Towards better treatment outcomes in childhood asthma

Abstract

Standard treatment for peadiatric asthmatics is based on regular use of inhaled corticosteroids (ICS) combined with short-acting beta-agonists (SABA). Despite the effectiveness of this standard treatment strategy in most patients, there is large variability in treatment response. Many factors can influence effectiveness of therapy, roughly these factors can be divided into three categories: (1) environmental factors, (2) medication use related factors and (3) genetic factors. In this thesis we aimed to contribute to the knowledge on asthma medication use and treatment outcomes in childhood asthma. In line with treatment guidelines, SABA and ICS were the most frequently prescribed drugs among the children included in our studies. We found that asthma medication was frequently initiated at an age at which an asthma diagnosis cannot yet be firmly made (before age 3). Furthermore, only few children used medication continuously. These findings might indicate that therapy initiation is used as diagnostic tool to strengthen or reject the possible diagnosis of asthma. Good adherence rates were observed in approximately half of the population. Increased fractional exhaled nitric oxide (FeNO) values, which are an indication for airway inflammation, were associated with lower adherence rates, this underlines the need of good adherence to reach sufficient disease control. Stronger parental necessity beliefs towards their child's medication use were associated with better adherence, as was Dutch ethnicity (non-immigrant). Up to half of the populations we studied suffered from uncontrolled asthma. Low maternal educational level and parental concerns about potential adverse consequence of medication use were associated with a higher risk of uncontrolled asthma. In addition, stronger necessity beliefs were also associated with uncontrolled asthma. Perhaps these strong need beliefs reflect more severe asthma and therefore an even higher need for medication. Immigrant children were more often non-adherent. We showed significant seasonal differences in asthma control. There was a decline in symptoms and asthma medication use during the summer period and a peak occurred from autumn to spring. To study genetic predictors of treatment response we initiated a new study: the PACMAN (Pharmacogenetics of Asthma medication in Children: Medication with ANti-inflammatory Effects)-study. Paediatric asthma medication users were recruited from community pharmacies and information was collected on respiratory symptoms, adherence, medication use and environmental factors. In addition, we measured FeNO values and collected saliva samples for DNA isolation. One of the main aims of the PACMAN-study is to investigate genetic factors related to treatment outcomes in childhood asthma. We found the T2206C FCER2 variant (encoding for the low-affinity IgE receptor) to be associated with ICS treatment outcomes. Carriers of the variant allele had more often asthma exacerbations, uncontrolled asthma and requirement for increased daily dose of ICS. Furthermore, we explored genetic variation in candidate genes that were part of the corticosteroid receptor complex. This study revealed genes that might play a role in ICS treatment effectiveness; however, these findings need to be confirmed in a larger population.