A subset of diffuse interstitial lung diseases (ILDs), apart from idiopathic pulmonary fibrosis (IPF), can present a progressive fibrosing (PF) phenotype known as progressive pulmonary fibrosis (PPF). This condition is characterized by increasing fibrotic changes observed on high-resolution computed tomography (HRCT), a progressive decline in lung function, and worsening respiratory symptoms [1-3]. Various definitions have been proposed and adopted across studies (Table 1) [1,2,4,5]. In the 2022 joint statement by the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society, and Asociación Latinoamericana de Tórax, this group of patients was formally defined as PPF (Table 1) [1]. Premature initiation of antifibrotic monotherapy may limit the potential benefits of immunomodulatory therapy, which is still suitable for selected patients with non-IPF fibrosing interstitial lung disease (fILD) at the time of presentation [2]. Therefore, according to an expert group consensus statement from the ERS, the term PPF was reserved for cases in which fibrosis continues to progress despite appropriate management, at which point antifibrotic therapy should be considered [2].

This phenotype is rare in the general population but becomes significantly more common with advancing age [6]. PPF includes a variety of etiologies, such as idiopathic interstitial pneumonias other than IPF. These include idiopathic nonspecific interstitial pneumonia (iNSIP), cryptogenic organizing pneumonia, unclassifiable interstitial lung disease (uILD), connective tissue disease (CTD)-associated ILD, fibrotic hypersensitivity pneumonitis (fHP), interstitial pneumonia with autoimmune features (IPAF), familial pulmonary fibrosis, drug-induced ILD, and sarcoidosis [2,7]. Although various subtypes of PPF share common pathophysiological mechanisms, clinical outcomes and prognoses can differ significantly based on age, underlying etiology, radiologic and physiologic features, telomere biology, and responses to available therapies [2,4,8]. Identifying prognostic factors within a pure PPF cohort remains challenging. Therefore, this article aims to examine the prevalence, prognostic factors, and outcomes associated with PPF.

Determining the prevalence of PPF is challenging due to the heterogeneous nature of its underlying diseases, the historical lack of approved therapies, and the evolving diagnostic criteria.

Among non-IPF ILDs, a significant proportion of patients develop a PF phenotype. A systematic review of 16 studies has reported that the prevalence of PF-ILD (progressive fibrosing interstitial lung disease) ranges from 13% to 40% of non-IPF ILD cases, with an estimated prevalence of 2.2 to 20 per 100,000 in Europe and 28 per 100,000 in the United States [9]. In a European cohort, 27.2% of patients with ILD other than IPF were reported to progress to PPF, with prevalence varying based on the underlying ILD etiology [10].

Among the various fibrotic ILDs, PPF is most fre quently observed in CTD-ILD, fHP, and iNSIP [2,7]. In contrast, its prevalence is lower in other fibrotic ILDs, such as sarcoidosis and drug-induced ILD [2,7]. The prevalence of PPF also varies regionally, reflecting differences in occupational and environmental exposures [8,11]. For example, fHP, a well-established etiological contributor to PPF, is more prevalent in agricultural and industrial regions due to the common prolonged exposure to organic dust and airborne antigens [8,11].

PPF predominantly affects older adults, with most cases diagnosed in patients over 60 years of age. This suggests that aging-related biological mechanisms, such as telomere shortening and cellular senescence, may contribute to the progression of ILD [12,13]. While the incidence of PPF is higher in men than in women, with a male-to-female ratio ranging from 1.5:1 to 2:1, certain forms of PPF, such as CTD-ILD, are more common in women. This reflects the higher prevalence of autoimmune diseases in females [4,14]. The prevalence of PPF varies according to each etiologic subtype as summarized in Table 2.

Few studies have evaluated the development of PPF according to current criteria within ILD cohorts. In a single-center study by Kim et al. [15] enrolling 110 patients with CTD-ILD, 24.5% progressed to PPF. Among those who developed PPF, rheumatoid arthritis (RA) was the most common underlying CTD (33%), followed by Sjögren's disease (30%), systemic sclerosis (SSc) (18%), and myositis (15%). In NSIP, a progressive phenotype is reported in 26.3% of iNSIP cases and in 49% of fibrotic NSIP [16,17]. In a study of SSc-ILD, where fibrosis extent on HRCT stratified individuals into three groups: >20% fibrosis, 1%-20% fibrosis, and no fibrosis, over a mean 3.1-year follow-up, annual fibrosis progression rate was highest (5.9%) in those who advanced from 1%-20% to >20% fibrosis [18]. Progression correlated with forced vital capacity (FVC) decline but not with diffusion capacity of the lungs for carbon monoxide (DLCO) [18]. According to a study in RA-ILD, 39.7% of patients (median predicted FVC 71% and DLCO 54.5%) reached a DLCO <40% predicted, and 21.6% reached an FVC <50% predicted within 5 years of diagnosis [19]. Among 348 patients with polymyositis/dermatomyositis, 32.7% showed improvement during follow-up, while 15.9% experienced progression, defined as a decline of ≥10% in FVC and/or ≥15% in DLCO [20]. In sarcoidosis, pulmonary fibrosis was observed in 17% of 740 patients [21]. Additionally, bronchiectasis detected on HRCT was linked to a higher frequency of acute worsening compared to patients without bronchiectasis [21]. In primary Sjögren’s syndrome, 55.3% had a PPF phenotype with usual interstitial pneumonia (UIP) in 42.3% of the cases and NSIP in 57.7% [22].

Multiple prognostic factors, including demographic characteristics, lung function decline, radiological features, genetic predisposition, and circulating biomarkers—some of which are specific to the disease—can influence the clinical trajectory of PPF, ultimately affecting both prognosis and therapeutic outcomes (Tables 3, 4) [2,8,10,23-29].

Despite etiologic heterogeneity, PPF confers a high risk of premature mortality across diverse ILDs (Table 3). Mortality is driven not only by the extent of fibrotic progression but also by the interplay of patient-specific factors and comorbidities (Table 3). Accordingly, multiple clinical, radiologic, and physiologic predictors of mortality have been identified.

Despite therapeutic advances, the relentless decline of lung function among patients with PPF often leads to respiratory failure and increased mortality, making it a life-threatening condition [10,38,60,61]. A yearly decline in FVC of ≥10% is associated with significantly increased mortality, and patients experiencing rapid FVC deterioration have markedly worse survival in PPF [10,41,44,62]. Similarly, worsening oxygen desaturation during 6MWT correlates with poorer survival rate [23].

Advanced age and multiple comorbidities are strongly associated with an increased mortality risk [2,10,63,64]. Pulmonary hypertension, which leads to right heart failure and worsens hypoxemia, is a significant predictor of poor prognosis [39,63,65]. Other significant comorbidities, such as cardiovascular disease, emphysema, and gastroesophageal reflux disease, can accelerate disease progression and further compromise survival rates [64].

These factors underscore the importance of a multidisciplinary management strategy that addresses both pulmonary and systemic complications. Underlying etiology is also associated with mortality, with autoimmune ILD demonstrating better survival compared to uILD or HP [10]. However, further prospective studies are required to validate these findings.

Mortality and progression of ILD were associated with ILD subtype-specific factors. In SSc, male sex, African American race, concomitant pulmonary hypertension, lower DLCO, lower FVC, early decline in lung function, the rate of decline in FVC, CCL18, the extent of disease on HRCT, and autoantibody status, including the absence of anticentromere antibody or the presence of anti-topoisomerase I antibody (anti-Scl-70), were identified as predictors of both mortality and ILD progression (Table 3) [28,35,36,66-71]. In HP, a history of smoking, the presence of honeycombing on HRCT, a decline in FVC, lower FVC, short telomere length, the SNP (MUC5B rs35705950), and the failure to identify an inciting antigen are all associated with a reduced survival rate [24,31,44,72].

AE of PPF is a life-threatening event marked by a sudden and severe deterioration of respiratory symptoms, often resulting in acute respiratory failure [1,2,73]. Although initially described in IPF, similar episodes have also been documented in PPF, and the definition of AE in PPF is generally adopted from that in IPF [4]. Epidemiological data further highlight distinctions between AE in IPF and non-IPF ILDs. Suzuki et al. [74] reported that the incidence of AE was significantly lower in fILD (3.21) than in IPF (8.38 per 100 patient-years). Subtype-specific incidences of AE (cases per 100 patient-years) included 1.77 in NSIP, 6.05 in fHP, 3.19 in CTD-ILD, 3.03 in uILD, and 3.16 in pathologically proven uILD [74]. More recently, Kim et al. [75] analyzed single-center data from Korea using the INBUILD criteria. They reported that during a median follow-up of 38 months after the diagnosis of PPF, 42 patients (31.6%) experienced an AE. The cumulative incidence of AEs was 12.5% at 1 year, 30.3% at 3 years, and 38.0% at 5 years [75]. Their study demonstrated that independent risk factors for AE included older age, RA-ILD, fibrotic HP, and reduced DLCO [75]. According to PROGRESS study, the rate of AE was 13.9% over the median follow-up duration of 46.2 months in PPF [10].

The causes and triggers of AE in PPF remain poorly understood. While many episodes are idiopathic, similar to IPF, potential contributors include viral infections, microaspiration due to gastroesophageal reflux, environmental exposures such as air pollution, drug-induced lung injury, and invasive surgical procedures [76,77]. Additional risk factors for AE in PPF include older age, lower DLCO, and a UIP pattern on imaging [26,75,78,79]. Furthermore, immunomodulatory medications may contribute to acute lung injury, thereby precipitating AE [80]. Measures of oxygenation, such as oxygen saturation and the ratio of partial pressure of arterial oxygen (PO₂) to the fraction of inspired oxygen (FiO₂), have been identified as independent predictors of survival in AECTD-ILD [78,81].

AE in both IPF and non-IPF ILDs is associated with a high risk of mortality and may lead to chronic respiratory failure, although outcomes in non-IPF ILDs appear to be slightly better or comparable to those of AEIPF [74,75,82].

In patients with PPF in the INBUILD trial, the estimated risks of death following an AE were 19.0% (95% confidence interval [CI], 8.9 to 29.2) within 30 days and 32.0% (95% CI, 19.7 to 44.2) within 90 days. The estimated risk of death within 180 days after an AE was 37% [79]. An observational study from Japan that enrolled 155 patients with CTD-ILD reported a median survival of 169 days following the onset of AE [83]. In an observational study of 174 consecutive patients experiencing a first episode of AE, the 90-day mortality rate was 29% in non-IPF ILDs and 33% in secondary ILDs, including CTD-ILD and chronic HP, compared with 57% in IPF [82]. The reported 90-day mortality rate in non-IPF ILDs ranges from 17% to 58%, with this variability largely attributed to differences in underlying etiologies [78,82,84]. Moreover, the presence of a pre-existing AE has been recognized as an independent prognostic factor for mortality in patients with ILD undergoing lung transplantation [85]. Consequently, AE is now regarded as a significant event in the disease trajectory of PPF. It serves as a key clinical endpoint in therapeutic trials and plays an important role in determining lung transplantation and initiating palliative care [75,85,86].

The introduction of antifibrotic therapies like nintedanib and pirfenidone has significantly changed the treatment approach for PPF by slowing the decline in lung function [87-91]. Pirfenidone shows promise in slowing disease progression in PPF, as indicated by smaller declines in FVC and DLCO; however, confirmation in larger, adequately powered studies is needed [5,87,90]. Nintedanib, in particular, has consistently shown benefits in slowing disease progression across a wide range of PF-ILDs [89,92]. The effect of nintedanib on survival rates in PPF requires further validation; however, one observational study has shown improved survival rates [87-89]. Nerandomilast is a novel phosphodiesterase-4 (PDE4) inhibitor that demonstrates approximately 10-fold greater inhibitory activity against the PDE4B isoform compared to PDE4D. The PDE4D isoform is believed to be primarily responsible for the gastrointestinal adverse effects commonly associated with PDE4 inhibition [93,94]. Preferential inhibition of PDE4B has anti-inflammatory and antifibrotic effects, with a lower potential for gastrointestinal adverse events compared to pan-PDE4 inhibition [92]. The most frequently reported adverse event associated with nerandomilast was diarrhea, which occurred in 36.6% of patients in the 18-mg nerandomilast group, compared to 24.7% in the placebo group [95]. However, the incidence of diarrhea with nerandomilast is lower than the 66.9% reported for nintedanib in the INBUILD trial [4]. In addition, nerandomilast has been demonstrated to reverse phenotypic changes in fibroblasts caused by transforming growth factor-β1 (TGF-β1) [95]. This effect correlates with a decrease in the expression of α-smooth muscle actin (ACTA2), connective tissue growth factor (CTGF), and plasminogen activator inhibitor-1 (PAI-1). Additionally, nerandomilast increases levels of mitogen-activated protein kinase phosphatase-1 (MKP-1) and enhances the dephosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) [95]. Nerandomilast has the potential to improve survival, as early evidence indicates a survival benefit and a reduction in lung function decline in PPF [96]. However, the effect of nerandomilast on mortality has yet to be validated in adequately powered clinical trials. Another promising agent is admilparant, an oral lysophosphatidic acid receptor 1 antagonist that has been shown to slow lung function decline and was found to be safe and well-tolerated in a phase 2, randomized, double-blind, placebo-controlled trial [97].

PPF represents a common clinical phenotype seen across various forms of fILDs. While patients with PPF share similar pathophysiological processes and clinical courses, their underlying etiologies are heterogeneous, requiring an individualized diagnostic and therapeutic approach. Accurate prediction of PPF and disease progression depends on the integrated interpretation of pulmonary function tests and HRCT, while also recognizing the limitations of current tools in estimating individual risk. Ongoing and future research into blood-based biomarkers, advanced imaging techniques, and functional assessment tools is expected to improve diagnostic accuracy and lead to more effective therapeutic strategies.