Variability in Disease Severity Among Cystic Fibrosis Patients carrying Residual Function Variants: Data from the European Cystic Fibrosis Society Patient Registry

Background Cystic Fibrosis (CF) variants that exhibit residual function (RF) of the CF transmembrane conductance regulator (CFTR) are considered to have a milder disease, however, the spectrum of CF phenotype within the different RF variants has not been extensively investigated.

Aim To characterise the spectrum of CF disease severity in people with CF (pwCF) carrying different RF variants, using the European CF 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 to pwCF homozygous for F508del. Among 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 compared to class V/F508del, both were milder than pwCF homozygous for F508del. FEV1pp declined already in childhood in all groups. For adults, the hazard ratio of death for class V/F508del versus Class IV/F508del was 2.14 (0.99–4.63, p=0.052). PwCF carrying 3849+10kbC>T/F508del and pwCF carrying R334W/F508del had age-specific FEV1pp and chronic bacterial colonisation similar to pwCF homozygous for F508del.

Conclusion There is a wide spectrum of disease severity between the different RF variants, while some such as 3849+10kbC>T have a a severe disease, which is similar to pwCF homozygous for F508del.