IntroductionChagas disease, caused by the parasite Trypanosoma cruzi, can lead to long term cardiac morbidity. Treatment of children with benznidazole is effective, but no pediatric pharmacokinetics data are available and clinical pharmacology information on the drug is scarce.Patients and MethodsProspective population pharmacokinetic (PK) cohort study in children 2–12 years old with Chagas disease treated with oral benznidazole 5–8 mg/kg/day BID for 60 days. (clinicaltrials.gov #NCT00699387).ResultsForty children were enrolled in the study. Mean age was 7.3 years. A total of 117 samples were obtained from 38 patients for PK analysis. A one compartment model best fit the data. Weight-corrected clearance rate (CL/F) showed a good correlation with age, with younger patients having a significantly higher CL/F than older children and adults. Simulated median steady-state benznidazole concentrations, based on model parameters, were lower for children in our study than for adults and lowest for children under 7 years of age. Treatment was efficacious in the 37 patients who completed the treatment course, and well tolerated, with few, and mild, adverse drug reactions (ADRs).DiscussionObserved benznidazole plasma concentrations in children were markedly lower than those previously reported in adults (treated with comparable mg/kg doses), possibly due to a higher CL/F in smaller children. These lower blood concentrations were nevertheless associated to a high therapeutic response in our cohort. Unlike adults, children have few adverse reactions to the drug, suggesting that there may be a direct correlation between drug concentrations and incidence of ADRs. Our results suggest that studies with lower doses in adults may be warranted.Trial RegistrationClinicalTrails.gov NCT00699387

Treatment with benznidazole was well tolerated in children. Most ADRs were mild and did not require treatment suspension. A strong association was observed between ADR incidence and patient age, and most ADRs occurred in children older than 7 years. We believe that anxiety over potential severe ADRs in children with Chagas disease is not justified and should not be an obstacle to using benznidazole.

It is currently unknown whether treatment of Chagas disease decreases the risk of congenital transmission from previously treated mothers to their infants. In a cohort of women with Chagas disease previously treated with benznidazole, no congenital transmission of the disease was observed in their newborns. This finding provides support for the treatment of Chagas disease as early as possible.

Background Evaluation of therapeutic response in chronic Chagas disease is a major challenge, due to prolonged persistence of Trypanosoma cruzi -specific antibodies, lack of sensitivity of parasitological tests, and need for long-term follow-up to observe negative seroconversion of conventional serological tests (CS). The objective of this study was to evaluate F2/3-ELISA serology, a promising early biomarker of therapeutic response, and T . cruzi Polymerase chain reaction (PCR) for T . cruzi Deoxyribonucleic acid (DNA), for neonatal diagnosis and evaluation of parasitemia after treatment. Methods Prospective cohort study, with three-year clinical, serological and parasitological follow-up of pediatric Chagas disease patients treated with benznidazole. Serology was evaluated by Enzyme-Linked ImmunoSorbent Assay (ELISA), Indirect hemagglutination (IHA) and F2/3-ELISA; Parasitemia by microhematocrit (MH) and PCR. Results A cohort of 107 pediatric patients treated with benznidazole was enrolled in the study. ELISA and IHA were initially reactive in 100% of patients, F2/3-ELISA serology was reactive in 80% (86/107) and 91% (97/107) had detectable parasitemia. Seventy-six (71%) patients completed at least 36 months of serological follow up after treatment. Although a similar decreasing linear trend was observed for all serological tests, F2/3-ELISA presented earlier, age dependent, negative seroconversion compared to CS. All patients reaching undetectable CS titers had previously seroreverted by F2/3-ELISA. All patients with persistently decreasing antibody titers had negative PCRs throughout the follow up period. No new cardiological lesions were observed during the 3 years follow-up period. Conclusions The data reported here, using CS, F2/3 ELISA and PCR provide support for the efficacy of benznidazole in congenital Chagas diseases. These results provide support for scaling up of screening, diagnosis and access to benznidazole treatment. Trial registration ClinicalTrials.gov 0028/04 in the Research Council, Secretary of Health Buenos Aires city Goberment.

Chagas disease (ChD), caused by Trypanosoma cruzi , has a global prevalence due to patient migration. However, despite its worldwide distribution, long-term follow-up efficacy studies with nifurtimox (NF) are scarce and have been conducted with only small numbers of patients. A retrospective study of a large cohort of ChD treated children and adults with NF.

Epstein-Barr virus (EBV) is related to the development of lymphomas and is also the etiological agent for infectious mononucleosis (IM). Sequence variation of the EBNA1 gene, consistently expressed in all EBV-positive cells, has been widely studied. Based on the amino acid at codon 487 five major EBNA1 variants have been described, two closely related prototypic variants (P-ala and P-thr) and three variant sequences (V-leu, V-val, and V-pro). Sub-variants were then further classified based on mutations other than the originally described. While several studies proposed associations with tumors and/or anatomical compartments, others argued in favor of a geographical distribution of these variants. In the present study, EBNA1 variants in 11 pediatric patients with IM and 19 pediatric EBV lymphomas from Argentina were compared as representatives of benign and malignant infection in children, respectively. A 3-month follow-up study of EBNA1 variants in peripheral blood cells and in oral secretions of patients with IM was performed. A new V-ala variant which includes five V-ala sub-variants and three new V-leu sub-variants was described. These data favor the geographical association hypothesis since no evidence for a preferential compartment distribution of EBNA1 variants and sub-variants was found. This is the first study to characterize EBNA1 variants in pediatric patients with infection mononucleosis worldwide.

ClinicalTrials.gov NCT01547533.

Epstein-Barr virus genotypes can be distinguished by polymorphic variations in the genes encoding EBNA2, 3A, 3B, and 3C. The immediate early gene BZLF1 plays a key role in modulating the switch from latency to lytic replication and therefore enabling viral propagation. The aim of this study was to investigate and compare BZLF1 promoter sequence (Zp) variation in pediatric infectious mononucleosis (IM) and in pediatric EBV positive lymphoma biopsies. Zp was sequenced from peripheral blood mononuclear cells (PBMC) and throat swabs from 10 patients with IM at the time of diagnosis (D0) and during convalescence; and from 13 lymphoma biopsies. Zp - P and Zp - V3 variants were found in eight and one IM patients, as well as in five and six tumor biopsies, respectively. A correlation between viral genotype and Zp variant was found significant for Zp - V3 and EBV2 (P = 0.0002). One IM patient harbored two concomitant Zp variants. Regardless of anatomical compartment or stage of disease all IM patients displayed the same Zp variant along the course of the study. No new infections or adaptative selection of different variants was evidenced. A new Zp variant (Zp - V3 + 49) was described in two Hodgkin lymphomas, but not in IM. This is the first study to describe Zp variants compartmentalization in children with acute EBV infection and convalescence in a developing country; and comparing them with Zp variants in pediatric lymphomas from the same geographic area.