Background Many critically ill children in South Africa are cared for in regional hospitals by general Paediatricians. Critically ill adults and children are usually cared for in the same units. There is limited data on the numbers of children admitted and the outcomes of these children. Objective To describe the patient profile and outcomes of children admitted to a general high care unit (HCU) in a regional hospital in the Western Cape, South Africa. Methods This was a retrospective descriptive study of all children admitted to the HCU of George Regional Hospital during a one year period (2016). Demographic data, HIV, anthropometric data, immunisation status, diagnoses, medical interventions, length of stay, death or survival, and referral data to the tertiary paediatric intensive care unit (PICU) were collected. The PIM3 score and Standardized Mortality Ratio (SMR) was calculated. Results Thirty percent (144/468) of the HCU admissions were children. Most (70%) were admitted after hours. Half were under 9 months (range 3 days to 149 months). Sixty-five percent of the children required respiratory support and 45% needed inotropic support. Twenty percent of the children were transferred to the PICU. Twelve children (8,5%) died with most deaths (75%) occurring at regional level. Half of the deaths were due to sepsis with pneumonia (25%) and diarrhoea with shock (25%) accounting for the rest. The cumulative PIM3 score was 9.049 (95%CI 6.430-11.668) with an SMR of 1.326 (95%CI 1.028-1.866) observed. Conclusion Critically ill children accounted for a third of HCU admissions. Most children needed medical interventions. These require specific training and equipment that are often lacking. After hours admissions also put strain on limited staff. Most children were successfully discharged demonstrating a good outcome. This was achievable with good channels of communication and transport to a tertiary PICU.

Bibliography: leaves 129-163. / There is little information on the aetiology and outcome of HIV-associated pneumonia in African children and no comprehensive data from South Africa. Studies of HIV-infected adult in Africa reported that the spectrum of pulmonary disease differs from that of developed countries with tuberculosis and pyogenic pneumonia predominating and Pneumocystis carinii pneumonia (PCP) occurring uncommonly. Knowledge of the aetiology and outcome of pneumonia is important for the development of paediatric management guidelines and of policies for allocation of resources especially in South Africa, where the HIV pandemic has resulted in increasing numbers of HIV-positive children requiring admission to hospital or intensive care units for pneumonia. Furthermore in countries with limited resources, development of cost effective diagnostic procedures to investigate the aetiology of pneumonia is necessary.

Includes bibliographical references / In this study we sought to more comprehensively analyse antigen-specific CD4 T cell responses induced by vaccination and to examine the effects of latent M. tb infection on these responses. We had two broad objectives: Firstly, to determine the effects of latent M. tb infection on epitope recognition by mycobacteria-specific CD4 T cells and to design HLA class II tetramers for detection of these cells. Secondly, to characterise antigen-specific CD4 T cells following vaccination with the novel vaccine candidate, H1:IC31, by measuring transcriptomic, phenotypic and functional attributes, and to determine the effects of latent infection on these responses. Firstly, we found that acquisition of M.tb infection did not alter the breadth and/or pattern of Ag85A/ B CD4 T cell epitopes recognised. We determined the HLA allele restriction of identified epitopes, and designed HLA class II tetramers for detection of Ag85-specific CD4 T cells. These results suggest that latent infection does not alter CD4 T cell epitope breadth within Ag85A/ B elicited by BCG vaccination and/or exposure to environmental mycobacteria. The second finding of this work is that underlying infection drives a more effector-like H1-specific CD4 T response after vaccination. Following vaccination M. tb-infected adolescents had higher frequencies of H1-specific CD4 T cells compared with uninfected adolescents. Additionally, H1-specific CD4 T cells from infected adolescents predominantly displayed a CCR7 - CD45RA - effector memory phenotype, had higher proportions of IFN-γ + TNF-α + IL-2 + cells, and expressed higher levels mRNA transcripts encoding effector molecules such as granzyme K and perforin, compared with uninfected adolescents. By contrast, H1-specific CD4 T cells in uninfected adolescents displayed a less differentiated memory phenotype, and had increased expression of central memory genes, compared to cells from infected adolescents. Thirdly, we found that Ag85B and ESAT-6-specific CD4 T cells exhibited markedly distinct transcriptomic profiles, memory phenotypes and cytokine expression patterns in M.tb infected adolescents. The data suggested that ESAT-6-specific cells preferentially drove the effector-like H1-specific response in M.tb infected adolescents. We conclude that while underlying M.tb infection does not affect the epitopes recognized by mycobacteria-specific CD4 T cells, but may promote and maintain effector memory antigen-specific CD4 T cells endowed with immediate effector function and tissue homing.

This work is concerned with the application of scintigraphy in studies of foregut motility in paediatric patients; notably oesophageal transit during swallowing, gastro oesophageal reflux (GOR) and stomach emptying as measured by the gastric contents 30 and 120 minutes after deglutition of liquid. Relevant anatomy, physiology, pathophysiology and non-radioisotopic methods of gastro oesophageal examination are outlined. The extremely important question of dose deposited by ionising radiation in paediatric patients is also considered. Because currently available estimations of absorbed dose after swallowing non- absorbable radionuclides are unsatisfactory and often contradictory, a new model was derived. It is based on more physiological principles than previous models, with a continuously varying exponential passage between four compartments in the gastrointestinal tract. From a review of previous work and our experience, a standard method of examination was developed. There is emphasis on normal physiological manoeuvres. The broad extent of useful information available in the study stems from the positions in which the patient is investigated, the quantity of labelled fluid swallowed, its physiological nature and observations of oesophageal transit, GOR, gastric emptying and pulmonary aspiration after two hours. The wide range of paediatric problems amenable to investigation by this means is described, including those of a life-threatening nature. Also, the importance of using this examination to determine the likelihood of successful surgical intervention in the gastro oesophageal region is explained. By using the observations made during swallows in neonates, the closure of the lower oesophageal sphincter (LOS) was observed during a short series of rapid deglutitions. This extends previous knowledge of the function of the neonatal LOS. These findings were very clearly demonstrated by the condensed image technique. A comparison between the abilities of radiology and scintigraphy to detect GOR in paediatric patients, with and without oesophagitis, gives unequivocal results in favour of scintigraphy. Two independent clear correlations between oesophageal transit time and the severity of GOR and age are demonstrated by variance and correlation analysis. The mean duration of GOR, maximum height of a GOR, gastric contents 30 and 120 min after deglutition, the effect of the nature of liquid swallowed and age are also examined and their relations are described. The application of the method to assess drug response is illustrated by the paediatric use of cisapride, an experimental drug which increases acetylcholinesterase release. The deductions from this work include values of the radiation dose deposited in paediatric patients of various ages, after swallowing non- absorbed Tc-99m compounds. Other contributions are a scintigraphic means to allow recognition of the importance of oesophageal dysmotility in paediatrics, especially in the absence of GOR and its relevance to the efficacy of surgery in cases of apparent GOR. Also, this gastro oesophageal scintigraphic study provided information on the paediatric use of cisapride, the relevance of GOR to repeated respiratory problems and the recognition of a new paediatric syndrome analogous to the diffuse oesophageal spasm syndrome of adulthood. It has been demonstrated that a routine, uncomplicated, paediatric scintigraphic examination, useful for investigating a wide range of problems in both a first and third world setting is possible for a nuclear medicine practitioner with normally available radiopharmaceuticals, equipment and radiographical expertise.

Background Acute kidney injury (AKI) is a frequent complication of children admitted to the paediatric intensive care unit and is associated with significant short term and long -term consequences. The causes vary from conditions that decrease intravascular volume to the use of nephrotoxic medications. One key management modality of AKI is the use of diuretics to reduce fluid overload which is an important indication for initiation of renal replacement therapy (RRT) - dialysis and also an important indicator of morbidity and mortality. Aminophylline, a drug that is well known for its use in the treatment of bronchial asthma is also purported to have diuretic effects on the kidneys. A paucity of data to support the use of aminophylline as diuretic and especially in children has occurred until a recent renewal of interest in this drug as a diuretic. In the Paediatric intensive care unit (PICU) of the Red Cross War Memorial Children's Hospital (RCWMCH), the use of aminophylline to augment urine output started in the early 2000s.This retrospective case-cross over study assesses the effect aminophylline in critically ill children with AKI; specifically, the effect on urine output, improvements in serum creatinine levels or limitations of renal replacement therapy as well as any age-related differences in aminophylline effects. Methods Children admitted to the PICU of RCWMCH with AKI (from 2012 to June 2018) were identified through a search of the PICU database, folders of cases were obtained, and a folder review carried out. Cases that fulfilled the inclusion criteria (that is children admitted to PICU with AKI who received aminophylline) were subsequently recruited. Data captured and analyzed included demographics, underlying disease conditions, medications, vital signs, urine output, renal function, arterial blood gases, RRT and outcomes of AKI. Results Thirty-five children were analyzed. Urine output increased from a median of 0.4mls/kg/hr [IQR: 0.1, 1.1] at six hours prior to aminophylline administration to 0.6mls/kg/hr[IQR: 0.2, 1.9] at six hours post aminophylline therap,1.0mls/kg/hr(IQR:0.2, 2.7) after twelve hours and 1.6 mls/kg/hr(IQR:0.2, 4.2) after twenty-four hours and this was statistically significant based on the Friedman's analysis of variance test (p=0.001).The median change in postaminophylline urine output after six hours was 0.05mls/kg/hr (IQR:0.0, 0.6) and this change did not vary significantly across the age groups (p=0.530). There was no significant change in serum creatinine levels six hours pre and post- aminophylline administration [109(77,227), 125.5(82,200) micromole/l] respectively, p=0.135. Sixteen out of the thirty-five children (45.7%) required renal replacement therapy.

Introduction: There are limited data on the chest X-ray (CXR) abnormalities in human immunodeficiency virus (HIV)-infected children in low- and middle-income countries (LMIC's). Aim: To investigate the evolution of CXR abnormalities in HIV-infected children in LMIC's, to correlate this with the severity of HIV-disease, and to assess the impact of anti-retroviral therapy (ART). Method: A prospective longitudinal study evaluating clinical, immunological and radiographic parameters at regular intervals over a minimum of 24 months. CXR abnormalities were stratified by severity and deemed persistent if present for 6 consecutive months or longer. Univariate and multiple logistic regression analyses assessed associations between radiological and clinical/immunological parameters at enrolment. An ordinal multiple logistic regression model assessed the association of enrolment and time-dependent variables with CXR findings over time.

Introduction/Purpose: Lennox-Gastaut Syndrome (LGS) is one of the most common refractory epilepsies of childhood with significant morbidity and mortality. However there is paucity of data of this syndrome in resource limited settings (RLS). We sought to delineate the phenomenology, diagnosis, aetiologies, management and outcomes of children referred with LGS in the Western Cape Province of South Africa. To further identify early clinical markers differentiating LGS from other types of epilepsy. Methods. This retrospective observational cohort study included all children between 1 to < 18 years of age in the neurology database with a referral label of LGS between 2000-2018. The group were critiqued for those who met the diagnostic criteria of LGS. Then were categorized into those with confirmed LGS and remainder were not- LGS. Data of the social demographics, age of seizure onset, etiology, preceding epileptic spasms, and semiology of epilepsy types, management interventions were reviewed to identify key diagnostic indicators to permit early and targeted interventions for children with this epilepsy syndrome. Results; Of 2551 children managed with epilepsy, 110 were suspected at presentation to have LGS of these 66 records were available for assessment. The median (IQR) age in months at presentation was 35(16.0-54.5) with a slight male (37/66) predominance. 43(65%) met the criteria LGS and 23(35%) were not-LGS. 34(52%) had no identifiable cause for their epilepsy whilst a structural and metabolic cause were identified in 25(38%) and 3(5%) respectively. Moderate or severe cognitive impairment was associated with LGS (OR 2.59, p = 0.02 and OR =3.15, p = 0.01) and so were tonic seizures (OR=4.03, p=0.04). The most common diagnoses in the not-LGS group were other types of DEE not meeting the LGS criteria (15%) and uncategorised epileptic syndromes 11%. Conclusion; Over third of the children in this cohort were erroneously referred with LGS early in their course. This has implications for their management and prognostic counselling. Identification of indicators such as tonic seizures and moderate or severe intellectual/cognitive impairment are useful early markers which support a diagnosis of LGS and could be viable for use in our setting.

Neurodevelopmental and behavioural tools, used to assess children's cognitive and psychological development, play important supportive roles in clinical decision-making processes. It is therefore important that inferences made based on the information generated by these tools are valid and reliable. Because validity and reliability are inextricably tied to the context in which the tool is administered, it is critical that tools, including established “gold standard” tools, undergo ongoing psychometric evaluation. This is particularly important when tools are used in contexts different to that in which the original tool was developed. The use of poorly performing measures in clinical settings may result in a higher risk of misinterpretation of results or misdiagnosis, carrying serious implications for provision of interventions. This dissertation explored the psychometric properties of two frequently used behavioural tools in a South African context. The first aim of the dissertation was to investigate the use, cultural appropriateness, and psychometric soundness of Achenbach System of Empirically Based Assessment (ASEBA) forms in sub-Saharan Africa. The ASEBA forms are used worldwide to screen children and adolescents for behavioural and emotional problems. To achieve this aim, I conducted a systematic review of the psychometric properties of the ASEBA forms in sub-Saharan Africa. The second aim was to evaluate the structural and construct validity of a commonly used measure of AttentionDeficit/Hyperactivity Disorder (ADHD), the Swanson, Nolan, and Pelham ADHD Rating Scale (SNAP-IV), in a sample of South African children with neurodevelopmental disorders (NDDs), including Autism Spectrum Disorder and Intellectual Disability. The systematic review identified 58 studies with sub-Saharan African participants that reported measurement properties of the ASEBA forms. Most studies came from Southern (n = 29, 50%) or East African (n = 25, 43%) countries. Forty-nine studies (84%) used translated versions of the tool, but details regarding the translation process, if available, were often sparse. Most studies (n = 47, 81%) only reported internal consistency (using coefficient alpha) for one or more subscales. The methodological quality of the psychometric evaluations varied considerably across all measurement properties, except for internal consistency. There is limited good quality psychometric evidence available for the ASEBA forms in sub-Saharan Africa. Recommendations include implementing a standardised procedure for conducting and reporting translation processes and conducting more comprehensive psychometric evaluations of the translated versions of the tools. Parents of 109 children with one or more diagnosed NDDs completed the SNAP-IV. A subset of parents (n = 79) also completed the ASEBA Child Behaviour Checklist (CBCL/6-18). We conducted a confirmatory factor analysis to inspect the two-factor structure of the SNAP-IV (Inattention + Hyperactivity-Impulsivity). We also calculated ordinal coefficient alpha (α) to estimate internal consistency. Finally, we correlated scores of SNAP-IV and CBCL/6-18 subscales to estimate concurrent, convergent (ADHD + externalizing behaviour), and discriminant (ADHD + internalizing behaviour) validity respectively. The two-factor model performed acceptably (χ2 (134) = 249.82, p < 0.001, TLI = 0.868, RMSEA = 0.089, p < 0.001). The model fit improved after removing three problematic items, two of which were dependent on the child's level of spoken language (χ2 (89) = 135.17, p < 0.01, TLI = 0.942, RMSEA = 0.069, p = 0.096). The revised SNAP-IV subscales had acceptable internal consistencies (α = 0.85-0.86). Correlation coefficients between the SNAP-IV and ADHD-related CBCL/6-18 subscales were significant (r = 0.53- 0.62, p < 0.001). Correlations between ADHD and externalizing behaviours (r = 0.45, p < 0.001) and internalizing behaviours (r = 0.38, p < 0.001) respectively were not significantly different (z = 0.97, p = 0.165). The findings tentatively support the use of the SNAP-IV in this group of children. However, there are limitations to its performance in this population likely related to the presence of NDDs. Taken together, the findings of these two studies highlight the need for clinicians and researchers to conduct ongoing psychometric testing of behavioural tools for use with linguistically and culturally diverse sub-Saharan African populations. The data also reveal important insights regarding problems associated with using standard behavioural tools in children with complex clinical presentations.

Background: Ventilator Associated Pneumonia (VAP) is a common hospital acquired infection in children leading to an increase in morbidity and mortality. A study conducted in our PICU in 2013, showed that VAP rates decreased dramatically after implementation of a VAP bundle and appointing a VAP coordinator, to 4/1000 ventilator days. As part of a “Plan, Do, Study, Act” cycle, it was necessary to evaluate the efficacy of these interventions. Objectives: To evaluate the VAP rate in the PICU over a two year period from 2017 - 2018, and secondly to describe the causative organisms and antibiotic sensitivity/resistance patterns during this period. Methods: This was a retrospective, descriptive study using the existing PICU VAP database to identify cases. Additional information was retrieved from the PICU admission database as well as clinical folders. Results: Over the 2 years, 31 VAP cases were identified. The VAP rate in 2017 was 4.0 /1000 ventilator days and 5.4 /1000 ventilator days in 2018. Compliance with the VAP bundle was 68% in 2017 and 70% in 2018. The median(IQR) duration of ventilation in 2017 was 9 (6-12) days and 15 (11-28) days in 2018. The median(IQR) length of PICU stay in 2017 was 11 (8 – 22) days and 25 (17-37) days in 2018. The most common cultured organism was an ESBL Klebsiella pneumoniae sensitive to Amikacin and carbapenems. Conclusion: Our VAP rate has not decreased further since 2013. The VAP rate was slightly higher in 2018, and it is imperative that we improve compliance with the VAP bundle, in order to reduce VAP rates. Klebsiella pneumoniae and Pseudomonas aeruginosa were the commonest organisms causing VAPs and empiric use of Piptazobactam and Amikacin is still appropriate.

The study aimed to evaluate the nutritional status of pre-school children (0-6 years), and the activities of a local CBNP serving these children, in the Ngwaritsi health district of the Northern Province. The following objectives were identified: o To determine the anthropometric status of children 0-6 years o To determine the dietary intake of children 0-6 years o To evaluate the nutrition services offered to these children by a local CBNP o To make recommendations, based on these findings, for improving existing strategies to address malnutrition in the area.