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

Abstract

IntroductionLittle is known about cystic fibrosis (CF) in low-middle income settings. This study aimed to describe the spectrum and outcomes of CF in South Africa (SA) from the recently established SA CF registry (SACFR).MethodsDemographic, diagnosis and clinical data was extracted from the SACFR. Cross-sectional univariable and multivariable regression analysis of best forced expiratory volume in 1 s (FEV1; age≥6 years) and nutrition (all ages) in 2018 was conducted to investigate factors associated with severe lung disease (SLD; FEV1 ≤3.0 z-score) and undernutrition.ResultsBy December 2018, ancestry of 447 individuals included in the SACFR was Caucasian (315; 70%), mixed (87; 19%) and black African (41; 9%). Median diagnosis age was 7.6 months (IQR 2.7,37.1). Genotype was p.Phe508del homozygous (220; 49%); p.Phe508del heterozygous (144; 32%) and neither p.Phe508del or unknown Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) variant in 83 (19%); the second most frequent CFTR variant was 3120+1G>A, common in black Africans. Median age of patients in 2018 was 14.7 years (IQR 7.4,24.4). SLD was independently associated with chronic methicillin resistant S.aureus (MRSA) (aOR 16.75; 95% CI 1.74–161.50), undernutrition (aOR 5.20; 95% CI 2.23–12.13) and age (aOR 2.23 per 10-years; 95% CI 1.50–3.31). Undernutrition was associated in univariable analysis with low weight at diagnosis, non-caucasian ancestry, chronic P.aeruginosa infection and lower socioeconomic status.ConclusionInterventions targeting MRSA infection and nutrition are needed to improve CF outcomes in SA. Most people with CF in SA are eligible for highly effective CFTR modulator therapy.

Trends in cystic fibrosis survival over 40 years in South Africa: An observational cohort study

“…This limits the generalisability of our findings to SA and the statistical power of our analyses to identify and accurately estimate associations or temporal changes in the younger age group. However, the clinical spectrum and profile of CF at our center are similar to that documented in the recently established SA CF registry, suggesting our findings may be informative of the rest of SA 18 . As demonstrated in simulations by Sykes et al, 29 more than 15% individuals LTFU may lead to underestimation of median survival age and censuring people receiving a lung transplant or missing deaths, an overestimation of median survival age.…”

“…Although the median survival age in those diagnosed in cohort A (before 2000) was 21 years (Figure 1), median survival age is projected to be significantly higher in those diagnosed in Cohort B (after 2000), but less than reported in Canada and Europe where median survival age now has reached 51 years 2,22 . Further evidence from the SA CF registry for lower survival age in SA compared to high‐income countries today is the higher proportion of children (56%) with CF compared to adults 18 …”

“…Thereafter patients are transitioned to adult services in either the private or public health sectors. Follow‐up survival status in December 2019 was established from different sources: 1) the RCWMCH CF clinic database which is continuously updated; 2) cross‐referencing the SA CF registry established in 2018 that prospectively collects data from 2018 onwards; and 3) personal communication with the SA CF Association which retains a strong network in the SA CF community 18 …”

Benchmarking AlphaMissense Pathogenicity Predictions Against Cystic Fibrosis Variants

“…Of note, AM predicts position 508 as intolerant to substitution. Deletion of the encoded phenylalanine (F508del) is the most frequently reported variant among worldwide CF populations 8,[42][43][44] . Most variations calculated as benign or ambiguous occur within helix 4/4b of the α-helical subdomain (residues 511-532) or SDR (residues 533-547) (Figure 1D).…”

Real-world disparities and ethical considerations with access to CFTR modulator drugs: Mind the gap!

“…However, the global demography of CFTR mutations is largely determined by race and ethnicity, with the proportion of F508del in at least one allele ranging between 80% and 90% in North America, Western Europe, and Australia, less than 20% in Turkey, and extremely rare in people with sub-Saharan African or Asian ancestry ( Stewart and Pepper, 2017 ; Lopes-Pacheco, 2020 ; McGarry et al, 2022 ). In people with African ancestry, the class-I variant 3120+1G>A is the most commonly reported mutation, present in a homozygous state in 56% of black South Africans with CF ( Zampoli et al, 2021 ). Race and ethnic diversity are thus important biological factors determining eligibility for CFTRm, strongly favoring populations where F508del is common.…”