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Background The lung clearance index (LCI) is increasingly used as an outcome in clinical trials of patients with mild cystic fibrosis (CF) lung disease. Yet, understanding the impact of standard CF respiratory therapy on LCI is needed. We assessed to what degree withdrawal of nebulised dornase alfa affected LCI in school-age children with CF not receiving CFTR modulators or hydrator therapy. Methods A single-centre, randomised, controlled, parallel group study to determine effects of one month's withdrawal of nebulised dornase alfa (intervention) in 5-18 years old children with CF. Remaining chronic maintenance therapy stayed unchanged. Outcome measures were assessed at two visits one month apart. Primary outcome was absolute change in LCI. Secondary outcomes were FEV1, FEF25–75 and CF Questionnaire-revised (CFQ-R) respiratory symptom score. Possible harmful effects were assessed by comparing the occurrence of pulmonary exacerbations between groups. Results Twenty-eight children (median age 10.4 [interquartile range: 7.6; 13.5] years) with CF received standard care (n = 14) or intervention (n = 14). Compared with the control group, LCI increased (worsened) 1.74 (95% confidence interval: 0.62; 2.86) during withdrawal of dornase alfa, while FEV1 (-6.8% predicted) and FEF25–75 (-13.1% predicted) decreased significantly. Change in CFQ-R respiratory symptom score and the occurrence of pulmonary exacerbations did not differ significantly between groups. Conclusions One month's withdrawal of dornase alfa caused increasing ventilation inhomogeneity and deteriorating FEV1 and FEF25–75 in school-age children with mild CF. Hence, adherence to dornase alfa optimally needs to be addressed when using LCI and spirometric parameters as endpoints, even in short-term clinical trials.

A mannose-binding lectin (MBL) deficiency, due to MBL2 gene polymorphisms, is suggested to increase susceptibility to respiratory tract infections, particularly in young children. This study aimed to determine whether a MBL deficiency might be associated with pulmonary morbidity in children with recurrent pulmonary infections of unknown pathogenesis. We performed a retrospective, cross-sectional study on children referred to a tertiary pediatric pulmonary center between 2006 and 2011. We included children with a conclusive MBL2 genotype that exhibited recurrent pulmonary infections without any obvious explanatory findings. Pulmonary morbidity was estimated by lung function, body mass index, antibiotic prescriptions, and the odds ratio of radiological structural lung changes, assessed with chest X-rays or high-resolution computed tomography. One hundred thirteen children were included. No significant differences in lung function (z-scores), body mass index, or the number of annual courses of antibiotics pe...

Introduction: Multiple breath washout (MBW) is used for early detection of cystic fibrosis (CF) lung disease, with SF6MBW commonly viewed as the reference method. The use of N2MBW in infants and toddlers has been questioned for technical and physiological reasons, but a new correction of the N2signal has minimized the technical part. The present study aimed to assess the remaining differences and the contributing mechanisms for the differences between SF6 and N2MBW,corrected—such as tidal volume reduction during N2 washout with pure O2. Method: This was a longitudinal multicenter cohort study. SF6MBW and N2MBW 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 SF6MBW. 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 N2MBWcorrected, compared to SF6MBW (−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 N2MBW did not affect differences. The corrected N2MBW can now be used with confidence in young children with CF, although not interchangeably with SF6.

Aim: As no data to our knowledge exist, the aim of the study was to describe the national prevalence and characteristics of Danish children and adolescents with severely impaired lung function. Methods: We performed a descriptive, cross-sectional Danish multi-centre study. Children and adolescents between 6 and 18 years old demonstrating severely impaired lung function from 2015 to 2018, defined by forced expiratory volume in 1 second (FEV1) 1 was 46.1% (10.1%) of predicted, and z-score was −4.5 (0.8). The most frequent diagnosis was cystic fibrosis (20.4%), followed by asthma (19.5%) and bronchiolitis obliterans (16.8%), while almost 25% had different elements of airway malformations or non-pulmonary conditions. Two adolescents with cystic fibrosis underwent lung transplantation. Conclusion: The estimated prevalence of severely impaired lung function in Danish children and adolescents was low, and extremely, few children underwent lung transplantation. The most frequent diagnosis was cystic fibrosis, while almost 25% had different elements of airway malformations or non-pulmonary conditions, which may require clinical attention.

Multiple breath washout (MBW) is used for early detection of cystic fibrosis (CF) lung disease, with SFThis was a longitudinal multicenter cohort study. SFMean functional residual capacity, FRCOnly minor residual differences between FRC

BACKGROUND Pulmonary chronic graft-vs-host disease (cGvHD) after hematopoietic stem cell transplantation (HSCT) is characterized by impairment of the small airways. Assessment of lung clearance index (LCI) gained from multiple breath washout (MBW) is more sensitive than spirometry in detection of small airways disease. The aim of this study was to describe the development of LCI during the first year after pediatric HSCT and how LCI relates to other pulmonary function parameters and cGvHD. METHODS This prospective, longitudinal study included 28 pediatric HSCT-recipients. Spirometry, Sulfur hexafluoride MBW and diffusion capacity of the lungs were performed before and at 3, 6, 9, and 12 months after HSCT. Respiratory symptoms and signs of cGvHD were recorded at each visit. RESULTS Before HSCT, 47.8% had abnormal LCI and 12.5% had abnormal forced expiratory volume in 1 second (FEV1 ). Patients with persisting respiratory symptoms 12 months post-HSCT had higher median LCI (factor 5.7, P = 0.0018) and lower FEV1 z-scores (-1.5, P = 0.033) post-HSCT compared to patients free of respiratory symptoms. Overall, post-HSCT LCI values were 3.49 times higher and FEV1 was 2.31 z-scores lower in eight patients with cGvHD in any organ system compared with patients without cGvHD (P = 0.0089 and P

Background: Exercise-induced laryngeal obstruction (EILO) is an important cause of exertional breathlessness and wheeze. Epidemiological understanding of EILO remains unclear and arises largely from Scandinavian countries. We provide the first international perspective on the demographic characteristics, laryngeal abnormalities and impact of EILO. Methods: Retrospective database review (from 5 expert centres in Denmark, UK, & USA), for patients undergoing clinical asthma and EILO work-up with continuous laryngoscopy during exercise (CLE) testing between 2014–2018. Results: A total of 1,007 individuals completed CLE, of these 586 (58%) demonstrated EILO. Demographic characteristics for cases with EILO were similar across centres; median age of 21 (80% were ≤ 34), a female preponderance (76%) and median 2-year delay to diagnosis; 20% were found to not have asthma despite prescription of inhalers. Half (49%) of subjects were elite athletes. Supraglottic EILO (i.e. collapse of the arytenoid structures) was the predominant form and only 18% had glottic level (i.e. vocal cord dysfunction [VCD]) closure. Conclusion: This international collaboration reveals similarities in the clinical characteristics of EILO highlighting delay to diagnosis, inappropriate asthma treatment and that exercise induced VCD is a misnomer. These findings help to further define this condition and improve clinician’s recognition.

Background Progression of structural lung disease (SLD) is a major risk factor for morbidity in patients with cystic fibrosis (CF). We studied changes in SLD and correlations with spirometry and nitrogen multiple breath washout (N2MBW) outcomes to explore associations in contemporary evolution between structural and functional abnormalities in CF lung disease. Methods Spirometry-controlled chest-CTs using PRAGMA-CF for scoring extent of SLD, spirometry, and N2MBW were performed at two-year intervals in school-age children with CF. Results Fifty-seven children aged 6–18 years were included. No significant progression in mean PRAGMA-CF scores was observed. Half of the children showed improvement in the proportion of bronchiectasis (%Bx). Lung Clearance Index (LCI) and the second moment ratio (M2) increased significantly and baseline values correlated significantly with SLD at follow-up (p ≤ 0.0002). The correlation between the change in M2 (∆M2) and the change in total SLD was R = 0.27 (p = 0.048). We found high negative predictive values (100%) for ∆M2 Conclusions We found no progression in SLD over 2 years in school-age children with CF, in contrast to both LCI and M2, which along with discordant outcomes in half of the children underlines that N2MBW and CT assess different aspects of CF lung disease. However, stable outcomes from N2MBW were associated with stable structural lung disease.

Ex-premature school children show mild-to-moderate airway obstruction and decreased CO diffusing capacity. Multiple breath nitrogen washout (N2MBW) and NO diffusing capacity (DLNO) measurements may provide new insight into long-term pulmonary and vascular impairment in bronchopulmonary dysplasia (BPD).We examined a randomly selected group of 70 ex-premature children (gestational age28 weeks or birth weight1500 g; 42 with and 28 without BPD) and 38 term-born healthy controls of 8-13 years of age. Subjects performed N2MBW (lung clearance index, LCI; Sacin, and Scond), DLNO (membrane related diffusing capacity, Dm and pulmonary capillary volume, Vc), Fractional exhaled NO, CO diffusing capacity, conventional spirometry (FEV1, FVC, FEF25-75) and plethysmography (RV, TLC). Respiratory symptoms were assessed by questionnaire.Compared to healthy controls, the BPD group had higher z-scores for lung clearance index (P = 0.003), Sacin (P = 0.005), lower CO diffusing capacity (P = 0.025), DLNO (P = 0.022), DLNO/VA z-scores (P = 0.025) and a significant larger proportion had respiratory complaints. Amongst ex-premature children, the BPD group did not differ from the non-BPD group except for a decreased Dm (P = 0.023). Ex-premature with BPD showed predominantly airway obstruction (FEV1/FVC; P 0.0001), signs of hyperinflation (RV/TLC-ratio; P = 0.028), and 25% had a positive bronchodilator response (12% in FEV1).Ex-premature school children exhibited relatively mild but significant long-term respiratory symptoms and pulmonary peripheral impairment judged by N2MBW and DLNO measurements along with well-known airway obstruction. Larger longitudinal studies are needed to assess the clinical use of these advanced methods of assessing ventilation inhomogeneity and DLNO.

Background Knowledge of between-session variability of nitrogen multiple-breath washout (N 2 MBW) indices is crucial when designing longitudinal interventional studies and in disease monitoring using N 2 MBW as end-point. Such information is currently sparse. Methods Monthly triplets of N 2 MBW were prospectively obtained from 14 children with CF during one year. Linear mixed models were used to analyze variability. Our aim was to assess between-session variability of N 2 MBW indices from repeated measurements and compare LCI derived from different software packages currently in use (TestPoint® vs. Spiroware®). Results Baseline LCI (median; range) was 9.37 (6.82; 12.08). Between-session differences in LCI measurements were up to 25%. Intra Class Correlation-Coefficient was 0.82. There was no systematic difference between LCI measurements derived from the two software packages ( p =0.18); however, variability was significantly higher using Spiroware®. Conclusions We report between-session variability of LCI using N 2 MBW in school-age children and adolescents with CF. LCI changes exceeding 25% may be considered clinically relevant. TestPoint® and Spiroware® can be used interchangeably in longitudinal studies.

Interstitial Lung disease, Nephrotic syndrome and Epidermolysis Bullosa, also referred to as ILNEB syndrome is an extremely rare autosomal recessive condition, caused by pathogenic variants in ITGA3. 11 patients have previously been diagnosed with ILNEB syndrome of whom 7 died in infancy or early childhood. We report the only patient with ILNEB syndrome who survived past adolescence, partly due to a double lung transplant. Additionally, our patient showed oral, nasal and gynecological symptoms not previously reported in patients with ILNEB syndrome.

Hypothesis Using increase in the lung clearance index (LCI) as a trigger for bronchoalveolar lavage (BAL) and associated antimicrobial treatment might benefit clinical outcomes in children with cystic fibrosis (CF). Methods A 2-year, longitudinal, interventional, randomized, controlled pilot study with quarterly visits in 5–18 years old children with CF. LCI and z-scores for the forced expired volume in 1 s (zFEV1) and body mass index (zBMI) were obtained at every visit, CF Questionnaire-revised (CFQ-R) yearly and BAL and chest computed tomography at first and last visit. Children in the intervention group had BAL performed if LCI increased >1 unit from a fixed baseline value established at first visit. If the presence of a pathogen was documented in the BAL fluid, treatment was initiated/altered accordingly. Results Twenty-nine children with CF were randomized to the control (n = 14) and intervention group (n = 15). The median (interquartile range) number of BAL procedures per child was 2.5 (2.0; 3.0) and 6.0 (4.0; 7.0) in the control and intervention group, respectively. There was no significant difference between groups in slope for the primary outcome LCI; difference was 0.21 (95% confidence interval: -0.45; 0.88) units/year. Likewise, there was no significant difference between groups in slope for the secondary outcomes zFEV1, zBMI, CFQ-R respiratory symptom score and the proportion of total disease and trapped air on chest computed tomography. Conclusions LCI-triggered BAL and associated antimicrobial treatment did not benefit clinical outcomes in a small cohort of closely monitored school-age children with CF.

This document provides recommendations for monitoring and treatment of children in whom bronchopulmonary dysplasia (BPD) has been established and who have been discharged from the hospital, or who were >36 weeks of postmenstrual age. The guideline was based on predefined Population, Intervention, Comparison and Outcomes (PICO) questions relevant for clinical care, a systematic review of the literature and assessment of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. After considering the balance of desirable (benefits) and undesirable (burden, adverse effects) consequences of the intervention, the certainty of the evidence, and values, the task force made conditional recommendations for monitoring and treatment of BPD based on very low to low quality of evidence. We suggest monitoring with lung imaging using ionising radiation in a subgroup only, for example severe BPD or recurrent hospitalisations, and monitoring with lung function in all children. We suggest to give individual advice to parents regarding daycare attendance. With regards to treatment, we suggest the use of bronchodilators in a subgroup only, for example asthma-like symptoms, or reversibility in lung function; no treatment with inhaled or systemic corticosteroids; natural weaning of diuretics by the relative decrease in dose with increasing weight gain if diuretics are started in the neonatal period; and treatment with supplemental oxygen with a saturation target range of 90–95%. A multidisciplinary approach for children with established severe BPD after the neonatal period into adulthood is preferable. These recommendations should be considered until new and urgently needed evidence becomes available.

The use of pulmonary function tests (PFTs) has been widely described in airway diseases like asthma and cystic fibrosis, but for children's interstitial lung disease (chILD), which encompasses a broad spectrum of pathologies, the usefulness of PFTs is still undetermined, despite widespread use in adult interstitial lung disease. A literature review was initiated by the COST/Enter chILD working group aiming to describe published studies, to identify gaps in knowledge and to propose future research goals in regard to spirometry, whole-body plethysmography, infant and pre-school PFTs, measurement of diffusing capacity, multiple breath washout and cardiopulmonary exercise tests in chILD. The search revealed a limited number of papers published in the past three decades, of which the majority were descriptive and did not report pulmonary function as the main outcome.PFTs may be useful in different stages of management of children with suspected or confirmed chILD, but the chILD spectrum is diverse and includes a heterogeneous patient group in all ages. Research studies in well-defined patient cohorts are needed to establish which PFT and outcomes are most relevant for diagnosis, evaluation of disease severity and course, and monitoring individual conditions both for improvement in clinical care and as end-points in future randomised controlled trials. ispartof: EUROPEAN RESPIRATORY REVIEW vol:29 issue:157 ispartof: location:England status: published

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

Introduction: Use of maintenance therapy with the macrolide antibiotic azithromycin (AZI) is increasing in different chronic respiratory disorders incl. primary ciliary dyskinesia (PCD), although no clear evidence exists in PCD. Aims and Objectives: The primary objective was to determine efficacy of AZI maintenance therapy on respiratory exacerbations in PCD. The secondary objectives were to determine efficacy on lung function, health-related quality of life, sputum microbiology, and hearing impairment, and assess safety. Methods: Patients with confirmed diagnosis of PCD, age 7-50 years, were enrolled in this European multi-centre, parallel group, double-blind, randomized, placebo-controlled trial. Participants were randomly assigned to AZI 250/500 mg according to body weight ( Results: A total of 90 participants were randomized - 49 assigned to AZI and 41 to placebo. The AZI group had significant lower rate of exacerbations (rate ratio 0.46, 95%CI: 0.27; 0.80, p=0.006) and pathogenic bacterial species in sputum (rate ratio 0.39, 95%CI: 0.24; 0.64, p=0.0002), compared to the placebo group. There was no significant difference between the treatment groups in lung function, hearing level, or Respiratory symptoms, Sinus symptoms and Ear & hearing symptoms on the quality of life measure. Gastrointestinal complaints were more common in the AZI group. Conclusions: This first multi-national randomized controlled trial on pharmacotherapy in PCD showed that maintenance AZI for 6 months was safe and reduced rate of respiratory exacerbations and rate of pathogenic bacterial species in sputum to less than half.

Compartment analysis (CA) based on nitrogen multiple-breath washout (NCross-sectional multicenter observational study in children with CF and healthy controls (HC) was done with the assessment of NA total of 125 children with CF and 177 HC, median age 10.8 (range, 2.8-18.9) years, were included in the analysis. CA could be calculated in 66 (53%) children with CF compared with 48 (27%) HC (P .0001). The proportion of the slower-ventilating lung compartment was significantly smaller in children with CF (53.5%; 95% confidence interval [CI]: 51.9%-55.7%) compared with HC (62.2%; 95% CI: 59.0%-65.0%) The regional specific ventilation of the slower compartment (rVCA is less feasible in children than in adults and correlated to other MBW parameters. The clinical value of CA is still unclear and is yet to be established.

OBJECTIVE Primary ciliary dyskinesia (PCD) is a congenital lung disease that leads to recurrent and chronic lung infection. The resulting inflammation causes lung damage and declines in lung function. Mannose-binding lectin (MBL) is a first line host defense protein of importance for the innate immunity. Polymorphisms in the MBL gene named MBL2 result in unstable and low functional levels MBL proteins. MBL insufficiency is linked to an increased risk of lung infection and to declines in lung function in patients with cystic fibrosis. We investigated whether there is a similar link in patients with PCD. METHODS This retrospective longitudinal study included 85 patients with PCD. Diagnostics and age at diagnosis were recorded, complete spirometry data starting at diagnosis, and Pseudomonas aeruginosa infection status over the last 2 years were collected, and the patients were grouped according to MBL2 genotype status (MBL2-sufficient or MBL2-deficient). RESULTS MBL-deficient patients were diagnosed almost 3 years earlier than MBL-sufficient patients (median 6.1 vs 8.9 years, P

Summary Background and aims: Exercise-induced inspiratory symptoms (EIIS) have multiple causes, one of which is exercise-induced laryngeal obstruction (EILO). There is limited knowledge regarding EIIS in children, both in primary care practices and in pediatric asthma clinics. The aim of this study was to describe the feasibility of a diagnostic methodology and its results in a cohort of children with EIIS referred to our tertiary pediatric pulmonary center. Methods: This study analyzed consecutively collected data in children from East Denmark and Greater Copenhagen referred during a 3½ years period. The continuous laryngoscopy exercise (CLE) test directly visualizes the larynx using a flexible laryngoscope during a maximal exercise test. A post-test questionnaire evaluated the subjective impact of the examination. Results: The study included 60 children (37 girls/23 boys) with a mean age of 14 years (range 9–18). The feasibility of the CLE test was 98%; 18 children (35%) had EILO, while 33 children (61%) showed no abnormalities. Other laryngeal abnormalities were observed in three children before the exercise test. Asthma medication was successfully discontinued in 13 (72%) children with EILO. A significantly greater proportion of children shown to have EILO in the CLE test reported coping better with their EIIS than children with negative test (85% vs. 45%; P = 0.03). Conclusions: Continuous laryngoscopy during exercise is feasible and useful for identifying children with EILO. A correct diagnosis of EILO can help relieve patient anxiety, improve their coping with symptoms, and prevent unnecessary long-term and potentially harmful asthma treatments involving high-dose inhaled steroids. Pediatr Pulmonol. 2016;51:1200–1205. © 2016 Wiley Periodicals, Inc.

Background: Severe postinfectious diffuse pulmonary disease may clinically mimic other entities of children's interstitial lung disease and is clinically challenging comprising various disease severities despite treatment. Long-term lung function trend and physical capacity in children with postinfectious diffuse pulmonary disease are rarely reported. We investigated trends in pulmonary function by long-term follow-up and assessed physical capacity in such patients. Methods: We performed a descriptive, single-center follow-up study in children with biopsy-verified postinfectious diffuse pulmonary disease. Patients with completed primary treatment course were eligible for follow-up, including pulmonary function and exercise (VO2peak) testing. Results: Thirty patients with postinfectious diffuse pulmonary disease were identified and included. Median (range) age at diagnose was 27.5 (2-172) months after a mean lag time of 23 months. H. influenzae and rhinovirus were the most frequent pathogens. Fifteen patients were available for follow-up after mean (range) 7.6 (2-15) years of treatment completion. Lung clearance index (LCI2.5), forced expiratory volume in 1 second (FEV1), and bronchodilator responsiveness were abnormal in 80%, 53%, and 44%, respectively. Diffusion capacity for monoxide was abnormal in 7% and total lung capacity in 33%. Only 8% demonstrated low VO2peak, while 40% reported difficulties during physical exertion. Longitudinal data on spirometry (n = 14) remained unchanged from end of treatment throughout follow-up. A significant association was found between zLCI2.5 and zFEV1 (multiple linear regression; r2 = 0.61; P = 0.0003). Conclusion: Postinfectious diffuse pulmonary disease in children carries a varying degree of chronic pulmonary impairment with onset of symptoms in the first months of life and a typical considerable lag time before diagnosis. Follow-up several years after the initial injury demonstrated moderate-to-severe peripheral airway impairment although no further lung function decline was found years after completion of treatment. Despite acceptable VO2peak, a considerable proportion struggled during heavy exercise.

Background and objective: Cross-sectional and longer-term studies have demonstrated abnormal yet stable multiple-breath inert gas washout (MBW) indices in patients with primary ciliary dyskinesia (PCD). This study aimed to assess the intermediate term evolution and the between-occasion variability of MBW indices in PCD over 1 year.Methods: Children and young adults with a confirmed diagnosis of PCD were included in this single-centre, prospective, observational, longitudinal study. Over 1 year, nitrogen (N2) MBW and spirometry were performed at three occasions during ordinary scheduled outpatient visits. Trends and variability in lung clearance index (LCI), moment ratios, normalized N2 concentration at six lung volume turnovers, and regional ventilation inhomogeneity indices of the conducting and intra-acinar airways (Scond*VT and Sacin*VT) were analysed using linear mixed models.Results: Forty-two patients, aged 6–29 years (median: 15.4), performed 116 N2 MBW test occasions and 96.6% were technically acceptable. A minimal, although significant, increase in LCI over 1 year (mean: 0.51 units, 95% CI: 0.12–0.91, p = 0.01) was found; while, all other N2 MBW indices and FEV1 remained unchanged. A moderate correlation was observed between LCI and FEV1 (r = −0.47, p = 0.0001). The limits of agreement between tests 1 year apart were for LCI: −1.96 to 2.98; Scond*VT: ± 0.039; Sacin*VT: −0.108 to 0.128.Conclusions: Children and young adults with PCD managed at a specialist centre showed slightly, but significant, increasing LCI and otherwise unchanged ventilation inhomogeneity indices and dynamic volumes over the intermediate term of 1 year. Estimates of the variability of N2 MBW indices may inform sample size calculations of future randomized controlled trials.

Summary Background Hypersensitivity pneumonitis (HP) is an immune-mediated diffuse lung disease. Significant improvement in lung function and diffusing capacity after treatment was previously demonstrated, while long-term data focusing specifically on peripheral airway impairment and peak oxygen uptake (fitness) are lacking. Hence, the aim of this study was to conduct a comprehensive study to determine the stability of pulmonary function and fitness in patients previously diagnosed with HP. Methods We performed a cross-sectional follow-up study with inclusion of longitudinal data if available in patients previously diagnosed with biopsy and high-resolution computed tomography-verified HP during childhood. We performed multiple breath wash-out (LCI2.5), spirometry (FEV1), bronchiodilator responsiveness test, diffusing capacity (DLCO and DLCO/VA), body-plethysmography (TLC), and peak oxygen uptake (VO2peak). St. George Respiratory Questionnaire was used as a measure of respiratory quality of life. Results Twenty two patients were assessed. LCI2.5 was abnormal in 47.4% compared to abnormal FEV1 in only 9.1% and without significant bronchiodilator responsiveness. DLCO and TLC were abnormal in 40.9 and 13.6%, respectively, while DLCO/VA was within normal range. Only 11.1% demonstrated abnormal VO2peak. All longitudinally assessed outcomes remained unchanged between end of treatment and time of follow up. Conclusions A large proportion of patients previously diagnosed with HP had abnormal LCI2.5 in contrast to normal spirometry. Spirometric outcomes, TLC, and diffusing capacity were persistently slightly reduced, but stable, and VO2peak was excellent at time of follow-up. Long-term prognosis in children with HP appears favorable although persistent peripheral airway involvement of unknown clinical significance was demonstrated in almost half of the patients. Pediatr Pulmonol. © 2015 Wiley Periodicals, Inc.

Rationale Nitrogen multiple-breath washout (N2 MBW) is a promising tool for assessing early lung damage in children with chronic obstructive pulmonary disease, but it can be a time-consuming procedure. We compared alternative test-shortening endpoints with the most commonly reported N2 MBW outcome, the lung clearance index, calculated as lung volume turnovers required to reach 2.5% of the starting N2 concentration (LCI2.5 ). Methods Cross-sectional study of triplicate N2 MBW measurements obtained in cystic fibrosis (CF) patients (N = 60), primary ciliary dyskinesia (PCD) patients (N = 28), and matched healthy controls (N = 48) aged 5-18 years. Bland-Altman analysis was used to compare LCI2.5 with earlier LCI endpoints (3%, 4%, 5%, 7%, and 9% of starting N2 concentration), Cn@TO6 (defined as % of N2 starting concentration when reaching six lung volume turnovers), and LCI derived from only two N2 MBW runs in each session. N2 MBW endpoints were analyzed as z-scores calculated from healthy controls. Results In PCD, Cn@TO6 and LCI2.5 exhibited similar values (mean [95%CI] difference: 0.33 [-0.24; 0.90] z-scores), reducing the test duration by one-third (5.4 min; 95%CI: 4.0; 6.8). All other tested alternative endpoints exhibited increasing disagreement with increasing LCI2.5 . With an average reduction in test duration of 40%, LCI2.5 derived from two runs exhibited good agreement in all children. Conclusions Cn@TO6 may be suggested as a potential test-shortening endpoint in school children with PCD. In CF, early test termination may reduce measurement power with advancing pulmonary disease, suggesting differences in underlying pathophysiology. Two technically acceptable N2 MBW runs may be sufficient in school children irrespective of diagnosis with CF or PCD. Pediatr Pulmonol. 2016;51:624-632. © 2015 Wiley Periodicals, Inc.

Introduction Preterm birth is associated with increased risk of respiratory symptoms in childhood, often treated with asthma medication. We designed a follow-up study to previous research and investigated whether the association of gestational age with purchasing asthma medication diminishes in adulthood. Methods We conducted a register-based study of a national cohort of all infants born in Denmark in 1980–2009 evaluating longitudinal data on individually prescribed asthma medication (both inhaled ß-2 receptor agonist and different controller treatment over 2-year periods) available from 1995–2011. We analyzed the effect of gestational age considering age, birth year, and perinatal variables using logistic regression with a Generalized Estimating Equations model. All data were unambiguously linked through the Civil Registration System. Results We included 1,819,743 individuals in our study population. We found an inverse dose-response relationship between gestational age and asthma medication in earlier age-groups with a gradual decrease in odds ratios with increasing age and loss of statistical significance in early adulthood (18–31 years). For our oldest generations, there was a significant effect of gestational age (p-value = 0.04), which became insignificant when adjusting for confounding and mediating factors (p = 0.44). There were significant interactions between gestational age and age (p

Bronchiolitis obliterans (BO) is a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Lung biopsy is the gold standard for diagnosis. This study describes the course of BO and assesses the congruity between biopsy-verified BO and a modified version of the National Institutes of Health's consensus criteria for BO syndrome (BOS) based exclusively on noninvasive measures. We included 44 patients transplanted between 2000 and 2010 who underwent lung biopsy for suspected BO. Of those, 23 were diagnosed with BO and 21 presented other noninfectious pulmonary pathologies, such as cryptogenic organizing pneumonia, diffuse alveolar damage, interstitial pneumonia, and nonspecific interstitial fibrosis. Compared with patients with other noninfectious pulmonary pathologies, BO patients had significantly lower values of forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity, and maximal mid-expiratory flow throughout follow-up, but there was no difference in the change in pulmonary function from the time of lung biopsy. The BO diagnosis was not associated with poorer overall survival. Fifty-two percent of patients with biopsy-verified BO and 24% of patients with other noninfectious pulmonary pathology fulfilled the BOS criteria. Pathological BO diagnosis was not superior to BOS criteria in predicting decrease in pulmonary function beyond the time of biopsy. A lung biopsy may provide a characterization of pathological patterns that can extend our knowledge on the pathophysiology of HSCT-related lung diseases.

Background Peak oxygen uptake (VO2peak) is associated with morbidity and mortality in health and disease, and provides important information of global physical health not achieved from standard pulmonary function tests. Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are genetically determined diseases involving different basic defects, but both showing impaired mucociliary clearance leading to chronic infections and pulmonary destruction early in life. PCD is generally considered a milder disease than CF and it is hypothesized that children with CF would have consistently lower VO2peak and pulmonary function than children with PCD. Methods We performed a prospective, observational single-center, clinical cohort study of VO2peak and pulmonary function in age and gender matched schoolchildren, at two occasions 12 months apart. Results VO2peak was persistently (at baseline and after 12 months) and significantly reduced in the 22 patients with PCD (z-score = −0.89 and −1.0) and 24 with CF (z-score = −0.94 and −1.1), included in the study. Abnormal VO2peak was detected in a larger proportion of children with PCD (≈30%) than CF (≈13%). Moreover, children with PCD exhibited persistently lower FEV1 (p Conclusion This is the first report indicating that cardiopulmonary fitness is equally and consistently reduced in both children with PCD and CF along with a consistent lower pulmonary function in PCD compared with CF. A certain reservation for possible selection bias and the small number of patients is necessary. However, increased focus on early diagnosis, evidence-based treatment regimens and close clinical monitoring in PCD are warranted.

It is presumed that early detection and treatment of the chronic lung diseases cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are crucial for improving the prognosis. Mucus stagnation and secondary infections and inflammation in the airways causes progressive lung damage from infancy in CF and PCD, which again causes early death in CF and reduced pulmonary function in PCD. Early detection of ongoing lung damage will facilitate early intervention with intensive treatment, enhance disease surveillance and further improve preventive treatment. This will improve quality of life for patients with both CF and PCD and likely improve survival in CF. Pulmonary function is an important marker of prognosis and effect of treatment, but current pulmonary function tests do not register the earliest damages in the lungs in school children – and are inappliccable for infants and toddlers due to requirements for good coorporation. For this reason there is a demand for more sensitive methods that can be used in all age groups. Gas washout – multiple breath inert gas washout (MBW) – is a method that meets these criteria and seems promising for detection of minimal lung damage prior to debut of clinical symptoms and detection by other methods. MBW is for the first time in Denmark established in the Pediatric Pulmonary Service at Copenhagen University Hospital, where a recently established ”Respiratory Physiology Lab for Children” offers a wide range of methods to detect lung disease in children. Aim: The aim of the Ph.D.-project is to investigate: Reliability of results conducted from MBW measurements under different standardized conditions (reproducibility), including establishment of a Danish reference material for children. Whether MBW can be used as a marker of early lung disease compared to conventional lung function methods in the chronic lung diseases CF and PCD. Whether MBW can be used as a relevant outcome to detect interventions in basic CF treatment. The Ph.D.-project will generate a new and more aggressive approach to surveillance and treatment of patients with CF and PCD with an overall aim to reduce morbidity and mortality and improve quality of life. Furthermore, it is expected that this project will generate new knowledge that can be used in the more common lung diseases asthma and COPD, which affects 10% and 15% of children and adults, respectively.

Introduction: Post-infectious Bronchiolitis Obliterans (PIBO) is a chronic obstructive lung disease in which treatment options and knowledge about prognosis are limited. The aim of this study was to describe lung function and fitness in children treated for PIBO. Methods: We performed a cross-sectional and longitudinal follow up study years after diagnosis of PIBO. Lung Clearance Index (LCI2,5), dynamic volumes (FEV1, FVC), bronchodilator responsiveness, diffusing capacity (DLCO) and peak oxygen uptake (zVO2peak) were measured. Abnormality was defined as z-score 1.96. Results: 15 patients (6 females) with a median age of 14.3 (7–28) years were included. The median follow up period from diagnosis was 7.5 (2–15) years. Treatment varied but consisted of pulse and oral corticosteroids, azathioprine, hydroxychloroquine and beta2-agonist. At follow up, LCI2.5 (zLCImedian=10.0) and FEV1 were abnormal in 79% and 47% with significant (>12%) beta-2-bronchodilation in 36%. DLCO was within normal range in 90%. Longitudinal data were available in 6 children and remained unchanged from end of treatment to time of follow-up (range 6-15 years): FEV1 (z-score -2.95 vs. -2.23, p=0.79), FVC (-0.35 vs. -0.26, p=0.63) and FEV1/FVC (z-score -2.46 vs. -2.50, p=0.27). VO2peak was only abnormal in 2 children. Conclusion: Despite treatment, a large proportion of children with PIBO revealed persistent abnormal spirometry and LCI2.5. Longitudinal data from 6 children showed unchanged abnormal lung function many years after treatment. The clinical significance seems uncertain as the vast majority demonstrated normal peak oxygen uptake.