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BackgroundLiver diseases of infectious and non-infectious etiology cause considerable morbidity and mortality, particularly in low- and middle-income countries (LMICs). However, data on the prevalence of liver diseases and underlying risk factors in LMICs are scarce. The objective of this study was to elucidate the occurrence of infectious diseases among individuals with chronic liver damage in a rural setting of Côte d'Ivoire.MethodologyIn 2021, we screened 696 individuals from four villages in the southern part of Côte d'Ivoire for hepatic fibrosis and steatosis, employing transient elastography (TE) and controlled attenuation parameter (CAP). We classified CAP ≥248 dB/m as steatosis, TE ≥7.2 kPa as fibrosis, and did subgroup analysis for participants with TE ranging from 7.2 kPa to 9.1 kPa. Clinical and microbiologic characteristics were compared to an age- and sex-matched control group (TE Principal findingsAmong 684 individuals with valid TE measurements, TE screening identified hepatic pathologies in 149 participants (17% with fibrosis and 6% with steatosis). 419 participants were included for further analyses, of which 261 had complete microbiologic analyses available. The prevalence of S. mansoni, hepatitis B, and hepatitis C were 30%, 14%, and 7%, respectively. Logistic regression analysis revealed higher odds for having TE results between 7.2 kPa and 9.1 kPa in individuals with S. mansoni infection (odds ratio [OR] = 3.02, 95% confidence interval [CI] = 1.58-5.76, P = 0.001), while HCV infection (OR = 5.02, 95% CI = 1.72-14.69, P = 0.003) and steatosis (OR = 4.62, 95% CI = 1.60-13.35, P = 0.005) were found to be risk factors for TE ≥9.2 kPa.Conclusions/significanceBesides viral hepatitis, S. mansoni also warrants consideration as a pathogen causing liver fibrosis in Côte d'Ivoire. In-depth diagnostic work-up among individuals with abnormal TE findings might be a cost-effective public health strategy.

Background/aimSchool-aged children in low- and middle-income countries carry the highest burden of intestinal helminth infections, such as soil-transmitted helminths (STH). STH infections have been associated with negative consequences for child physical and cognitive development and wellbeing. With the epidemiological transition and rise in cardiovascular disease (CVD), studies have shown that helminth infections may influence glucose metabolism by preventing obesity. Thus, the aim of this study was to determine the association of STH infections in schoolchildren from Gqeberha, focusing on physical activity, physical fitness, and clustered CVD risk score.MethodsThis cross-sectional study involved 680 schoolchildren (356 girls and 324 boys; mean age 8.19 years, SD±1.4) from disadvantaged communities in Gqeberha (formerly, Port Elizabeth), South Africa. Stool samples were collected and examined for STH infections using the Kato-Katz method. Physical activity (accelerometer) and physical fitness (grip strength, 20 m shuttle run) were measured using standard procedures. Furthermore, anthropometry, blood pressure, as well as glycated haemoglobin and lipid profile from capillary blood samples were assessed. We employed one-way ANOVAs to identify the associations of STH infections in terms of species and infection intensity with physical activity, physical fitness, and clustered CVD risk score.ResultsWe found a low STH infection prevalence (7.2%) in our study, with participants infected with at least one intestinal helminth species. In comparison to their non-infected peers, children infected with STH had lower mean grip strength scores, but higher mean VO2max estimation and higher levels of MVPA (p < .001). When considering type and intensity of infection, a positive association of A. lumbricoides infection and MVPA was found. In contrast, light T. trichiura-infected children had significantly lower grip strength scores compared to non and heavily-infected children. VO2max and MVPA were positively associated with light T. trichiura infection. No significant association between the clustered CVD risk score and infection with any STH species was evident.ConclusionsSTH-infected children had lower grip strength scores than their non-infected peers, yet, achieved higher VO2max and MVPA scores. Our study highlights that the type and intensity of STH infection is relevant in understanding the disease burden of STH infections on children's health. The findings of our study must be interpreted cautiously due to the low infection rate, and more research is needed in samples with higher prevalence rates or case-control designs.

[This corrects the article DOI: 10.1371/journal.pntd.0009144.].

BackgroundMost studies assessing praziquantel (PZQ) efficacy have used relatively insensitive diagnostic methods, thereby overestimating cure rate (CR) and intensity reduction rate (IRR). To determine accurately PZQ efficacy, we employed more sensitive DNA and circulating antigen detection methods.MethodologyA sub-analysis was performed based on a previously published trial conducted in children from Côte d'Ivoire with a confirmed Schistosoma mansoni infection, who were randomly assigned to a standard (single dose of PZQ) or intense treatment group (4 repeated doses of PZQ at 2-week intervals). CR and IRR were estimated based on PCR detecting DNA in a single stool sample and the up-converting particle lateral flow (UCP-LF) test detecting circulating anodic antigen (CAA) in a single urine sample, and compared with traditional Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA).Principal findingsIndividuals positive by all diagnostic methods (i.e., KK, POC-CCA, PCR, and UCP-LF CAA) at baseline were included in the statistical analysis (n = 125). PCR showed a CR of 45% (95% confidence interval (CI) 32-59%) in the standard and 78% (95% CI 66-87%) in the intense treatment group, which is lower compared to the KK results (64%, 95% CI 52-75%) and 88%, 95% CI 78-93%). UCP-LF CAA showed a significantly lower CR in both groups, 16% (95% CI 11-24%) and 18% (95% CI 12-26%), even lower than observed by POC-CCA (31%, 95% CI 17-35% and 36%, 95% CI 26-47%). A substantial reduction in DNA and CAA-levels was observed after the first treatment, with no further decrease after additional treatment and no significant difference in IRR between treatment groups.Conclusion/significanceThe efficacy of (repeated) PZQ treatment was overestimated when using egg-based diagnostics (i.e. KK and PCR). Quantitative worm-based diagnostics (i.e. POC-CCA and UCP-LF CAA) revealed that active Schistosoma infections are still present despite multiple treatments. These results stress the need for using accurate diagnostic tools to monitor different PZQ treatment strategies, in particular when moving toward elimination of schistosomiasis.Clinical trial registrationwww.clinicaltrials.gov, NCT02868385.

Abstract Background Soil-transmitted helminthiasis affects almost 2 billion people worldwide in tropical climates. Preventive chemotherapy, using the benzimidazoles (albendazole and mebendazole) is the current main recommended control strategy. Nevertheless, there is limited efficacy of these drugs against hookworm infection and, to a greater extent, against trichuriasis. We describe a protocol for a trial investigating the efficacy and safety of the co-administration of ivermectin and albendazole against trichuriasis. Methods A double-blind, placebo-controlled randomized controlled trial will be conducted in three countries (Côte d’Ivoire, Tanzania and Lao PDR) with the aim to determine the efficacy, safety and extended effects of co-administered ivermectin and albendazole compared to standard albendazole monotherapy. We will enroll 600 participants aged 6–60 years in each setting. The primary outcome is cure rate (CR) against Trichuris trichiura infection as assessed by Kato-Katz 14–21 days after treatment. Secondary outcomes include CRs against concomitant soil-transmitted helminth (STH) infections (Ascaris lumbricoides, hookworm and Strongyloides stercoralis) and egg reduction rates (ERRs) against STH at 14–21 days, 180 days and 360 days. Tolerability of treatment, infection status assessed by polymerase chain reaction (PCR), and potential benefits of deworming on nutritional and morbidity indicators will be assessed. The primary analysis will include an available-case set and use logistic regression models adjusted for age, sex and weight. Discussion This trial will provide robust results on the efficacy and safety of co-administration of ivermectin and albendazole with the aim to better inform WHO recommendations on control of STHs. Furthermore, secondary and explanatory outcomes will provide direct evidence on the extended effects of combination therapy and insight on the relationship between nutrition and morbidity parameters and infection status and intensity. Trial registration NCT03527732 (date assigned: 17 May 2018).

BackgroundThe prevalence of Schistosoma mansoni infection is usually assessed by the Kato-Katz diagnostic technique. However, Kato-Katz thick smears have low sensitivity, especially for light infections. Egg count models fitted on individual level data can adjust for the infection intensity-dependent sensitivity and estimate the 'true' prevalence in a population. However, application of these models is complex and there is a need for adjustments that can be done without modeling expertise. This study provides estimates of the 'true' S. mansoni prevalence from population summary measures of observed prevalence and infection intensity using extensive simulations parametrized with data from different settings in sub-Saharan Africa.MethodologyAn individual-level egg count model was applied to Kato-Katz data to determine the S. mansoni infection intensity-dependent sensitivity for various sampling schemes. Observations in populations with varying forces of transmission were simulated, using standard assumptions about the distribution of worms and their mating behavior. Summary measures such as the geometric mean infection, arithmetic mean infection, and the observed prevalence of the simulations were calculated, and parametric statistical models fitted to the summary measures for each sampling scheme. For validation, the simulation-based estimates are compared with an observational dataset not used to inform the simulation.Principal findingsOverall, the sensitivity of Kato-Katz in a population varies according to the mean infection intensity. Using a parametric model, which takes into account different sampling schemes varying from single Kato-Katz to triplicate slides over three days, both geometric and arithmetic mean infection intensities improve estimation of sensitivity. The relation between observed and 'true' prevalence is remarkably linear and triplicate slides per day on three consecutive days ensure close to perfect sensitivity.Conclusions/significanceEstimation of 'true' S. mansoni prevalence is improved when taking into account geometric or arithmetic mean infection intensity in a population. We supply parametric functions and corresponding estimates of their parameters to calculate the 'true' prevalence for sampling schemes up to 3 days with triplicate Kato-Katz thick smears per day that allow estimation of the 'true' prevalence.

BackgroundOral ivermectin is a safe broad spectrum anthelminthic used for treating several neglected tropical diseases (NTDs). Currently, ivermectin use is contraindicated in children weighing less than 15 kg, restricting access to this drug for the treatment of NTDs. Here we provide an updated systematic review of the literature and we conducted an individual-level patient data (IPD) meta-analysis describing the safety of ivermectin in children weighing less than 15 kg.Methodology/principal findingsA systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for IPD guidelines by searching MEDLINE via PubMed, Web of Science, Ovid Embase, LILACS, Cochrane Database of Systematic Reviews, TOXLINE for all clinical trials, case series, case reports, and database entries for reports on the use of ivermectin in children weighing less than 15 kg that were published between 1 January 1980 to 25 October 2019. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017056515. A total of 3,730 publications were identified, 97 were selected for potential inclusion, but only 17 sources describing 15 studies met the minimum criteria which consisted of known weights of children less than 15 kg linked to possible adverse events, and provided comprehensive IPD. A total of 1,088 children weighing less than 15 kg were administered oral ivermectin for one of the following indications: scabies, mass drug administration for scabies control, crusted scabies, cutaneous larva migrans, myiasis, pthiriasis, strongyloidiasis, trichuriasis, and parasitic disease of unknown origin. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported.Conclusions/significanceExisting limited data suggest that oral ivermectin in children weighing less than 15 kilograms is safe. Data from well-designed clinical trials are needed to provide further assurance.

BackgroundPreventive chemotherapy using praziquantel is the mainstay for schistosomiasis control. However, there is little evidence on what is supposed to be the most effective school-based treatment strategy to sustain morbidity control. The aim of this study was to compare differences in Schistosoma mansoni prevalence and infection intensity between three different schedules of school-based preventive chemotherapy in an area with moderate prevalence of S. mansoni in Côte d'Ivoire.MethodologySeventy-five schools were randomly assigned to one of three intervention arms: (i) annual school-based preventive chemotherapy with praziquantel (40 mg/kg) over four years; (ii) praziquantel treatment only in the first two years, followed by two years whithout treatment; and (iii) praziquantel treatment in years 1 and 3 without treatment in-between. Cross-sectional parasitologic surveys were carried out prior to each round of preventive chemotherapy. The difference in S. mansoni prevalence and infection intensity was assessed by multiple Kato-Katz thick smears, among children aged 9-12 years at the time of each survey. First-grade children, aged 5-8 years who had never received praziquantel, were also tested at baseline and at the end of the study.Principal findingsOverall, 7,410 children aged 9-12 years were examined at baseline and 7,223 at the final survey. The baseline prevalence of S. mansoni was 17.4%, 20.2%, and 25.2% in arms 1, 2, and 3, respectively. In the final year, we observed the lowest prevalence of 10.4% in arm 1, compared to 18.2% in arm 2 and 17.5% in arm 3. The comparison between arms 1 and 2 estimated an odds ratio (OR) of 0.52 but the difference was not statistically significant (95% confidence interval (CI) = 0.23-1.16). Likewise the difference between arms 1 and 3 lacked statistical significance (OR = 0.55, 95% CI = 0.23-1.29). There was no noteworthy difference observed between arms 2 and 3 (OR = 1.06, 95% CI = 0.64-1.75). The lowest S. mansoni fecal egg counts in the final year survey were observed in arm 1 (7.9 eggs per gram of stool (EPG)). However, compared with 11.5 EPG in arm 2 and 15.4 EPG in arm 3, the difference lacked statistical significance. There were 4,812 first-grade children examined at baseline and 4,513 in the final survey. The overall prevalence of S. mansoni in these children slightly decreased in arms 1 (from 4.5% to 3.6%) and 2 (from 4.7% to 4.3%), but increased in arm 3 (from 6.8% to 7.9%). However, there was no significant difference in prevalence and infection intensity observed between study arms.Conclusions/significanceThe three treatment schedules investigated led to a reduction in the prevalence and intensity of S. mansoni infection among children aged 9-12 years. Comparing intervention arms at the end of the study, no statistically significant differences were observed between annual treatement and the other two treatment schedules, neither in reduction of prevalence nor intensity of infection. It is important to combine our results with those of three sister trials conducted simultaneously in other African countries, before final recommendations can be drawn.

BackgroundBetter knowledge of the efficacy and safety of single-dose 40 mg/kg oral praziquantel in preschool-age children is required, should preventive chemotherapy programs for schistosomiasis be expanded to include this age group.MethodologyWe analyzed individual participant-level data from 16 studies (13 single-arm or cohort studies and three randomized trials), amounting to 683 preschool-age children (aged Principal findingsPreschool-age children had significantly lower baseline Schistosoma egg counts and more losses to follow-up compared to school-age children. No difference in efficacy was found between preschool- and school-age children using a general linear model of individual-participant ERR with baseline log-transformed egg count as covariate and study, age, and sex as fixed variables, and a mixed model with a random effect on the study. Safety was reported in only four studies (n = 1,128 individuals); few AEs were reported in preschool-age children 4 and 24 hours post-treatment as well as at follow-up. Three severe but not serious AEs were recorded in school-age children during follow-up.Conclusions/significanceThere is no indication that single-dose 40 mg/kg oral praziquantel would be less efficacious and less safe in preschool-age children compared to school-age children, with the caveat that only few randomized comparisons exist between the two age groups. Preventive chemotherapy might therefore be extended to preschool-age children, with proper monitoring of its efficacy and safety.

BACKGROUND:Preventive chemotherapy with praziquantel (PZQ) is the cornerstone of schistosomiasis control. However, a single dose of PZQ (40 mg/kg) does not cure all infections. Repeated doses of PZQ at short intervals might increase efficacy in terms of cure rate (CR) and intensity reduction rate (IRR). Here, we determined the efficacy of a single versus four repeated treatments with PZQ on Schistosoma mansoni infection in school-aged children from Côte d'Ivoire, using two different diagnostic tests. METHODS:An open-label, randomized controlled trial was conducted from October 2018 to January 2019. School-aged children with a confirmed S. mansoni infection based on Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA) urine cassette test were randomly assigned to receive either a single or four repeated doses of PZQ, administered at two-week intervals. The primary outcome was the difference in CR between the two treatment arms, measured by triplicate KK thick smears 10 weeks after the first treatment. Secondary outcomes included CR estimated by POC-CCA, IRR by KK and POC-CCA, and safety of repeated PZQ administration. PRINCIPAL FINDINGS:During baseline screening, 1,022 children were assessed for eligibility of whom 153 (15%) had a detectable S. mansoni infection, and hence, were randomized to the standard treatment group (N = 70) and the intense treatment group (N = 83). Based on KK, the CR was 42% (95% confidence interval (CI) 31-52%) in the standard treatment group and 86% (95% CI 75-92%) in the intense treatment group. Observed IRR was 72% (95% CI 55-83%) in the standard treatment group and 95% (95% CI 85-98%) in the intense treatment group. The CR estimated by POC-CCA was 18% (95% CI 11-27%) and 36% (95% CI 26-46%) in the standard and intense treatment group, respectively. Repeated PZQ treatment did not result in a higher number of adverse events. CONCLUSION/SIGNIFICANCE:The observed CR using KK was significantly higher after four repeated treatments compared to a single treatment, without an increase in adverse events. Using POC-CCA, the observed CR was significantly lower than measured by KK, indicating that PZQ may be considerably less efficacious as concluded by KK. Our findings highlight the need for reliable and more accurate diagnostic tools, which are essential for monitoring treatment efficacy, identifying changes in transmission, and accurately quantifying the intensity of infection in distinct populations. In addition, the higher CR in the intense treatment group suggests that more focused and intense PZQ treatment can help to advance schistosomiasis control. TRIAL REGISTRATION:www.clinicaltrials.gov NCT02868385.

Summary: Background: Mass deworming against soil-transmitted helminthiasis, which affects 1 billion of the poorest people globally, is one of the largest public health programmes for neglected tropical diseases, and is intended to be equitable. However, the extent to which treatment programmes for deworming achieve equitable coverage across wealth class and sex is unclear and the public health metric of national deworming coverage does not include representation of equity. This study aims to measure both coverage and equity in global, national, and subnational deworming to guide future programmatic evaluation, investment, and metric design. Methods: We used nationally representative, geospatial, household data from Demographic and Health Surveys that measured mother-reported deworming in children of preschool age (12–59 months). Deworming was defined as children having received drugs for intestinal parasites in the previous 6 months before the survey. We estimated deworming coverage disaggregated by geography, wealth quintile, and sex, and computed an equity index. We examined trends in coverage and equity index across countries, within countries, and over time. We used a regression model to compute the household correlates of deworming and ecological correlates of equitable deworming. Findings: Our study included 820 883 children living in 50 countries from Africa, the Americas, Asia, and Europe that are endemic for soil-transmitted helminthiasis using 77 Demographic and Health Surveys from December, 2003, to October, 2017. In these countries, the mean deworming coverage in preschool children was estimated at 33·0% (95% CI 32·9–33·1). The subnational coverage ranged from 0·5% to 87·5%, and within-country variation was greater than between-country variation. Of the 31 countries reporting that they reached the WHO goal of more than 75% national coverage, 30 had inequity in deworming, with treatment concentrated in wealthier populations. We did not detect systematic differences in deworming equity by sex. Interpretation: Substantial inequities in mass deworming programmes are common as wealthier populations have consistently higher coverage than that of the poor, including in countries reporting to have reached the WHO goal of more than 75% national coverage. These inequities seem to be geographically heterogeneous, modestly improving over time, with no evidence of sex differences in inequity. Future reporting of deworming coverage should consider disaggregation by geography, wealth, and sex with incorporation of an equity index to complement the conventional public health metric of national deworming coverage. Funding: Bill & Melinda Gates Foundation, Stanford University Medical Scientist Training Program.

BackgroundIntervention guidelines against Schistosoma mansoni are based on the Kato-Katz technique. However, Kato-Katz thick smears show low sensitivity, especially for light-intensity infections. The point-of-care circulating cathodic antigen (POC-CCA) is a promising rapid diagnostic test detecting antigen output of living worms in urine and results are reported as trace, 1+, 2+, and 3+. The use of POC-CCA for schistosomiasis mapping, control, and surveillance requires translation of the Kato-Katz prevalence thresholds into POC-CCA relative treatment cut-offs. Furthermore, the infection status of egg-negative but antigen-positive individuals and the intensity-dependent sensitivity of POC-CCA should be estimated to determine its suitability for verification of disease elimination efforts.MethodologyWe used data from settings in Africa and the Americas characterized by a wide range of S. mansoni endemicity. We estimated infection intensity-dependent sensitivity and specificity of each test at the unit of the individual, using a hierarchical Bayesian egg-count model that removes the need to define a 'gold' standard applied to data with multiple Kato-Katz thick smears and POC-CCA urine cassette tests. A simulation study was carried out based on the model estimates to assess the relation of the two diagnostic tests for different endemicity scenarios.Principal findingsPOC-CCA showed high specificity (> 95%), and high sensitivity (> 95%) for moderate and heavy infection intensities, and moderate sensitivity (> 75%) for light infection intensities, and even for egg-negative but antigen-positive infections. A 10% duplicate slide Kato-Katz thick smear prevalence corresponded to a 15-40% prevalence of ≥ trace-positive POC-CCA, and 10-20% prevalence of ≥ 1+ POC-CCA. The prevalence of ≥ 2+ POC-CCA corresponded directly to single slide Kato-Katz prevalence for all prevalence levels.Conclusions/significanceThe moderate sensitivity of POC-CCA, even for very light S. mansoni infections where the sensitivity of Kato-Katz is very low, and the identified relationship between Kato-Katz and POC-CCA prevalence thresholds render the latter diagnostic tool useful for surveillance and initial estimation of elimination of S. mansoni. For prevalence below 10% based on a duplicate slide Kato-Katz thick smear, we suggest using POC-CCA including trace results to evaluate treatment needs and propose new intervention thresholds that need to be validated in different settings.

The Kato-Katz technique is the most widely used diagnostic method in epidemiologic surveys and drug efficacy trials pertaining to intestinal schistosomiasis and soil-transmitted helminthiasis. However, the sensitivity of the technique is low, particularly for the detection of light-intensity helminth infections. Examination of multiple stool samples reduces the diagnostic error; yet, most studies rely on a single Kato-Katz thick smear, thus underestimating infection prevalence. We present a model which estimates the sensitivity of the Kato-Katz technique in Schistosoma mansoni and hookworm, as a function of infection intensity for repeated stool sampling and provide estimates of the age-dependent 'true' prevalence. We find that the sensitivity for S. mansoni diagnosis is dominated by missed light infections, which have a low probability to be diagnosed correctly even through repeated sampling. The overall sensitivity strongly depends on the mean infection intensity. In particular at an intensity of 100 eggs per gram of stool (EPG), we estimate a sensitivity of 50% and 80% for one and two samples, respectively. At an infection intensity of 300 EPG, we estimate a sensitivity of 62% for one sample and 90% for two samples. The sensitivity for hookworm diagnosis is dominated by day-to-day variation with typical values for one, two, three, and four samples equal to 50%, 75%, 85%, and 95%, respectively, while it is only weakly dependent on the mean infection intensity in the population. We recommend taking at least two samples and estimate the 'true' prevalence of S. mansoni considering the dependence of the sensitivity on the mean infection intensity and the 'true' hookworm prevalence by taking into account the sensitivity given in the current study.

Background: Praziquantel has been the drug of choice for schistosomiasis control for more than 40 years, yet surprisingly, the optimal dose for children younger than 4 years is not known. We aimed to assess the efficacy and safety of escalating praziquantel dosages in preschool-aged children (PSAC). Methods: We did a randomised controlled, parallel-group, single-blind, dose-ranging, phase 2 trial in PSAC (2–5 years) and school-aged children (SAC; aged 6–15 years) as a comparator group in southern Côte d'Ivoire. Children were randomly assigned (1:1:1:1) to 20 mg/kg, 40 mg/kg, or 60 mg/kg praziquantel or placebo. Participants, investigators, and laboratory technicians were masked to group assignment, while the investigator providing treatment was aware of the treatment group. The primary objective was to estimate the nature of the dose–response relation in terms of cure rate using the Kato Katz technique. Dose–response curves were estimated using Emax models. Available case analysis was done including all participants with primary endpoint data. This trial is registered with International Standard Randomised Controlled Trial, number ISRCTN15280205. Findings: Between Nov 11, 2014, and Feb 18, 2015, 660 PSAC and 225 SAC were assessed for eligibility; of whom 161 (24%) PSAC and 180 (80%) SAC had a detectable Schistosoma mansoni infection. 161 PSAC were randomly allocated of whom 154 received treatment: 42 were assigned to 20 mg/kg praziquantel, of whom 40 received treatment; 38 were assigned to 40 mg/kg praziquantel, of whom 38 received treatment; 41 were assigned to 60 mg/kg praziquantel, of whom 39 received treatment; and 40 were assigned to placebo, of whom 37 received placebo. 180 SAC were randomly allocated of whom 177 received treatment: 49 were assigned to 20 mg/kg praziquantel, of whom 47 received treatment; 46 were assigned to 40 mg/kg praziquantel, of whom 46 received treatment; 42 were assigned to 60 mg/kg praziquantel, of whom 42 received treatment; and 43 were assigned to placebo, of whom 43 received treatment. Follow-up (available-case) data were available for 143 PSAC and 174 SAC. In PSAC, the 20 mg/kg dose resulted in cure in 23 children (62%; 95% CI 44·8–77·5), 40 mg/kg in 26 children (72%; 54·8–85·8), 60 mg/kg in 25 children (71%; 53·7–85·4), and placebo in 13 children (37%; 21·5–55·1). In SAC, the 20 mg/kg dose resulted in cure in 14 children (30%; 95% CI 17·7–45·8), 40 mg/kg in 31 children (69%; 53·4–81·8), 60 mg/kg in 34 children (83%; 67·9–92·8), and placebo in five children (12%; 4·0–25·6). For both age groups, the number of adverse events was similar among the three praziquantel treatment groups, with fewer adverse events observed in the placebo groups. The most common adverse events in PSAC were diarrhoea (11 [9%] of 124) and stomach ache (ten [8%]) and in SAC were diarrhoea (50 [28%] of 177), stomach ache (66 [37%]), and vomiting (26 [15%]) 3 h post treatment. No serious adverse events were reported. Interpretation: Praziquantel shows a flat dose-response and overall lower efficacy in PSAC compared with in SAC. In the absence of treatment alternatives, a single dose of praziquantel of 40 mg/kg, recommended by the WHO for S mansoni infections in SAC can be endorsed for PSAC in preventive chemotherapy programmes. Funding: European Research Council.

BACKGROUND:Schistosoma haematobium infections are responsible for significant urinary tract (UT) complications. Schistosomiasis control programs aim to reduce morbidity, yet the extent of morbidity in preschool-aged children and the impact of treatment on morbidity reduction are not well studied. METHODOLOGY:Our study was embedded in a randomized, placebo-controlled, single-blind trial in Côte d'Ivoire, which evaluated the efficacy and safety of three doses (20, 40 and 60 mg/kg) of praziquantel in school-aged (SAC) and preschool-aged (PSAC) children infected with S. haematobium. Enrolled children were invited to participate in an ultrasound examination prior and six months after treatment. At these time points 3 urine samples were collected for parasitological and clinical examinations. PRINCIPAL FINDINGS:162 PSAC and 141 SAC participated in the ultrasound examination at baseline, of which 128 PSAC and 122 SAC were present at follow-up. At baseline 43% (70/162) of PSAC had UT morbidity, mostly at bladder level and 7% had hydronephrosis. 67% (94/141) of SAC revealed mainly moderate UT pathology, 4% presented pseudopolyps on the bladder wall, and 6% had pyelectasis. At follow up, 45% of PSAC and 58% of SAC were S. haematobium positive, mostly harboring light infection intensities (41% and 51%, respectively). Microhematuria was present in 33% of PSAC and 42% of SAC and leukocyturia in 53% and 40% of PSAC and SAC, respectively. 50% (64/128) of PSAC and 58% (71/122) of SAC presented urinary tract morbidity, which was mainly mild. A significant correlation (p

BACKGROUND:Schistosomiasis affects millions of people, yet treatment options are limited. The antimalarial Synriam (piperaquine 150 mg/arterolane 750 mg) and the anthelminthic moxidectin revealed promising antischistosomal properties in preclinical or clinical studies. METHODOLOGY:We conducted two single-blind, randomized exploratory Phase 2 trials in Schistosoma mansoni and S. haematobium-infected adolescents in northern and central Côte d'Ivoire. Our primary endpoints were cure rates (CRs) and egg reduction rates (ERRs) based on geometric mean and safety. Each subject was asked to provide two stool samples (S. mansoni trial) for Kato-Katz analysis or three urine samples (S. haematobium trial) for urine filtration and one finger prick for malaria screening at baseline and follow-up. Participants were randomly assigned to either moxidectin, Synriam, Synriam plus praziquantel or praziquantel. PRINCIPAL FINDINGS:128 adolescents (age: 12-17 years) were included in each study. Against S. haematobium moxidectin and Synriam revealed low efficacy. On the other hand, Synriam plus praziquantel and praziquantel yielded CRs of 60.0% and 38.5% and ERRs of 96.0% and 93.5%, respectively. CRs observed in the treatment of S. mansoni were 13.0%, 6.7%, 27.0%, and 27.6% for moxidectin, Synriam, Synriam plus praziquantel and praziquantel, respectively. ERRs ranged from 64.9% (Synriam) to 87.5% (praziquantel). CONCLUSION/SIGNIFICANCE:Synriam and moxidectin show low efficacy against S. haematobium, hence an ancillary benefit is not expected when these drugs are used for treating onchocerciasis and malaria in co-endemic settings. Further studies are needed to corroborate our findings that moxidectin and Synriam show moderate ERRs against S. mansoni.

A key epidemiologic feature of schistosomiasis is its focal distribution, which has important implications for the spatial targeting of preventive chemotherapy programs. We evaluated the diagnostic accuracy of a urine pooling strategy using a point-of-care circulating cathodic antigen (POC-CCA) cassette test for detection of Schistosoma mansoni, and employed simulation modeling to test the classification accuracy and efficiency of this strategy in determining where preventive chemotherapy is needed in low-endemicity settings.We performed a cross-sectional study involving 114 children aged 6-15 years in six neighborhoods in Azaguié Ahoua, south Côte d'Ivoire to characterize the sensitivity and specificity of the POC-CCA cassette test with urine samples that were tested individually and in pools of 4, 8, and 12. We used a Bayesian latent class model to estimate test characteristics for individual POC-CCA and quadruplicate Kato-Katz thick smears on stool samples. We then developed a microsimulation model and used lot quality assurance sampling to test the performance, number of tests, and total cost per school for each pooled testing strategy to predict the binary need for school-based preventive chemotherapy using a 10% prevalence threshold for treatment.The sensitivity of the urine pooling strategy for S. mansoni diagnosis using pool sizes of 4, 8, and 12 was 85.9%, 79.5%, and 65.4%, respectively, when POC-CCA trace results were considered positive, and 61.5%, 47.4%, and 30.8% when POC-CCA trace results were considered negative. The modeled specificity ranged from 94.0-97.7% for the urine pooling strategies (when POC-CCA trace results were considered negative). The urine pooling strategy, regardless of the pool size, gave comparable and often superior classification performance to stool microscopy for the same number of tests. The urine pooling strategy with a pool size of 4 reduced the number of tests and total cost compared to classical stool microscopy.This study introduces a method for rapid and efficient S. mansoni prevalence estimation through examining pooled urine samples with POC-CCA as an alternative to widely used stool microscopy.

BACKGROUND:Handheld light microscopy using compact optics and mobile phones may improve the quality of health care in resource-constrained settings by enabling access to prompt and accurate diagnosis. METHODOLOGY:Laboratory technicians were trained to operate two handheld diagnostic devices (Newton Nm1 microscope and a clip-on version of the mobile phone-based CellScope). The accuracy of these devices was compared to conventional light microscopy for the diagnosis of Schistosoma haematobium, S. mansoni, and intestinal protozoa infection in a community-based survey in rural Côte d'Ivoire. One slide of 10 ml filtered urine and a single Kato-Katz thick smear from 226 individuals were subjected to the Newton Nm1 microscope and CellScope for detection of Schistosoma eggs and compared to conventional microscopy. Additionally, 121 sodium acetate-acetic acid-formalin (SAF)-fixed stool samples were examined by the Newton Nm1 microscope and compared to conventional microscopy for the diagnosis of intestinal protozoa. PRINCIPAL FINDINGS:The prevalence of S. haematobium, S. mansoni, Giardia intestinalis, and Entamoeba histolytica/E. dispar, as determined by conventional microscopy, was 39.8%, 5.3%, 20.7%, and 4.9%, respectively. The Newton Nm1 microscope had diagnostic sensitivities for S. mansoni and S. haematobium infection of 91.7% (95% confidence interval (CI) 59.8-99.6%) and 81.1% (95% CI 71.2-88.3%), respectively, and specificities of 99.5% (95% CI 97.0-100%) and 97.1% (95% CI 92.2-99.1%), respectively. The CellScope demonstrated sensitivities for S. mansoni and S. haematobium of 50.0% (95% CI 25.4-74.6%) and 35.6% (95% CI 25.9-46.4%), respectively, and specificities of 99.5% (95% CI 97.0-100%) and 100% (95% CI 86.7-100%), respectively. For G. intestinalis and E. histolytica/E. dispar, the Newton Nm1 microscope had sensitivity of 84.0% (95% CI 63.1-94.7%) and 83.3% (95% CI 36.5-99.1%), respectively, and 100% specificity. CONCLUSIONS/SIGNIFICANCE:Handheld diagnostic devices can be employed in community-based surveys in resource-constrained settings after minimal training of laboratory technicians to diagnose intestinal parasites.

BACKGROUND:The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) has launched several large-scale trials to determine the best strategies for gaining and sustaining control of schistosomiasis and transitioning toward elimination. In Côte d'Ivoire, a 5-year cluster-randomized trial is being implemented in 75 schools to sustain the control of schistosomiasis mansoni. We report Schistosoma mansoni infection levels in children one year after the initial school-based treatment (SBT) with praziquantel and compare with baseline results to determine the effect of the intervention. METHODOLOGY:The baseline cross-sectional survey was conducted in late 2011/early 2012 and the first follow-up in May 2013. Three consecutive stool samples were collected from 9- to 12-year-old children in 75 schools at baseline and 50 schools at follow-up. Stool samples were subjected to duplicate Kato-Katz thick smears. Directly observed treatment (DOT) coverage of the SBT was assessed and the prevalence and intensity of S. mansoni infection compared between baseline and follow-up. PRINCIPAL FINDINGS:The S. mansoni prevalence in the 75 schools surveyed at baseline was 22.1% (95% confidence interval (CI): 19.5-24.4%). The DOT coverage was 84.2%. In the 50 schools surveyed at baseline and one year after treatment, the overall prevalence of S. mansoni infection decreased significantly from 19.7% (95% CI: 18.5-20.8%) to 12.8% (95% CI: 11.9-13.8%), while the arithmetic mean S. mansoni eggs per gram of stool (EPG) among infected children slightly increased from 92.2 EPG (95% CI: 79.2-105.3 EPG) to 109.3 EPG (95% CI: 82.7-135.9 EPG). In two of the 50 schools, the prevalence increased significantly, despite a DOT coverage of >75%. CONCLUSIONS/SIGNIFICANCE:One year after the initial SBT, the S. mansoni prevalence had decreased. Despite this positive trend, an increase was observed in some schools. Moreover, the infection intensity among S. mansoni-infected children was slightly higher at the 1-year follow-up compared to the baseline situation. Our results emphasize the heterogeneity of transmission dynamics and provide a benchmark for the future yearly follow-up surveys of this multi-year SCORE intervention study.

Background: More than 1·5 billion people are affected by schistosomiasis or soil-transmitted helminthiasis. WHO's recommendations for mass drug administration (MDA) against these parasitic infections emphasise treatment of school-aged children, using separate treatment guidelines for these two helminthiases groups. We aimed to evaluate the cost-effectiveness of expanding integrated MDA to the entire community in four settings in Côte d'Ivoire. Methods: We extended previously published, dynamic, age-structured models of helminthiases transmission to simulate costs and disability averted with integrated MDA (of praziquantel and albendazole) for schistosomiasis and soil-transmitted helminthiasis. We calibrated the model to data for prevalence and intensity of species-specific helminth infection from surveys undertaken in four communities in Côte d'Ivoire between March, 1997, and September, 2010. We simulated a 15-year treatment programme with 75% coverage in only school-aged children; school-aged children and preschool-aged children; adults; and the entire community. Treatment costs were estimated at US$0·74 for school-aged children and $1·74 for preschool-aged children and adults. The incremental cost-effectiveness ratio (ICER) was calculated in 2014 US dollars per disability-adjusted life-year (DALY) averted. Findings: Expanded community-wide treatment was highly cost effective compared with treatment of only school-aged children (ICER $167 per DALY averted) and WHO guidelines (ICER $127 per DALY averted), and remained highly cost effective even if treatment costs for preschool-aged children and adults were ten times greater than those for school-aged children. Community-wide treatment remained highly cost effective even when elimination of helminth infections was not achieved. These findings were robust across the four diverse communities in Côte d'Ivoire, only one of which would have received annual MDA for both schistosomiasis and soil-transmitted helminthiasis under the latest WHO guidelines. Treatment every 6 months was also highly cost effective in three out of four communities. Interpretation: Integrated, community-wide MDA programmes for schistosomiasis and soil-transmitted helminthiasis can be highly cost effective, even in communities with low disease burden in any helminth group. These results support an urgent need to re-evaluate current global guidelines for helminthiases control programmes to include community-wide treatment, increased treatment frequency, and consideration for lowered prevalence thresholds for integrated treatment. Funding: Stanford University Medical Scholars Programme, Mount Sinai Hospital-University Health Network AMO Innovation Fund.

BACKGROUND:The control of schistosomiasis emphasizes preventive chemotherapy with praziquantel, which aims at decreasing infection intensity and thus morbidity in individuals, as well as transmission in communities. Standardizing methods to assess treatment efficacy is important to compare trial outcomes across settings, and to monitor program effectiveness consistently. We compared customary methods and looked at possible complementary approaches in order to derive suggestions for standardizing outcome measures. METHODOLOGY/PRINCIPAL FINDINGS:We analyzed data from 24 studies conducted at African, Asian, and Latin American sites, enrolling overall 4,740 individuals infected with Schistosoma mansoni, S. haematobium, or S. japonicum, and treated with praziquantel at doses of 40-80 mg/kg. We found that group-based arithmetic and geometric means can be used interchangeably to express egg reduction rates (ERR) only if treatment efficacy is high (>95%). For lower levels of efficacy, ERR estimates are higher with geometric than arithmetic means. Using the distribution of individual responses in egg excretion, 6.3%, 1.7% and 4.3% of the subjects treated for S. haematobium, S. japonicum and S. mansoni infection, respectively, had no reduction in their egg counts (ERR = 0). The 5th, 10th, and 25th centiles of the subjects treated for S. haematobium had individual ERRs of 0%, 49.3%, and 96.5%; the corresponding values for S. japonicum were 75%, 99%, and 99%; and for S. mansoni 18.2%, 65.3%, and 99.8%. Using a single rather than quadruplicate Kato-Katz thick smear excluded 19% of S. mansoni-infected individuals. Whilst the effect on estimating ERR was negligible by individual studies, ERR estimates by arithmetic means were 8% lower with a single measurement. CONCLUSIONS/SIGNIFICANCE:Arithmetic mean calculations of Schistosoma ERR are more sensitive and therefore more appropriate to monitor drug performance than geometric means. However, neither are satisfactory to identify poor responders. Group-based response estimated by arithmetic mean and the distribution of individual ERRs are correlated, but the latter appears to be more apt to detect the presence and to quantitate the magnitude of suboptimal responses to praziquantel.

BACKGROUND: The Kato-Katz technique is widely used for the diagnosis of Schistosoma mansoni, but shows low sensitivity in light-intensity infections. We assessed the accuracy of a commercially available point-of-care circulating cathodic antigen (POC-CCA) cassette test for the diagnosis of S. mansoni in preschool-aged children before and after praziquantel administration. METHODOLOGY: A 3-week longitudinal survey with a treatment intervention was conducted in Azaguié, south Côte d'Ivoire. Overall, 242 preschoolers (age range: 2 months to 5.5 years) submitted two stool and two urine samples before praziquantel administration, and 86 individuals were followed-up posttreatment. Stool samples were examined with duplicate Kato-Katz thick smears for S. mansoni. Urine samples were subjected to POC-CCA cassette test for S. mansoni, and a filtration method for S. haematobium diagnosis. PRINCIPAL FINDINGS: Before treatment, the prevalence of S. mansoni, as determined by quadruplicate Kato-Katz, single CCA considering 'trace' as negative (t-), and single CCA with 'trace' as positive (t+), was 23.1%, 34.3% and 64.5%, respectively. Using the combined results (i.e., four Kato-Katz and duplicate CCA(t-)) as diagnostic 'gold' standard, the sensitivity of a single Kato-Katz, a single CCA(t-) or CCA(t+) was 28.3%, 69.7% and 89.1%, respectively. Three weeks posttreatment, the sensitivity of a single Kato-Katz, single CCA(t-) and CCA(t+) was 4.0%, 80.0% and 84.0%, respectively. The intensity of the POC-CCA test band reaction was correlated with S. mansoni egg burden (odds ratio = 1.2, p = 0.04). CONCLUSIONS/SIGNIFICANCE: A single POC-CCA cassette test appears to be more sensitive than multiple Kato-Katz thick smears for the diagnosis of S. mansoni in preschool-aged children before and after praziquantel administration. The POC-CCA cassette test can be recommended for the rapid identification of S. mansoni infections before treatment. Additional studies are warranted to determine the usefulness of POC-CCA for assessing drug efficacy and monitoring the impact of control interventions.

BACKGROUND: An accurate diagnosis of helminth infection is important to improve patient management. However, there is considerable intra- and inter-specimen variation of helminth egg counts in human feces. Homogenization of stool samples has been suggested to improve diagnostic accuracy, but there are no detailed investigations. Rapid disintegration of hookworm eggs constitutes another problem in epidemiological surveys. We studied the spatial distribution of Schistosoma mansoni and hookworm eggs in stool samples, the effect of homogenization, and determined egg counts over time in stool samples stored under different conditions. METHODOLOGY: Whole-stool samples were collected from 222 individuals in a rural part of south Côte d'Ivoire. Samples were cut into four pieces and helminth egg locations from the front to the back and from the center to the surface were analyzed. Some samples were homogenized and fecal egg counts (FECs) compared before and after homogenization. The effect of stool storing methods on FECs was investigated over time, comparing stool storage on ice, covering stool samples with a water-soaked tissue, or keeping stool samples in the shade. PRINCIPAL FINDINGS: We found no clear spatial pattern of S. mansoni and hookworm eggs in fecal samples. Homogenization decreased S. mansoni FECs (p = 0.026), while no effect was observed for hookworm and other soil-transmitted helminths. Hookworm FECs decreased over time. Storing stool samples on ice or covered with a moist tissue slowed down hookworm egg decay (p

In sub-Saharan Africa the recommended strategy to control schistosomiasis is preventive chemotherapy. Emphasis is placed on school-aged children, but in high endemicity areas, preschool-aged children are also at risk, and hence might need treatment with praziquantel. Since a pediatric formulation (e.g., syrup) is not available outside of Egypt, crushed praziquantel tablets are used, but the efficacy and safety of this treatment regimen is insufficiently studied.We assessed the efficacy and safety of crushed praziquantel tablets among preschool-aged children (

BACKGROUND: Promising results have been reported for a urine circulating cathodic antigen (CCA) test for the diagnosis of Schistosoma mansoni. We assessed the accuracy of a commercially available CCA cassette test (designated CCA-A) and an experimental formulation (CCA-B) for S. mansoni diagnosis. METHODOLOGY: We conducted a cross-sectional survey in three settings of Côte d'Ivoire: settings A and B are endemic for S. mansoni, whereas S. haematobium co-exists in setting C. Overall, 446 children, aged 8-12 years, submitted multiple stool and urine samples. For S. mansoni diagnosis, stool samples were examined with triplicate Kato-Katz, whereas urine samples were tested with CCA-A. The first stool and urine samples were additionally subjected to an ether-concentration technique and CCA-B, respectively. Urine samples were examined for S. haematobium using a filtration method, and for microhematuria using Hemastix dipsticks. PRINCIPAL FINDINGS: Considering nine Kato-Katz as diagnostic 'gold' standard, the prevalence of S. mansoni in setting A, B and C was 32.9%, 53.1% and 91.8%, respectively. The sensitivity of triplicate Kato-Katz from the first stool and a single CCA-A test was 47.9% and 56.3% (setting A), 73.9% and 69.6% (setting B), and 94.2% and 89.6% (setting C). The respective sensitivity of a single CCA-B was 10.4%, 29.9% and 75.0%. The ether-concentration technique showed a low sensitivity for S. mansoni diagnosis (8.3-41.0%). The specificity of CCA-A was moderate (76.9-84.2%); CCA-B was high (96.7-100%). The likelihood of a CCA-A color reaction increased with higher S. mansoni fecal egg counts (odds ratio: 1.07, p

BackgroundSchistosomiasis and soil-transmitted helminthiasis are important public health problems in sub-Saharan Africa causing malnutrition, anemia, and retardation of physical and cognitive development. However, the effect of these diseases on physical fitness remains to be determined.MethodologyWe investigated the relationship between schistosomiasis, soil-transmitted helminthiasis and physical performance of children, controlling for potential confounding of Plasmodium spp. infections and environmental parameters (i.e., ambient air temperature and humidity). A cross-sectional survey was carried out among 156 school children aged 7-15 years from Côte d'Ivoire. Each child had two stool and two urine samples examined for helminth eggs by microscopy. Additionally, children underwent a clinical examination, were tested for Plasmodium spp. infection with a rapid diagnostic test, and performed a maximal multistage 20 m shuttle run test to assess their maximal oxygen uptake (VO(2) max) as a proxy for physical fitness.Principal findingsThe prevalence of Schistosoma haematobium, Plasmodium spp., Schistosoma mansoni, hookworm and Ascaris lumbricoides infections was 85.3%, 71.2%, 53.8%, 13.5% and 1.3%, respectively. Children with single, dual, triple, quadruple and quintuple species infections showed VO(2) max of 52.7, 53.1, 52.2, 52.6 and 55.6 ml kg(-1) min(-1), respectively. The VO(2) max of children with no parasite infections was 53.5 ml kg(-1) min(-1). No statistically significant difference was detected between any groups. Multivariable analysis revealed that VO(2) max was influenced by sex (reference: female, coef. = 4.02, pConclusion/significanceSchool-aged children in Côte d'Ivoire showed good physical fitness, irrespective of their helminth infection status. Future studies on children's physical fitness in settings where helminthiasis and malaria co-exist should include pre- and post-intervention evaluations and the measurement of hemoglobin and hematocrit levels and nutritional parameters as potential co-factors to determine whether interventions further improve upon fitness.