Protective human IgE responses are promoted by comparable life-cycle dependent Tegument Allergen-Like expression in Schistosoma haematobium and Schistosoma mansoni infection.

Schistosoma haematobium is the most prevalent of the human-infecting schistosome species, causing significant morbidity in endemically exposed populations. Despite this, it has been relatively understudied compared to its fellow species, S. mansoni. Here we provide the first comprehensive characterization of the S. haematobium Tegument Allergen-Like protein family, a key protein family directly linked to protective immunity in S. mansoni infection. Comparable with observations for S. mansoni, parasite phylogenetic analysis and relative gene expression combined with host serological analysis support a cross-reactive relationship between S. haematobium TAL proteins, exposed to the host immune system as adult worms die, and closely related proteins, exposed during penetration by the infecting cercarial and early schistosomulae stages. Specifically, our results strengthen the evidence for host immunity driven by cross-reactivity between family members TAL3 and TAL5, establishing it for the first time for S. haematobium infection. Furthermore, we build upon this relationship to include the involvement of an additional member of the TAL protein family, TAL11 for both schistosome species. Finally, we show a close association between experience of infection and intensity of transmission and the development of protective IgE responses to these antigens, thus improving our knowledge of the mechanisms by which protective host immune responses develop. This knowledge will be critical in understanding how control efforts such as mass drug administration campaigns influence the development of host immunity and subsequent patterns of infection and disease within endemic populations.

Reconciling Egg- and Antigen-Based Estimates of Schistosoma mansoni Clearance and Reinfection: A Modeling Study.

BACKGROUND: Despite decades of interventions, 240 million people have schistosomiasis. Infections cannot be directly observed, and egg-based Kato-Katz thick smears lack sensitivity, affected treatment efficacy and reinfection rate estimates. The point-of-care circulating cathodic antigen (referred to from here as POC-CCA+) test is advocated as an improvement on the Kato-Katz method, but improved estimates are limited by ambiguities in the interpretation of trace results. METHOD: We collected repeated Kato-Katz egg counts from 210 school-aged children and scored POC-CCA tests according to the manufacturer's guidelines (referred to from here as POC-CCA+) and the externally developed G score. We used hidden Markov models parameterized with Kato-Katz; Kato-Katz and POC-CCA+; and Kato-Katz and G-Scores, inferring latent clearance and reinfection probabilities at four timepoints over six-months through a more formal statistical reconciliation of these diagnostics than previously conducted. Our approach required minimal but robust assumptions regarding trace interpretations. RESULTS: Antigen-based models estimated higher infection prevalence across all timepoints compared with the Kato-Katz model, corresponding to lower clearance and higher reinfection estimates. Specifically, pre-treatment prevalence estimates were 85% (Kato-Katz; 95% CI: 79%-92%), 99% (POC-CCA+; 97%-100%) and 98% (G-Score; 95%-100%). Post-treatment, 93% (Kato-Katz; 88%-96%), 72% (POC-CCA+; 64%-79%) and 65% (G-Score; 57%-73%) of those infected were estimated to clear infection. Of those who cleared infection, 35% (Kato-Katz; 27%-42%), 51% (POC-CCA+; 41%-62%) and 44% (G-Score; 33%-55%) were estimated to have been reinfected by 9-weeks. CONCLUSIONS: Treatment impact was shorter-lived than Kato-Katz-based estimates alone suggested, with lower clearance and rapid reinfection. At 3 weeks after treatment, longer-term clearance dynamics are captured. At 9 weeks after treatment, reinfection was captured, but failed clearance could not be distinguished from rapid reinfection. Therefore, frequent sampling is required to understand these important epidemiological dynamics.

Schistosomiasis - Assessing Progress toward the 2020 and 2025 Global Goals.

BACKGROUND: With the vision of "a world free of schistosomiasis," the World Health Organization (WHO) set ambitious goals of control of this debilitating disease and its elimination as a public health problem by 2020 and 2025, respectively. As these milestones become imminent, and if programs are to succeed, it is important to evaluate the WHO programmatic guidelines empirically. METHODS: We collated and analyzed multiyear cross-sectional data from nine national schistosomiasis control programs (in eight countries in sub-Saharan Africa and in Yemen). Data were analyzed according to schistosome species (Schistosoma mansoni or S. haematobium), number of treatment rounds, overall prevalence, and prevalence of heavy-intensity infection. Disease control was defined as a prevalence of heavy-intensity infection of less than 5% aggregated across sentinel sites, and the elimination target was defined as a prevalence of heavy-intensity infection of less than 1% in all sentinel sites. Heavy-intensity infection was defined as at least 400 eggs per gram of feces for S. mansoni infection or as more than 50 eggs per 10 ml of urine for S. haematobium infection. RESULTS: All but one country program (Niger) reached the disease-control target by two treatment rounds or less, which is earlier than projected by current WHO guidelines (5 to 10 years). Programs in areas with low endemicity levels at baseline were more likely to reach both the control and elimination targets than were programs in areas with moderate and high endemicity levels at baseline, although the elimination target was reached only for S. mansoni infection (in Burkina Faso, Burundi, and Rwanda within three treatment rounds). Intracountry variation was evident in the relationships between overall prevalence and heavy-intensity infection (stratified according to treatment rounds), a finding that highlights the challenges of using one metric to define control or elimination across all epidemiologic settings. CONCLUSIONS: These data suggest the need to reevaluate progress and treatment strategies in national schistosomiasis control programs more frequently, with local epidemiologic data taken into consideration, in order to determine the treatment effect and appropriate resource allocations and move closer to achieving the global goals. (Funded by the Children's Investment Fund Foundation and others.).

Paper-based microfluidics for DNA diagnostics of malaria in low resource underserved rural communities.

Rapid, low-cost, species-specific diagnosis, based upon DNA testing, is becoming important in the treatment of patients with infectious diseases. Here, we demonstrate an innovation that uses origami to enable multiplexed, sensitive assays that rival polymerase chain reactions (PCR) laboratory assays and provide high-quality, fast precision diagnostics for malaria. The paper-based microfluidic technology proposed here combines vertical flow sample-processing steps, including paper folding for whole-blood sample preparation, with an isothermal amplification and a lateral flow detection, incorporating a simple visualization system. Studies were performed in village schools in Uganda with individual diagnoses being completed in <50 min (faster than the standard laboratory-based PCR). The tests, which enabled the diagnosis of malaria species in patients from a finger prick of whole blood, were both highly sensitive and specific, detecting malaria in 98% of infected individuals in a double-blind first-in-human study. Our method was more sensitive than other field-based, benchmark techniques, including optical microscopy and industry standard rapid immunodiagnostic tests, both performed by experienced local healthcare teams (which detected malaria in 86% and 83% of cases, respectively). All assays were independently validated using a real-time double-blinded reference PCR assay. We not only demonstrate that advanced, low-cost DNA-based sensors can be implemented in underserved communities at the point of need but also highlight the challenges associated with developing and implementing new diagnostic technologies in the field, without access to laboratories or infrastructure.

Social network fragmentation and community health.

Community health interventions often seek to intentionally destroy paths between individuals to prevent the spread of infectious diseases. Immunizing individuals through direct vaccination or the provision of health education prevents pathogen transmission and the propagation of misinformation concerning medical treatments. However, it remains an open question whether network-based strategies should be used in place of conventional field approaches to target individuals for medical treatment in low-income countries. We collected complete friendship and health advice networks in 17 rural villages of Mayuge District, Uganda. Here we show that acquaintance algorithms, i.e., selecting neighbors of randomly selected nodes, were systematically more efficient in fragmenting all networks than targeting well-established community roles, i.e., health workers, village government members, and schoolteachers. Additionally, community roles were not good proxy indicators of physical proximity to other households or connections to many sick people. We also show that acquaintance algorithms were effective in offsetting potential noncompliance with deworming treatments for 16,357 individuals during mass drug administration (MDA). Health advice networks were destroyed more easily than friendship networks. Only an average of 32% of nodes were removed from health advice networks to reduce the percentage of nodes at risk for refusing treatment in MDA to below 25%. Treatment compliance of at least 75% is needed in MDA to control human morbidity attributable to parasitic worms and progress toward elimination. Our findings point toward the potential use of network-based approaches as an alternative to role-based strategies for targeting individuals in rural health interventions.

Profiling the best-performing community medicine distributors for mass drug administration: a comprehensive, data-driven analysis of treatment for schistosomiasis, lymphatic filariasis, and soil-transmitted helminths in Uganda.

BACKGROUND: The most prevalent neglected tropical diseases are treated through blanket drug distribution that is reliant on lay community medicine distributors (CMDs). Yet, treatment rates achieved by CMDs vary widely and it is not known which CMDs treat the most people. METHODS: In Mayuge District, Uganda, we tracked 6779 individuals (aged 1+ years) in 1238 households across 31 villages. Routine, community-based mass drug administration (MDA) was implemented for schistosomiasis, lymphatic filariasis, and soil-transmitted helminths. For each CMD, the percentage of eligible individuals treated (offered and ingested medicines) with at least one drug of praziquantel, albendazole, or ivermectin was examined. CMD attributes (more than 25) were measured, ranging from altruistic tendencies to socioeconomic characteristics to MDA-specific variables. The predictors of treatment rates achieved by CMDs were selected with least absolute shrinkage and selection operators and then analyzed in ordinary least squares regression with standard errors clustered by village. The influences of participant compliance and the ordering of drugs offered also were examined for the treatment rates achieved by CMDs. RESULTS: Overall, only 44.89% (3043/6779) of eligible individuals were treated with at least one drug. Treatment rates varied amongst CMDs from 0% to 84.25%. Treatment rate increases were associated (p value< 0.05) with CMDs who displayed altruistic biases towards their friends (13.88%), had friends who helped with MDA (8.43%), were male (11.96%), worked as fishermen/fishmongers (14.93%), and used protected drinking water sources (13.43%). Only 0.24% (16/6779) of all eligible individuals were noncompliant by refusing to ingest all offered drugs. Distributing praziquantel first was strongly, positively correlated (p value < 0.0001) with treatment rates for albendazole and ivermectin. CONCLUSIONS: These findings profile CMDs who treat the most people during routine MDA. Criteria currently used to select CMDs-community-wide meetings, educational attainment, age, years as a CMD, etc.-were uninformative. Participant noncompliance and the provision of praziquantel before albendazole and ivermectin did not negatively impact treatment rates achieved by CMDs. Engaging CMD friend groups with MDA, selecting CMDs who practise good preventative health behaviours, and including CMDs with high-risk occupations for endemic infections may improve MDA treatment rates. Evidence-based guidelines are needed to improve the monitoring, selection, and replacement of CMDs during MDA.

Schistosoma mansoni schistosomula antigens induce Th1/Pro-inflammatory cytokine responses.

Larvae of Schistosoma (schistosomula) are highly susceptible to host immune responses and are attractive prophylactic vaccine targets, although cellular immune responses against schistosomula antigens in endemic human populations are not well characterized. We collected blood and stool from 54 Schistosoma mansoni-infected Ugandans, isolated peripheral blood mononuclear cells and stimulated them for 24 hours with schistosome adult worm and soluble egg antigens (AWA and SEA), along with schistosomula recombinant proteins rSmKK7, Lymphocyte Antigen 6 isoforms (rSmLy6A and rSmLy6B), tetraspanin isoforms (rSmTSP6 and rSmTSP7). Cytokines, chemokines and growth factors were measured in the culture supernatants using a multiplex luminex assay, and infection intensity was determined before and at 1 year after praziquantel (PZQ) treatment using the Kato-Katz method. Cellular responses were grouped and the relationship between groups of correlated cellular responses and infection intensity before and after PZQ treatment was investigated. AWA and SEA induced mainly Th2 responses. In contrast, rSmLy6B, rSmTSP6 and rSmTSP7 induced Th1/pro-inflammatory responses. While recombinant antigens rSmKK7 and rSmLy6A did not induce a Th1/pro-inflammatory response, they had an association with pre-treatment infection intensity after adjusting for age and sex. Testing more schistosomula antigens using this approach could provide immune-epidemiology identifiers necessary for prioritizing next generation schistosomiasis vaccine candidates.

Antibody responses to Schistosoma mansoni schistosomula antigens.

While antigens from Schistosoma schistosomula have been suggested as potential vaccine candidates, the association between antibody responses with schistosomula antigens and infection intensity at reinfection is not well known. Schistosoma mansoni-infected individuals were recruited from a schistosomiasis endemic area in Uganda (n = 372), treated with 40 mg/kg praziquantel (PZQ) and followed up at five weeks and at one year post-treatment. Pre-treatment and five weeks post-treatment immunoglobulin (Ig) E, IgG1 and IgG4 levels against recombinant schistosomula antigens rSmKK7, rSmLy6A, rSmLy6B and rSmTSP7 were measured using ELISA. Factors associated with detectable pre-treatment or post-treatment antibody response against the schistosomula antigens and the association between five-week antibody responses and one year post-treatment reinfection intensity among antibody responders were examined. Being male was associated with higher pre-treatment IgG1 to rSmKK7, rSmLy6a and AWA. Five weeks post-treatment antibody responses against schistosomula antigens were not associated with one year post-treatment reinfection intensity among antibody responders' antibody levels against rSmKK7, rSmLy6B and rSmTSP7 dropped, but increased against rSmLy6A, AWA and SEA at five weeks post-treatment among antibody responders. S. mansoni-infected individuals exhibit detectable antibody responses to schistosomula antigens that are affected by treatment. These findings indicate that schistosomula antigens induce highly varied antibody responses and could have implications for vaccine development.

Profiling Nonrecipients of Mass Drug Administration for Schistosomiasis and Hookworm Infections: A Comprehensive Analysis of Praziquantel and Albendazole Coverage in Community-Directed Treatment in Uganda.

BACKGROUND: Repeated mass drug administration (MDA) with preventive chemotherapies is the mainstay of morbidity control for schistosomiasis and soil-transmitted helminths, yet the World Health Organization recently reported that less than one-third of individuals who required preventive chemotherapies received treatment. METHODS: Coverage of community-directed treatment with praziquantel (PZQ) and albendazole (ALB) was analyzed in 17 villages of Mayuge District, Uganda. National drug registers, household questionnaires, and parasitological surveys were collected to track 935 individuals before and after MDA. Multilevel logistic regressions, including household and village effects, were specified with a comprehensive set of socioeconomic and parasitological variables. The factors predicting who did not receive PZQ and ALB from community medicine distributors were identified. RESULTS: Drug receipt was correlated among members within a household, and nonrecipients of PZQ or ALB were profiled by household-level socioeconomic factors. Individuals were less likely to receive either PZQ or ALB if they had a Muslim household head or low home quality, belonged to the minority tribe, or had settled for more years in their village. Untreated individuals were also more likely to belong to households that did not purify drinking water, had no home latrine, and had no members who were part of the village government. CONCLUSIONS: The findings demonstrate how to locate and target individuals who are not treated in MDA. Infection risk factors were not informative. In particular, age, gender, and occupation were unable to identify non-recipients, although World Health Organization guidelines rely on these factors. Individuals of low socioeconomic status, minority religions, and minority tribes can be targeted to expand MDA coverage.

Reduced Efficacy of Praziquantel Against Schistosoma mansoni Is Associated With Multiple Rounds of Mass Drug Administration.

BACKGROUND: Mass drug administration (MDA) with praziquantel is the cornerstone of schistosomiasis control in sub-Saharan Africa. The effectiveness of this strategy is dependent on the continued high efficacy of praziquantel; however, drug efficacy is rarely monitored using appropriate statistical approaches that can detect early signs of wane. METHODS: We conducted a repeated cross-sectional study, examining children infected with Schistosoma mansoni from 6 schools in Uganda that had previously received between 1 and 9 rounds of MDA with praziquantel. We collected up to 12 S. mansoni egg counts from 414 children aged 6-12 years before and 25-27 days after treatment with praziquantel. We estimated individual patient egg reduction rates (ERRs) using a statistical model to explore the influence of covariates, including the number of prior MDA rounds. RESULTS: The average ERR among children within schools that had received 8 or 9 previous rounds of MDA (95% Bayesian credible interval [BCI], 88.23%-93.64%) was statistically significantly lower than the average in schools that had received 5 rounds (95% BCI, 96.13%-99.08%) or 1 round (95% BCI, 95.51%-98.96%) of MDA. We estimate that 5.11%, 4.55%, and 16.42% of children from schools that had received 1, 5, and 8-9 rounds of MDA, respectively, had ERRs below the 90% threshold of optimal praziquantel efficacy set by the World Health Organization. CONCLUSIONS: The reduced efficacy of praziquantel in schools with a higher exposure to MDA may pose a threat to the effectiveness of schistosomiasis control programs. We call for the efficacy of anthelmintic drugs used in MDA to be closely monitored.

A latent Markov modelling approach to the evaluation of circulating cathodic antigen strips for schistosomiasis diagnosis pre- and post-praziquantel treatment in Uganda.

Regular treatment with praziquantel (PZQ) is the strategy for human schistosomiasis control aiming to prevent morbidity in later life. With the recent resolution on schistosomiasis elimination by the 65th World Health Assembly, appropriate diagnostic tools to inform interventions are keys to their success. We present a discrete Markov chains modelling framework that deals with the longitudinal study design and the measurement error in the diagnostic methods under study. A longitudinal detailed dataset from Uganda, in which one or two doses of PZQ treatment were provided, was analyzed through Latent Markov Models (LMMs). The aim was to evaluate the diagnostic accuracy of Circulating Cathodic Antigen (CCA) and of double Kato-Katz (KK) faecal slides over three consecutive days for Schistosoma mansoni infection simultaneously by age group at baseline and at two follow-up times post treatment. Diagnostic test sensitivities and specificities and the true underlying infection prevalence over time as well as the probabilities of transitions between infected and uninfected states are provided. The estimated transition probability matrices provide parsimonious yet important insights into the re-infection and cure rates in the two age groups. We show that the CCA diagnostic performance remained constant after PZQ treatment and that this test was overall more sensitive but less specific than single-day double KK for the diagnosis of S. mansoni infection. The probability of clearing infection from baseline to 9 weeks was higher among those who received two PZQ doses compared to one PZQ dose for both age groups, with much higher re-infection rates among children compared to adolescents and adults. We recommend LMMs as a useful methodology for monitoring and evaluation and treatment decision research as well as CCA for mapping surveys of S. mansoni infection, although additional diagnostic tools should be incorporated in schistosomiasis elimination programs.

Baseline Prevalence of Trachoma in Refugee Settlements in Uganda: Results of 11 Population-based Surveys.

PURPOSE: There are several settlements in the Northern and Western Regions of Uganda serving refugees from South Sudan and Democratic Republic of Congo (DRC), respectively. Trachoma prevalence surveys were conducted in a number of those settlements with the aim of determining whether interventions for trachoma are required. METHODS: An evaluation unit (EU) was defined as all refugee settlements in one district. Cross-sectional population-based trachoma prevalence survey methodologies designed to adhere to World Health Organization recommendations were deployed in 11 EUs to assess prevalence of trachomatous inflammation-follicular (TF) in 1-9-year-olds and trachomatous trichiasis (TT) unknown to the health system in ≥15-year-olds. Household-level water, sanitation and hygiene coverage was also assessed in study populations. RESULTS: A total of 40,892 people were examined across 11 EUs between 2018 and 2020. The prevalence of TF in 1-9-year-olds was <5% in all EUs surveyed. The prevalence of trachomatous trichiasis (TT) unknown to the health system in ≥15-year-olds was <0.2% in 5 out of 11 EUs surveyed and ≥0.2% in the remaining 6 EUs. A high proportion of households had improved water sources, but a low proportion had improved latrines or quickly (within a 30-minute return journey) accessible water sources. CONCLUSIONS: Implementation of the antibiotic, facial cleanliness and environmental improvement components of the SAFE strategy is not needed for the purposes of trachoma's elimination as a public health problem in these refugee settlements; however, intervention with TT surgery is needed in six EUs. Since instability continues to drive displacement of people from South Sudan and DRC into Uganda, there is likely to be a high rate of new arrivals to the settlements over the coming years. These populations may therefore have trachoma surveillance needs that are distinct from the surrounding non-refugee communities.

Progressive cross-reactivity in IgE responses: an explanation for the slow development of human immunity to schistosomiasis?

People in regions of Schistosoma mansoni endemicity slowly acquire immunity, but why this takes years to develop is still not clear. It has been associated with increases in parasite-specific IgE, induced, some investigators propose, to antigens exposed during the death of adult worms. These antigens include members of the tegumental-allergen-like protein family (TAL1 to TAL13). Previously, in a group of S. mansoni-infected Ugandan males, we showed that IgE responses to three TALs expressed in worms (TAL1, -3, and -5) became more prevalent with age. Now, in a subcohort we examined associations of these responses with resistance to reinfection and use the data to propose a mechanism for the slow development of immunity. IgE was measured 9 weeks posttreatment and at reinfection at 2 years (n = 144). An anti-TAL5 IgE (herein referred to as TAL5 IgE) response was associated with reduced reinfection even after adjusting for age using regression analysis (geometric mean odds ratio, 0.24; P = 0.016). TAL5 IgE responders were a subset of TAL3 IgE responders, themselves a subset of TAL1 responders. TAL3 IgE and TAL5 IgE were highly cross-reactive, with TAL3 the immunizing antigen and TAL5 the cross-reactive antigen. Transcriptional and translational studies show that TAL3 is most abundant in adult worms and that TAL5 is most abundant in infectious larvae. We propose that in chronic schistosomiasis, older individuals have repeatedly experienced IgE antigens exposed when adult worms die (e.g., TAL3) and that this leads to increasing cross-reactivity with antigens of invading larvae (e.g., TAL5). Progressive accumulation of worm/larvae cross-reactivity could explain the age-dependent immunity observed in areas of endemicity.

Variation in water contact behaviour and risk of Schistosoma mansoni (re)infection among Ugandan school-aged children in an area with persistent high endemicity.

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.

Translating From Egg- to Antigen-Based Indicators for Schistosoma mansoni Elimination Targets: A Bayesian Latent Class Analysis Study.

Schistosomiasis is a parasitic disease affecting over 240-million people. World Health Organization (WHO) targets for Schistosoma mansoni elimination are based on Kato-Katz egg counts, without translation to the widely used, urine-based, point-of-care circulating cathodic antigen diagnostic (POC-CCA). We aimed to standardize POC-CCA score interpretation and translate them to Kato-Katz-based standards, broadening diagnostic utility in progress towards elimination. A Bayesian latent-class model was fit to data from 210 school-aged-children over four timepoints pre- to six-months-post-treatment. We used 1) Kato-Katz and established POC-CCA scoring (Negative, Trace, +, ++ and +++), and 2) Kato-Katz and G-Scores (a new, alternative POC-CCA scoring (G1 to G10)). We established the functional relationship between Kato-Katz counts and POC-CCA scores, and the score-associated probability of true infection. This was combined with measures of sensitivity, specificity, and the area under the curve to determine the optimal POC-CCA scoring system and positivity threshold. A simulation parametrized with model estimates established antigen-based elimination targets. True infection was associated with POC-CCA scores of ≥ + or ≥G3. POC-CCA scores cannot predict Kato-Katz counts because low infection intensities saturate the POC-CCA cassettes. Post-treatment POC-CCA sensitivity/specificity fluctuations indicate a changing relationship between egg excretion and antigen levels (living worms). Elimination targets can be identified by the POC-CCA score distribution in a population. A population with ≤2% ++/+++, or ≤0.5% G7 and above, indicates achieving current WHO Kato-Katz-based elimination targets. Population-level POC-CCA scores can be used to access WHO elimination targets prior to treatment. Caution should be exercised on an individual level and following treatment, as POC-CCAs lack resolution to discern between WHO Kato-Katz-based moderate- and high-intensity-infection categories, with limited use in certain settings and evaluations.

Effect of preventive chemotherapy with praziquantel on schistosomiasis among school-aged children in sub-Saharan Africa: a spatiotemporal modelling study.

BACKGROUND: Over the past 20 years, schistosomiasis control has been scaled up. Preventive chemotherapy with praziquantel is the main intervention. We aimed to assess the effect of preventive chemotherapy on schistosomiasis prevalence in sub-Saharan Africa, comparing 2000-10 with 2011-14 and 2015-19. METHODS: In this spatiotemporal modelling study, we analysed survey data from school-aged children (aged 5-14 years) in 44 countries across sub-Saharan Africa. The data were extracted from the Global Neglected Tropical Diseases database and augmented by 2018 and 2019 survey data obtained from disease control programmes. Bayesian geostatistical models were fitted to Schistosoma haematobium and Schistosoma mansoni survey data. The models included data on climatic predictors obtained from satellites and other open-source environmental databases and socioeconomic predictors obtained from various household surveys. Temporal changes in Schistosoma species prevalence were estimated by a categorical variable with values corresponding to the three time periods (2000-10, 2011-14, and 2015-19) during which preventive chemotherapy interventions were scaled up. FINDINGS: We identified 781 references with relevant geolocated schistosomiasis survey data for 2000-19. There were 19 166 unique survey locations for S haematobium and 23 861 for S mansoni, of which 77% (14 757 locations for S haematobium and 18 372 locations for S mansoni) corresponded to 2011-19. Schistosomiasis prevalence among school-aged children in sub-Saharan Africa decreased from 23·0% (95% Bayesian credible interval 22·1-24·1) in 2000-10 to 9·6% (9·1-10·2) in 2015-19, an overall reduction of 58·3%. The reduction of S haematobium was 67·9% (64·6-71·1) and that of S mansoni 53·6% (45·2-58·3) when comparing 2000-10 with 2015-19. INTERPRETATION: Our model-based estimates suggest that schistosomiasis prevalence in sub-Saharan Africa has decreased considerably, most likely explained by the scale-up of preventive chemotherapy. There is a need to consolidate gains in the control of schistosomiasis by means of preventive chemotherapy, coupled with other interventions to interrupt disease transmission. FUNDING: European Research Council and WHO.

Schistosoma mansoni infection risk for school-aged children clusters within households and is modified by distance to freshwater bodies.

BACKGROUND: The interaction of socio-demographic and ecological factors with Schistosoma mansoni (S. mansoni) infection risk by age and the household clustering of infections between individuals are poorly understood. METHODS: This study examined 1,832 individuals aged 5-90 years across 916 households in Mayuge District, Uganda. S. mansoni infection status and intensity were measured using Kato-Katz microscopy. Socio-demographic and ecological factors were examined as predictors of infection status and intensity using logistic and negative binomial regression models, respectively, with standard errors clustered by household. A subgroup analysis of children was conducted to examine the correlation of infection status between children and their caretakers. FINDINGS: Infection varied within age groups based on the distance to Lake Victoria. Children aged 9-17 years and young adults aged 18-29 years who lived ≤0.50km from Lake Victoria were more likely to be infected compared to individuals of the same age who lived further away from the lake. Infections clustered within households. Children whose caretakers were heavily infected were 2.67 times more likely to be infected. CONCLUSION: These findings demonstrate the focality of schistosome transmission and its dependence on socio-demographic, ecological and household factors. Future research should investigate the sampling of households within communities as a means of progressing towards precision mapping of S. mansoni infections.

Schistosomiasis Morbidity Hotspots: Roles of the Human Host, the Parasite and Their Interface in the Development of Severe Morbidity.

Schistosomiasis is the second most important human parasitic disease in terms of socioeconomic impact, causing great morbidity and mortality, predominantly across the African continent. For intestinal schistosomiasis, severe morbidity manifests as periportal fibrosis (PPF) in which large tracts of macro-fibrosis of the liver, visible by ultrasound, can occlude the main portal vein leading to portal hypertension (PHT), sequelae such as ascites and collateral vasculature, and ultimately fatalities. For urogenital schistosomiasis, severe morbidity manifests as pathology throughout the urinary system and genitals, and is a definitive cause of squamous cell bladder carcinoma. Preventative chemotherapy (PC) programmes, delivered through mass drug administration (MDA) of praziquantel (PZQ), have been at the forefront of schistosomiasis control programmes in sub-Saharan Africa since their commencement in Uganda in 2003. However, despite many successes, 'biological hotspots' (as distinct from 'operational hotspots') of both persistent high transmission and morbidity remain. In some areas, this failure to gain control of schistosomiasis has devastating consequences, with not only persistently high infection intensities, but both "subtle" and severe morbidity remaining prevalent. These hotspots highlight the requirement to revisit research into severe morbidity and its mechanisms, a topic that has been out of favor during times of PC implementation. Indeed, the focality and spatially-structured epidemiology of schistosomiasis, its transmission persistence and the morbidity induced, has long suggested that gene-environmental-interactions playing out at the host-parasite interface are crucial. Here we review evidence of potential unique parasite factors, host factors, and their gene-environmental interactions in terms of explaining differential morbidity profiles in the human host. We then take the situation of schistosomiasis mansoni within the Albertine region of Uganda as a case study in terms of elucidating the factors behind the severe morbidity observed and the avenues and directions for future research currently underway within a new research and clinical trial programme (FibroScHot).

Residence Time, Water Contact, and Age-driven Schistosoma mansoni Infection in Hotspot Communities in Uganda.

Schistosomiasis is the second most important parasitic infection after malaria in terms of its socioeconomic impact and is endemic in 78 countries. It affects more than 240 million people worldwide, with 90% of cases occurring in sub-Saharan Africa. In Uganda, Schistosoma mansoni is the most common species, with more than seven million people infected and 17 million living at risk despite mass drug administration (MDA) of praziquantel initiated more than 16 years ago. There has been a shift in the WHO schistosomiasis goals from controlling morbidity to elimination as a public health problem. Understanding the drivers of infection in persistent transmission hotspots despite ongoing control interventions is paramount. We conducted a cross-sectional epidemiological study of 381 individuals in Bugoto community, Mayuge district, Eastern Uganda, along with a structured survey to ascertain drivers of S. mansoni infection. Bugoto has had community-wide MDA since 2004. We detected a S. mansoni prevalence of 52% across the whole community and a prevalence of 71% in school-age children. This qualifies Bugoto as a highly endemic community according to WHO guidelines. Using a multivariate logistic regression, we found that S. mansoni infection was best explained by age group, longer residence times, and any daily contact with lake water. Schistosoma mansoni infection remains a large burden across this community. This study identifies opportunities for interventions that reduce lake water contact, expand treatment eligibility to all at risk, and improve MDA coverage for long-term residents in these settings to control schistosomiasis in persistent transmission hotspots.

Harnessing technology and portability to conduct molecular epidemiology of endemic pathogens in resource-limited settings.

Improvements in genetic and genomic technology have enabled field-deployable molecular laboratories and these have been deployed in a variety of epidemics that capture headlines. In this editorial, we highlight the importance of building physical and personnel capacity in low and middle income countries to deploy these technologies to improve diagnostics, understand transmission dynamics and provide feedback to endemic communities on actionable timelines. We describe our experiences with molecular field research on schistosomiasis, trypanosomiasis and rabies and urge the wider tropical medicine community to embrace these methods and help build capacity to benefit communities affected by endemic infectious diseases.