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OBJECTIVE: We evaluated the association between early-onset sepsis and neonatal encephalopathy in a low-middle-income setting. METHODS: We undertook a retrospective study in newborns with gestational age ≥35 weeks and/or birth weight ≥2500 grams, diagnosed with neonatal encephalopathy. Early-onset sepsis was defined as culture-confirmed sepsis or probable sepsis. RESULTS: Of 10,182 hospitalised newborns, 1027 (10.1%) were diagnosed with neonatal encephalopathy, of whom 52 (5.1%) had culture-confirmed and 129 (12.5%) probable sepsis. The case fatality rate for culture-confirmed sepsis associated neonatal encephalopathy was threefold higher compared to neonatal encephalopathy without sepsis (30.8% vs. 10.5%, p

Past studies have mainly investigated the association of serotype-specific capsular IgG in the mother and risk reduction of invasive Group B Streptococcus (GBS) in their young infants. The efficiency of transplacental transfer of IgG could be affected by multiple maternal factors. Hence, investigation of infant serum GBS anti-capsular IgG and risk reduction for invasive GBS disease may be more robust and generalizable. In a matched case-control study, infant serum serotype-specific capsular polysaccharide Ia and III IgG concentrations were analyzed in infants with invasive GBS cases and healthy controls born to women with recto-vaginal colonization by the homotypic serotype. Using Bayesian modeling, an antibody concentration of 2.5 µg/mL and 1 µg/mL predicted a 90% reduced risk of invasive disease for serotype Ia and III, respectively. These data contribute to the possible licensure of a GBS polysaccharide-protein conjugate vaccine, targeted at pregnant women, based on serological correlates of protection against invasive GBS disease.

Background Data are limited regarding long-term consequences of invasive GBS (iGBS) disease in early infancy, especially from low- and middle-income countries (LMIC) where most cases occur. We aimed to estimate risk of neurodevelopmental impairment (NDI) in children with a history of iGBS disease. Methods A multi-country matched cohort study was undertaken in South Africa, India, Mozambique, Kenya, and Argentina from October 2019 to April 2021. The exposure of interest was defined as a history of iGBS disease (sepsis or meningitis) before 90 days of age, amongst children now aged 1·5–18 years. Age and sex-matched, children without history of GBS were also recruited. Age-appropriate, culturally-adapted assessments were used to define NDI across multiple domains (cognitive, motor, hearing, vision, emotional-behaviour, growth). Pooled NDI risk was meta-analysed across sites. Association of iGBS exposure and NDI outcome was estimated using modified Poisson regression with robust variance estimator. Findings Amongst 138 iGBS survivors and 390 non-iGBS children, 38·1% (95% confidence interval [CI]: 30·0% – 46·6%) of iGBS children had any NDI, compared to 21·7% (95% CI: 17·7% - 26·0%) of non- iGBS children, with notable between-site heterogeneity. Risk of moderate/severe NDI was 15·0% (95% CI: 3·4% - 30·8%) among GBS-meningitis, 5·6% (95% CI: 1·5% - 13·7%) for GBS-sepsis survivors. The adjusted risk ratio (aRR) for moderate/severe NDI among iGBS survivors was 1.27 (95% CI: 0.65, 2.45), when compared to non-GBS children. Mild impairment was more frequent in iGBS (27.6% (95% CI: 20.3 – 35.5%)) compared to non-GBS children (12.9% (95% CI: 9.7% - 16.4%)). The risk of emotional-behavioural problems was similar irrespective of iGBS exposure (aRR=0.98 (95% CI: 0.55, 1.77)). Interpretation Our findings suggest that iGBS disease is on average associated with a higher risk of moderate/severe NDI, however substantial variation in risk was observed between sites and data are consistent with a wide range of values. Our study underlines the importance of long-term follow-up for at-risk neonates and more feasible, standardised assessments to facilitate diagnosis in research and clinical practice. Funding This work was supported by a grant (INV-009018) from the Bill & Melinda Gates Foundation to the London School of Hygiene & Tropical Medicine.

Background: Group B streptococcus (GBS) colonisation during pregnancy can lead to invasive GBS disease (iGBS) in infants, including meningitis or sepsis, with a high mortality risk. Other outcomes include stillbirths, maternal infections, and prematurity. There are data gaps, notably regarding neurodevelopmental impairment (NDI), especially after iGBS sepsis, which have limited previous global estimates. In this study, we aimed to address this gap using newly available multicountry datasets. Methods: We collated and meta-analysed summary data, primarily identified in a series of systematic reviews published in 2017 but also from recent studies on NDI and stillbirths, using Bayesian hierarchical models, and estimated the burden for 183 countries in 2020 regarding: maternal GBS colonisation, iGBS cases and deaths in infants younger than 3 months, children surviving iGBS affected by NDI, and maternal iGBS cases. We analysed the proportion of stillbirths with GBS and applied this to the UN-estimated stillbirth risk per country. Excess preterm births associated with maternal GBS colonisation were calculated using meta-analysis and national preterm birth rates. Findings: Data from the seven systematic reviews, published in 2017, that informed the previous burden estimation (a total of 515 data points) were combined with new data (17 data points) from large multicountry studies on neurodevelopmental impairment (two studies) and stillbirths (one study). A posterior median of 19·7 million (95% posterior interval 17·9–21·9) pregnant women were estimated to have rectovaginal colonisation with GBS in 2020. 231 800 (114 100–455 000) early-onset and 162 200 (70 200–394 400) late-onset infant iGBS cases were estimated to have occurred. In an analysis assuming a higher case fatality rate in the absence of a skilled birth attendant, 91 900 (44 800–187 800) iGBS infant deaths were estimated; in an analysis without this assumption, 58 300 (26 500–125 800) infant deaths from iGBS were estimated. 37 100 children who recovered from iGBS (14 600–96 200) were predicted to develop moderate or severe NDI. 40 500 (21 500–66 200) maternal iGBS cases and 46 200 (20 300–111 300) GBS stillbirths were predicted in 2020. GBS colonisation was also estimated to be potentially associated with considerable numbers of preterm births. Interpretation: Our analysis provides a comprehensive assessment of the pregnancy-related GBS burden. The Bayesian approach enabled coherent propagation of uncertainty, which is considerable, notably regarding GBS-associated preterm births. Our findings on both the acute and long-term consequences of iGBS have public health implications for understanding the value of investment in maternal GBS immunisation and other preventive strategies. Funding: Bill & Melinda Gates Foundation.

- Label: BACKGROUND NlmCategory: BACKGROUND content: "Sub-Saharan Africa and south Asia contributed 81% of 5\xC2\xB79 million under-5 deaths and 77% of 2\xC2\xB76 million stillbirths worldwide in 2015. Vital registration and verbal autopsy data are mainstays for the estimation of leading causes of death, but both are non-specific and focus on a single underlying cause. We aimed to provide granular data on the contributory causes of death in stillborn fetuses and in deceased neonates and children younger than 5 years, to inform child mortality prevention efforts." - Label: METHODS NlmCategory: METHODS content: "The Child Health and Mortality Prevention Surveillance (CHAMPS) Network was established at sites in seven countries (Baliakandi, Bangladesh; Harar and Kersa, Ethiopia; Siaya and Kisumu, Kenya; Bamako, Mali; Manhi\xC3\xA7a, Mozambique; Bombali, Sierra Leone; and Soweto, South Africa) to collect standardised, population-based, longitudinal data on under-5 mortality and stillbirths in sub-Saharan Africa and south Asia, to improve the accuracy of determining causes of death. Here, we analysed data obtained in the first 2 years after the implementation of CHAMPS at the first five operational sites, during which surveillance and post-mortem diagnostics, including minimally invasive tissue sampling (MITS), were used. Data were abstracted from all available clinical records of deceased children, and relevant maternal health records were also extracted for stillbirths and neonatal deaths, to incorporate reported pregnancy or delivery complications. Expert panels followed standardised procedures to characterise causal chains leading to death, including underlying, intermediate (comorbid or antecedent causes), and immediate causes of death for stillbirths, neonatal deaths, and child (age 1-59 months) deaths." - Label: FINDINGS NlmCategory: RESULTS content: Between Dec 10, 2016, and Dec 31, 2018, MITS procedures were implemented at five sites in Mozambique, South Africa, Kenya, Mali, and Bangladesh. We screened 2385 death notifications for inclusion eligibility, following which 1295 families were approached for consent; consent was provided for MITS by 963 (74%) of 1295 eligible cases approached. At least one cause of death was identified in 912 (98%) of 933 cases (180 stillbirths, 449 neonatal deaths, and 304 child deaths); two or more conditions were identified in the causal chain for 585 (63%) of 933 cases. The most common underlying causes of stillbirth were perinatal asphyxia or hypoxia (130 [72%] of 180 stillbirths) and congenital infection or sepsis (27 [15%]). The most common underlying causes of neonatal death were preterm birth complications (187 [42%] of 449 neonatal deaths), perinatal asphyxia or hypoxia (98 [22%]), and neonatal sepsis (50 [11%]). The most common underlying causes of child deaths were congenital birth defects (39 [13%] of 304 deaths), lower respiratory infection (37 [12%]), and HIV (35 [12%]). In 503 (54%) of 933 cases, at least one contributory pathogen was identified. Cytomegalovirus, Escherichia coli, group B Streptococcus, and other infections contributed to 30 (17%) of 180 stillbirths. Among neonatal deaths with underlying prematurity, 60% were precipitated by other infectious causes. Of the 275 child deaths with infectious causes, the most common contributory pathogens were Klebsiella pneumoniae (86 [31%]), Streptococcus pneumoniae (54 [20%]), HIV (40 [15%]), and cytomegalovirus (34 [12%]), and multiple infections were common. Lower respiratory tract infection contributed to 174 (57%) of 304 child deaths. - Label: INTERPRETATION NlmCategory: CONCLUSIONS content: Cause of death determination using MITS enabled detailed characterisation of contributing conditions. Global estimates of child mortality aetiologies, which are currently based on a single syndromic cause for each death, will be strengthened by findings from CHAMPS. This approach adds specificity and provides a more complete overview of the chain of events leading to death, highlighting multiple potential interventions to prevent under-5 mortality and stillbirths. - Label: FUNDING NlmCategory: BACKGROUND content: Bill & Melinda Gates Foundation.

Background Invasive group B Streptococcus (iGBS) sepsis and meningitis are important causes of child mortality, but studies on neurodevelopmental impairment (NDI) after iGBS are limited. Using Griffiths Mental Development Scales–Extended Revised (GMDS-ER), we described NDI in iGBS survivors and non-iGBS children from South Africa, as part of a 5-country study. Methods We identified children aged 5–8 years with a history of iGBS and children with no history of iGBS between October 2019 and January 2021. Children were matched on sex, and birth data (month, year) (matched cohort study). Moderate or Severe NDI was the primary outcome as a composite of GMDS-ER motor, GMDS-ER cognition, hearing, and vision. Secondary outcomes included mild NDI, any emotional-behavioral problems, and GMDS-ER developmental quotients (DQ) calculated by dividing the age equivalent GMDS-ER score by the chronological age. Results In total, 160 children (iGBS survivors, 43; non-iGBS, 117) were assessed. Among iGBS survivors 13 (30.2%) had meningitis, and 30 (69.8%) had sepsis. Six (13.9%) iGBS survivors, and 5 (4.3%) non-iGBS children had moderate or severe NDI. Children who survived iGBS were 5.56 (95% confidence interval [CI]: 1.07–28.93; P = .041) times more likely to have moderate or severe NDI at 5–8 years than non-iGBS children. Compared to the non-iGBS children, iGBS meningitis survivors had a significantly lower global median DQ (P Conclusions Children surviving iGBS, particularly meningitis, are more likely to have NDI at 5–8 years compared to non-iGBS children. Further research is required to improve detection and care for at-risk newborns.

Background Sepsis and meningitis are among the leading causes of neonatal deaths in sub-Saharan Africa (SSA). Neonatal sepsis caused ~400 000 deaths globally in 2015, half occurring in Africa. Despite this, there are few published data on the acute costs of neonatal sepsis or meningitis, with none in SSA. Methods We enrolled neonates admitted to 2 hospitals in South Africa and Mozambique between 16 April 2020 and 1 April 2021. In South Africa all cases were microbiologically confirmed, but in Mozambique both clinically suspected and microbiologically confirmed cases were included. Data were collected on healthcare resource use and length of stay, along with information on household expenditure and caregiving. We used unit costs of healthcare resources in local currencies to estimate healthcare provider costs per patient and costs per household. Results were converted to 2019 international dollars (I$). Results We enrolled 11 neonates in Mozambique and 18 neonates in South Africa. Mean length of stay was 10 days (median, 9 [interquartile range {IQR}, 4–14) and 16 days (median, 15 [IQR, 13–18]), respectively. In Mozambique we estimated mean household costs of I$49.62 (median, 10.19 [IQR, 5.10–95.12]) and hospitalization costs of I$307.58 (median, 275.12 [IQR, 149.43–386.12]). In South Africa these costs were I$52.31 (median, 30.82 [IQR, 19.25–73.08]) and I$684.06 (median, 653.62 [IQR, 543.33–827.53]), respectively. Conclusions We found substantial costs associated with acute neonatal bacterial (all-cause) sepsis and meningitis in SSA. Our estimates will inform economic evaluations of interventions to prevent neonatal invasive bacterial infections.

BackgroundHousehold contact tracing for tuberculosis (TB) may facilitate TB diagnosis and identify individuals who may benefit from TB preventive therapy (TPT). In this cluster-randomised trial, we investigated whether household contact tracing and intensive TB/HIV screening would improve TB-free survival.MethodsHousehold contacts of index TB patients in two Provinces of South Africa were randomised to home tracing and intensive HIV/TB screening (sputum Xpert and culture; HIV testing with treatment linkage; and TPT, if eligible), or standard of care (SOC, clinic referral letters). The primary outcome was incident TB or death at 15-months. Secondary outcomes included tuberculin skin test (TST) positivity in children ≤14 years and undiagnosed HIV. (ISRCTN16006202).ResultsFrom December 2016-March 2019, 1,032 index patients (4,459 contacts) and 1,030 (4,129 contacts) were randomised to the intervention and SOC arms. 3.2% (69/2166) of intervention arm contacts had prevalent microbiologically-confirmed TB. At 15-months, the cumulative incidence of TB or death did not differ between the intensive screening (93/3230, 2.9%) and SOC (80/2600, 3.1%) arms (hazard ratio: 0.90, 95% confidence interval (CI): 0.66-1.24). TST positivity was higher in the intensive screening arm (38/845, 4.5%) compared to the SOC arm (15/800, 1.9%, odds ratio: 2.25, 95% CI: 1.07-4.72). Undiagnosed HIV was similar between arms (41/3185, 1.3% vs. 32/2543, 1.3%; odds ratio: 1.02, 95% CI: 0.64-1.64).ConclusionsHousehold contact tracing with intensive screening and referral did not reduce incident TB or death. Providing referral letters to household contacts of index patients is an alternative strategy to home visits in high TB/HIV-prevalence settings.Author SummaryIn South Africa, household contacts of TB cases received referral letters or home-tracing with intensified TB/HIV screening. At 15-months, the cumulative incidence of TB or death did not differ between the intensive screening (93/3230, 2.9%) and SOC (80/2600, 3.1%) arms.

Background Household contact tracing for tuberculosis (TB) may facilitate diagnosis and access to TB preventive treatment (TPT). We investigated whether household contact tracing and intensive TB/human immunodeficiency virus (HIV) screening would improve TB-free survival. Methods Household contacts of index TB patients in 2 South African provinces were randomized to home tracing and intensive HIV/TB screening or standard of care (SOC; clinic referral letters). The primary outcome was incident TB or death at 15 months. Secondary outcomes included tuberculin skin test (TST) positivity in children ≤14 years and undiagnosed HIV. Results From December 2016 through March 2019, 1032 index patients (4459 contacts) and 1030 (4129 contacts) were randomized to the intervention and SOC arms. Of intervention arm contacts, 3.2% (69 of 2166) had prevalent microbiologically confirmed TB. At 15 months, the cumulative incidence of TB or death did not differ between the intensive screening (93 of 3230, 2.9%) and SOC (80 of 2600, 3.1%) arms (hazard ratio, 0.90; 95% confidence interval [CI], .66–1.24). TST positivity was higher in the intensive screening arm (38 of 845, 4.5%) compared with the SOC arm (15 of 800, 1.9%; odds ratio, 2.25; 95% CI, 1.07–4.72). Undiagnosed HIV was similar between arms (41 of 3185, 1.3% vs 32 of 2543, 1.3%; odds ratio, 1.02; 95% CI, .64–1.64). Conclusions Household contact tracing with intensive screening and referral did not reduce incident TB or death. Providing referral letters to household contacts of index patients is an alternative strategy to home visits. Clinical Trials Registration ISRCTN16006202.

We evaluated the association between early-onset sepsis and neonatal encephalopathy in a low-middle-income setting.We undertook a retrospective study in newborns with gestational age ≥35 weeks and/or birth weight ≥2500 grams, diagnosed with neonatal encephalopathy. Early-onset sepsis was defined as culture-confirmed sepsis or probable sepsis.Of 10,182 hospitalised newborns, 1027 (10.1%) were diagnosed with neonatal encephalopathy, of whom 52 (5.1%) had culture-confirmed and 129 (12.5%) probable sepsis. The case fatality rate for culture-confirmed sepsis associated neonatal encephalopathy was threefold higher compared to neonatal encephalopathy without sepsis (30.8% vs. 10.5%, p 0.001). Predictors of mortality for culture-confirmed sepsis associated neonatal encephalopathy included severe neonatal encephalopathy (aOR 6.51, 95%CI: 1.03-41.44) and seizures (aOR 10.64, 95%CI: 1.05-107.39).In this setting, 5% of neonatal encephalopathy cases was associated with culture-confirmed sepsis and a high case fatality rate.

Background Both pregnancy and human immunodeficiency virus (HIV) increase the risk of tuberculosis disease, which results in poor maternal, pregnancy, and infant outcomes. Isoniazid preventive therapy (IPT) reduces mortality among individuals living with HIV in high-burden settings but has recently been associated with adverse pregnancy outcomes when initiated during pregnancy. Methods In this secondary analysis, we used multivariable logistic regression to evaluate the association between IPT exposure and adverse pregnancy outcomes (fetal demise, prematurity, low birth weight, congenital anomaly) in pregnant women living with HIV enrolled as controls in the Tshepiso study, a prospective observational cohort of pregnant women living with HIV with and without tuberculosis disease in Soweto, South Africa, from 2011–2014. Results There were 151 women enrolled with known pregnancy outcomes; 69 (46%) reported IPT initiation during pregnancy. Of the 69 IPT-exposed women, 11 (16%) had an adverse pregnancy outcome compared with 23 (28%) IPT-unexposed women. The adjusted odds of having an adverse pregnancy outcome was 2.5 (95% confidence interval, 1.0–6.5; P = .048) times higher in IPT-unexposed women compared with IPT-exposed women after controlling for maternal age, CD4 count, viral load, antiretroviral regimen, body mass index, and anemia. Conclusions IPT exposure during pregnancy was not negatively associated with pregnancy outcomes after controlling for demographic, clinical, and HIV-related factors. These results provide some reassurance that IPT can be safely used in the second or third trimester of pregnancy. Additional research is needed to evaluate the safety of IPT and new short-course tuberculosis preventive therapies during pregnancy., In this secondary analysis of pregnant women living human immunodeficiency virus (HIV) with and without isoniazid exposure for tuberculosis prevention during pregnancy, we did not observe a negative association between isoniazid preventive therapy use and pregnancy outcomes after controlling for demographic, clinical, and HIV-related confounding factors.

Videos are increasingly being used for teaching clinical skills in medical education. However, most reports on the effectiveness and benefits of videos in medical teaching have come from developed countries. Resource constraints in South African academic hospitals, together with increasing numbers, may apply pressure on the standard of clinical teaching. This study investigated the potential for using video demonstrations to replace the bedside teaching of introductory paediatric clinical examination skills to large groups of medical students. Sixty medical students were randomised to an experimental group that watched a video of a paediatric abdominal examination or to a control group that received a bedside tutorial on the same topic. Immediately afterwards, experienced assessors observed and scored the students in a clinical examination. Data were analysed for the non-inferiority of the video group scores within a 10% margin of the bedside group. Students’ and clinician educators’ perceptions of the two teaching methods and their views on how video instruction could be integrated into the clinical teaching programme were explored. Qualitative data were analysed thematically. The video teaching was non-inferior to the bedside teaching within the 10% margin and did not significantly affect the pass/fail or distinction rates. Students and clinician educators suggested that the videos be used for teaching basic concepts, allowing bedside tutorials to focus on applied learning. The findings have important implications for using video demonstrations to supplement the teaching of clinical skills to large groups of medical students across multiple variably-resourced settings.

Diarrheal disease is a leading cause of childhood morbidity and mortality worldwide. Multiple interventions, including rotavirus vaccination to infants since 2009, have reduced the incidence of diarrheal disease in South African children. Our study aimed to determine the burden of diarrheal disease 5 years after rotavirus vaccine introduction at a tertiary-level hospital.A retrospective review of a discharge summary database of children less than 5 years of age hospitalized with acute diarrheal illness from 2015 to 2016 at the Chris Hani Baragwanath Academic Hospital.Diarrheal disease accounted for 14.8% of hospital admissions. The incidence (per 100,000 population) was 675.8 (95% CI: 638.8-714.3) in 2015 and 612.2 (95% CI: 577.0-648.9) in 2016. The case fatality ratio was 2.9% over the study period. The median age at diagnosis was 12 months (interquartile range: 6.2-21.4) and 50.4% of cases occurred during infancy. One third of cases were underweight and/or stunted. In a multivariable analysis using logistic regression, the adjusted odds ratio (aOR) for death was higher in children with an associated acute lower respiratory tract infection (aOR: 3.7, 95% CI: 1.2-11.5; P = 0.021), HIV infection (aOR: 9.1, 95% CI: 2.6-31.6; P = 0.001), and an age of less than 6 months (aOR: 6.9, 95% CI: 2.1-22.9; P = 0.002).Sustained reductions in diarrheal disease incidence were observed 5 years post rotavirus vaccine implementation. In children hospitalized with an acute diarrheal illness, an increased risk of mortality occurs in young infants, children that are HIV infected, and those with an associated acute lower respiratory tract infection.

Background. There is a paucity of data on the aetiology of neonatal sepsis in sub-Saharan Africa. Objectives. To investigate the incidence, aetiology and outcomes of physician-diagnosed sepsis in hospitalised neonates who had previously been discharged home after delivery in Soweto, South Africa. Methods. A retrospective review using data abstracted from clinical and laboratory databases identified physician-diagnosed sepsis cases in neonates admitted to the general paediatric wards at Chris Hani Baragwanath Academic Hospital from January 2015 to September 2016. Neonates with physician-diagnosed sepsis were categorised into two groups based on putative pathogens recovered from blood and/or cerebrospinal fluid specimens: ( i ) culture-confirmed sepsis; and ( ii ) culture-negative sepsis. Results. Of 1 826 neonatal admissions, 1 025 (56.2%) had physician-diagnosed sepsis: 166 (16.2%) with culture-confirmed sepsis and 859 (83.8%) with culture-negative neonatal sepsis. The commonest pathogens causing culture-confirmed neonatal sepsis were Streptococcus viridans ( n =53; 26.5%), S. agalactiae ( n =38; 19.0%), and Staphylococcus aureus ( n =25; 12.5%). The case fatality rates for culture-confirmed sepsis and culture-negative sepsis were 10.8% (18/166) and 2.6% (22/859), respectively. The odds of death occurring during hospitalisation was 10-fold (95% confidence interval 3.7 - 26.9) higher in neonates with culture-confirmed sepsis compared with culture-negative sepsis. Conclusions. In our setting, physician-diagnosed sepsis represents a huge disease burden in previously healthy neonates hospitalised from home. Most sepsis cases were attributed to S. viridans , S. agalactiae and S. aureus .

BACKGROUND Invasive group B streptococcal (GBS) disease causes considerable morbidity and mortality in young infants, and 18% of GBS-meningitis survivors have moderate-to-severe neurodevelopmental impairment. However, there is a paucity of data regarding neurologic impairment following GBS sepsis. METHODS A case-control study was undertaken in infants at 3 secondary-tertiary hospitals in Johannesburg, South Africa. Neurodevelopmental assessments were done at 1 year of age using the Denver II Developmental screening tool. A case was defined as isolation of GBS from blood or cerebrospinal fluid in infants less than 90 days of age. Three healthy controls (range: 1-6) were matched to maternal age, maternal HIV-infection status, gestational age and timing of enrollment. RESULTS Of 122 invasive GBS cases, 78 (63.9%) had sepsis and 44 (36.1%) meningitis. Twenty-two (18%) invasive GBS cases (17 of 78; 21.8% with sepsis and 5 of 44; 11.4% with meningitis) died during the course of hospitalization, and a further 2 (1.6%; 1 sepsis and 1 meningitis case) died by 1 year of age. Five (1.1%) of 449 controls died by 1 year of age. Of the 45 GBS sepsis cases and 141 matched controls followed through to 1 year of age, 11 (24.4%) cases (3 with moderate-to-severe impairment) and 10 (7.1%) controls had an abnormal Denver score with an adjusted (for gender) odds ratio of 3.51; 95% confidence interval (CI): 1.23-10.04; P = 0.019. Four (20%) of the 20 GBS meningitis cases compared with 1 (1.5%) control had neurologic impairment at 1-year of age (aOR: 8.29; 95% CI: 0.88-78.3; P = 0.065) CONCLUSION:: In this setting, invasive GBS disease is associated with a high mortality. Infant survivors of invasive GBS sepsis compared with controls had 3.5-fold greater odds of neurologic impairment by 1 year of age. This corroborates the need for strategies to prevent invasive GBS disease.

IntroductionHousehold contacts of patients with active pulmonary tuberculosis (TB) often have latent TB infection, and are at risk of progression to disease. We set out to investigate whether index TB case HIV status was linked to a higher probability of latent TB infection among household contacts.Materials and methodsData were collected prospectively from participants in the intervention arm of a household cluster-randomised trial in two South Africa provinces (Mangaung, Free State, and Capricorn, Limpopo). In intervention group households, TB contacts underwent HIV testing and tuberculin skin testing (TST). TST induration was estimated at two cut-offs (≥5mm, ≥10mm). Multilevel Bayesian regression models estimated posterior distributions of the percentage of household contacts with TST induration ≥5mm and ≥10mm by age group, and compared the odds of latent TB infection by key risk factors including HIV status index case age and study province.ResultsA total of 2,985 household contacts of 924 index cases were assessed, with most 2,725 (91.3%) undergoing TST. HIV prevalence in household contacts was 14% and 10% in Mangaung and Capricorn respectively. Overall, 16.8% (458/2,725) had TST induration of ≥5mm and 13.1% (359/2,725) ≥10mm. In Mangaung, children aged 0-4 years had a high TST positivity prevalence compared to their peers in Capricorn (22.0% vs. 7.6%, and 20.5% vs. 2.3%, using TST thresholds of ≥5mm and ≥10mm respectively). Compared to contacts from Capricorn, household contacts living in Mangaung were more likely to have TST induration ≥5mm (odds ratio [OR]: 3.08, 95% credibility interval [CI]: 2.13-4.58) and ≥10mm (OR: 4.52, 95% CI: 3.03-6.97). There was a 90% and 92% posterior probability that the odds of TST induration ≥5mm (OR: 0.79, 95% CI: 0.56-1.14) and ≥10mm (OR: 0.77, 95% CI: 0.53-1.10) respectively were lower in household contacts of HIV-positive compared to HIV-negative index cases.ConclusionsHigh TST induration positivity, especially among young children and people living in Mangaung indicates considerable TB transmission despite high antiretroviral therapy coverage. Household contact of HIV-positive index TB cases were less likely to have evidence of latent TB infection than contacts of HIV-negative index cases.

Sepsis and meningitis due to invasive group B Streptococcus (iGBS) disease during early infancy is a leading cause of child mortality. Recent systematic estimates of the worldwide burden of GBS suggested that there are 319,000 cases of infant iGBS disease each year, and an estimated 147,000 stillbirths and young-infant deaths, with the highest burden occurring in Sub-Saharan Africa. The following priority data gaps were highlighted: (1) long-term outcome data after infant iGBS, including mild disability, to calculate quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs) and (2) economic burden for iGBS survivors and their families. Geographic data gaps were also noted with few studies from low- and middle- income countries (LMIC), where the GBS burden is estimated to be the highest. In this paper we present the protocol for a multi-country matched cohort study designed to estimate the risk of long-term neurodevelopmental impairment (NDI), socioemotional behaviors, and economic outcomes for children who survive invasive GBS disease in Argentina, India, Kenya, Mozambique, and South Africa. Children will be identified from health demographic surveillance systems, hospital records, and among participants of previous epidemiological studies. The children will be aged between 18 months to 17 years. A tablet-based custom-designed application will be used to capture data from direct assessment of the child and interviews with the main caregiver. In addition, a parallel sub-study will prospectively measure the acute costs of hospitalization due to neonatal sepsis or meningitis, irrespective of underlying etiology. In summary, these data are necessary to characterize the consequences of iGBS disease and enable the advancement of effective strategies for survivors to reach their developmental and economic potential. In particular, our study will inform the development of a full public health value proposition on maternal GBS immunization that is being coordinated by the World Health Organization.

BACKGROUND: Before the wide availability of antiretroviral therapy (ART), tuberculosis and human immunodeficiency virus (HIV) disease among pregnant women resulted in poor maternal and neonatal outcomes, including high rates of mother-to-child transmission of both HIV and tuberculosis. We aimed to describe the impact of tuberculosis among HIV-infected mothers on obstetric and infant outcomes in a population with access to ART. METHODS: In this prospective cohort study, we followed up HIV-infected pregnant women with or without tuberculosis disease from January 2011 through January 2014 in Soweto, South Africa. Two controls were enrolled for each case patient, matched by enrollment time, maternal age, gestational age, and planned delivery clinic and followed up for 12 months after delivery. RESULTS: We recruited 80 case patients and 155 controls, resulting in 224 live-born infants. Infants of mothers with HIV infection and tuberculosis disease had a higher risk of low birth weight (20.8% vs 10.7%; P = .04), prolonged hospitalization at birth (51% vs 16%; P < .001), infant death (68 vs 7 deaths per 1000 births; P < .001), and tuberculosis disease (12% vs 0%; P < .001) despite appropriate maternal therapy and infant tuberculosis preventive therapy. HIV transmission was higher among these infants (4.1% vs 1.3%; P = .20), though this difference was not statistically significant. Obstetric outcomes in coinfected women were also poorer with higher risks of maternal hospitalization (25% vs 11%; P = .005) and preeclampsia (5.5% vs 0.7%; P = .03). CONCLUSIONS: Tuberculosis in HIV coinfected pregnant women remains a significant threat to the health of both mothers and infants. Improving tuberculosis prevention and early diagnosis among pregnant women is critical.

Background Household contact tracing of index TB cases has been advocated as a key part of TB control for many years, but has not been widely implemented in many low-resource setting because of the current dearth of high quality evidence for effectiveness. Innovative strategies for earlier, more effective treatment are particularly important in contexts with hyper-endemic levels of HIV, where levels of TB infection remain extremely high. Methods We present the design of a household cluster-randomised controlled trial of interventions aimed at improving TB-free survival and reducing childhood prevalence of Mycobacterium tuberculosis infection among household contacts of index TB cases diagnosed in two provinces of South Africa. Households of index TB cases will be randomly allocated in a 1:1 ratio to receive either an intensified home screening and linkage for TB and HIV intervention, or enhanced standard of care. The primary outcome will compare between groups the TB-free survival of household contacts over 15 months. All participants, or their next-of-kin, will provide written informed consent to participate. Discussion Evidence from randomised trials is required to identify cost-effective approaches to TB case-finding that can be applied at scale in sub-Saharan Africa. Trial registration ISRCTN16006202 (01/02/2017: retrospectively registered) and NHREC4399 (11/04/2016: prospectively registered). Protocol version: 4.0 (date: 18th January 2018).

Chylothorax is rare in children. Only a few cases of tuberculosis (TB)-associated chylothorax have been reported. We present a child on standard four-drug TB treatment who presented with wheezing and a chylothorax. Bronchoscopy showed caseating lymph nodes, and rifampicin-resistant TB was identified from the bronchoalveolar lavage specimen. There was marked clinical and radiological improvement 1 month after starting multidrug-resistant (MDR) TB treatment and steroids. The association of chylothorax and MDR-TB has not been described in children. MDR-TB should be considered in children who fail adherent, empirically started drug-susceptible TB treatment.

Background Animal-model studies have demonstrated less group B streptococcal (GBS) invasive disease and gastrointestinal colonization after enteral administration of serotype-specific capsular antibodies. There is, however, a paucity of information on the association of breast milk GBS serotype-specific capsular antibodies and risks for invasive disease in infants. The aim of this study was to explore the association between natural secretory immunoglobulin A (sIgA) capsular antibodies in breast milk and the occurrence of late-onset disease (LOD) in young infants. Methods A matched case-control study was undertaken in infants Results Breast milk samples were available for 31 LOD cases (8 serotype Ia and 23 serotype III), 21 recto-vaginally colonized matched controls (10 serotype Ia and 11 serotype III), and 84 serotype Ia and 105 serotype III noncolonized matched controls. Using a Bayesian model to estimate the probability of disease, there were 90% reductions in the risks of developing serotypes Ia and III LOD with sIgA concentrations ≥0.14 µg/mL and ≥2.52 µg/mL, respectively. Conclusions Breast milk sIgA capsular antibodies were associated with lower risks for LOD in young infants. The ability of GBS polysaccharide-protein conjugate vaccines currently under development to induce sIgA responses warrant investigation as potential mediators of protection against LOD.

Background. Hospital discharge summaries are deemed to be an essential part of the medical record in South Africa, but formal assessment of their quality is rarely undertaken. At Chris Hani Baragwanath Academic Hospital (CHBAH) in Johannesburg, medical admission notes (bedletters) are difficult to retrieve from the hospital archives and the discharge summary is often the only readily available medical record that documents details of the hospital admission. Objectives. To determine the proportion of discharge summaries that were appropriately completed for children admitted to the general paediatric wards at CHBAH. Methods. A retrospective review of discharge summaries completed for children admitted from 1 May to 31 July 2016 was undertaken. The completeness of the following demographic and clinical variables was assessed: patient identifiers, hospital outcome, HIV infection status and anthropometric status. The documentation of correct International Statistical Classification of Diseases and Related Health Problems , 10th revision (ICD-10) codes was assessed in children diagnosed with any form of lower respiratory tract infection (LRTI), which is the commonest diagnosis recorded in hospitalised children at CHBAH. Results. Discharge summaries were available for 1 148 (78.3%) of 1 466 children admitted during the study period. For completed discharge summaries, 80.1 - 93.3% of patient identifiers and 91.4% of patient outcomes were appropriately completed. HIV exposure was documented in 84.7% of summaries. Anthropometric parameters, including weight and length/height at admission and discharge weight, were appropriately completed in 91.4%, 70.9% and 50.0% of summaries, respectively. The ICD-10 code for children with LRTI was appropriately recorded by medical staff in 338 (67.2%) of 503 cases. ICD‑10 codes and anthropometric parameters, which are important clinical parameters in the paediatric follow-up consultation, were both correctly recorded for only 21.6% of children who required follow-up clinical consultations at CHBAH. Conclusions. Compared with similar studies, both the rate of completion and the quality of completed discharge summaries were modest in this tertiary academic teaching hospital. As discharge summaries are crucial medical documents, interventions to improve their completeness rate and quality need to be developed.

Purpose of review Maternal vaccination to prevent invasive Group B Streptococcus (GBS) disease in infants is an important alternative strategy to intrapartum antibiotic prophylaxis. Licensure of GBS vaccines could be expedited using immunological correlates of protection. Recent findings Between 2014 and 2015, we identified two studies that demonstrated an inverse association between invasive GBS disease and maternal serotype III capsular antibody levels greater than 1 μg/ml and greater than 3 μg/ml, and higher maternal antibody levels were associated with protection against serotype Ia disease. Furthermore, serotype Ia and III antibody levels greater than 3 μg/ml were associated with a reduced risk of GBS colonization in pregnant women.Experimental studies have investigated the use of GBS surface proteins as vaccine candidates. Although the immunogenic potential of pilus island and other surface proteins has been shown in animal-model studies, no association between maternal pilus island antibody levels and invasive GBS disease was demonstrated in infants. Additionally, several novel innate immune mediators that prevent GBS infection have been described in human and experimental studies. Summary Recent studies suggest that maternal capsular antibody thresholds may be used as immunological correlates of protection for vaccine licensure. Surface proteins, as candidate vaccines or conjugates to the polysaccharide-protein vaccine, may broaden protection against invasive GBS disease.

BACKGROUND. There is a paucity of information on empyema in children from low- and middle-income countries since the introduction of the pneumococcal conjugate vaccine. OBJECTIVES. To describe the aetiology and management of empyema in a setting of high HIV and tuberculosis (ih) prevalence. METHODS. A retrospective descriptive study was undertaken between January 2012 and December 2016 in children aged < 14 years at a large secondary-tertiary referral hospital in Soweto, South Africa. Cases of empyema were identified through administrative databases. Clinical, laboratory and radiological data were extracted from patient records. RESULTS. We identified 65 cases of protocol-defined empyema, including 22 (33.8%) referred from surrounding hospitals. The median age at presentation was 53.2 months (interquartile range (IQR) 19.5 - 103.6). Thirteen patients (20.0%) were HIV-infected and 6 (9.2%) were HIVexposed but uninfected. A bacterial pathogen was identified in 36 cases (55.3%). The commonest causative organisms were Staphylococcus aureus (14/65, 21.5%) and Streptococcus pneumoniae (5/65, 7.7%). Treatment for ih, initiated in 28 children (43.1%), was more frequent in HIV-infected children (10/13, 76.9%) (p=0.011); however, microbiological evidence of TB was present in only 5 cases (7.7%). Forty-three children (66.2%) had an intercostal drain (ICD) inserted and 16 (24.6%) a pigtail percutaneous catheter, while a fibrinolytic was only used in 6 (10.2%). Eight children (12.3%) had a thoracotomy and 7 (10.7%) had video-assisted thorascopic drainage, all of whom had a prior ICD inserted, a median of 20 days (IQR 10 - 33) before surgery. Overall, 7 children (10.8%) were mechanically ventilated and 1 (1.5%) died. CONCLUSIONS. Our study showed a dominance of S. aureus as a cause of empyema. A high proportion of HIV-infected children with empyema were initiated on ih treatment, highlighting challenges in managing ih-HIV co-infection. Although fibrinolytics or early surgery are recommended, neither practice was common in this setting.

Background Vaccinating pregnant women may prevent invasive Group B Streptococcus (GBS) disease in their young infants. In a low-middle income setting, we sought to determine an association between natural maternal antibody responses and the development of invasive GBS disease. Methods We undertook a matched case-control study in Johannesburg, South Africa. Maternal and infant antibody concentrations were compared between serotype-specific Ia and III GBS cases and well-baby controls in which the mother was colonized with the same serotype. Results The median maternal serotype Ia and III antibody concentrations (in μg/mL) were 0.05 (IQR: 0.02–0.24; n = 27) and 0.14 (IQR: 0.08–0.33; n = 29) in cases, and 0.29 (IQR: 0.06–1.60; n = 43) and 0.29 (IQR: 0.13–0.58; n = 31) in homotypic controls, respectively. A smaller proportion of cases as compared to homotypic controls had higher serotype Ia and III maternal antibody concentrations. Using Bayesian modeling, we demonstrated that the risk of invasive GBS disease was less than 10% with maternal antibody concentrations ≥6 μg/mL and ≥3 μg/mL for serotypes Ia and III, respectively. Conclusions Maternal capsular antibody concentrations are associated with the risk of invasive GBS disease in infants. In a low-middle income setting with a high burden of invasive disease, we have demonstrated a sero-correlate of protection for GBS serotypes Ia and III which could facilitate vaccine licensure.

Group B Streptococcus (GBS) surface-proteins have been shown to be immunogenic and potential vaccine candidates. We aim to determine the association between maternal IgG antibodies to select GBS surface-proteins and invasive GBS disease in their infants.Using a matched case-control study, maternal antibody levels for GBS-immunogenic bacterial adhesin, fibrinogen-binding protein A and pilus-island (PI) PI-1, PI-2a, PI-2b were compared between infants with invasive GBS disease and well-baby controls.The absolute risk of disease did not differ between cases and colonized controls with increasing antibody concentrations for these surface-proteins. There was, however, a relative risk reduction in invasive disease associated with fibrinogen-binding protein A, with an adjusted odds ratio of 0.04 (95% CI: 0.01-0.69) at antibody levels ≥10,000 AU/ml.We have not demonstrated an association between naturally occurring fibrinogen-binding protein A, GBS-immunogenic bacterial adhesin, and PI surface-protein antibodies and the risk of invasive disease in young infants. These surface-proteins may not be suitable GBS vaccine candidates.

BACKGROUND Human immunodeficiency virus (HIV)-exposed infants are at increased risk of invasive Group B Streptococcus (GBS) disease; however, the reason for this increased susceptibility has not been characterized. METHODS We compared GBS capsular and surface-protein maternal immunoglobin G antibody concentrations and cord-maternal ratios between HIV-infected and HIV-uninfected mother-newborn dyads. RESULTS Median capsular antibody concentrations (µg/mL) were lower in HIV-infected than HIV-uninfected women for serotypes Ib (P = .033) and V (P = .040); and for pilus island (PI)-1 (P = .016), PI-2a (P = .015), PI-2b (P = .015), and fibrinogen-binding protein A (P < .001). For serotypes Ia and III, cord-maternal ratios were 37.4% (P < .001) and 32.5% (P = .027) lower in HIV-infected compared to HIV-uninfected mother-newborn dyads. The adjusted odds of having capsular antibody concentration ≥2 µg/mL when comparing HIV-infected to -uninfected women were 0.33 (95% confidence interval [CI], .15-.75) and 0.34 (95% CI, .12-1.00) for serotypes Ia and III, respectively. Antibody levels and cord-maternal ratios were independent of CD4(+) lymphocyte counts or HIV-1 viral load. CONCLUSIONS The lower GBS antibody concentrations and reduced transplacental antibody transfer in HIV-infected women, which likely contribute to their infants being at heightened susceptibility for invasive GBS disease, could possibly be mitigated by vaccination with a GBS conjugate vaccine currently under clinical development.

Background Newborns of HIV-infected mothers are given daily doses of nevirapine to prevent HIV-1 acquisition. Infants born to mothers with TB should also receive TB preventive therapy. TB preventive regimens include isoniazid for 6 months or rifampicin plus isoniazid for 3 months (RH preventive therapy). The effect of concomitant RH preventive therapy on nevirapine concentrations in infants is unknown. Patients and methods Tshepiso was a prospective case-control cohort study of pregnant HIV-infected women with and without TB whose newborn infants received standard doses of nevirapine for HIV prophylaxis. Infants born to mothers with TB also received RH preventive therapy. Infant plasma nevirapine concentrations were measured at 1 and 6 weeks. The effects of RH preventive therapy on nevirapine disposition were investigated in a population pharmacokinetic model. Results Of 164 infants undergoing pharmacokinetic sampling, 46 received RH preventive therapy. After adjusting for weight using allometric scaling, the model estimated a 33% reduction in nevirapine trough concentrations with RH preventive therapy compared with TB-unexposed infants not receiving concomitant rifampicin and a 30% decline in trough concentrations in a typical infant between day 7 and 35 post-partum. Conclusions Rifampicin-based TB preventative treatment reduces nevirapine concentrations significantly in HIV-exposed infants. Although the nevirapine exposures required to prevent HIV acquisition in breastfeeding infants are undefined, given the potential risks associated with underdosing nevirapine in this setting, it is prudent to avoid rifampicin-based preventive therapy in HIV-exposed children receiving prophylactic nevirapine.

Introduction There is a paucity of longitudinal data on the serotype-specific burden of invasive group B Streptococcus (GBS) disease from low-middle income countries, which could inform selection of vaccine epitopes. Methods From 2005 to 2014, infants less than 90 days of age with invasive GBS disease were identified through sentinel laboratory and hospital admission surveillance at Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. Results We identified 820 cases of invasive GBS disease, including 55% among newborns

Objective To evaluate obstetric healthcare provider knowledge regarding the prevention of group B streptococcal disease in South African infants. Methods Questionnaires exploring knowledge, attitudes and beliefs around group B streptococcal prevention were administered to consenting doctors and maternity nurses in a tertiary academic hospital. Qualitative assessments (focus groups) were undertaken with junior doctors and nurses. Results 238 participants completed the questionnaire: 150 (63.0%) doctors and 88 (37.0%) nurses. Overall, 22.7% of participants correctly identified the risk-based prevention protocol recommended at this hospital. Most doctors (68.0%) and nurses (94.3%) could not correctly list a single risk factor. A third of doctors did not know the correct antibiotic protocols, and most (80.0%) did not know the recommended timing of antibiotics in relation to delivery. Focus group discussions highlighted the lack of knowledge, awareness and effective implementation of protocols regarding disease prevention. Conclusions Our study highlighted knowledge gaps on the risk-based prevention strategy in a setting which has consistently reported among the highest incidence of invasive group B streptococcal disease globally. In these settings, education and prioritization of the risk-based intrapartum antibiotic strategy is warranted, but an alternative vaccine-based strategy may prove more effective in preventing invasive group B streptococcal disease in the long-term.

Paediatric liver transplantation (PLT) is the only therapeutic option for many children with end-stage chronic liver disease or irreversible fulminant hepatic failure and is routinely considered as a therapy by paediatric gastroenterologists and surgeons working in developed countries. In South Africa (SA), a PLT programme is available at Red Cross War Memorial Children’s Hospital in Cape Town since November 1991, and another has rapidly developed at the Wits Donald Gordon Medical Centre in Johannesburg over the past decade. However, for most children with progressive chronic liver disease who are reliant on the services provided at public health facilities in SA, PLT is not an option because of a lack of resources in a mismanaged public health system. This article briefly outlines the services offered at Chris Hani Baragwanath Academic Hospital - which is typical of public health facilities in SA - and proposes that resources be allocated to establish an innovative, nationally funded centre that would enable greater numbers of children access to a PLT programme.

Introduction Group B Streptococcus (GBS) is a leading cause of neonatal sepsis and meningitis. We aimed to evaluate the burden of invasive early-onset (0–6 days of life, EOD) and late-onset (7–89 days, LOD) GBS disease and subsequent neurological sequelae in infants from a setting with a high prevalence (29.5%) of HIV among pregnant women. Methods A case-control study was undertaken at three secondary-tertiary care public hospitals in Johannesburg. Invasive cases in infants

Background Contact tracing, to identify source cases with untreated tuberculosis (TB), is rarely performed in high disease burden settings when the index case is a young child with TB. As TB is strongly associated with HIV infection in these settings, we used source case investigation to determine the prevalence of undiagnosed TB and HIV in the caregivers and household contacts of hospitalised young children diagnosed with TB in South Africa. Methods Caregivers and household contacts of 576 young children (age ≤7 years) with TB diagnosed between May 2010 and August 2012 were screened for TB and HIV. The primary outcome was the detection of laboratory-confirmed, newly-diagnosed TB disease and/or HIV-infection in close contacts. Results Of 576 caregivers, 301 (52·3%) self-reported HIV-positivity. Newly-diagnosed HIV infection was detected in 63 (22·9%) of the remaining 275 caregivers who self-reported an unknown or negative HIV status. Screening identified 133 (23·1%) caregivers eligible for immediate anti-retroviral therapy (ART). Newly-diagnosed TB disease was detected in 23 (4·0%) caregivers. In non-caregiver household contacts (n = 1341), the prevalence of newly-diagnosed HIV infection and TB disease was 10·0% and 3·2% respectively. On average, screening contacts of every nine children with TB resulted in the identification of one case of newly-diagnosed TB disease, three cases of newly diagnosed HIV-infection, and three HIV-infected persons eligible for ART. Conclusion In high burden countries, source case investigation yields high rates of previously undiagnosed HIV and TB infection in the close contacts of hospitalised young children diagnosed with TB. Furthermore, integrated screening identifies many individuals who are eligible for immediate ART. Similar studies, with costing analyses, should be undertaken in other high burden settings–integrated source case investigation for TB and HIV should be routinely undertaken if our findings are confirmed.

A trivalent Group B streptococcus (GBS) polysaccharide-protein conjugate vaccine for vaccination of pregnant women is under development to protect their newborns against invasive GBS disease. Establishing sero-correlates of protection against invasive GBS disease in infants could expedite the licensure pathway of polysaccharide-protein conjugate vaccine. A systematic review of studies reporting on the association of capsular antibodies and invasive GBS disease in infants and colonization in women or newborns was undertaken. Most studies that described maternal and/or infant capsular antibody levels in infants with invasive GBS disease identified an association between low capsular antibody levels in invasive GBS cases compared to controls. Different assay methods and the lack of standardized reference ranges for serotype-specific antibody levels makes it difficult to select an antibody level that may be used as a reliable sero-correlate of protection. Further studies using standardized methods are warranted.

BACKGROUND The tuberculin skin test (TST) is used to help diagnose tuberculosis (TB) in acutely ill hospitalised children. OBJECTIVE To investigate the potential augmentative effect of topical calcipotriol (a vitamin D analogue) or zinc on TST induration. METHODS Three TSTs were performed among 64 hospitalised children; each site was covered with topical aqueous cream (control), calcipotriol or zinc and assessed 24 and 48 h later by investigators blinded to all topical applications. RESULTS TSTs were reactive in 15 (23.4%) children, of whom 13 (20.3%) were TST-positive. Topical calcipotriol and zinc induced TST positivity in two children with reactive but negative control TSTs. These treatments, however, did not significantly increase TST positivity rates. In children with reactive TSTs, the median 48 h induration diameter was not significantly different between the control, calcipotriol- or zinc-treated groups, which were respectively 12.0 (25%-75% IQR 5.0 - 18.0), 14.0 (25%-75% IQR 10.0 - 15.0) and 12.0 (25%-75% IQR 8.0 - 15.0) mm. Topical treatments did not induce TST reactivity or TST positivity in children with culture-confirmed TB disease (n = 4), human immunodeficiency virus infection (n= 18) or kwashiorkor (n = 9). CONCLUSIONS Topical calcipotriol or zinc does not induce TST reactivity or significantly increase TST positivity rates in acutely ill hospitalised children. However, further studies are required to assess the effects of topical treatments on TST positivity in severely malnourished children.

Streptococcus agalactiae is an encapsulated Gram-positive coccus that colonises the gastrointestinal and genitourinary tracts. This organism belongs exclusively to Group B in Lancefield's grouping of Streptococcus species and therefore is referred to as Group B Streptococcus (GBS). Of the ten known serotypes, serotypes Ia and III account for most disease. The greatest burden of invasive GBS disease is seen in infants

This study assessed the value of routine CRP measurements to discriminate between bacterial and viral lower respiratory tract infection (LRTI) in HIV-1-infected and -uninfected children. A total of 570 children, prospectively enrolled, were categorised into four aetiological groups, as follows: (i) bacteraemic pneumonia (n = 50), (ii) respiratory virus-associated LRTI (n = 146), (iii) bacteraemic and respiratory virus-associated (mixed) LRTI (n = 10), and (iv) LRTI of undetermined aetiology (n = 364). The discriminative ability of threshold CRP values was evaluated, and values predicting bacteraemic pneumonia were used to construct receiver-operating characteristic (ROC) plots. Median CRP values were significantly higher in bacteraemic pneumonia (195 mg/L, p0.0001), and threshold CRP values ranging from 10 to 100 mg/L differentiated bacteraemic from virus-associated LRTI (p0.0001). The discriminative ability of CRP values assessed by ROC plots in pneumonia is 80%, and CRPor = 10 mg/L identified 90% of all bacteraemic pneumonia. In HIV-1 infection, median CRP values were significantly higher in bacteraemic pneumonia (200 mg/L) but correlated with levels in uninfected children, irrespective of LRTI aetiology. Although CRP responses are significantly different in bacteraemic and virus-associated LRTI, the considerable overlap between these aetiological groups hinders selection of threshold CRP values that are clinically useful in differentiating bacteraemic from virus-associated LRTI pneumonia.

This research report is submitted in partial fulfilment of the requirements for the degree of Master of Medicine in the Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Witwatersrand, Johannesburg August 2015