Genome-wide association studies of exacerbations in children using long-acting beta2-agonists.

BACKGROUND: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium. METHODS: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma. RESULTS: Genome-wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10-6 ) associated with exacerbations despite LABA use. CONCLUSION: No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.

Glutathione S-Transferase Genotype Protects against In Utero Tobacco-linked Lung Function Deficits.

Rationale:In utero tobacco exposure is associated with reduced lung function from infancy. Antioxidant enzymes from the glutathione S-transferase (GST) family may protect against these lung function deficits.Objectives: To assess the long-term effect of in utero smoke exposure on lung function into adulthood, and to assess whether GSTT1 and GSTM1 active genotypes have long-term protective effects on lung function.Methods: In this longitudinal study based on a general population (n = 253), lung function was measured during infancy and at 6, 11, 18, and 24 years. GSTM1 and GSTT1 genotype was analyzed in a subgroup (n = 179). Lung function was assessed longitudinally from 6 to 24 years (n = 199).Measurements and Main Results: Exposure to maternal in utero tobacco was associated with lower FEV1 and FVC longitudinally from 6 to 24 years (mean difference, -3.87% predicted, P = 0.021; -3.35% predicted, P = 0.035, respectively). Among those homozygous for the GSTM1-null genotype, in utero tobacco exposure was associated with lower FEV1 and FVC compared with those with no in utero tobacco exposure (mean difference, -6.2% predicted, P = 0.01; -4.7% predicted, P = 0.043, respectively). For those with GSTM1 active genotype, there was no difference in lung function whether exposed to maternal in utero tobacco or not. In utero tobacco exposure was associated with deficits in lung function among those with both GSTT1-null and GSTT1-active genotypes.Conclusions: Certain GST genotypes may have protective effects against the long-term deficits in lung function associated with in utero tobacco exposure. This offers potential preventative targets in antioxidant pathways for at-risk infants of smoking mothers.

Oxygen saturation targets in infants with bronchiolitis (BIDS): a double-blind, randomised, equivalence trial.

BACKGROUND: The American Academy of Pediatrics recommends a permissive hypoxaemic target for an oxygen saturation of 90% for children with bronchiolitis, which is consistent with the WHO recommendations for targets in children with lower respiratory tract infections. No evidence exists to support this threshold. We aimed to assess whether the 90% or higher target for management of oxygen supplementation was equivalent to a normoxic 94% or higher target for infants admitted to hospital with viral bronchiolitis. METHODS: We did a parallel-group, randomised, controlled, equivalence trial of infants aged 6 weeks to 12 months of age with physician-diagnosed bronchiolitis newly admitted into eight paediatric hospital units in the UK (the Bronchiolitis of Infancy Discharge Study [BIDS]). A central computer randomly allocated (1:1) infants, in varying length blocks of four and six and without stratification, to be clipped to standard oximeters (patients treated with oxygen if pulse oxygen saturation [SpO2] <94%) or modified oximeters (displayed a measured value of 90% as 94%, therefore oxygen not given until SpO2 <90%). All parents, clinical staff, and outcome assessors were masked to allocation. The primary outcome was time to resolution of cough (prespecified equivalence limits of plus or minus 2 days) in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN28405428. FINDINGS: Between Oct 3, and March 30, 2012, and Oct 1, and March 29, 2013, we randomly assigned 308 infants to standard oximeters and 307 infants to modified oximeters. Cough resolved by 15·0 days (median) in both groups (95% CI for difference -1 to 2) and so oxygen thresholds were equivalent. We recorded 35 serious adverse events in 32 infants in the standard care group and 25 serious adverse events in 24 infants in the modified care group. In the standard care group, eight infants transferred to a high-dependency unit, 23 were readmitted, and one had a prolonged hospital stay. In the modified care group, 12 infants were transferred to a high-dependency unit and 12 were readmitted to hospital. Recorded adverse events did not differ significantly. INTERPRETATION: Management of infants with bronchiolitis to an oxygen saturation target of 90% or higher is as safe and clinically effective as one of 94% or higher. Future research should assess the benefits and risks of different oxygen saturation targets in acute respiratory infection in older children, particularly in developing nations where resources are scarce. FUNDING: National Institute for Health Research, Health Technology Assessment programme.

Longitudinal assessment of airway responsiveness from 1 month to 18 years in the PIAF birth cohort.

The Perth Infant Asthma Follow-up (PIAF) study involves a birth cohort of unselected subjects who have undergone longitudinal assessments of airway responsiveness at 1, 6 and 12 months and 6, 11 and 18 years of age. The aim of this study was to determine the relationship between increased airway responsiveness throughout childhood and asthma in early adult life.Airway responsiveness to histamine, assessed as a dose-response slope (DRS), and a respiratory questionnaire were completed at 1, 6 and 12 months and 6, 11 and 18 years of age.253 children were initially recruited and studied. Airway responsiveness was assessed in 203, 174, 147, 103, 176 and 137 children at the above-mentioned time points, respectively (39 participants being assessed on all test occasions). Asthma at 18 years was associated with increased airway responsiveness at 6, 12 and 18 years, but not during infancy (slope 0.24, 95% CI 0.06-0.42; p=0.01; slope 0.25, 95% CI 0.08-0.49; p=0.006; and slope 0.56, 95% CI 0.29-0.83; p<0.001, respectively).Increased airway responsiveness and its association with asthma at age 18 years is established between infancy and 6 years. We propose that airway responsiveness in early life reflects the initial airway geometry and airway responsiveness later in childhood increasingly reflects immunological responses to environmental influences.

Paediatrics in Vienna.

The aim of this update is to describe, in the context of the current literature, major papers from the seven groups of the Paediatric Assembly (Respiratory Physiology; Asthma and Allergy; Cystic Fibrosis; Respiratory Infection and Immunology; Neonatology and Paediatric Intensive Care; Respiratory Epidemiology; and Bronchology) presented during the annual European Respiratory Society congress held in 2012 in Vienna, Austria.

'I'm not doing this for me': mothers' accounts of creating smoke-free homes.

This article explores mothers' narratives of changing home smoking behaviours after participating in an intervention (Reducing Families' Exposure to Smoking in the Home [REFRESH]) aimed at reducing families' exposure to secondhand smoke (SHS) in homes in Scotland. An analysis of qualitative findings illuminates quantitative changes in levels of SHS exposure. Prospective quantitative and qualitative data were drawn from 21 smoking mothers with at least one child under 6 years. Quantitative change was measured by home air quality, i.e. fine particulate matter <2.5µg (PM(2.5)). These measurements guided the organization of mothers into categories of change (smoke-free home at baseline [SFB], smoke-free home at final, some change and no change [NC]). Qualitative data from 17 mothers with non-SFB were analysed thematically within and across these categories. Three comparative case studies illustrate the varying changes made, barriers to change and how mothers valued such changes. The outcomes varied post-intervention, with homes smoke-free, partially smoke-free or making NC. The changes in home smoking behaviour were incremental, yet beneficial to reducing SHS exposure, and related to the nature of the restrictions and personal circumstances in the home pre-intervention. Across all change categories, mothers valued the changes they had made and expressed an intention to increase the changes.

Deriving and validating an asthma diagnosis prediction model for children and young people in primary care.

Introduction: Accurately diagnosing asthma can be challenging. We aimed to derive and validate a prediction model to support primary care clinicians assess the probability of an asthma diagnosis in children and young people. Methods: The derivation dataset was created from the Avon Longitudinal Study of Parents and Children (ALSPAC) linked to electronic health records. Participants with at least three inhaled corticosteroid prescriptions in 12-months and a coded asthma diagnosis were designated as having asthma. Demographics, symptoms, past medical/family history, exposures, investigations, and prescriptions were considered as candidate predictors. Potential candidate predictors were included if data were available in ≥60% of participants. Multiple imputation was used to handle remaining missing data. The prediction model was derived using logistic regression. Internal validation was completed using bootstrap re-sampling. External validation was conducted using health records from the Optimum Patient Care Research Database (OPCRD). Results: Predictors included in the final model were wheeze, cough, breathlessness, hay-fever, eczema, food allergy, social class, maternal asthma, childhood exposure to cigarette smoke, prescription of a short acting beta agonist and the past recording of lung function/reversibility testing. In the derivation dataset, which comprised 11,972 participants aged <25 years (49% female, 8% asthma), model performance as indicated by the C-statistic and calibration slope was 0.86, 95% confidence interval (CI) 0.85-0.87 and 1.00, 95% CI 0.95-1.05 respectively. In the external validation dataset, which included 2,670 participants aged <25 years (50% female, 10% asthma), the C-statistic was 0.85, 95% CI 0.83-0.88, and calibration slope 1.22, 95% CI 1.09-1.35. Conclusions: We derived and validated a prediction model for clinicians to calculate the probability of asthma diagnosis for a child or young person up to 25 years of age presenting to primary care. Following further evaluation of clinical effectiveness, the prediction model could be implemented as a decision support software.

A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing.

Background: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. Methods: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. Results: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p<6.7 × 10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge. Conclusions: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. Funding: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study.

Three-quarters of children hospitalized for wheezing or asthma symptoms are preschool-aged. Some will continue to experience breathing difficulties through childhood and adulthood. Others will undergo a complete resolution of their symptoms by the time they reach elementary school. The varied trajectories of young children with wheezing suggest that it is not a single disease. There are likely different genetic or environmental causes. Despite these differences, wheezing treatments for young children are 'one size fits all.' Studying the genetic underpinnings of wheezing may lead to more customized treatment options. Granell et al. studied the genetic architecture of different patterns of wheezing from infancy to adolescence. To do so, they used machine learning technology to analyze the genomes of 9,568 individuals, who participated in five studies in the United Kingdom from birth to age 18. The experiments found a new genetic variation in the ANXA1 gene linked with persistent wheezing starting in early childhood. By comparing mice with and without this gene, Granell et al. showed that the protein encoded by ANXA1 controls inflammation in the lungs in response to allergens. Animals lacking the protein develop worse lung inflammation after exposure to dust mite allergens. Identifying a new gene linked to a specific subtype of wheezing might help scientists develop better strategies to diagnose, treat, and prevent asthma. More studies are needed on the role of the protein encoded by ANXA1 in reducing allergen-triggered lung inflammation to determine if this protein or therapies that boost its production may offer relief for chronic lung inflammation.

Paediatrics in Amsterdam.

The aim of this update is to describe the paediatric highlights from the 2011 European Respiratory Society (ERS) Annual Congress in Amsterdam, the Netherlands. Abstracts from all seven groups of the ERS Paediatric Assembly (Paediatric Respiratory Physiology, Paediatric Asthma and Allergy, Cystic Fibrosis, Paediatric Respiratory Infection and Immunology, Neonatology and Paediatric Intensive Care, Paediatric Respiratory Epidemiology, and Paediatric Bronchology) are presented in the context of current literature.

Clinical utility of exhaled nitric oxide fraction in the management of asthma and COPD.

Exhaled nitric oxide fraction (F ENO) values can be easily measured using portable analysers and are a surrogate marker of airway eosinophilia. F ENO may be useful in diagnosing and monitoring conditions characterised by airway eosinophilia, i.e. asthma and possibly COPD. Many factors other than asthma and COPD affect F ENO, especially atopy, which is associated with elevated F ENO. One guideline recommends that F ENO should be used as part of the diagnostic pathway for asthma diagnosis in adults and children aged >5 years. The role of F ENO in monitoring asthma is even less clear, and most guidelines do not recommend its use outside of specialist asthma clinics. Currently, F ENO is not recommended for diagnosis or monitoring of COPD. Although F ENO is starting to find a place in the management of asthma in children and adults, considerably more research is required before the potential of F ENO as an objective measurement in asthma and COPD can be realised. KEY POINTS: For individuals aged ≥12 years, F ENO is not recommended by all guidelines as a test to diagnose asthma (recommended only by the UK National Institute for Health and Care Excellence guideline for asthma symptoms, which are likely to respond to corticosteroid treatment).F ENO may be used in conjunction with other investigations to diagnose asthma in 5-16-year-olds where there is diagnostic uncertainty, but further evidence is required.F ENO is not recommended as a routine test to monitor all patients with asthma or to titrate asthma treatment.F ENO is not recommended for routine clinical testing in adults with COPD.F ENO may be useful to identify patients with COPD who could benefit from the use of inhaled corticosteroids (asthma-COPD overlap). EDUCATIONAL AIMS: To understand what factors other than asthma and COPD affect F ENOTo understand the current controversies in the application of F ENO to diagnosis and management of asthma in childrenTo understand the current controversies in the application of F ENO to diagnosis and management of asthma and COPD in adults.

Applying UK real-world primary care data to predict asthma attacks in 3776 well-characterised children: a retrospective cohort study.

Current understanding of risk factors for asthma attacks in children is based on studies of small but well-characterised populations or pharmaco-epidemiology studies of large but poorly characterised populations. We describe an observational study of factors linked to future asthma attacks in large number of well-characterised children. From two UK primary care databases (Clinical Practice Research Datalink and Optimum Patient Care research Database), a cohort of children was identified with asthma aged 5-12 years and where data were available for ≥2 consecutive years. In the "baseline" year, predictors included treatment step, number of attacks, blood eosinophil count, peak flow and obesity. In the "outcome" year the number of attacks was determined and related to predictors. There were 3776 children, of whom 525 (14%) had ≥1 attack in the outcome year. The odds ratio (OR) for one attack was 3.7 (95% Confidence Interval (CI) 2.9, 4.8) for children with 1 attack in the baseline year and increased to 7.7 (95% CI 5.6, 10.7) for those with ≥2 attacks, relative to no attacks. Higher treatment step, younger age, lower respiratory tract infections, reduced peak flow and eosinophil count >400/µL were also associated with small increases in OR for an asthma attack during the outcome year. In this large population, several factors were associated with a future asthma attack, but a past history of attacks was most strongly associated with future attacks. Interventions aimed at reducing the risk for asthma attacks could use primary care records to identify children at risk for asthma attacks.

Lung function trajectories from pre-school age to adulthood and their associations with early life factors: a retrospective analysis of three population-based birth cohort studies.

BACKGROUND: Maximal lung function in early adulthood is an important determinant of mortality and COPD. We investigated whether distinct trajectories of lung function are present during childhood and whether these extend to adulthood and infancy. METHODS: To ascertain trajectories of FEV1, we studied two population-based birth cohorts (MAAS and ALSPAC) with repeat spirometry from childhood into early adulthood (1046 participants from 5-16 years and 1390 participants from 8-24 years). We used a third cohort (PIAF) with repeat lung function measures in infancy (V'maxFRC) and childhood (FEV1; 196 participants from 1 month to 18 years of age) to investigate whether these childhood trajectories extend from early life. We identified trajectories using latent profile modelling. We created an allele score to investigate genetic associations of trajectories, and constructed a multivariable model to identify their early-life predictors. FINDINGS: We identified four childhood FEV1 trajectories: persistently high, normal, below average, and persistently low. The persistently low trajectory (129 [5%] of 2436 participants) was associated with persistent wheezing and asthma throughout follow-up. In genetic analysis, compared with the normal trajectory, the pooled relative risk ratio per allele was 0·96 (95% CI 0·92-1·01; p=0·13) for persistently high, 1·01 (0·99-1·02; p=0·49) for below average, and 1·05 (0·98-1·13; p=0·13) for persistently low. Most children in the low V'maxFRC trajectory in infancy did not progress to the low FEV1 trajectory in childhood. Early-life factors associated with the persistently low trajectory included recurrent wheeze with severe wheezing exacerbations, early allergic sensitisation, and tobacco smoke exposure. INTERPRETATION: Reduction of childhood smoke exposure and minimisation of the risk of early-life sensitisation and wheezing exacerbations might reduce the risk of diminished lung function in early adulthood. FUNDING: None.

Comparative Effectiveness of Step-up Therapies in Children with Asthma Prescribed Inhaled Corticosteroids: A Historical Cohort Study.

BACKGROUND: In children with uncontrolled asthma prescribed low-dose inhaled corticosteroids (ICSs), various step-up options are available: fixed-dose combination ICS/long-acting ß2-agonist (FDC), increasing ICS dose, or adding leukotriene receptor antagonist (LTRA). However, evidence of their relative effectiveness is limited. OBJECTIVE: To compare the effectiveness of step-up treatment to FDC in children with asthma versus increased ICS dose, or LTRA. METHODS: This matched cohort study used UK primary-care databases to study children prescribed their first step-up treatment to FDC, increased ICS dose, or LTRA. A year of baseline data was used for matching and identifying confounders. Outcomes over the following year were examined. The primary outcome was severe exacerbation rate; secondary outcomes included overall asthma control, derived from databases (no asthma-related admissions/hospital attendances/oral corticosteroids or antibiotics prescribed with a respiratory review, and average prescribed salbutamol ≤200 µg/day). RESULTS: There were 971 matched pairs in the FDC and increased ICS dose cohorts (59% males; mean age, 9.4 years) and 785 in the FDC and LTRA cohorts (60% males; mean age, 9.0 years). Exacerbation rates in the outcome year were similar between FDC and increased ICS (adjusted incidence rate ratio [95% CI], 1.09 [0.75-1.59]) and FDC and LTRA (incidence rate ratio, 1.36 [0.93-2.01]). Increased ICS and LTRA significantly reduced the odds of achieving overall asthma control, compared with FDC (odds ratios [95% CI], 0.52 [0.42-0.64] and 0.53 [0.42-0.66], respectively)-this was driven by reduced short-acting beta-agonist use. CONCLUSIONS: FDC is as effective as increased ICS or LTRA in reducing severe exacerbation rate, but more effective in achieving asthma control.

Factors associated with quality of life in children with asthma living in Scotland.

INTRODUCTION: Asthma affects children's quality of life (QoL) but factors associated with QoL are not well understood. Our hypothesis was that there are factors linked to QoL which are amenable to treatment or environmental modification. METHODS: QoL was ascertained in a study designed to link environmental exposures to asthma outcomes. Univariate and multivariate analysis were used to determine which factors are associated with QoL. RESULTS: There were 553 children with asthma where QoL was determined, mean age 10.3 and 312 (58%) were boys. The median QoL score was 5.9 (interquartile range 4.6, 6.8). In the multivariate model, asthma severity (as evidenced by British Thoracic Society, BTS, treatment step), smoking exposure, socioeconomic status and rhinitis were associated with the QoL score. QoL score was reduced by (i) 30% [95% confidence interval 20, 39] for those on BTS step 4 compared to BTS step 1 treatment (ii) 11% [2, 19] for children with ≥ two resident smokers with reference to no resident smokers (iii) 3% [1, 5] for each quintile difference in deprivation compared to the most affluent and (iv) 9% [4, 14] for children with rhinitis compared to no rhinitis. CONCLUSIONS: The QoL for children with asthma in the UK is generally good. Clinicians caring children with asthma should consider routinely asking about smoke exposure and hayfever symptoms in addition to assessing asthma control.

Initial step-up treatment changes in asthmatic children already prescribed inhaled corticosteroids: a historical cohort study.

BACKGROUND: When standard doses of inhaled corticosteroids (ICS) fail to control symptoms in children aged >4 years, guidelines recommend the addition of a long-acting ß2-agonist (LABA), with other treatment options being available if symptoms persist. AIMS: To determine the proportion of initial 'step-up' episodes where LABAs were prescribed and to describe characteristics of individuals not stepped up with LABA. METHODS: Between 1999 and 2011, initial step-up episodes from ICS monotherapy were identified in children aged 5-12 years with asthma and in receipt of ICS. Data sources were the Clinical Practice Research Datalink and Optimum Patient Care Research Database. RESULTS: Initial step-up episodes were identified in 10,793 children. ICS dose was increased in 6,252 children (58%), LABA was introduced in 3,436 (32%; including 1,107 where fixed dose combination inhaler (FDC) replaced the ICS inhaler), and leukotriene receptor antagonist (LTRA) was added in 1,105 (10%). Compared with children stepped up to any LABA, others were younger and prescribed lower doses of ICS and reliever medication. ICS dose increase was more likely in obese children and LTRA prescribing was more likely in children with rhinitis and in receipt of antibiotics. Compared with FDC, step-up to separate LABA inhaler was more likely in younger, obese children who were using less oral steroids. CONCLUSIONS: One-third of initial step-up episodes in children with asthma treated with ICS are to add LABA. Different characteristics of children prescribed therapies other than LABA suggest that prescribers tailor treatment in some clinical settings.

Protease concentration in amniotic fluid at term and early childhood respiratory symptoms.

OBJECTIVE: Asthma is a common chronic disease associated with altered proteolytic activity. The present study tested the hypothesis that altered protease concentration in amniotic fluid (AF), an index of airway fluid at birth, precedes early cough and wheeze. METHODS: AF was collected and analysed for the following: matrix metalloproteinases (MMP) -2, -8 and -9, tissue inhibitor of metalloproteinases (TIMP) -1 and 2, plasminogen activator inhibitor (PAI)-1. Infant were followed up at ages 1, 2 and 3 years. RESULTS: Samples of AF were obtained in 92 infants. There were inconsistent and relatively small differences in some analytes between those individuals with and without symptoms at ages one and two years. PAI-1 concentrations were reduced in association with cough at age 1 year (p = 0.035). Reduced MMP-8:TIMP-2 ratio was associated with wheeze at age 2 years (p = 0.038). There were no associations between AF analytes and symptoms at 3 years of age. CONCLUSION: There is heterogeneity in concentrations of proteases and their inhibitors in airways at birth but in this exploratory study, there was no consistent evidence that protease concentration at birth was important to later respiratory symptoms.

Pharmacogenetic analysis of GLCCI1 in three north European pediatric asthma populations with a reported use of inhaled corticosteroids.

BACKGROUND: GLCCI1 rs37972 has previously been associated with decreased lung function improvement upon treatment with inhaled corticosteroids (ICS) in asthmatics. AIM: To assess whether variation in rs37972 is associated with altered ICS efficacy in north European asthmatic children and young adults with a reported use of ICS. PATIENTS & METHODS: rs37972 was genotyped in three cohort studies of asthmatic children with a reported use of ICS. As an indicator for asthma exacerbations, asthma-related hospital visits and oral corticosteroid use were studied. Asthma control was assessed using a questionnaire. RESULTS: rs37972 T allele was not significantly associated with an increased risk of oral corticosteroid use (summary odds ratio: 1.20; 95% CI: 0.99-1.45), an increased risk of asthma-related hospital visits (summary odds ratio: 1.07; 95% CI: 0.89-1.29), uncontrolled symptoms (summary odds ratio: 1.01; 95% CI: 0.75-1.36) or higher ICS dosages (summary ß: 0.01, 95% CI: -0.06-0.08). CONCLUSION: Variation in GLCCI1 rs37972 genotype does not seem to affect ICS efficacy in north European asthmatic children. Original submitted 26 November 2013; Revision submitted 13 February 2014.

Reduced infant lung function, active smoking, and wheeze in 18-year-old individuals.

UNLABELLED: IMPORTANCE This is the first study to link reduced lung function in early life, before the development of symptoms, to wheeze in 18-year-olds. Additionally, the study gives insight into factors other than reduced lung function that are also associated with persistent wheeze in young adults. OBJECTIVE: To test the hypothesis that reduced lung function in early life is associated with increased risk for persistent wheeze at age 18 years. DESIGN: Birth cohort study. SETTING: Perth, Western Australia. PARTICIPANTS: Individuals followed up from age 1 month to 18 years. MAIN OUTCOME MEASURES: Maximal flow at functional residual capacity (V'maxFRC) was measured in 1-month-old infants who were followed up at ages 6, 12, and 18 years. Based on reported symptoms, individuals were categorized as having remittent wheeze, later-onset wheeze, persistent wheeze, and no wheeze. Smoking status was noted at age 18 years. RESULTS: Of the 253 individuals originally recruited, 150 were followed up at age 18 years; 37 of the 150 had recent wheeze. Compared with the no-wheeze group (n = 96), persistent wheeze (n = 13) was independently associated with reduced percentage of predicted V'maxFRC (mean reduction, 43%; 95% CI, 13-74). Compared with the no-wheeze group, persistent wheeze was also associated with atopy in infancy (odds ratio = 7.1; 95% CI, 1.5-34.5), maternal asthma (odds ratio = 6.8; 95% CI, 1.4-32.3), and active smoking (odds ratio = 4.8; 95% CI, 1.0-21.3). When only wheeze at age 18 years was considered, reduced percentage of predicted V'maxFRC was associated with wheeze at age 18 years only among current smokers (P = .04). CONCLUSIONS AND RELEVANCE: Wheeze persisting from ages 6 to 18 years is associated with multiple factors, including reduced infant lung function, infant-onset atopy, maternal asthma, and active smoking. Wheeze at age 18 years (regardless of previous wheeze status) is associated with active smoking, but only among those with reduced lung function in infancy. These findings give unique insight into the cause of obstructive airways disease in 18-year-olds, and follow-up of this cohort might be expected to further extend our understanding.

Culture of airway epithelial cells from neonates sampled within 48-hours of birth.

INTRODUCTION: Little is known about how neonatal airway epithelial cell phenotype impacts on respiratory disease in later life. This study aimed to establish a methodology to culture and characterise neonatal nasal epithelial cells sampled from healthy, non-sedated infants within 48 hours of delivery. METHODS: Nasal epithelial cells were sampled by brushing both nostrils with an interdental brush, grown to confluence and sub-cultured. Cultured cells were characterised morphologically by light and electron microscopy and by immunocytochemistry. As an exemplar pro-inflammatory chemokine, IL-8 concentrations were measured in supernatants from unstimulated monolayers and after exposure to IL-1ß/TNF-α or house dust mite extract. RESULTS: Primary cultures were successfully established in 135 (91%) of 149 neonatal samples seeded, with 79% (n  =  117) successfully cultured to passage 3. The epithelial lineage of the cells was confirmed by morphological analysis and immunostaining. Constitutive IL-8 secretion was observed and was upregulated by IL-1ß/TNF-α or house dust mite extract in a dose dependent manner. CONCLUSION: We describe a safe, minimally invasive method of culturing nasal epithelial cells from neonates suitable for functional cell analysis offering an opportunity to study "naïve" cells that may prove useful in elucidating the role of the epithelium in the early origins of asthma and/or allergic rhinitis.

Nasal and bronchial airway epithelial cell mediator release in children.

OBJECTIVE: The present study was designed to test the hypothesis that airway epithelial cell (AEC) mediator release is similar in upper and lower airway AEC in children. METHODS: Nasal and bronchial AEC were collected by brushings from children scheduled for general anesthetic. AEC release of the following mediators was measured: interleukin (IL)-6, IL-8, Granulocyte Colony Stimulating Factor (G-CSF), regulated on activation, normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), matrix metallo proteinase (MMP)-9, and tissue inhibitor of metalloproteinases (TIMP)-1. RESULTS: AEC were cultured in 34 children, mean age 7.3 years. Release of IL-6, IL-8, and G-CSF was significantly higher in nasal compared with bronchial AEC but nasal and bronchial AEC release of other mediators was not significantly different. Treatment of AEC with IL-1 ß and tumor necrosis factor-α increased secretion of all mediators. Release of IL-6 and GSCF remained higher in nasal AEC compared with bronchial AEC following stimulation. CONCLUSIONS: In epidemiological studies, nasal AEC may be a useful surrogate for bronchial AEC for the study of RANTES, MCP-1, TIMP-1, and MMP-9 release in children but bronchial AEC will remain the gold standard.