Associations between respiratory pathogens and lung function in primary ciliary dyskinesia: cross-sectional analysis from the PROVALF-PCD cohort.

Introduction: Respiratory pathogens are frequently isolated from airway samples in primary ciliary dyskinesia (PCD) patients. Few studies have investigated associations between these pathogens and lung function, with current management based on evidence from cystic fibrosis. We investigated the association between commonly isolated respiratory pathogens and lung function in PCD patients. Methods: Using a cross-sectional design, we prospectively collected clinical and concurrent microbiology data from 408 participants with probable or confirmed PCD, aged ≥5 years, from 12 countries. We used Global Lung Function Initiative 2012 references to calculate forced expiratory volume in 1 s (FEV1) z-scores. For 351 patients (86%) with complete data, we assessed the association of the four most frequently isolated pathogens with lung function by fitting multilevel linear models with country as random intercept, adjusted for age at diagnosis, age at lung function, use of antibiotic prophylaxis and body mass index z-scores. Results: Individuals with Pseudomonas aeruginosa growth in culture had significantly lower FEV1 z-scores (ß= -0.87, 95% CI -1.40- -0.34), adjusted for presence of Haemophilus influenzae, methicillin-sensitive Staphylococcus aureus and Streptococcus pneumoniae, and for covariates. When stratified by age, associations remained strong for adults but not for children. Results were similar when ciliary defects by transmission electron microscopy were included in the models and when restricting analysis to only confirmed PCD cases. Conclusions: We found that P. aeruginosa was associated with worse lung function in individuals with PCD, particularly adults. These findings suggest that it is prudent to aim for P. aeruginosa eradication in the first instance, and to treat exacerbations promptly in colonised patients.

Tracheomalacia and surgical options: A case series perspective.

Tracheomalacia causes considerable morbidity in children, and the best treatment options remain debated. This paper presents a case series of seven Danish children who underwent surgical interventions, such as tracheopexy and aortopexy, demonstrating favourable clinical outcomes, notably with early intervention. We discuss the indications, timing and potential benefits of surgery for tracheomalacia in reducing respiratory symptoms caused by tracheal collapse. Our case series highlights the potential of surgical options in managing tracheomalacia, emphasising the need for standardised protocols, multidisciplinary and international collaboration, and further research to optimise treatment strategies and outcomes.

Long-Term Lung Function and Pseudomonas aeruginosa Infection in Genotyped Primary Ciliary Dyskinesia.

Rationale: Primary ciliary dyskinesia is a rare genetic disorder characterized by progressive lung disease. Pseudomonas aeruginosa is a major pathogen in this disease, known to impact lung function. Previous genotype-phenotype studies have been limited by cross-sectional designs, isolated adult or pediatric populations, small numbers, or short follow-up durations. Objectives: We aimed to explore long-term lung function in primary ciliary dyskinesia grouped by genotypes and ultrastructural defects, considering the influence of P. aeruginosa. Methods: In this retrospective, observational study, we analyzed 43 years of spirometry and 20 years of microbiology data. Using linear mixed-effects models, we estimated FEV1 z-score trends and compared them at ages 10, 25, and 50 years, while Generalized Estimating Equations were used to assess P. aeruginosa prevalence between groups. In a secondary analysis, we matched spirometry and microbiology samples to evaluate the influence of P. aeruginosa on lung function. Measurements and Main Results: We included 127 genotyped subjects, 6,691 spirometries and 10,082 microbiology samples. CCDC39 and CCDC40 variants showed early onset and sustained decline in lung function, while DNAH11 and HYDIN variants demonstrated relative stability. Lung function in the proximity of positive P. aeruginosa cultures were on average 0.06 z-score lower. Despite this, differences between groups remained largely unaffected by P. aeruginosa. Conclusion: Long-term lung function in primary ciliary dyskinesia follows discrete genotype specific profiles and appear independent of P. aeruginosa infection. We confirm and extend previous findings of CCDC39 and CCDC40 as variants associated with early onset severe lung function impairment persisting in the long term.

A systematic literature review of the clinical and socioeconomic burden of bronchiectasis.

BACKGROUND: The overall burden of bronchiectasis on patients and healthcare systems has not been comprehensively described. Here, we present the findings of a systematic literature review that assessed the clinical and socioeconomic burden of bronchiectasis with subanalyses by aetiology (PROSPERO registration: CRD42023404162). METHODS: Embase, MEDLINE and the Cochrane Library were searched for publications relating to bronchiectasis disease burden (December 2017-December 2022). Journal articles and congress abstracts reporting on observational studies, randomised controlled trials and registry studies were included. Editorials, narrative reviews and systematic literature reviews were included to identify primary studies. PRISMA guidelines were followed. RESULTS: 1585 unique publications were identified, of which 587 full texts were screened and 149 were included. A further 189 citations were included from reference lists of editorials and reviews, resulting in 338 total publications. Commonly reported symptoms and complications included dyspnoea, cough, wheezing, sputum production, haemoptysis and exacerbations. Disease severity across several indices and increased mortality compared with the general population was reported. Bronchiectasis impacted quality of life across several patient-reported outcomes, with patients experiencing fatigue, anxiety and depression. Healthcare resource utilisation was considerable and substantial medical costs related to hospitalisations, treatments and emergency department and outpatient visits were accrued. Indirect costs included sick pay and lost income. CONCLUSIONS: Bronchiectasis causes significant clinical and socioeconomic burden. Disease-modifying therapies that reduce symptoms, improve quality of life and reduce both healthcare resource utilisation and overall costs are needed. Further systematic analyses of specific aetiologies and paediatric disease may provide more insight into unmet therapeutic needs.

A range of 30-62% of functioning multiciliated airway cells is sufficient to maintain ciliary airway clearance.

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.

Long-term effects of high-dose systemic corticosteroids on growth and bone mineral density in patients treated for childhood interstitial lung disease (chILD).

BACKGROUND: Children's interstitial lung disease (chILD) is a rare and potentially life-threatening condition. For many chILD conditions, systemic corticosteroids (sCCS) are considered the primary treatment despite a broad spectrum of potential side effects. AIM: We aimed to determine the long-term effects of sCCS treatment on growth, bone mineral density (BMD), and body composition after chILD. MATERIALS AND METHODS: This descriptive cross-sectional single-center study included patients diagnosed with chILD before the age of 18 years treated with sCCS in the period 1998-2020. Dual-energy X-ray absorptiometry, anthropometric measurements, bone age determination, and blood tests were performed in 53 (55% males) of 89 eligible patients. RESULTS: Median (range) age was 19.3 (6.4;30.7 years). Participants received a median (range) cumulative sCCS dose of 1144 (135; 6178) mg over a 2.0 (0.1; 13.8) years period and latest dose was administered 11.7 (1.2; 19.6) years before follow-up. Mean delta height (height standard deviation scores [SDS] - target height SDS) was reduced at sCCS treatment initiation (mean: -0.55, 95% confidence interval [CI]: -0.91; -0.20, p < .005) and at sCCS treatment cessation (mean: -0.86, 95% CI:-1.22; -0.51, p < .001), but normalized in the majority at follow-up (mean: -0.29, 95% CI:-0.61; 0.03, p = .07). Mean (SD) BMD z-score for the spine and whole body was -0.34 (1.06) and 0.52 (1.13), with no significant correlation to sCCS dose. Excess body fat (>30% in females, >25% in males) was found in 58% of patients. CONCLUSION: Long-term treatment with sCCS did not cause significant long-term reduction of height but showed subtle effects on fat mass percentage and BMD. Given the severity of chILD, the observed long-term effects of sCCS on growth and BMD appear acceptable.

A BEAT-PCD consensus statement: a core outcome set for pulmonary disease interventions in primary ciliary dyskinesia.

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.

Safety and efficacy of the epithelial sodium channel blocker idrevloride in people with primary ciliary dyskinesia (CLEAN-PCD): a multinational, phase 2, randomised, double-blind, placebo-controlled crossover trial.

BACKGROUND: Mucociliary clearance is dysfunctional in people with primary ciliary dyskinesia, resulting in the accumulation of dehydrated mucus in the airways that is difficult to clear. We undertook a study to assess the benefit on lung function of treatment with a nebulised epithelial sodium channel (ENaC) blocker, idrevloride, with or without hypertonic saline, in people with primary ciliary dyskinesia. METHODS: The CLEAN-PCD trial was a phase 2, randomised, double-blind, placebo-controlled crossover trial conducted at 32 tertiary adult and paediatric care centres and university hospitals in Canada, Denmark, Germany, Italy, the Netherlands, Poland, the UK, and the USA. People with a confirmed diagnosis of primary ciliary dyskinesia, aged 12 years or older, with a percentage of predicted FEV1 (ppFEV1) in the range of 40% to <90%, were randomly assigned in a 2:2:1:1 ratio (block size=6), stratified by ppFEV1 at screening, to one of four sequences: (1) idrevloride in hypertonic saline in treatment period 1 then hypertonic saline in treatment period 2; (2) hypertonic saline in treatment period 1 then idrevloride in hypertonic saline in treatment period 2; (3) idrevloride in treatment period 1 then placebo in treatment period 2; and (4) placebo in treatment period 1 then idrevloride in treatment period 2. The idrevloride dose was 85 µg and hypertonic saline was 4·2% NaCl. 3 mL of each study treatment was nebulised twice daily for 28 days in treatment periods 1 and 2; the two 28-day treatment periods were separated by a 28-day washout period. The primary endpoint was absolute change from baseline in ppFEV1 after 28 days. Safety assessments and reports of adverse events were made at clinic visits during each treatment period and by a follow-up telephone call 28 days after the last dose of study drug. Additionally, adverse events could be reported at a follow-up telephone call 3 days after the start of dosing and as they arose. Participants who received at least one dose of study drug were included in the safety analyses (safety set), and those who also had spirometry data were included in the efficacy analyses (full analysis set). The completed study is registered (EudraCT 2015-004917-26; ClinicalTrials.govNCT02871778). FINDINGS: Between Sep 14, 2016, and May 31, 2018, 216 patients were screened and 123 were randomly assigned to one of four crossover sequences. Across the two treatment periods, treatment with idrevloride in hypertonic saline was initiated in 80 patients and completed in 78 patients (all 78 had data available and were included in the analysis); hypertonic saline initiated in 81 patients and completed in 76 patients (75 had data available and were included in the analysis); idrevloride initiated in 37 patients and completed in 35 patients (34 had data available and were included in the analysis); and placebo initiated in 36 patients and completed in 34 patients (all 34 had data available and were included in the analysis). Greater absolute increases in ppFEV1 from baseline to 28 days of treatment were seen with idrevloride in hypertonic saline (least-squares mean absolute change from baseline 1·0 percentage points, 95% CI -0·4 to 2·4) than with hypertonic saline alone (least-squares mean absolute change from baseline of -0·5 percentage points, -2·0 to 0·9; difference 1·5 percentage points, 95% CI <0·1 to 3·0; p=0·044). There was no significant difference in ppFEV1 for the parallel comparison of idrevloride in hypertonic saline compared with placebo or the crossover comparison of idrevloride with placebo. Adverse events were similar across treatments (57 to 65% of patients). Cough occurred in a greater proportion of participants during treatments that contained idrevloride or hypertonic saline compared with placebo, and oropharyngeal pain occurred in a greater proportion of participants during idrevloride treatments than during treatment with hypertonic saline alone or placebo, whereas chest discomfort was more common during treatments that included hypertonic saline. INTERPRETATION: In this phase 2 crossover study, idrevloride in hypertonic saline was safe and associated with improved lung function over a 28-day period in people with primary ciliary dyskinesia compared with hypertonic saline alone. Larger, longer clinical studies are warranted to explore the potential benefits of idrevloride in combination with hypertonic saline in people with primary ciliary dyskinesia. FUNDING: Parion Sciences, under agreement with Vertex Pharmaceuticals.

Pulmonary radioaerosol mucociliary clearance assessment: searching for genotype-specific differences and potential as an outcome measure in primary ciliary dyskinesia.

Background: Pulmonary radioaerosol mucociliary clearance (PRMC) is a reliable method for assessing in vivo whole lung mucociliary clearance and has been used at the Danish PCD Centre as a supplementary diagnostic test for primary ciliary dyskinesia (PCD) for more than two decades. This study aimed to investigate genotype-specific differences in PRMC measures and evaluate its potential as an outcome parameter. Material and methods: The study was based on a retrospective analysis of PRMC tests performed over a 24-year period (1999-2022) in individuals referred for PCD work-up and included patients with genetically confirmed PCD and non-PCD controls. Patients inhaled nebulised technetium-albumin-colloid before static and dynamic imaging was obtained. Three parameters were evaluated: 1-h lung retention (LR1), tracheobronchial velocity (TBV) and cough clearance. Results: The study included 69 patients from the Danish PCD cohort, representing 26 different PCD genotypes. Mucociliary clearance by PRMC was consistently absent in most PCD patients, regardless of genotype. However, a single patient with a CCDC103 mutation, preserved ciliary function and normal nasal nitric oxide levels exhibited normal LR1 and low TBV values. Voluntary cough significantly improved clearance, with a median improvement of 11% (interquartile range 4-24%). Conclusion: Absent mucociliary clearance by PRMC should be expected in PCD regardless of genotype but residual ciliary function could result in measurable PRMC. This indicates a potential for PRMC to detect improvements in ciliary function if this can be restored. Addressing involuntary cough and peripheral deposition of radioaerosol is important if PRMC is to be used as an outcome measure in future clinical PCD trials.

Nationwide lung function monitoring from infancy in newborn-screened children with cystic fibrosis.

Background: Cystic fibrosis (CF) lung disease starts in infancy and can be assessed for structural lung abnormalities using computed tomography or magnetic resonance scans, or for lung function impairment using multiple breath washout (MBW). However, in infancy these two methods are not well correlated. Trajectories of CF lung disease assessed by MBW in infants and toddlers remain poorly described, which is why we aimed to 1) describe the trajectory of lung function, 2) explore risk factors for progression and 3) explore the real-life effect of lumacaftor/ivacaftor. Methods: This was a nationwide observational cohort study (2018-2021) using data collected as part of the routine clinical surveillance programme (including MBW and monthly endo-laryngeal suction sampling for bacterial pathogens) in children born after implementation of newborn screening for CF (May 2016). Lumacaftor/ivacaftor commenced from age 2 years in children homozygous for F508del. Ventilation distribution efficiency (VDE), recently described to have advantages over lung clearance index (LCI), was reported as the primary MBW outcome after z-score calculations based on published reference data. Mixed effect linear regression models were the main statistical analyses performed in this study. Results: 59 children, aged 2-45 months, contributed with 211 MBW occasions (median (interquartile range (IQR)) 3 (2-5) MBW occasions per child) with a median (IQR) follow-up time of 10.8 (5.2-22.3) months. An overall mean annual deterioration rate of -0.50 (95% CI -0.78- -0.22) z-VDE was observed, starting from an estimated mean z-VDE of -1.68 (95% CI -2.15- -1.22) at age 0.0 years (intercept). Pseudomonas aeruginosa "ever" (n=14, MBWs 50) had a significantly worse z-VDE trajectory versus P. aeruginosa "never" (mean difference 0.53 (95% CI 0.16-0.89) per year; p=0.0047) and lumacaftor/ivacaftor treatment (n=22, MBWs 46) significantly improved the trajectory of z-VDE (mean difference 1.72 (95% CI 0.79-2.66) per year; p=0.0004), leading to a stable mean z-VDE trajectory after start of treatment. Conclusions: Infants and toddlers with CF demonstrated progressive deterioration in z-VDE over the first years of life. P. aeruginosa isolation "ever" was associated with an accelerated deterioration in lung function, while lumacaftor/ivacaftor therapy significantly improved and stabilised the trajectory.

Quantitative 99mTc-albumin colloid nasal mucociliary clearance as an outcome in primary ciliary dyskinesia.

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 99mTc-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.

Multiple breath washout and oscillometry after allogenic HSCT: a scoping review.

Pulmonary chronic graft-versus-host disease (cGVHD) is a substantial cause of pulmonary morbidity and mortality post-haematopoietic stem cell transplantation (HSCT). Current spirometry-based monitoring strategies have significant limitations. Understanding the utility of novel peripheral airway function tests - multiple breath washout (MBW) and oscillometry - is critical in efforts to improve detection, facilitate earlier intervention and improve outcomes. In this scoping review, we identified 17 studies investigating MBW or oscillometry, or both, after allogenic HSCT. Despite small study numbers limiting the ability to draw firm conclusions, several themes were evident. Detectable peripheral airway abnormality in MBW occurred in a substantial proportion prior to HSCT. MBW indices post-HSCT were more frequently abnormal than spirometry when reporting group data and among those with extrapulmonary cGVHD and pulmonary cGVHD. Changes in MBW indices over time may be more indicative of pulmonary complications than absolute values at any given time point. Oscillometry indices were often normal at baseline, but more frequently abnormal in those who developed pulmonary cGVHD. Pooling currently available individual participant data across these studies may improve our ability to formally compare their respective sensitivity and specificity at specific time points and assess the trajectory of MBW and oscillometry indices over time.

Towards the international interoperability of clinical research networks for rare diseases: recommendations from the IRDiRC Task Force.

BACKGROUND: Many patients with rare diseases are still lacking a timely diagnosis and approved therapies for their condition despite the tremendous efforts of the research community, biopharmaceutical, medical device industries, and patient support groups. The development of clinical research networks for rare diseases offers a tremendous opportunity for patients and multi-disciplinary teams to collaborate, share expertise, gain better understanding on specific rare diseases, and accelerate clinical research and innovation. Clinical Research Networks have been developed at a national or continental level, but global collaborative efforts to connect them are still lacking. The International Rare Diseases Research Consortium set a Task Force on Clinical Research Networks for Rare Diseases with the objective to analyse the structure and attributes of these networks and to identify the barriers and needs preventing their international collaboration. The Task Force created a survey and sent it to pre-identified clinical research networks located worldwide. RESULTS: A total of 34 responses were received. The survey analysis demonstrated that clinical research networks are diverse in their membership composition and emphasize community partnerships including patient groups, health care providers and researchers. The sustainability of the networks is mostly supported by public funding. Activities and research carried out at the networks span the research continuum from basic to clinical to translational research studies. Key elements and infrastructures conducive to collaboration are well adopted by the networks, but barriers to international interoperability are clearly identified. These hurdles can be grouped into five categories: funding limitation; lack of harmonization in regulatory and contracting process; need for common tools and data standards; need for a governance framework and coordination structures; and lack of awareness and robust interactions between networks. CONCLUSIONS: Through this analysis, the Task Force identified key elements that should support both developing and established clinical research networks for rare diseases in implementing the appropriate structures to achieve international interoperability worldwide. A global roadmap of actions and a specific research agenda, as suggested by this group, provides a platform to identify common goals between these networks.

Nasal nitric oxide measurement in children for the diagnosis of primary ciliary dyskinesia: European Respiratory Society technical standard.

Nasal nitric oxide (nNO) is extremely low in most people with primary ciliary dyskinesia (PCD) and its measurement is an important contributor to making the diagnosis. Existing guidelines and technical standards focus on nNO measurements in older, cooperative children using chemiluminescence analysers. However, measurements of nNO in pre-school-age children (age 2-5 years) may facilitate early diagnosis and electrochemical rather than chemiluminescence analysers are widely used. Pre-schoolers often need different methods to be employed when measuring nNO. Hence, a European Respiratory Society Task Force has developed this technical standard as the first step towards standardising sampling, analysis and reporting of nNO measured as part of the diagnostic testing for PCD in all age groups, including pre-school-age children. Furthermore, we considered both chemiluminescence and electrochemical analysers that are in use worldwide. There was a paucity of quality evidence for electrochemical analysers and sampling methods used in young children, and the Task Force proposes future research priorities to allow updates of this technical standard.

Turning lung clearance index on its head. Reference data for SF6 multiple-breath washout derived ventilation distribution efficiency.

Cystic fibrosis (CF) lung disease is characterized by increased ventilation inhomogeneity (VI), as measured by multiple-breath washout (MBW). Lung clearance index (LCI) is the most reported VI outcome. This study aimed to evaluate historically published reference equations for sulfur hexafluoride (SF6) MBW outcomes, to data collected using updated commercial SF6MBW equipment, and to produce device-specific equations if necessary. SF6MBW was performed in 327 healthy children aged 0.1-18.4 yr [151 (46%) girls], 191 (58.4%) <3 yr. z-Scores were calculated from published reference equations (FRC and LCI) and multivariate linear regression was performed to produce device-specific reference equations. Due to increasing residual standard deviations with increasing LCI values, investigation of methods for improvement were investigated, based on the relationship between VI and dead space ventilation (VD/VT; dead space volume/tidal volume) in a cohort of 59 healthy children, 26 children with CF (n = 138 test occasions), and 49 adults with lung disease. Historical SF6MBW reference equations were unsuitable for EXHALYZER D data. In contrast to LCI and log10(LCI), 1/LCI (ventilation distribution efficiency; VDE) was linearly related to VD/VT, with z-scores linearly related to its absolute values. Reference equations were reported for VDE and log10(FRC). Significant predictors for VDE and log10(FRC), respectively, were log10(age) and sex, and log10(height), sex, and posture. VDE is potentially a better index of VI than LCI, particularly in more advanced CF lung disease and also for longitudinal monitoring. Further confirmatory clinical studies, particularly longitudinal imaging studies of structural or ventilatory changes, are warranted.NEW & NOTEWORTHY Lung clearance index (LCI) is the most used outcome from the multiple-breath washout test. As known for decades, the LCI is not linearly related to dead space ventilation, giving difficulties interpreting changes over time and in clinical trials. We present a new and improved outcome based on LCI, the ventilation distribution efficiency (VDE), which solves this problem by being linearly related to dead space ventilation. A pediatric age range reference equation for VDE is presented.

An international survey on nasal nitric oxide measurement practices for the diagnosis of primary ciliary dyskinesia.

Nasal nitric oxide (nNO) measurements are used in the assessment of patients suspected of having primary ciliary dyskinesia (PCD), but recommendations for performing such measurements have not focused on children and do not include all current practices. To guide the development of a European Respiratory Society-supported technical standard for nNO measurement in children, an international online survey was conducted to better understand current measurement practices among providers involved in PCD diagnostics. 78 professionals responded, representing 65 centres across 18 countries, mainly in Europe and North America. Nearly all centres measured nNO in children and more than half performed measurements before 5 years of age. The test was often postponed in children with signs of acute airway infection. In Europe, the electrochemical technique was more frequently used than chemiluminescence. A similar proportion of centres performed measurements during exhalation against a resistance (49 out of 65) or during tidal breathing (50 out of 65); 15 centres used only exhalation against a resistance and 15 used only tidal breathing. The cut-off values used to discriminate PCD were consistent across centres using chemiluminescence analysers; these centres reported results as an output (nL·min-1). Cut-off values were highly variable across centres using electrochemical devices, and nNO concentrations were typically reported as ppb. This survey is the first to determine real-world use of nNO measurements globally and revealed remarkable variability in methodology, equipment and interpretation. These findings will help standardise methods and training.

Chronic airway disease in primary ciliary dyskinesia-spiced with geno-phenotype associations.

Primary ciliary dyskinesia (PCD) can be defined as a multiorgan ciliopathy with a dominant element of chronic airway disease affecting the nose, sinuses, middle ear, and in particular, the lower airways. Although most patients with PCD are diagnosed during preschool years, it is obvious that the chronic lung disease starts its course already from birth. The many faces of the clinical picture change, as does lung function, structural lung damage, the burden of infection, and of treatment throughout life. A markedly severe neutrophil inflammation in the respiratory tract seems pervasive and is only to a minimal extent ameliorated by a treatment strategy, which is predominantly aimed at bacterial infections. An ever-increasing understanding of the different aspects, their interrelationships, and possible different age courses conditioned by the underlying genotype is the focus of much attention. The future is likely to offer personalized medicine in the form of mRNA therapy, but to that end, it is of utmost importance that all patients with PCD be carefully characterized and given a genetic diagnosis. In this narrative review, we have concentrated on lower airways and summarized the current understanding of the chronic airway disease in this motile ciliopathy. In addition, we highlight the challenges, gaps, and opportunities in PCD lung disease research.

Lung function from school age to adulthood in primary ciliary dyskinesia.

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 (FEV1), forced vital capacity (FVC) and FEV1/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, FEV1, FVC and FEV1/FVC z-scores declined over time (average crude annual FEV1 decline was -0.07 z-scores), but not at the same rate for all patients. FEV1 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.

Contemporary N2 and SF6 multiple breath washout in infants and toddlers with cystic fibrosis.

INTRODUCTION: Multiple breath washout (MBW) is used for early detection of cystic fibrosis (CF) lung disease, with SF6 MBW commonly viewed as the reference method. The use of N2 MBW in infants and toddlers has been questioned for technical and physiological reasons, but a new correction of the N2  signal has minimized the technical part. The present study aimed to assess the remaining differences and the contributing mechanisms for the differences between SF6 and N2 MBW,corrected-such as tidal volume reduction during N2 washout with pure O2 . METHOD: This was a longitudinal multicenter cohort study. SF6 MBW and N2 MBW were performed prospectively at three CF centers in the same visits on 154 test occasions across 62 children with CF (mean age: 22.7 months). Offline analysis using identical algorithms to the commercially available program provided outcomes of N2,original and N2,corrected for comparison with SF6 MBW. RESULTS: Mean functional residual capacity, FRCN2,corrected was 14.3% lower than FRCN2, original , and 1.0% different from FRCSF6 . Lung clearance index, LCIN2,corrected was 25.2% lower than LCIN2,original , and 7.3% higher than LCISF6 . Mean (SD) tidal volume decreased significantly during N2 MBWcorrected , compared to SF6 MBW (-13.1 ml [-30.7; 4.6], p < 0.0001, equal to -12.0% [-25.7; 1.73]), but this tidal volume reduction did not correlate to the differences between LCIN2,corrected and LCISF6 . The absolute differences in LCI increased significantly with higher LCISF6 (0.63/LCISF6 ) and (0.23/LCISF6 ), respectively, for N2,original and N2,corrected , but the relative differences were stable across disease severity for N2,corrected , but not for N2,original . CONCLUSION: Only minor residual differences between FRCN2,corrected and FRCSF6 remained to show that the two methods measure gas volumes very similar in this age range. Small differences in LCI were found. Tidal volume reduction during N2 MBW did not affect differences. The corrected N2 MBW can now be used with confidence in young children with CF, although not interchangeably with SF6 .