Allergen skin test reactivity and asthma are inversely associated with ratios of IgG4/IgE and total IgE/allergen-specific IgE in Ugandan communities.

BACKGROUND: Serum inhibition of allergen-specific IgE has been associated with competing IgG4 and non-specific polyclonal IgE. In allergen immunotherapy, beneficial responses have been associated with high IgG4/IgE ratios. Helminths potentiate antibody class switching to IgG4 and stimulate polyclonal IgE synthesis; therefore, we hypothesized a role for helminth-associated IgG4 and total IgE in protection against atopic sensitization and clinical allergy (asthma) in tropical low-income countries. METHODS: Among community residents of Ugandan rural Schistosoma mansoni (Sm)-endemic islands and a mainland urban setting with lower helminth exposure, and among urban asthmatic schoolchildren and non-asthmatic controls, we measured total, Schistosoma adult worm antigen (SWA)-specific, Schistosoma egg antigen (SEA)-specific and allergen (house dust mite [HDM] and German cockroach)-specific IgE and IgG4 by ImmunoCAP® and/or ELISA. We assessed associations between these antibody profiles and current Sm infection, the rural-urban environment, HDM and cockroach skin prick test (SPT) reactivity, and asthma. RESULTS: Total IgE, total IgG4 and SWA-, SEA- and allergen-specific IgE and IgG4 levels were significantly higher in the rural, compared to the urban setting. In both community settings, both Sm infection and SPT reactivity were positively associated with allergen-specific and total IgE responses. SPT reactivity was inversely associated with Schistosoma-specific IgG4, allergen-specific IgG4/IgE ratios and total IgE/allergen-specific IgE ratios. Asthmatic schoolchildren, compared with non-asthmatic controls, had significantly higher levels of total and allergen-specific IgE, but lower ratios of allergen-specific IgG4/IgE and total IgE/allergen-specific IgE. CONCLUSIONS AND CLINICAL RELEVANCE: Our immuno-epidemiological data support the hypothesis that the IgG4-IgE balance and the total IgE-allergen-specific IgE balance are more important than absolute total, helminth- or allergen-specific antibody levels in inhibition of allergies in the tropics.

Risk factors associated with rhinitis, allergic conjunctivitis and eczema among schoolchildren in Uganda.

BACKGROUND: The prevalence of allergy-related diseases (ARDs), including rhinitis, allergic conjunctivitis and eczema, is on the increase globally. The causes of this increase are not well established. OBJECTIVES: To investigate the risk factors associated with ARDs among schoolchildren in Uganda. METHODS: We conducted a secondary data analysis of a large asthma case-control study involving 1700 schoolchildren, 5-17 years, in urban Uganda. ARDs were defined according to the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Skin prick testing (SPT) was conducted using standard procedures and allergen-specific IgE (asIgE) using ImmunoCAP® . We employed inverse probability weighted analysis to generate estimated prevalence data and weighted odds ratios. RESULTS: The lifetime estimated weighted prevalence of reported rhinitis, allergic conjunctivitis and eczema was 43.3%, 39.5% and 13.5%; weighted prevalence in 12 months was 10.1%, 9.1% and 2.3%, respectively. There was overlap of ARDs, with 66.3% of 1193 schoolchildren who reported having ever an ARDs (including asthma) reporting two or more. Risk factors associated with reported rhinitis in the last 12 months were city residence at birth [adjusted odds ratio (95% confidence interval) 2.66 (1.42-4.99) compared to rural]; father's [2.62 (1.79-3.83)] and mother's history of allergic disease [2.12 (1.48-3.02)]; frequent de-worming in the last 12 months [2.01 (1.30-3.11), ≥2 versus none]; current high frequency of 'trucks passing on the street near home' [2.59 (1.48-4.52), 'almost all the time' versus rarely] and positive SPT [1.54 (1.09-2.18)] but not asIgE [1.38 (0.60-3.15)]. The same pattern of risk factors was observed for allergic conjunctivitis and eczema. CONCLUSION: We found extensive multi-morbidity of, and overlap in the risk factors for, rhinitis, conjunctivitis and eczema-similar to asthma risk factors-among schoolchildren in urban Uganda. This suggests a similar underlying cause for all ARDs, associated with exposure to urban lifestyles and environment in Uganda.

Cross-reactive carbohydrate determinant-specific IgE obscures true atopy and exhibits ⍺-1,3-fucose epitope-specific inverse associations with asthma.

BACKGROUND: In high-income, temperate countries, IgE to allergen extracts is a risk factor for, and mediator of, allergy-related diseases (ARDs). In the tropics, positive IgE tests are also prevalent, but rarely associated with ARD. Instead, IgE responses to ubiquitous cross-reactive carbohydrate determinants (CCDs) on plant, insect and parasite glycoproteins, rather than to established major allergens, are dominant. Because anti-CCD IgE has limited clinical relevance, it may impact ARD phenotyping and assessment of contribution of atopy to ARD. METHODS: Using an allergen extract-based test, a glycan and an allergen (glyco)protein microarray, we mapped IgE fine specificity among Ugandan rural Schistosoma mansoni (Sm)-endemic communities, proximate urban communities, and importantly in asthmatic and nonasthmatic schoolchildren. RESULTS: Overall, IgE sensitization to extracts was highly prevalent (43%-73%) but allergen arrays indicated that this was not attributable to established major allergenic components of the extracts (0%-36%); instead, over 40% of all participants recognized CCD-bearing components. Using glycan arrays, we dissected IgE responses to specific glycan moieties and found that reactivity to classical CCD epitopes (core ß-1,2-xylose, α-1,3-fucose) was positively associated with sensitization to extracts, rural environment and Sm infection, but not with skin reactivity to extracts or sensitization to their major allergenic components. Interestingly, we discovered that reactivity to only a subset of core α-1,3-fucose-carrying N-glycans was inversely associated with asthma. CONCLUSIONS: CCD reactivity is not just an epiphenomenon of parasite exposure hampering specificity of allergy diagnostics; mechanistic studies should investigate whether specific CCD moieties identified here are implicated in the protective effect of certain environmental exposures against asthma.

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.

Parasites and allergy: Observations from Africa.

Population studies from the African continent have observed a marked increase in the prevalence of allergy-related diseases over the past few decades, but the cause of this rise is not fully understood. The most investigated potential risk factor has been the relationship between exposure to helminths and allergy-related outcomes. Immunologically, parallels exist between responses to helminths and to allergens as both are associated with elevated levels of immunoglobulin E, increased numbers of T helper 2 cells and other immune cells. However, epidemiological studies from the African continent have found inconsistent results. In this review, observations from population studies carried out in Africa over the last decade that focus on the relationship between helminth infections and allergy-related outcomes are examined. How these findings advance our understanding of the complex interactions between helminths and allergies at the population level is also explored as well as some of the underlying immune mechanisms involved. This knowledge is important for better diagnosis, treatment and prevention of allergy-related diseases and has wider global significance.

Effects of treating helminths during pregnancy and early childhood on risk of allergy-related outcomes: Follow-up of a randomized controlled trial.

BACKGROUND: Helminth infections, common in low-income countries, may protect against allergy-related disease. Early exposure may be a key. In the Entebbe Mother and Baby Study, treating helminths during pregnancy resulted in increased eczema rates in early childhood. We followed the cohort to determine whether this translated to increased asthma rates at school age. METHODS: This randomized, double-blind, placebo-controlled trial, conducted in Entebbe, Uganda, had three interventions. During pregnancy, women were randomized, simultaneously, to albendazole vs placebo and to praziquantel vs placebo. Their children were independently randomized to quarterly albendazole vs placebo from age 15 months to 5 years. We here report follow-up to age 9 years. Primary outcomes at 9 years were recent reported wheeze, skin prick test positivity (SPT) to common allergens and allergen-specific IgE positivity to dust mite or cockroach. Secondary outcomes were doctor-diagnosed asthma and eczema rates between 5 and 9 years, recent eczema, rhinitis and urticaria at 9 years, and SPT and IgE responses to individual allergens. RESULTS: 2507 pregnant women were enrolled; 1215 children were seen at age nine, of whom 1188 are included in this analysis. Reported wheeze was rare at 9 years (3.7%) while SPT positivity (25.0%) and IgE positivity (44.1%) were common. There was no evidence of a treatment effect for any of the three interventions on any of the primary outcomes. CONCLUSIONS: Prenatal and early-life treatment of helminths, in the absence of change in other exposures, is unlikely to increase the risk of atopic diseases later in childhood in this tropical, low-income setting.

Life-course of atopy and allergy-related disease events in tropical sub-Saharan Africa: A birth cohort study.

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.

Suppression of basophil histamine release and other IgE-dependent responses in childhood Schistosoma mansoni/hookworm coinfection.

BACKGROUND: The poor correlation between allergen-specific immunoglobulin E (asIgE) and clinical signs of allergy in helminth infected populations suggests that helminth infections could protect against allergy by uncoupling asIgE from its effector mechanisms. We investigated this hypothesis in Ugandan schoolchildren coinfected with Schistosoma mansoni and hookworm. METHODS: Skin prick test (SPT) sensitivity to house dust mite allergen (HDM) and current wheeze were assessed pre-anthelmintic treatment. Nonspecific (anti-IgE), helminth-specific, and HDM-allergen-specific basophil histamine release (HR), plus helminth- and HDM-specific IgE and IgG4 responses were measured pre- and post-treatment. RESULTS: Nonspecific- and helminth-specific-HR, and associations between helminth-specific IgE and helminth-specific HR increased post-treatment. Hookworm infection appeared to modify the relationship between circulating levels of HDM-IgE and HR: a significant positive association was observed among children without detectable hookworm infection, but no association was observed among infected children. In addition, hookworm infection was associated with a significantly reduced risk of wheeze, and IgG4 to somatic adult hookworm antigen with a reduced risk of HDM-SPT sensitivity. There was no evidence for S. mansoni infection having a similar suppressive effect on HDM-HR or symptoms of allergy. CONCLUSIONS: Basophil responsiveness appears suppressed during chronic helminth infection; at least in hookworm infection, this suppression may protect against allergy.

Maternal hookworm modifies risk factors for childhood eczema: results from a birth cohort in Uganda.

BACKGROUND: Worms may protect against allergy. Early-life worm exposure may be critical, but this has not been fully investigated. OBJECTIVES: To investigate whether worms in pregnancy and in early childhood are associated with childhood eczema incidence. METHODS: The 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. RESULTS: Data 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. Childhood Trichuris trichiura and hookworm were inversely associated with eczema. 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 for primary prevention of allergy.

Associations between maternal helminth and malaria infections in pregnancy and clinical malaria in the offspring: a birth cohort in entebbe, Uganda.

BACKGROUND: Helminth and malaria coinfections are common in the tropics. We investigated the hypothesis that prenatal exposure to these parasites might influence susceptibility to malaria in childhood. METHODS: In a birth cohort of 2345 mother-child pairs in Uganda, maternal helminth and malaria infection status was determined during pregnancy, and childhood malaria episodes were recorded from birth to age 5 years. We examined associations between maternal infections and malaria in the offspring. RESULTS: Common maternal infections were hookworm (45%), Mansonella perstans (21%), Schistosoma mansoni (18%), and Plasmodium falciparum (11%). At age 5 years, 69% of the children were still under follow-up. The incidence of malaria was 34 episodes per 100 child-years, and the mean prevalence of asymptomatic malaria at annual visits was 5.4%. Maternal hookworm and M. perstans infections were associated with an increased rate of childhood clinical malaria (adjusted hazard ratio [aHR], 1.24, 95% confidence interval [CI], 1.10-1.41; aHR, 1.20, 95% CI, 1.05-1.38, respectively). S. mansoni infection had no consistent association with childhood malaria. CONCLUSIONS: This is the first report of an association between helminth infections in pregnancy and malaria in the offspring and indicates that helminth infections in pregnancy may increase the burden of childhood malaria morbidity.

Gut microbiome signature and nasal lavage inflammatory markers in young people with asthma.

Background: Asthma is a complex disease and a severe global public health problem resulting from interactions between genetic background and environmental exposures. It has been suggested that gut microbiota may be related to asthma development; however, such relationships needs further investigation. Objective: This study aimed to characterize the gut microbiota as well as the nasal lavage cytokine profile of asthmatic and nonasthmatic individuals. Methods: Stool and nasal lavage samples were collected from 29 children and adolescents with type 2 asthma and 28 children without asthma in Brazil. Amplicon sequencing of the stool bacterial V4 region of the 16S rRNA gene was performed using Illumina MiSeq. Microbiota analysis was performed by QIIME 2 and PICRUSt2. Type 2 asthma phenotype was characterized by high sputum eosinophil counts and positive skin prick tests for house dust mite, cockroach, and/or cat or dog dander. The nasal immune marker profile was assessed using a customized multiplex panel. Results: Stool microbiota differed significantly between asthmatic and nonasthmatic participants (P = .001). Bacteroides was more abundant in participants with asthma (P < .05), while Prevotella was more abundant in nonasthmatic individuals (P < .05). In people with asthma, the relative abundance of Bacteroides correlated with IL-4 concentration in nasal lavage samples. Inference of microbiota functional capacity identified differential fatty acid biosynthesis in asthmatic compared to nonasthmatic subjects. Conclusion: The stool microbiota differed between asthmatic and nonasthmatic young people in Brazil. Asthma was associated with higher Bacteroides levels, which correlated with nasal IL-4 concentration.

Maternal HIV infection and other factors associated with growth outcomes of HIV-uninfected infants in Entebbe, Uganda.

OBJECTIVE: To assess the associations between maternal HIV infection and growth outcomes of HIV-exposed but uninfected infants and to identify other predictors for poor growth among this population. DESIGN: Within a trial of de-worming during pregnancy, the cohort of offspring was followed from birth. HIV status of the mothers and their children was investigated and growth data for children were obtained at age 1 year. Length-for-age, weight-for-age and weight-for-length Z-scores were calculated for each child; Z-scores ,22 were defined as stunting, underweight and wasting, respectively. SETTING: The study was conducted in Entebbe municipality and Katabi subcounty, Uganda. SUBJECTS: The sample consisted of 1502 children aged 1 year: HIV-unexposed (n 1380) and HIV-exposed not infected (n 122). RESULTS: Prevalence of stunting, underweight and wasting was 14.2%, 8.0% and 3.9%, respectively. There was evidence for an association between maternal HIV infection and odds of being underweight (adjusted OR52.32; 95% CI 1.32, 4.09; P=0.006) but no evidence for an association with stunting or with wasting. Young maternal age, low maternal education, low birth weight, early weaning and experiencing a higher number of episodes of malaria during infancy were independent predictors for stunting and underweight. A higher number of living children in the family was associated with wasting. CONCLUSIONS: Maternal HIV infection was associated with being underweight in HIV-exposed uninfected infants. The success of programmes for prevention of mother-to-child HIV transmission means that an increasing number of infants will be born to HIV-infected women without acquiring HIV. Therefore, viable nutritional interventions need to be identified for this population.

Asthma inflammatory phenotypes on four continents: most asthma is non-eosinophilic.

BACKGROUND: Most studies assessing pathophysiological heterogeneity in asthma have been conducted in high-income countries (HICs), with little known about the prevalence and characteristics of different asthma inflammatory phenotypes in low-and middle-income countries (LMICs). This study assessed sputum inflammatory phenotypes in five centres, in Brazil, Ecuador, Uganda, New Zealand (NZ) and the United Kingdom (UK). METHODS: We conducted a cross-sectional study of 998 asthmatics and 356 non-asthmatics in 2016-20. All centres studied children and adolescents (age range 8-20 years), except the UK centre which involved 26-27 year-olds. Information was collected using questionnaires, clinical characterization, blood and induced sputum. RESULTS: Of 623 asthmatics with sputum results, 39% (243) were classified as eosinophilic or mixed granulocytic, i.e. eosinophilic asthma (EA). Adjusted for age and sex, with NZ as baseline, the UK showed similar odds of EA (odds ratio 1.04, 95% confidence interval 0.37-2.94) with lower odds in the LMICs: Brazil (0.73, 0.42-1.27), Ecuador (0.40, 0.24-0.66) and Uganda (0.62, 0.37-1.04). Despite the low prevalence of neutrophilic asthma in most centres, sputum neutrophilia was increased in asthmatics and non-asthmatics in Uganda. CONCLUSIONS: This is the first time that sputum induction has been used to compare asthma inflammatory phenotypes in HICs and LMICs. Most cases were non-eosinophilic, including in settings where corticosteroid use was low. A lower prevalence of EA was observed in the LMICs than in the HICs. This has major implications for asthma prevention and management, and suggests that novel prevention strategies and therapies specifically targeting non-eosinophilic asthma are required globally.

Effect of single-dose anthelmintic treatment during pregnancy on an infant's response to immunisation and on susceptibility to infectious diseases in infancy: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Helminth 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. METHODS: In 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. FINDINGS: Data 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. INTERPRETATION: These 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. FUNDING: Wellcome Trust.

Anthelminthic treatment during pregnancy is associated with increased risk of infantile eczema: randomised-controlled trial results.

BACKGROUND: Allergy is commoner in developed than in developing countries. Chronic worm infections show inverse associations with allergy, and prenatal exposures may be critical to allergy risk. OBJECTIVE: To determine whether anthelminthic treatment during pregnancy increases the risk of allergy in infancy. METHODS: A randomised, double-blind, placebo-controlled trial on treatment in pregnancy with albendazole versus placebo and praziquantel versus placebo was conducted in Uganda, with a 2 × 2 factorial design; 2507 women were enrolled; infants' allergy events were recorded prospectively. The main outcome was doctor-diagnosed infantile eczema. RESULTS: Worms were detected in 68% of women before treatment. Doctor-diagnosed infantile eczema incidence was 10.4/100 infant years. Maternal albendazole treatment was associated with a significantly increased risk of eczema [Cox HR (95% CI), p: 1.82 (1.26-2.64), 0.002]; this effect was slightly stronger among infants whose mothers had no albendazole-susceptible worms than among infants whose mothers had such worms, although this difference was not statistically significant. Praziquantel showed no effect overall but was associated with increased risk among infants of mothers with Schistosoma mansoni [2.65 (1.16-6.08), interaction p = 0.02]. In a sample of infants, skin prick test reactivity and allergen-specific IgE were both associated with doctor-diagnosed eczema, indicating atopic aetiology. Albendazole was also strongly associated with reported recurrent wheeze [1.58 (1.13-2.22), 0.008]; praziquantel showed no effect. CONCLUSIONS: The detrimental effects of treatment suggest that exposure to maternal worm infections in utero may protect against eczema and wheeze in infancy. The results for albendazole are also consistent with a direct drug effect. Further studies are required to investigate mechanisms of these effects, possible benefits of worms or worm products in primary prevention of allergy, and the possibility that routine deworming during pregnancy may promote allergic disease in the offspring.

A description of congenital anomalies among infants in Entebbe, Uganda.

BACKGROUND: Data on congenital anomalies from developing countries of the sub-Saharan region are scarce. However, it is important to have comprehensive and reliable data on the description and prevalence of congenital anomalies to allow surveillance and the implementation of appropriate public health strategies for prevention and management. In this study, we describe the profile of congenital anomalies seen in a birth cohort in Entebbe, Uganda. METHODS: Congenital anomalies were defined as any structural defect present at birth. Pregnant women were recruited to the cohort between 2003 and 2005. Defects present at birth were recorded by the midwife at delivery and by physicians at the routine six-week postnatal visit and at illness-related visits until 1 year of life. The anomalies were classified by organ system according to the 10th version of the World Health Organization International Classification of Diseases (ICD-10). RESULTS: There were 180 infants with a congenital anomaly among 2365 births. The most commonly affected systems were the musculoskeletal (42.7 per 1000 births) and skin (16.1 per 1000 births). The prevalence of major anomalies was 20.3 per 1000 births; 1.7 per 1000 births for cardiac anomalies and 1.3 per 1000 births for neural system anomalies. Forty (22%) of the congenital anomalies were identified at birth, 131 (73%) at the 6-week postnatal visit, and nine (5%) at illness-related visits. CONCLUSION: Congenital anomalies are common in developing countries. Establishment of comprehensive databases for surveillance would be helpful for surveillance of effects of new exposures, for prevention, management, and health care planning.

Treatment with anthelminthics during pregnancy: what gains and what risks for the mother and child?

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.

Prevalence and correlates of neurocognitive impairment and psychiatric disorders among schoolchildren in Wakiso District, Uganda: a cross-sectional study.

Background: There is limited data on the burden of mental disorders among 'healthy' children in Africa. We examined the prevalence and correlates of neurocognitive and psychiatric disorders among schoolchildren in Uganda. Methods: This cross-sectional study enrolled 322 schoolchildren aged 5-17years in Wakiso, Uganda. We assessed for neurocognitive impairment using the Kaufmann-Assessment-Battery, and psychiatric disorders (major-depressive-disorder (MDD), attention-deficit-hyperactivity-disorder (ADHD), generalised-anxiety-disorder (GAD), and substance-use-disorder (SUD)) using the parent version of the Child and Adolescent Symptom Inventory-5, and Youth Inventory-4R Self Report. Prevalence and risk factors were determined using percentages and logistic regression. Results: Twenty-five participants (8%) had neurocognitive impairment. Nineteen (5.9%) participants had MDD, nine (2.8%) had ADHD, seven (2.2%) had GAD, 14 (8.6%) had SUD; and 30 (9.3%) had any psychiatric disorder. None of the factors examined were associated with the disorders. Conclusions: The unexpectedly high burden of mental disorders in this general population of children warrants targeted screening of those at risk, and treatment of those affected. Further, future studies should extensively investigate the factors that underlie the identified psychiatric disorders in this and similar general populations.

Infection-exposure in infancy is associated with reduced allergy-related disease in later childhood in a Ugandan cohort.

Background: Lack of early infection-exposure has been associated with increased allergy-related disease (ARD) susceptibility. In tropical Africa, little is known about which infections contribute to development of ARDs, and at which time. Methods: We used latent class analysis to characterise the early infection-exposure of participants in a Ugandan birth cohort and assessed ARDs in later childhood. Results: Of 2345 live births, 2115 children (90%) had data on infections within the first year of life while 1179 (50%) had outcome data at 9 years. We identified two latent classes of children based on first-year infection-exposure. Class 1 (32% membership), characterised by higher probabilities for malaria (80%), diarrhoea (76%), and lower respiratory tract infections (LRTI) (22%), was associated with lower prevalence of wheeze, eczema, rhinitis, and Dermatophagoides skin prick test (SPT) positivity at 9 years. Based on 5-year cumulative infection experience, class 1 (31% membership), characterised by higher probabilities for helminths (92%), malaria (79%), and LRTI (45%), was associated with lower probabilities of SPT positivity at 9 years. Conclusions: In this Ugandan birth cohort, early childhood infection-exposure, notably to malaria, helminths, LRTI, and diarrhoea, is associated with lower prevalence of atopy and ARDs in later childhood. Funding: This work was supported by several funding sources. The Entebbe Mother and Baby Study (EMaBS) was supported by the Wellcome Trust, UK, senior fellowships for AME (grant numbers 064693, 079110, 95778) with additional support from the UK Medical Research Council. LL is supported by a PhD fellowship through the DELTAS Africa Initiative SSACAB (grant number 107754). ELW received funding from MRC Grant Reference MR/K012126/1. SAL was supported by the PANDORA-ID-NET Consortium (EDCTP Reg/Grant RIA2016E-1609). HM was supported by the Wellcome's Institutional Strategic Support Fund (grant number 204928/Z/16/Z).