Search

Background: Elexacaftor–tezacaftor–ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing. Methods: We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor–tezacaftor–deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor–tezacaftor–deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor–deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)–tezacaftor–deutivacaftor or tezacaftor–ivacaftor active control for 4 weeks, following a 4-week tezacaftor–ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete. Findings: In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI –0·8 to 7·0) and 2·7 percentage points (–1·0 to 6·5) from baseline at week 12, respectively, versus –0·8 percentage points (–6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)–tezacaftor–deutivacaftor (n=9), vanzacaftor (10 mg)–tezacaftor–deutivacaftor (n=19), vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (−1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (−4·1 to 8·0), respectively, in sweat chloride concentration of −42·8 mmol/L (–51·7 to –34·0), −45·8 mmol/L (95% CI –51·9 to –39·7), −49·5 mmol/L (–55·9 to –43·1), and 2·3 mmol/L (−7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (−10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=18) and tezacaftor–ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor–ivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and −0·1 percentage points (−6·4 to 6·1), respectively, in sweat chloride concentration of −45·5 mmol/L (−49·7 to −41·3) and −2·6 mmol/L (−8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and −5·0 points (−16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor–tezacaftor–deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity. Interpretation: Once-daily dosing with vanzacaftor–tezacaftor–deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor–tezacaftor–deutivacaftor in phase 3 clinical trials compared with elexacaftor–tezacaftor–ivacaftor. Funding: Vertex Pharmaceuticals.

Zusammenfassung Ziel der Studie Die Zeit bis zu einer korrekten Diagnosestellung einer Seltenen Erkrankung kann sich über mehrere Jahre erstrecken. Patient*innen, bei denen der Verdacht auf eine Seltene Erkrankung besteht, haben oft bereits einen langen und belastenden Weg durch das Gesundheitssystem hinter sich. Bis heute ist wenig über die Lebensqualität von Patient*innen mit Verdacht auf eine Seltene Erkrankung bekannt. Ziel der vorliegenden Studie ist es, die gesundheitsbezogene Lebensqualität sowie die wahrgenommene Stressbelastung von Patient*innen mit Verdacht auf eine Seltene Erkrankung zu beschreiben und mit populationsbasierten Referenzwerten zu vergleichen. Methodik Achtzig Patient*innen mit Verdacht auf eine Seltene Erkrankung wurden im Rahmen der bundesweiten Interventionsstudie „ZSE-DUO“ rekrutiert und zu ihrer Lebensqualität und wahrgenommenen Belastung anhand des SF-8 und des Distress-Thermometers inklusive Problemliste befragt. Ergebnisse Die befragten Patient*innen bewerteten alle acht Dimensionen der Lebensqualität sowie die körperlichen und psychischen Summenskalen des SF-8 signifikant niedriger als die Allgemeinbevölkerung. Die wahrgenommene Belastung wurde signifikant höher bewertet. Zudem gaben über 90% der Stichprobe einen Wert im klinisch auffälligen Bereich an. Erschöpfung, Schmerzen, eingeschränkte Mobilität sowie Sorgen und Ängste wurden am häufigsten als konkrete Probleme genannt, mit Anteilen jeweils zwischen 73 und 90% der Gesamtstichprobe. Diskussion Im Vergleich zu deutschen Referenzdaten berichten Patient*innen mit dem Verdacht auf eine Seltene Erkrankung eine massive Beeinträchtigung ihrer Lebensqualität und eine hohe Belastung, die besonders durch körperliche und emotionale Probleme gekennzeichnet ist. Das Fehlen einer Diagnose könnte den hohen Anteil emotionaler Probleme erklären, da durch diese eine Form der Legitimation des eigenen Krankheitserlebens entstehen kann. Schlussfolgerung Die vorliegenden Ergebnisse unterstreichen die dringende Notwendigkeit der Forschung zu den psychosozialen Auswirkungen beim möglichen Vorliegen einer Seltenen Erkrankung.

Menschen mit Seltenen Erkrankungen werden optimalerweise durch spezialisierte interdisziplinar und multiprofessionell arbeitende Zentren versorgt, an denen auch die Aus‑, Fort- und Weiterbildung sowie Forschung zum jeweiligen Krankheitsbild bzw. der Krankheitsgruppe stattfindet. In Deutschland gibt es an Universitatskliniken mittlerweile mehr als 30 sogenannte Typ-A- oder Referenzzentren, die mit ihren angeschlossenen krankheits(gruppen)-spezifischen Typ-B- oder Fachzentren diese Aufgaben wahrnehmen. Die Zentren sind in verschiedenen Netzwerken national und international eng vernetzt und arbeiten eng mit Patientenorganisationen zusammen. Die aktuellen Herausforderungen an die Zentren betreffen die langfristig zu sichernde Finanzierung und den Aufbau einer vernetzten telemedizinischen Infrastruktur.

Patients suspected of having a rare (chronic) health condition have often gone a long way within the healthcare system. To date, little is known about the health-related quality of life of this group of patients. The study aims to describe the health-related quality of life and the perceived distress of patients suspected of having a rare (chronic) health condition and compare the results with standard values of the German population.Eighty patients suspected of having a rare (chronic) health condition were recruited in the nationwide intervention study "ZSE-DUO" and reported their health-related quality of life and perceived distress using the SF-8 and the Distress-Thermometer.The patients rated all eight dimensions of quality of life as well as the physical and mental component scores of the SF-8 significantly lower than the general population. On average, the perceived distress was rated significantly higher. More than 90% of the sample indicated distress in the clinical range. Exhaustion, pain, limited mobility as well as worries and fears were mentioned most frequently as concrete problems, with percentages ranging from 73% to 90% of the total sample.In comparison to German reference data, patients suspected of having a rare (chronic) health condition report a massive impairment of their quality of life and a high burden, which is especially characterized by physical and emotional problems. The lack of a diagnosis could explain the high proportion of emotional problems, as it can create a form of legitimation of one's own disease experience.The present results underline the need for research on the psychosocial impact of the possible presence of a rare (chronic) health condition. The high distress and the impact on the physical and psychological quality of life domains also highlight the need for care in this patient group.Die Zeit bis zu einer korrekten Diagnosestellung einer Seltenen Erkrankung kann sich über mehrere Jahre erstrecken. Patient*innen, bei denen der Verdacht auf eine Seltene Erkrankung besteht, haben oft bereits einen langen und belastenden Weg durch das Gesundheitssystem hinter sich. Bis heute ist wenig über die Lebensqualität von Patient*innen mit Verdacht auf eine Seltene Erkrankung bekannt. Ziel der vorliegenden Studie ist es, die gesundheitsbezogene Lebensqualität sowie die wahrgenommene Stressbelastung von Patient*innen mit Verdacht auf eine Seltene Erkrankung zu beschreiben und mit populationsbasierten Referenzwerten zu vergleichen.Achtzig Patient*innen mit Verdacht auf eine Seltene Erkrankung wurden im Rahmen der bundesweiten Interventionsstudie „ZSE-DUO“ rekrutiert und zu ihrer Lebensqualität und wahrgenommenen Belastung anhand des SF-8 und des Distress-Thermometers inklusive Problemliste befragt.Die befragten Patient*innen bewerteten alle acht Dimensionen der Lebensqualität sowie die körperlichen und psychischen Summenskalen des SF-8 signifikant niedriger als die Allgemeinbevölkerung. Die wahrgenommene Belastung wurde signifikant höher bewertet. Zudem gaben über 90% der Stichprobe einen Wert im klinisch auffälligen Bereich an. Erschöpfung, Schmerzen, eingeschränkte Mobilität sowie Sorgen und Ängste wurden am häufigsten als konkrete Probleme genannt, mit Anteilen jeweils zwischen 73 und 90% der Gesamtstichprobe.Im Vergleich zu deutschen Referenzdaten berichten Patient*innen mit dem Verdacht auf eine Seltene Erkrankung eine massive Beeinträchtigung ihrer Lebensqualität und eine hohe Belastung, die besonders durch körperliche und emotionale Probleme gekennzeichnet ist. Das Fehlen einer Diagnose könnte den hohen Anteil emotionaler Probleme erklären, da durch diese eine Form der Legitimation des eigenen Krankheitserlebens entstehen kann.Die vorliegenden Ergebnisse unterstreichen die dringende Notwendigkeit der Forschung zu den psychosozialen Auswirkungen beim möglichen Vorliegen einer Seltenen Erkrankung.

The ICD-10-GM coding system used in the German healthcare system only captures a minority of rare disease diagnoses. Therefore, information on the incidence and prevalence of rare diseases as well as necessary (financial) resources for the expert care required for evidence-based decisions by health insurers, care providers, and politicians are lacking. Furthermore, the missing information complicates and sometimes even precludes the generation of scientific knowledge on rare diseases. Therefore, starting in 2023, all in-patient cases in Germany with a rare disease diagnosis must be coded by an ORPHAcode using the Alpha-ID-SE file.The file Alpha-ID-SE links the ICD-10-GM codes to the internationally established ORPHAcodes for rare diseases. Commercially available software tools progressively support the coding of rare diseases. In several centers for rare diseases linked to university hospitals, IT tools and procedures were established to realize a complete coding of rare diseases. These include financial incentives for the institutions providing rare disease codes, systematic queries asking for rare disease codes during the coding process, and a semi-automated coding process for all patients with a rare disease previously seen at the institution. A combination of the different approaches probably results in the most complete coding.To get the complete picture of rare disease epidemiology and care requirements, a specific and unique coding of out-patient cases is also desirable. Furthermore, a structured reporting of phenotype is required, especially for complex rare diseases and for yet undiagnosed cases.Seltene Erkrankungen (SE) werden durch die im deutschen Gesundheitssystem verwendete Diagnosenklassifikation ICD-10-GM (International Statistical Classification of Diseases and Related Health problems, 10th Revision, German Modification) nur zu einem kleinen Teil eindeutig erfasst. Daher sind Aussagen zur Häufigkeit von SE sowie zum speziellen Versorgungs- und Finanzierungsbedarf nicht möglich, was zu einer lückenhaften Datenlage als Entscheidungsgrundlage für Krankenkassen, Leistungserbringer und Gesundheitspolitik führt. Das Fehlen exakter Informationen behindert auch die wissenschaftliche Arbeit. Daher wird deutschlandweit ab 2023 die Verwendung der Alpha-ID-SE-Datei und der ORPHAcodes für die spezifische Erfassung von SE bei stationären Fällen verpflichtend.Die Alpha-ID-SE-Datei verknüpft die ICD-10-GM-Kodes mit den international anerkannten ORPHAcodes für die Diagnose von SE. Kommerzielle Anbieter stellen zunehmend die benötigten IT-Tools zur Kodierung von SE zur Verfügung. An mehreren Universitätskliniken mit Zentren für SE wurden Lösungen etabliert, die eine vollständige Kodierung gewährleisten sollen. Hierzu gehören finanzielle Anreize für die kodierenden Bereiche, konkrete Nachfragen nach dem Vorliegen einer SE beim Kodiervorgang und eine semiautomatische Kodierung bei Patient*innen, die schon einmal mit einer SE an der Einrichtung betreut worden waren. Eine Kombination der verschiedenen Ansätze verspricht die höchste Wahrscheinlichkeit einer vollständigen Kodierung.Für ein umfängliches Bild der SE im Gesundheitssystem und um dem speziellen Versorgungs- und Finanzierungsbedarf besser Rechnung tragen zu können, wäre auch im ambulanten Bereich eine möglichst spezifische und eindeutige Kodierung wünschenswert. Für komplexe SE und bisher undiagnostizierte Patient*innen wird zusätzlich eine strukturierte Erfassung des Phänotyps benötigt.

Purpose Ultrashort echotime (UTE) sequences aim to improve the signal yield in pulmonary magnetic resonance imaging (MRI). We demonstrate the initial results of spiral 3-dimensional (3D) UTE-MRI for combined morphologic and functional imaging in pediatric patients. Methods Seven pediatric patients with pulmonary abnormalities were included in this observational, prospective, single-center study, with the patients having the following conditions: cystic fibrosis (CF) with middle lobe atelectasis, CF with allergic bronchopulmonary aspergillosis, primary ciliary dyskinesia, air trapping, congenital lobar overinflation, congenital pulmonary airway malformation, and pulmonary hamartoma.Patients were scanned during breath-hold in 5 breathing states on a 3-Tesla system using a prototypical 3D stack-of-spirals UTE sequence. Ventilation maps and signal intensity maps were calculated. Morphologic images, ventilation-weighted maps, and signal intensity maps of the lungs of each patient were assessed intraindividually and compared with reference examinations. Results With a scan time of ∼15 seconds per breathing state, 3D UTE-MRI allowed for sufficient imaging of both "plus" pathologies (atelectasis, inflammatory consolidation, and pulmonary hamartoma) and "minus" pathologies (congenital lobar overinflation, congenital pulmonary airway malformation, and air trapping). Color-coded maps of normalized signal intensity and ventilation increased diagnostic confidence, particularly with regard to "minus" pathologies. UTE-MRI detected new atelectasis in an asymptomatic CF patient, allowing for rapid and successful therapy initiation, and it was able to reproduce atelectasis and hamartoma known from multidetector computed tomography and to monitor a patient with allergic bronchopulmonary aspergillosis. Conclusion 3D UTE-MRI using a stack-of-spirals trajectory enables combined morphologic and functional imaging of the lungs within ~115 second acquisition time and might be suitable for monitoring a wide spectrum of pulmonary diseases.

Three-dimensional respiratory tissue models have been generated using, for example, human primary airway epithelial cells (hAEC) or respective cell lines. To investigate ciliopathies, such as primary ciliary dyskinesia, the presence of functional kinocilia in vitro is an essential prerequisite. Since access to hAEC of healthy donors is limited, we aimed to identify a respiratory epithelial cell line that is capable to display functional kinocilia on at least 60% of the apical surface. Thus, we cultured four different human respiratory cell lines with human primary airway fibroblasts under airlift conditions, characterized the morphology, and analyzed ciliary function. Only one of the tested cell lines showed beating kinocilia; however

The ICD-10-GM coding system used in the German healthcare system only captures a minority of rare disease diagnoses. Therefore, information on the incidence and prevalence of rare diseases as well as necessary (financial) resources for the expert care required for evidence-based decisions by health insurers, care providers, and politicians are lacking. Furthermore, the missing information complicates and sometimes even precludes the generation of scientific knowledge on rare diseases. Therefore, starting in 2023, all in-patient cases in Germany with a rare disease diagnosis must be coded by an ORPHAcode using the Alpha-ID-SE file. The file Alpha-ID-SE links the ICD-10-GM codes to the internationally established ORPHAcodes for rare diseases. Commercially available software tools progressively support the coding of rare diseases. In several centers for rare diseases linked to university hospitals, IT tools and procedures were established to realize a complete coding of rare diseases. These include financial incentives for the institutions providing rare disease codes, systematic queries asking for rare disease codes during the coding process, and a semi-automated coding process for all patients with a rare disease previously seen at the institution. A combination of the different approaches probably results in the most complete coding. To get the complete picture of rare disease epidemiology and care requirements, a specific and unique coding of out-patient cases is also desirable. Furthermore, a structured reporting of phenotype is required, especially for complex rare diseases and for yet undiagnosed cases. Seltene Erkrankungen (SE) werden durch die im deutschen Gesundheitssystem verwendete Diagnosenklassifikation ICD-10-GM (International Statistical Classification of Diseases and Related Health problems, 10th Revision, German Modification) nur zu einem kleinen Teil eindeutig erfasst. Daher sind Aussagen zur Häufigkeit von SE sowie zum speziellen Versorgungs- und Finanzierungsbedarf nicht möglich, was zu einer lückenhaften Datenlage als Entscheidungsgrundlage für Krankenkassen, Leistungserbringer und Gesundheitspolitik führt. Das Fehlen exakter Informationen behindert auch die wissenschaftliche Arbeit. Daher wird deutschlandweit ab 2023 die Verwendung der Alpha-ID-SE-Datei und der ORPHAcodes für die spezifische Erfassung von SE bei stationären Fällen verpflichtend. Die Alpha-ID-SE-Datei verknüpft die ICD-10-GM-Kodes mit den international anerkannten ORPHAcodes für die Diagnose von SE. Kommerzielle Anbieter stellen zunehmend die benötigten IT-Tools zur Kodierung von SE zur Verfügung. An mehreren Universitätskliniken mit Zentren für SE wurden Lösungen etabliert, die eine vollständige Kodierung gewährleisten sollen. Hierzu gehören finanzielle Anreize für die kodierenden Bereiche, konkrete Nachfragen nach dem Vorliegen einer SE beim Kodiervorgang und eine semiautomatische Kodierung bei Patient*innen, die schon einmal mit einer SE an der Einrichtung betreut worden waren. Eine Kombination der verschiedenen Ansätze verspricht die höchste Wahrscheinlichkeit einer vollständigen Kodierung. Für ein umfängliches Bild der SE im Gesundheitssystem und um dem speziellen Versorgungs- und Finanzierungsbedarf besser Rechnung tragen zu können, wäre auch im ambulanten Bereich eine möglichst spezifische und eindeutige Kodierung wünschenswert. Für komplexe SE und bisher undiagnostizierte Patient*innen wird zusätzlich eine strukturierte Erfassung des Phänotyps benötigt.

Rationale: The long-term effects of vigorous physical activity (PA) on lung function in cystic fibrosis are unclear. Objectives: To evaluate effects of a 12-month partially supervised PA intervention using motivational feedback. Methods: In a parallel arm multicenter randomized controlled trial (ACTIVATE-CF), relatively inactive patients aged ≥12 years were randomly assigned (1:1 ratio) to an intervention group or control group. The intervention group consented to add 3 hours of vigorous PA per week, while the control group was asked not to change their PA behavior. Primary endpoint was change in percent predicted forced expiratory volume in 1s (ΔFEV1) at 6 months. Secondary endpoints included PA, exercise capacity, exercise motives, time to first exacerbation and exacerbation rates, quality of life, anxiety, depression, and stress, and blood glucose control. Data were analyzed using mixed linear models. Measurements and Main Results: 117 patients (40% of target sample size) were randomized to an intervention (n=60) or control group (n=57). After 6 months, ΔFEV1 was significantly higher in the control group compared to the intervention group (2.70% predicted, 95% CI 0.13 to 5.26; p=0.04). The intervention group reported increased vigorous PA compared with the control group at each study visit, had higher exercise capacity at 6 and 12 months, and higher PA at 12 months. No effects were seen in other secondary outcomes. Conclusions: ACTIVATE-CF increased vigorous PA and exercise capacity, with effects carried over for the subsequent 6 months, but resulted in better FEV1 in the control group. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT01744561.

Orphanet journal of rare diseases : OJRD 17(1), 47 (2022). doi:10.1186/s13023-022-02176-1, Published by BioMed Central, London

Menschen mit Seltenen Erkrankungen werden optimalerweise durch spezialisierte interdisziplinär und multiprofessionell arbeitende Zentren versorgt, an denen auch die Aus‑, Fort- und Weiterbildung sowie Forschung zum jeweiligen Krankheitsbild bzw. der Krankheitsgruppe stattfindet. In Deutschland gibt es an Universitätskliniken mittlerweile mehr als 30 sogenannte Typ-A- oder Referenzzentren, die mit ihren angeschlossenen krankheits(gruppen)-spezifischen Typ-B- oder Fachzentren diese Aufgaben wahrnehmen. Die Zentren sind in verschiedenen Netzwerken national und international eng vernetzt und arbeiten eng mit Patientenorganisationen zusammen. Die aktuellen Herausforderungen an die Zentren betreffen die langfristig zu sichernde Finanzierung und den Aufbau einer vernetzten telemedizinischen Infrastruktur.

Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.

Rationale: The prognostic value of cardiopulmonary exercise testing (CPET) for survival in cystic fibrosis (CF) in the context of current clinical management, when controlling for other known prognostic factors, is unclear. Objectives: To determine the prognostic value of CPET-derived measures beyond peak oxygen uptake (VO 2 peak) following rigorous adjustment for other predictors. Methods: Data from 10 CF centers in Australia, Europe, and North America were collected retrospectively. A total of 510 patients completed a cycle CPET between January 2000 and December 2007, of which 433 fulfilled the criteria for a maximal effort. Time to death/lung transplantation was analyzed using Cox proportional hazards regression. In addition, phenotyping using hierarchical Ward clustering was performed to characterize high-risk subgroups. Measurements and Main Results: Cox regression showed, even after adjustment for sex, FEV1% predicted, body mass index (z-score), age at CPET, Pseudomonas aeruginosa status, and CF-related diabetes as covariates in the model, that VO 2 peak in % predicted (hazard ratio [HR], 0.964; 95% confidence interval [CI], 0.944-0.986), peak work rate (% predicted; HR, 0.969; 95% CI, 0.951-0.988), ventilatory equivalent for oxygen (HR, 1.085; 95% CI, 1.041-1.132), and carbon dioxide (HR, 1.060; 95% CI, 1.007-1.115) (all P < 0.05) were significant predictors of death or lung transplantation at 10-year follow-up. Phenotyping revealed that CPET-derived measures were important for clustering. We identified a high-risk cluster characterized by poor lung function, nutritional status, and exercise capacity. Conclusions: CPET provides additional prognostic information to established predictors of death/lung transplantation in CF. High-risk patients may especially benefit from regular monitoring of exercise capacity and exercise counseling.

Obwohl die Mehrheit der Jugendlichen primar gesund ist, fuhrt Bewegungsmangel zu zunehmenden Zivilisationskrankheiten mit Ubergewicht, kardiovaskularen Risikofaktoren und Haltungsschaden. Regelmasige Bewegung und Sport konnen diese weitestgehend verhindern. Wahrend allerdings Effekte auf die Gesundheit breit untersucht wurden, sind Studien zum Einfluss auf die Entwicklung nur sparlich vorhanden. Nicht zuletzt sind solche Effekte schwierig zu quantifizieren, zumal die Entwicklung, vor allem wahrend der Pubertat, extreme intraindividuelle Variabilitaten von bis zu 6 Jahren zeigt (s. Abschn. 3.1). Noch fehlen reprasentative Studien, die erlauben, zwischen Entwicklung mit und ohne Bewegung und Sport zu differenzieren, oder die erlauben, eine Dosis-Wirkungs-Beziehung zwischen Sport und Entwicklung zu erstellen. Wo immer moglich, wird aber im nachfolgenden Kapitel neben den Einflussen auf die Gesundheit auch auf die Entwicklung eingegangen. Neben den vielfaltigen Auswirkungen von Bewegung und Sport auf die Gesundheit und Entwicklung von Jugendlichen gibt es potenziell negative Auswirkungen, insbesondere bei Jugendlichen im Leistungssport, die hier oder zum Teil auch in anderen Kapiteln besprochen werden. Auf die Auswirkungen von Sport als Therapie bei chronischen Erkrankungen wird in anderen Kapiteln (s. Kap. 28–34) eingegangen.

Background Persistent tachypnea of infancy (PTI) is a rare pediatric lung disease of unknown origin. The diagnosis can be made by clinical presentation and chest high resolution computed tomography after exclusion of other causes. Clinical courses beyond infancy have rarely been assessed. Methods Patients included in the Kids Lung Register diagnosed with PTI as infants and now older than 5 years were identified. Initial presentation, extrapulmonary comorbidities, spirometry and clinical outcome were analyzed. Results Thirty-five children older than 5 years with PTI diagnosed as infants were analyzed. At the age of 5 years, 74% of the patients were reported as asymptomatic and did not develope new symptoms during the observational period at school-age (mean, 3.9 years; range, 0.3-6.3). At the age of about 10 years, none of the symptomatic children had abnormal oxygen saturation during sleep or exercise anymore. Lung function tests and breathing frequency were within normal values throughout the entire observational period. Conclusions PTI is a pulmonary disease that can lead to respiratory insufficiency in infancy. As at school age most of the previously chronically affected children became asymptomatic and did not develop new symptoms. We conclude that the overall clinical course is favorable.

Background In cystic fibrosis (CF), recurrent imaging and pulmonary function tests (PFTs) are needed for the assessment of lung function during disease management. Purpose To assess the clinical feasibility of pulmonary three-dimensional ultrashort echo time (UTE) MRI at breath holding for quantitative image analysis of ventilation inhomogeneity and hyperinflation in CF compared with PFT. Materials and Methods In this prospective study from May 2018 to June 2019, participants with CF and healthy control participants underwent PFTs and functional lung MRI by using a prototypical single breath-hold three-dimensional UTE sequence. Fractional ventilation (FV) was calculated from acquired data in normal inspiration and normal expiration. FV of each voxel was normalized to the whole lung mean (FVN), and interquartile range of normalized ventilation (IQRN; as a measure of ventilation heterogeneity) was calculated. UTE signal intensity (SI) was assessed in full expiration (SIN, normalized to aortic blood). Obtained metrics were compared between participants with CF and control participants. For participants with CF, MRI metrics were correlated with the standard lung clearance index (LCI) and PFT. Mann-Whitney U tests and Spearman correlation were used for statistical analysis. Results Twenty participants with CF (mean age, 17 years ± 9 [standard deviation]; 12 men) and 10 healthy control participants (24 years ± 8; five men) were included. IQRN was higher for participants with CF than for control participants (mean, 0.66 ± 0.16 vs 0.50 ± 0.04, respectively; P = .007). In the 20 participants with CF, IQRN correlated with obstruction markers forced expiratory volume in 1 second-to-forced vital capacity ratio (r = -0.70; 95% confidence interval [CI]: -0.92, -0.28; P < .001), mean expiratory flow 25% (r = 0.78; 95% CI: -0.95, -0.39; P < .001), and with the ventilation inhomogeneity parameter LCI (r = 0.90; 95% CI: 0.69, 0.96; P < .001). Mean SIN in full expiration was lower in participants with CF than in control participants (0.34 ± 0.08 vs 0.39 ± 0.03, respectively; P = .03). Conclusion Three-dimensional ultrashort echo time MRI in the lungs allowed for functional imaging of ventilation inhomogeneity within a few breath holds in patients with cystic fibrosis. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Wielputz in this issue.

Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory disorder of the skeletal system of yet unknown etiology. Patients present with local bone pain and inflammation and - to our experience - often suffer from functional impairment with significant disabilities of daily life. The objective of this study was to assess physical activity, fitness and health-related quality of life (HRQOL) in adolescents with established diagnosis of CNO versus healthy controls (HC).15 patients with CNO and 15 age and gender matched HC aged 13-18 years, completed questionnaires, performed an incremental exercise test with gas exchange measures up to voluntary fatigue and wore an accelerometer over 7 days at home to assess physical activity behavior.At the time of assessment, 5 CNO patients were in clinical, one in radiological and 5 in clinical and radiological remission. 7 did not receive any therapy at the time of assessment. The results of the exercise test and of the accelerometry did not show any significant difference between CNO and HC. However, reported sports participation was lower in patients with CNO and PedsQL3.0 and 4.0 showed significant lower values in most of the scores indicating reduced HRQOL.Although most CNO patients showed a favorable course of disease without any relevant differences in objective measurements of physical activity and fitness versus HC at the time of assessment, questionnaires revealed perceived limitations. Further studies are needed to measure HRQOL and to validate questionnaires in patients with CNO against objective measures including more participants with a higher level of disease activity.

Summary Background As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs. Methods We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy. Eligible patients had cystic fibrosis, were older than 10 years, and had newly diagnosed diabetes. We used a central randomisation schedule derived from a Geigy random number table to assign patients 1:1 to receive insulin or repaglinide, stratified by sex and age (10–15 years or >15 years). The primary outcome was glycaemic control assessed by mean change in HbA 1c concentration from baseline after 24 months of treatment. Differences between groups were assessed by linear models. The primary and safety analyses were done in the modified intention-to-treat population (including patients who stopped treatment early because of lack of efficacy). This trial is registered with ClinicalTrials.gov, number NCT00662714. Findings We enrolled 34 patients in the repaglinide group and 41 in the insulin group, of whom 30 and 37, respectively, were included in the analyses. At 24 months, glycaemic control was similar in the repaglinide and insulin groups (mean change in HbA 1c concentration from baseline 0·2% [SD 0·7%], 1·7 mmol/mol [8·1 mmol/mol] with repaglinide vs −0·2% [1·3%], −2·7 mmol/mol, [14·5 mmol/mol] with insulin; mean difference between groups −0·4%, (95% CI −1·1 to 0·2 [−4·4 mmol/mol, −11·5 to 2·7], p=0·15). The most frequent adverse events were pulmonary events (43 [40%] of 107 in the repaglinide group and 60 [45%] of 133 in the insulin group), and the most frequent serious adverse events were pulmonary events leading to hospital admission (five [50%] of ten and seven [54%] of 13, respectively). Interpretation Repaglinide for glycaemic control in patients with cystic-fibrosis-related diabetes is as efficacious and safe as insulin. Funding Mukoviszidose eV, Vaincre la Mucoviscidose, ABCF Association, and Novo Nordisk.

Purpose This study aimed to assess the feasibility of Self-gated Non–Contrast-Enhanced Functional Lung (SENCEFUL) MRI for detection of pulmonary perfusion deficits in patients with cystic fibrosis. Methods Twenty patients with cystic fibrosis and 20 matched healthy controls underwent SENCEFUL-MRI at 1.5 T with reconstruction of perfusion and perfusion phase maps (i.e. comparable to pulse wave delays). Four blinded readers rated both types of maps separately followed by simultaneous assessment thereof. Perfusion phase data was plotted in histograms and a Peak-to-Offset ratio was calculated for comparison to subjective scoring and correlation (Spearman) to lung function parameters. Sensitivity, specificity and positive and negative predictive values were calculated for subjective scoring and Peak-to-Offset ratios. Intraclass correlation (ICC) was used to assess the interrater agreement. Results Readers attributed pathological ratings 2.2–3.5 times more frequently to the CF-group. The sensitivity with regard to a correct assignment to CF was similar between ratings (perfusion only vs. perfusions phase only vs. simultaneous assessment: 0.54−0.56), while specificity increased from 0.75 to 0.85 for simultaneous assessment. ICC was 0.77−0.84 for subjective scoring. ROC-analysis of Peak-to-Offset ratios on a mean per-subject basis revealed a sensitivity of 0.75 and specificity of 0.85 (PPV 0.83, NPV 0.77). Functional pulmonary parameters indicative of bronchial obstruction and Peak-to-Offset ratios showed positive correlation (FEV1: 0.77; FEF75: 0.76). Conclusions SENCEFUL-MRI bears the potential for monitoring CF including disease-associated patterns of altered pulmonary perfusion. The proposed Peak-to-Offset ratio derived from pulmonary perfusion phase measurements could represent an objective future marker for perfusion impairment.

Purpose To assess the clinical feasibility of self-gated non-contrast-enhanced functional lung (SENCEFUL) magnetic resonance (MR) imaging for quantitative ventilation (QV) imaging in patients with cystic fibrosis (CF). Materials and Methods Twenty patients with CF and 20 matched healthy volunteers underwent functional 1.5-T lung MR imaging with the SENCEFUL imaging approach, in which a two-dimensional fast low-angle shot sequence is used with quasi-random sampling. The lungs were manually segmented on the ventilation-weighted images to obtain QV measurements, which were compared between groups. QV values of the patients were correlated with results of pulmonary function testing. Three radiologists rated the images for presence of ventilation deficits by means of visual inspection. Mann-Whitney U tests, receiver operating characteristic analyses, Spearman correlations, and Gwet agreement coefficient analyses were used for statistical analysis. Results QV of the entire lungs was lower for patients with CF than for control subjects (mean ± standard deviation, 0.09 mL/mL ± 0.03 vs 0.11 mL/mL ± 0.03, respectively; P = .007). QV ratios of upper to lower lung halves were lower in patients with CF than in control subjects (right, 0.84 ± 0.2 vs 1.16 ± 0.2, respectively [P.001]; left, 0.88 ± 0.3 vs 1.11 ± 0.1, respectively [P = .017]). Accordingly, ventilation differences between the groups were larger in the upper halves (Δ = 0.04 mL/mL, P ≤ .001-.002). QV values of patients with CF correlated with forced vital capacity (r = 0.7; 95% confidence interval [CI]: 0.21, 0.91), residual volume (static hyperinflation, r = -0.8; 95% CI: -0.94, 0.42), and forced expiratory volume in 1 second (airway obstruction, r = 0.7; 95% CI: 0.21, 0.91). Disseminated small ventilation deficits were the most frequent involvement pattern, present in 40% of the functional maps in CF versus 8% in the control subjects (P.001). Conclusion SENCEFUL MR imaging is feasible for QV assessment. Less QV, especially in upper lung parts, and correlation to vital capacity and to markers for hyperinflation and airway obstruction were found in patients with CF.

The objective of this document was to standardise published cardiopulmonary exercise testing (CPET) protocols for improved interpretation in clinical settings and multicentre research projects. This document: 1) summarises the protocols and procedures used in published studies focusing on incremental CPET in chronic lung conditions; 2) presents standard incremental protocols for CPET on a stationary cycle ergometer and a treadmill; and 3) provides patients' perspectives on CPET obtained through an online survey supported by the European Lung Foundation. We systematically reviewed published studies obtained from EMBASE, Medline, Scopus, Web of Science and the Cochrane Library from inception to January 2017. Of 7914 identified studies, 595 studies with 26 523 subjects were included. The literature supports a test protocol with a resting phase lasting at least 3 min, a 3-min unloaded phase, and an 8- to 12-min incremental phase with work rate increased linearly at least every minute, followed by a recovery phase of at least 2-3 min. Patients responding to the survey (n=295) perceived CPET as highly beneficial for their diagnostic assessment and informed the Task Force consensus. Future research should focus on the individualised estimation of optimal work rate increments across different lung diseases, and the collection of robust normative data. Funding was received from the European Respiratory Society, grant number TF-2016-12. The research of Jana De Brandt is financially supported by FWO (grant #11B4718N) and the research of Chris Burtin is partially sponsored by Limburg Kankerfonds. Funding information for this article has been deposited with the Crossref Funder Registry. Hebestreit, H (reprint author), Univ Kinderklin, ERN LUNG, Josef Schneider Str 2, D-97080 Wurzburg, Germany. hebestreit@uni-wuerzburg.de

INTRODUCTION Exercise ventilation efficiency index in cardiopulmonary exercise testing (CPET) is elevated in patients with heart failure providing useful information on disease progression and prognosis. Few data, however, exist for ventilation efficiency index among cystic fibrosis (CF) patients. AIMS To assess ventilation efficiency index (ΔVE/ΔVCO2 or V'E/V'CO2 slope) and intercept of ventilation (VE-intercept) in CF patients with mild, moderate, and severe cystic fibrosis (CF) lung disease. To assess possible correlations with ventilation inhomogeneity and structural damages as seen on high resolution computed tomography (HRCT). METHODS CF patients with mild (FEV1 > 80%, n = 47), moderate (60%