AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

American trypanosomiasis, also known as Chagas disease, affects millions of people throughout the Americas. Carlos Chagas first described this disease in 1911 when he discovered the parasite in the blood of a Brazilian child with fever, lymphadenopathy, and anemia. Trypanosoma cruzi, a protozoan hemoflagellate, is the parasite that causes this disease. When humans are infected, the parasite can cause acute illness; however, the infection is generally asymptomatic. In some cases, usually many years after initial infection, the affected individual has clinical signs and symptoms from damage to the heart or GI tract. The disease is the leading cause of congestive heart failure in areas of Latin America where it is endemic.

This review does not include discussion of African trypanosomiasis (sleeping sickness) because that disease in infants and children is indistinguishable from disease in adults. For information, see African Trypanosomiasis (Sleeping Sickness).

Pathophysiology

During the acute phase of illness, the parasite is believed to directly destroy host cells. The pathogenesis of the cardiac and GI alterations typical of the chronic phase is not well characterized. One theory suggests that ganglionic neurons and nerve fibers are lost. Another theory implicates the inflammatory reaction from an allergic response to parasitic antigens. Yet another theory points to an autoimmune mechanism, as suggested by the findings of monoclonal antibodies with cross-reactivity between T cruzi and mammalian nervous tissue.

A nodular swelling or chagoma develops at the site of entry. This area becomes infiltrated with macrophages surrounded by lymphocytes, eosinophils, and polymorphonuclear neutrophils. When T cruzi enters the human host, it produces an acute local inflammatory reaction. Lymphatic spread then carries the organism to regional lymph nodes. When the histiocytes or other inflammatory cells ingest the parasites, they transform into amastigotes. In the amastigote form, parasites can multiply in the cells of virtually every organ and tissue.

After local multiplication, the organisms can assume the trypomastigote form and invade the bloodstream, carrying the infection to all parts of the body. Cells of the reticuloendothelial system; cardiac, skeletal, and smooth muscles; and neural cells are preferentially parasitized. A marked host inflammatory reaction characterized by local accumulation of polymorphonuclear leukocytes, lymphocytes, and plasma cells is associated with these areas of cellular destruction.

In the acute phase, the heart is the main target organ. The severity of the acute infection widely varies, ranging from asymptomatic infection to severe tissue destruction. In all cases, the parasites have successfully entered various cells of the body and formed pseudocysts, each containing hundreds to thousands of amastigotes. Persons who recover from the acute illness carry these intracellular parasites for the remainder of their lives. The myocardium develops focal myonecrosis, contraction band necrosis, interstitial fibrosis, and lymphocytic infiltration. Interspersed among the degenerating fibers is a marked mixed inflammatory cell exudate, which becomes primarily mononuclear with time.

During the chronic phase, the ganglion cells are progressively destroyed; the affected organs widely vary in their tolerance to denervation. The myocardium often has diffuse fibrosis, with a small number of mononuclear cells scattered throughout. Cardiac function becomes compromised when approximately 20% of the neurons are destroyed, whereas esophageal function remains normal even when 80% of the neurons are nonfunctioning.

Early in the chronic stage of infection, the heart size may be normal or only slightly enlarged, although massive enlargement can occur later. The heart becomes dilated, with a thin muscular wall, especially in the right atrium. In more than one half of cases, an aneurysm is present at the apex of the left ventricle, which rarely ruptures. This is pathognomonic of chronic chagasic cardiopathy. Mural thrombosis develops in the right atrium, left atrium, and left ventricle, especially in the presence of atrial fibrillation. This mural thrombus increases the risk of embolization, especially to the brain, lungs, spleen, and kidneys. The right bundle branch is the most damaged part of the system and alterations in the atrioventricular conduction system are frequent.

In the GI system, the 2 principal organs affected are the esophagus and colon. Damage to the autonomic nervous system of the heart parallels that of the Auerbach plexus in the walls of the digestive tract. Abnormalities of secretion, absorption, and motility are present. Denervation and fibrosis occurs in the submucosal (Meissner) and myenteric (Auerbach) plexuses. Dysfunction of peristalsis may lead to arrest of transit, extreme dilatation, and hypertrophy.

Frequency

United States

Trypanosomiasis is extremely rare but has been reported in Texas,¹ Oklahoma, and California. As many as 5% of immigrants in Washington, DC, were found to carry trypanosomes and as many as 50,000-100,000 immigrants are thought to be infected. Transfusion-related cases, although rare, are increasingly recognized. Small mammals in the southern and southwestern United States can harbor T cruzi. Infected Triatoma protracta have been found in California, Arizona, and New Mexico.

International

The World Health Organization (WHO) has estimated that approximately 16-18 million people are infected. The incidence has been estimated at 200,000 cases per year. The disease is limited to the Western Hemisphere, in temperate, subtropical, and tropical regions. It is prevalent in Mexico, Central America, and South America. Human disease is most prevalent in Brazil, Argentina, and Venezuela.² Approximately 25% (90 million) of people in Latin America live in an area with endemic disease and are at risk of acquiring the infection. 

Mortality/Morbidity

• The overall mortality during the acute phase of Chagas disease is 5%. More than 70,000 people die from this disease annually. The disease is the leading cause of congestive heart failure in areas of Latin America where it is endemic and is responsible for one quarter of all deaths in persons aged 25-44 years in such areas. By far the most common cause of death is cardiac abnormalities. The 5-year mortality rate in patients with chronic Chagas disease and cardiac dysfunction is reportedly more than 50%. In infants and children younger than 5 years, the mortality rate is increased because of their predilection for CNS involvement.
• The relative prevalence of cardiac lesions versus megadisease among persons with chronic infection widely varies by location. In Brazil, GI involvement is as likely as cardiac alterations in persons with chronic infection. In contrast, neither megacolon nor megaesophagus has been associated with chronic trypanosomiasis infection in Colombia, Venezuela, Central America, or Mexico.

Race

No racial predilection is observed.

Sex

No sex predilection has been reported.

Age

This disease occurs in people of all ages. The most severe form occurs in children younger than 5 years, in whom symptoms of CNS involvement may predominate.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The early phase of the disease is asymptomatic and only about one third of patients have symptoms of acute Chagas disease. A small minority of patients have severe clinical disease, including heart failure or meningoencephalitis. As many as 10% of patients die in the early stage of severe myocarditis or meningoencephalitis. The vast majority of those who have clinical symptoms include infants, those who are rather defenseless in warding off the triatomid bite, and children aged 10 years or younger. However, the symptoms of the acute phase disappear within 4-8 weeks in most individuals.

• The incubation period for Chagas disease is 1-2 weeks. Chronic manifestations do not appear for years after infection. The incubation period is longer (20-40 d) in transfusion-acquired disease.
• Symptoms of parasitic infection and proliferation include the following:
• • The first symptom is a bug bite on the face. After 1-3 weeks, the organism proliferates, producing a red nodule known as a chagoma, which develops at the site of the original inoculation. The chagoma is usually located on the face or arms and can be painful. The surrounding skin becomes indurated and, later, hypopigmented. 
  • A few days after proliferation, the parasites can spread throughout the body, infecting many tissues, particularly the heart, skeletal muscles, and nervous system. This spread heralds the acute phase of the illness. During this stage, the infected patient may develop a flulike illness. Initial symptoms include a high temperature, chills, headache, irritability, tiredness, anorexia, malaise, myalgias, lymphadenopathy, and splenomegaly. The fever can be continuous, intermittent, or remitting and may last as long as 5 weeks. Epistaxis is common in young children.
  • Cardiac symptoms are observed in almost all patients shortly after proliferation of the parasite begins.
• In chronic disease, involvement of the GI system is common.
• • Symptoms include dysphagia, regurgitation, hiccups, constipation, and abdominal pain. Disturbances in swallowing are the most common manifestations. Symptoms may develop weeks to years after the initial infection and subsequent progression is typically slow.
  • Symptoms of esophageal involvement include dysphagia, regurgitation, heartburn, hiccups, odynophagia, and coughing. These symptoms generally develop insidiously. Less common symptoms of megaesophagus are severe malnutrition and aspiration with bronchitis and pneumonia.
  • Hypertrophy of the salivary glands, especially the parotids, is present in 25% of patients with chagasic megaesophagus. These patients have an excessive response to salivary stimuli and the increased volume of saliva can result in drooling.
• Second to the esophagus, the colon is the most frequently affected portion of the GI tract in patients with chronic Chagas disease. The rectum and sigmoid colon are affected most often.
• • The primary symptom is slowly progressive constipation. Most patients with megacolon have a bowel movement every 10 days.
  • Impaction, caused by a firm mass of stool or a true fecaloma, develops in a significant minority of cases. Symptoms range from vague abdominal pain and rectal fullness to symptoms of large bowel distention. Other symptoms include obstipation and meteorism.
• Megaduodenum is usually asymptomatic but can lead to nonspecific dyspepsia, prolonged nausea and vomiting, and, rarely, malnutrition.
• Neurologic symptoms, with involvement of the central, peripheral, or autonomic nervous systems, are present in few patients. Symptoms include paresis, cerebellar disturbance, convulsions, alterations in the dorsal root ganglia, and polyneuritis.

Physical

• If the bite occurs near the eye, unilateral periorbital edema of the eyelids, known as Romaña sign, develops. The edematous skin is violet, with conjunctivitis and enlargement of the ipsilateral preauricular lymph node. Unilateral ocular and facial edema that involves the ipsilateral preauricular lymph node is known as the oculoglandular syndrome. In a small number of infected individuals, the edema may be generalized and mistaken for nephrotic syndrome. The preauricular region can significantly swell, causing an initial impression of parotitis, such as that caused by the mumps virus.
• The spleen and liver are palpable but, in general, are not greatly enlarged. The disease is often not recognized at this stage and is accurately diagnosed in only a minority of patients.
• The younger the patient, the more severe the clinical manifestations. Occasionally, the illness is fatal, especially in children younger than 2 years. Generalized lymphadenopathy, moderate hepatosplenomegaly, anasarca, vomiting, and diarrhea, as well as signs of meningeal irritation, are common in infants. Skin lesions can vary from a generalized maculopapular or morbilliform rash to urticaria.
• Tachycardia is present and may not be related to fever; rather, it may result from destruction of the heart's parasympathetic innervation. As many as 30% of patients have cardiovascular abnormalities, which include cardiac enlargement, functional murmurs, and conduction blocks. Evidence of myocarditis is almost always found. Myocarditis is mild in the vast majority of cases. Biventricular heart failure rarely develops. Death from acute myocarditis occurs in 2-3% of patients. The prognosis is poor with the early development of premature ventricular contractions, atrial fibrillation, heart block, or congestive heart failure.
• Occasionally, meningoencephalitis can develop. This is more common in young infants and immunosuppressed patients. Death can occur in as many as 50% of these cases. Clinical manifestations include nuchal rigidity, convulsions, paralysis, and coma. Encephalitis can develop in patients who are immunosuppressed.
• The manifestations of the acute phase of Chagas disease generally last 2-4 weeks. In individuals who survive, the disease progresses to the indeterminate, or asymptomatic, phase. A low level of parasitemia is present. This phase can persist for years or even for the rest of the patient's life. As many as 30% of persons with disease in the indeterminate phase have cardiac, GI, or neurologic damage 10-20 years after infection. In other individuals, the illness progresses to the chronic phase.
• The most serious aspect of Chagas disease is the delayed damage that it can inflict on the heart and GI system during the chronic phase. Serious sequelae consist of cardiomyopathy, heart failure, megaesophagus, and megacolon. Clinical manifestations can develop years after the initial acute infection.
• Cardiac abnormalities are the most frequent manifestations of chronic Chagas disease and are the most serious causes of morbidity and mortality. Chagas cardiomyopathy develops in 30% of patients.
  
  
  • Congestive heart failure is the first sign of chagasic heart disease. Once heart failure occurs, it usually is intractable and difficult to control. Signs of right-sided heart failure are more common than signs of left-sided heart failure. Heart sounds may be distant, and functional murmurs of mitral and tricuspid insufficiency can develop. Other signs and symptoms include dyspnea upon exertion, peripheral edema, ascites, hepatomegaly, chest pain, and palpitations. If left ventricular failure is present, it usually causes mild symptoms.
  • Patients with cardiac abnormalities usually do not have acute pulmonary edema, and orthopnea is uncommon. The most important complications are systemic and pulmonary embolism and sudden death. Sudden death frequently occurs from a fatal dysrhythmia, such as ventricular fibrillation, or, less frequently, from a third-degree heart block or an embolism. In many advanced cases, the typical aneurysm develops at the apex of the left ventricle.
  • Predictors for poor prognosis include impaired left ventricular function, New York Heart Association class III/IV, cardiomegaly observed on radiographs, left ventricular systolic dysfunction observed on echocardiographs, nonsustained ventricular tachycardia on 24-hour Holter monitoring findings, low QRS voltage on electrocardiography findings, apical aneurysms, and male sex.
  • QT interval dispersion, a marker of inhomogeneous myocardial repolarization, has been shown to be an independent predictor of sudden cardiac death in patients with Chagas disease.
• Abnormalities in the GI system are the second most common manifestation of chronic Chagas disease. These occur in 8-10% of patients and vary from minor changes in motility to severe dilatation of the esophagus or colon.
• • Esophageal disease is the most common cause of symptoms in chronic disease. Most patients have symptoms when they are aged 20-40 years, and the rate of progression widely varies.
  • Less commonly involved organs include the duodenum; stomach; small intestine; and, rarely, the gallbladder and biliary tree. Involvement of the stomach leads to hypotonia; hypoperistalsis; delayed emptying and decreased acid secretion; and, rarely, dilatation. Abdominal examinations reveal abdominal distention and tympanism.
• Immunosuppression as a result of organ transplantation or human immunodeficiency virus (HIV) infection can lead to reactivation of the infection. Severe myocarditis and neurologic disease with brain abscesses, meningoencephalitis, and seizures caused by T cruzi have been major findings in patients infected with HIV.
• Intrauterine infection can cause spontaneous abortion or premature delivery. In its acute stage, congenital Chagas disease often resembles the acquired disease. The onset might be at birth or a few months later.
• • The infant has a low birth weight, hepatosplenomegaly, jaundice, anemia, fever, edema, and meningoencephalitis with convulsions, hypotonia, hyporeflexia, and tremors. Some patients have metastatic hemorrhagic chagomas in the skin or mucous membranes. Intracranial calcifications and ocular lesions have been described. Cardiac involvement is rare. GI abnormalities from megaesophagus present as dysphagia and cause death by aspiration.
  • Death frequently occurs within the first few weeks of life. Those who survive have severe neurologic sequelae with mental deficiency or behavioral and learning disabilities.
  • The differential diagnosis of intrauterine infection includes erythroblastosis fetalis, congenital toxoplasmosis, cytomegalovirus, parvovirus B19, lymphocytic choriomeningitis virus, and herpes simplex infections. A positive serologic result for specific immunoglobulin G (IgG) at 6-12 months is an indication for treatment.
• Transmission of this infection through infected mother's milk has been observed in breastfed babies.
• Rare findings ascribed to Chagas disease include bronchiectasia, hemosiderosis, and dilatation of the ureter or urinary bladder.

Causes

T cruzi, a protozoan hemoflagellate, causes American trypanosomiasis. T cruzi belongs to the order Kinetoplastida, suborder Trypanosomatina, genus Trypanosoma, and subgenus Schizotrypanum.

• These organisms undergo an obligatory developmental and reproductive cycle in the alimentary tract of a reduviid or triatomine insect. The reduviid or triatomine insects commonly are called assassins, cone-nose, or kissing bugs because of their predilection for biting the victim's face while he or she is sleeping.
• • The insects are large (2-3 cm in length), obligate hematophages that hide in crevices in mud walls, windows, door frames, and dark corners of poorly constructed adobe-style huts. These insects come out at night to feed on the blood of sleeping humans. They require blood to grow and mature.
  • The vector (ie, reduviid or triatomine insect) becomes infected by ingesting trypomastigotes present in the bloodstream of an infected mammal. Infection lasts for the life of the vector, which can be as long as 2 years.
• The developmental cycle of T cruzi includes 3 morphologic forms: amastigotes, trypomastigotes, and epimastigotes. The entire cycle takes place in the insect gut lumen over 6-15 days.
• • Within a few hours after the ingestion of infected blood, short, spindle-shaped forms lacking a free flagellum can be found in the insect's foregut. These develop into small epimastigote forms that divide and elongate, resulting in large (35-40-µm-long) epimastigotes. By the third or fourth day, these organisms attach to the rectal epithelium.
  • By the fifth day, the epimastigotes become rounded, short trypomastigotes, which then elongate.
  • By the seventh and eighth days, they become infective metacyclic trypomastigotes that are long (17-22 µm), slender, and spindle shaped. They have a large kinetoplast posterior to the nucleus and a flagellum. Each microliter of insect excreta may contain 3000-4000 organisms.
• Human transmission occurs through contact with infected insect excreta. These insects defecate while ingesting human blood, thereby excreting the infective trypanosomes. The person who is bitten is inoculated by inadvertently rubbing the insect's feces into the site of the bite. The organism can also enter through abraded skin or intact mucous membranes of the mouth, nose, and conjunctiva.
• • T cruzi invades cells near the inoculum. Once inside the cell, the infective metacyclic trypomastigote moves from the digestive vacuole to the cytosol. Next, they transform into intracellular amastigote forms and multiply by binary fission.
  • The amastigotes have a short flagellum and are spherical or oval and 2-4 µm in diameter. After a period of multiplication, amastigotes transform back into trypomastigotes; rupture the cell; enter the bloodstream; and invade other cells, predominantly reticuloendothelial, cardiac, skeletal and smooth muscle, and neuroglial cells.
• The parasites are transmitted through the feces of the insects of the triatomid or reduviid families. Natural infection occurs in a wide variety of animals, including guinea pigs, opossums, foxes, squirrels, armadillos, anteaters, porcupines, rats, mice, bats, and monkeys. After humans, birds are the most important blood sources; however, birds are not susceptible to infection. Domestic cats and dogs are the most important domestic reservoirs for human infection.
• The parasite can be congenitally transmitted or transmitted through organ transplantation, via infected breast milk, by blood transfusion, or accidentally in the laboratory. As much as 1.9-6.5% of the blood in some blood banks in Latin America is contaminated by T cruzi. In highly endemic areas, this figure can be as high as 20%. Transplacental transmission occurs in 2-10.5% of infected mothers.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Achalasia
Arteriosclerotic heart disease
Collagen vascular diseases
Congenital megacolon
Congestive heart failure
Conjunctivitis
Cellulitis
Parotitis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• During the acute illness, the CBC count may reveal leukocytosis with relative lymphocytosis, and transaminase levels are often elevated.
• During acute illness (ie, the first 6-12 wk), parasites are frequently seen in blood smears, using either Giemsa staining or direct wet-mount preparations (in which motile parasites may be seen). Sensitivity is 80-90%. Thickly-stained and thinly-smeared blood can allow morphologic characterization of the parasite and differentiation from other trypanosomes, but these preparations are less sensitive (60%). Concentration using centrifugation after red-cell lysis or clotting and examination of the buffy coat increases detection to 90-100%.
• In late infections, low levels of parasitemia are present; therefore, blood smear results are often negative. To confirm the diagnosis, parasites in the blood must be cultured on a special medium or identified by means of xenodiagnosis.
• Serologic tests for anti–T cruzi immunoglobulin M (IgM) play a limited role in the diagnosis because these tests are not widely available or standardized. In recent human infections, antibodies of the IgM class appear in the blood stream 15 days after infection, peak 17-45 days after infection, and persist for years. Antibodies of the IgM isotype predominate during the acute phase. Later, in the latent and chronic stages, antibodies are primarily from the IgG and IgA classes. Serologic tests include complement fixation (CF), indirect hemagglutination (IHA), and indirect immunofluorescence. False-positive results can occur with leishmaniasis, malaria, collagen vascular disease, and syphilis.
• • The CF test, or Machado-Guerreiro test, is considered the most reliable immunodiagnostic method for diagnosis. The indirect fluorescent antibody test (IFAT) is rapid and easy to perform, has a high sensitivity, and can be used to differentiate IgM antibodies from IgG antibodies. Enzyme-linked immunosorbent assay (ELISA) is as sensitive as the IFAT and can also be used to differentiate IgM antibodies from IgG antibodies.
  • Several agglutination tests have been developed that detect the presence of antibodies against T cruzi, such as the indirect IHA, direct agglutination (DA), latex agglutination (LA), and flocculation tests. IFAT reveals the earliest positive results for IgM antibodies after initial infection, followed by the DA method. All of these tests have been reported to provide positive results in more than 95% of the sera from infected humans.
  • A persistent problem with these tests is false-positive reactions. These have been observed with leishmaniasis, malaria, syphilis, infectious mononucleosis, tuberculosis, leprosy, and collagen vascular disease. The use of a minimum of 2 different, independently performed serologic tests is recommended to confirm infection.
  • In the United States, CF and IFAT are available from the Centers for Disease Control and Prevention (CDC). In addition, the Food and Drug Administration has approved assays based on the ELISA format for use in clinical testing; these are performed at Abbott Laboratories in Illinois and Gull Laboratories in Utah.
  • T cruzi kinetoplast DNA has been observed using polymerase chain reaction (PCR) amplification,^{3, 4} which can be used to identify as few as 1 parasite in 20 mL of blood with a sensitivity of 96-100%.
• Xenodiagnosis is the best method for parasitologic diagnosis in the latent or chronic phases. It consists of allowing laboratory-reared reduviid nymphs to feed on blood from an infected patient. The feces and intestines of the nymphs are examined 20-60 days later for the presence of the parasites. Test results are positive in approximately 50% of individuals.
• PCR has been used to detect T cruzi in congenital cases of trypanosomiasis and to follow the efficacy of patients treated for Chagas disease.
• Blood cultures have positive results in 100% of patients with acute-phase illness but only 40-50% in those with chronic illness.
• Blood banks in areas of endemic disease use either the IHA or LA tests for disease detection. Recent studies involving the use of ELISA for the detection of antibodies to T cruzi and a radioimmunoprecipitation assay had a sensitivity and specificity of 100%.
• In people who are immunosuppressed and thought to have Chagas disease, examine other specimens, such as lymph node aspirates, bone marrow, cerebrospinal fluid, and pericardial fluid, if the presence of T cruzi cannot be confirmed in the blood.
• In congenital Chagas disease, an indirect immunofluorescence test with anti-IgM has been introduced recently and it is effective in confirming acute congenital disease. Test infants of seropositive mothers as soon as possible for the presence of circulating parasites and specific IgM antibody.
• Atrial natriuretic factor is a sensitive marker capable of detecting gradual impairments in cardiac function and suggests poor survival in patients with Chagasic cardiomyopathy.  Brain natriuretic peptide has also been shown to be a marker for severity of disease in Chagas disease.
• N-terminal proBNP has been shown to be a marker of impaired left ventricular dysfunction.⁵

Imaging Studies

• In patients with cardiac involvement, chest radiography may reveal cardiac enlargement with clear lung fields.
• In patients with advanced esophageal involvement, chest radiography may reveal a tubular mass along the aorta and air-fluid level, which reflects the retention of swallowed material in the esophagus.
• Fluoroscopic esophagrams obtained with barium often show the absence of mucosal irregularities and a variably dilated esophagus with a narrow, conical segment at its lower end that represents the nonrelaxing sphincter (bird-beak appearance). In advanced disease, the diameter is grossly enlarged, causing it to fold over the diaphragm.
• Cine-esophagrams may show tertiary contractions and accumulation of the contrast material.
• Manometry in patients with Chagas disease typically reveals loss of peristalsis upon deglutition and an abnormally elevated pressure in the lower esophageal sphincter, which fails to relax.
• Scintigraphy is as sensitive as manometry in depicting esophageal dysmotility and it reveals patterns of transit similar to those described in idiopathic achalasia.
• In colonic involvement, barium enema examination is the cornerstone for diagnosis. The sigmoid colon is frequently dilated and elongated in nearly all cases, and the rectum is dilated in 80% of cases.
• Echocardiography is used to assess for evidence of acute chagasic myocarditis or chronic Chagas cardiomyopathy.⁶ In the acute setting, echocardiography may reveal pleural effusions, apical or anterior dyskinesis, and left ventricular dilatation. In patients with chronic disease, echocardiography may reveal left ventricular aneurysm, segmental wall abnormalities, left ventricular dilatation, decreased left ventricular ejection fraction, diastolic dysfunction, tricuspid, and mitral regurgitation.
• Thallium stress-redistribution myocardial perfusion scintigraphy may reveal reversible and irreversible perfusion defects in chronic Chagas cardiomyopathy. The perfusion defects occur in the presence of normal epicardial coronary arteries and probably represent myocardial fibrosis, coronary microvasculature abnormalities, or extensive impairment of cardiac sympathetic function.
• Cardiac MRI has been shown to be the most accurate method to detect myocardial fibrosis in patients with Chagas disease. CMR offers a wide variety of imaging tools to evaluate morphology, function, and other tissue characterization abilities, such as edema and fat.

Other Tests

• Electrocardiography may be useful.
• • The most common electrocardiographic abnormalities in acute infection include sinus tachycardia, prolongation of the PR interval, S-T segment depression and T-wave inversion, low voltage of the QRS complex, and prolongation of the QT interval.⁷
  • The most common electrocardiographic manifestations in chronic disease are intraventricular blocks (right bundle branch block and left anterior hemiblock), sinus bradycardia, atrioventricular (AV) block (first degree, second degree, complete), sinoatrial block, atrial fibrillation, and premature ventricular beats.
• Lumbar puncture may demonstrate pleocytosis with a predominance of lymphocytes and elevated protein level; often, it reveals the presence of T cruzi.
• Complex ventricular dysrhythmias during stress testing are a clinical marker for progressive cardiomyopathy in Chagas disease. 

Procedures

• Endoscopy is not essential to the diagnosis of chagasic achalasia. Its main value is in the identification of other disorders, such as gastric and esophageal cancer, which are more common in patients with chagasic megaesophagus.

Histologic Findings

The lesion at the parasite's portal of entry has a predominance of lymphocytic, monocytic, and eosinophilic infiltration, with the presence of giant cells. When the heart is invaded, myocardial fibers are often edematous and undergo various stages of focal necrosis, which primarily involves the contractile and conduction systems. Interspersed among the degenerating fibers is a markedly mixed inflammatory cell exudate consisting of granulocytes, lymphocytes, monocytes, mast cells, and plasma cells. Diffuse inflammation of the myocardium is present, as well as dense foci of fibrosis in the interstitial spaces and invasion of lymphocytes, plasma cells, and macrophages. In two thirds of the cases, the detection of parasites in the myocardium is difficult.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The acute phase of Chagas disease is treated with nifurtimox or benznidazole.^{8, 9} Cases of congenital Chagas disease have been successfully treated with either drug.

• The management of chronic Chagas disease is supportive.
• • Dysrhythmias usually respond to typical agents. Patients with bradydysrhythmias and atrial fibrillation with a slow ventricular response may require a permanent pacemaker if they are symptomatic. In the management of heart failure, digitalis or vasoactive drugs are not well tolerated and must be cautiously administered. However, diuretics are effective. Transplantation is not without risk, as immunosuppression reactivates the chronic trypanosome infection.
  • Embolism or evidence of thrombosis may necessitate anticoagulant therapy.
• Treatment of esophageal alterations in patients with Chagas disease is the same as in idiopathic achalasia.
• • The focus is on facilitating the transit of food and liquids through the achalasic lower esophageal sphincter. Dietary measures, such as eating soft foods or administering anticholinergic drugs, are generally of little use. Nifedipine or sublingual isosorbide dinitrate taken prior to meals may provide some relief in patients with a nondilated esophagus.
  • In most patients, symptomatic megaesophagus can benefit from pneumatic dilation of the lower esophageal sphincter. Relapse occurs in as many as 26% of patients, but patients might have good results with second dilations. Surgical approaches for chagasic megaesophagus are reserved for use when repeat dilation fails and for the most severe cases with dolichomegaesophagus.
• Treatment of patients with colonic dysfunction is as follows:
• • Patients with Chagas disease in the early stages of colonic dysfunction can be treated with a diet that is high in fiber and fluids, as well as laxatives. These patients occasionally require enemas.
  • Fecal impaction might occur as the disease progresses and requires manual disimpaction. Treat fecaloma with multiple mineral oil or saline enemas and colonic lavages with balanced salt solutions or tap water. In the most severe cases, manual emptying under general anesthesia may be necessary. Endoscopic emptying can be performed as the initial treatment in patients in whom no clinical, radiographic, or endoscopic signs of ischemia are present. Complicated cases require surgical decompression. Patients in whom conservative methods fail, as well as those with frequent fecal impaction or sigmoid volvulus, need surgical treatment.

Surgical Care

• Surgical care for those with esophageal dysfunction
• • Surgical approaches for chagasic megaesophagus are reserved for disease that fails to respond to repeated dilatation and the most severe cases with dolichomegaesophagus. Laparoscopic transhiatal subtotal esophagectomy has been successful with fewer complications than a transthoracic approach.
  • Good results have been evidenced after performing a Thal operation with a wide esophagocardiomyotomy on the anterior gastroesophageal junction combined with a valvuloplasty to reduce reflux. Surgical complications include pleural effusions and fistulas at the site of anastomosis.
  • Future approaches might include laparoscopic myotomy, which is successful in patients with severe idiopathic achalasia.
• Surgical care for those with colon dysfunction
• • Patients with megacolon in whom conservative methods fail, as well as those with frequent fecal impaction or sigmoid volvulus, need surgical treatment.
  • Various surgical procedures have been used to treat advanced megacolon. These procedures include resection of the sigmoid colon as well as a portion of the rectum.
  • Resection of part of the rectum has been found to be necessary to prevent subsequent recurrences of megacolon in the portion brought down and sutured to the rectum. Resection of the rectum requires an abdominal-perineal approach; the Duhamel procedure, as modified by Haddad, has been used with considerable success; however, it is a 2-stage procedure. Another procedure, the Habr-Gama technique, consists of abdominal rectosigmoidectomy with immediate posterior colorectal end-to-end stapling and also has good success.

Consultations

Consultations with an infectious diseases specialist, cardiologist, gastroenterologist, neurologist, and surgeon may be helpful; these specialists should be consulted as indicated by the patient's clinical condition.

Diet

Dietary measures are generally not effective, except for high-fiber and increased fluid intake for the treatment of mild colonic dysfunction.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The acute phase of Chagas disease is treated with nifurtimox or benznidazole. Both agents reduce the duration and severity of acute and congenital Chagas disease. Treatment is also indicated in a patient with HIV who has reactivation trypanosomiasis. Nifurtimox is available in the United States from the drug service of the CDC at the Parasite Drug Service, which can be reached at (404) 639-3670 during business hours and at (404) 639-2888 on evenings, weekends, and holidays.

Nifurtimox has been reported to be 75-90% effective. In some areas, such as Brazil, it is not as effective. Benznidazole has similar efficacy and may be better tolerated than nifurtimox. No evidence suggests that individuals in the indeterminate or chronic phases of the illness benefit from treatment. The drug might be effective for the chronic phase if parasites can be demonstrated in the blood.

A long-term follow-up study of patients with chronic disease treated with benznidazole revealed a significant decrease in the electrocardiographic changes, clinical deterioration, and rate of seropositivity. Allopurinol has been shown to be as effective as nifurtimox and benznidazole in suppressing parasitemia with fewer adverse effects.¹⁰ However, the open and nonrandomized study structure and the lack of well-defined criteria for cure make interpretation of these findings difficult. In addition, allopurinol has recently been ineffective in eradicating T cruzi in patients from Brazil. In Chile, the use of itraconazole has been shown to decrease electrocardiographic abnormalities in some patients with chronic Chagas disease.¹¹

Nifurtimox and recombinant interferon alfa were successfully used to treat Chagas disease in a child who acquired the disease through transfusion and in a laboratory worker who accidentally was infected. Interferon-alfa may improve the activation of macrophages that kill the organism.

Thioridazine is a phenothiazine with high antitrypanothionine reductase activity that has been shown to be effective in preventing chagasic myocardiopathy in mice when used in the acute phase of infection.¹²

Drug Category: Anthelmintics

These are used to treat acute and congenital Chagas disease. Parasite biochemical pathways are different from the human host, thus toxicity is directed to the parasite, egg, or larvae. Mechanism of action varies within the drug class. Antiparasitic actions may include the following:

• Inhibition of microtubules causes irreversible block of glucose uptake
• Tubulin polymerization inhibition
• Depolarizing neuromuscular blockade
• Cholinesterase inhibition
• Increased cell membrane permeability, resulting in intracellular calcium loss
• Vacuolization of the schistosome tegument
• Increased cell membrane permeability to chloride ions via chloride channels alteration

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• The clinical condition of the patient dictates further inpatient care.

Further Outpatient Care

• Observe infants born to seropositive mothers for at least 1 year.

Transfer

• Transfer to another facility is appropriate when required specialists and services are unavailable locally.

Deterrence/Prevention

• Educate people in areas with endemic disease about how trypanosomiasis is spread and methods of prevention.
• Inspect homes for presence of vectors and for measures that prevent vectors from entrance.
• • If reduviid or triatomine insects are found, a thorough disinfection with synthetic pyrethroid insecticides can help keep the home vector free for about 2 years.
  • Screens on windows and doors exclude the vectors. Improving the home by covering crevices and cracks significantly reduces triatomid insect infestation.
• Screen blood donors in areas of endemic disease with serologic tests.
• Blood recipients in areas of endemic disease can be protected by treating donated blood with gentian violet.
• • Gentian violet (250 mg/L blood, dilution of 1:4000 for 24 h at 4°C), an amphophilic cationic agent that acts photodynamically, has been used to kill the parasite in blood. Photoradiation of blood that contains gentian violet and ascorbate generates ascorbyl radicals and superoxide anions, which are potent trypanocides.
  • Other agents that can be added to the blood to treat the infection include mepacrine, an antimalarial agent, and maprotiline, an antidepressant.
• Regular insecticide spraying with benzene hexachloride could decrease transmission of the infection.

Complications

• Congestive heart failure
• Myocarditis
• Cardiomyopathy
• Dysrhythmias
• Sudden death
• Meningoencephalitis
• Megaesophagus: Esophagitis and esophageal cancer are the most common complications of megaesophagus.
• Megacolon: Fecaloma and volvulus of redundant sigmoid complicate megacolon. Fecaloma-associated stercoral ulceration, overflow incontinence, and ischemic colitis have been described.
• Embolic events (eg, cardioembolic stroke, small bowel infarction, splenic infarcts, kidney infarcts): Stroke has been found to be more frequent in patients with chagasic cardiomyopathy (15%) compared with other cardiomyopathies (6.3%).

Prognosis

• The prognosis depends on the clinical stage and the complications that develop.
• The acute phase is most serious in children younger than 2 years, and the disease is almost always fatal if heart failure or meningoencephalitis develops.
• In chronic disease with pronounced cardiac manifestations, the prognosis is poor, and death usually occurs within 5 years as a result of heart failure or pulmonary embolism.
• Right bundle branch block is an ominous sign in the acute phase.
• The prognosis with the digestive form of the illness is generally good.

Patient Education

• The use of proper preventive measures when one travels to endemic areas should be emphasized.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider the diagnosis in the appropriate clinical context

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Hanford EJ, Zhan FB, Lu Y, et al. Chagas disease in Texas: recognizing the significance and implications of evidence in the literature. Social Sci Med. Jul 2007;65(1):60-79. [Medline].
2. Anez N, Crisante G, Rojas A. Update on Chagas disease in Venezuela--a review. Mem Inst Oswaldo Cruz. Dec 2004;99(8):781-7. [Medline].
3. Avila HA, Pereira JB, Thiemann O, et al. Detection of Trypanosoma cruzi in blood specimens of chronic chagasic patients by polymerase chain reaction amplification of kinetoplast minicircle DNA: comparison with serology and xenodiagnosis. J Clin Microbiol. Sep 1993;31(9):2421-6. [Medline]. [Full Text].
4. Avila HA, Sigman DS, Cohen LM, et al. Polymerase chain reaction amplification of Trypanosoma cruzi kinetoplast minicircle DNA isolated from whole blood lysates: diagnosis of chronic Chagas' disease. Mol Biochem Parasitol. Oct 1991;48(2):211-21. [Medline].
5. Barbosa MM, P. Nunes Mdo Carmo, Ribeiro AL, et al. N-terminal proBNP levels in patients with Chagas disease: a marker of systolic and dyastolic dysfunction of the left ventricle. Eur J Echocardiography. Jun 2007;8(3):204-12. [Medline].
6. Acquatella H. Echocardiography in Chagas heart disease. Circulation. Mar 6 2007;115(9):1124-31. [Medline].
7. Corbucci HA, Haber DM, Bestetti RB, Cordeiro JA, Fioroni ML. QT interval dispersion in patients with chronic heart failure secondary to Chagas' cardiomyopathy: correlation with clinical variables of prognostic significance. Cardiovasc Pathol. Jan-Feb 2006;15(1):18-23. [Medline].
8. Bustamante JM, Lo Presti MS, Rivarola HW, et al. Treatment with benzidazole or thioridazine in the chronic phase of experimental Chagas disease improves cardiopathy. Int J Antimicrob Agents. Jun 2007;29(6):733-737. [Medline].
9. de Andrade AL, Zicker F, de Oliveira RM, et al. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet. Nov 23 1996;348(9039):1407-13. [Medline].
10. Gallerano RH, Marr JJ, Sosa RR. Therapeutic efficacy of allopurinol in patients with chronic Chagas' disease. Am J Trop Med Hyg. Aug 1990;43(2):159-66. [Medline].
11. Apt W, Arribada A, Zulantay I, et al. Itraconazole or allopurinol in the treatment of chronic American trypanosomiasis: the result of clinical and parasitological examinations 11 years post-treatment. Ann Trop Med Parasitol. Dec 2005;99(8):733-41. [Medline].
12. Lo Presti MS, Rivarola HW, Bustamante JM, et al. Thioridazine treatment prevents cardiomyopathy in Trypanosoma cruzi mice. Int J Antimicrob Agents. Jun 2004;23(6):634-636. [Medline].
13. Acosta Rodriguez EV, Zuniga EI, Montes CL, et al. Trypanosoma cruzi infection beats the B-cell compartment favouring parasite establishment: can we strike first?. Scand J Immunol. Aug-Sep 2007;66(2-3):137-42. [Medline].
14. Alter HJ, Stramer SL, Dodd RY. Emerging infectious diseases that threaten the blood supply. Semin Hematol. Jan 2007;44(1):32-41. [Medline].
15. Barbosa B. Noninvasive prognostic markers for cardiac death and ventricular arrhythmia in long-term follow-up of subjects with chronic Chagas' disease. Braz J Med Biol Res. 40(2);2007 Feb:167-178. [Medline].
16. Bern C, Montgomery SP, Herwaldt BL, et al. Evaluation and treatment of chagas disease in the United States: a systematic review. JAMA. Nov 14 2007;298(18):2171-81. [Medline].
17. Bittencourt AL. Congenital Chagas disease. Am J Dis Child. Jan 1976;130(1):97-103. [Medline].
18. Blood donor screening for chagas disease--United States, 2006-2007. MMWR Morb Mortal Wkly Rep. Feb 23 2007;56(7):141-3. [Medline].
19. Bocchi EA, Bellotti G, Mocelin AO, et al. Heart transplantation for chronic Chagas' heart disease. Ann Thorac Surg. Jun 1996;61(6):1727-33. [Medline].
20. Brun R, Balmer O. New developments in human African trypanosomiasis. Curr Opin Infect Dis. Oct 2006;19(5):415-20. [Medline].
21. Caballero ZC, Sousa OE, Marques WP, Saez-Alquezar A, Umezawa ES. Evaluation of serological tests to identify Trypanosoma cruzi infection in humans and determine cross-reactivity with Trypanosoma rangeli and Leishmania spp. Clin Vaccine Immunol. Aug 2007;14(8):1045-9. [Medline].
22. Carod-Artal FJ, Horan TA, Vargas AP, Ribeiro LS, Mamare EM. Cardioembolic stroke and ischemic small bowel infarction in a Chagas' disease patient. Eur J Neurol. May 2007;14(5):e8. [Medline].
23. Castro JA, de Mecca MM, Bartel LC. Toxic side effects of drugs used to treat Chagas' disease (American Trypanosomiasis). Hum Exp Toxicol. Aug 2006;25(8):471-79. [Medline].
24. Chagas' disease--an epidemic that can no longer be ignored. Lancet. Aug 19 2006;368(9536):619. [Medline].
25. Crema E, Ribeiro LB, Terra JA Jr, Silva AA. Laparoscopic transhiatal subtotal esophagectomy for the treatment of advanced megaesophagus. Ann Thorac Surg. Oct 2005;80(4):1196-201. [Medline].
26. Cui M, McCooeye MA, Fraser C, Mester Z. Quantitation of lysergic acid diethylamide in urine using atmospheric pressure matrix-assisted laser desorption/ionization ion trap mass spectrometry. Anal Chem. Dec 1 2004;76(23):7143-8. [Medline].
27. da Silveira AB, Lemos EM, Adad SJ, et al. Megacolon in Chagas disease: a study of inflammatory cells, enteric nerves, and glial cells. Hum Pathol. May 7 2007;[Medline].
28. de Melo-Jorge M, PereiraPerrin M. The Chagas' disease parasite Trypanosoma cruzi exploits nerve growth factor receptor TrkA to infect mammalian hosts. Cell Host Microbe. Jun 14 2007;1(4):251-61. [Medline].
29. de Oliveira RB, Troncon LE, Dantas RO, Menghelli UG. Gastrointestinal manifestations of Chagas' disease. Am J Gastroenterol. Jun 1998;93(6):884-9. [Medline].
30. de Souza W. Chagas' disease: facts and reality. Microbes Infect. Apr 2007;9(4):544-5. [Medline].
31. Docampo R, Moreno SN, Cruz FS. Enhancement of the cytotoxicity of crystal violet against Trypanosoma cruzi in the blood by ascorbate. Mol Biochem Parasitol. Jan 15 1988;27(2-3):241-7. [Medline].
32. Dutra WO, Rocha MO, Teixeira MM. The clinical immunology of human Chagas disease. Trends Parasitol. Dec 2005;21(12):581-7. [Medline].
33. Fabbro DL, Streiger ML, Arias ED, et al. Trypanocide treatment among adults with chronic Chagas disease living in Santa Fe (Argentina), over a mean follow-up of 21 years: parasitological, serological and clinical evaluation. Rev Soc Bras Med Trop. Jan-Feb 2007;40(1):1-10. [Medline].
34. Ferreira MS, Nishioka Sde A, Rocha A, et al. Acute fatal Trypanosoma cruzi meningoencephalitis in a human immunodeficiency virus-positive hemophiliac patient. Am J Trop Med Hyg. Dec 1991;45(6):723-7. [Medline].
35. Ferreira MS, Nishioka Sde A, Silvestre MT, et al. Reactivation of Chagas' disease in patients with AIDS: report of three new cases and review of the literature. Clin Infect Dis. Dec 1997;25(6):1397-400. [Medline].
36. Flores-Chavez M, Bosseno MF, Bastrenta B, et al. Polymerase chain reaction detection and serologic follow-up after treatment with benznidazole in Bolivian children infected with a natural mixture of Trypanosoma cruzi I and II. Am J Trop Med Hyg. Sep 2006;75(3):497-501. [Medline].
37. Garg N, Bhatia V. Current status and future prospects for a vaccine against American trypanosomiasis. Expert Rev Vaccines. Dec 2005;4(6):867-80. [Medline].
38. Grant IH, Gold JW, Wittner M, et al. Transfusion-associated acute Chagas disease acquired in the United States. Ann Intern Med. Nov 15 1989;111(10):849-51. [Medline].
39. Gurtler RE, Kitron U, Cecere MC, Segura EL, Cohen JE. Sustainable vector control and management of Chagas disease in the Gran Chaco, Argentina. Proc Natl Acad Sci U S A. Oct 9 2007;104(41):16194-9. [Medline].
40. Guzman-Bracho C. Epidemiology of Chagas disease in Mexico: an update. Trends Parasitol. Aug 2001;17(8):372-6. [Medline].
41. Hagar JM, Rahimtoola SH. Chagas' heart disease in the United States. N Engl J Med. Sep 12 1991;325(11):763-8. [Medline].
42. Heringer-Walther S, Moreira MC, Wessel N, et al. Brain natriuretic peptide predicts survival in Chagas' disease more effectively than atrial natriuretic peptide. Heart. Mar 2005;91(3):385-7. [Medline].
43. Hermann E, Alonso-Vega C, Berthe A, et al. Human congenital infection with Trypanosoma cruzi induces phenotypic and functional modifications of cord blood NK cells. Pediatr Res. Jul 2006;60(1):38-43. [Medline].
44. Jardim E, Takayanagui OM. Chagasic meningoencephalitis with detection of Trypanosoma cruzi in the cerebrospinal fluid of an immunodepressed patient. J Trop Med Hyg. Dec 1994;97(6):367-70. [Medline].
45. Kirchhoff LV. American trypanosomiasis (Chagas' disease)--a tropical disease now in the United States. N Engl J Med. Aug 26 1993;329(9):639-44. [Medline].
46. Lopes MF, Guillermo LV, Silva EM. Decoding caspase signaling in host immunity to the protozoan Trypanosoma cruzi. Trends Immunol. Aug 2007;28(8):366-72. [Medline].
47. Lowichik A, Ruff AJ. Parasitic infections of the central nervous system in children. Part II: Disseminated infections. J Child Neurol. Mar 1995;10(2):77-87. [Medline].
48. Lowichik A, Siegel JD. Parasitic infections of the central nervous system in children. Part I: Congenital infections and meningoencephalitis. J Child Neurol. Mar 1995;10(1):4-17. [Medline].
49. Marin-Neto JA, Cunha-Neto E, Maciel BC, Simoes MV. Pathogenesis of chronic Chagas heart disease. Circulation. Mar 6 2007;115(9):1109-23. [Medline].
50. Meneghelli UG. Chagasic enteropathy. Rev Soc Bras Med Trop. May-Jun 2004;37(3):252-60. [Medline].
51. Miles MA, Feliciangeli MD, de Arias AR. American trypanosomiasis (Chagas' disease) and the role of molecular epidemiology in guiding control strategies. BMJ. Jun 28 2003;326(7404):1444-8. [Medline]. [Full Text].
52. Moncayo A, Ortiz Yanine MI. An update on Chagas disease (human American trypanosomiasis). Ann Trop Med Parasitol. Dec 2006;100(8):663-77. [Medline].
53. Moon TD, Oberhelman RA. Antiparasitic therapy in children. Pediatr Clin North Am. Jun 2005;52(3):917-48, viii. [Medline].
54. Mora MC, Negrette OS, marco D, et al. Early diagnosis of congenital Trypanosoma cruzi infection using PCR, hemoculture, and capillary concentration, as compared with delayed serology. J Parasotol. Dec 2005;91(6):1468-1473. [Medline].
55. Nahas SC, Habr-Gama A, Nahas CS, et al. Surgical treatment of Chagasic megacolon by abdominal rectosigmoidectomy with immediate posterior end-to-side stapling (Habr-Gama technique). Dis Colon Rectum. Sep 2006;49(9):1371-8. [Medline].
56. Oliveira-Filho J, Viana LC, Vieira-de-Melo RM, et al. Chagas disease is an independent risk factor for stroke: baseline characteristics of a Chagas Disease cohort. Stroke. Sep 2005;36(9):2015-7. [Medline].
57. Ortega-Barria E, Pereira ME. Entry of Trypanosoma cruzi into eukaryotic cells. Infect Agents Dis. Jun 1992;1(3):136-45. [Medline].
58. Paglini-Oliva P, Rivarola HW. Central nervous system agents used as Trypanosoma cruzi infection chemotherapy: phenothiazines and related compounds. Anti-Infect Agents. 2003;2:323-33.
59. Peralta JM, Teixeira MG, Shreffler WG, et al. Serodiagnosis of Chagas' disease by enzyme-linked immunosorbent assay using two synthetic peptides as antigens. J Clin Microbiol. Apr 1994;32(4):971-4. [Medline]. [Full Text].
60. Pinto Dias JC. The treatment of Chagas disease (South American Tyrpanosomiasis). Ann Intern Med. May 16 2006;144(10):772-774. [Medline].
61. Piron M, Fisa R, Casamitjana N, et al. Development of a real-time PCR assay for Trypanosoma cruzi detection in blood samples. Acta Trop. Sep 2007;103(3):195-200. [Medline].
62. Prata A. Chagas' disease. Infect Dis Clin North Am. Mar 1994;8(1):61-76. [Medline].
63. Prata A. Clinical and epidemiological aspects of Chagas disease. Lancet Infect Dis. Sep 2001;1(2):92-100. [Medline].
64. Punukollu G, Gowda RM, Khan IA, et al. Clinical aspects of the Chagas' heart disease. Int J cardiol. Feb 14 2007;115(3):279-83. [Medline].
65. Ramasawmy R, Fae KC, Cunha-Neto E, et al. Variants in the promoter region of IKBL/NFKBIL1 gene may mark susceptibility to the development of chronic Chagas' cardiomyopathy among Trypanosoma cruzi-infected individuals. Mol Immunol. Jan 2008;45(1):283-8. [Medline].
66. Ramirez LE, Lages-Silva E, Pianetti GM, et al. Prevention of transfusion-associated Chagas' disease by sterilization of Trypanosoma cruzi-infected blood with gentian violet, ascorbic acid, and light. Transfusion. Mar 1995;35(3):226-30. [Medline].
67. Rassi A Jr, Rassi A, Little WC, et al. Development and validation of a risk score for predicting death in Chagas' heart disease. N Engl J Med. Aug 24 2006;355(8):799-808. [Medline].
68. Rassi A Jr, Rassi A, Rassi SG. Predictors of mortality in chronic Chagas disease: a systematic review of observational studies. Circulation. Mar 6 2007;115(9):1101-8. [Medline].
69. Rassi A, Luquetti AO, Rassi A Jr, et al. Specific treatment for Trypanosoma cruzi: lack of efficacy of allopurinol in the human chronic phase of Chagas disease. Am J Trop Med Hyg. Jan 2007;76(1):58-61. [Medline].
70. Reddy M, Gill SS, Kalkar SR, et al. Oral drug therapy for multiple neglected tropical diseases: a systematic review. JAMA. Oct 24 2007;298(16):1911-24. [Medline].
71. Reyes PA, Vallejo M. Trypanocidal drugs for late stage, symptomatic Chagas disease (Trypanosoma cruzi infection). Cochrane Database Syst Rev. 2005;(4):CD004102. [Medline].
72. Riarte A, Luna C, Sabatiello R, et al. Chagas' disease in patients with kidney transplants: 7 years of experience 1989-1996. Clin Infect Dis. Sep 1999;29(3):561-7. [Medline].
73. Riera C, Guarro A, El Kassab H, et al. Congenital transmission of Trypanosoma cruzi in Europe (Spain): a case report. Am J Trop Med Hyg. Dec 2006;75(6):1078-1081. [Medline].
74. Rocha MO, Teixeira MM, Ribeiro AL. An update on the management of Chagas cardiomyopathy. Expert Rev Anti Infect Ther. Aug 2007;5(4):727-43. [Medline].
75. Rochitte CE, Nacif MS, de Oliveira Junior AC, et al. Cardiac magnetic resonance in Chagas' disease. Artif Organs. Apr 2007;31(4):259-67. [Medline].
76. Salis GB, Mazzadi SA, Garcia AO, Chiocca JC. Pneumatic dilatation in achalasia of the esophagus: a report from Argentina. Dis Esophagus. 2004;17(2):124-8.