Foundational research at Vanderbilt University Medical Center into the etiology of interstitial lung disease (ILD) is laying the groundwork for personalized therapeutics, including tailored medication regimens and gene targeting.
Interstitial lung diseases comprise a large, heterogeneous group of disorders with an estimated incidence of about 30 per 100,000 people. The most common of these, idiopathic pulmonary fibrosis (IPF), is associated with progressive scarring of the lung interstitium and irreversible loss of lung function. Without lung transplantation, life expectancy is three to five years.
“We’ve known about fibrotic lung disease since X-rays became available, but the definition we’re using now has only been around since the first consensus statement in 2000,” said Lisa Lancaster, M.D., a pulmonologist and director of the Interstitial Lung Disease Program at Vanderbilt University Medical Center. “We’re very much in the infancy of studying these devastating diseases.”
Testing Pirfenidone
Lancaster participated in the studies that ultimately led to approval of the two drugs used to treat IPF – pirfenidone and nintedanib – in 2014. She was primary investigator on a recent study published in Pulmonology Therapy examining the perceived benefits of pirfenidone formulation on patient quality of life, IPF management and pill burden.
Forty-seven patients with IPF and 170 health care professionals (150 physicians in France, Germany, Spain and the U.S. and 20 nurses in the U.S.) completed online questionnaires regarding their use of traditional 267 mg pirfenidone tablets/capsules, versus newly available 801 mg tablets to reach a maintenance dose of 2,403 mg/day.
“We think in the end this is going to be a case of precision medicine. The challenge is determining whether IPF is something you’re born with or a mutation that occurs over your lifetime.”
Patients received the 267 mg formulation of pirfenidone for a median of six months prior to switching to an 801 mg formulation. Significant improvements were reported in emotional well-being, drug compliance and patient adherence. “The 801 mg formulation may provide an alternative to the 267 mg formulation in patients established on the recommended daily dose of pirfenidone,” wrote the authors.
Parsing the Genetics of ILDs
In addition to drug research, Vanderbilt has been at the forefront of ILD genetics research for more than three decades. Studies led by James Loyd, M.D., Timothy Blackwell, M.D., and Jonathan Kropski, M.D., have demonstrated a genetic component in IPF, and their estimates suggest as many as 20 percent of cases are familial. Since these early discoveries, genome-wide association studies have identified more than a dozen common genetic variants.
An ongoing, single-cell RNA sequencing study led by Vanderbilt researchers is further characterizing molecular drivers of the pulmonary fibrosis lung.
“We think in the end this is going to be a case of precision medicine,” Lancaster said, “tailoring antifibrotics to the mutation that ultimately leads to the pathway that leads to the phenotype. The challenge is determining whether IPF is something you’re born with or a mutation that occurs over your lifetime.”
Getting to Correct Diagnosis
Beyond idiopathic and familial disease, occupational exposure, toxins and drugs can play a role in ILD, and autoimmune diseases and other rare lung diseases may be mistakenly diagnosed as IPF.
“ILD diagnosis can sometimes take up to two years,” Lancaster said. “There is likely a pre-clinical period and ILDs may be misdiagnosed with other lung diseases or a heart condition. Part of diagnosing ‘idiopathic’ is to rule out the things that may suggest an alternative cause.”
Lancaster notes ILDs display specific patterns on high-resolution CT and lung biopsy. Yet, lung biopsy should be avoided when appropriate, she says. Vanderbilt is one of the few programs that has expertise in cryo-biopsy during bronchoscopy, which can help make lung biopsy more accessible.
The correct diagnosis of ILD requires strong interdisciplinary collaboration. Lancaster, along with other ILD specialists, meets weekly with experts in rheumatology, thoracic radiology, and pulmonary pathology to discuss complex and challenging cases¹. Vanderbilt has the only specialized ILD program in the region recognized for quality care by the Pulmonary Fibrosis Foundation.
Future Directions
The Vanderbilt ILD Program has led or participated in over 65 clinical trials in the last 20 years, Lancaster says, adding that the program’s patients have been generous in research participation. “We have a very giving patient population – they are really looking to help the patients who come after them.”
