Asthma Treatable Traits: How Far Do We Have to Go?
Authors: Honglei Shi, Kewu Huang
Affiliation: Department of Pulmonary and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
Introduction
Asthma is a prevalent chronic inflammatory disease of the airways, characterized by significant heterogeneity in clinical symptoms, severity, and treatment outcomes. It poses a serious threat to public health globally. According to the China Pulmonary Health (CPH) study, the prevalence of asthma among Chinese individuals aged 20 years and above is 4.2%. The Global Initiative for Asthma (GINA) emphasizes that the primary treatment goal for asthma is to achieve “overall control,” which includes managing current symptoms and reducing the risk of future exacerbations. However, the current approach to asthma control remains unsatisfactory worldwide, with severe asthma accounting for 5–10% of all cases and imposing a substantial economic burden on healthcare systems.
Severe asthma is a complex chronic airway disease that manifests as various types of airway inflammation, often accompanied by multiple comorbidities and risk factors. Due to the significant variability among asthma patients, a one-size-fits-all treatment approach is inadequate. In recent years, Agusti et al. proposed a precision medicine approach to diagnose and manage chronic airway diseases using treatable traits. This approach aims to provide tailored treatments based on genetic, biomarker, phenotypic, psychosocial, and other traits to meet the diverse needs of patients.
Treatable Traits in Severe Asthma
Treatable traits must fulfill three key characteristics: (1) clinical relevance—the trait should be associated with patient outcomes; (2) identifiability—the trait should be easily identifiable and measurable in clinical settings; and (3) treatability—treatment of the trait should result in positive clinical effects. These traits are categorized into three types: pulmonary, extrapulmonary, and risk factors/behavioral features.
Pulmonary Treatable Traits
Pulmonary treatable traits are fundamental in controlling asthma symptoms. These include airflow limitation, airway inflammation, systemic allergic inflammation, chronic bronchitis, and bronchiectasis.
Airflow Limitation
Airflow limitation refers to persistent airflow obstruction that remains despite the use of a β2-agonist, indicated by a forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio of less than 70% in lung function tests. The ATLANTIS study demonstrated that patients with persistent airflow limitation (PAL) have nearly twice the risk of acute exacerbations compared to those without PAL. PAL is considered a clinically relevant phenotype of asthma and is recognized as a treatable trait. Treatment options include inhaled corticosteroids (ICS) combined with long-acting β2-agonists (LABA) or long-acting muscarinic antagonists (LAMA).
Airway Inflammation
Airway inflammation is assessed through induced sputum examination, categorizing patients into eosinophilic asthma (EA) and neutrophilic asthma (NA). EA, characterized by sputum eosinophils of 2.5% or higher, accounts for 76.8% of severe asthma cases. Treatment includes inhaled or oral glucocorticoids and biological agents targeting interleukin-5 (IL-5) or its receptor (IL-5R). NA, often caused by non-allergic factors such as smoking or infections, lacks effective targeted biologics. Macrolide antibiotics, such as azithromycin, have shown efficacy in improving quality of life and reducing inflammation in NA patients.
Extrapulmonary Treatable Traits
Extrapulmonary traits include comorbidities such as obesity, underweight, anemia, allergic rhinitis, sinusitis, gastroesophageal reflux disease (GERD), anxiety, depression, and obstructive sleep apnea (OSA). These comorbidities significantly impact asthma control and exacerbations. For example, obesity (BMI ≥30 kg/m²) is associated with worse asthma outcomes, and weight loss interventions are recommended. Similarly, psychological conditions like anxiety and depression require specialized treatment to improve asthma control.
Risk Factors and Behavioral Traits
Risk factors and behaviors, such as medication nonadherence, inadequate inhaler technique, and smoking, are critical treatable traits. Poor adherence to prescribed treatment is common, with 49.8% of patients in Shanghai reporting nonadherence. Smoking cessation has been shown to improve lung function significantly, with FEV1 increasing by 407 mL after six weeks of cessation. Patient education on proper inhaler use and smoking cessation is essential for effective asthma management.
Other Possible Treatable Traits
Cough and Cough Hypersensitivity
Cough is a common symptom in asthma patients and is associated with poor control and exacerbations. Studies have shown that tiotropium, a LAMA, can improve cough symptoms and asthma control by modulating cough reflex sensitivity. Cough and cough hypersensitivity are emerging as treatable traits in asthma management.
Perception of Airway Obstruction
Patients’ perception of dyspnea can influence treatment compliance. Factors such as age, disease severity, and psychological conditions affect this perception. Bronchodilators and ICS can relieve dyspnea, but the perception of dyspnea itself may become a new treatable trait, assessed through tools like the Borg dyspnea scale.
Ventilation Heterogeneity (VH)
VH refers to the uneven distribution of inhaled gas within the lungs, a key pathophysiological mechanism in asthma. Studies have shown that biologic therapy can significantly improve VH, making it a potential novel treatable trait.
Impact of Treatable Traits on Clinical Outcomes
Treatable traits are closely associated with clinical outcomes such as quality of life, asthma control, and exacerbations. Studies have shown that the presence of multiple treatable traits increases the likelihood of uncontrolled asthma and reduces quality of life. Interventions targeting these traits have been shown to improve asthma control and reduce exacerbations.
Application of Treatable Traits in Clinical Practice
The treatable traits approach can be applied across various healthcare settings, from primary care to tertiary hospitals. In resource-limited settings, screening for common traits such as airflow limitation and airway inflammation phenotypes can be conducted using spirometry and blood tests. In severe cases, a multidisciplinary team approach involving respiratory physicians, allergists, and other specialists is recommended for comprehensive assessment and personalized treatment.
Future Perspectives
Future research should focus on identifying “super treatable traits” that have a significant impact on clinical outcomes. Clinical studies should confirm the relationship between various traits and patient outcomes to prioritize interventions. Additionally, economic evaluations comparing the costs of treating treatable traits versus standard treatments are essential to identify cost-effective personalized approaches.
Conclusion
The treatable traits strategy, characterized by personalized, flexible, and comprehensive features, offers a promising approach to asthma management. Multidimensional assessments pave the way for precise treatment, opening new avenues for personalized care. However, further research is needed to refine this strategy and integrate it into routine clinical practice.
Funding: This study was supported by Capital’s Funds for Health Improvement and Research (No. CFH2024-1-1061) and Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2024ZD0529804).
Conflicts of Interest: None.
DOI: doi.org/10.1097/CM9.0000000000003507
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