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.

The Impact of Intensive Versus Standard Anthelminthic Treatment on Allergy-related Outcomes, Helminth Infection Intensity, and Helminth-related Morbidity in Lake Victoria Fishing Communities, Uganda: Results From the LaVIISWA Cluster-randomized Trial.

BACKGROUND: The prevalence of allergy-related diseases is increasing in low-income countries. Parasitic helminths, common in these settings, may be protective. We hypothesized that intensive, community-wide, anthelminthic mass drug administration (MDA) would increase allergy-related diseases, while reducing helminth-related morbidity. METHODS: In an open, cluster-randomized trial (ISRCTN47196031), we randomized 26 high-schistosomiasis-transmission fishing villages in Lake Victoria, Uganda, in a 1:1 ratio to receive community-wide intensive (quarterly single-dose praziquantel plus albendazole daily for 3 days) or standard (annual praziquantel plus 6 monthly single-dose albendazole) MDA. Primary outcomes were recent wheezing, skin prick test positivity (SPT), and allergen-specific immunoglobulin E (asIgE) after 3 years of intervention. Secondary outcomes included helminths, haemoglobin, and hepatosplenomegaly. RESULTS: The outcome survey comprised 3350 individuals. Intensive MDA had no effect on wheezing (risk ratio [RR] 1.11, 95% confidence interval [CI] 0.64-1.93), SPT (RR 1.10, 95% CI 0.85-1.42), or asIgE (RR 0.96, 95% CI 0.82-1.12). Intensive MDA reduced Schistosoma mansoni infection intensity: the prevalence from Kato Katz examinations of single stool samples from each patient was 23% versus 39% (RR 0.70, 95% CI 0.55-0.88), but the urine circulating cathodic antigen test remained positive in 85% participants in both trial arms. Hookworm prevalence was 8% versus 11% (RR 0.55, 95% CI 0.31-1.00). There were no differences in anemia or hepatospenomegaly between trial arms. CONCLUSIONS: Despite reductions in S. mansoni intensity and hookworm prevalence, intensive MDA had no effect on atopy, allergy-related diseases, or helminth-related pathology. This could be due to sustained low-intensity infections; thus, a causal link between helminths and allergy outcomes cannot be discounted. Intensive community-based MDA has a limited impact in high-schistosomiasis-transmission fishing communities, in the absence of other interventions. CLINICAL TRIALS REGISTRATION: ISRCTN47196031.

Do helminth infections underpin urban-rural differences in risk factors for allergy-related outcomes?

BACKGROUND: It is proposed that helminth exposure protects against allergy-related disease, by mechanisms that include disconnecting risk factors (such as atopy) from effector responses. OBJECTIVE: We aimed to assess how helminth exposure influences rural-urban differences in risk factors for allergy-related outcomes in tropical low- and middle-income countries. METHODS: In cross-sectional surveys in Ugandan rural Schistosoma mansoni (Sm)-endemic islands, and in nearby mainland urban communities with lower helminth exposure, we assessed risk factors for atopy (allergen-specific skin prick test [SPT] reactivity and IgE [asIgE] sensitization) and clinical allergy-related outcomes (wheeze, urticaria, rhinitis and visible flexural dermatitis), and effect modification by Sm exposure. RESULTS: Dermatitis and SPT reactivity were more prevalent among urban participants, urticaria and asIgE sensitization among rural participants. Pairwise associations between clinical outcomes, and between atopy and clinical outcomes, were stronger in the urban survey. In the rural survey, SPT positivity was inversely associated with bathing in lakewater, Schistosoma-specific IgG4 and Sm infection. In the urban survey, SPT positivity was positively associated with age, non-Ugandan maternal tribe, being born in a city/town, BCG scar and light Sm infection. Setting (rural vs urban) was an effect modifier for risk factors including Sm- and Schistosoma-specific IgG4. In both surveys, the dominant risk factors for asIgE sensitization were Schistosoma-specific antibody levels and helminth infections. Handwashing and recent malaria treatment reduced odds of asIgE sensitization among rural but not urban participants. Risk factors for clinical outcomes also differed by setting. Despite suggestive trends, we did not find sufficient evidence to conclude that helminth (Sm) exposure explained rural-urban differences in risk factors. CONCLUSIONS AND CLINICAL RELEVANCE: Risk factors for allergy-related outcomes differ between rural and urban communities in Uganda but helminth exposure is unlikely to be the sole mechanism of the observed effect modification between the two settings. Other environmental exposures may contribute significantly.

The determinants of lipid profiles in early adolescence in a Ugandan birth cohort.

Dyslipidaemia in adolescence tracks into adulthood and is an important risk factor for cardiovascular disease. Little is known about the effects of environmental exposures and early-life exposure to infectious diseases common to tropical regions on lipids. In 1119 early adolescent participants in the Entebbe Mother and Baby Study, we used linear regression to examine whether prenatal, childhood or adolescent factors are associated with lipid levels. Reduced high-density lipoprotein (HDL) and elevated triglyceride levels were common (prevalence 31% and 14%, respectively), but elevated low-density lipoprotein (LDL) or total cholesterol (TC) were rare. Current malaria infection was associated with lower mean LDL (adjusted ß - 0.51; 95% CI - 0.81, - 0.21), HDL (adjusted ß - 0.40; 95% CI - 0.56, - 0.23), and TC levels (adjusted ß - 0.62; 95% CI - 0.97, - 0.27), but higher mean triglyceride levels (geometric mean ratio (GMR) 1.47; 95% CI 1.18-1.84). Early-life asymptomatic malaria was associated with modest reductions in HDL and TC. Body mass index (BMI) was positively associated with LDL, TC, and triglycerides. No associations with helminth infection were found. Our findings suggest that early-life factors have only marginal effects on the lipid profile. Current malaria infection and BMI are strongly associated with lipids and important to consider when trying to improve the lipid profile.

Population differences in vaccine responses (POPVAC): scientific rationale and cross-cutting analyses for three linked, randomised controlled trials assessing the role, reversibility and mediators of immunomodulation by chronic infections in the tropics.

INTRODUCTION: Vaccine-specific immune responses vary between populations and are often impaired in low income, rural settings. Drivers of these differences are not fully elucidated, hampering identification of strategies for optimising vaccine effectiveness. We hypothesise that urban-rural (and regional and international) differences in vaccine responses are mediated to an important extent by differential exposure to chronic infections, particularly parasitic infections. METHODS AND ANALYSIS: Three related trials sharing core elements of study design and procedures (allowing comparison of outcomes across the trials) will test the effects of (1) individually randomised intervention against schistosomiasis (trial A) and malaria (trial B), and (2) Bacillus Calmette-Guérin (BCG) revaccination (trial C), on a common set of vaccine responses. We will enrol adolescents from Ugandan schools in rural high-schistosomiasis (trial A) and rural high-malaria (trial B) settings and from an established urban birth cohort (trial C). All participants will receive BCG on day '0'; yellow fever, oral typhoid and human papilloma virus (HPV) vaccines at week 4; and HPV and tetanus/diphtheria booster vaccine at week 28. Primary outcomes are BCG-specific IFN-γ responses (8 weeks after BCG) and for other vaccines, antibody responses to key vaccine antigens at 4 weeks after immunisation. Secondary analyses will determine effects of interventions on correlates of protective immunity, vaccine response waning, priming versus boosting immunisations, and parasite infection status and intensity. Overarching analyses will compare outcomes between the three trial settings. Sample archives will offer opportunities for exploratory evaluation of the role of immunological and 'trans-kingdom' mediators in parasite modulation of vaccine-specific responses. ETHICS AND DISSEMINATION: Ethics approval has been obtained from relevant Ugandan and UK ethics committees. Results will be shared with Uganda Ministry of Health, relevant district councils, community leaders and study participants. Further dissemination will be done through conference proceedings and publications. TRIAL REGISTRATION NUMBERS: ISRCTN60517191, ISRCTN62041885, ISRCTN10482904.

Effect of intensive treatment for schistosomiasis on immune responses to vaccines among rural Ugandan island adolescents: randomised controlled trial protocol A for the 'POPulation differences in VACcine responses' (POPVAC) programme.

INTRODUCTION: Several licensed and investigational vaccines have lower efficacy, and induce impaired immune responses, in low-income versus high-income countries and in rural, versus urban, settings. Understanding these population differences is essential to optimising vaccine effectiveness in the tropics. We suggest that repeated exposure to and immunomodulation by chronic helminth infections partly explains population differences in vaccine response. METHODS AND ANALYSIS: We have designed an individually randomised, parallel group trial of intensive versus standard praziquantel (PZQ) intervention against schistosomiasis, to determine effects on vaccine response outcomes among school-going adolescents (9-17 years) from rural Schistosoma mansoni-endemic Ugandan islands. Vaccines to be studied comprise BCG on day 'zero'; yellow fever, oral typhoid and human papilloma virus (HPV) vaccines at week 4; and HPV and tetanus/diphtheria booster vaccine at week 28. The intensive arm will receive PZQ doses three times, each 2 weeks apart, before BCG immunisation, followed by a dose at week 8 and quarterly thereafter. The standard arm will receive PZQ at week 8 and 52. We expect to enrol 480 participants, with 80% infected with S. mansoni at the outset.Primary outcomes are BCG-specific interferon-γ ELISpot responses 8 weeks after BCG immunisation and for other vaccines, antibody responses to key vaccine antigens at 4 weeks after immunisation. Secondary analyses will determine the effects of intensive anthelminthic treatment on correlates of protective immunity, on waning of vaccine response, on priming versus boosting immunisations and on S. mansoni infection status and intensity. Exploratory immunology assays using archived samples will enable assessment of mechanistic links between helminths and vaccine responses. ETHICS AND DISSEMINATION: Ethics approval has been obtained from relevant ethics committes of Uganda and UK. Results will be shared with Uganda Ministry of Health, relevant district councils, community leaders and study participants. Further dissemination will be done through conference proceedings and publications. TRIAL REGISTRATION NUMBER: ISRCTN60517191.

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.

Effect of birth weight, exclusive breastfeeding and growth in infancy on fat mass and fat free mass indices in early adolescence: an analysis of the Entebbe Mother and Baby Study (EMaBs) cohort.

Background: There is limited data from Africa on the effect of pre- and post-natal growth and infant feeding on later body composition. This study's aim was to investigate the effect of birth weight, exclusive breastfeeding and infant growth on adolescent body composition, using data from a Ugandan birth cohort. Methods: Data was collected prenatally from pregnant women and prospectively from their resulting live offspring. Data on body composition (fat mass index [FMI] and fat free mass index [FFMI]) was collected from 10- and 11-year olds. Linear regression was used to assess the effect of birth weight, exclusive breastfeeding and infant growth on FMI and FFMI, adjusting for confounders. Results: 177 adolescents with a median age of 10.1 years were included in analysis, with mean FMI 2.9 kg/m 2 (standard deviation (SD) 1.2), mean FFMI 12.8 kg/m 2 (SD 1.4) and mean birth weight 3.2 kg (SD 0.5). 90 (50.9%) were male and 110 (63.2%) were exclusively breastfeeding at six weeks of age. Birth weight was associated with FMI in adolescence (regression coefficient ß= 0.66 per kg increase in birth weight, 95% confidence interval (CI) (0.04, 1.29), P=0.02), while exclusive breastfeeding (ß= -0.43, 95% CI (-1.06, 0.19), P=0.12), growth 0-6 months (ß= 0.24 95% CI (-0.43, 0.92), P=0.48) and growth 6-12 months (ß= 0.61, 95% CI (-0.23, 1.46), P=0.11) were not associated with FMI among adolescents. Birth weight (ß= 0.91, 95% CI (0.17, 1.65), P=0.01) was associated with FFMI in adolescence. Exclusive breastfeeding (ß= 0.17, 95% CI (-0.60, 0.94), P=0.62), growth 0-6 months (ß= 0.56, 95% CI (-0.20, 1.33), P= 0.10), and growth 6-12 months (ß= -0.02, 95% CI (-1.02, 0.99), P=0.97) were not associated with FFMI. Conclusions: Birth weight predicted body composition parameters in Ugandan early adolescents, however, exclusive breastfeeding at six weeks of age and growth in infancy did not.

A genome-wide association and replication study of blood pressure in Ugandan early adolescents.

BACKGROUND: Genetic association studies of blood pressure (BP) have mostly been conducted in non-African populations. Using the Entebbe Mother and Baby Study (EMaBS), we aimed to identify genetic variants associated with BP among Ugandan adolescents. METHODS: Systolic and diastolic BP were measured among 10- and 11-year olds. Whole-genome genotype data were generated using Illumina omni 2.5M arrays and untyped variants were imputed. Genome-wide association study (GWAS) was conducted using linear mixed model regression to account for population structure. Linear regression analysis was used to assess whether variants previously associated with BP (p < 5.0 × 10-8 ) in published BP GWASs were replicated in our study. RESULTS: Of the 14 million variants analyzed among 815 adolescents, none reached genome-wide significance (p < 5.0×10-8 ) for association with systolic or diastolic BP. The most strongly associated variants were rs181430167 (p = 6.8 × 10-7 ) for systolic BP and rs12991132 (p = 4.0 × 10-7 ) for diastolic BP. Thirty-three (17 single nucleotide polymorphisms (SNPs) for systolic BP, 15 SNPs for diastolic BP and one SNP for both) of 330 variants previously identified as associated with BP were replicated in this study, but none remained significant after accounting for multiple testing. CONCLUSION: Variants showing suggestive associations are worthy of future investigation. Replication results suggest that variants influencing adolescent BP may overlap somewhat with those already established in previous studies, largely based on adults in Western settings.