Background Helminth infection may influence cardiometabolic risk through effects on inflammation and metabolism. We hypothesised that helminths are protective and their treatment detrimental to metabolic outcomes. Methods We conducted a cluster-randomised trial in 26 fishing communities, Lake Victoria, Uganda. We investigated effects of community-wide intensive (quarterly single-dose praziquantel, triple dose albendazole) versus standard (annual single-dose praziquantel, six-monthly single-dose albendazole) anthelminthic treatment on metabolic outcomes, and observational associations between helminth infection and metabolic outcomes. The primary outcome, homeostatic model assessment of insulin resistance (HOMA-IR) and secondary outcomes (including blood pressure, fasting blood glucose and lipids) were assessed in a survey conducted after four years of intervention among individuals ≥10 years. Results We analysed 1898 participants. The intervention had no effect on HOMA-IR (adjusted geometric mean ratio [95%CI] 0.96 [0.86,1.07] p=0.42) but resulted in higher mean LDL-cholesterol in the intensive arm (2.86 vs 2.60 mmol/L, adjusted mean difference [95%CI] 0.26 [-0.03,0.56] p=0.08). Lower LDL-cholesterol levels were observed in S. mansoni (2.37 vs 2.80 mmol/L, -0.25 [-0.49,-0.02] p=0.04) and Strongyloides infected (2.34 vs 2.69mmol/L, -0.32 [-0.53,-0.12] p=0.003) participants compared with uninfected. S. mansoni infection was associated with lower total cholesterol levels (4.24 vs 4.64 mmol/L, -0.25 [-0.44,-0.07] p=0.01). Participants with moderate to heavy S. mansoni infection had lower triglycerides, LDL-cholesterol and diastolic blood pressure levels. Conclusions Helminth infections improve lipid profiles and may lower blood pressure. Further studies to confirm causality and investigate mechanisms will contribute to understanding the epidemiological transition and may suggest new approaches to prevent cardiometabolic disease. Clinical trials registration ISRCTN47196031

Summary 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.

Background Knowing the prevalence of schistosomiasis is key to informing programmes to control and eliminate the disease as a public health problem. It is also important to understand the impact of infection on child growth and development in order to allocate appropriate resources and effort to the control of the disease. Methods We conducted a survey to estimate the prevalence of schistosomiasis among school aged children in villages along the Albert-Nile shore line in the district of Pakwach, North Western Uganda. A total of 914 children aged between 10–15 years were screened for Schistosoma mansoni using the POC-CCA and Kato Katz (KK) techniques. The infection intensities were assessed by POC-CCA and KK as well as CAA tests. The KK intensities were also correlated with POC-CCA and with CAA intensity. Anthropometric measurements were also taken and multivariate analysis was carried out to investigate their association with infection status. Results The prevalence of schistosomiasis using the POC-CCA diagnostic test was estimated at 85% (95% CI: 83–87), being highest amongst children living closer to the Albert-Nile shoreline. Visual scoring of the POC-CCA results was more sensitive than the Kato Katz test and was positively correlated with the quantified infection intensities by the CAA test. The majority of the children were underweight (BMI<18.5), and most notably, boys had significantly lower height for age (stunting) than girls in the same age range (p < 0.0001), but this was not directly associated with S. mansoni infection. Conclusion High prevalence of S. mansoni infection in the region calls for more frequent mass drug administration with praziquantel. We observed high levels of stunting which was not associated with schistosomiasis. There is a need for improved nutrition among the children in the area.

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.

SummaryLow allergy‐related disease (ARD) prevalence in low‐income countries may be partly attributed to helminth infections. In the Schistosoma mansoni (Sm)‐endemic Lake Victoria islands (Uganda), we recently observed positive helminth‐allergy associations, despite low ARD prevalence. To understand how Sm‐induced cytokine and antibody profiles might influence allergic response profiles in this population, we assessed Schistosoma worm (SWA)‐ and egg antigen (SEA)‐specific Th1 (IFN‐γ), Th2 (IL‐5, IL‐13) and regulatory (IL‐10) cytokine profiles (n = 407), and total (n = 471), SWA‐, SEA‐ and allergen (house dust mite [HDM] and cockroach)‐specific (as)IgE and IgG4 profiles (n = 2117) by ELISA. Wheeze was inversely associated with SWA‐specific IFN‐γ (P < .001) and IL‐10 (P = .058), and SEA‐specific IL‐5 (P = .004). Conversely, having a detectable asIgE response was positively associated with SWA‐specific IL‐5 (P = .006) and IL‐10 (P < .001). Total, SWA‐, SEA‐ and allergen‐specific IgE and IgG4 responses were higher among Sm Kato‐Katz positive (SmKK+) and skin prick test (SPT)+ individuals compared to SmKK‐ and SPT‐ individuals. However, total and asIgG4/IgE ratios were lower among SPT+ and wheezing individuals. We conclude that, in this population, helminth‐induced antibody and cytokine responses may underlie individual positive helminth‐atopy associations, while the overall IgG4‐IgE balance may contribute to the low overall prevalence of clinical allergies in such settings.

Core β-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 β-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 β-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 β-1,2-xylose- and α-1,3-fucose-specific responses, and confirmed associations with Sm and the rural environment. Responses to core β-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.

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 fishing 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] 0.18 [-0.32, -0.05] p=0.01) and HOMA-IR (-0.26 [-0.40, -0.11] p=0.001) but higher blood pressure (systolic, 5.45 [3.75, 7.15] p<0.001; diastolic, 1.93 [0.57, 3.29] p=0.006). Current helminth infection did not explain the observed differences. Conclusions: In the Ugandan context, living in rural fishing communities may protect against hypertension but worsen glucose metabolism.

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