Vitamin D Concentrations in Infancy and the Risk of Tuberculosis Disease in Childhood: A Prospective Birth Cohort in Cape Town, South Africa.

BACKGROUND: Low vitamin D levels may increase the risk of tuberculosis disease; however, previous observational cohort studies showed variable results. We investigated the relationship between vitamin D levels in infancy and subsequent development of tuberculosis disease throughout childhood. METHODS: We enrolled pregnant women at 20-28 weeks' gestation attending antenatal care in a periurban South African setting in the Drakenstein Child Health Study. Serum 25(OH)D concentrations were measured in newborn infants aged 6-10 weeks. Children were followed prospectively for tuberculosis infection and disease using annual tuberculin skin testing, radiographic examinations, and microbiological diagnosis with GeneXpert, culture, and smear testing. Univariable and multivariable Cox regression was performed and HRs with 95% CIs were calculated. RESULTS: Children were followed for tuberculosis disease for a median of 7.2 years (IQR, 6.2-7.9). Among 744 children (<1% with human immunodeficiency virus (HIV), 21% HIV-exposed without HIV), those who were vitamin D deficient in early infancy were not at increased risk of developing tuberculosis disease (adjusted HR, .8; 95% CI, .4-1.6). Infants in the lowest vitamin D concentration tertile were at similar risk of tuberculosis as the highest tertile (adjusted HR, .7; 95% CI, .4-1.4). Vitamin D deficiency was associated with tuberculin conversion ≤2 years of age at a <30-nmol/L (adjusted OR, 1.9; 95% CI, 1.2-3.2), but not <50-nmol/L (adjusted OR, 1.5; 95% CI, .8-2.9), cutoff. CONCLUSIONS: In a setting with hyperendemic rates of tuberculosis, vitamin D concentrations in infancy did not predict tuberculosis disease at any point in childhood. However, very low vitamin D levels were associated with tuberculin conversion in young children.

Persistent Impact of Antenatal Maternal Anaemia on Child Brain Structure at 6-7 Years of Age: A South African Child Health Study.

Background: The study aim was to determine whether associations of antenatal maternal anaemia with smaller corpus callosum, putamen, and caudate nucleus volumes previously described in children at age 2-3 years persist to age 6-7 years in the Drakenstein Child Health Study (DCHS). Methods: This neuroimaging sub-study was nested within the DCHS, a South African population-based birth cohort. Pregnant women were enrolled (2012-2015) and mother-child dyads were followed prospectively. A sub-group of children had magnetic resonance imaging at 6-7 years of age (2018-2022). Mothers had haemoglobin measurements during pregnancy and a proportion of children were tested postnatally. Maternal anaemia (haemoglobin<11g/dL) and child anaemia were classified using WHO and local guidelines. Linear modeling was used to investigate associations between antenatal maternal anaemia status, maternal haemoglobin concentrations, and regional child brain volumes. Models included potential confounders and were conducted with and without child anaemia to assess the relative roles of antenatal versus postnatal anaemia. Results: Overall, 157 children (Mean [SD] age of 75.54 [4.77] months; 84 [53.50%] male) were born to mothers with antenatal haemoglobin data. The prevalence of maternal anaemia during pregnancy was 31.85% (50/157). In adjusted models, maternal anaemia status was associated with smaller volumes of the total corpus callosum (adjusted percentage difference, -6.77%; p=0.003), left caudate nucleus (adjusted percentage difference, -5.98%, p=0.005), and right caudate nucleus (adjusted percentage difference, -6.12%; p=0.003). Continuous maternal haemoglobin was positively associated with total corpus callosum (ß=0.239 [CI: 0.10 to 0.38]; p<0.001) and caudate nucleus (ß=0.165 [CI: 0.02 to 0.31]; p=0.027) volumes. In a sub-group (n=89) with child haemoglobin data (Mean [SD] age of 76.06[4.84]), the prevalence of antenatal maternal anaemia and postnatal child anaemia was 38.20% (34/89) and 47.19% (42/89), respectively. There was no association between maternal and child anaemia (c2 = 0.799; p=0.372), and child anaemia did not contribute to regional brain volume differences associated with maternal anaemia. Conclusions: Associations between maternal anaemia and regional child brain volumes previously reported at 2-3 years of age were consistent and persisted to 6-7 years of age. Findings support the importance of optimizing antenatal maternal health and reinforce these brain regions as a future research focus on intervention outcomes.

In-utero HIV exposure and cardiometabolic health among children 5-8 years: findings from a prospective birth cohort in South Africa.

OBJECTIVE: To evaluate if in-utero HIV exposure is associated with adverse cardiometabolic health outcomes at 5-8 years of age. DESIGN: Prospective cohort study. METHODS: We enrolled a random sample of HIV-exposed but uninfected (HEU) and HIV-unexposed children from the Drakenstein Child Health study, a longitudinal birth cohort study in Cape Town, South Africa, in a cardiometabolic health pilot study. Outcomes were assessed by trained study staff and included: anthropometry, body composition and size, blood pressure, fasting plasma glucose, HbA1c, lipids, and insulin resistance using HOMA-IR. We used multivariable linear and log-binomial regression to estimate associations between HIV-exposure and cardiometabolic outcomes, adjusted for child age, sex, height, body size, and maternal factors as appropriate. RESULTS: We included 260 children (HEU n = 100, HIV-unexposed n = 160). HEU children had older mothers (median age 30 vs. 26 years), with minimal differences in gestational age and size at birth by HIV-exposure status. In multivariable analyses, HEU children had lower weight-for-age (mean difference -0.35, 95% confidence interval -0.66, -0.05), and height-for-age (mean difference -0.29, 95% confidence interval -0.56, -0.03; z-scores). There were no differences in adiposity, impaired glucose metabolism, or lipid levels by HIV-exposure status. Overall, 12% of children had blood pressure more than 90th percentile, with no differences by HIV-exposure status. CONCLUSION: Overall, there were few differences in cardiometabolic outcomes between HEU and HIV-unexposed children in this South African cohort. Although these findings are reassuring, monitoring of cardiometabolic health is important as HEU and HIV-unexposed children enter adolescence and cardiometabolic risk trajectories become established.

Klebsiella pneumoniae Lower Respiratory Tract Infection in a South African Birth Cohort: a Longitudinal Study.

OBJECTIVES: The role of Klebsiella pneumoniae (KP) in lower respiratory tract infection (LRTI) is not well studied. We longitudinally investigated KP colonization and its association with LRTI in a South African birth cohort. METHODS: We conducted a case-control study of infants who developed LRTI and age-matched controls, followed twice weekly through infancy. Nasopharyngeal swabs taken fortnightly and at LRTI for 33-multipex Quantitative multiplex real-time polymerase chain reaction were tested at LRTI and twice weekly from 90 days preceding LRTI. Controls were tested over the equivalent period. Multivariate models investigated the factors associated with LRTI or with KP-associated LRTI (KP-LRTI). RESULTS: Among 885 infants, there were 439 LRTI episodes, of which 68 (15.5%) were KP-LRTI (OR 1.93; 95% CI 1.25-3.03). Infants with KP-LRTI were younger than those without KP-LRTI (median [IQR] 3.7 [2.1-5.9] vs 4.7 [2.8-7.9] months, P-value=0.009). Clinical features of KP and non-KP-LRTI were similar with 114 (26%) infants hospitalized. Prematurity (adjusted odds ratio [aOR] 11.86; 95% CI 5.22-26.93), HIV exposure (aOR 3.32; 95% CI 1.69-6.53), lower birthweight (aOR 0.68; 95% CI 0.51-0.91), and shorter breastfeeding time (aOR 0.79; 95% CI 0.65-0.96) were associated with KP-LRTI versus non-LRTI. These factors and younger age were associated with KP-LRTI versus non-KP-LRTI. CONCLUSION: KP was associated with a substantial proportion of LRTI, particularly in premature or HIV-exposed infants in whom strategies for treatment and prevention should be strengthened.

Natural and hybrid immunity following four COVID-19 waves: A prospective cohort study of mothers in South Africa.

Background: More than half the global population has been exposed to SARS-CoV-2. Naturally induced immunity influences the outcome of subsequent exposure to variants and vaccine responses. We measured anti-spike IgG responses to explore the basis for this enhanced immunity. Methods: A prospective cohort study of mothers in a South African community through ancestral/beta/delta/omicron SARS-CoV-2 waves (March 2020-February 2022). Health seeking behaviour/illness were recorded and post-wave serum samples probed for IgG to Spike (CoV2-S-IgG) by ECLISA. To estimate protective CoV2-S-IgG threshold levels, logistic functions were fit to describe the correlation of CoV2-S-IgG measured before a wave and the probability for seroconversion/boosting thereafter for unvaccinated and vaccinated adults. Findings: Despite little disease, 176/339 (51·9%) participants were seropositive following wave 1, rising to 74%, 89·8% and 97·3% after waves 2, 3 and 4 respectively. CoV2-S-IgG induced by natural exposure protected against subsequent SARS-CoV-2 infection with the greatest protection for beta and least for omicron. Vaccination induced higher CoV2-S-IgG in seropositive compared to naïve vaccinees. Amongst seropositive participants, proportions above the 50% protection against infection threshold were 69% (95% CrI: 62, 72) following 1 vaccine dose, 63% (95% CrI: 63, 75) following 2 doses and only 11% (95% CrI: 7, 14) in unvaccinated during the omicron wave. Interpretation: Naturally induced CoV2-S-IgG do not achieve high enough levels to prevent omicron infection in most exposed individuals but are substantially boosted by vaccination leading to significant protection. A single vaccination in those with prior immunity is more immunogenic than 2 doses in a naïve vaccinee and may provide adequate protection. Funding: UK NIH GECO award (GEC111), Wellcome Trust Centre for Infectious Disease Research in Africa (CIDRI), Bill & Melinda Gates Foundation, USA (OPP1017641, OPP1017579) and NIH H3 Africa (U54HG009824, U01AI110466]. HZ is supported by the SA-MRC. MPN is supported by an Australian National Health and Medical Research Council Investigator Grant (APP1174455). BJQ is supported by a grant from the Bill and Melinda Gates Foundation (OPP1139859). Stefan Flasche is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant number 208812/Z/17/Z).