Gold Standard Asthma Treatment May Not Be Effective for Most Patients with Mild Asthma

A routinely prescribed asthma-controller medication may not work any better than placebo for more than half of all patients who use it, according to a new study led by UC San Francisco.

The treatment is inhaled corticosteroids, a synthetic drug that mimics the steroid hormone cortisol. It works by reducing inflammation in the airways and is recommended for all patients with persistent asthma. However, the drug may target a specific type of inflammation that is found in significantly fewer patients than previously thought, say the authors of the paper publishing May 19, 2019, in the New England Journal of Medicine. 

Approximately 26 million Americans have asthma – or 7.7 percent of adults and 8.4 percent of children – according to the Centers for Disease Control and Prevention. Patients with persistent asthma are usually treated with a rescue inhaler, a fast-acting bronchodilator that opens the airways, plus inhaled steroids to prevent or reduce further attacks.

In this multicenter study coordinated by AsthmaNet, a clinical trials consortium supported by the National Heart, Lung and Blood Institute, researchers compared the effects of an inhaled steroid, mometasone, to placebo in 295 patients over the age of 12 with mild persistent asthma. 

Researchers categorized patients according to the level of eosinophils, a type of white blood cell, from their sputum. They found that 73 percent were “Eos low” – approximately 50 percent more than they had expected – and the remaining 27 percent were “Eos high.” Among those who were Eos low, there was no significant difference in the response to the inhaled steroid mometasone compared with placebo. Some 66 percent did as well or better with placebo.

In contrast, Eos-high patients were almost three times as likely to respond to inhaled steroids than to placebo (74 percent versus 26 percent). 

These findings are likely to be the same for Eos-low and Eos-high patients with moderate and severe asthma, according to first author Stephen Lazarus, MD, of the UCSF Division of Pulmonary and Critical Care Medicine, and the Cardiovascular Research Institute. 

Precision Medicine Could Match Future Patients with Best Meds

While the results raise questions about the use of inhaled steroids in Eos-low patients with mild asthma, screening for sputum eosinophils is problematic, said Lazarus. “Quantifying eosinophils in sputum is a very robust test in the hands of specialized labs, but it’s not something that can be done routinely in the real world,” he said. “Eventually, we may have a precision medicine approach, in which health care workers use other readily available biomarkers, such as blood eosinophils or exhaled nitric oxide, to select the best medicine for each asthma phenotype.”

A second outcome of this blinded crossover study was the comparison of tiotropium with placebo. Tiotropium is a long-acting bronchodilator that works by relaxing the muscles that tighten around the airways and is prescribed as an add-on therapy to inhaled steroids. Among those who were Eos low and did better on one of the treatments, 60 percent had superior results on tiotropium, versus 40 percent who had better symptom control on placebo. 

The authors caution that this difference is not enough to conclude that patients are more likely to do better on tiotropium, but suggest that alternatives to inhaled steroids should be studied further.

For both therapies, the researchers evaluated the effectiveness using a composite outcome that incorporated episodes of poor asthma control, symptoms, use of a rescue inhaler, nighttime awakenings and pulmonary function tests. 

“The take-home message is that many patients have a pattern of inflammation that makes them less likely to respond to inhaled steroids,” said Lazarus. “Doctors should consider this if patients are not responding, rather than just increasing the dose.”

Side Effects, Cost Also Factors for Inhaled-Steroid Users

While inhaled steroids are generally safe and side effects are mild, they may include thrush of the mouth or throat, cataracts, glaucoma, thinning of the skin and bone loss. At $200 to $400 per inhaler, they do not come cheap.

“Although our results suggest the need for re-evaluation of treatment guidelines, the appropriate maintenance treatment for these patients remains to be determined,” said Lazarus. Despite classification as “mild asthma,” close to one in four of the patients in the study had required hospitalization or urgent care in the last 12 months. 

However, patients should not stop their asthma treatment, he said. “They should discuss therapy options with their doctor if their treatment fails to adequately control their symptoms.” 

The researchers plan to conduct a larger, longer-term study comparing inhaled steroids with other treatments.

Co-Authors:  Senior author is Christine Sorkness, PharmD, from the University of Wisconsin-Madison. The paper lists 42 co-authors from institutions nationwide. 

Funding: National Heart, Lung and Blood Institute.

Disclosures: Lazarus has no conflicts of interest to report. Co-author disclosures will be published online at NEJM.org.

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals – UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland – as well as Langley Porter Psychiatric Hospital and Clinics, UCSF Benioff Children’s Physicians and the UCSF Faculty Practice. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. UCSF faculty also provide all physician care at the public Zuckerberg San Francisco General Hospital and Trauma Center, and the SF VA Medical Center. The UCSF Fresno Medical Education Program is a major branch of the University of California, San Francisco’s School of Medicine.