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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 (β= −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.

Background The effects of prenatal antibiotic exposure on respiratory morbidity in infancy and the involved mechanisms are still poorly understood. We aimed to examine whether prenatal antibiotic exposure in the third trimester is associated with nasal microbiome and respiratory morbidity in infancy and at school age, and whether this association with respiratory morbidity is mediated by the nasal microbiome. Methods We performed 16S ribosomal RNA gene sequencing (regions V3–V4) on nasal swabs obtained from 296 healthy term infants from the prospective Basel–Bern birth cohort (BILD) at age 4–6 weeks. Information about antibiotic exposure was derived from birth records and standardised interviews. Respiratory symptoms were assessed by weekly telephone interviews in the first year of life and a clinical visit at age 6 years. Structural equation modelling was used to test direct and indirect associations accounting for known risk factors. Results α-Diversity indices were lower in infants with antibiotic exposure compared to nonexposed infants (e.g. Shannon index p-value 0.006). Prenatal antibiotic exposure was also associated with a higher risk of any, as well as severe, respiratory symptoms in the first year of life (risk ratio 1.38, 95% CI 1.03–1.84; adjusted p-value (padj)=0.032 and risk ratio 1.75, 95% CI 1.02–2.97; padj=0.041, respectively), but not with wheeze or atopy in childhood. However, we found no indirect mediating effect of nasal microbiome explaining these clinical symptoms. Conclusion Prenatal antibiotic exposure was associated with lower diversity of nasal microbiome in infancy and, independently of microbiome, with respiratory morbidity in infancy, but not with symptoms later in life.

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.

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.

Background References from the Global Lung Function Initiative (GLI) are widely used to interpret children's spirometry results. We assessed fit for healthy schoolchildren. Methods LuftiBus in the School was a population-based cross-sectional study undertaken in 2013–2016 in the canton of Zurich, Switzerland. Parents and their children aged 6–17 years answered questionnaires about respiratory symptoms and lifestyle. Children underwent spirometry in a mobile lung function lab. We calculated GLI-based z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC and forced expiratory flow for 25–75% of FVC (FEF25–75) for healthy White participants. We defined appropriate fit to GLI references by mean values between +0.5 and −0.5 z-scores. We assessed whether fit varied by age, body mass index, height and sex using linear regression models. Results We analysed data from 2036 children with valid FEV1 measurements, of whom 1762 also had valid FVC measurements. The median age was 12.2 years. Fit was appropriate for children aged 6–11 years for all indices. In adolescents aged 12–17 years, fit was appropriate for FEV1/FVC z-scores (mean±sd −0.09±1.02), but not for FEV1 (−0.62±0.98), FVC (−0.60±0.98) and FEF25–75 (−0.54±1.02). Mean FEV1, FVC and FEF25–75 z-scores fitted better in children considered overweight (−0.25, −0.13 and −0.38, respectively) than normal weight (−0.55, −0.50 and −0.55, respectively; p-trend

Background Diagnosis of primary ciliary dyskinesia (PCD) is challenging since there is no gold standard test. The European Respiratory (ERS) and American Thoracic (ATS) Societies developed evidence-based diagnostic guidelines with considerable differences. Objective We aimed to compare the algorithms published by the ERS and the ATS with each other and with our own PCD-UNIBE algorithm in a clinical setting. Our algorithm is similar to the ERS algorithm with additional immunofluorescence staining. Agreement (Cohen's κ) and concordance between the three algorithms were assessed in patients with suspicion of PCD referred to our diagnostic centre. Results In 46 out of 54 patients (85%) the final diagnosis was concordant between all three algorithms (30 PCD negative, 16 PCD positive). In eight patients (15%) PCD diagnosis differed between the algorithms. Five patients (9%) were diagnosed as PCD only by the ATS, one (2%) only by the ERS and PCD-UNIBE, one (2%) only by the ATS and PCD-UNIBE, and one (2%) only by the PCD-UNIBE algorithm. Agreement was substantial between the ERS and the ATS (κ=0.72, 95% CI 0.53–0.92) and the ATS and the PCD-UNIBE (κ=0.73, 95% CI 0.53–0.92) and almost perfect between the ERS and the PCD-UNIBE algorithms (κ=0.92, 95% CI 0.80–1.00). Conclusion The different diagnostic algorithms lead to a contradictory diagnosis in a considerable proportion of patients. Thus, an updated, internationally harmonised and standardised PCD diagnostic algorithm is needed to improve diagnostics for these discordant cases.

Objectives Disease-specific, well-defined and validated clinical outcome measures are essential in designing research studies. Poorly defined outcome measures hamper pooling of data and comparisons between studies. We aimed to identify and describe pulmonary outcome measures that could be used for follow-up of patients with primary ciliary dyskinesia (PCD). Methods We conducted a scoping review by systematically searching MEDLINE, Embase and the Cochrane Database of Systematic Reviews online databases for studies published from 1996 to 2020 that included ≥10 PCD adult and/or paediatric patients. Results We included 102 studies (7289 patients). 83 studies reported on spirometry, 11 on body plethysmography, 15 on multiple-breath washout, 36 on high-resolution computed tomography (HRCT), 57 on microbiology and 17 on health-related quality of life. Measurement and reporting of outcomes varied considerably between studies (e.g. different scoring systems for chest HRCT scans). Additionally, definitions of outcome measures varied (e.g. definition of chronic colonisation by respiratory pathogen), impeding direct comparisons of results. Conclusions This review highlights the need for standardisation of measurements and reporting of outcome measures to enable comparisons between studies. Defining a core set of clinical outcome measures is necessary to ensure reproducibility of results and for use in future trials and prospective cohorts.

It has been postulated that some children with recurrent cough but no wheeze have a mild form of asthma (cough variant asthma), with similar risk factors and an increased risk of future wheeze. This longitudinal study compared risk factors for isolated night cough and for wheeze in the Leicester Respiratory Cohort in children aged 1, 4, 6 and 9 years and compared prognosis of children with isolated night cough, children with wheeze and asymptomatic children. We included 4101 children aged 1 year, 2854 aged 4 years, 2369 aged 6 years and 1688 aged 9 years. The prevalence of isolated night cough was 10% at age 1 year and 18% in older children. Prevalence of wheeze decreased from 35% at 1 year to 13% at 9 years. Although several risk factors were similar for cough and wheeze, day care, reflux and family history of bronchitis were more strongly associated with cough, and male sex and family history of asthma with wheeze. Over one-third of preschool children with cough continued to cough at school age, but their risk of developing wheeze was similar to that of children who were asymptomatic at earlier surveys. Wheeze tracked more strongly throughout childhood than cough. In conclusion, our study showed that only some risk factors for cough and wheeze were shared but many were not, and there was little evidence for an increased risk of future wheeze in children with isolated night cough. This provides little support for the hypothesis that recurrent cough without wheeze may indicate a variant form of asthma.

Background Volumetric capnography (VCap) is a simpler alternative to multiple-breath washout (MBW) to detect ventilation inhomogeneity in patients with cystic fibrosis (CF). However, its diagnostic performance is influenced by breathing dynamics. We introduce two novel VCap indices, the capnographic inhomogeneity indices (CIIs), that may overcome this limitation and explore their diagnostic characteristics in a cohort of CF patients. Methods We analysed 320 N2-MBW trials from 50 CF patients and 65 controls (age 4–18 years) and calculated classical VCap indices, such as slope III (SIII) and the capnographic index (KPIv). We introduced novel CIIs based on a theoretical lung model and assessed their diagnostic performance compared to classical VCap indices and the lung clearance index (LCI). Results Both CIIs were significantly higher in CF patients compared with controls (mean±sd CII1 5.9±1.4% versus 5.1±1.0%, p=0.002; CII2 7.7±1.8% versus 6.8±1.4%, p=0.002) and presented strong correlation with LCI (CII1 r2=0.47 and CII2 r2=0.44 in CF patients). Classical VCap indices showed inferior discriminative ability (SIII 2.3±1.0%/L versus 1.9±0.7%/L, p=0.013; KPIv 3.9±1.3% versus 3.5±1.2%, p=0.071), while the correlation with LCI was weak (SIII r2=0.03; KPIv r2=0.08 in CF patients). CIIs showed lower intra-subject inter-trial variability, calculated as coefficient of variation for three and relative difference for two trials, than classical VCap indices, but higher than LCI (CII1 11.1±8.2% and CII2 11.0±8.0% versus SIII 16.3±13.5%; KPIv 15.9±12.8%; LCI 5.9%±4.2%). Conclusion CIIs detect ventilation inhomogeneity better than classical VCap indices and correlate well with LCI. However, further studies on their diagnostic performance and clinical utility are required.

Primary ciliary dyskinesia (PCD) is a genetic, heterogeneous disease caused by dysfunction of cilia. Evidence is sparse and reports of lung function in PCD patients range from normal to severe impairment. This systematic review and meta-analysis of studies of lung function in PCD patients examines the spirometric indices of PCD patients and differences by age group and sex. We searched PubMed, Embase and Scopus for studies that described lung function in 10 or more patients with PCD. We performed meta-analyses and meta-regression to explain heterogeneity. We included 24 studies, ranging from 13 to 158 patients per study. The most commonly reported spirometric indices were forced expiratory volume in 1 s (FEV1) and forced vital capacity presented as mean and standard deviation of percent predicted values. We found considerable heterogeneity for both parameters (I2=94–96%). The heterogeneity remained when we stratified the analysis by age; however, FEV1 in adult patients was lower. Even after taking into account explanatory factors, the largest part of the between-studies variance remained unexplained. Heterogeneity could be explained by genetic differences between study populations, methodological factors related to the variability of study inclusion criteria or details on the performance and evaluation of lung function measurements that we could not account for. Prospective studies therefore need to use standardised protocols and international reference values. These results underline the possibility of distinct PCD phenotypes as in other chronic respiratory diseases. Detailed characterisation of these phenotypes and related genotypes is needed in order to better understand the natural history of PCD.

Pulmonary exacerbations are a cause of significant morbidity in patients with primary ciliary dyskinesia (PCD) and are frequently used as an outcome measure in clinical research into chronic lung diseases. So far, there has been no consensus on the definition of pulmonary exacerbations in PCD. 30 multidisciplinary experts and patients developed a consensus definition for children and adults with PCD. Following a systematic review, the panel used a modified Delphi process with a combination of face-to-face meetings and e-surveys to develop a definition that can be used in research settings for children and adults with PCD. A pulmonary exacerbation was defined by the presence of three or more of the following seven items: 1) increased cough, 2) change in sputum volume and/or colour, 3) increased shortness of breath perceived by the patient or parent, 4) decision to start or change antibiotic treatment because of perceived pulmonary symptoms, 5) malaise, tiredness, fatigue or lethargy, 6) new or increased haemoptysis, and 7) temperature >38°C. The consensus panel proposed that the definition should be used for future clinical trials. The definition should be validated and the usability assessed during these studies.

Acute respiratory tract infections (ARI) in infancy have been implicated in the development of chronic respiratory disease, but the complex interplay between viruses, bacteria and host is not completely understood. We aimed to prospectively determine whether nasal microbiota changes occur between the onset of the first symptomatic ARI in the first year of life and 3 weeks later, and to explore possible associations with the duration of respiratory symptoms, as well as with host, environmental and viral factors. Nasal microbiota of 167 infants were determined at both time-points by 16S ribosomal RNA-encoding gene PCR amplification and subsequent pyrosequencing. Infants were clustered based on their nasal microbiota using hierarchical clustering methods at both time-points. We identified five dominant infant clusters with distinct microbiota at the onset of ARI but only three clusters after 3 weeks. In these three clusters, symptom persistence was overrepresented in the Streptococcaceae-dominated cluster and underrepresented in the cluster dominated by “Others” (p

Chronic respiratory symptoms, such as cough, wheeze and dyspnoea, are common in children; however, most research has, with the exception of a few large-scale clinical cohort studies, been performed in the general population or in small, highly-selected samples. The Swiss Paediatric Airway Cohort (SPAC) is a national, prospective clinical cohort of children and adolescents who visit physicians for recurrent conditions, such as wheeze and cough, and exercise-related respiratory problems. The SPAC is an observational study and baseline assessment includes standardised questionnaires for families and data extracted from hospital records, including results of clinically indicated investigations, diagnoses and treatments. Outcomes are assessed through annual questionnaires, monthly symptom reporting via mobile phone and follow-up visits. The SPAC will address important questions about clinical phenotypes, diagnosis, treatment, and the short- and long-term prognosis of common respiratory problems in children. The cohort currently consists of 347 patients from four major hospitals (Bern, Zurich, Basel and Lucerne), with 70–80 additional patients joining each month. More centres will join and the target sample size is a minimum of 3000 patients. The SPAC will provide real-life data on children visiting the Swiss healthcare system for common respiratory problems and will provide a research platform for health services research and nested clinical and translational studies.

Children with frequent respiratory symptoms in infancy have an increased risk for later wheezing, but the association with symptom dynamics is unknown. We developed an observer-independent method to characterise symptom dynamics and tested their association with subsequent respiratory morbidity. In this birth-cohort of healthy neonates, we prospectively assessed weekly respiratory symptoms during infancy, resulting in a time series of 52 symptom scores. For each infant, we calculated the transition probability between two consecutive symptom scores. We used these transition probabilities to construct a Markov matrix, which characterised symptom dynamics quantitatively using an entropy parameter. Using this parameter, we determined phenotypes by hierarchical clustering. We then studied the association between phenotypes and wheezing at 6 years. In 322 children with complete data for symptom scores during infancy (16 864 observations), we identified three dynamic phenotypes. Compared to the low-risk phenotype, the high-risk phenotype, defined by the highest entropy parameter, was associated with an increased risk of wheezing (odds ratio (OR) 3.01, 95% CI 1.15–7.88) at 6 years. In this phenotype, infants were more often male (64%) and had been exposed to environmental tobacco smoke (31%). In addition, more infants had siblings (67%) and attended childcare (38%). We describe a novel method to objectively characterise dynamics of respiratory symptoms in infancy, which helps identify abnormal clinical susceptibility and recovery patterns of infant airways associated with persistent wheezing.

Nitrogen multiple-breath washout (N2MBW) is increasingly used in patients with cystic fibrosis. The current European Respiratory Society/American Thoracic Society consensus statement for MBW recommends the rejection of measurements with leaks. However, it is unclear whether this is necessary for all types of leaks. Here, our aim was to 1) model and 2) apply air leaks, and 3) to assess their influence on the primary MBW outcomes of lung clearance index and functional residual capacity. We investigated the influence of air leaks at various locations (pre-, intra- and post-capillary), sizes, durations and stages of the washout. Modelled leaks were applied to existing N2MBW data from 10 children by modifying breath tables. In addition, leaks were applied to the equipment during N2MBW measurements performed by one healthy adolescent. All modelled and applied leaks resulted in statistically significant but heterogeneous effects on lung clearance index and functional residual capacity. In all types of continuous inspiratory leaks exceeding a certain size, the end of the washout was not reached. For practical application, we illustrated six different “red flags”, i.e. signs that enable easy identification of leaks during measurements. Air leaks during measurement significantly influence N2MBW outcomes. The influence of leaks on MBW outcomes is dependent on the location, relation to breath cycle, duration, stage of washout and size of the leak. We identified a range of signs to help distinguish leaks from physiological noise.

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 (FEV 1 ) 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 FEV 1 z-scores (β= -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., Competing Interests: Conflict of interest: M. Boon declares receiving grants or contracts from the Fund Alphonse and Jean Forton, managed by the King Baudouin Foundation, and by the Belgian Cystic Fibrosis Association (number 2020-J1810150-217926); and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Vertex. Conflict of interest: S.B. Carr declares receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chiesi Pharmaceuticals, and participation on a Data Safety Monitoring Board or Advisory Board for Vertex Pharmaceuticals. Conflict of interest: S. Dillenhöfer declares receiving support for attending meetings and/or travel from Vertex (Advance Program 2022). Conflict of interest: B. Karadag declares receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from VEM Ilac, Abdi Ibrahim and OMRON, and participating on a Data Safety Monitoring Board or Advisory Board for Abdi Ibrahim. Conflict of interest: C. Koerner-Rettberg declares receiving speaker honoraria from Berlin Chemie, and advisory board participation and being a member of the medical board of the German PCD patient organisation. Conflict of interest: V. Martinu declares having received grants or contracts from Ministry of Health of the Czech Republic (grant number NV19-07-00210) and participation on an advisory board for indication of tobramycin in noncystic fibrosis bronchiectasis for Chiesi, and receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chiesi Pharmaceuticals. Conflict of interest: A. Moreno-Galdó declares receiving personal payment for lectures from AstraZeneca, Sanofi-Pasteur and Janssen, receiving support for attending meetings or travel from Sanofi-Pasteur and Vivisol, participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca and Sanofi-Pasteur, and is President of the Spanish Society of Pediatric Pulmonology. Conflict of interest: U. Ozcelik is Head of the Turkish Respiratory Disease and Cystic Fibrosis Society (unpaid). Conflict of interest: P. Pohunek declares receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GlaxoSmithKline, AstraZeneca and Chiesi, and consulting fees, support for attending meetings and/or travel, and participation on a Data Safety Monitoring Board or Advisory Board from AstraZeneca and GlaxoSmithKline. Conflict of interest: J. Raidt declares receiving the following funds: DFG CRU326 RA3522/1. Conflict of interest: P. Latzin declares receiving grants or contracts from Vertex and OM Pharma, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Vertex, Vifor and OM Pharma, and participating on a Data Safety Monitoring Board or Advisory Board for the following: Polyphor, Santhera (DMC), Vertex, OM Pharma, Vifor, Allecra and Sanofi Aventis. Conflict of interest: J.S. Lucas declares receiving support for the present manuscript (funds the clinical investigations (spirometry, microbiology)) from NHS England, to the institution; and grants or contracts from COST ACTION to fund the BEATPCD COST Action BM1407, which funded the network that undertook this work, and the institution managed the funding. Conflict of interest: The other authors have nothing to disclose., (Copyright ©The authors 2024.)

Background: The effects of prenatal antibiotic exposure on respiratory morbidity in infancy and the involved mechanisms are still poorly understood. We aimed to examine whether prenatal antibiotic exposure in the third trimester is associated with nasal microbiome and respiratory morbidity in infancy and at school age, and whether this association with respiratory morbidity is mediated by the nasal microbiome., Methods: We performed 16S ribosomal RNA gene sequencing (regions V3-V4) on nasal swabs obtained from 296 healthy term infants from the prospective Basel-Bern birth cohort (BILD) at age 4-6 weeks. Information about antibiotic exposure was derived from birth records and standardised interviews. Respiratory symptoms were assessed by weekly telephone interviews in the first year of life and a clinical visit at age 6 years. Structural equation modelling was used to test direct and indirect associations accounting for known risk factors., Results: α-Diversity indices were lower in infants with antibiotic exposure compared to nonexposed infants ( e.g. Shannon index p-value 0.006). Prenatal antibiotic exposure was also associated with a higher risk of any, as well as severe, respiratory symptoms in the first year of life (risk ratio 1.38, 95% CI 1.03-1.84; adjusted p-value (p adj )=0.032 and risk ratio 1.75, 95% CI 1.02-2.97; p adj =0.041, respectively), but not with wheeze or atopy in childhood. However, we found no indirect mediating effect of nasal microbiome explaining these clinical symptoms., Conclusion: Prenatal antibiotic exposure was associated with lower diversity of nasal microbiome in infancy and, independently of microbiome, with respiratory morbidity in infancy, but not with symptoms later in life., Competing Interests: Conflict of interest: C. Rüttimann is partially funded by the Freie Akademische Gesellschaft Basel. The other authors declare no conflict of interest., (Copyright ©The authors 2023.)

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.)

Background: References from the Global Lung Function Initiative (GLI) are widely used to interpret children's spirometry results. We assessed fit for healthy schoolchildren., Methods: LuftiBus in the School was a population-based cross-sectional study undertaken in 2013-2016 in the canton of Zurich, Switzerland. Parents and their children aged 6-17 years answered questionnaires about respiratory symptoms and lifestyle. Children underwent spirometry in a mobile lung function lab. We calculated GLI-based z-scores for forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), FEV 1 /FVC and forced expiratory flow for 25-75% of FVC (FEF 25-75 ) for healthy White participants. We defined appropriate fit to GLI references by mean values between +0.5 and -0.5 z-scores. We assessed whether fit varied by age, body mass index, height and sex using linear regression models., Results: We analysed data from 2036 children with valid FEV 1 measurements, of whom 1762 also had valid FVC measurements. The median age was 12.2 years. Fit was appropriate for children aged 6-11 years for all indices. In adolescents aged 12-17 years, fit was appropriate for FEV 1 /FVC z-scores (mean±sd -0.09±1.02), but not for FEV 1 (-0.62±0.98), FVC (-0.60±0.98) and FEF 25-75 (-0.54±1.02). Mean FEV 1 , FVC and FEF 25-75 z-scores fitted better in children considered overweight (-0.25, -0.13 and -0.38, respectively) than normal weight (-0.55, -0.50 and -0.55, respectively; p-trend <0.001, 0.014 and <0.001, respectively). FEV 1 , FVC and FEF 25-75 z-scores depended on both age and height (p-interaction 0.033, 0.019 and <0.001, respectively)., Conclusion: GLI-based FEV 1 , FVC, and FEF 25-75 z-scores do not fit White Swiss adolescents well. This should be considered when using reference equations for clinical decision-making, research and international comparison., Competing Interests: Conflict of interest: A. Moeller reports receiving consulting fees from Vertex; payments or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events received from Vertex and Vifor; participation on a data safety monitoring or advisory board for Vertex; and leadership or fiduciary roles in other boards, societies, committees or advocacy groups, paid or unpaid, held for ERS Assembly 7 (Secretary), SGP board, SGPP board, SWGCF (co-president) and SSSCS (vice-president). All disclosures made outside the submitted work. F. Singer reports support for the present manuscript received from the Bern Lung League foundation and Kinderinsel foundation; and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events received from Vertex and Novartis, outside the submitted work. P. Latzin reports receiving grants or contracts from Vertex and Vifor, outside the submitted work; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events received from Vertex, Vifor and OM Pharma, outside the submitted work; and participation on a data safety monitoring or advisory board for Polyphor, Santhera (DMC), Vertex, OM Pharma and Vifor, outside the submitted work. J. Usemann reports receiving grants or contracts from the Swiss Lung Foundation and Palatin Foundation, Basel, Switzerland, outside the submitted work; and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events received from Vertex, outside the submitted work. R. Mozun reports support for the present manuscript received from the Institute of Social and Preventive Medicine, University of Bern, at which she is employed. The remaining authors have nothing to disclose., (Copyright ©The authors 2022.)

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., Competing Interests: Conflict of interest: N. Beydon declares no competing interests. Conflict of interest: T. Ferkol declares no competing interests. Conflict of interest: A.L. Harris declares no competing interests. Conflict of interest: M. Colas declares no competing interests. Conflict of interest: S.D. Davis declares grant NIH U54 HL09640958 funded by the Office of Rare Diseases Research (NCATS) in the 36 months prior to manuscript submission, and membership of the PCD Foundation Medical and Scientific Advisory Council. Conflict of interest: E. Haarman declares no competing interests. Conflict of interest: C. Hogg declares no competing interests. Conflict of interest: E. Kilbride declares no competing interests. Conflict of interest: P. Kouis declares no competing interests. Conflict of interest: C.E. Kuehni declares no competing interests. Conflict of interest: P. Latzin declares grants to their institution from Vertex and Vifor; payment to their institution and themself for lectures, presentations, speaker bureaus, manuscript writing or educational events from Vertex, Vifor and OM Pharma; and paid (to their institution and/or themself) participation on data safety monitoring or advisory boards for Polyphor, Santhera (DMC), Vertex, OM Pharma, Vifor and Sanofi Aventis, all in the 36 months prior to manuscript submission. Conflict of interest: D. Marangu declares no competing interests. Conflict of interest: J. Marthin declares no competing interests. Conflict of interest: K.G. Nielsen declares no competing interests. Conflict of interest: P. Robinson declares no competing interests. Conflict of interest: N. Rumman declares no competing interests. Conflict of interest: M. Rutter declares no competing interests. Conflict of interest: W. Walker declares no competing interests. Conflict of interest: J.S. Lucas declares no competing interests., (Copyright ©The authors 2022.)

Background: Volumetric capnography (VCap) is a simpler alternative to multiple-breath washout (MBW) to detect ventilation inhomogeneity in patients with cystic fibrosis (CF). However, its diagnostic performance is influenced by breathing dynamics. We introduce two novel VCap indices, the capnographic inhomogeneity indices (CIIs), that may overcome this limitation and explore their diagnostic characteristics in a cohort of CF patients., Methods: We analysed 320 N 2 -MBW trials from 50 CF patients and 65 controls (age 4-18 years) and calculated classical VCap indices, such as slope III (SIII) and the capnographic index (KPIv). We introduced novel CIIs based on a theoretical lung model and assessed their diagnostic performance compared to classical VCap indices and the lung clearance index (LCI)., Results: Both CIIs were significantly higher in CF patients compared with controls (mean±sd CII 1 5.9±1.4% versus 5.1±1.0%, p=0.002; CII 2 7.7±1.8% versus 6.8±1.4%, p=0.002) and presented strong correlation with LCI (CII 1 r 2 =0.47 and CII 2 r 2 =0.44 in CF patients). Classical VCap indices showed inferior discriminative ability (SIII 2.3±1.0%/L versus 1.9±0.7%/L, p=0.013; KPIv 3.9±1.3% versus 3.5±1.2%, p=0.071), while the correlation with LCI was weak (SIII r 2 =0.03; KPIv r 2 =0.08 in CF patients). CIIs showed lower intra-subject inter-trial variability, calculated as coefficient of variation for three and relative difference for two trials, than classical VCap indices, but higher than LCI (CII 1 11.1±8.2% and CII 2 11.0±8.0% versus SIII 16.3±13.5%; KPIv 15.9±12.8%; LCI 5.9%±4.2%)., Conclusion: CIIs detect ventilation inhomogeneity better than classical VCap indices and correlate well with LCI. However, further studies on their diagnostic performance and clinical utility are required., Competing Interests: Conflicts of interest: S. Fouzas has nothing to disclose. Conflicts of interest: A-C. Kentgens repots no other conflicts of interest. Conflicts of interest: O. Lagiou has nothing to disclose. Conflicts of interest: B.S. Frauchiger has nothing to disclose. Conflicts of interest: F. Wyler has nothing to disclose. Conflicts of interest: I. Theodorakopoulos has nothing to disclose. Conflicts of interest: S. Yammine repots no other conflicts of interest. Conflicts of interest: P. Latzin reports grants from Vertex and Vifor paid to his institution, personal fees and honoraria paid to his institution from Vertex, Vifor and OM Pharma, fees for participation on a data safety monitoring or advisory board from Santhera (DMC), and personal fees paid to his institution from Polyphor, Vertex, OM pharma and Vifor, all outside the submitted work. Support statement: The work was supported by Swiss National Science Foundation Grants (Yammine 179905 and Latzin 182719). A-C. Kentgens is a recipient of the Swiss Government Excellence Scholarship from The Swiss Confederation. Funding information for this article has been deposited with the Crossref Funder Registry., (Copyright ©The authors 2022.)

Objectives: Disease-specific, well-defined and validated clinical outcome measures are essential in designing research studies. Poorly defined outcome measures hamper pooling of data and comparisons between studies. We aimed to identify and describe pulmonary outcome measures that could be used for follow-up of patients with primary ciliary dyskinesia (PCD)., Methods: We conducted a scoping review by systematically searching MEDLINE, Embase and the Cochrane Database of Systematic Reviews online databases for studies published from 1996 to 2020 that included ≥10 PCD adult and/or paediatric patients., Results: We included 102 studies (7289 patients). 83 studies reported on spirometry, 11 on body plethysmography, 15 on multiple-breath washout, 36 on high-resolution computed tomography (HRCT), 57 on microbiology and 17 on health-related quality of life. Measurement and reporting of outcomes varied considerably between studies ( e.g. different scoring systems for chest HRCT scans). Additionally, definitions of outcome measures varied ( e.g. definition of chronic colonisation by respiratory pathogen), impeding direct comparisons of results., Conclusions: This review highlights the need for standardisation of measurements and reporting of outcome measures to enable comparisons between studies. Defining a core set of clinical outcome measures is necessary to ensure reproducibility of results and for use in future trials and prospective cohorts., Competing Interests: Conflict of interest: M. Goutaki and C.E. Kuehni report that the BEAT-PCD COST Action supported their travel to and attendance of meetings during the period 2015–2019. P. Latzin reports personal fees from Vertex, Novartis, Roche, Polyphor, Vifor, Gilead, Schwabe, Zambon and Santhera, and grants from Vertex, outside the submitted work. J.S. Lucas reports that on 2 December 2019 she attended the Rare Lung and Airway Diseases on Childhood meeting at the Primary Ciliary Dyskinesia and Neonatal Interstitial Lung Diseases Conference in Jerusalem, Israel, to deliver an invited lecture on monitoring disease progression in PCD; her local travel and accommodation were arranged by the conference organisers, and her international travel was supported by BEAT-PCD. All other authors have nothing to disclose., (Copyright ©The authors 2021.)

Background: Diagnosis of primary ciliary dyskinesia (PCD) is challenging since there is no gold standard test. The European Respiratory (ERS) and American Thoracic (ATS) Societies developed evidence-based diagnostic guidelines with considerable differences., Objective: We aimed to compare the algorithms published by the ERS and the ATS with each other and with our own PCD-UNIBE algorithm in a clinical setting. Our algorithm is similar to the ERS algorithm with additional immunofluorescence staining. Agreement (Cohen's κ) and concordance between the three algorithms were assessed in patients with suspicion of PCD referred to our diagnostic centre., Results: In 46 out of 54 patients (85%) the final diagnosis was concordant between all three algorithms (30 PCD negative, 16 PCD positive). In eight patients (15%) PCD diagnosis differed between the algorithms. Five patients (9%) were diagnosed as PCD only by the ATS, one (2%) only by the ERS and PCD-UNIBE, one (2%) only by the ATS and PCD-UNIBE, and one (2%) only by the PCD-UNIBE algorithm. Agreement was substantial between the ERS and the ATS (κ=0.72, 95% CI 0.53-0.92) and the ATS and the PCD-UNIBE (κ=0.73, 95% CI 0.53-0.92) and almost perfect between the ERS and the PCD-UNIBE algorithms (κ=0.92, 95% CI 0.80-1.00)., Conclusion: The different diagnostic algorithms lead to a contradictory diagnosis in a considerable proportion of patients. Thus, an updated, internationally harmonised and standardised PCD diagnostic algorithm is needed to improve diagnostics for these discordant cases., Competing Interests: Conflict of interest: M. Nussbaumer has nothing to disclose. Conflict of interest: E. Kieninger has nothing to disclose. Conflict of interest: S.A. Tschanz has nothing to disclose. Conflict of interest: S.T. Savas has nothing to disclose. Conflict of interest: C. Casaulta has nothing to disclose. Conflict of interest: M. Goutaki has nothing to disclose. Conflict of interest: S. Blanchon has nothing to disclose. Conflict of interest: A. Jung has nothing to disclose. Conflict of interest: N. Regamey has nothing to disclose. Conflict of interest: C.E. Kuehni has nothing to dislose. Conflict of interest: M. Goutaki has nothing to disclose. Conflict of interest: P. Latzin reports grants and personal fees from Vertex and Vifor, and personal fees from OM Pharma, Polyphor and Santhera (DMC), outside the submitted work. Conflict of interest: L. Müller has nothing to disclose., (Copyright ©The authors 2021.)

It has been postulated that some children with recurrent cough but no wheeze have a mild form of asthma (cough variant asthma), with similar risk factors and an increased risk of future wheeze. This longitudinal study compared risk factors for isolated night cough and for wheeze in the Leicester Respiratory Cohort in children aged 1, 4, 6 and 9 years and compared prognosis of children with isolated night cough, children with wheeze and asymptomatic children. We included 4101 children aged 1 year, 2854 aged 4 years, 2369 aged 6 years and 1688 aged 9 years. The prevalence of isolated night cough was 10% at age 1 year and 18% in older children. Prevalence of wheeze decreased from 35% at 1 year to 13% at 9 years. Although several risk factors were similar for cough and wheeze, day care, reflux and family history of bronchitis were more strongly associated with cough, and male sex and family history of asthma with wheeze. Over one-third of preschool children with cough continued to cough at school age, but their risk of developing wheeze was similar to that of children who were asymptomatic at earlier surveys. Wheeze tracked more strongly throughout childhood than cough. In conclusion, our study showed that only some risk factors for cough and wheeze were shared but many were not, and there was little evidence for an increased risk of future wheeze in children with isolated night cough. This provides little support for the hypothesis that recurrent cough without wheeze may indicate a variant form of asthma., Competing Interests: Conflict of interest: M. Jurca has nothing to disclose. Conflict of interest: M. Goutaki has nothing to disclose. Conflict of interest: P. Latzin has nothing to disclose. Conflict of interest: E.A. Gaillard has nothing to disclose. Conflict of interest: B.D. Spycher has nothing to disclose. Conflict of interest: C.E. Kuehni has nothing to disclose., (Copyright ©ERS 2020.)

Primary ciliary dyskinesia (PCD) is a genetic, heterogeneous disease caused by dysfunction of cilia. Evidence is sparse and reports of lung function in PCD patients range from normal to severe impairment. This systematic review and meta-analysis of studies of lung function in PCD patients examines the spirometric indices of PCD patients and differences by age group and sex. We searched PubMed, Embase and Scopus for studies that described lung function in 10 or more patients with PCD. We performed meta-analyses and meta-regression to explain heterogeneity. We included 24 studies, ranging from 13 to 158 patients per study. The most commonly reported spirometric indices were forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity presented as mean and standard deviation of percent predicted values. We found considerable heterogeneity for both parameters ( I 2 =94-96%). The heterogeneity remained when we stratified the analysis by age; however, FEV 1 in adult patients was lower. Even after taking into account explanatory factors, the largest part of the between-studies variance remained unexplained. Heterogeneity could be explained by genetic differences between study populations, methodological factors related to the variability of study inclusion criteria or details on the performance and evaluation of lung function measurements that we could not account for. Prospective studies therefore need to use standardised protocols and international reference values. These results underline the possibility of distinct PCD phenotypes as in other chronic respiratory diseases. Detailed characterisation of these phenotypes and related genotypes is needed in order to better understand the natural history of PCD., Competing Interests: Conflict of interest: F.S. Halbeisen has nothing to disclose. Conflict of interest: A. Jose has nothing to disclose. Conflict of interest: C. de Jong has nothing to disclose. Conflict of interest: S. Nyilas has nothing to disclose. Conflict of interest: P. Latzin reports personal fees from Gilead, Novartis, Polyphor, Roche, Santhera, Schwabe, Vertex, Vifor and Zambon, all outside the submitted work. Conflict of interest: C.E. Kuehni has nothing to disclose. Conflict of interest: M. Goutaki has nothing to disclose.

Pulmonary exacerbations are a cause of significant morbidity in patients with primary ciliary dyskinesia (PCD) and are frequently used as an outcome measure in clinical research into chronic lung diseases. So far, there has been no consensus on the definition of pulmonary exacerbations in PCD. 30 multidisciplinary experts and patients developed a consensus definition for children and adults with PCD. Following a systematic review, the panel used a modified Delphi process with a combination of face-to-face meetings and e-surveys to develop a definition that can be used in research settings for children and adults with PCD. A pulmonary exacerbation was defined by the presence of three or more of the following seven items: 1) increased cough, 2) change in sputum volume and/or colour, 3) increased shortness of breath perceived by the patient or parent, 4) decision to start or change antibiotic treatment because of perceived pulmonary symptoms, 5) malaise, tiredness, fatigue or lethargy, 6) new or increased haemoptysis, and 7) temperature >38°C. The consensus panel proposed that the definition should be used for future clinical trials. The definition should be validated and the usability assessed during these studies., Competing Interests: Conflict of interest: J.S. Lucas reports grants, personal fees and nonfinancial support from Aerocrine/Circassia, grants and personal fees from Vertex, and grants from Parion, outside the submitted work. Conflict of interest: F. Gahleitner has nothing to disclose. Conflict of interest: A. Amorim reports personal fees from Zambon and personal fees from Vertex, outside the submitted work. Conflict of interest: M. Boon reports a postdoctoral research grant from KOOR, University Hospital Leuven, outside the submitted work. Conflict of interest: P. Brown has nothing to disclose. Conflict of interest: C. Constant has nothing to disclose. Conflict of interest: S. Cook has nothing to disclose. Conflict of interest: S. Crowley has nothing to disclose. Conflict of interest: D.M.S. Destouches has nothing to disclose. Conflict of interest: E. Eber has nothing to disclose. Conflict of interest: H. Mussaffi has nothing to disclose. Conflict of interest: E. Haarman has nothing to disclose. Conflict of interest: A. Harris has nothing to disclose. Conflict of interest: C. Koerner-Rettberg has nothing to disclose. Conflict of interest: C.E. Kuehni has nothing to disclose. Conflict of interest: P. Latzin reports personal fees from Vertex, Novartis, Roche, Polyphor, Vifor, Gilead, Schwabe, Zambon, Santhera and Vertex, outside the submitted work. Conflict of interest: M.R. Loebinger reports personal fees from Bayer, Griffols, Polyphor and Raptor, and other support from Parion, outside the submitted work. Conflict of interest: N. Lorent reports personal fees from Chiesi, and nonfinancial support from Insmed and Mylan, outside the submitted work. Conflict of interest: B. Maitre has nothing to disclose. Conflict of interest: A. Moreno-Galdó reports personal fees from AbbVie, and other support from AbbVie, Actelion and Novartis, outside the submitted work. Conflict of interest: K.G. Nielsen has nothing to disclose. Conflict of interest: U. Özçelik has nothing to disclosure Conflict of interest: L.K.D. Philipsen has nothing to disclose. Conflict of interest: P. Pohunek reports personal fees from Novartis, Sandoz and Teva, grants from Teva, and personal fees from Stallergenes, S&D Pharma, ALK and Boehringer Ingelheim, outside the submitted work. Conflict of interest: E. Polverino reports personal fees from Bayer, Insmed and Grifols, Zambon, grants and personal fees from Chiesi, and personal fees from Polyphor, during the conduct of the study; none of these fees and grants were strictly related with the topic of this manuscript. Conflict of interest: J. Rademacher has nothing to disclose. Conflict of interest: P. Robinson has nothing to disclose. Conflict of interest: D. Snijders has nothing to disclose. Conflict of interest: P. Yiallouros has nothing to disclose. Conflict of interest: S.B. Carr reports personal fees and other support from Vertex Pharmaceuticals, other support from Chiesi Ltd, personal fees from Teva Pharmaceutical Industries and other support from Pharmaxis Pharmaceuticals Ltd, outside the submitted work.

Chronic respiratory symptoms, such as cough, wheeze and dyspnoea, are common in children; however, most research has, with the exception of a few large-scale clinical cohort studies, been performed in the general population or in small, highly-selected samples. The Swiss Paediatric Airway Cohort (SPAC) is a national, prospective clinical cohort of children and adolescents who visit physicians for recurrent conditions, such as wheeze and cough, and exercise-related respiratory problems. The SPAC is an observational study and baseline assessment includes standardised questionnaires for families and data extracted from hospital records, including results of clinically indicated investigations, diagnoses and treatments. Outcomes are assessed through annual questionnaires, monthly symptom reporting via mobile phone and follow-up visits. The SPAC will address important questions about clinical phenotypes, diagnosis, treatment, and the short- and long-term prognosis of common respiratory problems in children. The cohort currently consists of 347 patients from four major hospitals (Bern, Zurich, Basel and Lucerne), with 70-80 additional patients joining each month. More centres will join and the target sample size is a minimum of 3000 patients. The SPAC will provide real-life data on children visiting the Swiss healthcare system for common respiratory problems and will provide a research platform for health services research and nested clinical and translational studies., Competing Interests: Conflict of interest: P. Latzin reports receiving personal fees from Gilead, Novartis, Roche, Schwabe, Vertex, Vifor and Zambon outside the submitted work.

Children with frequent respiratory symptoms in infancy have an increased risk for later wheezing, but the association with symptom dynamics is unknown. We developed an observer-independent method to characterise symptom dynamics and tested their association with subsequent respiratory morbidity. In this birth-cohort of healthy neonates, we prospectively assessed weekly respiratory symptoms during infancy, resulting in a time series of 52 symptom scores. For each infant, we calculated the transition probability between two consecutive symptom scores. We used these transition probabilities to construct a Markov matrix, which characterised symptom dynamics quantitatively using an entropy parameter. Using this parameter, we determined phenotypes by hierarchical clustering. We then studied the association between phenotypes and wheezing at 6 years. In 322 children with complete data for symptom scores during infancy (16 864 observations), we identified three dynamic phenotypes. Compared to the low-risk phenotype, the high-risk phenotype, defined by the highest entropy parameter, was associated with an increased risk of wheezing (odds ratio (OR) 3.01, 95% CI 1.15-7.88) at 6 years. In this phenotype, infants were more often male (64%) and had been exposed to environmental tobacco smoke (31%). In addition, more infants had siblings (67%) and attended childcare (38%). We describe a novel method to objectively characterise dynamics of respiratory symptoms in infancy, which helps identify abnormal clinical susceptibility and recovery patterns of infant airways associated with persistent wheezing., Competing Interests: Conflict of interest: P. Latzin reports receiving personal fees from Vertex, Novartis, Roche, Polyphor, Vifor and Gilead outside the submitted work.

Nitrogen MBW is susceptible to leaks; effects of leaks on sulfur hexafluoride MBW require further study http://ow.ly/iY6o30lGchV., Competing Interests: Conflict of interest: None declared.

Lung clearance index (LCI) is the main outcome of the multiple-breath washout (MBW) test. Current recommendations for LCI acquisition are based on low-grade evidence. The aim of this study was to challenge those recommendations using alternative methods for LCI analysis. Nitrogen MBW measurements from school-aged children, 20 healthy controls, 20 with cystic fibrosis (CF) and 17 with primary ciliary dyskinesia (PCD), were analysed using 1) current algorithms (standard), 2) three alternative algorithms to detect with higher precision the end of MBW testing and 3) two alternative algorithms to determine exhaled tracer gas concentrations. LCI values, intra-test repeatability, and ability to discriminate between health and lung disease were compared between these methods. The analysis methods strongly influenced LCI (mean±sd overall differences (%) between standard and alternative analysis methods: -4.9±5.7%; range: -66-19%), but did not improve intra-test variability. Discrimination between health and disease was comparable as areas under the receiver operator curves were not greater than that from standard analysis. This study supports current recommendations for LCI calculation in children. Alternative methods influence LCI estimates and hamper comparability between MBW setups. Alternative algorithms, whenever used, should be carefully reported., Competing Interests: Conflict of interest: None declared.

Nitrogen multiple-breath washout (N 2 MBW) is increasingly used in patients with cystic fibrosis. The current European Respiratory Society/American Thoracic Society consensus statement for MBW recommends the rejection of measurements with leaks. However, it is unclear whether this is necessary for all types of leaks. Here, our aim was to 1) model and 2) apply air leaks, and 3) to assess their influence on the primary MBW outcomes of lung clearance index and functional residual capacity. We investigated the influence of air leaks at various locations (pre-, intra- and post-capillary), sizes, durations and stages of the washout. Modelled leaks were applied to existing N 2 MBW data from 10 children by modifying breath tables. In addition, leaks were applied to the equipment during N 2 MBW measurements performed by one healthy adolescent. All modelled and applied leaks resulted in statistically significant but heterogeneous effects on lung clearance index and functional residual capacity. In all types of continuous inspiratory leaks exceeding a certain size, the end of the washout was not reached. For practical application, we illustrated six different "red flags", i.e. signs that enable easy identification of leaks during measurements. Air leaks during measurement significantly influence N 2 MBW outcomes. The influence of leaks on MBW outcomes is dependent on the location, relation to breath cycle, duration, stage of washout and size of the leak. We identified a range of signs to help distinguish leaks from physiological noise., Competing Interests: Conflict of interest: None declared.