Can Chronic Asthma Be Reversed? Experts Reopen the Debate

Medscape

14-05-2025

A new clinical horizon is emerging in asthma management, with the possibility of achieving sustained reversal of the disease and even remission. This involves altering and reversing the progression of diseases that are traditionally considered chronic. This possibility has led to significant therapeutic advances and sparked a clinical debate: Should sustained reversibility be considered a therapeutic goal in its own right or merely as an indirect marker of effective disease control?
Reversibility in asthma, understood as the ability to recover pulmonary function and maintain the absence of symptoms, has historically been an elusive goal. Recent research suggests that this challenge may be closer to resolution due to advances in biological therapies and a deeper understanding of the inflammatory phenotypes of asthma.
While reversibility remains a central marker in the diagnosis and monitoring of asthma, the scientific community emphasizes that not all patients with asthma experience complete reversibility. The persistence of obstruction may be attributed to structural remodeling of the airways.
Clinical Remission
Clinical remission is defined as the absence of symptoms and exacerbations for at least 12 months, even without medication. Complete remission is defined as the normalization of pulmonary function and disappearance of bronchial hyper-responsiveness and airway inflammation. However, patients in clinical remission who continue to show elevated inflammatory biomarker levels may still be at risk for future functional decline.
Although increasingly achievable in patients treated with biologics, complete remission is still limited by the persistence of certain pathophysiological processes. Airway remodeling in asthma, once it occurs, is difficult to reverse. Achieving complete and sustained disease control is considered the most ambitious goal, while reversibility is a more practical indicator of therapeutic response.
Guidelines such as the Global Initiative for Asthma (GINA) and Spanish Guide for Asthma Management (GEMA), recognize the prognostic value of sustained bronchodilator reversibility and its ability to help predict exacerbations but caution against using it alone. Therefore, we recommend incorporating it into a comprehensive assessment that includes symptoms, pulmonary function, rescue medication use, and quality of life.
Inflammatory Phenotypes
This integrated approach is particularly relevant when considering the dynamic variability of inflammatory phenotypes in asthma. The Spanish MEGA (Mechanism underlying the genesis and evolution of asthma) project analyzed the stability of inflammatory biomarkers and asthma phenotypes.
The results confirmed the instability of these phenotypes; although they remained stable during the first year, their instability increased thereafter. The study, led by the Spanish national research consortium CIBERES (Centro de Investigación Biomédica en Red de Enfermedades Respiratorias), showed that while 88% of patients initially presented a high T2 phenotype, only 61.3% maintained this classification after 2 years.
Similarly, 53.3% of patients had eosinophilic sputum at baseline, but only 37.5% maintained this at 24 months. These findings highlight the need for aggressive therapeutic adjustments.
Moreover, the correlations between different inflammatory phenotypes were moderate in the first 2 years but significantly decreased in the third year. Other biomarkers, such as fractional exhaled nitric oxide, total immunoglobulin E, and lung function, did not show significant variations during the study period. These results highlight the fluctuating nature of this disease and the necessity to adapt the therapeutic strategy to each patient's changing inflammatory profile.
Mechanical Damage
Another recent international study conducted by King's College London, London, England, identified a new pathophysiological mechanism in asthma that should be considered in clinical management.
Published in Science , the study revealed that pathological crowding of a broncho constrictive attack causes so much epithelial cell extrusion that it damages the airways, resulting in inflammation and mucous secretion.
This previously overlooked process perpetuates the characteristic inflammatory cycle of asthma, as repeated damage to the epithelium promotes chronic inflammation. It also results in scarring and permanent narrowing of the airways, contributing to the progression and severity of the disease.
Researchers, including Elena Ortiz-Zapater, PhD, from the University of Valencia, Valencia, Spain, have demonstrated that traditional treatments do not prevent this damage. In contrast, gadolinium, a cell extrusion inhibitor, counteracts mechanical damage and significantly reduces the inflammatory response. Although this breakthrough has only been demonstrated in animal models, it opens new avenues for therapies that not only alleviate asthma symptoms but also prevent structural damage in the airways, offering hope for more durable remission.
Biological Therapies
Focusing on treatments, biological therapies have marked a turning point in the treatment of severe asthma and type 2 inflammatory phenotypes. This allows many patients to achieve a sustained clinical remission. Some biologics target different inflammatory pathways, demonstrating improvements in baseline pulmonary function and reducing persistent obstruction. Thus, they facilitate more sustained reversibility and even remission in selected subgroups of patients.
Targeted drugs, such as omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab, have shown remarkable efficacy. Sustained improvements in pulmonary function, reduced exacerbations, and decreased systemic corticosteroid use have been observed.
Recent registries and multicenter studies have shown an increasing number of patients treated with biologics who meet the partial or clinical remission criteria. For instance, the PrecISE trial is evaluating how therapies targeting specific biomarkers such as interleukin (IL)-4/IL-13 and thymic stromal lymphopoietin can induce sustained reversibility in cases of refractory severe asthma.
In parallel, new molecules, such as amlitelimab, currently in phase 2 trials, demonstrate prolonged effects, even in phenotypes with mixed inflammation. These agents employ innovative mechanisms, such as targeting the OX40 pathway and using less frequent dosing, which could also facilitate adherence and sustainability of remission.
The latest updates from GINA and GEMA have formally incorporated remission as a treatment goal for patients with severe asthma, particularly in the context of biological therapies. A major challenge remains the achievement of complete and sustained remission without chronic treatment, guided by biomarkers, new drugs, and more personalized clinical follow-ups.
Short-Acting Beta-2 Agonists (SABAs)
Alongside pharmacological advances and strategies for remission, the SABINA study highlights a critical aspect of asthma management. It addresses the inappropriate use of SABAs and their effect on disease control. With over a million patients from 40 countries, including Spain, this is the largest real-world observational analysis of this therapeutic class.
The findings showed that approximately 28%-30% of patients with asthma in the country used three or more SABA inhalers annually.
This is associated with a higher risk for exacerbations, poor symptom control, and increased mortality. In contrast, 13%-15% of patients use fewer than four inhalers of inhaled corticosteroids annually, which compromises the control of the underlying inflammation.
SABAs provide immediate and temporary relief, which may contribute to a cycle of suboptimal control and symptom recurrence. Consequently, the GINA and GEMA guidelines discourage the use of SABA as monotherapy. These guidelines recommend combining inhaled corticosteroids with formoterol (a long-acting beta-2 agonist) as both maintenance and reliever therapy.
This combination ensures improved disease management through prevention and continuous anti-inflammatory treatment, which is essential for sustained functional reversibility and clinical remission.
Diagnostic Techniques
Recent updates in diagnostic techniques have improved the ability to assess asthma reversibility and remission, particularly in patients with nearly normal baseline lung function. The joint guidelines from the European Respiratory Society and the American Thoracic Society recommend that a significant bronchodilator response is an increase of more than 10% in forced expiratory volume in 1 second or forced vital capacity.
This adjustment improves the diagnostic sensitivity in patients with asthma, helping to identify cases that might have been previously overlooked and allowing earlier intervention.
Additionally, serial spirometry has become a key tool for confirming sustained reversibility, particularly when the initial response to bronchodilators is unclear. This practice of monitoring pulmonary function over time helps assess the effectiveness of treatment and the potential for achieving remission.
The integration of these updated diagnostic techniques into clinical practice improves diagnostic accuracy and regulates more personalized therapeutic strategies, increasing the chances of achieving sustained reversibility and, in some cases, complete remission of asthma.
In conclusion, the updated assessment of asthma reversibility and remission integrates functional testing, including spirometry, peak expiratory flow, and bronchial provocation testing, inflammatory biomarkers such as fractional exhaled nitric oxide and blood eosinophil counts, and structured clinical follow-up, enabling a more accurate and personalized evaluation of disease status and progression.