Factors associated with serious outcomes of pneumonia among children in a birth cohort in South Africa.

BACKGROUND: Child hospitalization for pneumonia remains common, and pneumonia is a major cause of child mortality. Early identification of clinical factors associated with serious outcomes may help target risk-mitigation strategies. METHODS: Pneumonia cases occurring in the Drakenstein Child Health Study, a prospective birth cohort outside Cape Town, South Africa were analysed, and factors associated with serious outcomes of pneumonia were identified. Pregnant women were enrolled antenatally, followed through pregnancy, and mother-child pairs from birth to 2 years. Active surveillance for pneumonia was done. Children hospitalized with pneumonia had chest radiography and blood drawn for inflammatory markers; course, outcome and duration of hospitalization were investigated. Serious outcomes were defined as in-hospital mortality or admission to intensive care unit (ICU). Prolonged hospitalization was also explored as a proxy for severity. Features associated with serious outcomes or prolonged hospitalization were analysed using modified Poisson regression. RESULTS: Among 1143 live born infants, there were 174 hospitalized pneumonia events in 133 children under 2 years. Three children (1.7%) died, 14 (8%) required ICU admission for respiratory support. In modified Poisson regression, age < 2 months, preterm birth, or hypoxia (oxygen saturation <92%) were significantly associated with serious outcomes. Preterm birth, low birth weight, HIV exposure, stunting, or underweight-for-age (UWFA) were associated with prolonged hospitalization. Chest radiography, elevated C reactive protein, white blood cell and neutrophil counts were not useful to predict death or ICU admission in children hospitalized with pneumonia. CONCLUSIONS: In this cohort, death from pneumonia was rare, but clinical features associated with serious outcomes and prolonged hospitalization were identified. These may help with risk stratification, to identify children who may benefit from enhanced monitoring or earlier escalation to respiratory support.

Early-life respiratory syncytial virus lower respiratory tract infection in a South African birth cohort: epidemiology and effect on lung health.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) in children. Early-life RSV LRTI might affect long-term health but there are few data from low-income and middle-income countries. We investigated the epidemiology and effect of early-life RSV LRTI on lung health in a South African birth cohort. METHODS: We conducted the Drakenstein Child Health Study (DCHS), an ongoing birth cohort longitudinal study in the Western Cape province, South Africa. We enrolled pregnant women aged 18 years or older during their second trimester of pregnancy at two public health clinics. We followed up study children from birth to 2 years. The primary outcome of the study was LRTI and RSV LRTI. LRTI and wheezing episodes were identified through active surveillance; respiratory samples were tested for RSV and other pathogens. Wheezing was longitudinally identified by caregiver report and ascertainment at health facilities. Lung function was measured from 6 weeks to 2 years. We analysed the associations between RSV LRTI and subsequent LRTI, wheezing, and lung function using generalised estimating equations and mixed-effects linear regression. FINDINGS: We enrolled 1137 mothers between March 5, 2012, and March 31, 2015. Among their 1143 infants, accruing 2093 child-years of follow-up, there were 851 cases of LRTI (incidence 0·41 episodes per child-year, 95% CI 0·38-0·43). Admission to hospital owing to LRTI occurred in 169 (20%) cases (incidence 0·08 episodes per child-year, 0·07-0·09), with a case-fatality ratio of 0·5%. RSV was detected in 164 (21%) of 785 LRTI events with a specimen available for qPCR, an incidence of 0·08 episodes per child-year (0·07-0·09); highest at age 0-6 months (0·15 episodes per child-year, 0·12-0·19). Children with a first RSV LRTI were three times as likely to develop recurrent LRTI compared with those with non-RSV LRTI (0·32 [0·22-0·48] vs 0·10 [0·07- 0·16] episodes per child-year; p<0·0001), particularly following hospitalised RSV LRTI. RSV LRTI and hospitalisation for all-cause LRTI were independently associated with recurrent wheezing (adjusted incident rate ratio 1·41, 95% CI 1·25-1·59, for RSV LRTI and 1·48, 1·30-1·68, for hospitalisation). LRTI or recurrent LRTI was associated with impaired lung function, but a similar outcome was observed following RSV LRTI or non-RSV LRTI. All-cause LRTI was associated with an average 3% higher respiratory rate (95% CI 0·01-0·06; p=0·013) and lower compliance (-0·1, -0·18 to 0·02) at 2 years compared with no LRTI. Recurrent LRTI was associated with further increased respiratory rate (0·01, 0·001-0·02), resistance (0·77 hPa s L-1, 0·07-1·47), and lower compliance (-0·6 mL hPa-1, -0·09 to -0·02) with each additional event. INTERPRETATION: RSV LRTI was common in young infants and associated with recurrent LRTI, particularly after hospitalised RSV. Hospitalisation for all-cause LRTI, especially for RSV-LRTI, was associated with recurrent wheezing. Impairments in lung function followed LRTI or recurrent episodes, but were not specific to RSV. New preventive strategies for RSV might have an effect on long-term lung health. FUNDING: Bill & Melinda Gates Foundation; South African Medical Research Council; National Research Foundation South Africa; National Institutes of Health, Human Heredity and Health in Africa; Wellcome Trust.

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.

Longitudinal Population Dynamics of Staphylococcus aureus in the Nasopharynx During the First Year of Life.

Background: Staphylococcus aureus colonization is a risk factor for invasive disease. Few studies have used strain genotype data to study S. aureus acquisition and carriage patterns. We investigated S. aureus nasopharyngeal carriage in infants in an intensively sampled South African birth cohort. Methods: Nasopharyngeal swabs were collected at birth and fortnightly from 137 infants through their first year of life. S. aureus was characterized by spa-typing. The incidence of S. aureus acquisition, and median carriage duration for each genotype was determined. S. aureus carriage patterns were defined by combining the carrier index (proportion of samples testing positive for S. aureus) with genotype diversity measures. Persistent or prolonged carriage were defined by a carrier index ≥0.8 or ≥0.5, respectively. Risk factors for time to acquisition of S. aureus were determined. Results: Eighty eight percent (121/137) of infants acquired S. aureus at least once. The incidence of acquisition at the species and genotype level was 1.83 and 2.8 episodes per child-year, respectively. No children had persistent carriage (defined as carrier index of >0.8). At the species level 6% had prolonged carriage, while only 2% had prolonged carriage with the same genotype. Carrier index correlated with the absolute number of spa-CCs carried by each infant (r = 0.5; 95% CI 0.35-0.62). Time to first acquisition of S. aureus was shorter in children from households with ≥5 individuals (HR 1.06, 95% CI 1.07-1.43), with S. aureus carrier mothers (HR; 1.5, 95% CI 1.2-2.47), or with a positive tuberculin skin test during the first year of life (HR; 1.81, 95% CI 0.97-3.3). Conclusion: Using measures of genotype diversity, we showed that S. aureus NP carriage is highly dynamic in infants. Prolonged carriage with a single strain occurred rarely; persistent carriage was not observed. A correlation was observed between carrier index and genotype diversity.

Indoor air pollution and tobacco smoke exposure: impact on nasopharyngeal bacterial carriage in mothers and infants in an African birth cohort study.

Indoor air pollution (IAP) or environmental tobacco smoke (ETS) exposure may influence nasopharyngeal carriage of bacterial species and development of lower respiratory tract infection (LRTI). The aim of this study was to longitudinally investigate the impact of antenatal or postnatal IAP/ETS exposure on nasopharyngeal bacteria in mothers and infants. A South African cohort study followed mother-infant pairs from birth through the first year. Nasopharyngeal swabs were taken at birth, 6 and 12 months for bacterial culture. Multivariable and multivariate Poisson regression investigated associations between nasopharyngeal bacterial species and IAP/ETS. IAP exposures (particulate matter, carbon monoxide, nitrogen dioxide, volatile organic compounds) were measured at home visits. ETS exposure was measured through maternal and infant urine cotinine. Infants received the 13-valent pneumococcal and Haemophilus influenzae B conjugate vaccines. There were 881 maternal and 2605 infant nasopharyngeal swabs. Antenatal ETS exposure was associated with Streptococcus pneumoniae carriage in mothers (adjusted risk ratio (aRR) 1.73 (95% CI 1.03-2.92)) while postnatal ETS exposure was associated with carriage in infants (aRR 1.14 (95% CI 1.00-1.30)) Postnatal particulate matter exposure was associated with the nasopharyngeal carriage of H. influenzae (aRR 1.68 (95% CI 1.10- 2.57)) or Moraxella catarrhalis (aRR 1.42 (95% CI 1.03-1.97)) in infants. Early-life environmental exposures are associated with an increased prevalence of specific nasopharyngeal bacteria during infancy, which may predispose to LRTI.

Longitudinal characterization of nasopharyngeal colonization with Streptococcus pneumoniae in a South African birth cohort post 13-valent pneumococcal conjugate vaccine implementation.

Monitoring changes in pneumococcal carriage is key to understanding vaccination-induced shifts in the ecology of carriage and impact on health. We longitudinally investigated pneumococcal carriage dynamics in infants. Pneumococcal isolates were obtained from nasopharyngeal (NP) swabs collected 2-weekly from 137 infants enrolled from birth through their first year of life. Pneumococci were serotyped by sequetyping, confirmed by Quellung. Pneumococci were isolated from 54% (1809/3331) of infants. Median time to first acquisition was 63 days. Serotype-specific acquisition rates ranged from 0.01 to 0.88 events/child-year and did not differ between PCV13 and non-PCV13 serotypes (0.11 events/child-year [95% CI 0.07-0.18] vs. 0.11 events/child-year [95% CI 0.06-0.18]). There was no difference in carriage duration between individual PCV13 and non-PCV13 serotypes (40.6 days [95% CI 31.9-49.4] vs. 38.6 days [95% CI 35.1-42.1]), however cumulatively the duration of carriage of non-PCV13 serotypes was greater than PCV13 serotypes (141.2 days (95% CI 126.6-155.8) vs. 30.7 days (95% CI 22.3-39.0). Frequently carried PCV13 serotypes included 19F, 9V, 19A and 6A, while non-PCV13 serotypes included 15B/15C, 21, 10A, 16F, 35B, 9N and 15A. Despite high immunization coverage in our setting, PCV13 serotypes remain in circulation in this cohort, comprising 22% of isolates. Individual PCV13 serotypes were acquired, on average, at equivalent rate to non-PCV13 serotypes, and carried for a similar duration, although the most common non-PCV13 serotypes were more frequently acquired than PCV13 serotypes.

Early-life exposure to indoor air pollution or tobacco smoke and lower respiratory tract illness and wheezing in African infants: a longitudinal birth cohort study.

BACKGROUND: Indoor air pollution (IAP) and environmental tobacco smoke (ETS) are associated with lower respiratory tract illness (LRTI) or wheezing in children. However, the effect of the timing of these exposures, specifically antenatal versus postnatal, and of alternate fuel sources such as the increasingly used volatile organic compounds have not been well studied. We longitudinally investigated the effect of antenatal or postnatal IAP and ETS on LRTI or wheezing prevalence and severity in African infants. METHODS: Mother and infant pairs enrolled over a 3-year period in a birth cohort study in two centres in Paarl, South Africa, were followed for the first year of life for LRTI or wheezing illness. We measured exposure to IAP (particulate matter, nitrogen dioxide, sulphur dioxide, carbon monoxide, and volatile organic compounds benzene and toluene) using devices placed in homes, antenatally and postnatally. We measured ETS longitudinally by maternal self-report and by urine cotinine measures. Study staff trained in recognition of LRTI or wheeze documented all episodes, which were categorised according to WHO case definition criteria. We used multivariate logistic and Poisson regressions to explore associations. FINDINGS: Between March 1, 2012, and March 31, 2015, we enrolled 1137 mothers with 1143 livebirths. Of 1065 infants who attended at least one study visit, 524 episodes of LRTI occurred after discharge with a wheezing prevalence of 0·23 (95% CI 0·21-0·26) episodes per child year. Exposures associated with LRTI were antenatal maternal smoking (incidence rate ratio 1·62, 95% CI 1·14-2·30; p=0·004) or particulate matter (1·43, 1·06-1·95; p=0·008). Subanalyses of LRTI requiring hospitalisation (n=137) and supplemental oxygen (n=69) found antenatal toluene significantly increased the risk of LRTI-associated hospitalisation (odds ratio 5·13, 95% CI 1·43-18·36; p=0·012) and need for supplemental oxygen (13·21, 1·96-89·16; p=0·008). Wheezing illness was associated with both antenatal (incidence rate ratio 2·09, 95% CI 1·54-2·84; p<0·0001) and postnatal (1·27, 95% CI 1·03-1·56; p=0·024) maternal smoking. Antenatally, wheezing was associated with maternal passive smoke exposure (1·70, 1·25-2·31; p=0·001) and, postnatally, with any household member smoking (1·55, 1·17 -2·06; p=0·002). INTERPRETATION: Antenatal exposures were the predominant risk factors associated with LRTI or wheezing illness. Toluene was a novel exposure associated with severe LRTI. Urgent and effective interventions focusing on antenatal environmental factors are required, including smoking cessation programmes targeting women of childbearing age pre-conception and pregnant women. FUNDING: Bill & Melinda Gates Foundation, Discovery Foundation, South African Thoracic Society AstraZeneca Respiratory Fellowship, Medical Research Council South Africa, National Research Foundation South Africa, and CIDRI Clinical Fellowship.

Determinants of early-life lung function in African infants.

BACKGROUND: Low lung function in early life is associated with later respiratory illness. There is limited data on lung function in African infants despite a high prevalence of respiratory disease. AIM: To assess the determinants of early lung function in African infants. METHOD: Infants enrolled in a South African birth cohort, the Drakenstein child health study, had lung function measured at 6-10 weeks of age. Measurements, made with the infant breathing via a facemask during natural sleep, included tidal breathing, sulfur hexafluoride multiple breath washout and the forced oscillation technique. Information on antenatal and early postnatal exposures was collected using questionnaires and urine cotinine. Household benzene exposure was measured antenatally. RESULTS: Successful tests were obtained in 645/675 (95%) infants, median (IQR) age of 51 (46-58) days. Infant size, age and male gender were associated with larger tidal volume. Infants whose mothers smoked had lower tidal volumes (-1.6 mL (95% CI -3.0 to -0.1), p=0.04) and higher lung clearance index (0.1 turnovers (95% CI 0.01 to 0.3), p=0.03) compared with infants unexposed to tobacco smoke. Infants exposed to alcohol in utero or household benzene had lower time to peak tidal expiratory flow over total expiratory time ratios, 10% (95% CI -15.4% to -3.7%), p=0.002) and 3.0% (95% CI -5.2% to -0.7%, p=0.01) lower respectively compared with unexposed infants. HIV-exposed infants had higher tidal volumes (1.7 mL (95% CI 0.06 to 3.3) p=0.04) compared with infants whose mothers were HIV negative. CONCLUSION: We identified several factors including infant size, sex, maternal smoking, maternal alcohol, maternal HIV and household benzene associated with altered early lung function, many of which are factors amenable to public health interventions. Long-term study of lung function and respiratory disease in these children is a priority to develop strategies to strengthen child health.

Home environment and indoor air pollution exposure in an African birth cohort study.

BACKGROUND: Household indoor air pollution (IAP) is a global health problem and a risk factor for childhood respiratory disease; the leading cause of mortality in African children. This study aimed to describe the home environment and measure IAP in the Drakenstein Child Health Study (DCHS), an African birth cohort. METHODS: An antenatal home visit to assess the home environment and measure IAP (particulate matter, sulphur dioxide, nitrogen dioxide, carbon monoxide and volatile organic compounds (VOCs)) was done on pregnant women enrolled to the DCHS, in a low-socioeconomic, peri-urban South African community. Urine cotinine measured maternal tobacco smoking and exposure. Dwellings were categorised according to 6 household dimensions. Univariate and multivariate analysis explored associations between home environment, seasons and IAP levels measured. RESULTS: 633 home visits were completed, with IAP measured in 90% of homes. Almost a third of participants were of the lowest socio-economic status and the majority of homes (65%) lacked 2 or more of the dwelling category dimensions. Most households had electricity (92%), however, fossil fuels were still used for cooking (19%) and heating (15%) in homes. Antenatal maternal smoking prevalence was 31%; 44% had passive smoke exposure. Of IAP measured, benzene (VOC) was significantly above ambient standards with median 5.6 µg/m3 (IQR 2.6-17.1). There were significant associations between the use of fossil fuels for cooking and increased benzene [OR 3.4 (95% CI 2.1-5.4)], carbon monoxide [OR 2.9 (95% CI 1.7-5.0)] and nitrogen dioxide [OR 18.6 (95% CI 3.9-88.9)] levels. A significant seasonal association was found with higher IAP levels in winter. CONCLUSION: In this low-socioeconomic African community, multiple environmental factors and pollutants, with the potential to affect child health, were identified. Measurement of IAP in a resource-limited setting is feasible. Recognising and quantifying these risk factors is important in effecting public health policy changes.

Mathematical modelling of immune regulation of type 1 diabetes.

Type 1 diabetes is a disease characterized by progressive loss of ß cell function due to an autoimmune reaction affecting the islets of Langerhans. Two types of T cells are involved in diabetes: turncoat auto-reactive T cells, or T cells gone bad, that kill the insulin-producing cells, and regulatory T cells that are unable to control the auto-reactive T cells. We formulate a mathematical model that incorporates the role of cytotoxic T cells and regulatory T cells in type 1 diabetes. This study shows that onset of type 1 diabetes is due to a collective, dynamical instability, rather than being caused by a single etiological factor. It is also a numbers game between regulatory T cells and auto-reactive T cells. The problem in the onset of this disease is that there are not enough of the regulatory cells that suppress the immune response against the body's insulin-producing pancreatic islet cells.