How to manage severe refractory asthma

Severe refractory asthma affects about 1%–5% of patients with asthma. It is defined as disease that remains uncontrolled despite treatment with high-dose inhaled corticosteroids (ICS) plus one or more additional controller therapy (e.g., long-acting β-agonist) in patients who are adherent to therapy, use correct inhaler technique, and are receiving treatment for comorbidities that may exacerbate asthma (e.g., allergic rhinitis, chronic rhinosinusitis, gastroesophageal reflux disease).Patients with severe refractory asthma may experience accelerated loss of lung function and have higher mortality rates associated with exacerbations compared to individuals with milder forms of asthma.Nonpharmacologic managementAll allergen-sensitized patients with asthma should reduce indoor exposures (e.g., dust mites, mold, pests) by using dust mite encasements for mattresses and pillows, washing bedding weekly in hot water, and vacuuming with high-efficiency particulate air filters. If present, pest and mold remediation are also recommended. During peak allergy season, patients with asthma and seasonal allergies should keep windows closed and bathe before bed to remove pollen from their skin and hair. They should also be informed about nonallergenic triggers, such as tobacco smoke, vaping, cannabis, biomass fuels (e.g., wood-burning stoves) and air pollution, which exacerbate airway inflammation. Avoiding or reducing these exposures can substantially improve asthma control. Allergen-specific immunotherapy can be beneficial, but should not be started until asthma is controlled and the forced expiratory volume in the first second of expiration (FEV1) exceeds 70% predicted. Pharmacologic managementFirst-line treatment for all patients with severe refractory asthma includes daily ICS, often in combination with a long-acting β-agonist and a long-acting muscarinic antagonist to target persistent airway inflammation and improve symptom control.Inhaler technique should be assessed for all patients to ensure correct administration. Patients who have difficulty with proper inhaler technique may benefit from changing delivery device (e.g., switching from a dry powder to a metered-dose inhaler) or using a spacer to improve medication delivery. Strategies that allow patients to escalate ICS therapy, along with a fast-acting bronchodilator (salbutamol or formoterol) for worsening symptoms, have been shown to significantly reduce asthma exacerbations. For example, in the PREPARE study, a patient-activated, reliever-triggered ICS strategy led to a 15% reduction in severe exacerbations and a 3.4-point improvement in Asthma Control Test scores in adults with moderate to severe asthma.If moderate to severe asthma remains uncontrolled despite treatment with an ICS plus a second controller, those with frequent asthma exacerbations and those who require maintenance oral corticosteroids should be referred to an asthma specialist for evaluation for biologic therapy. Currently, six biologics area approved by Health Canada for use in severe asthma: omalizumab (Xolair, Omlyclo), mepolizumab (Nucala), benralizumab (Fasenra), reslizumab (Cinqair), dupilumab (Dupixent) and tezepelumab (Tezspire). All are administered subcutaneously, except for reslizumab, which is administered by intravenous infusion.Direct comparisons of the efficacy of various biologics are limited, but their use has been associated with a 44% reduction in the annualized rate of asthma exacerbations and a 60% decrease in hospitalization rate, highlighting their substantial effect on clinical outcomes. Improvements in lung function and symptom control are generally more modest, with a mean increase in FEV1 of 0.11 L and a decrease in Asthma Control Questionnaire score of 0.34 points(minimum clinically important difference, 0.5). Omalizumab, mepolizumab, benralizumab, dupilumab and tezepelumab are approved for home subcutaneous administration by the patient or caregiver, enhancing convenience of administration. All of these biologics are expensive, with costs varying with dose and frequency of administration. A table comparing key features of biologics for severe refractory asthma, including mechanism of action, dosage and administration, and potential adverse effects, is available here. Reference:Cardet JC, Chiarella SE, Hernandez ML. Management of severe refractory asthma. JAMA 2025. Published online October 1, 2025. (accessed October 9, 2025).

How to manage severe refractory asthma

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