Longitudinal Magnetic Resonance Imaging of Changes in Lung Morphology and Perfusion in Children with Cystic Fibrosis From Infancy through Adolescence.

RATIONALE: The progression of lung changes in cystic fibrosis (CF) from infancy through adolescence remains poorly understood due to limited longitudinal imaging data. OBJECTIVES: To assess changes in lung morphology and perfusion in children with CF through the pediatric age range by longitudinal chest magnetic resonance imaging (MRI). METHODS: 1112 annual chest MRI were performed in 226 patients with CF aged 0-18yr. MRI was assessed using a validated MRI scoring system. MEASUREMENTS AND MAIN RESULTS: The MRI global score continuously increased from 5.5±4.6 at infancy (0yr) to 17.9±8.4 at adolescence (range 12-18yr), and the MRI morphology score from 5.0±3.9 to 12.4±6.0 (P<0.001). Bronchiectasis/wall thickening prevalence increased from 89.1% at infancy to approx. 100% from preschool age (1-5yr), and the subscore increased from 3.1±1.9 at infancy to 6.6±2.1 at adolescence (P<0.001). Mucus plugging prevalence increased from 55.4% at infancy to 83.5% at adolescence, and the subscore increased from 1.2±1.6 to 3.7±2.5 in the same period (P<0.001). Perfusion abnormalities were found in 44.4% at infancy, and increased to approx. 90% from preschool age (P<0.001). The MRI perfusion score increased from 1.1±1.6 at infancy to 5.6±3.0 at adolescence (P<0.001). Chronic Pseudomonas aeruginosa infection was associated with higher MRI scores from school age (6-11yr, P<0.05-0.001). CONCLUSIONS: This is the first study assessing longitudinal changes in lung morphology and perfusion in CF throughout the pediatric age range, providing percentiles as age-specific reference for lung disease severity. Our data may facilitate the use of MRI as an endpoint in clinical trials in children with CF.

ERS technical standard: Global Lung Function Initiative reference values for multiple breath washout indices.

BACKGROUND: Multiple breath washout is a lung function test based on tidal breathing that assesses lung volume and ventilation distribution. The aim of this analysis was to use the Global Lung Function Initiative methodology to develop all-age reference equations for the multiple breath washout indices lung clearance index (LCI) and functional residual capacity (FRC). METHODS: Multiple breath washout data from healthy individuals were collated from sites. Data were re-analysed using the latest software versions. Reference equations were derived using the lambda-mu-sigma (LMS) method using the generalised additive models of location shape and scale programme in R. The impact of equipment type, inert tracer gas, and equipment dead space volume on the derived reference ranges were investigated. RESULTS: Data from 23 sites (n=3647 test occasions) were submitted. Reference equations were derived from 1581 unique observations from participants between the ages of 2 and 81 years. Equipment type, inert tracer gas, and equipment dead space volume did not significantly affect the prediction equations for either LCI or FRC. Reference equations for LCI include age as the only predictor, whereas sex-specific reference equations for FRC included height and age. CONCLUSIONS: Global Lung Function Initiative reference equations for multiple breath washout variables provide a standard for reporting and interpretation of LCI and FRC.

Long-Term Impact of Lumacaftor/Ivacaftor Treatment on Cystic Fibrosis Disease Progression in Children 2-5 Years of Age Homozygous for F508del-CFTR: A Phase 2, Open-Label Clinical Trial.

Rationale: Clinical trials show that lumacaftor/ivacaftor (LUM/IVA) treatment has the potential to modify early cystic fibrosis (CF) disease progression in children as young as 2 years of age. Objectives: To assess the long-term impact of LUM/IVA treatment on CF disease progression in children aged 2-5 years. Methods: This phase 2 trial had two parts: part 1, a 48-week, randomized, double-blind, placebo-controlled study of LUM/IVA in children aged 2-5 years (previously reported) was followed by a 48-week open-label treatment period in which all children received LUM/IVA (part 2; reported here). Endpoints assessed in part 2 included absolute changes from baseline in chest magnetic resonance imaging (MRI) global score at Week 96; weight-for-age, stature-for-age, and body mass index (BMI)-for-age z-scores at Week 96; lung clearance index based on lung volume turnover required to reach 2.5% of starting N2 concentration (LCI2.5) through Week 96; chest MRI morphological score, chest MRI perfusion score, weight, stature, BMI, and microbiology cultures (oropharyngeal swabs) at Week 96; sweat chloride, amount of immunoreactive trypsinogen, fecal elastase-1 concentration, and fecal calprotectin through Week 96; and number of pulmonary exacerbations, time to first pulmonary exacerbation, and number of CF-related hospitalizations. Results: Forty-nine children received one or more doses of LUM/IVA in the open-label period (33 in the LUM/IVA to LUM/IVA group and 16 in the placebo to LUM/IVA group), with a mean exposure of 47.1 (standard deviation [SD], 5.2) weeks. The mean absolute change in MRI global score (negative value indicates improvement) from baseline at Week 96 was -2.7 (SD, 7.0; 95% confidence interval [CI], -5.2 to -0.1) in the LUM/IVA to LUM/IVA group and -5.6 (SD, 6.9; 95% CI, -9.2 to -1.9) in the placebo to LUM/IVA group. Improvements in LCI2.5, sweat chloride concentration, and markers of pancreatic function and intestinal inflammation were also observed in both groups. Growth parameters remained stable in both groups. The majority of children had adverse events considered mild (38.8%) or moderate (40.8%). Two (4.1%) children discontinued LUM/IVA treatment because of adverse events (distal intestinal obstruction syndrome [n = 1] and alanine aminotransferase increase [n = 1]). Conclusions: These findings confirm the potential for early LUM/IVA treatment to alter the trajectory of CF disease progression, including CF lung disease, in children as young as 2 years of age. Clinical trial registered with ClinicalTrials.gov (NCT03625466).

Impact of elexacaftor/tezacaftor/ivacaftor therapy on lung clearance index and magnetic resonance imaging in children with cystic fibrosis and one or two F508del alleles.

BACKGROUND: We recently demonstrated that elexacaftor/tezacaftor/ivacaftor (ETI) improves the lung clearance index (LCI) and abnormalities in lung morphology detected by magnetic resonance imaging (MRI) in adolescent and adult patients with cystic fibrosis (CF). However, real-world data on the effect of ETI on these sensitive outcomes of lung structure and function in school-age children with CF have not been reported. The aim of this study was therefore to examine the effect of ETI on the LCI and the lung MRI score in children aged 6-11 years with CF and one or two F508del alleles. METHODS: This prospective, observational, multicentre, post-approval study assessed the longitudinal LCI up to 12 months and the lung MRI score before and 3 months after initiation of ETI. RESULTS: A total of 107 children with CF including 40 heterozygous for F508del and a minimal function mutation (F/MF) and 67 homozygous for F508del (F/F) were enrolled in this study. Treatment with ETI improved the median (interquartile range (IQR)) LCI in F/MF (-1.0 (-2.0- -0.1); p<0.01) and F/F children (-0.8 (-1.9- -0.2); p<0.001) from 3 months onwards. Further, ETI improved the median (IQR) MRI global score in F/MF (-4.0 (-9.0-0.0); p<0.01) and F/F children (-3.5 (-7.3- -0.8); p<0.001). CONCLUSIONS: ETI improves early abnormalities in lung ventilation and morphology in school-age children with CF and at least one F508del allele in a real-world setting. Our results support early initiation of ETI to reduce or even prevent lung disease progression in school-age children with CF.

Contrast agent-free functional magnetic resonance imaging with matrix pencil decomposition to quantify abnormalities in lung perfusion and ventilation in patients with cystic fibrosis.

Background: Previous studies showed that contrast-enhanced (CE) morpho-functional magnetic resonance imaging (MRI) detects abnormalities in lung morphology and perfusion in patients with cystic fibrosis (CF). Novel matrix pencil decomposition MRI (MP-MRI) enables quantification of lung perfusion and ventilation without intravenous contrast agent administration. Objectives: To compare MP-MRI with established morpho-functional MRI and spirometry in patients with CF. Methods: Thirty-nine clinically stable patients with CF (mean age 21.6 ± 10.7 years, range 8-45 years) prospectively underwent morpho-functional MRI including CE perfusion MRI, MP-MRI and spirometry. Two blinded chest radiologists assessed morpho-functional MRI and MP-MRI employing the validated chest MRI score. In addition, MP-MRI data were processed by automated software calculating perfusion defect percentage (QDP) and ventilation defect percentage (VDP). Results: MP perfusion score and QDP correlated strongly with the CE perfusion score (both r = 0.81; p < 0.01). MP ventilation score and VDP showed strong inverse correlations with percent predicted FEV1 (r = -0.75 and r = -0.83; p < 0.01). The comparison of visual and automated parameters showed that both MP perfusion score and QDP, and MP ventilation score and VDP were strongly correlated (r = 0.74 and r = 0.78; both p < 0.01). Further, the MP perfusion score and MP ventilation score, as well as QDP and VDP were strongly correlated (r = 0.88 and r = 0.86; both p < 0.01). Conclusion: MP-MRI detects abnormalities in lung perfusion and ventilation in patients with CF without intravenous or inhaled contrast agent application, and correlates strongly with the well-established CE perfusion MRI score and spirometry. Automated analysis of MP-MRI may serve as quantitative noninvasive outcome measure for diagnostic monitoring and clinical trials.

[Cystic fibrosis in childhood and adulthood]. / Mukoviszidose im Kindes- und im Erwachsenenalter.

BACKGROUND: Cystic fibrosis (CF, or mucoviscidosis) is one of the rare diseases with a fatal course and with the highest prevalence. Formerly known as a purely childhood disease, this multisystemic disease follows an autosomal recessive inheritance pattern and results in a malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, leading to the production of viscous secretions. The prognosis and outcome of CF are determined by the severity of the involvement of the lungs. Other typically affected organs include the pancreas, liver and intestines. OBJECTIVE: This article reviews the clinical presentation and evolution of CF with a focus on the new era of the highly effective CFTR modulator treatment. MATERIAL AND METHODS: An overview of the current state of knowledge on the care for CF patients is presented. RESULTS AND DISCUSSION: The introduction of the CF newborn screening, the increased understanding of the disease and the development of novel treatment options have substantially increased the quality of life and life expectancy of people with CF. As a result, more than half of CF patients in Germany are now older than 18 years of age and the complications of a chronic disease as well as organ damage due to the intensive treatment are gaining in importance. The highly effective CFTR modulator treatment results in a significant improvement in CFTR function, lung function, body mass index and quality of life and is available to approximately 90% of patients in Germany, based on the genotype. Nevertheless, further research including the development of causal treatment, e.g., gene therapy, targeting the underlying defect in the remaining 10% of CF patients, is urgently needed. Even in adult patients, CF with a mild course or a CFTR-related disease should be considered, e.g., in cases of bronchiectasis and/or recurrent abdominal complaints.

Elexacaftor/tezacaftor/ivacaftor improves nasal nitric oxide in patients with cystic fibrosis.

BACKGROUND: In health, nitric oxide (NO) shows high concentrations in the upper airways, while nasal NO (nNO) is significantly lower in patients with sinonasal inflammation, such as people with cystic fibrosis (PwCF). In PwCF treated with elexacaftor/tezacaftor/ivacaftor (ETI; PwCF-ETI), clinical improvement of sinonasal symptoms and inflammation was observed. We therefore hypothesised that ETI may increase nNO in PwCF. METHODS: 25 PwCF-ETI underwent nNO measurement at baseline and after 3 to 24 months of ETI treatment. NNO was measured using velum closure (VC) techniques in cooperative patients and tidal breathing (TB) for all patients. As controls, 7 CF patients not eligible for ETI (PwCF-non ETI) and 32 healthy controls (HC) were also repeatedly investigated. RESULTS: In PwCF-ETI, sinonasal symptoms, lung function parameters and sweat chloride levels improved from baseline to follow-up whereas there was no change in PwCF-non ETI and HC. NNO increased from a median (IQR) value at baseline to follow-up from 348.2 (274.4) ppb to 779.6 (364.7) ppb for VC (P < 0.001) and from 198.2 (107.0) ppb to 408.3 (236.1) ppb for TB (P < 0.001). At follow-up, PwCF-ETI reached nNO values in the normal range. In PwCF-non ETI as well as HC, nNO did not change between baseline and follow-up. CONCLUSIONS: In PwCF-ETI, the nNO values significantly increased after several months of ETI treatment in comparison to baseline and reached values in the normal range. This suggests that nNO is a potential non-invasive biomarker to examine sinonasal inflammatory disease in PwCF and supports the observation of clinical improvement in these patients.

Multiple-breath washout to detect lung disease in patients with inborn errors of immunity.

Background: Pulmonary manifestations are the major cause of morbidity and mortality in patients with inborn errors of immunity (IEI). New and more sensitive diagnostic methods can potentially lead to earlier recognition and treatment of IEI lung disease and improve outcome. The aim of this study was to compare multiple-breath washout (MBW) and spirometry in patients with IEI and cystic fibrosis (CF) as well as healthy controls (HC) and to evaluate the sensitivity of lung clearance index (LCI) to assess lung disease in IEI. Methods: IEI patients (n=114) were recruited from our paediatric and adult immunodeficiency outpatient clinics and compared to age-matched CF patients (n=114) and HC (n=114). MBW measurements and spirometry were performed in the study participants, and MBW testing was repeated after 63-707 days in IEI patients (n=70). Results: The LCI was significantly higher in IEI patients than in HC (p<0.001) and significantly lower than in CF patients (p<0.001). The forced expiratory volume in 1 s (FEV1) z-score was significantly lower in IEI patients than in HC (p<0.01) and significantly higher than in CF patients (p<0.01). LCI and FEV1 z-score correlated moderately negatively in the total cohort, the IEI group and the CF group. Nineteen (20.7%) of 92 IEI patients and 35 (33.3%) of 105 CF patients had an elevated LCI but a normal FEV1 z-score. After a median of 364 days, the median LCI of 70 IEI patients increased significantly by 0.2. Conclusion: MBW is useful to detect lung disease in IEI and is more sensitive than spirometry.

ERS International Congress 2023: highlights from the Paediatrics Assembly.

Respiratory health in children is essential for general wellbeing and healthy development in the short and long term. It is well known that many respiratory diseases in adulthood have their origins in early life, and therefore research on prevention of respiratory diseases and management of children with respiratory diseases will benefit patients during the full life course. Scientific and clinical advances in the field of respiratory health are moving at a fast pace. This article summarises some of the highlights in paediatric respiratory medicine presented at the hybrid European Respiratory Society (ERS) International Congress 2023 which took place in Milan (Italy). Selected sessions are summarised by Early Career Members of the Paediatrics Assembly (Assembly 7) under the supervision of senior ERS officers, and cover a wide range of research areas in children, including respiratory physiology and sleep, asthma and allergy, cystic fibrosis, respiratory infection and immunology, neonatology and intensive care, respiratory epidemiology and bronchology.

Pharmacological Improvement of Cystic Fibrosis Transmembrane Conductance Regulator Function Rescues Airway Epithelial Homeostasis and Host Defense in Children with Cystic Fibrosis.

Rationale: Pharmacological improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes in patients with cystic fibrosis (CF). However, ETI effects on impaired mucosal homeostasis and host defense at the molecular and cellular levels in the airways of patients with CF remain unknown. Objectives: To investigate effects of ETI on the transcriptome of nasal epithelial and immune cells from children with CF at the single-cell level. Methods: Nasal swabs from 13 children with CF and at least one F508del allele aged 6 to 11 years were collected at baseline and 3 months after initiation of ETI, subjected to single-cell RNA sequencing, and compared with swabs from 12 age-matched healthy children. Measurements and Main Results: Proportions of CFTR-positive cells were decreased in epithelial basal, club, and goblet cells, but not in ionocytes, from children with CF at baseline and were restored by ETI therapy to nearly healthy levels. Single-cell transcriptomics revealed an impaired IFN signaling and reduced expression of major histocompatibility complex classes I and II encoding genes in epithelial cells of children with CF at baseline, which was partially restored by ETI. In addition, ETI therapy markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages. Conclusions: Pharmacological improvement of CFTR function improves innate mucosal immunity and reduces immune cell inflammatory responses in the upper airways of children with CF at the single-cell level, highlighting the potential to restore epithelial homeostasis and host defense in CF airways by early initiation of ETI therapy.

Elexacaftor/tezacaftor/ivacaftor improves chronic rhinosinusitis detected by magnetic resonance imaging in children with cystic fibrosis on long-term therapy with lumacaftor/ivacaftor.

INTRODUCTION: Previous studies using magnetic resonance imaging (MRI) demonstrated early onset and progression of chronic rhinosinusitis (CRS) from infancy to school age, and response to lumacaftor/ivacaftor (LUM/IVA) therapy in children with cystic fibrosis (CF). However, the effect of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on CRS detected by MRI in children with CF and at least one F508del mutation, and potential incremental effects of ELX/TEZ/IVA compared to LUM/IVA in F508del homozygous children have not been studied. METHODS: 30 children with CF with at least one F508del mutation underwent three longitudinal paranasal sinus MRI before (MRI1), without (n = 16) or with LUM/IVA therapy (n = 14, MRI2), and with ELX/TEZ/IVA therapy (MRI3, mean age at therapy initiation 11.1 ± 3.4y, range 6-16y). MRI were evaluated using the CRS-MRI score. RESULTS: After therapy initiation with ELX/TEZ/IVA, the prevalence and in maxillary and sphenoid sinuses the dominance of mucopyoceles decreased (35% vs. 0 %, p<0.001 and 26% vs. 8 %, p < 0.05, respectively). This leads to a reduction in mucopyocele subscore (-3.4 ± 1.9, p < 0.001), and sinus subscores in MRI3 (maxillary sinus: -5.3 ± 3.1, p < 0.001, frontal sinus: -1.0 ± 1.9, p < 0.01, sphenoid subscore: -2.8 ± 3.5, p < 0.001, ethmoid sinus: -1.7 ± 1.9, p < 0.001). The CRS-MRI sum score decreased after therapy initiation with ELX/TEZ/IVA by -9.6 ± 5.5 score points (p < 0.001). The strength in reduction of mucopyoceles subscore and CRS-MRI sum score was independent of a pretreatment with LUM/IVA from MRI1-MRI2 (p = 0.275-0.999). CONCLUSIONS: ELX/TEZ/IVA therapy leads to improvement of CRS in eligible children with CF. Our data support the role of MRI for comprehensive monitoring of CRS disease severity and response to therapy in children with CF.

Magnetic Resonance Imaging of Pulmonary and Paranasal Sinus Abnormalities in Children with Primary Ciliary Dyskinesia Compared to Children with Cystic Fibrosis.

Rationale: Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are characterized by inherited impaired mucociliary clearance leading to chronic progressive lung disease as well as chronic rhinosinusitis (CRS). The diseases share morphological and functional commonalities on magnetic resonance imaging (MRI) of the lungs and paranasal sinuses, but comparative MRI studies are lacking. Objectives: To determine whether PCD shows different associations of pulmonary and paranasal sinus abnormalities on MRI and lung function test results in children (infants to adolescents) compared with children with CF. Methods: Eighteen children with PCD (median age, 9.5 [IQR, 3.4-12.7] yr; range, 0-18 yr) and 36 age-matched CF transmembrane conductance regulator modulator-naive children with CF (median age, 9.4 [3.4-13.2] yr; range, 0-18 yr) underwent same-session chest and paranasal sinus MRI as well as spirometry (to determine forced expiratory volume in 1 s percent predicted) and multiple-breath washout (to determine lung clearance index z-score). Pulmonary and paranasal sinus abnormalities were assessed using previously validated chest MRI and CRS-MRI scoring systems. Results: Mean chest MRI global score was similar in children with PCD and CF (15.0 [13.5-20.8] vs. 15.0 [9.0-15.0]; P = 0.601). Consolidations were more prevalent and severe in children with PCD (56% vs. 25% and 1.0 [0.0-2.8] vs. 0.0 [0.0-0.3], respectively; P < 0.05). The chest MRI global score correlated moderately with forced expiratory volume in 1 second percent predicted in children with PCD and children with CF (r = -0.523 and -0.687; P < 0.01) and with lung clearance index in children with CF (r = 0.650; P < 0.001) but not in PCD (r = 0.353; P = 0.196). CRS-MRI sum score and mucopyocele subscore were lower in children with PCD than in children with CF (27.5 [26.3-32.0] vs. 37.0 [37.8-40.0] and 2.0 [0.0-2.0] vs. 7.5 [4.8-9.0], respectively; P < 0.01). CRS-MRI sum score did not correlate with chest MRI score in PCD (r = 0.075-0.157; P = 0.557-0.788) but correlated moderately with MRI morphology score in CF (r = 0.437; P < 0.01). Conclusions: MRI detects differences in lung and paranasal sinus abnormalities between children with PCD and those with CF. Lung disease does not correlate with CRS in PCD but correlates in CF.

Reanalysis of N2-lung clearance index and the comparison to SF6-lung clearance index and magnetic resonance imaging.

Since the finding and correction of an error in previous spiroware software versions commonly used with the Exhalyzer D for multiple-breath washout (MBW) analysis, there has been an ongoing discussion about its impact on MBW results. In this study, we reanalyzed previously published findings with the corrected spiroware version 3.3.1. In total, 31 infants and preschool children with cystic fibrosis (CF) (mean age 2.3 ±â€¯0.8 years) and 20 healthy controls (mean age 2.3 ±â€¯1.1 years) underwent consecutive sulfure hexafluoride (SF6)- and nitrogen (N2)-MBW. In addition, children with CF underwent chest magnetic resonance imaging (MRI) on the same day. After reanalysis of MBW data, the corrected N2-lung clearance index (LCI) decreased by 10-15% in both groups (P = 0.001) but remained significantly higher than the SF6-LCI (P<0.01). Diagnostic agreement between the MBW results remained moderate with a persistent correlation between SF6- and N2-MBW. The corrected upper limit of normal of the N2-LCI changed classification of nine children with CF, eight of which were within the normal range after correction. The correlation between the different LCI values and the chest MRI scores remained significant with strongest correlation with the MRI perfusion score. Consequently, the corrected N2-LCI is significantly lower than the previous N2-LCI, but key results published before are not affected by the reanalysis.

Impact of Reanalysis of Nitrogen Multiple-Breath Washout on its Relationship with Chest Magnetic Resonance Imaging Findings in Clinically Stable and Pulmonary Exacerbated Children with Cystic Fibrosis.

RATIONALE: Multiple-breath washout (MBW)-derived lung clearance index (LCI) detects lung disease in children with cystic fibrosis (CF). Correction of a cross-talk error in the software of the MBW device Exhalyzer D in a new software version has generated significant interest regarding its impact on previous MBW findings. Since LCI and chest magnetic resonance imaging (MRI) correlated before in CF children, this study aims to reassess previous MBW data after correction. PATIENTS/METHODS: Reanalysis of the main findings from a previously published study comparing MBW and MRI in a pediatric CF cohort by reassessment of nitrogen (N2) MBW of 61 stable children with CF, 75 age-matched healthy controls (HC), and 15 CF children with pulmonary exacerbation (PEx) in the corrected software version. RESULTS: The corrected LCI (N2LCIcor) decreased in the entire cohort (-17.0 (11.2)%), HC (-8.5 (8.2)%), stable CF children (-22.2 (11.1)%), and within the PEx group at baseline, at PEx and after antibiotic therapy (-21.5 (7.3)%; -22.5 (6.1)%; -21.4 (6.6)%; all P<0.01). N2LCIcor and N2LCIpre correlated with chest MRI scores in stable CF (r=0.70 to 0.84; all P<0.01) without a significant difference between N2LCIcor and N2LCIpre. Change in LCI from baseline to PEx and from PEx to after therapy decreased from N2LCIpre to N2LCIcor, but these changes remained significant (all P=0.001). DISCUSSION/CONCLUSIONS: Our results indicate that N2LCIcor is significantly lower than N2LCIpre, but key results published in the original study demonstrating N2MBW and MRI as complementary methods for clinical surveillance in children with CF remain unaffected.

What to expect of the first ERS/ECFS Adult Cystic Fibrosis Conference.

This article provides a brief overview of the Adult Cystic Fibrosis Conference (#ACFMilan2023) programme, which will be held on 1-2 December 2023, in Milan (Italy) and online. https://bit.ly/3sKpN6p.

Personalized CFTR Modulator Therapy for G85E and N1303K Homozygous Patients with Cystic Fibrosis.

CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with CF and at least one F508del allele in Europe. In the US, the ETI label has been expanded to 177 rare CFTR mutations responsive in Fischer rat thyroid cells, including G85E, but not N1303K. However, knowledge on the effect of ETI on G85E or N1303K CFTR function remains limited. In vitro effects of ETI were measured in primary human nasal epithelial cultures (pHNECs) of a G85E homozygous patient and an N1303K homozygous patient. Effects of ETI therapy in vivo in these patients were assessed using clinical outcomes, including multiple breath washout and lung MRI, and the CFTR biomarkers sweat chloride concentration (SCC), nasal potential difference (NPD) and intestinal current measurement (ICM), before and after initiation of ETI. ETI increased CFTR-mediated chloride transport in G85E/G85E and N1303K/N1303K pHNECs. In the G85E/G85E and the N1303K/N1303K patient, we observed an improvement in lung function, SCC, and CFTR function in the respiratory and rectal epithelium after initiation of ETI. The approach of combining preclinical in vitro testing with subsequent in vivo verification can facilitate access to CFTR modulator therapy and enhance precision medicine for patients carrying rare CFTR mutations.

Elexacaftor/Tezacaftor/Ivacaftor Improves Bronchial Artery Dilatation Detected by Magnetic Resonance Imaging in Patients with Cystic Fibrosis.

Rationale: Magnetic resonance imaging (MRI) detects improvements in mucus plugging and bronchial wall thickening, but not in lung perfusion in patients with cystic fibrosis (CF) treated with elexacaftor/tezacaftor/ivacaftor (ETI). Objectives: To determine whether bronchial artery dilatation (BAD), a key feature of advanced lung disease, indicates irreversibility of perfusion abnormalities and whether BAD could be reversed in CF patients treated with ETI. Methods: A total of 59 adults with CF underwent longitudinal chest MRI, including magnetic resonance angiography twice, comprising 35 patients with CF (mean age, 31 ± 7 yr) before (MRI1) and after (MRI2) at least 1 month (mean duration, 8 ± 4 mo) on ETI therapy and 24 control patients with CF (mean age, 31 ± 7 yr) without ETI. MRI was assessed using the validated chest MRI score, and the presence and total lumen area of BAD were assessed with commercial software. Results: The MRI global score was stable in the control group from MRI1 to MRI2 (mean difference, 1.1 [-0.3, 2.4]; P = 0.054), but it was reduced in the ETI group (-10.1 [-0.3, 2.4]; P < 0.001). In the control and ETI groups, BAD was present in almost all patients at baseline (95% and 94%, respectively), which did not change at MRI2. The BAD total lumen area did not change in the control group from MRI1 to MRI2 (1.0 mm2 [-0.2, 2.2]; P = 0.099) but decreased in the ETI group (-7.0 mm2 [-8.9, -5.0]; P < 0.001). This decrease correlated with improvements in the MRI global score (r = 0.540; P < 0.001). Conclusions: Our data show that BAD may be partially reversible under ETI therapy in adult patients with CF who have established disease.