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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 (LCI 2.5 ) 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 LCI 2.5 , 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).

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., Competing Interests: Conflicts of interest: M. Stahl, S.Y. Graeber and S. Thee are participants of the Berlin Institute of Health (BIH)-Charité Clinician Scientist Program, and J. Röhmel is participant of the Case Analysis and Decision Support (CADS) program funded by Charité – Universitätsmedizin Berlin and the BIH. M. Stahl reports an Independent Research Innovation Award and honoraria for lectures and participation in advisory boards, all by Vertex Pharmaceuticals Incorporated, outside of the submitted work; she is Chairman of the German CF Research Council (FGM), Treasurer of the German Society of Paediatric Pulmonology (GPP) and was Secretary of the Group CF of the Paediatric Assembly of the ERS. M. Dohna is a participant of the Ellen-Schmidt Habilitationsförderung funded by the Hannover Medical School. S.Y. Graeber reports grants from the German CF Foundation and Vertex Pharmaceuticals Incorporated, and honoraria from Chiesi GmbH and Vertex Pharmaceuticals Incorporated for lectures and participation in advisory boards, outside of the submitted work. O. Sommerburg reports grants and honoraria from Vertex Pharmaceuticals Incorporated for lectures, outside of the submitted work. S.T. Pallenberg is a member of the Else-Kröner Forschungskolleg TITUS. A. Voskrebenzev reports a grant and honoraria for lectures from Siemens Healthineers, outside of the submitted work, holds a patent for a method of quantitative magnetic resonance lung imaging (Voskrebenzev, Gutberlet, Vogel-Claussen; number EP3107066, US-2016-0367200-Al 22.12.2016), and is a stockholder and CEO of BioVisioneers GmbH. K. Schütz reports payments for attending meetings and/or travel from Vertex Pharmaceuticals Incorporated, outside of the submitted work. G. Hansen reports receipt of consultation fees from Sanofi GmbH, outside of the submitted work. F. Doellinger reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Bayer Vital, Berlin-Chemie Menarini, Boehringer Ingelheim and Chiesi GmbH, payment for expert testimony from Calyx, and support for attending meetings from Bayer. E. Steinke reports grants from Berlin Institute of Health at Charité Berlin, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex Pharmaceuticals Incorporated. S. Thee reports honoraria for lectures and payment for attending meetings and/or travel from Vertex Pharmaceuticals Incorporated and Viatris, outside of the submitted work. J. Röhmel reports honoraria for lectures from Vertex Pharmaceuticals Incorporated, outside the submitted work; additionally, he is work package leader in BEAT-PCD (ERS-CRC). M.O. Wielpütz reports a grant from Vertex Pharmaceuticals Incorporated, and receipt of consulting fees and honoraria for lectures from Vertex Pharmaceuticals Incorporated and Boehringer Ingelheim, outside of the submitted work. L. Naehrlich reports receipt of fees for a data quality project of the German CF Registry. He is the medical lead of the German CF Registry, the pharmacovigilance study manager of the European Cystic Fibrosis Society Patient Registry and part of the Trial Steering Committee for CF STORM. He also reports grants from the German Center for Lung Research, Vertex Pharmaceuticals and Mukoviszidose Institute, and receipt of medical writing services from Articulate Science. J. Vogel-Claussen reports grants from BMBF, Siemens Healthineers, AstraZeneca, Boehringer Ingelheim and GSK, royalties or licenses from Siemens Healthineers, receipt of consulting fees from AstraZeneca, honoraria for lectures from Siemens Healthineers, AstraZeneca, Boehringer Ingelheim, GSK, Roche, Coreline Soft and Bayer, payments for attending meetings and/or travel from Vertex Pharmaceuticals Incorporated, Bayer, GSK and AstraZeneca, and holds a patent for a method of quantitative magnetic resonance lung imaging (Voskrebenzev, Gutberlet, Vogel-Claussen; number EP3107066, US-2016-0367200-Al 22.12.2016). B. Tümmler reports support for the present study from Bundesministerium für Forschung und Technologie, grants from the German Research Foundation (DFG; CRC 900; Excellence cluster “RESIST”), consultancy fees from Helmholtz Institut für Infektionsforschung, payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex Pharmaceutical (Germany) Incorporated, participation on a data and safety monitoring board or advisory board with Vertex Pharmaceuticals Incorporated, and leadership roles with Christiane Herzog Stiftung and the Microbiome/Metagenome Group of the German Center for Lung Research (DZL). M.A. Mall reports grants from the German Research Foundation (DFG; SFB-TR 84, and project 450557679) and the German Innovation Fund (01NVF19008), outside of the submitted work. Additionally, he reports receipt of consulting fees from AbbVie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Santhera, Splisense and Vertex Pharmaceuticals Incorporated, of honoraria for lectures from Vertex Pharmaceuticals Incorporated and participation in advisory boards from AbbVie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari and Vertex Pharmaceuticals Incorporated, and of payment for travel from Vertex Pharmaceuticals Incorporated and Boehringer Ingelheim, all outside of the submitted work. He is a Fellow of ERS (FERS). A-M. Dittrich reports support for the present study from the German Center for Lung Research (DZL), Vertex Pharmaceuticals Incorporated and European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN), grants from Vertex Pharmaceuticals Incorporated, ECFS-CTN, DFG and Christiane Herzog Stiftung, consultancy fees from the c4c consortium, GSK and European Cystic Fibrosis Society. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Cystic Fibrosis (CF) is the most common autosomal recessive genetic multisystemic disease. In Germany, it affects at least 8000 people. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the airway epithelial lining fluid which leads to reduction of the mucociliary clearance.Even if highly effective, CFTR modulator therapy has been available for some years and people with CF are getting much older than before, recurrent and chronic infections of the airways as well as pulmonary exacerbations still occur. In adult CF life, Pseudomonas aeruginosa (PA) is the most relevant pathogen in colonisation and chronic infection of the lung, leading to further loss of lung function. There are many possibilities to treat PA-infection.This is a S3-clinical guideline which implements a definition for chronic PA-infection and demonstrates evidence-based diagnostic methods and medical treatment in order to give guidance for individual treatment options., Competing Interests: Eine Übersicht der Interessenkonflikt findet sich im Internet unter http://awmf.org; AWMF-Registernummer 026-022, (Thieme. All rights reserved.)

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.

Background: Cystic fibrosis (CF) is characterized by highly viscous mucus obstructing the lower and upper airways, chronic neutrophil inflammation and infection resulting not only in lung destruction but also in paranasal sinus involvement. The pathogenesis of CF-associated chronic rhinosinusitis (CRS) is still not well understood, and it remains unclear how the microbiome in the upper airways (UAW) influences paranasal sinus inflammation., Methods: In a cross-sectional study in pediatric patients with CF under stable disease conditions, we examined the microbiome in relation to inflammation by comparing nasal swabs (NS) and nasal lavage (NL) as two UAW sampling methods. The microbiota structure of both NS and NL was determined by 16S rRNA gene amplicon sequencing. In addition, pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and proteases (SLPI, TIMP-1, NE/A1-AT complex) as well as neutrophil elastase activity were measured in NL., Results: Simultaneous NS and NL samples were collected from 36 patients with CF (age range: 7 - 19 years). The microbiome of NS samples was shown to be significantly lower in α-diversity and evenness compared to NL samples. NS samples were particularly found to be colonized with Staphylococcus species. NL microbiome was shown to correlate much better with the sinonasal inflammation status than NS microbiome. Especially the detection of Moraxella in NL was associated with increased inflammatory response., Conclusion: Our results show that the NL microbiome reflects sinonasal inflammation better than NS and support NL as a promising tool for simultaneous assessment of the UAW microbiome and inflammation in children with CF., Competing Interests: Declaration of competing interest M.A.M. reports grants from Vertex Pharmaceuticals; fees for advisory board participation or consulting from Abbvie, Antabio, Arrowhead Pharmaceuticals, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Pari, Prieris, Recode, Santhera, Splisense, Vertex Pharmaceuticals; lecture honoraria from Vertex Pharmaceuticals; travel support from Boehringer Ingelheim and Vertex Pharmaceuticals outside the submitted work. The other authors have nothing to declare., (Copyright © 2023. Published by Elsevier B.V.)

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., Competing Interests: Declaration of competing interest HUK declares relationships with the following companies: Siemens, Philips, Bayer, Boehringer Ingelheim, Sanofi, Median. CPH declares advisory board membership with Boehringer Ingelheim unrelated to the present study. ME declares advisory board membership with Boehringer Ingelheim unrelated to the present study and speaker honoraria by Boehringer Ingelheim, Roche Pharma and Vertex Pharmaceuticals unrelated to the present study. MOW declares advisory board membership with Boehringer Ingelheim unrelated to the present study and receives study grants from Vertex Pharmaceuticals unrelated to the present study. MS received grants from Vertex Pharmaceuticals (Independent Research Innovation Award) and personal fees for participation in advisory boards from Vertex Pharmaceuticals, outside the submitted work. MAM received grants from Vertex Pharmaceuticals and personal fees for participation in advisory boards or consulting from Abbvie, Antabio, Arrowhead Pharmaceuticals, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Pieris Pharmaceuticals, Vertex Pharmaceuticals, outside the submitted work. Sources of support: This study was supported by grants from the German Federal Ministry of Education and Research (BMBF) (82DZL004A1, 82DZL009B1). SYG and MS are participants of the BIHCharité (Advanced) Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the BIH. Funders had no involvement in the collection, analysis and interpretation of data, in the writing of the report and in the decision to submit the article for publication., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 (N 2 ) 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 (N 2 LCI cor ) 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). N 2 LCI cor and N 2 LCI pre correlated with chest MRI scores in stable CF (r=0.70 to 0.84; all P<0.01) without a significant difference between N 2 LCI cor and N 2 LCI pre . Change in LCI from baseline to PEx and from PEx to after therapy decreased from N 2 LCI pre to N 2 LCI cor , but these changes remained significant (all P=0.001)., Discussion/conclusions: Our results indicate that N 2 LCI cor is significantly lower than N 2 LCI pre , but key results published in the original study demonstrating N 2 MBW and MRI as complementary methods for clinical surveillance in children with CF remain unaffected., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

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 mm 2 [-0.2, 2.2]; P  = 0.099) but decreased in the ETI group (-7.0 mm 2 [-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.

There is considerable activity with respect to diagnosis in the field of cystic fibrosis (CF). This relates primarily to developments in newborn bloodspot screening (NBS), more extensive gene analysis and improved characterisation of CFTR-related disorder (CFTR-RD). This is particularly pertinent with respect to accessibility to variant-specific therapy (VST), a transformational intervention for people with CF with eligible CFTR gene variants. This advance reinforces the need for a timely and accurate diagnosis. In the future, there is potential for trials to assess effectiveness of variant-specific therapy for CFTR-RD. The guidance in this paper reaffirms previous standards, clarifies a number of issues, and integrates emerging evidence. Timely and accurate diagnosis has never been more important for people with CF., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Rationale: Lumacaftor/ivacaftor (LUM/IVA) was shown to be safe and well tolerated in children 2 through 5 years of age with cystic fibrosis (CF) homozygous for F508del-CFTR in a Phase 3 open-label study. Improvements in sweat chloride concentration, markers of pancreatic function, and lung clearance index 2.5 (LCI 2.5 ), along with increases in growth parameters, suggested the potential for early disease modification with LUM/IVA treatment. Objective: To further assess the effects of LUM/IVA on CF disease progression in children 2 through 5 years of age using chest magnetic resonance imaging (MRI). Methods: This Phase 2 study had two parts: a 48-week, randomized, double-blind, placebo-controlled treatment period in which children 2 through 5 years of age with CF homozygous for F508del-CFTR received either LUM/IVA or placebo (Part 1) followed by an open-label period in which all children received LUM/IVA for an additional 48 weeks (Part 2). The results from Part 1 are reported. The primary endpoint was absolute change from baseline in chest MRI global score at Week 48. Secondary endpoints included absolute change in LCI 2.5 through Week 48 and absolute changes in weight-for-age, stature-for-age, and body mass index-for-age z -scores at Week 48. Additional endpoints included absolute changes in sweat chloride concentration, fecal elastase-1 levels, serum immunoreactive trypsinogen, and fecal calprotectin through Week 48. The primary endpoint was analyzed using Bayesian methods, where the actual Bayesian posterior probability of LUM/IVA being superior to placebo in the chest MRI global score at Week 48 was calculated using a vague normal prior distribution; secondary and additional endpoints were analyzed using descriptive summary statistics. Results: Fifty-one children were enrolled and received LUM/IVA ( n  = 35) or placebo ( n  = 16). For the change in chest MRI global score at Week 48, the Bayesian posterior probability of LUM/IVA being better than placebo (treatment difference, <0; higher score indicates greater abnormality) was 76%; the mean treatment difference was -1.5 (95% credible interval, -5.5 to 2.6). Treatment with LUM/IVA also led to within-group numerical improvements in LCI 2.5 , growth parameters, and biomarkers of pancreatic function as well as greater decreases in sweat chloride concentration compared with placebo from baseline through Week 48. Safety data were consistent with the established safety profile of LUM/IVA. Conclusions: This placebo-controlled study suggests the potential for early disease modification with LUM/IVA treatment, including that assessed by chest MRI, in children as young as 2 years of age. Clinical trial registered with www.clinicaltrials.gov (NCT03625466).

Rationale: Chronic rhinosinusitis (CRS) contributes to morbidity in patients with cystic fibrosis (CF). However, longitudinal data on CRS onset and progression is lacking. Objectives: To longitudinally evaluate CRS in CF from infancy to school age with paranasal sinus magnetic resonance imaging (MRI). Methods: A total of 64 children with CF (mean age at baseline, 1.1 ± 1.6 yr; range, 0-5 yr) underwent a mean of 5.8 ± 2.2 (range, 3-11 yr) subsequent annual MRI examinations. Additional 24 children (9.2 ± 4.4 yr; range, 3-17 yr) homozygous for the F508del mutation underwent MRI before and at least 2 months after starting lumacaftor/ivacaftor. MRI was assessed using the previously evaluated CRS-MRI score. Results: In infancy, 65-87% of paranasal sinuses were opacified, and mucosal swelling was the dominant abnormality (58-97%). At preschool age (1-5 yr), 79-94% of sinuses were opacified ( P  < 0.05 vs. infancy), and mucosal swelling was the most dominant abnormality (79-94%; P  < 0.05). At school age (at least 6 yr), almost all sinuses were opacified (71-99%; P  < 0.001-0.357 vs. preschool age), and mucopyoceles were the dominant abnormality in maxillary and frontal sinuses (53-56%; P  < 0.05-0.808). The CRS-MRI sum score increased from 22.4 ± 9.6 in infancy to 34.2 ± 9.6 in preschool age ( P  < 0.001) and was 34.0 ± 5.7 in school age ( P  = 0.052). In children under lumacaftor/ivacaftor therapy, the CRS-MRI sum score (-0.5 ± 3.3; P  < 0.05) and maxillary sinus subscore (-0.5 ± 1.5; P  < 0.05) improved. Conclusions: Longitudinal paranasal sinus MRI detects an early onset and progression of the severity of CRS from infancy to school age, and response to lumacaftor/ivacaftor therapy in children with CF. Our data support its role in the comprehensive noninvasive monitoring of CRS in children with CF. Clinical trial registered with www.clinicaltrials.gov (NCT02270476).

Background: The aim of this study was to record the current status of newborn bloodspot screening (NBS) for CF across Europe and assess performance., Methods: Survey of representatives of NBS for CF programmes across Europe. Performance was assessed through a framework developed in a previous exercise., Results: In 2022, we identified 22 national and 34 regional programmes in Europe. Barriers to establishing NBS included cost and political inertia. Performance was assessed from 2019 data reported by 21 national and 21 regional programmes. All programmes employed different protocols, with IRT-DNA the most common strategy. Six national and 11 regional programmes did not use DNA analysis., Conclusions: Integrating DNA analysis into the NBS protocol improves PPV, but at the expense of increased carrier and CFSPID recognition. Some programmes employ strategies to mitigate these outcomes. Programmes should constantly strive to improve performance but large datasets are needed to assess outcomes reliably., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Purpose: Cystic fibrosis (CF) was added to the German newborn bloodspot screening (NBS) panel in 2016. This study assesses parental perceptions of CF-NBS and confirmatory testing., Methods: Prospective questionnaire-based survey administered to parents of children with positive CF-NBS over 40 months after initiation of CF-NBS in Southwest Germany. Parental perceptions were compared to results from Bavaria and Switzerland., Results: Questionnaires with 29 standardized questions were sent to 343 families with children born between October 2016 and January 2020. A total of 178 (51.9%) replied. Although required by law, only a minority were informed about CF-NBS by a physician. The information provided about NBS was sufficient for 78% of parents. Regarding the information about positive CF-NBS, 52.9% were satisfied but the majority expressed negative emotions (89.5%). While most of these were resolved after confirmatory diagnostics, 17% of parents of children with false-positive CF-NBS and 66.7% of children confirmed with CF remained anxious. Waiting time for sweat testing was >3 days in 56.1%, considerably longer than in more centralized screening systems. Parents who waited for a maximum of 3 days were significantly more satisfied. 70.7% of parents were satisfied with the information given during confirmatory diagnostics and 91.4% were satisfied with participating in CF-NBS., Conclusions: CF-NBS stands in high regard with parents. Smooth organization, timely initiation of confirmatory testing, and professional communication are most important to limit parental anxiety. A more centralized system of confirmatory diagnostics appears advantageous in several regards as it reduces time from positive NBS to final diagnosis and increases parental satisfaction., (© 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

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)., (© 2023 S. Karger AG, Basel.)

Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approximately 90% of the morbidity and mortality are caused by pulmonary involvement. The mean life expectancy of patients with CF in 2020 was more than 52 years in Germany. The introduction of neonatal screening for CF and the development of a causally acting CFTR modulator treatment have clearly improved the prognosis of these patients. As an introduction, this article describes important aspects of CF in this context in order to go into details of the CF neonatal screening which was introduced in Germany in 2016., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Therapy with Elexacaftor/Tezacaftor/Ivacaftor (ETI) was recently approved for adult cystic fibrosis (CF) patients with at least one F508del mutation. However, its effects on structural and functional lung abnormalities and chronic rhinosinusitis have not been studied by imaging., Methods: 19 adults with CF (mean age 31±9y, range 19-55y) underwent standardized chest magnetic resonance imaging (MRI), and nine also same-session sinonasal MRI, before (MRI1) and after (MRI2) at least one month (mean duration 5 ± 3mon) on ETI. 24 control CF patients (30±7y, range 20-44y) without ETI underwent longitudinal chest MRI, and eleven also sinonasal MRI, twice (mean interval 40±15mon). MRI was assessed using the validated chest MRI score and chronic rhinosinusitis (CRS)-MRI score. Forced expiratory volume in 1 s percent predicted (FEV1%) was measured in all patients., Results: In controls, the chest MRI global score and CRS-MRI sum score were stable from MRI1 to MRI2. In patients under ETI, the chest MRI global score improved (-11.4 ± 4.6, P<0.001), mainly due to reduction of bronchiectasis/wall thickening and mucus plugging subscores (-3.3 ± 2.2 and -5.2 ± 1.5, P<0.001, respectively). The improvement in chest MRI score correlated well with improved FEV1% (r=-0.703, P<0.001). The CRS-MRI sum score also improved in patients under ETI (-6.9 ± 3.0, P<0.001), mainly due to a reduction of mucopyoceles in the maxillary and ethmoid sinus (-50% and -39%, P<0.05, respectively)., Conclusions: MRI detects improvements of chest MRI and CRS-MRI scores in adult CF patients who first received ETI, demonstrating reversibility of structural lung and paranasal sinus abnormalities in patients with established disease., Competing Interests: Declaration of Competing Interest HUK declares relationships with the following companies: Siemens, Philips, Bayer, Boehringer Ingelheim, Astra Zeneca, Merck Sharp Dohme. CPH declares advisory board membership with Boehringer Ingelheim unrelated to the present study. ME declares advisory board membership with Boehringer Ingelheim unrelated to the present study and speaker honoraria by Boehringer Ingelheim, Roche Pharma and Vertex Pharmaceuticals unrelated to the present study. MOW declares advisory board membership with Boehringer Ingelheim unrelated to the present study and receives study grants from Vertex Pharmaceuticals unrelated to the present study. The other authors have nothing to declare., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Previous studies showed that the lung clearance index (LCI) determined by multiple-breath washout (MBW) is sensitive to detecting early lung disease in preschool children with cystic fibrosis (CF). In preschool children with primary ciliary dyskinesia (PCD), data on the onset and severity of lung disease and on the sensitivity of the LCI as a noninvasive quantitative outcome measure remain limited., Research and Study Question: Is MBW feasible and sensitive to detect ventilation inhomogeneity in preschool children with PCD?, Study Design and Methods: This was a prospective, cross-sectional, multicenter study and included preschoolers with PCD, preschoolers with CF, and healthy control (HC) participants. LCI was determined using nitrogen MBW and was compared among the three groups., Results: LCI was determined in 27 children with PCD, 34 children with CF, and 30 HC participants (mean age, 4.8 years; range, 2.2-6.9 years). The LCI in preschool children with PCD was increased (median, 9.1; 95% CI, 8.6-10.3) compared with HC participants (median, 7.0; 95% CI, 6.7-7.1; P < .0001), but did not differ from preschool children with CF (median, 8.6; 95% CI, 8.4-9.7; P = .71). The feasibility in the PCD group was 93.1% and was similar to that in the CF group (91.9%) and in HC participants (85.7%; P = .55)., Interpretation: This study demonstrated early onset of lung disease in preschool children with PCD and indicated that lung disease severity in PCD may be similar to that in CF during preschool years. These data support a need for early diagnostic monitoring and therapy and suggest the LCI as a noninvasive diagnostic tool and as a potential end point in clinical trials testing early interventions in children with PCD., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

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).

Background: Previous studies suggest that PAP-based CF protocols are suitable for newborn screening (NBS) for cystic fibrosis (CF) when newborns designated as CFSPID should not be detected. However, there are still discussions about the performance of IRT/PAP algorithms. We present the final results of a pilot study evaluating a IRT/PAP protocol with an IRT-dependent safety net (SN) conducted from 2008 to 2016 in southwestern Germany on nearly 500,000 newborns., Methods: To achieve reliable data, all newborns were screened using both the PAP-based and a DNA-based CFNBS algorithm. PAP quantification and genetic analysis of the four most common CFTR mutations in Germany were performed in all newborns with IRT≥99.0 percentile. NBS was rated positive if either PAP was ≥1.6 µg/l and/or at least one CFTR mutation was detected. In addition, an IRT-dependent SN resulted in positive rating for both protocols if IRT was ≥99.9 percentile. To evaluate the IRT/PAP protocol, its performance was compared to that of the IRT/DNA protocol., Results: The IRT/PAP protocol with IRT-based SN used in the study achieved a sensitivity of 94%, if false-negative detected neonates with meconium ileus and those designated as CFSPID were excluded from analysis. CF/CFSPID ratio was 92. However, PPV of the IRT/PAP+SN protocol was with 10.3% very low., Conclusions: PAP-based CFNBS protocols can be used, if less detection of CFSPID is desired. The IRT/PAP protocol with IRT-dependent SN evaluated here achieved adequate sensitivity but should probably be used in combination with a third-tier test to also achieve an acceptable PPV., Competing Interests: Declarations of Competing Interest During the conduct of the study Dr. Sommerburg reports grants from German Federal Ministry of Education and Research and personal fees from Vertex Pharmaceuticals, both outside of the submitted work. Dr. Mall reports grants from German Federal Ministry of Education and Research, personal fees and other from Boehringer Ingelheim, personal fees from Arrowhead Pharmaceuticals, personal fees and other from Vertex Pharmaceuticals, personal fees from Santhera, personal fees from Galapagos, personal fees from Sterna Biologicals, personal fees from Enterprise Therapeutics, and personal fees from Antabio, all outside the submitted work. All other authors have nothing to disclose., (Copyright © 2021. Published by Elsevier B.V.)

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 FEV 1 % 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).

Progressive impairment in lung function caused by chronic polymicrobial airway infection remains the major cause of death in patients with cystic fibrosis (CF). Cross-sectional studies suggest an association between lung function decline and specific lung microbiome ecotypes. However, longitudinal studies on the stability of the airway microbiome are missing for adolescents with CF constituting the age group showing the highest rate of decline in lung function. In this study, we analyzed longitudinal lung function data and sputum samples collected over a period of 3 to 5 years from 12 adolescents with CF. The sputum microbiome was analyzed using 16S rRNA gene sequencing. Our results indicate that the individual course of the lung microbiome is associated with longitudinal lung function. In our cohort, patients with a dynamic, diverse microbiome showed a slower decline of lung function measured by FEV 1% predicted, whereas a more stable and less diverse lung microbiome was related to worse outcomes. Specifically, a higher abundance of the phyla Bacteroidetes and Firmicutes was linked to a better clinical outcome, while Proteobacteria were correlated with a decline in FEV 1% predicted. Our study indicates that the stability and diversity of the lung microbiome and the abundance of Bacteroidetes and Firmicutes are associated with the lung function decline and are one of the contributing factors to the disease severity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Metzger, Graeber, Stahl, Sommerburg, Mall, Dalpke and Boutin.)

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).

Over the past two decades there has been considerable progress with the evaluation and management of infants with an inconclusive diagnosis following Newborn Screening (NBS) for cystic Fibrosis (CF). In addition, we have an increasing amount of evidence on which to base guidance on the management of these infants and, importantly, we have a consistent designation being used across the globe of CRMS/CFSPID. There is still work to be undertaken and research questions to answer, but these infants now receive more consistent and appropriate care pathways than previously. It is clear that the majority of these infants remain healthy, do not convert to a diagnosis of CF in childhood, and advice on management should reflect this. However, it is also clear that some will convert to a CF diagnosis and monitoring of these infants should facilitate their early recognition. Those infants that do not convert to a CF diagnosis have some potential of developing a CFTR-RD later in life. At present, it is not possible to quantify this risk, but families need to be provided with clear information of what to look out for. This paper contains a number of changes from previous guidance in light of developing evidence, but the major change is the recommendation of a detailed assessment of the child with CRMS/CFSPID in the sixth year of age, including respiratory function assessment and imaging. With these data, the CF team can discuss future care arrangements with the family and come to a shared decision on the best way forward, which may include discharge to primary care with appropriate information. Information is key for these families, and we recommend consideration of a further appointment when the individual is a young adult to directly communicate the implications of the CRMS/CFSPID designation., (Copyright © 2020 European Cystic Fibrosis Society. All rights reserved.)

Airway dysbiosis has been associated with lung disease severity in patients with cystic fibrosis (CF). However, the relationship between dysbiosis, airway inflammation and lung function impairement remains poorly understood. The aim of this study was therefore to determine how the structure of the sputum microbiota, airway inflammation markers and spirometry are related in patients with CF. Sputum samples were collected from 106 CF patients between 12 and 72 years. These were analyzed by 16S rRNA gene amplicon sequencing. Moreover, levels of pro-inflammatory cytokines (IL-1β, IL-8, IL-6 and TNF-α) and Neutrophil elastase (NE) were determined. The relationship between the microbiota, inflammation markers and forced expiratory volume in one second percent predicted (FEV 1 % predicted) was evaluated by multi-parameter analysis. The microbiota α-diversity correlated inverse with inflammation markers IL-1β, IL-8, TNF-α, NE and positively with FEV 1 % predicted. Patients could be divided into 7 clusters based on their microbiota structure. The most diverse cluster was defined by oropharyngeal-like flora (OF) while the others were characterized by the dominance of a single pathogen. Patients with the diverse OF microbiota cluster had lower sputum inflammatory markers and higher FEV 1 % predicted compared to patients with a pathogen-dominated microbiota including Pseudomonas aeruginosa. Our results suggest that the diversity of the airway microbiota is an important biomarker of the severity of airway inflammation linking dysbiosis to lung function decline in patients with CF., Competing Interests: Declaration of Competing Interest DLF, SB, SAD, OS, SW, AHD have no conflict of interest to disclose. SYG receive personal fees from Chiesi GmbH outside of the submitted work. FJFH received personal money for aboard activities and lecture fees from Pulmonx, BTG, Olympus and Uptake. MS reports personal fees from Vertex Pharmaceuticals and TEVA outside of the submitted work. MAM reports personal fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Galapagos, Sterna Biologicals, Enterprise Therapeutics and Antabio outside the submitted work., (Copyright © 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Rationale: Previous studies showed that lumacaftor-ivacaftor therapy results in partial rescue of CFTR (cystic fibrosis [CF] transmembrane conductance regulator) activity and a moderate improvement of spirometry in Phe508del homozygous patients with CF. However, the effects of lumacaftor-ivacaftor on lung clearance index (LCI), lung morphology and perfusion detected by chest magnetic resonance imaging (MRI), and effects on the airway microbiome and inflammation remain unknown. Objectives: To investigate the effects of lumacaftor-ivacaftor on LCI, lung MRI scores, and airway microbiome and inflammation. Methods: In this prospective observational study we assessed clinical outcomes including spirometry and body mass index, LCI, lung MRI scores, sputum microbiome, and proinflammatory cytokines in 30 Phe508del homozygous patients with CF 12 years and older before and 8-16 weeks after initiation of lumacaftor-ivacaftor therapy. Results: Lumacaftor-ivacaftor had no effects on forced expiratory volume in 1 second (FEV 1 % predicted) (1.7%; 95% confidence interval [CI], -1.0% to 4.3%; P  = 0.211) but improved LCI (-1.6; 95% CI, -2.6 to -0.5; P  < 0.01) and MRI morphology (-1.3; 95% CI, -2.3 to -0.3; P  < 0.05) and perfusion score (-1.2; 95% CI, -2.3 to -0.2; P  < 0.05) in our study cohort. Furthermore, lumacaftor-ivacaftor decreased the total bacterial load (-1.8; 95% CI, -3.3 to -0.34; P  < 0.05) and increased the Shannon diversity of the airway microbiome (0.4; 95% CI, 0.1 to 0.8; P  < 0.05), and reduced IL-1β (interleukin-1β) concentration (median change, -324.2 pg/ml; 95% CI, -938.7 to 290.4 pg/ml; P  < 0.05) in sputum of Phe508del homozygous patients. Conclusions: This study shows that lumacaftor-ivacaftor has beneficial effects on lung ventilation, morphology, and perfusion, as well as on the airway microbiome and inflammation in Phe508del homozygous patients. Our results suggest that LCI and MRI may be more sensitive than FEV 1 % predicted to detect response to CFTR modulator therapy in patients with chronic CF lung disease. Clinical trial registered with ClinicalTrials.gov (NCT02807415).

Newborn screening for cystic fibrosis (CF-NBS) was introduced in Germany in 2016. Currently, systematic follow-up of positive CF-NBS results is not implemented or reimbursed in the NBS program. We investigated results of confirmatory testing over 24 months after implementation of CF-NBS for a large German NBS center before and after introduction of an active tracking system and performed a cost calculation for tracking. Results are compared with the federal state of Bavaria, where a centralized tracking system has been in place for many years. At the NBS center, 244 of 281,907 children had a positive CF-NBS result requiring diagnostic confirmation. Before implementation of a telephone tracking system, only 43% of confirmatory results were returned despite repeated written requests. The consecutive strategy including telephone tracking led to an increase of resolved cases to 84%. However, the centralized tracking system in Bavaria, assigning children with positive CF-NBS directly to a responsible CF-center, resolved 99% of cases. The calculated additional cost for a tracking system in Germany including telephone tracking is 1.20€ per newborn screened.Conclusion: The implementation of a tracking system achieves a distinct improvement in CF-NBS with justifiable costs. The effect can be limited by absence of centralized organization of confirmatory testing. What is Known: • Newborn screening for cystic fibrosis (CF-NBS) has been performed for many years in several countries worldwide • While many studies have focused on different CF-NBS strategies, the organization of confirmatory testing and process quality concerning returned information to the NBS center has so far received less attention. What is New: • The implementation of an active tracking system achieves a distinct improvement of clarified cases after positive CF-NBS with justifiable costs. • The effect of a tracking system can be limited by the absence of a centralized organization of confirmatory testing.

Background: Noninvasive monitoring of early abnormalities and therapeutic intervention in cystic fibrosis (CF) lung disease using MRI is important. Lung T 1 mapping has shown potential for local functional imaging without contrast material. Recently, it was discovered that observed lung T 1 depends on the measurement echo time (TE)., Purpose: To examine TE-dependence of observed T 1 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 T 1 (TE) mapping at five TEs including TE 1 = 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. T 1 (TE) was quantified automatically. Clinical data including spirometry (FEV1pred%) and lung clearance index (LCI) were collected., Statistical Tests: T 1 (TE) was correlated with the CF-MRI score, clinical data, and LCI., Results: T 1 (TE) showed a different curvature in CF than in healthy adults: T 1 at TE 1 was shorter in CF (1157 ms ± 73 ms vs. 1047 ms ± 70 ms, P < 0.001), but longer at TE 3 (1214 ms ± 72 ms vs. 1314 ms ± 68 ms, P < 0.001) and later TEs. The correlations of T 1 (TE) with patient age (ρ TE1-TE5 = -0.55, -0.44, -0.24, -0.30, -0.22), and LCI (ρ TE1-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 (ρ TE1-TE5 = -0.43, -0.51, -0.47, -0.46, -0.44) and FEV1pred% (ρ TE1-TE5 = +0.44, +0.44, +0.43, +0.40, +0.39) (P < 0.05)., Data Conclusion: TE should be considered when measuring lung T 1 , 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., (© 2020 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Clinical Issue: Disease severity and mortality in patients with cystic fibrosis (CF) is mainly determined by (progressive) pulmonary lung disease. Early diagnosis and therapy are important and of prognostic value to conserve lung function., Standard Radiological Methods: Primary imaging techniques for lung imaging are x‑ray and computed tomography (CT) to monitor disease severity and regional distribution., Methodical Innovations: Radiation-free imaging techniques such as magnetic resonance imaging (MRI) have gained interest over the last decade in order to prevent radiation damage., Performance: The main findings of CF lung disease are airway wall thickening, bronchiectasis, and mucus plugging, which are found in up to 60% of preschool age children. Pleural abnormalities and consolidations are often associated with pulmonary exacerbation. Young CF patients often show a mosaic pattern as functional changes and also perfusion defects can be seen from birth in 50% of CF patients by contrast-enhanced perfusion imaging, and in up to 90% of adult patients, with varying degrees of severity. Dilated bronchial arteries indicate an increased risk for hemoptysis., Achievements: Proton MRI is the sole imaging technique that can show structural and functional lung changes in one examination. Structured assessment using a scoring system helps to systematically grade the extent and severity of all CF-associated changes., Conclusions: Lung MRI for cystic fibrosis has been recently established as a clinical standard examination and is routinely performed at experienced centers. More recently, it has also been used as an endpoint within the framework of clinical studies.

With its high detail of morphological changes in lung parenchyma and airways as well as the possibilities for three-dimensional reconstruction, computed tomography (CT) represents a solid tool for the diagnosis and follow-up in patients suffering from cystic fibrosis (CF). Guidelines for standardized CT image acquisition in CF patients are still missing. In the mostly younger CF patients, an important issue is the well-considered use of radiation in CT imaging. The use of intravenous contrast agent is mainly restricted to acute emergency diagnostics. Typical morphological findings in CF lung disease are bronchiectasis, mucus plugging, or signs of decreased ventilation (air trapping) which can be detected with CT even in early stages. Various scoring systems that have become established over time are used to grade disease severity and for structured follow-up, e.g., in clinical research studies. With the technical development of CT, a number of postprocessing software tools were developed to help clinical reporting and overcome interreader differences for a standardized quantification. As an imaging modality free of ionizing radiation, magnetic resonance imaging (MRI) is becoming increasingly important in the diagnosis and follow-up of CF patients and is already frequently a substitute for CT for long-term follow-up at numerous specialized centers.

Cystic fibrosis (CF) is the most common fatal autosomal recessive disease in the Caucasian population. A mutation in the cystic fibrosis transmembrane regulator protein (CFTR) gene leads to the production of abnormally viscous mucus and secretions in the lungs of these patients. A similar pathology also occurs in other organs. In the abdomen, among others the gastrointestinal tract, the pancreas, and the hepatobiliary system are affected. The involvement of the pancreas leads to its exocrine and endocrine insufficiency. Hepatic manifestations include hepatic steatosis, focal biliary and multilobular cirrhosis, and portal hypertension. Biliary complications include cholelithiasis, microgallbladder, and sclerosing cholangitis. In the gastrointestinal tract, complications such as the distal intestinal obstruction syndrome, invaginations, chronic constipation, wall thickening, and fibrosis in the colon may occur. An important renal manifestation is nephrolithiasis. With currently rapidly increasing life expectancy of patients with cystic fibrosis, complications of extrapulmonary cystic fibrosis manifestations including hepatic and gastrointestinal malignancy could be an increasing cause of morbidity and mortality of these patients. It is therefore important for radiologists to know and recognize these clinical patterns and to monitor these manifestations in follow-up exams. Previous therapy of extrapulmonary manifestations has been largely symptomatic. Fortunately, the new CFTR modulators seem to represent an effective causal therapeutic approach here.

Rationale: Chronic rhinosinusitis (CRS) contributes to disease burden of patients with cystic fibrosis (CF). However, its onset and progression in infants and preschool children with CF remain poorly understood. Objectives: To determine the prevalence and extent of CRS in young children with CF using magnetic resonance imaging (MRI). Methods: MRI was performed in sedation in 67 infants and preschool children with CF (mean age 2.3 ± 2.1 yr; range 0-6 yr) and 30 non-CF control subjects (3.5 ± 2.0 yr; range 0-6 yr). Paranasal sinus dimensions and structural abnormalities, including mucosal swelling; mucopyoceles; and nasal polyps of the maxillary, frontal, sphenoid, and ethmoid sinuses; and, in addition, medial maxillary sinus wall deformation, were assessed using a dedicated CRS MRI scoring system. Results: Pneumatization and dimensions of paranasal sinuses did not differ between the two groups. MRI detected an increased prevalence of mucosal swelling (83% vs. 17%; P   <  0.001), mucopyoceles (75% vs. 2%; P   <  0.001), polyps (26% vs. 7%; P   <  0.001), and maxillary sinus wall deformation (68% vs. 2%; P   <  0.001) in infants and preschool children with CF compared with age-matched control subjects. Furthermore, the extent of these abnormalities was also increased with a MRI sum score of 22.9 ± 10.9 in CF compared with 4.5 ± 7.6 in non-CF control subjects ( P  < 0.001). Conclusions: MRI detected normal dimensions of paranasal sinuses, and a high prevalence and severity of paranasal sinus abnormalities due to CRS in infants and preschool children with CF without radiation exposure. Our results support the development of MRI for sensitive noninvasive diagnosis and monitoring of CRS in young children with CF, and as outcome measures for clinical trials.Clinical trial registered with www.clinicaltrials.gov (NCT00760071).

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.

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).

Objectives: To determine if morphological non-contrast enhanced magnetic resonance imaging (MRI) of the lung is sensitive to detect mosaic signal intensity in infants and preschool children with cystic fibrosis (CF)., Materials and Methods: 50 infant and preschool CF patients (mean age 3.5 ± 1.4y, range 0-6y) routinely underwent morphological (T2-weighted turbo-spin echo sequence with half-Fourier acquisition, HASTE) and contrast-enhanced 4D perfusion MRI (gradient echo sequence with parallel imaging and echo sharing, TWIST). MRI studies were independently scored by two readers blinded for patient age and clinical data (experienced Reader 1 = R1, inexperienced Reader 2 = R2). The extent of lung parenchyma signal abnormalities on HASTE was rated for each lobe from 0 (normal), 1 (<50% of lobe affected) to 2 (≥50% of lobe affected). Perfusion MRI was rated according to the previously established MRI score, and served as the standard of reference., Results: Inter-method agreement between MRI mosaic score and perfusion score was moderate with κ = 0.58 (confidence interval 0.45-0.71) for R1, and with κ = 0.59 (0.46-0.72) for R2. Bland-Altman analysis revealed a slight tendency of the mosaic score to underestimate perfusion abnormalities with a score bias of 0.48 for R1 and 0.46 for R2. Inter-reader agreement for mosaic score was substantial with κ = 0.71 (0.62-0.79), and a low bias of 0.02., Conclusions: This study demonstrates that non-contrast enhanced MRI reliably detects mosaic signal intensity in infants and preschool children with CF, reflecting pulmonary blood volume distribution. It may thus be used as a surrogate for perfusion MRI if contrast material is contra-indicated or alternative techniques are not available., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The relative risk for bone fractures in patients with cystic fibrosis (CF) and its relationship to macroscopic bone architecture assessed by pQCT and DXA are incompletely defined., Methods: In a cross-sectional study of 43 CF patients (age, 17.8±6.2years), rate and location of fractures, bone mass, density, geometry, and strength of the radius as well as forearm muscle size were investigated., Results: The fracture rate in CF was 9.2-fold higher compared to an age-matched German control population. The probability of remaining free of any fracture in CF patients at 25years was reduced to 39.8% compared to 84.6% in controls (P<0.001). Assessment of macroscopic bone architecture by DXA and pQCT allowed the differentiation of patients with multiple prevalent fractures with a high sensitivity (up to 100%) and specificity (up to 94.3%)., Conclusions: Bone densitometry is a useful tool for noninvasive assessment of fracture risk in CF patients., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background For the new cystic fibrosis (CF) newborn screening program in Germany the Federal Joint Committee (G-BA) implemented a new screening protocol using immunoreactive trypsinogen (IRT) as first and pancreatitis associated protein (PAP) as second tier. Gene analysis with a panel of 31 CFTR-mutations is used as third tier to increase the positive predictive value (PPV) which is known to be low in pure biochemical IRT/PAP protocols. Methods For post hoc analysis the data pool (n=372 906) of a study evaluating a pure biochemical IRT/PAP protocol was used for assessment of the 3-step G-BA protocol in comparison with an alternative screening protocol recommended by the authors. The difference between the 2 protocols is the procedure when IRT>99.9 th percentile. In the G BA protocol PAP and DNA analysis will be by-passed while in the alternative protocol only the PAP step will be circumvented. Results Both 3-tier IRT/PAP+SN/DNA protocols did not lose sensitivity due to addition of genetic analysis when the results were compared to those of the 2-tier biochemical IRT/PAP protocol. However, the protocols provide different results regarding PPV. The G-BA protocol showed with 351 a much higher number of false-positively detected newborns (PPV 20.2%) when compared to 31 false-positively detected newborns in the alternative protocol (PPV 69.6%). Conclusions The G-BA protocol had a worse performance when compared with the alternative protocol recommended by the authors. The higher number of false-positively detected newborns using the G-BA protocol will lead to more consultations including sweat tests, will create more anxiety in parents, and will result in higher costs after screening., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Newborn screening (NBS) for cystic fibrosis (CF) is a well-established public health strategy with international standards. The aim of this study was to provide an update on NBS for CF in Europe and assess performance against the standards., Methods: Questionnaires were sent to key workers in each European country., Results: In 2016, there were 17 national programmes, 4 countries with regional programmes and 25 countries not screening in Europe. All national programmes employed different protocols, with IRT-DNA the most common strategy. Five countries were not using DNA analysis. In addition, the processing and structure of programmes varied considerably. Most programmes were achieving the ECFS standards with respect to timeliness, but were less successful with respect to sensitivity and specificity., Conclusions: There has been a steady increase in national CF NBS programmes across Europe with variable strategies and outcomes that reflect the different approaches., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Objective: Cystic fibrosis (CF) can be difficult to diagnose, even when newborn screening (NBS) tests yield positive results. This challenge is exacerbated by the multitude of NBS protocols, misunderstandings about screening vs diagnostic tests, and the lack of guidelines for presumptive diagnoses. There is also confusion regarding the designation of age at diagnosis., Study Design: To improve diagnosis and achieve standardization in definitions worldwide, the CF Foundation convened a committee of 32 experts with a mission to develop clear and actionable consensus guidelines on diagnosis of CF with an emphasis on screened populations, especially the newborn population. A comprehensive literature review was performed with emphasis on relevant articles published during the past decade., Results: After reviewing the common screening protocols and outcome scenarios, 14 of 27 consensus statements were drafted that apply to screened populations. These were approved by 80% or more of the participants., Conclusions: It is recommended that all diagnoses be established by demonstrating dysfunction of the CF transmembrane conductance regulator (CFTR) channel, initially with a sweat chloride test and, when needed, potentially with newer methods assessing membrane transport directly, such as intestinal current measurements. Even in babies with 2 CF-causing mutations detected via NBS, diagnosis must be confirmed by demonstrating CFTR dysfunction. The committee also recommends that the latest classifications identified in the Clinical and Functional Translation of CFTR project [http://www.cftr2.org/index.php] should be used to aid with CF diagnosis. Finally, to avoid delays in treatment, we provide guidelines for presumptive diagnoses and recommend how to determine the age of diagnosis., (Copyright © 2016. Published by Elsevier Inc.)

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).

Background: Chronic rhinosinusitis is a hallmark of Cystic fibrosis (CF) impairing the patients' quality of life and overall health. However, therapeutic options have not been sufficiently evaluated. Bronchial inhalation of mucolytic substances is a gold standard in CF therapy. Previously, we found that sinonasal inhalation of dornase alfa as vibrating aerosol reduces symptoms of chronic rhinosinusitis more effectively than NaCl 0.9% (net treatment benefit: -5.87±2.3 points, p=0.017; SNOT-20 total score). This multicenter study compares the effect of NaCl 6.0% vs. NaCl 0.9% following the protocol from our preceding study with dornase alfa., Methods: Sixty nine CF patients with chronic rhinosinusitis in eleven German CF centers were randomized to receive sinonasal vibrating inhalation of either NaCl 6.0% or NaCl 0.9% for 28days. After 28days of wash-out, patients crossed over to the alternative treatment. The primary outcome parameter was symptom score in the disease-specific quality of life Sino-Nasal Outcome Test-20 (SNOT-20). Additionally, pulmonary function was assessed, as well as rhinomanometry and inflammatory markers in nasal lavage (neutrophil elastase, interleukin (IL)-1β, IL-6, and IL-8) in a subgroup., Results: Both therapeutic arms were well tolerated and showed slight improvements in SNOT-20 total scores (NaCl 6.0%: -3.1±6.5 points, NaCl 0.9%: -5.1±8.3 points, ns). In both treatment groups, changes of inflammatory parameters in nasal lavage from day 1 to day 29 were not significant. We suppose that the irritating properties of NaCl 6.0% reduced the suitability of the SNOT-20 scores as an outcome parameter. Alternative primary outcome parameters such as MR-imaging or the quantity of sinonasal secretions mobilized with both saline concentrations were, however, not feasible., Conclusion: Sinonasal inhalation with NaCl 6.0% did not lead to superior results vs. NaCl 0.9%, whereas dornase alfa had been significantly more effective than NaCl 0.9%., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: In cystic fibrosis newborn screening (CFNBS), immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) can be used as screening parameters. We evaluated the IRT×PAP product as second-tier parameter in CFNBS in newborns with elevated IRT., Methods: Data on 410,111 screened newborns including 78 patients with classical cystic fibrosis (CF) from two European centers were retrospectively analyzed by discrimination analysis to identify a screening protocol with optimal cutoffs. We also studied differences in PAP measurement methods and the association of IRT and PAP with age., Results: PAP values differed systematically between fluorometric and photometric assays. The IRT×PAP product showed better discrimination for classical CF than PAP only as second-tier screening parameter (p<0.001). In CF patients, IRT decreased while PAP values remained high over years. In newborns without CF, IRT decreased after birth over weeks while PAP increased within days., Conclusions: The IRT×PAP product performs well as second-tier cutoff parameter for CFNBS. Screening quality parameters depend on the analytic method and on age at blood collection., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Unlabelled: Progressive lung disease in cystic fibrosis (CF) is the life-limiting factor of this autosomal recessive genetic disorder. Increasing implementation of CF newborn screening allows for a diagnosis even in pre-symptomatic stages. Improvements in therapy have led to a significant improvement in survival, the majority now being of adult age. Imaging provides detailed information on the regional distribution of CF lung disease, hence longitudinal imaging is recommended for disease monitoring in the clinical routine. Chest X-ray (CXR), computed tomography (CT) and magnetic resonance imaging (MRI) are now available as routine modalities, each with individual strengths and drawbacks, which need to be considered when choosing the optimal modality adapted to the clinical situation of the patient. CT stands out with the highest morphological detail and has often been a substitute for CXR for regular severity monitoring at specialized centers. Multidetector CT data can be post-processed with dedicated software for a detailed measurement of airway dimensions and bronchiectasis and potentially a more objective and precise grading of disease severity. However, changing to CT was inseparably accompanied by an increase in radiation exposure of CF patients, a young population with high sensitivity to ionizing radiation and lifetime accumulation of dose. MRI as a cross-sectional imaging modality free of ionizing radiation can depict morphological hallmarks of CF lung disease at lower spatial resolution but excels with comprehensive functional lung imaging, with time-resolved perfusion imaging currently being most valuable., Key Points: • Hallmarks are bronchiectasis, mucus plugging, air trapping, perfusion abnormalities, and emphysema.• Imaging is more sensitive to disease progression than lung function testing.• CT provides the highest morphological detail but is associated with radiation exposure.• MRI shows comparable sensitivity for morphology but excels with additional functional information.• MRI sensitively depicts reversible abnormalities such as mucus plugging and perfusion abnormalities. Citation Format: • Wielpütz MO, Eichinger M, Biederer J et al. Imaging of Cystic Fibrosis Lung Disease and Clinical Interpretation. Fortschr Röntgenstr 2016; 188: 834 - 845., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Evidence from recent studies suggests that IRT/PAP protocols may be successfully used as a purely biochemical newborn screening (NBS) for cystic fibrosis (CF) that does not require genetic screening. However, the experience with the performance of different IRT/PAP protocols remains limited. In this study, we evaluated the performance of IRT/PAP-based CF-NBS used in two German regions between 2008 and 2013 in a large cohort., Methods: In both regions slightly different IRT/PAP protocols were used to screen newborns for CF. In contrast to the original IRT/PAP protocol published by Sarles et al., both German protocols contained an IRT-dependent safety net strategy (CF-NBS positive, if IRT≥99.9th percentile). Positive rating of the screening result led to confirmatory diagnostics using sweat chloride testing and clinical assessment., Findings: A total of 328,181 newborns were tested with IRT/PAP in Germany within 5 years. 639 of these newborns (0.19%) were tested positive, and 60 infants were diagnosed with CF leading to a sensitivity of 0.968 and a PPV (positive predictive value) of 0.097. Compared to IRT/DNA protocols, the PPV of IRT/PAP is lower, but PAP used as second tier test has the advantage of a lower detection rate of healthy carriers and CF patients with equivocal results., Conclusions: Our results obtained in a large cohort of ∼330,000 newborns support the use of a purely biochemical IRT/PAP protocol as an acceptable alternative when genetic CF-NBS has to be avoided., (© 2015 Wiley Periodicals, Inc.)

Patients with cystic fibrosis (CF) show decreased plasma concentrations of antioxidants due to malabsorption of lipid soluble vitamins and consumption by chronic pulmonary inflammation. β-Carotene is a major source of retinol and therefore is of particular significance in CF. The aim of this study was to investigate the effect of daily intake of red palm oil (RPO) containing high amounts of β-carotene on the antioxidant levels in CF patients. Sixteen subjects were recruited and instructed to enrich their food with 2 to 3 tablespoons of RPO (~1.5 mg of β-carotene) daily over 8 weeks. Carotenoids, retinol, and α-tocopherol were measured in plasma at baseline and after intervention. In addition β-carotene, lycopene, α-tocopherol, and vitamin C were measured in buccal mucosa cells (BMC) to determine the influence of RPO on antioxidant tissue levels. Eleven subjects completed the study properly. Plasma β-carotene, retinol, and α-carotene of these patients increased, but plasma concentrations of other carotenoids and α-tocopherol as well as concentrations of β-carotene, lycopene, α-tocopherol, and vitamin C in BMC remained unchanged. Since RPO on a daily basis did not show negative side effects the data suggest that RPO may be used to elevate plasma β-carotene in CF.

Rationale: Studies demonstrating early structural lung damage in infants and preschool children with cystic fibrosis (CF) suggest that noninvasive monitoring will be important to identify patients who may benefit from early therapeutic intervention. Previous studies demonstrated that magnetic resonance imaging (MRI) detects structural and functional abnormalities in lungs from older patients with CF without radiation exposure., Objectives: To evaluate the potential of MRI to detect abnormal lung structure and perfusion in infants and preschool children with CF, and to monitor the response to therapy for pulmonary exacerbation., Methods: MRI studies were performed in 50 children with CF (age, 3.1 ± 2.1 yr; range, 0-6 yr) in stable clinical condition (n = 40) or pulmonary exacerbation before and after antibiotic treatment (n = 10), and in 26 non-CF control subjects (age, 2.9 ± 1.9 yr). T1- and T2-weighted sequences before and after intravenous contrast and first-pass perfusion imaging were acquired, and assessed on the basis of a dedicated morphofunctional score., Measurements and Main Results: MRI demonstrated bronchial wall thickening/bronchiectasis, mucus plugging, and perfusion deficits from the first year of life in most stable patients with CF (global score, 10.0 ± 4.0), but not in non-CF control subjects (score, 0.0 ± 0.0; P < 0.001). In patients with exacerbations, the global MRI score was increased to 18.0 ± 2.0 (P < 0.001), and was significantly reduced to 12.0 ± 3.0 (P < 0.05) after antibiotic therapy., Conclusions: MRI detected abnormalities in lung structure and perfusion, and response to therapy for exacerbations in infants and preschool children with CF. These results support the development of MRI for noninvasive monitoring and as an end point in interventional trials for early CF lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT00760071).

Background: Cystic fibrosis (CF) lung disease starts in the first months of life often before the onset of clinical symptoms. Multiple breath washout (MBW) detects abnormal lung function in infants and young children in the laboratory setting., Objective: The aim of this study was to determine the feasibility of MBW in 0- to 4-year-old children with CF and non-CF controls in the clinical setting., Methods: Fourteen children with CF (mean age 1.3 ± 1.0 years) and 26 age-matched non-CF controls were sedated with chloral hydrate and MBW was performed with sulfur hexafluoride., Results: MBW measurements were successful in 27 of 40 children (67.5%). The mean lung clearance index (LCI) was significantly higher in CF patients compared to non-CF controls (p = 0.006). Further, the frequency of elevated LCI (z-score >1.96) was significantly increased in CF patients compared to controls (p = 0.0003)., Conclusions: We conclude that MBW is feasible and sensitive to detect abnormal lung function in infants and young children with CF in the clinical setting.

Background: In recent years different IRT/PAP protocols have been evaluated, but the individual performance remains unclear. To optimize the IRT/PAP strategy we compared protocols from three regional CF newborn screening centers (Heidelberg, Dresden, and Prague)., Methods: We evaluated the effect of elevating the IRT-cut-off from 50 to 65 μg/l (~97.5th to ~99.0th percentile), the need of a failsafe protocol (FS, IRT ≥ 99.9th percentile) and the relative performance using either two IRT-dependent PAP-cut-offs or one PAP-cut-off., Findings: Elevation of the IRT cut-off to 65 μg/l (~99.0th percentile) increased the PPV significantly (Dresden: 0.065 vs. 0.080, p < 0.0001, Prague: 0.052 vs. 0.074, p < 0.0001) without reducing sensitivity. All three IRT/PAP protocols showed a trend towards a higher sensitivity with FS than without and when using one PAP-cut-off instead of two IRT-dependent PAP-cut-offs., Conclusions: For best performance we suggest an IRT/PAP protocol with an IRT-cut-off close to the 99.0th percentile, FS, and a single PAP-cut-off., (© 2013.)