Diagnosis Of Idiopathic Pulmonary Fibrosis Research Articles

Comparison of the Effects of Nintedanib and Pirfenidone on Pulmonary Function Test Parameters and Radiological Findings in Patients with Idiopathic Pulmonary Fibrosis: A Real-Life Study

Background and Objectives: The aim of our study is to compare the effects of pirfenidone and nintedanib on lung function and radiologic findings in Idiopathic Pulmonary Fibrosis and to identify which drug is more appropriate for which patient group. Materials and Methods: The data of patients who were treated in our department for at least one year between 1 January 2010 and 31 December 2022 and who were started on pirfenidone or nintedanib treatment with the diagnosis of Idiopathic Pulmonary Fibrosis were retrospectively reviewed. The patients were divided into two groups—the nintedanib and pirfenidone groups—and both groups were compared in terms of progression in lung function tests (changes in FEV1, FVC, 6 MWT and DLCO values at the 3rd, 6th, 9th and 12th months compared to baseline values) and radiological findings (the presence of progression in findings such as ground-glass opacity, reticulation, honeycomb and traction bronchiectasis) within 1 year after diagnosis. Results: The study included 109 patients. The number of patients treated with pirfenidone (IPF patients) was 82 (75,2%) and the number of patients treated with nintedanib was 27 (24,8%). When the PFT values at 3, 6, 9 and 12 months were compared with the baseline values in both groups, there was no statistically significant difference in any parameter between the two groups. No significant difference was found in terms of radiological progression at the end of 1 year in both groups. Conclusions: The results of our study show that pirfenidone and nintedanib are equivalent in their effectiveness in preventing disease progression in patients with IPF.

Diagnostic and predictive values of m5C‑associated genes in idiopathic pulmonary fibrosis.

In patients with idiopathic pulmonary fibrosis (IPF), the role of 5‑methylcytosine (m5C)‑associated genes in the pathogenesis and development of the disease remains unclear. The present study aimed to identify reliable diagnostic markers based on the expression of m5C‑associated genes for the early detection of IPF. Count data were obtained by screening the IPF genome‑wide assay in the Gene Expression Omnibus database, followed by a comparison of m5C gene expression in patients with IPF and controls. The GSE150910 and GSE173355 datasets yielded a total of 23 differentially expressed m5C‑associated genes, which were then investigated for their functions. A diagnostic model was built using eight m5C genes and validated with training sets and the GSE124685 dataset. IPF subtypes were identified based on expression of m5C‑related genes as well as clinical and immunological characteristics. Furthermore, a pulmonary fibrosis model was established in mice by administering bleomycin into the trachea. Lungs were harvested and analyzed using quantitative PCR to determine the expression of m5C‑related genes. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that these genes were significantly enriched in 'base excision repair'. Immunoassay results revealed that 13 immune cell markers (naive, memory and B cell plasma, T cell CD4 naive, T cell CD4 memory resting, T cell follicular helper, T cell regulatory Tregs, NK cell resting, Monocyte, Macrophage M0, Mast cell activated, Eosinophil, and Neutrophil) were significantly associated with IPF. Patients with IPF had lower levels of resting memory CD4+ T cells, which were positively associated with Tet methylcytosine dioxygenase2 (TET2) and Thymine‑DNA glycosylase (TDG) but negatively correlated with NOP2/Sun RNA methyltransferase5 (NSUN5) expression. All samples were classified into based on the levels of the eight diagnostic m5C genes. Samples with high m5C scores are subtype 1, and those with low m5C scores are subtype 2. In subtype 2, male patients had lower levels of CD27 and CD70 but higher levels of CD274, CD86, Cytotoxic T‑lymphocyte‑associated protein4 and Hepatitis A virus cellular receptor2 (HAVCR2). When compared with normal mouse lung tissue samples, expression levels of NOP2/Sun RNA methyltransferase6 (NSUN6), Ubiquitin‑like with PHD and RING Finger Domains1, TDG and TET2 in lung fibrosis tissue samples were significantly higher, while expression levels of NSUN5, NTH‑like DNA glycosylase1, DNA (cytosine‑5‑)‑methyltransferase3 β and Methyl‑CpG binding domain protein 3) were lower. It is possible that m5C‑associated genes play an important role in the diagnosis and typing of IPF. These genes may facilitate investigation of the pathophysiology of IPF and identification of potential treatment targets.

Commonly prescribed medications and risk of pneumonia and all-cause mortality in people with idiopathic pulmonary fibrosis: a UK population-based cohort study

BackgroundA growing body of evidence suggests that prolonged use of inhaled corticosteroids (ICS) and proton pump inhibitors (PPIs) is associated with increased risks of pneumonia. A substantial proportion of people with idiopathic pulmonary fibrosis (IPF) are prescribed PPIs or ICS to treat common comorbidities, giving rise to concerns that use of these medications may be associated with potential harms in this patient population.MethodsWe used UK Clinical Practice Research Datalink (CPRD) Aurum primary care data linked to national mortality and hospital admissions data to create a cohort of people diagnosed with IPF on or after 1 January 2010. Patients were assigned to one of three exposure categories according to their prescribing history in the 12 months prior to IPF diagnosis as follows: “regular” users (≥ 4 prescriptions), “irregular” users (1–3 prescriptions) and “non-users” (no prescriptions). We explored the association between PPI/ICS prescription and pneumonia hospitalisation and all-cause mortality using multinomial Cox regression models.ResultsA total of 17,105 people met our study inclusion criteria; 62.6% were male and 15.9% were current smokers. Median age at IPF diagnosis was 76.7 years (IQR: 69.6–82.7). 19.9% were regularly prescribed PPIs, and 16.0% ICS, prior to IPF diagnosis. Regular prescribing of PPIs and ICS was positively associated with hospitalisation for pneumonia; the adjusted HR for pneumonia hospitalisation comparing regular PPI users with non-users was 1.14 (95%CI: 1.04–1.24); for regular ICS users the corresponding HR was 1.40 (95%CI: 1.25–1.55). We also observed a small increased risk for all-cause mortality in the “regular ICS user” group compared with the “non-user” control group (HRadj = 1.19, 1.06–1.33). We found no evidence of an association between PPI prescribing and all-cause mortality.ConclusionProlonged prescription of medications used to treat common comorbidities in IPF may be associated with increased risks for severe respiratory infections. These findings point to a need to adopt an adequate risk–benefit balance approach to the prescribing of ICS-containing inhalers and PPIs in people with IPF without evidence of comorbidities, especially older patients and/or those with more advanced disease in whom respiratory infections are more likely to result in poorer outcomes.

Treatment patterns and clinical profile in progressive pulmonary fibrosis: a Japanese cross-sectional survey.

There is a paucity of real-world data on patients with interstitial lung diseases (ILDs) that are progressive, other than idiopathic pulmonary fibrosis (IPF), including treatment patterns and attitudes toward treatment. This study aimed to investigate the diagnosis, clinical characteristics, treatment paradigm and current decision-making practices of IPF and progressive pulmonary fibrosis (PPF) in a Japanese real-world setting. Data were drawn from the Adelphi Real World PPF-ILD Disease Specific Programme™, a cross-sectional survey with retrospective data collection of pulmonologists and rheumatologists in Japan from April to October 2022. Physicians provided data for up to 12 consecutive patients with a physician-confirmed diagnosis of progressive ILD; patients were also invited to complete patient self-completion forms. Analyses were descriptive. A total of 63 physicians (43 pulmonologists and 20 rheumatologists) provided data on 312 patients with PPF and 70 patients with IPF. Patients had a mean (standard deviation [SD]) age at survey date of 68.0 (11.6) years, 43.5% were female, 50.3% were former smokers and 18.1% were employed full time. For breathlessness, 26.5% of patients had Grade 2 physician-reported breathlessness; this was 16.7% when reported by patients themselves. A total of 81.4% of patients were currently receiving treatment for ILD. Mean (SD) duration of current treatment was 1.5 (1.4) years. Slowing disease progression was the primary reason influencing physicians' choice of current ILD treatment (48.5%). A total of 16.0% had never been treated (most frequent physician-reported reason: disease was manageable without treatment, 55.7%) and 2.6% had treatment discontinued (most frequent reason: patient request, 70.0%). Physicians reported 82.3% of patients as fully compliant with their treatment regimen. As reported by patients themselves (n = 53), 49.1% never and 37.7% rarely missed a dose. This analysis of real-world data from Japan provides insights into the clinical profile of patients with IPF and PPF in Japan, and highlights differences between physicians and patients in perception of symptom severity and attitudes to treatment.

Comparing multi-texture fibrosis analysis versus binary opacity-based abnormality detection for quantitative assessment of idiopathic pulmonary fibrosis

Automated tools for quantification of idiopathic pulmonary fibrosis (IPF) can aid in ensuring reproducibility, however their complexity and costs can differ substantially. In this retrospective study, two automated tools were compared in 45 patients with biopsy proven (12/45) and imaging-based (33/45) IPF diagnosis (mean age 74 ± 9 years, 37 male) for quantification of pulmonary fibrosis in CT. First, a tool that identifies multiple characteristic lung texture features was applied to measure multi-texture fibrotic lung (MTFL) by combining the amount of ground glass, reticulation, and honeycombing. Opacity-based fibrotic lung (OFL) was measured by a second tool that performs a simpler binary classification of tissue into either normal or opacified lung and was originally developed for quantifying pneumonia. Differences in quantification of MTFL and OFL were assessed by Mann-Whitney U-test and Pearson correlation (r). Also, correlation with spirometry parameters (percent predicted total lung capacity (TLC), percent predicted vital capacity (VC), percent predicted forced expiratory volume in 1 s (FEV1), diffusing capacity of the lungs for carbon monoxide (DLCO), partial pressure of oxygen (PO2) and carbon dioxide (PCO2)) were assessed by r. The prognostic values for 3-year patient survival of OFL, LSS and MTFL were investigated by multivariable Cox-proportional-hazards (CPH) models including sex, age and TLC and including sex, age and VC. Also, Kaplan-Meier analysis with log rank test between subgroups separated by median OFL and MTFL were conducted. No significant difference between OFL and MTFL was observed (median and interquartile range: OFL = 29% [20-38%], MTFL = 31% [19-45%]; P = 0.44). For OFL significant correlation was observed to MTFL (r = 0.93, P < 0.01) and VC (r=-0.50, P = 0.03). For MTFL no significant correlation to spirometry parameters was found. The total time for one analysis was lower for the automated MTFL (MTFL: 313 ± 25s vs. OFL: 612 ± 61s, P < 0.001). Both analyses were significant predictors in the multivariable CPH analysis including TLC (hazard-ratios: MTFL 1.03 [1.01–1.06], P = 0.02; OFL 1.03 [1.00-1.06], P = 0.03). No parameter was a significant predictor in the CPH models including VC (hazard-ratios: MTFL 1.01 [0.98–1.04], P = 1; OFL 1.01 [0.97–1.05], P = 1). OFL showed significance in Kaplan-Meier analysis (MTFL: P = 0.17; OFL: P = 0.03). Using a simple opacity-based quantification of pulmonary fibrosis in IPF patients displayed similar results and prognostic value compared to a more complex multi-texture based analysis.

Pathology of idiopathic pulmonary fibrosis with particular focus on vascular endothelium and epithelial injury and their therapeutic potential.

Idiopathic pulmonary fibrosis (IPF) remains a challenging disease with no drugs available to change the trajectory. It is a condition associated with excessive and highly progressive scarring of the lungs with remodelling and extracellular matrix deposition. It is a highly "destructive" disease of the lungs. The diagnosis of IPF is challenging due to continuous evolution of the disease, which also makes early interventions very difficult. The role of vascular endothelial cells has not been explored in IPF in great detail. We do not know much about their contribution to arterial or vascular remodelling, extracellular matrix changes and contribution to pulmonary hypertension and lung fibrosis in general. Endothelial to mesenchymal transition appears to be central to such changes in IPF. Similarly, for epithelial changes, the process of epithelial to mesenchymal transition seem to be the key both for airway epithelial cells and type-2 pneumocytes. We focus here on endothelial and epithelial cell changes and its contributions to IPF. In this review we revisit the pathology of IPF, mechanistic signalling pathways, clinical definition, update on diagnosis and new advances made in treatment of this disease. We discuss ongoing clinical trials with mode of action. A multidisciplinary collaborative approach is needed to understand this treacherous disease for new therapeutic targets.

Impact of pulmonary rehabilitation on survival in people with Interstitial lung disease.

Pulmonary rehabilitation (PR) is a beneficial intervention for people with interstitial lung disease (ILD), however the effect of PR on survival is unclear. This study compared the survival outcomes in people with ILD who were allocated to PR versus those who were allocated to control in two published randomised controlled trials (RCTs). Does participation in PR impact survival among people with ILD? The combined data from the two previous RCTs of PR in ILD were included. Time from start of PR until date of death, lung transplantation or censoring was calculated. Kaplan-Meir and Cox proportional hazard regression analysis were used to assess the impact of PR on survival. Baseline variables of age at time of PR, gender, FVC, 6-minute walk distance (6MWD), exertional nadir SpO2 and diagnosis of idiopathic pulmonary fibrosis (IPF) were included as covariates. Of the 182 participants with ILD (87 IPF, 109 males, mean (SD) age 69(10), FVC%pred 76(19), TLCO%pred 48(16)), death occurred in 62%, 6% were transplanted, 20% were alive and 12% were lost to follow-up. Median survival for those who completed PR was 6.1 years (95% CI 4.4 to 7.9) compared to 4.7 years (95%CI 3.4 to 6.0) for those in the control group, however this was not significantly different (log rank p=0.7). After adjusting for baseline variables, at 5 years, completion of PR was associated a 44% lower risk of mortality (HR 0.56 (0.36-0.88), p=0.01). At 10 years, no difference in survival was observed between the PR and control group. Participation in PR among people with ILD may impact survival at 5 years. Along with clinical improvements following PR, the potential for a survival benefit further strengthens the importance of PR in the standard care of people with ILD.

An important radiological clue in idiopathic pulmonary fibrosis: Diffuse pulmonary ossification.

Diffuse pulmonary ossification (DPO) refers to the unusual formation of mature bone tissue within the lung parenchyma. It has been shown to be associated with a number of cardiac and chronic lung diseases. The relation between DPO and idiopathic pulmonary fibrosis (IPF) has been shown in the literature. We examined DPO, which is the supporting computed tomography (CT) finding of IPF. In this way, it was aimed to distinguish cases with an IPF-like pattern non-invasively. A retrospective analysis included 89 cases exhibiting a CT pattern typical of usual interstitial pneumonia (UIP). The cases were divided into two groups: One with an IPF diagnosis and the other with a nonIPF diagnosis. The presence of DPO was then assessed in each case according to the criteria outlined in the literature. Finally, the occurrence of DPO was compared between the IPF group and the non-IPF group. Forty-seven of 89 cases had a diagnosis of IPF (52.8%). DPO was observed in 31 patients (34.8%). Presence of DPO was detected in 28 (59.6%) patients in the IPF group. The presence of DPO was detected in 3 (7.1%) cases in the non-IPF UIP patient group. A moderate correlation was found between IPF and DPO, and a moderate correlation was found between IPF and the male sex (r= 0.549; r= 0.311, respectively). DPO is an important finding to support the diagnosis of IPF.

Exercise-Induced Oxygen Desaturation and Outcomes After Nintedanib Therapy for Fibrosing Interstitial Lung Disease in Patients Without Dyspnea.

Background: The degree of exercise-induced oxygen desaturation and outcomes following antifibrotic drug therapy in asymptomatic patients with fibrosing interstitial lung disease (FILD) remain unclear. Methods: We compared clinical data, incidence of annual FILD progression, overall survival, and tolerability after initiating nintedanib between 58 patients with dyspnea and 18 patients without. Annual FILD progression was defined as >10% decrease in forced vital capacity (FVC), >15% decrease in diffusing capacity of the lungs for carbon monoxide (DLCO), developing acute exacerbations, or FILD-related death within 1 year of starting nintedanib. Outcomes between the two groups were adjusted for covariates, including age, gender, FVC, DLCO, and diagnosis of idiopathic pulmonary fibrosis, all known prognostic factors for FILD. Results: In 6-min walk test, incidence of decrease to <90% of SpO2 was significantly lower in non-dyspnea group than in dyspnea group (24% vs. 55%, p = 0.028), but incidence of >4% decreases showed no significant difference (71% vs. 89%, p = 0.11) The incidence of annual progression was significantly lower in non-dyspnea than in dyspnea group (17% vs. 53%, adjusted p = 0.026). The relative change in DLCO was significantly slower in non-dyspnea group (adjusted p = 0.036), but FVC was not (adjusted p = 0.067). Overall survival was longer in non-dyspnea group (adjusted p = 0.0089). The discontinuation rate and therapeutic period of nintedanib were not significantly different between the groups. Conclusions: Asymptomatic patients with FILD have severe exercise-induced oxygen desaturation and better outcomes after nintedanib therapy than symptomatic patients. Antifibrotic drug therapy should not be avoided solely because of a lack of symptoms.

Impact of antifibrotic therapy on lung cancer incidence and mortality in patients with idiopathic pulmonary fibrosis.

Patients with idiopathic pulmonary fibrosis (IPF) are at risk of lung cancer development. Antifibrotic therapy could slow disease progression of IPF, but there is limited data on its effectiveness on lung cancer. Here, we aimed to investigate lung cancer incidence and the risk of mortality of patients with IPF receiving antifibrotic therapy. Data from the Korean National Health Insurance service database between October 2015 and September 2021 were used. The incidence of lung cancer and all-cause mortality in the IPF cohort was analyzed depending on pirfenidone treatment. Those who were diagnosed with lung cancer prior to IPF diagnosis were excluded. Among the 5,038 patients with IPF who were eligible for the study, pirfenidone was administered to 880 patients. Median follow-up duration was 4,872.8 and 23,612.1 person-years in the groups receiving and not receiving pirfenidone, respectively. The incidence of lung cancer was significantly higher in the pirfenidone group compared to non-users [2.44 vs. 1.56 per 100 person-years; risk ratio 1.56; 95% confidence interval (CI), 1.27-1.92]. However, the risk of mortality did not differ significantly between patients receiving pirfenidone and those who did not. Further analysis was conducted to assess lung cancer development and pirfenidone therapy. Among patients with lung cancer, those treated with pirfenidone demonstrated significantly improved survival compared to those not receiving pirfenidone therapy (log-rank test, P<0.001). Pirfenidone therapy was associated with a protective effect on mortality in IPF patients with lung cancer [hazard ratio, 0.61; 95% CI, 0.43-0.85]. Antifibrotic therapy was associated with improved survival in patients with IPF who develop lung cancer, even though the incidence of lung cancer was higher in those receiving antifibrotic treatment compared to those do not.

Differences Between Patients with Probable UIP and Definite UIP on HRCT in Idiopathic Pulmonary Fibrosis: A Real-World Cohort Study.

Background: Both a probable usual interstitial pneumonia (UIP) pattern (p-UIP) and a definite UIP pattern (d-UIP) on high-resolution computed tomography (HRCT) are sufficient to establish a diagnosis of idiopathic pulmonary fibrosis (IPF) without the need for a surgical lung biopsy, according to the 2022 IPF guidelines. However, it remains unknown whether patients with p-UIP and d-UIP have similar disease behaviors and clinical courses. Material and Methods: We retrospectively collected clinical data of patients with IPF and divided the patients into two groups according to their HRCT patterns: a p-UIP group and a d-UIP group. The baseline characteristics, survival rates, and pulmonary function tests were compared between the two groups. The risk factors for mortality were determined by Cox regression in p-UIP and d-UIP separately. Results: There were 304 patients in the p-UIP group and 480 patients in the d-UIP group. Patients in the d-UIP group were more likely to have smoking histories (p < 0.001) and had lower baseline FVC% (74% vs. 77%, p = 0.021) and DLCO% (50% vs. 58%, p < 0.001). Survival rates were higher in p-UIP compared with d-UIP (p = 0.004). There were no differences in changes in FVC% or DLCO% between the two groups. Baseline DLCO% was the only independent risk factor for mortality in p-UIP. Baseline FVC% was independently associated with mortality in d-UIP. Symptom of cough was a risk factor for disease progression (OR = 1.2, p = 0.002) in p-UIP, while symptom of dyspnea might be associated with disease progression in d-UIP (OR = 2.7, p = 0.065). Male patients (OR = 1.88, p = 0.002) with a smoking history (OR = 1.16, p = 0.002) were at higher risk of developing d-UIP. Conclusions: We observed the different disease trajectories between p-UIP and d-UIP. P-UIP on HRCT might identify a subgroup of IPF patients who are in the early stage with a better prognosis.

Investigating the Impact of Social Determinants of Health on Diagnostic Delays and Access to Antifibrotic Treatment in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a rare disease that is challenging to diagnose. Patients with IPF often spend years awaiting a diagnosis after the onset of initial respiratory symptoms, and only a small percentage receive antifibrotic treatment. In this study, we examine the associations between social determinants of health (SDoH) and two critical factors: time to IPF diagnosis following the onset of initial respiratory symptoms, and whether the patient receives antifibrotic treatment. To approximate individual SDoH characteristics, we extract demographic-specific averages from zip code-level data using the American Community Survey (via the U.S. Census Bureau API). Two classification models are constructed, including logistic regression and XGBoost classification. The results indicate that for time-to-diagnosis, the top three SDoH factors are education, gender, and insurance coverage. Patients with higher education levels and better insurance are more likely to receive a quicker diagnosis, with males having an advantage over females. For antifibrotic treatment, the top three SDoH factors are insurance, gender, and race. Patients with better insurance coverage are more likely to receive antifibrotic treatment, with males and White patients having an advantage over females and patients of other ethnicities. This research may help address disparities in the diagnosis and treatment of IPF related to socioeconomic status.

Pirfenidone and risk of lung cancer development in IPF: a nationwide population-based study.

Idiopathic pulmonary fibrosis (IPF) carries a high risk of lung cancer, but the effect of pirfenidone on lung cancer development remains uncertain. We investigated the association between pirfenidone use and lung cancer development in patients with IPF. We included 10 084 patients with IPF from the national claims database. Propensity score analysis with inverse probability of treatment weighting (IPTW) and landmark analyses were employed to evaluate lung cancer occurrence according to pirfenidone use. The association was evaluated using Cox regression models adjusted for clinical and socioeconomic variables. A single-center IPF clinical cohort (n=941) was used for validating the findings. The mean patient age was 69.4 years, 73.8% were men, and 31.6% received pirfenidone. Lung cancer developed in 766 patients with IPF (7.6%; 21.9 cases per 1000 person-years) during a median follow-up of 3.0 years. After IPTW, the pirfenidone group showed lower incidence (10.4 versus 27.9 cases per 1000 person-years) than the no-pirfenidone group. Landmark analysis at 6 months after IPF diagnosis also showed lower incidence of lung cancer in the pirfenidone group than in the no-pirfenidone group. Pirfenidone use was independently associated with a reduced lung cancer risk (weighted adjusted hazard ratio [HR]: 0.347; 95% confidence interval [CI]: 0.258-0.466). A clinical cohort showed similar association (weighted adjusted HR: 0.716; 95% CI: 0.517-0.991). The association persisted across subgroups defined by age or sex. Pirfenidone use may be associated with a reduced lung cancer risk in patients with IPF.

A Low Forced Vital Capacity (FVC)/Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) Ratio Increases Clinical Suspicion for Fibrotic Hypersensitivity Pneumonitis (FHP) Over Idiopathic Pulmonary Fibrosis (IPF).

Background and objective Fibrotic Hypersensitivity Pneumonitis (FHP) and idiopathic pulmonary fibrosis (IPF) are interstitial lung diseases (ILDs) that are challenging to differentiate with prognostic and therapeutic implications. Clinical observations suggest that patients with FHP may have a lower baseline ratio of forced vital capacity (FVC) to the diffusing capacity of the lung for carbon monoxide (DLCO), or FVC/DLCO (F/D) ratio, than patients with IPF. In light of this, we aimed todetermine whether patients with FHP have a significantly lower baseline F/D ratio than patients with IPF. Methods A retrospective chart review was performed at a single academic ILD center. Patients with a probable or definite diagnosis of FHP or IPF were considered for inclusion, while patients with poor-quality pulmonary function tests (PFTs) were excluded. The data collected included demographics, diagnosis modality, FVC and DLCO values within six months of diagnosis, as well as hemoglobin levels within three months of PFTs. Baseline F/D ratios were calculated using each patient's FVC percentage of predicted value divided by the DLCO percentage of predicted value adjusted for hemoglobin when available. One-tailed independent two-sample T-tests were performed. Results Eighty-nine patients met the inclusion criteria: 39 (44%) with FHP and 50 (56%) with IPF. The mean baseline F/D ratio was significantly lower for patients with FHP (M = 1.24, 95% CI: 1.14, 1.33) than for patients with IPF (M = 1.44, 95% CI: 1.31, 1.57, T(87) = 2.23, p = 0.014). A secondary analysis excluding patients with pulmonary hypertension and resting hypoxemia was performed, yielding 72 patients: 32 (44%) with FHP and 40 (56%) with IPF. The mean baseline F/D ratio was significantly lower for patients with FHP (M = 1.22, 95% CI: 1.12, 1.31) compared to patients with IPF (M = 1.37, 95% CI: 1.27, 1.46, T (70) = 2.37, p = 0.01). Conclusions In patients with probable to definite FHP versus IPF, the baseline F/D ratio was significantly lower in patients with FHP, even after excluding patients with coexisting pulmonary hypertension and resting hypoxemia. A lower baseline F/D ratio may be a novel, clinic-ready index to heighten clinical suspicion for FHP compared to IPF. Further larger prospective studies are needed to validate our findings.

Hypnotics and Mortality in Idiopathic Pulmonary Fibrosis: Hospital and National Data-based Analysis

Patients with idiopathic pulmonary fibrosis (IPF) may experience insomnia and use hypnotics. However, the effect of the use of hypnotics on their clinical course remains unclear. Is the use of hypnotics associated with an increased risk of mortality in patients with IPF? This study included 99 patients with IPF from the Hamamatsu hospital-based cohort and 123 patients with IPF from the Seirei hospital-based cohort, as well as 30,218 patients with IPF from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (the NDB cohort). To analyze the association of hypnotics use with outcomes avoiding immortal time bias, multivariable Cox models with time-dependent covariates and target trial emulation with a new user design were used for the hospital- and NDB-based cohorts. In the cohorts studied, the 3-year cumulative incidence of new use of hypnotics following the IPF diagnosis ranged from 13.4%to 24.1%. In both hospital-based cohorts, the continuous use of hypnotics was associated with an increased risk of all-cause mortality and disease progression. In the NDB cohort, the continuous use of hypnotics was also associated with an increased risk of all-cause mortality. Subgroup analysis found associations between the continuous use of hypnotics and increased mortality regardless of sex and comorbidities, excluding certain subpopulations. This study found that continuous use of hypnotics was associated with an increased risk of mortality in patients with IPF. Given the relatively high cumulative incidence of hypnotics use in this population, there is an urgent need to reassess the appropriate use of hypnotics for patients with IPF.

Gene polymorphisms and risk of idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

Idiopathic pulmonary fibrosis (IPF) has been widely hypothesized to occur as a result of an interplay between a nexus of environmental and genetic risk factors. However, not much is known about the genetic aspect of this disease. The objective of this review was to identify the genetic polymorphisms associated with the risk of developing IPF. We searched PubMed, EBSCO CINAHL Plus, Web of Science, and Wiley Cochrane Library databases for studies on risk factors of IPF published between March 2000 and November 2023. Studies with an IPF diagnosis based only on the American Thoracic Society and the European Respiratory Society guidelines were included. Thirty-one case-control studies were included with 3997 IPF and 20,925 non-IPF subjects. Two of the studies enrolled biopsy-proven IPF patients; 13 studies diagnosed IPF on the basis of clinical and high-resolution computed tomography (HRCT) findings; and 14 studies diagnosed based on both biopsy and clinical and HRCT findings. 16 studies with MUC5B rs35705950, IL-4 rs2243250, IL-4 rs2070874, and tumor necrosis factor α (TNFα)-308 were eligible for meta-analysis. The allele contrast model (T versus G) for MUC5B rs35705950 revealed statistically significant association of T allele with the risk of IPF [odds ratio (OR) 3.84, 95% confidence interval (CI) 3.20 to 4.61, adjusted p<0.0001), as was the allele contrast model for Asian (OR 2.83, 95% CI 1.51 to 5.32, adjusted p=0.009) and Caucasian (OR 4.11, 95% CI 3.56 to 4.75, adjusted p<0.0001). The allele contrast models for IL-4 rs2243250, IL-4 rs2070874, and TNFα-308 did not demonstrate any significant association with IPF. This review suggests an association of MUC5B rs35705950 T allele with the risk of developing IPF. To our knowledge, this study is the first to aggregate several genetic polymorphisms associated with IPF.

Longitudinal microcomputed tomography detects onset and progression of pulmonary fibrosis in conditional Nedd4-2 deficient mice.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease, which is usually diagnosed late in advanced stages. Little is known about the subclinical development of IPF. We previously generated a mouse model with conditional Nedd4-2 deficiency (Nedd4-2-/-) that develops IPF-like lung disease. The aim of this study was to characterize the onset and progression of IPF-like lung disease in conditional Nedd4-2-/- mice by longitudinal micro-computed tomography (CT). In vivo micro-CT was performed longitudinally in control and conditional Nedd4-2-/- mice at 1, 2, 3, 4, and 5 mo after doxycycline induction. Furthermore, terminal in vivo micro-CT followed by pulmonary function testing and post mortem micro-CT was performed in age-matched mice. Micro-CT images were evaluated for pulmonary fibrosis using an adapted fibrosis scoring system. Histological assessment of lung collagen content was conducted as well. Micro-CT is sensitive to detect the onset and progression of pulmonary fibrosis in vivo and to quantify distinct radiological IPF-like features along disease development in conditional Nedd4-2-/- mice. Nonspecific interstitial alterations were detected from 3 mo, whereas key features such as honeycombing-like lesions were detected from 4 mo onward. Pulmonary function correlated well with in vivo (r = -0.738) and post mortem (r = -0.633) micro-CT fibrosis scores and collagen content. Longitudinal micro-CT enables in vivo monitoring of the onset and progression and detects radiological key features of IPF-like lung disease in conditional Nedd4-2-/- mice. Our data support micro-CT as a sensitive quantitative endpoint for the preclinical evaluation of novel antifibrotic strategies.NEW & NOTEWORTHY IPF diagnosis, particularly in early stages, remains challenging. In this study, micro-CT is used in conditional Nedd4-2-/- mice to closely monitor the onset and progression of progressive pulmonary fibrosis in vivo. Together with high-resolution post mortem micro-CT, this allowed us to track how nonspecific lung lesions develop into key IPF-like features. This approach offers a noninvasive method to monitor pulmonary fibrosis, providing a quantitative endpoint for the preclinical evaluation of novel antifibrotic strategies.

Exploring the Mechanisms and Preventive Strategies for the Progression from Idiopathic Pulmonary Fibrosis to Lung Cancer: Insights from Transcriptomics and Genetic Factors.

Background: Idiopathic pulmonary fibrosis (IPF) leads to excessive fibrous tissue in the lungs, increasing the risk of lung cancer (LC) due to heightened fibroblast activity. Advances in nucleotide point mutation studies offer insights into fibrosis-to-cancer transitions. Methods: A two-sample Mendelian randomization (TSMR) approach was used to explore the causal relationship between IPF and LC. A weighted gene co-expression network analysis (WGCNA) identified shared gene modules related to immunogenic cell death (ICD) from transcriptomic datasets. Machine learning selected key genes, and a multi-layer perceptron (MLP) model was developed for IPF prediction and diagnosis. SMR and PheWAS were used to assess the expression of key genes concerning IPF risk. The impact of core genes on immune cells in the IPF microenvironment was explored, and in vivo experiments were conducted to examine the progression from IPF to LC. Results: The TSMR approach indicated a genetic predisposition for IPF progressing to LC. The predictive model, which includes eight ICD key genes, demonstrated a strong predictive capability (AUC = 0.839). The SMR analysis revealed that the elevated expression of MS4A4A was associated with an increased risk of IPF (OR = 1.275, 95% CI: 1.029-1.579; p = 0.026). The PheWAS did not identify any significant traits linked to MS4A4A expression. The rs9265808 locus in MS4A4A was identified as a susceptibility site for the progression of IPF to LC, with mutations potentially reprogramming lung neutrophils and increasing the LC risk. In vivo studies suggested MS4A4A as a promising therapeutic target. Conclusions: A causal link between IPF and LC was established, an effective prediction model was developed, and MS4A4A was highlighted as a therapeutic target to prevent IPF from progressing to LC.

Quantitative CT-analysis of over aerated lung tissue and correlation with fibrosis extent in patients with idiopathic pulmonary fibrosis

IntroductionThe usual interstitial pneumonia (UIP) pattern, hallmark of idiopathic pulmonary fibrosis (IPF), may induce harmful local overdistension during mechanical ventilation given the juxtaposition of different tissue elasticities. Mechanotransduction, linking mechanical stress and strain to molecular pro-fibrotic pathways, likely contributes to fibrosis progression. Understanding the mechanical forces and aeration patterns in the lungs of IPF patients is crucial for unraveling potential mechanisms of disease progression. Quantitative lung computed tomography (CT) can accurately assess the air content of lung regions, thus informing on zonal distension. This study aims to investigate radiological evidence of lung over aeration in spontaneously breathing UIP patients compared to healthy controls during maximal inspiration.MethodsPatients with IPF diagnosis referred to the Center for Rare Lung Diseases of the University Hospital of Modena (Italy) in the period 2020–2023 who underwent High Resolution Computed Tomography (HRCT) scans at residual volume (RV) and total lung capacity (TLC) using standardized protocols were retrospectively considered eligible. Patients with no signs of lung disease at HRCT performed with the same image acquisition protocol nor at pulmonary function test (PFTs) served as controls. Lung segmentation and quantitative analysis were performed using 3D Slicer software. Lung volumes were measured, and specific density thresholds defined over aerated and fibrotic regions. Comparison between over aerated lung at RV and TLC in the two groups and according to lung lobes was sought. Further, the correlation between aerated lung and the extent of fibrosis was assessed and compared at RV and TLC.ResultsIPF patients (N = 20) exhibited higher over aerated lung proportions than controls (N = 15) both at RV and TLC (4.5% vs. 0.7%, p < 0.0001 and 13.8% vs. 7%, p < 0.0001 respectively). Over aeration increased significantly from RV to TLC in both groups, with no intergroup difference (p = 0.67). Sensitivity analysis revealed significant variations in over aerated lung areas among lobes when passing from RV to TLC with no difference within lobes (p = 0.28). Correlation between over aeration and fibrosis extent was moderate at RV (r = 0.62, p < 0.0001) and weak at TLC (r = 0.27, p = 0.01), being the two significantly different at interpolation analysis (p < 0.0001).ConclusionsThis study provides the first evidence of radiological signs of lung over aeration in patients with UIP-pattern patients when passing from RV to TLC. These findings offer new insights into the complex interplay between mechanical forces, lung structure, and fibrosis and warrant larger and longitudinal investigations.

A STUDY ON PIRFENIDONE VERSUS NINTEDANIB IN PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS IN A TERTIARY CARE HOSPITAL: A CROSS SECTIONAL STUDY

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic condition with a poor prognosis and have an average life expectancy of 3-4 years. Two antifibrotic treatments have been approved to treat IPF: nintedanib and pirfenidone. These medications lower the decline in lung function and lower the risk of acute respiratory deterioration, which is linked with a high morbidity and death.Individual clinical trials have not been powered to demonstrate mortality decreases, however analysis of pooled data from clinical trials and observational research imply that anti-fibrotic drugs increase life expectancy. This study describes the utility of anti-fibrotic drugs and compare their efficacy. Methods and Materials: This 6 month cross-sectional study conducted at Santhiram Medical College and General Hospital in Nandyal.In patients with IPF , Clinical, functional and radiological data were gathered at baseline and during the follow-up, as per our Center procedure.This study compares and evaluates the efficacy of nintedanib and pirfenidone. A total of 40 patients over the age of 18 with IPF diagnosis were included. Patients under 18 years , those with known fibrosing lung diseases, bronchial asthma, COPD, HIV, Tuberculosis, or other organ failures were excluded. Results: At baseline, IPF patients treated with Pirfenidone had Forced vital capacity(FVC) and Forced expiratory volume at 1 second(FEV1) predicted percentages of 63.57 ± 8.34% and 72.31 ± 4.91%, respectively. In IPF patients treated with Nintedanib, at baseline(time 0), FVC and FEV1 percentages were 60.15±8.82% and 72.31±4.91% respectively. There were no significant variations in FVC and FEV1 percentages at time 0 between patients treated with the two medications (p=0.23,p=0.7,respectively). At 3-month follow-up, patients treated with Pirfenidone had predicted FVC and FEV1 values of 65.73 ± 7.84% and 72.94 ± 4.45%, respectively, whereas patients treated with Nintedanib had predicted valuesof 65.75 ± 7.67% and 72.42 ± 4.45%. At 6-month follow-up, patients on Pirfenidone had predicted FVC and FEV1 values of 66.9 ± 8.72% and 73.5 ± 4.50%, respectively. Nintedanib treatment resulted in 67.7±8.46% and 72.94±4.51% outcomes. Conclusion: our study shown that pirfenidone and nintedanib are equally effective at reducing FVC decline over a 6-month time frame.While nintedanib was slightly more beneficial in lowering FVC decline during the 6-month period. Both drugs were well tolerated, while nintedanib showing good tolerance in the majority of IPF patients.