2023 Rikke Sunde – MD

Asthma is an inflammatory airway disease that often debuts in early childhood. It is the most common chronic disease in childhood and represents a big burden for the affected children, their families, and society. Early life environmental exposures are believed to play an important role in the development of childhood asthma. Thus, both prenatal tobacco exposure and neonatal bacterial airway colonization are associated with an increased risk of asthma, but studies investigating the longitudinal effects of such exposures are lacking.

Fraction of exhaled nitric oxide (FeNO) is the only established biomarker of airway inflammation in asthma, but FeNO is also associated with allergy, and the longitudinal relationship between asthma, allergy, and FeNO during childhood remains unknown.

This PhD thesis is based on data collected in the at-risk prospective mother-child cohort COpenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000), a cohort of 411 children born to mothers with asthma. The objectives were (1) to investigate how prenatal tobacco exposure and neonatal bacterial airway colonization influence the risk of childhood asthma and related traits, and (2) to examine how the biomarker FeNO is influenced by asthma and allergy throughout childhood.

In paper I we examined the effect of prenatal tobacco exposure on asthma and allergy-related outcomes in childhood. We found that prenatal tobacco exposure increased the risk of asthma, exacerbations, lower respiratory tract infections, reduced lung function, and bronchial hyperresponsiveness up to age 7, but there was no association with allergy or Type 2 inflammation markers. The analyses also showed that the effect of prenatal tobacco exposure on asthma was dependent on the 17q12-21 genotype, with increased risk only in children with wild- type genotype. In conclusion, this study suggests that prenatal tobacco exposure increases the risk of non-atopic asthma and reduced lung function.

In paper II we examined the association between neonatal airway colonization with Streptococcus pneumoniae, Haemophilus influenzae, and/or Moraxella catarrhalis and the risk of asthma outcomes throughout childhood until age 18. We found that neonatal airway

colonization was associated with early onset asthma characterized by exacerbations, increased blood eosinophils, and elevated blood Tumor Necrosis Factor α (TNF-α) levels particularly in preschool age, whereafter the risk diminished and was no longer present at age 18. In conclusion, this study suggests that neonatal airway colonization increases the risk of a specific childhood asthma endotype with early onset, exacerbations, eosinophilia, and increased TNF-α levels, which may contribute to our understanding of the phenomenon that many children outgrow their asthma in childhood.

In paper III we investigated how asthma and sensitization to aeroallergens influenced FeNO levels over time from age 5 to 18 years. We found that both asthma and aeroallergen sensitization were associated with increased FeNO levels throughout childhood. However, asthma was only associated with increased FeNO among sensitized children and allergic sensitization only increased FeNO in children having an asthma diagnosis, i.e., there was an interaction between asthma and sensitization. In conclusion, these findings are important for clinicians working with children with asthma and allergy as elevated FeNO among children with asthma is dependent on allergy and vice versa.

Overall, the two first studies contribute to our understanding of early-life risk factors for asthma in childhood and suggest that specific risk factors are associated with specific childhood asthma endotypes and trajectories. The third study increases our understanding of how asthma and allergic sensitization influence FeNO levels throughout childhood and shows that elevated FeNO in children with asthma is dependent on sensitization and vice versa.