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

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

A novel non-invasive method allowing for discovery of pathologically relevant proteins from small airways.

BACKGROUND: There is a lack of early and precise biomarkers for personalized respiratory medicine. Breath contains an aerosol of droplet particles, which are formed from the epithelial lining fluid when the small airways close and re-open during inhalation succeeding a full expiration. These particles can be collected by impaction using the PExA® method (Particles in Exhaled Air), and are derived from an area of high clinical interest previously difficult to access, making them a potential source of biomarkers reflecting pathological processes in the small airways. RESEARCH QUESTION: Our aim was to investigate if PExA method is useful for discovery of biomarkers that reflect pathology of small airways. METHODS AND ANALYSIS: Ten healthy controls and 20 subjects with asthma, of whom 10 with small airway involvement as indicated by a high lung clearance index (LCI ≥ 2.9 z-score), were examined in a cross-sectional design, using the PExA instrument. The samples were analysed with the SOMAscan proteomics platform (SomaLogic Inc.). RESULTS: Two hundred-seven proteins were detected in up to 80% of the samples. Nine proteins showed differential abundance in subjects with asthma and high LCI as compared to healthy controls. Two of these were less abundant (ALDOA4, C4), and seven more abundant (FIGF, SERPINA1, CD93, CCL18, F10, IgM, IL1RAP). sRAGE levels were lower in ex-smokers (n = 14) than in never smokers (n = 16). Gene Ontology (GO) annotation database analyses revealed that the PEx proteome is enriched in extracellular proteins associated with extracellular exosome-vesicles and innate immunity. CONCLUSION: The applied analytical method was reproducible and allowed identification of pathologically interesting proteins in PEx samples from asthmatic subjects with high LCI. The results suggest that PEx based proteomics is a novel and promising approach to study respiratory diseases with small airway involvement.

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

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

Improved agreement between N2 and SF6 multiple-breath washout in healthy infants and toddlers with improved EXHALYZER D sensor performance.

Recent studies indicate limited utility of nitrogen multiple-breath washout (N2MBW) in infancy and advocate for using sulfur hexafluoride (SF6) MBW in this age-group. Modern N2MBW systems, such as EXHALYZER D (ECO MEDICS AG, Duernten, Switzerland), use O2 and CO2 sensors to calculate N2 concentrations (in principle, N2% = 100 - CO2% - O2%). High O2 and CO2 concentrations have now been shown to significantly suppress signal output from the other sensor, raising apparent N2 concentrations. We examined whether improved EXHALYZER D N2 signal, accomplished after thorough examination of this CO2 and O2 interaction on gas sensors and its correction, leads to better agreement between N2MBW and SF6MBW in healthy infants and toddlers. Within the same session, 52 healthy children aged 1-36 mo [mean = 1.30 (SD = 0.72) yr] completed SF6MBW and N2MBW recordings (EXHALYZER D, SPIROWARE version 3.2.1) during supine quiet sleep. SF6 and N2 SPIROWARE files were reanalyzed offline with in-house software using identical algorithms as in SPIROWARE with or without application of the new correction factors for N2MBW provided by ECO MEDICS AG. Applying the improved N2 signal significantly reduced mean [95% confidence interval (CI)] differences between N2MBW and SF6MBW recorded functional residual capacity (FRC) and lung clearance index (LCI): for FRC, from 26.1 (21.0, 31.2) mL, P < 0.0001, to 1.18 (-2.3, 4.5) mL, P = 0.5, and for LCI, from 1.86 (1.68, 2.02), P < 0.001, to 0.44 (0.33, 0.55), P < 0.001. Correction of N2 signal for CO2 and O2 interactions on gas sensors resulted in markedly closer agreement between N2MBW and SF6MBW outcomes in healthy infants and toddlers.NEW & NOTEWORTHY Modern nitrogen multiple-breath washout (N2MBW) systems such as EXHALYZER D use O2 and CO2 sensors to calculate N2 concentrations. New corrections for interactions between high O2 and CO2 concentrations on the gas sensors now provide accurate N2 signals. The correct N2 signal led to much improved agreement between N2MBW and sulfur hexafluoride (SF6) MBW functional residual capacity (FRC) and lung clearance index (LCI) in 52 sleeping healthy infants and toddlers, suggesting a role for N2MBW in this age-group.

Newly developed multiple-breath washout reference equations from the CHILD Cohort Study: implications of poorly fitting equations.

Using inappropriate reference equations would provide incorrect estimate of z-scores, which would cause misdiagnosis. Appropriate representative normative reference data must be available to correctly interpret individual lung function results. https://bit.ly/3dcNZ5p.

End-expiratory lung volume remains stable during N2 MBW in healthy sleeping infants.

We have previously shown that functional residual capacity (FRC) and lung clearance index were significantly greater in sleeping healthy infants when measured by N2 (nitrogen) washout using 100% O2 (oxygen) versus 4% SF6 (sulfur hexafluoride) washout using air. Following 100% O2 exposure, tidal volumes decreased by over 30%, while end-expiratory lung volume (EELV, i.e., FRC) rose markedly based on ultrasonic flow meter assessments. In the present study to investigate the mechanism behind the observed changes, N2 MBW was performed in 10 separate healthy full-term spontaneously sleeping infants, mean (range) 26 (18-31) weeks, with simultaneous EELV monitoring (respiratory inductance plethysmography, RIP) and oxygen uptake (V´O2 ) assessment during prephase air breathing, during N2 washout by exposure to 100% O2 , and subsequently during air breathing. While flow meter signals suggested a rise in ELLV by mean (SD) 26 (9) ml over the washout period, RIP signals demonstrated no EELV change. V'O2 /FRC ratio during air breathing was mean (SD) 0.43 (0.08)/min, approximately seven times higher than that calculated from adult data. We propose that our previously reported flow meter-based overestimation of EELV was in fact a physiological artifact caused by rapid and marked movement of O2 across the alveolar capillary membrane into the blood and tissue during 100% O2 exposure, without concomitant transfer of N2 to the same degree in the opposite direction. This may be driven by the high observed O2 consumption and resulting cardiac output encountered in infancy. Furthermore, the low resting lung volume in infancy may make this error in lung volume determination by N2 washout relatively large.

One-year evolution and variability in multiple-breath washout indices in children and young adults with primary ciliary dyskinesia.

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.

Early life determinants of lung function change from childhood to adolescence.

RATIONALE: Little is known about how perinatal and childhood factors influence lung function change between childhood and adolescence. OBJECTIVES: To investigate possible early life predictors of change in FEV1 between age 8 and 16 years. In addition, to investigate possible predictors of having persistently low lung function (FEV1 <25th percentiles both at age 8 and 16) up to adolescence. METHODS: The BAMSE birth cohort study collected data throughout childhood on environmental factors, individual characteristics, and spirometric measures at 8 and 16 years (n = 1425). Associations between early life predictors (n = 31) and FEV1 increase between 8 and 16 years were assessed with linear regression. Predictors of having persistently low lung function were examined. RESULTS: Few factors were consistently associated with altered lung function growth, although low birth weight, asthma heredity (paternal), secondhand smoke in infancy, and season of birth had a significant impact (p-value ≤0.01). The majority of subjects stayed however within the same category of lung function between ages 8 and 16 years (in total 821/1425 = 58%). Predictors associated with having persistently low lung function were gestational age, secondhand smoke (at 2 and 8 years of age), and factors related to lower respiratory tract infections in infancy. CONCLUSIONS: In summary, rather few exposures in childhood were identified to have a significant impact on lung function growth between childhood and adolescence. Our data support previous study findings indicating that lung function development is influenced by factors before birth and in infancy, including second hand tobacco smoke.

Tobacco smoke exposure in early life and adolescence in relation to lung function.

Maternal smoking during pregnancy is associated with impaired lung function among young children, but less is known about long-term effects and the impact of adolescents' own smoking. We investigated the influence of maternal smoking during pregnancy, secondhand smoke exposure and adolescent smoking on lung function at age 16 years.The BAMSE (Barn/Child, Allergy, Milieu, Stockholm, Epidemiology) birth cohort collected information on participants' tobacco smoke exposure through repeated questionnaires, and measured saliva cotinine concentrations at age 16 years. Participants performed spirometry and impulse oscillometry (IOS) at age 16 years (n=2295).Exposure to maternal smoking during pregnancy was associated with reduced forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio of -1.1% (95% CI -2.0 to -0.2%). IOS demonstrated greater resistance at 5-20 Hz (R5-20) in participants exposed to maternal smoking during pregnancy. Adolescents who smoked had reduced FEV1/FVC ratios of -0.9% (95% CI -1.8 to -0.1%) and increased resistance of 6.5 Pa·L-1·s (95% CI 0.7 to 12.2 Pa·L-1·s) in R5-20 Comparable associations for FEV1/FVC ratio were observed for cotinine concentrations, using ≥12 ng·mL-1 as a cut-off for adolescent smoking.Maternal smoking during pregnancy was associated with lower FEV1/FVC ratios and increased airway resistance. In addition, adolescent smoking appears to be associated with reduced FEV1/FVC ratios and increased peripheral airway resistance.

Preschool Multiple-Breath Washout Testing. An Official American Thoracic Society Technical Statement.

BACKGROUND: Obstructive airway disease is nonuniformly distributed throughout the bronchial tree, although the extent to which this occurs can vary among conditions. The multiple-breath washout (MBW) test offers important insights into pediatric lung disease, not available through spirometry or resistance measurements. The European Respiratory Society/American Thoracic Society inert gas washout consensus statement led to the emergence of validated commercial equipment for the age group 6 years and above; specific recommendations for preschool children were beyond the scope of the document. Subsequently, the focus has shifted to MBW applications within preschool subjects (aged 2-6 yr), where a "window of opportunity" exists for early diagnosis of obstructive lung disease and intervention. METHODS: This preschool-specific technical standards document was developed by an international group of experts, with expertise in both custom-built and commercial MBW equipment. A comprehensive review of published evidence was performed. RESULTS: Recommendations were devised across areas that place specific age-related demands on MBW systems. Citing evidence where available in the literature, recommendations are made regarding procedures that should be used to achieve robust MBW results in the preschool age range. The present work also highlights the important unanswered questions that need to be addressed in future work. CONCLUSIONS: Consensus recommendations are outlined to direct interested groups of manufacturers, researchers, and clinicians in preschool device design, test performance, and data analysis for the MBW technique.

Variability of lung clearance index in clinically stable cystic fibrosis lung disease in school age children.

BACKGROUND: Data on long term variability of Lung Clearance Index (LCI) in Cystic Fibrosis (CF) is urgently needed to guide test result interpretation. Our aim was to evaluate LCI variability in clinically stable CF lung disease in school age children. METHODS: Paediatric patients, aged 6 to 17years, attending the outpatient CF clinic performed Multiple Breath Nitrogen Washout (Exhalyzer® D) and spirometry every third month over a period of one year. Clinical stability was assessed by the Cystic Fibrosis Clinical Score (CFCS) at each visit. RESULTS: Twentyfive children were recruited: baseline median (range) FEV1% pred. 91 (55-122)%, LCI 9.1 (6.4-18.6), CFCS 15 (12-23). A total of 107 visits were included in the study, of which 93% were defined as clinically stable. In clinically stable visits, within-subject variability of LCI and FEV1% pred. were 10% and 16%, respectively. The upper limit of normal (ULN, 95% percentile) of LCI variability during clinical stability was 17%. CONCLUSIONS: LCI within-subject variability was low and comparable to FEV1% pred. which strengthen the use of LCI to monitor lung disease progression in CF patients. An increase in LCI >17% compared to previous LCI-measurement in clinically stable CF patients may therefore indicate early lung disease progression.

The effect of inert gas choice on multiple breath washout in healthy infants: differences in lung function outcomes and breathing pattern.

The detrimental effects on breathing pattern during multiple breath inert gas washout (MBW) have been described with different inhaled gases [100% oxygen (O2) and sulfur hexafluoride (SF6)] but detailed comparisons are lacking. N2- and SF6-based tests were performed during spontaneous quiet sleep in 10 healthy infants aged 0.7-1.3 yr using identical hardware. Differences in breathing pattern pre and post 100% O2 and 4% SF6 exposure were investigated, and the results obtained were compared [functional residual capacity (FRC) and lung clearance index (LCI)]. During 100% O2 exposure. mean inspiratory flow ("respiratory drive") decreased transiently by mean (SD) 28 (9)% ( P < 0.001), and end-tidal CO2 (carbon dioxide) increased by mean (SD) 0.3 (0.4)% units ( P < 0.05) vs. air breathing prephase. During subsequent N2 washin (i.e., recovery phase), the pattern of change reversed. No significant effect on breathing pattern was observed during SF6 testing. In vitro testing confirmed that technical artifacts did not explain these changes. Mean (SD) FRC and LCI in vivo were significantly higher with N2 vs. SF6 washout: 216 (33) vs. 186 (22) ml ( P < 0.001) and 8.25 (0.85) vs. 7.55 (0.57) turnovers ( P = 0.021). Based on these results, SF6 based MBW is the preferred methodology for tests in this age range. NEW & NOTEWORTHY Inert gas choice for multiple breath inert gas washout (MBW) in infants has important consequences on both breathing pattern during test performance and the functional residual capacity and lung clearance index values obtained. Data suggest the detrimental effect of breathing pattern of 100% O2 and movement of O2 across the alveolar capillary membrane, with direct effects on MBW outcomes. SF6 MBW during infancy avoids this and can be further optimized by addressing the sources of technical artifact identified in this work.

Clinical characteristics of adult asthma associated with small airway dysfunction.

Suboptimal asthma control is common despite modern asthma therapy. The degree of peripheral airway involvement remains unclear and poor medication delivery to these regions might be a contributing reason for this failure in obtaining adequate symptom control. A cohort of 196 adults (median (range) age 44 (18-61) years, 109 females, 54 ex-smokers, six current smokers) with physician-diagnosed asthma were recruited from primary care. Subjects were characterized clinically by interviews, questionnaires, skin prick tests (SPT) and blood eosinophil counts. Lung function was assessed by spirometry, impulse oscillometry (IOS) and nitrogen multiple breath washout (N2 MBW). IOS assessed peripheral airway resistance (FDR, frequency dependence of resistance). N2 MBW assessed global ventilation inhomogeneity (LCI, lung clearance index), specific indices of peripheral airway function (Scond × VT and Sacin × VT; VT, tidal volume), and inter-regional inhomogeneity (specific ventilation ratio). Never-smoking healthy cohorts of 158 and 400 adult subjects provided local reference values for IOS and N2 MBW variables, respectively. Peripheral airway dysfunction was detected in 31% (FDR or specific ventilation ratio) to 47% (Scond x VT) of subjects. Risk factors for peripheral airway dysfunction were identified. Among subjects with low FEV1 and either positive smoking history and/or blood eosinophilia (>4.0%), 63% had abnormality across all peripheral airway outcomes, whilst only one subject was completely normal. Abnormal peripheral airway function was present in a large proportion of adult asthmatics at baseline. Reduced FEV1, a positive smoking history, and/or blood eosinophilia identified "a small airway asthma subtype" that might benefit from peripheral airway targeted therapy.

Lung Function at 8 and 16 Years After Moderate-to-Late Preterm Birth: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVE: Knowledge regarding lung function after moderately preterm birth is limited. We therefore investigated lung function at early school age and adolescence among children born moderately preterm. METHODS: Data were used from the Swedish prospective birth cohort BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology study; N = 4089), with a 4.8% prevalence of moderate to late preterm birth defined as a gestational age of 32 to 36 weeks. Participants underwent spirometry at ages 8 and 16 years, and impulse oscillometry additionally at age 16 years. In total, 2621 children (149 preterm and 2472 term) provided lung function data. RESULTS: At age 8 years, adjusted forced expiratory volume in 1 second was lower in preterm female subjects (-64 mL [95% confidence interval (CI): -118 to -10]) compared with term female subjects but not in preterm male subjects. At age 16 years, both genders in the preterm group demonstrated lower forced expiratory volume in 1 second (female subjects: -116 mL [95% CI: -212 to -20]; male subjects: -177 mL [95% CI: -329 to -25]) compared with the term group. For the preterm group, impulse oscillometry demonstrated higher adjusted resistance at 5 Hz (female subjects: 31.3 Pa·L(-1)·s(-1) [95% CI: 6.3 to 56.3]; male subjects: 34.9 Pa·L(-1)·s(-1) [95% CI: 12.0 to 57.7]) and frequency dependence of resistance (resistance at 5 and 20 Hz) for male subjects (20.9 Pa·L(-1)·s(-1) [95% CI: 9.8 to 31.9]) compared with the term group. CONCLUSIONS: Measures of airway function assessed in adolescence were reduced in children born moderate to late preterm, and no catch-up in lung function between ages 8 and 16 years was observed.

Abbreviation modalities of nitrogen multiple-breath washout tests in school children with obstructed lung disease.

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.

Early-Life Exposure to Traffic-related Air Pollution and Lung Function in Adolescence.

RATIONALE: Exposure to air pollution during infancy has been related to lung function decrements in 8-year-old children, but whether the negative effects remain into adolescence is unknown. OBJECTIVES: To investigate the relationship between long-term air pollution exposure and lung function up to age 16 years. METHODS: A total of 2,278 children from the Swedish birth cohort BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological Survey) performed spirometry at age 16 years. Levels of outdoor air pollution from local road traffic were estimated (nitrogen oxides [NOx] and particulate matter with an aerodynamic diameter of <10 µm [PM10]) for residential, daycare, and school addresses during the lifetime using dispersion modeling. Associations between exposure in different time windows and spirometry indexes were analyzed by linear regression and mixed effect models. MEASUREMENTS AND MAIN RESULTS: Exposure to traffic-related air pollution during the first year of life was associated with FEV1 at age 16 years of -15.8 ml (95% confidence interval [CI], -33.6 to 2.0 for a 10 µg/m(3) difference in NOx), predominately in males (-30.4 ml; 95% CI, -59.1 to -1.7), and in subjects not exposed to maternal smoking during pregnancy or infancy. Later exposures appeared to have had an additional negative effect. High exposure during the first year of life was also associated with odds ratios for FEV1 and FVC less than the lower limit of normal (LLN) (defined as a z-score < -1.64 SD) of 3.8 (95% CI, 1.3-10.9) and of 4.3 (95% CI, 1.2-15.0), respectively. The results for PM10 were similar to those for NOx. CONCLUSIONS: Exposure to traffic-related air pollution in infancy is negatively associated with FEV1 at age 16 years, leading to increased risk of clinically important deficits.

Consensus statement for inert gas washout measurement using multiple- and single- breath tests.

Inert gas washout tests, performed using the single- or multiple-breath washout technique, were first described over 60 years ago. As measures of ventilation distribution inhomogeneity, they offer complementary information to standard lung function tests, such as spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in the detection of early lung damage. These benefits have led to a resurgence of interest in these techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout equipment specifications, test performance and analysis are lacking. This manuscript provides recommendations about these aspects, applicable to both the paediatric and adult testing environment, whilst outlining the important principles that are essential for the reader to understand. These recommendations are evidence based, where possible, but in many places represent expert opinion from a working group with a large collective experience in the techniques discussed. Finally, the important issues that remain unanswered are highlighted. By addressing these important issues and directing future research, the hope is to facilitate the incorporation of these promising tests into routine clinical practice.