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American trypanosomiasis, or Chagas disease, is caused by Trypanosoma cruzi, a flagellated protozoan transmitted to mammals by haematophagous reduviid insects (1337Kirchhoff, L.V. American Trypanosomiasis (Chagas' disease). In: Guerrant RL, Walker DH, Weller PF (eds). Tropical Infectious Diseases: Principles, Pathogens, & Practice. 2nd ed. Philadelphia: Elsevier;2006:1082-94.).

Chagas disease vectors have been reported in the Americas from 42°N to 46°S. The disease is distributed from the southern United States to the southern regions of Argentina and Chile. During a blood meal, T. cruzi parasites are deposited with the insect's feces when it defecates shortly after feeding. Humans usually become infected through mucous membranes or breaks in skin. Humans might also acquire trypanosomiasis from blood transfusions, and occasionally transplanted organ, maternal-fetal transmission, from ingesting contaminated food or drink, or from laboratory mishaps (1338Schmunis GA, Cruz JR. Safety of the blood supply in Latin America. Clin Microbiol Rev 2005;18(1):12-29., 1339CDC. Chagas disease after organ transplantationLos Angeles, California. MMWR 2006;55(29):798-800., 1340Herwaldt BL. Protozoa and helminths. In Fleming DO, Hunt DL (eds.). Biological Safety: Principles and Practices. 4th ed. Washington, DC: American Society for Microbiology. 2006;115-61.).

Chagas disease affects approximately 10 million persons in the Americas (1341Pan American Health Organization, Quantitative estimation of Chagas disease in the Americas. OPS/HDM/CD/425-06:6. 2005. For regional updates see www.paho.org/English/AD/DPC/CD/chagas.htm, last accessed December 22, 2008.). An estimated 50,000-100,000 persons in the United States have acquired T. cruzi; a majority are immigrants from disease-endemic areas. In the United States, vectorborne transmission of T. cruzi is rare, and the risk of transfusion-associated disease has been reduced recently. Screening of blood donations for anti-T. cruzi antibodies was introduced in 2007 by the American Red Cross and Blood Systems Laboratories (1342CDC. Initiation of blood donor screening for Chagas disease 2006-2007. MMWR 2007;56:141-3.).

In humans, acute T. cruzi infection is accompanied by moderate to high levels of parasitemia. After a few months, if untreated, the acute stage is followed by a lifelong chronic infection, characterized by low-grade and intermittent parasitemia in which tissue parasites are scarce and difficult to demonstrate. All patients with chronic infection are potentially able to transmit Chagas disease through triatomid insect bites, pregnancy, blood transfusion, or organ donation.

Among patients with HIV infection, symptomatic reactivation of chronic, latent T. cruzi infection can be triggered by profound immunosuppression (1343Cahn P, Belloso W, Murillo J, Prada-Trujillo G. AIDS in Latin America. Infect Dis Clin North Am 2000;14(1):185-209., 1344Rocha A, de Meneses ACO, De Meneses O, et al. Pathology of patients with Chagas' disease and acquired immunodeficiency syndrome. Am J Trop Med Hyg 1994;50(3):261-8., 1345Sartori AM, Ibrahim KY, Nunes Westphalen EV, et al. Manifestations of Chagas disease (American trypanosomiasis) in patients with HIV/AIDS. Ann Trop Med Parasitol 2007; 101(1):31-50., 1346Vaidian AK, Weiss, LM, Tanowitz HB. Chagas' disease and AIDS. Kinetoplastid Biol Dis 2004;3(1):2.).

Chagas disease can be divided into two stages: acute and chronic. The acute stage of Chagas disease, usually observed among children, begins shortly after infection and lasts 1-2 months. This stage of the disease is often asymptomatic, although fever, malaise, anorexia, induration around the inoculation site (chagoma), or periocular edema (Romaña's sign) might be observed. Generalized lymphadenopathy, splenomegaly, cardiac failure, or meningoencephalitis can also occur during acute disease.

The relatively high parasitemia and symptoms (if present) in acute Chagas disease subside, and the patient enters an asymptomatic phase of the illness with low and intermittent parasitemia. After one or two decades, 10%-30% of infected patients experience chronic cardiac and/or digestive tract disease.

Persons with chronic Chagas disease who are HIV infected usually have higher levels of T. cruzi parasitemias than their counterparts who are HIV negative (1345Sartori AM, Ibrahim KY, Nunes Westphalen EV, et al. Manifestations of Chagas disease (American trypanosomiasis) in patients with HIV/AIDS. Ann Trop Med Parasitol 2007; 101(1):31-50., 1347Sartori AMC, Neto JE, Nunes EV, et al. Trypanosoma cruzi parasitemia in chronic Chagas disease: comparison between human immunodeficiency virus (HIV)-positive and HIV-negative patients. J Infect Dis 2002;186(6): 872-5.). Clinical reactivation occurs in HIV-infected patients, as it does with patients who are immunosuppressed by other processes (1343Cahn P, Belloso W, Murillo J, Prada-Trujillo G. AIDS in Latin America. Infect Dis Clin North Am 2000;14(1):185-209., 1344Rocha A, de Meneses ACO, De Meneses O, et al. Pathology of patients with Chagas' disease and acquired immunodeficiency syndrome. Am J Trop Med Hyg 1994;50(3):261-8., 1345Sartori AM, Ibrahim KY, Nunes Westphalen EV, et al. Manifestations of Chagas disease (American trypanosomiasis) in patients with HIV/AIDS. Ann Trop Med Parasitol 2007; 101(1):31-50., 1346Vaidian AK, Weiss, LM, Tanowitz HB. Chagas' disease and AIDS. Kinetoplastid Biol Dis 2004;3(1):2.). One prospective study found reactivation in 11 (21%) of 53 patients during a median follow-up interval of 58 months (1345Sartori AM, Ibrahim KY, Nunes Westphalen EV, et al. Manifestations of Chagas disease (American trypanosomiasis) in patients with HIV/AIDS. Ann Trop Med Parasitol 2007; 101(1):31-50.). The majority of cases occur in patients with CD4⁺ counts <200 cells/µL or prior OIs.

The clinical features of reactivated Chagas disease among patients with HIV infection differ from those observed in persons who are immunosuppressed from other causes. Approximately 75% of HIV-infected patients with reactivation experience an acute meningoencephalitis that is indistinguishable clinically from toxoplasmosis (1343Cahn P, Belloso W, Murillo J, Prada-Trujillo G. AIDS in Latin America. Infect Dis Clin North Am 2000;14(1):185-209., 1344Rocha A, de Meneses ACO, De Meneses O, et al. Pathology of patients with Chagas' disease and acquired immunodeficiency syndrome. Am J Trop Med Hyg 1994;50(3):261-8., 1345Sartori AM, Ibrahim KY, Nunes Westphalen EV, et al. Manifestations of Chagas disease (American trypanosomiasis) in patients with HIV/AIDS. Ann Trop Med Parasitol 2007; 101(1):31-50., 1346Vaidian AK, Weiss, LM, Tanowitz HB. Chagas' disease and AIDS. Kinetoplastid Biol Dis 2004;3(1):2.). About 25%-50% of patients also have myocarditis at autopsy, but it is not usually the primary manifestation of reactivation.

T. cruzi infection should be considered in the differential diagnosis of CNS mass lesions and cardiac disease (arrhythmias or heart failure) among patients with HIV infection who have epidemiologic risk factors for Chagas disease. The imaging pattern of brain chagoma is similar to that of cerebral toxoplasmosis, although chagomas tend to be larger than Toxoplasma lesions. CT and MRI show subcortical hypodense lesions that enhance with contrast or gadolinium. These lesions most often involve brain white matter. Histopathology shows inflammation and the presence of T. cruzi amastigotes in glial cells and, less often, in neurons. CSF shows a mild pleocytosis (lymphocyte predominance), increased protein, and T. cruzi trypomastigotes (1343Cahn P, Belloso W, Murillo J, Prada-Trujillo G. AIDS in Latin America. Infect Dis Clin North Am 2000;14(1):185-209., 1344Rocha A, de Meneses ACO, De Meneses O, et al. Pathology of patients with Chagas' disease and acquired immunodeficiency syndrome. Am J Trop Med Hyg 1994;50(3):261-8., 1345Sartori AM, Ibrahim KY, Nunes Westphalen EV, et al. Manifestations of Chagas disease (American trypanosomiasis) in patients with HIV/AIDS. Ann Trop Med Parasitol 2007; 101(1):31-50., 1346Vaidian AK, Weiss, LM, Tanowitz HB. Chagas' disease and AIDS. Kinetoplastid Biol Dis 2004;3(1):2.).

A definitive diagnosis is established by brain biopsy or identification of the parasite (or its products) in tissue or blood. Direct tests for identifying T. cruzi microscopically are useful during the acute stage and in reactivation of chronic infection (e.g., in the setting of HIV infection). Circulating parasites are rarely detected microscopically in chronic Chagas disease in immunocompetent patients or in HIV-infected patients in the absence of reactivation. If observed in an immunocompromised HIV-positive patient, circulating parasites suggest reactivation and the need for treatment. Blood concentration techniques, such as capillary centrifugation (microhematocrit test), can improve sensitivity (1348Strout RG. A method for concentrating hemoflagellates. J Parasitol 1962; 48:100.). In centrifuged blood, T. cruzi trypomastigotes are found just above the buffy coat. Centrifugation of CSF also can be employed among patients with suspected CNS Chagas disease. Parasites also might be observed in lymph nodes, bone marrow, skin, pericardial fluid, and CNS mass lesions. Hemoculture is somewhat more sensitive than direct methods, but it might take 2-8 weeks to become positive. PCR of peripheral blood is not helpful for diagnosis of reactivation, because PCR is often positive in the absence of reactivation; however, PCR of CSF has been used to monitor reactivation in the CNS.

Serologic tests to detect the antibody responses to T. cruzi infection are useful for diagnosis of disease in chronically infected patients, to screen blood donors, and for seroepidemiologic studies. The techniques used include indirect hemagglutination, direct agglutination, complement fixation, indirect immunofluorescence, ELISA, and radioimmunoprecipitation assays. In the United States, multiple serologic tests are licensed for diagnosis. In late 2006, an ELISA assay for screening blood donors was licensed (1342CDC. Initiation of blood donor screening for Chagas disease 2006-2007. MMWR 2007;56:141-3.). As of December 2008, approximately 700 confirmed-positive donations have been reported (1349AABB Chagas' Biovigilance Network, http://www.aabb.org/Content/Programs_and_Services/Data_Center/Chagas. Last accessed December 22, 2008.). Detection of IgM antibodies is not sensitive, even during the acute stage of infection. Diagnosis based on serologic tests requires two positive tests performed with different techniques (1350WHO, Control of Chagas Disease, Brasilia, Brazil. World Health Organization. WHO Technical Report Series 905, 2002.).

Although the serologic tests for T. cruzi infection are reasonably sensitive and specific, both false-positive and false-negative reactions have been reported. Therefore, the diagnosis of Chagas disease should not be excluded based on negative serologic tests if the patient has epidemiologic risk factors and clinical findings compatible with Chagas disease. In this instance, parasitologic testing directly (e.g., microscopic examination of brain tissue and/or demonstration of parasitemia) or with PCR are the best diagnostic strategies. Neonates born to mothers with chronic T. cruzi infection will have positive antibody tests, yet might not be infected; parasitologic tests and repeat antibody testing at 6 and 12 months are recommended in this instance (1351Freilij H, Altcheh J, Muchinik G. Perinatal human immunodeficiency virus infection and congenital Chagas' disease. Pediatr Infect Dis J 1995;14(2):161-2.).

The reduviid insect vector of Chagas disease typically infests cracks and roofing of poor quality buildings constructed of adobe brick, mud, or thatch. The insects feed at night, and therefore HIV-infected persons living or visiting in areas where Chagas is endemic should avoid overnight stays in such dwellings or sleeping outdoors. They also should be aware that blood products in the United States or abroad might not always be screened routinely for T. cruzi. Transfusion, organ transplantation, and MTCT are the more likely infection routes in the United States. Better housing conditions and less efficient vectors might explain the lower risk of vectorial transmission in this country (1352Bern, C, Montgomery SP, Herwaldt BL, et al. Evaluation and treatment of Chagas disease in the United States: a systematic review. JAMA 2007;298(18):2171-81.).

No drugs or vaccines for preventing T. cruzi infection are available. Preventive measures include spraying infested dwellings with residual-action insecticide and if sleeping outdoors or in suspect dwellings cannot be avoided then sleeping under insecticide-treated bednets,

The clinical manifestations of Chagas disease in HIV-positive persons usually represent reactivation and not acute infection with T. cruzi. All HIV-infected persons with epidemiologic risk factors for Chagas disease should be tested for antibody to T. cruzi to detect latent infection (1353Technical Report. Recommendations for diagnosis, treatment and follow-up of the Trypanosoma cruzi: human immunodeficiency virus co-infection. Rev Soc Bras Med Trop 2006;39(4):392-415.). Antibody-positive patients who have not been previously treated, who are likely to have been infected for less than two decades, and who are without signs or symptoms of Chagas disease might benefit from a single course of medication with benznidazole or nifurtimox (CIII). Limited data and a lack of consensus exist regarding the benefit of chemotherapy in patients with longer-standing infection or chronic disease manifestations.

Optimization of ART might help prevent Chagas reactivation. The majority of cases have occurred in patients who were not taking ART.

Chemotherapy of Chagas disease with benznidazole or nifurtimox is effective in reducing parasitemia and preventing clinical manifestations for patients with acute, early chronic, and reactivated disease. However, these drugs are limited in achieving parasitological cure. Consultation with a specialist should be sought. Benznidazole, 5-8 mg/kg body weight/day for 30-60 days, is the initial treatment most commonly recommended (BIII). Nifurtimox, 8-10 mg/kg body weight/day, administered for 90-120 days is an alternative (CIII). However, the duration of therapy with either of these agents has not been studied for persons coinfected with HIV. Mortality is high, even in patients who receive chemotherapy. Limited data suggest that early recognition and treatment of reactivation might improve prognosis (1345Sartori AM, Ibrahim KY, Nunes Westphalen EV, et al. Manifestations of Chagas disease (American trypanosomiasis) in patients with HIV/AIDS. Ann Trop Med Parasitol 2007; 101(1):31-50.). Neither anti-trypanosomal drug is licensed in the United States; however, the drugs are available from the CDC Drug Service (404-639-3670) for use under investigational protocols.

ART is likely to reduce or prevent initial reactivation of T. cruzi or its recurrence. ART should be initiated or optimized once a patient with acute disease is clinically stable (AIII).

Patients undergoing treatment should be monitored closely because both benznidazole and nifurtimox are toxic (1354). Benznidazole causes peripheral neuropathy, rash, and granulocytopenia. Nifurtimox causes anorexia, nausea, vomiting, abdominal pain and weight loss, restlessness, tremors, and peripheral neuropathy. The adverse effects of both drugs wane when the drugs are discontinued.

No reports are available regarding T. cruzi infection and IRIS.

Although no data are available, retreatment with benznidazole or nifurtimox is recommended for HIV-infected patients who fail to respond or who relapse following initial therapy (AIII).

Patients with HIV infection are potentially at risk for recurrent or relapsing clinical manifestations because of intermittent reactivation of chronic infection. The drugs are only partially effective in the chronic stage of disease, are suppressive rather than curative, and might require lifelong administration to prevent relapse in the setting of continued immunosuppression. Because the drugs are toxic and experience with their use in HIV-infected patients is limited, expert advice about indicators and regimens should be sought. Whether secondary prophylaxis or chronic maintenance therapy should be used in HIV-infected patients with latent Chagas disease is unclear, particularly when modern ART is used.

The seroprevalence of T. cruzi infection among pregnant women in areas where the disease is endemic in Latin America can be as high as 50% in urban areas and 81% in rural areas. In the United States, one study of 3,765 pregnant women in Houston, Texas, confirmed antibody to T. cruzi in 0.4% of Hispanic women and 0.1% of non-Hispanic women (1355Di Pentima M, Hwang LY, Skeeter CM, Edwards MS. Prevalence of antibody to Trypanosoma cruzi in pregnant Hispanic women in Houston. Clin Infect Dis 1999;28(6):1281-5.).

Perinatal transmission rates among general populations of pregnant women seropositive for antibodies to T. cruzi range from 2% to 10% (1356Bittencourt AL. Possible risk factors for vertical transmission of Chagas' disease. Rev Inst Med Trop Sao Paulo 1992;34(5):403-8.). The effect of concurrent HIV infection in the mother on risk of perinatal transmission of T. cruzi is not known; however, limited data available at present suggest that rates of perinatal transmission might be higher for HIV-infected women than the rates previously documented for immunocompetent mothers (1345Sartori AM, Ibrahim KY, Nunes Westphalen EV, et al. Manifestations of Chagas disease (American trypanosomiasis) in patients with HIV/AIDS. Ann Trop Med Parasitol 2007; 101(1):31-50.). Infants coinfected with HIV and T. cruzi might be more likely to have symptoms, especially neurologic symptoms (1351Freilij H, Altcheh J, Muchinik G. Perinatal human immunodeficiency virus infection and congenital Chagas' disease. Pediatr Infect Dis J 1995;14(2):161-2., 1357Freilij H, Altcheh J. Congenital Chagas' disease: diagnostic and clinical aspects. Clin Infect Dis 1995;21(3):551-5.).

Congenital infection with T. cruzi might increase the risk of spontaneous abortion, stillbirth, and low birthweight (1356Bittencourt AL. Possible risk factors for vertical transmission of Chagas' disease. Rev Inst Med Trop Sao Paulo 1992;34(5):403-8.). Congenital Chagas disease in newborn infants ranges from subclinical to life threatening with severe neurologic and cardiac disease.

Minimal data are available on potential reproductive toxicity of benznidazole and nifurtimox, although both drugs have been associated with increased detection of chromosomal aberrations in children being treated for Chagas disease (1358Gorla NB, Ledesma OS, Barbieri GP, Larriba IB .Assessment of cytogenetic damage in chagasic children treated with benznidazole. Mutat Res 1988;206(2):217-20., 1359Gorla NB, Ledesma OS Barbieri GP, Larriba IB. Thirteenfold increase of chromosomal aberrations non-randomly distributed in chagasic children treated with nifurtimox. Mutat Res 1989;224(2):263-7.). Benznidazole crosses the placenta in rats and covalently binds to fetal proteins (1360de Toranzo EG, Masana M, Castro JA. Administration of benznidazole, a chemotherapeutic agent against Chagas disease, to pregnant rats. Covalent binding of reactive metabolites to fetal and maternal proteins. Arch Int Pharmacodyn Ther 1984;272(1):17-23.). Because of the toxicity and limited experience with use of these drugs in pregnancy, treatment of acute T. cruzi infection among pregnant women should only be undertaken in consultation with a specialist in this area, and treatment of chronic disease should be considered only after completion of the pregnancy. For HIV-infected pregnant women with symptomatic reactivation of T. cruzi infection, the immune response should be maximized with ART (AIII).