Background: Lung disease is a common complication of human immunodeficiency virus (HIV) infection in children and adolescents. As antiretroviral programmes have strengthened and HIV diagnosed earlier, survival of perinatally HIV-infected children has improved. Therefore, an increasing number of perinatally HIV-infected children are surviving into adolescence, with development of chronic multisystem disease including chronic lung disease (CLD). However, there is limited information on the determinants, spectrum and progression of lung disease. Lung function testing, an objective, non-invasive, reproducible tool, is useful in characterising CLD and in monitoring disease progression. Aim: To investigate the spectrum, determinants and progression of lung function in perinatally HIV-infected adolescents on antiretroviral therapy (ART) in Cape Town, South Africa. Specific objectives included describing the spectrum and determinants of lung function; investigating cardiopulmonary dysfunction and investigating progression of lung function over two years. Methods: The study population was from a prospective cohort, the Cape Town Adolescent Anti-retroviral cohort (CTAAC), that enrolled 515 perinatally HIV-infected adolescents on ART and 110 age-matched HIV-uninfected adolescents followed six-monthly for two years in Cape Town, South Africa. Eligibility criteria were adolescents, aged 9-14 years, with perinatally acquired HIV, who had been on ART for at least six months. Comprehensive lung function testing was done, and clinical and lung function data collected at baseline, 12 and 24 months. Results: At baseline, HIV-infected adolescents had lower forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, diffusing capacity for carbon monoxide, respiratory system compliance and functional residual capacity; and higher airway resistance and lung clearance index compared to HIV-uninfected adolescents, p< 0.05 for all. At 24 months, FEV1 and FVC remained lower in the HIV-infected compared to the uninfected, p< 0.05 for both. Impaired cardiopulmonary function was detected in 13% of HIV-infected adolescents and 8% of HIV-uninfected adolescents, p=0.136. Past PTB was significantly associated with a low cardiopulmonary function, OR 2.3, 95%CI 1.2-4.4. Conclusion: Perinatally HIV-infected adolescents had lower lung function and higher resistance and ventilation inhomogeneity compared to age-matched HIV-uninfected adolescents at baseline. Lung function tracked, remaining lower at two years. Previous PTB or severe LRTI were predictors of lower lung function. Co-existent cardiopulmonary dysfunction occurred in a minority. These data highlight respiratory disease risk in this vulnerable group and may inform policy to strengthen strategies to prevent and manage HIV-associated lung or cardiopulmonary disease. Four of the chapters (2-5) of this thesis are presented as published manuscripts. Chapter 1 encompasses an overview of the burden of HIV disease and the spectrum of HIV associated chronic lung disease in adolescents and the utility of lung function in the diagnosis of chronic lung disease. Study methodology is also detailed in this chapter. Chapter 2 (published manuscript) comprises a comprehensive review of published data on lung function (over and above the literature included in the individual papers) in HIV infected children and adolescents and summarises studies that have been done in Africa, USA, Europe and Asia. Chapter 3 (published manuscript) describes the spectrum and determinants of comprehensive lung function parameters (flow, volume, compliance, resistance, ventilation inhomogeneity) in perinatally HIV-infected adolescents with a comparator group of age-matched HIV-uninfected adolescents. Chapter 4 (published manuscript) further explores the prevalence and determinants of coexistent cardiopulmonary dysfunction in perinatally HIV-infected adolescents on ART. Chapter 5 (published manuscript) describes the progressive changes in spirometry over two years in perinatally HIV-infected adolescents compared to HIV-uninfected age matched controls. It also addresses the associations of low lung function, factors amenable to public health interventions. Chapter 6 is a summary of the study findings and recommendations.

Includes bibliographical references. / Hypoxic ischaemic encephalopathy (HIE) after birth is an important cause of neonatal morbidity and mortality, particularly in resource-limited regions. Therapeutic hypothermia initiated within the first 6 hours of life, in settings that can offer neonatal intensive care, is a therapy that can reduce death or severe disability in newborn infants with moderate or severe HIE. Therapeutic hypothermia has not been shown to be safe or effective in low-resource settings where neonatal intensive care is not available; however, there are situations such as in some centres in South Africa, where limited neonatal intensive care (NICU) is available against a background of moderate neonatal mortality rates, relatively low socio-economic conditions and limited capacity for long-term follow-up. In such settings, accurate case definition and early prediction of HIE and outcome may assist with the appropriate allocation of resources. The amplitude-integrated electro-encephalogram (aEEG) is an ideal tool to use for prediction of outcome and the need for cooling, but it’s availability is limited, particularly at primary and secondary hospitals.

The outcome of high risk infants provides an important audit of neonatal care. This audit renders valuable information to clinicians, parents and health care planners. Available outcome data from the developing world are sparse and urgently needed. This work was compiled with three aims in mind: to provide data from Cape Town on outcome of high risk infants (including both infants of very low birthweight and infants who have survived hypoxic ischaemic encephalopathy); to evaluate selected early neurodevelopmental assessments of these infants; and to propose a protocol for their effective follow-up. Three separate cohorts were selected and studied in order to achieve these aims. A prospective six-year follow-up study of infants with birth weights less than 1250 g was undertaken at Groote Schuur Hospital's Neonatal Intensive Care Unit. The aim of the study was to document the morbidity, mortality and neurodevelopmental outcome of these infants. Of 235 liveborn infants, 143 (61 %) survived to discharge. Better survival was documented for infants who weighed more than 900 g and were over 30 weeks gestation and whose mothers attended antenatal care. One hundred and six infants (83% of survivors) underwent clinical assessment at one year of age and were evaluated with the Griffiths Scales of Mental Development. Ninety six (91 %) of these survivors were seen and tested at two years of age and 80 (76%) were seen at six years of age together with 70 matched controls who had normal birthweights. Of the 106 infants assessed at one year of age, six infants were diagnosed as cerebral palsied, six were globally developmentally delayed without signs of cerebral palsy and one infant showed significant motor delay with a normal developmental quotient. At two years of age one further infant had cerebral palsy and nine more infants were developmentally delayed. At six years of age five infants had cerebral palsy, one was intellectually disabled and three were intellectually borderline. The major disability rate at one year of age was 11%, at two years of age was 22% and at six years of age was eight percent. The incidence of low birthweight children with possible learning disability was three times that of their matched controls and overall, the low birthweight children scored significantly less in all developmental measures. Forty-five infants who developed hypoxic ischaemic encephalopathy after birth were studied prospectively. A numeric scoring system for the assessment of hypoxic ischaemic encephalopathy during the neonatal period which had previously been developed at Groote Schuur Hospital was tested. The value of the score in predicting neurodevelopmental outcome at one year of age was assessed. Thirty five infants were evaluated at 12 months of age by full neurological examination and the Griffiths Scales of Mental Development. Five infants were assessed at an earlier stage, 4 who died before 6 months of age and one infant who was hospitalised at the time of the 12-month assessment. Twenty three (58%) of the infants were normal, 17 (42%) were abnormal, 16 with cerebral palsy and one with developmental delay. 25 infants were re-evaluated at 3 years of age. 15 of these 25 had been normal at one year of age and were evaluated with ten controls who had had an uneventful perinatal course. The Hypoxic lschaemic Encephalopathy Score was highly predictive for outcome. The best correlation with outcome was a combination of the peak score and evaluation on day seven; giving a positive predictive value of 92% and a negative predictive value of 100% for abnormal outcome, with a sensitivity of 100% and specificity of 93%. At three years of age the HIE survivors without cerebral palsy scored as well as their matched controls on Griffiths developmental evaluation. In these normal survivors no correlation between severity of HIE and developmental quotient was demonstrated. Infants with neurodevelopmental abnormality need to start therapy early and because of this, should be detected as soon as possible. Currently, no widely accepted method of early evaluation exists. A Perinatal Risk Rating, the Dubowitz Neurological Assessment and the Infant Neuromotor Assessment were compared in terms of predicting neurodevelopmental outcome at one year of age. A cohort of 130 consecutive neonatal intensive care unit graduates were selected according to high risk criteria. Each infant was examined at term gestational age on the Dubowitz Neurological Assessment and a Perinatal Risk Rating was allocated. The study infants were seen again at 18 weeks corrected age, when an Infant Neuromotor Assessment was done, and at one year of age the Griffiths Scales of Mental Developmental and full neurological examination were carried out. Of the 130 infants assessed at term, all were seen at 18 weeks. Thereafter five were lost to follow-up and two died. The outcome of all the remaining 123 infants is known. Prediction of a normal outcome at 1 year of age on the Dubowitz Neurological Assessment was 96% and for the Perinatal Risk Rating, 98%, but for an abnormal outcome they predicted only 56% and 42% respectively. The Infant Neurological Assessment at 18 weeks of age predicted a normal outcome at one year in 99% and an abnormal outcome in 82%. Very low birthweight infants are at higher risk for cerebral palsy and intellectual disability. In Groote Schuur Hospital, at six years of age, the major disability rate for infants with birthweights less than 1250 g was eight percent. Forty percent of term infants who survived hypoxic ischaemic encephalopathy had cerebral palsy with associated intellectual disability. The use of the Perinatal Risk Rating is appropriate in newborn facilities where cranial ultrasound is available. Otherwise the Dubowitz Neurological Assessment is an appropriate screening tool in the newborn period. Use of the Hypoxic Ischaemic Encephalopathy Score is recommended for clinical evaluation, prognostication and risk rating. It is proposed that high risk infants should be evaluated at 18 weeks corrected age with the Infant Neuromotor Assessment at a tertiary centre. If this assessment is normal, the infant can then be discharged to community clinic follow-up. Infants with more than one deviant sign at this age need continued review and those with more than three signs should be referred for neurodevelopmental therapy to a comprehensive neurodevelopmental clinic. Even those high-risk infants whose assessments are normal should be enrolled in a pre-school centre at five years of age to facilitate detection of learning problems prior to school entry.

Includes bibliographical references. / Background: The prevalence of food allergy in South Africa is unknown, but previously thought to be low, particularly in black South Africans. We hypothesised that food allergies would be low in Xhosa patients, even those at increased risk of food allergy such as children with atopic dermatitis (AD). This study aimed to determine the prevalence of, patterns and risk factors for, IgE-mediated food allergy in South African children with moderate to severe AD. It is the first food allergy prevalence study in South Africa to utilise controlled food challenges and component analysis, and is unique for its comparison of food allergy patterns between ethnic groups in the same geographical area. Methodology: This was a prospective, observational study in a paediatric university hospital in Cape Town. Children with moderate to severe AD, aged 6 months to 10 years, were randomly recruited from the dermatology clinic. They were assessed for sensitisation and allergy by questionnaire, skin prick tests (SPT), Immuno Solid Phase Allergen Chip (ISAC) test and incremental food challenges. Sensitised patients were also tested for specific IgE by ImmunoCAP test. Results: One hundred participants (59 black Africans and 41 of mixed race) were enrolled, median age 42 months. There were high overall rates of food sensitisation (66%) and food allergy (40%). Egg (25%) and peanut (24%) were the most common allergies. Black participants had comparable sensitisation (69% vs 61%) but lower allergy rates (34% vs 46%) than mixed race participants. This was especially evident for peanut allergy (15% vs 37%, p=0.01). Early onset AD (< 6 months), severe eczema, and young age < 2 years were significant risk factors for food allergy. The ISAC test was less sensitive than SPT and ImmunoCAP tests. Only 42% of cases of perceived food allergy were confirmed as true food allergy.

Background Neonatal infection is an important cause of morbidity and mortality in babies. The causative pathogens and their antibiotic susceptibility patterns should be monitored so that treatment regimens can be adjusted to maintain efficacy and avoid selection of resistant organisms. Objectives To compare the incidence of culture positive neonatal sepsis; and to describe the pathogens and antibiotic resistance profiles for significant organsims over a 15-year period in a tertiary nursery in Cape Town. Methods Retrospective blood culture data for 12 months were collected at three time points over a 15-year period. Blood cultures from 2004, 2013 and 2017 were analysed. All neonates with growth on blood cultures were included. Results During 2004 a total of 817 (43.3% of total admissions) blood cultures were taken, 171 (9.1% of total admissions) were culture positive. The most common invasive organisms were Klebsiella pneumoniae (31.8% of invasive organisms), S.aureus (26.1%) and enterococcus species (7.3%). There were 102 contaminants (12.5% of total cultures) of which 7.8% were due to Coagulase-negative Staphylococcus (CONS). In 2013 a total of 1070 (46.8% of total admissions) blood cultures were taken, 124 (5.4% of total admissions) were culture positive. Common invasive organisms were Klebsiella pneumoniae (53.8% of invasive organisms), E. coli (12.8%) and S. aureus (10.3% ). Forty-six blood cultures were deemed contaminated (4.3% of all cultures) and of these 2.1% were due to CONS. In 2017, there were 581 blood cultures taken (26.5% of total admissions), 56 were culture positive (2.6% of total admissions). Commonly occuring invasive organisms were Klebsiella pneumoniae (32.4% of invasive organisms), Group B streptococcus (16.2%) and Acinetobacter (13.5%). Twenty-nine blood cultures were considered contaminated (5.6% of cultures) of which 1.7% were CONS. The gram-negative organisms showed an increasing resistance to penicillin, ampicillin and aminoglycosides but remained sensitive to carbapenems. Conclusions The initial reduction in positive blood cultures from 2004 to 2013 was primarily due to the reduction of contaminants, probably reflecting improved blood sampling techniques. The large reduction in Gram-negative organisms from 2013 to 2017 suggests improved infection control measures , but gram-negative organisms remained prominent in all three cohorts. Emergence of resistant organisms is concerning and in keeping with other nurseries worldwide. These data illustrate the need for antibiotic stewardship, infection control measures and ongoing surveillance.

Background: Lumbar punctures (LPs) are frequently performed in the paediatric medical emergency unit (MEU) department to diagnose or exclude meningitis. Unsuccessful lumbar punctures (LPs) cause diagnostic uncertainty which may prolong hospital stay and result in unnecessary antibiotic treatment and increased costs to the hospital and patients. It is important to determine factors that may be effective in reducing unsuccessful LPs. There is a paucity of studies on this topic from sub-Saharan Africa. Previous studies have shown inconsistent results and the use of sedation has not previously been studied. Aims: To determine the prevalence of unsuccessful lumbar punctures(LPs) and the factors influencing this in the medical emergency unit (MEU) and short stay ward (SSW) at Red Cross War Memorial Children's Hospital, Cape Town.

Background: HIV rapid antibody assays are important for screening children aged <18 months for HIV exposure and children ≥ 18 months for HIV infection. Limited available data indicate variable performance of different HIV rapid tests in comparison to laboratory HIV antibody assays. The aim of this study was to evaluate the diagnostic accuracy of 6 HIV rapid tests currently used in South Africa for screening children using whole blood. Methods: A prospective descriptive cross-sectional laboratory study was conducted at two paediatric healthcare facilities in South Africa. Sensitivity and specificity analyses and positive and negative likelihood ratios were performed. The reference standard was the laboratory HIV enzyme-linked immunosorbent assay (ELISA) test and HIV polymerase chain reaction (PCR) test. Results: Blood samples from 1159 children (896 <18 months of age) with valid HIV ELISA test results were included in the analysis. A total of 5768 HIV rapid tests (4446 in children <18 months of age) were performed. Sensitivity of HIV rapid tests for detecting HIV exposure among children <18 months of age ranged from 38.7% to 94.7%. Four HIV rapid tests attained specificity in excluding HIV exposure among children <18 months of age of >98%. Seroreversion rates were lowest with the Determine rapid test. Three HIV rapid tests (Abon, Advanced Quality, Determine) detected 100% of HIV-infected children <18 months of age, the Reveal, SD Bioline and Insti rapid tests missed 27 (41.5%), 1 (4.5%) and 1 (1.5%) of the HIV-infected children respectively. In children ≥ 18 months of age, sensitivity of rapid tests for detecting HIV infection ranged from 69.2% to 100% and specificity of all rapid tests was 100%. Conclusions: None of the 6 HIV rapid tests evaluated achieved both the World Health Organisation recommended sensitivity and specificity standards for any antibody assay used in screening for HIV exposure in children <18 months. The Determine test showed the best overall diagnostic accuracy and is therefore recommended as the preferred screening test for children. Recommendations: on the use of specific HIV rapid tests in infants and young children should be based on evaluation of their performance in the population to be tested.

Background: Pneumonia is a leading cause of death in children under - five. Epidemiology in our province at regional level has not been described since 2004, when HAART was rolled out and pneumococcal conjugate vaccination (PCV) was introduced. Objectives: Describe the demographic profile, disease severity, risks for transfer and mortality and the management of children >2 months, admitted with CAP over a one year period. Methods: Retrospective descriptive study of every second patient (>2 months to 13 years) admitted to Somerset Hospital in 2012 with the diagnosis of CAP. Demographic, clinical and outcome data were extracted from hospital records and analysed using STATA®. Results: Of 380 cases reviewed, 90% had severe disease; the median age was 9.4 months (IQR 4.8 - 23). Of these 89 (23%) were LBW (<2500g) and 75 (20%) were born premature. Median age at presentation for these groups was 5.7 months compared with 10.6 months in t erm children ( p=0.0003 ). Forty - one (12%) were severely malnourished; 34 (9%) were HIV - positive. Children below 1 0 /12 were more likely to have incomplete immunisations (57/190, p=0.011). Only 15% of TB - exposed children < 5 years were on Isoniazid Prevention Therapy (IPT). Prevalence of comorbid conditions was high. Median duration of stay was 3 days (IQR 2 - 6); this increased to 6.5 (IQR 4.5 - 9.5) with neurological disease and 6 (IQR4 - 10) with proven RSV. Seventeen patients (4.5%) required transfer to tertiary level. Mortality rate was 0.5%. Conclusion: Preventative measures must focus on populations at risk - LBW and preterm children in first year of life, malnourished children and those with comorbidities like HIV. Immunisation and IPT rates can be improved.

The aim of this study is to investigate the combined effect of IPT [INH preventative therapy] and ART [antiretroviral therapy] on TB incidence in HIV-infected children. A cohort analysis will be performed using data from a prospective, double-blinded placebo controlled trial of INH versus placebo in HIV-infected children in Cape Town, South Africa.

Includes abstract. / Includes bibliographical references (leaves 151-165). / Aim: To describe the spectrum of tuberculosis in children <15 years of age attending Red Cross War Memorial Children's Hospital between January 2006 and December 2008. Methods: A retrospective review of a paper-based Notifications Register and a database of culture-confirmed tuberculosis were undertaken. Laboratory and clinical data were analysed. Results: 1,314 episodes of tuberculosis were identified amongst 1,300 children. 433 (33%) of all cases were culture-confirmed; however, 120 (27.7%) of all culture-confirmed cases were not recorded in the paper-based Notifications Register. Conclusions: To improve the clinical service, detection of HIV co-infection in children undergoing evaluation for tuberculosis should be enhanced and strategies adopted to ensure that all children with culture- confirmed disease are notified and access antituberculosis therapy.