搜索结果：Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society

Prenatal therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has recently emerged as a potential strategy to modify the early natural history of cystic fibrosis (CF). While case reports have described prevention of meconium ileus and pancreatic insufficiency, data on male reproductive outcomes remain extremely limited. We report a male infant with CF (homozygous F508del) whose heterozygous carrier mother initiated ETI at 27+4 weeks of gestation after prenatal diagnosis. Pregnancy was uneventful until preterm delivery at 35+2 weeks. The neonate presented with normal meconium passage, persistently normal fecal elastase, and no pulmonary abnormalities on magnetic resonance imaging. ETI was initiated directly in the infant at day 11 of life, with subsequent catch-up growth and discontinuation of pancreatic enzyme replacement therapy at 8 weeks. Remarkably, ultrasound at 8 weeks demonstrated bilateral vas deferens, a structure typically absent in nearly all male patients with CF at birth. Sweat chloride concentrations normalized under therapy, and no CF-typical manifestations were observed during the first 7 months of life. This is the first report of a male infant with CF in whom prenatal ETI via a heterozygous carrier mother, started in the second trimester and continued postnatally, was associated with preserved exocrine pancreatic function, absence of pulmonary disease, and presence of vas deferens. These findings suggest that prenatal CFTR modulation - even when initiated late in gestation - may alter the trajectory of CF-related organ manifestations, including male reproductive development. Long-term follow-up is essential to determine whether these early benefits translate into sustained preservation of fertility and multiorgan function.

Cystic fibrosis (CF) transplant recipients infected with SARS-CoV-2 are at high risk for hospitalization or death. We aimed to (1) assess whether time since solid organ transplantation impacts severity of SARS-CoV-2 infection and (2) to evaluate the impact of SARS-CoV-2 infection on the slope of lung function trajectory. This is a retrospective international cohort study of individuals with CF post-solid organ transplant with a confirmed SARS-CoV-2 infection between January 2020 and December 2021. The primary outcome was death or hospitalization. The secondary outcome was change in lung function trajectory following infection. To assess the impact of time from transplant on the primary outcome, logistic regression was performed while lung function trajectory was assessed using a linear mixed-effects model. A total of 526 SARS-CoV-2 infections from 19 countries were recorded. The median age at time of infection was 36 years (IQR 29-44). Median time since transplant was 5.8 years (IQR 3.3-10.8). The timing of transplant relative to infection was not significantly associated with hospitalization or death (OR 0.975 CI 0.928-1.025). A higher baseline ppFEV1 was associated with a decreased odds of death or hospitalization (OR 0.989, 95% CI 0.983, 0.995). In a subgroup of participants, lung function trajectory did not change significantly in the year following SARS-CoV-2 infection. In a diverse global post-transplant CF population, the timing of transplantation was not significantly associated with severe outcomes following SARS-CoV-2 infection. Those with more severe lung disease were at increased risk for worse outcomes and should be monitored closely.

Pregnancies among people with cystic fibrosis (PwCF) have increased in the CFTR modulator (CFTRm) era. However, pregnant PwCF were excluded from CFTRm trials, limiting evidence on offspring outcomes after in utero and breast milk exposure. Follow-up practices for exposed children vary, and no widely accepted recommendations exist. We aimed to develop the first international recommendations for clinical follow-up of children exposed to CFTRm in utero and/or via breastfeeding. An international survey of follow-up practices and a literature review informed item generation for a Delphi consensus survey. We recruited panellists from four clinician groups (paediatric CF, adult CF, non-CF physicians, and other healthcare professionals) and a group of PwCF. An a priori consensus threshold was set at ≥70 % overall agreement and ≥50 % agreement within each group, with up to three survey rounds. The Imperial College Research Ethics Committee granted ethical approval. The protocol was prospectively registered (DOI:10.17605/OSF.IO/VJ2Z8). Completed responses were submitted by 106, 101 and 107 panellists in rounds 1-3, respectively, representing 26 countries. Clinician panellists had a median of 18 years' clinical experience (IQR 10-25). Eight PwCF participated. Consensus was reached on 73 items, including follow-up setting, liver function monitoring, cataract screening, and potential false-negative CF newborn screening. In total, we received 941 free-text comments which we used to refine existing items and generate new ones for subsequent rounds. International consensus recommendations are now available to support consistent, implementable follow-up of children exposed to CFTRm in utero and/or via breastfeeding, adaptable to local practice.

In 2024-2025, the Cystic Fibrosis Foundation (US) and Cystic Fibrosis Trust (UK) hosted an International CFRD Consortium round-table webinar series for basic science, translational, and clinical researchers with the goal of sharpening mechanistic understanding of CFRD pathogenesis and prioritizing therapeutic development. This review summarizes the research priorities identified in the International CFRD Consortium, including (i) further investigation into the role of pancreatic fibrosis, vascular abnormalities, and α-cell dysfunction in the development of CFRD; (ii) the creation and refinement of novel animal and human cell- and tissue-based models to understand the complex interplay of exocrine and endocrine cells in the CF pancreas; (iii) development and validation of circulating and imaging biomarkers, together with dynamic glucose testing to explore β-cell function and kinetics in people with CF across the dysglycemia spectrum; and (iv) prospective clinical studies to guide CFRD treatment options and investigate the changing landscape of aging, increasing prevalence of obesity and diabetes and their complications in the era of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Collectively, these priorities aim to accelerate transition from mechanism to intervention and expand evidence-based care for people with CF at risk of, or living with, CFRD.

Liver involvement among people with cystic fibrosis (PwCF) has long been recognized as clinically important. However, a lack of consistent terminology, incomplete understanding of natural history, and poor clinical trial endpoints have historically hindered clinical and research advancements in this field. Recent efforts by the CF Foundation and international gastrointestinal societies have led to a phenotype-based classification for liver involvement, now referred to as Cystic Fibrosis Hepato-Biliary Involvement (CFHBI), with the most severe form of disease termed advanced CF liver disease (aCFLD). Longitudinal studies such as PUSH, combined with national patient registry data, has greatly improved our understanding of the natural history of CFHBI. Several studies have assessed the utility of conventional serological markers of liver disease, non-invasive liver fibrosis indices, and imaging with various elastography modalities to screen for CFHBI and monitor for progression to aCFLD. This has led to the first evidence-based consensus recommendations for the screening, evaluation and management of CFHBI in children. These recommendations provide a foundation from which future research can build from. Finally, while there is emerging population-level data suggesting that modulator therapies are decreasing the rates of aCFLD, the true impact of these medications on CFHBI remains unknown. In this review we provide an overview of the recent advancements leading to the recent consensus recommendations, summarize what is known about the impact of modulator therapies on CFHBI, and discuss the outstanding questions that need to be addressed to advance our understanding of CFHBI.

Approximately 20 percent of people with cystic fibrosis (CF) develop cystic fibrosis hepatobiliary involvement (CFHBI). Some show the more severe form advanced cystic fibrosis liver disease (aCFLD). The biliary tree is an important site for cystic fibrosis transmenbrane conductance regulator (CFTR) activity. Despite previous studies the impact of CFTR dysfunction on bile acid homeostasis, the composition of the different bile acids and its impact on hepatobiliary function remains unclear. Between November 2020 and July 2022 serum samples from children with CF were collected. Bile acids were analysed by liquid chromatography coupled to tandem mass spectrometry. Serum samples from otherwise healthy patients hospitalised for elective procedures served as controls. 73 children with CF, and 100 control patients were enrolled. Eight children of the CF cohort were diagnosed with aCFLD. In children with CF (n = 73), overall bile acid concentration as well as primary and secondary bile acids were significantly elevated, whereas the ratio of taurine conjugated bile acids was decreased. These alterations were not observed in infants and became more pronounced with age. Furthermore, children with aCFLD (n = 8, 11 %) showed significantly increased concentrations of secondary bile acids as well as lithocholic, glycolithocholic, deoxycholic and glycodeoxycholic acid. Our data show that bile acid composition is altered in children with CF. This difference is evident from preschool age onward. Moreover, different bile acid compositions are detected in children with and without aCFLD. These changes appear to aggravate with age, which could indicate an age-dependent increase in hepatobiliary impairment.

Burkholderia cepacia complex (BCC) comprises 25 species known to cause disease primarily in people with cystic fibrosis (pwCF). Isolation of BCC has major implications for infection control, eradication strategies, morbidity, and lung transplant eligibility. Although not considered part of the BCC, other Burkholderia species are known to cause respiratory disease in pwCF, namely Burkholderia gladioli and Burkholderia pseudomallei. The introduction of CFTR modulator therapy has improved pulmonary outcomes in pwCF, yet little is known about their impact on Burkholderia species acquisition, clearance, or long-term microbiological or clinical outcomes. We reviewed the outcomes of pwCF infected with Burkholderia species (including BCC, B. gladioli, or B. pseudomallei) receiving care in a large CF centre over the past 15 years, spanning the introduction of CFTR modulator therapy. Forty-four pwCF cultured one of these organisms between 2010 and 2025. Ten had only a single isolation with 28 (63.6%) deemed to have chronic infection and 6 (13.6%) exhibiting transient infection defined by having only two positive cultures. Notably, no new Burkholderia species acquisitions occurred after commencement of elexacaftor/tezacaftor/ivacaftor (ETI). The longitudinal incidence rates of chronic infection with Burkholderia species showed a reducing trend from 2017-2025 with rates of spontaneous clearance following ETI appearing similar to background clearance rates prior to modulator therapy. These findings contribute to the evolving understanding of Burkholderia species in the modulator era. While ETI does not eliminate the risk of chronic infection, it may reduce acquisition and support clearance in a subset of pwCF.

This review explores the changing landscape of drug safety in patients with cystic fibrosis (CF) prescribed Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator therapy. While serious adverse reactions are infrequent, they can necessitate treatment withdrawal and thereby negatively impact clinical outcomes. The CFTR correctors (vanzacaftor, elexacaftor, tezacaftor, lumacaftor) and potentiators (ivacaftor, deuterated ivacaftor) target the underlying CFTR defect to improve protein function. The CF patient population encounter a high prevalence of non-immediate adverse drug reactions and T-cell mediated hypersensitivity to β-lactam antibiotics are among the most well characterised. Piperacillin has been defined as a leading drug culprit within non-immediate drug allergy in patients with CF, with a growing body of evidence alluding to the central role of T-lymphocytes. The prevalence of reactions in CF is likely due to factors including exaggerated inflammation, overactive immune states and cumulative drug exposure. While the introduction of the CFTR modulators has led to improvements in patients inflammatory and immune states, some patients have been reported to develop drug-related allergies. Uniquely, patients presenting with drug hypersensitivity have been found to later tolerate CFTR modulators, often without the need for desensitisation protocols. This phenomenon has led us to hypothesise that increased levels of inflammation and dysregulation of regulatory T-cells in CF patients could propagate adverse reactions to CFTR modulators that resolve alongside underlying infection. The introduction of CFTR modulator therapies has been highly transformative for patients with CF, therefore, adverse reactions to these compounds that lead to cessation of treatment are serious and important to understand.

The pancreas is one of the earliest affected organs in cystic fibrosis (CF). Most newborn screening programs are based on pancreatic inflammation causing elevated trypsinogen at birth, and most individuals with CF are born with exocrine pancreatic insufficiency (PI) which requires lifelong treatment with pancreas enzyme replacement therapy (PERT). However, as CFTR modulating therapies (CFTRm) are administered earlier and earlier, these paradigms may be changing. In this article, we summarize updates on the diagnosis and treatment of exocrine pancreatic disease in CF in the era of CFTRm. We provide a concise review on the natural history of the exocrine pancreas in CF as a context to discuss new observations of CFTRm use at different time points in utero, in childhood, and in adulthood. Clinicians are encouraged to obtain objective exocrine function testing (i.e., fecal elastase) among individuals receiving CFTRm therapy, and to counsel patients and/or parents on the unknowns regarding natural history during CFTRm use. Few patients will regain pancreatic sufficiency (PS) and we encourage clinicians to de-escalate PERT stepwise, rather than discontinue abruptly. Lastly, it is important to note that most reports of improved exocrine function are described in children, and individuals who started CFTRm in adulthood are unlikely to experience reduction in PERT dose and should continue close monitoring for late complications of severe PI, like fat soluble vitamin deficiency and metabolic bone disease.

The introduction of CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ETI) has significantly altered the nutritional trajectory of children with cystic fibrosis (cwCF). While most eligible children in high-resource countries have commenced ETI, the rollout has outpaced the development of nutritional guidance. This study aimed to: (1) systematically review the literature on ETI and nutrition (2) develop expert consensus-based statements and (3) highlight existing research gaps and priorities. A systematic review and guideline development process was registered on PROSPERO (ID: CRD42024587618). An expert panel of 22 professionals, including dietitians, gastroenterologists, respirologists, endocrinologists, and a parent representative was convened with attention to global representation. Research questions were developed using the Population, Intervention, Comparison, Outcome (PICO) framework. A comprehensive literature search was conducted across Medline, Embase, CINAHL, and Cochrane (January 2010 to April 2025). Studies were independently screened, assessed for quality using Scottish Intercollegiate Guidelines Network (SIGN) criteria, and extracted into evidence tables. Draft statements were developed and refined through iterative feedback and online discussion. Final consensus was achieved using real-time Delphi, with ≥80% agreement required for endorsement. Reporting followed Accurate Consensus Reporting Document (ACCORD) guidelines. 67 consensus-based statements were developed. The top research priorities were identified based on the greatest proportion of "strongly agree" responses. ETI has altered nutritional requirements in cwCF, yet evidence remains limited. This study presents the first consensus-based guidance for the nutritional care of cwCF receiving ETI, providing interim, expert informed recommendations and highlighting research priorities, particularly the need to re-evaluate traditional BMI targets.

Several countries reported a reduction in lung transplants for people with cystic fibrosis (pwCF) after elexacaftor-tezacaftor-ivacaftor (ETI) was introduced. We sought to evaluate how lung transplant indications evolved in relation to CFTR genotypes and the use of ETI. All lung transplants performed on pwCF in France between 2015 and 2024 were identified using data from the French Agence de la Biom&#xe9;decine. Individual-level patient data, including CFTR genotypes and use of ETI at the time of transplant, were obtained from the French CF reference network centers. Between 2015 and 2024, a total of 538 lung transplants were performed, including 461 first-time transplants and 77 re-transplants. The rate of first-time lung transplant was 13.4 per 1000 non-transplanted patients/year versus 1.8 per 1000 non-transplanted patients/year for 2015-2019 (prior to ETI availability) and 2020-2024 (following ETI availability), respectively (P < 0.0001); the rate of lung re-transplant was 10.2 per 1000 transplanted patients/year versus 7.7 per 1000 transplanted patients/year (P = 0.70). Treatment with ETI was prescribed prior to transplant in all F508del pwCF who received a first-time transplant since 2021 and in all those with non-F508del ETI-responsive variants since 2022. Eleven patients treated with ETI required lung transplant due to adverse effects leading to ETI discontinuation, concomitant severe liver disease or insufficient improvement of respiratory failure. ETI has reduced, but not eliminated, the need for a first-time lung transplant in pwCF. Indications for a first-time lung transplant persist in a small subset of pwCF who respond to ETI and in those with nonresponsive CFTR genotypes. Re-transplant remains an option for selected transplant recipients with chronic lung allograft dysfunction.

Limited evidence exists to guide Elexacaftor-Tezacaftor-Ivacaftor (ETI) use in adults with cystic fibrosis (awCF) and preserved lung function (ppFEV1 >90%). To address the resulting variability in prescribing practices, we conducted a European survey among a group of adult CF centres aiming at identifying factors influencing ETI initiation decisions in adults with preserved lung function. Between April and June 2024, we invited 25 ECFS prescribers from 25 adult CF centres to participate in a web-based survey to explore factors influencing ETI initiation in adults with CF and ppFEV&#x2081; >90%. The survey questionnaire collected data on centre characteristics, prescribing ETI attitudes, and the impact of specific clinical variables on ETI prescription decision in this subgroup. Twenty-three CF specialists (92%) responded. Most specialists (69.6%) favoured early treatment initiation in all eligible patients. A key factors influencing ETI initiation decisions was the presence of respiratory symptoms. In adults with preserved lung function, however, microbiological and imaging features emerged as the most influential factors driving treatment decision. While patient willingness and symptoms strongly encouraged ETI use, factors like age over 50, a history of mental health issues, and pregnancy desire resulted in conflicting prescribing attitudes among centers. Although several disease markers more consistently support the decision to initiate ETI in individuals with preserved lung function, the absence of clear clinical guidance contributes to heterogeneous prescribing practices across centres. This highlights the need for longitudinal studies to clarify the long-term outcomes of ETI in this population.

Tracheobronchomalacia (TBM) is characterised by abnormal collapsibility of the trachea and bronchi, often seen in children with cystic fibrosis (CF). This study aims to determine the impact of TBM on hospital admissions in young children with CF. A retrospective study was conducted at a single paediatric tertiary CF centre, examining medical records of children with CF born between January 2009 and June 2019. TBM presence was identified through bronchoscopy records. Hospital admission data, including the number, length and reason for admissions, was collected and analysed. Of 101 children included, 59 had TBM. Children with TBM had significantly more hospital admissions and longer hospital stays compared to those without TBM. The risk of all hospital admissions increased by a factor of 2.00 in the first two years and 1.89 in the first four years of life. Risk of respiratory admissions were also higher, increasing by a factor of 3.06 and 2.17 respectively. The total number of days admitted to hospital for any reason increased by a factor of 2.3 in the first two years and 2.05 in the first four years, with respiratory bed days alone increasing by a factor of 3.14 in the first two years. TBM in young children with CF is associated with increased hospital admissions and longer hospital stays, particularly for respiratory issues. These findings highlight the need for proactive management to address the increased healthcare burden in this population, and identifies areas for further research on effective interventions aimed at reducing hospitalisations.

Levofloxacin inhalation solution (LIS) is approved for managing chronic Pseudomonas aeruginosa infections in adult patients with cystic fibrosis (CF). The European Medicines Agency made a provisional marketing authorisation of LIS conditional on its long-term safety evaluation in clinical practice. The safety of LIS was evaluated using data from the UK (2017-2021) and German CF Registries (2019-2021). Propensity score models were used to compare the LIS cohorts (patients treated with LIS at any time during observation) with the non-LIS cohorts (treated with other inhaled antibiotics). Primary endpoints included haemoptysis, liver disease, tendon rupture, antimicrobial resistance and treatment discontinuation. In the UK Registry, 103 and 511 adult patients were included in the LIS and non-LIS cohorts, respectively. In the German Registry, equivalent numbers were 524 and 1893. In the UK, no significant difference in haemoptysis rates was observed between the LIS and non-LIS cohorts (17.5% vs 19.6%, adjusted relative risk [aRR]: 0.88, 95%CI 0.56-1.39, P=0.583). In the German Registry, a higher risk of haemoptysis was observed in the LIS cohort (17% vs 12%; aRR: 1.30, 95%CI 1.06-1.59, P=0.012). There was no increased risk of liver disease associated with LIS treatment, and tendon ruptures were rare. Antimicrobial resistance patterns were similar in LIS and non-LIS cohorts, and treatment discontinuation due to adverse events was low in both registries. LIS was generally safe although may be associated with a higher risk of haemoptysis. No difference in liver disease, tendon rupture or treatment discontinuation compared to other inhaled antibiotics was observed.

Elevated levels of human epididymis protein 4 (HE4) have been observed in cystic fibrosis (CF), where its expression is directly affected by impaired CFTR through the NF-&#x3ba;B pathway in p.Phe508del-CFTR CFBE 41o- cells in vitro. Dysfunctional CFTR is also linked to epithelial-mesenchymal transition (EMT) in CF. However, no data is available whether HE4 expression changes and is associated with CF-related EMT. The level of EMT was compared between CFBE 41o- cells with the p.Phe508del-CFTR mutation and wt-CFTR by measuring epithelial and mesenchymal markers using fluorescence microscopy and RT-qPCR. EMT was also induced by TGF&#x3b2;1 in p.Phe508del-CFTR CFBE cells from 24 to 120 h to explore relationship between EMT development and the expression of HE4 and MMP9. VX-445/VX-661/VX-770 treatment restored CFTR function to observe changes in EMT phenotype. The direct effects of HE4 on EMT and MMP9 levels were examined in CFBE cells where HE4 expression was reduced through transfection with HE4-specific siRNA. Cell proliferation was assessed by Ki67 positivity. CFBE cells expressing p.Phe508del-CFTR were more prone to be mesenchymal than wt-CFTR CFBE cells and showed higher basal HE4 and MMP9 levels. In response to TGF&#x3b2;1, even lower E-cadherin with higher N-cadherin and MMP9 levels were observed in p.Phe508del-CFTR CFBE cells compared to untreated cells. In contrast, HE4 expression decreased after 48 h and continued to decline up to 120 h. CFTR modulator treatment could reverse the EMT phenotype, normalizing HE4 and MMP9 levels. Finally, downregulated HE4 promoted EMT, resulting in higher MMP9 expression and reduced cell proliferation in p.Phe508del-CFTR CFBE cells. EMT is accompanied by decreasing HE4 expression and upregulated MMP9 level in the airway epithelial cells of CF.

Change in sputum bacterial density has been used to measure efficacy in clinical trials of novel therapies for cystic fibrosis (CF); however, the baseline degree of day-to-day bacterial density change is not well understood. Recent data show that Pseudomonas density in CF sputum has the potential to vary considerably day-to-day even in the absence of antimicrobial treatment. Here we report daily variability of Burkholderia and Achromobacter density in 288 pairs of sputum samples obtained from eight adults with CF. Compared to similar previous analyses of Pseudomonas density, overall variability of day-to-day change for both Burkholderia and Achromobacter was relatively modest (SD=0.54 and 0.58 log10 16S rRNA gene copies/mL, respectively). Significant inter-person variability was observed among the Burkholderia cohort but not among the Achromobacter cohort (P = 0.001 and P = 0.07, respectively). Density changes for both Burkholderia and Achromobacter were inversely correlated with starting densities. This study provides context for the use of changes in sputum bacterial density as a response biomarker in clinical trials of CF therapeutics.

Liver stiffness measurement (LSM) has gained interest as a modality to screen for cystic fibrosis hepato-biliary involvement (CFHBI) and monitor for disease progression. Studies of its effectiveness in longitudinal prospective cohorts are lacking. The ELASTIC study evaluated LSM by FibroScan&#xae; in children with or without CFHBI. Liver ultrasound (US) and clinical data were collected annually. Changes in LSM were assessed for association with US grade and changes in noninvasive biomarkers of liver disease. Additionally, we evaluated intra-individual variation in LSM measurements utilizing the reliable change index. There were 96 participants completed longitudinal assessment by FibroScan&#xae; with US and laboratory data available within one-year. Nodular (NOD) and normal (NL) US patterns were significantly associated with decrease in LSM (-5.4% and -4.7% respectively), but within expected variability. No association with LSM was observed among heterogenous (HTG) or homogenous (HMG) US patterns. Reliable change index showed large intra-individual variation between FibroScan&#xae; examinations with a decrement of 48% through an increment of 93% being within the normal range of expected variation. Changes in LSM were associated (p < 0.001) with clinical variables including GGT (r= 0.64), spleen size z-score (r=0.42), platelets (r=-0.38), and APRI (r=0.34). There is considerable intra-individual variation of LSM by FibroScan&#xae; among children with or without CFHBI. We were unable to detect incremental changes in LSM in CFHBI. Significant association between changes in LSM and biomarkers of liver disease were observed. Further exploration is required to determine the clinical utility of LSM in the assessment of CFHBI.

Malnutrition, inflammation, limited exercise, and low muscle mass increase the risk of cystic fibrosis (CF) bone disease (CFBD). Additionally, dysfunction of the CF transmembrane conductance regulator (CFTR) directly affects bone-forming cells. Elexacaftor/Tezacaftor/Ivacaftor (ETI) could influence these aspects. We examined the impact of ETI on bone health in Danish people with CF. This nationwide cohort study evaluated changes in bone status in adults with CF after ETI treatment. Dual energy X-ray absorptiometry (DXA) was used to assess bone mineral density Z-scores in lumbar spine, femoral neck, and total hip. To assess calcium metabolism, plasma levels of vitamin D, calcium, and parathyroid hormone (PTH) were evaluated. Data were collected from 2 years pre- to 3.5 years post-ETI initiation, comparing pre-ETI levels with 1-, 2- and 3-year post-ETI measurements. Data were analyzed using linear mixed effects regression models and subgroup interaction analyses. 197 Danish adults with CF were included in the study, contributing 435 DXA scans. Mean change from pre-ETI period (95%CI) in femoral neck and total hip Z-scores showed a decrease by year 3 of -0.16 (-0.31; -0.01; p=0.04) and -0.15 (-0.30; <0.01; p=0.05), respectively, while lumbar spine showed a slight increase of 0.13 (-0.05, 0.31; p=0.15). Vitamin D levels initially decreased but subsequently increased by 8.9 nmol/L (4.5-13.3; p<0.01) by year 3 as compared to pre-ETI levels. Calcium and PTH levels remained stable. After 3 years of ETI treatment in Danish adults with CF, no clinically significant changes in bone health or calcium metabolism were observed.

Breath profile analysis of volatile organic compounds (VOCs) by electronic nose (eNose) technology can distinguish between healthy individuals and people with cystic fibrosis (pwCF). It remains, however, unclear whether CFTR modulator therapy, that corrects the underlying defect in treated pwCF, alters the exhaled breath profiles. In this prospective longitudinal study, eNose-derived exhaled breath profiles were obtained using the SpiroNose&#xae; (Breathomix, Leiden, The Netherlands) from 61 CF children before starting therapy with elexacaftor/tezacaftor/ivacaftor (ETI), and at follow-up visits less than 3 and more than 6 months after ETI initiation. Routine clinical outcomes and airway microbiology were assessed at all visits. Twenty-six healthy controls provided single measurements. Longitudinal SpiroNose sensor data were analyzed using linear mixed-effects models and permutational multivariate analysis of variance (PERMANOVA), and exploratory mixed-effects models to test for associations with Staphylococcus aureus (SA) airway infection and clearance. ETI led to improved sweat chloride concentrations, pulmonary function (ppFEV1) and BMI, but no significant changes in SpiroNose sensor signals were observed during follow-up. SpiroNose sensor signals reliably discriminated healthy controls from CF children at baseline and at follow-up on ETI, with consistent differences in multiple SpiroNose sensors. SA airway infection was captured (sensor S7), whereas SA clearance did not result in measurable changes in SpiroNose signals. CFTR modulator therapy with ETI does not significantly alter eNose-derived VOC breath profiles in children with CF. The ability of the eNose to distinguish CF from healthy controls remains unchanged after ETI initiation.