Page 15 - ADULT-ONSET ASTHMA PREDICTORS OF CLINICAL COURSE AND SEVERITY

PATHOPHYSIOLOGY
As some phenotypes already suggest, there are several underlying in ammatory and non- in ammatory mechanisms leading to these diseases. The combina on of these mechanis c (molecular) pathways and the associated phenotype is called an endotype. In this process an interplay exists between gene c suscep bility, func onal elements (like lung func on, airway hyper-responsiveness, obesity), environment, in amma on/immunity of the airways and response to treatment which leads to a certain disease manifesta on.41 In amma on and immunity play a central role in asthma therapy and therefore will be explained into more detail.
The classical asthma c airway in amma on (as in childhood asthma) is characterized by eosinophils, basophils and mast cells in ltra ng the airways.(see Figure 3) This in amma on is ini ated via allergens triggering the airway epithelium which leads to ac va on of dendri c cells and therea er T-helper-2 (Th2) cells secre ng pro-in ammatory cytokines (Interleukin(IL)-4, IL-5, IL-13).42 The in ammatory response eventually leads to mucus hypersecre on and triggers airway smooth muscle cells resul ng in hyper-responsiveness and airway wall remodeling. However, apart from this classic Th-2 pathway, more recently also the innate immune system was found to be able to ini ate eosinophilic airway in amma on.43 Innate lymphoid cells type 2 (ILC-2) are ac vated via interleukins 1, 25, 33 and thymic stromal lymphopoe n (TSLP) secreted by airway epithelium and macrophages a er triggering by pollutants, microbes or allergens. This leads to a more pronounced secre on of type 2 cytokines interleukins 4, 5 and 13 and hence eosinophilic airway in amma on.44 However, up to two thirds of asthma pa ents has no signs of eosinophilic in amma on.40, 45 In these pa ents neutrophilic airway in amma on may be present, although also pauci-granulocy c (no signs of granulocy c in amma on) asthma has been described.45 Neutrophilia is mainly ini ated by interleukin 17, interleukin 8 and tumor necrosis factor-α (TNF-α) secreted by T-helper-17 (Th17) and T-helper-1(Th1) cells. Environmental substances such as diesel exhaust and cigare e smoke are known to trigger this pathway.46 Finally, an interplay between Th17 and type 2 ac va on exists, which might be in uenced by asthma treatment.47
Knowledge of the airway in amma on type in a pa ent is important to monitor the disease and tailor asthma therapy. For instance, cor costeroid treatment guided by airway eosinophilia has been shown to reduce asthma exacerba on rate.48 Novel treatments directed against speci c type 2 pathway cytokines like mepolizumab49 and dupilumab50 can improve asthma outcomes even further. However the assessment of airway in amma on is quite invasive, unpleasant for pa ents, me consuming and costly. Therefore several biomarkers of eosinophilic airway in amma on (e.g. blood eosinophils, frac on of exhaled nitric oxide (FeNO) and serum IgE) have been inves gated in mixed asthma popula ons. Most studies found moderate accuracy for iden fying eosinophilic airway in amma on,40, 51, 52 without taking asthma phenotype into account.
GENERAL INTRODUCTION AND AIMS
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