Management and treatment decisions in progressive pulmonary fibrosis| Rassegna di Patologia dell'Apparato Respiratorio

Abstract

Background. Interstitial lung diseases (ILDs) include about 200 different, chronic, pathological entities characterized by similar clinical features. The development of interstitial fibrosis, during the course of these diseases is considered a common, unpredictable, irreversible and self-sustaining mechanism of progression with decline of pulmonary function and respiratory symptoms till death. In recent years many efforts and attention have been made by scientists bringing to definition of the “progressive phenotype” that can be considered as “a disease inside the disease” with similar genetic, pathological and clinical characteristic regardless of the initial fibrotic pathology.
Objective. In this review, we have explored the state of the art and the most recent literature around progressive pulmonary fibrosis (PPF); definition, early detection, molecular basis and therapy.
Methods. We searched papers published in English language on PubMed using the keywords: “interstitial lung disease”, “progressive pulmonary fibrosis”, “idiopathic pulmonary fibrosis”, “pirfenidone”, “nintedanib”. Results. Since the initial therapy must be set according the underlying desease, antifibrotic drugs (nintedanib and pirfenidone), initially indicated only to slow the progression in Idiopathic pulmonary fibrosis (IPF) have been recently considered effective to slow the progression in other ILDs.
Conclusion. It is extremely important to recognize early the PPF by means of physiological and radiological follow-up. Currently, no serum biomarkers are available for monitoring or predict disease progression so, we need more randomized clinical trial to better investigate the hallmarks of progression and the effects of antifibrotic drugs to modify prognosis of these patients.

Introduction

Interstitial lung diseases (ILDs) are a group of almost 200 different entities characterized by a heterogeneity in the extent of pulmonary inflammation and/or fibrosis. ILDs can be idiopathic or associated with environmental exposures, drugs assumption, irradiation, infections, connective tissue diseases (CTDs). Idiopathic pulmonary fibrosis (IPF) is the most common, progressive and with the highest morbidity and mortality among ILDs, but a similar progressive phenotype can be seen in a proportion of non-IPF fibrosing ILDs having overlapping genetic, pathophysiological and clinical features with IPF ¹.

Pulmonary fibrosis can occur in the context of many of these ILDs and definition of fibrotic ILDs includes radiological findings such as presence of traction bronchiectasis and/or honeycombing on chest High Resolution Computed Tomography (HRCT), histopathologic findings (if available) confident with Usual Interstitial Pneumoniae (UIP) pattern; occasionally, reticulation or ground glass at HRTC can be the only finding that represent a fine, diffuse, intralobular fibrosis highlighted on histopathology. Finally, fibrotic ILDs can be diagnosed at presentation or can occur at follow up as a progression of a non-fibrotic ILD.

In a patient with ILD of known or unknown etiology, progressive pulmonary fibrosis (PPF) is defined as at least two of the following three criteria occurring within the past year without alternative explanation: 1. worsening respiratory symptoms; 2. physiological evidence of disease progression (absolute decline in FVC > 5% predicted within 1 yr of follow-up, absolute decline in DL_CO > 10% predicted within 1 yr of follow-up); and 3. radiological evidence of disease progression (a. Increased extent or severity of traction bronchiectasis and bronchiolectasis, b. New ground-glass opacity with traction bronchiectasis, c. New fine reticulation, d. Increased extent or increased coarseness of reticular abnormality e. New or increased honeycombing, f. Increased lobar volume loss) ².

In this review we investigated most important and recent literature around PPF: definition, early detection, molecular basis and therapy.

Pathogenesis of progressive pulmonary fibrosis (PPF)

While collagen deposition is an essential response of the body in normal wound healing and against pathogens, in subjects with pulmonary fibrosis these mechanisms are overexpressed with loss of extracellular matrix (ECM) homeostasis leading to the destruction of the fine architecture of alveolar units and impaired gas exchange, ultimately causing death due to respiratory failure. Many molecular pathways are involved in this process such as various and often disease-specific triggers leading to an exaggerated cascade of inflammatory and subsequently fibrotic responses ³. Much is still unknown about the pathophysiology but, surely, a genetic predisposition plays an important role on the susceptibility to these diseases in addition to multiple environmental risk factors such as tobacco smoking, occupational exposures, air pollution, micro-aspiration, and viral infection, age.

In some patients, partial or complete resolution to normal lung tissue will occur either spontaneously, after antigen removal (e.g., in hypersensitivity pneumonitis), or with immunomodulatory treatment (e.g., in CTD-associated ILD) during the earlier inflammatory phase. After a prolonged alveolar or endothelial-cell injury or immune-activation and inflammation, fibroblasts can be activated by profibrotic cytokines and then proliferate and differentiate into myofibroblasts, which subsequently migrate to the alveolar interstice and are expressed as fibroblastic foci. This represents the irreversible phase of destruction leading to lung tissue remodeling and subpleural microscopic honeycombing. While different and disease-specific triggers are recognized in the initial-inflammatory phase, common and self-sustaining mechanisms seem to be involved in later-fibrotic phase ⁴.

A variant in MUC5B (a gene involved in airway clearance and bacterial host defense) is associated with risks of IPF in rheumatoid arthritis with ILD (RA–ILD) ⁵, while a telomere shortening and/or telomere-related gene mutations (TERT, TERC, RTEL1, and PARN) have been found in IPF, RA–ILD and chronic hypersensitivity pneumonitis (CHP) ⁶. Finally, genetic variants of telomere-related gene, are clearly associated with progressive disease ⁷.

Diagnostic approach and definition of PPF

The main presenting symptoms and signs in ILD’s are progressive exertional dyspnea, cough and chest fine or velcro-like crackles. The course of the disease is variable, unpredictable and needs to be identified individually; sometimes diagnosis should be changed on the basis of new radiological/pathological findings ⁸.

Despite more than a half of patients with a diagnosis of pulmonary fibrosis other than IPF have a stable disease or improvement with immunomodulatory therapy, a portion of patients will have a progression of the disease with worsening respiratory symptoms, decline in lung function, decreased quality of life and a risk of early death independently of the initial etiological classification of the ILD or medication. This led to recognition of a “progressive phenotype” that is considered an in-itself entity with self-sustaining fibrosis worthy of an in-depth analysis ⁹.

Three studies (n = 473) demonstrated that approximately 18-32% of patients with non-IPF ILDs develop PPF despite management within 61-80 months from the onset of symptoms ^10-12. No serum biomarker has been validated for monitoring or predict disease progression, or assessing the respective components of inflammation and fibrosis in pathogenesis. Scores and questionnaire, such as those based on sex, age, lung function (forced vital capacity-FVC), diffusing capacity of the lung for carbon monoxide (DL_CO), more extensive disease on HRCT imaging, greater impairment in lung function, presence of honeycombing and a UIP pattern on CT, broncho alveolar lavage (BAL) lymphocytosis < 20% on the total cell count, have been associated with poorer prognosis and worse survival ¹³.

It is demonstrated that an accurate knowledge of the initial diagnosis of the ILD subtype is associated with a better risk stratification and a reduced risk of progression, so when an initial ILD diagnosis cannot be made, or an unclassifiable form of ILD has been diagnosed the risk of progression is higher ¹⁴. Once the disease progresses despite optimal management, the risk of further progression does not appear to be influenced by the ILD subtype. In these cases, multidisciplinary discussion of the case, analysis of the histological pattern whether by surgical lung biopsy or transbronchial cryobiopsy, and BAL cellular profile, when appropriate, may give an advantage in the stratification of the risk of progression/exacerbation even if it does not influence immediate therapeutic decisions ¹⁵.

In the perspective of exclude any alternative cause of worsening respiratory symptom a chest HRCT with end-inspiratory breath-hold, full pulmonary function tests (PFTs), echocardiography and blood chemistry are recommended ¹³. Bronchoscopy with a BAL should be assessed mainly to exclude an infection and to analyze the bronchoalveolar cellularity. Differential diagnosis such as heart failure, pulmonary embolism, pneumoniae, should be considered and sometimes, as told, a comprehensive reanalysis of the case including a multidisciplinary discussion can be helpful.

Pugashetti at al. demonstrated that in a cohort of one thousand three hundred forty-one patients a 10% relative FVC decline was the strongest predictor of reduced Transplant Free Survival (TFS) and showed consistent TFS associations across cohorts, ILD subtypes, and treatment groups, resulting in a phenotype that closely resembled IPF. Six additional PPF criteria (satisfied in the absence of 10% relative FVC decline) such as 5-9% relative FVC decline, ≥ 15% relative DL_CO decline, CT progression of fibrosis, 5-9% relative FVC decline + worsening symptoms, 5-9% relative FVC decline and ≥ 15% relative DL_CO decline, CT progression + worsening symptoms were also associated with reduced survival ¹⁶.

Monitoring for progression

There is an unmet need for guidelines on the management of patients with progressive ILDs.

While virtually all patients with IPF will manifest disease progression similar to PPF, the proportion of patients with ILDs other than IPF who manifest PPF should be assessed with a radiological and physiological follow-up.

Frequency of PFT’s should be decided case by case considering a closer follow up (every 3-4 months) for the first 2 years after diagnosis and for the unclassified form; HRCT is not useful for routine purposes; it is helpful for corroborating clinical/physiologic decline and in case of discrepancy between symptoms and PFT’s.

Antifibrotic drugs in PPF

There is a growing interest in non-IPF ILDs exhibiting a progressive lung fibrosis so, in 2022, an expert committee, based on the similarities between IPF and PPF recommended the use of antifibrotic drugs for ILDs associated to a progressive phenotype in addiction or subsequently to the specific immunomodulatory/steroid therapy for the specific disease, oxygen therapy, rehabilitation and transplant.

Nintedanib, is an oral intracellular tyrosine kinase inhibitor that blocks pathways involved in fibrogenesis and received approval for IPF treatment in the United States, Japan, and Europe between 2014 and 2015 ¹⁷. Subsequently, it has been approved also for the use in subjects affected by systemic sclerosis-associated ILDs and progressive fibrosing ILDs based on the SENSCIS ¹⁸ and INBUILD ¹⁹ trials. A following post hoc analysis of the INBUILD population conducted by Wells and colleagues confirmed the effectiveness of nintedanib ²⁰.

The impact of nintedanib was analyzed on the annual rate of FVC decline, time to acute exacerbation, all-cause mortality, score change on the King’s Brief ILD questionnaire (K-BILD) and the main result was about the effectiveness to slow the decline in FVC regardless of UIP or not UIP pattern of pulmonary fibrosis, suggesting a possible protection against disease progression.

As already shown in IPF patients ^21,22, also in PPF patients the use of nintedanib has been associated with a non-negligible amount of side effects, especially in over 80 yr patients mainly gastro-enteral, requiring a high percentage of dose reduction or discontinuing treatment ^23,24.

Pirfenidone is a synthetic pyridine drug. It is an antifibrotic agent with anti-inflammatory and antioxidant properties. Although his mechanism of action is not yet fully understood, it is proposed to primarily regulate tumor necrosis factor (TNF) pathways and modulate cellular oxidation. It received approval for IPF treatment in United States, Japan and Europe between 2011 and 2014.

Regarding pirfenidone use in PPF, three main randomized placebo-control trials have been performed: it seems to reduce the decline of FVC in absolute (p = 0·0082) and in percentage of predict (p = 0·0028) value in AR-ILD patients ²⁵, in progressive fibrotic ILDs (p = 0·043) ²⁶, while in unclassifiable progressive fibrosing interstitial lung disease it seems to reduce the decline of FVC (p = 0.002), DL_CO and 6MWT over 24 week ²⁷.

The data available in literature did not highlight a mortality benefit or any improvement in respiratory symptom at questionnaire scores although the relatively short duration of the studies may have contributed to the lack of significant findings in these parameters.

The main side effects are gastrointestinal discomfort, photosensitivity, and often bring to discontinue treatment. Given the limited studies in the literature on this topic, additional research on PPF treatment with pirfenidone is necessary with larger samples ²⁸.

Conclusion

Since around ten years, antifibrotic drugs (nintedanib and pirfenidone) have been approved and largely used in IPF because of their effectiveness to modify significantly the natural history and ameliorate the prognosis of this devasting and progressive disease. Recent evidence demonstrated their effectiveness even in reducing progression in PPF other than IPF. This led scientists to shift their attention to highlight, during the course of an ILD, the “progressive phenotype” to offer an effective-alternative therapy to the patient regardless of the initial diagnosis. There is a need of more clinical trials to investigate: risk stratification, early detection, hallmarks, genetics and underlying phatophysiological mechanisms of PPF.

Author contributions

R.L. and M.D. conceived the study and it design, S.B. and A.E helped to draft the manuscript.

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