A contemporary practical approach to the multidisciplinary management of unclassifiable interstitial lung disease

Abstract

Fibrotic interstitial lung diseases (ILDs) frequently have nonspecific and overlapping clinical and radiological features, resulting in ∼10-20% of patients with ILD lacking a clear diagnosis and thus being labelled with unclassifiable ILD. The objective of this review is to describe how patients with unclassifiable ILD should be evaluated, and what impact specific clinical, radiological and histopathological features may have on management decisions, focusing on patients with a predominantly fibrotic phenotype. We highlight recent data that have suggested an increasing role for antifibrotic medications in a variety of fibrotic ILDs, but justify the ongoing importance of making an accurate ILD diagnosis given the benefit of immunomodulatory therapies in many patient populations. We provide a practical approach to support management decisions that can be used by clinicians and tested by clinical researchers, and further identify the need for additional research to support a rational and standardised approach to the management of patients with unclassifiable ILD.

FIGURE 1

Proposed approach to the classification of fibrotic interstitial lung disease (ILD). The establishment of diagnostic confidence is based on the proposal from Ryerson et al. [8]. The selected list of potential reasons for remaining unclassifiable is modified from Cottin and Wells [9]. HP: hypersensitivity pneumonitis; CTD: connective tissue disease; MDD: multidisciplinary discussion; UIP: usual interstitial pneumonia.

FIGURE 2

Proposed algorithm for assessment and management of patients with unclassifiable interstitial lung disease (ILD). The algorithm is divided into two phases that generally represent short-term and long-term management approaches. Short-term management is typically based on features that have developed over days to weeks, with corresponding potential for substantial improvement over days to weeks. Long-term management is typically based on features that have evolved over months, with corresponding potential to improve manifestations or slow progression over several months or more. HRCT: high-resolution computed tomography; CTD: connective tissue disease; Rx: prescription; HP: hypersensitivity pneumonitis; NSIP: nonspecific interstitial pneumonia; UIP: usual interstitial pneumonia; BAL: bronchoalveolar lavage.

FIGURE 3

Single-slice axial and coronal high-resolution computed tomography (HRCT) images demonstrating different parenchymal patterns that may influence multidisciplinary assessment of unclassifiable interstitial lung disease. a) The three-density pattern is present when normal-density lung (red arrows), high-density ground-glass opacities (yellow arrows) and low-density areas due to small airways disease (green arrows) coexist. When signs of fibrosis are also present, this pattern is specific for fibrotic hypersensitivity pneumonitis. b) Diffuse ground-glass opacities in a patient with nonfibrotic nonspecific interstitial pneumonia (NSIP). The absence of traction bronchiectasis as well as the homogenous, amorphous quality of the ground-glass opacification suggests this pattern reflects a nonfibrotic, inflammatory infiltrate. c) Fine reticulation mimicking ground-glass opacities in a patient with idiopathic pulmonary fibrosis. In contrast to b), this pattern has a coarse quality caused by fine intralobular septal thickening. The presence of traction bronchiectasis confirms the presence of fibrosis. d) Fine reticulation mimicking ground-glass opacities in a patient with fibrotic NSIP. The reticular quality of this pattern is more subtle than in c), but the presence of severe traction bronchiectasis helps to classify it as fibrotic. e) and f) Axial and coronal HRCT images depicting basal subpleural honeycombing, traction bronchiectasis and coarse reticular opacities typical of usual interstitial pneumonia.

FIGURE 4

Photomicrographs illustrating a range of fibrotic and nonfibrotic features that may influence multidisciplinary assessment of unclassifiable interstitial lung disease (ILD). a) A low-magnification image of a surgical lung biopsy shows features typical of usual interstitial pneumonia, including patchy fibrosis, scarring and honeycomb change, and fibroblast foci (haematoxylin and eosin stain; original magnification ×1.5). b) Non-necrotising granulomatous inflammation and lymphoid aggregates in a surgical lung biopsy from a patient with Sjögren syndrome. The biopsy findings are typical of neither lymphoid interstitial pneumonia nor follicular bronchiolitis, two overlapping forms of pulmonary lymphoid hyperplasia common in this setting. While this makes this lesion difficult to classify, assuming that an infectious aetiology has been vigorously excluded, one might reasonably predict that immunomodulatory strategies are likely to be more effective than antifibrotic medications (haematoxylin and eosin stain; original magnification ×3.3).