Congenital Trypanosoma cruzi infection is a highly pathogenic and underreported condition. Early recognition is essential for effective treatment. Umbilical chord blood from newborns (n = 302) to infected mothers was analyzed with microhematocrit, hemoculture, and PCR methods. Each subject was then followed serologically. In calibrated suspensions of T. cruzi in blood, the sensitivity of PCR was 27-fold higher than hemoculture. However, this advantage was not reflected during routine testing of samples from maternities, partly because of the uneven distribution of few parasites in small samples. Levels of detection of congenital infection were 2.9% (8/272) for microhematocrit, 6.3% (18/287) for hemoculture, 6.4% (15/235) for PCR, and 8.9% (27/302) for cumulated results. Evaluation against the standard of delayed serology indicates that the regular application of PCR, hemoculture, and microhematocrit to blood samples allows the rapid detection of about 90% of the congenitally infected newborns, in samples that can be obtained before the mother and child leave the maternity ward.

We studied the seroprevalence of antibodies against Trypanosoma cruzi in the human population along with domiciliary infestation by triatomine bugs in an area endemic for Chagas disease in the Chaco Province of Argentina. In addition, we carried out parasitologic surveys in patients, dogs, wild mammals, and vectors. The mean seroprevalence in humans was 27.81% (109 of 392) and 24.14% (63 of 261) in 1-15-year-old children. The minimum domiciliary infestation rate was 13.33%, with certain areas reaching 53.85%. The prevalence was 15.09% (16 of 106) in dogs and 35.71% (10 of 28) in opossums. Infection with T. cruzi was detected in 30.10% (59 of 196) of the Triatoma infestans tested. Compared with nationwide studies, our data suggest that 1) there are zones requiring immediate sanitary action, and 2) nationwide estimates are based on very heterogeneous epidemiologic situations. This heterogeneity emphasizes the importance of in-depth studies of restricted areas to provide additional information for a better understanding of the present status of Chagas disease in Argentina.

The addition of a hydroxymethyl group to the antimicrobial drug nitrofurazone generated hydroxymethylnitrofurazone (NFOH), which had reduced toxicity when its activity against Trypanosoma cruzi was tested in a murine model of Chagas' disease. Four groups of 12 Swiss female mice each received 150 mg of body weight/kg/day of NFOH, 150 mg/kg/day of nitrofurazone (parental compound), 60 mg/kg/day of benznidazole (BZL), or the solvent as a placebo. Treatments were administered orally once a day 6 days a week until the completion of 60 doses. NFOH was as effective as BZL in keeping direct parasitemia at undetectable levels, and PCR results were negative. No histopathological lesions were seen 180 days after completion of the treatments, a time when the levels of anti-T. cruzi antibodies were very low in mice treated with either NFOH or BZL. Nitrofurazone was highly toxic, which led to an overall rate of mortality of 75% and necessitated interruption of the treatment. In contrast, the group treated with its hydroxymethyl derivative, NFOH, displayed the lowest mortality (16%), followed by the BZL (33%) and placebo (66%) groups. The findings of histopathological studies were consistent with these results, with the placebo group showing the most severe parasite infiltrates in skeletal muscle and heart tissue and the NFOH group showing the lowest. The present evidence suggests that NFOH is a promising anti-T. cruzi agent.In 1909, Carlos Chagas described the protozoan parasite Trypanosoma cruzi as the causative agent of a widespread disease in Brazil that involved cardiac alterations and megaorgans. The parasite and its insect vectors were described in the original paper on the disease (7), and the parasite was soon confirmed to be present in patients throughout Latin America. Recent reports estimate the number of infected people to be between 9.8 million and 15 million in the Americas (29), with 28 million more being at risk of infection (26). In this scenario, congenital transmission of infection is a major problem in urban areas, along with risks from blood transfusion and migration of infected patients to areas of nonendemicity (28). In spite of the reduction in the number of new infections and the increased knowledge about the parasite, treatment of Chagas' disease relies on two drugs developed during the early 1970s: benznidazole (BNZ; Radanil, Roche) and nifurtimox (NFX; Bayer) (35). Both drugs are generally well tolerated by children but cause many undesirable side effects in adults and are not effective during the chronic phase of the disease. A well-tolerated, safe, and therapeutically efficient drug is not yet available. Several attempts have been made to create new drugs with more specificity toward the parasite and less toxicity for the mammalian host. Such attempts included inhibitors of cruzain (13, 14), C-14␣-demethylase (5, 10, 32), and chemical modifications of molecules with known trypanocidal activity, such as aromatic nitroheterocyclic compounds (1, 2). Nitrofurazone is an antimicrobial drug that is eff...

No abstract

ABSTRACT. Objective. Trypanosoma cruzi, the causative agent of Chagas' disease, is transmitted mainly by insect vectors, but congenital and transfusion-borne infections occasionally occur. The factors that are involved in transmission from mother to offspring are not well understood. The objective of this study was to study the presence of T cruzi infection in children who were born to infected mothers and in the children's siblings to evaluate the epidemiologic risk factors associated with congenital transmission of Chagas' disease.Methods. Congenital T cruzi infection was studied in 340 children who were born to chronically infected mothers in Salta, Argentina. Infection was detected in 31 children, who were selected for additional study as infected index cases (IIC). Of the 309 noninfected children, 31 were taken as noninfected index cases (NIIC). We compared the prevalence of congenital T cruzi transmission in the remaining siblings of the IIC and NIIC. Data and blood samples were collected in house-to-house visits. Diagnosis of infection was established mainly by serologic methods, indirect hemmagglutination, and enzymelinked immunosorbent assay.Results. The prevalence was 31.4% (32 of 102 children) for IIC siblings, whereas no infected siblings were found in families with NIIC (0 of 112). Clustering of congenital infection was found in 14 families, in which >1 child was infected. Second-generation congenital transmission (from grandmother to mother to newborn) was established in 4 families. The association among low weight at birth, prematurity, and congenital transmission was highly significant. An important observation was the absence of pathologic findings in a high proportion of infected children. The detection of asymptomatic infections was a consequence of population screening, as opposed to hospital-based diagnosis, for which symptomatic cases predominate. Congenital transmission was associated with the geographic origin of mothers: women from areas where insect vectors proliferate were less likely to give birth to infected offspring than women from areas under active vector control.Conclusions. Siblings of an infant infected with T cruzi are at high risk for infection themselves and, even in the absence of symptoms, should also be screened for infection. The findings of family clustering of infection and of second-generation congenital infection in vectorfree areas suggest that new modalities of transmission, other than classic vector-borne spread, may occur both in endemic and in nonendemic areas. Pediatrics 2005; 115:e668-e672. URL: www.pediatrics.org/cgi

BackgroundTreatment of Chagas disease, caused by Trypanosoma cruzi, relies on nifurtimox and benznidazole (BZL), which present side effects in adult patients, and natural resistance in some parasite strains. Hydroxymethylnitrofurazone (NFOH) is a new drug candidate with demonstrated trypanocidal activity; however, its safety is not known.MethodsHepG2 cells dose response to NFOH and BZL (5–100 µM) was assessed by measurement of ROS, DNA damage and survival. Swiss mice were treated with NFOH or BZL for short-term (ST, 21 d) or long-term (LT, 60 d) periods. Sera levels of cellular injury markers, liver inflammatory and oxidative stress, and fibrotic remodeling were monitored.ResultsHepG2 cells exhibited mild stress, evidenced by increased ROS and DNA damage, in response to NFOH, while BZL at 100 µM concentration induced >33% cell death in 24 h. In mice, NFOH ST treatment resulted in mild-to-no increase in the liver injury biomarkers (GOT, GPT), and liver levels of inflammatory (myeloperoxidase, TNF-α), oxidative (lipid peroxides) and nitrosative (3-nitrotyrosine) stress. These stress responses in NFOH LT treated mice were normalized to control levels. BZL-treated mice exhibited a >5-fold increase in GOT, GPT and TNF-α (LT) and a 20–40% increase in liver levels of MPO activity (ST and LT) in comparison with NFOH-treated mice. The liver inflammatory infiltrate was noted in the order of BZL>vehicle≥NFOH and BZL>NFOH≥vehicle, respectively, after ST and LT treatments. Liver fibrotic remodeling, identified after ST treatment, was in the order of BZL>vehicle>NFOH; lipid deposits, indicative of mitochondrial dysfunction and in the order of NFOH>vehicle>BZL were evidenced after LT treatment.ConclusionsNFOH induces mild ST hepatotoxicity that is normalized during LT treatment in mice. Our results suggest that additional studies to determine the efficacy and toxicity of NFOH are warranted.

Serological tests are the main laboratory procedures used for diagnosis during the indeterminate and chronic stages of Chagas' disease. A serological regression to negativity is the main criterion used to define parasitological cure in treated patients. The aim of this work was to monitor the individual specificities of antibody levels for 3 years posttreatment in 18 adult patients. Conventional serological techniques (hemagglutination assays and enzyme-linked immunosorbent assay [ELISA]) were modified by using recombinant antigens to detect early markers of treatment effectiveness. For this purpose, serum samples were taken before and during treatment and every 6 months after treatment for at least 3 years. When hemagglutination assays were used, a decrease in antibody levels was observed in only one patient. When ELISA with serum dilutions was used, antibody clearance became much more apparent: in 77.7% (14/18) of the patients, antibody titers became negative with time. This was observed at serum dilutions of 1/320 and occurred between the 6th and the 30th months posttreatment. The immune response and the interval for a serological regression to negativity were different for each patient. For some of the recombinant antigens, only 50% (9/18) of the patients reached the serological regression to negativity. Recombinant antigen 13 might be a good marker of treatment effectiveness, since 66.6% (six of nine) of the patients presented with an early regression to negativity for specific antibodies to this antigen (P ‫؍‬ 0.002).

HighlightsThis is the first meta-analysis of individual data in chronic Trypanosoma cruzi infection after treatment.The probability of seroreversion is variable along the course of follow-up.An interaction was found between age at treatment and country setting.The course of parasitological/molecular tests after treatment needs to be assessed.