Identification, Course, and Management of Progressive Pulmonary Fibrosis

ABSTRACT

The term “progressive pulmonary fibrosis” or “PPF” is generally used to describe progressive lung fibrosis in an individual with an interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF). Several sets of criteria have been proposed for the identification of PPF, most of which are based on a combination of a decline in forced vital capacity, worsening of respiratory symptoms, and increase in the extent of fibrosis on radiology. Although some risk factors for faster progression of fibrosing ILD have been identified, it remains challenging to predict which individuals will develop PPF. Close monitoring, including regular pulmonary function tests, is required to detect the earliest signs of worsening disease. PPF is associated with high rates of hospitalization and death. Management of PPF requires a multidisciplinary and multimodal approach, including pharmacological therapy and supportive care. Discussions about palliative care should begin at an early stage, individualized to the needs of the patient.

Am J Manag Care. 2024;30:S122-S130.

For author information and disclosures, see end of text.

Introduction

Interstitial lung diseases (ILDs) comprise a large group of disorders characterized by inflammation and/or fibrosis of the lung parenchyma. Some ILDs have a known cause, for example, ILDs related to autoimmune diseases¹ or occupational exposures,² while others are idiopathic, the most common of which is idiopathic pulmonary fibrosis (IPF).³ Environmental factors, such as exposures to dusts, molds, or chemicals,⁴ and genetic variants⁵ contribute to the development of ILD. A proportion of patients with ILDs develops pulmonary fibrosis that becomes progressive. The term “progressive pulmonary fibrosis” (PPF) or “progressive fibrosing ILD” (PF-ILD) is generally used to describe progressive lung fibrosis in an individual with an ILD other than IPF (which is, by definition, a progressive disease).³ This article describes the identification, course, and management of PPF.

Criteria for Defining PPF

Several sets of criteria have been proposed for the identification of PPF, mainly based on expert consensus and extrapolation from what is known about disease behavior and prognosis in IPF.^3,6-10 The most widely used criteria are those developed to identify patients with PPF for enrollment in the INBUILD trial of nintedanib6 and those later proposed in a clinical practice guideline published by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociacion Latinoamericana de Torax (ATS/ERS/JRS/ALAT) in May 2022 (Table).^3,6 Most definitions of PPF include some combination of a decline in forced vital capacity (FVC) and/or diffusing capacity for carbon monoxide (DLCO), a worsening of respiratory symptoms, and an increase in the extent of fibrosis on high-resolution CT (HRCT). However, there is variability in terms of the magnitude of change in these parameters that should define progression and the time period over which progression should be assessed. The ATS/ERS/JRS/ALAT guideline stated that the criteria for identification of PPF may be fulfilled at any time within a 1-year period,³ while other criteria use a 2-year window.^6,7,9,10 It is important to note that progression may occur at any time within the specified time period and needs not be assessed over its whole duration. Further, some experts have argued that no time frame should be applied when assessing progression in clinical practice, as progression is predictive of a poor prognosis regardless of the time period over which it occurs.¹¹

In addition to the debate over the criteria that should be used to define PPF, discussion continues over whether PPF should be identified only in patients in whom standard management for the respective ILD has failed. A requirement for patients to have progressed despite standard management was included in the inclusion criteria for the INBUILD trial of nintedanib in patients with PPF,⁶ the RELIEF trial of pirfenidone in patients with PPF,⁹ and a trial of pirfenidone in patients with progressive fibrotic hypersensitivity pneumonitis.¹² However, in many fibrotic ILDs, “standard management” is not well defined, and varies based on patient characteristics, drug availability and coverage, and other factors. The ATS/ERS/JRS/ALAT guideline did not mandate that patients receive standard management for ILD prior to PPF being identified; however, its conditional recommendation for the use of nintedanib in patients with PPF was limited to patients who have failed standard management.³ A consensus statement published by an expert group in 2023 suggested that a distinction should be made between a first presentation of PPF and PPF that has occurred despite management of the ILD, as this may have discrete treatment implications.¹³

Risk Factors for Development of PPF

PPF affects patients with a wide range of ILDs.^14-17 Different studies have provided broad estimates for the risk of PPF in patients with ILDs, depending on the population, criteria, and methodology.^18-21 Among 1749 patients with non-IPF fibrotic ILDs receiving care at 9 ILD referral centers, 14% met the INBUILD trial criteria for PPF.²² In a study of registry data from 753 patients with non-IPF fibrotic ILDs, 30% of patients met the international guideline criteria for PPF, 37% met the INBUILD trial criteria, 32% met the criteria from the trial of pirfenidone in patients with unclassifiable ILD, and 23% met the RELIEF trial criteria.²¹ In an analysis of claims data, 30,771 patients were identified as having a fibrosing ILD other than IPF and, of these, 47% were predicted to have progressive disease.¹⁸ Children with fibrosing ILDs such as those related to genetic diseases, autoimmune diseases, or exposures may also develop progressive lung fibrosis,²³ but the proportions of pediatric patients who fulfill specific criteria for PPF are unknown.

Different types of ILD appear to be associated with differing risks of PPF. In a retrospective analysis of 1227 consecutive patients with non-IPF fibrotic ILDs, the proportion of patients with PPF (defined as a relative decline in FVC % predicted ≥ 10%, or a relative decline in FVC % predicted ≥ 5 to < 10% plus any 1 of the following: hospitalization, increased extent of fibrosis on HRCT, increased oxygen use, or respiratory death, within 2 years) ranged from 10.3% in patients with ILD due to sarcoidosis to 41.9% in patients with unclassifiable idiopathic interstitial pneumonia.²¹

Several risk factors for progression of fibrotic ILDs have been identified. Demographic risk factors for progression include older age^24,25 and male sex.^26,27 Cigarette smoking is also a risk factor.^26,28 A lower FVC^15,29 or diffusing capacity of the lung for carbon monoxide (DLCO)^30,31 is also associated with a greater risk of short-term progression. Among 2746 patients in the CARE-PF registry, FVC < 70% predicted and DLCO < 75% predicted at baseline were independent risk factors for the development of PPF (defined as a relative decline in FVC % predicted ≥ 10%, death, lung transplant, or any 2 of a relative decline in FVC % predicted between ≥ 5 and < 10%, worsening respiratory symptoms, or worsening fibrosis on HRCT) over 2 years.²⁵ On radiology, a greater extent of lung fibrosis^15,24,32,33 and a usual interstitial pneumonia (UIP) pattern^24,26,34,35 are associated with faster progression. Genetic risk factors for faster progression of fibrotic ILDs have also been identified, such as mutations associated with short telomeres.³⁶

Although some risk factors have been identified, it remains challenging to predict which individuals with fibrosing ILD will progress, when, and at what rate. Recognition of PPF requires close monitoring of disease behavior to detect the earliest clinical, physiologic, and/ or radiologic signs of worsening disease. No biomarker has been shown to have sufficient accuracy to predict progression before it occurs. Patients with fibrosing ILDs should be monitored with regular symptom assessment and pulmonary function tests (PFTs) and repeat HRCT as clinically indicated, so that if progression has occurred, it is detected promptly.^13,37-39 Experts in the management of patients with ILD suggest that PFTs should be performed at least every 3 to 4 months.^13,38 HRCT should be performed less frequently, but may be valuable for assessing progression in patients in whom lung function has declined or symptoms have worsened.^13,37,39 Repeated HRCT may be appropriate in some patients (eg, every 12 to 24 months to evaluate for complications), as an adjunct to PFTs, to assess whether patients meet PPF criteria, as well as to screen for lung cancer,⁴⁰ which may be more common in patients with ILD.⁴¹ Other evaluations, such as a 6-minute walk test, may also provide valuable information about the progression of a patient’s ILD.⁴²

Course of PPF

The pathobiology of fibrosis involves fibroproliferation and excess production of extracellular matrix, leading to destruction of the lung architecture.^43,44 The mechanisms that drive fibrosis are selfperpetuating^43,44 and, in the absence of treatment, PPF will inevitably progress. Even in patients receiving proven therapies for PPF, lung function may continue to decline.^45-50 There is some evidence that decline in FVC may be more rapid in patients with PPF who have a UIP-like fibrotic pattern on HRCT.^51-53 Heterogeneity in the trajectory of FVC decline has been observed among patients with PPF and differing ILD diagnoses. In a retrospective analysis, the decline in FVC in patients with PPF due to autoimmune diseases was significantly smaller than in patients with PPF and either hypersensitivity pneumonitis or idiopathic interstitial pneumonia.⁵³ Differing risks of mortality have also been observed among patients with PPF and different ILD diagnoses (Figure 1).^18,52

Patients identified as having PPF using different criteria show differences in short-term mortality.^22,25,54 In a retrospective analysis of 1341 patients, the risk of death or lung transplant over ≥ 1 year was greater in patients who had PPF defined as a decline in FVC % predicted of > 10% than in patients who met other criteria indicating disease progression (Figure 2).⁵⁴ However, it is important to bear in mind that regardless of how PPF is identified, it is associated with high rates of hospitalization and death.^{18,19,22,25,54-56} In a descriptive analysis, over a mean follow-up of 69 months, 46% of 135 patients with PPF had a respiratory hospitalization compared with 22% of 261 patients with fibrosing ILD but without PPF at the same center.⁵⁵ In the same study, 5-year survival was 64.5% in the patients with PPF compared with 89.5% in the patients without PPF.⁵⁵ Patients with non-IPF fibrosing ILDs may experience acute lung function deterioration (acute exacerbation), which is associated with high mortality.^57-60

Monitoring of PPF

PPF progresses at a variable rate, which is not necessarily linear in an individual patient.^53,61 Further, lung function decline may not correlate with a patient’s perception of their health status or symptoms.^62,63 It is important that patients with PPF are regularly monitored so that progression can be evaluated and management, including the provision of supportive/palliative care, adjusted if necessary. Monitoring should comprise PFTs, assessment of symptoms, and where clinically indicated, repeat imaging. As well as monitoring disease progression, any adverse effects (AEs) of therapies should be identified and managed; the potential of immunosuppressant and antifibrotic therapies to cause AEs should not be underestimated.

Management of PPF

The management of PPF requires that patients receive an accurate diagnosis of the underlying ILD, ideally in the context of a multidisciplinary discussion.⁶⁴ This has implications for prognosis and guides the optimal approach to management. Many ILDs have an identifiable cause or associated condition, which may require distinct treatment approaches. The work-up includes obtaining a detailed medical, family, occupational, environmental, and social history and conducting a physical examination. Tests include PFTs, HRCT scans, and serologic testing to identify potential exposures and exclude autoimmune diseases. For patients who have undergone bronchoscopy or surgical biopsies, histopathological features should be integrated with clinical findings in multidisciplinary discussion, including, at minimum, input from pulmonology, radiology, and pathology.^65-68 In patients with hypersensitivity pneumonitis, identification and avoidance of the inciting antigen is associated with improved survival²⁸ and may help to prevent progression.⁶⁹

Management of PPF requires a multidisciplinary and multimodal approach (Figure 3).^37,38,69 Patients should be given adequate information about their disease and emotional support.^70-72 Supportive care focuses on symptom management and preserving quality of life and may include pulmonary rehabilitation, which can improve exercise capacity, quality of life and dyspnea.⁷³ Oxygen use is recommended for patients with ILD and severe chronic resting hypoxemia or severe exertional hypoxemia.⁷⁴ Worsening of health status, such as decline in physical functioning or initiation of oxygen, should prompt a consideration of palliative care to help manage symptoms and quality of life, individualized to the patient’s physical, emotional, and spiritual needs.⁷¹ Advance care planning, and discussion of the patient’s goals and preferences for end-of-life care, should be initiated as early as possible.^75,76 Referral for lung transplantation should be considered in individuals with PPF who meet relevant criteria.⁷⁷

Pharmacological Therapy for PPF

Pharmacologic therapy for PPF differs based on the ILD diagnosis. The standard treatment for ILD associated with autoimmune disease is immunosuppression, with antifibrotic therapy in certain cases. Randomized controlled trials have shown that cyclophosphamide,⁷⁸ mycophenolate,⁷⁹ nintedanib,⁸⁰ tocilizumab,⁸¹ and rituximab⁸² slow the progression of ILD associated with systemic sclerosis (SSc-ILD). Nintedanib and tocilizumab have been approved by the FDA for the treatment of SSc-ILD. A clinical practice guideline for the treatment of SSc-ILD published by the ATS in October 2023 included a strong recommendation for the use of mycophenolate and conditional recommendations for the use of cyclophosphamide, tocilizumab, nintedanib, nintedanib plus mycophenolate, and rituximab.⁸³ A guideline for the treatment of ILD in patients with autoimmune disease issued by the American College of Rheumatology (ACR) and American College of Chest Physicians (CHEST)⁸⁴ provided similar recommendations for the treatment of SSc-ILD and conditional recommendations for first-line treatment of autoimmune ILDs other than SSc-ILD for mycophenolate, azathioprine, rituximab, and cyclophosphamide.

Immunosuppressants are commonly used in patients with hypersensitivity pneumonitis,^85,86 and have shown benefits in some patients, but it is not clear whether they slow the progression of fibrotic forms of the disease, which often behave similarly to IPF.^87-90 The use of corticosteroids alone or combined with immunomodulatory therapy is not recommended in patients with IPF^91,92 and combination therapy with prednisone, azathioprine, and N-acetylcysteine is harmful in these patients.⁹³ Immunosuppressant therapies, including rituximab and tocilizumab, are associated with an increased risk of infection.^82,90,94 In addition, mycophenolate and azathioprine are associated with gastrointestinal AEs^79,86,88 and cyclophosphamide with leukopenia and neutropenia.⁷⁸

In patients with PPF, clinicians should consider use of a treatment shown to slow its progression. In the US, the FDA has approved nintedanib for the treatment of progressive fibrosing ILDs of any etiology. ATS/ERS/JRS/ALAT guidelines provide a conditional recommendation for nintedanib as a treatment option for patients with PPF for whom standard management (not defined) has failed.³ In the INBUILD trial in 663 patients with PPF despite management in clinical practice, nintedanib slowed the rate of decline in FVC over 52 weeks by 57% compared with placebo (–81 mL/year in the nintedanib group compared with –188 mL/year in the placebo group; P <.001),⁶ with a consistent effect among patients with different diagnoses (Figure 4)⁹⁵ and disease severities⁹⁶ and evidence of a significant benefit on respiratory symptoms based on patients’ responses to the Living with Pulmonary Fibrosis (L-PF) questionnaire.⁹⁷ The AEs associated with nintedanib are mainly gastrointestinal, particularly diarrhea, which was reported in 66.9% of patients in the nintedanib group and 23.9% of patients in the placebo group over 52 weeks of the INBUILD trial.⁶ Pirfenidone, an approved treatment for IPF, has also been investigated in randomized placebo-controlled trials in patients with other progressive fibrosing ILDs. In a trial in patients with progressive unclassifiable fibrosing ILD, the decline in FVC (mL) over 24 weeks was lower in the pirfenidone group (n = 118) (–17.8 mL) than in the placebo group (n = 119) (–113.0 mL) (P = .002).⁸ In the TRAIL1 trial in 123 patients with rheumatoid arthritis–associated ILD, pirfenidone slowed the decline in FVC over 52 weeks versus placebo (–66 vs –146 mL/year; P = .0082).⁹⁸ In the RELIEF trial, among 67 patients with progressive fibrosing ILDs related to autoimmune diseases, nonspecific interstitial pneumonia, hypersensitivity pneumonitis, or asbestosis, the decline in FVC over 48 weeks was numerically lower in patients treated with pirfenidone than placebo (–36.6 mL vs –114.4 mL), but the difference was not statistically significant (P = .21).⁹ Pirfenidone is not licensed in any country for the treatment of ILDs other than IPF. The ATS/ERS/JRS/ALAT guidelines issued a recommendation for more research into the efficacy of pirfenidone in PPF.³ AEs of pirfenidone include gastrointestinal discomfort and photosensitivity. In a meta-analysis of data from patients with PPF, pirfenidone use was associated with an increased risk of gastrointestinal discomfort (relative risk, 1.83; 95% CI, 1.29-2.60) and photosensitivity (relative risk, 4.88; 95% CI, 1.09-21.83) versus placebo.⁹⁹

Comorbidities such as gastroesophageal reflux disease, obstructive sleep apnea, pulmonary hypertension, and heart failure are common in patients with PPF,^55,56,100 and should be screened for and managed, as they can contribute to symptoms and morbidity. Pulmonary hypertension is associated with reduced exercise tolerance and poor prognosis in patients with ILDs.^101-103 In the INCREASE study in patients with pulmonary hypertension (documented by right heart catheterization) due to ILD, inhaled treprostinil was associated with an improvement in 6-minute walk test distance compared with placebo at week 16 (primary end point [mean difference vs placebo], 31.12 m; 95% CI, 16.85-45.39; P <.001).¹⁰⁴ Based on these results, the FDA approved inhaled treprostinil to improve exercise capacity in patients with pulmonary hypertension associated with ILD.

The randomized, placebo-controlled InPedILD trial investigated the effects of nintedanib, administered using weight-based dosing, in 39 children and adolescents with fibrosing ILD.⁴⁷ The proportion of patients with AEs over 24 weeks (primary end point relating to safety) was 84.6% in both the nintedanib and placebo groups. Diarrhea, the most frequent AE, was reported in 38.5% of patients in the nintedanib group and 15.4% of patients in the placebo group.⁴⁷ The trial was not powered to show a difference in FVC, but changes in FVC % predicted over 24 weeks were numerically in favor of nintedanib.⁴⁷

Conclusions

While various definitions are used for PPF, most include a combination of decline in lung function, worsening of symptoms, and increase in radiological abnormalities. In most trials, PPF was identified only in patients who had failed “standard management” for their particular ILD, but in most ILDs, standard management is not well defined. Patients with worse lung function, a greater extent of fibrosis on HRCT, or a UIP pattern on HRCT are at higher risk of progression of their ILD. However, predicting the onset of PPF remains challenging. PPF confers a poor prognosis and needs to be detected promptly. It is important that patients with fibrosing ILDs are closely monitored, including with regular lung function tests. Management of PPF requires a multimodal approach, including pharmacological therapy, supportive care, and the identification and treatment of comorbidities. Advance care planning and palliative care should be discussed with the patient from an early stage.

Acknowledgments

The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors. Editorial support was provided by Elizabeth Ng and Wendy Morris of Fleishman-Hillard, London, United Kingdom, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim was given the opportunity to review the article for medical and scientific accuracy as well as intellectual property considerations.

Author Affiliations: Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health (EFP), Denver, CO; Department of Medicine, Division of Pulmonary and Critical Care, Weill Cornell Medicine (AJP), New York, NY.

Source of Funding: This article is part of a supplement that was supported by Boehringer Ingelheim Pharmaceuticals, Inc. The authors did not receive any payment for their work on the articles. Boehringer Ingelheim was given the opportunity to review the article for medical and scientific accuracy as well as intellectual property considerations.

Author Disclosures: Dr Podolanczuk reports participating in consultancies or paid advisory boards for Boehringer Ingelheim, United Therapeutics, and Veracyte. Dr Fernandez Perez reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this supplement.

Authorship Information: Concept and design (AJP, EFP); analysis and interpretation of data (AJP); drafting of the manuscript (AJP, EFP); critical revision of the manuscript for important intellectual content (AJP, EFP); and supervision (AJP).

Address Correspondence to: Anna J. Podolanczuk, MD. Weill Cornell Medicine, 425 East 61st St, New York, NY, 10065. Email: ajp9012@med.cornell.edu

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