Copenhagen Prospective Study On Asthma In Childhood Research Articles

Genetic associations with viral respiratory illnesses and asthma control inchildren.

Viral respiratory infections can cause acute wheezing illnesses in children and exacerbations of asthma. We sought to identify variation in genes with known antiviral and pro-inflammatory functions to identify specific associations with more severe viral respiratory illnesses and the risk of virus-induced exacerbations during the peak fall season. The associations between genetic variation at 326 SNPs in 63 candidate genes and 10 phenotypes related to viral respiratory infection and asthma control were examined in 226 children enrolled in the RhinoGen study. Replication of asthma control phenotypes was performed in 2128 children in the Copenhagen Prospective Study on Asthma in Childhood (COPSAC). Significant associations in RhinoGen were further validated using virus-induced wheezing illness and asthma phenotypes in an independent sample of 122 children enrolled in the Childhood Origins of Asthma (COAST) birth cohort study. A significant excess of P values smaller than 0.05 was observed in the analysis of the 10 RhinoGen phenotypes. Polymorphisms in 12 genes were significantly associated with variation in the four phenotypes showing a significant enrichment of small P values. Six of those genes (STAT4, JAK2, MX1, VDR, DDX58, and EIF2AK2) also showed significant associations with asthma exacerbations in the COPSAC study or with asthma or virus-induced wheezing phenotypes in the COAST study. We identified genetic factors contributing to individual differences in childhood viral respiratory illnesses and virus-induced exacerbations of asthma. Defining mechanisms of these associations may provide insight into the pathogenesis of viral respiratory infections and virus-induced exacerbations of asthma.

Effect of delivery device on systemic exposure to inhaled fluticasone propionate in children with asthma

Effect of delivery device on systemic exposure to inhaled fluticasone propionate in children with asthma

Increased Risk of Pneumonia and Bronchiolitis after Bacterial Colonization of the Airways as Neonates

The frequency of pneumonia and bronchiolitis exhibits considerable variation in otherwise healthy children, and suspected risk factors explain only a minor proportion of the variation. We hypothesized that alterations in the airway microbiome in early life may be associated with susceptibility to pneumonia and bronchiolitis in young children. To investigate the relation between neonatal airway colonization and pneumonia and bronchiolitis during the first 3 years of life. Participants comprised children of the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) cohort, a prospective birth cohort study of 411 children born to mothers with asthma. Aspirates from the hypopharynx at age 4 weeks were cultured for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Clinical information on pneumonia and bronchiolitis within the first 3 years of life was prospectively collected by the research physicians at the center. Analyses were adjusted for covariates associated with pneumonia and bronchiolitis and bacterial airway colonization. Hypopharyngeal aspirates and full clinical follow-up until 3 years of age were available for 265 children. Of these, 56 (21%) neonates were colonized with S. pneumoniae, H. influenzae, and/or M. catarrhalis at 4 weeks of age. Colonization with at least one of these microorganisms (but not S. aureus) was significantly associated with increased incidence of pneumonia and bronchiolitis (adjusted incidence rate ratio, 1.79 [1.29-2.48]; P < 0.005) independently of concurrent or later asthma. Neonatal airway colonization with S. pneumoniae, H. influenzae, or M. catarrhalis is associated with increased risk of pneumonia and bronchiolitis in early life independently of asthma. This suggests a role of pathogenic bacterial colonization of the airways in neonates for subsequent susceptibly to pneumonia and bronchiolitis.

Use of Antibiotics During Pregnancy Increases the Risk of Asthma in Early Childhood

To investigate whether maternal use of antibiotics during pregnancy influences the development of asthma and eczema early in life.The Copenhagen Prospective Study on Asthma in Childhood (COPSAC), a birth cohort of 411 infants born between 1998 and 2001 to mothers with a history of asthma. The COPSAC data were supplemented by data from the Danish National Birth Cohort (DNBC) consisting of 101 042 pregnant women and their children recruited between 1997 and 2003. Both cohorts were followed prospectively for 5 years.History of maternal exposure to antibiotics in the third trimester was obtained during the first COPSAC enrollment visit. Asthma exacerbations were defined as need for oral prednisolone, high-dose inhaled corticosteroids (ICS), or asthma hospitalization. In the DNBC data, investigators defined maternal antibiotic use as at least 1 filled antibiotic prescription during pregnancy. Asthma was defined as either an asthma hospitalization or an ICS prescription filled at least once.In the COPSAC birth cohort, children of mothers who used antibiotics during the third trimester were at a significantly increased risk of developing early asthma exacerbation (hazard ratio [HR]: 1.98). Maternal use of antibiotics in the third trimester did not influence the child’s risk of eczema. An increased risk of asthma after maternal antibiotic exposure was confirmed via DNBC analysis: children of mothers exposed to antibiotics during pregnancy were at a higher risk of asthma hospitalization (HR: 1.17) and ICS use (HR: 1.18). For each additional antibiotic prescription filled during pregnancy, a progressively increased risk of asthma was demonstrated (adjusted P = .01).An increased risk of asthma was found in a prospectively followed cohort of children whose mothers received antibiotics during the third trimester of pregnancy. This finding was confirmed in an unselected national birth cohort of mothers. No increased risk of eczema was detected in either cohort.Perturbing the native microbiome in the lungs has been increasingly shown to affect both asthma development and clinical control. This study adds to the mounting evidence suggesting that changing the balance between beneficial and pathogenic bacteria may play a role in the development of asthma. In a prospective analysis, these investigators implicate in utero exposure to maternal antibiotics as a significant risk factor in early asthma pathogenesis.

Rhinovirus Wheezing Illness and Genetic Risk of Childhood-Onset Asthma

M Caliskan, YA Bochkov, E Kreiner-Moller. N Engl J Med. 2013;368(15):1398–1407 Genetic variations at the 17q21 locus, as well as human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illness, are associated with the development of asthma. This retrospective study aimed to determine the effects of these 2 factors independently and together on the risk of asthma. Data were compiled from the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts as well as a group of adult volunteers. For the COAST study, 289 newborns had at least 1 parent with respiratory allergies, a history of physician-diagnosed asthma, or both and 200 were evaluated for asthma …

Rhinovirus Wheezing Illness and Genetic Risk of Childhood-Onset Asthma

BackgroundBoth genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts.MethodsWe tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. Finally, we examined genotype-specific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs).ResultsThe 17q21 variants were associated with HRV wheezing illnesses in early life, but not with RSV wheezing illnesses. The associations of 17q21 variants with asthma were restricted to children who had had HRV wheezing illnesses, resulting in a significant interaction effect with respect to the risk of asthma. Moreover, the expression levels of ORMDL3 and of GSDMB were significantly increased in HRV-stimulated PBMCs, as compared with unstimulated PBMCs. The expression of these genes was associated with 17q21 variants in both conditions, although the increase with exposure to HRV was not genotype-specific.ConclusionsVariants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses and with expression of two genes at this locus. The expression levels of both genes increased in response to HRV stimulation, although the relative increase was not associated with the 17q21 genotypes. (Funded by the National Institutes of Health.)

Allergic rhinitis is associated with otitis media with effusion: a birth cohort study

Childhood otitis media with effusion is a common disease and a link to allergic diseases has been suggested. To investigate the association between atopic disease and otitis media with effusion diagnosed according to strict objective case definitions by age 6years. We evaluated 291 children in the 6th year of life from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) 2000 birth cohort. Otitis media with effusion was diagnosed based on tympanometric and objective evaluation. Asthma, eczema, allergic- and non-allergic rhinitis was diagnosed prospectively by pre-defined algorithms. Nasal mucosal swelling was assessed using acoustic rhinometry and nasal eosinophilia from scrapings. Analyses were performed using logistic regression and adjusted for dog, cat and smoking exposure, paternal atopy, household income, older siblings, gender and number of acute otitis media episodes. Otitis media with effusion was diagnosed in 39% of the cohort and was associated with allergic rhinitis (aOR=3.36, CI=1.26-8.96, P=0.02), but not with nasal mucosal swelling, nasal oeosinophilia, non-allergic rhinitis, asthma or eczema. Otitis media with effusion is closely associated with allergic rhinitis presumably caused by allergic inflammation, but not mechanical nasal mucosal swelling. These findings warrant an increased awareness of otitis media with effusion in children with allergic rhinitis.

Neonatal Cytokine Profile in the Airway Mucosal Lining Fluid Is Skewed by Maternal Atopy

Heredity from mother or father may impact differently in complex diseases, such as atopy. Maternal atopy is a stronger risk factor than paternal atopy for the development of atopy in the offspring. We hypothesized that mother's and father's atopy would have a differential imprinting on the cytokines and chemokines in the upper airway mucosal lining fluid of healthy neonates. To study parental atopic imprinting on the cytokines and chemokines in the upper airway mucosal lining fluid of healthy neonates. Eighteen cytokines and chemokines were quantified in nasal mucosal lining fluid in 309 neonates from the novel unselected Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohort. Maternal, but not paternal, atopic status (asthma, hay fever, or eczema with or without sensitization) was associated with general down-regulation of all 18 mediators assessed by principal component analysis (overall P = 0.015). Maternal atopy, but not paternal atopy, showed a strong linkage with a suppressed mucosal cytokine and chemokine signature in asymptomatic neonates, suggesting imprinting by the maternal milieu in utero or perinatal life.

Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth

Copenhagen Prospective Study on Asthma in Childhood (COPSAC) was one of the discovery cohorts of the association between eczema and variants in the filaggrin coding gene (FLG). Here, we study the FLG-associated risk of asthma symptoms in early life and describe the temporal relationship in the development of the different FLG-associated atopic outcomes: asthma, sensitization and eczema, assessed longitudinally from birth. A high-risk cohort of 411 children was assessed in a prospective clinical study from birth to school-age. Asthma, acute severe asthma exacerbations, sensitization and eczema were diagnosed prospectively by the investigators. FLG variants R501X and Del4 were determined in 382 Caucasians. Filaggrin variants increased risk of developing recurrent wheeze, asthma and asthma exacerbations (hazard ratio 1.82 [1.06-3.12], p = 0.03), which was expressed within the first 1.5 yr of life. Children with filaggrin variants had a marked and persistent increase in acute severe asthma exacerbations from 1 yr of age (incidence ratio 2.40 [1.19-4.81], p = 0.01) and increased risk of asthma by age 5 (odds ratio 2.62 [1.12-6.11], p = 0.03). FLG variants increased the risk of eczema, manifesting fully in the first year of life (point prevalence ratio for age 0-5 was 1.75 [1.29-2.37]; p-value = 0.0003) contrasting the increased risk of specific sensitization by age 4 (odds ratio 3.52 [1.72-7.25], p = 0.0007) but not age 1.5. This study describes a FLG-associated pattern of atopic diseases characterized by the early onset of asthma symptoms and eczema and later development of sensitization. The association of filaggrin variants with asthma suggests skin barrier dysfunction as a novel, and potentially modifiable, mechanism driving early childhood asthma.

Chromosome 17q21 Gene Variants Are Associated With Asthma and Exacerbations But Not Atopy in Early Childhood

Bisgaard H, Bonnelykke K, Sleiman PMA, et al. Am J Respir Crit Care Med . 2009;179(3):179–185 PURPOSE OF THE STUDY. To determine the association between the 17q12–q21 locus and various clinical characteristics of asthma and atopic sensitization during childhood. STUDY POPULATION. The Copenhagen Prospective Study on Asthma in Childhood (COPSAC) included a birth cohort of 411 children born to mothers with a history of asthma. Three hundred seventy-six …

Chromosome 17q21 Gene Variants Are Associated with Asthma and Exacerbations but Not Atopy in Early Childhood

An asthma predisposition locus on chromosome 17q12-q21 has recently been replicated in different ethnic groups. To characterize the asthma and atopy phenotypes in early childhood that associate with the 17q12-21 locus. The single nucleotide polymorphism (SNP), rs7216389, was genotyped in 376 of 411 children from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohort born to mothers with asthma together with 305 mothers and 224 fathers. Nineteen additional SNPs in the region were genotyped in the children. Investigator-diagnosed clinical endpoints were based on diary cards and clinic visits every 6 months and at acute symptoms from birth. Lung function, bronchial responsiveness, and sensitization were tested longitudinally from early infancy. rs7216389 was significantly associated with the development of wheeze (hazard ratio 1.64 [1.05-2.59], P value = 0.03), asthma (hazard ratio, 1.88 [1.15-3.07], P = 0.01), and acute severe exacerbations (hazard ratio 2.66 [1.58-4.48], P value = 0.0002). The effect on wheeze and asthma was observed for early onset but not late onset of disease. The increased risk of exacerbations persisted from 1 to 6 years of age (incidence ratio 2.48 [1.42-4.32], P value = 0.001), and increased bronchial responsiveness was present in infancy and at 4 years of age, but not at 6 years. In contrast, rs7216389 conferred no risk of eczema, rhinitis, or allergic sensitization. Variation at the chromosome 17q12-q21 locus was associated with approximately twofold increased risk of recurrent wheeze, asthma, asthma exacerbations, and bronchial hyperresponsiveness from early infancy to school age but without conferring risk of eczema, rhinitis, or allergic sensitization. These longitudinal clinical data show this locus to be an important genetic determinant of nonatopic asthma in children.

Sensitization Does Not Develop In Utero

Bønnelykke K, Pipper CB, Bisgaard H. J Allergy Clin Immunol. 2008;121(3):646–651 PURPOSE OF THE STUDY. To investigate the relationship of allergen-specific immunoglobulin E (IgE) in cord blood to sensitization in early infancy and the origin of such IgE. STUDY POPULATION. There were 243 children followed from birth. The patients were part of the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) and, thus, were considered to be at risk for atopy because of a maternal history of asthma. METHODS. Cord blood IgE was determined at the time of birth and again at 6 months of age. Total IgE, specific IgE to milk and egg, and a cumulative level of specific IgE to a panel of common aeroallergens were analyzed and compared with maternal IgE. Cord blood IgA was also assessed as a marker of maternal contamination of fetal blood, because IgA is not thought to cross the placental barrier during pregnancy. RESULTS. Specific IgE against mixed allergens was detected in 34 (14%) of the cord blood samples, and specific IgE against single allergens was detected in 22 samples. IgA was detected in 98% of the samples. None of the specific IgE found in cord blood was detected at 6 months of age. Cord blood IgE was not detected in any infants whose mothers were not sensitized, and the infants who did have cord blood IgE detected displayed a “fingerprint match” to maternal IgE. In every case, the IgE for a specific allergen detected in cord blood was the same as that detected in maternal blood, and it was present in a relatively similar concentration to that found in maternal blood. The cord blood IgA level also showed a linear relationship to the IgE level, suggesting that more maternal contamination resulted in higher IgE levels in cord blood. CONCLUSIONS. IgE in cord blood does not reflect in utero sensitization but seems to reflect maternofetal transfer of IgE. REVIEWER COMMENTS. The questions rarely change, but our answers often do. In recent years, the American Academy of Pediatrics recommended that some parents avoid certain foods during pregnancy to reduce the chance of their child developing atopic disease. These recommendations were based on studies that showed that the human fetus is capable of producing IgE as early as the 20th week of gestation and that cord blood IgE seemed to be a predictor of future atopy. Now the evidence seems to suggest that although sensitization could theoretically occur in utero, it simply does not. This study provides convincing evidence that the IgE in cord blood does not come from the infant but, rather, from the mixing of maternofetal blood, probably at the time of delivery. This study, along with other evidence that has come to light recently, raises questions about whether maternal dietary restriction of allergens during pregnancy impacts allergy outcomes to the avoided food/foods.

Filaggrin null alleles are not associated with hand eczema or contact allergy

The filaggrin protein is a key component of stratum corneum and homo- or heterozygotes for the filaggrin variant alleles R501X and 2282del4 have varying degrees of impaired skin barrier. The variant alleles have repeatedly been shown to be associated with atopic dermatitis. Any possible association with hand eczema or contact allergy are unexplored. To explore associations between the variant alleles, hand eczema, contact allergy and atopic dermatitis. In total, 183 adult individuals participated in a clinical examination of the hands, patch testing and filaggrin genotyping. Children without any evidence of atopic dermatitis from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) study were used as controls. The chi(2) test was used for comparison of allele frequencies. The majority (73%) had hand eczema, 25% had contact allergy and 14% had a diagnosis of atopic dermatitis. The association between atopic dermatitis and the filaggrin variant alleles was confirmed (odds ratio 3.5, P = 0.015). Allele frequencies in individuals with hand eczema or contact allergy were not statistically significantly increased. There is no association between the variant alleles and hand eczema or contact allergy.

The Copenhagen Prospective Study on Asthma in Childhood (COPSAC): design, rationale, and baseline data from a longitudinal birth cohort study

The atopic diseases asthma, atopic dermatitis, and allergic rhinitis are the most common chronic diseases in children, and their prevalence has increased recently in industrialized nations. Little is known about the genetic-environmental interaction factors driving such proliferation. To investigate the relationships among genetic, environmental, and lifestyle factors in the development of atopic diseases in high-risk children with the aim of developing evidence-based prevention strategies. The Copenhagen Prospective Study on Asthma in Childhood is a single-center, birth cohort study of children of asthmatic mothers. Objective assessments begin at birth, with scheduled visits every 6 months and when acute symptoms manifest. Clinical outcomes comprise preasthma, asthma, atopic dermatitis, allergic rhinitis, allergy, lung function, and bronchial responsiveness. Exposure assessments comprise respiratory, intestinal, and skin microbiology; the child's diet; indoor and outdoor air quality; allergens; and indicators of lifestyle. Genetic characteristics of probands and parents are evaluated. Quality assurance follows Good Clinical Practice guidelines. Four hundred eleven infants of asthmatic mothers were enrolled at the age of 1 month. The children were born between August 2, 1998, and December 28, 2001. Compared with the Copenhagen population, mothers of the cohort population were less likely to have given natural childbirth. The households were slightly less affluent, with fewer children and fewer pets. Whites may be overrepresented. At age 2 years, 93% of the infants were still actively participating in the cohort. This longitudinal birth cohort study of high-risk Danish infants consists of objective phenotyping, detailed information on exposure, high data quality, and a high participant retention rate.