AJRCCM : 100-Y ear A nniversary . Progress in Interstitial Lung Disease

The Interstitial Lung Diseases (ILD) encompass a broad array of conditions that diffusely affect the lung parenchyma. These include both acute and chronic diseases of known and unknown etiologies. The purpose of this centennial review is to highlight key observations in the field over the past 100 years and point to potential future directions in diagnosis and treatment. Given the large number of disorders, their divergent clinical presentations, natural histories, and underlying biologic mechanisms, it is impossible to even begin to adequately acknowledge all of the critical findings and investigators who have made important contributions to the field. Given space limitations, we have focused on only a handful of the more common diseases. For this we apologize, but are thankful to numerous individuals (see acknowledgment) who provided both personal insights and identified influential publications. The clinical entity of diffuse pulmonary fibrosis was initially reported by Hamman and Rich when they described three patients with acute/subacute onset of respiratory failure; at autopsy they demonstrated a combination of both acute parenchymal lung injury and chronic scarring (1). Austrian and colleagues described the concept of alveolar capillary diffusion block as a pathophysiologic mechanism (2), which was later revised by Finley and colleagues (3). Gaensler and coworkers described the safety and utility of surgical lung biopsy in diffuse parenchymal lung disease, which was then used to begin to characterize the pathology and specific diagnosis of idiopathic pulmonary fibrosis (IPF) (4, 5). Scadding and Hinson added detail to the histology and prognosis of lung fibrosis and proposed the term “fibrosing alveolitis” for the clinical syndrome, which was more fully expanded by Turner-Warwick and colleagues (6, 7). Liebow and Carrington exquisitely described specific subsets of the idiopathic ILDs, based on their underlying histopathology seen on surgical lung biopsy, including the most common histologic pattern, usual interstitial pneumonia (UIP) (8). Katzenstein, Fiorelli, and Myers performed detailed electron microscopic analyses of ILD, which lead to the recognition of both the fibroblast focus (a critical feature of UIP) and to the separation of nonspecific interstitial pneumonia from UIP within the broader group of the fibrosing interstitial pneumonias (9, 10). This led to the recognition of nonspecific interstitial pneumonia as a subgroup with a more favorable prognosis and response to therapy; a finding subsequently verified by several other investigators (11, 12). Müller and colleagues showed that visual patterns seen on high-resolution computerized tomographic (HRCT) of the chest often correlated well with specific histologic patterns from surgical lung biopsy (13). Acute exacerbation was described as an important clinical event in the natural history of patients with IPF that impacted prognosis (14). These observations were codified in 2002 in the American Thoracic Society (ATS)/European Respiratory Society (ERS) multidisciplinary consensus classification statement on the idiopathic interstitial pneumonias (IIP) (15). These guidelines were updated in 2011 with the ATS/ERS/Japanese Respiratory Society/Asociación Latinoamericana del Tórax IIP statement and amplified the importance of HRCT and histopathologic patterns, and the importance of a multidisciplinary discussion for final ILD diagnosis (16). The importance of these clarifying definitions is underscored by the observation that mortality from pulmonary fibrosis continues to increase (17, 18) and that traditional metrics of lung function do not adequately capture quality-of-life issues, resulting in the development of patient-reported outcomes as new endpoints for therapeutic trials in ILD (19).