Cystic fibrosis in South Africa: spectrum of disease, diagnosis, and determinants of outcome

Cystic fibrosis (CF) occurs with varying incidence in all populations throughout the world but much less is known about the epidemiology and outcomes of CF in low-or-middle income countries (LMIC) compared with high income settings. Continued improvement in CF-related outcomes and survival witnessed in the past decades is attributed to multiple factors yet sub-optimal quality of CF care, and limited CF diagnosis capacity continue to exist in most LMIC, including South Africa (SA). CF treatment and prognosis have been transformed by the recent introduction of highly effective cystic fibrosis transmembrane conductance regulator modulator drugs (CFTRm). However, access to these transformative drugs for those with eligible genotypes is currently limited to high-income countries. Understanding the clinical spectrum of CF in SA and investigating novel techniques to diagnose CF is important to advocate for improved quality of CF care including CFTRm drugs. The overall aim of this work was to document the spectrum and outcomes of CF in South Africans and to investigate more sensitive measures to diagnose CF and CFTR-related disorders in this population. The studies included in this thesis are divided into two components. This first component comprises observational cohort studies derived from a single-centre CF clinic dataset in Cape Town, SA, and the nation-wide South African CF registry, which was established in 2018 in preparation for this thesis. The CF registry cohort in SA was then compared in a cross-sectional study to a matched Canadian CF registry cohort, and differences in lung function and nutrition outcomes adjusted for known factors. The second component was a prospective study investigating the feasibility and diagnostic utility of the novel β-adrenergic sweat test in a cohort of South Africans with inconclusive CF diagnosis. The chapters of this thesis are presented as published manuscripts, which collectively address the overall aim of this body of work. The SA CF registry in its first year of inception captured a total of 447 people with CF across both private and public health sectors. Summary demographic descriptions of the cohort include median age of 14.7 years with self-identified White race making up 70% of the CF population, followed by Mixed-race ancestry (19%) and Black Africans (10%). Genotype pattern mirrored ancestry with F508del is the most common variant in Whites and people with Mixed-race ancestry, and 3120+1G>A (class I) the most common variant in Black Africans. Overall, 81% of people with CF (pwCF) in SA have at least one copy of F508del and are, thus, eligible for elexacaftor/tezacaftor/ivacaftor. A key finding of the registry-based studies was that lung function and nutrition outcomes in SA were significantly lower across all ages compared with Canada, attributed to differences in the quality of CF care and social determinants of CF health between the two countries. In SA, poor nutrition was the strongest factor independently associated with severe lung disease and was more prevalent in people living in lower 10 socioeconomic conditions, including people who were not White. Another key finding was despite significant improvement in overall CF survival at a single centre in Cape Town over the past 40 years, disparities between race groups still exist in SA with increased risk of mortality observed in young children who were not White. People with Black African ancestry, who form the majority of the SA population, are likely to be underrepresented in the SA CF registry, raising concern that CF is being missed or underdiagnosed in the majority of South Africans. Furthermore, the genotype of Black Africans means that none are eligible for CFTRm, which has serious implications for future treatment. These registry-based studies highlight disparities in CF care and outcomes both within SA and compared with a high-income setting – novel findings because SA is one of only a few LMIC with CF registries. Addressing these disparities affecting people with CF in SA will require interventions such as greater awareness of CF in SA, universal newborn screening for CF, focused attention on improving nutrition and overall improvement in the quality of essential CF care, especially as LMIC have disproportionally more pwCF who are ineligible for CFTRm drugs. The diagnosis of CF using standard approaches may remain inconclusive in a small proportion of individuals, which leads to unnecessary anxiety for families and inappropriate treatment where people do not actually have CF or a CFTR-related disorder. Furthermore, accurate diagnosis of CF is important for research and submission of registry data. The β-adrenergic sweat test was proposed as an easier alternative to other electrophysiological measurements of CFTR function such as nasal potential difference and intestinal current measurements, which are not available in SA. We therefore conducted a study evaluating this hypothesis in adult subject controls, and 32 individuals (mostly children) whose CF diagnosis was inconclusive. Key findings of this study were that the β-adrenergic sweat was superior to sweat chloride test in excluding CF in the majority of subjects and that βadrenergic sweat secretion in children was lower compared to adults. Implications and novelty of this research are that existing reference ranges for this test may not be applicable in children, and confirmation that the β-adrenergic sweat test is a viable alternative for measuring CFTR function. A number of families benefited from this study by reversal of their incorrect CF diagnosis. The overriding finding and impact of this work has been to highlight disparities in diagnosis, treatment, and outcomes of CF within SA and in the global context. The current status of CF care in SA mirrors many other LMIC that share similar challenges and barriers to improving CF care, including access to affordable CFTRm drugs. The findings of this thesis have made valuable contributions to local and global advocacy initiatives to improve CF care and access to CFTR drugs for many thousands of pwCF living in LMIC who are being left behind in this new era of CF treatment

Conducting research in Africa: Lessons from the COAST trial

No abstrac

Advancing pediatric lung health in Africa: COVID-19 and beyond

Respiratory illnesses in children are an important cause of morbidity and mortality in Africa where poverty, food insecurity, malnutrition, and human immunodeficiency virus infection are aggravating factors in many countries. These factors, in addition to under resourced health-care infrastructure, remain important barriers to improving child lung health outcomes in Africa. However, despite these challenges, there have been significant recent advancements in understanding the epidemiology, causes, measurement tools, and treatment of childhood respiratory illnesses. In this review, we highlight some advances in childhood pneumonia, tuberculosis, asthma, and other important non-communicable lung diseases common in children. Furthermore, we discuss the role of environmental influences on children’s lung health in Africa and highlight novel methods of measuring lung function in children. Although children contribute a small role in the global epidemiology of COVID-19 pandemic, socioeconomic and health-care delivery disruptions caused by government responses to contain the pandemic have resulted in significant indirect setbacks to child health. We further highlight how the COVID-19 pandemic has impacted areas of pediatric lung health and discuss ways to mitigate effects of COVID-19 in Africa

Pediatric interstitial lung disease

Interstitial lung disease in children (chILD) is rare and encompasses more than 200 entities, with new especially genetic causes being discovered. Several classifications have been proposed, and there is considerable overlap with entities which present in adult life. Presentation may be shortly after birth with acute respiratory distress and in infancy and childhood either with a primary respiratory presentation or with systemic symptoms such as poor feeding and failure to thrive. Newborn acute presentations are usually due either to a mutation in one of the surfactant protein (Sp) genes or the alveolar capillary dysplasia (ACD)-congenital alveolar dysplasia (CAD) spectrum. The latter usually progress rapidly to extracorporeal membrane oxygenation, and early lung biopsy is advisable to prevent prolonged futile treatment being offered. Outside the newborn period, a staged protocol for investigation is proposed. This starts with a computed tomography scan, which confirms or otherwise the presence of chILD, and occasionally can lead to a specific diagnosis. In particular in settings where there is a high burden of infection, infective mimics of chILD need to be excluded. The next investigations aim to try to move from pattern recognition to specific diagnoses, both genetic and environmental. The speed of progression to lung biopsy will depend on the clinical state of the child, and the biopsy itself may suggest a hunt for a new underlying cause, such as immunodeficiency. Specific genetic causing chILD includes mutations in SpB and SpC and processing genes (thyroid transcription factor-1 [TTF-1] and adenosine triphosphate-binding cassette subfamily A) (the last three can present at any time in the life course); genes involved in Sp catabolism (granulocyte-macrophage colony factor receptor A and B genes), an increasing number implicated in the ACD-CAD spectrum, and other non-Sp related genes such as Filamin-A and integrin genes. Environmental causes are also important and vary across the world. Vaping has been implicated as causing a large number of chILDs, and a vaping history is essential in any young person with an unusual respiratory illness. Medications, both prescribed and over-the-counter such as oily laxatives, are also causes of chILD. There are important conditions of unknown cause presenting in early childhood. Neuroendocrine cell hyperplasia of infancy (NEHI) and pulmonary interstitial glycogenosis generally have a good prognosis, and are probably best considered as part of a spectrum of pulmonary dysmaturity syndromes, in some of which underlying gene mutations have been detected, for example, TTF-1 for NEHI. Pulmonary alveolar proteinosis is an example of an umbrella description, which may present at any age, and has a number of underlying causes with different specific treatments, underscoring the need to move from pattern recognition to specific diagnoses. chILDs have important implications for adult physicians; there may be late as yet poorly described sequelae of the disease or its treatment in adult life; there may be genetic implications for the wider family; and there may be late chILD relapses. Smooth transition to adult services is essential for all chILD survivors, with pediatric and adult chest physicians working closely together

Antiretroviral treatment for children

No Abstract. South African Medical Journal Vol. 96(9) (Part 2) 2006: 988-99

Antiretroviral treatment for children

Objective: To describe the response of children during their first year on highly active antiretroviral therapy (HAART). Design: Retrospective, descriptive. Setting. Tertiary, referral hospital. Subjects: All HIV-infected children commenced on HAART from 1 August 2002 until 31 December 2004. Outcome measures: Children were retrospectively restaged using the WHO 4-stage clinical classification and CDC immunological staging system. After commencing HAART, patients were assessed at monthly intervals for the first 6 months and thereafter mostly 3-monthly. Baseline and 6- monthly CD4 counts and viral loads were performed. Results. Of 409 children commenced on HAART, 50.6% were < 2 years old, 62.7% had severe clinical disease and 76.6% had severe immune suppression. After 1 year, 65.8% were alive and continued HAART at the hospital, 11.2% had been transferred to another antiretroviral site, 15.4% had died, 4.6% were lost to follow-up and treatment had been discontinued in 2.9%. Kaplan-Meier survival estimate for 407 children at 1 year was 84% (95% confidence interval (CI) 80 - 87%). On multivariate analysis, survival was adversely affected in children with WHO stage 4 v. stage 2 and 3 disease (adjusted hazard ratio (HR): 5.26 (95% CI 2.25 - 12.32), p = 0.000), age < 12 months (adjusted HR: 2.46 (95% CI 1.48 - 4.09), p = 0.001) and CD4 absolute count (per 100 cell increase) (adjusted HR: 0.93 (95% CI 0.88 - 0.98), p = 0.013). In a separate multivariate model including only children with an initial viral load (N = 367), viral load r 1 million copies/ml (adjusted HR: 1.84 (95% CI 1.03 - 3.29)) and taking a protease inhibitor (PI)-based regimen (adjusted HR: 2.25 (95% CI 1.10 - 4.61)) were additionally independently associated with poorer survival; however, young age was not a significant predictor of mortality, after adjusting for viral load (p = 0.119). After 1 year of HAART 184/264 (69.7%) of children had a viral load < 400 copies/ml. Comparative analysis showed significant improvements in growth, immunological status and virological control. Conclusion: HAART can improve the health of many HIVinfected children with advanced disease, including those aged less than 2 years in resource-limited settings

Pneumocystis pneumonia in South African children diagnosed by molecular methods

Background: Pneumocystis pneumonia (PCP) is an important cause of hospitalization and mortality in HIV-infected children. However, the incidence of PCP has been underestimated due to poor sensitivity of diagnostic tests. The use of polymerase chain reaction (PCR) for pneumocystis has enabled more reliable diagnosis. This study describes the incidence, clinical features and outcome of PCP in South African children diagnosed using PCR. Methods: A prospective study of children hospitalised in South Africa with suspected PCP was done from November 2006 to August 2008. Clinical, laboratory and radiological information were collected. Lower respiratory tract specimens were obtained for PCP immunofluorescence (IF), real- time PCR for pneumocystis, bacterial and mycobacterial culture. Nasopharyngeal aspirates were taken for immunofluorescence (IF), real-time PCR for pneumocystis and PCR for respiratory viruses. A blood specimen for bacterial culture and for cytomegalovirus PCR was taken. Children were followed for the duration of their hospitalisation and the outcome was recorded. Results: 202 children [median (interquartile range, IQR) age 3.2 (2.1– 4.6) months] were enrolled; 124 (61.4%) were HIV infected. PCP was identified in 109 (54%) children using PCR, compared to 43 (21%) using IF and Grocott staining (p < 0.0001). Most PCP cases (88, 81%) occurred in HIV-infected children. All 21 cases (19%) occurring in HIV- negative children had another risk factor for PCP. On logistic regression, predictive factors for PCP were HIV infection, lack of fever, high respiratory rate and low oxygen saturation whilst cotrimoxazole prophylaxis was protective (OR 0.24; 95% CI 0.1 to 0.5; p < 0.002). The case fatality of children with PCP was higher than those without PCP (32.1% versus 17.2%; relative risk 1.87; 95% confidence interval (CI) 1.11 – 3.15). Amongst HIV-infected children, a CD4 less than 15% was the only independent predictor of mortality. Conclusions: The diagnostic yield for PCP is more than 2.5 times higher on PCR than other detection methods. PCP is a very common cause of severe hypoxic pneumonia and is associated with high mortality in HIV-infected African infants

Clinical and Experimental Determination of Protection Afforded by BCG Vaccination against Infection with Non-Tuberculous Mycobacteria: A Role in Cystic Fibrosis?

Mycobacterium abscessus is a nontuberculous mycobacterium (NTM) of particular concern in individuals with obstructive lung diseases such as cystic fibrosis (CF). Treatment requires multiple drugs and is characterised by high rates of relapse; thus, new strategies to limit infection are urgently required. This study sought to determine how Bacille Calmette-Gu&eacute;rin (BCG) vaccination may impact NTM infection, using a murine model of Mycobacterium abscessus infection and observational data from a non-BCG vaccinated CF cohort in Sydney, Australia and a BCG-vaccinated CF cohort in Cape Town, South Africa. In mice, BCG vaccination induced multifunctional antigen-specific CD up sup T cells circulating in the blood and was protective against dissemination of bacteria to the spleen. Prior infection with M. abscessus afforded the highest level of protection against M. abscessus challenge in the lung, and immunity was characterised by a greater frequency of pulmonary cytokine-secreting CD4 T cells compared to BCG vaccination. In the clinical CF cohorts, the overall rates of NTM sampling during a three-year period were equivalent; however, rates of NTM colonisation were significantly lower in the BCG-vaccinated (Cape Town) cohort, which was most apparent for M. abscessus. This study provides evidence that routine BCG vaccination may reduce M. abscessus colonisation in individuals with CF, which correlates with the ability of BCG to induce multifunctional CD4T cells recognising M. abscessus in a murine model. Further research is needed to determine the optimal strategies for limiting NTM infections in individuals with CF