Abstract Rationale Cystic fibrosis (CF) diagnosis in adults with bronchiectasis or nontuberculous mycobacterial (NTM) infections remains challenging due to atypical phenotypes, borderline sweat chloride (SC) concentrations, and varied CFTR genotypes. Accurate characterization of genotype-phenotype relationships in this population is essential to improve diagnostic precision and guide targeted management. Methods We analyzed data from 63 participants in the PRONTO (Prospective Research Cohort of Nontuberculous Mycobacteria and Bronchiectasis Patients) cohort who underwent SC testing via pilocarpine iontophoresis and/or CFTR genetic analysis. SC levels were classified as negative (30 mmol/L), intermediate (30-59 mmol/L), or elevated (≥60 mmol/L); intermediate and elevated values were combined as “abnormal” for analysis. Age, persistent cough status, and CFTR mutation type were assessed to evaluate diagnostic consistency and genotype-phenotype correlations. Results Median categorical age was 65-70 years (range: 20-85 years). Forty-one (65%) had negative SC results, twenty (32%) intermediate, two (3%) elevated. A moderate positive correlation was observed between age and SC concentration (R² = 0.41, p.01). Participants with persistent cough demonstrated higher ratios of abnormal SC results (45% (22/49)) compared to those without cough (25% (3/12)). Abnormal SC results occurred across all genetic subgroups: 32% (8/25) among those without genetic testing, 21% (3/14) with no mutations found, 50% (3/6) with heterozygous F508del, 33% (1/3) with R117H, 50% (2/4) with 5T alleles, and 100% (2/2) with 7T/11TG variants. Conclusions This study identified variability in SC values across diverse CFTR genetic profiles in adults with bronchiectasis and NTM infection. CFTR mutations were observed in patients across all SC categories, and conversely, abnormal SC results occurred in patients without identified mutations, suggesting a more complex genotype-phenotype relationship than categorical thresholds capture. Increasing age moderately explained the SC variance, while persistent cough was associated with higher proportion of patients with abnormal SC. The limited sample size, particularly for individual mutation subgroups, restricts definitive conclusions about genotype-specific associations. However, the observed patterns of genotype-phenotype discordance suggest potential limitations of discrete sweat chloride classification in capturing the spectrum of CFTR dysfunction in this population. Larger studies integrating continuous physiologic measurements, comprehensive genetic analysis, and clinical phenotyping may better characterize CFTR-related disease in complex bronchiectasis populations. This abstract is funded by: None
Ignatius et al. (Fri,) studied this question.