Karin C. Lødrup Carlsen

A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci.

There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.

Does Pet Ownership in Infancy Lead to Asthma or Allergy at School Age? Pooled Analysis of Individual Participant Data from 11 European Birth Cohorts

Objective To examine the associations between pet keeping in early childhood and asthma and allergies in children aged 6–10 years. Design Pooled analysis of individual participant data of 11 prospective European birth cohorts that recruited a total of over 22,000 children in the 1990s. Exposure definition Ownership of only cats, dogs, birds, rodents, or cats/dogs combined during the first 2 years of life. Outcome definition Current asthma (primary outcome), allergic asthma, allergic rhinitis and allergic sensitization during 6–10 years of age. Data synthesis Three-step approach: (i) Common definition of outcome and exposure variables across cohorts; (ii) calculation of adjusted effect estimates for each cohort; (iii) pooling of effect estimates by using random effects meta-analysis models. Results We found no association between furry and feathered pet keeping early in life and asthma in school age. For example, the odds ratio for asthma comparing cat ownership with “no pets” (10 studies, 11489 participants) was 1.00 (95% confidence interval 0.78 to 1.28) (I2 = 9%; p = 0.36). The odds ratio for asthma comparing dog ownership with “no pets” (9 studies, 11433 participants) was 0.77 (0.58 to 1.03) (I2 = 0%, p = 0.89). Owning both cat(s) and dog(s) compared to “no pets” resulted in an odds ratio of 1.04 (0.59 to 1.84) (I2 = 33%, p = 0.18). Similarly, for allergic asthma and for allergic rhinitis we did not find associations regarding any type of pet ownership early in life. However, we found some evidence for an association between ownership of furry pets during the first 2 years of life and reduced likelihood of becoming sensitized to aero-allergens. Conclusions Pet ownership in early life did not appear to either increase or reduce the risk of asthma or allergic rhinitis symptoms in children aged 6–10. Advice from health care practitioners to avoid or to specifically acquire pets for primary prevention of asthma or allergic rhinitis in children should not be given.

Severity of obstructive airways disease by age 2 years predicts asthma at 10 years of age

Background: Predicting school-age asthma from obstructive airways disease (OAD) in early life is difficult, even when parental and children’s atopic manifestations are taken into consideration. Objective: To assess if the severity of OAD in the first 2 years of life predicts asthma at 10 years of age. Methods: From a nested case control study within the Environment and Childhood Asthma study, 233 2-year-old subjects with recurrent (⩾2 episodes) bronchial obstruction (rBO+) and 216 subjects without bronchial obstruction (rBO−) underwent clinical examination, parental interview, treadmill test and metacholine bronchial hyperresponsiveness (BHR) measurement at 10 years. A severity score at 2 years was calculated by frequency, persistence of bronchial obstruction and hospital admissions because of OAD. Main outcomes: Current asthma at 10 years (asthma with symptoms and/or asthma medication during the past year and/or positive treadmill test). Secondary outcome was metacholine BHR at 10 years. Results: Compared with rBO− subjects, adjusted odds ratio (95% CI) of current asthma among rBO+ was 7.9 (4.1, 15.3), and among rBO+ with a severity score of >5, 20.2 (9.9, 41.3). In receiver operated characteristic analysis, positive and negative predictive values demonstrated the applicability and value of the score, with an optimal cut-off at severity score 5. Children with severity score >5 had severe BHR more often (PD20 metacholine <1 μmol) than children with a lower or 0 score (p = 0.0041). Conclusion: Using a simple scoring system, a high severity score of OAD by 2 years of age is a strong risk factor for, and may predict, current asthma at 10 years of age.

Urinary Biomarkers for Phthalates Associated with Asthma in Norwegian Children

Background: High-molecular-weight phthalates in indoor dust have been associated with asthma in children, but few studies have evaluated phthalate biomarkers in association with respiratory outcomes. Objectives: We explored the association between urinary concentrations of phthalate metabolites and current asthma. Methods: In a cross-sectional analysis, 11 metabolites of 8 phthalates [including four metabolites of di(2-ethylhexyl) phthalate] were measured in one first morning void collected from 2001 through 2004 from 623 10-year-old Norwegian children. Logistic regression models controlling for urine specific gravity, sex, parental asthma, and income were used to estimate associations between current asthma and phthalate metabolite concentrations by quartiles or as log10-transformed variables. Results: Current asthma was associated with both mono(carboxyoctyl) phthalate (MCOP) and mono(carboxynonyl) phthalate (MCNP), although the association was limited to those in the highest quartile of these chemicals. The adjusted odds ratio (aOR) for current asthma was 1.9 (95% CI: 1.0, 3.3) for the highest MCOP quartile compared with the lowest quartile, and 1.3 (95% CI: 0.98, 1.7) for an interquartile-range increase. The aOR for current asthma was 2.2 (95% CI: 1.2, 4.0) for the highest MCNP quartile and 1.3 (95% CI: 1.0, 1.7) for an interquartile-range increase. The other phthalate metabolites were not associated with current asthma. Conclusions: Current asthma was associated with the highest quartiles of MCOP and MCNP, metabolites of two high molecular weight phthalates, diisononyl phthalate and diisodecyl phthalate, respectively. Given the short biological half-life of the phthalates and the cross-sectional design, our findings should be interpreted cautiously.

Exercise-induced asthma.

Exercise-induced asthma (EIA) is common in asthmatic children and adolescents. Since it may cause limitations to daily life activities in up to 30%, mastering EIA is important in asthma management. EIA consists of bronchial obstruction occurring immediately, or soon after, physical exercise as a result of increased respiratory water and heat loss due to increased ventilation during exercise, with the subsequent release of mediators and stimulation of airways receptors. Diagnosis is best made by standardised exercise tests, preferably running on a treadmill for 6-8 minutes at an exercise load of 95% of maximum. The sensitivity of the test may be increased by cold air inhalation. EIA is best treated by inhaled steroids in addition to pre-treatment before exercise by inhaled beta(2)-agonists, short or long acting, and/or leukotriene antagonists. Physical training may improve physical fitness and quality of life in asthmatic children but baseline lung function and bronchial responsiveness are not improved.

Racemic Adrenaline and Inhalation Strategies in Acute Bronchiolitis

BACKGROUND Acute bronchiolitis in infants frequently results in hospitalization, but there is no established consensus on inhalation therapy--either the type of medication or the frequency of administration--that may be of value. We aimed to assess the effectiveness of inhaled racemic adrenaline as compared with inhaled saline and the strategy for frequency of inhalation (on demand vs. fixed schedule) in infants hospitalized with acute bronchiolitis. METHODS In this eight-center, randomized, double-blind trial with a 2-by-2 factorial design, we compared inhaled racemic adrenaline with inhaled saline and on-demand inhalation with fixed-schedule inhalation (up to every 2 hours) in infants (<12 months of age) with moderate-to-severe acute bronchiolitis. An overall clinical score of 4 or higher (on a scale of 0 to 10, with higher scores indicating more severe illness) was required for study inclusion. Any use of oxygen therapy, nasogastric-tube feeding, or ventilatory support was recorded. The primary outcome was the length of the hospital stay, with analyses conducted according to the intention-to-treat principle. RESULTS The mean age of the 404 infants included in the study was 4.2 months, and 59.4% were boys. Length of stay, use of oxygen supplementation, nasogastric-tube feeding, ventilatory support, and relative improvement in the clinical score from baseline (preinhalation) were similar in the infants treated with inhaled racemic adrenaline and those treated with inhaled saline (P>0.1 for all comparisons). On-demand inhalation, as compared with fixed-schedule inhalation, was associated with a significantly shorter estimated mean length of stay--47.6 hours (95% confidence interval [CI], 30.6 to 64.6) versus 61.3 hours (95% CI, 45.4 to 77.2; P=0.01) - as well as less use of oxygen supplementation (in 38.3% of infants vs. 48.7%, P=0.04), less use of ventilatory support (in 4.0% vs. 10.8%, P=0.01), and fewer inhalation treatments (12.0 vs. 17.0, P<0.001). CONCLUSIONS In the treatment of acute bronchiolitis in infants, inhaled racemic adrenaline is not more effective than inhaled saline. However, the strategy of inhalation on demand appears to be superior to that of inhalation on a fixed schedule. (Funded by Medicines for Children; ClinicalTrials.gov number, NCT00817466; EudraCT number, 2009-012667-34.).

The chitinase-like protein YKL-40: a possible biomarker of inflammation and airway remodeling in severe pediatric asthma

BACKGROUND Problematic severe childhood asthma includes a subgroup of patients who are resistant to therapy. The specific mechanisms involved are unknown, and novel biomarkers are required to facilitate treatment and diagnosis of therapy-resistant asthma. The chitinase-like protein YKL-40 has been related to asthma and airway remodeling. OBJECTIVES To compare serum YKL-40 levels in children with severe, therapy-resistant asthma (n = 34), children with controlled persistent asthma (n = 39), and healthy controls (n = 27), and to investigate correlations with biomarkers of inflammation and airway remodeling. METHODS The study protocol included questionnaires, measurement of exhaled nitric oxide in exhaled air, blood sampling for inflammatory biomarkers, and high-resolution computed tomography of the lungs to identify bronchial wall thickening (therapy-resistant only). Serum YKL-40 levels were measured by ELISA, and all asthmatic children were genotyped for a CHI3L1 promoter single nucleotide polymorphism (rs4950928). RESULTS Serum YKL-40 levels were significantly higher in children with therapy-resistant asthma than in healthy children (19.2 ng/mL vs 13.8 ng/mL, P = .03). Among children with severe, therapy-resistant asthma, YKL-40 levels correlated with fraction of exhaled nitric oxide in exhaled air (r = 0.48, P = .004), blood neutrophils (r = 0.63, P < .001), and bronchial wall thickening on high-resolution computed tomography (r = 0.45, P = .01). Following adjustment for CHI3L1 genotype, significantly greater levels of YKL-40 were found in children with therapy-resistant asthma than in children with controlled asthma. CONCLUSIONS YKL-40 levels are increased in children with severe, therapy-resistant asthma compared to healthy children, and also compared to children with controlled asthma following correction for genotype.

The Environment and Childhood Asthma (ECA) Study in Oslo: ECA‐1 and ECA‐2

An observed increase in asthma admissions in Oslo during the 1980s prompted a prospective birth cohort study to ask the following question: was air pollution (outdoor and indoor) (in a broad sense) associated with asthma development in young children? During 12 months from 1 January 1992, 3,754 children (birth weight ≥2000 g) in Oslo were enrolled at birth into the Environment and Childhood Asthma (ECA) study and followed to 2 years of age (ECA‐part I). Cord blood, a detailed questionnaire (family and pregnancy history of disease, environmental exposures, socio‐economic status) completed by the mother and lung function measurements (n = 803) were collated at birth. Detailed questionnaires completed every 6 months for 2 years included the childs disease history, feeding habits and environmental exposures. A nested case‐control study comprised 306 children with confirmed minimum two episodes of bronchial obstruction (rBO) and 306 controls (without lower respiratory tract disease) with clinical investigations (including tidal breathing lung function, beta‐2 responsiveness and allergy assessment) and environmental exposure assessments (indoor and outdoor). Home dampness and low ventilation, as well as maternal smoking in pregnancy, but not outdoor air pollution increased the risk of rBO. Lung function at birth was decreased among newborns whose mother smoked during pregnancy. To understand better the early risk factors for asthma and allergy development, a follow‐up study started (in 2001; ECA‐part II) of all cases and controls, and those with lung function measured at birth (total 1,230 invited) (9–10 years of age). This involved clinical investigation, allergy assessments, lung function, airway hyper responsiveness measures, exhaled nitric oxide and immunological as well as allergen exposure investigations.

Early childhood IgE reactivity to pathogenesis-related class 10 proteins predicts allergic rhinitis in adolescence

BACKGROUND Component-resolved diagnosis might improve the prediction of future allergy in young children. OBJECTIVE We sought to investigate the association between IgE reactivity to the pathogenesis-related class 10 (PR-10) protein family and allergic rhinitis to birch pollen (ARbp) from early childhood up to age 16 years. METHOD Questionnaire data and sera obtained at 4, 8, and 16 years of age from the Barn/Children Allergi/Allergy Milieu Stockholm Epidemiologic (BAMSE) study birth cohort were used. Sera from 764 children were analyzed for IgE reactivity to 9 PR-10 allergen proteins at the 3 time points by using an allergen chip based on ISAC technology. ARbp was defined as upper airway symptoms during birch pollen exposure. RESULTS IgE reactivity to Bet v 1 was found in 12%, 17%, and 25% of children at 4, 8, and 16 years of age. IgE reactivity of PR-10 proteins showed a hierarchic intrarelationship: Bet v 1 > Mal d 1 > Cor a 1.04 > Ara h 8 > Pru p 1 > Aln g 1 > Api g 1 > Act d 8 > Gly m 4. There was an increased risk of incidence and persistence of ARbp up to age 16 years with increasing levels of Bet v 1-specific IgE or increasing numbers of IgE-reactive PR-10 proteins at 4 years. Children with severe ARbp at age 16 years had higher levels of Bet v 1-specific IgE at age 4 years compared with children with mild symptoms. CONCLUSION ARbp at age 16 years can be predicted by analysis of IgE reactivity to PR-10 proteins in early childhood.

Respiratory effects of tobacco smoking on infants and young children

Second-hand smoke (SHS) and tobacco smoke products (TSPs) are recognised global risks for human health. The present article reviews the causal role of SHS and TSPs for respiratory disorders in infants and young children. Several studies have shown an effect of TSPs exposure during pregnancy upon lung function in the newborn infant and of SHS on symptoms and lung function after birth. From 1997 to 1999 a set of systematic reviews concerning the relationship between second-hand exposure to tobacco smoke and respiratory health in children was published in Thorax by Cook and Strachan, covering hundreds of published papers. The evidence for a causal relationship between SHS exposure and asthmatic symptoms and reduced lung function is quite strong, whereas the evidence related to the development of allergy is much weaker. There is recent evidence relating to an interaction between TSP exposure and genetic ploymorphisms, demonstrating that certain individuals are more susceptible to the effect of TSP exposure on lung health. In the present review, an overview is given for the effects of TSP exposure and SHS upon lung health in children, with a focus on infants and young children. There is a need for intervention to reduce TSP exposure in young children, by educating parents and adolescents about the health effects of TSP exposure. Recent legislation in many European countries related to smoking in the workplace is of great importance for exposure during pregnancy. Studies are needed to identify possible critical periods for TSPs to induce harmful effects upon lung health in young children and on environment-gene interactions in order to prevent harm.