Pathogenesis, clinical features, and phenotypes of pulmonary hypertension associated with interstitial lung disease: A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative - Group 3 Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a frequent complication of interstitial lung disease (ILD). Although PH has mostly been described in idiopathic pulmonary fibrosis, it can manifest in association with many other forms of ILD. Associated pathogenetic mechanisms are complex and incompletely understood but there is evidence of disruption of molecular and genetic pathways, with panvascular histopathologic changes, multiple pathophysiologic sequelae, and profound clinical ramifications. While there are some recognized clinical phenotypes such as combined pulmonary fibrosis and emphysema and some possible phenotypes such as connective tissue disease associated with ILD and PH, the identification of further phenotypes of PH in ILD has thus far proven elusive. This statement reviews the current evidence on the pathogenesis, recognized patterns, and useful diagnostic tools to detect phenotypes of PH in ILD. Distinct phenotypes warrant recognition if they are characterized through either a distinct presentation, clinical course, or treatment response. Furthermore, we propose a set of recommendations for future studies that might enable the recognition of new phenotypes.

Keywords: endophenotype; histology; idiopathic pulmonary fibrosis; pathophysiology; pulmonary vascular disease.

Figure 1

Proposed elements to define phenotypes in PH associated with ILD. These elements are not all necessary to establish a phenotype, but simply constitute traits that might be distinct in phenotypes of ILD‐PH. The arrows indicate how baseline might influence traits observed with progression of disease and vice versa, considering that the diagnosis of PH may be established when both ILD and PH are already advanced in the clinical course. 6MWT, 6‐minute walking test; BNP, brain natriuretic peptide; cMRI, cardiac magnetic resonance imaging; CPET, cardio‐pulmonary exercise test; DLCO, diffusion of carbon monoxide; ILD, interstitial lung disease; NT‐ProBNP, N‐terminal pro‐brain natriuretic peptide; PH, pulmonary hypertension; RV, right ventricle.

Figure 2

Pulmonary vascular disease histology in interstitial lung disease. On the left panel, a histologic section of explanted lung tissue from a patient with idiopathic pulmonary fibrosis (IPF) who underwent lung transplant, showing marked concentric arterial medial hypertrophy (arrows) (Haematoxylin & Eosin, x100). On the right panel, explanted lung tissue of a patient with IPF without pulmonary hypertension (mean pulmonary artery pressure of 20 mmHg and pulmonary vascular resistance 1.5 wood units, pulmonary arterial wedge pressure 10 mmHg; data obtained 4 months before transplant) but showing signs of venous occlusion. With permission and many thanks to Dr. H. Mani (Inova Fairfax Hospital).

Figure 3

Autoimmune disease, lung fibrosis, and vasculopathy. Autoimmune diseases share with lung fibrosis and pulmonary vascular diseases a variable component of inflammation which, in these entities, plays an important role both in pathogenesis and in symptoms burden. As the disease progresses, fibrosis and pulmonary vasculopathy may affect symptoms more prominently.

Figure 4

Mechanisms involved in the development of ILD and PH. This figure illustrates some of the potential mechanisms that may lead to the development of PH and ILD in its different forms. The disparate nature of the factors implicated, from prebirth development to exposures throughout life may in part explain the variability in clinical presentation and possibly the existence of different phenotypes. AIP, acute interstitial pneumonia; CHP, chronic hypersensitivity pneumonitis; CPFE, combined pulmonary fibrosis and emphysema; CTD‐ILD, connective tissue disease associated‐ILD; DIP, desquamative interstitial pneumonia; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; LAM, lymphangioleiomyomatosis; LIP, lymphocytic interstitial pneumonia; NSIP, nonspecific interstitial pneumonia; PH, pulmonary hypertension; PPFE, pleuroparenchymal fibro‐elastosis; TB, tuberculosis.

Figure 5

The tri‐dimensional spectrum of ILD, emphysema, and pulmonary vascular disease. The illustration shows the continuum of pathologic changes in the lung which may variably present in ILD‐PH patients. Colored dots are examples of different clinical situations with varying degrees of pathological alterations in the alveolar, interstitial, and vascular compartments and dashed lines indicate where they lay on the tri‐dimensional spectrum. CPFE, combined pulmonary fibrosis and emphysema; ILD, interstitial lung disease; PH, pulmonary hypertension.