Idiopathic Pulmonary Fibrosis Severity Research Articles

Updates on the controversial roles of regulatory lymphoid cells in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is the most common and severe form of pulmonary fibrosis, characterized by scar formation in the lung interstitium. Transforming growth factor beta (TGF-β) is known as a key mediator in the fibrotic process, acting on fibroblasts and mediating their proliferation and differentiation into myofibroblasts. Although the immune system is not considered responsible for the initiation of IPF, markers of tolerogenic immunity define the pro-fibrotic microenvironment in the lungs. In homeostatic conditions, regulatory T cells (Tregs) constitute the main lymphoid population responsible for maintaining peripheral tolerance. Similar to Tregs, regulatory B cells (Bregs) represent a recently described subset of B lymphocytes with immunosuppressive functions. In the context of IPF, numerous studies have suggested a role for Tregs in enhancing fibrosis, mainly via the secretion of TGF-β. In humans, most studies show increased percentages of Tregs associated with the severity of IPF, although their exact role remains unclear. In mice, the most commonly used model involves triggering acute lung inflammation with bleomycin, leading to a subsequent fibrotic process. Consequently, data are still conflicting, as Tregs may play a protective role during the inflammatory phase and a deleterious role during the fibrotic phase. Bregs have been less studied in the context of IPF, but their role appears to be protective in experimental models of lung fibrosis. This review presents the latest updates on studies exploring the implication of regulatory lymphoid cells in IPF and compares the different approaches to better understand the origins of conflicting findings.

A Pilot HRCT Follow-Up Study to Test the Feasibility of Predictive Efficacy of Serum Periostin in Idiopathic Pulmonary Fibrosis.

While serum periostin and Krebs von den Lungen-6 (KL-6) have been acknowledged as independent markers in idiopathic pulmonary fibrosis (IPF) diagnosis, the clinical combinatory potential of these biomarkers combined with high-resolution computed tomography (HRCT) has yet to be fully explored. This retrospective study involved 78 participants, comprising 51 UIP-IPF patients and 27healthy controls. All subjects underwent clinical and laboratory examinations, particularly the detection of periostin and KL-6 using ELISA with innovative HRCT fibrosis score evaluations at admission and discharge during hospitalization in UIP-IPF patients. In our cohort of patients with IPF, predominantly male, over an average follow-up period of 195.27 days. Serum levels of periostin and KL-6 were significantly elevated in IPF patients compared to healthy controls (*p < 0.05). Post-treatment, KL-6 levels decreased significantly, while periostin levels increased. Notably, periostin exhibited superior prognostic accuracy over KL-6, with a higher AUC of 0.875 than 0.639 in ROC analysis. An increase in periostin levels correlated with disease progression, as evidenced by worsened HRCT fibrotic scores and decreased survival probability. These findings underscore periostin's potential as a reliable biomarker for assessing IPF severity and therapeutic response. Our findings underscore the preeminence of serum periostin over KL-6 in UIP-IPF diagnosis, particularly when conjoined with HRCT fibrosis score.

Correlations between blood vessel distribution, lung function and structural change in idiopathic pulmonary fibrosis.

Correlations between the image analysis of CT scan, lung function and quality of life in patients with idiopathic pulmonary fibrosis (IPF) remain unclear. This study aimed to investigate the impacts of pulmonary blood-vessel distribution and the extent of fibrosis on the lung function and quality of life of patients with IPF. Patients were enrolled in an IPF registry and had completed pulmonary function tests, chest HRCT, St. George Respiratory Questionnaire (SGRQ) and echocardiography. Pulmonary blood-vessel distribution, specific image-derived airway volume (siVaw) and fibrosis extent (siVfib) were quantitatively calculated by functional respiratory imaging on HRCT. The study subjects were categorized into DLco <40% pred. (n = 40) and DLco ≥40% pred. (n = 19) groups. Patients with DLco <40% pred. had significantly higher scores of SGRQ, composite physiologic index (CPI), exercise oxygen desaturation (∆SpO2), siVaw, lower FVC% pred. and 6-minute walking distance% pred. The proportion of small blood vessels in the upper lobes (BV5PR-UL) was significantly correlated with CPI, DLco % Pred., FVC% pred., SGRQ and ∆SpO2. Only BV5PR-UL had a significant impact on all indices but not BV5PR in the lower lobes (BV5PR-LL). siVfib was significantly negatively correlated with BV5PR-UL, DLco% pred. and FVC% pred., as well as positively correlated with CPI, ∆SpO2 and siVaw. BV5PR-UL and siVfib had significant correlations with lung function and may become important indicators to assess the severity of IPF and the impact on quality of life.

Computational and in vitro screening validates the repositioning potential of Coxibs as anti-fibrotic agents

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with a survival rate of <5 years. The TGF-β plays a significant role in the progression and severity of IPF. The TGF-β receptor type1 TGFBR1 antagonists inhibit the process of fibrosis and may have a role in the treatment of IPF. The main objective of the study was to identify promising drug candidates against IPF using In-silico and In-vitro evaluation methods. An in-silico screening was carried out of the marketed Coxibs to find their TGFBR1 inhibitory potential considering their structural resemblance with the JZO—a co-crystalized ligand of the crystal structure of the TGFBR1. The virtual screening yielded rofecoxib as a TGFBR1 ligand with a significant docking score. To further validate the outcome of molecular docking studies, MD simulation of 200 ns was carried out followed by the determination of conformational stability, binding free energy calculation using MMPBSA/MMGBSA, and Free Energy Landscape (FEL). The therapeutic efficacy of rofecoxib was compared with that of nintedanib (a therapeutic agent used in the treatment of IPF) at equimolar concentrations (5 µM). The model of TGF-β1 (1 ng/ml)-induced EMT of A549 was used to determine the effect of rofecoxib on the EMT markers like cellular morphology, cytokine expressions, fibrosis associated protein, E-cadherin, and α-smooth muscle actin. In vitro results indicated that rofecoxib significantly suppresses the TGF-β1-induced EMT of A549 cells and validates the possible preventive/protective role of rofecoxib in pulmonary fibrosis. In conclusion, rofecoxib may be considered for repositioning as an anti-fibrotic agent. Communicated by Ramaswamy H. Sarma

Circulating metabolic profile in idiopathic pulmonary fibrosis: data from the IPF-PRO Registry

BackgroundThe circulating metabolome, reflecting underlying cellular processes and disease biology, has not been fully characterized in patients with idiopathic pulmonary fibrosis (IPF). We evaluated whether circulating levels of metabolites correlate with the presence of IPF, with the severity of IPF, or with the risk of clinically relevant outcomes among patients with IPF.MethodsWe analyzed enrollment plasma samples from 300 patients with IPF in the IPF-PRO Registry and 100 individuals without known lung disease using a set of targeted metabolomics and clinical analyte modules. Linear regression was used to compare metabolite and clinical analyte levels between patients with IPF and controls and to determine associations between metabolite levels and measures of disease severity in patients with IPF. Unadjusted and adjusted univariable Cox regression models were used to evaluate associations between circulating metabolites and the risk of mortality or disease progression among patients with IPF.ResultsLevels of 64 metabolites and 5 clinical analytes were significantly different between patients with IPF and controls. Among analytes with greatest differences were non-esterified fatty acids, multiple long-chain acylcarnitines, and select ceramides, levels of which were higher among patients with IPF versus controls. Levels of the branched-chain amino acids valine and leucine/isoleucine were inversely correlated with measures of disease severity. After adjusting for clinical factors known to influence outcomes, higher levels of the acylcarnitine C:16-OH/C:14-DC were associated with all-cause mortality, lower levels of the acylcarnitine C16:1-OH/C14:1DC were associated with all-cause mortality, respiratory death, and respiratory death or lung transplant, and higher levels of the sphingomyelin d43:2 were associated with the risk of respiratory death or lung transplantation.ConclusionsIPF has a distinct circulating metabolic profile characterized by increased levels of non-esterified fatty acids, long-chain acylcarnitines, and ceramides, which may suggest a more catabolic environment that enhances lipid mobilization and metabolism. We identified select metabolites that were highly correlated with measures of disease severity or the risk of disease progression and that may be developed further as biomarkers.Trial registrationClinicalTrials.gov; No: NCT01915511; URL: www.clinicaltrials.gov.

Assessment of lung deformation in patients with idiopathic pulmonary fibrosis with elastic registration technique on pulmonary three-dimensional ultrashort echo time MRI.

To assess lung deformation in patients with idiopathic pulmonary fibrosis (IPF) using with elastic registration algorithm applied to three-dimensional ultrashort echo time (3D-UTE) MRI and analyze relationship of lung deformation with the severity of IPF. Seventy-six patients with IPF (mean age: 62±6 years) and 62 age- and gender-matched healthy controls (mean age: 58±4 years) were prospectively enrolled. End-inspiration and end-expiration images acquired with a single breath-hold 3D-UTE sequence were registered using elastic registration algorithm. Jacobian determinants were calculated from deformation fields and represented on color maps. Jac-mean (absolute value of the log means of Jacobian determinants) and the Dice similarity coefficient (Dice) were compared between different groups. Compared with healthy controls, the Jac-mean of IPF patients significantly decreased (0.21±0.08 vs. 0.27±0. 07, p < 0.001). Furthermore, the Jac-mean and Dice correlated with the metrics of pulmonary function tests and the composite physiological index. The lung deformation in IPF patients with dyspnea Medical Research Council (MRC) ≥ 3 (Jac-mean: 0.16±0.03; Dice: 0.06±0.02) was significantly lower than MRC1 (Jac-mean: 0. 25±0.03, p < 0.001; Dice: 0.10±0.01, p < 0.001) and MRC 2 (Jac-mean: 0.22±0.11, p = 0.001; Dice: 0.08±0.03, p = 0.006). Meanwhile, Jac-mean and Dice correlated with health-related quality of life, 6 min-walk distance, and the extent of pulmonary fibrosis. Jac-mean correlated with pulmonary vascular-related indexes on high-resolution CT. The decreased lung deformation in IPF patients correlated with the clinical severity of IPF patients. Elastic registration of inspiratory-to-expiratory 3D UTE MRI may be a new morphological and functional marker for non-radiation and noninvasive evaluation of IPF. This prospective study demonstrated that lung deformation decreased in idiopathic pulmonary fibrosis (IPF) patients and correlated with the severity of IPF. Elastic registration of inspiratory-to-expiratory three-dimensional ultrashort echo time (3D UTE) MRI may be a new morphological and functional marker for non-radiation and noninvasive evaluation of IPF. • Elastic registration of inspiratory-to-expiratory three-dimensional ultrashort echo time (3D UTE) MRI could evaluate lung deformation. • Lung deformation significantly decreased in idiopathic pulmonary fibrosis (IPF) patients, compared with the healthy controls. • Reduced lung deformation of IPF patients correlated with worsened pulmonary function and the composite physiological index (CPI).

Elastic Registration Algorithm Based on Three-dimensional Pulmonary MRI in Quantitative Assessment of Severity of Idiopathic Pulmonary Fibrosis.

To quantitatively analyze lung elasticity in idiopathic pulmonary fibrosis (IPF) using elastic registration based on 3-dimensional pulmonary magnetic resonance imaging (3D-PMRI) and to assess its' correlations with the severity of IPF patients. Thirty male patients with IPF (mean age: 62±6y) and 30 age-matched male healthy controls (mean age: 62±6y) were prospectively enrolled. 3D-PMRI was acquired with a 3-dimensional ultrashort echo time sequence in end-inspiration and end-expiration. MR images were registered from end-inspiration to end-expiration with the elastic registration algorithm. Jacobian determinants were calculated from deformation fields on color maps. The log means of the Jacobian determinants (Jac-mean) and Dice similarity coefficient were used to describe lung elasticity between 2 groups. Then, the correlation of lung elasticity with dyspnea Medical Research Council (MRC) score, exercise tolerance, health-related quality of life, lung function, and the extent of pulmonary fibrosis on chest computed tomography were analyzed. The Jac-mean of IPF patients (-0.19, [IQR: -0.22, -0.15]) decreased (absolute value), compared with healthy controls (-0.28, [IQR: -0.31, -0.24], P<0.001). The lung elasticity in IPF patients with dyspnea MRC≥3 (Jac-mean: -0.15; Dice: 0.06) was significantly lower than MRC 1 (Jac-mean: -0.22, P=0.001; Dice: 0.10, P=0.001) and MRC 2 (Jac-mean: -0.21, P=0.007; Dice: 0.09, P<0.001). In addition, the Jac-mean negatively correlated with forced vital capacity % (r=-0.487, P<0.001), forced expiratory volume 1% (r=-0.413, P=0.004), TLC% (r=-0.488, P<0.001), diffusing capacity of the lungs for carbon monoxide % predicted (r=-0.555, P<0.001), 6-minute walk distance (r=-0.441, P=0.030) and positively correlated with respiratory symptoms (r=0.430, P=0.042). Meanwhile, the Dice similarity coefficient positively correlated with forced vital capacity % (r=0.577, P=0.004), forced expiratory volume 1% (r=0.526, P=0.012), diffusing capacity of the lungs for carbon monoxide % predicted (r=0.435, P=0.048), 6-minute walk distance (r=0.473, P=0.016), final peripheral oxygen saturation (r=0.534, P=0.004), the extent of fibrosis on chest computed tomography (r=-0.421, P=0.021) and negatively correlated with activity (r=-0.431, P=0.048). Lung elasticity decreased in IPF patients and correlated with dyspnea, exercise tolerance, health-related quality of life, lung function, and the extent of pulmonary fibrosis. The lung elasticity based on elastic registration of 3D-PMRI may be a new nonradiation imaging biomarker for quantitative evaluation of the severity of IPF.

Insight into the relationship between forced vital capacity and transfer of the lungs for carbon monoxide in patients with idiopathic pulmonary fibrosis

BackgroundForced vital capacity (FVC) is routinely used to quantify the severity and identify the progression of idiopathic pulmonary fibrosis (IPF). Although less commonly used, lung transfer of carbon monoxide (TLCO) correlates better with the severity of IPF than does FVC. MethodsAiming at studying how FVC behaves in relation to TLCO, we analysed cross-sectional data from 430 IPF patients, of which 221 had at least 2 assessments (performed 2.4 ± 1.9 years apart) available for longitudinal analyses. Thresholds for identifying “abnormal” FVC and TLCO values were the statistically-defined lower limits of normal (LLN). For patients with longitudinal data, mean annual absolute declines of FVC and TLCO were calculated. ResultsThe correlation between FVC and TLCO (%predicted) was weak (R2=0.21). FVC was “abnormal” (i.e., <LLN) in 38% of patients while 84% of patients had an “abnormal” TLCO. A large majority of the 268 patients with a “normal” FVC had nevertheless an “abnormal” TLCO (n = 209; 78%). On longitudinal analysis, 67/221 patients had an annual absolute decline in FVC≥5%, 34/221 had an annual absolute decline in TLCO ≥10%, and 22 had both. ConclusionIn IPF, a “normal” FVC should be viewed with caution as it is most often associated with an “abnormal” TLCO, a parameter that is strongly correlated with the morphological extent of the disease. Only 1/3 of the patients with a FVC-based progression criterion also had a TLCO progression criterion. In contrast, 2/3 of patients with a TLCO progression criterion also had a FVC progression criterion.

Quantitative analysis of high-resolution computed tomography features of idiopathic pulmonary fibrosis: a structure-function correlation study.

The quantitative analysis of high-resolution computed tomography (HRCT) is increasingly being used to quantify the severity and evaluate the prognosis of disease. Our aim was to quantify the HRCT features of idiopathic pulmonary fibrosis (IPF) and identify their association with pulmonary function tests. This was a retrospective, single-center, clinical research study. Patients with IPF were retrospectively included. Pulmonary segmentation was performed using the deep learning-based method. Radiologists manually segmented 4 findings of IPF, including honeycombing (HC), reticular pattern (RE), traction bronchiectasis (TRBR), and ground glass opacity (GGO). Pulmonary vessels were segmented with the automatic integration segmentation method. All segmentation results were quantified by the corresponding segmentation software. Correlations between the volume of the 4 findings on HRCT, volume of the lesions at different sites, pulmonary vascular-related parameters, and pulmonary function tests were analyzed. A total of 101 IPF patients (93 males) with a median age of 63 years [interquartile range (IQR), 58 to 68 years] were included in this study. Total lesion extent demonstrated a stronger negative correlation with diffusion capacity for carbon monoxide (DLco) compared to HC, RE, and TRBR [total lesion ratio, correlation coefficient (r) =-0.67, P<0.001; HC, r=-0.45, P<0.001; RE, r=-0.41, P<0.001; TRBR, r=-0.25, P<0.05, respectively]. Correlations with lung function were similar among various lesion sites with r from -0.38 to -0.61 (P<0.001). Pulmonary artery volume (PAV) displayed a slightly increased positive association with the DLco compared to total pulmonary vascular volume (PVV); for PAV, r=0.41 and P<0.001 and for total PVV, r=0.36 and P<0.001. Additionally, total lesion extent, HC, and RE indicated a negative relationship with vascular-related parameters, and the strength of the correlations was independent of lesion site. Quantitative analysis of HRCT features of IPF indicated a decline in function and an aggravation of vascular destruction with increasing lesion extent. Furthermore, a positive correlation between vascular-related parameters and pulmonary function was confirmed. This co-linearity indicated the potential of vascular-related parameters as new objective markers for evaluating the severity of IPF.

Soluble CD163 is produced by monocyte-derived and alveolar macrophages, and is not associated with the severity of idiopathic pulmonary fibrosis.

The soluble form of the membrane hemoglobin scavenger receptor CD163 (sCD163), released by shedding, is a strong marker for macrophage activation. Serum sCD163 levels rise in several acute inflammatory states and some fibrosing diseases. Monocyte-derived macrophages (MoDM) differentiated by macrophage colony-stimulating factor (M-MoDM) contribute to the pathophysiology of idiopathic pulmonary fibrosis (IPF), an irreversible and rapidly fatal interstitial lung disease. Since M-MoDM express high membrane CD163 levels, we thus postulated that sCD163 could be a relevant biomarker for macrophage activation in IPF. We found that M-MoDM constitutively released higher amounts of sCD163 (49.5 ± 24.5 ng/ml) than monocytes (0.45 ± 0.32 ng/ml) or MoDM differentiated with granulocyte macrophage-stimulating factor (2.24 ± 0.98 ng/ml). The basal production of sCD163 by M-MoDM was increased following stimulation with lipopolysaccharide (123.4 ± 54.9 ng/ml) or ATP (168.9 ± 41.8 ng/ml). The sCD163 release was controlled by metalloproteases but not through ADAM17 activation. Moreover, CD163-positive macrophages and sCD163 were detected in pulmonary tissues and alveolar fluids of Caucasian patients with IPF, respectively. IPF alveolar macrophages constitutively secreted sCD163 amounts (67.6 ± 44.6 ng/µg RNA) which were significantly higher than those released by alveolar macrophages isolated from controls (19.2 ± 7.6 ng/µg RNA) or patients with other interstitial lung disease (31.5 ± 16.6 ng/µg RNA). However, the concentrations of sCD163 in blood serum collected from 155 patients with IPF did not correlate with the severity of their disease. In conclusion, our results show that M-MoDM constituted a pertinent model to study the regulation of sCD163 production. Yet, serum sCD163 values could not provide a prognostic biomarker for IPF in our cohort.

Correlation of respiratory oscillometry with CT image analysis in a prospective cohort of idiopathic pulmonary fibrosis

BackgroundMarkers of idiopathic pulmonary fibrosis (IPF) severity are based on measurements of forced vital capacity (FVC), diffusing capacity (DLCO) and CT. The pulmonary vessel volume (PVV) is a novel quantitative...

Therapeutic decisions in a cohort of patients with idiopathic pulmonary fibrosis: a multicenter, prospective survey from Poland.

Background:Pirfenidone and nintedanib are considered as the standard of care in idiopathic pulmonary fibrosis (IPF), but there is no consensus as to which of these two agents should be regarded as first-line treatment.Objective:To provide real-world data on therapeutic decisions of pulmonary specialists, particularly the choice of the antifibrotic drug in patients with IPF.Methods:This was a multicenter, prospective survey collecting clinical data of patients with IPF considered as candidates for antifibrotic treatment between September 2019 and December 2020. Clinical characteristics and information on the therapeutic approach were retrieved. Statistical evaluation included multiple logistic regression analysis with stepwise model selection.Results:Data on 188 patients [74.5% male, median age 73 (interquartile range, 68–78) years] considered for antifibrotic therapy were collected. Treatment was initiated in 138 patients, while 50 patients did not receive an antifibrotic, mainly due to the lack of consent for treatment and IPF severity. Seventy-two patients received pirfenidone and 66 received nintedanib. Dosing protocol (p < 0.01) and patient preference (p = 0.049) were more frequently associated with the choice of nintedanib, while comorbidity profile (p = 0.0003) and concomitant medication use (p = 0.03) were more frequently associated with the choice of pirfenidone. Age (p = 0.002), lung transfer factor for carbon monoxide (TLCO) (p = 0.001), and gastrointestinal bleeding (p = 0.03) were significantly associated with the qualification for the antifibrotic treatment.Conclusion:This real-world prospective study showed that dose protocol and patient preference were more frequently associated with the choice of nintedanib, while the comorbidity profile and concomitant medication use were more frequently associated with the choice of pirfenidone. Age, TLCO, and history of gastrointestinal bleeding were significant factors influencing the decision to initiate antifibrotic therapy.

Lung Tissue Microbiome Is Associated With Clinical Outcomes of Idiopathic Pulmonary Fibrosis.

Background: Several studies using bronchoalveolar lavage fluid (BALF) reported that lung microbial communities were associated with the development and clinical outcome of idiopathic pulmonary fibrosis (IPF). However, the microbial communities in IPF lung tissues are not well known. This study is aimed to investigate bacterial microbial communities in lung tissues and determine their impact on the clinical outcomes of patients with IPF.Methods: Genomic DNA extracted from lung tissues of patients with IPF (n = 20; 10 non-survivors) and age- and sex-matched controls (n = 20) was amplified using fusion primers targeting the V3 and V4 regions of the 16S RNA genes with indexing barcodes.Results: Mean age of IPF subjects was 63.3 yr, and 65% were male. Alpha diversity indices did not significantly differ between IPF patients and controls, or between IPF non-survivors and survivors. The relative abundance of Lactobacillus, Paracoccus, and Akkermansia was increased, whereas that of Caulobacter, Azonexus, and Undibacterium decreased in patients with IPF compared with that in the controls. A decreased relative abundance of Pelomonas (odds ratio [OR], 0.352, p = 0.027) and Azonexus (OR, 0.013, p = 0.046) was associated with a diagnosis of IPF in the multivariable logistic analysis adjusted by age and gender. Multivariable Cox analysis adjusted for age and forced vital capacity (FVC) revealed that higher relative abundance of Streptococcus (hazard ratio [HR], 1.993, p = 0.044), Sphingomonas (HR, 57.590, p = 0.024), and Clostridium (HR, 37.189, p = 0.038) was independently associated with IPF mortality. The relative abundance of Curvibacter (r = 0.590) and Thioprofundum (r = 0.373) was correlated positively, whereas that of Anoxybacillus (r = −0.509) and Enterococcus (r = −0.593) was correlated inversely with FVC. In addition, the relative abundance of the Aquabacterium (r = 0.616) and Peptoniphilus (r = 0.606) genera was positively correlated, whereas that of the Fusobacterium (r = −0.464) and Phycicoccus (r = −0.495) genera was inversely correlated with distance during the 6-min walking test.Conclusions: The composition of the microbiome in lung tissues differed between patients with IPF and controls and was associated with the diagnosis, mortality, and disease severity of IPF.

A Soft Voting Ensemble-Based Model for the Early Prediction of Idiopathic Pulmonary Fibrosis (IPF) Disease Severity in Lungs Disease Patients.

Idiopathic pulmonary fibrosis, which is one of the lung diseases, is quite rare but fatal in nature. The disease is progressive, and detection of severity takes a long time as well as being quite tedious. With the advent of intelligent machine learning techniques, and also the effectiveness of these techniques, it was possible to detect many lung diseases. So, in this paper, we have proposed a model that could be able to detect the severity of IPF at the early stage so that fatal situations can be controlled. For the development of this model, we used the IPF dataset of the Korean interstitial lung disease cohort data. First, we preprocessed the data while applying different preprocessing techniques and selected 26 highly relevant features from a total of 502 features for 2424 subjects. Second, we split the data into 80% training and 20% testing sets and applied oversampling on the training dataset. Third, we trained three state-of-the-art machine learning models and combined the results to develop a new soft voting ensemble-based model for the prediction of severity of IPF disease in patients with this chronic lung disease. Hyperparameter tuning was also performed to get the optimal performance of the model. Fourth, the performance of the proposed model was evaluated by calculating the accuracy, AUC, confusion matrix, precision, recall, and F1-score. Lastly, our proposed soft voting ensemble-based model achieved the accuracy of 0.7100, precision 0.6400, recall 0.7100, and F1-scores 0.6600. This proposed model will help the doctors, IPF patients, and physicians to diagnose the severity of the IPF disease in its early stages and assist them to take proactive measures to overcome this disease by enabling the doctors to take necessary decisions pertaining to the treatment of IPF disease.

Progression of Idiopathic Pulmonary Fibrosis Is Associated with Silica/Silicate Inhalation

Recently, environmental dust exposure has emerged as a possible risk factor for interstitial pneumonia. Inhaled silica/silicates and titanium are associated with the progression of rapidly progressive pneumoconiosis. However, the relationship between inhaled elements and idiopathic pulmonary fibrosis (IPF) remains unclear. In this study, we focused on IPF presenting with histological usual interstitial pneumonia and investigated the relationship between inhaled elements and IPF progression. We examined the elements in the lungs using in-air micro-particle-induced X-ray emission analysis (PIXE). Lung tissue samples with IPF were analyzed and compared with control lung samples. There was a significant difference between IPF and the control lungs in terms of silicon, assumed to form silica/silicates. Inhaled silicon in the lungs significantly correlated with the annual decline in forced vital capacity in patients with IPF. Furthermore, IPF patients with higher accumulation of silicon showed a significantly poorer prognosis than those with lower accumulation of silicon in the lungs. These significant differences were also seen in multivariate analyses, including smoking history, IPF severity, and/or antifibrotic treatment. In-air micro-PIXE can be beneficial for detecting inhaled elements in the lung. These results indicate that inhaled silica/silicates in the lung may be partly involved in the progression of IPF.

Cyclophosphamide added to glucocorticoids in acute exacerbation of idiopathic pulmonary fibrosis (EXAFIP): a randomised, double-blind, placebo-controlled, phase 3 trial

The use of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF) is unknown. Our study was designed to evaluate the efficacy and safety of four cyclophosphamide pulses in addition to high-dose methylprednisolone in this population. In this double-blind, placebo-controlled trial done in 35 departments across 31 hospitals in France, adult patients (≥18 years) with acute exacerbation of IPF and those with suspected acute exacerbation of IPF were randomly assigned in a 1:1 ratio using a web-based system to receive either intravenous pulses of cyclophosphamide (600 mg/m2) plus uromitexan as haemorrhagic cystitis prophylaxis (200 mg/m2) at the time of cyclophosphamide administration and then again, 4 h later, or placebo at days 0, 15, 30, and 60. Random assignment was stratified according to the severity of IPF and was block-balanced with variable block sizes of four or six patients. Patients receiving mechanical ventilation, with active infection, with active cancer, or who were registered on the lung transplant waiting list were excluded. All patients received standardised high-dose glucocorticoids. The investigators, patients, and the sponsor were masked to the treatment assignments. The primary endpoint was 3-month all-cause mortality, analysed by a χ2 test adhering to an intention-to-treat principle. The trial is now complete and registered with ClinicalTrials.gov, NCT02460588. Between Jan 22, 2016, and July 19, 2018, 183 patients were assessed for eligibility, of whom 120 patients were randomly assigned and 119 patients (62 [52%] with severe IPF) received at least one dose of cyclophosphamide (n=60) or placebo (n=59), all of whom were included in the intention-to-treat analysis. The 3-month all-cause mortality was 45% (27/60) in patients given cyclophosphamide compared with 31% (18/59) in the placebo group (difference 14·5% [95% CI -3·1 to 31·6]; p=0·10). Similar results were found after adjustment by IPF severity (odds ratio [OR] 1·89 [95% CI 0·89-4·04]). The risk of death at 3 months, independent of the treatment received, was higher with severe than non-severe IPF (OR 2·62 [1·12-6·12]) and was lower with the use of antifibrotic therapy (OR 0·33 [0·13-0·82]). Adverse events were similar between groups by 6 months (25 [42%] in the cyclophosphamide group vs 30 [51%] in the placebo group) and their proportion, including infections, did not differ. Overall infection was the main adverse event and occurred in 20 (33%) of 60 patients in the cyclophosphamide group versus 21 (36%) of 59 patients in the placebo group. In patients with acute exacerbation of IPF, adding intravenous cyclophosphamide pulses to glucocorticoids increased 3-month mortality. These findings provide evidence against the use of intravenous cyclophosphamide in such patients. Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC 2014-502), Roche Pharmaceuticals.

Relationship between air pollution levels in Madrid and the natural history of idiopathic pulmonary fibrosis: severity and mortality

ObjectiveWe aimed to assess the relationship between major air pollutants and the natural history and mortality of idiopathic pulmonary fibrosis (IPF).MethodsWe conducted a retrospective cohort study from 2013 to 2019 among 52 patients with IPF from the pneumology department of a tertiary hospital. According to their geocoded residential address, each patient was assigned a mean concentration of carbon monoxide (CO), nitrogen dioxide, particulate matter 2.5 and 10, ozone, and sulfur dioxide, as measured at a single surveillance station in central Madrid, Spain. We analyzed forced vital capacity (FVC), CO diffusing capacity, 6-minute walking test, degree of dyspnea, radiologic pattern, and signs of pulmonary hypertension in all patients.ResultsPatients’ mean age was 66 ± 10 years, and 79% were men. The mean predicted FVC was 78.9 ± 0.5%. Forty-two patients met the criteria for severe disease, and 18 patients died. Mortality was significantly associated with increased CO exposure (for each 0.1 mg/m2 increase: odds ratio 2.45, 95% confidence interval 1.39–4.56). We observed no association between any of the other investigated contaminants and IPF mortality or severity.ConclusionsAir pollution, specifically that caused by carbon monoxide, can increase mortality in patients with IPF.

Antithrombin III as predictive indicator of survival in idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib: a preliminary study.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease often managed with nintedanib, a tyrosine kinase inhibitor targeting several profibrotic pathways. Although clotting processes are involved in wound healing and repair in the lung, there are no data on the role of antithrombin III (ATIII) in IPF patients treated with nintedanib. A previous proteomic analysis of serum of IPF patients before and after 1 year of nintedanib treatment showed differential protein expression of ATIII. Here we used quantitative methods to evaluate differential ATIII concentrations in IPF patients before and after 1 year of nintedanib treatment and to assess the potential of ATIII as a prognostic biomarker in IPF patients. Serum levels of ATIII were measured by enzyme-linked immunosorbent assay in 14 IPF patients before and after 1 year of nintedanib treatment. A statistically significant inverse correlation was found between serum ATIII concentrations and pulmonary function test parameters in all patients at baseline and follow up. Baseline serum ATIII and bronchoalveolar lavage (BAL) neutrophils proved to be reliable predictors of poor prognosis. A baseline ATIII threshold of 126.5 μg/mL discriminated survivors from non-survivors. After 12 months of antifibrotic treatment, IPF patients with high serum ATIII concentrations and high BAL neutrophil percentages had a poor prognosis and increased survival risk. The results of this preliminary study suggest that ATIII has potential as a biomarker of IPF severity and in predicting response to nintedanib therapy. As a marker, ATIII showed several advantages over BAL neutrophil percentage.

Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity

BackgroundIdiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity.MethodsThe genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5 × 10−8) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls).FindingsWe detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04–0·57], P = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92–1·20], P = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06–1·38], P = 4·24 × 10−3). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73–1·00], P = 2·99 × 10−2) .InterpretationThe strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors.FundingNovo Nordisk Foundation and Oak Foundation.

Systematic Review and Metanalysis of Oncomarkers in IPF Patients and Serial Changes of Oncomarkers in a Prospective Italian Real-Life Case Series.

Simple SummaryThis paper is a review of the literature on the clinical role of oncomarkers in idiopathic pulmonary fibrosis (IPF) progression, and a description of the routine oncomarker trend in IPF patients over the longest follow-up yet reported. This is the first meta-analysis to review the results of studies evaluating the predictive prognostic value of circulating oncomarkers (CEA, Ca15.3, Ca19.9, Ca125, and KL-6) for IPF. The study focused on the discovery of multiple biomarker signatures, such as combinations of oncomarkers, that are widely and routinely available in biochemistry laboratories. The combination of clinical parameters and biological markers could help achieve more accurate results regarding prognosis and response to treatment in IPF. Our results could pave the way for a more “personalized” medical approach to patients affected by IPF.Background: Idiopathic pulmonary fibrosis (IPF) is a severe progressive interstitial lung disease. At 5-year follow-up, 15% of IPF patients develop lung cancer, which significantly reduces the survival rate. Here we review the literature on the clinical role of oncomarkers in IPF progression, and describe the trend of routine oncomarkers in IPF patients over the longest follow-up yet reported. Materials and methods: A systematic search of the literature in PubMed was performed to find relevant studies published up to 24 September 2020. The most common oncomarkers were chosen to select papers related to pulmonary fibrosis. Then, 24 IPF patients and 25 non-IPF patients, followed at Careggi ILD Referral Centre and Siena Regional Referral Centre for ILD, were enrolled consecutively. Results: A few studies reported an association between serum oncomarkers and severity of IPF. NSE, CEA, Ca19.9, and Ca125 were higher in the IPF, than in the non-IPF, group at every follow-up (p < 0.05). Ca15.3 concentrations were higher in the IPF, than the non-IPF, group at t3 (p = 0.0080) and t4 (p = 0.0168). To improve the specificity and sensitivity of Ca15.3, a panel of biomarkers was analyzed, with the IPF group as dependent variable, and chitotriosidase, Cyfra 21.1, Ca15.3, Ca125, and Ca19.9 as independent variables. Conclusions: This study focused on the discovery of multiple biomarker signatures, such as combinations of oncomarkers, that are widely and routinely available in biochemistry laboratories. The combination of clinical parameters and biological markers could help achieve more accurate results regarding prognosis and response to treatment in IPF. Our results could pave the way for a more “personalized” medical approach to patients affected by IPF.