Pathogenesis of asthma: implications for precision medicine

Abstract

The pathogenesis of asthma is complex and multi-faceted. Asthma patients have a diverse range of underlying dominant disease processes and pathways despite apparent similarities in clinical expression. Here, we present the current understanding of asthma pathogenesis. We discuss airway inflammation (both T2 and T2), airway hyperresponsiveness (AHR) and airways remodelling as four key factors in asthma pathogenesis, and also outline other contributory factors such as genetics and co-morbidities. Response to current asthma therapies also varies greatly, which is probably related to the inter-patient differences in pathogenesis. Here, we also summarize how our developing understanding of detailed pathological processes potentially translates into the targeted treatment options we require for optimal asthma management in the future.

Modeling asthma: Pitfalls, promises, and the road ahead

“…Studies of sputum, blood, bronchial brushings, and airway tissue also delineate pathological and molecular features that contribute to our understanding of clinical phenotypes . Severe asthma has been defined as either T2 hi (eosinophilic) and T2 lo (noneosinophilic) . Within the T2 hi group, nonallergic asthma may be driven by epithelial damage/activation due to pollutants, infection, or even allergens containing protease activity (e.g.…”

“…Within the T2 hi group, nonallergic asthma may be driven by epithelial damage/activation due to pollutants, infection, or even allergens containing protease activity (e.g. house dust mite, molds), resulting in activation of the IL‐25/IL‐33 TSLP‐ILC2 pathway without a concomitant IgE response . T2 lo asthma can be associated with mixed T1/T17 responses and airway neutrophils, which might be due to chronic bacterial colonization; interestingly, treatment with azithromycin improved symptoms in this subgroup in a randomized, placebo controlled trial .…”

“…Such patients respond less well to anti‐inflammatory therapies but may improve with bronchial thermoplasty . Finally, it should be mentioned that the true incidence of T2 lo asthma is difficult to define as elements of T2 hi disease may be masked by chronic CCS usage …”

Pediatric asthma: An unmet need for more effective, focused treatments

“…Asthma comprises a serious personal, familial, and global economic burden, including school and employment absences, hospital care, and drug expenditures . To an even greater extent than has been observed for adult patients with asthma, considerable variation in pediatric asthma severity, natural disease history, clinical phenotype, and response to therapy can exist between patients, establishing asthma as a condition with significant heterogeneity …”

New and emerging drug treatments for severe asthma

“…In allergic asthma, dendritic cells stimulate T‐helper 2 (Th2) cells in the presence of coactivators such as epithelial‐derived thymic stromal lymphopoietin (TSLP), with subsequent production of the characteristic T2 cytokines interleukin (IL)‐4, IL5 and IL13. TSLP, along with the other epithelial “alarmins” IL25 and IL33, activates type‐2 innate lymphoid cells (ILC2) promoting T2 inflammation, and up‐regulating IL‐5 and 13 (but not 4) in response to epithelial insult in non‐allergic disease . IL5 is an integral cytokine involved in recruitment, maturation and survival of eosinophils.…”