B-Cell Responses in Chronic Chagas Disease: Waning of Trypanosoma cruzi-Specific Antibody-Secreting Cells Following Successful Etiological Treatment.

BACKGROUND: A drawback in the treatment of chronic Chagas disease (American trypanosomiasis) is the long time required to achieve complete loss of serological reactivity, the standard for determining treatment efficacy. METHODS: Antibody-secreting cells and memory B cells specific for Trypanosoma cruzi and their degree of differentiation were evaluated in adult and pediatric study participants with chronic Chagas disease before and after etiological treatment. RESULTS: T. cruzi-specific antibody-secreting cells disappeared from the circulation in benznidazole or nifurtimox-treated participants with declining parasite-specific antibody levels after treatment, whereas B cells in most participants with unaltered antibody levels were low before treatment and did not change after treatment. The timing of the decay in parasite-specific antibody-secreting B cells was similar to that in parasite-specific antibodies, as measured by a Luminex-based assay, but preceded the decay in antibody levels detected by conventional serology. The phenotype of total B cells returned to a noninfection profile after successful treatment. CONCLUSIONS: T. cruzi-specific antibodies in the circulation of chronically T. cruzi-infected study participants likely derive from both antigen-driven plasmablasts, which disappear after successful treatment, and long-lived plasma cells, which persist and account for the low frequency and long course to complete seronegative conversion in successfully treated participants.

Chagas disease in bone marrow transplantation: an approach to preemptive therapy.

The efficacy of preemptive therapy was evaluated in bone marrow transplantation (BMT) recipients associated with Chagas disease (CD). The criterion to include patients in the protocol was the serological reactivity for CD in recipients and/or donors before transplant. After BMT, the monitoring was performed using the direct Strout method (SM), which detects clinical levels of Trypanosome cruzi parasitemia, and CD conventional serological tests. Monitoring took place during 60 days in ABMT and throughout the immunosuppressive period in allogeneic BMT. Reactivation of CD was diagnosed by detecting T. cruzi parasites in blood or tissues. In primary T. cruzi infection, an additional diagnostic criterion was the serological conversion. A total of 25 CD-BMT patients were included. Two ABMT and four allogeneic BMT recipients showed CD recurrences diagnosed by SM. One patient also showed skin lesions with T. cruzi amastigotes. Benznidazole treatment (Roche Lab), an antiparasitic drug, was prescribed at a dose of 5 mg/kg/day during 4-8 weeks with recovery of patients. Primary T. cruzi infection was not observed. This report proves the relevance of monitoring CD in BMT patients and demonstrates that preemptive therapy was able to abrogate the development of clinical and systemic disease.

Proinflammatory and anti-inflammatory cytokines in pregnant women chronically infected with Trypanosoma cruzi.

Mother-to-child transmission of intracellular parasites could be related to the production of immunoregulatory cytokines. The levels of gamma interferon (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and lnterleukin (IL)-10 were evaluated during pregnancy in sera of women chronically infected with Trypanosoma cruzi that delivered infected or non-infected children. The levels of IL-10 increased in both, women only pregnant and only infected, compared to non-infected non-pregnant women. However, in pregnant women chronically infected with T. cruzi, IL-10 did not increase significantly, neither in the mothers of infected nor in the mothers of non-infected children. The levels of the inflammatory cytokine TNF-alpha were not affected in normal pregnancy but increased in the infected mothers of non-infected children. The levels of IFN-gamma did not increase in the groups studied, indicating that the production of this pro-inflammatory cytokine was controlled, even when the levels of IL-10 did not increase, as in pregnant women chronically infected with T. cruzi.

Long-term effects of a nationwide control program on the seropositivity for Trypanosoma cruzi infection in young men from Argentina.

Unselected nationwide cohorts of Argentine men 18 years of age summoned for military service were tested for antibodies to Trypanosoma cruzi each year from 1981 to 1993. After an initial screening using indirect hemagglutination test, the positive sera were retested by titrated indirect hemagglutination and immunofluorescence antibody tests at 39 laboratories or at the national reference center in Buenos Aires. Nearly 1.8 million men were examined for T. cruzi antibodies using the same standardized procedures under a quality assurance program. The prevalence of seropositivity for T. cruzi decreased significantly from 5.8% in 1981 to 1.9% in 1993, but the decrease was not homogeneous among provinces within each region or constant over time. Prior to the nationwide control campaign initiated in 1961-1962, 15 provinces had high (> 20%) percentages of houses with domiciliary infestation by Triatoma infestans bugs, which decreased to nine provinces in 1982, and four provinces in 1992. The observed decrease in the prevalence of seropositivity for T. cruzi may be mostly attributed to the spraying with insecticides to eliminate the domiciliary populations of Triatoma infestans. The lack of a sustainable triatomine surveillance program set a limit to the decrease of seropositivity rates and prompted a revised strategy based on community participation.

Chagas' disease in patients with kidney transplants: 7 years of experience 1989-1996.

Chagas' disease was present in 17.22% of persons undergoing kidney transplantation in an Argentine Hospital. The criterion for attributing reactivation of chronic Chagas' disease and transmission of Trypanosoma cruzi to grafts was detection of parasites in blood (patent parasitemia) or tissues. Reactivation was diagnosed in 5 (21.7%) of 23 recipients. Ten (43.4%) of 23 chagasic recipients without reactivation of chronic Chagas' disease had abrogation of serological reactivity. T. cruzi infection was transmitted to 3 (18.7%) of 16 non-chagasic recipients. Reactivation and infection were diagnosed by patent parasitemia or cutaneous panniculitis. For diagnosis, detection of parasites in blood and tissues had more relevance than serology. Sequential monitoring detected early reactivation and infection, permitting application of preemptive or therapeutic therapy with benznidazole, thus inhibiting, in all patients, severe clinical disease produced by a progressive and systemic replication of the parasite.

Reactivation of chronic Chagas' disease following allogeneic bone marrow transplantation and successful pre-emptive therapy with benznidazole.

This report shows the early detection of reactivation of chronic Chagas' disease (CCd) in a 27-year-old man with chronic myelogenous leukemia undergoing allogeneic bone marrow transplantation (ABMT). Pre-emptive therapy with benznidazole during a period of 7 weeks led to a rapid recovery of the patient, who remains free of parasitemia 2 years after the bone marrow transplantation.

Recipients and donors of bone marrow transplants suffering from Chagas' disease: management and preemptive therapy of parasitemia.

We report the clinical course of five adult patients with chronic Chagas' disease (Cd) who underwent BMT. Two patients with non-Hodgkin's lymphoma and one with ALL received an ABMT. Allogeneic BMT was performed in two patients with AML and CML respectively. One donor had chronic Cd. Samples of peripheral blood for parasite investigation by the Strout method, blood culture, and immunological studies by indirect immunofluorescent assay, ELISA and indirect hemagglutination tests were performed weekly from the start of chemotherapy until day +60 for ABMT and during the period of immunosuppression for allogeneic BMT. No prophylaxis was given to any of these patients. In only one ABMT patient were trypomastigotes detected early by blood culture without symptoms of reactivation. Benznidazole as preemptive treatment was administered at 5-8 mg/kg/daily for 30 days. Parasitemia was rapidly cleared and at the end of therapy xenodiagnosis was negative. The other Cd patients showed no evidence of relapse of parasitemia or signs and symptoms of reactivation. In brief, evidence of Cd should be sought in all BMT patients coming from endemic areas because parasitemia and reactivation are potential complications during the period of neutropenia and immunosuppression. The strategy used for early detection and treatment of parasitemia and reactivation was safe and effective.

Dynamics of transmission of Trypanosoma cruzi in a rural area of Argentina. IV. Serologic, parasitologic and electrocardiographic study of the human population.

A serologic and electrocardiographic study was carried out in people living in 18 households in La Invernada (LI), Departamento Figueroa, and in 20 houses in Amamá (A), Departamento Moreno, both in the province of Santiago del Estero, Argentina. Serological tests performed were indirect hemagglutination (IHAT) and indirect immunofluorescence antibody tests (IFAT). Complement fixation, direct agglutination and ELISA tests were also done for those sera, showing discordant results for either IHAT or IFAT. All people in LI and children up to 12 years old in A were studied by xenodiagnosis. Approximately 50% of the whole population was infected (50% in LI and 50.9% in A) and a similar prevalence rate was already recorded in children below 10 years. A moderate increase of infection rates was observed in successively older age groups, indicating that most of the people became infected in the first decade of life. Comparison of serological profiles of both populations suggests a protective effect of insecticidal control campaigns in those individuals born between 1961 and 1971. New surveys carried out in both populations 2 years later rendered a 4 times greater annual incidence rate in A as compared with LI (7.9% vs 1.8% respectively). No differences were found in the percentages of abnormal electrocardiograms among seropositive and seronegative individuals from both settlements. The prevalence of complete right bundle branch block (RBBB) was higher in seropositive than in seronegative people (4.8% vs 2.3%) but lower than those figures recorded for other parts of the country and the continent. This suggests that in spite of its high prevalence, Chagas' disease has low morbidity in both localities.

Dynamics of transmission of Trypanosoma cruzi in a rural area of Argentina. IV. Serologic, parasitologic and electrocardiographic study of the human population.

A serologic and electrocardiographic study was carried out in people living in 18 households in La Invernada (LI), Departamento Figueroa, and in 20 houses in Amamá (A), Departamento Moreno, both in the province of Santiago del Estero, Argentina. Serological tests performed were indirect hemagglutination (IHAT) and indirect immunofluorescence antibody tests (IFAT). Complement fixation, direct agglutination and ELISA tests were also done for those sera, showing discordant results for either IHAT or IFAT. All people in LI and children up to 12 years old in A were studied by xenodiagnosis. Approximately 50

of the whole population was infected (50

in LI and 50.9

in A) and a similar prevalence rate was already recorded in children below 10 years. A moderate increase of infection rates was observed in successively older age groups, indicating that most of the people became infected in the first decade of life. Comparison of serological profiles of both populations suggests a protective effect of insecticidal control campaigns in those individuals born between 1961 and 1971. New surveys carried out in both populations 2 years later rendered a 4 times greater annual incidence rate in A as compared with LI (7.9

vs 1.8

respectively). No differences were found in the percentages of abnormal electrocardiograms among seropositive and seronegative individuals from both settlements. The prevalence of complete right bundle branch block (RBBB) was higher in seropositive than in seronegative people (4.8

vs 2.3

) but lower than those figures recorded for other parts of the country and the continent. This suggests that in spite of its high prevalence, Chagas disease has low morbidity in both localities.