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.

Includes bibliographical references (leaves 54-59). / Central nervous system involvement contributes significantly to the morbidity and mortality of paediatric HIV infection. The spectrum of CNS morbidity varies from minor developmental disabilities to severe, progressive encephalopathy. Therefore regular developmental evaluation should be regarded as an essential component of the overall care of HIV-infected children. Antiretroviral therapy may arrest or even reverse neurocognitive and motor deficits associated with HIV infection.

Background: The most prevalent, most lethal of the inherited dystrophies is Duchenne Muscular Dystrophy (DMD) and globally, the incidence is 1 in 3500 live male births. Currently, DMD has no cure, the latest care guidelines, especially on corticosteroids, cardiac interventions, and non-invasive ventilation, are all associated with improved muscle function, survival and quality of life. This reflects the fact that the natural history of DMD has been changed by these effective measures. Despite these advances, the progression and disastrous outcome of the disease cannot be modified. Potential therapeutic approaches that target the causative genetic mutations raise hopes of promising treatment for DMD. Many clinical trials of molecular genetic therapies have been planned and conducted for DMD. In South Africa, even though mutational characteristics of South African DMD/BMD patients have been described in several studies, the development of experimental therapies faces many challenges due to the lack of epidemiological data, the natural history of the disease and information about clinical care amongst Africans. Understanding the disease course of the local population can lead to better care approaches, further with the possibility of gene therapy becoming available, patients that would qualify for such treatment need to be identified. Hence the need for a DMD specific disease registry. Objective: This study aims to describe the concept and design of the first DMD disease registry of South Africa using Research Electronic Data Capture (REDCap) Methods: A comprehensive literature review was undertaken to identify the key areas of DMD, which must be recorded to permit comparison across disease expression and intervention variables. The registry was developed using REDCap's web based online designer accessed through the Clinical Research Centre (CRC) in the Faculty of Health Sciences at the University of Cape Town, and the workflow methodology was adopted to manage the registry. Clinical data from DMD patients form the database and consists of seven parts: 1) Enrolment details, 2) Background data, 3) Current disease, 4) Schooling, career prospects, and life style/psychological details, 5) basic activity of living scale, 6) power chart, 7) current motor function/symptoms. Electronic case report forms were created from these clinical data by the use of REDCap and for specific variables serial entries were possible relating to disease progression. We adopted international data standards proposed by TREAT-NMD, a global network of registries on DMD to ensure our data is internationalised and comparable to other registries. Results: Retrospective data entry combined with dynamic prospective recording of data was utilized in this project. Building on an existing basic database, 100 confirmed DMD boys are currently eligible for inclusion into the registry. The registry database consists of 7 forms collecting information on clinical and genetic information, which is subdivided into 100 items making a total of 210 variables. As our registry is an on-going study, sequential analysis of accumulated data will be done going forward to review trends on our DMD patients. Conclusions: This work describes the concept and design of our DMD registry and the steps followed to its establishment with REDCap. The focus is to consolidate clinical and genetic information on South African DMD patients that will translate to clinical research and form the basis for this patient information to be linked nationally and internationally. It is the hope that such an effort can be replicated in the conceptualisation of new disease registries.

Background: Malawi has one of the highest HIV/AIDS prevalence rates in sub-Sahara Africa. It has the ninth largest HIV burden in the world. Following the 2010 WHO PMTCT recommendations Malawi started providing lifelong ART to HIV-infected pregnant and lactating women regardless of clinical stage or CD4 count (option B+) in July 2011. Aim To assess the outcome of pregnant and lactating mothers receiving ART (option B+) and their infants less than 24 months in a rural health district of Malawi. Methods: A retrospective cohort study of option B+ women who were initiated on ART between 1st July 2011 and 31st December 2012 was conducted in Ntchisi district. Their exposed infants were also enrolled in the study. The study participants were followed up to 31st December 2013. Data was mainly collected from ART registers, ANC registers and ART patient master cards using structured questionnaires. Data analysis was done using Microsoft Excel and Statistical Package for Social Science (SPSS). Results: A total of 201 option B+ mothers, 136 pregnant women and 65 lactating mothers were enrolled in our study. Their median age was 32 years. 19.9% of HIV pregnant mothers started ANC at less than 12 weeks gestation and 21% attended the recommended four ANC visits or more. The proportion of pregnant and lactating women tested for HIV was 89.6%. Uptake of ART in HIV positive pregnant and lactating women was 80.1%. Of 54 option B+ mothers enrolled in the July 2011-December 2011 cohort, 70.4%, 64.8%, 57.4% and 55.6 % were retained at 3, 6, 12 and 24 months respectively, and 73.5%, 66% and 65.3% of 147 option B+ mother enrolled in the January 2012-December 2012 cohort were retained at 3, 6 and 12 months respectively. Out of 126 option B+ who remained in care in December 2013, 89 (70.6%) had adherence rate of 95% or more in the last visit of the October-December 2013 quarter. Of all women who commenced option B+ during pregnancy, 56/ 77 (72.7%) who remained in care during the October-December 2013 quarter had adherence of at least 95%, while 33/49 (67.3%) of women who commenced option B+ during lactation and who remained in care during the October - Dec ember 2013 quarter had adherence of at least 95% or more. This difference was not statistically significant, OR = 1.2, 95% CI: 0.6-2.8. A total of 198 exposed infants were enrolled and their median birth weight was 3.2 kg. Uptake of PCR/rapid test for the infants was 73.7 %. 163/198 (82.3%) received NVP. Out of 53 exposed infants enrolled in Jul y 2011-Dec ember 2011 birth cohort, 81.1 %, 67.9 %, 5 1 % and 17 % were retained at 3, 6, 12 and 24 months respectively. In the January 2012-Dec ember 2012 cohort the proportion of exposed infant s retained were 89 %, 81.2 % and 47.6 % at 3, 6 and 12 months respectively. Of all infants tested for HIV infection during the study period, a higher proportion who were enrolled in the July-Dec ember 2011 birth cohort became HIV-infected compared to those enrolled in the January-December 2012 cohort, 7/ 3 4 ( 20. 6 %) versus 4/ 112 ( 3.6 %), OR = 7.0, 95% CI: 1.9 -25.7. A significantly higher proportion of HIV-exposed infants born to mothers who initiated ART during lactation acquired HIV infection than those born to mothers who initiated ART during pregnancy, 7/43 (16.3%) versus 4/103 (3.9%), OR = 4.8, 95% CI: 1.3 - 17.4. Conclusion: Our research findings suggest that the PMTCT programme in the Ntchisi district can be improved. Late booking during pregnancy, initiation of ART late during pregnancy or only during lactation, low retention in care for HIV pregnant and lactating mothers and their HIV-exposed infants, inadequate HIV testing of HIV-exposed infants and low ART adherence rate of HIV pregnant and lactating mothers should be addressed in order to optimize the administration and effectiveness of option B+.

Includes bibliographical references / Alcohol use and alcohol use disorders contribute a significant proportion of the burden of disease in low, middle, and high-income countries. As a result, fetal alcohol spectrum disorders (FASD) represent one of the most common preventable causes of intellectual disability globally. Understanding the core brain areas of susceptibility to prenatal alcohol as they manifest in early life is key to developing strategies for early focused identification and intervention. This thesis explored the relative impact of prenatal alcohol exposure on the brain in infants as measured by multimodal brain imaging and the relationship of these findings to early neurobehavioral and developmental status. The specific aims the thesis addressed included leveraging structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), proton magnetic resonance spectroscopy (1H-MRS) and resting sate functional MRI (rs-fMRI) scans in approximately 100 infants (50 alcohol exposed and a matched number of control, unexposed babies) at 2-4 weeks of age, to assess group differences in early brain development. Correlations between multimodal neuroimaging measures and neonatal neurobehavioral assessments and associations between early structural imaging findings and later infant developmental, as measured by the Bayley III assessment at 6 months, were further explored in the same group of infants. These studies addressed the hypothesis that maternal alcohol use in pregnancy would result in quantitative MRI abnormalities demonstrable at 2-4weeks of age and that these changes would correlate with early indicators of neurobehavior and development. Chapter 1 presents the rationale and outline of the thesis. The burden of fetal alcohol spectrum disorders (FASD) is described in the context of different resource settings around the world with detailed reference to South Africa. Chapter 2 presents a published systematic literature review of published studies of MRI in children and adolescents with prenatal alcohol exposure. Chapter 3 provides an overall description of the methods and context for this study. Although the results chapters each include a focused methods section, the word restrictions of journal articles did not allow for adequate contextual detail for the project as a whole.

Bibliography: leaves 101-110. / A specialised clinic for the diagnosis of primary immunodeficiency diseases was established at the Red Cross War Memorial Children's Hospital (RXH) in 1982. The patient load was significant as clinic records indicated that 122 primary immunodeficiency cases were diagnosed on clinical and laboratory data in the period between 1983-1999. More than fifty percent of these conditions were antibody deficiency. Of the rest, nine cases were ascribed to severe combined immunodeficiency (SCID). The aim of the project was to do (1) mutational analysis on the affected families, (2) on the basis of the mutational analysis, offer genetic counselling, (3) do carrier screening tests on the families studied, and (4) to try and find a genotype/phenotype relationship in the gamma chain gene.

Background: Children are transferred from various facilities into the paediatric intensive care unit (PICU) at the Red Cross War Memorial Children's Hospital for critical care, without a specialised paediatric transfer service. A previous audit in 2003 reported a high incidence of technical, clinical and critical adverse events during transfers. Objective: To conduct a follow -up audit on interfacility transfers into PICU to determine practice and outcome changes. Methodology: Prospective observational study of all patients transferred into PICU between 1 Dec ember 2013 and 30 November 2014 and compared to the 2003 audit by Hatherill et al. Results: Analysis was performed on 204 transfers (median (IQR) age 1.8 (0.2 – 12.6) months and compared to results reported by Hatherill et al (2003). The proportion of medical transfers decreased (49% to 34.3% p=0.003) as well as the referrals from metropolitan hospitals (34.7% to 17.6%, p = 0.0001), whilst the number of referrals from academic hospitals increased from 35.1% to 44.6% (p = 0.05). Staff accompanying transfers and transfer times remained unchanged. The proportion of fixed wing transfers increased from 14.4% to 25.5% (p=0.006) whilst Helicopter transfers decreased from 9.9% to 1% (p <0.0001). 58.4% of patients were in tubated for transfer in 2003 compared to 69.1% in 2014 (p = 0.02). The rate of technical (35.6% to 39.7%, p = 0.4), clinical (26.7% to 31.9%, p = 0.25), and critical (8.9% to 8.8%, p = 0.97) adverse events remained unchanged. PICU Mortality decreased from 16.8% to 9.45% (p=0.03) with a decrease in Standardized Mortality Rate from 1.11 to 0.68. Three children died on arrival to PICU. The communication tool was used in 45.1% of transfers and its use was noted to be associated with significantly less critical adverse events (4.3% vs. 12.5%, p = 0.048). Technical adverse events were positively correlated with the clinical adverse events (Spearman's R = 0.3; p=0.000008) and critical adverse events (Spearman's R = 0.1; p = 0.03). In turn the total number of clinical adverse events were positively correlated with the total number of critical adverse events (Spearman's R = 0.5; p < 0.000001). The multiple regression analysis for PICU mortality found the total number of clinical adverse events to be independently associated with ICU mortality (adjusted OR 95% CI 2.8 (1.7 -4.7); p = 0.0001) Conclusion: The rate and staffing structure of interfacility transfers into PICU have remained unchanged, and associated adverse event rates remain high. Changes are noted in the profile of transferred patients as well as adverse events. Efforts to formalize the paediatric transfer service must be strengthened whilst using interim measures to improve the current standard through education, improved skills and PICU support.

Includes bibiliographical references. / Mycobacterium bovis Bacille Calmette Guerin (BCG) is the only licensed tuberculosis (TB) vaccine. Despite the immunisation of 3 billion individuals with this vaccine, TB remains a major cause of mortality worldwide. Therefore, there is an urgent need for more effective TB vaccines. BCG is likely to remain central to future TB prevention strategies, which could include a BCG prime at birth, followed by boosts with novel TB vaccines within the first year of life, or at later ages. Therefore, a comprehensive understanding of BCG induced immunity is required for the successful design and implementation of novel TB vaccination strategies. This was addressed in the following two studies.The aim of the first study was to characterise specific T cell immunity following BCG vaccination. These data are critical to determine when to optimally boost BCG induced immunity in infants. We enrolled infants routinely vaccinated with BCG at birth, and determined the frequency of T cells induced by immunisation, at various time points over the first year of life. The T cells were identified by binding of cell surface markers and characterised by cell-specific cytokine production, following 12 hr incubation of infant whole blood with BCG. Multiparameter flow cytometry was used for the analysis. We found that the peak vaccine induced CD4+ T cell response occurred at 10 weeks, followed by a contraction phase. BCG specific CD4+ T cells became more poly functional, and acquired the profile of long-lived T cells (measured by Bcl-2 expression), over the first year of life.

The availability of an effective vaccine against Bordetella pertussis substantially reduced the morbidity and mortality from pertussis, however, in the last decade there appears to have been a substantial increase in pertussis cases as reported mainly in high income countries. Although it is believed that the greatest burden of pertussis, including deaths, is in low- and middle-income countries (LMICs), there seem to be little data available to back this up. This thesis set out to find data that will give some insight into the burden of pertussis in a low- and middle-income setting in infants and children with severe lower respiratory tract infection (LRTI). Given the paucity of data in LMICs, the thesis started by systematically searching for existing data that will give some indication of the possible extent of the pertussis problem in these countries. Secondly, a prospective study was conducted at a children's hospital. As hospital admission is a marker of severe disease, these children were targeted as the appropriate population in which to meaningfully conduct a primary study on the burden of pertussis. In addition to quantifying the burden by describing the prevalence of confirmed pertussis in this group of children, the study set out to look for potential factors that may be associated with increased risk of pertussis. LRTI are now commonly known to be associated with identification of multiple organisms in respiratory samples, this study aimed to also look at organisms that are detected with Bordetella pertussis; and investigate whether this association was in any way associated with severe disease or negative outcomes. Finally, this study hoped to identify clinical features that could be used to develop a more reliable clinical case definition of pertussis. Chapter 1 gives a background that justifies the undertaking of this study. In chapter 2 a systematic review quantifies, using the best available data, the burden of pertussis in LMICs. Chapter 3 clarifies the methods briefly described in the rest of the manuscript. The burden of pertussis due to the two organisms known to cause the disease, Bordetella pertussis and Bordetella parapertussis, is described in some detail. In both this chapter and the earlier mentioned systematic review (chapter 2), the burden of pertussis is stratified by subgroups to identify potential risk factors. The issue of risk is formally and specifically taken up in the chapter that follows (chapter 5) where potential risk factors are analysed, and the independent impact for some of these factors is established. The last two results chapters (chapters 6 and 7) deal respectively with the conundrum of finding other respiratory organism in the same specimen with Bordetella pertussis and failure to find useful clinical criteria that can help with improved diagnosis of pertussis. While there is no established pattern noted between pertussis and most organisms, a few give signals of being independently associated with Bordetella pertussis even if the clinical relevance is not clear at the moment. In the final chapter of the thesis (chapter 8) I conclude the thesis by making an argument that although there are still knowledge gaps, the thesis gives a clear indication that pertussis remains a serious problem in LMICs especially for some groups that show increased risk of the disease or its severe consequences.