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Background In the absence of a vaccine, Staphylococcus aureus (S. aureus) remains a major cause of morbidity and mortality in children. Studies describing S. aureus bloodstream infection (BSI) in children in Africa remain few. Methods This was a retrospective descriptive study conducted at Red Cross War Memorial Children’s Hospital (RCWMCH) in Cape Town, South Africa. All S. aureus positive blood culture results for the period 2018–2022 on the National Health Laboratory Service microbiology database were identified. Case records of participants with S. aureus positive blood cultures were retrieved. Demographic, clinical, antimicrobial management and participant outcome data were extracted from the case records. Continuous variables were presented as means and standard deviations or medians and interquartile ranges as appropriate. Parametric (Student t-test) and non-parametric (Wilcoxon rank sum test for independent variables) methods were used to compare continuous variables. Pearson’s Chi-square or Fisher’s exact tests were used to compare categorical variables. RStudio statistical computing software version 4.4.2 was used for the logistic regression analysis. Our findings were also compared with a similar study at our institution which analysed the epidemiology of Staphylococcus bloodstream infections between 2007 and 2011 (Naidoo et al. PLoS ONE 8(10):e78396, 2013). Results During the 5-year study period there were 245 S. aureus BSIs identified, with an overall annual incidence risk of 2.7 cases per 1000 admissions. Methicillin-resistant S. aureus (MRSA) caused 10% of the BSIs and was predominantly healthcare-associated (79.2%). Only 2.1% of participants were living with human immunodeficiency virus (HIV). However, underweight was present in 29.2% of children with S. aureus BSI. Healthcare-associated infection comprised 33.3% of all S. aureus BSIs. 70% of BSIs had an identifiable site of infection with skin and soft tissue (25%) being the commonest. All MRSA isolates were susceptible to linezolid, teicoplanin, tigecycline and vancomycin. The mortality rate within 28 days of S. aureus BSI diagnosis was 8.3%. The commonest attributable cause of death was septic shock (25%). Requiring intensive care unit (ICU) admission during a BSI, (adjusted Odds ratio (aOR): 5.4, 95% CI: 1.89–15.21) was associated with increased 28-day mortality rate. When compared to the 2007–2011 study, there has been a decline in the incidence risk of S. aureus BSI and the prevalence of healthcare-associated MRSA BSI. Conclusions S. aureus BSI remains a major cause of morbidity and mortality in children. Admission to ICU during a BSI episode was significantly associated with 28-day mortality. Furthermore, over time changes to the epidemiology of S. aureus BSI have occurred at RCWMCH. Clinical trial number Not applicable (study is not a clinical trial).

WHO recommends that Xpert MTB/RIF replaces smear microscopy for initial diagnosis of suspected HIV-associated tuberculosis or multidrug-resistant pulmonary tuberculosis, but no data exist for its use in children. We aimed to assess the accuracy of the test for the diagnosis of pulmonary tuberculosis in children in an area with high tuberculosis and HIV prevalences. In this prospective, descriptive study, we enrolled children aged 15 years or younger who had been admitted to one of two hospitals in Cape Town, South Africa, with suspected pulmonary tuberculosis between Feb 19, 2009, and Nov 30, 2010. We compared the diagnostic accuracy of MTB/RIF and concentrated, fluorescent acid-fast smear with a reference standard of liquid culture from two sequential induced sputum specimens (primary analysis). 452 children (median age 19·4 months, IQR 11·1–46·2) had at least one induced sputum specimen; 108 children (24%) had HIV infection. 27 children (6%) had a positive smear result, 70 (16%) had a positive culture result, and 58 (13%) had a positive MTB/RIF test result. With mycobacterial culture as the reference standard, MTB/RIF tests when done on two induced sputum samples detected twice as many cases (75·9%, 95% CI 64·5–87·2) as did smear microscopy (37·9%, 25·1–50·8), detecting all of 22 smear-positive cases and 22 of 36 (61·1%, 44·4–77·8) smear-negative cases. For smear-negative cases, the incremental increase in sensitivity from testing a second specimen was 27·8% for MTB/RIF, compared with 13·8% for culture. The specificity of MTB/RIF was 98·8% (97·6–99·9). MTB/RIF results were available in median 1 day (IQR 0–4) compared with median 12 days (9–17) for culture (p<0·0001). MTB/RIF testing of two induced sputum specimens is warranted as the first-line diagnostic test for children with suspected pulmonary tuberculosis. National Institutes of Health, the National Health Laboratory Service Research Trust, the Medical Research Council of South Africa, and Wellcome Trust.

Diagnosing active tuberculosis remains a challenge, especially in children. In this study, which included HIV-negative and HIV-positive children, a 51-transcript signature for active tuberculosis was evaluated as a potential diagnostic tool. Between 500,000 and 1 million new cases of childhood tuberculosis are diagnosed annually, but the true global burden of childhood tuberculosis is unknown because it is often difficult to confirm the diagnosis microbiologically. 1 – 3 Although most cases of tuberculosis in adults are diagnosed through detection of acid-fast bacilli on microscopic examination of a sputum specimen, in the majority of childhood cases, smears and cultures are negative for Mycobacterium tuberculosis, and the diagnosis is made solely on clinical grounds. 1 , 3 Since the symptoms and signs of childhood tuberculosis are seen in a range of other conditions, clinical diagnosis is unreliable. 4 Clinical . . .

There are few studies describing Escherichia coli (E. coli) bloodstream infection (BSI) among children in Africa, yet E.coli is increasing in importance as a cause of antibiotic resistant infection in paediatric settings. In this retrospective, descriptive study aspects of E. coli BSI epidemiology are described over a 10-year period including incidence risk, risk factors for extended-spectrum β-lactamase (ESBL)-producing E. coli BSI, antibiotic susceptibility of the bacterial isolates and outcome including risk factors for severe disease. There were 583 new E. coli BSI episodes among 217,483 admissions, an overall incidence risk of 2.7 events/1,000 hospital admissions. Of 455 of these E. coli BSI episodes that were analysed, 136 (29.9%) were caused by ESBL-producing isolates. Risk factors for ESBL-producing E. coli BSI included hospitalization in the 28-day period preceding E. coli BSI episodes, having an underlying chronic illness other than HIV infection at the time of the E. coli BSI and having a temperature of 38° Celsius or higher at the time of the E. coli BSI. None of the E. coli isolates were resistant to carbapenems or colistin. The mortality rate was 5.9% and admission to the intensive care unit was required in 12.3% of BSI episodes. Predictors of severe disease included age less than 1 month, hospitalization in the 28-day period preceding E. coli BSI and BSI without a definable focus. These findings extend our understanding of E. coli BSI in a sub-Saharan African setting, provide useful information that can guide empiric treatment choices for community- and hospital-acquired BSI and help inform prevention strategies.

Background Bloodstream infection (BSI) in children causes significant morbidity and mortality. There are few studies describing the epidemiology of BSI in South African children. Methods A retrospective descriptive cohort study was conducted at a paediatric referral hospital in Cape Town, South Africa. The National Health Laboratory Service (NHLS) microbiology database was accessed to identify positive blood culture specimens during the period 2011–2012. Demographic and clinical details, antimicrobial management and patient outcome information were extracted from medical and laboratory records. Antibiotic susceptibility results of identified organisms were obtained from the NHLS database. Results Of the 693 unique bacterial and fungal BSI episodes identified during the study period, 248 (35.8%) were community-acquired (CA), 371 (53.5%) hospital-acquired (HA) and 74 (10.7%) healthcare-associated (HCA). The overall risk was 6.7 BSI episodes per 1000 admissions. Escherichia coli, Staphylococcus aureus and Streptococcus pneumoniae were the most frequent causes of CA-BSI and Klebsiella pneumoniae, Acinetobacter baumanii and S.aureus were most commonly isolated in HA-BSI. On multivariable analysis, severe underweight, severe anaemia at the time of BSI, admission in the ICU at the time of BSI, and requiring ICU admission after BSI was diagnosed were significantly associated with 14-day mortality. Conclusion This study adds to the limited literature describing BSI in children in Africa. Further studies are required to understand the impact that BSI has on the paediatric population in sub-Saharan Africa.

Background Candida bloodstream infection (BSI) causes appreciable mortality in neonates and children. There are few studies describing the epidemiology of Candida BSI in children living in sub-Saharan Africa. Methods A retrospective descriptive study was conducted at three public sector hospitals in Cape Town, South Africa. Demographic and clinical details, antifungal management and patient outcome data were obtained by medical record review. Candida species distribution and antifungal susceptibility testing results were obtained from the National Health Laboratory Service database. Results Of the 97 Candida BSI episodes identified during a five-year period, 48/97 (49%) were Candida albicans (C. albicans) , and 49/97 (51%) were non- C. albicans species. The overall incidence risk was 0.8 Candida BSI episodes per 1000 admissions at Red Cross War Memorial Children’s Hospital. Of the 77/97 (79%) Candida BSI episodes with available clinical information, the median age (interquartile range) at the time of BSI was 7 (1–25) months, 36/77 (47%) were associated with moderate or severe underweight-for-age and vasopressor therapy was administered to 22/77 (29%) study participants. Most of the Candida BSI episodes were healthcare-associated infections, 63/77 (82%). Fluconazole resistance was documented among 17%, 0% and 0% of C. parapsilosis, C. tropicalis and C. albicans isolates, respectively. All Candida isolates tested were susceptible to amphotericin B and the echinocandins. The mortality rate within 30 days of Candida BSI diagnosis was 13/75 (17%). On multivariable analysis, factors associated with mortality within 30 days of Candida BSI diagnosis included vasopressor therapy requirement during Candida BSI, adjusted Odds ratio (aOR) 53 (95% confidence interval 2–1029); hepatic dysfunction, aOR 13 (95% CI 1–146); and concomitant bacterial BSI, aOR 10 (95% CI 2–60). Conclusion The study adds to the limited number of studies describing paediatric  Candida  BSI in sub-Saharan Africa. Non- C. Albicans BSI episodes occurred more frequently than C. albicans episodes, and vasopressor therapy requirement, hepatic dysfunction and concomitant bacterial BSI were associated with an increase in 30-day mortality.

Tuberculous meningitis (TBM) is the most severe form of TB with high rates of mortality and morbidity. Here we conduct RNA-sequencing on whole blood as well as on ventricular and lumbar cerebrospinal fluid (CSF) of pediatric patients treated for TBM. Differential transcript expression of TBM cases are compared with healthy controls in whole blood and with non-TB cerebral infection controls in CSF. Whole blood RNA-Seq analysis demonstrates a distinct immune response pattern in TBM, with significant increase in both canonical and non-canonical inflammasome activation and decrease in T-cell activation. In ventricular CSF, a significant enrichment associated with neuronal excitotoxicity and cerebral damage is detected in TBM. Finally, compartmental comparison in TBM indicates that the ventricular profile represents brain injury whereas the lumbar profile represents protein translation and cytokine signaling. Together, transcriptomic analysis shows that disease processes differ between the periphery and the central nervous system, and within brain compartments. Tuberculosis meningitis (TBM) is a severe form of TB with limited treatment options. Here, the authors perform RNA sequencing on whole blood and on ventricular and lumbar cerebrospinal fluid (CSF) samples from pediatric patients treated for TBM to characterize the immune response and tissue damage.

A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB), particularly in the context of HIV infection. We hypothesized that a unique host blood RNA transcriptional signature would distinguish TB from other diseases (OD) in HIV-infected and -uninfected patients, and that this could be the basis of a simple diagnostic test. Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture of Mycobacterium tuberculosis [M.TB] from sputum or tissue sample in a patient under investigation for TB), OD (i.e., TB was considered in the differential diagnosis but then excluded), or healthy individuals with latent TB infection (LTBI). Individuals were randomized into training (80%) and test (20%) cohorts. Blood transcriptional profiles were assessed and minimal sets of significantly differentially expressed transcripts distinguishing TB from LTBI and OD were identified in the training cohort. A 27 transcript signature distinguished TB from LTBI and a 44 transcript signature distinguished TB from OD. To evaluate our signatures, we used a novel computational method to calculate a disease risk score (DRS) for each patient. The classification based on this score was first evaluated in the test cohort, and then validated in an independent publically available dataset (GSE19491). In our test cohort, the DRS classified TB from LTBI (sensitivity 95%, 95% CI [87-100]; specificity 90%, 95% CI [80-97]) and TB from OD (sensitivity 93%, 95% CI [83-100]; specificity 88%, 95% CI [74-97]). In the independent validation cohort, TB patients were distinguished both from LTBI individuals (sensitivity 95%, 95% CI [85-100]; specificity 94%, 95% CI [84-100]) and OD patients (sensitivity 100%, 95% CI [100-100]; specificity 96%, 95% CI [93-100]). Limitations of our study include the use of only culture confirmed TB patients, and the potential that TB may have been misdiagnosed in a small proportion of OD patients despite the extensive clinical investigation used to assign each patient to their diagnostic group. In our study, blood transcriptional signatures distinguished TB from other conditions prevalent in HIV-infected and -uninfected African adults. Our DRS, based on these signatures, could be developed as a test for TB suitable for use in HIV endemic countries. Further evaluation of the performance of the signatures and DRS in prospective populations of patients with symptoms consistent with TB will be needed to define their clinical value under operational conditions. Please see later in the article for the Editors' Summary.

There are few studies describing colonisation with extended spectrum beta-lactamase-producing Enterobacterales (ESBL-PE) and carbapenem-resistant Enterobacterales (CRE) among children in sub-Saharan Africa. Colonisation often precedes infection and multi-drug-resistant Enterobacterales are important causes of invasive infection. In this prospective cross-sectional study, conducted between April and June 2017, 200 children in a tertiary academic hospital were screened by rectal swab for EBSL-PE and CRE. The resistance-conferring genes were identified using polymerase chain reaction technology. Risk factors for colonisation were also evaluated. Overall, 48% (96/200) of the children were colonised with at least one ESBL-PE, 8.3% (8/96) of these with 2 ESBL-PE, and one other child was colonised with a CRE (0.5% (1/200)). Common colonising ESBL-PE were Klebsiella pneumoniae (62.5%, 65/104) and Escherichia coli (34.6%, 36/104). The most frequent ESBL-conferring gene was blaCTX-M in 95% (76/80) of the isolates. No resistance- conferring gene was identified in the CRE isolate (Enterobacter cloacae). Most of the Klebsiella pneumoniae isolates were susceptible to piperacillin/tazobactam (86.2%) and amikacin (63.9%). Similarly, 94.4% and 97.2% of the Escherichia coli isolates were susceptible to piperacillin/tazobactam and amikacin, respectively. Hospitalisation for more than 7 days before study enrolment was associated with ESBL-PE colonisation. Approximately half of the hospitalised children in this study were colonised with ESBL-PE. This highlights the need for improved infection prevention and control practices to limit the dissemination of these microorganisms.

Introduction Globally, children living with HIV continue to lag behind UNAIDS targets for viral suppression (VS). Because studies with linked mother‐child data are limited, we describe VS and associated factors among young children in a setting with early infant HIV testing (at birth, age 10 weeks and 6 months) and early protease inhibitor‐based first‐line antiretroviral therapy (ART). Methods We analysed routinely collected mother‐child data for children living with HIV born 2018–2022 in Western Cape province, South Africa (followed through mid‐2023). We assessed associations between child and maternal viral load (VL) results at 12 and 24 months after child ART start using logistic regression, adjusted for child sex, birthyear, severity of child immunodeficiency at ART start, maternal age and timing of maternal HIV diagnosis. Results Among 2219 children living with HIV; 30% were diagnosed at birth (≤7 days), 41% before age 1 year (8−365 days) and 29% at age >1 year. Overall, 5% (n = 112/2219) of children died, a third of whom had not started ART; 90% of children (n = 1990) started ART, at median age 5 months (IQR 1–16). Median follow‐up from ART start was 26 months (IQR 14–40). Among children with available VL at 12 months (n = 853/1582), 24 months (n = 614/1129) and 36 months (n = 350/658) after ART start, 36%, 43% and 48% were virally suppressed, respectively (VL<100 copies/ml). VS among children at 12 and 24 months was more likely if maternal VL was <100 versus ≥100 copies/ml at 12 months (adjusted odds ratio [aOR] = 3.5; 95% CI 1.9−6.5) and 24 months (aOR = 6.1; 95% CI 2.8−13.1) after child ART start. Children with no/mild versus advanced/severe immunodeficiency at ART start were more likely to achieve VS at 12 months (aOR = 2.3; 95% CI 1.3−4.2) but not at 24 months. Eligible children with missing VL at 24 months (39%) were more likely to have gaps in care of >6 months than those with VL≥100 or VL<100 copies/ml (84% vs. 28% vs. 14%, respectively; p<0.001). Conclusions Less than half of children on ART achieved VS, and children were more likely to achieve VS if their mothers were also virally suppressed. Significant efforts are needed to support mother‐child dyads to achieve optimal VS.