PF-ILD

Overview

Interstitial lung diseases (ILDs) are a collective concept comprising more than 200 different diseases, many of which are characterized by chronic progressive fibrosis.¹ Within the spectrum of fibrosing ILDs is a subset of patients who have inexorable progression of pulmonary fibrosis despite treatment, which is known as the progressive fibrotic phenotype.² Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic ILD, the most severe of the chronic forms of ILDs and represents, by definition, the prototype of progressive fibrosing ILD characterized by decline in lung function and early mortality.³ Because these conditions share similarities regarding pathogenesis and clinical behavior, they are increasingly described under the umbrella terminology of progressive fibrosing ILDs (PF-ILDs) or fibrosing ILD with a progressive phenotype. In this editorial, PF-ILDs will refer to fibrosing ILDs other than IPF which have a progressive phenotype.³ Patients with PF-ILD typically have self-perpetuating fibrosis characterized by worsening lung function, dyspnea, physical performance, and quality of life, as well as a poor response to therapy and early mortality.⁴

Epidemiology⁵

Data on the prevalence and incidence of ILDs other than IPF with a progressive-fibrosing phenotype are limited, in part due to the complexity and rarity of diagnosis. Consequently, meaningful comparisons of the epidemiology of different PF-ILDs are difficult.⁵ Despite the global distribution of ILDs with a progressive-fibrosing phenotype, their incidence and prevalence are not well defined. This may be related to a number of reasons, potentially to the heterogeneous nature of the etiology, the complexity of diagnosis (and subsequent recording of cases), the low numbers of patients diagnosed and the methods employed to retrospectively analyze patient databases. ILDs that may present a progressive-fibrosing phenotype appear to be more common in older adults and are associated with a complex network of environmental and genetic factors.⁵

Prevalence⁶

Approximately 20-30% of patients with ILD are estimated to have PF-ILD; however, there is no standardized definition of PF-ILD that clinicians and researchers have agreed upon.⁴ In a France study, the estimated incidence of PF-ILD ranged from 4.0 to 4.7/100,000 person-years and the estimated prevalence from 6.6 to 19.4/100,000 persons between 2010 and 2017.⁶ The main diagnostic categories represented were exposure-related ILD other than hypersensitivity pneumonitis (n = 3,486; 24.2%), idiopathic interstitial pneumonia (n = 3,113; 21.6%) and rheumatoid arthritis-associated ILD (n = 2,521; 17.5%). Median overall survival using Kaplan–Meier estimation was 3.7 years from the start of progression.⁶

Pathogenesis^7,8

There are a number of clinical and mechanistic parallels between IPF and other fibrosing ILDs that may present a progressive phenotype; for example, IPF and systemic sclerosis ILD (SSc-ILD) have some overlapping pathogenic mechanisms, including lung parenchymal injury and transforming growth factor-β-mediated fibroblast activation and myofibroblast accumulation.⁷ The prognosis and clinical behavior of ILDs that may present a progressive-fibrosing phenotype, especially those with a usual interstitial pneumonia pattern are similar to those seen in IPF. Also, in a significant proportion of patients with PF-ILDs, the natural history appears to follow a disease course similar to IPF (i.e. worsening symptoms, lung function and health-related quality of life [QoL]), with variable rates of progression.⁷ Irrespective of the trigger for the lung injury, progressive fibrosing ILDs show commonalities not only in disease behavior but also in the pathogenic mechanisms that drive the fibrotic process, which culminate in irreversible loss of epithelial or endothelial barrier integrity, destruction of the lung architecture and loss of lung function.⁸

Risk factors^2,3,9

Patients with types of ILD other than IPF are at risk of developing a progressive fibrosing phenotype, including those with idiopathic nonspecific interstitial pneumonia (iNSIP), unclassifiable idiopathic interstitial pneumonias (IIPs), connective tissue disease-related ILDs (CTD-ILDs) such as those related to rheumatoid arthritis (RA-ILD) and SSc-ILD, chronic sarcoidosis, chronic hypersensitivity pneumonitis (HP) and exposure-related diseases such as asbestosis and silicosis.⁹ Figure 1 showed schematic representation of types of interstitial lung disease (ILD) that may be associated with a progressive fibrosing phenotype.³

Retrospective studies have identified risk factors that increase the likelihood of progression and mortality in PF-ILD including male sex, older age, lower FVC and DLCO at baseline, and certain morphological features.⁴ Several factors predispose certain patients to a higher risk of progressive fibrosis. (Table 1)²

Telomere dysfunction is now understood to be a key pathological determinant of the rate of progression of fibrosis and survival for patients with IPF and with non-IPF ILDs including NSIP, chronic hypersensitivity pneumonitis, and CTD-ILD. Patients with chronic HP and telomere dysfunction are more likely to have more extensive fibrosis, honeycombing, and traction bronchiectasis and worse survival.²