Background: Computed tomography (CT) imaging is an indispensable tool in the management of acute paediatric illness. It offers quick answers, allowing timely lifesaving decision-making. Clinical evidence is required to maximise its benefits against radiation-exposure risks to patients and cost to the healthcare system. Aims: The study aimed to retrospectively investigate clinical presentation and indications of head CT at a tertiary paediatric hospital. Methods: Records of children presenting with acute illness to the medical emergency unit, excluding trauma, of Red Cross War Memorial Children’s Hospital, Cape Town, over one year (2013) were retrospectively reviewed. Participants were included if they underwent head CT scan within 24 hours of presentation. Clinical data were extracted from records and CT findings reported by a paediatric radiologist. Results: Inclusion criteria were met by 311 patients; 188 (60.5%) were boys. The median age was 39.2 (IQR 12.6-84.0) months. Commonest indications were seizures (n=169;54.3%), reduced level of consciousness (n=140;45.0%), headache (n=74;23.8%) and suspected ventriculoperitoneal shunt (VPS) malfunction (n=61;19.7%). In 217 (69.8%) patients CT showed no adverse findings. In the 94 (30.2%) patients in whom CT abnormalities were detected, the predominant findings were hydrocephalus (n=54;57.4%) and cerebral oedema (n=29;30.9%). Abnormal CT findings were commoner in patients with nausea or vomiting (n=21;9.3%, p=0.05) papilloedema (n=3;1.3%, p=0.015) and long tract signs (n=23;10.2%, p=0.02). Forty-seven patients (15.1%) required surgical intervention after CT of which 40 (85.1%) needed a ventricular drainage procedure. A larger proportion of patients with VPS (25/62;40.3%) required surgical intervention compared to patients without VPS (22/249;8.8%, p <0.001) Conclusion: Most children presenting with acute illness (excluding trauma) and undergoing emergency head CT have normal findings. Patients with ventriculoperitoneal shunts constituted a large proportion of patients requiring intervention after CT. Considerations should be made to use clinical presentation to select patients most likely to benefit from CT.

Includes bibliographical references (leaves 284-314). / Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations on chromosome 7 in the gene for the CFTR protein. This gene encodes for a chloride channel on the apical surface of certain epithelial cells. The clinical manifestations of CF largely arise out of the resultant defect in water and electrolyte secretions in exocrine glands and epithelia such as are found in the pancreas, respiratory, gastrointestinal and genital tracts and sweat glands. First delineated as a clinical entity in the mid-20th century, CF was shown to be identifiable through the demonstration of elevated electrolyte levels in sweat - the sweat test. After many false starts, the underlying genetic defect was identified in the 1980s, culminating in the identification of the defective gene in 1989. This opened up possibilities of more accurate diagnosis and targeted treatments. Treatment of CF with pancreatic enzyme replacement therapy and antibiotics in the 1950s proved successful in controlling some of the severe and often fatal aspects of the disease. Further refinements to nutritional and antimicrobial therapies in the 1970s and 1980s produced rapid increases in longevity in many patients with CF. In SA, CF' has been identified since the 1950s. Clinical and research activities developed in the 1980s, mainly focused on the epidemiological and genetic aspects. Two clinical studies described features in children in Cape Town and adults in Johannesburg. My own clinical involvement in the RCCH's CF Service in Cape Town since 1992 led to the research activities that make up the bulk of this thesis. The thesis describes a number of aspects of CF as it affects patients in SA. The study population (described in Chapter 2) for most of the projects consists of 181 CF patients born between October 1974 and September 2003 who were identified by a combination of clinical features, positive sweat or genetic tests and/or post-mortem findings. All were resident in the Western Cape Province and received at least part of their health care at the RCCH. One hundred and sixty (88%) were born in the province and 21 settled in the province from elsewhere. Cape Town is unique in SA for its population demographics and the CF patients reflect this. CF has mainly been identified in coloured and white patients. Four black cases have been diagnosed. Compared with the CF population as described in the early 1980s, the CF population in the 21st century is larger (100 versus 64), older and there is a greater proportion of coloured patients. Nearly 3 in every 4 patients live in Cape Town.

Includes bibliographical references (leaves 85-96). / Infection with Mycobacterium tuberculosis is characterised by diverse outcomes; the majority of infected individuals remain well and yet others develop disease ranging from limited pulmonary tuberculosis to severe disseminated disease. The reasons for this diverse outcome are poorly understood, but host factors are thought to play an important role. In particular, a genetic component to susceptibility to tuberculosis has been proposed. An important clue was the description of a group of Maltese children with an unusual susceptibility to progressive non-tuberculous mycobacterial infections. These patients showed defective tumor necrosis factor (TNF) production in response to endotoxin and a failure to upregulate TNF production in response to interferon gamma as well as diminished interferon gamma production during T-cell proliferation. They were found to lack expression of the interferon gamma receptor ligand-binding chain (IFN-yR1) on their cell surfaces due to a single point substitution resulting in a truncated protein. Since then other defects in the type 1 cytokine pathway leading to susceptibility to non-tuberculous mycobacteria, as well as to tuberculosis, have been described in rare isolated cases. From these findings, the hypothesis arose that less severe mutations in such pathways might individually, or in combination, lead to increased susceptibility to tuberculosis in the general population. The following study forms part of a larger multi-centre collaboration, which aims to better understand the genetic basis of susceptibility to mycobacterial infection by addressing this hypothesis. The approach taken has been the recruitment and immuno-phenotyping of a large group of children with tuberculosis as well as control subjects. Candidate genes, of the type 1 cytokine pathways being investigated, include interferon gamma, interleukin­12 and their receptors and TNF. The focus of the study described in this thesis has been the screening of a sub-cohort of patients and control subjects for DNA sequence alterations in the TNF and TNFR1 genes. The individuals in this cohort were selected on the basis of their whole blood stimulation assays, where either high or low levels of TNF in response to non-specific stimulatory factors, were the determining criteria. It was assumed that these two phenotypic groupings would be enriched for gene variants contributing to the TNF responses recorded in the stimulation assays. Once identified, these polymorphisms would be screened for frequencies in the broader patient and control groupings and assessed for any association with susceptibility to tuberculosis. This study was considered important in attempting to explain which genes and their polymorphisms are involved in determining the high prevalence of tuberculosis in African populations.

Includes bibliographical references (leaf 13).

Background: Biliary atresia (BA) is a progressive obstructive cholangiopathy of unknown aetiology, occurring during the perinatal period. If left untreated it rapidly progresses to hepatic fibrosis and cirrhosis, with death occurring within 2 years. It is the leading cause of end-stage liver disease in the paediatric population and remains the most common indication for paediatric liver transplantation in South Africa. Objectives: Despite a wealth of information from developed countries, very little information is available in Africa and other developing nations. This study aimed to describe the age of presentation, clinical course and outcome of infants presenting to Red Cross War Memorial Children's Hospital (RCWMCH) with BA. Methods: A retrospective folder review was conducted on all patients with BA presenting to RCWMCH between January 2003 and December 2013. The main outcomes assessed were median time to presentation to tertiary services, clearance of jaundice post Kasai procedure (bilirubin <20μmol/L) and 2- and 5-year overall survival (OS) and survival with native liver (SNL). Results: The median age at presentation in the 80 cases reviewed was 70 days. Kasai procedure (KP) was performed in 62 (77.5%) patients at a median age of 68 days. 18 patients who presented late did not undergo KP. Clearance of jaundice was achieved in 39% of KPs. 13 patients underwent KP beyond 90 days with a success rate of 38%. 2- and 5-year SNL rates were 41% and 37.5% respectively with OS of 59% at 2-years and 56% at 5-years. Liver transplant was only performed in 12 of the 54 patients who showed progression to require transplantation. Conclusions: Jaundice clearance post KP and SNL compared favourably with international figures, however, lower overall survival rates reflected lack of access to transplantation. Age at KP was not a predictor of poor outcome.

Objective: Acute lower respiratory tract infection (ALRTI) remains an important cause of childhood morbidity and mortality in low and middle income countries (LMIC). This study aims to describe the clinical features of children admitted to a Pediatric Intensive Care Unit (PICU) with severe ALRTI and to investigate risk factors, clinical course and in-hospital outcome. Design: Retrospective cohort study Setting: Red Cross War Memorial Children's Hospital, Cape Town, South Africa Patients: 265 children (0-12years) admitted to the PICU during 2012 with a primary diagnosis of ALRTI. Intervention: None. Measurements and main results: 265 patients [median (interquartile range, IQR) age 4 months (2-12months)] were admitted with ALRTI, 157(59.3%) were male. Co-morbid disease was present in 102(38.5%) including cardiac disease in 42(15.9%) or tuberculosis in 7(6.4%) . While only 27(10.2%) were HIV infected, 87(32.8%) children were HIV exposed. The in-hospital mortality was 34(12.8%); 24(9.1%) died in PICU and a further 10 in the medical wards following discharge from PICU. The median duration of ICU and hospital stay was 4.0 days (2.0-8.0) and 12.5 days (7.9-28.0) respectively. Most [192 (72.5%)] children required invasive ventilatory support, while 42 (15.8%) patients required cardiac inotropic support. Risk factors for mortality included severe malnutrition (Odds ratio (OR) 8.25; 95% CI 1.47- 46.21); informal housing without access to piped water and/or electricity (OR11.87; CI 1.89- 20.81); or need for inotropic support (OR 44.35; CI 8.20-239.92). HIV exposure or infection was associated with a significantly longer duration of hospital stay (p=0.002). Conclusion: Severe ALRTI occurs predominantly in young infants and is associated with a high mortality. Several sociodemographic risk factors impact on the risk of severe disease and poorer outcome.

Includes bibliographical references. / Acute bacterial meningitis is defined as the inflammation of the meninges. It is caused by various bacteria and the specific aetiology is age dependant. In the neonatal period the causative organisms are: Group B streptococci, Gram - negative bacilli (e.g.: E. coli, Klebsiella spp, Enterobacter spp, Salmonella spp) and Listeria monocytogenes. In infants and children up to the age of 5 the most common causative organisms include: Streptococcus pneumoniae, Haemophilus influenzae type B (Hib)and Neiseria meningitidis. The two chief causes of bacterial meningitis in children older than 5 are S. pneumoniae and N. meningitidis. Various studies have been performed to look at the profile of meningitis among the paediatric population. Objective: To investigate the aetiology of acute bacterial meningitis in South African newborns and children from 2005 - 2010.

Introduction: Anaphylaxis is a severe, life-threatening generalized hypersensitivity reaction. The European Anaphylaxis Registry was established to review and improve medical management of these patients, facilitate accurate comparisons between centres, highlight public health implications, and examine trends in treatment over time. This is replicated here in a South African setting. Methods: Participants comprised patients treated at Red Cross War Memorial Children’s Hospital (RCWMCH) for severe allergic reactions between January 2014 and August 2016. Recruitment was by applying relevant ICD- 10 coding to the hospital’s clinical summary system of admissions and discharges, the pharmacy’s records of adrenaline autoinjector dispensing, and referrals from the allergy department’s clinical staff. Participants who were screened but did not meet inclusion criteria after preliminary questioning and/or folder review were excluded. 156 episodes were analyzed. A local web-based registry was established, and used to capture data collected via a questionnaire in interviews at the RCWMCH Allergy Clinic. Results: Males, younger children, and participants of coloured ethnicity were more frequently affected. Skin and mucosa was most commonly involved, followed by respiratory and gastrointestinal upset, with cardiovascular and other systemic involvement occurring infrequently. More than 40% of episodes were graded as severe. Specific IgE was the most frequently requested testing. Nearly two-thirds of patients were seen with a recurrent episode. Food-related triggers predominated and decreased with age: particularly peanut, hen’s egg, fish, cashew nuts and cows’ milk. There was a strong correlation with atopic conditions, in excess of international trends. 3 Adrenaline was rarely used, by both lay persons when previously prescribed, and by professional attenders. Hospital admissions were infrequent, and no deaths were recorded. Prophylactic measures were almost universally instituted, but the success thereof could be improved. Conclusion: This is the first local comprehensive description of anaphylactic trends. Further areas of research are suggested: to investigate the propensity for allergic reactions in the coloured population, our much higher rate of association with other atopic disorders compared to international patterns, comparison of our baseline comorbid conditions for contextual analysis, and a review of barriers to care. Ongoing education and training to patients, parents, teachers, and health care workers is identified as a major area requiring intensification.

Objectives: Cystic fibrosis (CF) is one of the commonest inherited disorders in South Africa, affecting all population groups. Progressive pulmonary disease with declining forced expiratory volume in one second (FEV1) is the main predictor of morbidity and mortality in individuals with CF. This study aimed to describe the change in lung function, nutritional status and mortality of children and adolescents with CF, attending the Red Cross War Memorial Children’s Hospital (RCWMCH) CF Clinic and to identify factors associated with poor pulmonary function outcomes and mortality. Methods: A retrospective study was conducted of the clinical records and annual pulmonary function tests, with matched body mass index (BMI), of children between 5 and 18 completed years of age attending the RCWMCH CF clinic in Cape Town, South Africa, between January 2007 and December 2016. Results: A total of 143 study participants (51.4% male; median age at diagnosis 5.5 months) were included. Population mean FEV1 and body mass index (BMI) Z scores improved from -2.5  1.70 to -1.9  1.70 (p = 0.1) and from -0.7  1.2 to -0.4  1.2 (p = 0.3) respectively from 2007 to 2016. FEV1 Z score declined by an average of 0.17 per year of age and this was mirrored by an average decline in BMI Z scores of 0.07 for each year of advancing age. FEV1 decline was greater in patients who died compared to those who survived (p = 0.03). Of the factors postulated to influence lung function decline, there was no significant correlation between FEV1 at any age and age of diagnosis, sex, ethnicity, genotype, geographical location, pancreatic status, or Methicillinresistant S. aureus or Aspergillus spp. infection. Participants who were ever infected or colonised with P. Aeruginosa had consistently lower FEV1, however this difference only became significant at certain ages. On multiple stepwise regression analysis, only FEV1 at age 6 was found to be a significant independent predictor of mortality (adjusted odds ratio (95% CI) 0.5 (0.3 – 0.8); p = 0.005). Conclusion: Pulmonary function of children with cystic fibrosis improved non-significantly over the 10-year study period. FEV1 at age 6 was identified as an independent predictor for CF-related mortality. Early diagnosis and measurement of pulmonary function in young children with CF is essential to identify children at risk of poor outcomes.

Includes bibliographical references. / Transportation of critically ill children by inexperienced personnel may be associated with increased risk of transfer-related adverse events and mortality. To audit paediatric intensive care unit (PICU) transfer activity and transfer-related adverse events in a resource-limited setting. Twenty-two bed regional PICU of a university children's hospital in Cape Town, South Africa. Prospective one-year audit of all children transferred directly to PICU from other hospitals. Data were collected for patient demographics and diagnostic category, referring hospital, transferring personnel, mode of transport, and the incidence of technical, clinical, and critical adverse events. Data are median (interquartile range, IQR). The transfers of 202 children, median age 2.8 months (1.1-14), median weight 3.5 kg (2.5-8.1) were analysed.