Airway Remodeling in Asthma

Asthma is a globally prevalent chronic respiratory condition affecting both children and adults.[1] It contributes to nearly 461,000 deaths globally each year, with India accounting for approximately 46% of these deaths, around 200,000 annually. The primary management strategy continues to rely on inhaled corticosteroids (ICS), which are effective in minimizing acute exacerbations.[2] However, longitudinal evidence indicates that while ICS improve symptom control, they do not significantly alter the long-term trajectory of the disease. Even when treatment is initiated in childhood, progression to irreversible airflow limitation remains a risk.[2] The first histological evidence of airway remodeling in asthma dates back to 1922, reported by Huber and Koessler.[3] Most contemporary insights stem from autopsy studies and large airway biopsies in adult fatal asthma cases.[4] Notably, signs of remodeling, such as epithelial thickening and smooth muscle alterations, are seen in young children aged 2–4, often before a clinical asthma diagnosis or prominent atopic inflammation.[4] A systematic review found insufficient evidence of eosinophilic inflammation as a prerequisite for remodeling in pediatric asthma.[5] Airway remodeling consists of multiple structural changes: (a) epithelial damage secondary to increased shedding, reduced integrity, and goblet cell hyperplasia contribute to excessive mucus production (the key mediators being epidermal growth factor, transforming growth factor [TGF]-β, and E-cadherin);[6] (b) airway smooth muscle (ASM) hypertrophy and hyperplasia being regulated by platelet derived growth factor and TGF-β with early ASM changes influencing asthma severity;[7] (c) sub-epithelial fibrosis (lamina reticularis thickens due to collagen, fibronectin, and proteoglycan deposition), which inversely correlates with forced expiratory volume [FEV] 1;[7] and (d) angiogenesis (though observed, its clinical relevance is still unclear).[7] Contrary to traditional thought, chronic inflammation may not always precede remodeling. Structural airway changes have been noted in children with severe wheeze and in those aged 6–16 years.[8] Remodeling and airway hyper-responsiveness can develop simultaneously and may not require persistent inflammation. Eosinophil-targeting therapies improve exacerbation control but have limited impact on structural progression.[9] Animal studies also indicate that remodeling can occur independent of evident inflammation. Neutrophils, once assumed harmful, may have a regulatory or protective role in remodeling. Historically assessed through autopsy, remodeling can now be evaluated using imaging. Advanced 3D computerized tomography imaging allows visualization of distal airway changes and quantifies air trapping and post-bronchoconstriction heterogeneity.[10] High mucus scores are often found in severe asthma patients with low FEV1, and the same airways are frequently involved across episodes.[10] No current therapy directly reverses remodeling. ICS modestly affects structure but does not halt remodeling progression.[7,11] While they may reduce ASM growth and TGF-β expression, persistent changes remain. Some studies even link ICS to epithelial apoptosis, potentially worsening remodeling.[12] Biologics offer new hope in severe asthma, and a verity with diverse mechanisms of action is available in market. These include: (a) Omalizumab (anti immunoglobulin E), which reduces reticular basement membrane thickness, fibronectin, and ASM mass causing improvement in FEV1; (b) mepolizumab (anti interleukin [IL] 5), which reduces eosinophils, TGF-β, and fibrosis; (c) reslizumab (anti IL-5), which improves FEV1; (d) benralizumab (anti-IL-5Rα), which reduces eosinophils and ASM; (e) dupilumab (anti-IL-4Rα), which has shown to reduce eosinophil infiltration; and (f) tezepelumab (anti-thymic stromal lymphopoietin), which increases airway lumen and decreases eosinophils. These therapies might improve quality of life, reduce oral steroid use, and lower exacerbation frequency in severe therapy resistant asthma cases.[13] Allergen Immunotherapy (subcutaneous or sublingual) may also positively influence structure if started early, though long-term evidence is limited.[14] To summarize, airway remodeling is central to asthma patho-physiology and remains insufficiently addressed by current therapies. Although biologics show promise in select populations, no intervention fully prevents or reverses structural progression. Continued investigation into disease-modifying treatments is essential. Author contribution MVK conceived the idea, designed the study, drafted the manuscript, and submitted it for publication. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.