3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item The epidemiology, risk factors and diagnosis of neonatal sepsis(2017) Velaphi, Sithembiso ChristopherBackground: In sub-Saharan Africa, sepsis is the third most common cause of deaths during the neonatal period. Both maternal human immunodeficiency virus (HIV) infection and vitamin D deficiency (VDD) have been identified as risk factors for infection in children. The relationship of these risk factors, especially VDD among neonates in developing countries is not well documented. The “gold” standard to diagnose sepsis is blood culture; however, it has low sensitivity. Therefore there is a need for tests with improved sensitivity, to improve estimates of the incidence and aetiology of neonatal sepsis. This could enable prompt and targeted use of antibiotics to reduce both mortality and mitigate against emergence of antimicrobial resistance. The aims of this study were to determine the epidemiology of early-onset sepsis (EOS) and community acquired sepsis (CAS) using standard blood culture. Further, we evaluated the role of molecular diagnostic using polymerase chain reaction (PCR) based technology (Taqman array card), and evaluated role of maternal HIV infection and vitamin D status as risk factors for EOS and CAS in neonates born in Soweto, South Africa. Methods and Procedures: Neonates born and/ or admitted with a diagnosis of possible serious bacterial infection (pSBI) with no previous hospital admission were prospectively enrolled into the study. They were grouped into EOS (onset of sepsis before 3 days of life) and CAS (onset of sepsis between 3-27 days of life). A subgroup of patients who met a predetermined definition of clinical or culture confirmed neonatal sepsis (protocol-defined sepsis), had blood and naso/oro-pharyngeal (NPOP) swabs tested using a PCR- based technique, Taqman array card (TAC) to identify possible causative pathogens. Healthy neonates were enrolled as controls, matched for age-group of cases with sepsis. In a separate cohort, mother-newborn dyads were enrolled soon after birth, and had blood taken to measure serum 25-hydroxyvitamin D [25(OH)D]. These newborns were grouped as being healthy or ill with sepsis. Sepsis in this cohort was defined as presence of clinical signs together with the presence of a positive blood culture and/or high C-reactive protein or interleukin-6. For both cohorts, cases and controls were stratified according to HIV exposure. Results: There were 34,808 live births in Soweto over the study period, August 2013 to September 2014. A total of 3260 neonates were enrolled, 2624 (80%) and 636 (20%) with a diagnosis of early-onset pSBI (EO-pSBI) and community acquired pSBI (CA-pSBI) respectively. Blood culture positivity rate due to pathogens in neonates with EO-pSBI was 3.7% (96/2624). The incidence (per 1000 live births) of EO-pSBI was 106 (95%CI 102-109 and 3.8 (95% CI 3.2-4.6) for culture-confirmed EOS. More than two thirds of putative pathogens isolated from neonates with culture-confirmed EOS (69.8%) were Gram positive bacteria. The common bacteria were Group B streptococcus (GBS; 35/105; 33%) , Viridans streptococcus (23/105; 22%), Enterococcus species (10/105; 10%) and Escherichia coli (E. coli; 10/105; 10%), with incidences (per 1000 live births) of 1.41 (95%CI 1.06-1.86), 0.92 (95%CI 0.65-1.30), 0.40 (95% CI 0.20-0.61) and 0.40 (95% CI 0.20-0.61) respectively. HIV exposed neonates had higher incidence of sepsis than HIV unexposed for EO-pSBI (OR:1.45; 95%CI 1.34-1.56). The overall case fatality rate was 9.0% (236/2624) for EOS. Blood culture positivity rate due to pathogens in neonates with CA-pSBI was 9% (55/636). The incidence of CA-pSBI and blood/CSF culture confirmed CAS were 33.4 (95%CI 31.6-35.4) and 3.53 (95%CI 2.96-4.22), respectively. More than three-quarters (76.7%) of putative pathogens isolated from CA-pSBI were Gram positive bacteria. Among, the culture-confirmed CAS, common organisms in blood were Viridans streptococci (17/60; 28%), GBS (14/60; 23%), Staphylococcus aureus (12/60; 20%), and E.coli (9/60; 15%); while in CSF the common organisms were GBS (9/25; 36%), Staphylococcus aureus (5/25; 20%), Viridans streptococcus (4/25; 16%) and Enterococcus species (4/25; 16%). The overall incidence for common organisms in blood and/ or CSF for CAS were 0.95 (95%CI 0.67-1.33), 0.90 (95%CI 0.63-1.27), 0.75 (95%CI 0.51-1.10) and 0.58 (95%CI 0.37-0.89) for Staphylococcus aureus, Viridans streptococcus, GBS and Enterococcus species respectively. HIV exposed neonates had higher incidence of blood/CSF culture confirmed CAS than HIV unexposed (OR:1.90;95%CI 1.32-2.74), including specifically for Staphylococcus aureus (OR:2.71; 95% CI 1.35-5.41), GBS (OR:4.82; 95%CI 2.13-10.9) and E.coli (OR:2.71; 95%CI 1.07-6.82). . The case fatality rate for CAS was 1.4% (9/636). Among protocol-defined sepsis cases tested with TAC, bacteria or viruses were detected in blood in 37.1% of cases with EOS. Although similar organisms were identified in blood of cases and controls, proportion of cases with positive TAC was higher than in controls (37.1% vs 19.5%; OR: 2.35; 95%CI 1.72-3.21). The common organisms identified in blood of EOS cases using TAC were Streptococcus pneumoniae (14.2%), Ureaplasma species (9.2%), Pseudomonas species (8.5%) and GBS (7.0%). In pharyngeal swabs there were fewer cases that tested positive with TAC compared to controls (44.1% vs 53.1%; OR:0.69; 95%CI 0.59-0.90), and the common organisms identified in cases were Ureaplasma species (19.9%), Klebsiella pneumoniae (11.9%) and GBS (8.5%). After applying modelling factoring positive blood culture, one was able to attribute aetiology to a specific pathogen for 26.7% of cases using blood culture and TAC, and therefore 73.3% of cases did not have an identifiable aetiology from the pathogens tested in culture or TAC. Among the positive TAC results in blood and pharyngeal swabs the organisms that were found to be attributable to EOS were Ureaplasma species (5.4%, 95% CI 3.6%-5.1%) , GBS (4.8%, 95%CI 4.1%-5.8%), and Viridans streptococcus (4.2%, 95%CI 3.5%-5.1%). There were no differences in number of cases and controls with positive TAC results between HIV exposed and unexposed neonates. In neonates with CAS protocol-defined sepsis cases tested with TAC, bacteria or viruses were detected in blood in 45.8% of cases. Proportion of cases with positive TAC in blood was higher than in controls (45.8% vs 27.4%; OR: 2.24; 95%CI 1.30-3.86). The common organisms identified included Streptococcus pneumoniae (15.7%), GBS (14.5%) and E. coli (8.3%). In pharyngeal swabs there were no differences in numbers with positive TAC results between cases and controls (75.0% vs 70.1%, OR:1.28; 95%CI 0.77-2.12), and the common organisms identified in cases were GBS (28.0%), Klebsiella pneumoniae (24.2%) and at equal rates (13.6%) were E. coli, Ureaplasma species and Streptococcus pneumoniae. Viruses were identified in 40% of cases in the pharyngeal swabs. There were no differences in number of cases and controls with positive TAC results between HIV exposed and unexposed neonates. Maternal and cord blood 25(OH)D levels were 54.7±30.1 and 39.0±21.3 nmol/L respectively, and prevalence of VDD (defined as a 25(OH)D level of <30 nmol/L) among the women and their newborns was 18.8% and 39.8% respectively. There were no significant differences in 25(OH)D levels or VDD between HIV infected and uninfected pregnant women. On multivariate analysis VDD in neonates was not associated with EOS. Conclusions: There is high burden of neonatal sepsis in Soweto, including significant mortality. Based on blood culture, GBS is the most common pathogen causing EOS; Viridans streptococcus and Staphylococcus aureus the most common causes of culture-confirmed CAS. HIV exposure contributes significantly to a higher burden of bacterial sepsis in neonates. Although molecular detection using the TAC assay identified more bacteria organisms than from blood culture, including non-culturable organisms like Ureaplasma species, its use as a diagnostic tool for sepsis warrants further evaluation due to high positivity rates among healthy neonates for many of the targeted organisms in blood and NPOP swabs. Nevertheless, after correcting for positive controls, a combination of blood culture and TAC improved the detection of organisms in neonates with sepsis. In this study, maternal and newborn VDD was not associated with sepsis; however, this warrants further evaluation since this study had a limited number of neonates with culture confirmed disease.Item Epidemiology and prevention of sepsis in young infants and the potential impact of maternal HIV infection on neonatal sepsis(2016) Cutland, Clare LouiseIntroduction: Neonatal infections contribute to 25% of all neonatal deaths, which account for approximately 44% of all under-5 childhood deaths globally. Pathogens responsible for sepsis in neonates and young infants can be acquired vertically prior to or during labour, or from the environment (community or hospital). This project evaluated the burden and aetiology of sepsis in neonates and young infants (≤90 days), and explored this association to in-utero exposure to human immunodeficiency virus. The study also included a specific focus on the epidemiology of invasive Group B Streptococcal disease in young infants. Additionally, we assessed the efficacy of intrapartum chlorhexidine vaginal washes for: (i) preventing early-onset neonatal sepsis; and (ii) vertical transmission of potentially pathogenic bacteria to the newborns. Furthermore, we evaluated risk factors for poor outcomes due to neonatal sepsis. Materials and methods: (i) A bacterial surveillance system was established at Chris Hani Baragwanath Academic Hospital (CHBAH) from 2004-2008 to identify young infants with bacterial sepsis hospitalised in the neonatal and paediatric wards. Medical and microbiological records were utilised to obtain clinical and laboratory data. Maternal HIV results were obtained from antenatal testing records or admission records. (ii) A blinded, randomised, placebo-controlled trial of 0.5% chlorhexidine maternal vaginal intrapartum wipes and newborn skin wipes was conducted at CHBAH between 2004 and 2007. Consented, eligible participants were randomised during labour to receive either chlorhexidine vaginal wipes or water external genitalia wipes. Newborns received either chlorhexidine full-body wipes (intervention arm) or foot wipes (control arm). Maternal and infant participants were followed up for admissions during the first month after delivery/ birth. A subset of 5144 maternal participants had an intrapartum lower vaginal swab collected, and skin swabs were collected from their newborns to assess colonisation with potentially pathogenic bacteria (Group B streptococcus, Escherichia coli and Klebsiella pneumoniae). Results: Group B streptococcus (GBS) was the most commonly isolated bacterial pathogen, causing 35.2% of culture-confirmed sepsis in infants ≤90 days, 41.6% of early-onset disease (EOD, 0-6 days), 40.5% of late-onset neonatal disease (LOD, 7-27 days) and 18.7% of young-infant community-acquired disease (YI-CAD, 28-90 days). Staphylococcus aureus (S. aureus), Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) contribute 16.2%, 12.2% and 3.4% to sepsis in young infants. Overall, incidence (per 1000 live births) of invasive GBS disease was 2.72 (95% confidence interval [95% CI]: 2.46 to 3.01), including an incidence of 1.50 and 1.22, respectively, in infants 0-6 days and 7-90 days of age. HIV-exposed infants were at greater risk of EOD (Relative risk [RR]: 1.69; 95% CI: 1.28-2.24) and LOD (RR= 3.18; 95% CI: 2.34-4.36) than HIV-unexposed infants. GBS serotypes Ia and III caused 84.0% of invasive GBS disease in young infants. Intrapartum chlorhexidine interventional wipes was not efficacious in prevention of any of: (i) vertical transmission of pathogenic bacteria (54% vs. 55%; efficacy -0.05, 95% CI: -9.5 to 7.9) to the newborns; (ii) sepsis in first 3 days of life (3% vs. 4%; p=0.65,); (iii) sepsis in the later neonatal period (both <1%; p=0.4444); or (iv) maternal puerperal sepsis(both <1%; p=0.56). Conclusion: GBS, S. aureus, E. coli and K. pneumoniae are the most commonly isolated bacterial pathogens in neonates and infants ≤90 days old. HIV-exposed infants are at greater risk of GBS sepsis. Intrapartum chlorhexidine intervention was not efficacious in reducing vertical transmission of pathogenic bacteria, neonatal or maternal sepsis. Alternative interventions to prevent sepsis in young infants, including maternal immunisation, need to be investigated in setting such as ours where there is a high prevalence of maternal HIV infection.