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Background: Sweat chloride (SC) concentrations in people with cystic fibrosis (PwCF) reflect relative CF transmembrane conductance regulator (CFTR) protein function, the primary CF defect. Populations with greater SC concentrations tend to have lesser CFTR function and more severe disease courses. CFTR modulator treatment can improve CFTR function within specific CF genotypes and is commonly associated with reduced SC concentration. However, SC concentrations do not necessarily fall to concentrations seen in the unaffected population, suggesting potential for better CFTR treatment outcomes. We characterized post-modulator SC concentration variability among CHEC-SC study participants by genotype and modulator., Methods: PwCF receiving commercially approved modulators for ≥90 days were enrolled for a single SC measurement. Clinical data were obtained from chart review and the CF Foundation Patient Registry (CFFPR). Variability of post-modulator SC concentrations was assessed by cumulative SC concentration frequencies., Results: Post-modulator SC concentrations (n = 3787) were collected from 3131 PwCF; most (n = 1769, 47 %) were collected after elexacaftor/tezacaftor/ivacaftor (ETI) treatment. Modulator use was associated with lower SC distributions, with post-ETI concentrations the lowest on average. Most post-ETI SC concentrations were <60 mmol/L (79 %); 26 % were <30 mmol/L. Post-ETI distributions varied by genotype. All genotypes containing at least one F508del allele had individuals with post-ETI SC ≥60 mmol/L, with the largest proportion being F508del/minimal function (31 %)., Conclusions: Post-modulator SC concentration heterogeneity was observed among all genotypes and modulators, including ETI. The presence of PwCF with post-modulator SC concentrations within the CF diagnostic range suggests room for additional treatment-associated CFTR restoration in this population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Objective: To assess the feasibility of enrolling people with CF (pwCF) taking the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI) in clinical trials of a new modulator., Methods: PwCF receiving ETI at CHEC-SC study (NCT03350828) enrollment were surveyed for interest in 2-week to 6-month placebo- (PC) and active-comparator (AC) modulator studies. Those taking inhaled antimicrobials (inhABX) were surveyed for interest in PC inhABX studies., Results: Of 1791 respondents, 75% [95% CI 73, 77] would enroll in a 2-week PC modulator study versus 51% [49, 54] for a 6-month study; 82% [81, 84] and 63% [61, 65] would enroll in 2-week and 6 month AC studies; 77% [74, 80] of 551 taking inhABX would enroll in a 2-week PC inhABX study versus 59% [55, 63] for a 6-month study. Previous clinical trial experience increased willingness., Conclusions: Study designs will affect feasibility of future clinical trials of new modulators and inhABX in people receiving ETI., Competing Interests: Declaration of Competing Interest The authors have no competing or conflicting interests to report., (Copyright © 2023. Published by Elsevier B.V.)

Background: CHEC-SC is an ongoing epidemiologic study characterizing modulator-induced sweat chloride (SC) responses across the CF population, with interim results available prior to the availability of triple combination modulator therapy., Methods: Eligible participants had been prescribed a modulator for ≥90 days with re-enrollment allowed upon establishment of a new modulator. Pre-modulator SC values were obtained from chart review; post-modulator sweat was collected and analyzed locally. SC changes were descriptively summarized with biologic sex effects adjusted for age, weight, and CFTR genotype. Heterogeneity in ivacaftor SC response was characterized in relation to published CFTR functional responses., Results: 1848 participants provided 2004 SC measurements, 26.2% on ivacaftor, 39.1% on lumacaftor/ivacaftor, and 34.7% on tezacaftor/ivacaftor. Average SC changes for all modulators were consistent with those reported in previous clinical studies, with greater variation in SC response observed among rarer mutations and notable shifts in the proportion with SC <60mmol/L independent of the magnitude of SC change. Ivacaftor induced in vitro CFTR functional change was significantly correlated with ivacaftor-modulated SC response (Pearson correlation= ‒0.52, 95% CI: ‒0.773, ‒0.129). Average SC change from ivacaftor to tezacaftor/ivacaftor was ‒4.9 mmol/L (n=17,95% CI:‒9.3, ‒0.5) and differed from those switching from lumacaftor/ivacaftor (10.0 mmol/L, n=139, 95% CI:7.8,12.3). Sex at birth was not associated with SC response., Conclusions: CHEC-SC is the largest study characterizing modulator-induced SC changes across the CF population. There was a strong association between ivacaftor induced in vitro CFTR function and SC response across a genotypically heterogenous cohort. Biological sex was not associated with SC response., Competing Interests: Conflict of Interest Statement NMH serves as a consultant through her institution in her role as Executive Director of the CF Therapeutics Development Network Coordinating Center (CF TDNCC) and has received personal consulting fees from Vertex Pharmaceuticals. She has received grant funding from the Cystic Fibrosis Foundation (CFF) and National Institutes of Health (NIH). DRV has received personal consulting fees from AbbVie, Albumedix, AN2, Aradigm, Armata, Arrevus, Calithera, Chiesi USA, Cipla, Corbus, CFF, Eloxx, Enbiotix, Eveo, Galephar, Horizon, IBF, ICON clinical sciences, Ionis, Kala, Merck, Microbion, NDA, Protalix, PTC, Pulmocide, Recida, Savara, Vast, and VRTX. MWK has received personal consulting fees for advisory board participation, grant support to his institution for clinical trial participation, and non-financial support from VRTX, Savara, Laurent, Corbus Pharmaceuticals, PTC, and AzurRx. He has received personal consulting fees and non-financial support from Chiesi, Celtaxsys, Merck, and Kala. Personal consulting fees were received from Albumedix, Paranta, Protalix, Santhera, pH Pharma, Novartis, Ionis, the Italian Cystic Fibrosis Foundation, and the Food and Drug Administration. SMR reports grants and personal fees from Vertex Pharmaceuticals Inc, during the conduct of the study; grants and personal fees from Novartis, grants and personal fees from Bayer, grants from Translate Bio, grants and non-financial support from Proteostasis, grants, personal fees and non-financial support from Galapagos/Abbvie, grants, personal fees and non-financial support from Synedgen/Synspira, grants from Eloxx, grants from Celtaxsys, grants, personal fees and non-financial support from Vertex Pharmaceuticals Inc, personal fees and non-financial support from Renovion, grants and personal fees from Arrowhead, grants, personal fees and non-financial support from Ionis, grants from Astra Zenica, personal fees from Cystetic Medicines, outside the submitted work. ETZ reports grants and personal consulting fees from Vertex Pharmaceuticals and the Cystic Fibrosis Foundation during the conduct of the study., (Copyright © 2022. Published by Elsevier B.V.)

Background: Antimicrobial susceptibility testing (AST) is a cornerstone of infection management in cystic fibrosis. However, there is little evidence that AST predicts the clinical outcome of CF antimicrobial treatment. It has been suggested there is a need for careful consideration of current AST use by the CF community., Methods: We engaged a group of experts consisting of pulmonary (adult and pediatric) and infectious disease clinicians, microbiologists, and pharmacists representing a broad international experience. We conducted an iterative systematic survey (Delphi) to determine and quantify consensus regarding key questions facing CF clinicians in the use of respiratory culture results including what tests to order, when to obtain them, and how to act upon the results of the testing., Results: Consensus was reached for many questions but there was not universal agreement to the questions that were addressed. There were some differences with respect to cultures obtained for surveillance compared to when there is clinical worsening. Areas of general consensus include when and how respiratory cultures should be performed, what information should be reported, and when AST should be performed. A key finding is that clinical response to treatment is used to guide treatment decisions rather than AST results., Conclusions: Recommendations are presented regarding questions related to microbiology testing for patients with CF. We have also offered recommendations for priority research questions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 European Cystic Fibrosis Society. All rights reserved.)

Background: Pseudomonas aeruginosa accounts for ~80% of cystic fibrosis (CF) airway infection. It shows a remarkable correlation with presence of autoantibody to bactericidal/permeability-increasing protein (BPI), which is not understood. In this study, we sought to better understand the characteristics of systemic and mucosal autoimmunity and their relation to humoral immunity to P. aeruginosa., Methods: Antibody titers and isotypes to BPI and P. aeruginosa were characterized in sera and bronchoalveolar lavage (BAL) of adult and pediatric CF patients (n = 131), by ELISA and/or immunoblot., Results: Serum BPI autoantibodies were common (~43%) in adult while rare (≪5%) in pediatric (≤18 yrs) CF patients. Serum BPI IgG autoantibodies were of high avidity and strongly correlated with anti-P. aeruginosa IgG responses. A parallel relationship was observed with IgA, but not IgG, responses in adult and pediatric CF patient in the BAL. Thus, BAL IgA anti-BPI antibodies were independent of age and correlated with the presence of BPI cleavage in BAL., Conclusions: IgG and IgA autoreactivity to BPI in CF patients was demonstrated in serum and BAL, respectively, and correlated with the isotype of the antibody response to P. aeruginosa. The co-occurrence of anti-BPI and anti-P. aeruginosa IgA in the BAL, but not serum, of pediatric CF patients suggests that BPI tolerance is broken in the P. aeruginosa-infected airway and that serologic IgG autoantibodies are later induced, potentially through a separate pathway. The relationship between P. aeruginosa, BPI cleavage, and IgA autoantibodies in the BAL suggests a role for cryptic epitope generation in the breaking of tolerance., (Copyright © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The effects of lumacaftor-ivacaftor therapy on glycemia have not been thoroughly investigated. Continuous glucose monitoring (CGM) provides detailed information about glycemic patterns and detects glucose abnormalities earlier than traditional screening tools for diabetes., Methods: CGM measures, HbA1c, and oral glucose tolerance test (OGTT) results were collected and within-subject results compared in F508del homozygous youth with CF before and after initiation of lumacaftor-ivacaftor using the Wilcoxon signed-rank test., Results: Nine youth with CF (6 males, median age 12.7 years) were enrolled. CGM was performed in all participants before (median 26 weeks) and after lumacaftor-ivacaftor (median 29 weeks). HbA1c and fasting plasma glucose increased (p = .02) after lumacaftor-ivacaftor initiation. No changes in OGTT 1 h or 2 h glucose nor CGM measures were observed overall. When analyzed by sex, males showed lower glycemic variability, as reflected by the mean amplitude of glycemic excursions, on the post-treatment CGM., Conclusions: Glycemic abnormalities persisted in CF patients treated with lumacaftor-ivacaftor, although sex-dependent differences in glycemic response to treatment may exist., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Cirrhosis (CIR) occurs in 5-7% of cystic fibrosis (CF) patients. We hypothesized that alterations in intestinal function in CF contribute to the development of CIR., Aims: Determine the frequency of macroscopic intestinal lesions, intestinal inflammation, intestinal permeability and characterize fecal microbiome in CF CIR subjects and CF subjects with no liver disease (CFnoLIV)., Methods: 11 subjects with CFCIR (6 M, 12.8 yrs ± 3.8) and 19 matched with CFnoLIV (10 M, 12.6 yrs ± 3.4) underwent small bowel capsule endoscopy, intestinal permeability testing by urinary lactulose: mannitol excretion ratio, fecal calprotectin determination and fecal microbiome characterization., Results: CFCIR and CFnoLIV did not differ in key demographics or CF complications. CFCIR had higher GGT (59±51 U/L vs 17±4 p = 0.02) and lower platelet count (187±126 vs 283±60 p = 0.04) and weight (-0.86 ± 1.0 vs 0.30 ± 0.9 p = 0.002) z scores. CFCIR had more severe intestinal mucosal lesions on capsule endoscopy (score ≥4, 4/11 vs 0/19 p = 0.01). Fecal calprotectin was similar between CFCIR and CFnoLIV (166 μg/g ±175 vs 136 ± 193 p = 0.58, nl <120). Lactulose:mannitol ratio was elevated in 27/28 subjects and was slightly lower in CFCIR vs CFnoLIV (0.08±0.02 vs 0.11±0.05, p = 0.04, nl ≤0.03). Small bowel transit time was longer in CFCIR vs CFnoLIV (195±42 min vs 167±68 p<0.001, nl 274 ± 41). Bacteroides were decreased in relative abundance in CFCIR and were associated with lower capsule endoscopy score whereas Clostridium were more abundant in CFCIR and associated with higher capsule endoscopy score., Conclusions: CFCIR is associated with increased intestinal mucosal lesions, slower small bowel transit time and alterations in fecal microbiome. Abnormal intestinal permeability and elevated fecal calprotectin are common in all CF subjects. Disturbances in intestinal function in CF combined with changes in the microbiome may contribute to the development of hepatic fibrosis and intestinal lesions.