Progressive Pulmonary Fibrosis: Current Status in Terminology and Future Directions

Abstract

The latest clinical practice guidelines for idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) were jointly published by the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Asociacion Latinoamericana de Thorax (ALAT) in 2022, and a new term—“PPF”—has been proposed to describe patients with non-IPF fibrosing interstitial lung diseases (ILDs), with defined criteria. However, the proposal of this new term has caused confusion amongst experts at a time when use of the term “progressive fibrosing interstitial lung disease” (PF-ILD), proposed in the phase 3 INBUILD trial of nintedanib, has become widely adopted by pulmonologists and rheumatologists in clinical practice. In this commentary, we discuss the background and concepts underpinning the terms PPF and PF-ILD and seek to provide pulmonologists and rheumatologists with a deeper understanding of the concept of PPF.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-025-03215-6.

Introduction

Interstitial lung disease (ILD) encompasses a heterogeneous group of lung disorders, which are characterized by chronic inflammation and/or fibrosis within the lung parenchyma [1, 2]. Historically, ILDs have been classified according to their underlying cause or etiology, with the American Thoracic Society (ATS)/European Respiratory Society (ERS) classification in 2013 categorizing ILDs into distinct subgroups, including whether they (1) have a known cause (e.g., occupational, toxic etc.), (2) are idiopathic/of unknown cause (both major and rare), or (3) are related to rare diseases or (4) are considered unclassifiable [3, 4]. However, this classification does not adequately take into consideration the underlying pathophysiological mechanisms driving the fibrosis or similarities in clinical symptoms and presentations between the various ILDs, which have important considerations for management. As our understanding and treatment of ILDs continue to evolve, updated classification has been suggested based on their underlying phenotype, i.e., either inflammatory, fibrotic, or mixed [5, 6].

Although idiopathic pulmonary fibrosis (IPF) is the most common of the fibrosing ILDs [5], studies show that almost a third of patients with non-IPF ILDs also develop a progressive fibrosing phenotype, characterized by irreversible fibrosis, decline in lung function, and high morbidity and mortality [7]. As a result of similarities in clinical behavior and underlying pathophysiological mechanisms, it has been suggested that classification of these non-IPF fibrosing ILDs may be consolidated for the purposes of clinical research and potentially treatment.

In recent years, advances have been made in the treatment of IPF, following the approval of two antifibrotic agents for the treatment of IPF. Nintedanib is a small tyrosine kinase inhibitor that targets growth factor pathways to prevent fibrosis [8], whereas pirfenidone is an anti-inflammatory and antifibrotic drug that inhibits the synthesis of collagen and reduces fibroblast proliferation [8, 9].

Following the proven efficacy of nintedanib in IPF and ILD associated with systemic sclerosis (SSc-ILD), the double-blind, placebo-controlled, phase 3 INBUILD trial was conducted to evaluate the efficacy of nintedanib in patients with fibrosing ILDs other than IPF who met specific criteria for ILD progression within the previous 2 years despite standard treatment [10]. In this trial, nintedanib decreased disease progression, as measured by forced vital capacity (FVC) decline, in patients with progressive pulmonary fibrosis (PPF) irrespective of the underlying ILD diagnosis. Nintedanib has been approved in Japan under the indication of progressive fibrosing interstitial lung disease (PF-ILD), while overseas approval is based on phenotype. Nintedanib was approved for the treatment of IPF on 15 October 2014 by the United States (US) Food and Drug Administration, before being approved in the European Union in January 2015, and in Japan in July 2015 for this indication. Pirfenidone was first approved in Japan for the treatment of IPF in October 2008 before being approved for use in the European Union in 2011 and in the US in October 2014. Although both agents are approved, the approved indications vary by country. For example, in the United Kingdom (UK), the approval permits the prescribing of nintedanib and pirfenidone for patients with IPF who have an FVC between 50% and 80%, although provisional approval has just been extended to patients with an FVC > 80% to facilitate earlier use. In Korea, antifibrotic agents only started to be covered for IPF by medical insurance in 2015 and treatment is largely determined by insurance coverage. Notably, the term PF-ILD (previously described as a chronic fibrosing ILD with a progressive phenotype) was also introduced, which became widely adopted by pulmonologists and rheumatologists in clinical practice. Pirfenidone has subsequently been investigated in a number of studies for the progressive phenotype in various ILDs, including the double-blind, randomized, placebo-controlled, phase 2 RELIEF and uILD studies [11].

At the time of publication of the results of the INBUILD trial, which demonstrated the efficacy of antifibrotic therapy in non-IPF PF-ILDs, the IPF guidelines were being developed by a panel of experts sponsored jointly by the ATS, ERS, Japanese Respiratory Society (JRS), and Asociacion Latinoamericana de Thorax (ALAT) [12]. On the basis of this new information, the scope of the guidelines was subsequently expanded to include criteria to define PPF. However, proposal of this new term has caused confusion amongst experts who had widely adopted the term “progressive fibrosing ILD”, proposed in the phase 3 INBUILD trial of nintedanib, in clinical practice. Furthermore, the criteria used in several studies, including the INBUILD trial, were different from those specified for PPF in the ATS/ERS/JRS/ALAT IPF/PPF clinical practice guidelines, and several outstanding issues remain (Table 1). Here, we examine the background and concepts underpinning the terms PPF in the 2022 ATS/ERS/JRS/ALAT IPF/PPF clinical practice guidelines, and PF-ILD in the INBUILD trial, and seek to provide pulmonologists and rheumatologists with a deeper understanding of the concept of PPF in the era of antifibrotic therapy.

Table 1.

Outstanding issues and problems regarding the definition and criteria used to define PPF

Tables specific reference/situation	Problem/issue
Terminology in clinical practice and guidelines	The term “PF-ILD” has become widely adopted by pulmonologists and rheumatologists in clinical practice, but “PPF” is specified in the guidelines
Clinical study criteria (including INBUILD, RELIEF, uILD)	Several clinical trials define PPF as part of inclusion criteria, with overlapping but different definitions to the ATS/ERS/JRS/ALAT IPF/PPF guidelines (Fig. 5)
General definition	Although IPF does not fall under the umbrella of PPF, it is included under the umbrella of PF-ILD in some articles [13]
Evidence in clinical trial	Evidence exists for the “PF-ILD” term from the INBUILD trial but “PPF” is a new term decided by consensus Results of clinical trials employing the PPF definition in the guidelines are awaited
Validation study [14]	Phenotypic variability in connective tissue disease ILD argues against a “one-size-fits-all” approach to PPF A stand-alone decline in FVC of ≥ 10% was proposed as a marker of ILD progression irrespective of symptomatic or radiologic worsening to avoid unnecessary exclusion of patients
General criteria	There is no clear consensus on what criteria to use, and the context in which PPF criteria are applied is important
Treatment	What agent(s) will be considered appropriate first-line treatment? Will selection be affected by various background factors and prior treatment?
Disease pathophysiology	Factors associated with the development of PPF are currently unknown (e.g., potential triggers, environmental, genetic predisposition, role of vascular remodeling)
Serum biomarkers	Validated serum biomarkers to identify those at risk of PPF are currently unknown
Deep learning methods	Validation of deep learning methods developed from large HRCT data sets are also unavailable, but may be useful for disease pattern recognition, prognostication, identifying progression, and characterization of incidentally detected interstitial lung abnormalities

ALAT Asociacion Latinoamericana de Thorax, ATS American Thoracic Society, ERS European Respiratory Society, FVC forced vital capacity, HRCT high-resolution computed tomography, IPF idiopathic pulmonary fibrosis, JRS Japanese Respiratory Society, PF-ILD progressive fibrosing interstitial lung disease

As this article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors, ethics approval was not required.

Examination of Terminology and Definitions of “Progressive Pulmonary Fibrosis” Proposed in the 2022 ATS/ERS/JRS/ALAT Clinical Practice Guidelines and “Progressive Fibrosing ILD” Used in the INBUILD Trial

PPF is a newly proposed concept in the 2022 ATS/ERS/JRS/ALAT clinical practice guidelines, but its definition is based on expert consensus rather than clinical trial evidence. In contrast, PF-ILD has been used in randomized controlled trials such as the INBUILD trial, where the utility of its diagnostic criteria has been at least partially validated. Given this, further research is required to verify the clinical utility of PPF.

The INBUILD trial was an international, randomized, double-blind, placebo-controlled, parallel-group phase 3 trial conducted at 153 sites across 15 countries to evaluate the efficacy of nintedanib in patients with non-IPF ILDs experiencing progression [10]. Results of the trial, which were published in 2019, showed that treatment with nintedanib 150 mg twice daily significantly lowered the annual rate of decline in FVC compared with placebo. Furthermore, specific criteria were provided to define those patients with progressive fibrosing disease, termed “progressive fibrosing ILD”. Following the publication of these results, there was a marked increase in the use of the term PF-ILD in papers published in PubMed (Fig. 1), which coincided with widespread uptake by pulmonologists and rheumatologists in clinical practice. For the definition of PF-ILD, the INBUILD criteria specified ≥ 1 measure of progression within 2 years despite management (Fig. 2) [10]:

1. A relative decline in FVC ≥ 10% predicted alone.

   1. However, a relative decline of ≥ 5 to < 10% was permitted if worsening respiratory symptoms or an increased extent of fibrosis on high-resolution computed tomography (HRCT) was also present.

2. Worsening or respiratory symptoms and increased extent of fibrosis on HRCT.

Fig. 1.

Analysis of PF-ILD and PPF terminology in published papers in PubMed by year (2017–2023). PF-ILD progressive fibrosing interstitial lung disease, PPF progressive pulmonary fibrosis

Fig. 2.

Comparison of the criteria used to define PF-ILD in the INBUILD trial and PPF in the 2022 ATS/ERS/JRS/ALAT clinical practice guidelines. ALAT Asociacion Latinoamericana de Thorax, ATS American Thoracic Society, DLco diffusing capacity of the lungs for carbon monoxide, ERS European Respiratory Society, FVC forced vital capacity, Hb hemoglobin, JRS Japanese Respiratory Society, HRCT high-resolution computed tomography, IPF idiopathic pulmonary fibrosis, PF-ILD progressive fibrosing interstitial lung disease, PPF progressive pulmonary fibrosis

Following on from this trial, updated ATS/ERS/JRS/ALAT clinical practice guidelines were published in 2022, which proposed new terminology for these patients and a consensus-based definition of progression in patients with non-IPF fibrosing ILDs [12]. The following rationale for the establishment of the newly proposed PPF terminology was provided (Fig. 3):

1. Disease progression occurs as a result of PPF beyond the interstitial space in the lung parenchyma.

2. Disease progression is similar to the clinical course in patients with IPF.

3. PPF is simple and compatible with the broadly used term of “pulmonary fibrosis” that is well known and currently used by both clinicians and patients.

Fig. 3.

Background to the establishment of the proposed “progressive pulmonary fibrosis” terminology. IPF idiopathic pulmonary fibrosis, PPF progressive pulmonary fibrosis

The guidelines also clarified that PPF is not a diagnosis but rather a disease concept that represents “disease behavior,” and refer to patients who have PPF despite appropriate disease management, consistent with the definition of PF-ILD used in the INBUILD trial [10, 12]. A comparison of the criteria used to define PF-ILD in the INBUILD trial and PPF in the 2022 ATS/ERS/JRS/ALAT clinical practice guidelines is presented in Fig. 2 [10, 12]. When comparing the criteria in the 2022 ATS/ERS/JRS/ALAT clinical practice guidelines for defining PPF with the criteria for PF-ILD defined in the INBUILD study, there were three major differences: (1) the observation period (2 years vs 1 year); (2) the method of assessing FVC decline (absolute vs relative change); and (3) the presence or absence of lung diffusing capacity (DLco) (corrected for hemoglobin [Hb]) assessment. The difference between the definitions of PF-ILD and PPF is whether IPF is included. It is important to understand that the PF-ILD defined in the INBUILD trial does not include IPF.

Compared to the INBUILD criteria, which required one or more criteria being met within the past 2 years [10], the 2022 ATS/ERS/JRS/ALAT clinical practice guidelines required at least two of the following three clinical, physiological, and radiological criteria within the past year with no alternative explanation [12]:

1. Worsening respiratory symptoms

2. Physiological evidence of disease progression, including:

   1. Absolute decline in FVC of ≥ 5% predicted within 1 year of follow-up
   2. Absolute decline in DLco (Hb-corrected) of ≥ 10% predicted within 1 year of follow-up
3. And radiological evidence of disease progression, defined as ≥ 1 of the following:

   1. Increased extent or severity of traction bronchiectasis and bronchiolectasis
   2. New ground-glass opacity with traction bronchiectasis
   3. New fine reticulation
   4. Increased extent or increased coarseness of reticular abnormality
   5. New or increased honeycombing
   6. Increased loss of lobar volume

Additional context was provided to support their agreed criteria for disease progression. For the absolute decline in FVC of ≥ 5% predicted within 1 year of follow-up, this value was extrapolated from the IPF literature [15], and instead of relative change, as was used in the INBUILD trial, absolute change was preferred as it is more easily applied in clinical practice and is an important predictor of mortality in IPF. For the absolute decline in DLco (corrected for Hb) of ≥ 10% within 1 year of follow-up, change in DLco (corrected for Hb) was considered a consistent and strong predictor of mortality in patients with a variety of fibrotic ILDs. A clinically meaningful decline in DLco was defined as an absolute decline of ≥ 10% (corrected for Hb), with the higher threshold justified based on technical limitations affecting the reproducibility of this measurement. Although the methodology used to measure DLco has not been standardized across institutions, its widespread accessibility and ease of measurement makes it a valuable measurement in clinical practice. Regarding radiologic evidence of disease progression, CT is routinely used to follow progression of pulmonary fibrosis. Development of the criteria for PPF reflect multiple clinical trials because the committee believed that no single trial should guide antifibrotic therapy (even though trials used different criteria, they each identified populations whose disease progressed similarly). However, it should be noted that the new definition of PPF was associated only with prognosis, and it is unclear if it also identifies patients best suited for antifibrotic therapy.

Prognosis of Patients with PPF by Criteria in Seminal Publications

A retrospective multicenter cohort study evaluated data from patients with non-IPF fibrotic ILDs (N = 753) from Australian and Canadian registries which defined PPF by multiple criteria and compared survival outcomes in adults with IPF and non-IPF fibrotic ILDs according to these definitions [16]. Four non-independent cohorts of patients with PPF were determined according to trial criteria (INBUILD, RELIEF, uILD) or the 2022 ATS/ERS/JRS/ALAT guidelines. At least one of the four definitions of PPF was met in 403 (54%) patients, with 68 (17%) patients meeting all four definitions (Fig. 4). A large proportion of patients (54/276, 20%) who met the INBUILD trial definition for PPF did so on the basis of achieving > 10% FVC decline [10]. Although cases diagnosed with PPF vary by diagnostic criteria, it is important to note that when using criteria other than uILD criteria, cases diagnosed with PPF have a poor prognosis comparable to that of IPF. Rates of transplant-free survival (TFS) of patients with PPF were similar at 1 and 3 years (91% and 68%, respectively), irrespective of the use of the INBUILD criteria or the 2022 ATS/ERS/JRS/ALAT guidelines (Fig. 4). Patients with PPF identified by the different criteria had similar background characteristics.

Fig. 4.

Survival of patients with PPF according to different definitions used in seminal trials and guidelines (N = 403). IPF idiopathic pulmonary fibrosis, PPF progressive pulmonary fibrosis. Reprinted with permission of the American Thoracic Society.

Copyright © 2025 American Thoracic Society. All rights reserved. Cite: Khor YH et al./2023/Patient characteristics and survival for progressive pulmonary fibrosis using different definitions./Am J Respir Crit Care Med/207/102-5 [16]. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society

Similarly, a retrospective observational study of patients with ILD (N = 5934) in a single center in the USA demonstrated a cumulative incidence of progression over 24 months that was comparable when assessed by either INBUILD or 2022 ATS/ERS/JRS/ALAT guideline criteria (33.1% vs 37.9%, respectively) irrespective of ILD etiology, with the exception of sarcoidosis [17]. Interestingly, patients with sarcoidosis were significantly more likely to have progressive disease when defined by the 2022 ATS/ERS/JRS/ALAT guideline compared with the INBUILD criteria. Similarly, in a retrospective comparison, patients with rheumatoid arthritis ILD (RA-ILD) (N = 70) referred to a pulmonary outpatient clinic in Belgium were classified as having progression using different criteria [18]. Again, there was no difference in classifying patients with progression, or in mortality, when using either the INBUILD or 2022 ATS/ERS/JRS/ALAT guideline criteria.

In 2022, a retrospective multicenter cohort analysis was conducted to evaluate whether the PPF criteria proposed by the 2022 ATS/ERS/JRS/ALAT guidelines predicted TFS in patients with non-IPF forms of ILD from three US centers and one UK center [14]. A ≥ 10% relative FVC decline was the strongest predictor of reduced TFS and showed consistent TFS association across cohorts, ILD subtypes, and treatment groups, resulting in a phenotype that closely resembled IPF (Table 2). In the absence of 10% relative FVC decline, six additional PPF criteria were associated with reduced TFS, including three stand-alone features (5–9% relative FVC decline, > 15% relative decline in diffusing capacity of the lungs for carbon monoxide (DLco) [corrected for Hb], and CT progression of fibrosis) and three that required combinations of physiologic, radiologic, and symptomatic worsening. Criteria requiring combined features showed similar TFS prediction compared with their stand-alone components but captured a smaller number of patients.

Table 2.

Risk of death or lung transplantation after satisfying proposed progressive pulmonary fibrosis criteria in US test and UK validation cohorts [14]

PPF criterion	US cohort (n = 828)			UK cohort (n = 513)			P valuea	Combined cohort
	n	HR (95% CI)	P value	n	HR (95% CI)	P value		HR (95% CI)
≥ 10% relative FVC decline	404/828	3.11 (2.37–4.08)	< 0.001	241/513	3.34 (2.35–4.73)	< 0.001	0.702	3.11 (2.51–3.85)
Excluding those with concurrent ≥ 10% relative FVC decline
5–9% relative FVC decline	291/577	2.87 (2.04–4.03)	< 0.001	183/366	2.36 (1.53–3.63)	< 0.001	0.428	2.58 (1.98–3.35)
5–9% absolute FVC decline	146/535	2.50 (1.70–3.68)	< 0.001	80/328	2.02 (1.22–3.33)	0.006	0.461	b
≥ 10% absolute DLco decline	203/624	1.93 (1.41–2.65)	< 0.001	43/394	0.91 (0.45–1.81)	0.779	0.057	b
≥ 15% relative DLco decline	253/611	2.28 (1.65–3.13)	< 0.001	116/366	2.19 (1.43–3.35)	< 0.001	0.893	2.20 (1.71–2.83)
CT progression of fibrosis	135/524	1.81 (1.27–2.59)	0.001	62/324	2.43 (1.45–4.08)	0.001	0.577	1.99 (1.49–2.66)
5–9% relative FVC decline and worsening symptoms	190/574	2.68 (1.94–3.72)	< 0.001	133/356	2.14 (1.41–3.27)	< 0.001	0.420	2.42 (1.87–3.12)
5–9% absolute FVC decline and worsening symptoms	86/541	2.41 (1.58–3.67)	< 0.001	44/323	1.89 (1.01–3.52)	0.046	0.542	b
5–9% relative FVC decline and ≥ 15% relative DLco decline	129/596	2.40 (1.70–3.40)	< 0.001	67/368	2.29 (1.42–3.70)	< 0.001	0.725	2.29 (1.73–3.02)
≥ 10% absolute DLco decline and worsening symptoms	126/648	1.85 (1.32–2.59)	< 0.001	29/396	0.87 (0.37–2.00)	0.736	0.094	b
CT progression of fibrosis and worsening symptoms	93/525	2.26 (1.56–3.28)	< 0.001	51/324	2.62 (1.54–4.48)	< 0.001	0.961	2.32 (1.72–3.14)
CT progression of fibrosis and 5–9% relative FVC decline	50/493	1.63 (0.99–2.70)	0.055	25/302	1.33 (0.62–2.85)	0.467	0.402	b
CT progression of fibrosis and 5–9% absolute FVC decline	27/487	1.93 (1.01–3.71)	0.047	10/293	1.30 (0.38–4.39)	0.675	0.439	b
CT progression of fibrosis and ≥ 10% absolute DLco decline	35/486	2.13 (1.23–3.67)	0.007	9/288	1.00 (0.23–4.29)	0.988	0.324	b

The analysis involving CT progression excluded those for whom follow-up CT was not performed. The analysis involving symptomatic worsening excluded those for whom change in symptoms could not be ascertained. Estimates adjusted for the gender, age, and physiology interstitial lung disease index at the time of analysis entry

Reprinted with permission of the American Thoracic Society. Copyright © 2025 American Thoracic Society. All rights reserved

Cite: Pugashetti JV et al./2023/Validation of Proposed Criteria for Progressive Pulmonary Fibrosis/Am J Respir Crit Care Med/207/69-76 [14]

The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. As this is a reproduction, the authors of this manuscript do not have access to the dataset and cannot verify the validity of the results or the methodology used beyond what was published

CI confidence interval, CT computed tomography, DLco diffusing capacity of the lungs for carbon monoxide, FVC forced vital capacity, HR hazard ratio, PPF progressive pulmonary fibrosis, UK United Kingdom, US United States

^aTest of whether transplant-free survival association for PPF criteria varied by cohort

^bNot performed because of absence of transplant-free survival association across derivation and validation cohorts at P < 0.0036, with Bonferroni adjustment for 14 tests

Relative Usage of “Progressive Pulmonary Fibrosis” Versus “Progressive Fibrosing ILD” Terminology Currently and in the Future, and the Issue of Unvalidated Guideline Criteria in Clinical Trials

An examination of the literature was performed using PubMed to evaluate the relative usage of PF-ILD and PPF terminology in published papers by year from 2017 to December 2023. Results of the analysis showed that use of the terms PPF and PF-ILD gradually increased from 2017 (when the INBUILD study design was published) to 2021 (Fig. 1). Notably, there was a plateau in the number of citations using the terms PPF and PF-ILD in 2022 at the time of the publication of the guidelines, followed by a steep increase in the number of citations using PPF terminology, which greatly exceeded those using PF-ILD, in 2023. This suggests widespread uptake of the term PPF in the literature following publication of the guidelines.

Clinical trials are advancing the field of pulmonary fibrosis and have undoubtedly had a significant impact on terminology. For example, the fact that the INBUILD trial included the term “PF-ILD” in its title likely contributed to the increased use of “PF-ILD” from 2017, and particularly 2019 (when the results of the study were published) onwards until the publication of the ATS/ERS/JRS/ALAT clinical practice guidelines in 2022. Several phase 3 trials are currently underway, including studies to evaluate the efficacy and safety of inhaled treprostinil (NCT05943535), admilparant/BMS-986278 (NCT06025578), and nerandomilast/BI 1015550 in the FIBRONEER study (NCT05321082). The patient selection criteria for these studies included some of the criteria used for the INBUILD trial (Table S1). Once the results of these studies are published, it will be interesting to note whether “PPF” will be used to refer to these studies. If that happens, it is anticipated that the term PPF will traverse from the clinical trials space into routine clinical practice and use of the PF-ILD terminology will further decline. However, no clinical trials utilizing the guideline criteria have been conducted to date. Consequently, the term PPF has been widely accepted rather than PF-ILD as an umbrella term for the disease behavior mimicking IPF, which is defined by several criterion (Figs. 1, 5). Definite criteria for the term PPF require further evaluation to attain evidence and consensus. Although the background and prognosis of patients selected by the PPF and PF-ILD criteria are similar, when employing the term PPF in a publication, it is important to specify the criteria used. Additionally, whether the specific PPF concept defined by the guideline criteria will gain widespread adoption will likely depend on whether clinical trials using the criteria are conducted or whether proactive initiatives are undertaken by guideline committees.

Fig. 5.

Relationship between the concept and criteria for PPF specified in the ATS/ERS/JRS/ALAT 2022 clinical practice guidelines and those specified in pivotal clinical trials. ALAT Asociacion Latinoamericana de Thorax, ATS American Thoracic Society, ERS European Respiratory Society, FVC forced vital capacity, IPF idiopathic pulmonary fibrosis, JRS Japanese Respiratory Society, PPF progressive pulmonary fibrosis

Future Areas for Research

While PPF and PF-ILD differ in their diagnostic criteria and definitions, there is currently insufficient evidence available on how these differences influence treatment decisions. For example, while the INBUILD trial demonstrated the efficacy of nintedanib for PF-ILD, it remains unclear whether a similar treatment strategy would be applicable when using the PPF diagnostic criteria. Future studies should further investigate how differences between the guideline criteria and the INBUILD criteria affect treatment efficacy and prognosis to establish optimal treatment strategies.

The area of ILDs is rapidly evolving, driven in large part by the development and approval of two antifibrotic agents, nintedanib and pirfenidone, for the treatment of IPF. The number of approved antifibrotic agents is expected to increase substantially in the coming years, with several agents currently under clinical development for the treatment of IPF and PPF. Although the 2022 ATS/ERS/JRS/ALAT IPF/PPF clinical practice guidelines have addressed some of these issues, many unresolved issues remain (Table 1). For example, which agent will be considered appropriate first-line treatment for patients with PPF? Should patients receive treatment with different agents based on various background factors and prior treatment? And what are these? Prioritization of research on the timing and sequence of antifibrotic drugs in relation to corticosteroids and immunosuppressants in the ILDs that can manifest PPF is also warranted. It will be necessary to discuss the management criteria before determination of disease progression, such as what treatment is appropriate not only when the disease progresses despite appropriate treatment but also when future progression is highly predictable. As the criteria are evolving, in the future clinicians should be able to identify suitable progressive patients, irrespective of terminology used, and supported by clinical evidence.

Conclusion

The criteria used to identify progressive disease in patients with non-IPF ILDs varies, but it is expected that the terminology used will be unified to PPF moving forward. We advise clinicians in clinical practice to review the criteria referred to in pivotal clinical trials in the literature and apply them where appropriate. It is clear that PPF remains an evolving area of research and many questions remain, such as why some patients with ILD develop PPF, as well as those surrounding epidemiology and optimal management strategies for PPF. Several phase 3 clinical trials in PPF are currently underway, and it is hoped that the results of this research will shed further light on some of these topics.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Yasuhiro Kondoh and Yoshikazu Inoue contributed to the focus and scope, as well as concept, of this review. Yasuhiro Kondoh and Yoshikazu Inoue reviewed the text for intellectual content, read and approved drafts, and takes responsibility for the content of the review. All authors met ICMJE authorship criteria and agree to be accountable for all aspects of the work.

Funding

Medical writing assistance for the preparation of this review and any costs associated with publication (e.g., the journal’s Rapid Service Fee) were funded by Nippon Boehringer Ingelheim Co., Ltd.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

The authors did not receive payment for development of this manuscript. Yasuhiro Kondoh reports advisory board fees from Asahi Kasei Pharma Corp, Boehringer Ingelheim, Chugai Pharmaceutical Co., Ltd., GSK, Healios K.K., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., LTD, Sanofi K.K., Shionogi Co, Ltd., Taiho Pharmaceutical Co., and lecture fees from Asahi Kasei Pharma Corp, Bristol Myers Squibb, Boehringer Ingelheim, Eisai Co, Ltd, Janssen Pharmaceutical K.K., KYORIN Pharmaceutical Co, Ltd, Mitsubishi Tanabe Pharma, NIPPON SHINYAKU CO., LTD, Novartis Pharma K.K., Shionogi Co, Ltd., Teijin Pharma Ltd. Yoshikazu Inoue reports grants from the Japanese Ministry of Health, Labour, and Welfare and the Japan Agency for Medical Research and Development; payment for presentations from Boehringer Ingelheim, Kyorin, Shionogi, GlaxoSmithKline, ThermoFisher; and has served as a consultant or steering committee member for Boehringer Ingelheim, Galapagos, Roche, Taiho, CSL Behring, Vicore Pharma, Savara.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.