Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease of unknown cause occurring primarily in middle-aged and older adults. IPF is characterized by progressive scarring in the lungs and affects some 200,000 people in the U.S. each year. Though uncommon, its incidence appears to be on the rise and is expected to increase with the aging population. IPF has a high mortality with a median survival of three to five years.

Despite years of investigations, the origin of IPF has remained elusive, with possible roles played by alveolar epithelial injury, the microbiome inducing immune activation, a genetic predisposition, cigarette smoke, or any combination thereof.

Dr. Robert J. Kaner

“While two-thirds of people who have the disease are former smokers, the cause for this disease is not certain,” says Robert J. Kaner, MD, a pulmonologist in the Division of Pulmonary and Critical Care Medicine at NewYork-Presbyterian/Weill Cornell Medical Center, whose clinical expertise focuses on interstitial lung diseases. “We believe there is definitely a genetic predisposition; about 5 percent of patients will have a first-degree relative who also has this disease. However, how the genetic predisposition interacts with environmental and other factors is not well understood at this point.”

Currently, two FDA-approved drugs are available to slow the progression of the worsening of lung function – nintedanib and pirfenidone. Surgical therapy with lung transplantation is available to only a small minority of patients. As IPF gradually progresses, an individual becomes more impaired in terms of dyspnea, cough, and ability to exercise and carry out activities of daily living, requiring supplemental oxygen.

“Fifty years ago, it was thought that lung tissue was sterile. Now we know that there is a specific microbiome signature that correlates with increased risk of disease progression in idiopathic pulmonary fibrosis.”

— Dr. Robert J. Kaner

“This disease causes widespread scarring throughout the lungs, with a prognosis that is not much better than lung cancer,” says Dr. Kaner. “Because the two drugs we have now are not curative, we desperately need new approaches.”

A possible answer to a new treatment for the disease, says Dr. Kaner, may reside in recent research suggesting that the lung microbiome correlates with outcome in IPF, either by initiating fibrosis or as a trigger in exacerbations. “Two small studies conducted overseas, one in India and one in the United Kingdom, looked at treating IPF with antibiotics in which patients appeared to have better outcomes. This suggests that the microbiome may be relevant.”

Recent pathological findings in the lung support this path of investigation. “Fifty years ago, it was thought that lung tissue was sterile,” says Dr. Kaner. “Now we know that there is a host microbial community that can be identified by studies of bacterial DNA. Those studies have been done with bronchoalveolar lavage, a procedure by which a bronchoscope is passed into the airways enabling the collection of epithelial lining fluid. From those studies has come the recognition that there is a specific microbiome signature that correlates with increased risk of disease progression in idiopathic pulmonary fibrosis.”

CleanUP IPF

Following that lead, in 2016 the National Institutes of Health launched CleanUP IPF, a multicenter clinical trial to evaluate an antimicrobial approach to improving the outcome of individuals with idiopathic pulmonary fibrosis. The study is under the leadership of Fernando J. Martinez, MD, MS, Chief of Pulmonary and Critical Care Medicine at Weill Cornell, and a renowned clinician and translational investigator who specializes in fibrotic lung disease and airway disorders.

CleanUP IPF aims to enroll 500 patients across approximately 30 medical centers across the U.S., including Weill Cornell. The unblinded phase 3 study, the first pragmatic study in IPF ever performed, seeks to determine if antimicrobial therapy in addition to standard care compared to standard care alone in individuals with IPF will improve clinical outcomes, such as the length of time to a rehospitalization. Patients will be randomized to receive co-trimoxazole or doxycycline – off patent and readily available antibiotics – and remain in the trial for up to 42 months with three clinic visits over two years and follow-up phone calls.

“This is a pragmatic clinical trial designed to make it as easy as possible for participants to follow,” says Dr. Kaner. “Patients will know upon randomization if they are assigned to the antibiotic arm or usual care arm. Even if assigned to the antibiotic arm, they also can choose to remain on their usual care for idiopathic pulmonary fibrosis, which in most cases will include the FDA-approved drugs.”

With an enrollment goal of 15 patients, the Weill Cornell investigators hope to conduct a bronchoscopic sub-study, including the collection of lung samples comparing the microbiome and lung immune cells before and after administration of antibiotics, as well as gene expression in the distal airways. “We are planning to propose this sub-study working with Dr. David Artis and Dr. Laurel Monticelli, Weill Cornell immunologists, to correlate the changes in the microbiome with changes in innate lymphoid cells,” says Dr. Kaner.