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Schistosomiasis remains a global-health problem with over 90% of its burden concentrated in Africa. Field studies reflect the complex ways in which socio-cultural and socio-economic variables, affect the distribution of Schistosoma infections across different populations. This review set out to systematically investigate and quantify the differences in Schistosoma infection burdens between males and females in Africa for two of the most prevalent Schistosoma species-Schistosoma mansoni and Schistosoma haematobium. We searched (from inception to 11th March 2020) Embase, MEDLINE, PubMed, and Web of Science for relevant studies on schistosomiasis. We included studies that report S. mansoni and/or S. haematobium prevalence and/or intensity data distributed between males and females. We conducted meta-analyses on the male to female (M:F) prevalence of infection ratios. Subgroup analyses were performed according to study baseline prevalence, sample size and the lower and upper age limit of study participants. We also present a descriptive analysis of differential risk and intensity of infection across males and females. Evidence for differences in the prevalence of schistosomiasis infection between males and females is presented, stratified by Schistosoma species. We identified 128 relevant studies, with over 200,000 participants across 23 countries. Of all the reported differences in the prevalence of infection between males and females, only 41% and 34% were statistically significant for S. mansoni and S. haematobium, respectively. Similar proportions of studies (27% and 34% for for S. haematobium and S. mansoni, respectively) of the reported differences in intensity of infection between males and females were statistically significant. The meta-analyses summarized a higher prevalence of infection in males; pooled random-effects weighted M:F prevalence of infection ratios were 1.20 (95% CI 1.11-1.29) for S. haematobium and 1.15 (95% CI 1.08-1.22) for S. mansoni. However, females are underrespresented in some of the studies. Additionally, there was significant heterogeneity across studies (Higgins I2 statistic (p-values < 0.001, I2values>95%)). Results of the subgroup analysis showed that the baseline prevalence influenced the M:F prevalence ratios for S. haematobium and S. mansoni, with higher M:F prevalence of infection ratios in settings with a lower baseline prevalence of infection. Across the studies, we identified four major risk factors associated with infection rates: occupational and recreational water contact, knowledge, socio-economic factors and demographic factors. The effect of these risk factors on the burden of infection in males and females varied across studies. We find evidence of differences in prevalence of infection between males and females which may reflect differences in gender norms and water contact activities, suggesting that policy changes at the regional level may help ameliorate gender-related disparities in schistosomiasis infection burden. Collecting, robustly analysing, and reporting, sex-disaggregated epidemiological data, is currently lacking, but would be highly informative for planning effective treatment programmes and establishing those most at risk of schistosomiasis infections.

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

Over 240 million people are infected with schistosomiasis, the majority in sub-Saharan Africa. In Uganda, high infection rates exist in communities on the shores of Lake Victoria. Praziquantel mass drug administration (MDA) delivered by village health teams is the mainstay of schistosomiasis control. However, treatment uptake remains suboptimal, with many people unaware of treatment or thinking it is only for children. Furthermore, people are often rapidly reinfected post-treatment due to continued exposure. In three Schistosoma mansoni high endemicity lake-shore communities in Mayuge district, Eastern Uganda, we investigated the sources of schistosomiasis information, remembered content of information, and the perception of information and related practices towards the control of schistosomiasis. Data were collected from September 2017 to March 2018 using a rapid ethnographic assessment that included transect walks, observations, individual in-depth interviews and focus group discussions. Data were analysed thematically using iterative categorisation. We found that the main sources of schistosomiasis information included health workers at government facilities, village health teams, teachers, and radio programmes produced by the Ministry of Health. These messages described the symptoms of schistosomiasis, but did not mention the side effects of praziquantel treatment. Despite this messaging, the main cause of the disease and transmission was unclear to most participants. The translation of schistosomiasis on the radio into the local language 'ekidada'-meaning swollen stomach-increased, rather than reduced, confusion about the cause(s) of schistosomiasis, due to believed links between ekidada and witchcraft, and prompted a reluctance to engage with treatment or preventative efforts. This study highlights gaps in schistosomiasis messaging. We recommend MDA is complemented by effective, evidence-based messaging on schistosomiasis transmission, prevention, and treatment, that is sensitive to local language and context issues, resulting in clear, concise, and consistent messages, to increase effectiveness.

Schistosomiasis is the second most widespread parasitic disease affecting humans. A key component of today’s infection control measures is the diagnosis and monitoring of infection, informing individual- and community-level treatment. However, newly acquired infections and/or low parasite burden are still difficult to diagnose reliably. Furthermore, even though the pathological consequence of schistosome egg sequestration in host tissues is well described, the evidence linking egg burden to morbidity is increasingly challenged, making it inadequate for pathology monitoring. In the last decades, omics-based instruments and methods have been developed, adjusted, and applied in parasitic research. In particular, the profiling of the most reliable determinants of phenotypes, metabolites by metabolomics, emerged as a powerful boost in the understanding of basic interactions within the human host during infection. As such, the fine detection of host metabolites produced upon exposure to parasites such as Schistosoma spp. and the ensuing progression of the disease are believed to enable the identification of Schistosoma spp. potential biomarkers of infection and associated pathology. However, attempts to provide such a comprehensive understanding of the alterations of the human metabolome during schistosomiasis are rare, limited in their design when performed, and mostly inconclusive. In this review, we aimed to briefly summarize the most robust advances in knowledge on the changes in host metabolic profile during Schistosoma infections and provide recommendations for approaches to optimize the identification of metabolomic signatures of human schistosomiasis.

Control and elimination of the parasitic disease schistosomiasis relies on mass administration of praziquantel. Whilst these programmes reduce infection prevalence and intensity, their impact on parasite transmission and evolution is poorly understood. Here we examine the genomic impact of repeated mass drug administration on Schistosoma mansoni populations with documented reduced praziquantel efficacy. We sequenced whole-genomes of 198 S. mansoni larvae from 34 Ugandan children from regions with contrasting praziquantel exposure. Parasites infecting children from Lake Victoria, a transmission hotspot, form a diverse panmictic population. A single round of treatment did not reduce this diversity with no apparent population contraction caused by long-term praziquantel use. We find evidence of positive selection acting on members of gene families previously implicated in praziquantel action, but detect no high frequency functionally impactful variants. As efforts to eliminate schistosomiasis intensify, our study provides a foundation for genomic surveillance of this major human parasite. Schistosomiasis control strategies rely on mass drug administration (MDA) using praziquantel. Here, Berger et al. perform whole-genome sequencing of larvae from infected children across Ugandan regions with differing MDA histories. They find extensive gene flow with limited positive selection suggesting minimal change post MDA.

As China is moving onto schistosomiasis elimination/eradication, diagnostic methods with both high sensitivity and specificity for Schistosoma japonicum infections in humans are urgently needed. Microscopic identification of eggs in stool is proven to have poor sensitivity in low endemic regions, and antibody tests are unable to distinguish between current and previous infections. Polymerase chain reaction (PCR) technologies for the detection of parasite DNA have been theoretically assumed to show high diagnostic sensitivity and specificity. However, the reported performance of PCR for detecting S. japonicum infection varied greatly among studies. Therefore, we performed a meta-analysis to evaluate the overall diagnostic performance of variable-temperature PCR technologies, based on stool or blood, for detecting S. japonicum infections in humans from endemic areas. We searched literatures in eight electronic databases, published up to 20 January 2021. The heterogeneity and publication bias of included studies were assessed statistically. The risk of bias and applicability of each eligible study were assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool (QUADAS-2). The bivariate mixed-effects model was applied to obtain the summary estimates of diagnostic performance. The hierarchical summary receiver operating characteristic (HSROC) curve was applied to visually display the results. Subgroup analyses and multivariate regression were performed to explore the source of heterogeneity. This research was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and was registered prospectively in PROSPERO (CRD42021233165). A total of 2791 papers were retrieved. After assessing for duplications and eligilibity a total of thirteen publications were retained for inclusion. These included eligible data from 4268 participants across sixteen studies. High heterogeneity existed among studies, but no publication bias was found. The pooled analyses of PCR data from all included studies resulted in a sensitivity of 0.91 (95% CI: 0.83 to 0.96), specificity of 0.85 (95% CI: 0.65 to 0.94), positive likelihood ratio of 5.90 (95% CI: 2.40 to 14.60), negative likelihood ratio of 0.10 (95% CI: 0.05 to 0.20) and a diagnostics odds ratio of 58 (95% CI: 19 to 179). Case-control studies showed significantly better performances for PCR diagnostics than cross-sectional studies. This was further evidenced by multivariate analyses. The four types of PCR approaches identified (conventional PCR, qPCR, Droplet digital PCR and nested PCR) differed significantly, with nested PCRs showing the best performance. Variable-temperature PCR has a satisfactory performance for diagnosing S. japonicum infections in humans in endemic areas. More high quality studies on S. japonicum diagnostic techniques, especially in low endemic areas and for the detection of dual-sex and single-sex infections are required. These will likely need to optimise a nested PCR alongside a highly sensitive gene target. They will contribute to successfully monitoring endemic areas as they move towards the WHO 2030 targets, as well as ultimately helping areas to achieve these goals.

Schistosomiasis is a neglected tropical disease and a serious global-health problem with over 230 million people requiring treatment, of which the majority live in Africa. In Uganda, over 4 million people are infected. Extensive parasitological data exist on infection prevalence, intensities and the impact of repeated praziquantel mass drug administration (MDA). However, how perceptions of schistosomiasis shape prevention and treatment practices and their implications for control measures are much less well understood. Rapid ethnographic appraisals were performed for six weeks in each of three Schistosoma mansoni high endemicity communities on the shores of Lake Victoria, Mayuge District, Uganda. Data were collected between September 2017 and April 2018. Data were collected through structured observations, transect walks, and participant observation, and sixty in-depth interviews and 19 focus group discussions with purposively recruited participants. Data were analyzed thematically using iterative categorization, looking at five key areas: perceptions of 1) the symptoms of schistosomiasis; 2) the treatment of schistosomiasis; 3) how schistosomiasis is contracted; 4) how schistosomiasis is transmitted onwards and responsibilities associated with this; and 5) how people can prevent infection and/or onward transmission. Observations revealed open defecation is a common practice in all communities, low latrine coverage compared to the population, and all communities largely depend on lake water and contact it on a daily basis. Perceptions that a swollen stomach was a sign/symptom of 'ekidada' (caused by witchcraft) resulted in some people rejecting free praziquantel in favour of herbal treatment from traditional healers at a fee. Others rejected praziquantel because of its perceived side effects. People who perceived that schistosomiasis is caught from drinking unboiled lake water did not seek to minimize skin contact with infected water sources. Community members had varied perceptions about how one can catch and transmit schistosomiasis and these perceptions affect prevention and treatment practices. Open defecation and urinating in the lake were considered the main route of transmission, all communities attributed blame for transmission to the fishermen which was acknowledged by some fishermen. And, lastly, schistosomiasis was considered hard to prevent due to lack of access to safe water. Despite over 15 years of MDA and associated education, common misconceptions surrounding schistosomiasis exist. Perceptions people have about schistosomiasis profoundly shape not only prevention but also treatment practices, greatly reducing intervention uptake. Therefore, we advocate for a contextualized health education programme, alongside MDA, implementation of improved access to safe-water and sanitation and continued research.

Over 240 million people have schistosomiasis. Mass drug administration (MDA) with the anthelmintic praziquantel is the cornerstone of control. Treatment side effects are commonly observed and may be associated with dying worms. Side effects have also been reported as a reason for reduced MDA uptake, potentially resulting in those most in need refusing repeated treatment. An improved understanding of the association between side effects and infection intensity, pre-treatment health, and drug efficacy, may help inform education campaigns to facilitate increased MDA uptake. Using latent class analyses, Beta regression, and dose response curves, we analysed egg and antigen parasitological data alongside health and side-effects survey data pre- and post-praziquantel-treatment from two primary schools (Bugoto Lake View (LV) and Musubi Church of God (CoG)) in Schistosoma mansoni high endemicity Ugandan villages to understand whether pre-treatment infection status or intensity were related to 1) pre-treatment symptoms, 2) post-treatment side effects, and 3) whether parasite clearance after treatment was associated with side effects. At Bugoto LV: Abdominal pain, blood-in-stool, and itching/rash symptoms were non-linearly associated with infection intensity; Diarrhoea, headache and vomiting side effects were non-linearly associated with infection intensity. At Musubi CoG: Blood-in-stool, headache, and pain-when-urinating symptoms were non-linearly associated with infection intensity; Abdominal pain, diarrhoea, and vomiting side effects were non-linearly associated with infection intensity. There was no relationship between infection status (infected/ uninfected) and symptoms or side effects at either school. No association was found between infection clearance and the presence of side effects at either school. We show no evidence that being infected predisposes someone to side effects, nor that side effects are related to treatment efficacy. Relationships between pre-treatment infection intensity and pre-treatment symptoms or post-treatment side effects varied by school suggesting unmeasured factors such as co-infections or other health conditions could impact symptom and side effect reporting.

Background Annual mass drug administration with praziquantel has reduced schistosomiasis transmission in some highly endemic areas, but areas with persistent high endemicity have been identified across sub-Saharan Africa, including Uganda. In these areas many children are rapidly reinfected post treatment, while some children remain uninfected or have low-intensity infections. The aim of this mixed-methods study was to better understand variation in water contact locations, behaviours and infection risk in school-aged children within an area with persistent high endemicity to inform additional control efforts. Methods Data were collected in Bugoto, Mayuge District, Uganda. Two risk groups were identified from a longitudinal cohort, and eight children with no/low-intensity infections and eight children with reinfections were recruited. Individual structured day-long observations with a focus on water contact were conducted over two periods in 2018. In all identified water contact sites, four snail surveys were conducted quarterly over 1 year. All observed Biomphalaria snails were collected, counted and monitored in the laboratory for Schistosoma mansoni cercarial shedding for 3 weeks. Results Children came into contact with water for a range of purposes, either directly at the water sources or by coming into contact with water collected previously. Although some water contact practices were similar between the risk groups, only children with reinfection were observed fetching water for commercial purposes and swimming in water sources; this latter group of children also came into contact with water at a larger variety and number of sites compared to children with no/low-intensity infection. Households with children with no/low-intensity infections collected rainwater more often. Water contact was observed at 10 sites throughout the study, and a total of 9457 Biomphalaria snails were collected from these sites over four sampling periods. Four lake sites had a significantly higher Biomphalaria choanomphala abundance, and reinfected children came into contact with water at these sites more often than children with no/low-intensity infections. While only six snails shed cercariae, four were from sites only contacted by reinfected children. Conclusions Children with reinfection have more high-risk water contact behaviours and accessed water sites with higher B. choanomphala abundance, demonstrating that specific water contact behaviours interact with environmental features to explain variation in risk within areas with persistent high endemicity. Targeted behaviour change, vector control and safe water supplies could reduce reinfection in school-aged children in these settings. Graphical Abstract

The World Health Organization identified Uganda as one of the 10 highly endemic countries for schistosomiasis. Annual mass drug administration (MDA) with praziquantel has led to a decline in intensity of Schistosoma mansoni infections in several areas. However, as hotspots with high (re)infection rates remain, additional research on risk factors and implementing interventions to complement MDA are required to further reduce disease burden in these settings. Through a mixed-methods study we aimed to gain deeper understanding of how gender may impact risk and reinfection in order to inform disease control programmes and ascertain if gender-specific interventions may be beneficial. In Bugoto, Mayuge District, Eastern Uganda we conducted ethnographic observations (n = 16) and examined epidemiology (n = 55) and parasite population genetics (n = 16) in school-aged children (SAC), alongside a community-wide household survey (n = 130). Water contact was frequent at home, school and in the community and was of domestic, personal care, recreational, religious or commercial nature. Qualitative analysis of type of activity, duration, frequency, level of submersion and water contact sites in children showed only few behavioural differences in water contact between genders. However, survey data revealed that adult women carried out the vast majority of household tasks involving water contact. Reinfection rates (96% overall) and genetic diversity were high in boys (pre-He = 0.66; post-He = 0.67) and girls (pre-He = 0.65; post-He = 0.67), but no differences in reinfection rates (p = 0.62) or genetic diversity by gender before (p = 0.54) or after (p = 0.97) treatment were found. This mixed methods approach showed complementary findings. Frequent water exposure with few differences between boys and girls was mirrored by high reinfection rates and genetic diversity in both genders. Disease control programmes should consider the high reinfection rates among SAC in remaining hotspots of schistosomiasis and the various purposes and settings in which children and adults are exposed to water.