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SUMMARYSARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic South African children who were seropositive or seronegative for SARS-CoV-2. SARS-CoV-2-specific CD4+ T cell responses were detectable in 83% of seropositive and 60% of seronegative children. Although the magnitude of the CD4+ T cell response did not differ significantly between the two groups, their functional profiles were distinct, with SARS-CoV-2 seropositive children exhibiting a higher proportion of polyfunctional T cells compared to their seronegative counterparts. The frequency of SARS-CoV-2-specific CD4+ T cells in seronegative children was associated with the endemic human coronavirus (HCoV) HKU1 IgG response. Overall, the presence of SARS-CoV-2-responding T cells in seronegative children may result from cross-reactivity to endemic coronaviruses and could contribute to the relative protection from disease observed in SARS-CoV-2-infected children.

Background Transcriptomic profiling of adult tuberculosis patients has become increasingly common, predominantly for diagnostic and risk prediction purposes. However few studies have evaluated signatures in children, particularly in identifying those at risk for developing TB disease. We investigated the relationship between gene expression obtained from umbilical cord blood and both tuberculin skin test conversion as well as incident tuberculosis disease through the first 5 years of life. Methods We conducted a nested case-control study in the Drakenstein Child Health Study, a longitudinal, population-based birth cohort in South Africa. We applied transcriptome-wide screens to umbilical cord blood samples from neonates born to a subset of selected mothers (n=131). Signatures identifying tuberculin conversion and risk of subsequent tuberculosis disease were identified from genome wide analysis of RNA expression. Results Gene expression signatures revealed clear differences predictive of tuberculin conversion (n=26) and tuberculosis disease (n=10); 114 genes were associated with tuberculin conversion and 30 genes were associated with the progression to tuberculosis disease among children with early infection. Co-expression network analysis revealed six modules associated with risk of tuberculosis infection or disease, including a module associated with neutrophil activation in immune response (p Conclusions These findings suggest multiple detectable differences in gene expression at birth which were associated with risk of tuberculosis infection or disease throughout early childhood. Such measures may provide novel insights into tuberculosis pathogenesis and susceptibility.

To evaluate if in-utero HIV exposure is associated with adverse cardiometabolic health outcomes at 5-8 years of age.Prospective cohort study.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.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.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.

Item does not contain fulltext BACKGROUND: Allergens can act as disease-triggering factors in atopic dermatitis (AD) patients. The aim of the study was to elucidate the molecular IgE sensitization profile in children with and without AD living in urban and rural areas of South Africa. METHODS: Specific IgE reactivity was assessed in 166 Black South African children aged 9-38 months using a comprehensive panel of microarrayed allergens. According to clinical characterization children fell in four groups, urban AD cases (n = 32), urban controls (non-AD, n = 40), rural cases (n = 49) and rural controls (non-AD, n = 45). RESULTS: IgE reactivity to at least one of the allergens was detected in 94% of urban and 86% of rural AD children. House dust mite (HDM; 81% urban, 74% rural AD) and animal-derived allergens (50% urban, 31% rural AD) were the most frequently recognized respiratory allergens, whereas IgE to pollen allergens was almost absent. Urban AD children showed significantly higher frequency of IgE reactivity (50%) to mouse lipocalin, Mus m 1, than rural AD children (12%). The most frequently recognized food allergens were from egg (63% urban, 43% rural AD), peanut (31% vs 41%), and soybean (22% vs 27%), whereas milk sensitization was rare. α-gal-specific IgE almost exclusively occurred in rural children (AD: 14%, non-AD: 49%). CONCLUSION: Molecular allergy diagnosis detects frequent IgE sensitization to HDM, animal but not pollen allergens and to egg, peanut, and soy, but not milk allergens in African AD children. Urban AD children reacted more often to Mus m 1, whereas α-gal sensitization is more common in rural children likely due to parasite exposure.

Background IgE to galactose alpha-1,3 galactose (alpha-gal) causes alpha-gal syndrome (delayed anaphylaxis after ingestion of mammalian meat). Development of sensitization has been attributed to tick bites; however, the possible role of other parasites has not been well studied. Objective Our aims were to assess the presence, relative abundances, and site of localization of alpha-gal–containing proteins in common ectoparasites and endoparasites endemic in an area of high prevalence of alpha-gal syndrome, as well as to investigate the ability of ascaris antigens to elicit a reaction in a humanized rat basophil in vitro sensitization model. Methods Levels of total IgE, Ascaris-specific IgE, and alpha-gal IgE were measured in sera from patients with challenge-proven alpha-gal syndrome and from controls without allergy. The presence, concentration, and localization of alpha-gal in parasites were assessed by ELISA, Western blotting, and immunohistochemistry. The ability of Ascaris lumbricoides antigen to elicit IgE-dependent reactivity was demonstrated by using the RS-ATL8 basophil reporter system. Results Alpha-gal IgE level correlated with A lumbricoides–specific IgE level. Alpha-gal protein at 70 to 130 kDa was detected in A lumbricoides at concentrations higher than those found in Rhipicephalus evertsi and Amblyomma hebraeum ticks. Immunohistochemistry was used to localize alpha-gal in tick salivary acini and the helminth gut. Non–alpha-gal–containing A lumbricoides antigens activated RS-ATL8 basophils primed with serum from subjects with alpha-gal syndrome. Conclusion We demonstrated the presence, relative abundances, and site of localization of alpha-gal–containing proteins in parasites. The activation of RS-ATL8 IgE reporter cells primed with serum from subjects with alpha-gal syndrome on exposure to non–alpha-gal–containing A lumbricoides proteins indicates a possible role of exposure to A lumbricoides in alpha-gal sensitization and clinical reactivity.

BackgroundMore 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.MethodsA prospective cohort study in a South African community through the ancestral/beta/delta/omicron SARS-CoV-2 waves. Health seeking behaviour/illness were recorded and post-wave serum samples probed for IgG to Spike (CoV2-S-IgG). 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.FindingsDespite 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 the 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.InterpretationNaturally 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 thus may provide adequate protection.FundingUK 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).Research in contextEvidence before this studyNatural infection with ancestral SARS-CoV-2 virus provides partial protection against re-infection with the same and closely related SARS-CoV-2 variants, but higher rates of re-infection have been described with Omicron. In addition, vaccination against SARS-CoV2 provides relatively lower protection against symptomatic Omicron infection than for other variants. Hybrid immunity, a combination of immunity induced by natural infection and vaccination is of critical interest due to the high incidence of natural infection in many populations and increased availability of vaccination. Vaccination following infection may provide more robust immunity than either infection or vaccination alone, but there are limited data on the impact of hybrid immunity for protection against different variants or on the optimal vaccination strategy following natural infection.Added value of this studyWe leveraged a unique South African birth cohort in a poor peri-urban area, to longitudinally investigate infection, illness and serological responses to natural exposure to SARS-CoV-2 over 4 waves of the pandemic in healthy mothers. We also investigated the impact of prior natural exposure on BNT162b2 mRNA vaccine responses. We used this information to derive estimates of levels of spike-specific IgG associated with protection for subsequent infection following natural or hybrid immunity. Despite little disease, most participants were seropositive with rates rising from 52% to 74%, 90% and 97% after waves 1, 2, 3 and 4 respectively. Antibodies to spike protein induced by natural exposure protected against subsequent infection with the greatest protection for beta and the least for omicron. Antibody levels following vaccination were significantly higher in those who were seropositive prior to vaccine, compared to those seronegative. Amongst seropositive participants, proportions above the 50% protection against infection threshold were 69% following 1 vaccine dose, 63% following 2 doses and only 11% in unvaccinated during the omicron wave. In those seropositive prior to vaccination no significant increase in antibody levels occurred after the 2nd dose of vaccine, unlike the increase in seronegative participants. A single dose of vaccine in seropositive individuals induced higher antibody concentrations than two doses in seronegative recipients.Implications of all the available evidenceNaturally induced spike antibodies 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 natural immunity is more immunogenic than 2 doses in seronegative people and may provide adequate protection against omicron and other variants. Vaccination programs in populations with high seroprevalence using a single vaccination as a primary strategy should be considered.

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 ( 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.

Atopic dermatitis (AD) is one of the most common diseases in pediatric patients, with over 12.5% of US children diagnosed with the condition.1 Previous studies have shown that the impaired skin barrier caused by AD leads to the development of other atopic conditions later in life.2 The rate of AD among black children in Africa is similar to reported rates among African Americans (AA), while the rate of other atopic diseases such as asthma and food allergy (FA) in black children living in African countries are lower compared to most western populations. 3 The lower rate of asthma and FA, despite similar AD rates among rural African children, calls into question the critical role environment plays in protection against the progression of the atopic march. Previous evidence suggests gut microbiota differences are linked to the initiation and progression of atopic diseases.4 It is possible that changes in the environment including diet, exposure to microbes, and lifestyle factors result in alteration in the gut microbiome and contribute to the risk of atopic diseases. In certain African countries, many individuals still live in completely natural settings. Studying these populations provides the opportunity to evaluate the protective role of environment and lifestyle on gut microbiota and atopic diseases.

Background Previous studies have shown that a child's risk of developing atopic disease is impacted by both genetic and environmental factors. Because small children spend the majority of their time in their homes, exposure to microbial factors in their home environment may be protective or risk factors for development of atopic diseases, such as atopic dermatitis. Methods Dust samples from the homes of 86 Black South African children 12 to 36 months old were collected for analysis of the bacterial microbiome. This case-control study design included children with and without atopic dermatitis from rural and urban environments. Results Significant differences in bacterial composition and diversity were found when comparing children with and without atopic dermatitis. Furthermore, house dust microbiota was significantly different in rural and urban areas. Differences were best accounted for by higher relative abundance of Ruminococcaceae, Lachnospiraceae, and Bacteroidaceae families in rural compared with urban houses. Levels of Ruminococcaceae were also found to be significantly depleted in the house dust of rural children with atopic dermatitis as compared to control children. Conclusions House dust composition may be an important risk factor for the development of atopic disease, and this association may be driven in part by the gut microbiome. Low levels of the Ruminococcaceae family from Clostridia class in particular may explain the association between urban living and atopy. However, further research is needed to elucidate these links.

Item does not contain fulltext BACKGROUND: Environmental exposures are involved in the pathogenesis of the allergic phenotype and in determining which individual triggers a person becomes sensitized to. Atopic dermatitis (AD) may modulate these effects through increased penetration through the skin modifying the immune system and AD may be triggered or intensified by environmental exposures. These exposures and immune-modulating factors may differ in urban and rural environments. OBJECTIVES: To compare house dust composition in urban and rural settings and correlate them with AD outcomes. METHODS: Dust samples were collected from the beds of 156 children aged 6 months to 3 years. 42% of participants had atopic dermatitis. Samples were analyzed for bacterial endotoxin, fungal (β-1,3-glucan) levels, and house dust mite, cockroach, dog, cat, mouse, and peanut allergen. Exposures were compared in urban and rural environments and in participants with and without AD. RESULTS: Endotoxin but not fungal β-glucan exposure is higher in the environment of healthy controls than children with AD in both urban and rural settings. House dust mite allergen exposure is high in urban and rural settings with Dermatophagoides detected in 100% of samples. Cat and dog allergen exposure mirrors pet ownership patterns which differ slightly between groups and environments. Mouse allergen exposure is higher in urban homes. CONCLUSION: Environmental endotoxin may be protective against AD in both urban and rural settings. There are marked differences in allergen exposure in urban and rural settings, but these are unlikely to be important protective or risk factors.

Contains fulltext : 208818.pdf (Publisher’s version ) (Closed access) This study describes and compares allergic diseases and sensitization in urban and rural children in the SAFFA study cohort as well as infant feeding patterns and nutritional status. We assessed the relationship between nutritional status, breastfeeding, complementary feeding patterns, and atopic diseases including aeroallergen and food allergen sensitization, self-reported atopic dermatitis, allergic rhinitis, asthma, and challenge-proven food allergy (FA). METHODOLOGY: A total of 1185 urban and 398 rural toddlers aged 12-36 months were screened for food sensitization (FS) and FA using skin prick testing and oral food challenges. Of these, 535 and 347, respectively, were additionally screened for aeroallergen sensitization. Information was collected on infant feeding practices, and anthropometric measurements and clinical signs for atopy were documented. RESULTS: Markedly higher rates of allergy (asthma 9.0% vs 1.0%, eczema 25.6% vs 2.0%, rhinitis 25.3% vs 3.3%, and FA 2.5% vs 0.5%) exist in urban vs rural children. 13.1% unselected urban South African children were sensitized to aeroallergens compared to 3.8% of their rural counterparts and 9.0% to any food compared to 0.5%. Exclusive breastfeeding duration was longer, and there was a later introduction of allergenic foods in rural communities. Obesity rates were similar between the two groups, but rural children were more likely to be stunted. Being overweight was associated with asthma in urban but not rural settings. In the urban cohort, children with FS and allergy were thinner than their peers. CONCLUSION: Allergy and sensitization rates are significantly higher in unselected urban South African toddlers than their rural counterparts. Risk and protective factors for allergy and atopy may differ between urban and rural settings.

Background The prevalence of allergic diseases differs in urban and rural populations. Objective We sought to assess associations between environmental and dietary factors with allergic diseases in urban and rural South African children. Methods Toddlers aged 12 to 36 months were assessed for food allergen and aeroallergen sensitization, atopic dermatitis, allergic rhinitis, asthma, and challenge-proved food allergy. Information was collected on family history of allergic diseases, household size, socioeconomic status, delivery mode, antibiotic and probiotic use, exposure to fermented and unpasteurized milk, antihelminth treatment, sunlight exposure, pet and farm animal exposure, cigarette smoke, and household cooking and heating fuels. Antenatal exposures to pets, livestock, and cigarette smoke were assessed. A subsection completed questions on consumption of fruits and vegetables, fast foods, soft drinks/fruit juices, and fried/microwaved meat. Results Risk and protective factors differed between urban and rural settings. Exposure to farm animals in infants and their mothers during pregnancy was protective against allergic outcomes in the rural population. Consumption of unpasteurized milk is uncommon in this group of rural children and is unlikely to be an important factor in rural protection. In urban children birth by cesarean section is associated with food allergy, and consumption of fermented milk products is associated with reduced asthma and atopic dermatitis. In both cohorts antenatal maternal smoking and environmental smoking exposure were predominantly associated with asthma, and consumption of fast foods and fried meats were associated with allergy. Conclusion In this rural environment exposure to livestock is the strongest protective factor. In urban communities, where animal contact is rare, risk factors include cesarian section, and protective factors include consumption of fermented milk products. Modifiable risk factors urgently require interventions to prevent increasing allergy rates in countries undergoing rapid urbanization.

Food sensitization and challenge-proved food allergy (FA) have not been compared in urban and rural settings.We sought to determine and compare the prevalence of food sensitization and challenge-proved IgE-mediated FA in urban and rural South African toddlers aged 12 to 36 months.This cross-sectional study of unselected children included 1185 participants in urban Cape Town and 398 in the rural Eastern Cape. All participants completed a questionnaire and underwent skin prick tests (SPTs) to egg, peanut, cow's milk, fish, soya, wheat, and hazelnut. Participants with SPT responses of 1 mm or greater to 1 or more foods and not tolerant on history underwent an open oral food challenge.The prevalence of FA was 2.5% (95% CI, 1.6% to 3.3%) in urban children, most commonly to raw egg white (1.9%), followed by cooked egg (0.8%), peanut (0.8%), cow's milk (0.1%), and fish (0.1%). Urban sensitization (SPT response ≥1 mm) to any food was 11.4% (95% CI, 9.6% to 13.3%) and 9.0% (95% CI, 7.5% to 10.8%) at an SPT response of 3 mm or greater. Sensitization in rural cohorts was significantly lower than in the urban cohort (1-mm SPT response, 4.5% [95% CI, 2.5% to 6.6%]; 3-mm SPT response, 2.8% [95% CI, 1.4% to 4.9%]; P .01). In the rural black African cohort 0.5% (95% CI, 0.1% to 1.8%) of children had food allergy, all to egg. This is significantly lower than the prevalence of the urban cohort overall (2.5%) and urban black African participants (2.9%; 95% CI, 1.5% to 4.3%; P = .006).FA prevalence in Cape Town is comparable with rates in industrialized middle-income countries and is significantly greater than in rural areas. Further analysis will describe and compare environmental exposures and other risk factors in this cohort.

Background Severe meat allergy with anaphylaxis may be caused by sensitization to alpha-gal. Levels of alpha-gal sensitization that correlate with high risk of meat allergy are currently unknown. We have identified an area with a high prevalence of reported red meat allergy which offered the opportunity to evaluate the diagnostic value of IgE antibody tests. Methods To determine levels of alpha-gal IgE and alpha-gal:total IgE ratio in a large cohort of subjects with challenge-proven meat allergy compared with control subjects from the same environment, we conducted fieldwork assessing 131 participants who reported adverse reactions to meat, and 26 control subjects, by questionnaires, IgE sensitization to alpha-gal and oral food challenge to beef sausage. Results Eighty-four participants were diagnosed with alpha-gal allergy. Alpha-gal IgE ranged between 0.7 and 344.5 kU/L. Alpha-gal:total IgE ratio ranged from 0.1% to 67.6%. Logistic regression analysis showed both alpha-gal IgE and alpha-gal:total IgE ratio strongly correlated with meat allergy, with AUC of 0.95. The values giving the best correct classification were IgE of 2.00 kU/L and ratio of 0.75%. The value above which there is a 95% probability of meat allergy is IgE>5.5 kU/L and ratio of 2.12%. Conclusion Alpha-gal allergy in a population with a high prevalence of reported red meat allergy showed a more rapid onset of symptoms than previously described and a high prevalence of isolated subjective gastrointestinal manifestations. Cutoff values are described for levels of sensitization to alpha-gal IgE and alpha-gal:total IgE ratio that are highly likely to result in clinically significant meat allergy.

Background Few studies exist on food sensitization and challenge-proven food allergy in low- and middle-income countries. Objective To describe the study design and methodology to recruit infants from an African population for skin prick testing and oral food challenges and the use of preliminary data to investigate the extent to which the study sample is representative of the target population. Methods Children 12 to 36 months old were recruited from childcare education facilities in Cape Town. Children underwent skin prick testing to foods. Those with a reactive wheal of at least 1 mm larger than the negative control and not clearly tolerant according to history to a full age-appropriate portion to at least 1 food underwent oral food challenges. Parents who chose not to participate completed a nonparticipant questionnaire. Interim analysis of at least 500 respondents was performed. Demographic features of participating children were compared with those of nonparticipants and the population demographics of the most recent Cape Town census data. Results The response rate was 60.1%, with high participation and completion rates of 96.5% and 97.5%, respectively. Demographics of the completed participant sample were similar to those of the Cape Town census. Use of a nonrespondent questionnaire indicated no selection bias in favor of increased participation of participants with allergy. No ethnic differences in sensitization or food allergy were evident. Conclusion The study was safe and feasible and the recruitment was effective and representative of the target population. Future studies will aim to increase the precision of the prevalence of food sensitization and allergy, describe environmental risk factors, and include a rural black African cohort.

METHODS: This cross-sectional study recruited 12-36 month old toddlers from randomly selected registered creches in Cape Town. Parents of eligible children in the creche completed a questionnaire and the children had skin prick tests (SPT) for cow’s milk, egg, soya, wheat, peanut, hazelnut and fish (cod). Participants with SPT test >1 mm, who were not tolerant to that food had an OFC to assess for IgE-mediated food allergy. Parents choosing not to participate completed a non-participant questionnaire to control for bias.