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An Update in Progressive Pulmonary Fibrosis

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Interstitial lung diseases (ILD) comprise a group of almost 200 entities characterized by heterogeneity in the extent of inflammation and/or fibrosis. Idiopathic pulmonary fibrosis (IPF), the archetypal fibrosing lung disease, is progressive and associated with significant morbidity and mortality. A proportion of patients with fibrotic ILDs, including idiopathic non-specific interstitial pneumonia, connective tissue disease-associated ILDs, chronic hypersensitivity pneumonitis, unclassifiable ILD, pneumoconiosis, and sarcoidosis, demonstrate a progressive phenotype similar to IPF despite conventional therapy. This cohort of patients with known or unknown etiology of ILD (except IPF) are determined to have progressive pulmonary fibrosis (PPF) per the recently published ATS/ERS/JRS/ALAT clinical practice guidelines. 

PPF is characterized by at least two of the three criteria within the past year with no alternative explanation: worsening of respiratory symptoms, physiological evidence of disease progression with a decline in forced vital capacity (FVC) and/or diffusion capacity for carbon monoxide (DLCO) and/or radiological evidence of disease progression. With increasing recognition of this entity, the estimated incidence and prevalence of PPF have been on the rise and negatively impact quality of life among patients with ILD. 

There have been significant advances in understanding the pathogenesis of PPF, and despite differences in the underlying ILD, the later phase of fibrogenesis in all ILDs is akin to IPF. The fibrotic phase is characterized by dysregulated wound repair and altered epithelial–mesenchymal communication with excessive extracellular matrix deposition after repetitive epithelial injury. This overlap in the pathogenesis of PPF and IPF leads to further investigations of the antifibrotic drugs, pirfenidone and nintedanib, which were initially developed and approved for treating IPF. 

Nintedanib was approved for patients with PPF based on results of IN-BUILD trial; criteria applied here differed from current definition where in all participants had progressive disease defined as a 10% FVC decline, ≥5% FVC decline with symptom or imaging progression, or worsening symptoms and imaging over a two-year period. While two similar studies for pirfenidone in progressive fibrotic ILDs showed promise, the guideline committee concluded that further evidence is warranted. Therapies targeting inflammatory/immune responses are the mainstay for several fibrotic ILDs. However, with the exception of scleroderma ILD, these practices are based on retrospective or small observational studies and/or expert opinion. Currently, there are no specific guidelines on therapeutic management of these patients in steady disease state and during acute exacerbations. There are several conundrums, including escalation of immunosuppressants versus antifibrotic agents when patients have progressive disease, the role of HRCT patterns in treatment decisions, consideration of potential therapeutic complications and further monitoring for disease progression.

Our session will focus on the recognition of PPF and discuss the risk factors and clinical implications for PPF. I will discuss the management of patients with PPF, including challenges such as timing of these medications, non-pharmacological management and monitoring.

Dr. Kulkarni is employed by the University of Alabama at Birmingham, has received grants from the NIH, and has received consulting fees from Consultation to United Therapeutics Corporation, PureTech Lyt-100 Inc., and Boehringer Ingelheim Inc. 

Image: Mopic / shutterstock

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