Nursing Student Leads Potentially Important Study for Asthma Patients

March 2013Diana Austin

Asthma affects the lives of nearly 19 million Americans. For some the impact is intermittent, but for others it can be a daily, at times life-threatening, struggle. Inhaled corticosteroids (ICS) are usually the first-line treatment for persistent asthma, but UCSF Master’s Entry Program in Nursing student Kelly Wong McGrath recently led a research project that suggests ICS may not be beneficial to a significant population of mild-to-moderate asthma sufferers.

If that is the case, then finding alternative treatments has the potential to save the health care system millions of dollars annually and to protect this subset of asthma patients from the risks of ICS, says McGrath, who also serves as a project manager for the UCSF arm of the National Institutes of Health (NIH)’s multicenter Severe Asthma Research Program.

From Asthma Educator to Researcher

Kelly Wong McGrath McGrath’s interest in asthma research began even before she became a nursing student. While working as a clinical research analyst with asthma expert Susan Janson – the Mary Harms/Nursing Alumni Endowed Chair in Nursing at UCSF School of Nursing – McGrath looked at issues affecting adherence to prescribed care among patients with chronic disease.

“I got interested in areas that weren’t being addressed by traditional medical asthma research, like behavior and adherence,” she says. Anxious to work directly with patients, she became a certified asthma educator in 2007.

A move to the UCSF Airway Clinical Research Center exposed her to more-basic science. “I was still interested in looking at behavior,” she says, “but it enabled me to tie that to cellular characteristics of asthma.” At the time, John Fahy, director of the center, was looking at the sputum of asthmatics, trying to answer the question of how it differed from that of healthy people or those with other diseases.

While looking at studies that came out of the National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network (ACRN), McGrath and Fahy recognized that the 10-plus years of robust data represented there might hold additional clues to the ways the cellular characteristics of asthmatics’ sputum reflected how patients’ disease worked. The result was a retrospective study published in the March 15, 2012, issue of the American Journal of Respiratory and Critical Care Medicine.

Identifying Asthma Subtypes

In the study, McGrath and her co-investigators (including UCSF’s Fahy, Homer Boushey and Stephen Lazarus) looked at sputum and blood samples from the data set, searching for eosinophilia, which indicates a higher-than-normal level of one of the five major types of white blood cells and serves as a marker for inflammation. Eosinophilia is believed to be a common feature in asthma. The research team was surprised to find that among 995 subjects with mild-to-moderate asthma, nearly half (47 percent) did not have airway eosinophilia.

“What’s exciting about this work,” says Lazarus, a pulmonologist and director of the UCSF Training Program in Pulmonary and Critical Care Medicine, “is that it challenges the basic premise that all asthma is the same. We found that almost half of the people didn’t have what everybody thought of as the classical finding in asthma.”

Implications for Asthma Treatment

That finding has important implications for continuing to use ICS as a first-line treatment in all asthma patients, because ICS work by reducing airway inflammation. So McGrath and her colleagues next looked at how the different groups responded to ICS compared with another therapy. They cross-matched the three phenotypes they had identified (persistently eosinophilic, intermittently eosinophilic and persistently noneosinophilic) against data from the National Heart, Lung, and Blood Institute’s Improving Asthma Control Trial (IMPACT), in which different asthma therapies were tested, including ICS as part of a combined therapy. Those who were persistently noneosinophilic did not respond to the combined therapy but did improve using a nonsteroid bronchodilator.

“The going theory in the literature had been that people with noneosinophilic asthma didn’t respond to corticosteroids because they just weren’t as sick [as people with eosinophilic asthma],” says McGrath. “We showed that they actually did have room for improvement. The first-line therapies we were using were just not working.”

This suggests that there is benefit to determining whether a patient with asthma has the eosinophilic type or the persistently noneosinophilic type and tailoring treatment appropriately.

“When every guideline says that everybody should get inhaled steroids, and 50 percent don’t have eosinophils, then number one, you’re wasting a lot of money,” says Lazarus. “Number two, you’re subjecting patients unnecessarily to the potential risks and adverse effects of inhaled steroids.”

Building on the Research with a Prospective Clinical Trial

Lazarus has proposed a prospective clinical trial to validate the findings from the earlier study, determine which patients (if any) are unlikely to benefit from ICS as a first-line therapy and potentially identify more-effective treatments for that group. The Steroids in Eosinophil Negative Asthma (SIENA) trial will investigate how 384 patients with mild-to-moderate asthma who meet the criteria for receiving ICS therapy respond to the standard treatment (ICS and a bronchodilator) compared with a “second-line” controller therapy and with placebo.

At the same time, investigators will also attempt to identify biomarkers that will allow clinicians in the community to identify which subtype of asthma a patient has. Currently, an induced sputum test is the only reliable way to determine if eosinophilia is present in an asthmatic patient, but it isn’t practical for use outside academic medical centers with specially trained staff, says Lazarus. He hopes to build on research done by Fahy, Prescott Woodruff and their colleagues, which has suggested that periostin, a protein measurable in blood, correlates with the presence of eosinophils in sputum. This could lead to a simple blood test that determines which patients are likely to benefit from ICS and which are not, potentially saving millions of health care dollars annually.

The study protocol and design has been approved by the AsthmaNet’s steering committee and the director of the National Heart, Lung, and Blood Institute, and Lazarus hopes to begin implementing it in the second half of 2013.

McGrath helped Lazarus and their UCSF colleagues develop the study proposal, and although she will work with patients in the clinic for the UCSF arm of the study, she will not serve as an investigator on SIENA. She received her RN in July 2012 and will finish her master’s program in Occupational and Environmental Health Nursing in 2014. While her current work is with patients with more severe asthma, she is hopeful that her research, combined with the outcome of the SIENA trial, will pave the way for more-effective treatments for those with mild-to-moderate disease. “Our goal ultimately is to help clinicians figure out which patients will respond best to which treatments.”