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 characterize 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, 6,192 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 vs 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 colonization 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.