[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.197.124.106. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF
Figure 1. Study Selection
Image description not available.
Figure 2.Trypanosoma cruzi
Image description not available.

A, The trypomastigote forms of Trypanosoma cruzi in a peripheral blood smear from a patient with acute Chagas disease. Arrowhead indicates the kinetoplast (Giemsa stain, original magnification ×1000). B, Nest of T cruzi amastigotes within a cardiac myocyte in a patient with chronic Chagas disease. Arrowhead indicates the kinetoplast (hematoxylin-eosin, original magnification ×1000). Courtesy of the Division of Parasitic Diseases, US Centers for Disease Control and Prevention.

Figure 3. Baseline Evaluation of the Patient Newly Diagnosed With Chronic Trypanosoma cruzi Infection
Image description not available.

aQRS interval 0.10 to 0.11 seconds in adults. Criteria based on the Minnesota Code Manual of Electrocardiographic Findings ,74 with modifications from Maguire et al.71 Different criteria may be required for ECGs in children.

Table 1. Prospective Controlled Trials of Benznidazole or Nifurtimox for Chronic Chagas Disease in the Published Literature
Image description not available.
Table 2. Recommendations for Antitrypanosomal Drug Treatment According to Chagas Disease Phase and Form, Patient Age, and Clinical Status
Image description not available.
1.
Maguire JH. Trypanosoma. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious Diseases. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:2327-2334
2.
Magill AJ, Reed SG. American trypanosomiasis. In: Strickland GT, ed. Hunter's Tropical Medicine and Emerging Diseases. 8th ed. Philadelphia, PA: WB Saunders Co; 2000:653-664
3.
Benchimol Barbosa PR. The oral transmission of Chagas' disease: an acute form of infection responsible for regional outbreaks.  Int J Cardiol. 2006;112(1):132-133PubMedArticle
4.
Organizacion Panamericana de la Salud.  Estimacion cuantitativa de la enfermedad de Chagas en las Americas. Montevideo, Uruguay: Organizacion Panamericana de la Salud; 2006
5.
Remme JHF, Feenstra P, Lever PR.  et al.  Tropical diseases targeted for elimination: Chagas disease, lymphatic filariasis, onchocerciasis, and leprosy. In: Jamison DT, Breman JG, Measham AR, et al, eds. Disease Control Priorities in Developing Countries. New York, NY: The World Bank and Oxford University Press; 2006:433-449
6.
 Regional PAHO Regional Program on Chagas Disease. Pan American Health Organization Web site. http://www.paho.org/english/ad/dpc/cd/dch-program-page.htm. Accessed July 1, 2007
7.
Kirchhoff LV. Changing epidemiology and approaches to therapy for Chagas disease.  Curr Infect Dis Rep. 2003;5(1):59-65PubMedArticle
8.
Leiby DA, Herron RM Jr, Read EJ, Lenes BA, Stumpf RJ. Trypanosoma cruzi in Los Angeles and Miami blood donors: impact of evolving donor demographics on seroprevalence and implications for transfusion transmission.  Transfusion. 2002;42(5):549-555PubMedArticle
9.
Bradley KK, Bergman DK, Woods JP, Crutcher JM, Kirchhoff LV. Prevalence of American trypanosomiasis (Chagas disease) among dogs in Oklahoma.  J Am Vet Med Assoc. 2000;217(12):1853-1857PubMedArticle
10.
Pung OJ, Banks CW, Jones DN, Krissinger MW. Trypanosoma cruzi in wild raccoons, opossums, and triatomine bugs in southeast Georgia, U.S.A.  J Parasitol. 1995;81(2):324-326PubMedArticle
11.
Herwaldt BL, Grijalva MJ, Newsome AL.  et al.  Use of polymerase chain reaction to diagnose the fifth reported US case of autochthonous transmission of Trypanosoma cruzi, in Tennessee, 1998.  J Infect Dis. 2000;181(1):395-399PubMedArticle
12.
Dorn PL, Perniciaro L, Yabsley MJ.  et al.  Autochthonous transmission of Trypanosoma cruzi, Louisiana.  Emerg Infect Dis. 2007;13(4):605-607PubMedArticle
13.
Centers for Disease Control and Prevention.  Blood donor screening for Chagas disease—United States, 2006-2007.  MMWR Morb Mortal Wkly Rep. 2007;56(7):141-143PubMed
14.
 Chagas' Biovigilance Network. AABB Web site. http://www.aabb.org/Content/Programs_and_Services/Data_Center/Chagas/. Accessed September 12, 2007
15.
Rassi A Jr, Rassi A, Rassi SG. Predictors of mortality in chronic Chagas disease: a systematic review of observational studies.  Circulation. 2007;115(9):1101-1108PubMedArticle
16.
Rassi A Jr, Rassi A, Little WC. Chagas' heart disease.  Clin Cardiol. 2000;23(12):883-889PubMedArticle
17.
Hagar JM, Rahimtoola SH. Chagas' heart disease.  Curr Probl Cardiol. 1995;20(12):825-924PubMed
18.
de Oliveira RB, Troncon LE, Dantas RO, Menghelli UG. Gastrointestinal manifestations of Chagas' disease.  Am J Gastroenterol. 1998;93(6):884-889PubMed
19.
Gascón J, Albajar P, Canas E.  et al.  Diagnosis, management and treatment of chronic Chagas' heart disease in areas where Trypanosoma cruzi infection is not endemic [in Spanish].  Rev Esp Cardiol. 2007;60(3):285-293PubMedArticle
20.
Ministério da Saúde Brasil.  Brazilian Consensus on Chagas disease [in Portuguese].  Rev Soc Bras Med Trop. 2005;38:(suppl 3)  7-29PubMedArticle
21.
Sociedad Argentina de Cardiología.  Consejo de Enfermedad de Chagas.  Rev Argent Cardiol. 2002;70:(suppl 1)  1-87
22.
Pinto Dias JC. Natural history of Chagas' disease.  Arq Bras Cardiol. 1995;65(4):359-366PubMed
23.
Maguire JH, Hoff R, Sherlock I.  et al.  Cardiac morbidity and mortality due to Chagas' disease: prospective electrocardiographic study of a Brazilian community.  Circulation. 1987;75(6):1140-1145PubMedArticle
24.
Marin-Neto JA, Cunha-Neto E, Maciel BC, Simoes MV. Pathogenesis of chronic Chagas heart disease.  Circulation. 2007;115(9):1109-1123PubMedArticle
25.
Kuschnir E, Sgammini H, Castro R, Evequoz C, Ledesma R, Brunetto J. Evaluation of cardiac function by radioisotopic angiography, in patients with chronic Chagas cardiopathy [in Spanish].  Arq Bras Cardiol. 1985;45(4):249-256PubMed
26.
Carrasco HA, Barboza JS, Inglessis G, Fuenmayor A, Molina C. Left ventricular cineangiography in Chagas' disease: detection of early myocardial damage.  Am Heart J. 1982;104(3):595-602PubMedArticle
27.
Acquatella H. Echocardiography in Chagas heart disease.  Circulation. 2007;115(9):1124-1131PubMedArticle
28.
Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  J Am Coll Cardiol. 2005;46(6):e1-e82PubMedArticle
29.
de Rezende JM, Moreira H. Chagasic megaesophagus and megacolon: historical review and present concepts.  Arq Gastroenterol. 1988;25:(special issue)  32-43PubMed
30.
Mota E, Todd CW, Maguire JH.  et al.  Megaesophagus and seroreactivity to Trypanosoma cruzi in a rural community in northeast Brazil.  Am J Trop Med Hyg. 1984;33(5):820-826PubMed
31.
de Oliveira RB, Rezende Filho J, Dantas RO, Iazigi N. The spectrum of esophageal motor disorders in Chagas' disease.  Am J Gastroenterol. 1995;90(7):1119-1124PubMed
32.
Atías A. A case of congenital chagasic megaesophagus: evolution until death caused by esophageal neoplasm, at 27 years of age [in Spanish].  Rev Med Chil. 1994;122(3):319-322PubMed
33.
Brücher BL, Stein HJ, Bartels H, Feussner H, Siewert JR. Achalasia and esophageal cancer: incidence, prevalence, and prognosis.  World J Surg. 2001;25(6):745-749PubMedArticle
34.
Miles MA, Feliciangeli MD, de Arias AR. American trypanosomiasis (Chagas' disease) and the role of molecular epidemiology in guiding control strategies.  BMJ. 2003;326(7404):1444-1448PubMedArticle
35.
Campbell DA, Westenberger SJ, Sturm NR. The determinants of Chagas disease: connecting parasite and host genetics.  Curr Mol Med. 2004;4(6):549-562PubMedArticle
36.
Bittencourt AL. Congenital Chagas disease.  Am J Dis Child. 1976;130(1):97-103PubMed
37.
Torrico F, Alonso-Vega C, Suarez E.  et al.  Maternal Trypanosoma cruzi infection, pregnancy outcome, morbidity, and mortality of congenitally infected and non-infected newborns in Bolivia.  Am J Trop Med Hyg. 2004;70(2):201-209PubMed
38.
Bocchi EA, Bellotti G, Mocelin AO.  et al.  Heart transplantation for chronic Chagas' heart disease.  Ann Thorac Surg. 1996;61(6):1727-1733PubMedArticle
39.
Fiorelli AI, Stolf NA, Honorato R.  et al.  Later evolution after cardiac transplantation in Chagas' disease.  Transplant Proc. 2005;37(6):2793-2798PubMedArticle
40.
Maldonado C, Albano S, Vettorazzi L.  et al.  Using polymerase chain reaction in early diagnosis of re-activated Trypanosoma cruzi infection after heart transplantation.  J Heart Lung Transplant. 2004;23(12):1345-1348PubMedArticle
41.
Riarte A, Luna C, Sabatiello R.  et al.  Chagas' disease in patients with kidney transplants: 7 years of experience 1989-1996.  Clin Infect Dis. 1999;29(3):561-567PubMedArticle
42.
Altclas J, Sinagra A, Dictar M.  et al.  Chagas disease in bone marrow transplantation: an approach to preemptive therapy.  Bone Marrow Transplant. 2005;36(2):123-129PubMedArticle
43.
Sartori 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):31-50PubMedArticle
44.
Vaidian AK, Weiss LM, Tanowitz HB. Chagas' disease and AIDS.  Kinetoplastid Biol Dis. 2004;3(1):2PubMedArticle
45.
Wegner DH, Rohwedder RW. The effect of nifurtimox in acute Chagas' infection.  Arzneimittelforschung. 1972;22(9):1624-1635PubMed
46.
Kirchhoff LV. American trypanosomiasis (Chagas disease). In: Guerrant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases: Principles, Pathogens and Practice. 2nd ed. New York, NY: Churchill Livingstone; 2006:1082-1094
47.
WHO Expert Committee.  Control of Chagas Disease. Brasilia, Brazil: World Health Organization; 2002. WHO technical report series 905
48.
Castro AM, Luquetti AO, Rassi A, Rassi GG, Chiari E, Galvao LM. Blood culture and polymerase chain reaction for the diagnosis of the chronic phase of human infection with Trypanosoma cruzi.  Parasitol Res. 2002;88(10):894-900PubMedArticle
49.
Freilij H, Altcheh J. Congenital Chagas' disease: diagnostic and clinical aspects.  Clin Infect Dis. 1995;21(3):551-555PubMedArticle
50.
 Congenital infection with Trypanosoma cruzi: from mechanisms of transmission to strategies for diagnosis and control.  Rev Soc Bras Med Trop. 2003;36(6):767-771PubMedArticle
51.
Miles MA. American trypanosomiasis (Chagas disease). In: Cook GC, Zumla AI, eds. Manson's Tropical Disease. London, England: Elsevier Science Limited; 2003:1325-1335
52.
Andersson J, Orn A, Sunnemark D. Chronic murine Chagas' disease: the impact of host and parasite genotypes.  Immunol Lett. 2003;86(2):207-212PubMedArticle
53.
Bustamante JM, Rivarola HW, Fernandez AR.  et al.  Indeterminate Chagas' disease: Trypanosoma cruzi strain and re-infection are factors involved in the progression of cardiopathy.  Clin Sci (Lond). 2003;104(4):415-420PubMedArticle
54.
Laucella SA, Postan M, Martin D.  et al.  Frequency of interferon-gamma-producing T cells specific for Trypanosoma cruzi inversely correlates with disease severity in chronic human Chagas disease.  J Infect Dis. 2004;189(5):909-918PubMedArticle
55.
Acquatella H, Catalioti F, Gomez-Mancebo JR, Davalos V, Villalobos L. Long-term control of Chagas disease in Venezuela: effects on serologic findings, electrocardiographic abnormalities, and clinical outcome.  Circulation. 1987;76(3):556-562PubMedArticle
56.
Carrasco HA, Parada H, Guerrero L, Duque M, Duran D, Molina C. Prognostic implications of clinical, electrocardiographic and hemodynamic findings in chronic Chagas' disease.  Int J Cardiol. 1994;43(1):27-38PubMedArticle
57.
Acquatella H, Schiller NB, Puigbo JJ.  et al.  M-mode and two-dimensional echocardiography in chronic Chagas heart disease: a clinical and pathologic study.  Circulation. 1980;62(4):787-799PubMedArticle
58.
Marin-Neto JA, Bromberg-Marin G, Pazin-Filho A, Simoes MV, Maciel BC. Cardiac autonomic impairment and early myocardial damage involving the right ventricle are independent phenomena in Chagas' disease.  Int J Cardiol. 1998;65(3):261-269PubMedArticle
59.
Pazin-Filho A, Romano MM, Almeida-Filho OC.  et al.  Minor segmental wall motion abnormalities detected in patients with Chagas' disease have adverse prognostic implications.  Braz J Med Biol Res. 2006;39(4):483-487PubMedArticle
60.
Viotti R, Vigliano C, Lococo B.  et al.  Clinical predictors of chronic chagasic myocarditis progression [in Spanish].  Rev Esp Cardiol. 2005;58(9):1037-1044PubMedArticle
61.
Viotti R, Vigliano C, Lococo B.  et al.  Exercise stress testing as a predictor of progression of early chronic Chagas heart disease.  Heart. 2006;92(3):403-404PubMedArticle
62.
Viotti RJ, Vigliano C, Laucella S.  et al.  Value of echocardiography for diagnosis and prognosis of chronic Chagas disease cardiomyopathy without heart failure.  Heart. 2004;90(6):655-660PubMedArticle
63.
Rassi A Jr, Rassi A, Little WC.  et al.  Development and validation of a risk score for predicting death in Chagas' heart disease.  N Engl J Med. 2006;355(8):799-808PubMedArticle
64.
Mady C, Cardoso RH, Barretto AC, da Luz PL, Bellotti G, Pileggi F. Survival and predictors of survival in patients with congestive heart failure due to Chagas' cardiomyopathy.  Circulation. 1994;90(6):3098-3102PubMedArticle
65.
Salles G, Xavier S, Sousa A, Hasslocher-Moreno A, Cardoso C. Prognostic value of QT interval parameters for mortality risk stratification in Chagas' disease: results of a long-term follow-up study.  Circulation. 2003;108(3):305-312PubMedArticle
66.
Carod-Artal FJ. Chagas cardiomyopathy and ischemic stroke.  Expert Rev Cardiovasc Ther. 2006;4(1):119-130PubMedArticle
67.
Rassi A Jr, Rassi SG, Rassi A. Sudden death in Chagas' disease.  Arq Bras Cardiol. 2001;76(1):75-96PubMedArticle
68.
Bocchi EA, Fiorelli A.First Guidelines Group for Heart Transplantation of the Brazilian Society of Cardiology.  The paradox of survival results after heart transplantation for cardiomyopathy caused by Trypanosoma cruzi.  Ann Thorac Surg. 2001;71(6):1833-1838PubMedArticle
69.
Castro C. Longitudinal radiological study of the esophagus in Chagas disease.  Mem Inst Oswaldo Cruz. 1999;94:(suppl 1)  329-330PubMedArticle
70.
Castro C, Macedo V, Rezende JM, Prata A. Longitudinal radiologic study of the esophagus, in an endemic area of Chagas disease, in a period of 13 years [in Portuguese].  Rev Soc Bras Med Trop. 1994;27(4):227-233PubMedArticle
71.
Maguire JH, Mott KE, Souza JA, Almeida EC, Ramos NB, Guimaraes AC. Electrocardiographic classification and abbreviated lead system for population-based studies of Chagas' disease.  Bull Pan Am Health Organ. 1982;16(1):47-58PubMed
72.
Lázzari JO, Pereira M, Antunes CM.  et al.  Diagnostic electrocardiography in epidemiological studies of Chagas' disease: multicenter evaluation of a standardized method.  Rev Panam Salud Publica. 1998;4(5):317-330PubMedArticle
73.
Maguire JH, Mott KE, Lehman JS.  et al.  Relationship of electrocardiographic abnormalities and seropositivity to Trypanosoma cruzi within a rural community in northeast Brazil.  Am Heart J. 1983;105(2):287-294PubMedArticle
74.
Prineas RJ, Crowe RS, Blackburn H. The Minnesota Code Manual of Electrocardiographic Findings. Boston, MA: John Wright; 1982
75.
Marin-Neto JA, Marzullo P, Marcassa C.  et al.  Myocardial perfusion abnormalities in chronic Chagas' disease as detected by thallium-201 scintigraphy.  Am J Cardiol. 1992;69(8):780-784PubMedArticle
76.
Simões MV, Dantas RO, Ejima FH, Meneghelli UG, Maciel BC, Marin-Neto JA. Esophageal origin of precordial pain in chagasic patients with normal subepicardial coronary arteries [in Portuguese].  Arq Bras Cardiol. 1995;64(2):103-108PubMed
77.
Meneghelli UG, Peria FM, Darezzo FM.  et al.  Clinical, radiographic, and manometric evolution of esophageal involvement by Chagas' disease.  Dysphagia. 2005;20(1):40-45PubMedArticle
78.
Dantas RO. Dysphagia in patients with Chagas' disease.  Dysphagia. 1998;13(1):53-57PubMedArticle
79.
Dantas RO, Deghaide NH, Donadi EA. Esophageal manometric and radiologic findings in asymptomatic subjects with Chagas' disease.  J Clin Gastroenterol. 1999;28(3):245-248PubMedArticle
80.
Rodriques Coura J, deCastro SL. A critical review on Chagas disease chemotherapy.  Mem Inst Oswaldo Cruz. 2002;97(1):3-24PubMedArticle
81.
Ferreira RCC, Ferreira LCS. Mutagenicity of nifurtimox and benznidazole in the Salmonella microsoma assay.  Braz J Med Biol Res. 1986;19(1):19-25PubMed
82.
Gorla NB, Ledesma OS, Barbieri GP, Larripa IB. Thirteenfold increase of chromosomal aberrations non-randomly distributed in chagasic children treated with nifurtimox.  Mutat Res. 1989;224(2):263-267PubMedArticle
83.
Teixeira AR, Cordoba JC, Souto Maior I, Solorzano E. Chagas' disease: lymphoma growth in rabbits treated with benznidazole.  Am J Trop Med Hyg. 1990;43(2):146-158PubMed
84.
Teixeira AR, Silva R, Cunha Neto E, Santana JM, Rizzo LV. Malignant, non-Hodgkin's lymphomas in Trypanosoma cruzi-infected rabbits treated with nitroarenes.  J Comp Pathol. 1990;103(1):37-48PubMedArticle
85.
Bocchi EA, Higuchi ML, Vieira ML.  et al.  Higher incidence of malignant neoplasms after heart transplantation for treatment of chronic Chagas' heart disease.  J Heart Lung Transplant. 1998;17(4):399-405PubMed
86.
Kirchhoff LV. Chagas disease: American trypanosomiasis.  Infect Dis Clin North Am. 1993;7(3):487-502PubMed
87.
de Andrade AL, Zicker F, de Oliveira RM.  et al.  Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection.  Lancet. 1996;348(9039):1407-1413PubMedArticle
88.
Sosa Estani S, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis C. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas' disease.  Am J Trop Med Hyg. 1998;59(4):526-529PubMed
89.
Coura JR, de Abreu LL, Willcox HP, Petana W. Comparative controlled study on the use of benznidazole, nifurtimox and placebo, in the chronic form of Chagas' disease, in a field area with interrupted transmission, I: preliminary evaluation [in Portuguese].  Rev Soc Bras Med Trop. 1997;30(2):139-144PubMedArticle
90.
Viotti R, Vigliano C, Lococo B.  et al.  Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial.  Ann Intern Med. 2006;144(10):724-734PubMedArticle
91.
Cancado JR, Brener Z. Terapeutica. In: Brener Z, Andrade Z, eds. Trypanosoma cruzi e doenca de Chagas. Rio de Janeiro, Brazil: Guanabara Koogan; 1979:362-424
92.
Altcheh J, Biancardi M, Lapena A, Ballering G, Freilij H. Congenital Chagas disease: experience in the Hospital de Niños, Ricardo Gutíerrez, Buenos Aires, Argentina [in Spanish].  Rev Soc Bras Med Trop. 2005;38:(suppl 2)  41-45PubMed
93.
Rassi A, Ferreira HO. Tentativas de tratmento especifico da fase aguda da doenca de Chagas com nifurtimox em esquema de duracao prolongada.  Rev Soc Bras Med Trop. 1971;5:235-262Article
94.
Boainain E. Tratamento etiologico da doenca de Chagas na fase cronica.  Rev Goiania Med. 1979;25:1-60
95.
Camandaroba EL, Reis EA, Goncalves MS, Reis MG, Andrade SG. Trypanosoma cruzi: susceptibility to chemotherapy with benznidazole of clones isolated from the highly resistant Colombian strain.  Rev Soc Bras Med Trop. 2003;36(2):201-209PubMedArticle
96.
Veloso VM, Carneiro CM, Toledo MJ.  et al.  Variation in susceptibility to benznidazole in isolates derived from Trypanosoma cruzi parental strains.  Mem Inst Oswaldo Cruz. 2001;96(7):1005-1011PubMedArticle
97.
Russomando G, de Tomassone MM, de Guillen I.  et al.  Treatment of congenital Chagas' disease diagnosed and followed up by the polymerase chain reaction.  Am J Trop Med Hyg. 1998;59(3):487-491PubMed
98.
Sosa-Estani S, Segura EL. Etiological treatment in patients infected by Trypanosoma cruzi: experiences in Argentina.  Curr Opin Infect Dis. 2006;19(6):583-587PubMedArticle
99.
 The BENEFIT trial: evaluation of the use of an antiparasital drug (benznidazole) in the treatment of chronic Chagas' disease. http://clinicaltrials.gov/show/NCT00123916. Accessibility verified October 11, 2007
100.
Gross PA, Barrett TL, Dellinger EP.  et al. Infectious Diseases Society of America.  Purpose of quality standards for infectious diseases.  Clin Infect Dis. 1994;18(3):421PubMedArticle
101.
Estani SS, Segura EL. Treatment of Trypanosoma cruzi infection in the undetermined phase: experience and current guidelines of treatment in Argentina.  Mem Inst Oswaldo Cruz. 1999;94:(suppl 1)  363-365PubMedArticle
102.
Rassi A, Luquetti AO. Specific treatment for Trypanosoma cruzi infection (Chagas disease). In: Tyler KM, Miles MA, eds. American Trypanosomiasis. Boston, MA: Kluwer Academic Publishers; 2003:117-125
Clinical Review
Clinician's Corner
November 14, 2007

Evaluation and Treatment of Chagas Disease in the United StatesA Systematic Review

Author Affiliations
 

Clinical Review Section Editor: Michael S. Lauer, MD. We encourage authors to submit papers for consideration as a Clinical Review. Please contact Michael S. Lauer, MD, at michael.lauer@jama-archives.org.

 

Author Affiliations: Parasitic Diseases Branch, Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia (Drs Bern, Montgomery, Herwaldt, and Moore); Anis Rassi Hospital, Goiania, Brazil (Dr Rassi); Medical School of Ribeirão Preto, University of Sao Paulo, Ribeirão Preto, Sao Paolo, Brazil (Drs Marin-Neto and Dantas); University of Maryland, Baltimore (Dr Maguire); Universidad Central de Venezuela, Caracas, Venezuela (Dr Acquatella); McMaster University, Hamilton, Ontario, Canada (Dr Morillo); University of Iowa, Iowa City (Dr Kirchhoff); Johns Hopkins University, Baltimore, Maryland (Dr Gilman); I. Chávez National Institute of Cardiology, Mexico City, Mexico (Dr Reyes); and Pan American Health Organization, Montevideo, Uruguay (Dr Salvatella).

JAMA. 2007;298(18):2171-2181. doi:10.1001/jama.298.18.2171
Context

Context Because of population migration from endemic areas and newly instituted blood bank screening, US clinicians are likely to see an increasing number of patients with suspected or confirmed chronic Trypanosoma cruzi infection (Chagas disease).

Objective To examine the evidence base and provide practical recommendations for evaluation, counseling, and etiologic treatment of patients with chronic T cruzi infection.

Evidence Acquisition Literature review conducted based on a systematic MEDLINE search for all available years through 2007; review of additional articles, reports, and book chapters; and input from experts in the field.

Evidence Synthesis The patient newly diagnosed with Chagas disease should undergo a medical history, physical examination, and resting 12-lead electrocardiogram (ECG) with a 30-second lead II rhythm strip. If this evaluation is normal, no further testing is indicated; history, physical examination, and ECG should be repeated annually. If findings suggest Chagas heart disease, a comprehensive cardiac evaluation, including 24-hour ambulatory ECG monitoring, echocardiography, and exercise testing, is recommended. If gastrointestinal tract symptoms are present, barium contrast studies should be performed. Antitrypanosomal treatment is recommended for all cases of acute and congenital Chagas disease, reactivated infection, and chronic T cruzi infection in individuals 18 years or younger. In adults aged 19 to 50 years without advanced heart disease, etiologic treatment may slow development and progression of cardiomyopathy and should generally be offered; treatment is considered optional for those older than 50 years. Individualized treatment decisions for adults should balance the potential benefit, prolonged course, and frequent adverse effects of the drugs. Strong consideration should be given to treatment of previously untreated patients with human immunodeficiency virus infection or those expecting to undergo organ transplantation.

Conclusions Chagas disease presents an increasing challenge for clinicians in the United States. Despite gaps in the evidence base, current knowledge is sufficient to make practical recommendations to guide appropriate evaluation, management, and etiologic treatment of Chagas disease.

Quiz Ref IDChagas disease is caused by Trypanosoma cruzi, a protozoan parasite usually transmitted by infected triatomine bugs. Transmission also occurs through transfusion or organ transplantation, from mother to infant, and rarely by ingestion of contaminated food or drink.13 Vector-borne transmission occurs exclusively in the Americas, where an estimated 8 million to 10 million people have Chagas disease.4,5 Historically, transmission has occurred predominantly in rural areas of Latin America, where poor housing conditions have promoted contact with infected vectors. Successful programs to reduce vector- and blood-borne transmission, as well as migration within and beyond endemic countries, have changed the epidemiology of the disease.4,6,7

In endemic settings, T cruzi infection is usually acquired in childhood. The vectors defecate during or immediately after feeding; the parasite is present in large numbers in the feces of infected bugs and enters the human body through the bite wound, conjunctiva, or other mucous membrane. An estimated 100 000 infected persons live in the United States; most acquired the disease while residing in endemic areas.8 However, T cruzi–infected vectors and animals are found in many parts of the United States,9,10 and rare cases of autochthonous transmission have been documented.11,12 Better housing conditions and less efficient vectors may explain the low risk of vectorial transmission; transfusion, organ transplantation, and mother-to-infant transmission are more likely infection routes in the United States.

On December 13, 2006, the US Food and Drug Administration approved a Chagas disease screening assay for donated blood.13 As of September 6, 2007, 193 donations confirmed positive had been reported.14 Blood donor screening is also likely to lead to heightened awareness and increased requests for diagnostic testing in the wider community. Nearly all T cruzi infections in newly diagnosed patients will be in the chronic phase, and most will be asymptomatic. Appropriate management of patients with Chagas disease requires specialized clinical expertise, laboratory diagnostic support, and access to antitrypanosomal drugs, all of which are limited in the United States.

This article aims to provide clinicians with practical guidance for the evaluation, management, and etiologic treatment of Chagas disease, with a primary focus on the chronic phase. The detailed management of Chagas cardiac1517 and gastrointestinal tract18 disease is beyond the scope of this article; primary care clinicians should consult with experienced subspecialists. This article is based on a comprehensive systematic literature review supplemented by extensive input from experts and the experience of the US Centers for Disease Control and Prevention (CDC) and takes into account the drugs and medical technology available in the United States.

EVIDENCE ACQUISITION

The literature was reviewed based on MEDLINE searches using the term Chagas disease with the subheadings evaluation, diagnosis, prognosis, treatment, congenital, gastrointestinal, transplant, HIV, nifurtimox, benznidazole, clinical trials, adverse effects, and the limiter human. Articles published from 1966 through July 1, 2007, in English, Spanish, and Portuguese were included. These searches yielded 3820 potentially relevant articles (Figure 1). Other pertinent articles, reports, monographs, and book chapters were located through citations in the literature or suggested by experts. Recent guidelines by expert committees in Brazil, Argentina, and Spain were also consulted.1921 We reviewed titles, abstracts, or both to determine relevance to this article. Observational studies were cited if the design and outcome measures were clearly described and appropriate. Prospective drug treatment trials were included if criteria for patient inclusion and group allocation were clearly described and unbiased and if outcome measures were well defined and appropriate. Trials of drugs other than benznidazole and nifurtimox were excluded, because no other drugs have been demonstrated to have efficacy in human T cruzi infection.

EVIDENCE SYNTHESIS
Clinical Aspects of Chagas Disease

Quiz Ref IDMost T cruzi–infected persons pass through the acute phase with mild symptoms or a nonspecific febrile illness; most acute infections are unrecognized.1 Severe manifestations, such as acute myocarditis or meningoencephalitis, are rarely detected.1 The acute phase lasts 4 to 8 weeks. Infected individuals then enter the chronic phase and, in the absence of successful treatment, remain infected for life. Persons with chronic infection but without signs or symptoms are considered to have the indeterminate form of Chagas disease. The strict definition of the indeterminate form requires positive anti–T cruzi serology results, no symptoms or physical examination abnormalities, normal 12-lead electrocardiogram (ECG) findings, and normal findings on radiological examination of the chest, esophagus, and colon.20

Approximately 70% to 80% of infected individuals remain in the indeterminate form throughout their lives, whereas as many as 20% to 30% of those who initially have the indeterminate form progress over a period of years to decades to clinically evident disease, most commonly affecting the heart.22,23Quiz Ref IDAffected patients have a chronic inflammatory process that involves all heart chambers, conduction system damage, and often an apical aneurysm. The pathogenesis is hypothesized to involve parasite persistence in cardiac tissue and immune-mediated myocardial injury.24 The earliest manifestations are usually conduction system abnormalities, most frequently right bundle-branch block or left anterior fascicular block and segmental left ventricular wall motion abnormalities.23 Later manifestations include (1) complex ventricular extrasystoles and nonsustained and sustained ventricular tachycardia; (2) sinus node dysfunction, usually leading to sinus bradycardia; (3) high-degree heart block; (4) pulmonary and systemic thromboembolic phenomena due to thrombus formation in the dilated left ventricle or aneurysm; and (5) progressive dilated cardiomyopathy with congestive heart failure.17 These abnormalities lead to palpitations, presyncope, syncope, and a high risk of sudden death.15 Often there are both bradyarrhythmias and tachyarrhythmias. A substantial proportion of patients have atypical chest pain, hypothesized to be related to microvascular perfusion defects.24 Several classification schemes for Chagas heart disease are used in Latin America (Box).20,2528 The most important discriminating factors are ECG status and presence or absence of congestive heart failure. One system incorporates the recently updated American College of Cardiology/American Heart Association staging of congestive heart failure.27,28

Box Section Ref IDBox. Classification Schemes to Grade Presence and Severity of Chagas Cardiomyopathy

Modified Kuschnir Classification

  • 0: Normal ECG findings and normal heart size (usually based on chest radiography)

  • I: Abnormal ECG findings and normal heart size (usually based on chest radiography)

  • II: Left ventricular enlargement

  • III: Congestive heart failure

Brazilian Consensus Classification

  • A: Abnormal ECG findings, normal echocardiogram findings, no signs of CHF

  • B1: Abnormal ECG findings, abnormal echocardiogram findings with LVEF >45%, no signs of CHF

  • B2: Abnormal ECG findings, abnormal echocardiogram findings with LVEF <45%, no signs of CHF

  • C: Abnormal ECG findings, abnormal echocardiogram findings, compensated CHF

  • D: Abnormal ECG findings, abnormal echocardiogram findings, refractory CHF

Modified Los Andes Classification

  • IA: Normal ECG findings, normal echocardiogram findings, no signs of CHF

  • IB: Normal ECG findings, abnormal echocardiogram findings, no signs of CHF

  • II: Abnormal ECG findings, abnormal echocardiogram findings, no signs of CHF

  • III: Abnormal ECG findings, abnormal echocardiogram findings, CHF

Classification Incorporating American College of Cardiology/American Heart Association Staging27,28

  • A: Normal ECG findings, normal heart size, normal LVEF, NYHA class I

  • B: Abnormal ECG findings, normal heart size, normal LVEF, NYHA class I

  • C: Abnormal ECG findings, increased heart size, decreased LVEF, NYHA class II-III

  • D: Abnormal ECG findings, increased heart size, decreased LVEF, NYHA class IV

  • Abbreviations: CHF, congestive heart failure; ECG, electrocardiogram; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

Chagas gastrointestinal tract disease results from damage to intramural neurons and predominantly affects the esophagus, colon, or both.18,29,30 The esophageal effects comprise a spectrum ranging from asymptomatic motility disorders through mild achalasia to severe megaesophagus.31 Manifestations include dysphagia, odynophagia, esophageal reflux, weight loss, aspiration, cough, and regurgitation. As in idiopathic achalasia, the risk of esophageal carcinoma is increased.32,33 Colonic involvement leads to prolonged constipation, abdominal pain, and fecaloma. Patients with megacolon have an increased risk of volvulus and consequent bowel ischemia. Gastrointestinal tract involvement is less common than Chagas heart disease, is seen almost exclusively in patients infected in the Southern Cone (Argentina, Bolivia, Chile, Paraguay, southern Peru, Uruguay, and parts of Brazil), and is rare in northern South America, Central America, and Mexico. This geographical pattern is thought to be linked to differences in parasite strains.34,35

In approximately 1% to 10% of pregnancies in women with chronic Tcruzi infection, the infant is born with congenital infection.1,36,37 Most infected newborns are asymptomatic or have nonspecific findings such as low birth weight, prematurity, or low Apgar scores. Other signs include hepatosplenomegaly, anemia, and thrombocytopenia. Serious manifestations, including myocarditis, meningoencephalitis, and respiratory distress, are uncommon but carry a high risk of mortality.37

Trypanosoma cruzi infection in patients who become immunocompromised may reactivate, leading to increases in intracellular parasite replication and parasitemia detectable by microscopy. Reactivation occurs in a minority of patients with chronic Chagas disease who are coinfected with human immunodeficiency virus or are receiving immunosuppressive drugs. Although the incidence in patients undergoing transplantation is not well defined, reactivation is more common in patients treated with highly immunosuppressive regimens.38 Reactivated infection has features that differ from those of acute infection, and patients with drug-induced immunosuppression have a clinical picture distinct from that of those with AIDS. In recipients of solid organ or bone marrow transplants, reactivation is associated with subcutaneous parasite-containing nodules, panniculitis, and myocarditis; central nervous system involvement has rarely been reported.3942 By contrast, in patients with AIDS, the most common manifestations are meningoencephalitis and space-occupying central nervous system lesions that can be confused with toxoplasmosis.43,44 Acute myocarditis, sometimes superimposed on preexisting cardiomyopathy due to chronic Chagas disease, can lead to rapid-onset congestive heart failure.43,44

Diagnostic Considerations

In the acute phase, the level of parasitemia is high, and motile trypomastigotes are often detected by microscopy of fresh preparations of anticoagulated blood or buffy coat (Figure 2).1 The parasitemia decreases within 90 days of infection, even without treatment,45 and is undetectable by microscopy in the chronic phase. Nevertheless, low-level parasitemias account for transmission from chronically infected individuals through blood transfusions, organ transplants, mother-to-infant transmission, or via the vector. Diagnosis of chronic Chagas disease relies on serologic methods, most commonly enzyme-linked immunosorbent assay and immunofluorescent antibody test. No single assay has sufficient sensitivity and specificity to be relied on alone; 2 tests based on different antigens or techniques are used in parallel to increase the accuracy of the diagnosis.46,47 When results are discordant, a third assay may be used to confirm or refute the diagnosis, or repeat sampling may be required.

Identification of the parasite by microscopy, hemoculture, or polymerase chain reaction (PCR)-based methods provides definitive diagnosis of Chagas disease. However, the sensitivity of these methods is limited by the level of parasitemia, and a negative result does not exclude the diagnosis. PCR-based methods have high sensitivity in acute T cruzi infection, but their performance in chronic Chagas disease is variable and currently they are primarily research tools.48 Because positive PCR results can occur in chronic infection in the absence of reactivation, laboratory monitoring for reactivated infection relies primarily on microscopic examination of fresh blood or buffy coat.

Programs to identify congenital infection rely on serologic diagnosis of infected mothers, followed by microscopic and PCR-based examination of cord blood, peripheral blood specimens, or both from their infants during the first 1 to 2 months of life.36,49 If results of parasitological testing are negative or if testing is not performed early in life, the infant should be tested by enzyme-linked immunosorbent assay and immunofluorescent antibody test at ages 9 to 12 months, after the level of transferred maternal antibody has decreased.50 All other children of infected mothers should also be tested.

Prognosis

The most important determinant of prognosis for T cruzi–infected persons is the likelihood of progression to heart disease. Most reviews estimate that 20% to 30% of infected persons will develop clinically apparent disease during their lifetimes, but estimates vary across published studies.1,2,47,51 This variability reflects, in part, methodological differences such as study population, definitions of progression, and length and completeness of follow-up. Animal models suggest that T cruzi strain is an important determinant of clinical manifestations and severity52; other possible factors include the severity of the acute infection and age at which it occurred, host immune response, and human genetic factors.2,35,53,54 Community-based studies demonstrate that survival of individuals whose disease remains in the indeterminate form is equivalent to that of the general population.23,55,56 Echocardiography, radionuclide angiography, or autonomic testing may reveal minor abnormalities in as many as one-third of T cruzi–infected individuals with normal ECG and chest radiography results,5759 but these findings have not been shown to indicate a worse prognosis.

Ventricular conduction defects precede onset of symptoms by years to decades.23 During 6.7 years of follow-up in one community-based study, right bundle-branch block alone was associated with a 7-fold increase, and right bundle-branch block with at least 1 ventricular extrasystole on resting ECG with a 12-fold increase, in the risk of mortality compared with seropositive persons having normal ECG findings.23 Later manifestations associated with poor prognosis include ventricular tachycardia or complex ventricular arrhythmias, increased left ventricular systolic diameter, and segmental or global left ventricular wall motion abnormalities.15,5962 A rigorous analysis identified congestive heart failure (New York Heart Association class III or IV), cardiomegaly, left ventricular systolic dysfunction on echocardiography, nonsustained ventricular tachycardia on 24-hour ambulatory monitoring, low QRS voltage, and male sex as the strongest predictors of mortality.63 This study and others confirm that congestive heart failure and left ventricular ejection fraction less than 30% identify a group of patients with less than 30% survival at 2 to 4 years.15,55,56,64 Patients with Chagas cardiomyopathy have sudden death due to ventricular arrhythmias or complete heart block, or die from intractable congestive heart failure or embolic phenomena.56,63,65 The presence of an apical aneurysm is associated with a high risk of stroke.66

In selected patients with Chagas heart disease, empirical use of amiodarone or angiotensin-converting enzyme inhibitors, or implantation of a pacemaker or intracardiac defibrillator, may improve survival.15,16,67 However, few controlled clinical trials have been conducted to evaluate the efficacy of specific pharmacological treatment or devices in Chagas cardiomyopathy. Experience in Brazil demonstrates that survival after heart transplantation for Chagas cardiomyopathy is equal to or better than that among patients receiving transplants for idiopathic or ischemic dilated cardiomyopathy; careful management of immunosuppressive therapy is essential.38,68

Longitudinal data to address the prognosis of Chagas gastrointestinal tract disease are sparse. Once disease is clinically apparent, progression is usually slow.18,69,70 There are no data to suggest that antitrypanosomal therapy alters the course of the disease. Management focuses on symptom amelioration through dietary, medical, and surgical interventions.18

Evaluation of the Patient Newly Diagnosed With Chagas Disease

The initial evaluation consists of the medical history, including evidence of potential T cruzi exposure in endemic areas via blood transfusion or other routes; complete physical examination; and resting 12-lead ECG with a 30-second lead II rhythm strip (Figure 3).23,71,72 The history should include a thorough review of systems, with an emphasis on symptoms suggestive of cardiac arrhythmias, early congestive heart failure, and gastrointestinal tract disease. Infected persons should be counseled not to donate blood. Diagnostic screening should be offered for children of seropositive women, family members of patients, and other individuals with a history of potential exposure to the parasite in endemic settings.

For practical purposes, a seropositive patient with no evidence of cardiac or gastrointestinal tract alterations evident on this evaluation is considered to have the indeterminate form, even if chest radiography and barium examination of the colon and esophagus are not performed. Because the prognosis of asymptomatic patients with normal ECG findings is good, the predominant view of the authors is that further initial evaluation is unnecessary and that subsequent follow-up should rely on annual history, physical examination, and ECG findings (Figure 3).

For patients with symptoms, signs, or abnormal ECG findings, further evaluation should be tailored to the clinical picture. Patients with symptoms or ECG changes consistent with Chagas heart disease23,71,73,74 should undergo a comprehensive cardiac evaluation, including ambulatory 24-hour ECG monitoring to detect arrhythmias; exercise testing to identify exercise-induced arrhythmias and assess functional capacity and chronotropic response; and 2-dimensional echocardiography to assess biventricular function, wall motion, and structure. For asymptomatic patients with nonspecific ECG changes (eg, rsR′ not meeting criteria for right bundle-branch block or a minor increase in PR interval), the need for further evaluation should be judged on an individual basis.

Certain signs and symptoms raise immediate concern. Syncope, indicators of ventricular dysfunction, 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.67 These findings should trigger an intensive search for arrhythmias and conduction system abnormalities, proceeding to electrophysiologic studies if indicated by the results of noninvasive testing. Chest pain warrants evaluation for ischemia and noncardiac causes, such as esophagitis.24,75,76 In patients with chest pain, cardiac scintigraphy scans may reveal perfusion defects thought to reflect microvascular ischemia or fibrosis, but angiography usually shows normal coronary arteries.24

In patients without gastrointestinal tract symptoms, no barium studies are recommended. Patients with symptoms suggestive of esophageal or colonic involvement should undergo a barium swallow or enema, respectively. Following barium swallow, radiographs should be taken at 10 seconds and at 5 and 10 minutes.77 Esophageal manometry may detect more subtle changes and may be indicated if results of the barium study are inconclusive.78,79 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 indicated, especially if a change in symptoms has occurred. Patients with Chagas gastrointestinal tract disease should be evaluated for heart disease following the algorithm outlined above.

Antitrypanosomal Drug Therapy

Benznidazole and nifurtimox are the only drugs with proven efficacy against Chagas disease.2,80 Because benznidazole is better tolerated, this drug is viewed by most experts as the first-line treatment. Nevertheless, individual tolerance varies; if one drug must be discontinued, the other can be used as an alternative. Neither drug is approved in the United States; both can be obtained from the CDC and used under investigational protocols. Adults should be treated with benznidazole (5-7 mg/kg per day) in 2 divided doses for 60 days or with nifurtimox (8-10 mg/kg per day) in 3 divided doses for 90 days. Consultations about diagnostic testing, management, drug requests, and dosage regimens for special circumstances (eg, pediatric or immunocompromised patients) should be addressed to the CDC Division of Parasitic Diseases Public Inquiries line (770-488-7775; e-mail: ncidpdbpi@cdc.gov); the CDC Drug Service (404-639-3670); or, for emergencies after business hours, on weekends, and on federal holidays, the CDC Emergency Operations Center (770-488-7100).

Benznidazole (Radanil, Rochagan, Roche 7-1051), introduced in 1971, is a nitroimidazole derivative active against both the trypomastigote and amastigote forms. The drug is rapidly absorbed from the gastrointestinal tract; the average biological half-life is 12 hours. Elimination is predominantly renal; 22% of excretion is fecal. Children have fewer adverse effects than adults and tolerate higher doses. Dermatologic adverse effects occur in approximately 30% of patients and consist of rashes due to photosensitization, rarely progressing to exfoliative dermatitis. The dermatitis is usually mild to moderate and manageable with topical or low-dose systemic corticosteroids. However, the drug should be discontinued immediately in case of severe or exfoliative dermatitis or of dermatitis associated with fever and lymphadenopathy. Approximately 30% of patients experience a dose-dependent peripheral neuropathy. It occurs most commonly late in the treatment course and should trigger cessation of treatment; it is nearly always reversible but may take months to resolve. Bone marrow suppression is rare and should prompt immediate treatment interruption. Additional reported adverse effects include anorexia and weight loss, nausea and/or vomiting, insomnia, and dysgeusia. Laboratory testing (complete blood cell count and levels of hepatic enzymes, bilirubin, serum creatinine, and blood urea nitrogen) should be performed before beginning treatment; the complete blood cell count should be repeated every 2 to 3 weeks during the treatment course. Patients should be monitored for dermatitis beginning 9 to 10 days after initiation of treatment. Concurrent alcohol use can lead to disulfiram-like effects (abdominal cramps, nausea, vomiting, flushing, headache) and should be avoided.

Nifurtimox (Lampit, Bayer 2502), introduced in 1965, is a nitrofuran compound, also with activity against trypomastigotes and amastigotes.80 The drug is rapidly absorbed from the gastrointestinal tract and extensively metabolized in the liver, where nitroreduction occurs through cytochrome P450 reductase. Elimination of metabolites is predominantly renal. In humans, plasma levels peak at 1 hour after a single oral dose and have an elimination half-life of 3 hours. Like benznidazole, nifurtimox is better tolerated by children,51 and dosage recommendations differ by age.

Adverse effects are frequent but usually resolve when treatment is stopped. Gastrointestinal tract complaints occur in 30% to 70% of patients and include anorexia leading to weight loss, nausea, vomiting, and abdominal discomfort. Symptoms of central nervous system toxicity include irritability, insomnia, disorientation, and, less often, tremors. More serious but less common adverse effects include paresthesias, polyneuropathy, and peripheral neuritis. The peripheral neuropathy is dose-dependent, appears late in the treatment course, and should prompt interruption. Additional adverse effects include dizziness or vertigo, nervous excitation, mood changes, and myalgias. Laboratory testing (complete blood cell count and levels of hepatic enzymes, bilirubin, serum creatinine, and blood urea nitrogen) should be performed before beginning treatment, 4 to 6 weeks into the course, and at the end of treatment. Patients should be weighed and monitored for symptoms and signs of peripheral neuropathy every 2 weeks, especially during the second and third months of treatment. Concurrent alcohol use increases the risk of adverse effects and should be avoided.

Benznidazole and nifurtimox are both mutagenic81,82 and have been reported to increase risk of lymphomas in experimental animals.83,84 Although a higher incidence of neoplasms was reported in a small series of T cruzi–infected heart transplant recipients,85 no increase in incidence of human lymphoma has been reported among the larger population of treated patients in countries where the 2 drugs have been in use for decades.86 Nevertheless, definitive data on this issue are lacking.

Efficacy of Drug Treatment for Chagas Disease

Despite the public health importance of Chagas disease, few rigorous clinical trials have been conducted (Table 1).8790 The complex natural history of the infection and inadequate tools to assess cure have made it difficult to define appropriate end points and follow-up intervals. The published randomized, placebo-controlled trials assessed primarily parasite-related outcomes, antibody-related outcomes, or both rather than clinical outcomes.

Treatment of Acute and Congenital Infection

Quiz Ref IDBased on several early trials and subsequent clinical experience in acute and early congenital Chagas disease, both drugs are known to reduce symptom severity and to shorten the clinical course and duration of detectable parasitemia.2,45,86,91 Parasitological cure is thought to occur in 60% to 85% of patients in the acute phase and in more than 90% of congenitally infected infants treated in the first year of life.45,80,91,92 Geographic variability in efficacy has been reported for acute93 and chronic94 infection and in animal models.95,96 Treatment of infected infants should begin as soon as the diagnosis is made; the drugs are well tolerated in infancy.45,97 Neither drug is available in a pediatric formulation; for infants and young children, the tablets should be prepared in a compounding pharmacy to provide the appropriate dose.

Treatment in the Chronic Phase

In the 1990s, 2 randomized, double-blinded, placebo-controlled trials of benznidazole for children aged 6 to 12 years with asymptomatic T cruzi infection demonstrated approximately 60% efficacy, as assessed by conversion from positive to negative serology results 3 to 4 years posttreatment (Table 1).87,88 In 1 trial, treated children also showed a marked reduction in positive xenodiagnoses compared with the placebo group.88 Benznidazole was well tolerated in these pediatric trials (Table 1). Together with growing clinical experience across Latin America, these studies prompted recommendations for early diagnosis and antitrypanosomal therapy for all infected children.20,47 In a recently published, nonrandomized, nonblinded trial, benznidazole treatment appeared to slow the development and progression of Chagas cardiomyopathy in adults.90 Based on these and other data, a number of experts now recommend treatment of adults with chronic T cruzi infection in the absence of advanced Chagas cardiomyopathy.90,98 A multicenter, randomized, double-blinded, placebo-controlled trial of benznidazole for patients with mild to moderate Chagas cardiomyopathy is currently under way.99 Data from this study should help clarify treatment decisions for this group of patients.

Reactivated

Data from series of patients who underwent transplantation with reactivated infection showed that standard doses of benznidazole given for 30 to 180 days led to resolution of signs and symptoms and reduced intensity of parasitemia.3942 A standard 60-day benznidazole regimen decreased parasitemia and resulted in clinical improvement in a small series of patients coinfected with human immunodeficiency virus and T cruzi.43 The optimal duration of therapy in immunocompromised patients and the usefulness of secondary prophylaxis have not been established.

Indications for Antitrypanosomal Therapy

Based on the literature reviewed above, recommendations for antitrypanosomal therapy vary by phase and form of Chagas disease and by patient age and are graded based on Infectious Diseases Society of America quality-of-evidence standards.100 Drug therapy is recommended in all cases of acute and congenital infection, reactivated infection, and in children 18 years or younger with chronic T cruzi infection (Table 2).45,49,87,88,101 For adults aged 19 to 50 years without advanced Chagas cardiomyopathy, antitrypanosomal drug treatment should generally be offered.47,90,101,102 For those older than 50 years, the risk of drug toxicity may be higher than in younger adults,45 and treatment is considered optional. The rationale for treatment in adults rests on data that are suggestive, but not yet conclusive, that treatment may prevent or slow progression of cardiomyopathy.90 Individualized treatment decisions for adults should take into account the current lack of certainty of benefit, prolonged course, and frequent adverse effects. Because drug treatment might be expected to reduce the probability of congenital transmission, stronger consideration may be warranted for reproductive-aged women; nevertheless, data are lacking on this issue.

Similarly, antitrypanosomal treatment should be given stronger consideration in situations in which future immunosuppression is anticipated, for example, among previously untreated T cruzi–infected patients awaiting organ transplantation, or patients coinfected with human immunodeficiency virus. However, many experts recommend close posttransplantation monitoring for reactivation through periodic microscopic examination of the buffy coat and clinical evaluations for signs and symptoms such as fever and skin lesions, with treatment only if reactivation is demonstrated. Reactivation risk varies considerably, depending primarily on the degree of immunosuppression.41,42

For patients with advanced Chagas cardiomyopathy, antiparasitic treatment is not recommended, because existing pathology will not be affected; the focus is on supportive therapy. For patients with Chagas gastrointestinal tract disease, treatment decisions should be based on the potential to decrease risk of development or progression of cardiomyopathy; the same factors, such as age and the possibility of congenital transmission, should be considered as for other patients without advanced heart disease. In patients with megaesophagus, drug absorption may be impaired; treatment should be delayed until after corrective surgery. Benznidazole and nifurtimox are contraindicated in pregnancy and in patients with severe renal or hepatic dysfunction.

Documentation of Response After Treatment

For monitoring response to treatment, hemoculture and direct examination of blood or the buffy coat have high sensitivity in acute, early congenital, or reactivated T cruzi infection. In the chronic phase, there is no assay of proven value for documentation of response. The 2 key placebo-controlled trials each used a different experimental serologic assay, neither of which is widely available.87,88 Negative seroconversion by conventional assays occurs after successful treatment but takes years to decades.102 PCR-based techniques are useful in monitoring for treatment failure in persons with acute T cruzi infection, but their variable sensitivity limits their usefulness in those with chronic Chagas disease.

COMMENT

Quiz Ref IDBecause of newly instituted blood bank screening, increased community awareness, and demographic changes, United States–based clinicians are likely to encounter more patients with Chagas disease in the future. Baseline evaluation should include complete history, physical examination, and resting ECG with a 30-second lead II rhythm strip. Persons infected with T cruzi should be counseled not to donate blood, and screening should be offered for family members with a similar exposure history and for children of infected women. For patients with negative baseline evaluation results, follow-up should consist of yearly history, physical examination, and ECG. Antitrypanosomal treatment should always be offered for T cruzi–infected children aged up to 18 years and for patients with acute or reactivated disease and should generally be offered to patients aged 19 to 50 years without advanced heart disease. For patients older than 50 years without advanced cardiomyopathy, antiparasitic treatment is considered optional. Currently available drugs require a prolonged course, pose a significant risk of adverse effects, and require careful monitoring.

Back to top
Article Information

Corresponding Author: Caryn Bern, MD, MPH, Parasitic Diseases Branch, Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne and Enteric Diseases, Centers for Disease Control and Prevention, 4770 Buford Hwy NE, MS F-22, Atlanta, GA 30341 (cbern@cdc.gov).

Author Contributions: Drs Bern, Montgomery, and Moore had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Bern, Montgomery, Herwaldt, Marin-Neto, Moore.

Acquisition of data: Bern, Montgomery, Herwaldt, Rassi, Marin-Neto, Dantas, Maguire, Morillo, Moore.

Analysis and interpretation of data: Bern, Montgomery, Herwaldt, Rassi, Marin-Neto, Dantas, Maguire, Acquatella, Kirchhoff, Gilman, Reyes, Salvatella, Moore.

Drafting of the manuscript: Bern, Montgomery, Moore.

Critical revision of the manuscript for important intellectual content: Bern, Montgomery, Herwaldt, Rassi, Marin-Neto, Dantas, Maguire, Acquatella, Morillo, Kirchhoff, Gilman, Reyes, Salvatella, Moore.

Obtained funding: Herwaldt, Moore.

Administrative, technical, or material support: Bern, Montgomery, Moore.

Study supervision: Bern, Montgomery, Moore.

Financial Disclosures: Dr Kirchhoff reported receiving funding from a National Institutes of Health grant through a subcontract with InBios International Inc; having consultancy relationships with Abbott Laboratories and Ortho-Clinical Diagnostics Inc; receiving payments through licensing agreements with Abbott Laboratories, Ortho-Clinical Diagnostics Inc, and Quest Diagnostics Inc; and owning an equity interest in Goldfinch Diagnostics Inc. All other authors declare no conflicts of interest.

Funding/Support: This study was supported by intramural funding from the US Centers for Disease Control and Prevention (CDC).

Role of the Sponsor: Employees of the CDC were involved in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; and the preparation, review, and approval of the manuscript.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the CDC.

Additional Contributions: We thank Sergio Sosa Estani, MD, PhD (Tulane University, New Orleans, Louisiana, and Centro National de Diagnóstico e Investigación de Endemo-epidemias, ANLIS “Dr Carlos G. Malbrán,” Ministerio de Salud y Ambiente, Buenos Aires, Argentina), Monica Parise, MD, Mark Eberhard, PhD, and Matt Kuehnert, MD (CDC, Atlanta, Georgia), Dan Colley, PhD, and Rick Tarleton, PhD (University of Georgia, Athens), and Dennis Juranek, DVM (retired, CDC, Atlanta), for scientific review and helpful comments; Henry S. Bishop (CDC, Atlanta) for providing parasite images; and Carolyn Erling (CDC, Atlanta) for administrative support. None of these individuals received compensation for their contributions.

REFERENCES
1.
Maguire JH. Trypanosoma. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious Diseases. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:2327-2334
2.
Magill AJ, Reed SG. American trypanosomiasis. In: Strickland GT, ed. Hunter's Tropical Medicine and Emerging Diseases. 8th ed. Philadelphia, PA: WB Saunders Co; 2000:653-664
3.
Benchimol Barbosa PR. The oral transmission of Chagas' disease: an acute form of infection responsible for regional outbreaks.  Int J Cardiol. 2006;112(1):132-133PubMedArticle
4.
Organizacion Panamericana de la Salud.  Estimacion cuantitativa de la enfermedad de Chagas en las Americas. Montevideo, Uruguay: Organizacion Panamericana de la Salud; 2006
5.
Remme JHF, Feenstra P, Lever PR.  et al.  Tropical diseases targeted for elimination: Chagas disease, lymphatic filariasis, onchocerciasis, and leprosy. In: Jamison DT, Breman JG, Measham AR, et al, eds. Disease Control Priorities in Developing Countries. New York, NY: The World Bank and Oxford University Press; 2006:433-449
6.
 Regional PAHO Regional Program on Chagas Disease. Pan American Health Organization Web site. http://www.paho.org/english/ad/dpc/cd/dch-program-page.htm. Accessed July 1, 2007
7.
Kirchhoff LV. Changing epidemiology and approaches to therapy for Chagas disease.  Curr Infect Dis Rep. 2003;5(1):59-65PubMedArticle
8.
Leiby DA, Herron RM Jr, Read EJ, Lenes BA, Stumpf RJ. Trypanosoma cruzi in Los Angeles and Miami blood donors: impact of evolving donor demographics on seroprevalence and implications for transfusion transmission.  Transfusion. 2002;42(5):549-555PubMedArticle
9.
Bradley KK, Bergman DK, Woods JP, Crutcher JM, Kirchhoff LV. Prevalence of American trypanosomiasis (Chagas disease) among dogs in Oklahoma.  J Am Vet Med Assoc. 2000;217(12):1853-1857PubMedArticle
10.
Pung OJ, Banks CW, Jones DN, Krissinger MW. Trypanosoma cruzi in wild raccoons, opossums, and triatomine bugs in southeast Georgia, U.S.A.  J Parasitol. 1995;81(2):324-326PubMedArticle
11.
Herwaldt BL, Grijalva MJ, Newsome AL.  et al.  Use of polymerase chain reaction to diagnose the fifth reported US case of autochthonous transmission of Trypanosoma cruzi, in Tennessee, 1998.  J Infect Dis. 2000;181(1):395-399PubMedArticle
12.
Dorn PL, Perniciaro L, Yabsley MJ.  et al.  Autochthonous transmission of Trypanosoma cruzi, Louisiana.  Emerg Infect Dis. 2007;13(4):605-607PubMedArticle
13.
Centers for Disease Control and Prevention.  Blood donor screening for Chagas disease—United States, 2006-2007.  MMWR Morb Mortal Wkly Rep. 2007;56(7):141-143PubMed
14.
 Chagas' Biovigilance Network. AABB Web site. http://www.aabb.org/Content/Programs_and_Services/Data_Center/Chagas/. Accessed September 12, 2007
15.
Rassi A Jr, Rassi A, Rassi SG. Predictors of mortality in chronic Chagas disease: a systematic review of observational studies.  Circulation. 2007;115(9):1101-1108PubMedArticle
16.
Rassi A Jr, Rassi A, Little WC. Chagas' heart disease.  Clin Cardiol. 2000;23(12):883-889PubMedArticle
17.
Hagar JM, Rahimtoola SH. Chagas' heart disease.  Curr Probl Cardiol. 1995;20(12):825-924PubMed
18.
de Oliveira RB, Troncon LE, Dantas RO, Menghelli UG. Gastrointestinal manifestations of Chagas' disease.  Am J Gastroenterol. 1998;93(6):884-889PubMed
19.
Gascón J, Albajar P, Canas E.  et al.  Diagnosis, management and treatment of chronic Chagas' heart disease in areas where Trypanosoma cruzi infection is not endemic [in Spanish].  Rev Esp Cardiol. 2007;60(3):285-293PubMedArticle
20.
Ministério da Saúde Brasil.  Brazilian Consensus on Chagas disease [in Portuguese].  Rev Soc Bras Med Trop. 2005;38:(suppl 3)  7-29PubMedArticle
21.
Sociedad Argentina de Cardiología.  Consejo de Enfermedad de Chagas.  Rev Argent Cardiol. 2002;70:(suppl 1)  1-87
22.
Pinto Dias JC. Natural history of Chagas' disease.  Arq Bras Cardiol. 1995;65(4):359-366PubMed
23.
Maguire JH, Hoff R, Sherlock I.  et al.  Cardiac morbidity and mortality due to Chagas' disease: prospective electrocardiographic study of a Brazilian community.  Circulation. 1987;75(6):1140-1145PubMedArticle
24.
Marin-Neto JA, Cunha-Neto E, Maciel BC, Simoes MV. Pathogenesis of chronic Chagas heart disease.  Circulation. 2007;115(9):1109-1123PubMedArticle
25.
Kuschnir E, Sgammini H, Castro R, Evequoz C, Ledesma R, Brunetto J. Evaluation of cardiac function by radioisotopic angiography, in patients with chronic Chagas cardiopathy [in Spanish].  Arq Bras Cardiol. 1985;45(4):249-256PubMed
26.
Carrasco HA, Barboza JS, Inglessis G, Fuenmayor A, Molina C. Left ventricular cineangiography in Chagas' disease: detection of early myocardial damage.  Am Heart J. 1982;104(3):595-602PubMedArticle
27.
Acquatella H. Echocardiography in Chagas heart disease.  Circulation. 2007;115(9):1124-1131PubMedArticle
28.
Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  J Am Coll Cardiol. 2005;46(6):e1-e82PubMedArticle
29.
de Rezende JM, Moreira H. Chagasic megaesophagus and megacolon: historical review and present concepts.  Arq Gastroenterol. 1988;25:(special issue)  32-43PubMed
30.
Mota E, Todd CW, Maguire JH.  et al.  Megaesophagus and seroreactivity to Trypanosoma cruzi in a rural community in northeast Brazil.  Am J Trop Med Hyg. 1984;33(5):820-826PubMed
31.
de Oliveira RB, Rezende Filho J, Dantas RO, Iazigi N. The spectrum of esophageal motor disorders in Chagas' disease.  Am J Gastroenterol. 1995;90(7):1119-1124PubMed
32.
Atías A. A case of congenital chagasic megaesophagus: evolution until death caused by esophageal neoplasm, at 27 years of age [in Spanish].  Rev Med Chil. 1994;122(3):319-322PubMed
33.
Brücher BL, Stein HJ, Bartels H, Feussner H, Siewert JR. Achalasia and esophageal cancer: incidence, prevalence, and prognosis.  World J Surg. 2001;25(6):745-749PubMedArticle
34.
Miles MA, Feliciangeli MD, de Arias AR. American trypanosomiasis (Chagas' disease) and the role of molecular epidemiology in guiding control strategies.  BMJ. 2003;326(7404):1444-1448PubMedArticle
35.
Campbell DA, Westenberger SJ, Sturm NR. The determinants of Chagas disease: connecting parasite and host genetics.  Curr Mol Med. 2004;4(6):549-562PubMedArticle
36.
Bittencourt AL. Congenital Chagas disease.  Am J Dis Child. 1976;130(1):97-103PubMed
37.
Torrico F, Alonso-Vega C, Suarez E.  et al.  Maternal Trypanosoma cruzi infection, pregnancy outcome, morbidity, and mortality of congenitally infected and non-infected newborns in Bolivia.  Am J Trop Med Hyg. 2004;70(2):201-209PubMed
38.
Bocchi EA, Bellotti G, Mocelin AO.  et al.  Heart transplantation for chronic Chagas' heart disease.  Ann Thorac Surg. 1996;61(6):1727-1733PubMedArticle
39.
Fiorelli AI, Stolf NA, Honorato R.  et al.  Later evolution after cardiac transplantation in Chagas' disease.  Transplant Proc. 2005;37(6):2793-2798PubMedArticle
40.
Maldonado C, Albano S, Vettorazzi L.  et al.  Using polymerase chain reaction in early diagnosis of re-activated Trypanosoma cruzi infection after heart transplantation.  J Heart Lung Transplant. 2004;23(12):1345-1348PubMedArticle
41.
Riarte A, Luna C, Sabatiello R.  et al.  Chagas' disease in patients with kidney transplants: 7 years of experience 1989-1996.  Clin Infect Dis. 1999;29(3):561-567PubMedArticle
42.
Altclas J, Sinagra A, Dictar M.  et al.  Chagas disease in bone marrow transplantation: an approach to preemptive therapy.  Bone Marrow Transplant. 2005;36(2):123-129PubMedArticle
43.
Sartori 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):31-50PubMedArticle
44.
Vaidian AK, Weiss LM, Tanowitz HB. Chagas' disease and AIDS.  Kinetoplastid Biol Dis. 2004;3(1):2PubMedArticle
45.
Wegner DH, Rohwedder RW. The effect of nifurtimox in acute Chagas' infection.  Arzneimittelforschung. 1972;22(9):1624-1635PubMed
46.
Kirchhoff LV. American trypanosomiasis (Chagas disease). In: Guerrant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases: Principles, Pathogens and Practice. 2nd ed. New York, NY: Churchill Livingstone; 2006:1082-1094
47.
WHO Expert Committee.  Control of Chagas Disease. Brasilia, Brazil: World Health Organization; 2002. WHO technical report series 905
48.
Castro AM, Luquetti AO, Rassi A, Rassi GG, Chiari E, Galvao LM. Blood culture and polymerase chain reaction for the diagnosis of the chronic phase of human infection with Trypanosoma cruzi.  Parasitol Res. 2002;88(10):894-900PubMedArticle
49.
Freilij H, Altcheh J. Congenital Chagas' disease: diagnostic and clinical aspects.  Clin Infect Dis. 1995;21(3):551-555PubMedArticle
50.
 Congenital infection with Trypanosoma cruzi: from mechanisms of transmission to strategies for diagnosis and control.  Rev Soc Bras Med Trop. 2003;36(6):767-771PubMedArticle
51.
Miles MA. American trypanosomiasis (Chagas disease). In: Cook GC, Zumla AI, eds. Manson's Tropical Disease. London, England: Elsevier Science Limited; 2003:1325-1335
52.
Andersson J, Orn A, Sunnemark D. Chronic murine Chagas' disease: the impact of host and parasite genotypes.  Immunol Lett. 2003;86(2):207-212PubMedArticle
53.
Bustamante JM, Rivarola HW, Fernandez AR.  et al.  Indeterminate Chagas' disease: Trypanosoma cruzi strain and re-infection are factors involved in the progression of cardiopathy.  Clin Sci (Lond). 2003;104(4):415-420PubMedArticle
54.
Laucella SA, Postan M, Martin D.  et al.  Frequency of interferon-gamma-producing T cells specific for Trypanosoma cruzi inversely correlates with disease severity in chronic human Chagas disease.  J Infect Dis. 2004;189(5):909-918PubMedArticle
55.
Acquatella H, Catalioti F, Gomez-Mancebo JR, Davalos V, Villalobos L. Long-term control of Chagas disease in Venezuela: effects on serologic findings, electrocardiographic abnormalities, and clinical outcome.  Circulation. 1987;76(3):556-562PubMedArticle
56.
Carrasco HA, Parada H, Guerrero L, Duque M, Duran D, Molina C. Prognostic implications of clinical, electrocardiographic and hemodynamic findings in chronic Chagas' disease.  Int J Cardiol. 1994;43(1):27-38PubMedArticle
57.
Acquatella H, Schiller NB, Puigbo JJ.  et al.  M-mode and two-dimensional echocardiography in chronic Chagas heart disease: a clinical and pathologic study.  Circulation. 1980;62(4):787-799PubMedArticle
58.
Marin-Neto JA, Bromberg-Marin G, Pazin-Filho A, Simoes MV, Maciel BC. Cardiac autonomic impairment and early myocardial damage involving the right ventricle are independent phenomena in Chagas' disease.  Int J Cardiol. 1998;65(3):261-269PubMedArticle
59.
Pazin-Filho A, Romano MM, Almeida-Filho OC.  et al.  Minor segmental wall motion abnormalities detected in patients with Chagas' disease have adverse prognostic implications.  Braz J Med Biol Res. 2006;39(4):483-487PubMedArticle
60.
Viotti R, Vigliano C, Lococo B.  et al.  Clinical predictors of chronic chagasic myocarditis progression [in Spanish].  Rev Esp Cardiol. 2005;58(9):1037-1044PubMedArticle
61.
Viotti R, Vigliano C, Lococo B.  et al.  Exercise stress testing as a predictor of progression of early chronic Chagas heart disease.  Heart. 2006;92(3):403-404PubMedArticle
62.
Viotti RJ, Vigliano C, Laucella S.  et al.  Value of echocardiography for diagnosis and prognosis of chronic Chagas disease cardiomyopathy without heart failure.  Heart. 2004;90(6):655-660PubMedArticle
63.
Rassi A Jr, Rassi A, Little WC.  et al.  Development and validation of a risk score for predicting death in Chagas' heart disease.  N Engl J Med. 2006;355(8):799-808PubMedArticle
64.
Mady C, Cardoso RH, Barretto AC, da Luz PL, Bellotti G, Pileggi F. Survival and predictors of survival in patients with congestive heart failure due to Chagas' cardiomyopathy.  Circulation. 1994;90(6):3098-3102PubMedArticle
65.
Salles G, Xavier S, Sousa A, Hasslocher-Moreno A, Cardoso C. Prognostic value of QT interval parameters for mortality risk stratification in Chagas' disease: results of a long-term follow-up study.  Circulation. 2003;108(3):305-312PubMedArticle
66.
Carod-Artal FJ. Chagas cardiomyopathy and ischemic stroke.  Expert Rev Cardiovasc Ther. 2006;4(1):119-130PubMedArticle
67.
Rassi A Jr, Rassi SG, Rassi A. Sudden death in Chagas' disease.  Arq Bras Cardiol. 2001;76(1):75-96PubMedArticle
68.
Bocchi EA, Fiorelli A.First Guidelines Group for Heart Transplantation of the Brazilian Society of Cardiology.  The paradox of survival results after heart transplantation for cardiomyopathy caused by Trypanosoma cruzi.  Ann Thorac Surg. 2001;71(6):1833-1838PubMedArticle
69.
Castro C. Longitudinal radiological study of the esophagus in Chagas disease.  Mem Inst Oswaldo Cruz. 1999;94:(suppl 1)  329-330PubMedArticle
70.
Castro C, Macedo V, Rezende JM, Prata A. Longitudinal radiologic study of the esophagus, in an endemic area of Chagas disease, in a period of 13 years [in Portuguese].  Rev Soc Bras Med Trop. 1994;27(4):227-233PubMedArticle
71.
Maguire JH, Mott KE, Souza JA, Almeida EC, Ramos NB, Guimaraes AC. Electrocardiographic classification and abbreviated lead system for population-based studies of Chagas' disease.  Bull Pan Am Health Organ. 1982;16(1):47-58PubMed
72.
Lázzari JO, Pereira M, Antunes CM.  et al.  Diagnostic electrocardiography in epidemiological studies of Chagas' disease: multicenter evaluation of a standardized method.  Rev Panam Salud Publica. 1998;4(5):317-330PubMedArticle
73.
Maguire JH, Mott KE, Lehman JS.  et al.  Relationship of electrocardiographic abnormalities and seropositivity to Trypanosoma cruzi within a rural community in northeast Brazil.  Am Heart J. 1983;105(2):287-294PubMedArticle
74.
Prineas RJ, Crowe RS, Blackburn H. The Minnesota Code Manual of Electrocardiographic Findings. Boston, MA: John Wright; 1982
75.
Marin-Neto JA, Marzullo P, Marcassa C.  et al.  Myocardial perfusion abnormalities in chronic Chagas' disease as detected by thallium-201 scintigraphy.  Am J Cardiol. 1992;69(8):780-784PubMedArticle
76.
Simões MV, Dantas RO, Ejima FH, Meneghelli UG, Maciel BC, Marin-Neto JA. Esophageal origin of precordial pain in chagasic patients with normal subepicardial coronary arteries [in Portuguese].  Arq Bras Cardiol. 1995;64(2):103-108PubMed
77.
Meneghelli UG, Peria FM, Darezzo FM.  et al.  Clinical, radiographic, and manometric evolution of esophageal involvement by Chagas' disease.  Dysphagia. 2005;20(1):40-45PubMedArticle
78.
Dantas RO. Dysphagia in patients with Chagas' disease.  Dysphagia. 1998;13(1):53-57PubMedArticle
79.
Dantas RO, Deghaide NH, Donadi EA. Esophageal manometric and radiologic findings in asymptomatic subjects with Chagas' disease.  J Clin Gastroenterol. 1999;28(3):245-248PubMedArticle
80.
Rodriques Coura J, deCastro SL. A critical review on Chagas disease chemotherapy.  Mem Inst Oswaldo Cruz. 2002;97(1):3-24PubMedArticle
81.
Ferreira RCC, Ferreira LCS. Mutagenicity of nifurtimox and benznidazole in the Salmonella microsoma assay.  Braz J Med Biol Res. 1986;19(1):19-25PubMed
82.
Gorla NB, Ledesma OS, Barbieri GP, Larripa IB. Thirteenfold increase of chromosomal aberrations non-randomly distributed in chagasic children treated with nifurtimox.  Mutat Res. 1989;224(2):263-267PubMedArticle
83.
Teixeira AR, Cordoba JC, Souto Maior I, Solorzano E. Chagas' disease: lymphoma growth in rabbits treated with benznidazole.  Am J Trop Med Hyg. 1990;43(2):146-158PubMed
84.
Teixeira AR, Silva R, Cunha Neto E, Santana JM, Rizzo LV. Malignant, non-Hodgkin's lymphomas in Trypanosoma cruzi-infected rabbits treated with nitroarenes.  J Comp Pathol. 1990;103(1):37-48PubMedArticle
85.
Bocchi EA, Higuchi ML, Vieira ML.  et al.  Higher incidence of malignant neoplasms after heart transplantation for treatment of chronic Chagas' heart disease.  J Heart Lung Transplant. 1998;17(4):399-405PubMed
86.
Kirchhoff LV. Chagas disease: American trypanosomiasis.  Infect Dis Clin North Am. 1993;7(3):487-502PubMed
87.
de Andrade AL, Zicker F, de Oliveira RM.  et al.  Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection.  Lancet. 1996;348(9039):1407-1413PubMedArticle
88.
Sosa Estani S, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis C. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas' disease.  Am J Trop Med Hyg. 1998;59(4):526-529PubMed
89.
Coura JR, de Abreu LL, Willcox HP, Petana W. Comparative controlled study on the use of benznidazole, nifurtimox and placebo, in the chronic form of Chagas' disease, in a field area with interrupted transmission, I: preliminary evaluation [in Portuguese].  Rev Soc Bras Med Trop. 1997;30(2):139-144PubMedArticle
90.
Viotti R, Vigliano C, Lococo B.  et al.  Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial.  Ann Intern Med. 2006;144(10):724-734PubMedArticle
91.
Cancado JR, Brener Z. Terapeutica. In: Brener Z, Andrade Z, eds. Trypanosoma cruzi e doenca de Chagas. Rio de Janeiro, Brazil: Guanabara Koogan; 1979:362-424
92.
Altcheh J, Biancardi M, Lapena A, Ballering G, Freilij H. Congenital Chagas disease: experience in the Hospital de Niños, Ricardo Gutíerrez, Buenos Aires, Argentina [in Spanish].  Rev Soc Bras Med Trop. 2005;38:(suppl 2)  41-45PubMed
93.
Rassi A, Ferreira HO. Tentativas de tratmento especifico da fase aguda da doenca de Chagas com nifurtimox em esquema de duracao prolongada.  Rev Soc Bras Med Trop. 1971;5:235-262Article
94.
Boainain E. Tratamento etiologico da doenca de Chagas na fase cronica.  Rev Goiania Med. 1979;25:1-60
95.
Camandaroba EL, Reis EA, Goncalves MS, Reis MG, Andrade SG. Trypanosoma cruzi: susceptibility to chemotherapy with benznidazole of clones isolated from the highly resistant Colombian strain.  Rev Soc Bras Med Trop. 2003;36(2):201-209PubMedArticle
96.
Veloso VM, Carneiro CM, Toledo MJ.  et al.  Variation in susceptibility to benznidazole in isolates derived from Trypanosoma cruzi parental strains.  Mem Inst Oswaldo Cruz. 2001;96(7):1005-1011PubMedArticle
97.
Russomando G, de Tomassone MM, de Guillen I.  et al.  Treatment of congenital Chagas' disease diagnosed and followed up by the polymerase chain reaction.  Am J Trop Med Hyg. 1998;59(3):487-491PubMed
98.
Sosa-Estani S, Segura EL. Etiological treatment in patients infected by Trypanosoma cruzi: experiences in Argentina.  Curr Opin Infect Dis. 2006;19(6):583-587PubMedArticle
99.
 The BENEFIT trial: evaluation of the use of an antiparasital drug (benznidazole) in the treatment of chronic Chagas' disease. http://clinicaltrials.gov/show/NCT00123916. Accessibility verified October 11, 2007
100.
Gross PA, Barrett TL, Dellinger EP.  et al. Infectious Diseases Society of America.  Purpose of quality standards for infectious diseases.  Clin Infect Dis. 1994;18(3):421PubMedArticle
101.
Estani SS, Segura EL. Treatment of Trypanosoma cruzi infection in the undetermined phase: experience and current guidelines of treatment in Argentina.  Mem Inst Oswaldo Cruz. 1999;94:(suppl 1)  363-365PubMedArticle
102.
Rassi A, Luquetti AO. Specific treatment for Trypanosoma cruzi infection (Chagas disease). In: Tyler KM, Miles MA, eds. American Trypanosomiasis. Boston, MA: Kluwer Academic Publishers; 2003:117-125
×