By Christian Carlsson
Chariman: Klaus Gottlob Müller
Opponent: Tuomas Jartti
Opponent: Henrik C. Schønheyder
Episodic asthma-like symptoms are highly prevalent in preschool children with the cumulative prevalence of episodes in westernized countries reaching almost 50% at 6 years of age. As a result, they are a leading cause of acute hospitalization and health care resource utilization in pediatric patients. Despite the large costs in human and economic terms there is limited evidence regarding the pathophysiology of these episodes, which likely differs from that of asthma in older children and adults. Current knowledge is mainly derived from stimulated in vitro airway models or studies using airway lavage techniques, which may not convey a representative picture of the in vivoimmune system of the airways. Uncertain efficacy of several asthma treatments used in school- aged children has prompted investigations into other potential pharmacological therapies including macrolide antibiotics, which reduces duration of episodes of asthma-like symptoms, through antimicrobial and/or immunomodulating effects. Tools for predicting treatment response in the individual child are needed to limit injudicious use of antibiotics.
This thesis is based on two prospective pediatric cohort studies; the Copenhagen Prospective Studies of Asthma in Childhood (COPSAC). In the two cohorts 411 and 700 children were followed from birth and attended the research clinic at several pre-scheduled visits, as well as for acute care visits during episodes of asthma-like symptoms in the first three years of life. A wide range of investigations including determination of airway microbial pathogens and levels of upper airway immune mediators (i.e. cytokines and chemokines) were performed at both pre-scheduled and acute care visits and respiratory symptoms were continuously monitored by the parents on daily diary cards.
Paper I addresses the common notion of attributing the clinical course of episodes of asthma-like symptoms in young children to the specific microbial trigger. It was demonstrated that the duration of episodes is independent of the infecting pathogenic viral or bacterial species and also of a range of host and environmental factors (i.e. sex, age, passive smoking, father’s asthma, socioeconomic determinants, allergic sensitization and chromosome 17q21 gene variant). This suggests that other factors intrinsic or extrinsic to the host are responsible for the disease course.
In Paper II we used a non-invasive filter-paper method to compare upper airway immune mediator levels during episodes of asthma-like symptoms and in asymptomatic periods. An immune mediator profile consistent with neutrophilic inflammation as the primary acute disease process during episodes was demonstrated. Furthermore, we found that pre-treatment levels of certain immune mediators predicted treatment response to oral azithromycin in a nested randomized controlled trial. The upper airway immune mediator profile may therefore potentially be used as a point-of-care investigation for precision treatment in episodes of asthma-like symptoms in early childhood.
Collectively, these findings contribute to the understanding of microbial, environmental and immunological factors in the pathology of episodes of asthma-like symptoms in early childhood. The application of upper airway immune mediators for precision treatment is promising and needs further evaluation in studies designed to test reproducibility and accuracy.