental programs were started in 1991 to eliminate domestic vectors by a combination of spraying residual insecticides in houses, the use of insecticidal paints, and the deployment of fumigant canisters. The countries covered in the two initiatives, the second of which started in 1997, are shown. The latter program instituted universal blood screening to avoid transmission from infected blood donors. In less than a decade, remarkable progress has been made. Transmission by the major vector *Triatoma infestans* was eliminated in Uruguay by 1997 and in Chile by 1999. Major reductions in transmission have also been reported from other endemic countries but, to date, not complete control.

From Hoffman R: *Hematology, basic principles and practice*, ed 6, Philadelphia, 2013, Elsevier.

FIG.E2

Lifecycle of *Trypanosoma cruzi.*

From Souhami RL, Mozham J: *Textbook of*

Diagnosis

Differential Diagnosis

Acute disease

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Early African trypanosomiasis
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New World cutaneous and mucocutaneous leishmaniasis

Chronic disease

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Idiopathic cardiomyopathy
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Idiopathic achalasia
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Congenital or acquired megacolon

Workup

Principal considerations in diagnosis:

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A history of residence where transmission is known to occur
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Recent receipt of a blood product while in an endemic area
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Occupational exposure in a laboratory

Laboratory Tests

For acute diagnosis:

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Demonstration of T. cruzi in wet preparations of blood (Fig. E3), buffy coat, or Giemsa-stained smears
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Xenodiagnosis, a technique involving laboratory-reared insect vectors fed on subjects with suspected infection thereafter examined for parasites, and culture of body fluids in liquid media to establish diagnosis
1. 1.
  
  Hampered by the length of time required for completion
2. 2.
  
  Of limited use in clinical decision making with regard to drug therapy
3. 3.
  
  Although xenodiagnosis and broth culture are considered to be more sensitive than microscopic examination of body fluids, sensitivities may not exceed 50%
•

Recent advances in serologic testing include immunoblot assay, in situ indirect fluorescent antibody, PCR-based techniques, and an immunochromatographic assay (Chagas Stat Pak).
•

Response to treatment in acute, reactivated, or congenital infection can be assessed by quantitative PCR.

For chronic T. cruzi infection:

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Traditional serologic tests, including complement fixation (CF), indirect immunofluorescence (IIF), indirect hemagglutination, and enzyme-linked immunosorbent assay (ELISA).
•

Serologic tests have variable sensitivity and specificity and frequent false-positive results.
•

Saliva ELISA may be useful as a screening diagnostic test in epidemiologic studies of chronic trypanosomiasis infection in endemic areas.
•

Confirmation requires at least two different tests, and if discordant, three tests.

FIG.E3

*T. cruzi* in human blood film.

The causative agent occurs in blood films characteristically

Treatment

Nonpharmacologic Therapy

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Chronic chagasic heart disease: mainly supportive
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Megaesophagus: symptoms usually amenable to dietary measures or pneumonic dilation of the esophagogastric junction
•

Chagasic megacolon: in its early stages, responsive to a high-fiber diet, laxatives, and enemas

Acute General Rx

It is now recommended that all patients—acute, indeterminate, and chronic—be treated with antiparasitic therapy. Treatment for individuals older than 50 years requires consideration of risk versus benefit because the treatment appears to be more toxic at this age.

A single course of benznidazole or nifurtimox is thought to offer an approximately 50% cure rate. Consultations and requests for drugs can be made to: Parasitic Diseases Public Inquiries Line (770-448-7775), parasites.cdc.gov, www.cdc.gov/parasites/chagas, CDC Drug Service (404-639-3670).

Benznidazole, a nitroimidazole derivative:

1.

Has demonstrated similar efficacy as nifurtimox in limited trials; is usually better tolerated and is viewed by most experts as first-line treatment
2.

Recommended oral dosage: 5 to 7 mg/kg/day for 30 to 90 days

Nifurtimox:

1.

Recommended oral dosage for adults: 8 to 10 mg/kg/day given in 3 to 4 divided daily doses and continued for 90 to 120 days
2.

Parasitologic cure in approximately 50% of those treated; should be begun as early as possible

Neither drug can be used during pregnancy.

Do not use in cases of severe renal or hepatic dysfunction.

Triazoles offer a new class of therapy but are so far disappointing. Case reports have had success with posaconazole. Trials have shown that posaconazole has antitrypanosomal activity in patients with chronic Chagas’ disease. However, significantly more patients in the posaconazole groups than in the benznidazole group had treatment failure during follow-up.

Chronic Rx

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Yearly cardiac evaluations and 12 lead ECG should be performed in all persons with T. cruzi infection regardless of treatment.
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In patients with indeterminate phase or chronic disease: some evidence of benefit in a recent uncontrolled trial with benznidazole in patients with chagasic cardiomyopathy
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In patients exhibiting bradyarrhythmias: pacemakers
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In individuals with congestive heart failure:
1. 1.
  
  Treat with standard modalities for dilated, right-sided cardiomyopathic disease.
2. 2.
  
  Cardiac transplant is an option for end-stage cardiomyopathy; moreover, reactivation rate found to be low and amenable to therapy without subsequent infection of the allograft.
3. 3.
  
  Myotomy or esophageal resection is reserved for patients with advanced disease.
•

In advanced chagasic megacolon associated with chronic fecal impaction, perforation, or, less commonly, volvulus: surgical resection

Disposition

Based on a few prospective studies, although most patients infected with T. cruzi will not develop symptomatic Chagas’ disease, 20% to 30% likely will.

Referral

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For consultation with an infectious disease specialist or communication with the CDC when the disease is acutely suspected
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To a cardiologist for pacemaker implantation for patients with bradyarrhythmias
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To a surgeon for symptomatic disease with chagasic megaesophagus or megacolon

Pearls & Considerations

Comments

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All children of an infected mother should be screened for Chagas’ disease; household members should also be screened.
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In recipients of solid organ or bone marrow transplants, patients with AIDS, or those receiving chemotherapy, there may be reactivation of indeterminate phase disease.
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Mortality predictors associated with chagasic cardiomyopathy include CHF, QT-interval dispersion, left ventricular end-systolic dimension, the presence of pathologic Q waves, frequent PVCs, and isolated LAFB on ECG.
•

Chagasic esophageal disease has an increased incidence of esophageal malignancy.
•

The use of pyrethroid-impregnated curtains may represent an option for the reduction or elimination of Chagas’ disease transmission in certain endemic areas.
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Randomized trials of benznidazole for chronic Chagas’ cardiomyopathy have shown significant serum parasite detection but no significant reduction in clinical deterioration through 5 years of follow-up (Morillo CA, et al: NEJM 373:1295-1306, 2015).

Ferri – Chagas’ Disease