BackgroundElexacaftor/tezacaftor/ivacaftor (ETI) is the standard of care for most people with cystic fibrosis (CF) who carry at least one F508del allele. However, predicting responses to CFTR modulators in rare or complex CFTR genotypes is challenging. Sweat chloride concentration (SCC) and patient-derived functional assays assessing CFTR-mediated chloride transport are commonly used to classify modulator responsiveness. Carriers of the p.Leu467Phe;p.Phe508del (henceforward legacy nomenclature: L467F;F508del) complex CFTR allele have been considered unlikely to respond to ETI, based on short-term clinical, biomarker and ex vivo evidence. We report a discordant long-term response in an adult carrying this complex allele, with clinically meaningful benefit despite persistently negative CFTR chloride transport biomarkers.Case presentationWe describe an 8-year longitudinal pre- and post-treatment assessment of an adult woman with CF, adherent to therapy, with the L467F;F508del complex allele compounded with the non-responsive c.489 + 1G > T (621 + 1G > T) variant in trans. She has pancreatic insufficiency, progressive lung disease, and recurrent pulmonary exacerbations. After ETI commencement (at 40.5 years; July 2021) SCC remained unchanged at ∼100 mmol/L. Intestinal organoid and primary nasal epithelial cell assays showed no measurable ETI-related CFTR-mediated chloride transport rescue. Nevertheless, BMI increased from 22.0 to 26.8 kg/m2, annual exacerbations decreased from 5 to 3, and ppFEV₁ improved from 51% to 55–59%. Serial chest CT showed a shift from pre-ETI progression to post-ETI stabilisation, with reductions in air trapping and the extent of bronchiectasis on manual Brody II scoring and LungQ/PRAGMA-AI quantification. Exploratory in vitro exposure of nasal epithelial cells to vanzacaftor/tezacaftor/ivacaftor yielded ∼5% CFTR-mediated rescue, contrasting with the negative ETI response.ConclusionPersistent CFTR biomarker negativity may not fully exclude clinically meaningful ETI-associated benefit in rare or complex CFTR genotypes. The pulmonary and extrapulmonary improvements observed in this case support multidimensional response assessment beyond single-biomarker endpoints. These hypothesis-generating observations support individualised long-term monitoring and comprehensive interpretation of CFTR biomarkers in the clinical context. AI-assisted chest CT may provide complementary real-world evidence. An exploratory in vitro rescue study with vanzacaftor/tezacaftor supports the evaluation of emerging CFTR modulators. It suggests that similar studies should be conducted in other cases involving complex CFTR alleles.

INTRODUCTION:Congenital lung malformations (CLM) comprise various developmental respiratory tract anomalies. Long-term outcomes in adulthood remain poorly defined because structured follow-up often ends after childhood. We aimed to determine the clinical, functional, and imaging characteristics of adults with CLM. METHODS:A retrospective study was carried out in adults with CLM followed up at our center. We assessed clinical characteristics, spirometry measures (FEV1, FVC, FEV1/FVC, and MMEF25-75), adult body plethysmography (TLC, RV, RV/TLC), and longitudinal volumetric quantification of CLM size on computed tomography (CT). RESULTS:Thirty patients with CLM were included (14 diagnosed prenatally, 16 referred). Seventeen (57%) underwent surgery at a median age of 4 years (interquartile range 0-24.5). Adult symptoms occurred in 17 (57%) patients, with 86% of episodes managed conservatively. Two pulmonary malignancies (pleuropulmonary blastoma and adenocarcinoma) were identified in referrals, aged 24 and 31 respectively. Childhood spirometry showed reduced mean z-scores for FEV1 (-1.1 ± 1.6; p = 0.02) and FEV1/FVC (-1.3 ± 1.6; p = 0.01), as well as scores below the lower limit of normal (LLN; z-score < -1.64) for MMEF25-75 (-1.7 ± 1.4; p < 0.001). In adulthood, mean z-scores remained negative for all indices, with FEV1 (-1.7 ± 1.5; p < 0.001) and MMEF25-75 (-1.8 ± 1.3; p < 0.001) averaging below the LLN, while body plethysmography outcomes were mixed. Longitudinal volumetric CT analysis revealed that lesion size increased in 8 patients, fluctuated in 2, and decreased in 6. CONCLUSION:Adults with CLM show persistent functional impairments and heterogeneous lesion progression on imaging. These findings mandate a standardized, multimodal surveillance protocol beyond childhood to proactively monitor for signs of late-onset disease progression.

INTRODUCTION:The current cystic fibrosis (CF) care era, while hugely welcome, raises new challenges, particularly the need for more sensitive pulmonary outcome measures. Seeking further optimisation, we previously developed a Short extension to multiple breath washout measure (MBWShX) which captures previously overlooked, under-ventilated lung units but lacks regional information. Functional lung MRI addresses this limitation. We hypothesised these measures would be more sensitive to change in tracking CF lung disease than usual clinical respiratory function tests. METHODS:Forty-six people with (pw)CF, median age 15 (range 6-55) years were recruited to a single-centre study. While clinically stable, pwCF performed OE-MRI, MBW+/-ShX and spirometry at baseline and at 6 monthly intervals over 18 months of follow-up. A subgroup of pwCF (n=20) and age-matched healthy controls (HC, n=20) performed two repeatability visits within 6 weeks. RESULTS:OE-MRI/MBWShX were well tolerated, differentiated HC and CF groups, and were repeatable with negligible differences between two visits <6 weeks apart. OE-MRI/MBWShX parameters worsened at 12 months (p<0.05) and 18 months (p<0.01). In contrast, conventional measures of pulmonary function (FEV1+ LCI2.5) did not change significantly. CONCLUSIONS:OE-MRI/MBWShX are novel, sensitive tools to track progression of abnormalities in lung structure/function. Such progression may not be detected by conventional outcome measures. CF transmembrane conductance regulator (CFTR) modulators have been transformative for many pwCF and generally lead to substantial improvements in lung health. Stable FEV1 over longer time periods and, during mucoactive treatment withdrawal, may give false reassurance. OE-MRI/MBWShX reveal the likely less welcome reality that lung-disease progresses despite CFTR modulators. These measures could be considered in future studies when enhanced sensitivity is required.

INTRODUCTION:Infants with severe bronchopulmonary dysplasia (BPD) are at increased risk of hypoxemia and often fail hypoxic challenge testing (HCT). The predictive value of clinical characteristics and structural lung abnormalities on HCT outcomes is unclear. METHODS:This prospective cohort study included preterm-born infants (≤ 32 weeks of gestation) with severe BPD enrolled in a standardized follow-up program. Perinatal and neonatal data were extracted from medical records. At 6 months corrected gestational age, structural lung abnormalities were quantified on chest CT using PRAGMA-BPD scoring. HCT was performed using a sealed body plethysmograph and failure was defined as inability to maintain oxygen saturation ≥ 85% for 20 min. Univariate and multivariable logistic regression analyses identified predictors of HCT failure. RESULTS:Among 156 infants, 28.8% failed HCT. Of the perinatal and neonatal factors, patent ductus arteriosus (odds ratio 2.73, 95% confidence interval 1.29-6.14), pulmonary hypertension (2.57, 0.99-6.62), and longer duration of supplemental oxygen therapy (odds ratio per interquartile range increase [ORIQR] 2.40, 1.55-3.71) were associated with failure. For structural lung abnormalities, higher composite PRAGMA-BPD scores (ORIQR 2.18, 1.36-3.48), higher hyper-attenuation (ORIQR 1.75, 1.17-2.63), and hypo-attenuation (ORIQR 1.45, 1.08-1.98) scores predicted failure. In multivariable analysis, only longer duration of supplemental oxygen therapy (ORIQR 2.04, 1.22-3.42) and higher composite PRAGMA-BPD scores (ORIQR 1.95, 1.15-3.31) remained independent predictors. CONCLUSION:Duration of supplemental oxygen therapy and structural lung abnormalities independently predict HCT failure, highlighting the clinical relevance of both structural and functional impairments in severe BPD.

RATIONALE:Progressive structural lung disease (SLD) is a key hallmark of cystic fibrosis (CF). Elexacaftor/tezacaftor/ivacaftor (ETI) is associated with short-term improvements in SLD measured on chest computed tomography (CT). Longer-term changes in SLD outcomes with ETI are unknown. OBJECTIVES:Using multicenter standardized image collection and automated analysis, we sought to establish whether improvements in SLD with ETI continued in the second year of treatment. METHODS:Spirometry-controlled CT scans were performed at 6 sites in people with CF aged ≥12 years homozygous for the F508del mutation or heterozygous for the F508del and a minimum function mutation at baseline and 12 months and 24 months after commencing ETI. CT scans were analyzed using the automated LungQ platform (Thirona) to measure mucus plugging, trapped air, and bronchus-artery (BA) pair measurements: bronchial outer diameter (Bout), bronchial inner diameter (Bin), bronchial wall thickness (Bwt), arterial diameter (A), and BA ratios: Bout/A, Bin/A, Bwt/A, and bronchial wall area/bronchial outer area (Bwa/Boa). Scans were also visually scored using the PRAGMA-CF scoring system, divided into % disease (%DIS), % bronchiectasis (%BX), % mucus plugging (%MP), % bronchial wall thickening (%BWT), and % trapped air (%TA). RESULTS:CT scans were performed on 79 participants at baseline, 64 at 12 months, and 52 at 24 months. Automated analysis showed a significant reduction BwtA, and Bwa/Boa at 12 months, which were sustained to 24 months. No change was seen in Bin/A or Bout/A at 12 or 24 months. Improvements in mucus plug numbers, plug volume, and %TA at 12 months were sustained at 24 months. ETI was associated with a reduction in the ratio of pulmonary blood volume in the arterial system compared to the venous system in vessels of <1 mm, 1-2 mm, and >2 mm diameter. Manual PRAGMA-CF scores demonstrated improvements in %DIS, %BX, %MP, %BWT, and %TA at 12 months, and these changes were sustained, unchanged to 24 months. CONCLUSIONS:ETI is associated with substantial improvements in bronchial wall thickening, mucus plugging, and trapped air at 12 months. Changes were maintained to 24 months and did not continue to improve. Abnormal bronchial widening remained stable and did not improve with ETI therapy. Changes in the distribution of pulmonary arterial/venous blood volumes with ETI suggest a beneficial impact on pulmonary vascular pressures.

BACKGROUND:Elexacaftor-tezacaftor-ivacaftor (ETI) is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator that improves clinical outcomes in adolescents with cystic fibrosis. We aimed to investigate the effect of ETI on lung structural damage. METHODS:The Modul-CF prospective observational study is based at 33 paediatric cystic fibrosis reference centres in France. In the present analysis, we assessed the adolescent cohort of individuals with cystic fibrosis (aged 12-18 years) from the Modul-CF study who initiated treatment with ETI as part of routine care. These individuals were either homozygous for F508del and previously treated with lumacaftor-ivacaftor (LI), or F508del homozygous or compound heterozygous for F508del with a minimal function or residual function variant and naive to CFTR modulator treatment. The primary outcome measure was chest CT to investigate the effect of CFTR restoration on the natural history of cystic fibrosis lung disease. Secondary outcomes were sweat chloride, weight and height Z scores, quality of life, pulmonary function tests, lung clearance index at 2·5% of starting concentration (LCI2·5) from nitrogen multiple breath washout, and proinflammatory biomarkers in sputum (calprotectin, neutrophil elastase, IL-1β, IL-6, IL-8, and TNF-α) and blood (C-reactive protein and polymorphonuclear neutrophils). Outcome data were collected from baseline (in the 4 weeks before commencement of ETI [denoted month 0]) up to 1 year of ETI treatment (denoted month 12), with low-dose inspiratory-controlled chest CT done at month 0 and month 12. Changes in outcome measures from month 0 to month 12 were assessed with non-parametric Wilcoxon tests. Modul-CF was registered with ClinicalTrials.gov, NCT04301856, and is ongoing and open to recruitment. The data cutoff for the present analysis was July 28, 2023. FINDINGS:Between March 22, 2021, and May 25, 2022, a total of 330 adolescents with cystic fibrosis were enrolled in the study, of whom 320 were treated with ETI for 12 months and included in analyses (mean age at ETI initiation 14·1 years [SD 1·5]; 162 [51%] female and 158 [49%] male participants). Of the 320 participants, 112 (35%) were switched from LI to ETI, and 208 (65%) were CFTR modulator-naive. In the overall population, improvement in percent predicted FEV1 (ppFEV1) was observed from the first month of ETI treatment and was sustained at 12 months (mean absolute ppFEV1 change from month 0 to month 12, 14·0% [95% CI 12·4-15·7], p<0·0001, n=306). From month 0 to month 12, there were significant reductions in lung hyperinflation on plethysmography, and in mucus plugs, bronchial wall thickening, and bronchial dilatation on chest CT. Significant improvements were also observed in sweat chloride, weight Z score, LCI2.5, quality of life, and sputum and blood proinflammatory biomarkers. In 188 participants with available imaging analysis at both month 0 and month 12, the mean percentage of severely dilated bronchi (based on a bronchial outer diameter to adjacent artery diameter ratio [Bout/A] of ≥1·5) in bronchial generations G1-6 decreased by 10·7%, from 40·3% (SD 18·9) at month 0 to 29·6% (16·8) at month 12 (p<0·0001). Based on median Bout/A values of bronchus-artery pairs in the G1-6 region, 32 (17%) of 188 participants improved from severe to moderate dilatation (Bout/A ≥1·1 and <1·5) and 19 (10%) from moderate to normal dilatation (Bout/A <1·1) between month 0 and month 12. 14 (7%) participants progressed to a worse dilatation category. The changes in lung imaging metrics were correlated with the changes in sputum proinflammatory biomarkers. INTERPRETATION:Bronchial dilatations can reverse in adolescents with cystic fibrosis treated with ETI. The correlation with reduced airway inflammation provides insight into the effect of ETI on cystic fibrosis lung disease. FUNDING:Vaincre La Mucoviscidose, Mucoviscidose ABCF2, and the Cystic Fibrosis Foundation.

Introduction:Early cystic fibrosis (CF) lung disease monitoring is crucial for understanding responses to therapy and preventing progressive pulmonary decline. Structural lung disease (SLD) is a major cause of pulmonary decline in CF. We aimed to identify metabolites in CF bronchoalveolar lavage (BAL) associated with and predictive of SLD. Methods:We applied untargeted metabolomics to 84 BAL samples from a cross-sectional cohort of 67 clinically stable children with CF aged 1-5 years across two sites. We used a linear mixed-effects model to select metabolites associated with SLD, BAL neutrophils, and myeloperoxidase (MPO) and neutrophil elastase (NE) activities. An independent longitudinal cohort of infants who either did or did not exhibit bronchiectasis by age 9 years was analysed to determine whether metabolites associated with SLD could also predict future lung disease. Results:In the cross-sectional cohort, 10 BAL metabolites, including methionine sulfoxide (MetO), ornithine and N-acetylmethionine (NAcMet), were associated with SLD, neutrophils, MPO and NE. The percentage of methionine oxidation (%OxMet) and the arginine-ornithine ratio were also associated with these outcomes. In the longitudinal cohort, MetO, %OxMet, ornithine and NAcMet predicted bronchiectasis development, and MetO plus ornithine was a more sensitive predictor than either alone. At age 0-2 years, these metabolites outperformed established biomarkers such as NE, MPO and interleukin-8. Conclusions:We identified BAL metabolites associated with SLD, MPO and NE, detectable in the earliest stages of CF. MetO, %OxMet, NAcMet and ornithine predicted bronchiectasis development, outperforming established biomarkers. These metabolites reflect oxidising, proteolytic and other enzymatic activities of neutrophils, highlighting potential therapeutic avenues.

Background: PRAGMA-CF is a clinically validated visual chest CT scoring method, quantifying relevant components of structural airway damage in CF. We aimed to validate a newly developed AI-based automated PRAGMA-AI and Mucus Plugging algorithm using the visual PRAGMA-CF as reference. Material and Methods: The study included 363 retrospective chest CT's of 178 CF patients (100 New-Zealand and Australian, 78 Dutch) with at least one inspiratory CT matching the image selection criteria. Eligible CT scans were analyzed using visual PRAGMA-CF, automated PRAGMA-AI and Mucus Plugging algorithm. Outcomes were compared using descriptive statistics, correlation, intra-and interclass correlation and Bland-Altman plots. Sensitivity analyses evaluated the impact of disease severity, study cohort, number of slices and convolution kernel (soft vs. hard). Results: The algorithm successfully analyzed 353 (97 %) CT scans. A strong correlation between the methods was found for %bronchiectasis ( %BE) and %disease (%DIS), but weak for %Airway wall thickening (%AWT). The automated Mucus plugging outcomes showed strong correlation with visual %mucus plugging ( %MP). ICC's between visual and automated sub-scores witnessed average agreement for %BE and %DIS, except for %AWT which was weak. Sensitivity analyses revealed that convolution kernel did not affect the correlation between visual and automated outcomes, but harder kernels yielded lower disease scores, especially for %BE and %AWT. Conclusion: Our results show that AI-derived outcomes are not identical to visual PRAGMA-CF scores in size, but strongly correlated on measures of bronchiectasis, bronchial-disease and mucus plugging. They could therefore be a promising alternative for time-consuming visual scoring, especially in larger studies.