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 becritical, but this has not been fully investigated.Objectives: To investigate whether worms in pregnancy and in early childhood areassociated 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 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. 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. 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

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

Effect of birth weight, exclusive breastfeeding and growth in infancy on fat mass and fat free mass indices in early adolescence: an analysis of the Entebbe Mother and Baby Study (EMaBs) cohort

Background: There is limited data from Africa on the effect of pre- and post-natal growth and infant feeding on later body composition. This study's aim was to investigate the effect of birth weight, exclusive breastfeeding and infant growth on adolescent body composition, using data from a Ugandan birth cohort. Methods: Data was collected prenatally from pregnant women and prospectively from their resulting live offspring. Data on body composition (fat mass index [FMI] and fat free mass index [FFMI]) was collected from 10- and 11-year olds. Linear regression was used to assess the effect of birth weight, exclusive breastfeeding and infant growth on FMI and FFMI, adjusting for confounders. Results: 177 adolescents with a median age of 10.1 years were included in analysis, with mean FMI 2.9 kg/m2 (standard deviation (SD) 1.2), mean FFMI 12.8 kg/m2 (SD 1.4) and mean birth weight 3.2 kg (SD 0.5). 90 (50.9%) were male and 110 (63.2%) were exclusively breastfeeding at six weeks of age. Birth weight was associated with FMI in adolescence (regression coefficient ?= 0.66 per kg increase in birth weight, 95% confidence interval (CI) (0.04, 1.29), P=0.02), while exclusive breastfeeding (?= -0.43, 95% CI (-1.06, 0.19), P=0.12), growth 0-6 months (?= 0.24 95% CI (-0.43, 0.92), P=0.48) and growth 6-12 months (?= 0.61, 95% CI (-0.23, 1.46), P=0.11) were not associated with FMI among adolescents. Birth weight (?= 0.91, 95% CI (0.17, 1.65), P=0.01) was associated with FFMI in adolescence. Exclusive breastfeeding (?= 0.17, 95% CI (-0.60, 0.94), P=0.62), growth 0-6 months (?= 0.56, 95% CI (-0.20, 1.33), P= 0.10), and growth 6-12 months (?= -0.02, 95% CI (-1.02, 0.99), P=0.97) were not associated with FFMI. Conclusions: Birth weight predicted body composition parameters in Ugandan early adolescents, however, exclusive breastfeeding at six weeks of age and growth in infancy did not

Safety and immunogenicity of ChAdOx1 85A prime followed by MVA85A boost compared with BCG revaccination among Ugandan adolescents who received BCG at birth: a randomised, open-label trial

Background BCG confers reduced, variable protection against pulmonary tuberculosis. A more effective vaccine is needed. We evaluated the safety and immunogenicity of candidate regimen ChAdOx1 85A–MVA85A compared with BCG revaccination among Ugandan adolescents. Methods After ChAdOx1 85A dose escalation and age de-escalation, we did a randomised open-label phase 2a trial among healthy adolescents aged 12–17 years, who were BCG vaccinated at birth, without evident tuberculosis exposure, in Entebbe, Uganda. Participants were randomly assigned (1:1) using a block size of 6, to ChAdOx1 85A followed by MVA85A (on day 56) or BCG (Moscow strain). Laboratory staff were masked to group assignment. Primary outcomes were solicited and unsolicited adverse events (AEs) up to day 28 and serious adverse events (SAEs) throughout the trial; and IFN-γ ELISpot response to antigen 85A (day 63 [geometric mean] and days 0–224 [area under the curve; AUC). Findings Six adults (group 1, n=3; group 2, n=3) and six adolescents (group 3, n=3; group 4, n=3) were enrolled in the ChAdOx1 85A-only dose-escalation and age de-escalation studies (July to August, 2019). In the phase 2a trial, 60 adolescents were randomly assigned to ChAdOx1 85A–MVA85A (group 5, n=30) or BCG (group 6, n=30; December, 2019, to October, 2020). All 60 participants from groups 5 and 6 were included in the safety analysis, with 28 of 30 from group 5 (ChAdOx1 85A–MVA85A) and 29 of 30 from group 6 (BCG revaccination) analysed for immunogenicity outcomes. In the randomised trial, 60 AEs were reported among 23 (77%) of 30 participants following ChAdOx1 85A–MVA85A, 31 were systemic, with one severe event that occurred after the MVA85A boost that was rapidly self-limiting. All 30 participants in the BCG revaccination group reported at least one mild to moderate solicited AE; most were local reactions. There were no SAEs in either group. Ag85A-specific IFN-γ ELISpot responses peaked on day 63 in the ChAdOx1 85A–MVA85A group and were higher in the ChAdOx1 85A-MVA85A group compared with the BCG revaccination group (geometric mean ratio 30·59 [95% CI 17·46–53·59], p<0·0001, day 63; AUC mean difference 57 091 [95% CI 40 524–73 658], p<0·0001, days 0–224). Interpretation The ChAdOx1 85A–MVA85A regimen was safe and induced stronger Ag85A-specific responses than BCG revaccination. Our findings support further development of booster tuberculosis vaccines. Funding UK Research and Innovations and Medical Research Council. Translations For the Swahili and Luganda translations of the abstract see Supplementary Materials section

Hunger, waiting time and transport costs: Time to confront challenges to ART adherence in Africa

International audienceAdherence levels in Africa have been found to be better than those in the US. However around one out of four ART users fail to achieve optimal adherence, risking drug resistance and negative treatment outcomes. A high demand for 2nd line treatments (currently ten times more expensive than 1st line ART) undermines the sustainability of African ART programs. There is an urgent need to identify context-specific constraints to adherence and implement interventions to address them. We used rapid appraisals (involving mainly qualitative methods) to find out why and when people do not adhere to ART in Uganda, Tanzania and Botswana. Multidisciplinary teams of researchers and local health professionals conducted the studies, involving a total of 54 semi-structured interviews with health workers, 73 semi-structured interviews with ART users and other key informants, 34 focus group discussions, and 218 exit interviews with ART users. All the facilities studied in Botswana, Tanzania and Uganda provide ARVs free of charge, but ART users report other related costs (e.g. transport expenditures, registration and user fees at the private health facilities, and lost wages due to long waiting times) as main obstacles to optimal adherence. Side effects and hunger in the initial treatment phase are an added concern. We further found that ART users find it hard to take their drugs when they are among people to whom they have not disclosed their HIV status, such as co-workers and friends. The research teams recommend that (i) health care workers inform patients better about adverse effects; (ii) ART programmes provide transport and food support to patients who are too poor to pay; (iii) recurrent costs to users be reduced by providing three-months, rather than the one-month refills once optimal adherence levels have been achieved; and (iv) pharmacists play an important role in this follow-up care

Possible role of anthropogenic climate change in the record-breaking 2020 Lake Victoria levels and floods

Heavy rainfall in eastern Africa between late 2019 and mid 2020 caused devastating floods and landslides throughout the region. These rains drove the levels of Lake Victoria to a record-breaking maximum in the second half of May 2020. The combination of high lake levels, consequent shoreline flooding, and flooding of tributary rivers caused hundreds of casualties and damage to housing, agriculture, and infrastructure in the riparian countries of Uganda, Kenya, and Tanzania. Media and government reports linked the heavy precipitation and floods to anthropogenic climate change, but a formal scientific attribution study has not been carried out so far. In this study, we characterize the spatial extent and impacts of the floods in the Lake Victoria basin and then investigate to what extent human-induced climate change influenced the probability and magnitude of the record-breaking lake levels and associated flooding by applying a multi-model extreme event attribution methodology. Using remote-sensing-based flood mapping tools, we find that more than 29 000 people living within a 50 km radius of the lake shorelines were affected by floods between April and July 2020. Precipitation in the basin was the highest recorded in at least 3 decades, causing lake levels to rise by 1.21 m between late 2019 and mid 2020. The flood, defined as a 6-month rise in lake levels as extreme as that observed in the lead-up to May 2020, is estimated to be a 63-year event in the current climate. Based on observations and climate model simulations, the best estimate is that the event has become more likely by a factor of 1.8 in the current climate compared to a pre-industrial climate and that in the absence of anthropogenic climate change an event with the same return period would have led lake levels to rise by 7 cm less than observed. Nonetheless, uncertainties in the attribution statement are relatively large due to large natural variability and include the possibility of no observed attributable change in the probability of the event (probability ratio, 95 % confidence interval 0.8–15.8) or in the magnitude of lake level rise during an event with the same return period (magnitude change, 95 % confidence interval 0–14 cm). In addition to anthropogenic climate change, other possible drivers of the floods and their impacts include human land and water management, the exposure and vulnerability of settlements and economic activities located in flood-prone areas, and modes of climate variability that modulate seasonal precipitation. The attribution statement could be strengthened by using a larger number of climate model simulations, as well as by quantitatively accounting for non-meteorological drivers of the flood and potential unforced modes of climate variability. By disentangling the role of anthropogenic climate change and natural variability in the high-impact 2020 floods in the Lake Victoria basin, this paper contributes to a better understanding of changing hydrometeorological extremes in eastern Africa and the African Great Lakes region.</p

Are birthweight and postnatal weight gain in childhood associated with blood pressure in early adolescence? Results from a Ugandan birth cohort.

BACKGROUND: In Africa, where low birthweight (LBW), malnutrition and high blood pressure (BP) are prevalent, the relationships between birthweight (BW), weight gain and BP later in life remain uncertain. We examined the effects of early life growth on BP among Ugandan adolescents. METHODS: Data were collected prenatally from women and their offspring were followed from birth, with BP measured following standard protocols in early adolescence. Weight-for-age Z-scores (WAZ) were computed using World Health Organization references. Linear regression was used to relate BW, and changes in WAZ between birth and 5 years, to adolescents' BP, adjusting for confounders. RESULTS: Among 2345 live offspring, BP was measured in 1119 (47.7%) adolescents, with mean systolic BP 105.9 mmHg and mean diastolic BP 65.2 mmHg. There was little evidence of association between BW and systolic [regression coefficient β = 0.14, 95% confidence interval (CI) (-1.00, 1.27)] or diastolic [β = 0.43, 95% CI (-0.57, 1.43)] BP. Accelerated weight gain between birth and 5 years was associated with increased BP: systolic β = 1.17, 95% CI (0.69, 1.66) and diastolic β = 1.03, 95% CI (0.59, 1.47). Between birth and 6 months of age, effects of accelerated weight gain on adolescent BP were strongest among the LBW (both premature and small-for-gestational-age) children [BW < 2.5 kg: β = 2.64, 95% CI (0.91, 4.37), BW≥2.5 kg: β = 0.58, 95% CI (0.01, 1.14), interaction P-value =  0.024]. CONCLUSIONS: Findings from this large tropical birth cohort in Uganda suggest that postnatal weight gain rather than BW is important in the developmental programming of BP, with fast-growing LBW children at particular risk. Efforts to control BP should adopt a life course approach

BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial.

BACKGROUND: Trials done in infants with low birthweight in west Africa suggest that BCG vaccination reduces all-cause mortality in the neonatal period, probably because of heterologous protection against non-tuberculous infections. This study investigated whether BCG alters all-cause infectious disease morbidity in healthy infants in a different high-mortality setting, and explored whether the changes are mediated via trained innate immunity. METHODS: This was an investigator-blind, randomised, controlled trial done at one hospital in Entebbe, Uganda. Infants who were born unwell (ie, those who were not well enough to be discharged directly home from the labour ward because they required medical intervention), with major congenital malformations, to mothers with HIV, into families with known or suspected tuberculosis, or for whom cord blood samples could not be taken, were excluded from the study. Any other infant well enough to be discharged directly from the labour ward was eligible for inclusion, with no limitation on gestational age or birthweight. Participants were recruited at birth and randomly assigned (1:1) to receive standard dose BCG 1331 (BCG-Danish) on the day of birth or at age 6 weeks (computer-generated randomisation, block sizes of 24, stratified by sex). Investigators and clinicians were masked to group assignment; parents were not masked. Participants were clinically followed up to age 10 weeks and contributed blood samples to one of three immunological substudies. The primary clinical outcome was physician-diagnosed non-tuberculous infectious disease incidence. Primary immunological outcomes were histone trimethylation at the promoter region of TNF, IL6, and IL1B; ex-vivo production of TNF, IL-6, IL-1β, IL-10, and IFNγ after heterologous stimulation; and transferrin saturation and hepcidin levels. All outcomes were analysed in the modified intention-to-treat population of all randomly assigned participants except those whose for whom consent was withdrawn. This trial is registered with the International Standard Randomised Controlled Trial Number registry (#59683017). FINDINGS: Between Sept 25, 2014, and July 31, 2015, 560 participants were enrolled and randomly assigned to receive BCG at birth (n=280) or age 6 weeks (n=280). 12 participants assigned to receive BCG at birth and 11 participants assigned to receive BCG at age 6 weeks were withdrawn from the study by their parents shortly after randomisation and were not included in analyses. During the first 6 weeks of life before the infants in the delayed vaccination group received BCG vaccination, physician-diagnosed non-tuberculous infectious disease incidence was lower in infants in the BCG at birth group than in the delayed group (98 presentations in the BCG at birth group vs 129 in the delayed BCG group; hazard ratio [HR] 0·71 [95% CI 0·53-0·95], p=0·023). After BCG in the delayed group (ie, during the age 6-10 weeks follow-up), there was no significant difference in non-tuberculous infectious disease incidence between the groups (88 presentations vs 76 presentations; HR 1·10 [0·87-1·40], p=0·62). BCG at birth inhibited the increase in histone trimethylation at the TNF promoter in peripheral blood mononuclear cells occurring in the first 6 weeks of life. H3K4me3 geometric mean fold-increases were 3·1 times lower at the TNF promoter (p=0·018), 2·5 times lower at the IL6 promoter (p=0·20), and 3·1 times lower at the IL1B promoter (p=0·082) and H3K9me3 geometric mean fold-increases were 8·9 times lower at the TNF promoter (p=0·0046), 1·2 times lower at the IL6 promoter (p=0·75), and 4·6 times lower at the IL1B promoter (p=0·068), in BCG-vaccinated (BCG at birth group) versus BCG-naive (delayed BCG group) infants. No clear effect of BCG on ex-vivo production of TNF, IL-6, IL-1β, IL-10, and IFNγ after heterologous stimulation, or transferrin saturation and hepcidin concentration, was detected (geometric mean ratios between 0·68 and 1·68; p≥0·038 for all comparisons). INTERPRETATION: BCG vaccination protects against non-tuberculous infectious disease during the neonatal period, in addition to having tuberculosis-specific effects. Prioritisation of BCG on the first day of life in high-mortality settings might have significant public-health benefits through reductions in all-cause infectious morbidity and mortality. FUNDING: Wellcome Trust. TRANSLATIONS: For the Luganda and Swahili translations of the abstract see Supplementary Materials section

The determinants of lipid profiles in early adolescence in a Ugandan birth cohort

Dyslipidaemia in adolescence tracks into adulthood and is an important risk factor for cardiovascular disease. Little is known about the effects of environmental exposures and early-life exposure to infectious diseases common to tropical regions on lipids. In 1119 early adolescent participants in the Entebbe Mother and Baby Study, we used linear regression to examine whether prenatal, childhood or adolescent factors are associated with lipid levels. Reduced high-density lipoprotein (HDL) and elevated triglyceride levels were common (prevalence 31% and 14%, respectively), but elevated low-density lipoprotein (LDL) or total cholesterol (TC) were rare. Current malaria infection was associated with lower mean LDL (adjusted ß - 0.51; 95% CI - 0.81, - 0.21), HDL (adjusted ß - 0.40; 95% CI - 0.56, - 0.23), and TC levels (adjusted ß - 0.62; 95% CI - 0.97, - 0.27), but higher mean triglyceride levels (geometric mean ratio (GMR) 1.47; 95% CI 1.18-1.84). Early-life asymptomatic malaria was associated with modest reductions in HDL and TC. Body mass index (BMI) was positively associated with LDL, TC, and triglycerides. No associations with helminth infection were found. Our findings suggest that early-life factors have only marginal effects on the lipid profile. Current malaria infection and BMI are strongly associated with lipids and important to consider when trying to improve the lipid profile