Michael S. Schechter

1. Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder resulting from variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [1]. Dysfunctional CFTR leads ...

Rationale: Modulator therapies like ivacaftor have revolutionized clinical management of cystic fibrosis, showing marked short-term benefits in trials but heterogeneous findings in long-term observational studies. Since newer modulators have become the standard of care for the majority living with cystic fibrosis in the United States, characterizing long-term effectiveness with real-world data is increasingly difficult because of the lack of contemporary comparator groups for performing between-subjects analyses. Objectives: To determine the extent to which ivacaftor preserves long-term lung function and compare the results of within- and between-subjects analyses for evaluating its real-world effectiveness. Methods: This retrospective cohort study used data from the U.S. Cystic Fibrosis Foundation Patient Registry (2003–2016). We used two approaches to evaluate ivacaftor effectiveness on percent predicted forced expiratory volume in 1 second (ppFEV1): 1) within-subject comparisons of ppFEV1 before and after ivacaftor initiation; and 2) comparisons between ivacaftor-treated and untreated individuals with similar disease pathology. We modeled data from 560 ivacaftor-treated individuals with the G551D variant. For between-subjects comparisons, we used propensity scores to match the treated group with 2,800 untreated F508del homozygous individuals. Modulator initiation bias was assessed and accounted for in each model. Results: Our results showed an initial average improvement in ppFEV1 in ivacaftor-treated children and adults (ranging from 4.54% to 6.53% predicted based on within-subject comparison of before vs. after ivacaftor initiation). There was a slower decline in adults, compared with children. These ivacaftor-treated cohorts experienced less decline relative to their F508del homozygous counterparts (between-group differences in treated vs. control ranged from 0.36% to 0.64% predicted). Both the within- and between-subjects comparisons demonstrated similar degrees of ivacaftor effectiveness. However, small differences between the two approaches were observed in younger individuals. Conclusions: Ivacaftor was associated with improved ppFEV1 across all age groups, with the magnitude of improvement roughly 50% of that observed in clinical trials. The results support the need to account for modulator initiation bias and the use of within-subject analysis in future CFTR (cystic fibrosis transmembrane conductance regulator) modulator effectiveness studies, but caution is advised in younger individuals because of developmental changes that may affect pre- and post-treatment comparability.

Background: The benefit of antibiotic treatment of acute drops in FEV ₁ percent predicted (FEV ₁ pp) has been clearly established, but data from the early 2000s showed inconsistent treatment. Further, there is no empirical evidence for what magnitude of drop is clinically significant. Methods: We used data from the CF Foundation Patient Registry (CFFPR) from 2016 to 2019 to determine the association between treatment (any IV antibiotics, only oral or newly prescribed inhaled antibiotics, or no antibiotic therapy) following a decline of ≥5% from baseline FEV ₁ pp and return to 100% baseline FEV ₁ pp days using multivariable logistic regression including an interaction between the magnitude of decline and treatment category. Results: Overall, 16,495 PWCF had a decline: 16.5% were treated with IV antibiotics, 25.0% non‐IV antibiotics, and 58.5% received no antibiotics. Antibiotic treatment was more likely for those with lower lung function, history of a positive PA culture, older age and larger FEV ₁ decline ( p < 0.001). Treatment with IV antibiotics or oral/inhaled antibiotics was associated with a higher odds of recovery to baseline compared to no treatment across all levels of decline, including declines of 5%–10%. Conclusions: A large proportion of acute drops in FEV1 _pp continue to be untreated, especially in younger patients and those with higher baseline lung function. Acute drops as small as 5% predicted are less likely to be recovered if antibiotic treatment is not prescribed. These findings suggest the need for more aggressive antimicrobial treatment of acute drops in FEV ₁ , including those of a magnitude previously believed to be associated with self‐recovery.

Background: The benefit of antibiotic treatment of acute drops in FEV ₁ percent predicted (FEV ₁ pp) has been clearly established, but data from the early 2000’s showed inconsistent treatment. Further, there is no empirical evidence for what magnitude of drop is clinically significant. Methods: We used data from the CF Foundation Patient Registry (CFFPR) from 2016-2019 to determine the association between treatment (any IV antibiotics, only oral or newly prescribed inhaled antibiotics, or no antibiotic therapy) following a decline of ≥5% from baseline FEV ₁ pp and return to 100% baseline FEV ₁ pp days using multivariable logistic regression including an interaction between the magnitude of decline and treatment category. Results: Overall, 16,495 PWCF had a decline : 16.5% were treated with IV antibiotics, 25.0% non-IV antibiotics, and 58.5% received no antibiotics. Antibiotic treatment was more likely for those with lower lung function, history of a positive PA culture, older age and larger FEV ₁ decline (pConclusions: A large proportion of acute drops in FEV1 _pp continue to be untreated, especially in younger patients and those with higher baseline lung function. Acute drops as small as 5% predicted are less likely to be recovered if antibiotic treatment is not prescribed. These findings suggest the need for more aggressive antimicrobial treatment of acute drops in FEV ₁ , including those of a magnitude previously believed to be associated with self-recovery.