Astrid Sevelsted

A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 years of age in a total of 1,173 cases and 2,522 controls. Cases were identified from national health registries of hospitalization, and DNA was obtained from the Danish Neonatal Screening Biobank. We identified five loci with genome-wide significant association. Four of these, GSDMB, IL33, RAD50 and IL1RL1, were previously reported as asthma susceptibility loci, but the effect sizes for these loci in our cohort were considerably larger than in the previous genome-wide association studies of asthma. We also obtained strong evidence for a new susceptibility gene, CDHR3 (encoding cadherin-related family member 3), which is highly expressed in airway epithelium. These results demonstrate the strength of applying specific phenotyping in the search for asthma susceptibility genes.

Cesarean Section and Chronic Immune Disorders

OBJECTIVES: Immune diseases such as asthma, allergy, inflammatory bowel disease, and type 1 diabetes have shown a parallel increase in prevalence during recent decades in westernized countries. The rate of cesarean delivery has also increased in this period and has been associated with the development of some of these diseases. METHODS: Mature children born by cesarean delivery were analyzed for risk of hospital contact for chronic immune diseases recorded in the Danish national registries in the 35-year period 1977–2012. Two million term children participated in the primary analysis. We studied childhood diseases with a suspected relation to a deviant immune-maturation and a debut at young age. The effect of cesarean delivery on childhood disease incidences were estimated by means of confounder-adjusted incidence rate ratios with 95% confidence intervals obtained in Poisson regression analyses. RESULTS: Children delivered by cesarean delivery had significantly increased risk of asthma, systemic connective tissue disorders, juvenile arthritis, inflammatory bowel disease, immune deficiencies, and leukemia. No associations were found between cesarean delivery and type 1 diabetes, psoriasis, or celiac disease. CONCLUSIONS: Cesarean delivery exemplifies a shared environmental risk factor in early life associating with several chronic immune diseases. Understanding commonalities in the underlying mechanisms behind chronic diseases may give novel insight into their origin and allow prevention.

Association between respiratory infections in early life and later asthma is independent of virus type

Background Lower respiratory tract infections in the first years of life are associated with later asthma, and this observation has led to a focus on the potential causal role of specific respiratory viruses, such as rhinoviruses and respiratory syncytial virus, in asthma development. However, many respiratory viruses and bacteria trigger similar respiratory symptoms and it is possible that the important risk factors for asthma are the underlying susceptibility to infection and the exaggerated reaction to such triggers rather than the particular triggering agent. Objective We sought to study the association between specific infections in early life and development of asthma later in childhood. Methods Three hundred thirteen children were followed prospectively in the Copenhagen Prospective Studies of Asthma in Childhood2000 high-risk birth cohort. Nine respiratory virus types (respiratory syncytial virus, rhinoviruses, other picornaviruses, coronaviruses 229E and OC43, parainfluenza viruses 1-3, influenza viruses AH1, AH3, and B, human metapneumovirus, adenoviruses, and bocavirus) and 3 pathogenic airway bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were identified in airway secretions sampled during episodes of troublesome lung symptoms in the first 3 years of life. Asthma was determined by age 7 years. Results In unadjusted analyses, all viruses and pathogenic bacteria identified during episodes of troublesome lung symptoms were associated with increased risk of asthma by age 7 years with similar odds ratios for all viruses and pathogenic bacteria. After adjustment for the frequency of respiratory episodes, the particular triggers were no longer associated with asthma. Conclusion The number of respiratory episodes in the first years of life, but not the particular viral trigger, was associated with later asthma development. This suggests that future research should focus on the susceptibility and exaggerated response to lower respiratory tract infections in general rather than on the specific triggering agent.

Maternal propensity for infections and risk of childhood asthma: a registry-based cohort study

BACKGROUND Maternal use of antibiotics during pregnancy has been associated with the development of asthmatic disorders in the offspring. The human microbiome has been suggested to act as an intermediary in this process. To provide clarification on this theory, we studied the temporal relation between maternal use of antibiotics and the risk of childhood asthma. METHODS According to national registries, during the observation period (1997-2010), 910,301 children were born in Denmark and were included in the analysis. From these registries, data for cases of childhood asthma were obtained based on hospital admissions, outpatient attendance at a hospital, or use of inhaled corticosteroids. The effect of timing of maternal antibiotic use on the risk of asthma in the offspring was studied by analysis of maternal antibiotic use in the 80 weeks before pregnancy, during pregnancy, and the 80 weeks after pregnancy. Results were adjusted for age and calendar year, birthweight, gestational age, sex, mode of delivery, parity, multiple births, season of birth, and several maternal factors (age, smoking during pregnancy, employment status, and asthma). FINDINGS In this study, we replicated our previous finding that maternal use of antibiotics in pregnancy was associated with an increased risk of childhood asthma: the adjusted incidence rate ratio (aIRR) was 1·24 (95% CI 1·18-1·30) for inpatient admission, 1·22 (1·18-1·26) for outpatient attendance, and 1·18 (1·15-1·20) for inhaled corticosteroid use. A similar and independent association was also recorded for maternal antibiotic use in the 80 weeks before and after the pregnancy. A dose-related association occurred between the risk of childhood asthma and the number of maternal antibiotic treatments and was recorded separately for antibiotic treatment for respiratory tract infections and for other types of infections. INTERPRETATION Maternal use of antibiotics has a dose-related association with the risk of asthma in the offspring, but this association is independent of the temporal relationship with the pregnancy period. This finding suggests that maternal antibiotic use is a surrogate marker of a mothers general propensity for infections as the underlying link between a mothers use of antibiotics and risk of asthma in the offspring. FUNDING The Danish Council for Strategic Research, The Lundbeck Foundation, The Pharmacy Foundation of 1991, the Danish Medical Research Council, and National Finance Act.

Infant acetaminophen use associates with early asthmatic symptoms independently of respiratory tract infections: The Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC2000) cohort

We thank Professor Paul Miller, PhD, for his invaluable help in reviewing the language of the manuscript. Gracia Javaloyes, MD* Maria J. Goikoetxea, MD, PhD* Ignacio Garc ıa Nu~ nez, MD Ana Aranda, PhD Maria L. Sanz, MD, PhD Miguel Blanca, MD, PhD Araceli Diaz Perales, PhD Juliana da Souza, BS Irene Esparza, PhD Victoria del Pozo, MD, PhD Ana B. Blazquez, PhD Stephan Scheurer, PhD Stefan Vieths, PhD Marta Ferrer, MD, PhD

Neonatal size in term children is associated with asthma at age 7, but not with atopic dermatitis or allergic sensitization

We hypothesized that anthropometrics in the newborn is associated with development of asthma later in life.

Preeclampsia Associates with Asthma, Allergy and Eczema in Childhood.

Rationale: Preeclampsia reflects an unusual increase in systemic inflammation during pregnancy. Objectives: We studied associations between preeclampsia and asthma, allergy, and eczema in Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) and in national registries. Methods: COPSAC2000 is a high‐risk birth cohort of 411 Danish children. Asthma, allergy, and eczema were diagnosed prospectively, and lung function measured at age 1 month and 7 years. Sensitization was evaluated at age 6 months, 18 months, 4 years, and 6 years by skin prick tests and IgE measurements. The register‐based cohort included 1.7 million children from Danish national registries in the 35‐year period 1977‐2012. Children born to mothers with preeclampsia were analyzed regarding risk of asthma, allergy, and eczema. Measurements and Main Results: In the COPSAC2000 cohort, 5.6% (n = 23) were diagnosed with preeclampsia. Preeclampsia was associated with increased risk of treatment with inhaled corticosteroids at age 7 years (adjusted odds ratio, 4.01 [95% confidence interval (CI), 1.11‐14.43]; P = 0.0337), increased bronchial responsiveness to methacholine (adjusted &bgr;‐coefficient log‐&mgr;mol, ‐0.80 [95% CI, ‐1.55 to ‐0.06]; P = 0.0348), and allergic rhinitis (adjusted odds ratio, 4.83 [95% CI, 1.58‐14.78]; P = 0.0057) in the 7‐year‐old children. Furthermore, the children had an increased risk of sensitization to both aeroallergens and food allergens, and increased amount of total IgE during childhood. In the registry‐based cohort, 3.7% (n = 62,728) were born to mothers with preeclampsia. Preeclampsia was associated with increased risk of asthma, eczema, and aeroallergen and food allergy, especially pronounced after a duration of preeclampsia of 14 days or more. Maternal asthma increased the risk of preeclampsia. Conclusions: Preeclampsia is a shared prenatal risk factor for asthma, eczema, and allergy in childhood pointing toward in utero immune programming of the child.

Risk of Asthma from Cesarean Delivery Depends on Membrane Rupture

OBJECTIVE To assess our prospective mother-child cohort and the national registry data to analyze the risk of asthma by delivery mode and whether cesarean delivery before or after membrane rupture affects this risk differently. STUDY DESIGN The Copenhagen Prospective Studies on Asthma in Childhood2000 is a high-risk birth cohort of 411 Danish children. Asthma was diagnosed prospectively by physicians at the research site, and associations with cesarean delivery were investigated using Cox proportional hazard models. From the Danish national prospective registry we included data from 1997-2010. Childhood asthma was defined from recurrent use of inhaled corticosteroids filled at pharmacies. Cesarean delivery was classified as either before or after rupture of membranes, and the risk of asthma was compared with vaginal delivery. Results were adjusted stepwise for age and calendar year, sex, birth weight, gestational age, multiple births, parity, and maternal factors (age, smoking/antibiotics during pregnancy, employment status, and asthma). RESULTS In the Copenhagen Prospective Studies on Asthma in Childhood2000 cohort, the adjusted hazard ratio for asthma was increased by cesarean delivery relative to vaginal birth 2.18 (1.27-3.73). Registry data replicated these findings. Cesarean delivery performed before rupture of membranes carried significantly higher risk of asthma, (incidence rate ratio to vaginal delivery 1.20 [1.16-1.23]) than cesarean delivery after rupture of membranes (incidence rate ratio to vaginal delivery 1.12 [1.09-1.16]). CONCLUSIONS We confirmed cesarean delivery to be a risk factor for childhood asthma. This effect was more pronounced for cesarean delivery performed before rupture of membranes.

Maternal antibiotic use and risk of asthma in offspring--Authors' reply.

We read with great interest the Article by Thomas Köhnlein and colleagues showing that non-invasive positive pressure ventilation (NPPV) improved outcomes in patients with severe stable chronic obstructive pulmonary disease (COPD). However, we think that there are some aspects to discuss before the results are interpreted. First, the authors have made an effort to exclude patients with obesity (body-mass index [BMI] ≥35 kg/m2). However, sleep disorders are an important co-factor for chronic respiratory insufficiency, and sleep apnoea and obesity hypoventilation syndrome (OHS) should have been excluded in these patients before their inclusion in the study. Since OHS is defi ned as a combination of obesity (a BMI of 30 kg/m2 or more) and Authors’ reply We thank Martin J Blaser and Maria Bello for their interest in our study. Our original discovery of an association between use of antibiotics in pregnancy and an offspring’s risk of asthma was replicated in the COPSAC2000 birth cohort and another Danish birth cohort, as well as in national registries. We interpreted this association between use of antibiotics in pregnancy and the child’s risk of asthma as one that was mediated through changes in the microbiome. In our study we aimed to test this hypothesis by investigating the temporal associations between maternal antibiotics and childhood asthma. 1 We showed similar associations when mothers had taken the antibiotics in the 80 week period before pregnancy or in the 80 week period after pregnancy, even if none were taken during pregnancy. If changes in the microbiome were the causal factor, then we would expect a stronger association to be seen in those who took antibiotics closer to time of bacterial colonization of the child. But there was no such temporal relation. Similarly, we have now done a subanalysis with higher resolution around the most crucial period for any possible drug adverse effects, intrauterine inflammation, or bacterial colonisation of the child. We show equal eff ect sizes for maternal antibiotics given across the three pregnancy trimesters, before pregnancy, and after birth, on the three end points that we used (table). Again this indicates that the timing of treatment is not important for the association. In a registry study, causal mechanisms cannot be proved. However, we can use large registry data to try to falsify our hypotheses. In our study, the data strongly suggest that the causal factor is not maternal antibiotic use during pregnancy but rather a general maternal tendency to infections, hence they will use antibiotics. Maternal antibiotic intake might serve as a proxy for several other exposures. We were able to adjust for some other exposures, including birthweight and caesarean section, but other potential explanations could not be adjusted for such as nutritional factors and other lifestyle factors increasing the risk of infections. We prefer the simpler interpretation that the strong, and dose-dependent, relation between maternal use of antibiotics and asthma in the off spring is caused by maternal susceptibility to infections inherited by the child, but we will continue falsification as our research strategy.

Public Hygiene Campaign in Denmark during the 2009 H1N1 Pandemic Had No Effect on Hospitalization Rate of Communicable Diseases in Children

Background During the 2009 H1N1 pandemic the Danish National board of Health carried out massive public hygiene campaigns to limit spread of disease. We aimed to investigate whether this resulted in lower incidences of communicable diseases in the paediatric population. Methods The study compared annual hospitalization rates for childhood infections from 2005 to 2011. Results Admission rates for infections were higher during the year of the pandemic compared to the rest of the period. Conclusion There were no indications of a preventive effect by the hygiene campaign on incidence of severe common childhood infections.