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RATIONALE: New treatment strategies are needed to improve airway clearance and reduce the morbidity and the time burden associated with cystic fibrosis (CF). OBJECTIVES: To determine whether long-term treatment with inhaled mannitol, an osmotic agent, improves lung function and morbidity. METHODS: Double-blind, randomized, controlled trial of inhaled mannitol, 400 mg twice a day (n = 192, 'treated' group) or 50 mg twice a day (n = 126, 'control' group) for 26 weeks, followed by 26 weeks of open-label treatment. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was absolute change in FEV(1) from baseline in treated versus control groups, averaged over the study period. Secondary endpoints included other spirometric measurements, pulmonary exacerbations, and hospitalization. Clinical, microbiologic, and laboratory safety were assessed. The treated group had a mean improvement in FEV(1) of 105 ml (8.2% above baseline). The treated group had a relative improvement in FEV(1) of 3.75% (P = 0.029) versus the control group. Adverse events and sputum microbiology were similar in both treatment groups. Exacerbation rates were low, but there were fewer in the treated group (hazard ratio, 0.74; 95% confidence interval, 0.42-1.32; P = 0.31), although this was not statistically significant. In the 26-week open-label extension study, FEV(1) was maintained in the original treated group, and improved in the original control group to the same degree. CONCLUSIONS: Inhaled mannitol, 400 mg twice a day, resulted in improved lung function over 26 weeks, which was sustained after an additional 26 weeks of treatment. The safety profile was also acceptable, demonstrating the potential role for this chronic therapy for CF. Clinical trial registered with www.clinicaltrials.gov (NCT 00630812). [ABSTRACT FROM AUTHOR]

Background: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterised by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes., Methods: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, forced expiratory volume in 1 s (FEV 1 )) were collected from 19 countries using the European Reference Network's ERN-LUNG international PCD Registry. Genetic data were evaluated according to American College of Medical Genetics and Genomics guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV 1 ., Results: The study included 1236 individuals carrying 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%, range 47-100%) and laterality defects (mean 42%, range 28-69%) varied widely among countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV 1 z-score (-1.66). Median FEV 1 z-scores were significantly lower in CCNO (-3.26), CCDC39 (-2.49) and CCDC40 (-2.96) variant groups, while the FEV 1 z-score reductions were significantly milder in DNAH11 (-0.83) and ODAD1 (-0.85) variant groups compared to the whole PCD cohort., Conclusion: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of the genetic epidemiology of PCD and indicates that the genetic variant can predict diagnostic and phenotypic features such as the course of lung function., Competing Interests: Conflict of interest: The authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Rationale: Bronchiectasis is a pathological dilatation of the bronchi in the respiratory airways associated with environmental or genetic causes (e.g., cystic fibrosis, primary ciliary dyskinesia, and primary immunodeficiency disorders), but most cases remain idiopathic. Objectives: To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary Pseudomonas aeruginosa infection. Methods: DNA was analyzed by next-generation or targeted Sanger sequencing. RNA was analyzed by quantitative PCR and single-cell RNA sequencing. Patient-derived cells, cell cultures, and secretions (mucus, saliva, seminal fluid) were analyzed by Western blotting and immunofluorescence microscopy, and mucociliary activity was measured. Blood serum was analyzed by electrochemiluminescence immunoassay. Protein structure and proteomic analyses were used to assess the impact of a disease-causing founder variant. Measurements and Main Results: We identified biallelic pathogenic variants in WAP four-disulfide core domain 2 ( WFDC2 ) in 11 individuals from 10 unrelated families originating from the United States, Europe, Asia, and Africa. Expression of WFDC2 was detected predominantly in secretory cells of control airway epithelium and also in submucosal glands. We demonstrate that WFDC2 is below the limit of detection in blood serum and hardly detectable in samples of saliva, seminal fluid, and airway surface liquid from WFDC2 -deficient individuals. Computer simulations and deglycosylation assays indicate that the disease-causing founder variant p.Cys49Arg structurally hampers glycosylation and, thus, secretion of mature WFDC2. Conclusions: WFDC2 dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways. A commercially available blood test combined with genetic testing allows its diagnosis.

Introduction: Nearly all patients with primary ciliary dyskinesia (PCD) report ear-nose-throat (ENT) symptoms. However, scarce evidence exists about how ENT symptoms relate to pulmonary disease in PCD. We explored possible associations between upper and lower respiratory disease among patients with PCD in a multicentre study., Methods: We included patients from the ENT Prospective International Cohort (EPIC-PCD). We studied associations of several reported ENT symptoms and chronic rhinosinusitis (defined using patient-reported information and examination findings) with reported sputum production and shortness of breath, using ordinal logistic regression. In a subgroup with available lung function results, we used linear regression to study associations of chronic rhinosinusitis and forced expiratory volume in 1 s (FEV 1 ) accounting for relevant factors., Results: We included 457 patients (median age 15 years, interquartile range 10-24 years; 54% males). Shortness of breath associated with reported nasal symptoms and ear pain of any frequency, often or daily hearing problems, headache when bending down (OR 2.1, 95% CI 1.29-3.54) and chronic rhinosinusitis (OR 2.3, 95% CI 1.57-3.38) regardless of polyp presence. Sputum production associated with daily reported nasal (OR 2.2, 95% CI 1.20-4.09) and hearing (OR 2.0, 95% CI 1.10-3.64) problems and chronic rhinosinusitis (OR 2.1, 95% CI 1.48-3.07). We did not find any association between chronic rhinosinusitis and FEV 1 ., Conclusion: Reported upper airway symptoms and signs of chronic rhinosinusitis associated with reported pulmonary symptoms, but not with lung function. Our results emphasise the assessment and management of upper and lower respiratory disease as a common, interdependent entity among patients with PCD., Competing Interests: Conflict of interest: J-F. Papon reports personal fees from Sanofi, GSK, Medtronic and ALK, outside the submitted work. Conflict of interest: M. Alexandru received personal fees from Sanofi and ALK outside the submitted work. Conflict of interest: M. Boon reports grants from Forton grant (King Baudouin Foundation) 2020-J1810150-217926 for cystic fibrosis research and personal fees from Vertex outside the submitted work. Conflict of interest: N. Lorent received honoraria to her institution from GSK, INSMED and AN2 Therapeutics outside the submitted work, and a travel grant from Pfizer. Conflict of interest: J. Roehmel received grants, clinical study reimbursement from Vertex, INSMED, Medical Research Council/UK, BMBF and Mukoviszidose Institut, outside the submitted work. Conflict of interest: The other authors report no competing interests., (Copyright ©The authors 2024.)

Background: Consistent use of reliable and clinically appropriate outcome measures is a priority for clinical trials, with clear definitions to allow comparability. We aimed to develop a core outcome set (COS) for pulmonary disease interventions in primary ciliary dyskinesia (PCD)., Methods: A multidisciplinary international PCD expert panel was set up. A list of outcomes was created based on published literature. Using a modified three-round e-Delphi technique, the panel was asked to decide on relevant end-points related to pulmonary disease interventions and how they should be reported. First, inclusion of an outcome in the COS was determined. Second, the minimum information that should be reported per outcome. The third round finalised statements. Consensus was defined as ≥80% agreement among experts., Results: During the first round, experts reached consensus on four out of 24 outcomes to be included in the COS. Five additional outcomes were discussed in subsequent rounds for their use in different subsettings. Consensus on standardised methods of reporting for the COS was reached. Spirometry, health-related quality-of-life scores, microbiology and exacerbations were included in the final COS., Conclusion: This expert consensus resulted in a COS for clinical trials on pulmonary health among people with PCD., Competing Interests: Conflict of interest: S. Aliberti has received fees outside of this work from Insmed, Zambon, AstraZeneca, CSL Behring GmbH, Grifols, Fondazione Internazionale MENARINI, MSD Italia S.r.l., Brahms, Physioassist SAS and GlaxoSmithKline. S.D. Dell has received grants outside of this work from Boehringer Ingelheim, Vertex and Sanofi, and she owns the copyright to the PCD-QOL Questionnaires. T.W. Ferkol has received consulting fees from Translate Bio and Arrowhead Pharmaceuticals. R.A. Athanazio has received personal fees outside of this work from Astrazeneca, Chiesi, GSK, Omron, Sanofi, Vertex and Zambon. K.G. Nielsen is part of the European Reference Network on respiratory diseases (ERN-LUNG) and director of PCD CTN. F.C. Ringshauen has received fees outside of this work from AstraZeneca, Boehringer Ingelheim, Celtaxsys, Corbus, Insmed, Novartis, Parion, University of Dundee, Vertex and Zambon. M. Shteinberg has received consulting fees from AstraZeneca, Boehringer Ingelheim, Dexcel, Kamada, Synchrony Medical, Trumed and Zambon. J.D. Chalmers has received grants outside of this work from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Gilead Sciences, Grifols, Insmed, Janssen, Novartis, Pfizer and Zambon; and is an associate editor of this journal. The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Background: Patients with COPD are at high risk of lung cancer developing, but no validated predictive biomarkers have been reported to identify these patients. Molecular profiling of exhaled breath by electronic nose (eNose) technology may qualify for early detection of lung cancer in patients with COPD., Research Question: Can eNose technology be used for prospective detection of early lung cancer in patients with COPD?, Study Design and Methods: BreathCloud is a real-world multicenter prospective follow-up study using diagnostic and monitoring visits in day-to-day clinical care of patients with a standardized diagnosis of asthma, COPD, or lung cancer. Breath profiles were collected at inclusion in duplicate by a metal-oxide semiconductor eNose positioned at the rear end of a pneumotachograph (SpiroNose; Breathomix). All patients with COPD were managed according to standard clinical care, and the incidence of clinically diagnosed lung cancer was prospectively monitored for 2 years. Data analysis involved advanced signal processing, ambient air correction, and statistics based on principal component (PC) analysis, linear discriminant analysis, and receiver operating characteristic analysis., Results: Exhaled breath data from 682 patients with COPD and 211 patients with lung cancer were available. Thirty-seven patients with COPD (5.4%) demonstrated clinically manifest lung cancer within 2 years after inclusion. Principal components 1, 2, and 3 were significantly different between patients with COPD and those with lung cancer in both training and validation sets with areas under the receiver operating characteristic curve of 0.89 (95% CI, 0.83-0.95) and 0.86 (95% CI, 0.81-0.89). The same three PCs showed significant differences (P < .01) at baseline between patients with COPD who did and did not subsequently demonstrate lung cancer within 2 years, with a cross-validation value of 87% and an area under the receiver operating characteristic curve of 0.90 (95% CI, 0.84-0.95)., Interpretation: Exhaled breath analysis by eNose identified patients with COPD in whom lung cancer became clinically manifest within 2 years after inclusion. These results show that eNose assessment may detect early stages of lung cancer in patients with COPD., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: Otologic disease is common among people with primary ciliary dyskinesia (PCD), yet little is known about its spectrum and severity., Objective: To characterize otologic disease among participants with PCD using data from the Ear-Nose-Throat Prospective International Cohort., Design, Setting, and Participants: This cross-sectional analysis of baseline cohort data from February 2020 through July 2022 included participants from 12 specialized centers in 10 countries. Children and adults with PCD diagnoses; routine ear, nose, and throat examinations; and completed symptom questionnaires at the same visit or within 2 weeks were prospectively included., Exposures: Potential risk factors associated with increased risk of ear disease., Main Outcomes and Measures: The prevalence and characteristics of patient-reported otologic symptoms and findings from otologic examinations, including potential factors associated with increased risk of ear inflammation and hearing impairment., Results: A total of 397 individuals were eligible to participate in this study (median [range] age, 15.2 [0.2-72.4] years; 186 (47%) female). Of the included participants, 204 (51%) reported ear pain, 110 (28%) reported ear discharge, and 183 (46%) reported hearing problems. Adults reported ear pain and hearing problems more frequently when compared with children. Otitis media with effusion-usually bilateral-was the most common otoscopic finding among 121 of 384 (32%) participants. Retracted tympanic membrane and tympanic sclerosis were more commonly seen among adults. Tympanometry was performed for 216 participants and showed pathologic type B results for 114 (53%). Audiometry was performed for 273 participants and showed hearing impairment in at least 1 ear, most commonly mild. Season of visit was the strongest risk factor for problems associated with ear inflammation (autumn vs spring: odds ratio, 2.40; 95% CI, 1.51-3.81) and age 30 years and older for hearing impairment (41-50 years vs ≤10 years: odds ratio, 3.33; 95% CI, 1.12-9.91)., Conclusion and Relevance: In this cross-sectional study, many people with PCD experienced ear problems, yet frequency varied, highlighting disease expression differences and possible clinical phenotypes. Understanding differences in otologic disease expression and progression during lifetime may inform clinical decisions about follow-up and medical care. Multidisciplinary PCD management should be recommended, including regular otologic assessments for all ages, even without specific complaints.

Esophageal atresia (EA) is a rare birth defect in which respiratory tract disorders are a major cause of morbidity. It remains unclear whether respiratory tract disorders are in part caused by alterations in airway epithelial cell functions such as the activity of motile cilia. This can be studied using airway epithelial cell culture models of patients with EA. Therefore, the aim of this study was to evaluate the feasibility to culture and functionally characterize motile cilia function in the differentiated air-liquid interface cultured airway epithelial cells and 3D organoids derived from nasal brushings and bronchoalveolar lavage (BAL) fluid from children with EA. We demonstrate the feasibility of culturing differentiated airway epithelia and organoids of nasal brushings and BAL fluid of children with EA, which display normal motile cilia function. EA patient-derived airway epithelial cultures can be further used to examine whether alterations in epithelial functions contribute to respiratory disorders in EA.

Background: Sinonasal symptoms are a common feature of primary ciliary dyskinesia (PCD); however, literature about their severity and frequency, particularly during the life course, is scarce. Using baseline data from the Ear, nose and throat (ENT) Prospective International Cohort of PCD patients, we describe sinonasal disease in PCD., Methods: We included participants who had a routine sinonasal examination during which they completed a symptoms questionnaire. We compared frequency of reported symptoms and examination findings among children and adults, and identified characteristics potentially associated with higher risk of sinonasal disease using ordinal regression., Results: 12 centres contributed 384 participants; median age was 16 years (IQR 9-22), and 54% were male. Chronic nasal problems were the most common feature, reported by 341 (89%). More adults (33; 24%) than children (10; 4%) described hyposmia. Quality of life was moderately affected by rhinosinusitis among 136 participants with completed SNOT-22 questionnaires (median score 31; IQR 23-45). Examinations revealed nasal polyps among 51 of 345 participants (15%) and hypertrophic inferior nasal turbinates among 127 of 341 participants (37%). Facial pain was detected in 50 of 342 participants (15%). Nasal polyps, hypertrophic turbinates, deviated septum and facial pain were found more commonly in adults than children. The only characteristic associated with higher risk of sinonasal disease was age 10 years and older., Conclusions: Based on our findings, regular sinonasal examinations are relevant for patients with PCD of all ages. There is a need for improved management of sinonasal disease supported by evidence-based guidelines., Competing Interests: Conflict of interest: P. Latzin received grants or honoraria for participation in data safety monitoring boards or advisory boards from Vertex, Vifor, OM Pharma, Polyphor, Santhera (DMC) and Sanofi Aventis within the last 36 months. J. Roehmel received grants and clinical study remuneration from Vertex, INSMED, Medical Research Council/UK, BMBF and Mukoviszidose Institut. All other authors have nothing to declare., (Copyright ©The authors 2023.)

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane conductance regulator modulator, which has shown efficacy in CF patients (≥6 years) with ≥1 Phe508del mutation and a minimal function mutation. In October 2019, ETI became available on compassionate use basis for Dutch CF patients with severe lung disease. Our objective was to investigate safety and efficacy of ETI in this patient group in a real-life setting. A multicenter longitudinal observational study was conducted to examine changes in FEV 1 , BMI, and adverse events at initiation and 1, 3, 6, and 12 months after starting ETI. The number of exacerbations was recorded in the 12 months before and the 12 months after ETI treatment. Patients eligible for compassionate use had a FEV 1 <40% predicted. Wilcoxon signed-rank test analyzed changes over time. Twenty subjects were included and followed up for up to 12 months after starting ETI. Treatment was well tolerated with mild side effects reported, namely, rash (15%) and stomach ache (20%) with 80% resolving within 1 month. Mean absolute increase of FEV 1 was 11.8/13.7% (p ≤ .001) and BMI was 0.49/1.87 kg/m 2 (p < .001-0.02) after 1/12 months, respectively. In comparison to the number of exacerbations pretrial, there was a marked reduction in exacerbations after initiation. Our findings show long-term effects of treatment with ETI in patients with severe CF lung disease in a real-life setting. Treatment with ETI is associated with increased lung function and BMI, less exacerbations, and only mild side effects., (© 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Primary ciliary dyskinesia (PCD) presents with symptoms early in life and the disease course may be progressive, but longitudinal data on lung function are scarce. This multinational cohort study describes lung function trajectories in children, adolescents and young adults with PCD. We analysed data from 486 patients with repeated lung function measurements obtained between the age of 6 and 24 years from the International PCD Cohort and calculated z-scores for forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC ratio using the Global Lung Function Initiative 2012 references. We described baseline lung function and change of lung function over time and described their associations with possible determinants in mixed-effects linear regression models. Overall, FEV 1 , FVC and FEV 1 /FVC z-scores declined over time (average crude annual FEV 1 decline was -0.07 z-scores), but not at the same rate for all patients. FEV 1 z-scores improved over time in 21% of patients, remained stable in 40% and declined in 39%. Low body mass index was associated with poor baseline lung function and with further decline. Results differed by country and ultrastructural defect, but we found no evidence of differences by sex, calendar year of diagnosis, age at diagnosis, diagnostic certainty or laterality defect. Our study shows that on average lung function in PCD declines throughout the entire period of lung growth, from childhood to young adult age, even among patients treated in specialised centres. It is essential to develop strategies to reverse this tendency and improve prognosis., Competing Interests: Conflict of interest: P. Latzin reports grants from Vertex and Vifor, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Vertex, Vifor and OM Pharma, and participation on a data safety monitoring board or advisory board for Polyphor, Santhera (DMC), Vertex, OM Pharma and Vifor. M.R. Loebinger reports consultancy fees from Insmed, AstraZeneca and Grifols, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Insmed and Grifols. The remaining authors disclose no potential conflicts of interest., (Copyright ©The authors 2022.)

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients., Competing Interests: Conflict of interest: J. Raidt declares grants for Clinical Research Unit “Male Germ Cells: from Genes to Function” (CRU 326) – Subproject RA3522/1-1 from the Deutsche Forschungsgemeinschaft, in connection with the present manuscript; that they are a holder of patent WO 2020/165352 A1 (Treatment of ciliopathies); and an unpaid role as a Deputy Director of PCD-CTN. Conflict of interest: B. Maitre declares unpaid roles as a Deputy Director of PCD-CTN and as a member of the scientific committee of RADICO PCD. Conflict of interest: P. Pennekamp declares research grants to their institution from NEOCYST (BMBF, 01GM1903A); and that they are a holder of patent WO 2020/165352 A1 (Treatment of ciliopathies). Conflict of interest: M. Armengot declares research grant FIS PI19/00949 from Instituto de Salud Carlos III, in connection with the present manuscript. Conflict of interest: M. Boon declares Forton grant 2020-J1810150-217926 from the King Baudouin Foundation, in the 36 months prior to manuscript submission. Conflict of interest: S.B. Carr declares grants to their institution from the National Institute of Health Research (Programme Development Grant 202952; Health Technology Assessment Grant NIHR121889; HTA grant 14/22/23; NIHR RfPb QOL-PCD; NIHR RfPb VALU- CF); consulting fees paid to their institution by Vertex Pharmaceuticals; personal and institutional honoraria from Chiesi Pharmaceuticals; payment to their institution for participation on a Data Safety Monitoring Board or Advisory Board from Profile Pharma, Pharmaxis and Vertex Pharmaceuticals, all in the 36 months prior to manuscript submission; and that they are Chair of the UK CF Registry Steering Committee (payment to their institution) and of the European CF Society Patient Registry Scientific Committee (unpaid). Conflict of interest: M.A. Mall declares research grant 82DZL009B1 from the German Federal Ministry of Education and Research, in connection with the present manuscript. Conflict of interest: M. Narayanan declares that they have been a co-applicant on the National Institute for Health Research – Research for patient benefit (NIHR –RfPB) grant for ‘Parent reported quality of life measures for young children with primary ciliary dyskinesia (QOL-PCD study)’ in the 36 months prior to manuscript submission; and that they are a member of the British Paediatric Respiratory Society executive committee and the British Thoracic Society standards of care committee. Conflict of interest: P. Pohunek declares research grants from the Ministry of Health of the Czech Republic (NV19-07-00210) and Charles University Grant Agency (670119P) in connection with the present manuscript. Conflict of interest: S. Range declares an unpaid role as medical advisor to PCD Support. Conflict of interest: F.C. Ringshausen declares grants to their institution from the German Center for Lung Research (DZL), the German Center for Infection Research (DZIF), IMI (EU/EFPIA), iABC Consortium (including Alaxia, Basilea, Novartis and Polyphor), Mukoviszidose Institute, Novartis, Insmed Germany, Grifols, Bayer and InfectoPharm; consulting fees from Parion, Grifols, Zambon, Insmed and the Helmholtz-Zentrum für Infektionsforschung; payments or honoraria from I!DE Werbeagentur GmbH; Interkongress GmbH; AstraZeneca; Insmed; Grifols and Universitätsklinikum Frankfurt am Main; payment to their institution for expert testimony at the Social Court Cologne; support for attending meetings from German Kartagener Syndrome and PCD PAG and Mukoviszidose e.V; participation on a Data Safety Monitoring Board or Advisory Board for Insmed, Grifols and Shionogi; fees for clinical trial participation paid to their institution by Abbvie, AstraZeneca, Boehringer Ingelheim, Celtaxsys, Corbus, Insmed, Novartis, Parion, University of Dundee, Vertex and Zambon; and honorary roles as Coordinator of the ERN-LUNG Bronchiectasis Core Network, Chair of the German Bronchiectasis Registry PROGNOSIS, Member of the SteerCo of the European Bronchiectasis Registry EMBARC, Member of the SteerCo of the European NTM Registry EMBARC-NTM, Co-Speaker of the Medical Advisory Board of the German Kartagener Syndrome and PCD PAG, Speaker of the Respiratory Infections and TB group of the German Respiratory Society (DGP), Speaker of the Cystic Fibrosis group of German Respiratory Society (DGP), PI of the DZL, member of the protocol review committee of the PCD-CTN and Member of Physician Association of the German Cystic Fibrosis PAG. Conflict of interest: J. Roehmel declares payments or honoraria from Vertex Pharmaceuticals, in the 36 months prior to manuscript submission. Conflict of interest: G. Thouvenin declares unpaid membership of the RADICO PCD scientific committee. Conflict of interest: H. Omran declares grants for Clinical Research Unit “Male Germ Cells: from Genes to Function” (CRU 326) – Subproject RA3522/1-1 from the Deutsche Forschungsgemeinschaft, from Interdisziplinaeres Zentrum für Klinische Forschung Muenster (Om2/009/12; Om2/015/16; Om2/010/20), from BESTCILIA (EU FP7 GA 305404) and from Registry Warehouse (Horizon2020 GA 777295), all in connection with the present manuscript; in addition to grants to their institution from LYSOCIL (Horizon2020 GA n°811087) NEOCYST (BMBF, 01GM1903A) and Transkripttherapie für primäre ziliäre Dyskinesien (Zentrales Innovationsprojekt Mittelstand (ZIM), BMWi; ZF-4610102SK8), in the 36 months prior to manuscript submission; that they are a holder of patent WO 2020/165352 A1 (Treatment of ciliopathies); and unpaid roles as Head of the ERN-LUNG PCD Core and as a member of the PCD Family Support Group medical advisory board. Conflict of interest: K.G. Nielsen declares funding for the present manuscript from the Danish Children's Lung Foundation (Børnelungefonden); and an unpaid role as a Director of the PCD-CTN. Conflict of interest: All other authors declare no competing interests., (Copyright ©The authors 2022.)

Primary ciliary dyskinesia (PCD) is a heterogeneous disease, with impaired mucociliary clearance causing respiratory tract infections. A founding CCDC114 mutation has led to a relatively homogeneous and large Dutch PCD population in Volendam. Our aim was to describe their phenotype. Therefore, all Volendam PCD patients seen at the Amsterdam UMC were included in this study. Data were collected on lung function, microbiology, radiology, and ear-nose-throat (ENT) symptoms. A mixed effects model estimated lung function decline in %point per year (95% confidence interval [CI]). Thirty-three (60%) out of approximately 56 Volendam PCD patients were treated at our center and included in this study. Only 30% of patients had situs inversus. FEV 1 declined in children (-1.43%/year, CI: -1.80/-1.05), but not in adults (0.01%/year, CI: -0.36/0.38). Pseudomonas aeruginosa was cultured in 21% of children and 60% of adults, respectively. Patients who have been infected at some point with P. aeruginosa had a steeper decline in FEV 1 as compared to patients that have never been infected. Neonatal symptoms (79%) and ENT problems (94%) were common; fertility issues however, were not (11%) common. Compared to other PCD cohorts, the Volendam/CCDC114 patients have a moderately severe phenotype with lung function decline predominantly occurring in childhood., (© 2022 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

Background: With the continued advancement of CFTR modulator therapies there is likely to be a burgeoning population of adult cystic fibrosis (CF) patients unable to expectorate sputum. Consequently, the detection and surveillance of pulmonary colonisation, previously reliant on sputum culture, needs re-examining. We hypothesised that cough swabs analysed with culture-independent analysis of the 16S gene could serve as a surrogate for colonisation of the lower airways., Methods: Cough swabs and sputum samples were prospectively collected from consecutive adults and children with CF across two sites at regular outpatient appointments. Conventional culture analysis and next generation sequencing were used to compare paired same day samples., Results: Twenty-two adults and 8 paediatric patients provided 75 paired cough swabs and sputum samples. Alpha diversity measures showed increased bacterial richness in sputum, while evenness and Simpson's diveristy index were higher in cough swabs. Within each sampling technique, microbial composition showed greater similarity when considering intra-patient variation. Poor concordance was observed between culture independent cough swabs and culture dependent/independent sputum analysis for specific pathogens, with cough swabs unable to accurately identify commonly associated CF pathogens (AUROCC range: 0.51 to 0.64)., Conclusion: Culture independent analysis of cough swabs provides an inaccurate diagnosis of lower respiratory tract colonisation and should not be used as a diagnostic test in patients with CF., Competing Interests: Declaration of Competing Interest Dr Dominic Fenn has nothing to disclose Dr Abdel-Aziz has nothing to disclose Dr Brinkman has nothing to disclose Ms Kos has nothing to disclose, (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Pseudomonas aeruginosa (PA) is an important respiratory pathogen for cystic fibrosis (CF) patients. Routine microbiology surveillance is time-consuming, and is best performed on expectorated sputum. As alternative, volatile organic compounds (VOCs) may be indicative of PA colonisation. In this study, we aimed to identify VOCs associated with PA in literature and perform targeted exhaled breath analysis to recognize PA positive CF patients non-invasively., Methods: This study consisted of 1) a literature review to select VOCs of interest, and 2) a cross-sectional CF study. Definitions used: A) PA positive, PA culture at visit/chronically; B) PA free, no PA culture in ≥12 months. Exhaled VOCs were identified via quadrupole MS. The primary endpoint was the area under the receiver operating characteristics curve (AUROCC) of individual VOCs as well as combined VOCs against PA culture., Results: 241 VOCs were identified in literature, of which 56 were further evaluated, and 13 could be detected in exhaled breath in our cohort. Exhaled breath of 25 pediatric and 28 adult CF patients, PA positive (n=16) and free (n=28) was available. 3/13 VOCs were significantly (p<0.05) different between PA groups in children; none were in adults. Notably, a composite model based on 5 or 1 VOC(s) showed an AUROCC of 0.86 (CI 0.71-1.0) and 0.87 (CI 0.72-1.0) for adults and children, respectively., Conclusions: Targeted VOC analysis appears to discriminate children and adults with and without PA positive cultures with clinically acceptable sensitivity values., Competing Interests: Declaration of Competing Interests AHM and PB are supported by an innovation grant from Vertex Pharmaceuticals B.V. PJS is scientific advisor and has a formally inconsiderable interest in the SME Breathomix AHM reports grants and personal fees from GSK, Boehringer Ingelheim, and AstraZeneca, and grants from Chiesi, outside the submitted work., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: Primary ciliary dyskinesia (PCD) is a rare, genetic, multiorgan disease with an estimated prevalence of 1 in 10 000. It affects mainly the upper and lower airways due to impaired mucociliary clearance. Almost all patients have sinonasal or otologic (ear-nose-throat, ENT) problems, although the ENT clinical phenotype may present great variability. Despite that, data on PCD ENT manifestations are scarce and based on small single-centre studies. To date, we know little about the spectrum and severity of PCD ENT disease, its association with lung disease, its course over life and its determinants of prognosis.This study protocol describes the aims and methods of the first prospective, observational, multinational cohort study focusing on ENT disease in patients with PCD., Methods and Analysis: The ENT prospective international cohort of patients with PCD (EPIC-PCD) is a prospective standardised observational clinical cohort set up as a multinational multicentre study, embedded into routine patient care. It aims to longitudinally characterise ENT disease in patients with PCD and its association with lung disease, and to identify determinants of its prognosis. Patients of all ages, diagnosed with PCD who undergo an ENT clinical assessment at least once a year at one of the participating centres will be invited to participate. Collected data include diagnostic test results, results of ENT examinations, lung function measurements, information on management of ENT disease and patient-reported data on clinical symptoms and health-related quality of life (QoL). Data are collected using the standardised PCD-specific FOLLOW-PCD form and the validated QoL-PCD questionnaire., Ethics and Dissemination: The study has been reviewed and approved by the Human Research Ethics Committees at all participating centres, based on local legislation. The results of the study will be published in scientific journals, presented at scientific conferences and disseminated to participants and national patient organisations., Trial Registration: NCT04611516., Competing Interests: Competing interests: PL reports personal fees from Gilead, Novartis, OM pharma, Polyphor, Roche, Santhera, Schwabe, Vertex, Vifor and Zambon, and grants from Vertex, all outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy in which mucociliary clearance is disturbed by the abnormal motion of cilia or there is a severe reduction in the generation of multiple motile cilia. Lung damage ensues due to recurrent airway infections, sometimes even resulting in respiratory failure. So far, no causative treatment is available and treatment efforts are primarily aimed at improving mucociliary clearance and early treatment of bacterial airway infections. Treatment guidelines are largely based on cystic fibrosis (CF) guidelines, as few studies have been performed on PCD. In this review, we give a detailed overview of the clinical studies performed investigating PCD to date, including three trials and several case reports. In addition, we explore precision medicine approaches in PCD, including gene therapy, mRNA transcript and read-through therapy.

Background: Primary ciliary dyskinesia (PCD) is a heterogeneous inherited disorder caused by mutations in approximately 50 cilia-related genes. PCD genotype-phenotype relationships have mostly arisen from small case series because existing statistical approaches to investigating relationships have been unsuitable for rare diseases., Methods: We applied a topological data analysis (TDA) approach to investigate genotype-phenotype relationships in PCD. Data from separate training and validation cohorts included 396 genetically defined individuals carrying pathogenic variants in PCD genes. To develop the TDA models, 12 clinical and diagnostic variables were included. TDA-driven hypotheses were subsequently tested using traditional statistics., Results: Disease severity at diagnosis, measured by forced expiratory volume in 1 s (FEV 1 ) z-score, was significantly worse in individuals with CCDC39 mutations (compared to other gene mutations) and better in those with DNAH11 mutations; the latter also reported less neonatal respiratory distress. Patients without neonatal respiratory distress had better preserved FEV 1 at diagnosis. Individuals with DNAH5 mutations were phenotypically diverse. Cilia ultrastructure and beat pattern defects correlated closely to specific causative gene groups, confirming these tests can be used to support a genetic diagnosis., Conclusions: This large scale, multi-national study presents PCD as a syndrome with overlapping symptoms and variations in phenotype according to genotype. TDA modelling confirmed genotype-phenotype relationships reported by smaller studies ( e.g. FEV 1 worse with CCDC39 mutation) and identified new relationships, including FEV 1 preservation with DNAH11 mutations and diversity of severity with DNAH5 mutations., Competing Interests: Conflict of interest: B. Rubbo has nothing to disclose. Conflict of interest: M. Legendre has nothing to disclose. Conflict of interest: M.R. Fassad has nothing to disclose. Conflict of interest: E.G. Haarman has nothing to disclose. Conflict of interest: S. Best has nothing to disclose. Conflict of interest: I.C.M. Bon has nothing to disclose. Conflict of interest: J. Brandsma has nothing to disclose. Conflict of interest: P-R. Burgel reports personal fees for lectures and advisory board work from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Teva and Vertex, as well as personal fees for lectures from GSK, Pfizer and Zambon, outside the submitted work. Conflict of interest: G. Carlsson has nothing to disclose. Conflict of interest: S.B. Carr reports non-financial support and other (advisory board, lecture fee, travel, steering committee) from Vertex Pharmaceuticals, other (advisory board) from Profile Pharmaceuticals and other (lectures) from Teva Pharmaceuticals, as well as non-financial support and other (advisory board, travel, accommodation) from Chiesi Pharmaceuticals, outside the submitted work. Conflict of interest: M. Carroll has nothing to disclose. Conflict of interest: M. Edwards has nothing to disclose. Conflict of interest: E. Escudier has nothing to disclose. Conflict of interest: I. Honoré has nothing to disclose. Conflict of interest: D. Hunt has nothing to disclose. Conflict of interest: G. Jouvion has nothing to disclose. Conflict of interest: M.R. Loebinger reports personal fees for advisory board work and consultancy from AstraZeneca, Insmed, Polyphor, Bayer and Griffols, outside the submitted work. Conflict of interest: B. Maitre has nothing to disclose. Conflict of interest: D. Morris-Rosendahl has nothing to disclose. Conflict of interest: J-F. Papon has nothing to disclose. Conflict of interest: C.M. Parsons has nothing to disclose. Conflict of interest: M.P. Patel has nothing to disclose. Conflict of interest: N.S. Thomas has nothing to disclose. Conflict of interest: G. Thouvenin has nothing to disclose. Conflict of interest: W.T. Walker has nothing to disclose. Conflict of interest: R. Wilson has nothing to disclose. Conflict of interest: C. Hogg has nothing to disclose. Conflict of interest: H.M. Mitchison has nothing to disclose. Conflict of interest: J.S. Lucas has nothing to disclose. Conflict of interest: A. Shoemark has nothing to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Molecular profiling of exhaled breath by electronic nose (eNose) might be suitable as a noninvasive tool that can help in monitoring of clinically unstable COPD patients. However, supporting data are still lacking. Therefore, as a first step, this study aimed to determine the accuracy of exhaled breath analysis by eNose to identify COPD patients who recently exacerbated, defined as an exacerbation in the previous 3 months. Data for this exploratory, cross-sectional study were extracted from the multicentre BreathCloud cohort. Patients with a physician-reported diagnosis of COPD (n=364) on maintenance treatment were included in the analysis. Exacerbations were defined as a worsening of respiratory symptoms requiring treatment with oral corticosteroids, antibiotics or both. Data analysis involved eNose signal processing, ambient air correction and statistics based on principal component (PC) analysis followed by linear discriminant analysis (LDA). Before analysis, patients were randomly divided into a training (n=254) and validation (n=110) set. In the training set, LDA based on PCs 1-4 discriminated between patients with a recent exacerbation or no exacerbation with high accuracy (receiver operating characteristic (ROC)-area under the curve (AUC)=0.98, 95% CI 0.97-1.00). This high accuracy was confirmed in the validation set (AUC=0.98, 95% CI 0.94-1.00). Smoking, health status score, use of inhaled corticosteroids or vital capacity did not influence these results. Exhaled breath analysis by eNose can discriminate with high accuracy between COPD patients who experienced an exacerbation within 3 months prior to measurement and those who did not. This suggests that COPD patients who recently exacerbated have their own exhaled molecular fingerprint that could be valuable for monitoring purposes., Competing Interests: Conflict of interest: J.J.M.H. van Bragt reports an unrestricted research grant from Boehringer Ingelheim during the conduct of the study. Conflict of interest: P. Brinkman has nothing to disclose. Conflict of interest: R. de Vries is COO of and has a considerable interest in the start-up company Breathomix BV. Conflict of interest: S.J.H. Vijverberg has nothing to disclose. Conflict of interest: E.J.M. Weersink has nothing to disclose. Conflict of interest: E.G. Haarman has nothing to disclose. Conflict of interest: F.H.C. de Jongh has nothing to disclose. Conflict of interest: S. Kester has nothing to disclose. Conflict of interest: A. Lucas has nothing to disclose. Conflict of interest: J.C.C.M. in 't Veen reports faculty grants from Boehringer Ingelheim, Teva and Chiesi, and personal fees for an international advisory board from Sanofi, outside the submitted work. Conflict of interest: P.J. Sterk reports being scientific advisor to and having a formally inconsiderable interest in the start-up company Breathomix BV. Conflict of interest: E.H.D. Bel reports grants and personal fees from AstraZeneca, GSK, Novartis, and Teva, and personal fees from Sanofi/Regeneron, Boehringer Ingelheim, Vectura, and Sterna, outside the submitted work. Conflict of interest: A.H. Maitland-van der Zee reports personal fees for advisory boards from AstraZeneca and Boehringer Ingelheim, and unrestricted research grants from Boehringer Ingelheim and GSK, during the conduct of the study., (Copyright ©ERS 2020.)

Chest computed tomography (CT) is the gold standard for detecting structural abnormalities in patients with primary ciliary dyskinesia (PCD) such as bronchiectasis, bronchial wall thickening and mucus plugging. There are no studies on quantitative assessment of airway and artery abnormalities in children with PCD. The objectives of the present study were to quantify airway and artery dimensions on chest CT in a cohort of children with PCD and compare these with control children to analyse the influence of covariates on airway and artery dimensions. Chest CTs of 13 children with PCD (14 CT scans) and 12 control children were collected retrospectively. The bronchial tree was segmented semi-automatically and reconstructed in a three-dimensional view. All visible airway-artery (AA) pairs were measured perpendicular to the airway centre line, annotating per branch inner and outer airway and adjacent artery diameter and computing inner airway diameter/artery ratio (AinA ratio), outer airway diameter/artery ratio (AoutA ratio), wall thickness (WT), WT/outer airway diameter ratio (Awt ratio) and WT/artery ratio. In the children with PCD (38.5% male, mean age 13.5 years, range 9.8-15.3) 1526 AA pairs were measured versus 1516 in controls (58.3% male, mean age 13.5 years, range 8-14.8). AinA ratio and AoutA ratio were significantly higher in children with PCD than in control children (both p<0.001). Awt ratio was significantly higher in control children than in children with PCD (p<0.001). Our study showed that in children with PCD airways are more dilated than in controls and do not show airway wall thickening., Competing Interests: Conflict of interest: V. Ferraro has nothing to disclose. Conflict of interest: E-R. Andrinopoulou has nothing to disclose. Conflict of interest: A.M.M. Sijbring has nothing to disclose. Conflict of interest: E.G. Haarman has nothing to disclose. Conflict of interest: H.A.W.M. Tiddens reports unconditional research grants outside the submitted work from Roche, Novartis, CFF, Vertex, Chiesi, Vectura and Gilead; he has participated in the last 5 years in expert panels for Vertex and Gilead. In addition, Dr Tiddens has a patent licensed for the PRAGMA-CF scoring system. He heads the Erasmus MC–Sophia Children's Hospital core laboratory Lung Analysis. FLUIDDA has developed computational fluid dynamic modelling based on chest CTs obtained from Erasmus MC–Sophia for which royalties are received by Sophia Research BV. All financial aspects for the grants are handled by Sophia Research BV. Conflict of interest: M.W.H. Pijnenburg has nothing to disclose., (Copyright ©ERS 2020.)

Rationale: Severe acute asthma (SAA) can be fatal, but is often preventable. We previously observed in a retrospective cohort study, a three-fold increase in SAA paediatric intensive care (PICU) admissions between 2003 and 2013 in the Netherlands, with a significant increase during those years of numbers of children without treatment of inhaled corticosteroids (ICS)., Objectives: To determine whether steroid-naïve children are at higher risk of PICU admission among those hospitalised for SAA. Furthermore, we included the secondary risk factors tobacco smoke exposure, allergic sensitisation, previous admissions and viral infections., Methods: A prospective, nationwide multicentre study of children with SAA (2-18 years) admitted to all Dutch PICUs and four general wards between 2016 and 2018. Potential risk factors for PICU admission were assessed using logistic regression analyses., Measurements and Main Results: 110 PICU and 111 general ward patients were included. The proportion of steroid-naïve children did not differ significantly between PICU and ward patients. PICU children were significantly older and more exposed to tobacco smoke, with symptoms >1 week prior to admission. Viral susceptibility was not a significant risk factor for PICU admission., Conclusions: Children with SAA admitted to a PICU were comparable to those admitted to a general ward with respect to ICS treatment prior to admission. Preventable risk factors for PICU admission were >7 days of symptoms without adjustment of therapy and exposure to tobacco smoke. Physicians who treat children with asthma must be aware of these risk factors., Competing Interests: Conflict of interest: S.A. Boeschoten has nothing to disclose. Conflict of interest: A.L. Boehmer has nothing to disclose. Conflict of interest: P.J. Merkus reports grants from Chiesi Netherlands BV and Novartis Netherlands BV during the conduct of the study. Conflict of interest: J. van Rosmalen has nothing to disclose. Conflict of interest: J.C. de Jongste has nothing to disclose. Conflict of interest: P.L.A. Fraaij reports grants from EU FP7 PREPARE (#602525). Conflict of interest: R. Molenkamp has nothing to disclose. Conflict of interest: S.G. Heisterkamp has nothing to disclose. Conflict of interest: J.B. van Woensel has nothing to disclose. Conflict of interest: B. Kapitein has nothing to disclose. Conflict of interest: E.G. Haarman has nothing to disclose. Conflict of interest: R.M. Wösten-van Asperen has nothing to disclose. Conflict of interest: M.C. Kneyber has nothing to disclose. Conflict of interest: J. Lemson has nothing to disclose. Conflict of interest: S. Hartman has nothing to disclose. Conflict of interest: D.A. van Waardenburg has nothing to disclose. Conflict of interest: H.E. Bunker-Wiersma has nothing to disclose. Conflict of interest: C.M. Brouwer has nothing to disclose. Conflict of interest: B.E. van Ewijk has nothing to disclose. Conflict of interest: A.M. Landstra has nothing to disclose. Conflict of interest: M. Verwaal has nothing to disclose. Conflict of interest: A.A. Vaessen-Verberne has nothing to disclose. Conflict of interest: S. Hammer has nothing to disclose. Conflict of interest: C.M. Buysse reports grants from the AMMODO and SAB foundations outside the submitted work. Conflict of interest: M. de Hoog reports grants from the AMMODO and SAB foundations outside the submitted work., (Copyright ©ERS 2020.)

Background: Use of maintenance antibiotic therapy with the macrolide azithromycin is increasing in a number of chronic respiratory disorders including primary ciliary dyskinesia (PCD). However, evidence for its efficacy in PCD is lacking. We aimed to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in patients with PCD., Methods: The Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia (BESTCILIA) trial was a multicentre, double-blind, parallel group, randomised, placebo-controlled phase 3 trial done at 6 European PCD clinics (tertiary paediatric care centres and university hospitals in Denmark, Germany, Netherlands, Switzerland, and UK). Patients with a confirmed diagnosis of PCD, aged 7-50 years old, and predicted FEV 1 greater than 40% were recruited. Participants were randomly assigned (1:1), stratified by age and study site, via a web-based randomisation system to azithromycin 250 mg or 500 mg as tablets according to bodyweight (

Background: Lung resection is a controversial and understudied therapeutic modality in Primary Ciliary Dyskinesia (PCD). We assessed the prevalence of lung resection in PCD across countries and compared disease course in lobectomised and non-lobectomised patients., Methods: In the international iPCD cohort, we identified lobectomised and non-lobectomised age and sex-matched PCD patients and compared their characteristics, lung function and BMI cross-sectionally and longitudinally., Results: Among 2896 patients in the iPCD cohort, 163 from 20 centers (15 countries) underwent lung resection (5.6%). Among adult patients, prevalence of lung resection was 8.9%, demonstrating wide variation among countries. Compared to the rest of the iPCD cohort, lobectomised patients were more often females, older at diagnosis, and more often had situs solitus. In about half of the cases (45.6%) lung resection was performed before presentation to specialized PCD centers for diagnostic work-up. Compared to controls (n = 197), lobectomised patients had lower FVC z-scores (- 2.41 vs - 1.35, p = 0.0001) and FEV1 z-scores (- 2.79 vs - 1.99, p = 0.003) at their first post-lung resection assessment. After surgery, lung function continued to decline at a faster rate in lobectomised patients compared to controls (FVC z-score slope: - 0.037/year Vs - 0.009/year, p = 0.047 and FEV1 z-score slope: - 0.052/year Vs - 0.033/year, p = 0.235), although difference did not reach statistical significance for FEV1. Within cases, females and patients with multiple lobe resections had lower lung function., Conclusions: Prevalence of lung resection in PCD varies widely between countries, is often performed before PCD diagnosis and overall is more frequent in patients with delayed diagnosis. After lung resection, compared to controls most lobectomised patients have poorer and continuing decline of lung function despite lung resection. Further studies benefiting from prospective data collection are needed to confirm these findings.

Primary ciliary dyskinesia (PCD) has been considered a relatively mild disease, especially compared to cystic fibrosis (CF), but studies on lung function in PCD patients have been few and small.This study compared lung function from spirometry of PCD patients to normal reference values and to published data from CF patients. We calculated z-scores and % predicted values for forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) using the Global Lung Function Initiative 2012 values for 991 patients from the international PCD Cohort. We then assessed associations with age, sex, country, diagnostic certainty, organ laterality, body mass index and age at diagnosis in linear regression models. Lung function in PCD patients was reduced compared to reference values in both sexes and all age groups. Children aged 6-9 years had the smallest impairment (FEV 1 z-score -0.84 (-1.03 to -0.65), FVC z-score -0.31 (-0.51 to -0.11)). Compared to CF patients, FEV 1 was similarly reduced in children (age 6-9 years PCD 91% (88-93%); CF 90% (88-91%)), but less impaired in young adults (age 18-21 years PCD 79% (76-82%); CF 66% (65-68%)). The results suggest that PCD affects lung function from early in life, which emphasises the importance of early standardised care for all patients., Competing Interests: Conflict of interest: N. Schwerk reports personal fees for lecturing from Novartis, Allergopharma and Infectopharm, and grants from FP7-ChILD EU, outside the submitted work. Conflict of interest: P. Yiallouros reports grants from European Union's Seventh Framework Programme under EG-GA (number 35404 BESTCILIA), during the conduct of the study. Conflict of interest: P. Latzin reports personal fees from Gilead, Novartis, Polyphor, Roche, Santhera, Schwabe, Vertex, Vifor and Zambon, outside the submitted work. Conflict of interest: H. Mazurek reports grants from Bestcilia, during the conduct of the study., (Copyright ©ERS 2018.)

We aimed to determine the diagnostic yield of a targeted-exome panel in a cohort of 74 Dutch primary ciliary dyskinesia (PCD) patients. The panel consisted of 26 PCD-related and 284 candidate genes. To prioritize PCD candidate genes, we investigated the transcriptome of human airway cells of 12 healthy volunteers during in vitro ciliogenesis and hypothesized that PCD-related genes show significant upregulation. We compared gene expression in epithelial precursor cells grown as collagen monolayer and ciliated cells grown in suspension by RNA sequencing. All genes reported as PCD causative, except NME8, showed significant upregulation during in vitro ciliogenesis. We observed 67.6% diagnostic yield when testing the targeted-exome panel in our cohort. There was relatively high percentage of DNAI and HYDIN mutations compared to other countries. The latter may be due to our solution for the problem of the confounding HYDIN2 pseudogene. Candidate genes included two recently published PCD-related genes DNAJB13 and PIH1D3; identification of the latter was a direct result of this study. In conclusion, we demonstrate 67.6% diagnostic yield by targeted exome sequencing in a Dutch PCD population and present a highly sensitive and moderately specific approach for identification of PCD-related genes, based on significant upregulation during in vitro ciliogenesis., (© 2018 Wiley Periodicals, Inc.)

Asthma and chronic obstructive pulmonary disease (COPD) are complex and overlapping diseases that include inflammatory phenotypes. Novel anti-eosinophilic/anti-neutrophilic strategies demand rapid inflammatory phenotyping, which might be accessible from exhaled breath.Our objective was to capture clinical/inflammatory phenotypes in patients with chronic airway disease using an electronic nose (eNose) in a training and validation set.This was a multicentre cross-sectional study in which exhaled breath from asthma and COPD patients (n=435; training n=321 and validation n=114) was analysed using eNose technology. Data analysis involved signal processing and statistics based on principal component analysis followed by unsupervised cluster analysis and supervised linear regression.Clustering based on eNose resulted in five significant combined asthma and COPD clusters that differed regarding ethnicity (p=0.01), systemic eosinophilia (p=0.02) and neutrophilia (p=0.03), body mass index (p=0.04), exhaled nitric oxide fraction (p<0.01), atopy (p<0.01) and exacerbation rate (p<0.01). Significant regression models were found for the prediction of eosinophilic (R 2 =0.581) and neutrophilic (R 2 =0.409) blood counts based on eNose. Similar clusters and regression results were obtained in the validation set.Phenotyping a combined sample of asthma and COPD patients using eNose provides validated clusters that are not determined by diagnosis, but rather by clinical/inflammatory characteristics. eNose identified systemic neutrophilia and/or eosinophilia in a dose-dependent manner., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2018.)

Chronic respiratory disease can affect growth and nutrition, which can influence lung function. We investigated height, body mass index (BMI), and lung function in patients with primary ciliary dyskinesia (PCD).In this study, based on the international PCD (iPCD) Cohort, we calculated z-scores for height and BMI using World Health Organization (WHO) and national growth references, and assessed associations with age, sex, country, diagnostic certainty, age at diagnosis, organ laterality and lung function in multilevel regression models that accounted for repeated measurements.We analysed 6402 measurements from 1609 iPCD Cohort patients. Height was reduced compared to WHO (z-score -0.12, 95% CI -0.17 to -0.06) and national references (z-score -0.27, 95% CI -0.33 to -0.21) in male and female patients in all age groups, with variation between countries. Height and BMI were higher in patients diagnosed earlier in life (p=0.026 and p<0.001, respectively) and closely associated with forced expiratory volume in 1 s and forced vital capacity z-scores (p<0.001).Our study indicates that both growth and nutrition are affected adversely in PCD patients from early life and are both strongly associated with lung function. If supported by longitudinal studies, these findings suggest that early diagnosis with multidisciplinary management and nutritional advice could improve growth and delay disease progression and lung function impairment in PCD., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Objective: The evaluation of discomfort in paediatric research is scarcely evidence-based. In this study, we make a start in describing children's self-reported discomfort during common medical research procedures and compare this with discomfort during dental check-ups which can be considered as a reference level of a 'minimal discomfort' medical procedure. We exploratory study whether there are associations between age, anxiety-proneness, gender, medical condition, previous experiences and discomfort. We also describe children's suggestions for reducing discomfort., Design: Cross-sectional descriptive study., Setting: Paediatric research at three academic hospitals., Patients: 357 children with and without illnesses (8-18 years, mean=10.6 years) were enrolled: 307 from paediatric research studies and 50 from dental care., Main Outcome Measures: We measured various generic forms of discomfort (nervousness, annoyance, pain, fright, boredom, tiredness) due to six common research procedures: buccal swabs, MRI scans, pulmonary function tests, skin prick tests, ultrasound imaging and venepunctures., Results: Most children reported limited discomfort during the research procedures (means: 1-2.6 on a scale from 1 to 5). Compared with dental check-ups, buccal swab tests, skin prick tests and ultrasound imaging were less discomforting, while MRI scans, venepunctures and pulmonary function tests caused a similar degree of discomfort. 60.3% of the children suggested providing distraction by showing movies to reduce discomfort. The exploratory analyses suggested a positive association between anxiety-proneness and discomfort., Conclusions: The findings of this study support the acceptability of participation of children in the studied research procedures, which stimulates evidence-based research practice. Furthermore, the present study can be considered as a first step in providing benchmarks for discomfort of procedures in paediatric research., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Hypertonic saline inhalation lowers airway mucous viscosity. Increased cough transportability may improve quality of life (QoL) in primary ciliary dyskinesia (PCD).In this randomised controlled trial (RCT), PCD patients received twice-daily inhalations of hypertonic (7%) saline or isotonic (0.9%) saline for 12 weeks, with 4 weeks washout during crossover. Primary outcome was change in QoL measured by the St George's Respiratory Questionnaire (SGRQ) total score. Secondary outcomes were SGRQ subscores, Quality of Life Questionnaire-Bronchiectasis (QoL-B) scores, lower respiratory tract infection symptoms, exacerbations, spirometry, systemic and sputum inflammatory markers, adherence, and adverse events.There was no significant change in median (interquartile range) SGRQ total score between hypertonic saline (-2.6 (-9.0-1.5)) and isotonic saline (-0.3 (-8.1-6.1)) in 22 patients (age range 22-73 years) (p=0.38). QoL-B Health Perception scale improved with hypertonic saline (p=0.03). Adverse events occurred more frequently with hypertonic saline, but were mild.12 weeks of inhaled hypertonic saline did not improve SGRQ total score in adult PCD patients in this RCT, but the sample size was small. On the secondary and more disease-specific end-point of the QoL-B, a significant improvement was observed in the Health Perception scale. This study found little evidence to support the hypothesis that hypertonic saline improves QoL in PCD patients. We advise the use of disease-specific outcome measures in future trials., (Copyright ©ERS 2017.)

Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right body axis disturbance. Here we report maternally inherited and de novo mutations in PIH1D3 in four men affected with PCD. PIH1D3 is located on the X chromosome and is involved in the preassembly of both outer (ODA) and inner (IDA) dynein arms of cilia and sperm flagella. Loss-of-function mutations in PIH1D3 lead to absent ODAs and reduced to absent IDAs, causing ciliary and flagellar immotility. Further, PIH1D3 interacts and co-precipitates with cytoplasmic ODA/IDA assembly factors DNAAF2 and DNAAF4. This result has clinical and genetic counseling implications for genetically unsolved male case subjects with a classic PCD phenotype that lack additional phenotypes such as intellectual disability or retinitis pigmentosa., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Rhinovirus (RV) is a frequent pathogen in young children, eliciting symptoms ranging from common colds to wheezing illnesses and lower respiratory tract infections. The recently identified RV-C seems to be associated with asthma exacerbations and more severe disease, but results vary. We studied the prevalence and severity of infection with RV in an unselected birth cohort. Children with respiratory symptoms entered the symptomatic arm of the cohort and were compared with asymptomatic children. Severity of wheezing and other respiratory symptoms was registered. Respiratory viruses were evaluated using throat and nasopharyngeal swabs on first presentation and after recovery (wheezing children). RV genotyping was performed on RV-PCR positive samples. RV was the most prevalent respiratory virus and was found in 58/140 symptomatic children (41%), 24/96 (25%) control children and 19/74 (26%) wheezing symptomatic children after recovery (p <0.05) and did not differ between wheezing and non-wheezing symptomatic children-respectively, 42% (38/90) and 40% (20/50). RV-A was the most commonly detected species (40/68, 59%), followed by RV-C (22/68, 32%) and RV-B (6/68, 9%). RV-B was more frequently detected in asymptomatic children (5/6, p <0.05). There was no significant difference in the frequency of RV species between wheezing and non-wheezing symptomatic children. Children with RV mono-infection had more severe symptoms, but no association between RV species and severity of disease was seen. In an unselected birth cohort from the Netherlands with mild respiratory disease RV was the most prevalent respiratory virus. RV(-C) infection was not associated with more severe disease or wheezing., (Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

We evaluated the in vitro glucocorticoid (GC) responsiveness of 117 pediatric acute myeloid leukemia cells by considering GC resistance, GC-induced proliferation, and GC-induced differentiation. None of the samples was highly GC sensitive, and only 15% were intermediately sensitive. GC-induced differentiation was not observed, while GC-induced proliferation was observed in 27% of the samples. Samples with French-American-British classification (FAB) type M5 or activating Fms-like tyrosine kinase 3 (FLT3) mutations were significantly more prone to this phenomenon. Although we could not confirm this in our study, if induced proliferation in vitro is paralleled in vivo, GCs during consolidation may have adverse effects on minimal residual leukemic cells, which might increase relapse risk., (© 2016 Wiley Periodicals, Inc.)