From Quiet Asthma to Clinical Remission: Can Optimized Maximal Inhaled Therapy Achieve Biologic-Free Remission in Difficult-to-Treat and Severe Asthma?

Clinical remission, defined as sustained multidomain disease stability encompassing symptom control, freedom from exacerbations and from maintenance oral corticosteroid use, and stable or improved lung function, has emerged as a major therapeutic goal in severe asthma, largely driven by the success of biologic therapies. Consequently, remission is often regarded as an outcome primarily achievable through biologic treatment, whereas the potential contribution of optimized inhaled triple therapy has received comparatively less attention. This narrative review examines the evidence supporting biologic-free clinical remission across difficult-to-treat and severe asthma populations and explores the mechanisms that may contribute to sustained multidomain disease stability during optimized inhaled triple therapy. Importantly, we distinguish remission achieved after correction of previously unrecognized modifiable factors-which may reflect successful management of difficult-to-treat asthma-from on-treatment remission occurring in patients in whom severe asthma had already been established after appropriate treatment optimization. We review contemporary remission definitions, the biological rationale for remission achieved during optimized inhaled therapy, and evidence from historical cohorts, national registries, randomized clinical trials, post hoc analyses, and prospective real-world studies. Collectively, these data indicate that optimized inhaled triple therapy can be associated with clinically meaningful multidomain disease-stability states and, when established remission criteria are fulfilled, clinical remission, although the strength of evidence specifically in patients fulfilling current severe-asthma criteria remains more limited. Particular emphasis is placed on the contribution of small-airway dysfunction, the evolution of the quiet asthma concept as a proposed small-airway remission phenotype, and the potential roles of pharmacological synergy, improved peripheral drug deposition, and restoration of distal airway homeostasis. We also discuss the durability of remission, the need for continued multidomain follow-up, and the clinical and health-economic implications of achieving remission without biologic therapy. Current evidence suggests that optimized inhaled triple therapy should be considered not only a key component of severe asthma management but also a potential remission-oriented strategy in appropriately selected patients, including those who may achieve remission without subsequent biologic escalation. Future research should identify the phenotypes most likely to achieve biologic-free remission, clarify the underlying mechanisms, and prospectively validate remission-oriented inhaled treatment strategies.