More than 18 million adults and 9 percent of children currently have asthma in the United States, with urban areas and minorities bearing the greatest burden. The large urban patient population receiving care at the NYU Langone Health and NYC Health + Hospitals/Bellevue’s Asthma Clinic is providing researchers and clinicians with an opportunity to address some of the most pressing issues in asthma management.
Asthma is one of the most common chronic illnesses seen by urban physicians. “We’re focused on expanding our molecular, environmental, and clinical understanding of urban asthma,” says Joan Reibman, MD, professor of medicine and director of the Asthma Airways Environment Program.
As a principal investigator of the New York Consortium of the American Lung Association (ALA) Airways Clinical Research Centers (ALA ACRC), the nation’s largest not-for-profit network of clinical research centers dedicated to asthma and chronic obstructive pulmonary disease, Dr. Reibman and her team design and conduct interventional clinical trials at Bellevue and NYU Langone. “At the same time, our biorepository and gene-banking program support basic and translational research that is expanding our understanding of the molecular mechanisms of disease, which will lead to improved diagnosis, prognosis, and clinical management,” says Dr. Reibman. “Our recent findings on asthma stem out of years of running both a research and a clinical program.”
Optimal Approaches to Step-Down Therapy
On the clinical side, as part of ALA ACRC, Dr. Reibman just published findings from two recent ALA-supported studies on medication step-down therapy for patients with asthma. National and international guidelines recommend reducing medications in patients with well-controlled asthma to minimize potential adverse effects from sustained high doses of medications. Yet despite multiple studies on optimal approaches to stepping down therapy, there is no consensus on how best to do it, in part due to the heterogeneity of asthma. In addition, for some individuals, reducing or eliminating asthma medications can lead to exacerbations, lung function decline, or treatment failure. This uncertainty can leave clinicians reluctant to recommend step-down therapy to their patients, despite the fact that many are candidates.
One of the most controversial issues in step-down therapy is how to reduce medications in patients receiving combinations of inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA). Lowering the ICS dose or discontinuing LABA can both appear to be reasonable options. To provide more guidance on tapering medications, the team compared two regimen options for patients who take combination ICS and LABA. In a randomized, double-masked trial, investigators tracked the progress of 459 adults and adolescent patients across the country over the course of 48 weeks to determine whether lowering the ICS dose or stopping LABA is the superior step-down approach. They found no difference in terms of treatment failure, but lung-function decline and hospitalization rates were significantly greater in the LABA-step-off group.
In another study that used data collected from these same subjects, the team looked at potential risk factors that could impact the success of step-down therapy. Interestingly, exposure to environmental tobacco smoke did not impact patient outcomes, but unexpected emergency room visits in the previous year were associated with increased risk for exacerbations and treatment failure during step-down. Ultimately, the researchers concluded that clinicians may need to more carefully monitor patients undergoing step-down therapy if they have reduced pulmonary function, a history of exacerbations, or early-onset disease.
A Biomarker for Asthma Severity
Dr. Reibman has created a biobank using blood DNA and protein samples from patients with and without asthma. These samples have been used to characterize the interaction of the microbiome and asthma, asthma phenotypes, gene and environment interactions, and techniques for genetic analyses. The link between YKL-40 protein levels and asthma severity has recently been established and its utility as an asthma biomarker is of increasing interest.
Now, researchers are trying to uncover the distinct molecular mechanisms present in the airways of asthmatics who have elevated YKL-40 levels. To that end, Dr. Reibman is collaborating with investigators at Yale University to understand how they can use YKL-40 measurements, in combination with clinical and physiological features of asthma, to identify specific subgroups of patients who are more at risk for serious complications and conditions, such as severe airflow obstruction, near-fatal asthma, frequent exacerbations, and severe asthma with non-T2 inflammation.
As part of a multi-institution, cross-sectional study of YKL-40 levels in three large cohorts of asthma patients, including one of the largest from the NYU Langone–Bellevue repository, researchers conducted a clustering analysis to identify four YKL-40 subgroups—two with low levels of the biomarker and two with high levels. In fact, the elevated YKL-40 subgroups correlated with two distinct clinical asthma phenotypes: one with irreversible airway obstruction and another with severe exacerbations. These findings not only suggest how YKL-40 could be used as a more specific biomarker and indicator of risk, but they also reveal clues about the underlying mechanisms behind these associations, paving the way for future research.