Hans Bisgaard

Bacteria‐induced histamine release from human bronchoalveolar cells and blood leukocytes

Histamine release induced by Staphylococcus aureus was examined in cells obtained by bronchoalveolar lavage (BAL) in non‐topic individuals. Approximately half of the individuals responded with mediatior release to the bacterium, and the release was found to be time‐ and concentration dependent. No difference was found between the patients obtained by who responded and those who did not respond in regard to age, sex, smoker/nonsmoker % recovery of BAL‐fluid, total cell count, differential cell counts, histamine content per mast cell, or diagnoses. Also stimulation of the BAL‐cells with the calcium‐ionophore A23187 resulted in histamine release, S. aureus‐induced histamine release from basophils was examined in leukocyte suspensions obtained from the same individuals, and in all experiments release was found. The dose‐response curves were similar to those obtained with BAL cells‐ The bacteria‐induced mediator release from superficially lying cells in the airways epithelium might be of importance for the precipitation or exacerbation of bronchial asthma in respiratory tract infections.

CDHR3 Genetics and Rhinovirus C Respiratory Illnesses

Rationale: Experimental evidence suggests that CDHR3 (cadherin‐related family member 3) is a receptor for rhinovirus (RV)‐C, and a missense variant in this gene (rs6967330) is associated with childhood asthma with severe exacerbations. Objectives: To determine whether rs6967330 influences RV‐C infections and illnesses in early childhood. Methods: We studied associations between rs6967330 and respiratory infections and illnesses in the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) and COAST (Childhood Origins of Asthma Birth Cohort Study) birth cohorts, where respiratory infections were monitored prospectively for the first 3 years of life. Nasal samples were collected during acute infections in both cohorts and during asymptomatic periods in COAST and analyzed for RV‐A, RV‐B, and RV‐C, and other common respiratory viruses. Measurements and Main Results: The CDHR3 asthma risk allele (rs6967330‐A) was associated with increased risk of respiratory tract illnesses (incidence risk ratio [IRR] = 1.14 [95% confidence interval, 1.05‐1.23]; P = 0.003). In particular, this variant was associated with risk of respiratory episodes with detection of RV‐C in COPSAC2010 (IRR = 1.89 [1.14‐3.05]; P = 0.01) and in COAST (IRR = 1.37 [1.02‐1.82]; P = 0.03) children, and in a combined meta‐analysis (IRR = 1.51 [1.13‐2.02]; P = 0.006). In contrast, the variant was not associated with illnesses related to other viruses (IRR = 1.07 [0.92‐1.25]; P = 0.37). Consistent with these observations, the CDHR3 variant was associated with increased detection of RV‐C, but not of other viruses during scheduled visits at specific ages. Conclusions: The CDHR3 asthma risk allele is associated specifically with RV‐C illnesses in two birth cohorts. This clinical evidence supports earlier molecular evidence indicating that CDHR3 functions as an RV‐C receptor, and raises the possibility of preventing RV‐C infections by targeting CDHR3.

Neonates colonized with pathogenic bacteria in the airways have a low-grade systemic inflammation

The development of childhood asthma is associated with neonatal colonization with pathogenic bacteria in hypopharynx. Furthermore, established asthma is associated with systemic low‐grade inflammation. We here report on the association between neonatal colonization with pathogenic bacteria in hypopharynx and the development of systemic low‐grade inflammation.

NKG2D gene variation and susceptibility to viral bronchiolitis in childhood

BackgroundGenetic factors associated with bronchiolitis are inadequately characterized. We therefore inspected a selected subpopulation of our previous genome-wide association study (GWAS) of bronchiolitis for overlap with known quantitative trait loci (QTLs) to identify susceptibility loci that potentially affect mRNA and protein levels.MethodsGWAS included a Finnish–Swedish case–control population (nu2009=u2009187), matched for age and site. We integrated GWAS variants (pu2009<u200910−4) with QTL data. We subsequently verified allele-specific expression of identified QTLs by flow cytometry. Association of the resulting candidate loci with bronchiolitis was tested in three additional cohorts from Finland and Denmark (nu2009=u20091201).ResultsBronchiolitis-susceptibility variant rs10772271 resided within QTLs previously associated with NKG2D (NK group 2, member D) mRNA and protein levels. Flow cytometric analysis confirmed the association with protein level in NK cells. The GWAS susceptibility allele (A) of rs10772271 (odds ratio [OR]u2009=u20092.34) corresponded with decreased NKG2D expression. The allele was nominally associated with bronchiolitis in one Finnish replicate (ORu2009=u20091.50), and the other showed directional consistency (ORu2009=u20091.43). No association was detected in Danish populationConclusionsThe bronchiolitis GWAS susceptibility allele was linked to decreased NKG2D expression in the QTL data and in our expression analysis. We propose that reduced NKG2D expression predisposes infants to severe bronchiolitis.