Helminths and allergic disease in Vietnam

Background: Allergic disease is uncommon in developing countries, especially in rural areas. A protective effect of helminth infection has been implicated as a potential explanation. Objectives: To determine whether reduced exposure to helminth infection is associated with a higher risk of allergen skin sensitisation and allergic disease, and whether such an association could be explained by a helminth-induced up-regulation of certain cytokines, in particular anti-inflammatory IL-10. Methods: We invited 1,742 rural Vietnamese schoolchildren to take part in a cross-sectional baseline survey followed by a randomised, double blind, placebo-controlled trial of anti-helminthic therapy at 0, 3, 6, and 9 months to compare the change in exercise-induced bronchospasm (primary outcome), wheeze, rhinitis, eczema, and allergen skin sensitisation (secondary outcomes) at 12 months. 244 secondary schoolchildren also had venous blood taken to measure helminth induced IL-10, IFN-gamma, IL-5, and IL-13. Out of these 244 children, 144 were infected with hookworm and had bloods taken again at 12 months. Results: Baseline survey 1,601 schoolchildren (92% of those eligible) in grades 1-9 aged 6-18 participated in the baseline survey. 0.4% (6/1601) of children had a fall in peak flow after exercise of at least 15%. Doctor-diagnosed asthma was equally rare (0.4%, 6/1601), while 5.0% (80/1601) of children had experienced wheezing over the past 12 months. 6.9% (110/1601) of parents reported that their children had suffered of hay fever in the past 12 months, and in 2.6% (41/1601) of cases this diagnosis was confirmed by a doctor. 5.6% of children (89/1601) reported an itchy rash over the past 12 months. 0.9% (14/1601) had a history of flexural involvement and on examination 0.5% (8/1601) proved to have flexural eczema on the day of the survey. Skin prick test positivity was commoner than allergic disease. 33.5% (537/1601) of children had at least one positive skin prick test (dustmites 14.4%, cockroach 27.6%). The cross-sectional analysis yielded only significant results for allergen skin sensitisation. In univariate analysis, sensitisation was less frequent in children with hookworm or Ascaris infection, and increased in those with better santitation, including flush toilets and piped drinking water. In multivariate analysis, the risk of allergen skin sensitisation to house dust mite was reduced in those with Ascaris lumbricoides infection (adjusted OR=0.28, 95% CI 0.10-0.78) and in children with higher hookworm burden (adjusted OR for 350+ versus no eggs per gram faeces=0.61, 0.39-0.96), and increased in those using flush toilets (adjusted OR for flush toilet versus none/bush/pit=2.51, 1.00-6.28). In contrast, sensitisation to cockroach was not independently related to helminth infection but was increased in those regularly drinking piped or well water rather than from a stream (adjusted OR=1.33, 1.02-1.75). Intervention study 1,566 children in grades 1-8 completed the baseline survey and all consented to be randomised to either anti-helminthic treatment or placebo. 1487 children (95%) completed the intervention study. There was no effect of therapy on the primary outcome, exercise-induced bronchoconstriction (within-participant mean % fall in peak flow from baseline after anti-helminthic treatment 2.25 (SD 7.3) vs placebo 2.19 (SD 7.8, mean difference 0.06 (95% CI -0.71-0.83), p=0.9), or on the prevalence of the secondary clinical outcomes questionnaire-reported wheeze (adjusted OR=1.16, 0.35-3.82), rhinitis (adjusted OR= 1.39, 0.89-2.15), or flexural eczema (adjusted OR=1.17, 0.39-3.49). However, anti-helmithic therapy was associated with a significant allergen skin sensitisation risk increase in the treatment compared to the placebo group (adjusted OR=1.31, 1.02-1.67). In post-hoc analysis this effect was particularly strong for children infected with Ascaris lumbricoides at baseline (adjusted OR=4.90, 1.48-16.19), the majority of whom were co-infected with hookworm. Cytokine profiles Hookworm-induced IL-10 was inversely related to allergen skin sensitisation (any positive skin prick test) at baseline, but this result missed conventional statistical significance (univariate OR=0.70, 0.48-1.03; adjusted OR=0.72, 0.44-1.18). No other cytokine response was associated with skin prick test positivity at baseline (univariate OR IFN-gamma=1.15, 0.71-1.85; univariate OR IL-5=0.84, 0.53-1.33). Similary, no significant changes in any of the cytokine profiles were observed following anti-helminthic therapy in the treatment compared to the placebo group (p=0.3 for all three cytokines). Conclusion The baseline study suggested that hookworm and Ascaris infection, sanitation and water supply independently reduce the risk of allergic sensitisation. The intervention study confirmed that helminth infection and allergic sensitisation are inversely related and that the effect of Ascaris and hookworm infections on skin prick test responses is additive. However, we found little evidence to suggest that this effect was mediated by IL-10. There was also insufficient evidence to suggest that loss of exposure to gut worms for 12 months results in an increase in clinical allergic disease. The effect of more prolonged de-worming warrants further research