The primary treatment for asthma may actually worsen the disease, according to a recent study published in the journal JCI Insight. While corticosteroids are the mainstay for asthma treatment, researchers at the University of Pittsburgh Schools of the Health Sciences and University of Pittsburgh Medical Center (UPMC) suggest the therapy may worsen the disease in some patients.
About 18.4 million adults in the United States suffer from asthma, according to the Centers for Disease Control and Prevention (CDC), and about 6.2 million children have the respiratory problem. Characterized by airway inflammation that often leads to wheezing, coughing and breathlessness, asthma is a chronic, lifelong disorder that can sometimes be fatal.
Asthma is the primary diagnosis for about 1.6 million visits to emergency departments each year. And the number of people living with asthma is increasing, according to the American Academy of Allergy, Asthma and Immunology (AAAAI), so emergency departments will likely see an increasing number of patients presenting with asthma.
While inhaled corticosteroids treat asthma by reducing airway inflammation, they are ineffective in 5 to 10 percent of those with severe asthma. This makes current corticosteroid treatments inadequate for the subset of patients with a severe form of asthma.
Medical science needs to gain a better understanding of severe forms of asthma and determine why these forms respond so poorly to corticosteroids. This understanding can help future researchers identify novel therapeutic targets.
Some patients with severe asthma produce high levels of the inflammatory protein, interferon-gamma, in their airways. In fact, researchers found increased levels of interferon-gamma in the airways of about half of the severe asthma patients included in a previous study. The researchers also used a mouse model to show that interferon-gamma caused poor lung function.
In the new study, the scientists wanted to determine whether interferon-gamma signaling is responsible for poor corticosteroid response in some severe asthmatics. They focused on a specific inflammatory protein induced by interferon-gamma, known as CXCL10. The interesting thing about CXCL10 is that it is both induced by interferon-gamma and it recruits immune cells that produce interferon-gamma, thereby perpetuating the cycle of inflammation.
The researchers found elevated CXCL10 in the lung cells of about 50 percent of severe asthma patients who had received high-dose corticosteroid treatments. CXCL10 levels were also higher in patients with severe asthma than in those who managed milder symptoms with steroids or other treatments.
The investigators grouped the asthma patients into two categories — high and low CXCL10 — and used emergency department visits and asthma flare-ups within the previous year to determine asthma control. They found that patients in the high CXCL10 group had worse control over their asthma.
The scientists also uncovered a surprising mechanism that suggests corticosteroids could, in fact, worsen asthma. Corticosteroids have wide immunosuppressive and anti-inflammatory functions that should make them the ideal treatment for asthma.
The team used cultured immune cells in this study to show that corticosteroids fail to suppress CXCL10 gene expression in immune cells. They discovered that the failure occurs because corticosteroids actually stabilize interferon-gamma’s signal to produce more CXCL10.
"Our findings show that CXCL10 is elevated in some patients with severe asthma and that corticosteroids have little impact on its production," said Sally Wenzel, M.D., co-senior author of the study. "While corticosteroids are the mainstay asthma treatment, our findings suggest that these medications are of limited help to patients with high levels of interferon-gamma and CXCL10, and may even be harmful over time."
The team will continue its investigation into the pathway and search for ways to block the inflammatory loop perpetuated by interferon-gamma and CXCL10.
"Over the next few years, we also hope to show that CXCL10 can be used as a biomarker in the clinic to help identify patients who will not respond to corticosteroids, sparing them from the significant side effects of these medications," said Anuradha Ray, Ph.D., professor of immunology and medicine and Endowed Chair in Lung Immunology at University of Pittsburgh School of Medicine.
