Schistosomiasis, a highly prevalent parasitic disease, affects more than 200 million people worldwide. Current diagnostics based on parasite egg detection in stool detect infection only at a late stage, and current antibody-based tests cannot distinguish past from current infection. Here, we developed and used a multiplexed antibody profiling platform to obtain a comprehensive repertoire of antihelminth humoral profiles including isotype, subclass, Fc receptor (FcR) binding, and glycosylation profiles of antigen-specific antibodies. Using Essential Regression (ER) and SLIDE, interpretable machine learning methods, we identified latent factors (context-specific groups) that move beyond biomarkers and provide insights into the pathophysiology of different stages of schistosome infection. By comparing profiles of infected and healthy individuals, we identified modules with unique humoral signatures of active disease, including hallmark signatures of parasitic infection such as elevated immunoglobulin G4 (IgG4). However, we also captured previously uncharacterized humoral responses including elevated FcR binding and specific antibody glycoforms in patients with active infection, helping distinguish them from those without active infection but with equivalent antibody titers. This signature was validated in an independent cohort. Our approach also uncovered two distinct endotypes, nonpatent infection and prior infection, in those who were not actively infected. Higher amounts of IgG1 and FcR1/FcR3A binding were also found to be likely protective of the transition from nonpatent to active infection. Overall, we unveiled markers for antibody-based diagnostics and latent factors underlying the pathogenesis of schistosome infection. Our results suggest that selective antigen targeting could be useful in early detection, thus controlling infection severity.

Sudan is endemic for multiple neglected tropical diseases, including trachoma, onchocerciasis (OV), lymphatic filariasis (LF), and schistosomiasis (SCH). In 2019, dried blood spot samples were collected for a baseline trachoma serosurvey in three localities (El Seraif, Kotom, and Saraf Omrah) in North Darfur State. None were classified previously as OV- or LF-endemic, although low levels of SCH had been identified in all three. Approximately 30 households from 25 communities in each locality were selected by multistage cluster random sampling. Collections of DBSs were analyzed by multiplex bead assay for antibodies to multiple pathogens. This paper presents data on OV (Ov16), LF (Wb123, Bm14, Bm33), and SCH (soluble egg antigen [SEA], Sm25) antibodies among 8,322 individuals from 2,119 households. The survey-adjusted seroprevalence estimates for Ov16 were <0.3% in all localities. Lymphatic filariasis-antigen seroprevalences were discordant. Seroprevalence estimates ranged from 4.6-6.0% (Wb123), 0.99-1.4% (Bm14), and 29.2-33.3% (Bm33). Schistosomiasis seroprevalence estimates among school-aged children ranged from 2.7-8.0% (SEA) and 10.9-15.6% (Sm25). Ov16 seropositivity was low and supported the localities' classification as nonendemic. The results suggested LF exposure, but discordance between antigens, challenges defining seropositivity thresholds, and the absence of programmatic guidance based on antibody serology alone for Wuchereria bancrofti indicate a need for remapping surveys to confirm transmission. Schistosomiasis antibody levels were high enough to warrant further mapping to guide treatment decisions. The lack of gold standards limited interpretation of results, particularly for LF, but in resource-challenged areas, integrated serological surveillance offers the possibility of efficient monitoring of exposure to multiple diseases.

We determined the in vitro minimum lethal concentration (MLC) of secnidazole (SEC) and assessed correlation with clinical susceptibility among T. vaginalis isolates obtained from 71 women, of whom 66 were successfully treated with this medication. An MLC ≤12.5 μg/ml correlated with clinical susceptibility in this study.

OBJECTIVE: To determine if the prevalence of schistosomiasis in children aged 9-12 years is associated with the prevalence in 5-8-year-olds and adults after preventive chemotherapy in schools or the community. METHODS: We combined data from four community-randomized, preventive chemotherapy trials in treatment-naïve populations in Côte d'Ivoire, Kenya and the United Republic of Tanzania during 2010-2016 according to the number of praziquantel treatments and the delivery method. Schistosoma mansoni infection was sought on two slides prepared from each participant's first stool using the Kato-Katz technique. We assessed associations between S. mansoni prevalence in 9-12-year-olds and 5-8-year-olds and adults in the community before and after treatment using Bayesian regression models. FINDINGS: Stool samples from 47 985 5-8-year-olds, 81 077 9-12-year-olds and 20 492 adults were analysed. We found associations between the prevalence in 9-12-year-olds and that in 5-8-year-olds and adults after preventive treatment, even when only school-age children were treated. When the prevalence in 9-12-year-olds was under 10%, the prevalence in 5-8-year-olds was consistently under 10%. When the prevalence in 9-12-year-olds was under 50%, the prevalence in adults after two or four rounds of preventive chemotherapy was 10%-15% lower than before chemotherapy. Post-chemotherapy age-group associations were consistent with pre-chemotherapy associations in this analysis and previous studies. CONCLUSION: The prevalence of S. mansoni infection in 9-12-year-olds was associated with the prevalence in other age groups and could be used to guide community treatment decisions.

Background: The World Health Organization estimates that 56 million women and girls live with female genital schistosomiasis (FGS) in sub-Saharan Africa. FGS is often confused with symptoms of other genital abnormalities, and gold standard diagnosis with colposcopy is infeasible in most health facilities. Schistosomiasis haematobium is endemic in Zambia, yet routine screening or diagnostic efforts for FGS remain unavailable. Our study aimed to develop and pilot test a feasible FGS screening algorithm to implement in Zambian government clinics. Methodology/Principal Findings: We recruited 499 women from a longitudinal cohort of HIV-negative adult women in Lusaka and Ndola, Zambia. We used demographic, risk factor, and symptom data collected from standardized surveys, gynecological exams, and laboratory tests to develop a screening algorithm for FGS among a derivation cohort (n=349). After cross-validation using 5-fold iterative resampling, the algorithm was applied in a holdout sample of the cohort (n=150). The prevalence of FGS (ascertained by expert review) was 23.4% in the study population. The screening algorithm included childhood and travel exposure to rivers and streams; testing positive for visual inspection of the cervix with acetic acid; hematuria; reporting less than the median average age at sexual debut (<17 years); when asked what diseases can be transmitted via freshwater exposure, reporting ‘none’; being born outside of Lusaka or Copperbelt Province; and reporting occupation as ‘Housekeeper’. The screening algorithm had reasonable discrimination in the derivation cohort (area under the curve [AUC]=0.69, 95% confidence interval [CI]: 0.66-0.79, p-value<0.001). Using a score cut off ≥ 2 the risk algorithm in the derivation cohort had 77% sensitivity, 48% specificity, 35% positive predictive value, and 85% negative predictive value. Conclusions/Significance: Given the prevalence of FGS and associated morbidities, improved screening for FGS is imperative. We developed a simple screening algorithm to improve the diagnosis and treatment of FGS among adult women in Zambian government clinics. Copyright © 2024 Rogers, Mwangelwa, Kabengele, Kilembe, Vwalika, Inambao, Mumba, Chanda, Secor, Musale, Himukumbwa, Parker, Tichacek, Bougouma, Allen and Wall.

We evaluated changes in female genital schistosomiasis (FGS) 6 to 12 months after praziquantel treatment among 43 adult Zambian women. Most women (60%) experienced decreased FGS severity and 23% experienced complete lesion resolution. This is the first study to demonstrate a meaningful effect of praziquantel treatment of FGS in adult women.

Urinary and intestinal schistosomiasis are endemic in Senegal, with prevalence heterogeneous throughout the country. Because of their way of life, nomadic pastoralists are not typically included in epidemiological surveys, and data on the prevalence of schistosomiasis in Senegalese nomadic populations are largely non-existent. The purpose of this study was to determine the seroprevalence of schistosomiasis in Senegalese nomadic pastoralists. A modified snowball sampling survey was conducted among 1,467 nomadic pastoralists aged 6 mo and older in 5 districts in northern Senegal. Dried blood spots from participants of all ages and data regarding demographics were collected to assess IgG antibody responses against Schistosoma mansoni soluble egg antigen (SEA) using a bead-based multiplex assay. Out of 1,467 study subjects, 1,464 (99.8%) provided IgG serological data that cleared quality assurance. Of the participants with appropriate data, 56.6% were male, the median age was 22 yr, and 31.6% were under 15 yr of age. The overall anti-SEA IgG seroprevalence was 19.1% (95% confidence interval [CI]: 17.1-21.1%) with the highest estimates observed in Dagana (35.9%) and the lowest observed in Podor nomadic groups (3.4%). Antibody responses increased significantly with age except for the oldest age groups (>40 yr of age), which saw lower levels of antibody response compared to younger adults. When controlling for age and location by multivariate regression, the male sex was associated with a 2-fold greater odds of anti-SEA IgG seropositivity (aPOR: 2.0; 95% CI: 1.5-2.7). Serosurveys for anti-SEA IgG among nomadic peoples in northern Senegal found a substantial percentage of individuals with evidence for current or previous Schistosoma spp. infection with the highest levels of exposure in the district adjacent to the Diama dam along the Senegal River. With IgG prevalence increased by age except in the older adults, and the male sex significantly associated with seropositivity, these data point toward sex-associated behavioral practices and human environmental modification as risk factors for Schistosoma exposure.

The first nationally representative, population-based study of schistosomiasis seroprevalence in Nigeria was conducted using blood samples and risk-factor data collected during the 2018 Nigeria HIV/AIDS Indicator and Impact Survey (NAIIS). Schistosomiasis seroprevalence was estimated by analyzing samples for reactivity to schistosome soluble egg antigen (SEA) in a multiplex bead assay; NAIIS survey data were assessed to identify potential risk factors for seropositivity. The SEA antibody data were available for 31,459 children aged 0 to 14 years. Overall seroprevalence was 17.2% (95% CI: 16.3-18.1%). Seropositive children were identified in every age group, including children < 5 years, and seroprevalence increased with increasing age (P < 0.0001). Several factors were associated with increased odds of seropositivity, including being a boy (odds ratio [OR] = 1.34, 95% CI: 1.24-1.45), living in a rural area (OR = 2.2, 95% CI: 1.9-2.5), and animal ownership (OR = 1.67, 95% CI: 1.52-1.85). Access to improved sanitation and drinking water sources were associated with decreased odds of seropositivity (OR = 0.52, 95% CI: 0.47-0.58 and OR = 0.53, 95% CI: 0.47-0.60, respectively) regardless of whether the child lived in a rural (sanitation: adjusted odds ratio [aOR] = 0.7, 95% CI: 0.6-0.8; drinking water: aOR = 0.7, 95% CI: 0.6-0.8) or urban area (sanitation: aOR = 0.6, 95% CI: 0.5-0.7; drinking water: aOR = 0.5, 95% CI: 0.4-0.6), highlighting the importance of these factors for schistosomiasis prevention and control. These results identified additional risk populations (children < 5 years) and a new risk factor (animal ownership) and could be used to monitor the impact of control programs.

Identifying populations with active transmission and monitoring changes in transmission is centrally important in guiding schistosomiasis control programs. Traditionally, human Schistosoma mansoni infections have been detected in stool using microscopy, which is logistically difficult at program scale and has low sensitivity when people have low infection burdens. We compared serological measures of transmission based on antibody response to schistosomiasis soluble egg antigen (SEA) with stool-based measures of infection among 3,663 preschool-age children in an area endemic for S. mansoni in western Kenya. Serological measures of transmission closely aligned with stool-based measures of infection, and serological measures provided better resolution for between-community differences at lower levels of infection. Serology enabled fine- scale measures of heterogeneity in force of infection both geographically and by age. Our results show that serologic surveillance platforms represent an important new opportunity to guide and monitor schistosomiasis control programs.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was supported by the National Institutes of Allergy and Infectious Diseases (K01 AI119180 to BFA) and the Bill &amp; Melinda Gates Foundation (OPP1022543 to PJL). The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the Public Health Service or by the U.S. Department of Health and Human Services.Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData and replication files required to conduct the analyses are available through GitHub and the Open Science Framework: https://osf.io/rnme8. Community location data required to replicate the geostatistical model fits is not publicly available to protect participant confidentiality but is available from the corresponding author upon request, pending appropriate human subjects review and approval. https://osf.io/rnme8

Epigenetic mechanisms, like DNA methylation, determine immune cell phenotype. To understand the epigenetic alterations induced by helminth co-infections, we evaluated the longitudinal effect of ascariasis and schistosomiasis infection on CD4+ T cell DNA methylation and the downstream tuberculosis (TB)-specific and BCG-induced immune phenotype. All experiments were performed on human primary immune cells from a longitudinal cohort of recently TB-exposed children. Compared to age-matched uninfected controls, children with active Schistosoma haematobium and Ascaris lumbricoides infection had 751 differentially DNA methylated genes with 72% hyper-methylated. Gene ontology pathway analysis identified inhibition of IFN-γ signaling, cellular proliferation, and the Th1 pathway. Targeted RT-PCR after methyl-specific endonuclease digestion confirmed DNA hyper-methylation of the transcription factors BATF3, ID2, STAT5A, IRF5, PPARg, RUNX2, IRF4 and NFATC1 and cytokines or cytokine receptors IFNGR1, TNFS11, RELT (TNF receptor), IL12RB2 and IL12B (p&lt; 0.001; Sidak-Bonferroni). Functional blockage of the IFN-γ signaling pathway was confirmed with helminth-infected individuals having decreased up-regulation of IFN-γ-inducible genes (Mann-Whitney p &lt; 0.05). Hypo-methylation of the IL-4 pathway and DNA hyper-methylation of the Th1 pathway was confirmed by antigen-specific multidimensional flow cytometry demonstrating decreased TB-specific IFN-γ and TNF and increased IL-4 production by CD4+ T cells (Wilcoxon signed rank P &lt;0.05). In S.haematobium infected individuals, these DNA methylation and immune phenotypic changes persisted at least six months after successful deworming. This work demonstrates that helminth infection induces DNA methylation and immune perturbations that inhibit TB-specific immune control and that the duration of these changes are helminth-specific.

Trichomonas vaginalis is the most common non-viral sexually transmitted infection. 5-nitroimidazoles are the only FDA-approved medications for T. vaginalis treatment. However, 5-nitroimidazole resistance has been increasingly recognized and may occur in up to 10% of infections. We aimed to delineate mechanisms of T. vaginalis resistance using transcriptome profiling of metronidazole (MTZ)-resistant and sensitive T. vaginalis clinical isolates. In vitro, 5-nitroimidazole susceptibility testing was performed to determine minimum lethal concentrations (MLCs) for T. vaginalis isolates obtained from women who had failed treatment (n = 4) or were successfully cured (n = 4). RNA sequencing, bioinformatics, and biostatistical analyses were performed to identify differentially expressed genes (DEGs) in the MTZ-resistant vs. sensitive T. vaginalis isolates. RNA sequencing identified 304 DEGs, 134 upregulated genes and 170 downregulated genes in the resistant isolates. Future studies with more T. vaginalis isolates with a broad range of MLCs are needed to determine which genes may represent the best alternative targets in drug-resistant strains.

Schistosomiasis is a globally prevalent, debilitating disease that is poorly controlled by chemotherapy and for which no vaccine exists. While partial resistance in people may develop over time with repeated infections and treatments, some animals, including the brown rat (Rattus norvegicus), are only semi-permissive and have natural protection. To understand the basis of this protection, we explored the nature of the immune response in the brown rat to infection by Schistosoma mansoni. Infection leads to production of IgG to Infection leads to production of IgG to parasite glycoproteins parasite glycoproteins with complex-type N-glycans that contain a non-mammalian-type modification by core α2-Xylose and core α3-Fucose (core Xyl/Fuc). These epitopes are expressed on the surfaces of schistosomula and adult worms. Importantly, IgG to these epitopes can kill schistosomula by a complement-dependent process in vitro. Additionally, sera from both infected rhesus monkey and infected brown rat were capable of killing schistosomula in a manner inhibited by glycopeptides containing core Xyl/Fuc. These results demonstrate that protective antibodies to schistosome infections in brown rats and rhesus monkeys include IgG responses to the core Xyl/Fuc epitopes in surface-expressed N-glycans, and raise the potential of novel glyco-based vaccines that might be developed to combat this disease.

BACKGROUND: The only drugs approved by the U.S. Food and Drug Administration for oral treatment of trichomoniasis belong to the 5-nitroimidazole group. Most individuals infected with Trichomonas vaginalis can be cured with a standard treatment of metronidazole or tinidazole, but it is estimated that more than 159,000 people fail treatment each year. Although a minimal lethal concentration (MLC) corresponding to treatment failure has been reported for metronidazole, the MLC for tinidazole associated with treatment failure has not been determined. We conducted a study using T. vaginalis isolates from women with reported treatment success or failure to determine these values. METHODS: We measured MLCs of 47 isolates obtained from women who had failed metronidazole treatment, 33 isolates from women who had failed tinidazole treatment, and 48 isolates from women successfully cured with metronidazole. The cutoff was calculated as the 95th percentile of MLCs of susceptible isolates for each drug. RESULTS: Our data confirmed the MLC previously associated with metronidazole treatment failure is ≥50 μg/ml and identified the MLC associated with tinidazole treatment failure as ≥6.3 μg/ml. For metronidazole, the agreement between laboratory result and treatment outcome was 93.7%, for tinidazole this agreement was 88.9%. CONCLUSIONS: The T. vaginalis susceptibility assay is useful for determining whether 5-nitroimidazole treatment failure in persons with trichomoniasis can be attributed to drug resistance. These results are useful for establishing interpretive guidance of test results and MLC levels can help guide appropriate patient treatment.

WHO's 2021-30 road map for neglected tropical diseases (NTDs) outlines disease-specific and cross-cutting targets for the control, elimination, and eradication of NTDs in affected countries. For schistosomiasis, the criterion for elimination as a public health problem (EPHP) is defined as less than 1% prevalence of heavy-intensity infections (ie, 50 Schistosoma haematobium eggs per 10 mL of urine or 400 Schistosoma mansoni eggs per g of stool). However, we believe the evidence supporting this definition of EPHP is inadequate and the shifting distribution of schistosomiasis morbidity towards more subtle, rather than severe, morbidity in the face of large-scale control programmes requires guidelines to be adapted. In this Viewpoint, we outline the need for more accurate measures to develop a robust evidence-based monitoring and evaluation framework for schistosomiasis. Such a framework is crucial for achieving the goal of widespread EPHP of schistosomiasis and to meet the WHO road map targets. We encourage use of overall prevalence of schistosome infection (instead of the prevalence of heavy-intensity infections), development of species-dependent and age-dependent morbidity markers, and construction of a standardised monitoring and evaluation protocol.

BACKGROUND: Long-term persistence of Ebola virus (EBOV) in immunologically-privileged sites has been implicated in recent outbreaks of Ebola Virus Disease (EVD) in Guinea and the Democratic Republic of Congo. This study was designed to understand how the acute course of EVD, convalescence, and host immune and genetic factors may play a role in prolonged viral persistence in semen. METHODS: A cohort of 131 male EVD survivors in Liberia were enrolled in a case-case study. "Early clearers" were defined as those with two consecutive negative EBOV semen tests by real-time reverse transcriptase polymerase chain reaction (rRT-PCR) at least two weeks apart within 1 year after discharge from the Ebola Treatment Unit (ETU) or acute EVD. "Late clearers" had detectable EBOV RNA by rRT-PCR over one year following ETU discharge or acute EVD. Retrospective histories of their EVD clinical course were collected by questionnaire, followed by complete physical exams and blood work. RESULTS: Compared to early clearers, late clearers were older (median 42.5 years, p = 0.0001) and experienced fewer severe clinical symptoms (median 2, p = 0.006). Late clearers had more lens opacifications (OR 3.9, 95%CI 1.1-13.3, p = 0.03), after accounting for age, higher total serum IgG3 titers (p = 0.007) and increased expression of the HLA-C*03:04 allele (OR 0.14, 95% CI 0.02-0.70, p = 0.007). CONCLUSIONS: Older age, decreased illness severity, elevated total serum IgG3 and HLA-C*03:04 allele expression may be risk factors for the persistence of EBOV in the semen of EVD survivors. EBOV persistence in semen may also be associated with its persistence in other immunologically protected sites, such as the eye.

Trichomonas vaginalis is likely the most prevalent nonviral sexually transmitted infection, affecting an estimated 3.7 million women and men in the United States. Health disparities are prominent in the epidemiology of trichomoniasis, as African Americans are >4 times more likely to be infected than persons of other races. Since publication of the 2015 Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines, additional data have bolstered the importance of T. vaginalis infection sequelae in women, including increased risk of human immunodeficiency virus (HIV) acquisition, cervical cancer, preterm birth, and other adverse pregnancy outcomes. Less is known about the clinical significance of infection in men. Newly available diagnostic methods, including point-of-care assays and multiple nucleic acid amplification tests, can be performed on a variety of genital specimens in women and men, including urine, allowing more accurate and convenient testing and screening of those at risk for infection. Repeat and persistent infections are common in women; thus, rescreening at 3 months after treatment is recommended. In vitro antibiotic resistance to 5-nitroimidazole in T. vaginalis remains low (4.3%) but should be monitored. High rates of T. vaginalis among sexual partners of infected persons suggest a role for expedited partner treatment. A randomized controlled trial in HIV-uninfected women demonstrated that multidose metronidazole 500 mg twice daily for 7 days reduced the proportion of women with Trichomonas infection at 1 month test of cure compared with women receiving single-dose therapy (2 g). The 2-g single-dose oral metronidazole regimen remains the preferred treatment in men.

The WHO guidelines for monitoring and evaluating Schistosoma mansoni control programs are based on the Kato-Katz (KK) fecal examination method; however, there are limitations to its use, particularly in low prevalence areas. The point-of-care urine circulating cathodic antigen (POC-CCA) assay has emerged as a useful tool for mapping schistosomiasis prevalence, but its use in monitoring and evaluating control programs has not been evaluated. Before POC-CCA can be used for these programs, it must be determined how previous guidance based on the KK method can be translated to the POC-CCA assay; furthermore, its performance in different endemicity settings must be evaluated. Urine and stool specimens were collected from students attending public primary schools in western Kenya before mass treatment with praziquantel at baseline (51 schools), year 1 (45 schools), year 2 (34 schools), and year 3 (20 schools). Prevalence and infection intensity were determined by the KK method and POC-CCA assay. Changes in prevalence and intensity were compared within the strata of schools grouped according to the baseline prevalence determined by the KK method (0-10%, > 10-20%, > 20%). The prevalence determined by the POC-CCA assay was higher than that determined by the KK method at all time points for all strata. The prevalence determined by the KK method decreased from baseline to 2 and 3 years, as did infection intensity (with one exception). A corresponding decrease was not always replicated by the POC-CCA assay results. The POC-CCA assay did not perform as expected, and the concordance of results of the two tests was poor. Furthermore, there are emerging concerns regarding the specificity of the POC-CCA assay. Therefore, it is impossible to translate historical data and programmatic guidelines based on the KK method results to the POC-CCA assay.

BACKGROUND: Current World Health Organization guidelines utilize prevalence of heavy-intensity infections (PHIs), that is, ≥50 eggs per 10 mL of urine for Schistosoma haematobium and ≥400 eggs per gram of stool for S. mansoni, to determine whether a targeted area has controlled schistosomiasis morbidity or eliminated schistosomiasis as a public health problem. The relationship between these PHI categories and morbidity is not well understood. METHODS: School-age participants enrolled in schistosomiasis monitoring and evaluation cohorts from 2003 to 2008 in Burkina Faso, Mali, Niger, Tanzania, Uganda, and Zambia were surveyed for infection and morbidity at baseline and after 1 and 2 rounds of preventive chemotherapy. Logistic regression was used to compare morbidity prevalence among participants based on their school's PHI category. RESULTS: Microhematuria levels were associated with the S. haematobium PHI categories at all 3 time points. For any other S. haematobium or S. mansoni morbidity that was measured, PHI categories did not differentiate morbidity prevalence levels consistently. CONCLUSIONS: These analyses suggest that current PHI categorizations do not differentiate the prevalence of standard morbidity markers. A reevaluation of the criteria for schistosomiasis control is warranted.

BACKGROUND: Recent research suggests that schistosomiasis targets for morbidity control and elimination as a public health problem could benefit from a reanalysis. These analyses would define evidence-based targets that control programs could use to confidently assert that they had controlled or eliminated schistosomiasis as a public health problem. We estimated how low Schistosoma haematobium infection levels diagnosed by urine filtration in school-age children should be decreased so that microhematuria prevalence was at, or below, a "background" level of morbidity. METHODOLOGY: Data obtained from school-age children in Burkina Faso, Mali, Niger, Tanzania, and Zambia who participated in schistosomiasis monitoring and evaluation cohorts were reanalyzed before and after initiation of preventive chemotherapy. Bayesian models estimated the infection level prevalence probabilities associated with microhematuria thresholds ≤10%, 13%, or 15%. PRINCIPAL FINDINGS: An infection prevalence of 5% could be a sensible target for urogenital schistosomiasis morbidity control in children as microhematuria prevalence was highly likely to be below 10% in all surveys. Targets of 8% and 11% infection prevalence were highly likely to result in microhematuria levels less than 13% and 15%, respectively. By contrast, measuring heavy-intensity infections only achieves these thresholds at impractically low prevalence levels. CONCLUSIONS/SIGNIFICANCE: A target of 5%, 8%, or 11% urogenital schistosomiasis infection prevalence in school-age children could be used to determine whether a geographic area has controlled or eliminated schistosomiasis as a public health problem depending on the local background threshold of microhematuria.

BACKGROUND: World Health Organization (WHO) guidelines for measuring global progress in schistosomiasis control classify individuals with Schistosoma spp. infections based on the concentration of excreted eggs. We assessed the associations between WHO infection intensity categories and morbidity prevalence for selected S. haematobium and S. mansoni morbidities in school-age children. METHODOLOGY: A total of 22,488 children aged 6-15 years from monitoring and evaluation cohorts in Burkina Faso, Mali, Niger, Uganda, Tanzania, and Zambia from 2003-2008 were analyzed using Bayesian logistic regression. Models were utilized to evaluate associations between intensity categories and the prevalence of any urinary bladder lesion, any upper urinary tract lesion, microhematuria, and pain while urinating (for S. haematobium) and irregular hepatic ultrasound image pattern (C-F), enlarged portal vein, laboratory-confirmed diarrhea, and self-reported diarrhea (for S. mansoni) across participants with infection and morbidity data. PRINCIPAL FINDINGS: S. haematobium infection intensity categories possessed consistent morbidity prevalence across surveys for multiple morbidities and participants with light infections had elevated morbidity levels, compared to negative participants. Conversely, S. mansoni infection intensity categories lacked association with prevalence of the morbidity measures assessed. CONCLUSIONS/SIGNIFICANCE: Current status infection intensity categories for S. haematobium were associated with morbidity levels in school-age children, suggesting urogenital schistosomiasis morbidity can be predicted by an individual's intensity category. Conversely, S. mansoni infection intensity categories were not consistently indicative of childhood morbidity at baseline or during the first two years of a preventive chemotherapy control program.

Chronic intestinal schistosomiasis can cause severe hepatosplenic disease and is a neglected tropical disease of public health importance in sub-Saharan Africa, including Kenya. Although the goal of control programs is to reduce morbidity, milestones for program performance focus on reductions in prevalence and intensity of infection, rather than actual measures of morbidity. Using ultrasound to measure hepatosplenic disease severity is an accepted method of determining schistosomiasis-related morbidity; however, ultrasound has not historically been considered a field-deployable tool because of equipment limitations and unavailability of expertise. A point-of-care tablet-based ultrasound system was used to perform abdominal ultrasounds in a field investigation of schistosomiasis-related morbidity in western Kenya; during the study, other pathologies and pregnancies were also identified via ultrasound, and participants referred to care. Recent technological advances may make it more feasible to implement ultrasound as part of a control program and can also offer important benefits to the community.

BACKGROUND: Female genital schistosomiasis (FGS) affects up to 56 million women in sub-Saharan Africa and may increase risk of HIV infection. METHODS: To assess the association of schistosomiasis with HIV infection, we examined peer-reviewed literature published until December 31, 2018 and generated a pooled estimate for the odds ratio using Bayesian random effects models. RESULTS: Of the 364 abstracts identified, 26 were included in the summary. Eight reported odds ratios of the association between schistosomiasis and HIV; one reported a transmission hazard ratio (HR) of 1·8 (95% confidence interval [CI]: 1·2-2·6) among women and 1·4 (95% CI: 1·0-1·9) among men; 11 described the prevalence of schistosomiasis among HIV-positive persons (range, 1·5%-36·6%); and six reported the prevalence of HIV among persons with schistosomiasis (range, 5·8%-57·3%). Six studies were selected for quantitative analysis. The pooled estimate for the odds ratio of HIV among persons with schistosomiasis was 2·3 (95% CI: 1·2-4·3). CONCLUSIONS: We found a significant association of schistosomiasis with HIV. However, we could not generate a specific summary estimate for FGS. We provide a research agenda to determine the effect of FGS on HIV infection. WHO's policy on mass drug administration for schistosomiasis may prevent HIV.

Female genital schistosomiasis as a result of chronic infection with Schistosoma haematobium (commonly known as bilharzia) continues to be largely ignored by national and global health policy-makers. International attention for large-scale action against the disease focuses on whether it is a risk factor for the transmission of human immunodeficiency virus (HIV). Yet female genital schistosomiasis itself is linked to pain, bleeding and sub-or infertility, leading to social stigma, and is a common issue for women in schistosomiasis-endemic areas in sub-Saharan Africa. The disease should therefore be recognized as another component of a comprehensive health and human rights agenda for women and girls in Africa, alongside HIV and cervical cancer. Each of these three diseases has a targeted and proven preventive intervention: antiretroviral therapy and pre-exposure prophylaxis for HIV; human papilloma virus vaccine for cervical cancer; and praziquantel treatment for female genital schistosomiasis. We discuss how female genital schistosomiasis control can be integrated with HIV and cervical cancer care. Such a programme will be part of a broader framework of sexual and reproductive health and rights, women’s empowerment and social justice in Africa. Integrated approaches that join up multiple public health programmes have the potential to expand or create opportunities to reach more girls and women throughout their life course. We outline a pragmatic operational research agenda that has the potential to optimize joint implementation of a package of measures responding to the specific needs of girls and women.

BACKGROUND: Trichomonas vaginalis is the most common non-viral sexually transmitted infection. 5-Nitroimidazoles [metronidazole (MTZ) and tinidazole (TDZ)] are FDA-approved treatments. To better understand treatment failure, we conducted a systematic review on mechanisms of 5-nitroimidazole resistance. METHODS: PubMed, ScienceDirect and EMBASE databases were searched using keywords Trichomonas vaginalis, trichomoniasis, 5-nitroimidazole, metronidazole, tinidazole and drug resistance. Non-English language articles and articles on other treatments were excluded. RESULTS: The search yielded 606 articles, of which 550 were excluded, leaving 58 articles. Trichomonas vaginalis resistance varies and is higher with MTZ (2.2-9.6%) than TDZ (0-2%). Resistance can be aerobic or anaerobic and is relative rather than absolute. Differential expression of enzymes involved in trichomonad energy production and antioxidant defenses affects 5-nitroimidazole drug activation; reduced expression of pyruvate:ferredoxin oxidoreductase, ferredoxin, nitroreductase, hydrogenase, thioredoxin reductase and flavin reductase are implicated in drug resistance. Trichomonas vaginalis infection with Mycoplasma hominis or T. vaginalis virus has also been associated with resistance. Trichomonas vaginalis has two genotypes, with greater resistance seen in type 2 (vs type 1) populations. DISCUSSION: 5-Nitroimidazole resistance results from differential expression of enzymes involved in energy production or antioxidant defenses, along with genetic mutations in the T. vaginalis genome. Alternative treatments outside of the 5-nitroimidazole class are needed.

Schistosomiasis is among the most common parasitic diseases in the world, with over 142 million people infected in low- and middle-income countries. Measuring population-level transmission is centrally important in guiding schistosomiasis control programs. Traditionally, human Schistosoma mansoni infections have been detected using stool microscopy, which is logistically difficult at program scale and has low sensitivity when people have low infection burdens. We compared serological measures of transmission based on antibody response to S. mansoni soluble egg antigen (SEA) with stool-based measures of infection among 3,663 preschool-age children in an area endemic for S. mansoni in western Kenya. We estimated force of infection among children using the seroconversion rate and examined how it varied geographically and by age. At the community level, serological measures of transmission aligned with stool-based measures of infection (ρ = 0.94), and serological measures provided more resolution for between-community differences at lower levels of infection. Force of infection showed a clear gradient of transmission with distance from Lake Victoria, with 94% of infections and 93% of seropositive children in communities <1.5 km from the lake. Force of infection increased through age 3 y, by which time 65% (95% CI: 53%, 75%) of children were SEA positive in high-transmission communities-2 y before they would be reached by school-based deworming programs. Our results show that serologic surveillance platforms represent an important opportunity to guide and monitor schistosomiasis control programs, and that in high-transmission settings preschool-age children represent a key population missed by school-based deworming programs.

INTRODUCTION: Globally, schistosomes infect approximately 200 million people, with 90% of infections in sub-Saharan Africa. Schistosomiasis is hypothesized to increase HIV-1 acquisition risk, and multiple cross-sectional studies reported strong associations. We evaluated this hypothesis within four large prospective cohorts. METHODS: We conducted nested case-control analyses within three longitudinal cohorts of heterosexual HIV-1 serodiscordant couples and one female sex worker (FSW) cohort from Kenya and Uganda. The serodiscordant couples studies were conducted between 2004 and 2012 while the FSW cohort analysis included participant follow-up from 1993 to 2014. Cases HIV-1 seroconverted during prospective follow-up; three controls were selected per case. The presence of circulating anodic antigen in archived serum, collected prior to HIV-1 seroconversion, identified participants with active schistosomiasis; immunoblots determined the schistosome species. Data from serodiscordant couples cohorts were pooled, while the FSW cohort was analysed separately to permit appropriate confounder adjustment. RESULTS: We included 245 HIV-1 seroconverters and 713 controls from the serodiscordant couples cohorts and 330 HIV-1 seroconverters and 962 controls from the FSW cohort. The prevalence of active schistosomiasis was 20% among serodiscordant couples and 22% among FSWs. We found no association between schistosomiasis and HIV-1 acquisition risk among males (adjusted odds ratio (aOR) = 0.99, 95% CI 0.59 to 1.67) or females (aOR = 1.21, 95% CI 0.64 to 2.30) in serodiscordant couples. Similarly, in the FSW cohort we detected no association (adjusted incidence rate ratio (aIRR) = 1.11, 95% CI 0.83 to 1.50). Exploring schistosome species-specific effects, there was no statistically significant association between HIV-1 acquisition risk and Schistosoma mansoni (serodiscordant couples: aOR = 0.90, 95% CI 0.56 to 1.44; FSW: aIRR = 0.83, 95% CI 0.53 to 1.20) or Schistosoma haematobium (serodiscordant couples: aOR = 1.06, 95% CI 0.46 to 2.40; FSW: aIRR = 1.64, 95% CI 0.93 to 2.87) infection. CONCLUSIONS: Schistosomiasis was not a strong risk factor for HIV-1 acquisition in these four prospective studies. S. mansoni was responsible for the majority of schistosomiasis in these cohorts, and our results do not support the hypothesis that S. mansoni infection is associated with increased HIV-1 acquisition risk. S. haematobium infection was associated with a point estimate of elevated HIV-1 risk in the FSW cohort that was not statistically significant, and there was no trend towards a positive association in the serodiscordant couples cohorts.

Efforts to control Schistosoma mansoni infection depend on the ability of programs to effectively detect and quantify infection levels and adjust programmatic approaches based on these levels and program goals. One of the three major objectives of the Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) has been to develop and/or evaluate tools that would assist Neglected Tropical Disease program managers in accomplishing this fundamental task. The advent of a widely available point-of-care (POC) assay to detect schistosome circulating cathodic antigen (CCA) in urine with a rapid diagnostic test (the POC-CCA) in 2008 led SCORE and others to conduct multiple evaluations of this assay, comparing it with the Kato-Katz (KK) stool microscopy assay-the standard used for more than 45 years. This article describes multiple SCORE-funded studies comparing the POC-CCA and KK assays, the pros and cons of these assays, the use of the POC-CCA assay for mapping of S. mansoni infections in areas across the spectrum of prevalence levels, and the validation and recognition that the POC-CCA, although not infallible, is a highly useful tool to detect low-intensity infections in low-to-moderate prevalence areas. Such an assay is critical, as control programs succeed in driving down prevalence and intensity and seek to either maintain control or move to elimination of transmission of S. mansoni.

The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) was funded in 2008 to conduct research that would support country schistosomiasis control programs. As schistosomiasis prevalence decreases in many places and elimination is increasingly within reach, a sensitive and specific test to detect infection with Schistosoma mansoni and Schistosoma haematobium has become a pressing need. After obtaining broad input, SCORE supported Leiden University Medical Center (LUMC) to modify the serum-based antigen assay for use with urine, simplify the assay, and improve its sensitivity. The urine assay eventually contributed to several of the larger SCORE studies. For example, in Zanzibar, we demonstrated that urine filtration, the standard parasite egg detection diagnostic test for S. haematobium, greatly underestimated prevalence in low-prevalence settings. In Burundi and Rwanda, the circulating anodic antigen (CAA) assay provided critical information about the limitations of the stool-based Kato-Katz parasite egg-detection assay for S. mansoni in low-prevalence settings. Other SCORE-supported CAA work demonstrated that frozen, banked urine specimens yielded similar results to fresh ones; pooling of specimens may be a useful, cost-effective approach for surveillance in some settings; and the assay can be performed in local laboratories equipped with adequate centrifuge capacity. These improvements in the assay continue to be of use to researchers around the world. However, additional work will be needed if widespread dissemination of the CAA assay is to occur, for example, by building capacity in places besides LUMC and commercialization of the assay. Here, we review the evolution of the CAA assay format during the SCORE period with emphasis on urine-based applications.

The Schistosomiasis Consortium for Operational Research (SCORE) was funded in 2008 to improve the evidence base for control and elimination of schistosomiasis-better understanding of the systemic morbidities experienced by children in schistosomiasis-endemic areas and the response of these morbidities to treatment, being essential for updating WHO guidelines for mass drug administration (MDA) in endemic areas. This article summarizes the SCORE studies that aimed to gauge the impact of MDA-based treatment on schistosomiasis-related morbidities. Morbidity cohort studies were embedded in the SCORE's larger field studies of gaining control of schistosomiasis in Kenya and Tanzania. Following MDA, cohort children had less undernutrition, less portal vein dilation, and increased quality of life in Year 5 compared with baseline. We also conducted a pilot study of the Behavioral Assessment System for Children (BASC-2) in conjunction with the Kenya gaining control study, which demonstrated beneficial effects of treatment on classroom behavior. In addition, the SCORE's Rapid Answers Project performed systematic reviews of previously available data, providing two meta-analyses related to morbidity. The first documented children's infection-related deficits in school attendance and achievement and in formal tests of learning and memory. The second showed that greater reductions in egg output following drug treatment correlates significantly with reduced odds of most morbidities. Overall, these SCORE morbidity studies provided convincing evidence to support the use of MDA to improve the health of school-aged children in endemic areas. However, study findings also support the need to use enhanced metrics to fully assess and better control schistosomiasis-associated morbidity.

This report summarizes the design and outcomes of randomized controlled operational research trials performed by the Bill & Melinda Gates Foundation-funded Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) from 2009 to 2019. Their goal was to define the effectiveness and test the limitations of current WHO-recommended schistosomiasis control protocols by performing large-scale pragmatic trials to compare the impact of different schedules and coverage regimens of praziquantel mass drug administration (MDA). Although there were limitations to study designs and performance, analysis of their primary outcomes confirmed that all tested regimens of praziquantel MDA significantly reduced local Schistosoma infection prevalence and intensity among school-age children. Secondary analysis suggested that outcomes in locations receiving four annual rounds of MDA were better than those in communities that had treatment holiday years, in which no praziquantel MDA was given. Statistical significance of differences was obscured by a wider-than-expected variation in community-level responses to MDA, defining a persistent hot spot obstacle to MDA success. No MDA schedule led to elimination of infection, even in those communities that started at low prevalence of infection, and it is likely that programs aiming for elimination of transmission will need to add supplemental interventions (e.g., snail control, improvement in water, sanitation and hygiene, and behavior change interventions) to achieve that next stage of control. Recommendations for future implementation research, including exploration of the value of earlier program impact assessment combined with intensification of intervention in hot spot locations, are discussed.