Approach
More than 99% of patients with Chagas disease remain undiagnosed in the US and Latin America.[134] Assessment of suspected or confirmed Chagas disease should include a thorough medical history (including identification of risk factors for exposure to the vector and parasite in endemic or nonendemic settings), a full review of systems with a focus on signs characteristic of Chagas disease, serologic testing, and, in some cases, parasitologic evaluation. A 12-lead ECG with a 30-cm lead II rhythm strip is necessary for all patients, and additional examinations (e.g., echocardiogram, 24-hour ambulatory ECG monitoring, barium studies of the esophagus or colon) may be performed if symptoms or signs indicate the need. Histology or biopsy is not recommended for diagnosis; histology is only carried out at autopsy for fatal cases.
Chagas disease is a reportable condition in six US states (Arizona, Arkansas, Louisiana, Mississippi, Tennessee, and Texas).[11]
History
Careful history-taking, identifying possible risks for infection, is helpful. Risk factors include exposure to Triatoma species and the presence of infected reservoirs; travel to or living in rural areas of endemic regions (recently or in the past); deforestation; poor housing and low socioeconomic status; oral ingestion of possibly contaminated food; transfusion with possibly infected blood; organ transplantation from an infected donor; accidental exposure to infected material (surgical, laboratory); Chagas disease during pregnancy (vertical transmission); and living in areas of risk in the US. The presence of Chagas disease in other family members is also a strong indicator. Most adults with Trypanosoma cruzi infection are unaware of their diagnosis and history consistent with acute Chagas disease from years prior is rarely given.[135]
Chagas disease is a heterogeneous condition with a wide variation in clinical presentation. Approximately 60% to 70% of infected people remain asymptomatic throughout their life.[2] The condition has two phases: acute and chronic. The acute phase usually lasts for 3 to 8 weeks (up to 12 weeks in some cases). Patients may be asymptomatic, present with mild symptoms, or a nonspecific febrile syndrome. Symptoms of the acute-phase may include fatigue, diarrhea, headache, vomiting, myalgia, irritability (children), and anorexia; these may be more severe after infection via oral transmission or in immunosuppressed patients. After the acute phase, most patients develop a chronic indeterminate form of the disease in which they have no signs or symptoms. Chronic-phase disease develops if the acute phase is undiagnosed or untreated though symptoms may not occur until decades later.[13]
Patients with manifestations of acute myocarditis may have symptoms such as cough, dyspnea, and atypical chest pain. Those who have ingested contaminated food or drink may have symptoms that include hematemesis, epigastric abdominal pain, melena, and hematochezia. In children the morbidity caused by the acute phase of Chagas disease is more pronounced than in adults.
In the chronic phase of Chagas disease, indeterminate forms do not exhibit any signs or symptoms consistent with cardiac or digestive issues. Additionally, ECGs and radiological exams of the heart, esophagus, and intestine show normal results. The gastrointestinal and cardiac manifestations of chronic disease usually become apparent years or decades after the infection, and occur almost exclusively in adults.[26][136][137] However, rarely patients can progress directly from acute infection to the chronic cardiac form.
Patients with cardiac forms of chronic-phase disease may present with symptoms that include palpitations, syncope, presyncope, dizziness, and even sudden death. Cardiomyopathy may cause symptoms of congestive heart failure (e.g., dyspnea, decreased exercise tolerance, peripheral edema). Thromboembolic phenomena may present with stroke or pulmonary embolism due to emboli from an intracardiac thrombus.
Patients with gastrointestinal forms of chronic disease may present with symptoms of esophagopathy (e.g., dysphagia, regurgitation, aspiration, odynophagia, substernal discomfort) and colonopathy (e.g., prolonged constipation, abdominal pain). Advanced cases of gastrointestinal disease may present with weight loss, acute abdominal pain, and evidence of complications (e.g., fecaloma, bowel obstruction, volvulus); these patients may also require surgical evaluation or treatment. Gastric dilation (with alterations of gastric motility and secretion) is a relatively rare manifestation.
Seizures and tremors may occur in patients with meningoencephalitis (acute or reactivation). Megaureter (with repeated urinary tract infections, back pain, nausea, or vomiting) is a relatively rare manifestation.
Physical examination
Examination of patients with acute-phase disease may reveal prolonged fever, rash, swelling around the site of inoculation, splenomegaly, hepatomegaly, and/or enlarged lymph nodes. There may be a history of an obvious portal of entry (e.g., inoculation chagoma, Romaña sign) in a small number of cases or the port of entry may be unknown. Chagoma (T. cruzi skin abscess) and the Romaña sign (unilateral conjunctivitis and painless swelling of the upper and lower eyelids) are pathognomonic, but only occur in a minority of patients, predominantly in children.[2] Patients with acute myocarditis may have tachycardia, hypotension, cardiomegaly, and/or signs of pericarditis. Jaundice may be present in patients who have ingested contaminated food or drink.
Examination of patients with indeterminate forms of chronic-phase disease will usually not reveal any specific signs. Patients with cardiac forms of chronic disease may have signs of congestive cardiac failure (jugular venous distention, cardiomegaly, lung rales or pleural effusion, edema) or evidence of thromboembolic phenomena (e.g., signs suggestive of stroke).[4][14] Gastrointestinal forms of chronic disease may reveal evidence of gastrointestinal complications (e.g., abdominal rebound tenderness, a sign of peritoneal irritation).
Patients with meningoencephalitis (acute or reactivation) may have specific clinical signs of meningeal irritation (predominant meningeal inflammation, Kernig sign, Brudzinski sign, nuchal rigidity, spinal rigidity), or clinical signs of cerebral mass lesions (mental status changes, seizures, focal motor or sensory abnormalities).
General laboratory investigations
Complete blood count (CBC) and liver function tests (LFTs) are nonspecific but are important for baseline profile as well as monitoring disease severity in the acute phase and adverse effects due to antiparasitic therapy. CBC is indicated to identify leukopenia or leukocytosis (mild or moderate), with a left shift. Lymphocytosis may be observed, but lymphocyte levels may also be normal or low. Hypochromic anemia and low platelet counts are also observed. Abnormal LFTs in acute Chagas disease, especially with suspected ingestion of contaminated food or drink, suggest hepatic lesions.
Coagulation tests are important in cases with hepatic failure or hemorrhagic manifestations. Pregnancy testing in women is recommended prior to specific treatment. Urine sediment examination, with evidence of compromised urinary function and bleeding, is important in monitoring treatment. Lumbar puncture with cerebrospinal fluid (CSF) analysis is required in cases of neurologic involvement.
Parasitologic and serologic evaluation
Diagnosis can be confirmed by parasitologic evaluation (recommended for acute-phase disease and reactivation) or serologic evaluation (recommended for chronic-phase disease).[13][34][138][139][140][141] Diagnostic testing for Chagas disease is not widely available in the US or other nonendemic countries.
Parasitologic evaluation
Direct methods are based on a search for the parasite in blood, CSF, or tissues (e.g., direct fresh test, stained smear). Indirect methods depend on the growth of the parasite in culture (hemoculture) to evaluate the life cycle in the vector after a blood meal on a patient (xenodiagnosis). Sensitivity depends on the level of parasitemia. Molecular diagnosis (e.g., polymerase chain reaction [PCR]) can be used when available.
Acute phase: direct examination of blood by microscopy of fresh preparations of anticoagulated blood is recommended. The trypomastigotes are translucent and are usually detected by the corresponding movement of red blood cells. Parasitic concentration methods (e.g., Strout method; quantitative buffy coat [QBC] test; microhematocrit) for evidence of trypomastigote forms are also used. Stained thin and thick blood smears may be examined for diagnosis; however, these have a lower sensitivity than other microscopy methods.[13][24] PCR is also a highly sensitive test in acute infection, and may show rising parasite loads before the parasites are detectable by microscopy.[2]
Chronic phase: although parasitologic evaluation is not the first option for the diagnosis of chronic-phase disease, diagnosis can be confirmed by blood or CSF culture (low sensitivity, high specificity) or xenodiagnosis (low sensitivity, high specificity). A meta-analysis has suggested that PCR has a relatively low sensitivity but very high specificity in chronic disease; therefore, it is not recommended.[141]
Reactivation phase: confirmed by direct examination of blood or CSF. This involves thick blood smear and applying parasitic concentration methods (e.g., Strout method, QBC, microhematocrit) for evidence of trypomastigote forms. Real-time PCR may also be used for early detection of reactivation in immunocompromised patients. Indirect parasitologic methods and qualitative PCR are not valid to confirm reactivation.[2]
Serologic evaluation
Test of choice for chronic-phase disease. Based on the identification of IgM antibodies (acute phase) and IgG antibodies (chronic phase) to T. cruzi. IgM preparations are rarely available, even in endemic countries.
Tests include enzyme-linked immunoassay (ELISA), indirect immunofluorescence antibody test, radioimmunoassay precipitation assay, indirect hemagglutination, and chemiluminescence which use whole or semipurified extracts of the epimastigotes of T. cruzi. A considerable variation in the reproducibility and reliability of the results is observed. Performance of ELISA tests is considered good.[141]
For chronic-phase disease, at least two serologic tests based on different antigens or techniques are used to increase the accuracy of diagnosis. When results are discordant, a third assay may be used to confirm or refute the diagnosis, or repeat sampling may be required.
Physiologic cardiac tests
Assessment of cardiac disease is essential in all patients with confirmed T. cruzi infection in order to detect early cardiac disease, with ongoing routine monitoring. Patients with acute or chronic disease require cardiac evaluation by ECG. Indicators of ventricular dysfunction, such as nonsustained or sustained ventricular tachycardia on resting ECG or ambulatory monitoring, severe sinus node dysfunction, and high-degree heart block, are major predictors of sudden death.[4][14][142][143][144][145]
Resting 12-lead ECG with 30-second lead II rhythm strip
Indicated in acute- and chronic-disease patients at the first evaluation, and then annually thereafter.
The most frequent cardiac alterations in acute-phase disease are similar to other cases of acute myocarditis and include sinus tachycardia, low QRS voltage, prolonged PR and/or QT intervals, and primary alterations of the T wave. Ventricular extrasystoles, atrial fibrillation, or complete right bundle branch block (rare in this phase) indicate a fatal outcome.
The most frequent cardiac alterations in chronic-phase disease are right bundle branch block; incomplete right bundle branch block; left anterior fascicular block; first-degree AV block; second-degree AV block (Mobitz type I or II); complete AV block; bradycardia; sinus node dysfunction; ventricular extrasystoles (often frequent, multifocal); or paired ventricular tachycardia (nonsustained or sustained). Less common, but clinically significant when present, are atrial fibrillation or flutter, left bundle branch block, low QRS voltage, primary alterations of repolarization, and Q waves.
Ambulatory 24-hour ECG
Indicated in patients with symptoms or ECG changes consistent with Chagas heart disease.
Must be monitored to detect arrhythmias.
Exercise testing
Indicated in patients with symptoms or ECG changes consistent with Chagas heart disease.
Necessary for evaluation and identification of exercise-induced arrhythmias, and assessment of functional capacity and chronotropic response.
Imaging
Chest x-ray is indicated in all patients to define baseline status and to evaluate cardiac or pulmonary complications. It may demonstrate different stages of cardiomegaly and pleural effusion (and other congestive signs) in cases with cardiac failure. Echocardiography is indicated in patients with clinical, radiologic, or ECG evidence of functional cardiac disturbance. This enables assessment of biventricular function, wall motion, and structure.[4][14][146] Cardiac magnetic resonance imaging (MRI) can be performed in select patients with Chagas cardiomyopathy to assess the extent of fibrosis. Nuclear medicine testing is an option to assess biventricular function when echocardiography is inadequate. Cardiac catheterization and coronary angiography may be required in patients with disabling, angina-like symptoms to rule out concomitant coronary artery disease. Right cardiac catheterization is necessary in patients with advanced heart failure to assess the feasibility of cardiac transplantation.[2]
Barium swallow or enema studies (esophagography or colonography) are indicated in patients with gastrointestinal symptoms for diagnosis of achalasia or megacolon. Upper gastrointestinal endoscopy is not indicated for the diagnosis of megaesophagus; however, patients with impaired esophageal motility are at increased risk of reflux esophagitis and esophageal carcinoma, and screening for these conditions may be necessary, especially if a change in symptoms has occurred.[114] Esophageal manometry is employed to evaluate the extent and intensity of peristalsis impairment.
Cranial computed tomography or MRI are indicated in cases of suspected meningoencephalitis and in patients with acute or reactivation-phase disease and neurologic symptoms. It may also be indicated in patients with suspicion of cardioembolic stroke associated with chronic-phase disease with cardiac involvement.
Emerging investigations
Immunochromatography tests for Chagas disease, such as rapid diagnostic tests (RDTs) or lateral flow assays, are emergent investigations that have been developed and used for Chagas disease diagnosis.[147]
RDTs were developed as an easy-to-use alternative to conventional tests. Although they have high validity for diagnosing chronic Chagas disease, they are not yet used for this purpose.[148] RDT use is limited to diagnostic screening in the field. If the test is positive, confirmation with other serological tests is necessary.
Commercial PCR kits for the detection and quantification of T. cruzi in blood samples are available.[149] The kits may become a standard test for molecular diagnosis in endemic countries in the future.
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