Disease pathology in fibrotic interstitial lung disease: is it all about usual interstitial pneumonia?

Summary

The interstitial pneumonias comprise a diverse group of diseases that are typically defined by their cause (either idiopathic or non-idiopathic) and their distinct histopathological features, for which radiology, in the form of high-resolution CT, is often used as a surrogate. One trend, fuelled by the failure of conventional therapies in a subset of patients and the broad-spectrum use of antifibrotic therapies, has been the focus on the progressive fibrosing phenotype of interstitial lung disease. The histological pattern, known as usual interstitial pneumonia, is the archetype of progressive fibrosis. However, it is clear that progressive fibrosis is not exclusive to this histological entity. Techniques including immunohistochemistry and single-cell RNA sequencing are providing pathogenetic insights and, if integrated with traditional histopathology, are likely to have an effect on the pathological classification of interstitial lung disease. This review, which focuses on the histopathology of interstitial lung disease and its relationship with progressive fibrosis, asks the question: is it all about usual interstitial pneumonia?

Introduction

Diffuse interstitial lung diseases (ILDs) are often progressive, with associated high morbidity and mortality. Specific and often unknown triggers initiate injuries, activating distinct pathways that drive the fibrosis of differing histological patterns, in individuals who are genetically susceptible. The individual diagnoses that are categorised as diffuse ILDs have changed substantially over the last few decades, which is largely attributable to improvements in radiology (ie, high-resolution CT) and a better understanding of ILD histology. In current clinical practice, histology is only required in a subset of patients, in whom a diagnosis cannot be reached by combining clinical history and features, serological investigations, chest high-resolution CT findings, and bronchoalveolar lavage, where appropriate. However, although the role of radiology is not to be undervalued, it has been the histological distinctions that have specifically informed the diagnosis of idiopathic interstitial pneumonias, and shaped the associated guidelines.¹

Lately, there has also been a greater recognition of disease behaviour, regardless of the underlying disease histology. This shift has largely been driven by the observation of progressive fibrosis outside of idiopathic usual interstitial pneumonia (ie, idiopathic pulmonary fibrosis [IPF]), the quintessential progressive fibrosing ILD (PF-ILD). Evidence showing the broad-spectrum antifibrotic effects of nintedanib and pirfenidone has lent further support for PF-ILD.2, 3 As a result, the distinctions in ILD histology are at risk of losing relevance in this new era.

In this review, we aim to show the ongoing value of ILD histology and new methods to define disease pathogenesis with reference to PF-ILD behaviour. An appreciation of the similarities and differences in the histology and pathogenesis of ILD entities is crucial to informing approaches to diagnosis and the development of novel treatment targets. We will focus on the most common fibrotic ILD pathological patterns associated with, or potentially associated with, a progressive fibrotic phenotype, including usual interstitial pneumonia, both in the idiopathic setting (ie, IPF) and in association with other entities (table 1; figure 1). Other fibrotic patterns, including non-specific interstitial pneumonia (both idiopathic and associated with other entities), organising pneumonia with concomitant interstitial fibrosis, fibrotic hypersensitivity pneumonitis, and pleuroparenchymal fibroelastosis have been summarised (table 1). We did not review other entities potentially associated with progressive fibrosis, including smoking-related interstitial fibrosis, desquamative interstitial pneumonia, drug-induced ILD, fibrotic sarcoidosis, pneumoconiosis, and fibrotic Langerhans cell histiocytosis.