Edith T. Zemanick

Aims: We evaluated long-term safety and efficacy of lumacaftor (LUM)/ivacaftor (IVA) in children aged 12 to F508del . Methods: This international, 96-week, phase 3, open-label study enrolled children who completed parent study 809-122 (after 2-week washout) or were LUM/IVA-naïve. The primary end-point was safety and tolerability. The secondary efficacy end-point was change from baseline in sweat chloride concentration. Results: 52 children (39 from 809-122; 13 LUM/IVA-naïve) participated. Mean± sd exposure to LUM/IVA was 597±162 days. All children had at least one adverse event, which were mostly mild (32.7%) or moderate (55.8%) in severity and consistent with common manifestations of CF or early childhood illnesses. One child (1.9%) discontinued study drug due to a treatment-emergent adverse event of increased alanine/aspartate aminotransferases that resolved after discontinuation. 12 (23.1%) children had serious adverse events, none of which was considered related to LUM/IVA. At week 96, mean absolute change from pre-treatment baseline in sweat chloride concentration was −21.0 (95% CI −27.6 to −14.3) mmol·L ⁻¹ . Growth parameters, which did not change significantly, were in the normal range throughout the 96-week treatment period. Improvements from baseline were observed in mean fecal elastase-1, fecal calprotectin, and serum immunoreactive trypsinogen. Conclusions: LUM/IVA remained generally safe and well-tolerated over 96 weeks. Improvements in sweat chloride concentration and markers of pancreatic function and intestinal inflammation were consistent with the parent study. These results demonstrate the long-term safety and efficacy of LUM/IVA in the 12 to 24-month-old population.

Background: Olfactory dysfunction (OD) is prevalent in people with cystic fibrosis (PwCF); however, its overall impact in this population is understudied. No systematic review on this topic is currently available. Objective: The objective of this study was to systematically review the existing literature on OD in PwCF. Methods: A systematic review was performed using PRISMA guidelines. Inclusion criteria consisted of articles that examined OD in PwCF using psychophysical olfactory testing. PubMed, Ovid Medline, Google Scholar, Cochrane Library, MedRxiv, and Web of Science databases were searched on 13 June 2022. The Newcastle–Ottawa Scale was used to assess the quality and determine risk of bias for the studies included in the meta-analysis. Results: A total of 87 articles were initially identified; ten were ultimately included. All ten studies were prospective and observational. A total of 420 PwCF were included in these studies (209 females, mean age = 26 years). Psychophysical olfactory testing was performed via the 40-Question Smell Identification Test (n = 4 studies), Sniffin’ Sticks Testing (n = 4 studies), and other odor identification tests (n = 2 studies). The mean prevalence of OD was 61% (range 10–88%), while rates of anosmia ranged from 5 to 14. The meta-analysis demonstrated that PwCF had lower threshold, discrimination, and identification scores compared to controls, with a very large effect size (Hedges’ g = −1.57, 95% CI = −2.51 to −0.63). Five studies revealed impairment in odor identification. Five studies assessed potential associations between OD and body mass index. Conclusions: OD is common in PwCF. Most PwCF have hyposmia, while anosmia is less common. Olfactory limitations have not been well characterized in pediatric patients. Understanding how OD affects PwCF is critical to optimization of disease management and quality of life.

Rational: Remote health‐monitoring technologies such as cough monitors can track longitudinal changes in health status in children with cystic fibrosis (cwCF). We assessed the feasibility of a bedside cough monitor and hypothesized that cwCF would have a higher baseline cough frequency compared to healthy controls (HC), which would increase during pulmonary exacerbations (PEx). Methods: Cough monitors capturing continuous audio data during pre‐set sleep times were provided for 3 months. Data were analyzed over 3 s intervals using a proprietary algorithm (CurieAi, Santa Clara, CA) to identify cough events. Multivariable modeling was used to compare baseline cough frequency (coughs per night) between cwCF and HC. Results: We enrolled 40 children (20 cwCF and 20 HC; median [range] age 11 years [2−18]) between February and August 2024. Most participants were White, 3 (7.5%) identified as Hispanic and/or Latino. CwCF were all treated with elexacaftor/tezacaftor/ivacaftor (ETI); baseline median (range) ppFEV ₁ was 107% (86%−124%). Data were captured over 82% of nights in the study period (median of 75.5 nights per participant, range 4−106). CwCF were more likely to cough at least once during the night compared to HC (IRR = 0.279, p = 0.02), and cough at a higher, albeit non‐statistically significant rate (IRR = 1.805, p = 0.082). We could not determine whether cough frequency changed during PEx due to limited data collection surrounding reported PEx. Conclusions: A passive cough monitor detected nighttime cough in cwCF and HC. CwCF with preserved lung function have more nights with cough than HC despite being on elexacator/tezacaftor/ivacaftor (ETI).

Introduction: Evaluation for respiratory pathogens is a key component of cystic fibrosis (CF) care but is often lacking during remote visits. We aimed to address the impact of shipping and home collection of respiratory samples on CF pathogen identification and the feasibility of home collection in children with CF. Methods: Participants were enrolled during a routine well clinic visit. Three respiratory samples (clinic obtained with immediate processing per CF center guidelines, clinic obtained with delayed processing, and a home sample obtained within 1 week of clinic visit) were collected and concordance between CF pathogens was evaluated using Fleiss' Kappa comparisons. Survey to assess feasibility and acceptability was completed, and descriptive statistics were used to report results. Results: Fifty children were enrolled, and home samples were returned by 46 (92%). Fleiss' Kappa value for methicillin‐susceptible Staphylococcus aureus was 0.676, suggesting substantial agreement. No significant differences were seen in pathogen detection between immediately processed (gold standard) and delayed processed or home collected samples. Home collection was acceptable based on participant survey responses related to ease of collection and shipping, and willingness to repeat a home collection. No significant barriers to collection or shipping were identified. Conclusion: Good concordance between CF pathogens identified on culture between the three sample types and good accuracy between pairwise comparisons were observed in children with CF. Home collection of respiratory samples for culture in children with CF was feasible and acceptable based on high sample return rate and survey responses.

Objective: Although studies have examined changes in C‐reactive protein (CRP) during pulmonary exacerbations (PEX) in people with cystic fibrosis (PwCF), few have evaluated CRP profiles across age groups. Here, we characterize age‐related CRP responses to PEX treatment. Methods: We measured CRP concentrations at the beginning and end of intravenous (IV) antibiotic therapy for PEX in 100 pediatric and 147 adult PwCF at 10 US CF Centers. We examined relationships between CRP and age, lung function, severity of PEX symptoms, and time to next PEX. Results: CRP measured at initiation of IV antibiotic treatment for PEX was higher in adults than children, median 8 mg/L (IQR 4, 32) versus 5 mg/L (IQR 2, 10), respectively ( p < 0.001). There was a significant correlation between the initial CRP and drop in lung from baseline to the beginning of IV antibiotics in adults and children. Adjusted CRP dropped in response to PEX treatment more commonly in adults than in children (70% vs. 48%, respectively). The range of treatment responses was greater in adults, in those with higher symptom scores, and in those with more advanced lung disease. In adults elevated CRP at the end of treatment was also associated with incomplete recovery of lung function. CRP at the start of IV antibiotics was inversely related to time until the next PEX. Conclusion: In children and adults with CF, CRP is increased at the initiation of IV antibiotic therapy for PEX and declines with treatment. The response is more pronounced in highly symptomatic adults with advanced lung disease.