Long-Term Lung Function and <i>Pseudomonas aeruginosa</i> Infection in Genotyped Primary Ciliary Dyskinesia

<b>Rationale:</b> Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by progressive lung disease. <i>Pseudomonas aeruginosa</i> is a major pathogen in this disease and is known to impact lung function. Previous genotype-phenotype studies have been limited by cross-sectional designs, isolated adult or pediatric populations, small numbers, or short follow-up durations. <b>Objectives:</b> We aimed to explore long-term lung function in PCD grouped by genotypes and ultrastructural defects, considering the influence of <i>P. aeruginosa</i>. <b>Methods:</b> In this retrospective observational study, we analyzed 43 years of spirometry and 20 years of microbiology data. Using linear mixed-effects models, we estimated forced expiratory volume in 1 second <i>z</i>-score trends and compared them at ages 10, 25, and 50 years, whereas generalized estimating equations were used to assess <i>P. aeruginosa</i> prevalence between groups. In a secondary analysis, we matched spirometry and microbiology samples to evaluate the influence of <i>P. aeruginosa</i> on lung function. <b>Results:</b> We included 127 genotyped patients, 6,691 spirometry measurements, and 10,082 microbiology samples. <i>CCDC39</i> and <i>CCDC40</i> variants showed early-onset and sustained decline in lung function, whereas <i>DNAH11</i> and <i>HYDIN</i> variants demonstrated relative stability. Lung function in the proximity of positive <i>P. aeruginosa</i> cultures was on average 0.06 <i>z</i>-score lower. Despite this, differences between groups remained largely unaffected by <i>P. aeruginosa</i>. <b>Conclusions:</b> Long-term lung function in PCD follows discrete genotype-specific profiles and appears independent of <i>P. aeruginosa</i> infection. We confirm and extend previous findings of <i>CCDC39</i> and <i>CCDC40</i> as variants associated with early-onset severe lung function impairment persisting in the long term.