Trypanosoma American

OVERVIEW: What every clinician needs to know

Parasite name and classification

Trypanosoma cruzi is a protozoan parasite and the agent of Chagas disease.

What is the best treatment?

Benznidazole is the preferred agent for the treatment of Chagas disease.

Obtain a baseline complete blood count and metabolic panel prior to treatment.
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Major adverse effects include bone marrow suppression (rare), peripheral neuropathy, and rash.

Benznidazole can cause a disulfiram-like reaction, so alcohol should be avoided.

5-7 mg/kg/day orally in two divided doses for 60 days (patient aged >12 years)

5-7.5 mg/kg/day orally in two divided doses for 60 days (patient aged <12 years)

Nirfurtimox

Obtain a baseline complete blood count and metabolic panel prior to treatment.

Major adverse effects include gastrointestinal (GI) symptoms (anorexia, nausea/vomiting, and abdominal pain) and central nervous system effects (irritability, insomnia, and peripheral neuropathy late in treatment).

8–10 mg/kg/day orally in four divided doses for 90 to 120 days (patient aged >17 years)

12–15 mg/kg/day orally in four divided doses for 90 days (patient aged 11–16 years)

15–20 mg/kg/day orally in four divided doses for 90 days (patient aged ≤10 years)

Both benznidazole and nifurtimox are contraindicated in pregnancy.

These agents are only obtained in the United States through the US Centers for Disease Control and Prevention (CDC) via its Division of Parasitic Diseases. The phone number for inquiries is 770-488-7775 (Monday to Friday, 9am to 5 pm, Eastern time) or 770-488-7100 (after hours).

Infants with congenital Chagas disease should be treated with the regimens above, as there is a high cure rate expected of >90% and children tolerate treatment better than adults do.

Antitrypanosomal treatment is not indicated for adult patients with severe chronic cardiac or GI disease as it does not reverse the existing disease. Instead, treatment is focused on managing symptoms (balloon dilation of the lower esophageal sphincter, surgical resection and reconstruction, high fiber diet, manual disimpaction in GI disease) and reducing risk of cardiac death (antiarrhythmic agents, implantable cardioverter defibrillator, cardiac transplantation in some cases). The exception is in cases of early chronic cardiac disease, where treatment with benznidazole may slow the progression of cardiomyopathy.

Other less studied treatments include posaconazole, which has shown to be less effective than benznidazole for chronic Chagas, or combination antitrypanosomal therapy.

What are the clinical manifestations of infection with this organism?

The acute phase begins 1 to 2 weeks after initial infection, and typically is mild with some fever and malaise.

Many patients are asymptomatic.

Some people develop swelling, or chagoma, at the site of inoculation. Chagoma near the eye after conjunctival inoculation is called Romana sign.

Less than 1% of patients develop severe acute disease, including myocarditis, pericarditis, and meningoencephalitis.

The risk of severe acute disease increases with age.

Symptoms in mild acute disease usually resolve in a few weeks.

In the indeterminate phase, the infection may be identified through serologic or other testing, but there are no clinically apparent symptoms or signs.

The chronic phase begins weeks or months after the initial infection but symptoms may not be apparent until decades after infection.

Symptoms are most commonly of cardiovascular or GI disease.

Cardiac disease is the leading cause of mortality (up to 44%) in patients with chronic Chagas disease, and is associated with left ventricular dysfunction and aneurysm.

Symptoms of cardiac Chagas disease are those of resultant heart failure, arrhythmias, and thromboembolism (both pulmonary and systemic) due to cardiac mural thrombi.

Atypical chest pain may be present, due either to cardiac disease or pulmonary thromboembolism.

Esophageal disease is most common, followed by colonic disease, and then other parts of the GI tract. In all locations, pathogenesis involves destruction of submucosal and myenteric nerves that lead to progressive dilation.

Megaesophagus and megacolon may result with dysphagia, regurgitation, malnutrition, constipation, abdominal pain, and volvulus.

Congenital Chagas disease occurs in up to 10% of pregnancies in infected women, and is generally asymptomatic and only detected on screening the infant. Rarely, neonates develop severe symptoms after congenital infection with meningoencephalitis, anemia, low birthweight, or respiratory insufficiency any of which confer a high mortality rate.

Patients with chronic disease and cardiac involvement may have a cardiac heave, mitral or tricuspid regurgitation, as well as elevated jugular venous pulses, peripheral edema, and tachycardia.

Physical exam of patients with chronic GI disease secondary to Chagas may show cachexia, abdominal distention and tenderness, and impacted stool.

Do other diseases mimic its manifestations?

Acute infection is usually nonspecific and the differential includes malaria, typhoid, tuberculosis, influenza, and noninfectious causes of fever and malaise including connective tissue disease and malignancy.

Chagoma in a patient from an endemic region is pathognomonic.

Chronic disease with cardiac and GI involvement may be mistaken for noninfectious causes; clues may be sudden cardiac death or marked wasting, acute abdomen, or perforation in a relatively young person.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Standard laboratory blood tests are not helpful in making the diagnosis.

The electrocardiogram often has a right bundle branch block, and nonspecific ST segment changes. Abnormal Q waves, AV block, and prolonged QT intervals may also be seen.

Results that confirm the diagnosis

In acute infection, parasitemia is highest, and trypomastigotes can be seen on blood smears. Even without treatment, parasite load decreases, and smears in the chronic phase are negative.

For congenital cases, microscopic examination of cord or neonatal blood was previously the preferred method for diagnosis prior to clearance of maternal antibody; however, the use of polymerase chain reaction (PCR) assay has replaced this due to the increased sensitivity of the technique.

Serological testing for immunoglobulin G to T. cruzi is the method of choice in indeterminate or chronic infection.

There is no ‘gold standard’, so two types of tests must be used (e.g. enzyme immunoassay and immunofluorescence antibody assay, or two enzyme immunoassay kits based on different antigens). If there are discordant results, a third serologic test must be used.

In the United States, the CDC acts as a reference laboratory via its Division of Parasitic Diseases (see above).

A PCR assay offers higher sensitivity than blood smears to detect parasitemia in early acute infection.

In chronic infection, there is no clear role for PCR, and serology in combination with epidemiology and the clinical picture should be used instead.

Other test methods that are more difficult to perform include identification of the organism through hemoculture or through using laboratory-raised, uninfected triatomine bugs to bite the patient and then be dissected to examine for parasites.

What imaging studies will be helpful in making or excluding the diagnosis?

In chronic cardiac disease, a chest X ray will usually show cardiomegaly and mild or absent pulmonary edema ($). ($ = 60–125, $$ 125–500, $$$ 500–1,000, $$$$ >1,000).

Echocardiography is usually normal in the acute phase, but can show severely impaired left ventricular dysfunction and hypokinesis, akinesis, or an apical aneurysm in chronic disease ($$).

Other cardiac evaluation may include radionuclide perfusion imaging ($$$), cardiac angiography ($$$$), cardiac magnetic resonance imaging ($$$), and electrophysiologic studies ($$$$).

In GI disease, chest and abdominal radiographs may show air fluid levels in the dilated esophagus or bowel ($).

What complications can be associated with this parasitic infection, and are there additional treatments that can help to alleviate these complications?

Congenital Chagas disease is a complication in 10% of infants born to infected mothers. Some of these will manifest initial severe disease with meningoencephalitis, anemia, low birthweight, or respiratory insufficiency, any of which confer a high mortality rate.

Those that are not treated and survive have the same risk of GI and cardiac disease as individuals infected through noncongenital routes (20–30% overall risk).

Infants aged <1 year tolerate treatment with antitrypanosomal drugs well, and have a greater than 90% cure rate, so it is important to identify and treat congenital cases early.

The complications of cardiac and GI disease are discussed at length above.

In patients who become immunosuppressed, including transplant recipients and those with human immunodeficiency virus/acquired immune deficiency syndrome, reactivation of T. cruzi can occur and this complication should be sought.

Treatment for reactivation is with standard doses of antitrypanosomal therapy.

Chemoprophylaxis for these patients is not recommended.

Rarely, infection can be transmitted through organ transplantation, blood transfusion, or breast feeding.

What is the life cycle of the parasite, and how does the life cycle explain infection in humans? What is the epidemiology of this infection?

The most common cause of infection is being bitten by an infected triatomine bug. Oral infection through ingestion of contaminated food can also occur, as can congenital transmission and rarely, transmission through organ transplantation, blood transfusion, or breast feeding.

Parasite life cycle

The trypanomastigote form is present in the feces of the triatomine bug. During a blood meal, the bug defecates, and the organism enters via the bite wound, although entry through mucus membranes or the conjunctivae can also occur. The bug bites at night, and the host does not usually notice.

An uninfected bug may then bite an infected host for a blood meal; in acute infection there are large numbers of parasites in the host blood in the trypanomastigote form. These then migrate to the bug’s midgut where they multiply as epimastigotes, and then in the hindgut become infectious trypanomastigotes, completing the cycle.

The complete life cycle can be found on the CDC website. Centers for Disease Control and Prevention. Parasites—American Trypanosomiasis (also known as Chagas Disease). Available at: http://www.cdc.gov/parasites/chagas/biology.html. Accessed 29 May 2012.

The key vectors are various species of the triatomine bug (kissing bug).

Epidemiology

The infection occurs in the distribution of the vector, which is from the southern United States through southern Argentina.

Old or poor housing in which triatomine bugs reside in proximity to human hosts are a major risk factor for infection. This has typically been most evident in rural, impoverished areas.

An estimated 8 to 10 million people are infected.

In endemic areas, infection is most often acquired in childhood.

There is not significant seasonal variation in transmission.

Aggressive vector control measures in many endemic countries, including spraying long lasting insecticides along housing foundations and improving housing construction, have reduced or interrupted transmission although pockets of transmission remain.

Screening of the blood supply has decreased transfusion related infections.

Infection control issues

Isolation precautions are not required.

Using insecticide treated bednets can help avoid night time bites by triatomine bugs that transmit the infection.

There is no available vaccine.

How does this organism cause disease?

The mechanisms of T. cruzi-host immune interaction are being actively investigated.

The chronic cardiac and GI disease may reflect autoimmune activity.

A protective immune response appears to require an intact type 1 helper T cell immune profile.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Clinical management

Bern, C. “Chagas’ Disease”. N Engl J Med. vol. 373. 2015. pp. 456-466. (Comprehensive review of epidemiology, clinical manifestations, pathogenesis, diagnosis, and management of disease.)

Le Loup, G, Pialoux, G, Lescure, FX. “Update in treatment of Chagas disease”. Curr Opin Infect Dis. vol. 24. 2011. pp. 428-34. (Comprehensive overview of the treatment options for patients with Chagas disease.)

Sosa-Estani, S, Colantonio, L, Segura, EL. “Therapy of chagas disease: implications for levels of prevention”. J Trop Med. vol. 2012. 2012. pp. 292138(Good overview of the principles of treatment for Chagas disease for secondary prevention of complications, as well as primary prevention of transmission to susceptible individuals.)

Pérez-Molina, JA, Norman, F, López-Vélez, R. “Chagas disease in non-endemic countries: epidemiology, clinical presentation and treatment”. Curr Infect Dis Rep. vol. 14. 2012. pp. 263-74. (Useful review of presentation and management outside of endemic areas.)

Microbiology

Junqueira, C, Caetano, B, Bartholomeu, DC. “The endless race between and host immunity: lessons for and beyond Chagas disease”. Expert Rev Mol Med. vol. 12. 2010 Sep 15. pp. e29(Overview of the basic pathogenesis and immunology of T. cruzi, expands this discussion to application in other disease states.)

Teixeira, AR, Hecht, MM, Guimaro, MC, Sousa, AO, Nitz, N. “Pathogenesis of chagas' disease: parasite persistence and autoimmunity”. Clin Microbiol Rev. vol. 24. 2011. pp. 592-630. (General overview of the basic pathogenesis and immunology of Chagas disease.)

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