Policies for type 2 diabetes and non-communicable disease management during the COVID-19 pandemic in Kenya and Tanzania: a desk review and views of decision-makers.

BACKGROUND: The COVID-19 pandemic caused disruptions in care that adversely affected the management of non-communicable diseases (NCDs) globally. Countries have responded in various ways to support people with NCDs during the pandemic. This study aimed to identify policy gaps, if any, in the management of NCDs, particularly diabetes, during COVID-19 in Kenya and Tanzania to inform recommendations for priority actions for NCD management during any future similar crises. METHODS: We undertook a desk review of pre-existing and newly developed national frameworks, policy models and guidelines for addressing NCDs including type 2 diabetes. This was followed by 13 key informant interviews with stakeholders involved in NCD decision-making: six in Kenya and seven in Tanzania. Thematic analysis was used to analyse the documents. RESULTS: Seventeen guidance documents were identified (Kenya=10; Tanzania=7). These included pre-existing and/or updated policies/strategic plans, guidelines, a letter, a policy brief and a report. Neither country had comprehensive policies/guidelines to ensure continuity of NCD care before the COVID-19 pandemic. However, efforts were made to update pre-existing documents and several more were developed during the pandemic to guide NCD care. Some measures were put in place during the COVID-19 period to ensure continuity of care for patients with NCDs such as longer supply of medicines. Inadequate attention was given to monitoring and evaluation and implementation issues. CONCLUSION: Kenya and Tanzania developed and updated some policies/guidelines to include continuity of care in emergencies. However, there were gaps in the documents and between policy/guideline documents and practice. Health systems need to establish disaster preparedness plans that integrate attention to NCD care to enable them to better handle severe disruptions caused by emergencies such as pandemics. Such guidance needs to include contingency planning to enable adequate resources for NCD care and must also address evaluation of implementation effectiveness.

Respiratory morbidity in Schistosoma mansoni infection: a rapid review of literature.

Background: Schistosomiasis contributes to 2.5 million disability-adjusted life years globally. Acute and chronic respiratory morbidity of Schistosoma mansoni (S. mansoni) is poorly documented in the literature. We conducted a rapid literature review of the burden of respiratory symptoms and lung function abnormalities among patients with S. mansoni. We also report the immunologic and lung imaging findings from the studies reviewed. Methods: We carried out a comprehensive literature search in Embase and MEDLINE from the inception of the databases to 13th March 2023. Results: A total of 2243 patients with S. mansoni were reported from 24 case reports, 11 cross-sectional studies, 7 case series, 2 cohort studies and 2 randomized controlled trials. The prevalence of any respiratory symptom was 13.3-63.3% (total number of patients studied, n = 149). The prevalence of the individual symptoms among patients with S. mansoni in whom respiratory symptoms were sought for was as follows: cough (8.3-80.6%, n = 338), dyspnea (1.7-100.0%, n = 200), chest pain (9.0-57.1%, n = 86), sputum production (20.0-23.3%, n = 30) and wheezing (0.0 - 20.0%, n = 1396). The frequency of the symptoms tended to be higher in acute schistosomiasis. Restrictive lung disease was prevalent in 29.0% (9/31). The commonest chest imaging findings reported were nodules (20-90%, n = 103) and interstitial infiltrates (12.5-23.0%, n = 89). Peripheral blood eosinophilia was prevalent in 72.0-100.0% of patients (n = 130) with acute schistosomiasis and correlated with symptoms and imaging abnormalities. Three case reports in chronic S. mansoni reported elevated C-reactive protein, leucocyte, neutrophil and absolute eosinophil counts, eosinophil percentage, IgE and IgG4. Conclusion: There is a high prevalence of respiratory morbidity among patients with S. mansoni, particularly in the acute stage of the infection, although the studies are relatively small. Larger studies are needed to characterize respiratory morbidity in chronic schistosomiasis and determine the underlying clinical and immunological mechanisms.

Respiratory problems in people with bilharzia Bilharzia causes significant health problems among those affected. However, little is known about respiratory problems associated with bilharzia. We systematically searched for studies published on bilharzia and respiratory problems in literature. We found that a high proportion of people with bilharzia report cough, difficulty in breathing, chest pain, sputum production and wheezing. Also, a good number have lung function impairment and abnormalities on X-ray imaging. Blood eosinophils tended to be associated with the respiratory symptoms and imaging abnormalities which suggests that eosinophils may be involved in causing respiratory problems. We conclude that lung problems are common among people with bilharzia although the studies reviewed were small and mostly among people with acute infection. Larger studies are needed to further characterise lung problems in Bilharzia.

Establishing a single-sex controlled human Schistosoma mansoni infection model for Uganda: protocol for safety and dose-finding trial.

Control of schistosomiasis depends on a single drug, praziquantel, with variable cure rates, high reinfection rates, and risk of drug resistance. A vaccine could transform schistosomiasis control. Preclinical data show that vaccine development is possible, but conventional vaccine efficacy trials require high incidence, long-term follow-up, and large sample size. Controlled human infection studies (CHI) can provide early efficacy data, allowing the selection of optimal candidates for further trials. A Schistosoma CHI has been established in the Netherlands but responses to infection and vaccines differ in target populations in endemic countries. We aim to develop a CHI for Schistosoma mansoni in Uganda to test candidate vaccines in an endemic setting. This is an open-label, dose-escalation trial in two populations: minimal, or intense, prior Schistosoma exposure. In each population, participants will be enrolled in sequential dose-escalating groups. Initially, three volunteers will be exposed to 10 cercariae. If all show infection, seven more will be exposed to the same dose. If not, three volunteers in subsequent groups will be exposed to higher doses (20 or 30 cercariae) following the same algorithm, until all 10 volunteers receiving a particular dose become infected, at which point the study will be stopped for that population. Volunteers will be followed weekly after infection until CAA positivity or to 12 weeks. Once positive, they will be treated with praziquantel and followed for one year. The trial registry number is ISRCTN14033813 and all approvals have been obtained. The trial will be subjected to monitoring, inspection, and/or audits.

Assessing the Readiness to Provide Integrated Management of Cardiovascular Diseases and Type 2 Diabetes in Kenya: Results from a National Survey.

Introduction: Integrated chronic disease management is the desired core function of a responsive healthcare system. However, many challenges surround its implementation in Sub-Saharan Africa. The current study assessed the readiness of healthcare facilities to provide integrated management of cardiovascular diseases (CVDs) and type 2 diabetes in Kenya. Methods: We used data from a nationally representative cross-sectional survey of 258 public and private health facilities conducted in Kenya between 2019 and 2020. Data were collected using a standardised facility assessment questionnaire and observation checklists modified from the World Health Organization Package of Essential Non-communicable Diseases. The primary outcome was the readiness to provide integrated care for CVDs and diabetes-defined as the mean availability of tracer items comprising trained staff and clinical guidelines, diagnostic equipment, essential medicines, diagnosis, treatment and follow-up. A cut-off threshold of ≥70% was used to classify facilities as 'ready'. Gardner-Altman plots and modified Poisson regression were used to examine the facility characteristics associated with care integration readiness. Results: Of the surveyed facilities, only a quarter (24.1%) were ready to provide integrated care for CVDs and type 2 diabetes. Care integration readiness was lower in public versus private facilities [aPR = 0.6; 95% CI 0.4 to 0.9], and primary healthcare facilities were less likely to be ready compared to hospitals [aPR = 0.2; 95% CI 0.1 to 0.4]. Facilities located in Central Kenya [aPR = 0.3; 95% CI 0.1 to 0.9], and the Rift Valley region [aPR = 0.4; 95% CI 0.1 to 0.9], were less likely to be ready compared to the capital Nairobi. Conclusions: There are gaps in the readiness of healthcare facilities particularly primary healthcare facilities in Kenya to provide integrated care services for CVDs and diabetes. Our findings inform the review of current supply-side interventions for integrated management of CVDs and type 2 diabetes, especially in lower-level public health facilities in Kenya.

Effect of Patient Support Groups for Hypertension on Blood Pressure among Patients with and Without Multimorbidity: Findings from a Cohort Study of Patients on a Home-Based Self-Management Program in Kenya.

Introduction: Patient support group interventions have been widely used to manage chronic diseases in Kenya. However, the potential benefits of these groups on patient health outcomes, and how this is influenced by multimorbidity, have not been rigorously evaluated. Objective: We assessed the effect of a patient support group intervention on blood pressure (BP) management and the potential moderating effect of multimorbidity among low- and middle-income patients with hypertension in Kenya. Methods: We analysed data from a non-randomized, quasi-experimental study of 410 patients with hypertension on a home-based self-management program conducted from September 2019 to September 2020. The program included the formation and participation in patient support groups. Using a modified STEPS questionnaire, data were collected on BP, anthropometry and other measurements at enrolment and after 12 months of follow-up. Multimorbidity was defined as the simultaneous presence of hypertension and at least one or more related conditions with similar pathophysiology (concordant multimorbidity) or unrelated chronic conditions (discordant multimorbidity). Propensity score (PS) weighting was used to adjust for baseline differences among 243 patients who participated in the support groups and 167 who did not. We estimated the effects of patient support groups and moderating effects of multimorbidity on BP management using multivariable ordinary linear regression weighted by PS. Findings: Participation in support groups significantly reduced systolic BP by 5.4 mmHg compared to non-participation in the groups [ß = -5.4; 95% CI -1.9 to -8.8]. However, among participants in the support group intervention, the mean systolic BP at follow-up assessment for those with concordant multimorbidity was 8.8 mmHg higher than those with no multimorbidity [ß = 8.8; 95% CI 0.8 to 16.8]. Conclusion: Although patient support groups are potentially important adjuncts to home-based self-care, multimorbidity attenuates their effectiveness. There is a need to tailor patient support group interventions to match the needs of the people living with multimorbidity in low- and middle-income settings in Kenya.

Cardiometabolic Multimorbidity Associated with Moderate and Severe Disabilities: Results from the Study on Global AGEing and Adult Health (SAGE) Wave 2 in Ghana and South Africa.

Background: Integrated management of cardiometabolic diseases is crucial in improving the quality of life of older persons. The objective of the study was to identify clusters of cardiometabolic multimorbidity associated with moderate and severe disabilities in Ghana and South Africa. Methods: Data were from the World Health Organization (WHO) study on global AGEing and adult health (SAGE) Wave-2 (2015) conducted in Ghana and South Africa. We analysed the clustering of cardiometabolic diseases including angina, stroke, diabetes, obesity, and hypertension with unrelated conditions such as asthma, chronic lung disease, arthritis, cataracts, and depression. The WHO Disability Assessment Instrument version 2.0 was used to assess functional disability. We used latent class analysis to calculate the multimorbidity classes and disability severity levels. Ordinal logistic regression was used to identify the clusters of multimorbidity associated with moderate and severe disabilities. Results: Data from 4,190 adults aged over 50 years were analysed. The prevalence of moderate and severe disabilities was 27.0% and 8.9% respectively. Four latent classes of multimorbidity were identified. These included a relatively healthy group with minimal cardiometabolic multimorbidity (63.5%), general and abdominal obesity (20.5%), hypertension, abdominal obesity, diabetes, cataracts, and arthritis (10.0%), and angina, chronic lung disease, asthma, and depression (6.0%). Compared to the participants with minimal cardiometabolic multimorbidity, the odds of moderate and severe disabilities were higher among participants with multimorbidity comprising hypertension, abdominal obesity, diabetes, cataract and arthritis [aOR = 3.0; 95% CI 1.6 to 5.6], and those with angina, chronic lung disease, asthma and depression [aOR = 2.7; 95% CI 1.6 to 4.5]. Conclusions: Cardiometabolic diseases among older persons in Ghana and South Africa cluster in distinct multimorbidity patterns that are significant predictors of functional disabilities. This evidence may be useful for defining disability prevention strategies and long-term care for older persons living with or at risk of cardiometabolic multimorbidity in sub-Saharan Africa.

Multimorbidity of cardiometabolic diseases: a cross-sectional study of patterns, clusters and associated risk factors in sub-Saharan Africa.

OBJECTIVE: To determine the patterns of cardiometabolic multimorbidity and associated risk factors in sub-Saharan Africa (SSA). DESIGN: We used data from the WHO STEPwise approach to non-communicable disease risk factor surveillance cross-sectional surveys conducted between 2014 and 2017. PARTICIPANTS: The participants comprised 39, 658 respondents aged 15-69 years randomly selected from nine SSA countries using a multistage stratified sampling design. PRIMARY OUTCOME MEASURE: Using latent class analysis and agglomerative hierarchical clustering algorithms, we analysed the clustering of cardiometabolic diseases (CMDs) including high blood sugar, hypercholesterolaemia, hypertension and cardiovascular diseases (CVDs) such as heart attack, angina and stroke. Clusters of lifestyle risk factors: harmful salt intake, physical inactivity, obesity, tobacco and alcohol use were also computed. Prevalence ratios (PR) from modified Poisson regression were used to assess the association of cardiometabolic multimorbidity with sociodemographic and lifestyle risk factors. RESULTS: Two distinct classes of CMDs were identified: relatively healthy group with minimal CMDs (95.2%) and cardiometabolic multimorbidity class comprising participants with high blood sugar, hypercholesterolaemia, hypertension and CVDs (4.8%). The clusters of lifestyle risk factors included alcohol, tobacco and harmful salt consumption (27.0%), and physical inactivity and obesity (5.8%). The cardiometabolic multimorbidity cluster exhibited unique sociodemographic and lifestyle risk profiles. Being female (PR=1.7, 95% CI (1.5 to 2.0), middle-aged (35-54 years) (3.9 (95% CI 3.2 to 4.8)), compared with age 15-34 years, employed (1.2 (95% CI 1.1 to 1.4)), having tertiary education (2.5 (95% CI 2.0 to 3.3)), vs no formal education and clustering of physical inactivity and obesity (2.4 (95% CI 2.0 to 2.8)) were associated with a higher likelihood of cardiometabolic multimorbidity. CONCLUSION: Our findings show that cardiometabolic multimorbidity and lifestyle risk factors cluster in distinct patterns with a disproportionate burden among women, middle-aged, persons in high socioeconomic positions, and those with sedentary lifestyles and obesity. These results provide insights for health systems response in SSA to focus on these clusters as potential targets for integrated care.

Effectiveness of self-financing patient-led support groups in the management of hypertension and diabetes in low- and middle-income countries: Systematic review.

OBJECTIVE: There is insufficient evidence on the role of self-financing patient support groups in the control of blood pressure (BP) and/or diabetes in low- and middle-income countries (LMICs). We conducted a systematic review to investigate the effectiveness of these groups in BP and glycaemic control. METHODS: We searched PubMed, Embase, SCOPUS, Web of Science, Global Health, African Journals Online, CINAHL and African Index Medicus for published peer-reviewed articles from inception up to November 2021. Grey literature was obtained from OpenGrey. Studies on patient support groups for hypertension and/or diabetes with a component of pooling financial resources, conducted in LMICs, were included. Narrative reviews, commentaries, editorials and articles published in languages other than English and French were excluded. Study quality and risk of bias were assessed using the National Institutes of Health Quality assessment tool and the revised Cochrane risk-of-bias tool. Results are reported according to PRISMA guidelines. RESULTS: Of 724 records screened, three studies met the criteria: two trials conducted in Kenya and a retrospective cohort study conducted in Cambodia. All studies reported improvement in BP control after 12 months follow-up with reductions in systolic BP of 23, 14.8, and 16.9 mmHg, respectively. Two studies reported diabetes parameters. The first reported improvement in HbA1c (reduction from baseline 10.8%, to 10.6% at 6 months) and random blood sugar (baseline 8.9 mmol/L, to 8.5 mmol/L at 6 months) but these changes did not achieve statistical significance. The second reported a reduction in fasting blood glucose (baseline-216 mg/dl, 12 months-159 mg/dl) in diabetic patients on medication. CONCLUSION: Self-financing patient support groups for diabetes and hypertension are potentially effective in the control of BP and diabetes in LMICs. More studies are needed to add to the scarce evidence base on the role of self-financing patient support groups.

Availability and affordability of essential medicines and diagnostic tests for diabetes mellitus in Africa.

OBJECTIVE: To investigate the current status of the availability and affordability of specific essential medicines and diagnostics for diabetes in Africa. METHODS: Systematic review and meta-analysis. Studies conducted in Africa that reported any information on the availability and affordability of short-acting, intermediate-acting, and premixed insulin, glibenclamide, metformin, blood glucose, glycated haemoglobin or HbA1c, and lipid profile tests were included. Random-effect model meta-analysis and descriptive statistics were performed to determine the pooled availability and affordability, respectively. RESULTS: A total of 21 studies were included. The pooled availability of each drug was as follows: short-acting insulin 33.5% (95% CI: 17.8%-49.2%, I2  = 95.02%), intermediate-acting insulin 23.1% (95% CI: 6.3%-39.9%, I2  = 91.6%), premixed insulin 49.4% (95% CI: 24.9%-73.9%, I2  = 90.57%), glibenclamide 55.9% (95% CI: 43.8%-68.0%, I2  = 96.7%), and metformin 47.0% (95% CI: 34.6%-59.4%, I2  = 97.54%). Regarding diagnostic tests, for glucometers the pooled availability was 49.5% (95% CI: 37.9%-61.1%, I2  = 97.43%), for HbA1c 24.6% (95% CI: 3.1%-46.1%, I2  = 91.64), and for lipid profile tests 35.7% (95% CI: 19.4%-51.9%, I2  = 83.77%). The median (IQR) affordability in days' wages was 7 (4.7-7.5) for short-acting insulin, 4.4 (3.9-4.9) for intermediate-acting insulin, 7.1 (5.8-16.7) for premixed insulin, 0.7 (0.7-0.7) for glibenclamide, and 2.1 (1.8-2.8) for metformin. CONCLUSION: The availability of the five essential medicines and three diagnostic tests for diabetes in Africa is suboptimal. The relatively high cost of insulin, HbA1c, and lipid profile tests is a significant barrier to optimal diabetes care. Pragmatic country-specific strategies are urgently needed to address these inequities in access and cost.

Genome-wide analysis of Schistosoma mansoni reveals limited population structure and possible praziquantel drug selection pressure within Ugandan hot-spot communities.

Populations within schistosomiasis control areas, especially those in Africa, are recommended to receive regular mass drug administration (MDA) with praziquantel (PZQ) as the main strategy for controlling the disease. The impact of PZQ treatment on schistosome genetics remains poorly understood, and is limited by a lack of high-resolution genetic data on the population structure of parasites within these control areas. We generated whole-genome sequence data from 174 individual miracidia collected from both children and adults from fishing communities on islands in Lake Victoria in Uganda that had received either annual or quarterly MDA with PZQ over four years, including samples collected immediately before and four weeks after treatment. Genome variation within and between samples was characterised and we investigated genomic signatures of natural selection acting on these populations that could be due to PZQ treatment. The parasite population on these islands was more diverse than found in nearby villages on the lake shore. We saw little or no genetic differentiation between villages, or between the groups of villages with different treatment intensity, but slightly higher genetic diversity within the pre-treatment compared to post-treatment parasite populations. We identified classes of genes significantly enriched within regions of the genome with evidence of recent positive selection among post-treatment and intensively treated parasite populations. The differential selection observed in post-treatment and pre-treatment parasite populations could be linked to any reduced susceptibility of parasites to praziquantel treatment.

Allergen skin test reactivity and asthma are inversely associated with ratios of IgG4/IgE and total IgE/allergen-specific IgE in Ugandan communities.

BACKGROUND: Serum inhibition of allergen-specific IgE has been associated with competing IgG4 and non-specific polyclonal IgE. In allergen immunotherapy, beneficial responses have been associated with high IgG4/IgE ratios. Helminths potentiate antibody class switching to IgG4 and stimulate polyclonal IgE synthesis; therefore, we hypothesized a role for helminth-associated IgG4 and total IgE in protection against atopic sensitization and clinical allergy (asthma) in tropical low-income countries. METHODS: Among community residents of Ugandan rural Schistosoma mansoni (Sm)-endemic islands and a mainland urban setting with lower helminth exposure, and among urban asthmatic schoolchildren and non-asthmatic controls, we measured total, Schistosoma adult worm antigen (SWA)-specific, Schistosoma egg antigen (SEA)-specific and allergen (house dust mite [HDM] and German cockroach)-specific IgE and IgG4 by ImmunoCAP® and/or ELISA. We assessed associations between these antibody profiles and current Sm infection, the rural-urban environment, HDM and cockroach skin prick test (SPT) reactivity, and asthma. RESULTS: Total IgE, total IgG4 and SWA-, SEA- and allergen-specific IgE and IgG4 levels were significantly higher in the rural, compared to the urban setting. In both community settings, both Sm infection and SPT reactivity were positively associated with allergen-specific and total IgE responses. SPT reactivity was inversely associated with Schistosoma-specific IgG4, allergen-specific IgG4/IgE ratios and total IgE/allergen-specific IgE ratios. Asthmatic schoolchildren, compared with non-asthmatic controls, had significantly higher levels of total and allergen-specific IgE, but lower ratios of allergen-specific IgG4/IgE and total IgE/allergen-specific IgE. CONCLUSIONS AND CLINICAL RELEVANCE: Our immuno-epidemiological data support the hypothesis that the IgG4-IgE balance and the total IgE-allergen-specific IgE balance are more important than absolute total, helminth- or allergen-specific antibody levels in inhibition of allergies in the tropics.

Cross-reactive carbohydrate determinant-specific IgE obscures true atopy and exhibits ⍺-1,3-fucose epitope-specific inverse associations with asthma.

BACKGROUND: In high-income, temperate countries, IgE to allergen extracts is a risk factor for, and mediator of, allergy-related diseases (ARDs). In the tropics, positive IgE tests are also prevalent, but rarely associated with ARD. Instead, IgE responses to ubiquitous cross-reactive carbohydrate determinants (CCDs) on plant, insect and parasite glycoproteins, rather than to established major allergens, are dominant. Because anti-CCD IgE has limited clinical relevance, it may impact ARD phenotyping and assessment of contribution of atopy to ARD. METHODS: Using an allergen extract-based test, a glycan and an allergen (glyco)protein microarray, we mapped IgE fine specificity among Ugandan rural Schistosoma mansoni (Sm)-endemic communities, proximate urban communities, and importantly in asthmatic and nonasthmatic schoolchildren. RESULTS: Overall, IgE sensitization to extracts was highly prevalent (43%-73%) but allergen arrays indicated that this was not attributable to established major allergenic components of the extracts (0%-36%); instead, over 40% of all participants recognized CCD-bearing components. Using glycan arrays, we dissected IgE responses to specific glycan moieties and found that reactivity to classical CCD epitopes (core ß-1,2-xylose, α-1,3-fucose) was positively associated with sensitization to extracts, rural environment and Sm infection, but not with skin reactivity to extracts or sensitization to their major allergenic components. Interestingly, we discovered that reactivity to only a subset of core α-1,3-fucose-carrying N-glycans was inversely associated with asthma. CONCLUSIONS: CCD reactivity is not just an epiphenomenon of parasite exposure hampering specificity of allergy diagnostics; mechanistic studies should investigate whether specific CCD moieties identified here are implicated in the protective effect of certain environmental exposures against asthma.

Anthelminthic treatment receipt and its predictors in Lake Victoria fishing communities, Uganda: Intervention coverage results from the LaVIISWA cluster randomised trial.

BACKGROUND: Mass drug administration (MDA) is a cornerstone of control of parasitic helminths. In schistosomiasis-endemic areas with >50% of school-aged children infected, community-wide MDA with praziquantel is recommended by the World Health Organisation (WHO), with target coverage of >75%. Using data from a cluster-randomised trial of MDA treatment strategies, we aimed to describe the proportion of eligible residents who received MDA and predictors of treatment receipt, and to assess associations with helminth prevalence. METHODS: In the Koome islands of Lake Victoria, Uganda, where baseline schistosomiasis prevalence (by single stool sample, Kato Katz) was 52% overall (all ages) and 67% among school-aged children, we conducted a cluster-randomised trial of community-wide, intensive MDA (quarterly single-dose praziquantel 40mg/kg; triple-dose albendazole 400mg) versus standard, Uganda government intervention (annual single-dose praziquantel 40mg/kg; 6-monthly single-dose albendazole). Twenty-six fishing villages were randomised, 13 per trial arm, for four years. At each treatment round, praziquantel treatment and the first dose of albendazole treatment were directly observed by the study team, registers of village residents were updated and the proportion receiving treatment among those eligible recorded. RESULTS: During the four-year MDA, at each treatment round an average of 13,382 people were registered in the 26 villages (7,153 and 6,229 in standard and intensive intervention villages, respectively). Overall, the proportion of those eligible receiving praziquantel was lower than for albendazole (60% versus 65%), particularly in the standard arm (61% versus 71%) compared to the intensive arm (60% versus 62%). Albendazole receipt was lower when given concurrently with praziquantel. Absence was the commonest reason for non-receipt of treatment (81% albendazole, 77% praziquantel), followed by refusal (14% albendazole, 18% praziquantel). Proportions receiving treatment were lowest among school-aged children, but did not differ by sex. Longitudinal analysis of a subgroup of residents who did not move during the study period found that persistent non-receipt of treatment in this subgroup was rare. Refusal to receive treatment was highest among adults and more common among females. CONCLUSION: In schistosomiasis high-risk communities, a combination of approaches to increasing treatment coverage, such as extended periods of treatment delivery, and the provision of incentives, may be required to achieve WHO targets.

Contrasting impact of rural, versus urban, living on glucose metabolism and blood pressure in Uganda.

Background: The burden of cardiometabolic diseases, including cardiovascular diseases and diabetes, is increasing in sub-Saharan Africa and this has been linked to urbanisation. Helminths, through their immunomodulatory properties, may protect against these disorders. We hypothesised that the rural environment protects against cardiometabolic diseases and that helminths may influence rural-urban disparity of cardiometabolic disease risk. Methods: We compared metabolic parameters of individuals aged ≥10 years living in rural, high-helminth-transmission and urban, lower-helminth-transmission settings in Uganda. Cross-sectional surveys were conducted in rural Lake Victoria island communities and in urban sub-wards in Entebbe municipality. Helminth infection and outcomes, including insulin resistance (computed using the homeostatic model assessment of insulin resistance [HOMA-IR]), fasting blood glucose, fasting blood lipids, blood pressure, body mass index (BMI), waist and hip circumference, were assessed. Results: We analysed 1,898 rural and 930 urban participants. Adjusting for BMI, exercise, smoking, alcohol intake, age and sex, urban residents had lower mean fasting glucose (adjusted mean difference [95%CI] -0.13 [-0.24, -0.01] p=0.04) and HOMA-IR (-0.13 [-0.25, -0.01] p=0.04) but higher blood pressure (systolic, 4.64 [3.23, 6.06] p<0.001; diastolic, 1.89 [0.81, 2.97] p=0.001). Current helminth infection did not explain the observed differences. Conclusions: In low-income countries, rural living may protect against hypertension but impair glucose metabolism.

Urban-rural differences in immune responses to mycobacterial and tetanus vaccine antigens in a tropical setting: A role for helminths?

Several vaccines elicit lower efficacy or impaired immune responses in rural compared to urban settings, and in tropical low-income countries compared to high-income countries. An unresolved hypothesis is that immunomodulation by parasitic infections such as helminths (prevalent in rural tropical settings) contributes to suppression of vaccine responses. Among 1-17-year-old Ugandan residents of rural Schistosoma mansoni (Sm)-endemic islands and proximate urban communities with lower helminth exposure, we assessed plasma antibody and whole blood assay cytokine responses to tetanus toxoid (TT) and purified protein derivative of Mycobacterium tuberculosis (PPD). These were taken to represent recall responses to tetanus and BCG vaccination in infancy. PPD-specific responses are additionally induced by tuberculous and non-tuberculous mycobacterial exposure. Urban-rural comparisons showed that PPD-specific IFN-γ and IL-13 and TT-specific IL-13 and IgG concentrations were lower in the rural setting, but that PPD-specific IgE concentrations were higher. Among rural participants, Sm infection was inversely associated with PPD-specific IFN-γ, while nematode infection was positively associated with PPD-specific IgG. Among urban participants, Sm infection was positively associated with PPD-specific responses but inversely associated with TT-specific responses, while nematode infection was inversely associated with TT-specific IgG and IgG4, but no associations were observed with PPD-specific responses. Despite these associations, for the urban-rural comparisons there were no notable changes in test statistics after adjusting for current helminth infections, suggesting that helminths were not the sole explanation for the urban-rural differences observed. Helminths likely work in concert with other environmental exposures and operational factors to influence vaccine response.

Does Intensive Treatment Select for Praziquantel Resistance in High-Transmission Settings? Parasitological Trends and Treatment Efficacy Within a Cluster-Randomized Trial.

BACKGROUND: Praziquantel mass drug administration (MDA) is recommended in schistosomiasis-endemic areas. Animal models demonstrate Schistosoma parasite resistance to praziquantel after repeated exposure. METHODS: We conducted a parasitological survey in 26 fishing communities in Uganda after 4 years of quarterly (13 communities) or annual (13 communities) praziquantel MDA, with Schistosoma infection detected by single-stool-sample Kato-Katz. A test of cure was done in participants who were positive on both urine circulating cathodic antigen test and 3-sample Kato-Katz. We calculated cure rates (CRs) and egg reduction rates (ERRs) based on 3-sample Kato-Katz and infection intensity using worm-specific circulating anodic antigen (CAA) in blood, comparing these between quarterly and annually treated participants. RESULTS: Single-sample Kato-Katz Schistosoma mansoni prevalence was 22% in 1,056 quarterly treated participants and 34% in 1,030 annually treated participants (risk ratio, 0.62; 95% confidence interval [CI], 0.40 to 0.94). Among 110 test-of-cure participants, CRs were 65% and 51% in annually and quarterly treated villages, respectively (odds ratio, 0.65; 95% CI, 0.27 to 1.58); ERRs were 94% and 81% (difference, -13%; 95% CI, -48% to 2%). There was no impact of quarterly vs annual praziquantel on S. mansoni by CAA. CONCLUSIONS: In this schistosomiasis hot spot, there was little evidence of decreased praziquantel efficacy. However, in the absence of alternative therapies, there remains a need for continued vigilance of praziquantel efficacy in the MDA era.

The Effect of Helminth Infections and Their Treatment on Metabolic Outcomes: Results of a Cluster-Randomized Trial.

BACKGROUND: Helminths may protect against cardiometabolic risk through effects on inflammation and metabolism; their treatment may be detrimental to metabolic outcomes. METHODS: In a cluster-randomized trial in 26 Ugandan fishing communities we investigated effects of community-wide intensive (quarterly single-dose praziquantel, triple-dose albendazole) vs standard (annual single-dose praziquantel, biannual single-dose albendazole) anthelminthic treatment on metabolic outcomes, and observational associations between helminths and metabolic outcomes. The primary outcome, homeostatic model assessment of insulin resistance (HOMA-IR), and secondary outcomes (including blood pressure, fasting blood glucose, lipids) were assessed after 4 years' intervention among individuals aged ≥10 years. RESULTS: We analyzed 1898 participants. Intensive treatment had no effect on HOMA-IR (adjusted geometric mean ratio, 0.96 [95% confidence interval {CI}, .86-1.07]; P = .42) but resulted in higher mean low-density lipoprotein cholesterol (LDL-c) (2.86 vs 2.60 mmol/L; adjusted mean difference, 0.26 [95% CI, -.03 to .56]; P = .08). Lower LDL-c levels were associated with Schistosoma mansoni (2.37 vs 2.80 mmol/L; -0.25 [95% CI, -.49 to -.02]; P = .04) or Strongyloides (2.34 vs 2.69 mmol/L; -0.32 [95% CI, -.53 to -.12]; P = .003) infection. Schistosoma mansoni was associated with lower total cholesterol (4.24 vs 4.64 mmol/L; -0.25 [95% CI, -.44 to -.07]; P = .01) and moderate to heavy S. mansoni infection with lower triglycerides, LDL-c, and diastolic blood pressure. CONCLUSIONS: Helminth infections improve lipid profiles and may lower blood pressure. Studies to confirm causality and investigate mechanisms may contribute to understanding the epidemiological transition and suggest new approaches to prevent cardiometabolic disease. CLINICAL TRIALS REGISTRATION: ISRCTN47196031.

Kaposi's sarcoma-associated herpesvirus seropositivity is associated with parasite infections in Ugandan fishing communities on Lake Victoria islands.

We investigated the impact of helminths and malaria infection on Kaposi's sarcoma associated herpesvirus (KSHV) seropositivity, using samples and data collected from a cluster-randomised trial of intensive versus standard anthelminthic treatment. The trial was carried out in 2012 to 2016 among fishing communities on Lake Victoria islands in Uganda. Plasma samples from 2881 participants from two household surveys, the baseline (1310 participants) and the final (1571 participants) surveys were tested for KSHV IgG antibody responses to K8.1 and ORF73 recombinant proteins using ELISA. The baseline survey was carried out before the trial intervention while the final survey was carried out after three years of the trial intervention. Additionally, a subset sample of 372 participants from the final survey was tested for IgE, IgG and IgG4 antibody concentrations to S. mansoni adults worm antigen (SWA) and S. mansoni egg antigen (SEA) using ELISA. Infection by helminths (S. mansoni, N. americanus, T. trichiura and S. stercoralis) was diagnosed using real-time PCR, urine circulating cathodic antigen (CCA) and stool microscopy (Kato-Katz method) while malaria infection was diagnosed using microscopy. We analysed the relationship between helminth and malaria infections and KSHV seropositivity using regression modelling, allowing for survey design. At baseline, 56% of the participants were male while 48% of the participants were male in the final survey. The most prevalent helminth infection was S. mansoni (at baseline 52% and 34% in the final survey by microscopy, 86% by CCA and 50% by PCR in the final survey). KSHV seropositivity was 66% (baseline) and 56% (final survey) among those 1-12 years and >80% in those 13+ years in both surveys; malaria parasitaemia prevalence was 7% (baseline) and 4% (final survey). At baseline, individuals infected with S. mansoni (detected by microscopy) were more likely to be KSHV seropositive (aOR = 1.86 (1.16, 2.99) p = 0.012) and had higher anti-K8.1 antibody levels (acoefficient = 0.03 (0.01, 0.06) p = 0.02). In the final survey, S. mansoni (by microscopy, adjusted Odds Ratio (aOR = 1.43 (1.04-1.95), p = 0.028) and malaria parasitaemia (aOR = 3.49 (1.08-11.28), p = 0.038) were positively associated with KSHV seropositivity. Additionally, KSHV seropositive participants had higher S. mansoni-specific IgE and IgG antibody concentrations in plasma. Furthermore, HIV infected individuals on cART were less likely to be KSHV seropositive compared to HIV negative individuals (aOR = 0.46 (0.30, 0.71) p = 0.002). Schistosoma species skew the immune response towards Th2 and regulatory responses, which could impact on KSHV reactivation if co-infected with both organisms.

Microarray assessment of N-glycan-specific IgE and IgG profiles associated with Schistosoma mansoni infection in rural and urban Uganda.

Core ß-1,2-xylose and α-1,3-fucose are antigenic motifs on schistosome N-glycans, as well as prominent IgE targets on some plant and insect glycoproteins. To map the association of schistosome infection with responses to these motifs, we assessed plasma IgE and IgG reactivity using microarray technology among Ugandans from rural Schistosoma mansoni (Sm)-endemic islands (n = 209), and from proximate urban communities with lower Sm exposure (n = 62). IgE and IgG responses to core ß-1,2-xylose and α-1,3-fucose modified N-glycans were higher in rural versus urban participants. Among rural participants, IgE and IgG to core ß-1,2-xylose were positively associated with Sm infection and concentration peaks coincided with the infection intensity peak in early adolescence. Responses to core α-1,3-fucose were elevated regardless of Sm infection status and peaked before the infection peak. Among urban participants, Sm infection intensity was predominantly light and positively associated with responses to both motifs. Principal component and hierarchical cluster analysis reduced the data to a set of variables that captured core ß-1,2-xylose- and α-1,3-fucose-specific responses, and confirmed associations with Sm and the rural environment. Responses to core ß-1,2-xylose and α-1,3-fucose have distinctive relationships with Sm infection and intensity that should further be explored for associations with protective immunity, and cross-reactivity with other exposures.