Trypanosoma cruzi (American Trypanosomiasis or Chagas Disease)

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PARASITOLOGY

Trypanosoma cruzi is a single-celled protozoan parasite that causes American trypanosomiasis, or Chagas disease (1). This organism has a complex life cycle and it infects many mammalian species, including humans, as well as triatomine insect vectors. Most instances of transmission of T. cruzi to humans result from contact with parasite-containing feces of infected vectors, but transmission by transfusion of blood donated by persons harboring T. cruzi is a major problem in some endemic areas (2).

EPIDEMIOLOGY

Epidemiology of Chagas Disease in Latin America

Historically, humans have become part of the cycle of T. cruzi transmission as land is opened up in enzootic regions. When this process occurs, vectors such as Rhodnius prolixus, Triatoma infestans, and Panstrongylus megistus invade the nooks and crannies of the primitive mud-walled, wood, and stone houses that are typical of rural Latin America. In this manner the insects become domiciliary and establish a cycle of transmission involving humans and domestic mammals that is independent of the sylvatic cycle (3, 4). For the most part Chagas disease has been a problem of poor people in rural areas. In recent decades, however, large numbers of T. cruzi-infected people have migrated to cities seeking jobs, thus urbanizing the disease and resulting in frequent transmission by transfusion of contaminated blood (2, 5, 6).

Few age-specific and geographic data regarding the incidence of acute Chagas disease have been available historically because most cases go undetected due to its mild nature and a lack of access to medical care among those at highest risk. Early reports indicated that most cases of acute Chagas disease that came to medical attention occurred in children (7). PAHO recently estimated that 16-18 million people are infected with T. cruzi and that approximately 45,000 deaths each year are attributable to the disease (8, 9). In recent years, however, the epidemiology of T. cruzi infection has been improving in several endemic countries, as blood bank and vector control programs have been implemented, and prevalence rates in younger age groups decreased in many areas (10-13). A major international control program in the Southern Cone countries of South America (Bolivia, Chile, Argentina, Uruguay, Paraguay, and Brazil) has provided the context for much of this progress. If current trends continue, by 2003 transmission will be for the most part eliminated in much of the endemic range (8,9). The obstacles hindering the elimination of T. cruzi transmission to humans are political and economic, and no technological advances, such as the development of a vaccine, are necessary for its completion.

The epidemiology of symptomatic chronic Chagas disease merits mention. As many as 70-90% of persons who harbor T. cruzi chronically never develop the associated gastrointestinal or cardiac symptoms. This reflects near-perfect parasitism in that the mammalian hosts of T. cruzi remain infective for life but rarely die of the infection. Among persons who do develop either type of symptoms the mean age of onset is 35-45 years, although the range is quite broad. In the past, the relatively high frequency of sudden death among young adults in some areas has been attributed to dysrrhythmias of chronic Chagas disease. Among Brazilian patients with chronic T. cruzi infection the prevalence of megadisease ranges from 2.6% to 17.3% (14,15). There is considerable geographic variation in the relative prevalence of cardiac and megadisease in patients with chronic T. cruzi infections. It is not known if parasite strain differences or host factors cause these different patterns of clinical manifestations.

Epidemiology of Chagas Disease in the United States

Although the sylvatic cycle of T. cruzi is present in many parts of the southern and western U. S., only five cases of autochthonous transmission there have been described (16-18). The low overall vector density and our relatively high housing standards probably underlie the rarity of transmission of T. cruzi to humans in the U. S. In the last 26 years nine imported infections and seven laboratory-acquired cases of acute T. cruzi infection have been reported to the Centers for Disease Control and Prevention (CDC), but none of the imported cases occurred in returning tourists (Navin TA, personal communication). Although the number of autochthonous and imported cases of acute Chagas disease may be many times the number reported, the fact remains that the illness is rare in the United States.

In contrast, the number of people in the U. S. with chronic T. cruzi infections has grown markedly in recent years. Since 1972 more than 5.5 million persons have emigrated to the U. S. legally from countries in which Chagas disease is endemic (19), and several million more may have entered illegally. A large percentage of these immigrants have come from Central America, a region in which T. cruziprevalence is high (2, 20). A study among Nicaraguans and Salvadorans in Washington, D. C., found a 5% prevalence rate of T. cruzi infection (21). Studies done in a Los Angeles hospital where 50% of donors are Hispanic have shown that between 1:1,000 and 1: 500 donors are infected with T. cruzi (22-24). In another study, performed in seven blood banks in three Southwestern states, roughly 1 in 600 donors with Hispanic last names was found to be infected (25). In a much larger investigation done in Los Angeles and Miami, the prevalence rate of T. cruzi infection was found to be 1: 8,800 in the general donor population and 1: 710 among donors who had spent a month or more in an endemic area (26). I estimate from these findings and census data at least 50,000 to 100,000 T. cruzi infected persons now live in the U. S. These immigrants create a risk for transfusion-associated transmission of the parasite in the U. S. and in other areas to which Latin Americans have emigrated (27, 28). To date seven such cases have been reported in the U. S., Canada, and Europe (29-34). These cases all occurred in immunosuppressed patients in whom the diagnosis of T. cruzi infection was made because of the fulminant course of the illness. Given that most transfusions are given to immunocompetent patients in whom acute Chagas disease would cause only mild symptoms, it is reasonable to infer that many other instances of transfusion-associated transmission of T. cruzi have occurred in the U. S. and have not been detected. In the last few years, however, the risk may have been reduced by screening prospective blood donors with questions relating to residence in endemic countries (23).

CLINICAL MANIFESTATIONS

The acute form of Chagas disease is usually a mild illness involving fevers, malaise, and anorexia. The case fatality rate is less than five percent. Muscles, including the heart, are often heavily parasitized, and severe inflammation of the heart develops in a small proportion of patients. The acute illness resolves spontaneously over a period of four to six weeks in most patients, who then enter the indeterminate phase of T. cruzi infection. In this phase there are no symptoms, but there are lifelong, low-grade parasitemias in association with generally easily detectable antibodies to T. cruzi. Most people remain in the indeterminate phase for life, and this sets the stage for insect-borne and transfusion-associated transmission of the parasite. Ten to thirty percent of persons who harbor T. cruzi chronically develop symptoms as a consequence of the infection. The heart is the organ most commonly affected, and rhythm disturbances as well as cardiomyopathy are the primary problems. Patients chronically infected with T. cruzican also develop problems of the gastrointestinal tract, and megaesophagus, or enlargement of the distal esophagus, is the most common manifestation. This can result in difficulty in eating, malnutrition, and in extreme cases, death. Megacolon, which is the enlargement of the large intestine, also occurs, and this can lead to bowel obstruction requiring surgical intervention.

LABORATORY DIAGNOSIS

The diagnosis of acute T. cruzi infection is made by detection of the parasite. Most commonly, this is done by seeing the motile parasites in anticoagulated blood viewed through a microscope. When this effort fails in a patient suspected of being acutely infected with T. cruzi, hemoculture can be attempted. This involves mixing blood from the patient with specialized culture medium and then waiting two to six weeks to see if parasites multiply to concentrations that can be seen microscopically. Results obtained to date suggest that PCR-based assays may be more sensitive than other methods, but further experimental work remains to be done.

Clinical criteria cannot be depended upon for recognizing chronic T. cruzi infection, and thus blood tests are of paramount importance, both in patient care settings and in blood banks. Essentially all persons with chronic T. cruzi infections have detectable anti-T. cruzi antibodies, and the diagnosis is almost always made by detecting these antibodies. Conventional serologic assays, such as complement fixation and indirect immunofluorescence tests, and enzyme-linked immunosorbent assays, generally are highly sensitive but often lack specificity. False positive results typically occur with specimens from persons with parasitic and other infectious diseases. This creates major problems in some areas for uninfected persons labeled as harboring T. cruzi, and also in blood banks where donated units are discarded needlessly because of false positive test results. The roles of assays for diagnosing chronic T. cruzi infections that are based on recombinant parasite proteins and PCR have not yet been defined.

SUSCEPTIBILITY IN VITRO AND IN VIVO

Benznidazole and nifurtimox are the only drugs that should be used for treating infection with T. cruzi. For assessing the effects of new drugs on T. cruzi, there are several model systems that can be used. Epimastigotes, which are the multiplying form found in the intestines of the parasites triatomine vectors, grow well in specialized culture medium in vitro in axenic culture. Parasite density can be determined without difficulty by hemocytometer or automated methods, and thus assessment of growth rate suppression or killing resulting from drugs added to the medium is straightforward. The usefulness of this approach is limited, however, because epimastigotes may have patterns of drug sensitivities different from those of the trypomastigote and amastigote forms of the parasite that are found in humans and other mammals. Fortunately, T. cruzi infects a broad range of mammals, including all those used in laboratories. Mice can be infected experimentally quite easily and provide an excellent model for both acute and chronic T. cruziinfection. Thus the murine model is most commonly used to assess the activity of new drugs against T. cruzi, but other rodents, as well as dogs and primates, can be used as well.

ANTIPARASITIC THERAPY

Drugs of Choice

Unfortunately, T. cruzi is not susceptible to most of the long list of drugs tested for activity over the past several decades, including those effective against African trypanosomes, Leishmania spp., and other parasitic protozoans, and thus current therapy is unsatisfactory. Nevertheless, the current consensus recommendation is that all persons infected with T. cruzi be treated with one of two available antiparasitic drugs, regardless of the clinical phase of the infection, even though side effects of the drugs are common and their efficacies are low (35).

Two drugs are currently being used to treat patients infected with T. cruzi (36-38). The first of these, the nitrofuran derivative nifurtimox (Lampit, Bayer 2502), has been in use for more than three decades, and extensive clinical experience has accumulated. In acute and congenital Chagas disease, nifurtimox markedly reduces the duration and severity of the illness, and decreases mortality. However, it results in parasitologic cure only in about 70 percent of treated patients, can cause severe side effects, and must be taken for prolonged periods (39,40). Cure rates with nifurtimox are higher in Argentina and Chile than in Brazil and some other countries. Therapy with nifurtimox should be initiated as early as possible in cases of acute or congenital Chagas disease. Moreover, when laboratory accidents occur in which there is a reasonable likelihood that T. cruzi infection will become established, therapy should be initiated without waiting for clinical or parasitologic indications of infection.

A large proportion of patients treated with nifurtimox experience adverse side effects. Gastrointestinal complaints include abdominal pain, nausea, vomiting, anorexia, and weight loss. Possible neurologic symptoms include restlessness, insomnia, twitching, paresthesias, and seizures. These symptoms generally disappear when the dosage is reduced or therapy is discontinued.

Nifurtimox is supplied as 30-and 120-mg tablets. The recommended oral dosage for adults is 8 10 mg/kg body weight per day. The dose for adolescents is 12.5-15 mg/kg per day, and for children 1-10 years of age it is 15-20 mg/kg per day. The drug should be given in four divided doses each day, and therapy should be continued for 90-120 days. Nifurtimox can be obtained from the Drug Service of the CDC (770-639-3670 [weekdays], 770-639-2888 [off hours]).

Benznidazole (Rochagan, Roche 7-1051), a nitroimidazole derivative, is the second agent used to treat patients with Chagas disease. The efficacy of this drug is similar to that of nifurtimox, with the exception that geographic differences in its efficacy have not been observed (40). Side effects include peripheral neuropathy, rash, and granulocytopenia. The recommended oral dosage of benznidazole is 5 mg/kg/day for 60 days. Benznidazole is used widely in Latin America, where it is viewed as the drug of choice by many specialists. It also can be obtained from the CDC Drug Service.

The question of whether patients in the indeterminate or chronic symptomatic phases of T. cruzi infection should be given antiparasitic therapy has been debated for decades. Recent studies of T. cruzi -infected laboratory animals and humans indicate that the presence of parasites in cardiac muscle is specifically associated with inflammation, thereby implicating the organisms in the chronic pathogenesis (41-43). Furthermore, in several limited studies the appearance of and/ or progression of heart lesions in drug-treated patients appeared to be less than in untreated controls (44-46). After reviewing these findings, an international panel of experts convened by the World Health Organization recently concluded that all infected persons with T. cruzi be treated with either benznidazole or nifurtimox, regardless of their clinical status or the time elapsed since acquiring the infection (35). Additional, long-term studies are needed to assess adequately the usefulness of anti-parasitic treatment in asymptomatic patients with chronic Chagas disease.

Special Situations

Immunocompromised Hosts, Transplant Recipients, and HIV Patients

Immuno- suppression of patients chronically harboring T. cruzi can lead to reactivation of the infection, frequently with an intensity that is atypical of acute Chagas disease in immunocompetent patients. The incidence of reactivation of T. cruzi in chronically infected patients who are immunosuppressed is unknown, and both its occurrence (47-49) and absence (50) have been described. A handful of reports of reactivations of chronic T. cruzi infections after renal transplantation have appeared, and in two of these cases the central nervous system was involved (51-53). Although chronic Chagas disease should not be considered a contraindication for renal transplantation, the possibility of reactivation should be kept in mind during follow-up care.

Cardiac transplantation is an option in persons with severe Chagas heart disease, and well over one hundred T. cruzi-infected patients have undergone the procedure in Brazil and the United States (1,54). Interestingly, long-term survival in these individuals is greater than in heart transplant patients with other types of cardiac disease. Moreover, it is curious that patients who have had transplants for Chagas heart disease often develop skin lesions containing high numbers of parasites. Such reactivations have not been reported in patients who have had other types of organ transplants, nor have they been observed in persons immunosuppressed by HIV.

Persons coinfected with T. cruzi and HIV are also at risk for reactivation of the former. Several dozen cases of this type have been described (55, 56), and the fact that a large proportion of these patients developed T. cruzi brain abscesses, which do not occur in immunocompetent persons with Chagas disease, is noteworthy. Calculations based on the epidemiologies of T. cruzi and HIV in Latin America suggest that the incidence of T. cruzi brain abscesses in co-infected persons is extremely low. The diagnosis of T. cruzi brain abscesses in HIV-infected persons is complicated by the difficulty in distinguishing these lesions from those of cerebral toxoplasmosis in imaging studies.

Experimental Therapy

Over a decade ago Reed showed that the severity of acute T. cruzi infection in mice was reduced by injection of recombinant interferon-gamma (IFN-γ) ( 57). To my knowledge recombinant IFN-γ has been given to two patients with acute Chagas disease. The first was an immunosuppressed patient who acquired the parasite from a contaminated transfusion (31), and the other became infected through laboratory work with T. cruzi (H. B. Tanowitz, personal communication). Both patients received IFN-γ as well as nifurtimox and recovered. Serologic and PCR-based studies done on one of these patients eight years after treatment indicate that the treatment was curative, and this issue has not been addressed in the second. Additional studies need to be done before a recommendation regarding the use of IFN-γ in patients with acute Chagas disease can be made.

The usefulness of itraconazole, fluconazole, ketoconazole, and allopurinol has been studied extensively in laboratory animals and to a lesser extent in persons with Chagas disease. None of these four drugs has shown a level of anti-T. cruzi activity that warrants its use in patients. Finally, posaconazole, a new antifungal agent in development, has been shown to cure acute T. cruzi infections in mice (58, 59) but its usefulness in patients with Chagas disease has not been assessed.

ADJUNCTIVE THERAPY

The vast majority of patients with acute T. cruzi infections do not require therapy other than benznidazole or nifurtimox since this phase of the illness generally resolves spontaneously, even in the absence of antiparasitic treatment. Management of the occasional severely ill patient with acute chagasic myocarditis or meningoencephalitis is for the most part supportive. The therapy of patients with symptomatic chronic Chagas heart disease is also supportive. All patients with chronic T. cruzi infections should have EKGs done every six months or so, because pacemakers have been shown to be useful in controlling the rhythm disturbances of chronic Chagas disease (60). Congestive heart failure caused by Chagas cardiomyopathy is generally treated with measures used in patients with cardiomyopathies resulting from other processes (61,62).

Megaesophagus in chagasic patients should be treated in the same way as idiopathic achalasia. Balloon dilation of the lower esophageal sphincter provides symptomatic relief for most patients (63). Patients not responding to repeated dilations should be treated surgically (64,65). The procedure most frequently used is esophagocardiomyectomy of the anterior gastroesophageal junction, combined with valvuloplasty for control of reflux. In the industrialized nations the use of laparoscopic myotomy for treating idiopathic achalasia is becoming common. This relatively simple approach may become the treatment of choice for idiopathic achalasia and severe Chagas megaesophagus if the encouraging results achieved to date continue.

Patients with Chagas disease and early colonic dysfunction can be managed with high fiber diets and occasional laxatives and enemas. Fecal impaction necessitating manual disimpaction can occur, as can toxic megacolon, which requires surgical treatment (66). Volvulus is another complication of megacolon that requires surgical intervention. Initially endoscopic emptying can be done in patients without clinical, radiographic, or endoscopic signs of ischemia in the affected portion of the colon. More complicated cases require surgical decompression. In either event surgery eventually is required because recurrence of the volvulus is highly likely. Several surgical procedures have been used to treat severe chagasic megacolon, all of which include removal of part of the rectum and resection of the sigmoid colon.

ENDPOINTS FOR MONITORING THERAPY

Unfortunately, the methods available for assessing the effect of specific treatment of T. cruzi infections are not straightforward. In general, immunocompetent patients with acute or chronic T. cruzi infections are given full courses of either nifurtimox or benznidazole and are not retreated, even if subsequent studies demonstrate that the infection has not been eradicated. This approach is taken under the assumption that the parasite and/or host factors that prevent eradication of the parasite during the first course of therapy would result in failure a second time around as well. Consistently decreasing levels of anti-T. cruzi antibodies over time after standard treatment are a reliable indicator of parasitologic cure, but it often takes years for this pattern to be come clearly evident. On the other hand, evidence of treatment failure can be obtained by hemoculture, xenodiagnosis, or PCR, but these tests are not widely available and their utility in this context is questionable because, as noted, treated patients are not given a second round of therapy. In immunocompromised patients, in whom standard therapy is highly likely to fail in eliminating T. cruzi infection, in the context of an acute febrile illness evidence of reactivation should be sought by microscopic study of anticoagulated blood, as well as examination of pericardial fluid and lymph node aspirates.

VACCINES

No vaccines are available for preventing transmission of T. cruzi.

ANTIPARASITIC DRUG PROPHYLAXIS

Chemoprophylaxis for preventing vector-borne transmission of T. cruzi is not recommended. In some endemic countries crystal violet at a final dilution of 1: 4,000 has been used effectively to kill T. cruzi in blood donated by infected donors. Due to potential side effects of this approach, however, it cannot be recommended and serological screening of donors is preferred.

REFERENCES

1. Kirchhoff LV. American trypanosomiasis (Chagas' disease) -- A tropical disease now in the United States. N Engl J Med. 1993;329:639-44. [PubMed]

2. Schmunis GA. Trypanosoma cruzi , the etiologic agent of Chagas' disease: status in the blood supply in endemic and nonendemic countries. Transfusion. 1991;31:547-57. [PubMed]

3. Starr MD, Rojas JC, Zeledon R, Hird DW, Carpenter TE. Chagas' disease: risk factors for house infestation by Triatoma dimidiata, the major vector of Trypanosoma cruzi in Costa Rica. Am J Epidemiol. 1991;133:740-747. [PubMed]

4. Gurtler RE, Cecere MC, Petersen RM, Rubel DN, Schweigmann NJ. Chagas disease in north-west Argentina: association between Trypanosoma cruzi parasitaemia in dogs and cats and infection rates in domestic Triatoma infestans. Trans R Soc Trop Med Hyg. 1993;87:12-15. [PubMed]

5. Carrasco R, Miguez H, Camacho C, Echalar L, Revollo S, Ampuero T et al. Prevalence of Trypanosoma cruzi infection in blood banks of seven departments of Bolivia. Mem Inst Oswaldo Cruz. 1990;85:69-73. [PubMed]

6. Grijalva MJ, Rowland EC, Powell MR, McCormick TS, Escalante L. Blood donors in a vector-free zone of Ecuador potentially infected with Trypanosoma cruzi. Am J Trop Med Hyg. 1995;52:360-363. [PubMed]

7. Laranja FS, Dias E, Nobrega G, Miranda A. Chagas' disease: A clinical, epidemiologic, and pathologic study. Circulation. 1956;14:1035-60. [PubMed]

8. Anonymous. Chagas disease, Chile. Certification of interruption of transmission. Wkly Epidemiol Rec. 2000;75:10-12. [PubMed]

9. Anonymous. Chagas disease -- Interruption of transmission, Brazil. Wkly Epidemiol Rec. 1997;72:1-8. [PubMed]

10. 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;76:556-62. [PubMed]

11. Mota EA, Guimaraes AC, Santana OO, Sherlock I, Hoff R, Weller TH. A nine year prospective study of Chagas' disease in a defined rural population in Northeast Brazil. Am J Trop Med Hyg. 1990;42:429-40. [PubMed]

12. Goldsmith RS, Zarate RJ, Zarate LG, Morales G, Kagan I, Drickey R et al. Clinical and epidemiologic studies of Chagas' disease in rural communities of Oaxaca, Mexico, and an eight-year followup: II. Chila. Bull Pan Am Health Organ. 1992;26:47-59. [PubMed]

13. de Andrade AL, Zicker F, Luquetti AO, Oliveira RM, Silva SA, Souza JM, Martelli CM. Surveillance of Trypanosoma cruzi transmission by serological screening of schoolchildren. Bull WHO. 1992;70:625-29. [PubMed]

14. Barbosa AJ, Pittella JE, Tafuri WL. Incidência de cardiopatia chagásica em 15.000 necrópsias consecutivas e sua associaçao com os "megas". Rev Soc Bras Med Trop. 1970;4:219-23. [PubMed]

15. Chapadeiro E, Lopes ER, de Mesquita PM, Pereira FE. Incidência de "megas" associados à cardiopatia chagásica. Rev Inst Med Trop Sao Paulo. 1964;6:287-91. [PubMed]

16. Schiffler RJ, Mansur GP, Navin TR, Limpakarnjanarat K. Indigenous Chagas' disease (American trypanosomiasis) in California. JAMA. 1984;251:2983-84. [PubMed]

17. Ochs DE, Hnilica V, Moser DR, Smith JH, Kirchhoff LV. Postmortem diagnosis of autochthonous acute chagasic myocarditis by polymerase chain reaction amplification of a species-specific DNA sequence ofTrypanosoma cruzi. Am J Trop Med Hyg. 1996;34:526-29. [PubMed]

18. Herwaldt BL, Grijalva MJ, Newsome AL, McGhee CR, Powell MR, Nemec DJ 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;181:395-99. [PubMed]

19. Bureau of Census. Statistical Abstract of the United States. The National Data Book. 116 ed. Washington, D.C.: United States Department of Commerce, 1996.[PubMed]

20. Cedillos RA. Chagas' disease in El Salvador. PAHO Bull. 1975;9:135-41. [PubMed]

21. Kirchhoff LV, Gam AA, Gilliam FC. American trypanosomiasis (Chagas' disease) in Central American immigrants. Am J Med. 1987;82:915-20. [PubMed]

22. Kerndt PR, Waskin HA, Kirchhoff LV, Steurer F, Waterman SH, Nelson JM et al. Prevalence of antibody to Trypanosoma cruzi among blood donors in Los Angeles, California. Transfusion. 1991;31:814-18. [PubMed]

23. Appleman MD, Shulman IA, Saxena S, Kirchhoff LV. Use of a questionnaire to identify potential donors at risk for infection with Trypanosoma cruzi. Transfusion. 1993;33:61-64. [PubMed]

24. Shulman IA, Appleman MD, Saxena S, Hiti AL, Kirchhoff LV. Specific antibodies to Trypanosoma cruzi among blood donors in Los Angeles, California. Transfusion. 1997;37:727-31. [PubMed]

25. Winkler MA, Brashear RJ, Hall HJ, Schur JD, Pan AA. Detection of antibodies to Trypanosoma cruzi among blood donors in the southwestern and western United States. II. Evaluation of a supplemental enzyme immunoassay and radioimmunoprecipitation assay for confirmation of seroreactivity. Transfusion. 1995;35:219-25. [PubMed]

26. Leiby DA, Read EJ, Lenes BA, Yund AJ, Stumpf RJ, Kirchhoff LV et al. Seroepidemiology of Trypanosoma cruzi, etiologic agent of Chagas' disease, in U.S. blood donors. J Infect Dis. 1997;176:1047-52. [PubMed]

27. Kirchhoff LV. Is Trypanosoma cruzi a new threat to our blood supply? Ann Intern Med. 1989;111:773-75. [PubMed]

28. Frank M, Hegenscheid B, Janitschke K, Weinke T. Prevalence and epidemiologic significance of Trypanosoma cruzi infection among Latin American immigrants in Berlin, Germany. Infection. 1997;25:1-4. [PubMed]

29. Geiseler, P. J., Ito, J. I., Tegtmeier, B. R., Kerndt, P. R., and Krance, R. Fulminant Chagas disease (CD) in bone marrow transplantation (BMT). Abstracts of the 1987 Interscience Conference on Antimicrobial Agents and Chemotherapy , 169. 1987. [PubMed]

30. Nickerson P, Orr P, Schroeder M-L, Sekla L, Johnston JB. Transfusion-associated Trypanosoma cruzi infection in a non-endemic area. Ann Intern Med. 1989;111:851-53. [PubMed]

31. Grant IH, Gold JWM, Wittner M, Tanowitz HB, Nathan C, Mayer K et al. Transfusion-associated acute Chagas disease acquired in the United States. Ann Intern Med. 1989;111:849-51. [PubMed]

32. Cimo PL, Luper WE, Scouros MA. Transfusion-associated Chagas' disease in Texas: report of a case. Texas Med. 1993;89:48-50. [PubMed]

33. Leiby DA, Lenes BA, Tibbals MA, Tames-Olmedo MT. Prospective evaluation of a patient with Trypanosoma cruzi infection transmitted by transfusion [letter]. N Engl J Med. 1999;341:1237-39. [PubMed]

34. Villalba R, Fornes G, Alvarez MA, Roman J, Rubio V, Fernandez M et al. Acute Chagas' disease in a recipient of a bone marrow transplant in Spain: case report. Clin Infect Dis. 1992;14:594-95. [PubMed]

35. Anonymous. Tratamiento Etiologico de la Enfermedad de Chagas. Conclusiones de una Consulta Tecnica. OPS/HCP/HCT/140/99. 1999. Geneva, Pan American Health Organization. [PubMed]

36. Marr JJ, Docampo R. Chemotherapy for Chagas' disease: a perspective on current therapy and considerations for future research. Rev Infect Dis. 1986;8:884-903. [PubMed]

37. Levi GC, Lobo IM, Kallas EG, Amato Neto V. Etiological drug treatment of human infection by Trypanosoma cruzi . Rev Inst Med Trop Sao Paulo. 1996;38:35-38. [PubMed]

38. Coura JR. Current prospects of specific treatment of Chagas' disease [Spanish]. Bol Chil Parasitol. 1996;51:69-75. [PubMed]

39. Rassi A, Ferreira HO. Tentativas de tratamento específico da fase aguda da doença de Chagas com nitrofuranos em esquemas de duração prolongada. Rev Soc Bras Med Trop. 1971;5:235-62. [PubMed]

40. Ferreira HO. Tratamento específico na fase aguda da doença de Chagas. Jornal de Pediatria. 1988;64:1-3. [PubMed]

41. Jones EM, Colley DG, Tostes S, Lopes ER, Vnencak-Jones CL, McCurley TL. Amplification of a Trypanosoma cruzi DNA sequence from inflammatory lesions in human Chagasic cardiomyopathy. Am J Trop Med Hyg. 1993;48:348-57. [PubMed]

42. Andrade SG, Stocker-Guerret S, Pimentel AS, Grimaud JA. Reversibility of cardiac fibrosis in mice chronically infected with Trypanosoma cruzi, under specific chemotherapy. Mem Inst Oswaldo Cruz. 1991;86:200. [PubMed]

43. Bellotti G, Bocchi EA, de Moraes AV, Higuchi ML, Barbero-Marcial M, Sosa E et al. In vivo detection of Trypanosoma cruzi antigens in hearts of patients with chronic Chagas' heart disease. Am Heart J. 1996;131:301-7. [PubMed]

44. Andrade ALSS, Zicker F, Oliveira RM, Silva SA, Luquetti A, Travassos LR et al. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet. 1996;348:1407-13. [PubMed]

45. Fragata Filho AA, Boianain E, Silva MAD, Correia EB, Borges Filho R, Martins C et al. Validade do tratamento etiológico da fase crônica da doença de Chagas com benznidazol. Arq Bras Cardiol. 1995;65(Supl.1):71. [PubMed]

46. Viotti R, Vigliano C, Armenti H, Segura E. Treatment of chronic Chagas' disease with benznidazole: clinical and serologic evolution of patients with long-term follow-up. Am Heart J. 1994;127:151-62. [PubMed]

47. Rivero I, Moravenik M, Morales J, Gomez M, De Rosas JM. Chagas' disease - another hazard in acute leukemia. N Engl J Med. 1974;290:285-85. [PubMed]

48. Kohl S, Pickering LK, Frankel LS, Yaeger RG. Reactivation of Chagas' disease during therapy of acute lymphocytic leukemia. Cancer. 1982;50:827-28. [PubMed]

49. Salgado PR, Gorski AG, Aleixo AR, de Barros EOM. Tumor-like lesion due to Chagas' disease in a patient with lymphocytic leukemia. Rev Inst Med Trop Sao Paulo. 1996;38:285-88. [PubMed]

50. Barousse AP, Costa JA, Esposto M, Laplume H, Segura EL. Enfermedad de Chagas e inmunosupresión. Medicina (B Aires). 1980;40 Supl.1:17-26. [PubMed]

51. Leiguarda R, Roncoroni A, Taratuto AL, Jost L, Berthier M, Nogues M et al. Acute CNS infection by Trypanosoma cruzi (Chagas' disease) in immunosuppressed patients. Neurology. 1990;40:850-851. [PubMed]

52. Pizzi TP, De Criozret VA, Smok G, Diaz M. Enfermedad de Chagas en un paciente con transplante renal y tratamiento inmunosupresor. Rev Med Chile. 1982;110:1207-11. [PubMed]

53. Mocelin AJ, Brandina L, Gordon PA, Baldy JLS, Chieffi PP. Immunosuppression and circulating Trypanosoma cruzi in a kidney transplant recipient. Transplantation. 1977;23:163-63. [PubMed]

54. Bocchi EA, Fiorelli A. The paradox of survival results after heart transplantation for cardiomyopathy caused by Trypanosoma cruzi. First Guidelines Group for Heart Transplantation of the Brazilian Society of Cardiology. Annals of Thoracic Surgery. 2001;71:1833-38. [PubMed]

55. Rocha A, Oliveira de Meneses AC, da Silva AM, Ferreira MS, Nishioka SA, Burgarelli MKN et al. Pathology of patients with Chagas' disease and acquired immunodeficiency syndrome. Am J Trop Med Hyg. 1994;50:261-68. [PubMed]

56. Sartori AM, Shikanai-Yasuda MA, mato Neto V, Lopes MH. Follow-up of 18 patients with human immunodeficiency virus infection and chronic Chagas' disease, with reactivation of Chagas' disease causing cardiac disease in three patients. Clin Infect Dis. 1998;26:177-79. [PubMed]

57. Reed SG. In vivo administration of recombinant IFN-gamma induces macrophage activation, and prevents acute disease, immune suppression, and death in experimental Trypanosoma cruzi infections. J Immunol. 1988;140:4342-47. [PubMed]

58. Urbina JA, Payares G, Contreras LM, Liendo A, Sanoja C, Molina J et al. Antiproliferative effects and mechanism of action of SCH 56592 against Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies. Antimicrobial Agents & Chemotherapy. 1998;42:1771-77. [PubMed]

59. Molina J, Martins-Filho O, Brener Z, Romanha AJ, Loebenberg D, Urbina JA. Activities of the triazole derivative SCH 56592 (posaconazole) against drug-resistant strains of the protozoan parasiteTrypanosoma (Schizotrypanum) cruzi in immunocompetent and immunosuppressed murine hosts. Antimicrobial Agents & Chemotherapy. 2000;44:150-155. [PubMed]

60. Chuster M. Implante de marcapasso nas bradiarritmias chagásicas. In: Cançado JR, Chuster M, eds. Cardiopatia Chagásica. Belo Horizonte, Brazil: Fundação Carlos Chagas, 1985: 289-97. [PubMed]

61. Hagar JM, Rahimtoola SH. Chagas' heart disease in the United States. N Engl J Med. 1991;325:763-68. [PubMed]

62. Hagar JM, Rahimtoola SH. Chagas' heart disease. Curr Probl Cardiol. 1995;20:827-924. [PubMed]

63. Salis GB, Chiocca JC, Perisse E, Acosta E, Mazure PA. Acalasia del esófago: Veinte años de experiencia en el tratamiento no quirúrgico. Acta Gastroent Latinoamer. 1991;21:249-54. [PubMed]

64. Pinotti HW, Felix VN, Zilberstein B, Cecconello I. Surgical complications of Chagas' disease: megaesophagus, achalasia of the pylorus, and cholelithiasis. World J Surg. 1991;15:198-204. [PubMed]

65. Pinotti HW, Habr-Gama A, Cecconello I, Felix VN, Zilberstein B. The surgical treatment of megaesophagus and megacolon. Dig Dis. 1993;11:206-15. [PubMed]

66. Kobayasi S, Mendes EF, Rodrigues MAM, Franco MF. Toxic dilatation of the colon in Chagas' disease. Br J Surg. 1992;79:1202-3. [PubMed]

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