eMedicine Specialties > Infectious Diseases > Parasitic Infections

Chagas Disease (American Trypanosomiasis)

Louis V Kirchhoff, MD, MPH, Professor, Departments of Internal Medicine (Infectious Diseases) and Epidemiology, Carver College of Medicine and College of Public Health, University of Iowa; Staff Physician, Medical Service, Iowa City Veterans Affairs Medical Center

Updated: Nov 24, 2008

Introduction

Background

Chagas disease, also known as American trypanosomiasis, is caused by infection with the protozoan parasite Trypanosoma cruzi. The organism T cruzi and infection in humans were first described in 1909 by the Brazilian physician Carlos R. J. Chagas.¹ T cruzi is found mostly in blood‑sucking triatomine insects (kissing bugs) and small mammals in a sylvatic cycle that is enzootic from the southern and southwestern United States to central Argentina and Chile. T cruzi infection in humans occurs in a spotty distribution throughout the range of the sylvatic cycle.

New cases of vector-borne T cruzi infection usually occur in persons who live in primitive houses in an area where the sylvatic cycle is active. The living quarters are invaded by infected triatomines, which become domiciliary. Infected insects take blood meals from humans and their domestic animals and deposit parasite‑laden feces. The parasites are then transmitted via contact with breaks in the skin, mucosal surfaces, or the conjunctivas. Transmission can also occur congenitally or via blood transfusion or organ transplantation.

T cruzi infection is life-long. A minority of persons with long-standing T cruzi infection develop the serious cardiac and gastrointestinal problems that characterize chronic symptomatic Chagas disease.

The parasite

T cruzi is a member of the family Trypanosomatidae in the order Kinetoplastida and belongs to a special section called Stercoraria. The infective forms of T cruzi are contained in the feces of the insect vectors and gain entry into its mammalian hosts through contamination. This mechanism of transmission contrasts with that of the two subspecies of African trypanosomes that cause human disease, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which are transmitted via the saliva of their vectors, and with the mechanism by which the nonpathogenic trypanosome found in the Americas, Trypanosoma rangeli, is transmitted to its mammalian hosts.

Numerous biological, biochemical, and molecular studies have shown that the population of T cruzi is heterogeneous.^2,3,4 Although T cruzi is a diploid organism in which some genetic exchange may occur in insect vectors,⁵ its genetic and phenotypic diversity mainly results from the clonal multiplication of the epimastigote and amastigote forms. The current consensus is that T cruzi can be divided into two principal groups: T cruzi I and T cruzi II. The latter is more frequently involved in the domiciliary cycle, whereas T cruzi I is more often associated with the sylvatic cycle.⁶

Vectors of T cruzi

Triatomines, which transmit T cruzi, belong to the family Reduviidae in the order Hemiptera. Reduviidae has 22 subfamilies, including the Triatominae (Image: Triatoma infestans, a major vector of T cruzi).⁷ ] Although the vectors of T cruzi are occasionally referred to as reduviids, this term is not appropriate since the vast majority of the species in the family Reduviidae are phytophagous or insectivorous and do not transmit the parasite.

All triatomine species are able to transmit T cruzi to humans, but only a handful become domiciliary to any great extent and are important as T cruzi vectors. Many more triatomine species are involved in the widespread sylvatic cycles. Triatomines have 5 nymphal stages (instars), all of which can harbor and transmit T cruzi (Image: Rhodnius prolixus, various stages of this important vector of T cruzi).

The three vector species most important in the transmission of T cruzi to humans include Triatoma infestans, Rhodnius prolixus, and Triatoma dimidiata. Historically, T infestans has been by far the most important, as it has been the primary vector in the sub-Amazonian endemic regions. Since the early 1990s, many Chagas disease control programs have focused on eliminating domiciliary T infestans. These efforts have been successful in Uruguay, Chile, and, most recently, Brazil, all of which have been declared transmission‑free by the Pan American Health Organization.⁸

Major progress has also been made in Argentina and Bolivia. R prolixus is typically found in Central America and in the Andean nations. The range of T dimidiata is similar but also extends far into Mexico. Other domiciliary species occupy more restricted areas and play less-important roles in the transmission of T cruzi to humans. The sylvatic species can also colonize human dwellings and thus present a potential risk for transmission.

Mammalian hosts of T cruzi

T cruzi infection has been found in more than 100 mammalian species throughout the range mentioned above, which includes the southern and southwestern United States. Mammals typically involved in sylvatic cycles of transmission include opossums, armadillos, raccoons, monkeys, wood rats, and coyotes, among many others.

Pets such as dogs and cats can become infected in enzootic regions, likely as they eat parasitemic prey or ingest infected insects.⁹ It is of interest that Carlos Chagas observed T cruzi in the blood of wild marmosets and a domestic cat before he discovered the parasite in the blood of his first infected patient, Berenice.¹ In some situations, dogs have been shown to be an important link in the maintenance of the domiciliary cycle and consequent transmission to humans.¹⁰

Livestock have occasionally been found to be infected with T cruzi, but the parasite is not known to affect the health of livestock. Birds, amphibians, and reptiles are naturally resistant to T cruzi infection; however, in some situations, birds may be important sources of blood meals for triatomines.

The modes of transmission of T cruzi to humans

Historically, most transmissions of T cruzi to humans have resulted from the contamination of vulnerable surfaces (eg, breaks in the skin, mucosae, and the conjunctivas) with the feces of infected vectors. However, as noted, vector‑borne transmission has been reduced markedly in many endemic countries.^8,11,12 Transfusion-related transmission was a major public health problem in endemic countries for decades, but, as accurate serologic assays for T cruzi infection were developed, mandatory screening of donated blood became widespread.

Currently, transfusion-related transmission of T cruzi has been all but eliminated in most endemic countries and substantially reduced in a remaining few.¹³ Not surprisingly, T cruzi can also be transmitted via transplantation of organs obtained from persons with chronic infection, and occasional reports of this in Latin America^14,15 and in the United States^16,17 have appeared.

The rate of transplacental transmission from mothers with chronic T cruzi infection to their newborns is 2‑10%. To date, no measures have been defined to reduce or eliminate this form of transmission.^18,19 In contrast to Toxoplasma gondii, vertical transmission of T cruzi is possible with successive pregnancies. Transmission of T cruzi via breast milk appears to be extremely rare.²⁰ Several instances of transmission of T cruzi to groups of people via ingestion of food or drink presumably contaminated with the feces of infected vectors have been reported.^21,22,23 Finally, the facility of producing infective forms of T cruzi in the laboratory has resulted in numerous accidental transmissions in this context.²⁴

Pathophysiology

An inflammatory lesion caused by T cruzi that may appear at the site of entry in patients with acute Chagas disease is called a chagoma.²⁵ Histologic changes may include interstitial edema, lymphocytic infiltration, and reactive hyperplasia of adjacent lymph nodes due to intracellular parasitism of muscle and other subcutaneous tissues. When parasitized host cells rupture, trypomastigotes are released and can often be detected by microscopic examination of anticoagulated blood. As the infection spreads systemically, muscles, including the myocardium, and various other tissues become parasitized.

Acute myocarditis, consisting of patchy areas of necrosis and infected cells, may develop.^26,27 The pseudocysts occasionally seen in sections of infected tissues are intracellular aggregates of amastigotes (Image: T cruzi amastigotes in the heart muscle of a baby who died of Chagas myocarditis in Texas). The patent parasitemias of the acute illness may be accompanied by lymphocytosis, and transaminase levels may be elevated. The cerebrospinal fluid may contain parasites.²⁸

The heart is the most commonly affected organ in persons with chronic Chagas disease (Image: Cardiomegaly and pacemaker wires seen in a chest radiograph of a Bolivian patient with Chagas disease). Autopsy may reveal marked bilateral ventricular enlargement, often involving the right side more than the left, in the heart of patients who die of chagasic heart failure. The ventricular walls are often thin, and mural thrombi and apical aneurysms may be present. In addition, diffuse interstitial fibrosis, widespread lymphocytic infiltration, and atrophy of myocardial cells may all be present.

T cruzi parasites are rarely found during microscopic examination of stained sections of myocardial tissue; however, in numerous studies, T cruzi ‑specific polymerase chain reaction (PCR) assays have demonstrated parasites in areas of focal inflammation.^29,30,31,32 Pathologic changes in the conduction systems of chronic chagasic hearts are also common and often correlate with dysrhythmias.³³ Chronic inflammatory lesions and dense fibrosis frequently involve the right branch and the left anterior branch of the bundle of His, but lesions may also be found in other segments of the conduction system.

Salient features on gross examination of the colon (Image: Megacolon in a Bolivian patient with Chagas disease) or esophagus (Image: Megaesophagus in a Brazilian patient with Chagas disease) in patients with chronic chagasic gastrointestinal disease (megadisease) include dilatation and muscular hypertrophy of the affected organs.^34,35 Focal inflammatory lesions with lymphocytic infiltration are visible on microscopy. The number of neurons in the myenteric plexus is often markedly reduced, and periganglion and intraganglion fibrosis with accompanying Schwann cell proliferation, along with lymphocytosis, are present. In most patients with megadisease, the functional effects of this parasympathetic denervation are limited to the esophagus or colon, but clinically manifest dysfunctions of the ureters, biliary tree, and other hollow viscera have been reported.

The pathogenesis of cardiac and gastrointestinal lesions of chronic Chagas disease has been a focus of debate for decades.^36,37,38 In recent years, convincing evidence has shown that low levels of parasites in chronically affected tissue, detectable with molecular methods, provokes a chronic inflammatory response that eventually leads to the pathologic changes observed microscopically and organ dysfunction.^31,39

Frequency

United States

Despite the presence of the sylvatic cycle of T cruzi transmission in the southern and southwestern United States, only 6 cases of autochthonous transmission of the parasite have been reported.^26,40 Although many cases of T cruzi infection probably go unnoticed or unreported, autochthonous acute Chagas disease is rare in the United States. This concept is supported by the extreme rarity of T cruzi infection among US blood donors who were not born in or who have not traveled extensively in endemic countries (Susan Stramer, PhD, personal communication). The rarity of vector‑borne transmission of T cruzi to humans in the United States is likely due to the overall sparsity of vectors and the overall higher housing standards, which help prevent the vectors from becoming domiciliary.

In contrast, the epidemiology of chronic T cruzi infection in the United States has changed markedly in the last few decades owing to the large number of people from endemic countries who have moved to the United States. According to one recent estimate, 13 million persons from endemic countries now live in the United States, 80,000-120,000 of whom have chronic T cruzi infection.⁴¹ Approximately two thirds of immigrants from endemic countries are from Mexico, where the overall prevalence of T cruzi infection is 0.5-1%.

Five cases of transfusion-associated transmission of T cruzi have been reported in the United States, all in immunocompromised patients.⁴² Authorities believe that a substantially larger number of such cases have occurred but have not been recognized because the newly infected transfusion recipients were immunocompetent and presented with relatively few signs and symptoms. Five recipients of organ transplants from 3 donors with T cruzi infection developed acute Chagas disease in the United States, one of whom died of the illness.^16,17

The number of blood donors with chronic T cruzi infection in the United States has been of great concern among US blood bank authorities since the first reported case of transfusion-related transmission in 1987. At a meeting of the Blood Products Advisory Committee of the Food and Drug Administration (FDA) in 2002, guidance was provided regarding the requirements for the development of tests for screening donated blood. In December 2006, the Ortho T cruzi ELISA Test System^43,44,45 was approved by the FDA for blood screening, and, the following month, screening was implemented by the American Red Cross and Blood Systems, which together process about 70% of the blood donated in the United States.⁴⁶ As of this writing, approximately 90% of units donated in the United States are screened for Chagas disease.

The radioimmune precipitation assay (RIPA) is performed by Quest Diagnostics for confirmatory testing of units that are found to be repeatedly reactive on Ortho assay.

The data accumulated so far indicate that about 1 in every 29,000 US blood donors is infected with T cruzi (ie, repeatedly reactive on the Ortho assay and positive on the RIPA), which is consistent with estimates by groups familiar with the epidemiology of T cruzi in the United States prior to the initiation of screening. However, this prevalence rate cannot be used to estimate the total number of persons infected with T cruzi in the United States because blood donors are not representative of the general population in a demographic sense. However, the screening data are shedding light on the frequency of autochthonous transmission. As noted above, RIPA positivity in persons who have no geographic risk for T cruzi infection is rare. In-depth perspectives on the frequency of autochthonous transmission of T cruzi in the United States will develop as millions of more donors are tested in the future.

International

T cruzi is found only in the Americas, except in isolated cases in which infected travelers have carried the parasites to other regions (eg, (the Far East, Australia, Europe).^{47,48,49,50,51} The Pan American Health Organization (PAHO) estimates that 7.7 million persons currently have T cruzi infection in the 21 endemic countries, which have a total population of 532 million.⁵² The PAHO also estimates that approximately 41,200 new vector‑borne cases of T cruzi infection arise per year and that 14,400 infants are born with congenital Chagas disease annually. According to PAHO estimates, the following are the countries most affected by Chagas disease: Bolivia (6.8% of reported cases); Argentina (4.1%); El Salvador (3.4%); Honduras (3.1%); Paraguay (2.5%); Guatemala (2%); Ecuador (1.7%); French Guyana, Guyana, and Surinam (1.2%); Venezuela (1.2%); Nicaragua (1.1%); Brazil (1%); and Mexico (1%).

In recent years, the epidemiology of T cruzi infection has improved markedly in many endemic countries, as blood bank and vector-control programs have been implemented. Because of the success of programs directed at domiciliary vector programs, prevalence rates in younger age groups have been decreasing in many areas.^8,53,54,55 All endemic countries have statutory or regulatory mandates for screening donated blood for T cruzi, and, with a few notable exceptions, effective universal screening has been implemented.¹³

A major international vector-control program in the "Southern Cone" countries of South America (Bolivia, Argentina, Paraguay, Brazil, Chile, Uruguay), orchestrated by the World Health Organization (WHO) and PAHO, has provided the framework for much of this progress. As noted above, Uruguay and Chile were certified as free of T cruzi transmission in 1997 and 1999, respectively, and Brazil was certified in 2006. Argentina is approaching certification, and major progress toward this goal has also been made in both Paraguay and Bolivia. Importantly, similar control programs have been set up in the Andean nations and in Central America. In Mexico, legislation mandating nationwide screening is under consideration, and this reflects a growing awareness of T cruzi infection as a public health problem in that country.^41,56 Currently, only about 13% of the blood donated in Mexico is screened for T cruzi.

In the author’s view, the enormous progress made in controlling Chagas disease in recent decades clearly indicates that the obstacles hindering the complete elimination of T cruzi transmission to humans are primarily economic and political. In this context, no additional major advances, such as a more detailed understanding of the pathogenesis of Chagas disease,⁵⁷ further genetic analyses,⁵⁸ new diagnostic techniques, or breakthroughs in vaccine development,⁵⁹ are necessary for its completion. Other investigators take an opposing view regarding the application of high-technology approaches to the problem of Chagas disease.⁶⁰

Mortality/Morbidity

Approximately 20,000 deaths attributable to Chagas disease occur annually, typically due to myocarditis²⁶ or, much less frequently, meningoencephalitis.⁶¹ In persons with chronic T cruzi infection, mortality is primarily due to the rhythm disturbances and congestive heart failure that result from the chronic inflammatory cardiomyopathy due to the persistence presence of parasites in the heart tissue.⁶² Embolization of intraventricular clots to the cerebrum and lungs can also contribute to mortality. Patients with severe megaesophagus who do not receive medical attention can die of malnutrition and/or chronic aspiration pneumonitis. Megacolon can also result in death, usually when volvulus develops and is not resolved surgically.

Race

T cruzi infection does not have a racial predilection.

Sex

T cruzi infection does not have a sexual predilection.

Age

Morbidity during the acute phase of Chagas disease is more pronounced in children than in adults. The gastrointestinal and cardiac manifestations of chronic T cruzi infection become apparent many years or even decades after initial infection and thus occur almost exclusively in adults.

Clinical

History

• Incubation period: The incubation period of vector-borne acute Chagas disease is thought to be 7-14 days, but definitive data are not available because persons who live in areas of active transmission are generally continually at risk for exposure to the vectors. Although newly infected persons may be aware that their living quarters are infested by triatomine vectors, most blood meals are taken while people are asleep, so they are unlikely to recall being bitten. The incubation period of acute T cruzi infection acquired through blood transfusion may be somewhat longer, but precise data are also lacking in this regard.
• Acute phase
  • In most instances of acute T cruzi infection, a specific diagnosis is not made because of the nonspecific nature of the signs and symptoms and because most cases occur in poor people who have limited access to medical care.
  • Acute Chagas disease carries a mortality rate of less than 5%. However, this is likely a high estimate, since acute Chagas disease is rarely diagnosed specifically; thus, the denominator for the calculation of the fatality rate is not known. As noted above, death is typically caused by myocarditis⁶³ and, less commonly, by meningoencephalitis.
  • In the vast majority of persons with acute Chagas disease, the manifestations resolve spontaneously within 3-8 weeks. This is followed by the chronic latent or indeterminate (asymptomatic) phase of the disease.
• Indeterminate phase
  • By definition, the indeterminate phase of Chagas disease does not cause any symptoms.
  • Most adults with T cruzi infection are unaware of their parasitosis, and a history consistent with acute Chagas disease from years prior is rarely given.
  • Persons who are diagnosed with indeterminate Chagas disease are typically identified by chance through blood-donor screening or pre-employment serologic testing.
• Chronic symptomatic Chagas disease
  • Ten to 30% of persons with chronic Chagas disease develop clinical manifestations of the disease. The most common and serious problems are cardiac, which are caused by an inflammatory cardiopathy that results from the persistence presence of the parasites in the heart.
    • A wide variety of atrial and ventricular rhythm disturbances, including right bundle branch block, left anterior hemiblock, and third-degree atrioventricular block can result in palpitations, dizziness, syncope, and even sudden death.
    • Cardiomyopathy and consequent congestive heart failure can result in shortness of breath, decreased exercise tolerance, easy fatigability, lower-extremity edema, and nocturia, as well as other signs and symptoms.
    • Thromboembolism can result in stroke, as well as pulmonary and arterial embolization.
  • The gastrointestinal symptoms associated with chronic T cruzi infection typically result from denervation of hollow viscera and consequent dysfunction.
    • Megaesophagus is the most common anatomic finding and typically results in symptoms similar to those of achalasia, such as dysphagia, odynophagia, substernal discomfort, and a sensation that ingested food and liquids do not move forward properly.
    • Megacolon usually results in constipation and pain, and some affected patients can go for long periods between bowel movements. In advanced cases, bowel obstruction and/or volvulus can occur, requiring surgical treatment.
    • Gastric dilatation in patients with Chagas disease has been described, as has megaureter, but these manifestations appear to be relatively rare.

Physical

• Acute phase
  • Symptoms of acute Chagas disease may include malaise, anorexia, myalgia, and headache, but many recently infected persons are asymptomatic.
  • Intermittent fever occurs, but its frequency is unknown.
  • Some patients have lesions at the portal of entry of the parasites. Romaña sign (Image: Unilateral periorbital edema in an Argentinean child with acute Chagas disease) (unilateral painless periorbital and palpebral edema) occurs when the parasites have contaminated the conjunctivae. Romaña sign is viewed as a classic sign of acute Chagas disease but develops in few newly infected persons. A chagoma, which is an indurated inflammatory skin lesion, may develop when parasites enter through a break in the skin. Romaña sign and chagomas may persist for several weeks. The lymph nodes that drain either of these lesions may be enlarged.
  • Hepatomegaly and splenomegaly may occur in children with acute Chagas disease, often accompanied by generalized lymphadenopathy.
  • Varying degrees of generalized edema may occur in acutely infected persons, particularly children.
  • Some patients with acute T cruzi infection develop a nonpruritic morbilliform rash called schizotrypanides (Image: Rash associated with acute Chagas disease in a Mexican patient).
  • Persistent tachycardia may be present.
  • Signs of acute myocarditis and resulting heart failure may develop in a small minority of patients with acute Chagas disease.²⁶
  • Neurologic dysfunction may develop in acutely infected children with meningoencephalitis.⁶⁴
  • Any of the physical findings of acute T cruzi infection can occur in chronically infected persons in whom the infection is reactivating due to natural (HIV infection) or iatrogenic immunosuppression.⁶⁵
• Chronic chagasic cardiomyopathy
  • Signs of congestion due to isolated left-sided heart failure may be present in the early stages of chronic chagasic cardiomyopathy. Biventricular failure with peripheral edema, hepatomegaly, ascites, and pulmonary congestion are more common in the later stages.
  • Signs of thromboembolism may appear, mostly with embolization to the brain, lungs, and extremities.
• Chronic chagasic megaesophagus
  • Weight loss and cachexia (in severe cases)
  • Hypertrophy of the salivary glands
  • Pneumonitis related to regurgitation and aspiration of the stomach contents (particularly during sleep)
  • Erosive esophagitis, with increased risk for esophageal cancer
• Chronic chagasic megacolon
  • Abdominal distention
  • Fecaloma
  • Signs of intestinal occlusion, sigmoid volvulus

Causes

It is not known which host factors or parasite characteristics cause some persons with chronic T cruzi infection to develop clinically apparent cardiac and gastrointestinal lesions, while others remain infected for life but develop no apparent symptoms. Parasite strain, host immunogenetics, nutrition, age at first infection, other medical conditions, and various other factors may play roles in the pathogenesis of chronic symptomatic Chagas disease. Currently, there is no way to predict if an infected person in the indeterminate phase of T cruzi infection is likely to develop symptomatic disease.

Differential Diagnoses

Workup

Laboratory Studies

The diagnosis of acute Chagas disease, which includes congenital Chagas disease and reactivation of chronic T cruzi infection in immunosuppressed persons, is based on direct detection of the parasites. In contrast, the diagnosis of chronic infection (indeterminate or chronic symptomatic phases) is generally based on serologic testing, since the low level of circulating parasites precludes microscopic detection.

• Parasitologic diagnosis
  • One useful method for identification of parasites in the blood is to put 1.5 µL of anticoagulated blood under a 12-mm circular cover slip and examine 200 fields under 400 X magnification.⁶⁶ This allows for the examination of 0.44 µL of blood with each round, which should take about 30 minutes of careful looking. The trypomastigotes are translucent; thus, they are usually detected based on the corresponding movement of RBCs. This approach has no set threshold for deciding that the result is negative. Simply stated, the greater the number of fields examined, the greater the probability of detecting a parasite in an acutely infected person.
  • Stained thin and thick blood smears may also be examined microscopically. The author is not aware of any comparative data that shed light on the relative sensitivity of examining stained smears versus wet preparations, although the movement of the parasites in the latter would seem to be advantageous.
  • Another method of evaluation involves using heparinized microhematocrit tubes. This method has been used extensively to test for congenital Chagas disease in infants born to chronically infected mothers.⁶⁷ The tubes are typically filled directly from the source and spun. The buffy coat at the interface of the plasma and RBCs is then examined microscopically. The curvature of the tube makes this somewhat difficult, but this problem can be resolved by cutting the tube and examining the buffy coat as if it were fresh blood. This procedure carries a risk of accidental transmission and thus should be performed only by experienced personnel.
  • Indirect parasitologic methods include xenodiagnosis and hemoculture.
    • In xenodiagnosis, 30-40 laboratory-reared insects are allowed to feed directly or indirectly on the blood of a person suspected to have Chagas disease. At least one month later, intestinal contents of the insects are extracted and examined microscopically for the presence of parasites. Xenodiagnosis is tedious, requires a long time to perform, and yields a sensitivity of only 50% in the best of hands.
    • Hemoculture, which involves a specialized liquid culture medium that is not available commercially, takes roughly the same amount of time as xenodiagnosis and has roughly the same level of sensitivity, but it is less tedious.
    • Neither xenodiagnosis nor hemoculture has any reasonable role in the diagnosis of acute Chagas disease, since the results are not available in time for short-term treatment decisions. In addition, their role in diagnosing chronic T cruzi infection is largely limited because of their insensitivity. However, these tests may have a role in resolving borderline serologic results or in evaluating treatment failures. These methods can yield specificity rates of up to 100% in the hands of practitioners who can morphologically differentiate T cruzi from T rangeli, which is co-endemic in some regions. Nonetheless, these methods are being viewed increasingly as historical oddities.
• Serologic diagnosis
  • Tests for anti– T cruzi immunoglobulin M (IgM) are not standardized, are not available commercially, and play no role in the diagnosis of acute Chagas disease.
  • Serologic testing for specific antibodies to T cruzi is the cornerstone of diagnosing chronic T cruzi infection.
  • More than 30 serologic assays have, at one time, been available in Latin America for testing clinical and donor specimens for chronic T cruzi infection. The most widely used today are indirect immunofluorescence (IIF), enzyme-linked immunosorbent assay (ELISA), and indirect hemagglutination. Most use lysates of epimastigotes as target antigens, but several are based on recombinant proteins.
  • Many of the available assays yield suboptimal sensitivity and/or specificity rates. WHO Chagas experts and other authorities have recommended that each specimen undergo testing with two types of assays, and this approach is generally followed for blood donor testing in endemic countries.
  • In the United States, the Ortho T cruzi ELISA Test System is the only assay approved by the FDA for donor screening. Its approval for clinical testing is imminent as of this writing (October 2008). After approval, it will be offered for testing clinical samples by Quest Diagnostics.
  • The Chagas Radioimmune Precipitation Assay (Chagas RIPA) is currently being used by Quest Diagnostics for confirmatory testing of donor specimens that are repeat positive in the Ortho assay.⁶⁸ The RIPA is available for research and limited clinical testing in the author’s laboratory at the University of Iowa.
  • Currently, two ELISAs are approved by the FDA for clinical testing (Hemagen Chagas Kit, Hemagen Diagnostics, Inc.; Chagatest ELISA Recombinante v. 3.0, Laboratorios Wiener). For initial testing, the author suggests using the latter through the Division of Parasitic Diseases of the Centers for Disease Control and Prevention (CDC). When the Ortho assay is approved for clinical use, the author recommends that samples be sent to Quest Diagnostics for testing. In all cases, positive and indeterminate results should be confirmed with the Chagas RIPA.
• Diagnosis via polymerase chain reaction–based assays
  • The use of PCR-based tests for detecting T cruzi has been studied extensively over the past 20 years, and dozens of articles have described this approach.⁶⁹
  • The use of many distinct primer pairs has been described; the accumulated evidence suggests that assays based on TCZ1/TCZ2 (nuclear repetitive sequence)⁷⁰ and S35/S35 (kDNA minicircle conserved region)⁷¹ are the most sensitive.
  • Methodologies for PCR-based assays for T cruzi have not been standardized, and no kits are available commercially. In this context, false-positive results have been an intermittent but persistent problem.
  • Although PCR-based assays generally appear to yield better sensitivity rates than xenodiagnosis or hemoculture, it is not high enough to justify their use for primary or confirmatory testing. The variable sensitivity is likely due to the extremely low parasite burden in chronically infected persons, meaning that the small blood samples taken for DNA extraction may not contain even a single parasite.
  • Given the variable sensitivity, the intermittent lack of specificity, and the lack of standardization and commercial availability of PCR-based assays for T cruzi, these tests currently have almost no role in the diagnosis of chronic T cruzi infection other than in the evaluation of treatment failures .
  • PCR-based assays for T cruzi may have a role in detecting acute Chagas disease, particularly congenital T cruzi infection, since their sensitivities have been shown to be greater than microscopic examination in several contexts.^72,73,74

Imaging Studies

No imaging studies are specific for Chagas disease. However, the manifestations of Chagas disease (eg, cardiac, esophageal, and colonic dysfunction) should be evaluated with the appropriate imaging studies, as they would be when resulting from any disease process.

Other Tests

• Electrocardiography and 24-hour continuous monitoring are the cornerstones of assessing possible dysrhythmias in patients with chronic T cruzi infections, as is the case with rhythm disturbances of any cause. Infected persons should undergo electrocardiography every 6-12 months to monitor for the development of ominous arrhythmias that would require suppressive drug treatment or pacemaker placement.
• Esophageal manometry and endoscopy may be useful in assessing and managing patients with Chagas disease who have symptoms that suggest esophageal dysfunction. Endoscopy can be used to differentiate chagasic megaesophagus from other causes of esophageal dysfunction (eg, cancer).

Treatment

Medical Care

• The goals of therapy in persons with T cruzi infection are to eliminate the parasites with specific drug treatment and to manage the signs and symptoms that result from the largely irreversible lesions associated with the disease. Two drugs, benznidazole and nifurtimox (see Medication), are available through the CDC for specific treatment of T cruzi infection. As noted below, both benznidazole and nifurtimox are limited in their capacity to effect parasitologic cure, especially in chronically infected patients. In fact, the usefulness of treating chronic infection has not been established in properly structured treatment trials; thus, the use of these drugs in such patients is controversial.⁷⁵
• Acute Chagas disease
  • All patients with acute Chagas disease, including those with congenital infection and those with reactivation of chronic infections due to immunosuppression, should be treated with either benznidazole or nifurtimox.
  • In general, the younger the patient and the closer to acquisition of the infection, the higher the probability of parasitologic cure. Babies with congenital Chagas disease have the greatest chance for cure. Data from Argentina show that the cure rate exceeds 90% if treatment is given within the first year of life.⁷⁶ Some sources have stated that the overall parasitologic cure rate in persons with acute Chagas disease is 70%, although the author is unaware of specific data that support this estimate.
  • The usefulness of corticosteroids or interferon-γ in patients with acute Chagasic myocarditis or meningoencephalitis has not been established.
• Indeterminate-phase Chagas disease
  • All children with chronic T cruzi infection should receive either benznidazole or nifurtimox. Good data indicate that a high proportion of these patients will be cured parasitologically.⁷⁷
  • In contrast, the probability of parasitologic cure with full courses of either drug in adults with long-standing T cruzi infection, most of whom were infected while quite young, is less than 10%.^78,79,80 Although such treatment suppresses the infection and reduces the likelihood of isolation of parasites via xenodiagnosis or hemoculture after treatment, the overall effect of this transient suppression is unknown. No properly structured comparative trials have been completed to determine whether treatment imparts a long-term benefit in these patients. A detailed discussion of this issue, which resulted from a 2-day meeting of a panel of Latin American and US Chagas experts late in 2006, was recently published.⁷⁵
  • A large, blinded, placebo-controlled trial of benznidazole therapy in persons with T cruzi infection is currently underway in Colombia and Brazil (the BENEFIT trial), but results will not be available until 2010.
  • No data support the concept that treatment of chronic infection in women prior to pregnancy reduces the probability of congenital transmission. Likewise, no information is available on which to base guidance for prophylactic treatment of chronic infection in persons who will undergo immunosuppression (eg, pretransplant) or in persons who are already immunosuppressed (eg, those with HIV infection).
• Chronic symptomatic Chagas disease: The consensus among experts is that persons who have already developed cardiac or gastrointestinal symptoms should not be given antiparasitic treatment.
• General medical treatment: As with diagnostic approaches, the medical treatment of cardiac and gastrointestinal signs and symptoms attributable to Chagas disease is similar to that instituted for similar problems caused by other etiologies. Such patients should be referred to specialists for appropriate evaluation and management.

Surgical Care

• Cardiopathy
  • Atrial and ventricular rhythm disturbances may require pacemaker placement. Ablation procedures for tachyarrhythmias, as well as implanted defibrillators, have been used in some patients with Chagas disease.
  • The usefulness of resection of the left ventricular apical aneurysms that develop in some patients with Chagas cardiomyopathy has not been established.
  • Cardiac transplantation is an option for some patients with end-stage Chagas heart disease. More than 100 such procedures have been performed, mostly in Brazil, but also in the United States. Interestingly, the survival rate among patients with Chagas disease who have undergone cardiac transplantation is better than that in the general group of patients who have undergone cardiac transplantation for other reasons,⁸¹ probably because the pathogenic process that results in cardiomyopathy in Chagas disease is not systemic, as is the case in diabetes mellitus, for example. Reactivation of the underlying T cruzi infection was a severe problem when the first such transplantations were performed in the late 1980s in Brazil; however, this is less of a problem now with the reduced dosing of immunosuppressives.^82,83
• Megaesophagus
  • Patients with Chagasic megaesophagus in whom esophageal dilatation is inadequate often undergo wide esophagocardiomyectomy of the anterior gastroesophageal junction, combined with valvuloplasty to reduce reflux. Laparoscopic myotomy is being used increasingly to manage severe megaesophagus.
  • Partial esophageal resection with reconstruction with esophagogastroplasty has been used in extreme cases.
• Megacolon
  • Patients with chagasic megacolon may benefit from the Duhamel-Haddad operation typically used in the treatment of idiopathic congenital megacolon.⁸⁴
  • In some cases, patients with sigmoid volvulus awaiting the Duhamel-Haddad procedure have undergone anterior sigmoidostomy with an eventual resection of the necrosed segment.

Consultations

Depending on the phase of T cruzi infection, the following consultations may be appropriate.

• Infectious diseases specialist
• Cardiologist and cardiac surgeon
• Gastroenterologist and general surgeon

Diet

• A diet appropriate for patients with congestive heart failure should be recommended as appropriate.
• Ingestion of warm and pasty food, in small volumes with water, is recommended in patients with megaesophagus. Such patients should not eat in the hours before bedtime to reduce the likelihood of regurgitation and aspiration.
• A high-fiber diet is recommended in patients with chagasic megacolon.

Activity

• Activity should be as tolerated.

Medication

The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications.

Antiprotozoal agents

These agents are used to treat infections caused by the protozoan T cruzi.

Nifurtimox (Lampit, Bayer 2502)

Available only from the CDC. Well absorbed by digestive tract. Trypanocidal drug that acts on circulating trypomastigotes, as well as intracellular amastigotes. The mechanism of action may depend on the formation of nitro anion radicals, but precise details are not known. Efficacy can be assessed by monitoring disappearance of T cruzi –specific antibodies, although this may take several years in some patients. Repeated hemoculture or PCR-based assay can be used to look for treatment failure.

Dosing

Adult

8-10 mg/kg/d PO

Pediatric

<1 year: Not established
1-12 years: 15-20 mg/kg/d PO divided qid; administer 90-120 d
>12 years: 12.5-15 mg/kg/d PO

Interactions

None reported

Contraindications

Documented hypersensitivity or previous adverse reactions to drug

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Has poor therapeutic index; relative contraindication in hepatic or renal impairment; gastrointestinal problems may include nausea, vomiting, abdominal pain, anorexia, and weight loss; neurologic problems can include restlessness, insomnia, paresthesias, tics, disorientation, and seizures (side effects generally disappear when treatment reduced or stopped); development of tumors reported in mice and rabbits treated with nifurtimox is worrisome⁸⁵

Benznidazole (Rochagan, Radanil, Ragonil)

Available only from CDC. Well absorbed by digestive tract. Trypanocidal drug that acts on circulating trypomastigotes, as well as intracellular amastigotes. Little is known regarding mode of action. Efficacy can be assessed by monitoring disappearance of T cruzi –specific antibodies, although this may take several years in some patients. Repeated hemoculture or PCR-based assay can be used to look for treatment failure.

Dosing

Adult

5 mg/kg/d PO divided bid for 60 d

Pediatric

Same as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity or previous adverse reactions to drug

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Benznidazole has poor therapeutic index; relative contraindication in hepatic or renal impairment, as well as hematologic or neurologic disease; peripheral neuropathy and rash are most common side effects; allergic dermatitis (immediate hypersensitivity) appearing 5-18 d posttreatment (sometimes accompanied with generalized edema, fever, lymphadenopathy, arthralgia, and myalgia; treatment with corticosteroids sometimes allows continuation of treatment, whereas antihistaminics are ineffective); peripheral polyneuritis (sometimes irreversible of unknown mechanism) granulocytopenia can occur and may be severe (WBC should be monitored weekly during treatment); side effects usually resolve with reduction in dose or discontinuation of treatment; development of tumors in mice and rabbits treated with benznidazole is worrisome,^85,86 as is the increased incidence of malignant tumors in patients with Chagas disease treated with benznidazole after heart transplantation⁸⁷

Follow-up

Further Inpatient Care

• The level of care depends on the clinical condition of the patient.

Further Outpatient Care

• Monitor infants of mothers with T cruzi infection. Infants who are parasite-negative at birth should be tested serologically at ages 6 and 9 months, after maternal antibodies have disappeared. Treatment should be instituted when results are positive.
• Persons with T cruzi infection should undergo electrocardiography every 6-12 months to look for dysrhythmias (see Other Tests).
• Patients with clinically manifest cardiac or gastrointestinal Chagas disease should be managed by appropriate specialists (see Consultations).
• Weekly WBC counts should be performed in patients being treated with benznidazole to evaluate for agranulocytosis.
• Immunosuppressed persons with T cruzi infection who have unexplained febrile illnesses should be evaluated parasitologically for reactivation of the infection.

Deterrence/Prevention

• Collective prophylaxis
  • No vaccination is available for T cruzi infection, and primary chemoprophylaxis in uninfected persons who plan to visit endemic regions is not recommended because of the extremely low risk of the infection, as evidenced by extreme rarity of infection in such circumstances (only 3 such cases have been reported⁵¹ ).
  • The proven effective approaches for eliminating vector-borne transmission of T cruzi to humans is through improvement of housing conditions, use of residual insecticides, and education of persons at risk for acquiring the infection.⁸
  • Transmission of T cruzi via transfusion of contaminated blood can be eliminated with serologic identification and permanent deferral of infected donors.
  • Although some risk factors for congenital transmission of T cruzi have been identified,⁸⁸ no approaches for reducing this risk have been defined. The critical element in controlling congenital Chagas disease is the thorough parasitologic and serologic evaluation of babies born to mothers with T cruzi infection.
• Personal prophylaxis
  • Secondary chemoprophylaxis to reduce the risk of reactivation of T cruzi infection in persons with concomitant HIV infection cannot be recommended.
  • Laboratory personnel who work with T cruzi or infected vectors should take protective measures appropriate for this risk group 2 organism.
  • Persons who travel to endemic areas should avoid sleeping in primitive buildings and should take general measures to protect themselves from insects.

Complications

• Acute phase - Myocarditis, meningoencephalitis
• Chronic chagasic cardiomyopathy - Congestive heart failure, apical aneurysm, thromboembolism, sudden death
• Chronic chagasic megaesophagus - Esophagitis, esophageal cancer
• Chronic chagasic megacolon - Fecaloma, volvulus of sigmoid colon

Prognosis

The overall prognosis among persons in the indeterminate phase of T cruzi infection is excellent, given that only 10-30% of infected persons ever develop signs and symptoms attributable to the disease, and those who do are generally asymptomatic for decades prior to developing cardiac or gastrointestinal problems.

Patient Education

Education of at-risk persons living in areas of active transmission is a key element in reducing the incidence of new infections. Data indicate that having dogs sleep outside the home can be an important factor in reducing transmission.¹⁰

Miscellaneous

Medicolegal Pitfalls

• Patients in the indeterminate phase of infection should not be excluded from any work activities.

Multimedia

Media file 1: Chagas disease (American trypanosomiasis). The trypomastigote is the infective flagellated form of the parasite found in the blood of the mammalian hosts (blood trypomastigote) and in the hindgut of vectors (metacyclic trypomastigote). Image courtesy of Peter Darben, MD.

Media file 2: Chagas disease (American trypanosomiasis). The epimastigote form is the multiplying stage of the parasite in the insect vector and in the acellular culture medium. Image courtesy of Peter Darben, MD.

Media file 3: Chagas disease (American trypanosomiasis). Megacolon.

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Keywords

Chagas disease, American trypanosomiasis, Trypanosoma cruzi, T cruzi, Trypanosoma infection , T cruzi infection , Chagas cardiomyopathy, parasitic protozoan, triatomine, kissing bugs, Trypanosomatidae, Stercoraria, trypanosome, trypomastigote, epimastigote, amastigote, Triatominae, Triatoma, triatomine, autochthonous acute Chagas disease, Triatoma infestans, T infestans, Rhodnius prolixus, R prolixus, Triatoma dimidiata, T dimidiata, acute Chagas disease, Romaña sign, congenital Chagas disease, chronic Chagas heart disease, chronic Chagas gastrointestinal disease

Contributor Information and Disclosures

Author

Louis V Kirchhoff, MD, MPH, Professor, Departments of Internal Medicine (Infectious Diseases) and Epidemiology, Carver College of Medicine and College of Public Health, University of Iowa; Staff Physician, Medical Service, Iowa City Veterans Affairs Medical Center
Louis V Kirchhoff, MD, MPH is a member of the following medical societies: American Association of Blood Banks and American Society of Tropical Medicine and Hygiene
Disclosure: Abbott Laboratories, Inc. Consulting fee Consulting; Quest Diagnostics Inc. Consulting fee Consulting; Goldfinch Diagnostics Inc. Royalty Equity owner

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Mary Nettleman, MD, MS, Chair, Department of Medicine, Michigan State University
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John W King, MD, Professor of Medicine, Section of Infectious Diseases, Louisiana State University Health Sciences Center; Director, Viral Therapeutics Clinics for Hepatitis; Consulting Staff, Department of Infectious Diseases, Overton Brook Veterans Affairs Medical Center
John W King, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Association of Subspecialty Professors, Infectious Diseases Society of America, and Sigma Xi
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CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
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Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
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