Distinct T cell polyfunctional profile in SARS-CoV-2 seronegative children associated with endemic human coronavirus cross-reactivity.

SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on SARS-CoV-2 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.

Predictors of within-individual variability in cognitive performance in schizophrenia in a South African case-control study.

INTRODUCTION: Cognitive dysfunction in schizophrenia may be assessed by measuring within-individual variability (WIV) in performance across a range of cognitive tests. Previous studies have found increased WIV in people with schizophrenia, but no studies have been conducted in low- to middle-income countries where the different sociocultural context may affect WIV. We sought to address this gap by exploring the relationship between WIV and a range of clinical and demographic variables in a large study of people with schizophrenia and matched controls in South Africa. METHODS: 544 people with schizophrenia and 861 matched controls completed an adapted version of The University of Pennsylvania Computerized Neurocognitive Battery (PennCNB). Demographic and clinical information was collected using the Structured Clinical Interview for DSM-IV Diagnoses. Across-task WIV for performance speed and accuracy on the PennCNB was calculated. Multivariate linear regression was used to assess the relationship between WIV and a diagnosis of schizophrenia in the whole sample, and WIV and selected demographic and clinical variables in people with schizophrenia. RESULTS: Increased WIV of performance speed across cognitive tests was significantly associated with a diagnosis of schizophrenia. In people with schizophrenia, increased speed WIV was associated with older age, a lower level of education and a lower score on the Global Assessment of Functioning scale. Increased accuracy WIV was significantly associated with a younger age in people with schizophrenia. CONCLUSIONS: Measurements of WIV of performance speed can add to the knowledge gained from studies of cognitive dysfunction in schizophrenia in resource-limited settings.

Normal values of respiratory oscillometry in South African children and adolescents.

Introduction: Noninvasive measurement of respiratory impedance by oscillometry can be used in young children aged from 3 years and those unable to perform forced respiratory manoeuvres. It can discriminate between healthy children and those with respiratory disease. However, its clinical application is limited by the lack of reference data for African paediatric populations. The aim of the present study was to develop reference equations for oscillometry outcomes in South African children and adolescents. Methods: Healthy subjects, enrolled in the Drakenstein Child Health Study, HIV-uninfected adolescents in the Cape Town Adolescent Antiretroviral Cohort and healthy children attending surgical outpatient clinics at Red Cross War Memorial Children's Hospital were measured with conventional spectral (6-32 Hz) and intra-breath (10 Hz) oscillometry. Stepwise linear regression was used to assess the relationship between respiratory variables and anthropometric predictors (height, sex, ancestry) to generate reference equations. Results: A total of 692 subjects, 48.4% female, median age of 5.2 years (range: 3-17 years) were included. The median (interquartile range (IQR)) for weight for age z-score and height for age z-score was -0.42 (-1.11-0.35) and -0.65 (-1.43-0.35), respectively. Stepwise regression demonstrated that all the variables were significantly dependent on height only. Comparison to previous reference data indicated slightly higher resistance and lower compliance values in the smallest children. Conclusion: We established the first respiratory oscillometry reference equations for African children and adolescents, which will facilitate use in early identification and management of respiratory disease. Our results suggest differences in oscillometry measures by ancestry but also highlight the lack of standardisation in methodology.

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).

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.

Maternal emotional and physical intimate partner violence and early child development: investigating mediators in a cross-sectional study in a South African birth cohort.

OBJECTIVES: This study investigated associations between recent maternal intimate partner violence (IPV) (emotional, physical and sexual) and child development at 2 years as well as whether maternal depression or alcohol use mediated these relationships. DESIGN: Cross-sectional study nested in a South African birth cohort. SETTING: Two primary care clinics in Paarl, South Africa. PARTICIPANTS: 626 mother-child pairs; inclusion criteria for maternal antenatal enrolment were clinic attendance and remaining in the study area for at least 1 year; women were excluded if a minor. PRIMARY OUTCOME MEASURES: Child cognitive, language and motor development composite scores. These were assessed using the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Emotional IPV was associated with lower cognitive (ß=-0.32; 95% CI -0.60 to -0.04), language (ß=-0.36; 95% CI -0.69 to -0.01) or motor composite scores (ß=-0.58; 95% CI -0.95 to -0.20) in children at 2 years of age. Physical IPV was associated with lower motor scores (ß=-0.42; 95% CI -0.75 to -0.09) at 2 years. Sexual IPV was unrelated to developmental outcomes, possibly due to low prevalence. Neither recent maternal depression nor alcohol use were shown to mediate the relationship between IPV and developmental outcomes. CONCLUSIONS: Interventions to reduce maternal physical and emotional IPV and early-life interventions for infants and toddlers are needed to promote optimal child development.

Antibodies to Seasonal Coronaviruses Rarely Cross-React With SARS-CoV-2: Findings From an African Birth Cohort.

Antibodies to seasonal human-coronaviruses (sHCoV) may cross-protect against SARS-CoV-2. We investigated antibody responses in biobanked serum obtained before the pandemic from infants with polymerase chain reaction-confirmed sHCoV. Among 141 samples with antibodies to sHCoV, 4 (2.8%) were positive for SARS-CoV-2-S1 and 8 (5.7%) for SARS-CoV-2-S2. Antibodies to sHCoV rarely cross-react with SARS-CoV-2 antigens and are unlikely to account for mild pediatric illness.

A Longitudinal Study of the Epidemiology of Seasonal Coronaviruses in an African Birth Cohort.

BACKGROUND: Since non-epidemic, seasonal human coronaviruses (sHCoV) commonly infect children, an improved understanding of the epidemiology of these infections may offer insights into the context of severe acute respiratory syndrome (SARS)-CoV-2. We investigated the epidemiology of sHCoV infection during the first year of life, including risk factors and association with lower respiratory tract infection (LRTI). METHODS: We conducted a nested case-control study of infants enrolled in a birth cohort near Cape Town, South Africa, from 2012 to 2015. LRTI surveillance was implemented, and nasopharyngeal swabs were collected fortnightly over infancy. Quantitative PCR detected respiratory pathogens, including coronaviruses-229E, -NL63, -OC43, and -HKU1. Swabs were tested from infants at the time of LRTI and from the 90 days prior as well as from age-matched control infants from the cohort over the equivalent period. RESULTS: In total, 885 infants were included, among whom 464 LRTI events occurred. Of the 4751 samples tested for sHCoV, 9% tested positive, with HCoV-NL63 the most common. Seasonal HCoV detection was associated with LRTI; this association was strongest for coronavirus-OC43, which was also found in all sHCoV-associated hospitalizations. Birth in winter was associated with sHCoV-LRTI, but there were no clear seasonal differences in detection. Co-detection of Streptococcus pneumoniae was weakly associated with sHCoV-LRTI (odds ratio: 1.8; 95% confidence interval: 0.9-3.6); detection of other respiratory viruses or bacteria was not associated with sHCoV status. CONCLUSIONS: Seasonal HCoV infections were common and associated with LRTI, particularly sHCoV-OC43, which is most closely related to the SARS group of coronaviruses. Interactions of coronaviruses with bacteria in the pathogenesis of LRTI require further study.

Association between maternal psychological adversity and lung function in South African infants: A birth cohort study.

OBJECTIVE: The association of perinatal psychological adversity (ie, stressors and distress) with infant lung function (ILF) and development is not well studied in Africa and elsewhere. We determined the association between maternal perinatal psychological adversity and ILF in African infants. DESIGN: Prospective longitudinal follow up of the Drakenstein Child Health Study birth cohort. PARTICIPANTS: Seven hundred and sixty-two infants aged 6 to 10 weeks and 485 infants who had data for both maternal perinatal psychological adversity and ILF (measured at 6 to 10 weeks and 12 months). METHODS: The main analyses were based on cross-sectional measures of ILF at each assessment (6 to 10 weeks or 12 months), using generalized linear models, and then on the panel-data of both longitudinal ILF assessments, using generalised estimating equations, that allowed specification of the within-group correlation structure. RESULTS: Prenatal intimate partner violence (IPV) exposure was associated with reduced respiratory resistance at 6 to 10 weeks (beta coefficient [ß] = -.131, P = .023); postnatal IPV with reduced ratio of time to peak tidal expiratory flow over total expiratory time (tPTEF /tE ) at 12 months (ß = -.206, P = .016); and prenatal depression with lower respiratory rate at 6 to 10 weeks (ß = -.044, P = .032) and at 12 months (ß = -.053, P = .021). Longitudinal analysis found an association of prenatal IPV with reduced tPTEF /tE (ß = -.052, P < .0001); postnatal IPV with decreased functional residual capacity (FRC; ß = -.086, P < .0001); prenatal posttraumatic stress disorder with increased FRC (ß = .017, P < .0001); prenatal depression with increased FRC (ß = .026, P < .0001) and postnatal depression with increased FRC (ß = .021, P < .0001). CONCLUSION: Screening for psychological adversity and understanding the mechanisms involved may help identify children at risk of altered lung development and inform approaches to treatment.

Impact of HIV and antiretroviral drug exposure on lung growth and function over 2 years in an African Birth Cohort.

OBJECTIVE: To assess the impact of HIV and antiretroviral exposure without infection on lung growth and function over the first 2 years of life. DESIGN: Prospective observational study of an African birth cohort, Drakenstein Child Health Study. METHOD: Infants enrolled antenatally had lung function measured at 6 weeks, 1 and 2 years. HIV-infected women received antiretroviral therapy (ART) as per local guidelines. The association between HIV and antiretroviral exposure with lung function was assessed using mixed effects modelling. RESULTS: Of 1143 infants born, two HIV-infected infants were excluded from analysis; 909 (80%) infants had lung function collected at 6 weeks [190 (21%) were HIV-exposed uninfected (HEU)]; 782 (69%) at 1 year and 741 (65%) at 2 years. At 6 weeks HEU infants had larger tidal volume compared with HIV-unexposed infants (1.13 ml, confidence interval: 0.02-2.23, P = 0.045). High maternal viral load was associated with a 17% lower expiratory flow over 2 years (0.17, confidence interval 0.00-0.34, P = 0.046). First-line ART initiated during pregnancy was associated with lower infant tidal volume at 6 weeks compared with those who initiated ART before pregnancy (-2.7 ml, -5.31 to -0.10, P = 0.042), and low maternal CD4 cell counts associated with lower infant tidal over 2 years (-11.1 ml, -18.58-3.58, P = 0.004). CONCLUSION: HIV exposure is associated with altered lung function in early life, with a vulnerable HEU subgroup based on maternal disease severity, immunological compromise and ART exposure. These data highlight the importance of ongoing surveillance of respiratory health in HEU children.

Maternal psychosocial risk factors and lower respiratory tract infection (LRTI) during infancy in a South African birth cohort.

OBJECTIVE: To investigate the association between maternal antenatal and/or postnatal psychosocial risk factors (including depression, psychological distress, alcohol abuse and intimate partner violence (IPV) and infant lower respiratory tract infection (LRTI) in a low- and middle-income-country (LMIC). STUDY DESIGN: Pregnant women (n = 1137) enrolled in a South African birth cohort study, the Drakenstein Child Health Study (DCHS) were longitudinally assessed for psychosocial risk factors including depression, psychological distress, alcohol abuse and/or intimate partner violence (IPV). Infants were followed from birth until one year of age for the development of LRTI by active surveillance. Two outcomes were evaluated: any LRTI, and severe and/or hospitalised LRTI. Logistic regression was used to identify associations between individual maternal psychosocial risk factors and LRTI outcomes. Analyses stratified by age were also performed to determine which age groups related to infant LRTI were linked with maternal psychosocial risk factors. RESULTS: There were 606 LRTI episodes in 369 infants in the first year (crude incidence rate = 0.53 episodes per person-year, 95%CI: 0.50; 0.56); 31% (n = 186) of episodes were severe or hospitalised events. Maternal psychosocial risk factors were associated with LRTI and severe LRTI, particularly postnatal and long-term maternal psychological distress, antenatal maternal alcohol consumption, and postnatal maternal IPV. Age stratified analyses found that antenatal maternal alcohol consumption was associated with early infant LRTI, while antenatal maternal depression was linked with infant severe LRTI between 3 and 6 months of age, and postnatal maternal IPV was associated with early LRTI and severe forms of LRTI. CONCLUSION: The associations between maternal psychosocial risk factors and infant LRTI highlight the potential value of screening for maternal psychosocial risk factors in clinical settings and developing targeted interventions. Such interventions may not only improve maternal well-being, but also help reduce the burden of infant LRTI in LMIC settings.

Associations between maternal mental health and early child wheezing in a South African birth cohort.

BACKGROUND: Wheezing in early childhood is common and has been identified in high-income countries (HIC) as associated with maternal antenatal or postnatal psychosocial risk factors. However, the association between maternal mental health and childhood wheezing has not been well studied in low and middle-income countries (LMIC), such as South Africa. METHODS: A total of 1137 pregnant women over 18 year old, between 20 and 28 weeks' gestation, and attending either of two catchment area clinics were enrolled in a South African parent study, the Drakenstein Child Health Study (DCHS). Psychosocial risk factors including maternal depression, psychological distress, early adversity, and intimate partner violence (IPV), were measured antenatally and postnatally by validated questionnaires. Two outcomes were evaluated: Presence of wheeze (at least one episode of child wheeze during the first 2 years of life); and recurrent wheeze (two or more episodes of wheezing in a 12-month period). Logistic regression was used to investigate the association between antenatal or postnatal psychosocial risk factors and child wheeze, adjusting for clinical and socio-demographic covariates. RESULTS: Postnatal psychological distress and IPV were associated with both presence of wheeze (adjusted OR = 2.09, 95%CI: 1.16-3.77 and 1.63, 95%CI: 1.13-2.34, respectively), and recurrent child wheeze (adjusted OR = 2.26, 95%CI: 1.06-4.81 and 2.20, 95%CI: 1.35-3.61, respectively). CONCLUSION: Maternal postnatal psychological distress and IPV were associated with wheezing in early childhood. Thus, screening and treatment programs to address maternal psychosocial risk factors may be potential strategies to reduce the burden of childhood wheeze in LMICs.