SummaryBackgroundHelminth infections affect the human immune response. We investigated whether prenatal exposure to and treatment of maternal helminth infections affects development of an infant's immune response to immunisations and unrelated infections.MethodsIn this randomised, double-blind, placebo-controlled trial, we enrolled 2507 women in the second or third trimester of pregnancy who were planning to deliver in Entebbe General Hospital, Entebbe, Uganda. With a computer-generated random number sequence in blocks of 100, we assigned patients to 440 mg albendazole and 40 mg/kg praziquantel (n=628), 440 mg albendazole and a praziquantel-matching placebo (n=625), 40 mg/kg praziquantel and an albendazole-matching placebo (n=626), or an albendazole-matching placebo and praziquantel-matching placebo (n=628). All participants and hospital staff were masked to allocation. Primary outcomes were immune response at age 1 year to BCG, tetanus, and measles immunisation; incidence of infectious diseases during infancy; and vertical HIV transmission. Analysis was by intention-to-treat. This trial is registered, number ISRCTN32849447.FindingsData were available at delivery for 2356 women, with 2345 livebirths; 2115 (90%) of liveborn infants remained in follow-up at 1 year of age. Neither albendazole nor praziquantel treatments affected infant response to BCG, tetanus, or measles immunisation. However, in infants of mothers with hookworm infection, albendazole treatment reduced interleukin-5 (geometric mean ratio 0·50, 95% CI 0·30–0·81, interaction p=0·02) and interleukin-13 (0·52, 0·34–0·82, 0·0005) response to tetanus toxoid. The rate per 100 person-years of malaria was 40·9 (95% CI 38·3–43·7), of diarrhoea was 134·1 (129·2–139·2), and of pneumonia was 22·3 (20·4–24·4). We noted no effect on infectious disease incidence for albendazole treatment (malaria [hazard ratio 0·95, 95% CI 0·79–1.14], diarrhoea [1·06, 0·96–1·16], pneumonia [1·11, 0·90–1·38]) or praziquantel treatment (malaria [1·00, 0·84–1·20], diarrhoea [1·07, 0·98–1·18], pneumonia [1·00, 0·80–1·24]). In HIV-exposed infants, 39 (18%) were infected at 6 weeks; vertical transmission was not associated with albendazole (odds ratio 0·70, 95% CI 0·35–1·42) or praziquantel (0·60, 0·29–1·23) treatment.InterpretationThese results do not accord with the recently advocated policy of routine antenatal anthelmintic treatment, and the value of such a policy may need to be reviewed.FundingWellcome Trust.

BackgroundHelminth infections may modulate immune responses to unrelated pathogens and allergens; these effects may commence prenatally. We addressed the hypothesis that anthelminthic treatment in pregnancy and early childhood would improve responses to immunisation and modulate disease incidence in early childhood with both beneficial and detrimental effects.Methods and FindingsA randomised, double-blind, placebo-controlled trial was conducted in Entebbe, Uganda [ISRCTN32849447]. In three independent randomisations, 2507 pregnant women were allocated to receive single-dose albendazole or placebo, and praziquantel or placebo; 2016 of their offspring were randomised to receive quarterly single-dose albendazole or placebo from age 15 months to 5 years. Primary outcomes were post-immunisation recall responses to BCG and tetanus antigens, and incidence of malaria, diarrhoea, and pneumonia; incidence of eczema was an important secondary outcome. Analysis was by intention-to-treat. Of 2345 live births, 1622 (69%) children remained in follow-up at age 5 years. 68% of mothers at enrolment, and 11% of five-year-olds, had helminth infections. Maternal hookworm and Schistosoma mansoni were effectively treated by albendazole and praziquantel, respectively; and childhood hookworm and Ascaris by quarterly albendazole. Incidence rates of malaria, diarrhoea, pneumonia, and eczema were 34, 65, 10 and 5 per 100 py, respectively. Albendazole during pregnancy caused an increased rate of eczema in the children (HR 1.58 (95% CI 1.15–2.17), p = 0.005). Quarterly albendazole during childhood was associated with reduced incidence of clinical malaria (HR 0.85 (95% CI 0.73–0.98), p = 0.03). There were no consistent effects of the interventions on any other outcome.ConclusionsRoutine use of albendazole in pregnancy may not always be beneficial, even in tropical developing countries. By contrast, regular albendazole treatment in preschool children may have an additional benefit for malaria control where helminths and malaria are co-endemic. Given the low helminth prevalence in our children, the effect of albendazole on malaria is likely to be direct.Trial registrationCurrent Controlled Trials ISRCTN32849447

SummaryIt is suggested that helminths, particularly hookworm and schistosomiasis, may be important causes of anaemia in pregnancy. We assessed the associations between mild-to-moderate anaemia (haemoglobin >8.0 g/dl and <11.2 g/dl) and helminths, malaria and HIV among 2507 otherwise healthy pregnant women at enrolment to a trial of deworming in pregnancy in Entebbe, Uganda. The prevalence of anaemia was 39.7%. The prevalence of hookworm was 44.5%, Mansonella perstans 21.3%, Schistosoma mansoni 18.3%, Strongyloides 12.3%, Trichuris 9.1%, Ascaris 2.3%, asymptomatic Plasmodium falciparum parasitaemia 10.9% and HIV 11.9%. Anaemia showed little association with the presence of any helminth, but showed a strong association with malaria (adjusted odds ratio (AOR) 3.22, 95% CI 2.43–4.26) and HIV (AOR 2.46, 95% CI 1.90–3.19). There was a weak association between anaemia and increasing hookworm infection intensity. Thus, although highly prevalent, helminths showed little association with mild-to-moderate anaemia in this population, but HIV and malaria both showed a strong association. This result may relate to relatively good nutrition and low helminth infection intensity. These findings are pertinent to estimating the disease burden of helminths and other infections in pregnancy. [Clinical Trial No. ISRCTN32849447]

BackgroundThe 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/DesignThe 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.DiscussionThe 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 registrationThis trial was registered with Current Controlled Trials (identifier: ISRCTN47196031) on 7 September 2012.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-0702-5) contains supplementary material, which is available to authorized users.

BackgroundParasitic helminths are potent immunomodulators and chronic infections may protect against allergy‐related disease and atopy. We conducted a cross‐sectional survey to test the hypothesis that in heavily helminth‐exposed fishing villages on Lake Victoria, Uganda, helminth infections would be inversely associated with allergy‐related conditions.MethodsA household survey was conducted as baseline to an anthelminthic intervention trial. Outcomes were reported wheeze in last year, atopy assessed both by skin prick test (SPT) and by the measurement of allergen‐specific IgE to dust mites and cockroach in plasma. Helminth infections were ascertained by stool, urine and haemoparasitology. Associations were examined using multivariable regression.ResultsTwo thousand three hundred and sixteen individuals were surveyed. Prevalence of reported wheeze was 2% in under‐fives and 5% in participants ≥5 years; 19% had a positive SPT; median Dermatophagoides‐specific IgE and cockroach‐specific IgE were 1440 and 220 ng/ml, respectively. S. mansoni, N. americanus, S. stercoralis, T. trichiura, M. perstans and A. lumbricoides prevalence was estimated as 51%, 22%, 12%, 10%, 2% and 1%, respectively. S. mansoni was positively associated with Dermatophagoides‐specific IgE [adjusted geometric mean ratio (aGMR) (95% confidence interval) 1.64 (1.23, 2.18)]; T. trichiura with SPT [adjusted odds ratio (aOR) 2.08 (1.38, 3.15)]; M. perstans with cockroach‐specific IgE [aGMR 2.37 (1.39, 4.06)], A. lumbricoides with wheeze in participants ≥5 years [aOR 6.36 (1.10, 36.63)] and with Dermatophagoides‐specific IgE [aGMR 2.34 (1.11, 4.95)]. No inverse associations were observed.ConclusionsContrary to our hypothesis, we found little evidence of an inverse relationship between helminths and allergy‐related outcomes, but strong evidence that individuals with certain helminths were more prone to atopy in this setting.

Summaryobjective To describe uptake of HIV and syphilis testing in a prevention of mother-to-child HIV transmission programme in Uganda.methods Analysis of data from routine HIV and syphilis testing at Entebbe Hospital antenatal services. results A total of 20 738 women attended antenatal services. Exactly 62.8% of women, but only 1.8% of their male partners, accepted testing for HIV; 82.2% of women, but only 1.1% of their male partners accepted syphilis testing. Partners of women with positive HIV results were more likely to come for subsequent testing. Of 200 couples whose partners accepted HIV-testing within 30 days of one another, 19 (9.5%) were HIV-discordant, representing 65.5% of couples with at least one partner HIVpositive. HIV prevalence was 12.6% for women and 10.8% for men; syphilis prevalence was 4.0% for women and 6.2% for men.conclusion Uptake of HIV and syphilis testing was fairly good among pregnant women attending antenatal clinics at Entebbe Hospital, but very low among their male partners. The level of HIVdiscordant couples was high. These clinics should be made more couples-friendly to identify both HIVpositive men for treatment and discordant couples for HIV prevention.

BackgroundWorms may protect against allergy. Early-life worm exposure may be critical, but this has not been fully investigated.ObjectivesTo investigate whether worms in pregnancy and in early childhood are associated with childhood eczema incidence.MethodsThe Entebbe Mother and Baby Study, an anthelminthic treatment trial, enrolled pregnant women between 2003 and 2005 in Uganda. Mothers were investigated for worms during pregnancy and children annually. Eczema was doctor-diagnosed from birth to age five years. A planned observational analysis was conducted within the trial cohort to investigate associations between worms and eczema.ResultsData for 2345 live-born children were analysed. Hookworm was the most prevalent maternal worm (45%). Childhood worms were less prevalent. Eczema incidence was 4.68/100 person-years. Maternal hookworm was associated with reduced 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 eczema incidence if the mother had no hookworm [2.72(1.11–6.63), 0.03], but not if the mother had hookworm [0.41(0.10–1.69), 0.22], interaction p-value = 0.03. Similar interactions were 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.ConclusionsMaternal 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 for primary prevention of allergy.

BackgroundVaccine failure is an important concern in the tropics with many contributing elements. Among them, it has been suggested that exposure to natural infections might contribute to vaccine failure and recurrent disease outbreaks. We tested this hypothesis by examining the influence of co-infections on maternal and infant measles-specific IgG levels.MethodsWe conducted an observational analysis using samples and data that had been collected during a larger randomised controlled trial, the Entebbe Mother and Baby Study (ISRCTN32849447). For the present study, 711 pregnant women and their offspring were considered. Helminth infections including hookworm, Schistosoma mansoni and Mansonella perstans, along with HIV, malaria, and other potential confounding factors were determined in mothers during pregnancy and in their infants at age one year. Infants received their measles immunisation at age nine months. Levels of total IgG against measles were measured in mothers during pregnancy and at delivery, as well as in cord blood and from infants at age one year.ResultsAmong the 711 pregnant women studied, 66% had at least one helminth infection at enrolment, 41% had hookworm, 20% M. perstans and 19% S. mansoni. Asymptomatic malaria and HIV prevalence was 8% and 10% respectively. At enrolment, 96% of the women had measles-specific IgG levels considered protective (median 4274 mIU/ml (IQR 1784, 7767)). IgG levels in cord blood were positively correlated to maternal measles-specific IgG levels at delivery (r = 0.81, p < 0.0001). Among the infants at one year of age, median measles-specific IgG levels were markedly lower than in maternal and cord blood (median 370 mIU/ml (IQR 198, 656) p < 0.0001). In addition, only 75% of the infants had measles-specific IgG levels considered to be protective. In a multivariate regression analysis, factors associated with reduced measles-specific antibody levels in infancy were maternal malaria infection, infant malaria parasitaemia, infant HIV and infant wasting. There was no association with maternal helminth infection.ConclusionMalaria and HIV infection in mothers during pregnancy, and in their infants, along with infant malnutrition, may result in reduction of the antibody response to measles immunisation in infancy. This re-emphasises the importance of malaria and HIV control, and support for infant nutrition, as these interventions may have benefits for vaccine efficacy in tropical settings.