Treatment of Trypanosoma cruzi infection in the undetermined phase. Experience and current guidelines of treatment in Argentina

Trypanosoma cruzi; undetermined phase; treatment; Argentina

Treatment of Trypanosoma cruzi Infection in the Undetermined Phase. Experience and Current Guidelines of Treatment in Argentina

Vol. 94, Suppl. I: 363-365, 1999

Sergio Sosa Estani, Elsa Leonor Segura

Centro Nacional de Diagnóstico e Investigación de Endemoepidemias, Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán", Casilla Postal 1063, Buenos Aires, Argentina

Key words: Trypanosoma cruzi - undetermined phase - treatment - Argentina

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The goals of specific treatment against Trypanosoma cruzi infection, at an individual level, are to eliminate the parasite, to diminish the probability of developing illness (Chagas disease), and to hinder the chain of T. cruzi transmission as actions for the control of vectorial and non vectorial transmission (Sosa Estani 1993). Around 1930, investigations began in Argentina to obtain an effective drug against T. cruzi. Of all the substances evaluated, only nifurtimox (1972) and benznidazol (1974) have been accepted by the Ministry of Health as anti-T. cruzi drugs. Both drugs began to be assessed on the acute phase, and later, on the chronic phase of the disease.

The experiences

In patients treated with nifurtimox following recommended guidelines, xenodiagnoses turned negative for 88 to 100% of the cases evaluated up to 123 months after treatment, although in the chronic patients, serology rarely became negative. Some researches found negativization to occur between 28 and 38% of the cases (Cerisola 1969, Boca Tourres 1969, Cançado 1969, Cichero et al. 1969).

Until 1983, in Argentina, it was recommended to treat exclusively patients in the acute phase of Chagas disease, because in the undetermined and chronic phases, conventional serology persisted reactive, in spite of negative xenodiagnoses. However, different authors (Cichero et al. 1969, Cançado 1969, Rubio & Donoso 1969, Schenone et al. 1969, Ferreira 1969, 1990, Cerisola 1977), concluded that these drugs were also effective in the undetermined phase. This was inferred based on the evaluation of parasitemia through xenodiagnoses, which became undetectable or decreased. It must be stressed that in most cases serology persisted reactive (Rubio & Donoso 1969, Schenone et al. 1969, Cerisola 1977). Some of these authors indicated a decrease of serologic titers (Ferreira 1969, Viotti et al. 1994, de Andrade et al. 1996, Sosa Estani et al. 1998). Some authors suggested the possibility that lack of parasitic clearance was the cause of reactive serology. It was also suggested that the difference of antibodies (Abs) involved in the conventional serology and those Abs that unite to the circulating forms of the parasite would influence the serological evaluation of the specific treatment (Krettli & Brener 1982, Krettli et al. 1984).

In 1994, Viotti et al. in an eight year follow-up of adult and young patients non treated or treated with benznidazol, showed that 23% of the controls had unfavorable changes in their electrocardiograms (ECGs). Those alterations were seen in 5% of the treated patients (p <0.05). However among those that maintained a reactive serology, the alterations of the ECGs were observed in 29% of the control patients and 2% of the patients treated with benznidazol. The authors concluded that specific treatment has a protective effect during the chronic phase of the infection.

Between 1991 and 1995 a controlled clinical trial was carried out to evaluate the effectiveness of treatment with benznidazol in children during the undetermined phase of Chagas disease (Sosa Estani et al. 1998). After a four year follow-up, this study demonstrated a significant decrease on the titers of Abs in patients that received benznidazol, while changes were not observed in those that received placebo. In patients that showed reactivity against the recombinant antigen (Ag) F29 (Porcel et al. 1996), negativization of serology at the end of the follow-up was 62.1% among children treated with benznidazol and 0% among those that received placebo. After seven years of follow-up, the negativization in children treated with benznidazol was around 69% (manuscript in preparation). Other authors found similar results using Ags not currently used in conventional serology (Galvão et al. 1993, Gazzinelli et al. 1993, Krautz et al. 1995, de Andrade et al. 1996). Xenodiagnoses at the end of the follow-up was positive in 4.7% of patients treated with benznidazol and 51.2% among control children (p<0.05). Our study concluded that the effectiveness was over 60%, and that children infected with T. cruzi that inhabited rural areas may be successfully treated with benznidazol in an outpatient modality. There are good opportunities of administering specific treatment, and obtaining the cure of the infection in the first decade of life (Cichero et al. 1969, de Andrade et al. 1996, Cançado 1997). The cure of infection will also eliminate the risk of developing visceral alterations due to Chagas disease (Viotti et al. 1994) and will contribute to the interruption of T. cruzi transmission in areas under vector surveillance. Moreover, our study provided a new serological marker of cure after treatment, implemented as a quick and simple serological procedure. In a preliminary observation in this same population, we also found that at the end of treatment, the plasmatic concentration of p-Selectin (molecule of adhesion) was significantly lower in patients treated with benznidazol compared with the controls, evaluated through an enzymatic immune assay (Laucella et al. manusc. in prep.). These studies are being completed. Other clinical trials that reproduce the results previously mentioned have been documented in the last years in Argentina, although they were not performed under controlled conditions (del Barco et al. 1993, Blanco et al. 1997, Fabro et al. 1997).

Side effects

Different authors refer that side effects appear among 4% and 30% of cases (Barclay et al. 1978, Lugones 1978, Castro & Diaz de Toanzo 1988, Blanco et al. 1997, Sosa Estani et al. 1998). These could include dermal (cutaneous maculopapular rush), or gastrointestinal (colic, nausea, vomits) manifestations, central neurotoxicity (nervous irritability, insomnia, headache, anorexia), and peripheral neurotoxicity (paresthesia, hiperesthesia), mioartralgias. Laboratory tests showed normal bilirrubin values, while elevation of transaminases could sometimes be observed (Lugones et al. 1969, Castro & Diaz de Toanzo 1988); leucopenia or plaquetopenias are exceptionally observed (Cançado 1997). Side effects are directly related with the dose and the patient's age, being more tolerated in children and babies than in adolescents and adults (Bocca Tourres 1969, Cerisola 1977, Moya et al. 1985). In our experience, in all cases, side effects disappear when the dose is diminished or the treatment suspended. The treatment always demands direct medical supervision (Coura 1996).

Evaluation of treatment

To evaluate the response to specific chemotherapy, it is advisable to use clinical, immu-noserological and parasitological methods. For the last years in Argentina and other countries like Brazil, the response to specific treatment has also been performed using new tools, such as recombinants Ags, tripomastigote Ags, the polimerase chain reaction or adhesion molecules, that complete those already in existence. Presently, to evaluate the effectiveness of treatment, it is necessary to consider the absence of parasites and a significant decrease of Ab concentration, or until negativization of serology.

Current situation

Since 1994, the Control Program of Chagas in Argentina included the subprogram "Detection and treatment in children between 0 to 14 years old infected by T. cruzi", detecting children inhabiting the households under surveillance for triatomine populations. This is a necessary condition for the administration of specific treatment (OPAS 1998). In 1997, the guidelines for treatment of the chagasic patient in Argentina were revised and the current criteria has been elaborated based on results obtained through scientific investigations on medical care, and health system support. At the moment, treatment is recommended for (a) all patients undergoing the acute phase of Chagas disease; (b) children and young people undergoing the undetermined phase of Chagas disease; (c) adults undergoing the undetermined phase or with incipient heart lesions; and (d) transplant recipients or donors.

^REFERENCES

• Barclay CA, Cerisola JA, Lugones H, Ledesma O, Lopez Silva J, Mouzo G 1978. Aspectos farmacológicos y resultados terapéuticos del benznidazol en el tratamiento de la infección chagásica.

  La Prensa Médica Argentina 65: 239-244.

• Blanco S, Spillman C, Zarate J, Flores I, Medina J, Sosa Estani S 1997. Tratamiento y seguimiento de 147 niños de 1 a 14 años, infectados por

  T. cruzi, en el área rural del departamento Pellegrini, en vigilancia entomológica. Santiago del Estero.Argentina.

  Medicina

  57 (Supl. III): 43-44.

• Bocca Tourres CL 1969. La enfermedad de Chagas en período agudo y su tratamiento con el Bay 2502.

  Bol Chile Parasitol

  24: 24-27.

• Cançado JR 1969. A toxocidad y valor terapéutico del Bay 2502 en la enfermedad de Chagas crónica en tres esquemas posológicos.

  Bol Chile Parasitol

  24: 28-32.

• Cançado R 1997. Terapeutica específica, p. 323-351. In J Pinto Dias & J Rodrigues Coura (eds),

  Clínica e Terapeutica da Doenca de Chagas. Uma Aborgagem Prática para o Clínico Geral, Fiocruz, Rio de Janeiro.

• Castro JA, Diaz de Toranzo EG 1988. Toxic effects of nifurtimox and benznidazol, two grugs used against American trypanosomiasis (Chagas disease).

  Biomed Eviron Sci 1:19-33.

• Cerisola JA 1969. Evolución serológica de pacientes con enfermedad de Chagas aguda tratados con Bay 2502.

  Bol Chile Parasitol 24: 54-59.

• Cerisola JA 1977. Chemotherapy of Chagas' infection in man. Scientific Publication, PAHO, No. 347.

• Cichero JA, Segura E, Quatrochi JC 1969. Evolución clínico parasitológica y tolerancia a la droga de 33 niños con infección chagásica crónica tratados con Bay 2502.

  Bol Chile Parasitol

  24: 59-62.

• Coura JR 1996. Perspectivas actuales del tratamiento específico de la enfermedad de Chagas.

  Bol Chil Parasitol

  51: 69-73.

• de Andrade ALS, Zicker F, de Oliveira RM, Almeida y Siva S, Luquetti A, Travassos LR, Almeida IC, de Andrade SS, de Andrade JG, Martelli CMT 1996. Randomosed trial of efficacy of benznidazole in treatment of early

  Trypanosoma cruzi infection.

  Lancet

  348: 1407-1413.

• del Barco M, Streiger M, Arias E, Fabro D, Amicone N 1993. Respuesta al tratamiento en niños con infec-ción chagásica crónica.

  Medicina 53 (Supl. I): 78.

• Fabro D, Arias E, Streiger M, Piacenza R, Ingaramo M, Del Barco M, Amicone N 1997. Infectados chagásicos en fase indeterminada con mas de 15 años de seguimiento-evaluación de la quimioterapia específica.

  Medicina

  55 (Supl. III): 42-43.

• Ferreira H de O 1969. Comparación de la tolerancia medicamentosa de la nitrofurazona, la levofural-tadona (NF-602) y el Bay 2502.

  Bol Chile Parasitol

  24 : 101-103.

• Ferreira H de O 1990. Tratamento da forma indeter-minada da doença de Chagas com nifurtimox e benznidazole.

  Rev Soc Bras Med Trop

  23: 209.

• Galvão LMC, Nunes RMB, Cançado JR, Krettli AU 1993. Lytic antibody as a means of assessimg cure after treatment of Chagas diasease: a 10 years follow-up study.

  Trans R Soc trop Med Hyg

  87: 220-223.

• Gazzinelli RT, Galvão LM, Krautz G, Lima PC, Cançado JR, Scharfstein J, Krettli AU 1993. Use of

  Trypanosoma cruzi purified glycoprotein (GP57/51) or trypomasrigote-shed antigens to asses cure for human Chagas disease.

  Am J Trop Med Hyg

  49: 625-635.

• Krautz GM, Galvão LMC, Cançado JR, Guevara-Espinoza A, Ouaissi A, Krettli AU 1995. Use of a 24-kilodalton

  Trypanosoma cruzi recombinant protein to monitor cure of human Chagas disease.

  J Clin Microbiol

  33: 2086-2090.

• Krettli AU, Brener Z 1982. Resistence against

  Trypanosoma cruzi associated to anti-living trypomastigote antibodies.

  J Immunol

  128: 5.

• Krettli AU, Cançado JR, Brener Z 1984. Criterion of cure of human Chagas disease after specific chemotherapy, recent advances.

  Mem Ins Oswaldo Cruz

  79: 157-164.

• Laucella S Luna C, Sosa Estani S, Velazques E, Prado N, De Rissio A, Sinagra A, Segura EL, Riarte A 1997. Variaciones en los niveles de VCAM-1 y P-Selectina solubles, en niños chagásicos tratados con benznidazol en fase indeterminada.

  Medicina

  55 (Supl. III): 40-41.

• Lugones H 1978. Actualización terapéutica. Tratamiento de la enfermedad de Chagas agudo en niños.

  Pediatría

  2: 103-105.

• Lugones H, Peralta F, Canal Feijóo D, Marteleur A 1969. Evolución de la sintomatología clnica y la función hepática en la enfermedad de Chagas agudo tratada con Bay 2502.

  Bol Chile Parasitol

  24: 19-24.

• Moya PR, Paolasso RD, Blanco S, Lapasset M, Sanmartino C, Baso B, Moretti E, Cura D 1985. Tratamiento de la enfermedad de Chagas con nifurtimox durante los primeros meses de vida.

  Medicina 45: 553-558.

• OPAS - Organización Panamericana de la Salud 1998. Iniciativa del Cono Sur para la eliminación del

  Triatoma infestans y la interrupción de la trsnmisión de la tripanosomiasis americana por transfusión.

  OPS/HPC/HCT/98 114: 7-13.

• Porcel B, Bontempi E, Heriksson, Rydaker M, Aslund L, Segura EL, Petterson U, Ruiz AM 1996.

  Trypanosoma rangeli and

  Trypanosoma cruzi: molecular characterization of genes encoding putative calcium-binding proteins, highly conserved in trypanoso-matids.

  Exp Parasitol

  84: 387-399.

• Rubio M, Donoso F 1969. Enfermedad de Chagas en niños y tratamiento con Bay 2502.

  Bol Chile Parasitol

  24: 43-48.

• Schenone H, Concha L, Aranda R, Rojas A, Alfaro E 1969. Experiencia terapéutica con el Bay 2502 en la infección chagásica crónica del adulto. Importancia del uso adecuado del xenodiagnóstico.

  Bol Chile Parasitol

  24: 66-69.

• Sosa Estani S 1993. Tratamiento específico anti-

  T. cruzi, p. 279-287. In R Madoeri, C Madoeri & MI Cámera (eds),

  Actualización en Enfermedad de Chagas, Grafiquil, Organización Congreso Facultad de Medicina, Buenos Aires.

• Sosa Estani S, Segura EL, Ruiz AM, Velazquez E, Porcel B, Yampotis C 1998. Chemotherapy with benznidazole in children in undetermined phase of Chagas disease.

  Am J Trop Med Hyg 59: 526-529.

• Viotti R, Vigliano C, Armenti A, Segura EL 1994. Treatment of chronic Chagas' disease with benznidazole: clinical and serologic evolution of patients with long-term follow-up.

  American Heart J 127: 151-161.

Received 9 June 1999

Accepted 9 August 1999

Publication Dates

• Publication in this collection
  18 Aug 2004
• Date of issue
  Sept 1999

History

• Accepted
  09 Aug 1999
• Received
  09 June 1999