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Background In high‐income countries, allergy‐related diseases (ARDs) follow a typical sequence, the ‘Atopic March’. Little is known about the life‐course of ARDs in the markedly different, low‐income, tropical environment. We describe ARDs in a tropical, African birth cohort. Methods Ugandan children were followed from birth to 9 years. ISAAC questionnaires were completed at intervals; doctor‐diagnosed ARDs were recorded throughout follow‐up. Skin prick tests (SPTs) were performed at 3 and 9 years. Atopy was defined as ≥1 positive SPT. Results Of the 2345 live‐born children, 1214 (52%) were seen at 9 years. Wheeze and eczema were common in infancy, but by 9 years, only 4% reported recent wheeze, 5% eczema and 5% rhinitis. Between 3 and 9 years, atopy prevalence increased from 19% to 25%. Atopy at 3 or 9 years was associated with reported ARD events at 9 years, for example OR = 5.2 (95% CI 2.9–10.7) for atopy and recent wheeze at 9 years. Reported or doctor‐diagnosed ARD events in early childhood were associated with the same events in later childhood, for example OR = 4.4 (2.3–8.4) for the association between reported wheeze before 3 years with reported recent wheeze at 9 years, but progression from early eczema to later rhinitis or asthma was not observed. Conclusion Allergen sensitization started early in childhood and increased with age. Eczema and wheeze were common in infancy and declined with age. Atopy was strongly associated with ARD among the few affected children. The typical Atopic March did not occur. Environmental exposures during childhood may dissociate atopy and ARD.

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

Highlights • Urban residence and history of TB contact/disease were associated with increased risk of latent TB infection at age five years. • BCG vaccine strain, LTBI, HIV and malaria infections, and anthropometry predict anti-mycobacterial immune responses. • Helminth infections do not influence response to BCG vaccination. • Cytokine responses at one year were not associated with LTBI at age five years., Background BCG is used widely as the sole licensed vaccine against tuberculosis, but it has variable efficacy and the reasons for this are still unclear. No reliable biomarkers to predict future protection against, or acquisition of, TB infection following immunisation have been identified. Lessons from BCG could be valuable in the development of effective tuberculosis vaccines. Objectives Within the Entebbe Mother and Baby Study birth cohort in Uganda, infants received BCG at birth. We investigated factors associated with latent tuberculosis infection (LTBI) and with cytokine response to mycobacterial antigen at age five years. We also investigated whether cytokine responses at one year were associated with LTBI at five years of age. Methods Blood samples from age one and five years were stimulated using crude culture filtrates of Mycobacterium tuberculosis in a six-day whole blood assay. IFN-γ, IL-5, IL-13 and IL-10 production was measured. LTBI at five years was determined using T-SPOT.TB® assay. Associations with LTBI at five years were assessed using multivariable logistic regression. Multiple linear regression with bootstrapping was used to determine factors associated with cytokine responses at age five years. Results LTBI prevalence was 9% at age five years. Only urban residence and history of TB contact/disease were positively associated with LTBI. BCG vaccine strain, LTBI, HIV infection, asymptomatic malaria, growth z-scores, childhood anthelminthic treatment and maternal BCG scar were associated with cytokine responses at age five. Cytokine responses at one year were not associated with acquisition of LTBI by five years of age. Conclusion Although multiple factors influenced anti-myocbacterial immune responses at age five, factors likely to be associated with exposure to infectious cases (history of household contact, and urban residence) dominated the risk of LTBI.

BACKGROUND: The Hygiene Hypothesis proposes that infection exposure protects against inflammatory conditions. Helminths possess allergen-like molecules and may specifically modulate allergy-related immunological pathways to inhibit responses which protect against them. Mass drug administration is recommended for helminth-endemic communities to control helminth-induced pathology, but may also result in increased rates of inflammation-mediated diseases in resource-poor settings. Immunological studies integrated with implementation of helminth control measures may elucidate how helminth elimination contributes to ongoing epidemics of inflammatory diseases. We present the design of the Lake Victoria Island Intervention Study on Worms and Allergy-related diseases (LaVIISWA), a cluster-randomised trial evaluating the risks and benefits of intensive versus standard anthelminthic treatment for allergy-related diseases and other health outcomes. METHODS/DESIGN: The setting is comprised of island fishing communities in Mukono district, Uganda. Twenty-six communities have been randomised in a 1:1 ratio to receive standard or intensive anthelminthic intervention for a three-year period. Baseline characteristics were collected immediately prior to intervention rollout, commenced in February 2013. Primary outcomes are reported wheeze in the past 12 months and atopy (skin prick test response and allergen-specific immunoglobulin (asIg) E concentration). Secondary outcomes are visible flexural dermatitis, helminth infections, haemoglobin, growth parameters, hepatosplenomegaly, and responses to vaccine antigens. The trial provides a platform for in-depth analysis of clinical and immunological consequences of the contrasting interventions. DISCUSSION: The baseline survey has been completed successfully in a challenging environment. Baseline characteristics were balanced between trial arms. Prevalence of Schistosoma mansoni, hookworm, Strongyloides stercoralis and Trichuris trichiura was 52%, 23%, 13%, and 12%, respectively; 31% of Schistosoma mansoni infections were heavy (>400 eggs/gram). The prevalence of reported wheeze and positive skin prick test to any allergen was 5% and 20%, respectively. Respectively, 77% and 87% of participants had Dermatophagoides- and German cockroach-specific IgE above 0.35 kUA/L. These characteristics suggest that the LaVIISWA study will provide an excellent framework for investigating beneficial and detrimental effects of worms and their treatment, and the mechanisms of such effects. TRIAL REGISTRATION: This trial was registered with Current Controlled Trials (identifier: ISRCTN47196031) on 7 September 2012.

In 1994 and 2002, respectively, the World Health Organisation proposed that treatment for hookworm and schistosomiasis could be provided during pregnancy. It was hoped that this might have benefits for maternal anaemia, fetal growth and perinatal mortality; a beneficial effect on the infant response to immunisation was also hypothesised. Three trials have now been conducted. Two have examined the effects of benzimidazoles; one (the Entebbe Mother and Baby Study) the effects of albendazole and praziquantel. All three were conducted in settings of high prevalence but low intensity helminth infection. Results suggest that, in such settings and given adequate provision of haematinics, the benefit of routine anthelminthics during pregnancy for maternal anaemia may be small; none of the other expected benefits has yet been demonstrated. The Entebbe Mother and Baby Study found a significant adverse effect of albendazole on the incidence of infantile eczema in the whole study population, and of praziquantel on the incidence of eczema among infants of mothers with Schistosoma mansoni. Further studies are required in settings that differ in helminth species and infection intensities. Further research is required to determine whether increased rates of infantile eczema translate to long-term susceptibility to allergy, and to explore the underlying mechanisms of these effects. The risks and benefits of routine anthelminthic treatment in antenatal clinics may need to be reconsidered.

Background: Worms may protect against allergy. Early-life worm exposure may becritical, but this has not been fully investigated.Objectives: To investigate whether worms in pregnancy and in early childhood areassociated with childhood eczema incidence. \ud \ud Methods: The Entebbe Mother and Baby Study, an anthelminthic treatment trial,enrolled pregnant women between 2003 and 2005 in Uganda. Mothers were investigatedfor worms during pregnancy and children annually. Eczema was doctor-diagnosed frombirth to age five years. A planned observational analysis was conducted within the trialcohort to investigate associations between worms and eczema. \ud \ud Results: Data for 2345 live-born children were analysed. Hookworm was the mostprevalent maternal worm (45%). Childhood worms were less prevalent. Eczemaincidence was 4.68/100 person-years. Maternal hookworm was associated withreduced eczema incidence [adjusted hazard ratio (95% confidence interval), p-value:0.71(0.51–0.99), 0.04] and modified effects of known risk factors for eczema:Dermatophagoides-specific IgE in children was positively associated with eczemaincidence if the mother had no hookworm [2.72(1.11–6.63), 0.03], but not if the motherhad hookworm [0.41(0.10–1.69), 0.22], interaction p-value = 0.03. Similar interactionswere seen for maternal history of eczema {[2.87(1.31–6.27, 0.008) vs. [0.73(0.23–2.30),0.60], interaction p-value = 0.05}, female gender {[1.82(1.22–2.73), 0.004 vs. [0.96(0.60–1.53), 0.87], interaction p-value = 0.04} and allergen-specific IgE. ChildhoodTrichuris trichiura and hookworm were inversely associated with eczema. \ud \ud Conclusions: Maternal hookworm modifies effects of known risk factors for eczema.Mechanisms by which early-life worm exposures influence allergy need investigation.Worms or worm products, and intervention during pregnancy have potential forprimary prevention of allergy.