Bridging gaps in pulmonary fibrosis management: Insights into diagnosis, treatment and future directions

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown cause; imaging and histology results indicate fibrosis and the characteristic features of usual interstitial pneumonia (UIP).¹ IPF primarily affects older adults and leads to progressive breathlessness and lung function decline.¹

Progressive pulmonary fibrosis (PPF) is defined by radiological evidence of pulmonary fibrosis (PF) in patients with interstitial lung disease (ILD) of known or unknown etiology that is other than IPF.¹ PPF is characterized by at least two of the following three criteria occurring within the past year that have no alternative explanation: 1) worsening respiratory symptoms; 2) physiological evidence of disease progression such as an absolute decline in forced vital capacity (FVC) of at least 5% predicted or a decline in diffusing capacity for carbon monoxide (DL_CO) corrected for hemoglobin of at least 10% predicted, both within one year of follow-up; and 3) radiological evidence of disease progression, which may include increased extent or severity of traction bronchiectasis and bronchiolectasis, new ground-glass opacity with traction bronchiectasis, new fine reticulation, increased extent or coarseness of reticular abnormalities, new or increased honeycombing or increased lobar volume loss.¹

In all, IPF and PPF are chronic, debilitating lung diseases characterized by progressive fibrosis and declining lung function.¹ This article explores the clinical and epidemiological landscape of these conditions and details their risk factors, symptoms, diagnostic challenges, economic burden and current treatment approaches.

Exploring IPF and PPF

Risk factors and epidemiology

PF refers to a range of chronic and often progressive lung disorders that predominantly impact the pulmonary interstitium.² These conditions are marked by inflammation and fibrosis within the interstitial space that lead to impaired gas exchange, dyspnea, reduced quality of life (QOL) and, in many cases, progression to respiratory failure and death.² The lung interstitium is greatly involved in diseases contributing to PF; thus, these diseases are collectively known as ILDs.² However, ILDs also include disorders associated with alveolar filling or vascular abnormalities.² ILDs are generally categorized into five groups: rare and ultra-rare diseases, sarcoidosis, exposure-related, autoimmune-related and idiopathic.²

In the United States, IPF mortality rates have continued to rise for both males and females over the past decades, and higher rates have been observed among males and individuals of White or American Indian/Alaska Native descent.³ The overall mortality rate increased from 18.81 per 100,000 in 2000 to 20.66 per 100,000 in 2017.³ The disease primarily affects men older than 60 years, and untreated patients have a median survival of three to five years.^1,2,4

Whereas IPF is universally progressive, the course and prognosis of other forms of PF can vary due to heterogeneity in underlying causes.² Mortality rates continue to increase as more individuals are diagnosed, with age, sex and race all contributing to the differences in outcomes.³ These trends suggest a need for further research into genetic, environmental and behavioral factors along with improved treatment strategies for high-risk populations.³

IPF and PPF share several risk factors. Both diseases are influenced by intrinsic, comorbid and extrinsic factors.⁵ Common risk factors for IPF include genetics, aging, sex and environmental exposures (e.g., cigarette smoking, air pollution) along with comorbidities (e.g., gastroesophageal reflux, obstructive sleep apnea).⁵ In addition, lung microbiome disturbances with UIP patterns are key risk factors, with each ILD subtype carrying its own progression risks.⁶ For non-IPF ILDs, risk factors such as low baseline FVC, oxygen desaturation and smoking are also linked to progression.⁶ Therefore, while the underlying diseases differ, certain risk factors can contribute to the progression of both IPF and PPF.^5,6

Symptoms, diagnosis, and prognosis

Symptoms of PF include shortness of breath, dry cough, fatigue, unintended weight loss, muscle and joint aches and digital clubbing (i.e., the widening and rounding of the fingertips or toes).⁷ The severity of symptoms and the rate of disease progression can vary widely.⁷ Some individuals experience rapid onset and severe disease, whereas others have milder symptoms that worsen gradually over months or years.⁷ In some cases, particularly in IPF, shortness of breath can suddenly worsen over a few days or weeks in a condition known as an acute exacerbation.⁷ These episodes are potentially life-threatening; although they may be triggered by infections or other underlying conditions, their cause is often unknown.⁷

To diagnose IPF, specialists assess medical history, risk factors and physical examination findings such as clubbing, cyanosis and high-pitched lung crackles.⁸ Diagnostic tools include high-resolution CT scans to detect honeycombing, lung biopsy for tissue analysis, chest X-rays to detect scarring, lung function tests and additional tests (e.g., bloodwork), bronchoalveolar lavage and genetic screening to rule out other conditions.⁸ For PPF, similar criteria are used, but recognizing progression within the first year is essential.¹ This progression is demonstrated through worsening symptoms, a decline in lung function (FVC or DL_CO) and radiological signs like increased reticulation or honeycombing.¹ Although both conditions share common features, PPF requires evidence of disease progression, which distinguishes it from IPF.¹

Misdiagnosis of IPF and progressive PPF is a significant challenge due to the overlap with other ILDs. In one 2019 retrospective cohort study, data from 372 patients in the Pulmonary Fibrosis Foundation Patient Registry were analyzed to assess factors associated with delayed diagnosis of IPF.⁹ The analysis found that male sex, older age and prior treatment for alternative diagnoses were linked to longer time to diagnosis (median delay, 2.1 years).⁹ Patients with a delayed diagnosis had more severely impaired lung function at presentation. Limitations of the study included potential selection bias and reliance on registry data that may not fully reflect all diagnostic experiences.⁹ The study results suggested that earlier recognition and referral for high-resolution CT imaging may help reduce diagnostic delays in IPF.⁹

IPF typically follows a progressive decline in lung function that leads to respiratory failure and death within an average of four to five years after diagnosis.¹⁰ However, prognosis varies widely among individuals; it is influenced by factors such as disease progression rate, acute exacerbations and comorbidities.¹⁰ The median survival ranges from two to five years, but between 20% and 25% of patients live beyond 10 years.¹⁰ In PPF, the prognosis varies similarly with some patients experiencing rapid lung function decline, particularly those with significant baseline impairment.¹¹ Patients with worse initial lung function often face higher mortality risk, underscoring the impact of disease severity on survival.¹¹

Economic burden and quality of life

The substantial economic burden of IPF and PPF is driven primarily by hospitalizations, treatments and exacerbations.¹² One study aimed to assess the economic burden of ILDs including PPF and IPF by reviewing direct and indirect costs across multiple studies to quantify hospital-related costs, medication expenses and productivity losses.¹² Results for 2020 showed considerable variation in direct annual medical costs that ranged from $1,824 to $116,927 per patient; these expenditures were driven by hospitalizations and treatments.¹² The analysis also found that both IPF and PPF contributed to higher costs that were particularly due to exacerbations and the need for advanced therapies, which underscores the economic impact of these conditions.¹²

Health-related QOL (HRQOL) in patients with IPF is significantly affected by symptoms like dyspnea, reduced mobility and persistent cough that disrupt various aspects of life.¹³ Despite therapies aimed at slowing disease progression, IPF patients often report poor HRQOL.¹³ Disease management strategies that go beyond pharmacological treatment (e.g., individualized care plans, continuous reassessment) are essential for improving HRQOL.¹³ Strong patient-provider relationships and family caregiver involvement play critical roles in managing the disease and enhancing overall well-being.¹³

For PPF, the disease’s impact on QOL is similarly profound, with patients experiencing significant reductions in lung function, exercise capacity and daily activities.¹⁴ This progression leads to increased disability and worsened survival outcomes.¹⁴ Early diagnosis and personalized treatment strategies are crucial in managing disease progression and maintaining QOL.¹⁴

Current treatment approaches

Conventional therapies and clinical guidelines

The American Thoracic Society (ATS) guidelines, updated in 2022, provide evidence-based recommendations for diagnosing and managing ILD.¹ These guidelines include updated diag­nostic criteria for both IPF and PPF and offer treatment recommendations while also emphasizing the need for further research.¹ This is particularly relevant in the current use of antifibrotic agents like pirfenidone and nintedanib to treat these ILDs.^1,15,16

Treatment algorithms and gaps

Nintedanib and pirfenidone are FDA-approved treatments for IPF.^15,16 Nintedanib is a tyrosine kinase inhibitor, and pirfenidone has anti-inflammatory and antifibrotic properties; both of these antifibrotic agents slow disease progression.¹ These medications help to reduce the decline in FVC in patients with fibrotic ILDs.¹

In addition to IPF, nintedanib is approved for chronic fibrosing ILDs with a progressive phenotype; these include PPF.^15,17 Nintedanib has shown efficacy in reducing the rate of lung function decline across the PPF subtypes.¹⁵

Pirfenidone exhibits antifibrotic effects by inhibiting TGF-beta signaling, reducing myofibroblast differentiation and suppressing collagen production; in addition, it has anti-inflammatory actions that modulate immune cell activity and cytokine release.¹⁸ These mechanisms suggest potential benefits in stabilizing lung function and improving QOL in progressive fibrosing ILDs and IPF.¹⁸

In clinical studies, pirfenidone was reported to cause side effects in 10% or more of patients.^15,16 These include nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, anorexia, gastroesophageal reflux disease, sinusitis, insomnia, weight loss and arthralgia.¹⁵ Nintedanib has been associated with side effects in 5% or more of patients; these include diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevations, decreased appetite, weight loss, headache and hypertension.¹⁶

Both therapies show clinical benefits in improving lung function and reducing exacerbations but they do not significantly affect mortality.¹ Early initiation of these drugs is crucial for slowing disease progression.¹ However, better management strategies, particularly those that target the underlying mechanisms of fibrosis and improve symptom control, are needed.¹

Despite advancements in the understanding of IPF pathobiology, refinement of diagnostic criteria and the approval of antifibrotic therapies, such as nintedanib and pirfenidone, and the development of other truly efficacious treatments remains challenging.¹⁹ Significant barriers include incomplete knowledge of disease mechanisms, the absence of a prioritization framework for therapeutic targets and the limitations of existing animal models that fail to replicate the progressive nature of IPF.¹⁹ Patient selection for clinical trials is complicated by variability in disease progression and the need to evaluate novel therapies against a standard of care rather than placebo.¹⁹ Short trial durations, heterogeneous patient populations and inconsistent improvements in patient-centered outcomes further hinder therapeutic advancement.¹⁹ Real-world data and pulmonary rehabilitation have been useful in devising strategies to manage IPF, but clinical trials often exclude patients with advanced disease or comorbidities and limit external validity.¹⁹ Prior failed trials have expanded the understanding of IPF biology and end points, yet innovative approaches to optimize treatment and improve clinical outcomes still are urgently needed.¹⁹

Emerging therapies and investigational agents

Ongoing research into IPF and PPF continues to drive the development of novel therapies to slow disease progression, improve lung function and enhance patient outcomes (Table).^18,20-28

Pathways and novel mechanisms

The phosphodiesterase 4B (PDE4B) pathway plays a key role in regulating inflammation and fibrosis, making it an important target in treating IPF and PPF.²⁹ Selective inhibition of PDE4B has both anti-inflammatory and antifibrotic effects, addressing key pathological factors of these diseases.²⁹ Compared to pan-PDE4 inhibitors, PDE4B-specific inhibitors tend to cause fewer gastrointestinal side effects, potentially offering better tolerability for patients.²⁹

Nerandomilast, an oral PDE4B inhibitor, is being investigated as a treatment for IPF and PPF.^20,30 It has shown potential in stabilizing lung function and reducing fibrosis in clinical trials. The ongoing FIBRONEER clinical program, which includes the largest phase 3 trial for IPF to date, is evaluating the safety and efficacy of nerandomilast through two phase 3 randomized, double-blind, placebo-controlled trials—FIBRONEER™-IPF (NCT05321069) in patients with IPF and FIBRONEER™-ILD (NCT05321082) in individuals with other progressive fibrosing ILDs.^20,30 In the FIBRONEER-IPF study, the drug met its primary end point–showing improvement in FVC at 52 weeks compared to placebo.²⁰ With data from 1,177 patients across 30 countries and its receipt of an FDA breakthrough therapy designation in February 2022, nerandomilast is being further studied for its potential to address the needs of patients with these progressive conditions.²⁰ Submission of a new drug application for nerandomilast is planned for 2025.²¹

Lysophosphatidic acid (LPA), a bioactive lipid mediator, also may have a key role in the development of PF.³¹ Elevated LPA levels have been observed following lung injury, and its signaling through the LPA1 receptor is associated with fibroblast recruitment, vascular leak and fibrotic responses in lung tissue.³¹ Use of the oral LPA1 receptor antagonist admilparant targets this pathway; it may mitigate these profibrotic processes by reducing fibroblast accumulation and vascular permeability.^31,32

Admilparant has shown notable results in a phase 2 trial, demonstrating a 69% relative reduction in the decline of lung function as measured by FVC compared to placebo over 26 weeks with consistent effects regardless of background therapy.^32,33 Currently, the drug is being evaluated in the global phase 3 ALOFT program, which includes trials for both PPF (NCT06025578) and IPF (NCT06003426).^34,35 These studies will assess the long-term efficacy and safety of admilparant and provide further insights into its potential as a novel treatment for fibrotic lung diseases.^34,35

Future directions and opportunities

Artificial intelligence (AI) has the potential to significantly enhance the diagnosis and management of ILDs including IPF.³⁶ By using quantitative software, AI can analyze complex imaging data such as those provided by high-resolution CT scans to objectively identify and quantify fibrotic patterns, supporting more precise diagnoses.³⁶ Additionally, AI can integrate diverse datasets including demographic, laboratory, genomic, metabolomic and proteomic information to develop comprehensive clinical profiles.³⁶ This may enable more detailed disease characterization and inform personalized treatment strategies, potentially improving outcomes in ILDs like IPF.³⁶

The Pulmonary Fibrosis Foundation and other organizations engage in advocacy and support efforts to address the needs of patients with PFs such as IPF and PPF.³⁷ These organizations focus on increasing awareness among policymakers about the impact of PF, advocating for increased federal funding for PF research and supporting legislative measures that improve access to care and treatment options.³⁷ The organization also works toward ensuring equitable access to healthcare services, supports the inclusion of PF in broader respiratory health initiatives and fosters collaboration with regulatory agencies to streamline drug development and approval processes. These efforts aim to enhance research, access and support for those affected by PF conditions.³⁷

Conclusion

Management of IPF and PPF presents challenges, but there have been key advances in ILD treatment. FDA-approved therapies including nintedanib and pirfenidone help to slow disease progression and improve lung function. Emerging therapies, including the PDE4B inhibitor nerandomilast and the LPA1 receptor antagonist admilparant, offer promise by directly targeting the underlying mechanisms of fibrosis. The crucial need for therapies that not only slow progression but also improve long-term outcomes highlights the importance of ongoing research and novel treatment options for these progressive fibrotic lung diseases.

References

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