Characteristics, Phenotypes, Mechanisms, and Management of Severe Asthma

Asthma is a global health problem affecting approximately 300 million people worldwide, with a significant mortality rate of around 250,000 deaths annually. Severe asthma, a subset of this condition, is defined as asthma that remains uncontrolled despite high-dose inhaled corticosteroids (ICS) combined with a second controller and/or systemic corticosteroids. This review delves into the characteristics, phenotypes, underlying mechanisms, and management strategies for severe asthma, emphasizing the importance of precision medicine in its treatment.

Introduction

Asthma is a heterogeneous disease characterized by chronic airway inflammation, presenting with symptoms such as wheezing, shortness of breath, chest tightness, and cough. Severe asthma, which accounts for a small but significant proportion of asthma cases, poses a substantial economic burden due to its high healthcare costs and associated morbidity. The prevalence of severe asthma ranges from 3.4% to 8.3% among asthmatics in various studies, with higher mortality rates observed in lower-income countries.

The last two decades have seen significant advancements in understanding asthma’s complexity, leading to the identification of various clinical and molecular phenotypes. This has paved the way for targeted therapies, particularly monoclonal antibodies, which have revolutionized the management of severe asthma.

Defining Severe Asthma

Severe asthma is defined as asthma that requires high-dose ICS plus a second controller to prevent it from becoming uncontrolled or remains uncontrolled despite this therapy. The state of control is assessed based on symptoms, exacerbations, and the degree of airflow obstruction. Diagnosis involves confirming asthma, assessing its severity, reviewing comorbidities, risk factors, and triggers, and ensuring proper treatment adherence and administration.

Phenotyping Severe Asthma

Phenotyping severe asthma has become crucial for tailoring treatment strategies. One prominent phenotype is severe eosinophilic asthma, characterized by recurrent exacerbations despite high-dose ICS, elevated blood eosinophil counts, and increased exhaled nitric oxide levels. This phenotype is associated with Type-2 (T2) inflammation, driven by interleukins IL-4, IL-5, and IL-13. Molecular phenotyping has also identified non-T2 inflammatory phenotypes, such as Type-1 and Type-17 driven inflammation.

Molecular Mechanisms Underlying Severe Asthma

Type-2 (T2) Inflammation

T2 inflammation is driven by cytokines IL-4, IL-5, and IL-13, which play critical roles in eosinophil recruitment, IgE production, and airway hyperresponsiveness. Alarmins such as thymic stromal lymphopoietin (TSLP) and IL-33, produced by airway epithelial cells in response to environmental stimuli, further amplify T2 inflammation. This pathway is predominant in severe eosinophilic asthma, making it a target for biologic therapies.

Non-T2 Inflammation

Non-T2 inflammation involves pathways such as Type-1 and Type-17 immune responses, characterized by interferon-gamma (IFNγ) and IL-17 cytokines, respectively. These pathways are associated with neutrophilic inflammation and corticosteroid insensitivity. Inflammasome activation and oxidative stress also contribute to non-T2 inflammation, particularly in severe asthma with persistent airflow obstruction and frequent exacerbations.

Airway Remodeling

Airway remodeling, a hallmark of severe asthma, involves structural changes such as increased airway smooth muscle mass, subepithelial fibrosis, and goblet cell hyperplasia. These changes contribute to chronic airflow obstruction and bronchial hyperresponsiveness. High-resolution computed tomography (HRCT) scans often reveal bronchial wall thickening, bronchiectasis, and mucus plugging in severe asthma patients.

Corticosteroid Insensitivity

Corticosteroid insensitivity is a defining feature of severe asthma, where patients show poor therapeutic response to corticosteroid therapy. Mechanisms include impaired glucocorticoid receptor function, activation of mitogen-activated protein kinase pathways, and increased oxidative stress. Factors such as smoking, obesity, and bacterial infections exacerbate corticosteroid insensitivity.

Diagnosing and Managing Severe Asthma

Diagnostic Approach

Diagnosing severe asthma involves a systematic assessment within a multidisciplinary team setting. Confirmation of asthma diagnosis, evaluation of severity, and exclusion of alternative diagnoses are essential. Assessing adherence to treatment, inhalation technique, and comorbidities is crucial. Biomarkers such as blood eosinophil counts, fractional exhaled nitric oxide (FeNO), and sputum eosinophils aid in phenotyping and guiding treatment.

Management Strategies

Current Controller Treatments

Patients with severe asthma typically require high-dose ICS combined with long-acting beta-agonists (LABA) and sometimes long-acting muscarinic antagonists (LAMA). Leukotriene modifiers and oral corticosteroids (OCS) may also be considered. The maintenance and reliever therapy approach using a single inhaler of formoterol and ICS has shown efficacy in reducing severe exacerbations.

Biologic Therapies

Biologic therapies targeting T2 inflammation have significantly improved severe asthma management. These include:

• Omalizumab: An anti-IgE antibody used for severe allergic asthma, reducing exacerbations and improving quality of life.
• Anti-IL-5/IL-5Ra antibodies (Mepolizumab, Reslizumab, Benralizumab): These reduce exacerbations and OCS dependence in severe eosinophilic asthma.
• Dupilumab: An anti-IL-4Ra antibody that blocks IL-4 and IL-13, effective in reducing exacerbations and improving lung function in severe asthma.

Other Therapies

• Bronchial Thermoplasty: A bronchoscopic procedure that reduces airway smooth muscle mass, showing modest benefits in severe asthma.
• Long-term Macrolide Therapy: Azithromycin has shown efficacy in reducing exacerbations in both eosinophilic and non-eosinophilic asthma.

Future Directions

The future of severe asthma management lies in precision medicine, with ongoing research focusing on identifying specific molecular pathways and developing targeted therapies. Anti-TSLP and anti-IL-33 antibodies are promising candidates that may benefit both T2-high and T2-low phenotypes. Early intervention with biologic therapies may modify disease progression, highlighting the need for further studies to determine the optimal timing and selection of treatments.

Conclusion

Severe asthma is a complex and heterogeneous condition requiring a multifaceted approach to diagnosis and management. Advances in understanding its phenotypes and underlying mechanisms have led to the development of targeted biologic therapies, significantly improving outcomes for patients. Precision medicine, guided by biomarkers and molecular phenotyping, holds the key to optimizing treatment strategies and reducing the burden of severe asthma.

doi.org/10.1097/CM9.0000000000001990

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