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Background: Primary ciliary dyskinesia is a genetic disorder caused by aberrant motile cilia function that results in defective ciliary airway clearance and subsequently leads to recurrent airway infections and bronchiectasis. We aimed to determine: how many functional multiciliated airway cells are sufficient to maintain ciliary airway clearance?, Methods: To answer this question we exploited the molecular defects of the X-linked recessive primary ciliary dyskinesia variant caused by pathogenic variants in DNAAF6 ( PIH1D3 ), characterised by immotile cilia in affected males. We carefully analysed the clinical phenotype and molecular defect (using immunofluorescence and transmission electron microscopy) and performed in vitro studies (particle tracking in air-liquid interface cultures) and in vivo studies (radiolabelled tracer studies) to assess ciliary clearance of respiratory cells from female individuals with heterozygous and male individuals with hemizygous pathogenic DNAAF6 variants., Results: Primary ciliary dyskinesia male individuals with hemizygous pathogenic DNAAF6 variants displayed exclusively immotile cilia, absence of ciliary clearance and severe primary ciliary dyskinesia symptoms. Owing to random or skewed X-chromosome inactivation in six female carriers with heterozygous pathogenic DNAAF6 variants, 54.3±10% (range 38-70%) of multiciliated cells were defective. Nevertheless, in vitro and in vivo assessment of the ciliary airway clearance was normal or slightly abnormal. Consistently, heterozygous female individuals showed no or only mild respiratory symptoms., Conclusions: Our findings indicate that having 30-62% of multiciliated respiratory cells functioning can generate either normal or slightly reduced ciliary clearance. Because heterozygous female carriers displayed either no or subtle respiratory symptoms, complete correction of 30% of cells by precision medicine could improve ciliary airway clearance in individuals with primary ciliary dyskinesia, as well as clinical symptoms., Competing Interests: Conflict of interest: The authors have no potential conflicts of interest to declare., (Copyright ©The authors 2024.)

Background: Primary ciliary dyskinesia (PCD) is an inherited disorder in which dyskinetic cilia cause impaired mucociliary clearance of upper and lower airways. Airway ciliary movement can be indirectly tested in vivo after administration of a radiolabelled tracer to the lower airways for assessment of pulmonary mucociliary clearance or to the nose for assessing nasal mucociliary clearance (NMC). With this study, we investigated NMC as a quantifiable study outcome parameter in patients with PCD., Material and Methods: This single centre proof-of-concept study on NMC velocity investigated patients with PCD across different genotypes and nasal nitric oxide (nasal NO) levels. Healthy controls were used for comparison. NMC was determined as velocity in mm·min -1 of a nasally applied 99m Tc-albumin colloid tracer. Using a gamma camera, repeated dynamic series of images each lasting 30 s were acquired during a 10-minute period and digitally stored., Results: NMC velocity was investigated in seven patients with PCD (aged 9-31 years) and five adult healthy controls. Mean NMC velocity in healthy controls (8.5 mm·min -1 ) was significantly higher compared with people with PCD (0.00 mm·min -1 , p<0.0001). NMC was completely absent in all included patients with PCD across different PCD genotypes and regardless of nasal NO values. The success rate of the test was 100% in both groups., Conclusion: NMC velocity discriminated highly significantly between patients with PCD and healthy controls. We suggest here a fast and feasible set up for NMC measurements that is easily applicable for any clinical trial involving PCD medication aimed for the nasal compartment, a step before or parallel to conducting clinical trials investigating whole-lung ciliary function in PCD., Competing Interests: Conflict of interest: The authors J.K. Marthin, K.G. Nielsen and J. Mortensen have no conflicts of interests to disclose., (Copyright ©The authors 2023.)

Background: OligoG is a low molecular-weight alginate oligosaccharide that improves the viscoelastic properties of cystic fibrosis (CF) mucus and disrupts biofilms, thereby potentiating the activity of antimicrobial agents. The efficacy of inhaled OligoG was evaluated in adult patients with CF., Methods: A randomised, double-blind, placebo-controlled multicentre crossover study was used to demonstrate safety and efficacy of inhaled dry powder OligoG. Subjects were randomly allocated to receive OligoG 1050 mg per day (10 capsules three times daily) or matching placebo for 28 days, with 28-day washout periods following each treatment period. The primary end-point was absolute change in percentage predicted forced expiratory volume in 1 s (FEV 1 ) at the end of 28-day treatment. The intention-to-treat (ITT) population (n=65) was defined as randomised to treatment with at least one administration of study medication and post-dosing evaluation., Results: In this study, 90 adult subjects were screened and 65 were randomised. Statistically significant improvement in FEV 1 was not observed in the ITT population. Adverse events included nasopharyngitis, cough and pulmonary exacerbation. The number and proportions of patients with adverse events and serious adverse events were similar between OligoG and placebo group., Conclusions: Inhalation of OligoG-dry powder over 28 days was safe in adult CF subjects. Statistically significant improvement of FEV 1 was not reached. The planned analyses did not indicate a significant treatment benefit with OligoG compared to placebo. Post hoc exploratory analyses showed subgroup results that indicate that further studies of OligoG in this patient population are justified., Competing Interests: Conflict of interest: S. van Koningsbruggen-Rietschel reports grants from Horizon 2020 and personal fees from DZIF, outside the submitted work. Conflict of interest: J.C. Davies reports work on an advisory board and as a clinical trial lead for Algipharma AS, work as UK Lead Investigator and on an advisory board for Bayer AG, work on an advisory board for Boehringer Ingelheim Pharma GmbH & Co. KG, work on an advisory board and clinical trial leadership for Galapagos NV, advisory and clinical trial design assistance for ImevaX GmbH, work on an advisory board for Nivalis Therapeutics, Inc., work on an advisory board and clinical trial design advice for ProQR Therapeutics III B.V., advisory work and clinical trial leadership for Proteostasis Therapeutics, Inc., advisory work for Raptor Pharmaceuticals, Inc., work on an advisory board and National Co-ord/Global Co-I for Vertex Pharmaceuticals (Europe) Limited, work on advisory boards for Enterprise, Novartis, Pulmocide and Flatley, grants from the CF Trust, and educational activities for Teva, outside the submitted work. Conflict of interest: T. Pressler has nothing to disclose. Conflict of interest: R. Fischer has nothing to disclose. Conflict of interest: G. MacGregor has nothing to disclose. Conflict of interest: S.H. Donaldson reports grants from AlgiPharma during the conduct of the study; and grants from Vertex Pharmaceuticals, AstraZeneca and Proteostasis Therapeutics outside the submitted work. Conflict of interest: K. Smerud reports that his employer, Smerud Medical Research International AS, is a contract research organisation that delivered clinical trial management services (clinical trial management, clinical trial applications, data management, statistical planning and analysis, monitoring, and medical writing) to Algipharma and was remunerated for that work. Conflict of interest: N. Meland reports grants from AlgiPharma AS during the conduct of the study. Conflict of interest: J. Mortensen has nothing to disclose. Conflict of interest: M.Ø. Fosbøl has nothing to disclose. Conflict of interest: D.G. Downey reports grants and personal fees from Vertex, Proteostasis, Chiesi and Gilead, outside the submitted work. Conflict of interest: A.H. Myrset reports grants from Cystic Fibrosis Foundation during the conduct of the study, and holds stock in AlgiPharma AB outside the submitted work. Conflict of interest: H. Flaten reports grants from Cystic Fibrosis Foundation during the conduct of the study; and is a qualified person for Pharmacovigilance for AlgiPharma and holds stock in AlgiPharma AB, outside the submitted work. Conflict of interest: P.D. Rye reports grants from Cystic Fibrosis Foundation during the conduct of the study, and is Chief Scientific Officer at AlgiPharma and holds stock in AlgiPharma AB, outside the submitted work; in addition, he has patents WO 2015/128495 and WO 2016/151051 pending., (Copyright ©ERS 2020.)

The aim of this study was to determine reference equations for the combined measurement of diffusing capacity of the lung for carbon monoxide (CO) and nitric oxide (NO) ( D LCONO ). In addition, we wanted to appeal for consensus regarding methodology of the measurement including calculation of diffusing capacity of the alveolo-capillary membrane ( D m ) and pulmonary capillary volume ( V c ). D LCONO was measured in 282 healthy individuals aged 18-97 years using the single-breath technique and a breath-hold time of 5 s (true apnoea period). The following values were used: 1) specific conductance of nitric oxide (θ NO )=4.5 mL NO ·mL blood -1 ·min -1 ·mmHg -1 ; 2) ratio of diffusing capacity of the membrane for NO and CO ( D mNO / D mCO )=1.97; and 3) 1/red cell CO conductance (1/θ CO )=(1.30+0.0041·mean capillary oxygen pressure)·(14.6/Hb concentration in g·dL -1 ).Reference equations were established for the outcomes of D LCONO , including D LCO and D LNO and the calculated values D m and V c Independent variables were age, sex, height and age squared.By providing new reference equations and by appealing for consensus regarding the methodology, we hope to provide a basis for future studies and clinical use of this novel and interesting method., Competing Interests: Conflict of interest: M. Munkholm reports grants from Danish Lung Association, Boehringer Ingelheim, GlaxoSmithKline, Novartis and Alere, and non-financial support from Intra Medic, during the conduct of the study. Conflict of interest: L. Bjerre-Kristensen reports grants from Danish Lung Association, Boehringer Ingelheim, GlaxoSmithKline, Novartis and Alere, and non-financial support from Intra Medic, during the conduct of the study. Conflict of interest: F. Madsen reports grants from Allergy and Lung Clinic Helsingør, during the conduct of the study. Conflict of interest: O.F. Pedersen reports grants from Danish Lung Association, Boehringer Ingelheim, GlaxoSmithKline, Novartis and Alere, and non-financial support from Intra Medic, during the conduct of the study. Conflict of interest: P. Lange reports grants from Danish Lung Association, Boehringer Ingelheim, GlaxoSmithKline, Novartis and Alere, and non-financial support from Intra Medic, during the conduct of the study. Conflict of interest: J. Mortensen reports grants from Danish Lung Association, Boehringer Ingelheim, GlaxoSmithKline, Novartis and Alere, and non-financial support from Intra Medic, during the conduct of the study. Conflict of interest: J.L. Marott reports grants from Danish Lung Association, Boehringer Ingelheim, GlaxoSmithKline, Novartis and Alere, and non-financial support from Intra Medic, during the conduct of the study., (Copyright ©ERS 2018.)