Progressive Fibrotic Lung Disease Research Articles

Cromolyn sodium and masitinib combination inhibits fibroblast-myofibroblast transition and exerts additive cell-protective and antioxidant effects on a bleomycin-induced invitro fibrosis model.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an invitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA-approved mast cell stabilizer. This study aims to investigate the anti-fibrotic and antioxidant effects of the masitinib-cromolyn sodium combination in an invitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H2O2) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple-immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl-2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H2O2-induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti-fibrotic, cell-protective, and antioxidant effects of the masitinib-cromolyn sodium combination in an invitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously.

Quantitative CT analysis of idiopathic pulmonary fibrosis and correlation with lung function study

BackgroundIdiopathic Pulmonary Fibrosis (IPF) is a progressive fibrotic lung disease. However, the field of quantitative CT scan analysis in conjunction with pulmonary function test for IPF patients remains relatively understudied. In this study, we evaluated the diagnostic value of features derived high-resolution computed tomography (HRCT) for patients with IPF and correlated them with pulmonary function tests.MethodsWe retrospectively analyzed the chest HRCT images and pulmonary function test results of 52 patients with IPF during the same period (1 week) and selected 52 healthy individuals, matched for sex, age, and body mass index (BMI) and with normal chest HRCT as controls. HRCT scans were performed using a Philips 256-row Brilliance iCT scanner with standardized parameters. Lung function tests were performed using a Jaeger volumetric tracer for forced vital capacity (FVC), total lung capacity (TLC), forced expiratory volume in first second (FEV1), FEV1/FVC, carbon monoxide diffusing capacity (DLCO), and maximum ventilation volume (MVV) metrics. CT quantitative analysis, including tissue segmentation and threshold-based quantification of lung abnormalities, was performed using 3D-Slicer software to calculate the percentage of normal lung areas (NL%), percentage of ground-glass opacity areas (GGO%), percentage of fibrotic area (F%) and abnormal lesion area percentage (AA%). Semi-quantitative analyses were performed by two experienced radiologists to assess disease progression. The aortic-to-sternal distance (ASD) was measured on axial images as a standardized parameter. Spearman or Pearson correlation analysis and multivariate stepwise linear regression were used to analyze the relationship between the data in each group, and the ROC curve was used to determine the optimal quantitative CT metrics for identifying IPF and controls.ResultsROC curve analysis showed that F% distinguished the IPF patient group from the control group with the largest area under the curve (AUC) of 0.962 (95% confidence interval: 0.85–0.96). Additionally, with F% = 4.05% as the threshold, the Youden’s J statistic was 0.827, with a sensitivity of 92.3% and a specificity of 90.4%. The ASD was significantly lower in the late stage of progression than in the early stage (t = 5.691, P < 0.001), with a mean reduction of 2.45% per month. Quantitative CT indices correlated with all pulmonary function parameters except FEV1/FVC, with the highest correlation coefficients observed for F% and TLC%, FEV1%, FVC%, MVV% (r = − 0.571, − 0.520, − 0.521, − 0.555, respectively, all P-values < 0.001), and GGO% was significantly correlated with DLCO% (r = − 0.600, P < 0.001). Multiple stepwise linear regression analysis showed that F% was the best predictor of TLC%, FEV1%, FVC%, and MVV% (R2 = 0.301, 0.301, 0.300, and 0.302, respectively, all P-values < 0.001), and GGO% was the best predictor of DLCO% (R2 = 0.360, P < 0.001).ConclusionsQuantitative CT analysis can be used to diagnose IPF and assess lung function impairment. A decrease in the ASD may indicate disease progression.

Fibroblast activation protein is a cellular marker of fibrotic activity in canine idiopathic pulmonary fibrosis.

Canine idiopathic pulmonary fibrosis (CIPF) is a progressive fibrotic interstitial lung disease of unknown etiology, afflicting aging West Highland white terriers (WHWTs) and leading to progressive respiratory failure. Fibroblast activation protein (FAP), a protease overexpressed in many cancers, is upregulated in idiopathic pulmonary fibrosis in humans. The aim of this study was to investigate FAP as a marker of active fibrosis in lung biopsies from WHWTs affected with CIPF, as well as the potential of plasmatic FAP as a biomarker. After establishing a scoring system to evaluate the severity and activity of fibrosis on histopathological lung sections, anti-FAP immunohistochemistry was performed on healthy and CIPF samples. FAP expression was characterized using both visual and digital quantitative pathology software analyses and then correlated to fibrosis severity and activity. Levels of plasmatic FAP in WHWTs affected with CIPF were measured by enzyme-linked immunosorbent assay and compared with healthy dogs. Lung samples from 22 WHWTs affected with CIPF were collected. According to the fibrosis scoring system, they were classified as cases of mild (5), moderate (9) and severe (8) fibrosis and were attributed scores of fibrosis activity. Fifteen healthy lung samples were classified as non-fibrotic. Healthy lung samples were FAP-negative, whereas fibroblasts were FAP-positive in 20 CIPF samples. FAP immunohistochemical expression correlated mildly with fibrosis severity (p < 0.05; R 2 = 0.22) but highly with fibrosis activity scores (p < 0.001; R 2 = 0.68). Digital image analysis detected a higher percentage of FAP-positive cells in areas of active fibrosis (p < 0.001) and FAP-positive cells were distributed outside mature fibrosis lesions, clustered in active fibrosis areas or scattered within alveolar septa. On the other hand, plasmatic FAP was significantly lower in dogs affected with CIPF compared with healthy dogs (p < 0.01). In conclusion, this study provides a valuable histological scoring system to assess the severity and activity of fibrosis in CIPF. It demonstrates that FAP is a good cellular marker of fibrotic activity in CIPF, and thus constitutes a promising target to be exploited for diagnostic and therapeutic applications. Additionally, it suggests that plasmatic FAP, although non-specific, could be altered in CIPF.

PGC1-Alpha/Sirt3 Signaling Pathway Mediates the Anti-Pulmonary Fibrosis Effect of Hirudin by Inhibiting Fibroblast Senescence.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease for which there is a lack of effective pharmacological treatments. Hirudin, a natural peptide extracted from leeches, has been used for broad pharmacological purposes. In this study, we investigated the therapeutic effects of hirudin on IPF and its related mechanism of action. By constructing a mouse model of pulmonary fibrosis and treating it with hirudin in vivo, we found that hirudin exerted anti-fibrotic, anti-oxidative, and anti-fibroblast senescence effects. Moreover, using an in vitro model of stress-induced premature senescence in primary mouse lung fibroblasts and treating with hirudin, we observed inhibition of fibroblast senescence and upregulation of PGC1-alpha and Sirt3 expression. However, specific silencing of PGC1-alpha or Sirt3 suppressed the anti-fibroblast senescence effect of hirudin. Thus, the PGC1-alpha/Sirt3 pathway mediates the anti-fibroblast senescence effect of hirudin, potentially serving as a molecular mechanism underlying its anti-fibrosis and anti-oxidative stress effects exerted on the lungs.

Genomic Profiling for Predictive Treatment Strategies in Fibrotic Interstitial Lung Disease.

Idiopathic pulmonary fibrosis (IPF) has traditionally been considered the archetype of progressive fibrotic interstitial lung diseases (f-ILDs), but several other f-ILDs can also manifest a progressive phenotype. Integrating genomic signatures into clinical practice for f-ILD patients may help to identify patients predisposed to a progressive phenotype. In addition to the risk of progressive pulmonary fibrosis, there is a growing body of literature examining how pharmacogenomics influences treatment response, particularly regarding the efficacy and safety profiles of antifibrotic and immunomodulatory agents. In this narrative review, we discuss current studies in IPF and other forms of pulmonary fibrosis, including systemic autoimmune disorders associated ILDs, sarcoidosis and hypersensitivity pneumonitis. We also provide insights into the future direction of research in this complex field.

Iminium ion metabolites are formed from nintedanib by human CYP3A4

Nintedanib is used to treat idiopathic pulmonary fibrosis, systemic sclerosis, interstitial lung disease, and progressive fibrotic interstitial lung disease. It is primarily cleared via hepatic metabolism, hydrolysis, and glucuronidation. In addition, formation of the iminium ion, a possible reactive metabolite, was predicted based on the chemical structure of nintedanib. To obtain a hint which may help to clarify the cause of nintedanib-induced liver injury, we investigated whether iminium ions were formed in the human liver. To detect unstable iminium ions using liquid chromatography-tandem mass spectrometry (LC-MS/MS), potassium cyanide was added to the reaction mixture as a trapping agent. Human liver and intestinal microsomes were incubated with nintedanib in the presence of NADPH to form two iminium ion metabolites on the piperazine ring. Their formation is strongly inhibited by ketoconazole, a potent cytochrome P450 (CYP) 3A4 inhibitor. Among the recombinant P450s, only CYP3A4 formed cyanide adducts. The role of CYP3A4 was supported by the positive correlation between CYP3A4 protein abundance, as determined by LC-MS-based proteomics, and the formation of cyanide adducts in 25 individual human liver microsomes. In conclusion, we have demonstrated that iminium ion metabolites are formed from nintedanib by CYP3A4 as potential reactive metabolites.

What has antifibrotic therapy changed for patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial lung disease of unknown cause. IPF is characterized by excessive production and deposition of extracellular matrix components, which lead to irreversible violations of the architectonics of lung tissue and loss of function. Without treatment, the average survival rate of patients after diagnosis does not exceed 3–5 years. However, published observations report improved survival over the past decade, due to the advent of antifibrotic drugs and earlier diagnosis. The benefits of antifibrotic therapy include a slower rate of reduction in forced lung capacity (FVC) and a reduction in mortality. Pirfenidone and nantedanib are the only currently approved antifibrotic drugs for the treatment of IPF. Several generic drugs with the INN pirfenidone are registered on the Russian market, including the drug PIRFASPEC® (267 mg capsules). Their efficacy and safety have been demonstrated both in randomized clinical trials and in real clinical practice studies. IPF patient registries, which have been maintained in many countries since 2010, provide additional information regarding the progression of the disease, the effectiveness of therapy, and the frequency of adverse events. Although they have a different mechanism of action and safety profile, their effectiveness in slowing the decline of FVC and reducing the risk of mortality over time is similar. However, IPF is still characterized by progressive shortness of breath and poor prognosis, as treatment can only delay the progression of IPF and cannot stop or reverse the damage. Although clinical trials of new drugs for the treatment of IPF are currently underway, no other drugs have yet been approved in the Russian Federation.

CCT6A alleviates pulmonary fibrosis by inhibiting HIF-1α-mediated lactate production.

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive fibrotic lung disease. The development of IPF involves different molecular and cellular processes, and recent studies indicate that lactate plays a significant role in promoting the progression of the disease. Nevertheless, the mechanism by which lactate metabolism is regulated and the downstream effects remain unclear. The molecular chaperone CCT6A performs multiple functions in a variety of biological processes. Our research has identified a potential association between CCT6A and serum lactate levels in IPF patients. Herein, we found that CCT6A was highly expressed in type 2 alveolar epithelial cells (AEC2s) of fibrotic lung tissues and correlated with disease severity. Lactate increases the accumulation of lipid droplets in epithelial cells. CCT6A inhibits lipid synthesis by blocking the production of lactate in AEC2s and alleviates bleomycin-induced pulmonary fibrosis in mice. In addition, our results revealed that CCT6A blocks HIF-1α-mediated lactate production by driving the VHL-dependent ubiquitination and degradation of HIF-1α and further inhibits lipid accumulation in fibrotic lungs. In conclusion, we propose that there is a pivotal regulatory role of CCT6A in lactate metabolism in pulmonary fibrosis, and strategies aimed at targeting these key molecules could represent potential therapeutic approaches for pulmonary fibrosis.

Proportion and predictors of FVC decline in patients with interstitial lung disease

RationaleThe proportion of patients who develop progressive pulmonary fibrosis (PPF), along with risk factors for progression remain poorly understood. ObjectivesTo examine factors associated with an increased risk of developing PPF among patients at a referral center. MethodsWe identified patients with a diagnosis of interstitial lung disease (ILD) seen within the Cleveland Clinic Health System. Utilizing a retrospective observational approach we estimated the risk of developing progression by diagnosis group and identified key clinical predictors using the FVC component of both the original progressive fibrotic interstitial lung disease (PFILD) and the proposed PPF (ATS) criteria. ResultsWe identified 5934 patients with a diagnosis of ILD. The cumulative incidence of progression over the 24 months was similar when assessed with the PFILD and PPF criteria (33.1 % and 37.9 % respectively). Of those who met the ATS criteria, 9.5 % did not meet the PFILD criteria. Conversely, 4.3 % of patients who met PFILD thresholds did not achieve the 5 % absolute FVC decline criteria. Significant differences in the rate of progression were seen based on underlying diagnosis. Steroid therapy (HR 1.46, CI 1.31–1.62) was associated with an increased risk of progressive fibrosis by both PFILD and PPF criteria. ConclusionRegardless of the definition used, the cumulative incidence of progressive disease is high in patients with ILD in the 24 months following diagnosis. Some differences are seen in the risk of progression when assessed by PFILD and PPF criteria. Further work is needed to identify modifiable risk factors for the development of progressive fibrosis.

Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine.

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common SNPs. The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis and clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. In addition, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multiomic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.

Niclosamide - encapsulated lipid nanoparticles for the reversal of pulmonary fibrosis

Pulmonary fibrosis (PF) is a serious and progressive fibrotic interstitial lung disease that is possibly life-threatening and that is characterized by fibroblast accumulation and collagen deposition. Nintedanib and pirfenidone are currently the only two FDA-approved oral medicines for PF. Some drugs such as antihelminthic drug niclosamide (Ncl) have shown promising therapeutic potentials for PF treatment. Unfortunately, poor aqueous solubility problems obstruct clinical application of these drugs. Herein, we prepared Ncl-encapsulated lipid nanoparticles (Ncl-Lips) for pulmonary fibrosis therapy. A mouse model of pulmonary fibrosis induced by bleomycin (BLM) was generated to assess the effects of Ncl-Lips and the mechanisms of reversing fibrosis in vivo. Moreover, cell models treated with transforming growth factor β1 (TGFβ1) were used to investigate the mechanism through which Ncl-Lips inhibit fibrosis in vitro. These findings demonstrated that Ncl-Lips could alleviate fibrosis, consequently reversing the changes in the levels of the associated marker. Moreover, the results of the tissue distribution experiment showed that Ncl-Lips had aggregated in the lung. Additionally, Ncl-Lips improved the immune microenvironment in pulmonary fibrosis induced by BLM. Furthermore, Ncl-Lips suppressed the TGFβ1-induced activation of fibroblasts and epithelial−mesenchymal transition (EMT) in epithelial cells. Based on these results, we demonstrated that Ncl-Lips is an efficient strategy for reversing pulmonary fibrosis via drug-delivery.

Imaging of Pulmonary Fibrosis: An Update, From the AJR Special Series on Imaging of Fibrosis.

Pulmonary fibrosis is recognized as occurring in association with a wide and increasing array of conditions, and it presents with a spectrum of chest CT appearances. Idiopathic pulmonary fibrosis (IPF), which corresponds histologically with usual interstitial pneumonia and represents the most common idiopathic interstitial pneumonia, is a chronic progressive fibrotic interstitial lung disease (ILD) of unknown cause. Progressive pulmonary fibrosis (PPF) describes the radiologic development of pulmonary fibrosis in patients with ILD of a known or unknown cause other than IPF. The recognition of PPF impacts management of patients with ILD-for example, in guiding initiation of antifibrotic therapy. Interstitial lung abnormalities are an incidental CT finding in patients without suspected ILD and may represent an early intervenable form of pulmonary fibrosis. Traction bronchiectasis and/or bronchiolectasis, when detected in the setting of chronic fibrosis, is generally considered evidence of irreversible disease, and progression predicts worsening mortality risk. Awareness of the association between pulmonary fibrosis and connective tissue diseases, particularly rheumatoid arthritis, is increasing. This review provides an update on the imaging of pulmonary fibrosis, with attention given to recent advances in disease understanding with relevance to radiologic practice. The essential role of a multidisciplinary approach to clinical and radiologic data is highlighted.

Morphine for treatment of cough in idiopathic pulmonary fibrosis (PACIFY COUGH): a prospective, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial

Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease, with most patients reporting cough. Currently, there are no proven treatments. We examined the use of low dose controlled-release morphine compared with placebo as an antitussive therapy in individuals with idiopathic pulmonary fibrosis. The PACIFY COUGH study is a phase 2, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial done in three specialist centres in the UK. Eligible patients aged 40-90 years had a diagnosis of idiopathic pulmonary fibrosis within 5 years, self-reported cough (lasting >8 weeks), and a cough visual analogue scale (VAS) score of 30 mm or higher. Patients were randomly assigned (1:1) to placebo twice daily or controlled-release morphine 5 mg orally twice daily for 14 days followed by crossover after a 7-day washout period. Patients were randomised sequentially to a sequence group defining the order in which morphine and placebo were to be given, according to a computer-generated schedule. Patients, investigators, study nurses, and pharmacy personnel were masked to treatment allocation. The primary endpoint was percentage change in objective awake cough frequency (coughs per h) from baseline as assessed by objective digital cough monitoring at day 14 of treatment in the intention-to-treat population, which included all randomised participants. Safety data were summarised for all patients who took at least one study drug and did not withdraw consent. This study was registered at ClinicalTrials.gov, NCT04429516, and has been completed. Between Dec 17, 2020, and March 21, 2023, 47 participants were assessed for eligibility and 44 were enrolled and randomly allocated to treatment. Mean age was 71 (SD 7·4) years, and 31 (70%) of 44 participants were male and 13 (30%) were female. Lung function was moderately impaired; mean forced vital capacity (FVC) was 2·7 L (SD 0·76), mean predicted FVC was 82% (17·3), and mean predicted diffusion capacity of carbon monoxide was 48% (10·9). Of the 44 patients who were randomised, 43 completed morphine treatment and 41 completed placebo treatment. In the intention-to-treat analysis, morphine reduced objective awake cough frequency by 39·4% (95% CI -54·4 to -19·4; p=0·0005) compared with placebo. Mean daytime cough frequency reduced from 21·6 (SE 1·2) coughs per h at baseline to 12·8 (1·2) coughs per h with morphine, whereas cough rates did not change with placebo (21·5 [SE 1·2] coughs per h to 20·6 [1·2] coughs per h). Overall treatment adherence was 98% in the morphine group and 98% in the placebo group. Adverse events were observed in 17 (40%) of 43 participants in the morphine group and six (14%) of 42 patients in the placebo group. The main side-effects of morphine were nausea (six [14%] of 43 participants) and constipation (nine [21%] of 43). One serious adverse event (death) occurred in the placebo group. In patients with cough related to idiopathic pulmonary fibrosis, low dose controlled-release morphine significantly reduced objective cough counts over 14 days compared with placebo. Morphine shows promise as an effective treatment to palliate cough in patients with idiopathic pulmonary fibrosis, and longer term studies should be the focus of future research. The Jon Moulton Charity Trust.

U-net convolutional neural network applied to progressive fibrotic interstitial lung disease: Is progression at CT scan associated with a clinical outcome?

BackgroundComputational advances in artificial intelligence have led to the recent emergence of U-Net convolutional neural networks (CNNs) applied to medical imaging. Our objectives were to assess the progression of fibrotic interstitial lung disease (ILD) using routine CT scans processed by a U-Net CNN developed by our research team, and to identify a progression threshold indicative of poor prognosis. MethodsCT scans and clinical history of 32 patients with idiopathic fibrotic ILDs were retrospectively reviewed. Successive CT scans were processed by the U-Net CNN and ILD quantification was obtained. Correlation between ILD and FVC changes was assessed. ROC curve was used to define a threshold of ILD progression rate (PR) to predict poor prognostic (mortality or lung transplantation). The PR threshold was used to compare the cohort survival with Kaplan Mayer curves and log-rank test. ResultsThe follow-up was 3.8 ± 1.5 years encompassing 105 CT scans, with 3.3 ± 1.1 CT scans per patient. A significant correlation between ILD and FVC changes was obtained (p = 0.004, ρ = -0.30 [95% CI: -0.16 to -0.45]). Sixteen patients (50%) experienced unfavorable outcome including 13 deaths and 3 lung transplantations. ROC curve analysis showed an aera under curve of 0.83 (p < 0.001), with an optimal cut-off PR value of 4%/year. Patients exhibiting a PR ≥ 4%/year during the first two years had a poorer prognosis (p = 0.001). ConclusionsApplying a U-Net CNN to routine CT scan allowed identifying patients with a rapid progression and unfavorable outcome.

Therapeutic effects of fatty acid binding protein 1 in mice with pulmonary fibrosis by regulating alveolar epithelial regeneration

IntroductionIdiopathic pulmonary fibrosis is a progressive fibrotic lung disease with limited therapeutic options and high lethality, related to alveolar type II epithelial (ATII) cell dysregulation, the abnormal repair of alveolar...

Efficacy of Pirfenidone According to Dose in Patients with Idiopathic Pulmonary Fibrosis: A Prospective, Observational, Single-Center Cohort Study.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with a poor prognosis. Pirfenidone is approved and widely used for the treatment of IPF and reduces lung function decline. The aim of this study was to evaluate the efficacy of different doses of pirfenidone for the prevention of disease progression in patients with IPF. This was a prospective, observational, single-center cohort study conducted in Haeundae Paik Hospital, Republic of Korea, from April 2021 to March 2023. IPF patients were assigned to three groups according to the dose of pirfenidone (600 mg, 1200 mg, 1800 mg). Disease progression was defined as an absolute decline to ≥5% of forced vital capacity (FVC) (% predicted value) or an absolute decline to ≥10% of diffusing capacity of the lung for carbon monoxide (DLco) (% predicted value) over 12 months. The primary endpoint was to evaluate the clinical effects of pirfenidone of each dosage on disease progression in IPF patients by comparing the FVC (% predicted value) and DLco (% predicted value) values over 12 months. The secondary endpoint was to evaluate the prognostic value of Krebs von den Lungen-6 (KL-6) in the disease progression in IPF patients using the baseline KL-6 value and the change in KL-6 values between the baseline and 12 months. A total of 44 patients were enrolled, of whom 39 completed the study, with 13 patients assigned to each of the three groups. The median age was 71.7 years, and 79.5% of patients were men. The baseline characteristics were similar across groups, except the 600 mg group was older (75.9 vs. 69.2 vs. 68.2 years, p = 0.016). The overall median change in FVC and DLco over 12 months was -2.7% (IQR: -9.1%, -1.2%) and -3.8% (IQR: -13.6%, -3.7%), respectively. There was no difference in the decline in FVC (change in FVC, % predicted value: -3.23 vs. -4.08 vs. -1.54, p = 0.621) and DLco (change in DLco, % predicted value: 0.00 vs. -3.62 vs. -3.15, p = 0.437) among the three groups. Fourteen patients (35.9%) suffered disease progression. The rate of disease progression did not differ according to the dose of pirfenidone (38.5 vs. 38.5 vs. 30.8%, p = 1.000). In multivariable logistic regression analysis, KL-6 was not a statistically significant predictor of disease progression. In our study, regardless of dose, consistent pirfenidone use for 12 months resulted in similar efficacy for the prevention of disease progression in patients with IPF. Large-scale, randomized, double-blind, placebo-controlled clinical trials are needed.

Molecular and Genetic Biomarkers in Idiopathic Pulmonary Fibrosis: Where Are We Now?

Idiopathic pulmonary fibrosis (IPF) represents a chronic progressive fibrotic interstitial lung disease of unknown cause with an ominous prognosis. It remains an unprecedent clinical challenge due to its delayed diagnosis and unpredictable clinical course. The need for accurate diagnostic, prognostic and predisposition biomarkers in everyday clinical practice becomes more necessary than ever to ensure prompt diagnoses and early treatment. The identification of such blood biomarkers may also unravel novel drug targets against IPF development and progression. So far, the role of diverse blood biomarkers, implicated in various pathogenetic pathways, such as in fibrogenesis (S100A4), extracellular matrix remodelling (YKL-40, MMP-7, ICAM-1, LOXL2, periostin), chemotaxis (CCL-18, IL-8), epithelial cell injury (KL-6, SP-A, SP-D), autophagy and unfolded protein response has been investigated in IPF with various results. Moreover, the recent progress in genetics in IPF allows for a better understanding of the underlying disease mechanisms. So far, the causative mutations in pulmonary fibrosis include mutations in telomere-related genes and in surfactant-related genes, markers that could act as predisposition biomarkers in IPF. The aim of this review is to provide a comprehensive overview from the bench to bedside of current knowledge and recent insights on biomarkers in IPF, and to suggest future directions for research. Large-scale studies are still needed to confirm the exact role of these biomarkers.

Neutrophil levels correlate with quantitative extent and progression of fibrosis in IPF: results of a single-centre cohort study

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Clinical studies have demonstrated association between different blood leucocytes and mortality and forced vital capacity (FVC) decline....

Combination of Bronchoalveolar Lavage and CT Differentiates Progressive and Non-Progressive Fibrotic Lung Diseases.

Identifying patients with pulmonary fibrosis (PF) at risk of progression can guide management. We explore the utility of combining baseline bronchoalveolar lavage (BAL) and CT in differentiating progressive and non-progressive PF. The derivation cohort consisted of incident cases of PF, for whom BAL was performed as part of diagnostic work-up. A validation cohort were prospectively recruited with identical inclusion criteria. Baseline thoracic CTs were scored for fibrosis extent and UIP pattern. BAL lymphocyte proportion was recorded. Annualized forced vital capacity decline >10% or death within one year defined disease progression. Multivariable logistic regression identified determinants of outcome. Optimum binary thresholds (maximal Wilcoxon rank statistic) at which CT fibrosis extent and BAL lymphocyte proportion could distinguish disease progression were identified. BAL lymphocyte proportion, UIP pattern and fibrosis extent were significantly and independently associated with disease progression in the derivation cohort (n=240 individuals). Binary thresholds for raised BAL lymphocyte proportion and extensive fibrosis were identified as 25% and 20% respectively. Raised BAL lymphocyte proportion was rare in patients with a UIP pattern (8/135[5.9%]) or with extensive fibrosis (7/144[4.9%]). In the validation cohort (n=290 subjects), a raised BAL lymphocyte proportion was associated with a significantly lower probability of disease progression in patients with non-extensive fibrosis or a non-UIP pattern. BAL lymphocytosis is rare in patients with extensive fibrosis or a UIP pattern on CT. In patients without a UIP pattern or with limited fibrosis, a BAL lymphocyte proportion of ≥ 25% was associated with a lower likelihood of progression.

Design of a phase III, double-blind, randomised, placebo-controlled trial of BI 1015550 in patients with progressive pulmonary fibrosis (FIBRONEER-ILD)

IntroductionProgressive pulmonary fibrosis (PPF) includes any diagnosis of progressive fibrotic interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF). However, disease progression appears comparable between PPF and IPF, suggesting...