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.

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 with CF and one or two F508del alleles aged 6 to 11 years. METHODS: This prospective, observational, multicenter, post-approval study assessed the longitudinal LCI up to 12 months and the lung MRI score before and three 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 LCI in F/MF children (-1.0; IQR, -2.0 to -0.1; p<0.01) and F/F children (-0.8; IQR, -1.9 to -0.2; p<0.001) from 3 months onwards. Further, ETI improved the MRI global score in F/MF (-4.0; IQR, -9.0 to 0.0; p<0.01) and F/F children (-3.5; IQR, -7.3 to -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 alleles 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.

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.

Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on sputum viscoelastic properties, airway infection and inflammation in patients with cystic fibrosis.

BACKGROUND: Recent studies demonstrated that the triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function and reduces pulmonary exacerbations in cystic fibrosis (CF) patients with at least one F508del allele. However, effects of ETI on downstream consequences of CFTR dysfunction, i.e. abnormal viscoelastic properties of airway mucus, chronic airway infection and inflammation have not been studied. The aim of this study was to determine the longitudinal effects of ETI on airway mucus rheology, microbiome and inflammation in CF patients with one or two F508del alleles aged ≥12 years throughout the first 12 months of therapy. METHODS: In this prospective observational study, we assessed sputum rheology, the microbiome, inflammation markers and proteome before and 1, 3 and 12 months after initiation of ETI. RESULTS: In total, 79 patients with CF and at least one F508del allele and 10 healthy controls were enrolled in this study. ETI improved the elastic modulus and viscous modulus of CF sputum at 3 and 12 months after initiation (all p<0.01). Furthermore, ETI decreased the relative abundance of Pseudomonas aeruginosa in CF sputum at 3 months and increased the microbiome α-diversity at all time points. In addition, ETI reduced interleukin-8 at 3 months (p<0.05) and free neutrophil elastase activity at all time points (all p<0.001), and shifted the CF sputum proteome towards healthy. CONCLUSIONS: Our data demonstrate that restoration of CFTR function by ETI improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one F508del allele over the first 12 months of therapy; however, levels close to healthy were not reached.

Survival-Adjusted FEV1 and BMI Percentiles for Patients with Cystic Fibrosis before the Era of Triple CFTR Modulator Therapy in Germany.

BACKGROUND: Pulmonary disease is the major cause for morbidity and mortality in cystic fibrosis (CF). In CF, forced expiratory volume in 1 s (FEV1) referenced against a healthy population (FEV1%predicted) and body mass index (BMI) do not allow for the comparison of disease severity across age and gender. OBJECTIVES: We aimed to determine updated FEV1 and BMI percentiles for patients with CF and to study their dependence on mortality attrition. METHODS: Age- and height-adjusted FEV1 and BMI percentiles for CF patients aged 6-50 years were calculated from 4,947 patients of the German CF Registry for the period 2016-2019 utilizing quantile regression and a Generalized Additive Model for Location, Scale and Shape (GAMLSS). Further, survival-adjusted percentiles were estimated. RESULTS: In patients with CF, FEV1 increased throughout childhood until maximal median values at 16 years in females (2.46 L) and 18 years in males (3.27 L). During adulthood, FEV1 decreased substantially. At 17 years of age, the 25th BMI percentile of patients with CF (females 18.50 and males 18.15 kg/m2) was below the 10th BMI percentile of the German reference cohort. From the age of 20 years, survival (96.3%) decreased tremendously. At 50 years of age (survival 15.0%), the 50th CF-specific FEV1 or BMI percentile among the survivors corresponded to the 92.5th percentile among the total CF birth cohort. CONCLUSIONS: Continuously updated disease-specific FEV1 and BMI percentiles with correction for survival may serve as age-independent measure of disease severity in CF (accessible via https://cfpercentiles.statup.solutions).

Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on Lung Clearance Index and Magnetic Resonance Imaging in Patients with Cystic Fibrosis and One or Two F508del Alleles.

Rationale: We recently demonstrated that triple-combination CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) improves CFTR function in airway and intestinal epithelia to 40-50% of normal in patients with cystic fibrosis (CF) with one or two F508del alleles. In previous studies, this improvement of CFTR function was shown to improve clinical outcomes; however, effects on the lung clearance index (LCI) determined by multiple-breath washout and abnormalities in lung morphology and perfusion detected by magnetic resonance imaging (MRI) have not been studied. Objectives: To examine the effect of ELX/TEZ/IVA on LCI and lung MRI scores in patients with CF and one or two F508del alleles aged ⩾12 years. Methods: This prospective, observational, multicenter, postapproval study assessed LCI and lung MRI scores before and 8-16 weeks after initiation of ELX/TEZ/IVA. Measurements and Main Results: A total of 91 patients with CF, including 45 heterozygous for F508del and a minimal function mutation (MF) and 46 homozygous for F508del, were enrolled in this study. Treatment with ELX/TEZ/IVA improved LCI in F508del/MF (-2.4; interquartile range [IQR], -3.7 to -1.1; P < 0.001) and F508del homozygous (-1.4; IQR, -2.4 to -0.4; P < 0.001) patients. Furthermore, ELX/TEZ/IVA improved the MRI global score in F508del/MF (-6.0; IQR, -11.0 to -1.3; P < 0.001) and F508del homozygous (-6.5; IQR, -11.0 to -1.3; P < 0.001) patients. Conclusions: Our data demonstrate that improvement of CFTR function by ELX/TEZ/IVA improves lung ventilation and abnormalities in lung morphology, including airway mucus plugging and wall thickening, in adolescent and adult patients with CF and one or two F508del alleles in a real-world, postapproval setting. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).

Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on CFTR Function in Patients with Cystic Fibrosis and One or Two F508del Alleles.

Rationale: The CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to improve clinical outcomes and sweat chloride concentration in patients with cystic fibrosis (CF) and one or two F508del alleles. However, the effect of ELX/TEZ/IVA on CFTR function in the airways and intestine has not been studied. Objectives: To assess the effect of ELX/TEZ/IVA on CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles aged 12 years and older. Methods: This prospective, observational, multicenter study assessed clinical outcomes including FEV1% predicted and body mass index and the CFTR biomarkers sweat chloride concentration, nasal potential difference, and intestinal current measurement before and 8-16 weeks after initiation of ELX/TEZ/IVA. Measurements and Main Results: A total of 107 patients with CF including 55 patients with one F508del and a minimal function mutation and 52 F508del homozygous patients were enrolled in this study. In patients with one F508del allele, nasal potential difference and intestinal current measurement showed that ELX/TEZ/IVA improved CFTR function in nasal epithelia to a level of 46.5% (interquartile range [IQR], 27.5-72.4; P < 0.001) and in intestinal epithelia to 41.8% of normal (IQR, 25.1-57.6; P < 0.001). In F508del homozygous patients, ELX/TEZ/IVA exceeded improvement of CFTR function observed with TEZ/IVA and increased CFTR-mediated Cl- secretion to a level of 47.4% of normal (IQR, 19.3-69.2; P < 0.001) in nasal and 45.9% (IQR, 19.7-66.6; P < 0.001) in intestinal epithelia. Conclusions: Treatment with ELX/TEZ/IVA results in effective improvement of CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).

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.

Magnetic Resonance Imaging Detects Progression of Lung Disease and Impact of Newborn Screening in Preschool Children with Cystic Fibrosis.

Rationale: Previous cross-sectional studies have demonstrated that chest magnetic resonance imaging (MRI) is sensitive to detect early lung disease in infants and preschool children with cystic fibrosis (CF) without radiation exposure. However, the ability of MRI to detect the progression of lung disease and the impact of early diagnosis in preschool children with CF remains unknown. Objectives: To investigate the potential of MRI to detect progression of early lung disease and impact of early diagnosis by CF newborn screening (NBS) in preschool children with CF. Methods: An annual MRI was performed from diagnosis over 4 years in a cohort of 96 preschool children with CF (age, 0-4 yr) who received concurrent diagnoses on the basis of NBS (n = 28) or clinical symptoms (n = 68). MRI scans were evaluated using a dedicated morphofunctional score, and the relationship between longitudinal MRI score and respiratory symptoms, pulmonary exacerbations, upper airway microbiology, and mode of diagnosis was determined. Measurements and Main Results: The MRI global score increased in the total cohort of children with CF during preschool years (P < 0.001) and was associated with cough, pulmonary exacerbations (P < 0.0001), and the detection of Staphylococcus aureus and Haemophilus influenzae (P < 0.05). MRI-defined abnormalities in lung morphology-especially airway wall thickening/bronchiectasis-were lower in children with CF diagnosed by NBS than in children with clinically diagnosed CF throughout the observation period (P < 0.01). Conclusions: MRI detected progression of early lung disease and benefits of early diagnosis by NBS in preschool children with CF. These findings support MRI as a sensitive outcome measure for diagnostic monitoring and early intervention trials in preschool children with CF. Clinical trial registered with www.clinicaltrials.gov (NCT02270476).

A multi-centre, randomized, controlled trial on coaching and telemonitoring in patients with cystic fibrosis: conneCT CF.

BACKGROUND: The extend of lung disease remains the most important prognostic factor for survival in patients with cystic fibrosis (CF), and lack of adherence is the main reason for treatment failure. Early detection of deterioration in lung function and optimising adherence are therefore crucial in CF care. We implement a randomized controlled trial to evaluate efficacy of telemonitoring of adherence, lung function, and health condition in combination with behavior change interventions using innovative digital technologies. METHODS: This is a multi-centre, randomized, controlled, non-blinded trial aiming to include 402 patients ≥ 12 years-of-age with CF. A standard-of-care arm is compared to an arm receiving objective, continuous monitoring of adherence to inhalation therapies, weekly home spirometry using electronic devices with data transmission to patients and caring physicians combined with video-conferencing, a self-management app and professional telephone coaching. The duration of the intervention phase is 18 months. The primary endpoint is time to the first protocol-defined pulmonary exacerbation. Secondary outcome measures include number of and time between pulmonary exacerbations, adherence to inhalation therapy, changes in forced expiratory volume in 1 s from baseline, number of hospital admissions, and changes in health-related quality of life. CF-associated medical treatment and care, and health care related costs will be assessed by explorative analysis in both arms. DISCUSSION: This study offers the opportunity to evaluate the effect of adherence interventions using telemedicine capable devices on adherence and lung health, possibly paving the way for implementation of telemedicine in routine care for patients with CF. TRIAL REGISTRATION: This study has been registered with the German Clinical Trials Register (Identifier: DRKS00024642, date of registration 01 Mar 2021, URL: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024642 ).

Normative data for multiple breath washout outcomes in school-aged Caucasian children.

BACKGROUND: The multiple breath nitrogen washout (N2MBW) technique is increasingly used to assess the degree of ventilation inhomogeneity in school-aged children with lung disease. However, reference values for healthy children are currently not available. The aim of this study was to generate reference values for N2MBW outcomes in a cohort of healthy Caucasian school-aged children. METHODS: N2MBW data from healthy Caucasian school-age children between 6 and 18 years old were collected from four experienced centres. Measurements were performed using an ultrasonic flowmeter (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) and were analysed with commercial software (Spiroware version 3.2.1, Eco Medics AG). Normative values and upper limits of normal (ULN) were generated for lung clearance index (LCI) at 2.5% (LCI2.5%) and at 5% (LCI5%) of the initial nitrogen concentration and for moment ratios (M1/M0 and M2/M0). A prediction equation was generated for functional residual capacity (FRC). RESULTS: Analysis used 485 trials from 180 healthy Caucasian children aged from 6 to 18 years old. While LCI increased with age, this increase was negligible (0.04 units·year-1 for LCI2.5%) and therefore fixed ULN were defined for this age group. These limits were 7.91 for LCI2.5%, 5.73 for LCI5%, 1.75 for M1/M0 and 6.15 for M2/M0, respectively. Height and weight were found to be independent predictors of FRC. CONCLUSION: We report reference values for N2MBW outcomes measured on a commercially available ultrasonic flowmeter device (Exhalyzer D, Eco Medics AG) in healthy school-aged children to allow accurate interpretation of ventilation distribution outcomes and FRC in children with lung disease.

Echo Time-Dependence of Observed Lung T1 in Patients With Cystic Fibrosis and Correlation With Clinical Metrics.

BACKGROUND: Noninvasive monitoring of early abnormalities and therapeutic intervention in cystic fibrosis (CF) lung disease using MRI is important. Lung T1 mapping has shown potential for local functional imaging without contrast material. Recently, it was discovered that observed lung T1 depends on the measurement echo time (TE). PURPOSE: To examine TE-dependence of observed T1 in patients with CF and its correlation with clinical metrics. STUDY TYPE: Prospective. POPULATION: In all, 75 pediatric patients with CF (8.6 ± 6.1 years, range 0.1-23 years), with 32 reexamined after 1 year. FIELD STRENGTH/SEQUENCE: Patients were examined at 1.5T using an established MRI protocol and a multiecho inversion recovery 2D ultrashort echo time (UTE) sequence for T1 (TE) mapping at five TEs including TE1 = 70 µs. ASSESSMENT: Morphological and perfusion MRI were assessed by a radiologist (M.W.) with 11 years of experience using an established CF-MRI scoring system. T1 (TE) was quantified automatically. Clinical data including spirometry (FEV1pred%) and lung clearance index (LCI) were collected. STATISTICAL TESTS: T1 (TE) was correlated with the CF-MRI score, clinical data, and LCI. RESULTS: T1 (TE) showed a different curvature in CF than in healthy adults: T1 at TE1 was shorter in CF (1157 ms ± 73 ms vs. 1047 ms ± 70 ms, P < 0.001), but longer at TE3 (1214 ms ± 72 ms vs. 1314 ms ± 68 ms, P < 0.001) and later TEs. The correlations of T1 (TE) with patient age (ρTE1-TE5 = -0.55, -0.44, -0.24, -0.30, -0.22), and LCI (ρTE1-TE5 = -0.43, -0.42, -0.33, 0.27, -0.22) were moderate at ultra-short to short TE (P < 0.001) but decreased for longer TE. Moderate but similar correlations at all TE were found with MRI perfusion score (ρTE1-TE5 = -0.43, -0.51, -0.47, -0.46, -0.44) and FEV1pred% (ρTE1-TE5 = +0.44, +0.44, +0.43, +0.40, +0.39) (P < 0.05). DATA CONCLUSION: TE should be considered when measuring lung T1 , since observed differences between CF and healthy subjects strongly depend on TE. The different variation of correlation coefficients with TE for structural vs. functional metrics implies that TE-dependence holds additional information which may help to discern effects of tissue structural abnormalities and abnormal perfusion. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1 J. MAGN. RESON. IMAGING 2020;52:1645-1654.

Preventive Inhalation of Hypertonic Saline in Infants with Cystic Fibrosis (PRESIS). A Randomized, Double-Blind, Controlled Study.

Rationale: Cystic fibrosis (CF) lung disease starts in early infancy, suggesting that preventive treatment may be most beneficial. Lung clearance index (LCI) and chest magnetic resonance imaging (MRI) have emerged as promising endpoints of early CF lung disease; however, randomized controlled trials testing the safety and efficacy of preventive therapies in infants with CF are lacking. Objectives: To determine the feasibility, safety, and efficacy of preventive inhalation with hypertonic saline (HS) compared with isotonic saline (IS) in infants with CF, including LCI and MRI as outcome measures. Methods: In this randomized, double-blind, controlled trial, 42 infants with CF less than 4 months of age were randomized across five sites to twice-daily inhalation of 6% HS (n = 21) or 0.9% IS (n = 21) for 52 weeks. Measurements and Main Results: Inhalation of HS and IS was generally well tolerated by infants with CF, and the number of adverse events did not differ between groups (P = 0.49). The change in LCI from baseline to Week 52 was larger in infants with CF treated with HS (-0.6) than in those treated with IS (-0.1; P < 0.05). In addition, weight gain was improved in infants with CF treated with HS (P < 0.05), whereas pulmonary exacerbations and chest MRI scores did not differ in the HS group versus the IS group. Conclusions: Preventive inhalation with HS initiated in the first months of life was safe and well tolerated and resulted in improvements in LCI and weight gain in infants with CF. Our results support the feasibility of LCI as an endpoint in randomized controlled trials in infants with CF. Clinical trial registered with www.clinicaltrials.gov (NCT01619657).

[Clinical presentation of lung disease in cystic fibrosis]. / Klinisches Bild der Lungenerkrankung bei zystischer Fibrose.

Although cystic fibrosis (CF) is a multiorgan disease, the extent of CF lung disease is decisive for the course and survival of patients. The optimization of symptomatic therapies has led to a significant improvement in the life expectancy of those affected in recent decades. Regular monitoring of the course of CF lung disease with microbiological, pulmonary function, and imaging examinations is essential for early detection of problems and individualized therapy. With new, causal therapy options in the form of cystic fibrosis transmembrane conductance regulator (CFTR) modulators and early diagnosis through newborn screening, a further normalization of life expectancy and quality of life of CF patients can be expected.

Ten years of chest MRI for patients with cystic fibrosis : Translation from the bench to clinical routine.

BACKGROUND: Despite recent advances in our knowledge about the pathophysiology and treatment of cystic fibrosis (CF), pulmonary involvement remains the most important determinant of morbidity and mortality in patients with CF. Since lung function testing may not be sensitive enough for subclinical disease progression, and because young children may have normal spirometry results over a longer period of time, imaging today plays an increasingly important role in clinical routine and research for the monitoring of CF lung disease. In this regard, chest magnetic resonance imaging (MRI) could serve as a radiation-free modality for structural and functional lung imaging. METHODS: Our research agenda encompassed the entire process of development, implementation, and validation of appropriate chest MRI protocols for use with infant and adult CF patients alike. RESULTS: After establishing a general MRI protocol for state-of-the-art clinical 1.5-T scanners based on the available sequence technology, a semiquantitative scoring system was developed followed by cross-validation of the method against the established modalities of computed tomography, radiography, and lung function testing. Cross-sectional studies were then set up to determine the sensitivity of the method for the interindividual variation of the disease and for changes in disease severity after treatment. Finally, the MRI protocol was implemented at multiple sites to be validated in a multicenter setting. CONCLUSION: After more than a decade, lung MRI has become a valuable tool for monitoring CF in clinical routine application and as an endpoint for clinical studies.

Comparison of Lung Clearance Index and Magnetic Resonance Imaging for Assessment of Lung Disease in Children with Cystic Fibrosis.

RATIONALE: Early onset and progression of lung disease in children with cystic fibrosis (CF) indicates that sensitive noninvasive outcome measures are needed for diagnostic monitoring and early intervention clinical trials. The lung clearance index (LCI) and chest magnetic resonance imaging (MRI) were shown to detect early lung disease in CF; however, the relationship between the two measures remains unknown. OBJECTIVES: To correlate the LCI with abnormalities detected by MRI and compare the sensitivity of the two techniques to detect responses to therapy for pulmonary exacerbations in children with CF. METHODS: LCI determined by age-adapted multiple breath washout techniques and MRI studies were performed in 97 clinically stable children with CF across the pediatric age range (0.2-21.1 yr). Furthermore, LCI (n = 26) or MRI (n = 10) were performed at the time of pulmonary exacerbation and after antibiotic therapy. MRI was evaluated using a dedicated morphofunctional score. MEASUREMENTS AND MAIN RESULTS: The LCI correlated with the global MRI score as well as MRI-defined airway wall abnormalities, mucus plugging, and abnormal lung perfusion in infants and toddlers (P < 0.05 to P < 0.001) and in older children (P < 0.001) with CF. LCI and MRI were sensitive to detect response to antibiotic therapy for pulmonary exacerbations. CONCLUSIONS: Our results indicate that LCI and MRI may be useful complementary tools for noninvasive monitoring and as quantitative endpoints in early intervention trials in children with CF. In this context, MRI enables detection of disease heterogeneity, including regional mucus plugging associated with abnormal lung perfusion in early CF lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT 02270476).