Theses and Dissertations (Paediatrics and Child Health)

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An Evaluation of Factors Associated with Early Infant HIV Acquisition, Infant Outcomes, and 9-12 Month Infant HIV Seroreversion in the Context of PMTCT Option B+ : Prospective Data from an HIV Exposed Birth Cohort.
(University of Pretoria, 2018) Pepper, Michael Sean; Goga, Ameena Ebrahim; Avenant, T.J. (Theunis Johannes); nicolette.duplessis@up.ac.za; Du Plessis, Nicolette Marie
This PhD dissertation reports data from the very early infant diagnosis (VEID) study that was conceptualized when universal birth HIV PCR testing at Kalafong Provincial Tertiary Hospital was mandated. Three research questions were addressed: (1) What factors are associated with early infant HIV acquisition?; (2) What are the growth outcomes of HIV exposed, uninfected (HEU) infants?; and (3) What is the 9-month infant HIV seroreversion rate in the context of PMTCT Option B+ when using different rapid HIV tests? The first research chapter demonstrates that maternal HIV viral load detectable in the perinatal period, maternal combination antiretroviral therapy (cART) with a duration <1 month, and having a symptomatic infant at birth are significant predictors of early infant HIV acquisition. Small-for-gestational-age was included with the above three characteristics in multivariate analyses. Two-risk (maternal cART duration and viral load), three-risk (maternal cART duration, maternal viral load and symptomatic newborn), and four-risk (maternal cART duration, maternal viral load, symptomatic and SGA newborn) models for HIV acquisition were developed with a predictive probability score of a newborn PCR positive test of 0.28, 0.498, and 0.57 respectively. These findings could guide a targeted approach to infant HIV-testing at birth. However, using the three- and four-risk scores at a probability of 0.02 and 0.04, 20% and 24% of HIV infected infants will be missed respectively at birth compared with universal testing. Therefore, we support universal birth PCR testing within the South African PMTCT context. The second research chapter describes growth outcomes of HEU infants in relation to maternal and infant birth characteristics. Mothers were mostly breastfeeding at birth and on universal lifelong cART. Maternal to child transmission of HIV after birth were less than 1% (0.31%) and occurred mostly by 6 weeks of age. HIV infection was associated with symptoms and signs of HIV-associated immunosuppression, such as growth faltering. The hospitalization rate was 41.3/1000 person-years. Longitudinal growth trends illustrated lower weight-for-age (WAZ) and length-for-age (LAZ) in males. HEU newborns that had one or more symptoms suggestive of HIV-associated immunosuppression had lower weight trends and newborns with a birth weight <2.5kg had significantly lower WAZ, LAZ and head circumference (HC) trends. The significance of poor LAZ trends, especially in male HEU infants, remains a concern. The impact on final height and body mass index (BMI) need careful follow up to ascertain if these growth trends will have a negative impact such as higher BMI values and possibly more obesity among HEU male adolescents/young adults. Lastly, we describe seroreversion at 9 months amongst HEU infants whose mothers received cART. We observed that different rapid assays vary in performance, with specificity ranging between 45-97%. HIV ELISA testing did not document any seroreversion at nine months in our cohort. This finding highlights the need for further research to determine the age at seroreversion within the context of the PMTCT option B+ / universal maternal access to lifelong cART. It is possible that uninfected infants will remain seropositive beyond 18 months of age. Hence, future recommendations might include HIV PCR testing in infants up to 24 month of age.
Atopy and acquired immune deficiency - issues of control of two extremes of a spectrum of paediatric respiratory disorders with an immunological basis
(University of Pretoria, 2014-01-08) Van Heerden, W.F.P. (Willem Francois Petrus), 1958-; Ker, James A.; robin.green@up.ac.za; Green, Robin J.
Twenty publications are submitted. All deal with the issues of control of two ends of the spectrum of immune-mediated respiratory disorders in children, namely atopic (asthma and allergic rhinitis) and HIV-related lung disease. This submission summarises the research by the author into this spectrum of lung diseases of children in South Africa, highlighting the diversity of conditions that are not only clinically important, but also common. Understanding of all conditions is required to improve the health of children in this region. Management of chronic conditions requires two major end points - adequate and timely diagnosis and - management to control the condition. The author has a passion for improving the quality of life of children and firmly believes that the research findings will, and have, led to transformation in management of both these common disorders. This document follows the progression of the authors research work and highlights how interesting and important is the scope of two disorders which could be thought to have a central origin, namely in the T-cell. T-cells form the basis of cellular immunity and an excess of T-helper 2 cell activity promotes atopy, whilst the human immunodeficiency (HI) virus infects T-helper cells and promotes cellular immune deficiency and its attendant clinical disorders. The author’s research work is not based on the immunological basis of these conditions but does deal with the clinical implications and especially aspects relating to control of these two extremes of a clinical spectrum of disorders. To take the clarity of two diseases at the end of a spectrum to its natural conclusion these extremes are defined in aetiology or pathophysiological differences (excess versus suppression of the immune system), occurring in the affluent and poor alike versus just the poor, control being required to improve quality of life versus to save lives and finally that management requires anti-inflammatory therapy versus antibiotic and anti-infective therapy. For the eight publications based on atopic respiratory disease in children the themes are firstly that children with asthma and chronic rhinitis are diagnosed late, that most individuals with these conditions are not well controlled and finally that the reasons for lack of control are becoming obvious. For the first time, the significant lack of asthma and allergic rhinitis control in South Africa is documented. These studies suggest that, like surveys from the rest of the world, asthma control is seriously under-estimated and neglected in all asthmatics in South Africa, in both the privileged and the under-privileged. The research also defines reasons for poor asthma and allergic rhinitis control in this region. As in many studies published from around the world it is now evident that poor asthma and allergic rhinitis control cannot be blamed on any one source. A multitude of reasons underlie this phenomenon and each of the subsequent papers in this section illustrates attempts at defining these principles. The three most important reasons for poor control are probably that most asthmatics are managed in the wrong hands (by doctors who don’t understand adequate control and who aren’t empowered to use the correct therapy), that control may actually be a pipe dream and practically difficult to do or even impossible to achieve and lastly that the allergic basis of asthma is over emphasised and may not in fact determine all asthma. The subsequent papers summarise research work in the field of HV infection in children and exposes the opposite end of a spectrum of Paediatric respiratory disease and highlight research into the conditions common in HIV-infected children. Eleven papers are presented. For the diseases associated with the HI virus the major complications of inadequate diagnosis and prevention in children are acute pneumonia (especially severe pneumonia) and bronchiectasis. Bronchiolitis is not common in HIV infected children, despite epidemics of this condition in non-infected children. Passive smoking does not aggrevate or worsen disease progression in children. The complications of HIV related diseases in children require the same principles of adequate diagnosis and control as would apply to the chronic atopic conditions. Once the author delved into the disorders at the other end of the clinical spectrum, namely those associated with immune deficiency secondary to HIVinfection he faced the question of a possible relationship between the conditions. One submission explores that relationship. This research has a unique perspective, conferred by the fact that these two conditions do not occur to the same extent anywhere else in the world. Atopic respiratory conditions and HIV-related lung diseases occur side by side in abundance in this region. This perspective has created a clarity for research to address the two most important aims in clinical medicine, namely to diagnose correctly and then to manage the condition so that control is achieved. These must be universal principles of the successful practice of medicine.
Audit of neonatal transfers to a tertiary centre in the Tshwane metropolitan area
(University of Pretoria, 2005-08-03) refiloe.masekela@up.ac.za; Masekela, Refiloe; Prof M Kruger
Aim: This is an audit to determine the referral diagnosis, any resuscitation or interventional measures taken, the condition on arrival and the outcome of neonates transferred from Mamelodi Hospital to Pretoria Academic and Kalafong hospitals. Methods: Data was collected of all neonates transferred from Mamelodi hospital to the neonatal intensive care units (NICU) at Pretoria Academic and Kalafong hospitals between September 2003 and October 2004. The data was analysed for referral criteria, pre-transport resuscitation, condition on arrival and outcomes. Results: There were 42 neonates enrolled in the study. The most common reason for referral was prematurity (71.4%). Forty six percent of the full term baby referrals were for birth asphyxia. Hypothermia was found in 79% of all patients on arrival at the tertiary care NICU. There were no intravenous lines in 52% of patients, while 23% had hypoglycaemia on arrival at the receiving hospital. The mortality rate was 26.1% with five of 12 full term neonates and six of 30 preterm neonates dying. Conclusion: The study highlights the need for adequate pre-transport stabilization of neonates, which include interventions to avoid hypothermia and insertion of intravenous line with 10% Dextrose solution to prevent hypoglycaemia. There is a need to train health care staff to effectively resuscitate neonates to prevent or minimise birth asphyxia. Mothers in pre-term labour should be referred early to centres that can manage premature babies. This data will be used to develop transport protocols for transfers of high-risk neonates.
Chronic inflammatory lung disease in human immunodeficiency virus (HIV)-infected children. Epidemiological considerations, aetiological determinants and the efficacy of low dose erythromycin in bronchiectasis
(University of Pretoria, 2012) Green, Robin J.; refilwe.masekela@up.ac.za; Masekela, Refilwe
Human immunodeficiency virus (HIV) infection has reached epidemic proportions in South Africa. The availability of highly active anti-retroviral therapy (HAART) prolongs life in HIV-infected persons, who may subsequently present with chronic manifestations of HIV-infection. The respiratory morbidity attendant to HIV-infection, even in the presence of HAART is high, the aftermath of which is lung tissue destruction and bronchiectasis. As a consequence of the political decision not to offer HAART to HIV-infected children, a number of children in South Africa have been left with severe consequences of uncontrolled HIV-infection. Bronchiectasis is one of those and because children with this devastating condition were numerous in the Pretoria region, the author and her colleagues began a Chronic Lung Disease Clinic in that region. This prompted the idea of investigating both the epidemiological profiles of these children and an attempt to intervene with both standard bronchiectasis guideline care and the use of a form of therapy commonly employed in other forms of bronchiectasis. This thesis explores those ideas. Important new and novel findings that were consequent were; that bronchiectasis is diagnosed late in HIV-infected children at a mean age of 6.9 years. The predominant organisms cultured from the airways are Haemophilus influenzae and parainfluenzae in 49% of samples. Pseudomonas aeruginosa (PA), common in cystic fibrosis (CF)-bronchiectasis is an uncommon pathogen in HIV-related bronchiectasis; isolated in only 2% of specimens. Tuberculosis (TB), at least as reported, is a significant antecedent of bronchiectasis, reported in 48.5%of children. A further 21.2% of the patients had received more than two courses of anti-TB treatment. However, proof of TB infection has been lacking. Respiratory morbidity is significant with the mean forced expiratory flow in one second (FEV1) of 53%, in this cohort at the time of presentation. Thirty-six percent of all children were exposed to environmental tobacco smoke, although this was not correlated with disease severity or HIVdisease progression. There is elevation of immunoglobulins in HIV-related bronchiectasis, with a mean IgE of 79 kU/l. This was not, though, associated with HIV disease progression as previously described in adult studies, nor with the presence of allergic bronchopulmonary aspergillosis (ABPA). The elevation in IgE was also not associated with an elevation of T helper-2 mediated cytokines, confirming the lack of association with atopy. The predominant cytokine, identified is interleukin (IL)-8, both systemically and locally (in airway secretions). There was elevation of other T helper-1 driven cytokines, reflecting an ability to mediate adequate inflammatory responses, which was independent of the level of immunosuppression. With the presence of HAART, there was a decline in the pro-inflammatory cytokines over time, which may be attributed to the ongoing effect of HAART that ties in to, or goes beyond the restoration of T cell numbers. Soluble triggering receptor expressed on myeloid cells (sTREM), an innate immune marker, is elevated in children with HIV-related bronchiectasis when compared to a control group of children with cystic fibrosis-related bronchiectasis. sTREM is not associated with the presence of exacerbations and the level of immunosuppression. The use of an anti-inflammatory drug erythromycin also did not impact the sTREM values. There was also no relationship between sTREM and pro and antiinflammatory cytokines and chemokines. Fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) could not reliably predict the presence of pulmonary exacerbations. Its diagnostic value was limited to identifying disease activity in acute pneumonia. 18F-FDG PET also had no significant correlation with CRP, inflammatory cytokines or markers of HIV disease activity. In a randomised controlled trial of erythromycin, a cost-effective immunomodulatory drug, compared to placebo, erythromycin was ineffective in reducing the number of pulmonary exacerbations. Erythromycin also failed to demonstrate any effect on systemic and local pro- and anti-inflammatory cytokines/chemokines. With access to anti-retroviral therapy, airway clearance, nutritional rehabilitation and vigilant follow up there was an improvement in pulmonary function parameters and stability of the degree of bronchiectasis that we propose is probably in keeping with an organ system disease modifying effect that may be, an as yet, undefined and undescribed byproduct of HAART.
Association between postnatal maternal nutritional status, maternal HIV disease progression and infant feeding practices in 4 clinics in Pretoria, South Africa
(University of Pretoria, 2010-03-12) MacIntyre, Una Elizabeth; Wittenberg, Dankwart F.; jmatji@unicef.org; Matji, J.N. (Joan Nteboheleng)
Introduction A group of 317 HIV-1 infected pregnant women and 53 postpartum HIV-negative women were recruited for a two-year prospective descriptive study of psychosocial and other determinants of antenatally planned and actual postnatal feeding, associations between maternal status and infant feeding practices, and health outcomes. Methods The subjects were interviewed periodically for 2 years using structured research instruments. Anthropometric measurements, biomarkers of nutritional status and measurements of pysychosocial wellbeing were obtained from the mothers. Data was collected on infant feeding and outcomes for the babies. Results At recruitment, 74% of mothers planned to formula-feed. Significant differences between these women and those who planned to breastfeed emerged. After delivery, 25% of the women who antenatally planned to formula-feed changed their minds and actually breastfed. Conversely, half of the women who antenatally planned to breastfeed actually formula-fed. Some significant reasons emerged for these feeding changes. Most mothers were well-nourished or overweight. Breastfeeding mothers lost little weight between six weeks and six months after delivery. At the end of follow-up, 65% were obese. While there were differences between HIV-infected and uninfected women in respect of micronutrients, no deficiencies were observed. Vitamin A and selenium concentrations were higher in the HIV-infected women than uninfected women at six weeks. There were no significant micronutrient changes over time. Most mothers maintained an adequate immune status with only slow deterioration of CD4 counts. At two years postpartum, 60% had a CD4 cell count greater than 500cells/mm³, and only about 8% less than 200/mm3. HIV transmission was 15% by 24 months of follow-up. Among the 65 ever breastfed children, 16 (24.6%) were HIV-infected compared to 12.8% of never breastfed children. Most children were growing normally, suggesting that, overall, maternal HIV status did not interfere with feeding ability. Eight mothers (3%) and 33 children (11%) died. Only 12 of 33 children who had died had a positive HIV-PCR. By 2 years, 78% surviving HIV-infected children had been initiated onto ARV therapy. Maternal adherence to HAART was poor. Conclusion HIV and infant feeding counselling is inadequate in the routine PMTCT programme, with stigma and lack of disclosure continuing as major barriers to appropriate care. Whilst maternal obesity was common, most children were growing normally. Weaknesses in routine PMTCT services were identified, and compliance with HAART was poor.

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