Variability in disease severity among cystic fibrosis patients carrying residual-function variants: data from the European Cystic Fibrosis Society Patient Registry

Background: People with cystic fibrosis (CF) variants that exhibit residual function (RF) of the CF transmembrane conductance regulator are considered to have a milder disease; however, the spectrum of CF phenotype within the different RF variants has not been extensively investigated. The aim of the present study was to characterise the spectrum of CF disease severity in people with CF (pwCF) carrying different RF variants, using the European Cystic Fibrosis Society Patient Registry (ECFSPR) data.

Methods: A retrospective cross-sectional and longitudinal cohort study included data from the ECFSPR during 2008-2016. Demographic and clinical characteristics of pwCF carrying different RF variants were compared with the characteristics of pwCF who are homozygous for F508del. Among those with RF, a distinction was made between pwCF carrying class IV or class V variants and pwCF carrying specific RF variants.

Results: Out of 56 701 pwCF in the ECFSPR, 6192 carried RF variants and 22 766 were homozygous for F508del. Class IV/F508del variants were associated with a milder course than class V/F508del; both were milder than pwCF homozygous for F508del. Forced expiratory volume in 1 s % predicted (FEV₁pp) declined in childhood in all groups. For adults, the hazard ratio of death for class V/F508del versus class IV/F508del was 2.14 (95% confidence interval 0.99-4.63, p=0.052). PwCF carrying 3849+10 kb C→T/F508del and pwCF carrying R334W/F508del had age-specific FEV₁pp and chronic bacterial colonisation similar to those of pwCF homozygous for F508del.

Conclusion: There is a wide spectrum of disease severity between the different RF variants. Some, such as those carrying 3849+10 kb C→T, have severe disease, similar to that of pwCF homozygous for F508del.