Long-term lung function and Pseudomonas aeruginosa in genotyped primary ciliary dyskinesia

<bold>Introduction:</bold> Primary ciliary dyskinesia (PCD) is a rare, chronic, genetic disorder characterized by severe progressive lung disease. <italic>Pseudomonas aeruginosa</italic> is a major pathogen in this disease, known to impact lung function. Previous genotype-phenotype studies have been limited by either cross-sectional designs, isolated adult or paediatric populations, small numbers, or short follow-up. <bold>Aims and objectives:</bold> We explored long-term lung function trends among genotypes and ultrastructural defect groups at key age milestones, while considering the influence of <italic>P. aeruginosa</italic>. <bold>Methods:</bold> In this observational, retrospective study, we included 43 years of spirometry data and 20 years of microbiology samples. FEV1 z-score trends were estimated using linear mixed-effects models and compared among groups at ages 10, 25, and 50 years. In a secondary analysis, measurements were matched to microbiology samples including <italic>P. aeruginosa</italic>. <bold>Results:</bold> We included 127 genotyped individuals with PCD, 6,691 spirometry measurements and 10,082 microbiology samples. CCDC39 and CCDC40 were associated with a persistent reduction in lung function with early onset. Conversely, DNAH11 and HYDIN mutations were associated with a better maintained lung function. <italic>P. aeruginosa</italic> had an annual prevalence of 28%, were found in 72% of subjects, and showed an average impact on lung function of -0.06 z-score with a non-significant age-related effect. <bold>Conclusion:</bold> We highlight a diverse lung function among genotypes independent of <italic>P. aeruginosa</italic> presence. We confirm and extend previous findings of CCDC39 and CCDC40 as variants associated with early onset severe lung function impairment persisting in the long term.