Chagas Disease

Chagas Disease – 11 Interesting Facts

Chagas disease is an infection caused by the protozoan Trypanosoma cruzi, which is endemic to regions of Central and South America ¹
Infection is typically transmitted by contact with the feces of infected triatomine bugs; however, infection can also be transmitted congenitally or via blood transfusion, organ transplant, or contaminated food or drink
Acute phase of infection is usually mild or asymptomatic; rarely associated with myocarditis or meningoencephalitis, predominantly in immunocompromised patients or infants
Chronic phase of infection is associated with cardiac and gastrointestinal complications in approximately 40% to 50% of cases; typically appears 10 to 30 years after the initial infection ²
Dilated cardiomyopathy is the most important and severe manifestation of chronic disease and is characterized by heart failure, arrhythmias, thromboembolic phenomena, and sudden death
Diagnosis of acute-phase Chagas disease is confirmed by observation of motile parasite trypomastigotes in a blood smear
Diagnosis of chronic-phase Chagas disease is based on serology, followed by investigation of any cardiovascular symptoms or ECG changes with comprehensive cardiac evaluation
Investigate gastrointestinal symptoms with imaging of the involved area (esophagus, colon), including investigation for occult cardiac involvement
Treatment with benznidazole (first line) or nifurtimox is indicated for all patients with acute, congenital, or reactivated Chagas disease and for patients younger than 18 years with chronic-phase disease; also recommended for adults between ages 19 and 50 years with chronic-phase disease without advanced Chagas cardiomyopathy ³
Chagas cardiomyopathy is managed by treating the various clinical manifestations (eg, with diuretics, ACE inhibitors, β-adrenergic blockers, anticoagulants, and antiarrhythmic agents); implantation of a pacemaker or intracardiac defibrillator or heart transplant may be required
Management of gastrointestinal disease involves ameliorating symptoms through dietary, medical, and surgical measures

Urgent Action

Ventricular arrhythmias (especially in conjunction with heart failure) substantially increase the risk for sudden death and may necessitate placement of a defibrillator
Thromboembolic complications require urgent medical or surgical management
Tamponade, a rare complication of acute myocarditis, requires urgent pericardiocentesis

Pitfalls

Asymptomatic patients may develop cardiomyopathy decades after initial infection; follow up at annual or biannual intervals ⁴

Introduction

Chagas disease (American trypanosomiasis) is a systemic infection caused by the protozoan Trypanosoma cruzi⁵
- Endemic throughout Mexico and Central and South America; most cases in the United States and Europe are acquired in endemic countries
- Typically transmitted through contact with the feces of infected triatomine bugs, bloodsucking insects that feed on humans and animals
- Patients with chronic-phase infection can also transmit infection congenitally, via blood transfusion, and via organ transplant
Chronic infection is associated with cardiac or gastrointestinal complications in approximately 40% to 50% of cases ²

Classification

Acute phase
- Lasts from 4 to 8 weeks after infection, usually asymptomatic but may be accompanied by mild symptoms in 5% of cases ³
- Severe complications, such as acute myocarditis or meningoencephalitis, occur in fewer than 1% of cases and can be fatal ⁴
- Severe myocarditis may lead to cardiac tamponade
Chronic phase
- Approximately 2 months after inoculation, Chagas disease progresses from the acute phase to a decades-long period of chronic infection ⁶
- This chronic phase is further categorized as one of the following:
  - Indeterminate (has no signs or symptoms; most patients are unaware of infection status) ²
    - This applies to most patients with chronic-phase Chagas disease
  - Determinate (has clinical manifestations) ²
    - 40% to 50% of patients progress to this phase over the course of their lives
    - Clinical manifestations (cardiomyopathy and/or motility disturbances, such as megacolon and megaesophagus) typically appear 10 to 30 years after the initial infection
  - Reactivation
    - Defined as detectable parasitemia with or without clinical symptoms ⁷
    - Reactivation of infection may occur in patients with chronic-phase Chagas disease who become immunosuppressed (eg, HIV infection, immunosuppression to prevent transplant rejection)
      - Clinical manifestations are similar to those of severe acute infection ⁴
      - Panniculitis, subcutaneous nodules, and myocarditis are reported among organ transplant recipients; meningoencephalitis is more common in patients with AIDS ⁷
Chagas cardiomyopathy stages ⁸
- A (indeterminate form)
  - Positive serology but no structural cardiomyopathy or heart failure symptoms; normal ECG findings
  - At risk for developing heart failure
- B1 (Chagas cardiomyopathy)
  - Structural cardiomyopathy as evidenced by ECG or echocardiographic changes, but normal ventricular function and no signs and symptoms of heart failure
- B2 (Chagas dilated cardiomyopathy/heart failure)
  - Structural cardiomyopathy characterized by ventricular dysfunction but no signs and symptoms of heart failure
- C (Chagas dilated cardiomyopathy/heart failure)
  - Ventricular dysfunction and symptoms of heart failure (New York Heart Association functional classes I-IV)
- D (Chagas dilated cardiomyopathy/heart failure)
  - Refractory symptoms of heart failure at rest despite optimized clinical treatment
  - Requires specialized intervention

Diagnosis

Clinical Presentation

History

The incubation period after exposure to vector-borne Trypanosoma cruzi is 1 to 2 weeks but may extend to 4 months if transmitted by blood transfusion ³
Acute phase ⁴⁶
- Approximately 95% of patients are asymptomatic ³
- Most symptomatic patients experience nonspecific, mild symptoms (eg, myalgia, headache, fever) ⁶
- May have swelling at site of inoculation with parasite
- Very rarely, symptoms associated with meningoencephalitis or myocarditis are present
  - Headache, confusion
  - Dyspnea, chest pain, palpitations
Chronic phase
- Most patients are asymptomatic
- Cardiac symptoms develop in 20% to 30% of cases as a result of conduction abnormalities and progressive dilated cardiomyopathy ²
  - Dyspnea is the most common symptom of cardiac involvement in the chronic stage ⁶
  - Generalized fatigue or weakness is a common concern ⁹
  - Chest pain is often present, possibly with dizziness and dyspnea ⁴
  - Palpitations and presyncope or syncope may occur
  - Patients are at risk for sudden cardiac death ⁴
- Digestive symptoms occur in 10% to 15% of cases ²
  - Constipation is the most common symptom of digestive involvement during the chronic phase ⁶
  - Megaesophagus is typically characterized by dysphagia, odynophagia, and epigastric pain ³
    - Weight loss, cough, and regurgitation may also occur ⁴
  - Megacolon can result in prolonged constipation, abdominal pain, or both ³
- Cardiac and digestive manifestations may coexist ¹⁰
Reactivation
- May present as cardiac (eg, dyspnea, palpitations, edema) or central nervous system (headache, altered mental status, focal weakness) disease ¹¹
  - Central nervous system involvement tends to occur more commonly in patients with HIV ¹²
Congenital infection varies from minimal to severe clinical disease
- May be associated with premature birth

Physical examination

Acute phase
- Nonspecific findings include fever, tachycardia, and lymphadenopathy ² ³
- Portal-of-entry evidence is seen in approximately 50% of cases, either Romaña sign (most common) or a chagoma ³
  - Romaña sign (ie, unilateral edema of the upper and lower eyelid) occurs if conjunctiva is site of inoculation, when vector feces has accidentally come into contact with eye
  - A chagoma (ie, localized subcutaneous edema and induration) may be found at the site of inoculation, typically on face or extremities
- Hepatosplenomegaly or generalized subcutaneous edema may be present in the acute phase ³
- Subcutaneous nodules or skin ulcers may be seen in immunocompromised patients with reactivated disease ³
- The rare patient with meningoencephalitis may exhibit a decreased level of consciousness or focal neurologic signs
- Signs of heart failure (eg, pulmonary rales, irregular and/or rapid pulse, third heart sound, peripheral edema) characterize the uncommon presentation of acute myocarditis
- Patients who develop Chagas disease as a result of receiving an organ transplant tend to have more severe disease manifestations ¹¹
Chronic infection
- Cardiac involvement includes tachyarrhythmia or bradyarrhythmia and signs of congestive heart failure (eg, jugular venous distention, pulmonary rales, peripheral edema)
  - Findings of pulmonary embolism, stroke, cardiac or mesenteric infarction, or acute ischemia of an extremity may result from embolization of mural thrombi
- Parotid hypertrophy may be seen in patients with megaesophagus ²
- Megacolon may be associated with abdominal distention
Reactivation ¹¹
- Nodular skin lesions are common
- Cardiac manifestations may include jugular venous distention, pulmonary rales, rapid and/or irregular heartbeat, third heart sound, and peripheral edema
Congenital infection ¹¹
- Manifestations may include low birth weight, low Apgar scores, hepatosplenomegaly, respiratory distress, abdominal distention, and generalized edema

Causes

Trypanosoma cruzi infection occurs when vector feces containing the parasites contaminate the vector bite wound, skin excoriation, or mucous membrane
- Triatoma infestans, Rhodnius prolixus, and Triatoma dimidiata are the 3 most common vector species in transmission to humans ³

Risk factors and/or associations

Age

Children and adolescents are the predominant population infected via vector; adults are more likely to acquire infection via blood transfusion or organ transplant ³

Other risk factors/associations

Travel to or residence in endemic regions or immigration from these regions, especially Central and South America ³
- Poor housing in rural areas is an additional risk factor, especially for populations living in mud and thatched dwellings, which provide an ideal habitat for the vectors ¹³
- Trypanosoma cruzi–infected triatomine bugs and animal reservoirs are present in the United States, mainly in the Southwest, but vector-borne disease is rarely acquired in United States ⁴
  - Outdoor activities, such as camping and hiking, are the main sources of risk for transmission in the United States
Ingestion of contaminated food or liquid ³
- Consuming contaminated food (eg, sugar cane juice, açaí fruit juice, raw meat) is a rare cause of Chagas disease; typically associated with severe parasitic infestation, acute symptoms, and high mortality
Blood and blood product transfusion
- 10% to 20% risk of acquiring Chagas disease after transfusion of 1 unit of blood from an infected donor ³
- However, widespread implementation of screening in endemic countries has reduced the role of blood transfusion in disease transmission ⁷
- Highest risk of infection is associated with platelet transfusion ⁷
Organ or bone marrow transplant from a chronically infected donor ¹¹
Vertical transmission from mother to infant ⁵
- Approximately 1% to 10% of pregnant patients with chronic Trypanosoma cruzi infection transmit the infection to their infants
Sexual transmission ¹⁴
Accidental laboratory exposure

Diagnostic Procedures

Primary diagnostic tools

Testing for Chagas disease may be prompted by clinical presentation and epidemiologic risk factors (primarily a history of living in or travel to an endemic area)
Most patients are asymptomatic; infection may be detected incidentally during screening of potential blood donors ⁴
Acute-phase Chagas disease is confirmed by observation of motile parasite trypomastigotes in a blood smear ⁴
- Molecular diagnosis by polymerase chain reaction analysis is indicated in cases of acute disease transmitted by blood transfusion or organ transplant and cases of early congenital infection ¹⁵
Evaluate patients with acute symptomatic disease and symptoms using ECG and echocardiography to rule out left ventricle dysfunction due to myocarditis or significant pericardial effusion, which may lead to tamponade ¹⁶ ¹⁷
Diagnosis of chronic-phase Chagas disease is based on results of serologic testing, most commonly enzyme immunoassay, indirect fluorescent antibody tests, and indirect hemagglutination ²
- To increase accuracy of the diagnosis, use 2 tests based on different antigens or techniques in parallel ⁴¹⁸
  - If the results do not agree, use a third assay ¹⁸ or repeat sampling to confirm the diagnosis
Further evaluation of seropositive patients includes detailed history with emphasis on symptoms suggestive of cardiac and gastrointestinal involvement, physical examination, assessment of resting 12-lead ECG, and chest radiography ²¹⁸
- Evaluate all newly diagnosed patients using echocardiography to exclude left ventricle dysfunction, aneurysms, conduction abnormalities, and arrhythmias ¹⁶ ¹⁸
- Asymptomatic patients with no evidence of cardiac or gastrointestinal involvement on physical examination and no abnormal ECG or echocardiographic findings are considered to have an indeterminate form of disease
- Patients with symptoms or abnormal findings require further assessment tailored to individual status
  - Comprehensive cardiac evaluation to grade presence and severity of Chagas cardiomyopathy may include 24-hour ambulatory ECG monitoring, cardiac MRI, exercise stress testing, nuclear medicine testing, electrophysiology studies, and cardiac catheterization ² ⁸ ¹⁶
  - Use barium swallow or barium enema to evaluate gastrointestinal symptoms ⁴
Diagnosis of Chagas disease reactivation is made by identifying the parasite or its products in tissue or fluid (eg, brain biopsy, lymph node specimen, cerebrospinal fluid, pericardial fluid, blood, skin lesion) ¹²
- Conventional polymerase chain reaction is not useful, as it can yield a positive result in chronic infection without reactivation
- Quantitative polymerase chain reaction assays performed on serial blood specimens showing rising parasitemia over time can provide an early indicator of reactivation

Laboratory

Microscopic examination of blood smear ¹⁵
- Giemsa-stained smear is generated using fresh preparations of anticoagulated blood or buffy coat
- Motile trypomastigotes can be detected in the acute phase ⁴
- Parasitemia decreases within 90 days of infection, even without treatment, and becomes undetectable after that point ⁴
Serologic testing ¹⁵
- An indirect fluorescent antibody test and a commercial ELISA are available from the CDC
- Positive test result identifies IgG antibodies to Trypanosoma cruzi antigen
Polymerase chain reaction analysis ¹⁵
- Molecular detection of trypanosome DNA in blood
- Indicated for cases of congenital and transfusion- or transplant-associated Chagas disease

Imaging

Echocardiography ²¹⁶
- Indicated for all patients with acute Chagas disease and those with chronic disease and cardiovascular or gastrointestinal symptoms or ECG changes as part of comprehensive cardiac evaluation to grade presence and severity of Chagas cardiomyopathy ³ ⁸
- Evaluates ventricular function, wall motion, and structure ⁴
- In acute myocarditis, significant pericardial effusions and decreased contractility may be noted
- Features characteristic of Chagas cardiomyopathy ¹⁹
  - Left ventricular diastolic dysfunction
  - Wall motion abnormalities in the inferolateral wall and apex, including left ventricular aneurysm in a significant number
  - Mural thrombi
  - Prominent right ventricular dysfunction
Cardiac MRI
- Indicated for selected patients with Chagas cardiomyopathy to evaluate extension of fibrosis ⁸
- Useful for sudden cardiac death and thromboembolic risk stratification and prognosis ¹⁶
Chest radiography ⁹
- Indicated for asymptomatic patients with normal ECG findings to confirm indeterminate Chagas disease or for patients with cardiovascular or gastrointestinal symptoms or ECG changes as part of comprehensive cardiac evaluation ⁸
- Used to assess baseline heart size and pulmonary congestion and to detect alternative diseases that may contribute to the patient’s symptoms ⁸
Barium swallow ⁴
- Indicated for patients with gastrointestinal symptoms that suggest megaesophagus
- Evaluates size and motility of esophagus
- Esophageal enlargement and impaired swallowing indicates megaesophagus
Barium enema ⁴
- Indicated for patients with gastrointestinal symptoms that suggest megacolon
- Evaluates colon size and obstruction cause
- Obstruction (fecaloma) or abnormal shape of megacolon may be observed

Functional testing

ECG
- Resting 12-lead ECG with a 30-second lead II rhythm strip ⁴
  - Indicated for all patients who are seropositive for Chagas disease (acute or chronic)
  - Findings in acute-phase Chagas disease may include sinus tachycardia, first-degree atrioventricular block, low QRS voltage, and primary T-wave changes
  - Findings in chronic-phase Chagas disease may include right bundle branch block, left anterior fascicular block, ventricular premature beats, ST-T changes, abnormal Q waves, and low QRS voltage
    - The combination of right bundle branch block and left anterior fascicular block is typical of Chagas heart disease ³
- 24-Hour ambulatory ECG monitoring
  - Indicated for all patients with abnormal ECG findings or symptoms suggestive of arrhythmias ⁸
  - Arrhythmias may be detected in patients with Chagas cardiomyopathy, including: ³
    - Frequent, complex ventricular premature beats, including couplets and runs of nonsustained ventricular tachycardia ¹⁰
    - Bradyarrhythmias, advanced atrioventricular block, or sick sinus syndrome ¹⁰
Exercise test on a treadmill (Bruce protocol) ⁴
- Indicated for patients with cardiovascular symptoms (especially chest pain) or ECG changes as part of comprehensive cardiac evaluation to grade presence and severity of Chagas cardiomyopathy ⁸
- Evaluates for exercise-induced arrhythmias and functional capacity; can exclude myocardial ischemia as cause of symptoms

Differential Diagnosis

Most common

Acute phase
- Ocular conditions (eg, conjunctivitis, ocular trauma, orbital cellulitis, retro-orbital thrombosis)
  - Eyelid edema associated with ocular conditions may mimic Romaña sign
  - Eye pain, tearing, conjunctival injection, and history of injury or local infection associated with ocular conditions are not present with Romaña sign
  - Can usually be differentiated based on history and physical examination findings
- Insect bite
  - Erythematous, indurated lesion at site of insect bite may resemble a chagoma
  - Insect bite is more likely than a chagoma to be associated with pruritus; chagoma is more likely to involve regional lymphadenopathy
  - Can usually be differentiated based on history and physical examination findings
- Infectious mononucleosis (Epstein-Barr virus infection)
  - Self-limited viral infection caused by Epstein-Barr virus
  - Like Chagas disease, infectious mononucleosis may present with nonspecific signs and symptoms, such as malaise, fever, and lymphadenopathy
  - Pharyngitis and posterior cervical lymphadenopathy are characteristic features of Epstein-Barr virus infection but not Chagas disease; neither Romaña sign nor a chagoma occurs in Epstein-Barr virus infection
  - Diagnosed based on clinical presentation and serologic test results that confirm presence of antibodies to various Epstein-Barr virus antigens
- Acute toxoplasmosis
  - Infection with parasite Toxoplasma gondii
  - Like Chagas disease, may present with nonspecific signs and symptoms, such as myalgias, malaise, fever, and lymphadenopathy
  - Occasionally associated with eye pain, photophobia, and blurred vision, which are not features of Chagas disease
  - Diagnosed based on clinical presentation and serologic test results that confirm presence of toxoplasma-specific antibodies
Chronic phase
- Cardiac
  - Dilated cardiomyopathy, either idiopathic, ischemic, hypertensive, or valvular causes¹⁰
    - Similarities include symptoms and physical findings of dysrhythmias and heart failure
    - Negative Trypanosoma cruzi serology excludes Chagas cardiomyopathy; however, positive serology does not necessarily rule out an alternative cause for cardiac disease
    - Differentiated by cardiologist based on clinical, epidemiologic, ECG, and echocardiographic findings; myocardial biopsy may be required for definitive diagnosis ¹⁷
- Gastrointestinal ²⁰
  - Other conditions associated with dysphagia, odynophagia, and epigastric discomfort include idiopathic achalasia, esophagitis, esophageal carcinoma, and gastroesophageal reflux disease
    - Differentiated based on endoscopy, esophageal manometry, and barium swallow findings
  - Other causes of colonic inertia or obstruction (eg, fecal impaction; colonic malignancy; idiopathic, congenital, or acquired causes of megacolon)
    - Diagnosis is based on results of plain radiography, barium enema, colonoscopy, or anal manometry
  - Idiopathic achalasia
    - Motor disorder of the esophagus characterized by aperistalsis and incomplete lower esophageal sphincter relaxation without evidence of mechanical obstruction
    - Similarities include sensation of incomplete swallowing, dysphagia, fullness or pain in chest, regurgitation, halitosis; barium swallow showing dilated esophagus, retained contrast
    - Megaesophagus due to Chagas disease may be associated with megacolon or cardiac manifestations of Chagas disease, unlike idiopathic achalasia
    - Differentiated by absence of antibodies to Trypanosoma cruzi
    - Diagnose using high-resolution esophageal manometry; in the presence of suggestive symptoms, diagnosis is confirmed by the combination of aperistalsis and incomplete lower esophageal sphincter relaxation without evidence of mechanical obstruction
  - Reflux esophagitis
    - Esophageal irritation due to gastroesophageal reflux disease
    - Similarities include dysphagia, chest pain, and regurgitation
    - Reflux esophagitis does not typically cause retention of food in esophagus and is not associated with other features of Chagas disease, such as megacolon or cardiomyopathy (although may coexist with cardiomyopathy due to other causes, such as ischemia)
    - Differentiated by absence of esophageal dilation or contrast retention on barium swallow (which may demonstrate reflux) and by absence of antibodies to Trypanosoma cruzi
      - Can be diagnosed based on symptoms, and diagnosis may be confirmed with endoscopy
  - Hiatal hernia
    - Displacement of abdominal organs, most commonly the stomach, through the esophageal hiatus of the diaphragm into the mediastinum
    - Similarities include dysphagia, pain in chest, and eructation
    - Not associated with other features of Chagas disease, such as megacolon or cardiomyopathy (although may coexist with cardiomyopathy due to other causes, such as ischemia)
    - Differentiated by appearance of hiatal hernia on barium swallow, absence of contrast retention in esophagus (though may be present in the hernia), absence of antibodies to Trypanosoma cruzi
  - Esophageal carcinoma
    - Cancer of any of several upper gastrointestinal tract cancer types originating in esophagus or esophagogastric junction
    - Similarities include dysphagia, sense of fullness in esophagus, sensation of incomplete swallowing, chest pain, and weight loss
    - Not associated with other features of Chagas disease, such as megacolon or cardiomyopathy (although may coexist with cardiomyopathy due to other causes, such as ischemia)
    - Barium swallow or chest CT may show an esophageal mass, but definitive distinction is by biopsy
- Reactivation
  - Differential diagnosis includes other opportunistic infections characterized by skin lesions, brain lesions, or both
    - Toxoplasmosis
      - Infection caused by the protozoan parasite Toxoplasma gondii; reactivation of central nervous system disease may occur in immunocompromised patients
      - As in reactivation of Chagas disease, common symptoms include fever, altered mental status, and focal neurologic signs in immunocompromised patients; MRI or CT of brain may show one or more space-occupying lesions
      - As in Chagas disease, toxoplasmosis may include cardiac involvement
      - In contrast to Chagas disease, toxoplasmosis rarely includes skin lesions
      - Differentiated serologically or by biopsy
    - Nocardiosis
      - An acute or chronic infectious disease characterized by pulmonary and systemic involvement caused by gram-positive bacteria of the genus Nocardia
      - As with reactivated Chagas disease, may involve the central nervous system, causing headaches, focal neurologic deficits, and/or seizures
      - Similarities include fever and nodular skin lesions in an immunocompromised host with or without neurologic signs
      - Nocardiosis often includes pulmonary nodules, unlike Chagas disease
      - Diagnosis of nocardiosis is made by aspiration or biopsy of a lesion for microscopy and culture
- Congenital
  - Congenital disease may be undetected or very mild, but severe infection may present similarly to the following:
    - Neonatal sepsis
      - Infection characterized by bacteremia or bacterial meningitis presenting in the first 30 days of life ²¹
      - Similarities include association with prematurity, low birth weight, respiratory distress, bradyarrhythmias or tachyarrhythmias, and hepatosplenomegaly
      - In some cases, may be differentiated by an obvious alternate source (eg, maternal chorioamnionitis, erythema surrounding umbilical stump, herpetic skin lesions)
      - Differentiation made definitively by positive polymerase chain reaction for Chagas disease or definitive alternate diagnosis (eg, positive blood or spinal fluid cultures)
    - Hemolytic disease of the newborn (hydrops fetalis)
      - Isoimmune hemolytic disease of the newborn occurs when fetal RBC antigens not shared by the mother pass into maternal circulation and trigger antibody production in the mother
      - Similarities include poor Apgar scores, respiratory distress, abdominal distention, hepatosplenomegaly, and generalized edema
      - Early development of jaundice is characteristic of hydrops fetalis but not Chagas disease
      - Definitive diagnosis by ABO and Rh testing of infant and mother, peripheral smear, and Coombs test of infant

Treatment

Goals

Eliminate Trypanosoma cruzi parasitemia in acute, congenital, or reactivated phase of disease and in patients younger than 18 years with chronic phase of disease
Prevent or slow progression of cardiomyopathy in chronic disease ⁵

Disposition

Admission criteria

Severe complications of acute-phase Chagas disease (eg, acute myocarditis, meningoencephalitis)

Chronic-phase Chagas cardiomyopathy and refractory or hemodynamically unstable congestive heart failure or arrhythmias

Criteria for ICU admission

May be required for refractory arrhythmias or severe heart block

Recommendations for specialist referral

Evaluate and manage all cases in consultation with an infectious disease specialist
- The CDC Division of Parasitic Diseases offers advice about diagnostic testing, management, drug requests, and dosage regimens ¹⁵
Refer patients with Chagas cardiomyopathy to a cardiologist
Refer patients with gastrointestinal manifestations to a gastroenterologist

Treatment Options

Treatment with benznidazole or nifurtimox is indicated for all patients with acute, congenital, or reactivated Chagas disease and for patients younger than 18 years with chronic-phase disease ⁵

Treatment is also recommended for adult patients between ages 19 and 50 years with chronic-phase disease but without advanced Chagas cardiomyopathy ³
Drug treatment is optional for patients older than 50 years because risk of drug toxicity is higher and benefit has not been proved in this age group; when considering drug treatment, take into account age, clinical status, overall health, and patient preference ³
Antimicrobial treatment is not recommended for patients with advanced Chagas cardiomyopathy, as it has no effect on existing cardiac disease ⁴
Treatment of patients with gastrointestinal disease is the same as treatment of patients without advanced cardiomyopathy
- Drug absorption may be impaired in patients with megaesophagus; delay treatment until the condition is corrected by surgery

Benznidazole and nifurtimox ⁴are the only drugs with proven efficacy in treatment of Chagas disease; benznidazole is the first line agent because it is better tolerated ⁴ ²²

Both agents reduce symptom severity and shorten clinical course and duration of parasitemia in acute phase and slow development and progression of cardiomyopathy in adults with chronic-phase disease that is not yet advanced
Treatment achieves parasitologic cure in 60% to 85% of patients with acute-phase disease, more than 90% of infants with congenital infection (when treated in first year of life), and 60% of children between ages 6 and 12 years with asymptomatic chronic-phase infection ⁴
Both agents are FDA approved in pediatrics; resources on obtaining benznidazole can be found at https://www.benznidazoletablets.com ²³
Treatment adherence is low owing to high burden of adverse effects, including the following: ⁴
- Common adverse effects of benznidazole include allergic dermatitis (30%), peripheral neuropathy (30%), anorexia, weight loss, and insomnia
- Common adverse effects of nifurtimox include gastrointestinal symptoms such as nausea, vomiting, and anorexia leading to weight loss (30%-70%), headache, dizziness, vertigo, and polyneuropathy
- Patients should avoid concurrent alcohol consumption
- Better tolerated by younger patients, allowing use of higher-dose regimens

Treatment of Chagas cardiomyopathy should be managed by a cardiologist and address the various clinical manifestations; treatment may consist of diuretics, ACE inhibitors, β-adrenergic blockers, anticoagulants, and antiarrhythmic agents ⁸ ⁹ ¹⁰

Pacemaker or intracardiac defibrillator implant or heart transplant may be required ⁹

Management of gastrointestinal disease is directed at ameliorating symptoms and should be undertaken by a gastroenterologist

May involve dietary, medical, or surgical interventions ³

Drug therapy

Antiparasitic agents ²²⁴
- Benznidazole
  - Benznidazole Oral tablet; Infants and Children younger than 2 years†: 5 to 8 mg/kg/day PO divided twice daily for 60 days.
  - Benznidazole Oral tablet; Children 2 to 12 years weighing less than 15 kg: 5 to 8 mg/kg/day PO divided twice daily for 60 days; for ease of administration, a dose of 50 mg PO twice daily is recommended.
  - Benznidazole Oral tablet; Children 2 to 12 years weighing 15 to 19 kg: 5 to 8 mg/kg/day PO divided twice daily for 60 days; for ease of administration, a dose of 62.5 mg PO twice daily is recommended.
  - Benznidazole Oral tablet; Children 2 to 12 years weighing 20 to 29 kg: 5 to 8 mg/kg/day PO divided twice daily for 60 days; for ease of administration, a dose of 75 mg PO twice daily is recommended.
  - Benznidazole Oral tablet; Children 2 to 12 years weighing 30 to 39 kg: 5 to 8 mg/kg/day PO divided twice daily for 60 days; for ease of administration, a dose of 100 mg PO twice daily is recommended.
  - Benznidazole Oral tablet; Children 2 to 12 years weighing 40 to 59 kg: 5 to 8 mg/kg/day PO divided twice daily for 60 days; for ease of administration, a dose of 150 mg PO twice daily is recommended.
  - Benznidazole Oral tablet; Children 2 to 12 years weighing 60 kg or more: 5 to 8 mg/kg/day PO divided twice daily for 60 days; for ease of administration, a dose of 200 mg PO twice daily is recommended.
  - Benznidazole Oral tablet; Adolescents†: 5 to 8 mg/kg/day (Max: 400 mg/day) PO divided twice daily for 60 days.
  - Benznidazole Oral tablet; Adults†: 5 to 8 mg/kg/day (Max: 400 mg/day) PO divided twice daily for 60 days.
- Nifurtimox ²⁴
  - Nifurtimox Oral tablet; Term Neonates and Infants weighing 2.5 to 4.5 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 15 mg PO 3 times daily is recommended.
  - Nifurtimox Oral tablet; Term Neonates and Infants weighing 4.6 to 8 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 30 mg PO 3 times daily is recommended.
  - Nifurtimox Oral tablet; Infants and Children weighing 9 to 12 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 45 mg PO 3 times daily is recommended.
  - Nifurtimox Oral tablet; Children weighing 13 to 17 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 60 mg PO 3 times daily is recommended.
  - Nifurtimox Oral tablet; Children weighing 18 to 21 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 75 mg PO 3 times daily is recommended.
  - Nifurtimox Oral tablet; Children weighing 22 to 26 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 90 mg PO 3 times daily is recommended.
  - Nifurtimox Oral tablet; Children and Adolescents weighing 27 to 34 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 120 mg PO 3 times daily is recommended.
  - Nifurtimox Oral tablet; Children and Adolescents weighing 35 to 40 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 180 mg PO 3 times daily is recommended.
  - Nifurtimox Oral tablet; Children and Adolescents weighing 41 to 50 kg: 8 to 10 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 120 mg PO 3 times daily is recommended.
  - Nifurtimox Oral tablet; Children and Adolescents weighing 51 to 70 kg: 8 to 10 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 180 mg PO 3 times daily is recommended.
  - Nifurtimox Oral tablet; Adolescents weighing 71 to 90 kg: 8 to 10 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 240 mg PO 3 times daily is recommended.
  - Nifurtimox Oral tablet; Adolescents weighing 91 kg or more: 8 to 10 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 300 mg PO 3 times daily is recommended.
  - Nifurtimox Oral tablet; Adults†: 8 to 10 mg/kg/day (Max: 900 mg/day) PO divided 3 times daily for 60 days.

Nondrug and supportive care

Diet
- Antioxidant therapy might attenuate oxidative damage caused by chronic Chagas disease–associated cardiopathy, leading to a better prognosis for patients. ²⁵

Comorbidities

Severe renal or hepatic insufficiency ⁴
- Benznidazole and nifurtimox should not be taken by patients with kidney or liver failure. ²⁶
Immunocompromised status (eg, patients with AIDS, patients who are undergoing chemotherapy, patients receiving immunosuppressive regimens for organ transplant) ³
- May experience reactivation of chronic-phase infection with increased parasite replication and parasitemia detectable on microscopy
- Reactivation features differ from acute phase and according to underlying cause of immunosuppression ⁴
  - Subcutaneous nodules, myocarditis, and panniculitis are common in infected recipients of solid organ or bone marrow transplants
  - Meningoencephalitis and central nervous system lesions (mimicking toxoplasmosis) are common in patients with AIDS ¹²
- Treatment with standard dose regimen of benznidazole or nifurtimox is recommended; optimal duration of therapy has not been established ⁴

Special populations

Pregnant and breastfeeding patients ⁴
- Benznidazole and nifurtimox should not be taken during pregnancy
- Safety for infants exposed through breastfeeding is uncertain; treatment is not recommended during breastfeeding
Patients with congenital infection
- Occurs in 1% to 10% of infants born to chronically infected mothers
- Most are asymptomatic or have nonspecific findings such as low birth weight, prematurity, or low Apgar scores ⁴
- Less commonly, hypotonicity, fever, hepatosplenomegaly, and signs of anemia (eg, pallor, irritability) may appear at birth or develop within weeks after delivery ³
- Rarely associated with myocarditis, meningoencephalitis, or pneumonitis, which have high mortality rates
- Programs to identify congenital infection rely on serologic diagnosis of infected mothers
  - Evaluate infants for congenital infection if mother has been diagnosed with Chagas disease or comes from an endemic area and has not been screened, or if infant has signs or symptoms suggestive of infection ²⁴
  - Diagnosis is based on microscopic examination of blood smears and polymerase chain reaction–based examination of cord blood, peripheral blood specimens, or both from neonates in the first 1 to 2 months after birth ⁴
  - If results are negative or testing is not done early in the infant’s life, obtain serologic tests at ages 9 and 12 months after the level of transferred maternal antibody has decreased ⁴
  - Test other children of infected mothers ⁴
- Treatment with standard dose regimen is recommended as soon as diagnosis has been made; it is well tolerated in infants and achieves high rate of parasitologic cure ⁴
  - Benznidazole is FDA approved for administration to children aged 2 to 12 years ²⁴
  - Nifurtimox is FDA approved for treatment of children from birth up to 18 years (weighing 2.5 kg or less) ²⁴

Monitoring

Monitor during drug therapy as follows: ⁴
- Nifurtimox
  - Obtain CBC and hepatic and renal function tests before commencing therapy, at 4 to 6 weeks, and at end of treatment
  - Check weight and evaluate for signs or symptoms of peripheral neuropathy every 2 weeks
  - Contraindicated for people with a background of neurologic or psychiatric disorders.
- Benznidazole
  - Obtain CBC and hepatic and renal function tests before starting therapy. Repeat CBC every 2 to 3 weeks during course of treatment
  - Evaluate for dermatitis and signs or symptoms of peripheral neuropathy beginning 10 days after start of treatment
  - Discontinue therapy if evidence of peripheral neuropathy, severe or exfoliative dermatitis, or bone marrow suppression is observed
Long-term follow-up ²⁷
- History and physical examination at least annually
- Annual ECG and serologic testing
- Echocardiography every 2 to 3 years depending on symptoms and disease severity

Complications

Complications of acute-phase disease are observed in fewer than 1% of all cases and include the following: ³
- Acute myocarditis
- Meningoencephalitis ²
- Infection in pregnancy may result in spontaneous abortion or placentitis
- Cardiomyopathy; estimated rate is 4.6% for patients with acute disease ²⁸
Complications of severe dilated cardiomyopathy in chronic phase of Chagas disease include the following: ³
- Congestive heart failure
- Ventricular aneurysm
- Thromboembolic events (eg, stroke)
- Arrhythmias, including ventricular tachycardia and atrial fibrillation
- Sudden cardiac death
- Pericardial effusion (rare)
- The estimated annual rate of cardiomyopathy is 1.9% for patients with indeterminate chronic disease ²⁸
Complications of Chagas megacolon include fecaloma and sigmoid volvulus ³
Complications of megaesophagus include aspiration, malnutrition, and parotid hypertrophy; patients with megaesophagus also have an increased risk for esophageal cancer ²

Prognosis

Manifestations of acute phase of Chagas disease resolve spontaneously in approximately 90% of infected people even if the infection is not treated with trypanocidal drugs ³
- 95% of patients are asymptomatic during this phase
- Mortality among symptomatic patients is 5% to 10%; usually due to severe myocarditis or meningoencephalitis
  - Children younger than 2 years are at higher risk for these manifestations
- Orally transmitted Trypanosoma cruzi infection is associated with more severe acute morbidity and higher mortality
Approximately 60% to 70% of patients develop the indeterminate form of chronic-phase Chagas disease and do not have clinically apparent disease ²
Approximately 30% to 40% of patients develop the determinate form of chronic-phase Chagas disease; cardiac and/or gastrointestinal manifestations develop 10 to 30 years after initial infection ²
- Sudden cardiac death is the most common form of mortality in patients with cardiac involvement, accounting for 66% of all deaths, followed by refractory heart failure (25%-30%), and thromboembolism (10%-15%) ²
- Patients with impaired left ventricular function, New York Heart Association functional class III/IV, cardiomegaly, or nonsustained ventricular tachycardia have a poorer prognosis ²⁹

Screening

At-risk populations

All Latin American immigrants (except those from the Caribbean region) who may have been exposed to Trypanosoma cruzi ²⁷
Females of childbearing age who have lived in areas of Mexico or South or Central America with endemic Chagas disease ¹⁸
Children whose mothers were born in endemic areas or are known to be infected ⁴ ²⁷
Pregnant patients who may have potentially been exposed to Trypanosoma cruzi ⁵ ³⁰
Family members of infected patients with similar exposure history ⁴
People with confirmed or highly suspected exposure (bites and/or triatomines found in home) in areas known to have triatomine species capable of transmitting Trypanosoma cruzi ¹⁸
Travelers with confirmed exposure to triatomines or related risk factors in areas where disease is endemic ¹⁸
Recipients of organ transplants from infected donors ³¹
- Transplantation programs can consider transplant of kidneys and livers from Trypanosoma cruzi–infected donors with informed consent from recipients; heart transplant from infected donors is not recommended

Screening tests

Children or family members of infected patients are screened with serologic tests, indirect fluorescent antibody test, or a commercial ELISA ⁴
- Definitive diagnosis requires a positive result obtained with use of 2 distinct serologic techniques ³⁰
When transplant of an organ from an infected donor has occurred, closely monitor the recipient by observing Trypanosoma cruzi polymerase chain reaction and microscopy of blood specimens weekly for the first 2 months, every 2 weeks during the third month, then monthly until at least 6 months after transplant ³¹

Prevention

Vector control is the main preventive measure in endemic areas ³²
Strategies to prevent transmission via blood transfusion and organ donation are important in areas where disease is not endemic, such as the United States: ³¹
- Universal screening of blood donors ³³
- Targeted screening of potential organ donors born in Mexico and Central and South America

References

1.Bern C et al: An estimate of the burden of Chagas disease in the United States. Clin Infect Dis. 49(5):e52-4, 2009