A general framework to support cost-efficient fecal egg count methods and study design choices for large-scale STH deworming programs-monitoring of therapeutic drug efficacy as a case study.

BACKGROUND: Soil-transmitted helminth (STH) control programs currently lack evidence-based recommendations for cost-efficient survey designs for monitoring and evaluation. Here, we present a framework to provide evidence-based recommendations, using a case study of therapeutic drug efficacy monitoring based on the examination of helminth eggs in stool. METHODS: We performed an in-depth analysis of the operational costs to process one stool sample for three diagnostic methods (Kato-Katz, Mini-FLOTAC and FECPAKG2). Next, we performed simulations to determine the probability of detecting a truly reduced therapeutic efficacy for different scenarios of STH species (Ascaris lumbricoides, Trichuris trichiura and hookworms), pre-treatment infection levels, survey design (screen and select (SS); screen, select and retest (SSR) and no selection (NS)) and number of subjects enrolled (100-5,000). Finally, we integrated the outcome of the cost assessment into the simulation study to estimate the total survey costs and determined the most cost-efficient survey design. PRINCIPAL FINDINGS: Kato-Katz allowed for both the highest sample throughput and the lowest cost per test, while FECPAKG2 required both the most laboratory time and was the most expensive. Counting of eggs accounted for 23% (FECPAKG2) or ≥80% (Kato-Katz and Mini-FLOTAC) of the total time-to-result. NS survey designs in combination with Kato-Katz were the most cost-efficient to assess therapeutic drug efficacy in all scenarios of STH species and endemicity. CONCLUSIONS/SIGNIFICANCE: We confirm that Kato-Katz is the fecal egg counting method of choice for monitoring therapeutic drug efficacy, but that the survey design currently recommended by WHO (SS) should be updated. Our generic framework, which captures laboratory time and material costs, can be used to further support cost-efficient choices for other important surveys informing STH control programs. In addition, it can be used to explore the value of alternative diagnostic techniques, like automated egg counting, which may further reduce operational costs. TRIAL REGISTRATION: ClinicalTrials.gov NCT03465488.

Impact of a 5-Year Mass Drug Administration Programme for Soil-Transmitted Helminthiases on the Spatial Distribution of Childhood Anaemia in Burundi from 2007 to 2011.

Background: Childhood anaemia affects 1.8 billion people globally. Little is known about the long-term impact of mass drug administration (MDA) for the control of soil-transmitted helminthiases (STH) on the spatiotemporal variation of anaemia prevalence and severity. We describe the long-term spatiotemporal impact of a 5-year STH MDA programme (2007−2011) on the prevalence of anaemia and anaemia severity in school-aged children (SAC) in Burundi. Methodology/Principal Findings: We used annual haemoglobin concentration and STH data collected during 2007−2011 in 31 schools in Burundi. Spatial dependence in prevalence and severity of anaemia was assessed using semivariograms. Bayesian geostatistical models were developed to (a) quantify the role of STH (adjusted for other anaemia determinants) in the spatiotemporal distribution of anaemia prevalence/severity, and (b) predict the geographical variation of both outcomes across Burundi. Adjusted population data were used to estimate the geographical distribution of the number of SAC at risk of anaemia and with low and moderate/severe anaemia. Infections with Ascaris lumbricoides and Trichuris trichiura were positively and significantly associated with childhood anaemia; hookworm infections were not. A significant decrease in anaemia prevalence, from 40−50% (2008) to 10−20% (2011) was predicted in western areas. The predicted prevalence of low-severity anaemia decreased from 40−50% (2008) to <20% (2011) in southern and eastern areas. Moderate/high-severity anaemia was concentrated in western regions of Burundi, with pockets of moderate/high-severity anaemia in central and northern regions in 2008. The overall number of predicted anaemic children decreased from 443,657 (2008) to 232,304 (2011), with a resurgence after MDA disruption in 2010 (to 480,605). Prevalence of low- and moderate-severity anaemia was higher in boys than in girls. Conclusions/Significance: Despite ongoing MDA, the prevalence of anaemia in SAC remained high and increased in certain parts of the country. It is recommended that MDA programmes targeting STH are complemented with specific anaemia interventions.

A systematic literature review of schistosomiasis in urban and peri-urban settings.

BACKGROUND: Schistosomiasis is a parasitic disease caused by trematode worms of the genus Schistosoma and belongs to the neglected tropical diseases. The disease has been reported in 78 countries, with around 290.8 million people in need of treatment in 2018. Schistosomiasis is predominantly considered a rural disease with a subsequent focus of research and control activities in rural settings. Over the past decades, occurrence and even expansion of schistosomiasis foci in peri-urban and urban settings have increasingly been observed. Rural-urban migration in low- and middle-income countries and subsequent rapid and unplanned urbanization are thought to explain these observations. Fifty-five percent (55%) of the world population is already estimated to live in urban areas, with a projected increase to 68% by 2050. In light of rapid urbanization and the efforts to control morbidity and ultimately achieve elimination of schistosomiasis, it is important to deepen our understanding of the occurrence, prevalence, and transmission of schistosomiasis in urban and peri-urban settings. A systematic literature review looking at urban and peri-urban schistosomiasis was therefore carried out as a first step to address the research and mapping gap. METHODOLOGY: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic computer-aided literature review was carried out using PubMed, ScienceDirect, and the World Health Organization Database in November 2019, which was updated in March 2020. Only papers for which at least the abstract was available in English were used. Relevant publications were screened, duplicates were removed, guidelines for eligibility were applied, and eligible studies were reviewed. Studies looking at human Schistosoma infections, prevalence, and intensity of infection in urban and peri-urban settings were included as well as those focusing on the intermediate host snails. PRINCIPAL FINDINGS: A total of 248 publications met the inclusion criteria. The selected studies confirm that schistosomiasis is prevalent in peri-urban and urban areas in the countries assessed. Earlier studies report higher prevalence levels in urban settings compared to data extracted from more recent publications, yet the challenge of migration, rapid uncontrolled urbanization, and resulting poor living conditions highlight the potential for continuous or even newly established transmission to take place. CONCLUSIONS: The review indicates that schistosomiasis has long existed in urban and peri-urban areas and remains a public health problem. There is, however, a challenge of comparability of settings due to the lack of a clear definition of what constitutes urban and peri-urban. There is a pressing need for improved monitoring of schistosomiasis in urban communities and consideration of treatment strategies.

The history of the neglected tropical disease movement.

The history of the neglected tropical disease movement is seen through the lens of authors who worked during the last 4 decades in different roles and in different settings, from Western-based laboratories to clinical roles in endemic countries and in critical policy roles in the World Health Organization (WHO). The authors seek to identify key players from the introduction of the word 'neglected' by the late Kenneth Warren in his Rockefeller Foundation-supported Great Neglected Diseases of Mankind movement through to the more recent developments after the London Declaration of 2012. The role of the various actors-endemic countries, major pharmaceutical companies, the WHO, non-government development organizations, bilateral donors and academia-are discussed. The critical events and decisions are highlighted that were essential enabling factors in creating a viable and successful movement and with a resultant massive global public health and antipoverty impact. The importance of advocacy is emphasized in creating the momentum to establish a globally recognized public health 'brand' as a target in the United Nations Sustainable Development Goals.

Evaluating the impact of biannual school-based and community-wide treatment on urogenital schistosomiasis in Niger.

BACKGROUND: The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) coordinated a five-year study implemented in several countries, including Niger, to provide an evidence-base for programmatic decisions regarding cost-effective approaches to preventive chemotherapy for schistosomiasis control. METHODS: This was a cluster-randomised trial investigating six possible combinations of annual or biannual community-wide treatment (CWT), school-based treatment (SBT), and holidays from mass treatment over four years. The most intense arm involved two years of annual CWT followed by 2 years of biannual CWT, while the least intensive arm involved one year of annual SBT followed by a year without treatment and two more years of annual SBT. The primary outcome of interest was prevalence and intensity of Schistosoma haematobium among 100 children aged 9-12 years sampled each year. In addition, 100 children aged 5-8 years in their first year of school and 50 adults (aged 20-55 years) were tested in the first and final fifth year of the study. RESULTS: In total, data were collected from 167,500 individuals across 225 villages in nine districts within the Niger River valley, Western Niger. Overall, the prevalence of S. haematobium decreased from baseline to Year 5 across all study arms. The relative reduction of prevalence was greater in biannual compared with annual treatment across all arms; however, the only significant difference was seen in areas with a high starting prevalence. Although adults were not targeted for treatment in SBT arms, a statistically significant decrease in prevalence among adults was seen in moderate prevalence areas receiving biannual (10.7% to 4.8%) SBT (P < 0.001). Adults tested in the annual SBT group also showed a decrease in prevalence between Year 1 and Year 5 (12.2% to 11.0%), but this difference was not significant. CONCLUSIONS: These findings are an important consideration for schistosomiasis control programmes that are considering elimination and support the idea that scaling up the frequency of treatment rounds, particularly in areas of low prevalence, will not eliminate schistosomiasis. Interestingly, the finding that prevalence decreased among adults in SBT arms suggests that transmission in the community can be reduced, even where only school children are being treated, which could have logistical and cost-saving implications for the national control programmes.

National mapping of soil-transmitted helminth and schistosome infections in Ethiopia.

BACKGROUND: An accurate understanding of the geographical distributions of both soil-transmitted helminths (STHs; Ascaris lumbricoides, Trichuris trichiura, and the hookworms Necator americanus and Ancylostoma duodenale) and schistosomes (SCH; Schistosoma mansoni and S. haematobium) is pivotal to be able to effectively design and implement mass drug administration (MDA) programmes. The objective of this study was to provide up-to-date data on the distribution of both STH and SCH in Ethiopia to inform the design of the national control program and to be able to efficiently achieve the 75% MDA coverage target set by the WHO. METHODS: Between 2013 and 2015, we assessed the distributions of STH and SCH infections in a nationwide survey covering 153,238 school-aged children (aged 5-15 years), from 625 woredas (districts), representing all nine Regional States and two City Administrations of Ethiopia. Nationwide disease maps were developed at the woreda level to enable recommendations on the design of the national MDA programme. RESULTS: The prevalence of any STH infection across the study population was 21.7%, with A. lumbricoides (12.8%) being the most prevalent STH, followed by hookworms (7.6%) and T. trichiura (5.9%). The prevalence for any SCH was 4.0% in areas where both SCH species were evaluated. Schistosoma mansoni was the most prevalent SCH (3.5 vs 0.3%). STHs were more prevalent in southwest Ethiopia, whereas SCH was found mostly in the west and northeast of the country. The prevalence of moderate-to-heavy intensity infections was 2.0% for STHs and 1.6% for SCH. For STH, a total of 251 woredas were classified as moderately (n = 178) or highly endemic (n = 73), and therefore qualify for an annual and biannual MDA program, respectively. For SCH, 67 woredas were classified as endemic and 8 as highly endemic, and hence they require every two years and annual MDA programme, respectively. CONCLUSIONS: The results confirm that Ethiopia is endemic for both STHs and SCH, posing a significant public health problem. Following the WHO recommendations on mass drug administration, 18 and 14 million school-aged children are in need of MDA for STHs and SCH, respectively, based on the number of SACs that live on the eligible geographical areas.

Correction: Female genital schistosomiasis and HIV/AIDS: Reversing the neglect of girls and women.

[This corrects the article DOI: 10.1371/journal.pntd.0007025.].

Impact of Different Mass Drug Administration Strategies for Gaining and Sustaining Control of Schistosoma mansoni and Schistosoma haematobium Infection in Africa.

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.

Parasite associations predict infection risk: incorporating co-infections in predictive models for neglected tropical diseases.

BACKGROUND: Schistosomiasis and infection by soil-transmitted helminths are some of the world's most prevalent neglected tropical diseases. Infection by more than one parasite (co-infection) is common and can contribute to clinical morbidity in children. Geostatistical analyses of parasite infection data are key for developing mass drug administration strategies, yet most methods ignore co-infections when estimating risk. Infection status for multiple parasites can act as a useful proxy for data-poor individual-level or environmental risk factors while avoiding regression dilution bias. Conditional random fields (CRF) is a multivariate graphical network method that opens new doors in parasite risk mapping by (i) predicting co-infections with high accuracy; (ii) isolating associations among parasites; and (iii) quantifying how these associations change across landscapes. METHODS: We built a spatial CRF to estimate infection risks for Ascaris lumbricoides, Trichuris trichiura, hookworms (Ancylostoma duodenale and Necator americanus) and Schistosoma mansoni using data from a national survey of Rwandan schoolchildren. We used an ensemble learning approach to generate spatial predictions by simulating from the CRF's posterior distribution with a multivariate boosted regression tree that captured non-linear relationships between predictors and covariance in infection risks. This CRF ensemble was compared against single parasite gradient boosted machines to assess each model's performance and prediction uncertainty. RESULTS: Parasite co-infections were common, with 19.57% of children infected with at least two parasites. The CRF ensemble achieved higher predictive power than single-parasite models by improving estimates of co-infection prevalence at the individual level and classifying schools into World Health Organization treatment categories with greater accuracy. The CRF uncovered important environmental and demographic predictors of parasite infection probabilities. Yet even after capturing demographic and environmental risk factors, the presences or absences of other parasites were strong predictors of individual-level infection risk. Spatial predictions delineated high-risk regions in need of anthelminthic treatment interventions, including areas with higher than expected co-infection prevalence. CONCLUSIONS: Monitoring studies routinely screen for multiple parasites, yet statistical models generally ignore this multivariate data when assessing risk factors and designing treatment guidelines. Multivariate approaches can be instrumental in the global effort to reduce and eventually eliminate neglected helminth infections in developing countries.

Mapping Schistosoma mansoni endemicity in Rwanda: a critical assessment of geographical disparities arising from circulating cathodic antigen versus Kato-Katz diagnostics.

BACKGROUND: Schistosomiasis is a neglected tropical disease caused by Schistosoma parasites. Intervention relies on identifying high-risk regions, yet rapid Schistosoma diagnostics (Kato-Katz stool assays (KK) and circulating cathodic antigen urine assays (CCA)) yield different prevalence estimates. We mapped S. mansoni prevalence and delineated at-risk regions using a survey of schoolchildren in Rwanda, where S. mansoni is an endemic parasite. We asked if different diagnostics resulted in disparities in projected infection risk. METHODS: Infection data was obtained from a 2014 Rwandan school-based survey that used KK and CCA diagnostics. Across 386 schools screened by CCA (N = 19,217). To allow for uncertainty when interpreting ambiguous CCA trace readings, which accounted for 28.8% of total test results, we generated two presence-absence datasets: CCA trace as positive and CCA trace as negative. Samples (N = 9,175) from 185 schools were also screened by KK. We included land surface temperature (LST) and the Normalized Difference Vegetation and Normalized Difference Water Indices (NDVI, NDWI) as predictors in geostatistical regressions. FINDINGS: Across 8,647 children tested by both methods, prevalence was 35.93% for CCA trace as positive, 7.21% for CCA trace as negative and 1.95% for KK. LST was identified as a risk factor using KK, whereas NDVI was a risk factor for CCA models. Models predicted high endemicity in Northern and Western regions of Rwanda, though the CCA trace as positive model identified additional high-risk areas that were overlooked by the other methods. Estimates of current burden for children at highest risk (boys aged 5-9 years) varied by an order of magnitude, with 671,856 boys projected to be infected by CCA trace as positive and only 60,453 projected by CCA trace as negative results. CONCLUSIONS: Our findings show that people in Rwanda's Northern, Western and capital regions are at high risk of S. mansoni infection. However, variation in identification of environmental risk factors and delineation of at-risk regions using different diagnostics likely provides confusing messages to disease intervention managers. Further research and statistical analyses, such as latent class analysis, can be used to improve CCA result classification and assess its use in guiding treatment regimes.

The association between child Schistosoma spp. infections and morbidity in an irrigated rice region in Mali: A localized study.

BACKGROUND: Schistosomiasis is one of the neglected tropical diseases endemic to Mali. There has been insufficient investigation of the morbidity burden in highly endemic irrigated rice areas with the ongoing mass drug administration with praziquantel. In February 2005, a year after an initial mass drug administration in 2004, we performed the first cross-sectional survey of schistosomiasis in the Kokry-Bozo village in the Office du Niger rice irrigation region. In the fourteen years since this survey, there has been almost no research into schistosomiasis morbidity in Mali due to lack of funding. Therefore, the 2005 survey supplies near-baseline data for any future research into the treatment impacts in the area. METHODS: One hundred and ninety-four children aged 6-14 years from two schools were assessed for bladder pathology by ultrasound, and for anaemia and micro-haematuria by laboratory tests. Schistosoma eggs were examined microscopically in fresh stool and urine samples. Multivariate logistic regression analysis quantified the association of Schistosoma infections with anaemia, bladder pathology and micro-haematuria. Akaike's information criterion was used to test the assumption of linear effects of infection intensity classes and used to compare across models. RESULTS: The overall prevalence of schistosomiasis in 189 school children was 97%; 17% (33/189) had a single infection (S. mansoni,13%, or S. haematobium, 4%) and 80% (156/189) were co-infected with S. mansoni and S. haematobium. The overall prevalence of S. mansoni with light infection was 27% (53/194), moderate infection was 24% (47/194) and heavy infection was 42% (81/194). Of the 194 of children investigated for S. haematobium 59% (114/194) had light infection and 26% (50/194) had heavy infection. No hookworm eggs were detected. The level of abnormal bladder pathology was 18% (35/189) with the highest found in 10-14 year old children. The prevalence of anaemia was 91% (172/189) and was twice as likely to be associated (OR 2.0, 95% CI 1.1-3.9) with S. mansoni infections than in children without infection. As infection intensity with S. mansoni increased the risk of anaemia (OR 2.0, 95% CI 1.1-3.9) also increased. As infection intensity with S. haematobium increased bladder pathology (OR 2.4, 95%CI 1.3-4.5), haematuria (OR 6.7, 95%CI 3.3-13.6) and micro-haematuria increased (OR 2.4, 95%CI 1.3-4.5). CONCLUSION: Our research contributes an important micro-geographical assessment of the heavy burden of schistosomiasis and associated morbidity in children who live in the rice irrigation regions. Our literature review found that there has been very limited research conducted on the impact of the treatment to control morbidity in the ON. Therefore, there is a need to do a comparable, but more extensive, study to identify any changes in morbidity and to indicate current requirements for the control programme. Our results from 2005 called for routine integration of iron supplementation, food fortification and diet diversification into the deworming program.

Egypt's schistosomiasis control programme in the 1980s prepared the ground for the global elimination of schistosomiasis by 2030.

A paper published in 1990 by Webbe and El Hag described the progress being made in the control of schistosomiasis with the introduction of a new medicine 'Praziquantel' to treat infected individuals, and the use of a molluscicide 'niclosamide', with which to kill the intermediate host snails. Almost 30 years from the date of publication, the situation in Egypt and indeed globally has changed out of all recognition. Almost every country in Africa has a school health programme to deworm children, each country has a national plan which includes school health, and praziquantel is now donated through the World Health Organization for countries to treat school aged children to protect them from the serious consequences of chronic schistosomiasis. As the socio-economic status in Africa improves the chances seem good for elimination of schistosomiasis as a public health problem in most areas in Africa.

Mapping Soil-Transmitted Helminth Parasite Infection in Rwanda: Estimating Endemicity and Identifying At-Risk Populations.

Soil-transmitted helminth (STH) infections are globally distributed intestinal parasite infections caused by Ascaris lumbricoides, Trichuris trichiura, and hookworms (Ancylostoma duodenale and Necator americanus). STH infection constitutes a major public health threat, with heavy burdens observed in many of the world's tropical and subtropical regions. Mass drug administration and sanitation improvements can drastically reduce STH prevalence and associated morbidity. However, identifying targeted areas in need of treatment is hampered by a lack of knowledge on geographical and population-level risk factors. In this study, we applied Bayesian geostatistical modelling to data from a national school-based STH infection survey in Rwanda to (1) identify ecological and population-level risk factors and (2) provide comprehensive precision maps of infection burdens. Our results indicated that STH infections were heterogeneously distributed across the country and showed signatures of spatial clustering, though the magnitude of clustering varied among parasites. The highest rates of endemic clustering were attributed to A. lumbricoides infection. Concordant infection patterns among the three parasite groups highlighted populations currently most at-risk of morbidity. Population-dense areas in the Western and North-Western regions of Rwanda represent areas that have continued to exhibit high STH burden across two surveys and are likely in need of targeted interventions. Our maps support the need for an updated evaluation of STH endemicity in western Rwanda to evaluate progress in MDA efforts and identify communities that need further local interventions to further reduce morbidity caused by STH infections.

Accuracy of the WHO praziquantel dose pole for large-scale community treatment of urogenital schistosomiasis in northern Mozambique: Is it time for an update?

BACKGROUND: A pioneering strategy developed by the World Health Organization (WHO) for the control of schistosomiasis was the concept of a height-based dose pole to determine praziquantel (PZQ) dosing in large-scale treatment campaigns. However, some recent studies have shown variable accuracy for the dose pole in terms of predicting correct mg/Kg dosing, particularly for treatment of adults. According to the WHO, 91 million adults in 52 countries are targeted to be treated by 2020. METHODS/PRINCIPAL FINDINGS: The present study aimed to test the accuracy of the dose pole in determining PZQ dosage by comparing the number of tablets determined by the dose pole with the number of tablets determined according to total body weight. The analysis included height-for-weight data from 9,827 school-aged children (SAC) and adults from 42 villages in the province of Cabo Delgado in Mozambique. The results revealed that of the 7,596 SAC, 91.8% has received an appropriate dose (30-60mg/Kg), 6% received an insufficient dose (<30mg/Kg) and 2% an excessive dose (> 60mg/Kg). On the other hand, 13.7% out of 2,231 adults were treated inaccurately with 13.5% receiving an insufficient dose and 0.2% an excessive dose. When the percentage of insufficient dosing was disaggregated by gender, the frequency of adult females who were underdosed reached 18.3% versus 10.8% of adult males. Of note, Adult females aged 21-55 years were found to have an underdose frequency of 21.3%, compared to 11.8% of adult males in the same age range. The performance of a proposed modified dose pole was compared using the same dataset of adult Mozambicans. The results showed that the modified dose pole reduced the underdose frequency among adults from 13.5% to 10.4%, and subsequently increased the percentage of optimal dosing from 33.7% to 45.3%. CONCLUSIONS: Our findings highlight the need to update the WHO-dose pole to avoid administration of insufficient PZQ doses to adults and therefore minimize the potential emergence of PZQ-resistant strains. TRIAL REGISTRATION: International Standard Randomized Controlled Trial registry under ISRTC number 14117624.