By Kim G Nielsen, MD, DMSci
Chairman: Mikkel Østergaard
Opponent: Peter Oluf Schiøtz
Opponent: Asger Dirksen
This thesis is a review of 7 publications based on studies performed in the period from 1995 to 2002 during my appointment as first clinical research fellow and later as consultant and pediatric pulmonologist at the Department of Pediatrics, Clinic I, Pulmonary Service, Rigshospitalet, Copenhagen University Hospital. The work is part of The Copenhagen Prospective Study on Asthma in Childhood (COPSAC).
Longitudinal cohort studies suggest that outcomes such as lung function and bronchial hyperresponsiveness (BHR) in school children and adults with asthma probably are determined already in in fancy. Likewise in cystic fibrosis (CF), significant reduction in lung function has been found at a very early age even in the absence of clinically recognized lung disease. The reason for early and longitu dinal assessment of lung function and BHR is as obvious as the goals: to enable early diagnosis and intervention, and improve prognosis in asthma and CF. Currently, diagnostics and management of young children with chronic lung diseases rely completely on clinical judgment, implicating risk of inappropriate and useless treatment or no treatment, although needed. Lung function methods for infants and schoolchildren are not applicable in children between these age groups, i.e. young children 2 to 5 years of age.
Three lung function methods have previously qualified as applicable in young children: measurement of specific Resistance of the airways (sRaw) by whole body plethysmography, Resistance of the respiratory system (Rint) by the interrupter technique and Resistance (R) and reactance (X) of the respiratory system by Impulse Oscillometry technique (IOS). They all assess respiratory mechanics by measuring the relationship between respiratory airflow and the pressure generating this airflow. Focus has primarily been on methodology rather than clinical application. BHR defined as an abnormal increase in airflow limitation following a relevant stimulus to the airways, is a major pathophysiological phenomenon of asthma. Indirect challenges probably induce airflow limitation by acting on inflammatory cells, epithelial cells and nerves, which upon stimulation release mediators or neurotransmitters that induce airway smooth muscle contraction and may better reflect the ongoing airway inflammation in contrast to direct acting pharmacologic tests.
The principal aim of this thesis was to evaluate the clinical appli cation and discriminatory capacity of the mentioned methods as lung function tests in healthy, asthmatics and children with CF. The primary aim was to develop and implement a test for indirect bron chial challenge and assess its validity as judgement of BHR. More over the purpose was to compare tests for measurement of baseline lung function and BHR and finally to validate such tests through the studies of documented efficacious anti asthma medications in asth matic young children.
376 children participated in the different studies. Principally all children were 2 to 5 years, but in the CF study the children were 2 to 7 years at inclusion.
Whole body plethysmography (sRaw) was superior to Rint and IOS in discriminating between health and diseases such as asthma and CF using cross sectional or longitudinal baseline measurements.
We were first to develop, implement and validate a simple, convenient and safe indirect bronchial challenge test applying eucapnic hyperventilation with 15°C cold air in young children. This test fully substitutes the time consuming and less relevant direct methacholine challenge test. A simpler and less expensive test employing eucapnic hyperventilation with dry room temperature air was also established, however, this test seemed to exhibit diminished responsiveness, probably due to lack of the cooling stimulus.
Responsiveness to cold air challenge (CACh) and bronchodilators as measured by sRaw proved applicable as diagnostic tests for asthma in young children.
sRaw also demonstrated clinically relevant measurements in the assessments of efficacy of classic anti-asthma drugs such as inhaled corticosteroids (ICS), short and long acting beta-2 agoists (SABA and LABA), and a leukotriene receptor antagonist (LTRA) during double blind placebo controlled studies. Applying these tests, we provided for the first time concomitantly objective evidence for the expected efficacy of these drugs in young children, although efficacy is already well proven by studies based on parental symptom scoring. BHR was reduced by ICS as measured with CACh and sRaw, probably reflecting reduced bronchial inflammation. Concomitantly we found a reduction in symptoms and exacerbations. SABA and LABA provided a relevant time course of significant bronchodilation and bronchoprotection against CACh. Indeed, we were first to provide data to suggest that the initial time course of protection from the LABA formoterol and a SABA was similar. Furthermore, we demonstrated a relevant time course of significant bronchoprotection against CACh with the LTRA montelukast. Future research should address the relationship between BR to CACh and asthma severity and risk for an exacerbation in young asthmatics. We should also assess the value of CACh in the short and long term monitoring of asthma control and treatment in young children, and we need to investigate if CACh responsiveness can serve as prognostic factor for ongoing asthma beyond preschool age.
In conclusion, the research in this thesis provided evidence that sRaw measurement and assessment of BHR by the newly developed CACh method may serve as useful clinical and research tools for earlier diagnosis of asthma and detection of deteriorating lung function in chronic lung diseases, better judgment of efficacy of anti asthma medication such as ICS and a more rational management based on phenotyping in young asthmatic children and children with CF.