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Poorly Controlled Asthma

CME

Steps I Take in Poorly Controlled Asthma

Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™

Released: August 24, 2020

Expiration: August 23, 2021

Michael E. Wechsler
Michael E. Wechsler, MD, MMSc
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Current therapies used to treat asthma—such as inhaled corticosteroids and long-acting beta agonists—are effective for most of the more than 25 million people in the United States with asthma. They help reduce symptoms, prevent exacerbations, and minimize use of rescue medications.

However, a subset of patients remains poorly controlled despite inhaled corticosteroid and long-acting beta agonist therapy. For those patients, we now have other therapeutic options.

First Steps
It is first important to understand why a person’s asthma remains poorly controlled. It may be because the person has other comorbidities such as gastroesophageal reflux, sinusitis, vocal cord dysfunction, or sleep apnea. One must also investigate whether the person is fully adherent to his/her asthma medication regimen, thereby allowing the medications to fulfill their potential. Finally, one must ascertain that the patient actually has asthma and not an alternative diagnosis such as vocal cord dysfunction or aspiration (including that of a foreign body).

Step up for Severe Asthma
Once a workup to evaluate for those comorbidities or complicating factors is completed and adherence to traditional asthma medications is ascertained or addressed, if the asthma is still uncontrolled, then it is considered severe. In such patients, it’s time to consider alternative medication options. These may include addition of an antimuscarinic agent such as tiotropium; addition of a biologic therapy such as anti-IgE, anti–interleukin (IL)-5, or anti–IL-4/13; or consideration of bronchial thermoplasty or a macrolide antibiotic.

Endotypes and Treatment Choices
How does one choose among these options? It’s crucial to get a better sense of the type of asthma one is addressing: One must determine the endotype—the asthma’s underlying pathophysiologic mechanism. The endotype designations that we currently use are type 2 inflammation (which can be eosinophilic or allergic or both) and non–type 2 inflammation.

Type 2 Inflammation
Type 2 inflammation is generally stimulated by allergens at the epithelial layer, which activate Th2 (T-helper 2) cells and ILC2 (innate lymphoid) cells that, in turn, produce the cytokines IL-4, IL-5, and IL-13.

  • IL-4 stimulates B-cell production of different antibodies, including IgE, the antibody that binds to mast cells and results in mast cell degranulation in response to different allergens. IL-4 is also involved in eosinophil trafficking into the tissue.
  • IL-13 acts at the epithelial layer and results in airway hyperreactivity, mucous production, and production of exhaled nitric oxide. Like IL-4, IL-13 also plays a role in eosinophil trafficking.
  • IL-5 is involved in eosinophil maturation, proliferation, and activation.

So IL-4, IL-5, and IL-13 are the key type 2 cytokines, and the key biomarkers for type 2 inflammation include IgE, exhaled nitric oxide, and blood or sputum eosinophils. After identifying these biomarkers and thus determining that the patient in question has type 2 inflammation, one could consider biologic therapies that will target these cytokines and prevent the downstream inflammation. Targeting the inflammation should prevent exacerbations and improve asthma symptoms and lung function.

These are exciting times for the management of asthma and, in particular, severe asthma. The new biologic therapies that have emerged during the last 2 decades—including omalizumab (which targets IgE); mepolizumab, reslizumab, and benralizumab (which target IL-5 or its receptor); and dupilumab (which targets the IL-4/IL-13 receptor)—have all shown efficacy in improving asthma outcomes and have changed the treatment and response landscape for those with severe asthma.

Non–Type 2 Inflammation
In contrast to type 2 inflammation, non–type 2 inflammation usually is stimulated by irritants, pollutants, and viruses. These triggers activate Th1 and Th17 cells to produce IL-6, interferon gamma, and other cytokines that, in turn, promote neutrophilic inflammation.

There are currently no approved targeted therapies for non–type 2 inflammation, but other treatment options include bronchial thermoplasty and azithromycin; these seem to be effective and could serve as bona fide options for patients with both type 2 and non–type 2 asthma.

Through identification of asthma endotypes—or through identification of phenotypes that are associated with different endotypes (eg, presence of chronic rhinosinusitis or nasal polyps, atopic dermatitis, urticaria, or early-onset allergic asthma)—we can now offer our patients effective therapies.

Your Thoughts?
For customized expert advice, I encourage you to visit the online decision support tool, “Managing Severe Asthma,” that I developed with my colleagues, Bradley E. Chipps, MDFAAP, FACAAI, FAAAAI, FCCP; Nicola Alexander Hanania, MD, MS; Linda Rogers, MD; and Eileen Wang, MD, MPH. In this decision support tool, you can enter the details of your patient and learn how 5 experts would proceed.

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