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Genetic consequences of mass human chemotherapy for Schistosoma mansoni: population structure pre- and post-praziquantel treatment in Tanzania.

ABSTRACT: Recent shifts in global health policy have led to the implementation of mass drug administration (MDA) for neglected tropical diseases. Here we show how population genetic analyses can provide vital insights into the impact of such MDA on endemic parasite populations. We show that even a single round of MDA produced a genetic bottleneck with reductions in a range of measures of genetic diversity of Schistosoma mansoni. Phylogenetic analyses and indices of population differentiation indicated that schistosomes collected in the same schools in different years were more dissimilar than those from different schools collected within either of the study's 2 years, in addition to distinguishing re-infection from non-clearance (that might indicate putatively resistant parasites) from within those children infected at both baseline and follow-up. Such unique results illustrate the importance of genetic monitoring and examination of long lived multi-cellular parasites such as these under novel or increased chemotherapeutic selective pressures.

SUBMITTER: Norton AJ

PROVIDER: S-EPMC2946775 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Genetic consequences of mass human chemotherapy for Schistosoma mansoni: population structure pre- and post-praziquantel treatment in Tanzania.

Norton Alice J AJ Gower Charlotte M CM Lamberton Poppy H L PH Webster Bonnie L BL Lwambo Nicholas J S NJ Blair Lynsey L Fenwick Alan A Webster Joanne P JP

The American journal of tropical medicine and hygiene 20101001 4

Recent shifts in global health policy have led to the implementation of mass drug administration (MDA) for neglected tropical diseases. Here we show how population genetic analyses can provide vital insights into the impact of such MDA on endemic parasite populations. We show that even a single round of MDA produced a genetic bottleneck with reductions in a range of measures of genetic diversity of Schistosoma mansoni. Phylogenetic analyses and indices of population differentiation indicated tha ...[more]

PMID: 20889898

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Project description:Schistosomes infect over 200 million people worldwide, but few studies have characterized the effects of Schistosoma mansoni infection and effective treatment on the lower gastrointestinal mucosa. In this prospective cohort study, we compared the clinical findings on sigmoidoscopy and laboratory measures in Tanzanian adults with and without S. mansoni infection at baseline and 6 months after praziquantel treatment. Grading of the endoscopic findings was done using the Mayo Scoring System for Assessment of Ulcerative Colitis Activity. Schistosome infection was confirmed by stool microscopy and serum circulating anodic antigen (CAA). Baseline comparisons were performed in Stata using Fisher's exact and Wilcoxon rank-sum tests, and pre- and post-treatment comparisons using Wilcoxon matched-pairs signed-rank and McNemar's tests. We investigated the clinical characteristics of 48 individuals: 32 with and 16 without S. mansoni infection. Infected individuals had greater severity of sigmoid and rectal mucosal abnormalities and higher Mayo scores and serum eosinophils (all p < 0.05) than uninfected individuals at initial evaluation. At 6 months, 28 individuals completed repeat blood tests and sigmoidoscopy. Of these, 14 cleared their baseline infection (n = 7) or experienced a greater than 7-fold decrease in serum CAA (n = 7). Follow-up sigmoidoscopies revealed some improvements in sigmoid and rectal mucosal findings, although Mayo scores were not significantly lower. Both the median erythrocyte sedimentation rates (32.5→12.5 mm/hr) and percent of eosinophils (7.1→3.1%) decreased in this group from baseline to follow-up. S. mansoni infection was associated with mild-to-moderate lower gastrointestinal mucosal abnormalities that were grossly visible during sigmoidoscopy, and these improved partially 6 months after effective treatment with praziquantel. Additional studies, of longer duration and focused on both clinical and mucosal immunologic effects of S. mansoni, could provide additional insight.

Project description:BACKGROUND:Current World Health Organization (WHO) guidelines recommend annual mass drug administration using praziquantel in areas with high schistosome endemicity. Yet little is known about incidence and reinfection rates after treatment in women with frequent exposure to schistosomes. We sought to quantify response to anti-schistosome treatment and incident S. mansoni infections in a cohort of rural women living in a schistosome-endemic area of northwest Tanzania. METHODS AND PRINCIPAL FINDINGS:We enrolled women with and without S. mansoni infection into a 12-month longitudinal cohort. Every 3 months, women were tested for schistosome infection using microscopic examinations for ova on filtered urine, Kato Katz slides, and serum Circulating Anodic Antigen (CAA). Those with schistosome infection received treatment with praziquantel 40 mg/kg according to the standard of care. We studied 35 women who were S. mansoni positive by stool microscopy and 46 women without schistosome infection who returned for at least one follow-up. Of the women who were initially infected, 14 (40%) were schistosome-positive at a follow-up visit. Four women developed incident infections, for a cumulative incidence of 8.7% and incidence rate of 0.99 per 100 person-months throughout the year among initially uninfected women. Only 3 women were egg-positive at any follow-up. Women with persistent, recurrent, or incident infection during the study period were significantly younger (p = 0.032) and had fewer children than women who remained uninfected or those who cleared the infection and did not experience recurrence (p = 0.003). Having fewer children remained significant after controlling for age (p = 0.023). There was no difference in initial intensity of infection by CAA or stool egg count, HIV status, or socioeconomic status. Although most water contact behaviors were comparable between the two groups, women with recurrent or incident schistosome infections were significantly more likely to have recently swum in the lake (p = 0.023). CONCLUSIONS:Our data suggests that annual praziquantel treatment reduces intensity of schistosome infections but is insufficient in providing stable parasite eradication in over a third of women in endemic communities. Furthermore, microscopy lacks adequate sensitivity to evaluate efficacy of treatment in this population. Our work demonstrates that further investigation into treatment efficacy and reinfection rates is warranted and suggests that increased frequency of praziquantel treatment is needed to improve cure rates in high-risk populations.

Project description:BackgroundTwo Kato-Katz thick smears (Kato-Katzs) from a single stool are currently recommended for diagnosing Schistosoma mansoni infections to map areas for intervention. This 'gold standard' has low sensitivity at low infection intensities. The urine point-of-care circulating cathodic antigen test (POC-CCA) is potentially more sensitive but how accurately they detect S. mansoni after repeated praziquantel treatments, their suitability for measuring drug efficacy and their correlation with egg counts remain to be fully understood. We compared the accuracies of one to six Kato-Katzs and one POC-CCA for the diagnosis of S. mansoni in primary-school children who have received zero to ten praziquantel treatments. We determined the impact each diagnostic approach may have on monitoring and evaluation (M&E) and drug-efficacy findings.Method/principle findingsIn a high S. mansoni endemic area of Uganda, three days of consecutive stool samples were collected from primary school-aged children (six - 12 years) at five time-points in year one: baseline, one-week-post-, four-weeks-post-, six-months-post-, and six-months-one-week-post-praziquantel and three time-points in years two and three: pre-, one-week-post- and four-weeks-post-praziquantel-treatment/retreatment (n = 1065). Two Kato-Katzs were performed on each stool. In parallel, one urine sample was collected and a single POC-CCA evaluated per child at each time-point in year one (n = 367). At baseline, diagnosis by two Kato-Katzs (sensitivity = 98.6%) or one POC-CCA (sensitivity = 91.7%, specificity = 75.0%) accurately predicted S. mansoni infections. However, one year later, a minimum of three Kato-Katzs, and two years later, five Kato-Katzs were required for accurate diagnosis (sensitivity >90%) and drug-efficacy evaluation. The POC-CCA was as sensitive as six Kato-Katzs four-weeks-post and six-months-post-treatment, if trace readings were classified as positive.Conclusions/significanceSix Kato-Katzs (two/stool from three stools) and/or one POC-CCA are required for M&E or drug-efficacy studies. Although unable to measure egg reduction rates, one POC-CCA appears to be more sensitive than six Kato-Katzs at four-weeks-post-praziquantel (drug efficacy) and six-months-post-praziquantel (M&E).

Dataset Information

Genetic consequences of mass human chemotherapy for Schistosoma mansoni: population structure pre- and post-praziquantel treatment in Tanzania.

Publications

Genetic consequences of mass human chemotherapy for Schistosoma mansoni: population structure pre- and post-praziquantel treatment in Tanzania.

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