The association of systemic inflammation and cognitive functions of pre-school aged children residing in a Schistosoma haematobium endemic area in Zimbabwe.

Background: Cognitive function is negatively impacted by schistosomiasis and might be caused by systemic inflammation which has been hypothesized to be one of the mechanisms driving cognitive decline, This study explored the association of systemic inflammatory biomarkers; interleukin (IL)-10, IL-6, IL-17, transforming growth factor (TGF-ß), tumor necrosis factor (TNF-α), C-reactive protein (CRP) and hematological parameters with cognitive performance of preschool-aged children (PSAC) from an Schistosoma haematobium endemic area. Methods: The Griffith III tool was used to measure the cognitive performance of 136 PSAC. Whole blood and sera were collected and used to quantify levels of IL-10, TNF-α, IL-6, TGF-ß, IL-17 A and CRP using the enzyme-linked immunosorbent assay and hematological parameters using the hematology analyzer. Spearman correlation analysis was used to determine the relationship between each inflammatory biomarker and cognitive performance. Multivariate logistic regression analysis was used to determine whether systemic inflammation due to S. haematobium infection affected cognitive performance in PSAC. Results: Higher levels of TNF-α and IL-6, were correlated with lower performance in the Foundations of Learning domain (r = -0.30; p < 0.001 and r = -0.26; p < 0.001), respectively. Low cognitive performance in the Eye-Hand-Coordination Domain was observed in PSAC with high levels of the following inflammatory biomarkers that showed negative correlations to performance; TNF-α (r = -0.26; p < 0.001), IL-6 (r = -0.29; p < 0.001), IL-10 (r = -0.18; p < 0.04), WBC (r = -0.29; p < 0.001), neutrophils (r = -0.21; p = 0.01) and lymphocytes (r = -0.25; p = 0.003) The General Development Domain correlated with TNF-α (r = -0.28; p < 0.001) and IL-6 (r = -0.30; p < 0.001). TGF-ß, L-17A and MXD had no significant correlations to performance in any of the cognitive domains. The overall general development of PSAC was negatively impacted by S. haematobium infections (OR = 7.6; p = 0.008) and (OR = 5.6; p = 0.03) where the PSAC had higher levels of TNF-α and IL-6 respectively. Conclusion: Systemic inflammation and S. haematobium infections are negatively associated with cognitive function. We recommend the inclusion of PSAC into mass drug treatment programs.

Multiplex peptide microarray profiling of antibody reactivity against neglected tropical diseases derived B-cell epitopes for serodiagnosis in Zimbabwe.

INTRODUCTION: Peptides (B-cell epitopes) have broad applications in disease diagnosis and surveillance of pathogen exposure. In this framework, we present a pilot study to design and produce a peptide microarray for the integrated surveillance of neglected tropical diseases. The peptide microarray was evaluated against peptides derived from Ascaris lumbricoides, Necator americanus, Schistosoma haematobium, Schistosoma mansoni, Trichuris trichiura, Bacillus anthracis, Mycobacterium leprae, Wuchereria bancrofti, Rabies lyssavirus, Chlamydia trachomatis and Trypanosoma brucei. METHODS: S. haematobium was diagnosed using the urine filtration technique. S. mansoni, A. lumbricoides, N. americanus and T. trichiura were diagnosed using the Kato Katz and formal ether concentration techniques. Immunogenic peptides were retrieved from the Tackling Infection to Benefit Africa infectious diseases epitope microarray. Further peptides were predicted using ABCpred. IgG and IgM reactivity against the derived peptides were evaluated using peptide microarray multiplex immunoassays. Positive response was defined as fluorescence intensity ≥ 500 fluorescence units. Immunodominant peptides were identified using color-coded heat maps and bar graphs reflecting the obtained fluorescence signal intensities. Receiver Operating Characteristic analysis and Mann-Whitney-U test were performed to determine the diagnostic validity of the peptides. RESULTS: Species-specific responses with at least one peptide derived from each NTD pathogen were observed. The reactive peptides included; for S. haematobium, XP_035588858.1-206-220 and XP_035588858.1-206-220 immunodominant for IgG and IgM respectively, for S. mansoni, P20287.1-58-72 immunodominant for both antibodies and for T. trichiura, CDW52482.1-326-340 immunodominant for IgG and CDW57769.1-2017-2031 and CDW57769.1-1518-1532 immunodominant for IgM. According to ROC analysis most of the peptides selected were inaccurate; with AUC < 0.5. Some peptides had AUC values ranging from 0.5 to 0.5875 for both IgM and IgG suggesting no discrimination. CONCLUSION: Multiplex peptide microarrays are a valuable tool for integrated NTDs surveillance and for screening parasites exposure in endemic areas. Species sero-reactivity observed in the study maybe indicative of exposure to the different NTDs parasites. However, although peptides with the least cross reactivity were selected there is need to validate the sero-reactivity with recombinant antigens and immune-blotting techniques such as western blotting.

Review of 2022 WHO guidelines on the control and elimination of schistosomiasis.

Schistosomiasis is a helminthiasis infecting approximately 250 million people worldwide. In 2001, the World Health Assembly (WHA) 54.19 resolution defined a new global strategy for control of schistosomiasis through preventive chemotherapy programmes. This resolution culminated in the 2006 WHO guidelines that recommended empirical treatment by mass drug administration with praziquantel, predominately to school-aged children in endemic settings at regular intervals. Since then, school-based and community-based preventive chemotherapy programmes have been scaled-up, reducing schistosomiasis-associated morbidity. Over the past 15 years, new scientific evidence-combined with a more ambitious goal of eliminating schistosomiasis and an increase in the global donated supply of praziquantel-has highlighted the need to update public health guidance worldwide. In February, 2022, WHO published new guidelines with six recommendations to update the global public health strategy against schistosomiasis, including expansion of preventive chemotherapy eligibility from the predominant group of school-aged children to all age groups (2 years and older), lowering the prevalence threshold for annual preventive chemotherapy, and increasing the frequency of treatment. This Review, written by the 2018-2022 Schistosomiasis Guidelines Development Group and its international partners, presents a summary of the new WHO guideline recommendations for schistosomiasis along with their historical context, supporting evidence, implications for public health implementation, and future research needs.

Characterisation of tetraspanins from Schistosoma haematobium and evaluation of their potential as novel diagnostic markers.

Schistosoma haematobium is the leading cause of urogenital schistosomiasis and it is recognised as a class 1 carcinogen due to the robust association of infection with bladder cancer. In schistosomes, tetraspanins (TSPs) are abundantly present in different parasite proteomes and could be potential diagnostic candidates due to their accessibility to the host immune system. The large extracellular loops of six TSPs from the secretome (including the soluble excretory/secretory products, tegument and extracellular vesicles) of S. haematobium (Sh-TSP-2, Sh-TSP-4, Sh-TSP-5, Sh-TSP-6, Sh-TSP-18 and Sh-TSP-23) were expressed in a bacterial expression system and polyclonal antibodies were raised to the recombinant proteins to confirm the anatomical sites of expression within the parasite. Sh-TSP-2, and Sh-TSP-18 were identified on the tegument, whereas Sh-TSP-4, Sh-TSP-5, Sh-TSP-6 and Sh-TSP-23 were identified both on the tegument and internal tissues of adult parasites. The mRNAs encoding these TSPs were differentially expressed throughout all schistosome developmental stages tested. The potential diagnostic value of three of these Sh-TSPs was assessed using the urine of individuals (stratified by infection intensity) from an endemic area of Zimbabwe. The three Sh-TSPs were the targets of urine IgG responses in all cohorts, including individuals with very low levels of infection (those positive for circulating anodic antigen but negative for eggs by microscopy). This study provides new antigen candidates to immunologically diagnose S. haematobium infection, and the work presented here provides compelling evidence for the use of a biomarker signature to enhance the diagnostic capability of these tetraspanins.

Assessing early child development and its association with stunting and schistosome infections in rural Zimbabwean children using the Griffiths Scales of Child Development.

There is a paucity of reference early childhood development (ECD) data at community level in rural Africa. Our objective was to conduct a comprehensive assessment of ECD in rural Zimbabwe and determine the impact of stunting and schistosome infections on ECD. Using the Griffiths Scales of Child Development, we conducted a cross sectional assessment of Eye and Hand Coordination (EHC), Personal-Social-Emotional (PSE), Language and Communication (LC), Foundations of Learning (FL) and Gross Motor (GM) domains and the summary General Development (GD) in 166 children aged 6-72 months. The effects of stunting, malnutrition and Schistosoma haematobium infection on ECD was determined. The impact of praziquantel curative treatment of schistosome infection on the developmental scores was determined through a longitudinal follow up at 6 and 12 months. From an initial 166 children, 11 were found to have developmental deficits warranting further investigation. Of the remaining 155, 58.7% recorded a good (≥ average) score for the overall General Development (GD). Proportions of children scoring above the cut-off (≥ average) for each domain were GM (84.5%), PSE (80.6%), EHC (61.9%), FL (43.9%) and LC (44.5%). The prevalence of stunting was 26.8% (95% CI = 20.1%-34.8%) Scores for stunted children were significantly lower for EHC (p = 0.0042), GM (p = 0.0099), and GD (p = 0.0014) with the fraction of lower scores attributable to stunting being GM = 63.4%, GD = 46.6%, EHC = 45%, and LC = 21%. S. haematobium infection prevalence was 39.7% and mean infection intensity was 5.4 eggs/10 ml urine. Infected children had poorer cognitive performance scores for the FL (p = 0.0005) with 30.8% of poor FL attributable to the infection. Performance in all domains improved to the expected normal or above reference levels at 6 and 12 months post curative treatment of schistosome infections. Our study documented reference values for ECD in rural Zimbabwean children. The study detected deficiencies in the FL domain, which were more pronounced in children, infected with schistosomes, highlighting the need for provision of cognitive stimulation tools and access to early childhood foundation education. There is also need for improved child nutrition and treatment of schistosome infections to improve child development outcomes.

Immunomics-Guided Antigen Discovery for Praziquantel-Induced Vaccination in Urogenital Human Schistosomiasis.

Despite the enormous morbidity attributed to schistosomiasis, there is still no vaccine to combat the disease for the hundreds of millions of infected people. The anthelmintic drug, praziquantel, is the mainstay treatment option, although its molecular mechanism of action remains poorly defined. Praziquantel treatment damages the outermost surface of the parasite, the tegument, liberating surface antigens from dying worms that invoke a robust immune response which in some subjects results in immunologic resistance to reinfection. Herein we term this phenomenon Drug-Induced Vaccination (DIV). To identify the antigenic targets of DIV antibodies in urogenital schistosomiasis, we constructed a recombinant proteome array consisting of approximately 1,000 proteins informed by various secretome datasets including validated proteomes and bioinformatic predictions. Arrays were screened with sera from human subjects treated with praziquantel and shown 18 months later to be either reinfected (chronically infected subjects, CI) or resistant to reinfection (DIV). IgG responses to numerous antigens were significantly elevated in DIV compared to CI subjects, and indeed IgG responses to some antigens were completely undetectable in CI subjects but robustly recognized by DIV subjects. One antigen in particular, a cystatin cysteine protease inhibitor stood out as a unique target of DIV IgG, so recombinant cystatin was produced, and its vaccine efficacy assessed in a heterologous Schistosoma mansoni mouse challenge model. While there was no significant impact of vaccination with adjuvanted cystatin on adult worm numbers, highly significant reductions in liver egg burdens (45-55%, P<0.0001) and intestinal egg burdens (50-54%, P<0.0003) were achieved in mice vaccinated with cystatin in two independent trials. This study has revealed numerous antigens that are targets of DIV antibodies in urogenital schistosomiasis and offer promise as subunit vaccine targets for a drug-linked vaccination approach to controlling schistosomiasis.

Determining the burden of fungal infections in Zimbabwe.

Zimbabwe currently faces several healthcare challenges, most notably HIV and associated infections including tuberculosis (TB), malaria and recently outbreaks of cholera, typhoid fever and COVID-19. Fungal infections, which are also a major public health threat, receive considerably less attention. Consequently, there is dearth of data regarding the burden of fungal diseases in the country. We estimated the burden of fungal diseases in Zimbabwe based on published literature and 'at-risk' populations (HIV/AIDS patients, survivors of pulmonary TB, cancer, chronic obstructive pulmonary disease, asthma and patients receiving critical care) using previously described methods. Where there was no data for Zimbabwe, regional, or international data was used. Our study revealed that approximately 14.9% of Zimbabweans suffer from fungal infections annually, with 80% having tinea capitis. The annual incidence of cryptococcal meningitis and Pneumocystis jirovecii pneumonia in HIV/AIDS were estimated at 41/100,000 and 63/100,000, respectively. The estimated prevalence of recurrent vulvovaginal candidiasis (RVVC) was 2,739/100,000. The estimated burden of fungal diseases in Zimbabwe is high in comparison to other African countries, highlighting the urgent need for increased awareness and surveillance to improve diagnosis and management.

Efficacy of praziquantel has been maintained over four decades (from 1977 to 2018): A systematic review and meta-analysis of factors influence its efficacy.

BACKGROUND: The antihelminthic drug praziquantel has been used as the drug of choice for treating schistosome infection for more than 40 years. Although some epidemiological studies have reported low praziquantel efficacy in cure rate (CR) and/or egg reduction rate (ERR), there is no consistent robust evidence of the development of schistosome resistance to praziquantel (PZQ). There is need to determine factors that lead to variable treatment CR and/or ERR. Therefore, we conducted a systematic review and meta-analysis to review CR and ERR as well as identify their predictors. METHODOLOGY/PRINCIPAL FINDINGS: In this systematic review and meta-analysis, a literature review was conducted using Biosis Citation Index, Data Citation Index, MEDLINE, and Web of Science Core Collection all of which were provided through Web of Science. Alongside these, EMBASE, and CAB abstracts were searched to identify relevant articles. Random effect meta-regression models were used to identify the factors that influence CR and/or ERR by considering differences in host characteristics and drug dose. In total, 12,127 potential articles were screened and 146 eligible articles (published from 1979 to 2020) were identified and included for the meta-analysis. We found that there has been no significant reduction in CR or ERR over the study period. The results showed more variability in CR, compared with ERR which was more consistent and remained high. The results showed a positive effect of "PZQ treatment dose" with the current recommended dose of 40 mg/kg body weight achieving 57% to 88% CR depending on schistosome species, age of participants, and number of parasitological samples used for diagnosis, and ERR of 95%. CONCLUSIONS/SIGNIFICANCE: Based on a review of over 40 years of research there is no evidence to support concerns about schistosomes developing resistance to PZQ. These results indicate that PZQ remains effective in treating schistosomiasis.

Schistosoma haematobium infection is associated with alterations in energy and purine-related metabolism in preschool-aged children.

Helminths are parasitic worms that infect over a billion people worldwide. The pathological consequences from infection are due in part, to parasite-induced changes in host metabolic pathways. Here, we analyse the changes in host metabolic profiles, in response to the first Schistosoma haematobium infection and treatment in Zimbabwean children. A cohort of 83 schistosome-negative children (2-5 years old) as determined by parasitological examination, guardian interviews and examination of medical records, was recruited at baseline. Children were followed up after three months for parasitological diagnosis of their first S. haematobium infection, by detection of parasite eggs excreted in urine. Children positive for infection were treated with the antihelminthic drug praziquantel, and treatment efficacy checked three months after treatment. Blood samples were taken at each time point, and capillary electrophoresis mass spectrometry in conjunction with multivariate analysis were used to compare the change in serum metabolite profiles in schistosome-infected versus uninfected children. Following baseline at the three-month follow up, 11 children had become infected with S. haematobium (incidence = 13.3%). Our results showed that infection with S. haematobium was associated with significant increases (>2-fold) in discriminatory metabolites, linked primarily with energy (G6P, 3-PG, AMP, ADP) and purine (AMP, ADP) metabolism. These observed changes were commensurate with schistosome infection intensity, and levels of the affected metabolites were reduced following treatment, albeit not significantly. This study demonstrates that early infection with S. haematobium is associated with alterations in host energy and purine metabolism. Taken together, these changes are consistent with parasite-related clinical manifestations of malnutrition, poor growth and poor physical and cognitive performance observed in schistosome-infected children.

Association of schistosomiasis and risk of prostate cancer development in residents of Murehwa rural community, Zimbabwe.

BACKGROUND: Prostatic male genital schistosomiasis and prostate cancer co-existence cases are uncommon however, some studies have indicated that schistosomiasis may trigger development of prostate cancer regardless of age. Schistosomiasis is a public health problem in sub-Saharan Africa and may account for some undocumented cases of schistosomiasis prostatic cancer in schistosome endemic rural communities. It is against this background that we investigated the association between schistosomiasis and risk of prostate cancer development in residents of Murehwa Community, a schistosomiasis endemic area. METHODOLOGY: We conducted a cross sectional study involving 366 men residing in Murehwa District, Zimbabwe. Schistosoma haematobium and S. mansoni infection was diagnosed using urine filtration and Kato Katz techniques, respectively. Haematuria was detected using urinalysis reagent strip test. A structured questionnaire was used to obtain history of schistosomiasis infection among study participants. Risk of prostate cancer development was assessed by measuring prostate-specific antigen levels in serum using the ELISA. RESULTS: Prevalence of S. haematobium and S. mansoni infection was 12.3% and 1.4%, respectively. Individuals with schistosomiasis had higher prostate-specific antigen levels (mean 1.208 ± SD 1.557 ng/mL) compared to those without schistosomiasis (mean 0.7721 ± SD 1.173 ng/mL; p < 0.05). Older individuals > 50 years had higher prostate specific antigen levels (mean 0.7212 ± SD 1.313 ng/mL) compared to individuals < 50 years old (mean 0.4159 ± SD 0.8622 ng/mL; p < 0.05). Prostate-specific antigen levels log10 (mean 0.2584 ± SD 0.2128 ng/mL) and were associated to S. haematobium infection intensity log10 (mean 1.121 ± SD 0.5371 eggs/10 mL), r(s) = - 0.3225, p < 0.05. There was a correlation between prostate-specific antigen levels log10 (mean 0.2246 ± SD 0.1858 ng/mL) and S. haematobium infection intensity log10 (mean 1.169 ± SD 0.5568 eggs/10 mL) among participants with a history of schistosomiasis infection (r(s) = - 0.3520; p < 0.05). There was no correlation between prostate-specific antigen levels of > 4 ng/mL (mean 5.324 ± SD1.568 ng/mL) and schistosome eggs log10 (mean 1.057 ± SD 0.6730 eggs/10 mL; p > 0.05). CONCLUSION: Urogenital schistosome infections and history of schistosome infections were associated with prostate specific antigen levels, an indicator for risk of prostate cancer. Therefore, S. haematobium schistosome egg burden was associated with the risk of prostate cancer development in adult males residing in Murehwa District, Zimbabwe.

Drug metabolism and pharmacokinetics of praziquantel: A review of variable drug exposure during schistosomiasis treatment in human hosts and experimental models.

Schistosomiasis control is heavily reliant on the drug praziquantel (PZQ), which is used as preventive chemotherapy as part of national helminth control strategies. Given the heavy reliance on PZQ for mass drug administration, there has been considerable research on the potential of parasites developing resistance to the drug, resulting in decreased drug efficacy. However, there have been comparatively fewer studies of other factors that can potentially alter PZQ efficacy. Here, we investigate whether host PZQ metabolism contributes towards variable cure rates. We evaluate factors that can influence the metabolism of PZQ and the resultant effect on the efficacy of PZQ treatment to determine factors that potentially influence an individual's response to the drug. The literature search was directed at published studies from three online databases: Web of Science, PubMed, and EMBASE. The search terms for the review comprised of ([praziquantel OR PZQ] AND [schistosom* OR bilharzia] AND [pharmaco*]) and included studies evaluating PZQ metabolism. Publications were categorised into pharmacokinetics, drug-drug interactions, pharmacogenetics, and metabolite analysis. Forty publications describing human and experimental studies fitted the inclusion criteria and were subjected to data extraction and analysis. The analyses showed that variable exposure to PZQ was associated with alterations in the liver's capacity to metabolise PZQ and observed drug-drug interactions. Other factors influencing the efficacy of PZQ were brand, formulation, and co-administered food. Although some work has been performed on metabolite identification, there was minimal information on PZQ's metabolic pathway, and no pharmacogenetics studies were identified. The study indicated that in both human and experimental studies alterations in the liver's capacity to metabolise PZQ as well as drug-drug interactions affected systemic levels of PZQ that could result in variable cure rates. The study confirmed previous findings of higher antischistosomal activity of (R)-PZQ enantiomer when administered alone compared to the racemate at the same dose as well as improved efficacy when the drug is administered with food. The study also highlighted the need for more comprehensive studies of the PZQ metabolic pathway and PZQ pharmacogenetic studies in humans.

Positive impact of preventative chemotherapy during a national helminth control program: Perception and KAP.

Helminth control at the national level is currently based on mass drug administration (MDA) programs. Perception of the MDA programs for helminth control by the affected populations influences compliance and future designs of the programs. We determined the perception of Zimbabwe's National Helminth Control Program (2012-2017) with a specific focus on schistosomiasis in the school children treated with praziquantel, schoolteachers and village health workers (VHW). The study enrolled 409 children from Grades 6 and 7 who had the full benefit of the 6 years of MDA from 2012 to 2017. Thirty-six schoolteachers and 22 VHW serving the schools were also recruited. A structured questionnaire developed in English, translated into the local language Shona, and validated prior to the study was administered to the children and the adults. The questions focused on the perceived impact on health, school attendance and performance and Knowledge Attitudes and Practice (KAP) among the school children. Data were captured electronically on android platforms using the Open Data Kit. Overall, 84% of the children responded that their awareness of schistosomiasis (transmission, disease, treatment and infection avoidance) had improved because of participating in the MDAs. Of the 151 children self-diagnosed with schistosomiasis, 74% reported that their health had improved following treatment with praziquantel. This included resolution of haematuria, painful urination, sore stomach, tiredness and falling asleep during class lessons. The children and teachers reported improvements in both pupil school attendance and performance at school while the VHW and teachers reported an increase in health-seeking behaviour amongst the school children for schistosomiasis treatment in-between MDAs. The majority of VHW (96%) reported improvement in handwashing behaviour, schistosomiasis awareness (96%) and treatment uptake (91%) within the communities where the school children belonged. However, only 59% of the VHW reported improvement in toilet use while only 50% of the VHW reported improvement in clean water use within their communities. This study indicated that the surveyed children perceived the MDA program had improved their health, school attendance, school performance and awareness of schistosomiasis. The VHW also perceived that the MDA program had improved the community KAP.

Efficacy and safety of single-dose 40 mg/kg oral praziquantel in the treatment of schistosomiasis in preschool-age versus school-age children: An individual participant data meta-analysis.

BACKGROUND: Better 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. METHODOLOGY: We 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 <6 years) and 2,010 school-age children (aged 6-14 years). Children had a documented Schistosoma mansoni or S. haematobium infection, were treated with single 40 mg/kg oral praziquantel, and assessed between 21 and 60 days post-treatment. Efficacy was expressed as arithmetic mean and individual egg reduction rate (ERR) and meta-analyzed using general linear models and mixed models. Safety was summarized using reported adverse events (AEs). PRINCIPAL FINDINGS: Preschool-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/SIGNIFICANCE: There 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.

Six rounds of annual praziquantel treatment during a national helminth control program significantly reduced schistosome infection and morbidity levels in a cohort of schoolchildren in Zimbabwe.

BACKGROUND: The World Health Organization recommends that schistosomiasis be treated through Mass Drug Administration (MDA). In line with this recommendation, Zimbabwe commenced a national helminth control program in 2012 targeting schoolchildren throughout the country for 6 years. This study, part of a larger investigation of the impact of helminth treatment on the overall health of the children, determined the effect of annual praziquantel treatment on schistosome infection and morbidity in a cohort of children during Zimbabwe's 6-year national helminth control program. METHODOLOGY/PRINCIPAL FINDINGS: A school-based longitudinal study was carried out in 35 sentinel sites across Zimbabwe from September 2012 to November 2017. The sentinel sites were selected following a countrywide survey conducted in 280 primary schools. Schistosoma haematobium was diagnosed using the urine filtration technique. Schistosoma mansoni was diagnosed using both the Kato-Katz and formol-ether concentration techniques. S. haematobium morbidity was determined through detection of macro and microhaematuria. A cohort of children aged 6-15 years old was surveyed annually before MDA and 6 weeks post treatment. Maximum treatment coverage reached 90% over the 6 rounds of MDA. At baseline S. haematobium infection prevalence and intensity were 31.7% (95% CI = 31.1-32.2) and 28.75 eggs/10ml urine (SEM = 0.81) respectively, while S. mansoni prevalence and intensity were 4.6% (95% CI = 4.4-4.8) and 0.28 eggs/25mg (SEM = 0.02). Prior to the 6th round of MDA, S. haematobium infection prevalence had reduced to 1.56% (p<0.001) and infection intensity to 0.07 (SEM 0.02). Six weeks later after the 6th MDA, both were 0. Similarly the prevalence of S. haematobium morbidity as indicated by haematuria also fell significantly from 32.3% (95% CI = 29.9-34.6) to 0% (p< 0.0001) prior to the final MDA. For S.mansoni, both prevalence and intensity had decreased to 0 prior to the 6th MDA. After 6 rounds of annual MDA, prevalence and intensity of both schistosome species decreased significantly to 0% (p< 0.0001). CONCLUSION: Zimbabwe's helminth control program significantly reduced schistosome infection intensity and prevalence and urogenital schistosomiasis morbidity prevalence in a cohort of school-aged children, moving the schistosome prevalence in the children from moderate to low by WHO classification. These findings will inform the design of the country's next stage interventions for helminth control and eventual elimination.

Possible association and co-existence of schistosome infection and prostate cancer: A systematic review.

Male genital schistosomiasis (MGS) may result in eggs lodged in the prostate causing persistent inflammation that may play a major role in prostate carcinogenesis. Globally, prostate cancer (PCa) is one of the most common cancers and the global distribution of PCa overlaps with that of schistosomiasis infections, suggesting a probable causal relationship. Objectives of this review were to assess evidence of co-existence of schistosomiasis and PCa and possible causal association between the two diseases. Relevant literature published between 1950 and 2019 yielded 20 publications on schistosomiasis and PCa co-existence. Schistosoma (S.) haematobium and S. mansoni were associated with MGS manifestation and mostly prostate adenocarcinoma diagnosis. Effects of prostatic MGS infection progressed over time with high Schistosoma egg burden thought to contribute to the development of PCa. Causal association and mechanistic pathways of MGS on PCa development and the role of Schistosoma eggs on the development of PCa remains unestablished.

Elevation of C-reactive protein, P-selectin and Resistin as potential inflammatory biomarkers of urogenital Schistosomiasis exposure in preschool children.

BACKGROUND: Schistosomiasis is known to induce inflammatory immune responses. C-reactive protein (CRP), resistin and P-selectin are serological inflammatory markers that rise during the acute stages of infection. Here, we propose such inflammatory biomarkers have a potential for use in urogenital schistosomiasis diagnostic screening for exposure and infection in preschool-aged children. METHODS: As part of a larger study on urogenital schistosomiasis, 299 preschool children aged 1-5 years were included in this cross-sectional study. Parasitological diagnosis was conducted using urine filtration for Schistosoma haemtobium infection, and Kato Katz for S. mansoni infection. Serum levels of P-selectin, resistin, CRP, and antibodies against S. haematobium cercarial antigen preparation (CAP) and soluble worm antigen preparation (SWAP) were measured by ELISA. RESULTS: Of the 299 participants, 14% were egg positive for S. haematobium. Serology showed 46 and 9% of the participants to have been exposed to S. haematobium cercarial antigens and adult worm antigens, respectively. Levels of P-selectin were significantly higher in participants infected with S. haematobium (egg-positive) than in uninfected participants (p = 0.001). Levels of P-selectin were also higher in those exposed to cercarial antigen than in unexposed participants (p = 0.019). There was a positive correlation between P-selectin and infection intensity (r = 0.172; p = 0.002), as well as with IgM responses to CAP and SWAP (r = 0.183; p = 0.001); (r = 0.333; p < 0.0001) respectively. CRP significantly correlated with IgM responses to CAP (r = 0.133; p = 0.029) while resistin correlated with IgM responses to CAP and SWAP (r = 0.127; p = 0.016); (r = 0.197; p = 0.0004). CRP levels were higher in those exposed to cercarial and adult worm antigens than unexposed participants (p = 0.035); (p = 0.002) respectively, while resistin was higher in participants exposed to cercarial antigen than unexposed participants (p = 0.024). CONCLUSION: In this preschool population, P-selectin is significantly associated with urogenital schistosome infection and intensity; hence a potential biomarker for infection diagnosis and disease monitoring. The inflammatory biomarkers (P-selectin, Resistin and CRP) were significantly higher in participants exposed to cercarial antigens than unexposed individuals indicating an underlying inflammatory environment.

In-depth proteomic characterization of Schistosoma haematobium: Towards the development of new tools for elimination.

BACKGROUND: Schistosomiasis is a neglected disease affecting hundreds of millions worldwide. Of the three main species affecting humans, Schistosoma haematobium is the most common, and is the leading cause of urogenital schistosomiasis. S. haematobium infection can cause different urogenital clinical complications, particularly in the bladder, and furthermore, this parasite has been strongly linked with squamous cell carcinoma. A comprehensive analysis of the molecular composition of its different proteomes will contribute to developing new tools against this devastating disease. METHODS AND FINDINGS: By combining a comprehensive protein fractionation approach consisting of OFFGEL electrophoresis with high-throughput mass spectrometry, we have performed the first in-depth characterisation of the different discrete proteomes of S. haematobium that are predicted to interact with human host tissues, including the secreted and tegumental proteomes of adult flukes and secreted and soluble egg proteomes. A total of 662, 239, 210 and 138 proteins were found in the adult tegument, adult secreted, soluble egg and secreted egg proteomes, respectively. In addition, we probed these distinct proteomes with urine to assess urinary antibody responses from naturally infected human subjects with different infection intensities, and identified adult fluke secreted and tegument extracts as being the best predictors of infection. CONCLUSION: We provide a comprehensive dataset of proteins from the adult and egg stages of S. haematobium and highlight their utility as diagnostic markers of infection intensity. Protein composition was markedly different between the different extracts, highlighting the distinct subsets of proteins that different development stages present in their different niches. Furthermore, we have identified adult fluke ES and tegument extracts as best predictors of infection using urine antibodies of naturally infected people. This study provides the first steps towards the development of novel tools to control this important neglected tropical disease.

Benefits of annual chemotherapeutic control of schistosomiasis on the development of protective immunity.

BACKGROUND: Schistosomiasis is a devastating parasitic disease. The mainstay of schistosomiasis control is by praziquantel treatment. The study aimed to determine benefits of annual chemotherapy of schistosomiasis on development of protective immunity in school children in a selected endemic rural area in Zimbabwe. METHODS: Urine specimens from 212 school children (7-13 years) were collected and examined to determine prevalence, intensity and reinfection of S.haematobium at baseline, 6 weeks and 2 years following annual rounds of praziquantel treatment. Blood samples from the participants were assayed for total and S. haematobium (Sh13)-specific antibodies before and 2 years after annual rounds of treatment. RESULTS: Annual treatment reduced the prevalence of S. haematobium infection (p < 0.05) from 23.1% at baseline to 0.47% after 2 years. Overall cure rate was 97.8%. Intensity of infection declined (p < 0.05) from 15.9 eggs/10 ml urine at baseline to 2 eggs/10 ml urine. After two years, overall rate of reinfection was 0.96%. At baseline, total IgG4 was higher in S. haematobium-infected children (p = 0.042) ,while all other immunoglobulins were within normal ranges. There was an increase in total IgG2 (p = 0.044) levels and a decrease in total IgG4 (p = 0.031) levels 2 years post-treatment; and no significant changes in other total immunoglobulins. Schistosoma-infected children at baseline showed an increase in anti-Sh13 IgG1 (p = 0.005) and a decrease in Sh13 IgG4 levels (p = 0.012) following treatment. CONCLUSION: Annual praziquantel treatment delivered to school children over 2 years significantly reduce prevalence, intensity of infection and reinfection of S. haematobium infection. Treatment was also observed to cause a reduction in schistosome-specific blocking IgG4 and an increase in Schistosoma-specific protecting IgG1.

The anthelmintic drug praziquantel promotes human Tr1 differentiation.

Praziquantel (PZQ) is an anthelminthic human and veterinary drug used to treat trematode and cestode worms. Changes in immune responses have been demonstrated in humans following curative PZQ treatment of schistosome infections. These changes have been attributed to the removal of immunosupressive worms and immune responses to parasite antigens exposed from dying worms. To date, there has been no study investigating the potential direct effect of PZQ on the host immune cells. Herein, we analyzed the effect of PZQ on human CD4+ T cells classically costimulated by CD3/CD28 or costimulated by the complement regulator CD46 to induce Type 1 regulatory T cells (Tr1). Our results show that PZQ enhanced T-cell proliferation, increased secretion of IL-17 and IL-10 but had no effect on secretion of GM-CSF or IFNγ. Moreover, PZQ increased the coexpression of CD49b and LAG-3, a hallmark of Tr1 cells, suggesting increased Tr1 differentiation. Indeed, supernatants from PZQ-treated cells were able to decrease bystander T-cell activation, and this was partly reduced when blocking IL-10. Hence, our study demonstrates that PZQ directly modulates human T-cell activation and promotes Tr1 differentiation, suggesting that PZQ may have immunomodulatory functions in parasite-unrelated human inflammatory diseases.

Population level changes in schistosome-specific antibody levels following chemotherapy.

AIMS: Previous studies have reported that chemotherapy of schistosomiasis by praziquantel in humans boosts protective antibody responses against S mansoni and S haematobium. A number of studies have reported schistosome-specific antibody levels before and after chemotherapy. Using these reports, a meta-analysis was conducted to identify predictors of population level change in schistosome-specific antibody levels after chemotherapy. METHODS AND RESULTS: Following a systematic review, 92 observations from 26 articles published between 1988 and 2013 were included in this study. Observations were grouped by antigen type and antibody isotypes for the classification and regression tree (CART) analysis. The study showed that the change in antibody levels was variable: (a) between different human populations and (b) according to the parasite antigen and antibody isotypes. Thus, while anti-worm responses predominantly increased after chemotherapy, anti-egg responses decreased or did not show a significant trend. The change in antibody levels depended on a combination of age and infection intensity for anti-egg IgA, IgM, IgG1, IgG2 and anti-worm IgM and IgG. CONCLUSION: The study results are consistent with praziquantel treatment boosting anti-worm antibody responses. However, there is considerable heterogeneity in post-treatment changes in specific antibody levels that is related to host age and pre-treatment infection intensity.