The role of point-of-care ultrasound in the assessment of schistosomiasis-induced liver fibrosis: A systematic scoping review.

BACKGROUND: Abdominal ultrasound imaging is an important method for hepatic schistosomiasis diagnosis and staging. Several ultrasound staging systems have been proposed, each attempting to standardise schistosomal periportal fibrosis (PPF) diagnosis. This review aims to establish the role of ultrasound in the diagnosis and staging of schistosomal PPF, and to map the evolution of ultrasound staging systems over time, focusing on internal validation and external reproducibility. METHODS: A systematic search was undertaken on 21st December 2022 considering the following databases: PubMed/MEDLINE (1946-present), Embase (1974-present), Global Health (1973-present), Global Index Medicus (1901-present), and Web of Science Core Collection-Science Citation Index Expanded (1900-present) and the Cochrane Central Register of Controlled Trials (1996-present). Case reports, systematic reviews and meta-analyses, and studies exclusively using transient or shear-wave elastography were excluded. Variables extracted included study design, study population, schistosomal PPF characteristics, and diagnostic methods. The PRISMA-ScR (2018) guidelines were followed to inform the structure of the scoping analysis. RESULTS: The initial search yielded 573 unique articles, of which 168 were removed after screening titles and abstracts, 43 were not retrieved due to full texts not being available online or through inter-library loans, and 170 were excluded during full text review. There were 192 remaining studies eligible for extraction. Of the extracted studies, 61.8% (76/123) of studies that reported study year were conducted after the year 2000. Over half of all extracted studies (59.4%; 114/192) were conducted in Brazil (26.0%; 50/192), China (18.8%; 36/192) or Egypt (14.6%; 28/192). For the species of schistosome considered, 77.6% (149/192) of studies considered S. mansoni and 21.4% (41/192) of studies considered S. japonicum. The ultrasound staging systems used took on three forms: measurement-based, feature-based and image pattern-based. The Niamey protocol, a measurement and image pattern-based system, was the most used among the staging systems (32.8%; 63/192), despite being the most recently proposed in 1996. The second most used was the Cairo protocol (20.8%; 40/192). Of the studies using the Niamey protocol, 77.8% (49/63) only used the image patterns element. Where ultrasound technology was specified, studies after 2000 were more likely to use convex transducers (43.4%; 33/76) than studies conducted before 2000 (32.7%; 16/49). Reporting on ultrasound-based hepatic diagnoses and their association with clinical severity was poor. Just over half of studies (56.2%; 108/192) reported the personnel acquiring the ultrasound images. A small number (9.4%; 18/192) of studies detailed their methods of image quality assurance, and 13.0% (25/192) referenced, discussed or quantified the inter- or intra-observer variation of the staging system that was used. CONCLUSIONS: The exclusive use of the image patterns in many studies despite lack of specific acquisition guidance, the increasing number of studies over time that conduct ultrasound staging of schistosomal PPF, and the advances in ultrasound technology used since 2000 all indicate a need to consider an update to the Niamey protocol. The protocol update should simplify and prioritise what is to be assessed, advise on who is to conduct the ultrasound examination, and procedures for improved standardisation and external reproducibility.

Associations of water contact frequency, duration, and activities with schistosome infection risk: A systematic review and meta-analysis.

BACKGROUND: Schistosomiasis is a water-borne parasitic disease which affects over 230 million people globally. The relationship between contact with open freshwater bodies and the likelihood of schistosome infection remains poorly quantified despite its importance for understanding transmission and parametrising transmission models. METHODS: We conducted a systematic review to estimate the average effect of water contact duration, frequency, and activities on schistosome infection likelihood. We searched Embase, MEDLINE (including PubMed), Global Health, Global Index Medicus, Web of Science, and the Cochrane Central Register of Controlled Trials from inception until May 13, 2022. Observational and interventional studies reporting odds ratios (OR), hazard ratios (HR), or sufficient information to reconstruct effect sizes on individual-level associations between water contact and infection with any Schistosoma species were eligible for inclusion. Random-effects meta-analysis with inverse variance weighting was used to calculate pooled ORs and 95% confidence intervals (CIs). RESULTS: We screened 1,411 studies and included 101 studies which represented 192,691 participants across Africa, Asia, and South America. Included studies mostly reported on water contact activities (69%; 70/101) and having any water contact (33%; 33/101). Ninety-six percent of studies (97/101) used surveys to measure exposure. A meta-analysis of 33 studies showed that individuals with water contact were 3.14 times more likely to be infected (OR 3.14; 95% CI: 2.08-4.75) when compared to individuals with no water contact. Subgroup analyses showed that the positive association of water contact with infection was significantly weaker in children compared to studies which included adults and children (OR 1.67; 95% CI: 1.04-2.69 vs. OR 4.24; 95% CI: 2.59-6.97). An association of water contact with infection was only found in communities with ≥10% schistosome prevalence. Overall heterogeneity was substantial (I2 = 93%) and remained high across all subgroups, except in direct observation studies (I2 range = 44%-98%). We did not find that occupational water contact such as fishing and agriculture (OR 2.57; 95% CI: 1.89-3.51) conferred a significantly higher risk of schistosome infection compared to recreational water contact (OR 2.13; 95% CI: 1.75-2.60) or domestic water contact (OR 1.91; 95% CI: 1.47-2.48). Higher duration or frequency of water contact did not significantly modify infection likelihood. Study quality across analyses was largely moderate or poor. CONCLUSIONS: Any current water contact was robustly associated with schistosome infection status, and this relationship held across adults and children, and schistosomiasis-endemic areas with prevalence greater than 10%. Substantial gaps remain in published studies for understanding interactions of water contact with age and gender, and the influence of these interactions for infection likelihood. As such, more empirical studies are needed to accurately parametrise exposure in transmission models. Our results imply the need for population-wide treatment and prevention strategies in endemic settings as exposure within these communities was not confined to currently prioritised high-risk groups such as fishing populations.

Diarrhoeal outcomes in young children depend on diarrhoeal cases of other household members: a cross-sectional study of 16,025 people in rural Uganda.

BACKGROUND: There is a limited understanding of how diarrhoeal cases across other household members influence the likelihood of diarrhoea in young children (aged 1-4 years). METHODS: We surveyed 16,025 individuals from 3421 households in 17 villages in Uganda. Using logistic regressions with standard errors clustered by household, diarrhoeal cases within households were used to predict diarrhoeal outcomes in young children. Regressions were adjusted for socio-demographic, water, sanitation, and hygiene (WASH), and ecological covariates. Selection bias for households with (1632/3421) and without (1789/3421) young children was examined. RESULTS: Diarrhoeal prevalence was 13.7% (2118/16,025) across all study participants and 18.5% (439/2368) in young children. Young children in households with any other diarrhoeal cases were 5.71 times more likely to have diarrhoea than young children in households without any other diarrhoeal cases (95% CI: 4.48-7.26), increasing to over 29 times more likely when the other diarrhoeal case was in another young child (95% CI: 16.29-54.80). Diarrhoeal cases in older household members (aged ≥ 5 years) and their influence on the likelihood of diarrhoea in young children attenuated with age. School-aged children (5-14 years) had a greater influence on diarrhoeal cases in young children (Odds Ratio 2.70, 95% CI: 2.03-3.56) than adults of reproductive age (15-49 years; Odds Ratio 1.96, 95% CI: 1.47-2.59). Diarrhoeal cases in individuals aged ≥ 50 years were not significantly associated with diarrhoeal outcomes in young children (P > 0.05). These age-related differences in diarrhoeal exposures were not driven by sex. The magnitude and significance of the odds ratios remained similar when odds ratios were compared by sex within each age group. WASH factors did not influence the likelihood of diarrhoea in young children, despite influencing the likelihood of diarrhoea in school-aged children and adults. Households with young children differed from households without young children by diarrhoeal prevalence, household size, and village WASH infrastructure and ecology. CONCLUSIONS: Other diarrhoeal cases within households strongly influence the likelihood of diarrhoea in young children, and when controlled, removed the influence of WASH factors. Future research on childhood diarrhoea should consider effects of diarrhoeal cases within households and explore pathogen transmission between household members.

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.

The division of labour between community medicine distributors influences the reach of mass drug administration: A cross-sectional study in rural Uganda.

BACKGROUND: Despite decades of community-based mass drug administration (MDA) for neglected tropical diseases, it remains an open question as to what constitutes the best combination of community medicine distributors (CMDs) for achieving high (>65%/75%) treatment rates within a village. METHODS: Routine community-based MDA was evaluated in Mayuge District, Uganda. For one month, we tracked 6,148 individuals aged 1+ years in 1,118 households from 28 villages. Praziquantel, albendazole, and ivermectin were distributed to treat Schistosoma mansoni, lymphatic filariasis, and soil-transmitted helminths. The similarity/diversity between CMDs was observed and used to predict the division of labour and overall village treatment rates. The division of labour was calculated by dividing the lowest treatment rate by the highest treatment rate achieved by two CMDs within a village. CMD similarity was measured for 16 characteristics including friendship network overlap, demographic and socioeconomic factors, methods of CMD selection, and years as CMD. Relevant variables for MDA outcomes were selected through least absolute shrinkage and selection operators with leave-one-out cross validation. Final models were run with ordinary least squares regression and robust standard errors. RESULTS: The percentage of individuals treated with at least one drug varied across villages from 2.79-89.74%. The only significant predictor (p-value<0.05) of village treatment rates was the division of labour. The estimated difference between a perfectly equal (a 50-50 split of individuals treated) and unequal (one CMD treating no one) division of labour was 39.69%. A direct tie (close friendship) between CMDs was associated with a nearly twofold more equitable distribution of labour when compared to CMDs without a direct tie. CONCLUSIONS: An equitable distribution of labour between CMDs may be essential for achieving treatment targets of 65%/75% within community-based MDA. To improve the effectiveness of CMDs, national programmes should explore interventions that seek to facilitate communication, friendship, and equal partnership between CMDs.

More medicines alone cannot ensure the treatment of neglected tropical diseases.

Neglected tropical diseases afflict more than 1 billion of the world's poorest people. Pharmaceutical donations of preventive chemotherapy for neglected tropical diseases enable the largest en masse treatment campaigns globally with respect to the number of people targeted for treatment. However, the blanket distribution of medicines at no cost to individuals in need of treatment does not guarantee that those individuals are treated. In this Personal View, we aim to examine the next steps that need to be taken towards ensuring equitable treatment access, including health system integration and the role of endemic countries in ensuring medicines are delivered to patients. We argue that the expansion of medicine donation programmes and the development of new medicines are not the primary solutions to sustaining and expanding the growth of neglected tropical disease programmes. Treatment is often not verified by a medical professional, independent surveyor, or national programme officer. Additionally, access to medicines might not be equitable across at-risk populations, and treatment targets for disease control remain largely unmet within many endemic countries. To enable equitable access and efficient use of existing medicines, research is needed now on how best to integrate the treatment of neglected tropical diseases into local health systems. A comprehensive approach should be used, which combines mass drug administration with on-demand access to treatment. Increased commitment by endemic countries, when possible, around the ownership of treatment campaigns is essential to improve access to medicines for neglected tropical diseases.

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.

Precision global health and comorbidity: a population-based study of 16 357 people in rural Uganda.

In low-income countries, complex comorbidities and weak health systems confound disease diagnosis and treatment. Yet, data-driven approaches have not been applied to develop better diagnostic strategies or to tailor treatment delivery for individuals within rural poor communities. We observed symptoms/diseases reported within three months by 16 357 individuals aged 1+ years in 17 villages of Mayuge District, Uganda. Symptoms were mapped to the Human Phenotype Ontology. Comorbidity networks were constructed. An edge between two symptoms/diseases was generated if the relative risk greater than 1, ϕ correlation greater than 0, and local false discovery rate less than 0.05. We studied how network structure and flagship symptom profiles varied against biosocial factors. 88.05% of individuals (14 402/16 357) reported at least one symptom/disease. Young children and individuals in worse-off households-low socioeconomic status, poor water, sanitation, and hygiene, and poor medical care-had dense network structures with the highest comorbidity burden and/or were conducive to the onset of new comorbidities from existing flagship symptoms, such as fever. Flagship symptom profiles for fever revealed self-misdiagnoses of fever as malaria and sexually transmitted infections as a potentially missed cause of fever in individuals of reproductive age. Network analysis may inform the development of new diagnostic and treatment strategies for flagship symptoms used to characterize syndromes/diseases of global concern.

Diffusion of treatment in social networks and mass drug administration.

Information, behaviors, and technologies spread when people interact. Understanding these interactions is critical for achieving the greatest diffusion of public interventions. Yet, little is known about the performance of starting points (seed nodes) for diffusion. We track routine mass drug administration-the large-scale distribution of deworming drugs-in Uganda. We observe friendship networks, socioeconomic factors, and treatment delivery outcomes for 16,357 individuals in 3491 households of 17 rural villages. Each village has two community medicine distributors (CMDs), who are the seed nodes and responsible for administering treatments. Here, we show that CMDs with tightly knit (clustered) friendship connections achieve the greatest reach and speed of treatment coverage. Importantly, we demonstrate that clustering predicts diffusion through social networks when spreading relies on contact with seed nodes while centrality is unrelated to diffusion. Clustering should be considered when selecting seed nodes for large-scale treatment campaigns.

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.

Community-directed mass drug administration is undermined by status seeking in friendship networks and inadequate trust in health advice networks.

Over 1.9 billion individuals require preventive chemotherapy through mass drug administration (MDA). Community-directed MDA relies on volunteer community medicine distributors (CMDs) and their achievement of high coverage and compliance. Yet, it is unknown if village social networks influence effective MDA implementation by CMDs. In Mayuge District, Uganda, census-style surveys were conducted for 16,357 individuals from 3,491 households in 17 villages. Praziquantel, albendazole, and ivermectin were administered for one month in community-directed MDA to treat Schistosoma mansoni, hookworm, and lymphatic filariasis. Self-reported treatment outcomes, socioeconomic characteristics, friendship networks, and health advice networks were collected. We investigated systematically missed coverage and noncompliance. Coverage was defined as an eligible person being offered at least one drug by CMDs; compliance included ingesting at least one of the offered drugs. These outcomes were analyzed as a two-stage process using a Heckman selection model. To further assess if MDA through CMDs was working as intended, we examined the probability of accurate drug administration of 1) praziquantel, 2) both albendazole and ivermectin, and 3) all drugs. This analysis was conducted using bivariate Probit regression. Four indicators from each social network were examined: degree, betweenness centrality, closeness centrality, and the presence of a direct connection to CMDs. All models accounted for nested household and village standard errors. CMDs were more likely to offer medicines, and to accurately administer the drugs as trained by the national control programme, to individuals with high friendship degree (many connections) and high friendship closeness centrality (households that were only a short number of steps away from all other households in the network). Though high (88.59%), additional compliance was associated with directly trusting CMDs for health advice. Effective treatment provision requires addressing CMD biases towards influential, well-embedded individuals in friendship networks and utilizing health advice networks to increase village trust in CMDs.

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.

Influence of Schistosoma mansoni and Hookworm Infection Intensities on Anaemia in Ugandan Villages.

BACKGROUND: The association of anaemia with intestinal schistosomiasis and hookworm infections are poorly explored in populations that are not limited to children or pregnant women. METHODS: We sampled 1,832 individuals aged 5-90 years from 30 communities in Mayuge District, Uganda. Demographic, village, and parasitological data were collected. Infection risk factors were compared in ordinal logistic regressions. Anaemia and infection intensities were analyzed in multilevel models, and population attributable fractions were estimated. FINDINGS: Household and village-level predictors of Schistosoma mansoni and hookworm were opposite in direction or significant for single infections. S. mansoni was found primarily in children, whereas hookworm was prevalent amongst the elderly. Anaemia was more prevalent in individuals with S. mansoni and increased by 2.86 fold (p-value<0.001) with heavy S. mansoni infection intensity. Individuals with heavy hookworm were 1.65 times (p-value = 0.008) more likely to have anaemia than uninfected participants. Amongst individuals with heavy S. mansoni infection intensity, 32.0% (p-value<0.001) of anaemia could be attributed to S. mansoni. For people with heavy hookworm infections, 23.7% (p-value = 0.002) of anaemia could be attributed to hookworm. A greater fraction of anaemia (24.9%, p-value = 0.002) was attributable to heavy hookworm infections in adults (excluding pregnant women) as opposed to heavy hookworm infections in school-aged children and pregnant women (20.2%, p-value = 0.001). CONCLUSION: Community-based surveys captured anaemia in children and adults affected by S. mansoni and hookworm infections. For areas endemic with schistosomiasis or hookworm infections, WHO guidelines should include adults for treatment in helminth control programmes.

Social network analysis predicts health behaviours and self-reported health in African villages.

The provision of healthcare in rural African communities is a highly complex and largely unsolved problem. Two main difficulties are the identification of individuals that are most likely affected by disease and the prediction of responses to health interventions. Social networks have been shown to capture health outcomes in a variety of contexts. Yet, it is an open question as to what extent social network analysis can identify and distinguish among households that are most likely to report poor health and those most likely to respond to positive behavioural influences. We use data from seven highly remote, post-conflict villages in Liberia and compare two prominent network measures: in-degree and betweenness. We define in-degree as the frequency in which members from one household are named by another household as a friends. Betweenness is defined as the proportion of shortest friendship paths between any two households in a network that traverses a particular household. We find that in-degree explains the number of ill family members, whereas betweenness explains engagement in preventative health. In-degree and betweenness independently explained self-reported health and behaviour, respectively. Further, we find that betweenness predicts susceptibility to, instead of influence over, good health behaviours. The results suggest that targeting households based on network measures rather than health status may be effective for promoting the uptake of health interventions in rural poor villages.

Exploring network theory for mass drug administration.

Network theory is a well-established discipline that uses mathematical graphs to describe biological, physical, and social systems. The topologies across empirical networks display strikingly similar organizational properties. In particular, the characteristics of these networks allow computational analysis to contribute data unattainable from examining individual components in isolation. However, the interdisciplinary and quantitative nature of network analysis has yet to be exploited by public health initiatives to distribute preventive chemotherapies. One notable application is the 2012 World Health Organization (WHO) Roadmap for Neglected Tropical Diseases (NTDs) where there is a need to upscale distribution capacity and to target systematic noncompliers. An understanding of local networks for analysing the distributional properties of community-directed treatment may facilitate sustainable expansion of mass drug-administration (MDA) programs.