Difficult-to-Treat and Severe Asthma: Management Strategies


Asthma is a common chronic inflammatory disease in the United States. Up to 17% of asthma cases are classified as difficult to treat, and 3.7% of these are considered severe. Uncontrolled asthma is characterized by poor symptom control or frequent exacerbations. In difficult-to-treat asthma, the asthma is uncontrolled despite adherence to inhaled corticosteroid therapy in combination with a second controller, an oral corticosteroid is needed to achieve control, or it is uncontrolled despite oral corticosteroid therapy. Severe asthma is a subset of difficult-to-treat asthma in which the disease is uncontrolled despite adherence to optimal management or it worsens when high-intensity therapy is decreased. The diagnosis of asthma should be confirmed and modifiable factors and comorbidities addressed in patients with difficult-to-treat asthma. An adequate trial of an inhaled corticosteroid and long-acting beta agonist should be implemented with nonbiologic add-on therapies, such as a long-acting muscarinic agent or leukotriene receptor antagonist. Evaluation of severe asthma involves assessment of asthma phenotype. Evidence of type 2 inflammation indicates that the patient may benefit from newer biologic agents. Breathing exercises may improve quality of life, asthma symptoms, lung function, and number of exacerbations. Vitamin D and soy supplementation are ineffective. Bronchial thermoplasty is a procedural option that may be considered if there is inadequate response to other therapies.

Asthma is a common chronic inflammatory disease in the United States, affecting 40 million people in their lifetime.1 Primary care physicians manage most patients with asthma, with 22% regularly treated by a specialist.2 Up to 17% of asthma cases are classified as difficult to treat, and 3.7% of these are considered severe.3 Severe asthma accounts for up to 60% of the cost of asthma.4 The costs for individuals with severe asthma are approximately 1.7-fold to fivefold greater than that for individuals with mild asthma.5 Patients with severe asthma experience significant disruptions in work, school, family life, and activities.2

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Clinical recommendationEvidence ratingComments

The first steps in the evaluation of difficult-to-treat asthma are confirming the diagnosis and addressing contributing factors.9


Evidence-based guideline

Adding a long-acting muscarinic antagonist to inhaled corticosteroid monotherapy improves asthma control in patients with severe asthma; however, there is no benefit to adding a long-acting muscarinic antagonist to long-acting beta agonist plus inhaled corticosteroid combination therapy.13


Systematic review and meta-analysis of RCTs

Omalizumab (Xolair) is effective in reducing exacerbations, hospitalizations, and inhaled corticosteroid dosage in patients with allergic asthma based on positive results on skin testing or elevated immunoglobulin E on a respiratory allergen panel.15


Cochrane review of RCTs with consistent findings

Bronchial thermoplasty modestly improves quality of life and lowers rates of asthma exacerbation in patients with moderate to severe asthma.20


Cochrane review of limited-quality patient-oriented evidence

RCT = randomized controlled trial.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

The Author

KRISHNAN NARASIMHAN, MD, is an associate professor in the Department of Community and Family Medicine at Howard University College of Medicine, Washington, DC.

Author disclosure: No relevant financial affiliations.

Address correspondence to Krishnan Narasimhan, MD (email: krishnanmd1@gmail.com). Reprints are not available from the author.


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