The asthmatic airway response – effects on physiology and biomarkers

Abstract: Asthma is a common airway inflammatory disease, associated with a variable degree of airway obstruction. It is a heterogeneous condition with large variations in severity and clinical presentation. Moreover, disease activity can vary from time to time. Taken together, these factors make the diagnosis, monitoring and treatment of asthma challenging. Peripheral airway inflammation has been shown to be of clinical importance in asthma, but the methods used to assess the airways in clinical practice today are not adequately designed to detect peripheral airway dysfunction. Exhaled breath temperature (EBT) has been suggested as a marker of airway inflammation, and club cell protein (CC16) has been suggested as a marker of airway epithelial dysfunction.The aim of this thesis was to explore the different aspects of the asthmatic airway response, beyond the mechanisms that can be measured by the traditional physiology assessment, i.e. spirometry. To study the airway response, we used different types of airway provocations that are often used in asthma research and occasionally in clinical practice to confirm the diagnosis of asthma or assess airway inflammatory status.Five different types of airway provocations were used to elicit airway responses in asthmatic subjects: exercise, eucapnic voluntary hyperventilation (EVH), methacholine challenge test (MCT), mannitol and inhaled allergen challenge. Responses to exercise, EVH and MCT were also tested in healthy controls for comparison. EBT was measured before and repeatedly after exercise, MCT, EVH and allergen challenge. Small airway physiology was measured with impulse oscillometry (IOS), inert gas washout (IGW) and body plethysmography before and repeatedly after the allergen challenge. Levels of CC16 were measured in several compartments before and after exercise and allergen challenge.We found that EBT is increased after exercise, EVH, MCT and during the late phase of the allergic airway response. The increase in EBT correlated to the drop in FEV1 after exercise and EVH, but not after the MCT, indicating an airway epithelial effect. EBT did not differ between asthmatic subjects and healthy controls before or after provocations, suggesting that an increase in EBT is a normal physiological response rather than a specific sign of airway inflammation. However, the duration of the increase in EBT was longer in asthmatic subjects with a more pronounced airway response after exercise, indicative of a sustaining effect of airway inflammation. CC16 is increased in plasma after exercise and during the early phase of the allergic response. It is also increased in urine after exercise but not after the allergen challenge, indicating differences in renal excretion after the two provocations. A late phase response after the allergen challenge was associated with a significant small airway dysfunction, consisting of both increased airway resistance and ventilation heterogeneity.Our results have increased our understanding of effects on the airway physiology, the respiratory epithelium and small airway dysfunction by different types of stimuli that are known to elicit asthmatic airway responses. We have explored effects on physiology parameters and biomarkers that may be used in research and care of pulmonary diseases in the near future.