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Background and Objectives: Pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and secondary pulmonary fibrosis (SPF), is a progressive lung disease that significantly impairs respiratory function. Accurate differentiation between IPF and SPF is crucial for effective management. This study explores the association between pulmonary fibrosis and hepatic conditions, evaluating the utility of various hemogram-derived ratios and hepatic fibrosis scores in distinguishing between IPF and SPF. Materials and Methods: We conducted a retrospective study involving patients diagnosed with IPF or SPF at the "Leon Daniello" Clinical Hospital of Pneumology in Cluj-Napoca, Romania. Pulmonary fibrosis was confirmed via imaging techniques, and hepatic steatosis and fibrosis were assessed using non-invasive scores. We analyzed clinical, laboratory, and pulmonary function data, focusing on hemogram-derived ratios and hepatic scores. Statistical analyses, including ROC curves, were used to evaluate the effectiveness of these biomarkers in differentiating IPF from SPF. Results: We included a total of 38 patients with IPF and 28 patients with SPF. Our findings revealed that IPF patients had a significantly higher FIB-4 score compared to SPF patients, suggesting increased hepatic fibrosis risk in IPF, as well as an increased RDW/PLT ratio. Conversely, SPF patients exhibited elevated PLR, PNR, and SII, reflecting a more pronounced inflammatory profile. PLR and PNR demonstrated the highest discriminatory ability between IPF and SPF, while traditional hepatic fibrosis scores showed limited differentiation capabilities. No significant differences in pulmonary function tests were observed across hepatic fibrosis risk categories. Conclusions: The study highlights the value of biomarkers like PLR and PNR in differentiating between IPF and SPF, offering additional diagnostic insights beyond traditional imaging. Integrating hepatic assessments into the management of pulmonary fibrosis could improve diagnostic accuracy and patient care.

Objectives: To synthesize the clinical experience of patients with COVID-19-associated acute respiratory distress syndrome (ARDS) or pulmonary fibrosis (PF) receiving lung transplantation (LTx) and compare the characteristics and outcomes of COVID-19 and non-COVID-19 LTx patients., Methods: A literature search of online databases (PubMed, Web of Science, Embase, the Cochrane Library, China Science and Technology Journal Database, and Wan Fang databases) was performed regarding LTx for COVID-19-associated ARDS or PF. This study was registered on PROSPERO (CRD2024507647)., Results: Eight eligible studies were included with 478 COVID-19 LTx patients and 163 non-COVID-19 LTx patients. In COVID-19 LTx patients, the pooled hospital mortality and follow-up survival rate was 0.00% (95% CI 0.00-0.03) and 87.40% (95% CI 0.76-0.96). Compared to non-COVID-19 LTx patients, COVID-19 LTx patients were associated with significantly higher rate of primary graft dysfunction (odds ratio [OR] 8.72, 95% CI 3.54-21.47, P < 0.001) but significantly higher follow-up survival rate (OR 2.48, 95% CI 1.02-6.01, P = 0.04), within an overall similar follow-up period., Conclusions: For patients with COVID-19-associated ARDS or PF, LTx offers acceptable short-term outcomes and is suggested as a viable lifesaving treatment., Competing Interests: Declarations of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: To assess the characteristics of patients enrolled in the ILD-PRO Registry., Methods: The ILD-PRO Registry is a multicentre US registry of patients with progressive pulmonary fibrosis. This registry is enrolling patients with an interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis who have reticular abnormality and traction bronchiectasis on HRCT, and who meet criteria for ILD progression within the prior 24 months. Patient characteristics were analysed based on the number of patients with available data., Results: Of the first 491 patients enrolled, the majority were white (75.4%) and female (60.6%); 47.4% had a history of smoking. Reported ILDs were autoimmune disease-associated ILDs (47.2%), hypersensitivity pneumonitis (17.5%), idiopathic non-specific interstitial pneumonia (9.1%), interstitial pneumonia with autoimmune features (8.9%), unclassifiable ILD (7.6%), other ILDs (9.7%). At enrolment, median (Q1, Q3) FVC % predicted was 62.2 (49.4, 72.4) and DLco % predicted was 39.2 (30.2, 49.2). Median (Q1, Q3) total score on the St. George's Respiratory Questionnaire was 50.8 (35.9, 64.7). The most common comorbidities were gastroesophageal reflux disease (61.1%) and sleep apnoea (29.6%). Overall, 64.5% of patients were receiving immunosuppressive or cytotoxic therapy, 61.1% proton-pump inhibitors, 53.2% oral steroids, 19.8% nintedanib and 3.6% pirfenidone., Conclusions: Patients enrolled into the ILD-PRO Registry have a variety of ILD diagnoses, marked impairment in lung function and health-related quality of life, and high medication use. Longitudinal data from this registry will further our knowledge of the course of progressive pulmonary fibrosis., Trial Registration: ClinicalTrials.gov, NCT01915511; registered August 5, 2013., (© 2024. The Author(s).)

Purpose of Review: To review the current understanding of the impact, mechanisms and treatments for cough in patients with interstitial lung disease (ILD). Evidence suggests that cough is a prevalent symptom in patients with ILD and has a significant impact on patients., Recent Findings: There is increasing interest in the role of cough hypersensitivity as seen in chronic refractory cough in patients with ILD, and encouraging recent results suggest that ILD-associated cough responds to opiate therapy., Summary: Understanding the aetiology of cough in patients with ILD is crucial to continue to develop therapies which might be effective in reducing cough and increasing quality of life., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Unilateral lung fibrosis is uncommon and few cases secondary to parenchymal hypoperfusion have been reported, requiring further understanding of this entity. This study aims to report the chest computed tomography (CT) findings of patients with unilateral lung fibrosis related to parenchymal hypoperfusion observed in our institution., Patients and Methods: Patients with a chest CT between 2004 and 2022 showing a condition causing hypoperfusion of either lung and ipsilateral unilateral lung fibrosis were retrospectively identified. Clinical and scintigraphic data were collected. Pattern and distribution of fibrosis were recorded, and its progression was evaluated when follow-up was available. In adequate CTs, fibrosis was quantified using data-driven textural analysis (DTA). Affected and contralateral lungs and baseline and follow-up data were compared using the Wilcoxon signed-rank test., Results: Thirteen patients (male: 7, female: 6, median age: 61 y) were included; 5 with congenital unilateral absence of a pulmonary artery and 8 with fibrosing mediastinitis. The mean scintigraphic perfusion of affected lungs was 3.3% ± 1.1 compared with 96.7% ± 1.1 contralaterally (n = 7, P = 0.017). Fibrosis had a UIP pattern in one case, indeterminate in the others, and was most commonly diffuse craniocaudally and peripheral or central axially. DTA in 12 patients showed a mean fibrotic score of 32% ± 24.6 compared with 0.5% ± 0.4 in the contralateral lungs ( P = 0.002). Median follow-up was 4.5 years (minimum to maximum: 1 to 13 y). Of 10 patients, fibrosis was progressive in 60%. DTA of 5 follow-up CTs showed increased reticulations ( P = 0.043)., Conclusion: In patients with lung hypoperfusion, the possible complication of lung fibrosis should be considered., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Progressive pulmonary fibrosis is the symptomatic, physiological, and radiological progression of interstitial lung diseases. The aim of this study was to examine the relationship between progressive pulmonary fibrosis and demographic characteristics and to evaluate the effect on clinical outcomes and mortality., Methods: This cross-sectional study included 221 patients diagnosed with non-idiopathic pulmonary fibrosis interstitial lung diseases who were followed in the last 5 years. Patient symptoms, clinical, radiological, and demographic data were examined. Risk factors for the development of progressive pulmonary fibrosis and the relationship with clinical outcomes and mortality were examined., Results: Of the patients, 33.0% (n = 73) had fibrotic idiopathic nonspecific interstitial pneumonia (iNSIP), 35.7% (n = 79) had fibrotic hypersensitivity pneumonia (HP), 18.1% (n = 40) had fibrotic connective tissue disease (CTD) interstitial lung diseases (ILD), and 13.1% (n = 29) had postinfectious fibrotic ILD. The progressive pulmonary fibrosis development rates of the subtypes were 46.5% iNSIP (n = 34), 86.0% fibrotic HP (n = 68), 42.5% fibrotic CTD-ILD (n = 17), and 20.7% postinfectious ILD (n = 6). The presence of progressive pulmonary fibrosis was associated with the development of respiratory failure and mortality (odds ratio [OR]: 2.70, 95% CI: 1.04-7.05 and OR: 2.13, 95% CI: 1.23-3.69). Progressive pulmonary fibrosis development was higher in hypersensitivity pneumonia patients with farmer's lung (OR: 5.06, 95% CI: 1.02-25.18)., Conclusion: Progressive pulmonary fibrosis was more prevalent in older patients. Farming was an important risk factor in the development of hypersensitivity pneumonia-progressive pulmonary fibrosis. Respiratory failure and mortality were higher in those who developed progressive pulmonary fibrosis., (© 2024. The Author(s).)

Background: Severe COVID-19 infection has been associated with the development of pulmonary fibrosis, a condition that significantly affects patient prognosis. Understanding the underlying cellular communication mechanisms contributing to this fibrotic process is crucial., Objective: In this study, we aimed to investigate the role of the TNFSF12-TNFRSF12A pathway in mediating communication between alveolar macrophages and fibroblasts, and its implications for the development of pulmonary fibrosis in severe COVID-19 patients., Methods: We conducted single-cell RNA sequencing (scRNA-seq) analysis using lung tissue samples from severe COVID-19 patients and healthy controls. The data was processed, analyzed, and cell types were annotated. We focused on the communication between alveolar macrophages and fibroblasts and identified key signaling pathways. In vitro experiments were performed to validate our findings, including the impact of TNFRSF12A silencing on fibrosis reversal., Results: Our analysis revealed that in severe COVID-19 patients, alveolar macrophages communicate with fibroblasts primarily through the TNFSF12-TNFRSF12A pathway. This communication pathway promotes fibroblast proliferation and expression of fibrotic factors. Importantly, silencing TNFRSF12A effectively reversed the pro-proliferative and pro-fibrotic effects of alveolar macrophages., Conclusion: The TNFSF12-TNFRSF12A pathway plays a central role in alveolar macrophage-fibroblast communication and contributes to pulmonary fibrosis in severe COVID-19 patients. Silencing TNFRSF12A represents a potential therapeutic strategy for mitigating fibrosis in severe COVID-19 lung disease., (© 2024. The Author(s).)

Background: Silicosis is an irreversible fibrotic disease of the lung caused by chronic exposure to silica dust, which manifests as infiltration of inflammatory cells, excessive secretion of pro-inflammatory cytokines, and pulmonary diffuse fibrosis. As the disease progresses, lung function further deteriorates, leading to poorer quality of life of patients. Currently, few effective drugs are available for the treatment of silicosis. Bicyclol (BIC) is a compound widely employed to treat chronic viral hepatitis and drug-induced liver injury. While recent studies have demonstrated anti-fibrosis effects of BIC on multiple organs, including liver, lung, and kidney, its therapeutic benefit against silicosis remains unclear. In this study, we established a rat model of silicosis, with the aim of evaluating the potential therapeutic effects of BIC., Methods: We constructed a silicotic rat model and administered BIC after injury. The FlexiVent instrument with a forced oscillation system was used to detect the pulmonary function of rats. HE and Masson staining were used to assess the effect of BIC on silica-induced rats. Macrophages-inflammatory model of RAW264.7 cells, fibroblast-myofibroblast transition (FMT) model of NIH-3T3 cells, and epithelial-mesenchymal transition (EMT) model of TC-1 cells were established in vitro. And the levels of inflammatory mediators and fibrosis-related proteins were evaluated in vivo and in vitro after BIC treatment by Western Blot analysis, RT-PCR, ELISA, and flow cytometry experiments., Results: BIC significantly improved static compliance of lung and expiratory and inspiratory capacity of silica-induced rats. Moreover, BIC reduced number of inflammatory cells and cytokines as well as collagen deposition in lungs, leading to delayed fibrosis progression in the silicosis rat model. Further exploration of the underlying molecular mechanisms revealed that BIC suppressed the activation, polarization, and apoptosis of RAW264.7 macrophages induced by SiO 2 . Additionally, BIC inhibited SiO 2 -mediated secretion of the inflammatory cytokines IL-1β, IL-6, TNF-α, and TGF-β1 in macrophages. BIC inhibited FMT of NIH-3T3 as well as EMT of TC-1 in the in vitro silicosis model, resulting in reduced proliferation and migration capability of NIH-3T3 cells. Further investigation of the cytokines secreted by macrophages revealed suppression of both FMT and EMT by BIC through targeting of TGF-β1. Notably, BIC blocked the activation of JAK2/STAT3 in NIH-3T3 cells required for FMT while preventing both phosphorylation and nuclear translocation of SMAD2/3 in TC-1 cells necessary for the EMT process., Conclusion: The collective data suggest that BIC prevents both FMT and EMT processes, in turn, reducing aberrant collagen deposition. Our findings demonstrate for the first time that BIC ameliorates inflammatory cytokine secretion, in particular, TGF-β1, and consequently inhibits FMT and EMT via TGF-β1 canonical and non-canonical pathways, ultimately resulting in reduction of aberrant collagen deposition and slower progression of silicosis, supporting its potential as a novel therapeutic agent., (© 2024. The Author(s).)

Rationale: A visual analog scale (VAS) is a simple and easily administered tool for measuring the impact of disease; however, little is known about the use of a dyspnea VAS in interstitial lung disease (ILD). Objectives: To validate the use of a dyspnea VAS in a large and heterogeneous cohort of patients with fibrotic ILD, including its minimal clinically important difference (MCID), responsiveness to change, and prognostic significance. Methods: Patients with fibrotic ILD were identified from a large prospective registry. The validity of a 100-mm dyspnea VAS was assessed by testing its correlation in change score with other measures of ILD severity, including the University of California San Diego Shortness of Breath Questionnaire, the King's Brief Interstitial Lung Disease quality of life questionnaire Breathlessness and Activities Domain, the European Quality of Life VAS, forced vital capacity, and diffusing capacity of the lung for carbon monoxide. The responsiveness of the dyspnea VAS was qualitatively confirmed on the basis of there being an observable difference in the change in dyspnea VAS across tertiles of change in anchor variables. The MCID in dyspnea VAS was calculated using both anchor (linear regression) and distribution (one-half standard deviation) approaches, with anchors including the above variables that had a correlation with dyspnea VAS (| r | ≥ 0.30). The association of dyspnea VAS with time to death or transplant was determined. Results: The cohort included 826 patients with fibrotic ILD, including 127 patients with follow-up measurements at 6 months. The mean baseline dyspnea VAS was 53 ± 24 mm. Dyspnea VAS change scores were moderately correlated with the University of California San Diego Shortness of Breath Questionnaire (| r | = 0.55) and the King's Brief Interstitial Lung Disease quality of life questionnaire Breathlessness and Activities Domain (| r | = 0.44) and weakly correlated with the European Quality of Life VAS (| r | = 0.19), forced vital capacity percent predicted (| r | = 0.21), and diffusing capacity of the lung for carbon monoxide percent predicted (| r | = 0.05). The MCID was 2.7 to 4.5 using the more reliable anchor-based methods and 12.0 based on distribution-based methods. Dyspnea VAS was associated with time to death or transplant in unadjusted models and after adjustment for age and sex (hazard ratios, 1.16 and 1.15, respectively; P  < 0.05 for both). Conclusions: This study provides support for the use of the dyspnea VAS in patients with fibrotic ILD, with an estimated anchor-based MCID of 5 mm.

Rationale: The proportion of patients who develop progressive pulmonary fibrosis (PPF), along with risk factors for progression remain poorly understood., Objectives: To examine factors associated with an increased risk of developing PPF among patients at a referral center., Methods: We 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., Results: We 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., Conclusion: Regardless 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., Competing Interests: Declaration of competing interest The study is funded by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). Maeve Macmurdo, Xinge Ji, Alex Milinovich, Blaine Martyn-Dow, Aman Pande, Alex Zajichek, Janine Bauman, David Sugano, Michael W. Kattan and Daniel A. Culver are employed by the Cleveland Clinic which received research support from BIPI to collaborate on this project. Pratik Pimple, Amy L. Olson, Shaun Bender, and Craig Conoscenti are employees of BIPI. Daniel Culver received honoraria from BIPI for his participation in a Steering Committee, from Pliant for his participation in an Adjudication Committee and coverage for travel costs from Roche. All other members of the Cleveland Clinic study team cited no other disclosures., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The purpose of this study was to describe lung abnormalities observed on computed tomography (CT) in patients meeting the 2016 American College of Rheumatology/European League Against Rheumatism (EULAR) classification criteria for primary Sjögren's disease (pSD)., Materials and Methods: All patients with pSD seen between January 2009 and December 2020 in the day care centre of our National Reference Center for rare systemic autoimmune diseases, who had at least one chest CT examination available for review and for whom the cumulative EULAR Sjögren's Syndrome Disease Activity Index (cumESSDAI) could be calculated were retrospectively evaluated. CT examinations were reviewed, together with clinical symptoms and pulmonary functional results., Results: Seventy-seven patients (73 women, four men) with a median age of 51 years at pSD diagnosis (age range: 17-79 years), a median follow-up time of 6 years and a median cumESSDAI of 7 were included. Sixty-six patients (86%) had anti-SSA antibodies. Thirty-three patients (33/77; 43%) had respiratory symptoms, without significant alteration in pulmonary function tests. Forty patients (40/77; 52%) had abnormal lung CT findings of whom almost half of them had no respiratory symptoms. Abnormalities on chest CT were more frequently observed in patients with anti-SSA positivity and a history of lymphoma. Air cysts (28/77; 36%) and mosaic perfusion (35/77; 35%) were the predominant abnormalities, whereas lung fibrosis was observed in five patients (5/77; 6%)., Conclusion: More than half of patients with pSD have abnormal CT findings, mainly air cysts and mosaic perfusion, indicative of small airways disease, whereas lung fibrosis is rare, observed in less than 10% of such patients., Competing Interests: Declaration of competing interest The other authors have no conflicts of interest related to this work to declare., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Differences in disease behaviour and genotypes are described in Asian and Western interstitial lung disease (ILD) cohorts. Short leukocyte telomere length (LTL) correlates with poor outcomes in Western ILD cohorts but its significance in Asian populations is unknown. We aim to characterise the burden and clinical implications of short LTL in Singaporean ILD patients., Methods: Patients diagnosed with ILD at Singapore General Hospital were prospectively recruited and compared against 36 healthy controls. The primary outcome was transplant-free survival. Genomic DNA from peripheral blood was extracted and LTL measured using quantitative polymerase chain reaction assay (qPCR)., Results: Amongst 165 patients, 37% had short LTL. There was a higher proportion of combined pulmonary fibrosis and emphysema (CPFE) patients with short LTL (n = 21, 34.4% vs n = 16, 15.4%; p < 0.001). Short LTL patients had reduced survival at 12-, 24- and 36-months and median survival of 24 months (p < 0.001) which remained significant following adjustment for smoking, GAP Stage and radiological UIP pattern (Hazard Ratio (HR), 2.74; 95%CI:1.46, 5.11; p = 0.002). They had increased respiratory-related mortality and acute exacerbation incidences. Despite similar baseline lung function, short LTL patients had a faster decline in absolute forced vital capacity (FVC) of -105.3 (95% CI: 151.4, -59.1) mL/year compared to -58.2 (95% CI: 82.9, -33.6) mL/year (p < 0.001) in normal LTL patients., Conclusion: Short LTL correlated with increased mortality and faster lung function decline in our Singaporean ILD cohort with a magnitude similar to that in Western ILD cohorts. Further research is needed to integrate LTL assessment into clinical practice., Competing Interests: Declaration of competing interest MLW Kam reports having received research funding from Singapore General Hospital, Singapore and Singapore Health Services (Singhealth), Singapore and having received speaker honorarium from Boehringer Ingelheim, Singapore. YH Tan reports having received speaker honorarium from Boehringer Ingelheim, Singapore. SY Low reports having received research funding, consulting fees, speaker honorarium and support for meetings and travel from Boehringer Ingelheim, Singapore and speaker honorarium from Astra Zeneca, Singapore. JYY Ngeow reports having received research funding from Astra Zeneca, Singapore and the National Medical Research Council Clinician Scientist Award, Singapore. The other authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Lung biopsy remains the gold standard in the diagnosis of fibrotic interstitial lung disease (F-ILD), but there is a growing appreciation of the role of pathogenic gene variants in telomere and surfactant protein genes, especially in familial pulmonary fibrosis (FPF). Pleuroparenchymal fibroelastosis (PPFE) is a rare disease that can coexist with different patterns of F-ILD, including FPF. It can be progressive and often leads to respiratory failure and death. This study tested the hypothesis that genetic testing goes beyond radiological and histological findings in PPFE and other F-ILD further informing clinical decision-making for patients and affected family members by identifying pathological gene variants in telomere and surfactant protein genes., Methods: This is a retrospective review of 70 patients with F-ILD in the setting of FPF or premature lung fibrosis. Six out of 70 patients were diagnosed with PPFE based on radiological or histological characteristics. All patients underwent telomere length evaluation in peripheral blood by Flow-FISH or genetic testing using a customized exome-based panel that included telomere and surfactant protein genes associated with lung fibrosis., Results: Herein, we identified six individuals where radiographic or histopathological analyses of PPFE were linked with telomere biology disorders (TBD) or variants in surfactant protein genes. Each case involved individuals with either personal early-onset lung fibrosis or a family history of the disease. Assessments of telomere length and genetic testing offered insights beyond traditional radiological and histopathological evaluations., Conclusion: Detecting anomalies in TBD-related or surfactant protein genes can significantly refine the diagnosis and treatment strategies for individuals with PPFE and other F-ILD., (© 2024. The Author(s).)

Pulmonary fibrosis (PF) is the major complication and death-related factor of acute respiratory distress syndrome (ARDS). This study evaluated the significance of miR-141-3p in ARDS and its complication of PF aiming to identify a potential biomarker for screening ARDS and predicting the occurrence of PF. A total of 137 ARDS patients and 69 healthy individuals were enrolled in this study and the serum samples were collected from all participants. The serum miR-141-3p levels were analyzed by polymerase chain reaction. The significance of miR-141-3p in the diagnosis and development of ARDS, and the occurrence of PF was evaluated by receiver operating curve, Chi-square test, and logistic regression analysis. MiR-141-3p was downregulated in ARDS patients and showed significant potential in its diagnosis. Reduced miR-141-3p was significantly associated with the increasing Murray and APACHEII score and the occurrence of PF in ARDS patients. MiR-141-3p, Murray score, and APACHEII score were identified as risk factors for the occurrence of PF in ARDS, and miR-141-3p was also found to be downregulated in ARDS patients with PF. Additionally, miR-141-3p could discriminate ARDS patients with PF and without PF, and was closely associated with the decreased total lung capacity, carbon monoxide diffusing capacity, and forced vital capacity of ARDS patients with PF. Downregulated miR-141-3p served as a biomarker for ARDS screening disease onset and indicating the severity. Reduced miR-141-3p was also identified as a risk factor for PF in ARDS patients and was associated with the severe progression of PF.

The causal attribution of asbestos-related diseases to past asbestos exposures is of crucial importance in clinical and legal contexts. Often this evaluation is made based on the history of exposure, but this method presents important limitations. To assess past asbestos exposure, pleural plaques (PP), lung fibrosis and histological evidence of ferruginous bodies (FB) can be used in combination with anamnestic data. However, such markers have never been associated with a threshold value of inhaled asbestos. With this study we attempted to shed light on the dose-response relationship of PP, lung fibrosis and FBs, investigating if their prevalence in exposed individuals who died from malignant mesothelioma (MM) is related to the concentration of asbestos in lungs assessed using scanning electron microscopy equipped with energy dispersive spectroscopy. Moreover, we estimated the values of asbestos concentration in lungs associated with PP, lung fibrosis and FB. Lung fibrosis showed a significant positive relationship with asbestos lung content, whereas PP and FB did not. We identified, for the first time, critical lung concentrations of asbestos related to the presence of PP, lung fibrosis and FB at histology (respectively, 19 800, 26 400 and 27 400 fibers per gram of dry weight), that were all well-below the background levels of asbestos identified in our laboratory. Such data suggest that PP, lung fibrosis and FB at histology should be used with caution in the causal attribution of MM to past asbestos exposures, while evaluation of amphibole lung content using analytical electron microscopy should be preferred., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Sarcoidosis is a systemic granulomatous disorder that affects individuals of all racial/ethnic origins and occurs at any time of life. Spontaneous remission is frequent and may occur in 2 of 3 patients, while the remaining cases have chronic, progressive disease, with some patients presenting with organ- and life-threatening involvements. Many reports have investigated which features may be related to poor outcomes in patients with sarcoidosis. Pulmonary hypertension and respiratory failure from pulmonary fibrosis are the most common complications associated with the cause of death in sarcoidosis. Other major causes of death include cardiac, neurologic, hepatic involvement, and hemoptysis from aspergilloma., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Fibrotic pulmonary sarcoidosis (fPS) affects about 20% of patients. fPS carries a significant morbidity and mortality. However, its prognosis is highly variable, depending mainly on fibrosis extent, functional impairment severity, and the development of pulmonary hypertension. Moreover, fPS outcomes are also influenced by several other complications, including acute exacerbations, and infections. fPS natural history is unknown, in particular regarding the risk of progressive self-sustaining fibrosis. The management of fPS is challenging, including anti-inflammatory treatment if granulomatous activity persists, rehabilitation, and in highly selected patients antifibrotic treatment and lung transplantation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome characterized by the coexistence of emphysema and fibrotic interstitial lung disease (ILD). The aim of this study was to examine the effect of CPFE on lung cancer risk and lung cancer-related mortality in patients with rheumatoid arthritis (RA)., Methods: We conducted a multicenter retrospective cohort study of patients newly diagnosed with lung cancer at five community hospitals between June 2006 and December 2021. Patients were followed until lung cancer-related death, other-cause death, loss to follow-up, or the end of the study. We used the cumulative incidence function with Gray's test and Fine-Gray regression analysis for survival analysis., Results: A total of 563 patients with biopsy-proven lung cancer were included (82 RA patients and 481 non-RA patients). The prevalence of CPFE was higher in RA patients than in non-RA patients (40.2% vs.10.0%) at lung cancer diagnosis. During follow-up, the crude incidence rate of lung cancer-related death was 0.29 and 0.10 per patient-year (PY) in RA and non-RA patients, and 0.32 and 0.07 per PY in patients with CPFE and patients without ILD or emphysema, respectively. The estimated death probability at 5 years differed between RA and non-RA patients (66% vs. 32%, p<0.001) and between patients with CPFE and patients without ILD or emphysema (71% vs. 24%, p<0.001). In addition to clinical cancer stage and no surgery within 1 month, RA and CPFE were identified as independent predictive factors for increased lung cancer-related mortality (RA: adjusted hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.65-4.76; CPFE: adjusted HR 2.01; 95% CI 1.24-3.23)., Conclusions: RA patients with lung cancer had a higher prevalence of CPFE and increased cancer-related mortality compared with non-RA patients. Close monitoring and optimal treatment strategies tailored to RA patients with CPFE are important to improve the poor prognosis of lung cancer., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: S. Mori received honoraria for lectures from AbbVie GK, Eli Lilly Japan K.K., Pfizer Japan Inc., Chugai Pharmaceutical Co. Ltd., Janssen Pharmaceutical K.K., Boehringer Ingelheim Japan, and Taisho Pharma Co., Ltd. and received research funds from AbbVie GK, Asahikasei Pharma Corp, and Chugai Pharmaceutical Co., Ltd. Y. Ueki received honoraria for lectures from AbbVie GK, Eli Lilly Japan K.K., Pfizer Japan Inc., Asahikasei Pharma Corp., Astellas Pharma Inc., Bristol-Myers K.K., Chugai Pharmaceutical Co. Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Ono Pharmaceutical Co., and Takeda Pharmaceutical Co., Ltd. T. Hidaka received honoraria for lectures from AbbVie GK, Eli Lilly Japan K.K., Pfizer Japan Inc., Asahi Kasei Pharma Corp., Bristol-Myers K.K., Chugai Pharmaceutical Co., Ltd., and Eisai Co. K. Nakamura received honoraria for lectures from AstraZeneca K.K. The other authors had no financial relationships that could create a potential conflict of interest or the appearance of a conflict of interest with regard to the work. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Mori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Whether COVID-19 leads to long-term pulmonary sequelae or not remains unknown. The aim of this study was to assess the prevalence of persisting radiological pulmonary fibrotic lesions in patients hospitalized for COVID-19., Materials and Methods: We conducted a prospective single-center study among patients hospitalized for COVID-19 between March and May 2020. Patients with residual symptoms or admitted into intensive care units were investigated 4 months after discharge by a chest CT (CCT) and pulmonary function tests (PFTs). The primary endpoint was the rate of persistent radiological fibrotic lesions after 4 months. Secondary endpoints included further CCT evaluation at 9 and 16 months, correlation of fibrotic lesions with clinical and PFT evaluation, and assessment of predictive factors., Results: Among the 1151 patients hospitalized for COVID-19, 169 patients performed a CCT at 4 months. CCTs showed pulmonary fibrotic lesions in 19% of the patients (32/169). These lesions were persistent at 9 months and 16 months in 97% (29/30) and 95% of patients (18/19) respectively. There was no significant clinical difference based on dyspnea scale in patients with pulmonary fibrosis. However, PFT evaluation showed significantly decreased diffusing lung capacity for carbon monoxide (p < 0.001) and total lung capacity (p < 0.001) in patients with radiological lesions. In multivariate analysis, the predictive factors of radiological pulmonary fibrotic lesions were pulmonary embolism (OR = 9.0), high-flow oxygen (OR = 6.37), and mechanical ventilation (OR = 3.49)., Conclusion: At 4 months, 19% of patients investigated after hospitalization for COVID-19 had radiological pulmonary fibrotic lesions; they persisted up to 16 months., Clinical Relevance Statement: Whether COVID-19 leads to long-term pulmonary sequelae or not remains unknown. The aim of this study was to assess the prevalence of persisting radiological pulmonary fibrotic lesions in patients hospitalized for COVID-19. The prevalence of persisting lesions after COVID-19 remains unclear. We assessed this prevalence and predictive factors leading to fibrotic lesions in a large cohort. The respiratory clinical impact of these lesions was also assessed., Key Points: • Nineteen percent of patients hospitalized for COVID-19 had radiological fibrotic lesions at 4 months, remaining stable at 16 months. • COVID-19 fibrotic lesions did not match any infiltrative lung disease pattern. • COVID-19 fibrotic lesions were associated with pulmonary function test abnormalities but did not lead to clinical respiratory manifestation., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Chest Computed tomography (CT) scans detect lung nodules and assess pulmonary fibrosis. While pulmonary fibrosis indicates increased lung cancer risk, current clinical practice characterizes nodule risk of malignancy based on nodule size and smoking history; little consideration is given to the fibrotic microenvironment., Purpose: To evaluate the effect of incorporating fibrotic microenvironment into classifying malignancy of lung nodules in chest CT images using deep learning techniques., Materials and Methods: We developed a visualizable 3D classification model trained with in-house CT dataset for the nodule malignancy classification task. Three slightly-modified datasets were created: (1) nodule alone (microenvironment removed); (2) nodule with surrounding lung microenvironment; and (3) nodule in microenvironment with semantic fibrosis metadata. For each of the models, tenfold cross-validation was performed. Results were evaluated using quantitative measures, such as accuracy, sensitivity, specificity, and area-under-curve (AUC), as well as qualitative assessments, such as attention maps and class activation maps (CAM)., Results: The classification model trained with nodule alone achieved 75.61% accuracy, 50.00% sensitivity, 88.46% specificity, and 0.78 AUC; the model trained with nodule and microenvironment achieved 79.03% accuracy, 65.46% sensitivity, 85.86% specificity, and 0.84 AUC. The model trained with additional semantic fibrosis metadata achieved 80.84% accuracy, 74.67% sensitivity, 84.95% specificity, and 0.89 AUC. Our visual evaluation of attention maps and CAM suggested that both the nodules and the microenvironment contributed to the task., Conclusion: The nodule malignancy classification performance was found to be improving with microenvironment data. Further improvement was found when incorporating semantic fibrosis information., (© 2024. The Author(s).)

A 70-year-old man who smoked was referred to our hospital because of progressive cough and dyspnea. Radiologic images showed ground-glass attenuation predominantly in the lower lung lobes. A surgical lung biopsy was performed, and a diagnosis of desquamative interstitial pneumonia (DIP) was made. The patient's symptoms improved with smoking cessation and steroid treatment, but the ground-glass attenuation did not completely resolve. At 10 years after the diagnosis, the fibrotic lesions deteriorated and treatment with nintedanib was subsequently initiated. Careful observation is needed in patients with DIP whose lung involvement does not completely improve with initial treatment.

A 48-year-old woman was admitted to our hospital with acute respiratory failure. Chest computed tomography showed ground-glass opacity and patchy emphysematous lesions in both lungs. Corticosteroid therapy was effective; however, the disease worsened with the tapering of corticosteroids. Bronchoalveolar lavage revealed hemosiderin-laden macrophages, and video-assisted thoracic surgery showed diffuse interstitial fibrosis with diffuse alveolar hemorrhage (DAH). There was no evidence of vasculitis nor autoimmune diseases. This patient was diagnosed with idiopathic pulmonary hemosiderosis (IPH) that progressed to end-stage pulmonary fibrosis despite treatment. Autopsy demonstrated DAH with pulmonary fibrosis and emphysematous change, suggesting IPH-related pulmonary lesions.

COVID-19-related acute respiratory distress syndrome (ARDS) can lead to long-term pulmonary fibrotic lesions. Alveolar fibroproliferative response (FPR) is a key factor in the development of pulmonary fibrosis. N-terminal peptide of procollagen III (NT-PCP-III) is a validated biomarker for activated FPR in ARDS. This study aimed to assess the association between dynamic changes in alveolar FPR and long-term outcomes, as well as mortality in COVID-19 ARDS patients. We conducted a prospective cohort study of 154 COVID-19 ARDS patients. We collected bronchoalveolar lavage (BAL) and blood samples for measurement of 17 pulmonary fibrosis biomarkers, including NT-PCP-III. We assessed pulmonary function and chest computed tomography (CT) at 3 and 12 mo after hospital discharge. We performed joint modeling to assess the association between longitudinal changes in biomarker levels and mortality at day 90 after starting mechanical ventilation. 154 patients with 284 BAL samples were analyzed. Of all patients, 40% survived to day 90, of whom 54 completed the follow-up procedure. A longitudinal increase in NT-PCP-III was associated with increased mortality (HR 2.89, 95% CI: 2.55-3.28; P < 0.001). Forced vital capacity and diffusion for carbon monoxide were impaired at 3 mo but improved significantly at one year after hospital discharge ( P = 0.03 and P = 0.004, respectively). There was no strong evidence linking alveolar FPR during hospitalization and signs of pulmonary fibrosis in pulmonary function or chest CT images during 1-yr follow-up. In COVID-19 ARDS patients, alveolar FPR during hospitalization was associated with higher mortality but not with the presence of long-term fibrotic lung sequelae within survivors. NEW & NOTEWORTHY This is the first prospective study on the longitudinal alveolar fibroproliferative response in COVID-19 ARDS and its relationship with mortality and long-term follow-up. We used the largest cohort of COVID-19 ARDS patients who had consecutive bronchoalveolar lavages and measured 17 pulmonary fibroproliferative biomarkers. We found that a higher fibroproliferative response during admission was associated with increased mortality, but not correlated with long-term fibrotic lung sequelae in survivors.

The concept of progressive pulmonary fibrosis (PPF) has been introduced to predict the diverse prognosis of interstitial lung disease (ILD). However, the incidence and effect of PPF on outcomes in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD) need to be elucidated. This study reviewed 197 patients with CTD-ILD. Symptomatic worsening, pulmonary function decline, and radiological deterioration were investigated to assess the fulfillment of PPF diagnostic criteria. Clinical outcomes, including mortality, were compared based on the presence or absence of PPF. The median follow-up duration was 17.4 months. The mean age of the patients was 64.0 years, and 60.9% were female. Among the underlying CTDs, rheumatoid arthritis (42.1%), inflammatory myositis (19.8%), and systemic sclerosis (13.2%) were the most common. Of the 197 patients, 37 (18.8%) met the diagnostic criteria for PPF during the follow-up period. Even after adjusting for other significant risk factors, PPF was independently associated with mortality [hazard ratio (HR) 3.856; 95% confidence interval (CI) 1.387-10.715; P = 0.010] and baseline albumin was marginally significantly associated with mortality (HR 0.549; CI 0.298-1.010; P = 0.054). The median survival was also significantly shorter in the PPF group than in the non-PPF group (72.3 ± 12.9 vs. 126.8 ± 15.5 months, P < 0.001). Baseline KL-6 ≥ 1000 (U/mL) was a significant risk factor for PPF (HR 2.885; CI 1.165-7.144; P = 0.022). In addition to increased mortality, the PPF group had significantly higher rates of respiratory-related hospitalizations, pneumonia, acute exacerbations, and weight loss than the non-PPF group. PPF is a significant prognostic indicator in patients with CTD-ILD. Thus, healthcare professionals should know that patients with CTD-ILD are at risk of PPF., (© 2023. The Author(s).)

Interstitial lung disease (ILD) is a frequent manifestation of connective tissue diseases (CTDs), with incidence and prevalence variously assessed in the literature but reported in up to 30% of patients, with higher frequency in rheumatoid arthritis (RA) and systemic sclerosis (SSc). Recent years have seen a growing interest in the pulmonary manifestations of ILD-CTDs, mainly due to the widening of the use of anti-fibrotic drugs initially introduced exclusively for IPF, and radiologists play a key role because the lung biopsy is very rarely used in these patients where the morphological assessment is essentially left to imaging and especially HRCT. In this narrative review we will discuss, from the radiologist's point of view, the most recent findings in the field of ILD secondary to SSc and RA, with a special focus about the progression of disease and in particular about the 'progressive pulmonary fibrosis' (PPF) phenotype, and we will try to address two main issues: How to predict a possible evolution and therefore a worse prognosis when diagnosing a new case of ILD-CTDs and how to assess the progression of an already diagnosed ILD-CTDs., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Importance: The COVID-19 pandemic led to the use of lung transplant as a lifesaving therapy for patients with irreversible lung injury. Limited information is currently available regarding the outcomes associated with this treatment modality., Objective: To describe the outcomes following lung transplant for COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis., Design, Setting, and Participants: In this cohort study, lung transplant recipient and donor characteristics and outcomes following lung transplant for COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis were extracted from the US United Network for Organ Sharing database from March 2020 to August 2022 with a median (IQR) follow-up period of 186 (64-359) days in the acute respiratory distress syndrome group and 181 (40-350) days in the pulmonary fibrosis group. Overall survival was calculated using the Kaplan-Meier method. Cox proportional regression models were used to examine the association of certain variables with overall survival., Exposures: Lung transplant following COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis., Main Outcomes and Measures: Overall survival and graft failure rates., Results: Among 385 included patients undergoing lung transplant, 195 had COVID-19-related acute respiratory distress syndrome (142 male [72.8%]; median [IQR] age, 46 [38-54] years; median [IQR] allocation score, 88.3 [80.5-91.1]) and 190 had COVID-19-related pulmonary fibrosis (150 male [78.9%]; median [IQR] age, 54 [45-62]; median [IQR] allocation score, 78.5 [47.7-88.3]). There were 16 instances of acute rejection (8.7%) in the acute respiratory distress syndrome group and 15 (8.6%) in the pulmonary fibrosis group. The 1-, 6-, and 12- month overall survival rates were 0.99 (95% CI, 0.96-0.99), 0.95 (95% CI, 0.91-0.98), and 0.88 (95% CI, 0.80-0.94) for the acute respiratory distress syndrome cohort and 0.96 (95% CI, 0.92-0.98), 0.92 (95% CI, 0.86-0.96), and 0.84 (95% CI, 0.74-0.90) for the pulmonary fibrosis cohort. Freedom from graft failure rates were 0.98 (95% CI, 0.96-0.99), 0.95 (95% CI, 0.90-0.97), and 0.88 (95% CI, 0.79-0.93) in the 1-, 6-, and 12-month follow-up periods in the acute respiratory distress cohort and 0.96 (95% CI, 0.92-0.98), 0.93 (95% CI, 0.87-0.96), and 0.85 (95% CI, 0.74-0.91) in the pulmonary fibrosis cohort, respectively. Receiving a graft from a donor with a heavy and prolonged history of smoking was associated with worse overall survival in the acute respiratory distress syndrome cohort, whereas the characteristics associated with worse overall survival in the pulmonary fibrosis cohort included female recipient, male donor, and high recipient body mass index., Conclusions and Relevance: In this study, outcomes following lung transplant were similar in patients with irreversible respiratory failure due to COVID-19 and those with other pretransplant etiologies.

Combined pulmonary fibrosis and emphysema (CPFE) syndrome refers to co-occurrence of two disease processes in the lung that can be difficult to diagnose but is associated with high morbidity and mortality burden. Diagnosis of CPFE is challenging because the two diseases can counterbalance respective impairments resulting in deceivingly normal-appearing chest radiography and spirometry in a dyspneic patient. Although an international committee published the terminology and definitions of CPFE in 2022, consensus on exact diagnostic criteria and optimal management strategy is yet to be determined. Herein, we provide a narrative review summarizing the literature on CPFE from 1990 to 2022, including historical background, epidemiology, pathogenesis, clinical features, imaging and pulmonary function findings, diagnosis, prognosis, complications, and treatment. Although CPFE was initially conceived as a variant presentation of idiopathic pulmonary fibrosis, it has been recognized to occur in patients with a wide variety of interstitial lung diseases, including connective tissue disease-associated interstitial lung diseases, and hypersensitivity pneumonitis. The affected patients have a heightened risk for pulmonary hypertension and lung cancer. Clinicians need to recognize the characteristic presenting features of CPFE along with prognostic implications of this entity., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Type 1 diabetes (T1D) is a metabolic disease characterized by hyperglycemia and can affect multiple organs, leading to life-threatening complications. Increased prevalence of pulmonary disease is observed in T1D patients, and diabetes is a leading cause of comorbidity in several lung pathologies. A deficiency of alpha-1 antitrypsin (AAT) can lead to the development of emphysema. Decreased AAT plasma concentrations and anti-protease activity are documented in T1D patients. The objective of this study was to determine whether T1D exacerbates the progression of lung damage in AAT deficiency. First, pulmonary function testing (PFT) and histopathological changes in the lungs of C57BL/6J streptozotocin (STZ)-induced T1D mice were investigated 3 and 6 months after the onset of hyperglycemia. PFT demonstrated a restrictive pulmonary pattern in the lungs of STZ-injected mice, along with upregulation of mRNA expression of pro-fibrotic markers Acta2, Ccn2, and Fn1. Increased collagen deposition was observed 6 months after the onset of hyperglycemia. To study the effect of T1D on the progression of lung damage in AAT deficiency background, C57BL/6J AAT knockout (KO) mice were used. Control and STZ-challenged AAT KO mice did not show significant changes in lung function 3 months after the onset of hyperglycemia. However, histological examination of the lung demonstrated increased collagen accumulation and alveolar space enlargement in STZ-induced AAT KO mice. AAT pretreatment on TGF-β-stimulated primary lung fibroblasts reduced mRNA expression of pro-fibrotic markers ACTA2, CCN2, and FN1. Induction of T1D in AAT deficiency leads to a combined pulmonary fibrosis and emphysema (CPFE) phenotype in male mice., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Park et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Rationale: Although studies have evaluated emphysema and fibrotic interstitial lung abnormality individually, less is known about their combined progression. Objectives: To define clinically meaningful progression of fibrotic interstitial lung abnormality in smokers without interstitial lung disease and evaluate the effects of fibrosis and emphysema progression on mortality. Methods: Emphysema and pulmonary fibrosis were assessed on the basis of baseline and 5-year follow-up computed tomography scans of 4,450 smokers in the COPDGene Study using deep learning algorithms. Emphysema was classified as absent, trace, mild, moderate, confluent, or advanced destructive. Fibrosis was expressed as a percentage of lung volume. Emphysema progression was defined as an increase by at least one grade. A hybrid distribution and anchor-based method was used to determine the minimal clinically important difference in fibrosis. The relationship between progression and mortality was evaluated using multivariable shared frailty models using an age timescale. Measurements and Main Results: The minimal clinically important difference for fibrosis was 0.58%. On the basis of this threshold, 2,822 (63%) had progression of neither emphysema nor fibrosis, 841 (19%) had emphysema progression alone, 512 (12%) had fibrosis progression alone, and 275 (6.2%) had progression of both. Compared with nonprogressors, hazard ratios for mortality were 1.42 (95% confidence interval, 1.11-1.82) in emphysema progressors, 1.49 (1.14-1.94) in fibrosis progressors, and 2.18 (1.58-3.02) in those with progression of both emphysema and fibrosis. Conclusions: In smokers without known interstitial lung disease, small changes in fibrosis may be clinically significant, and combined progression of emphysema and fibrosis is associated with increased mortality.

Objectives: Some patients with rheumatoid arthritis develop interstitial lung disease (RA-ILD) that develops into progressive pulmonary fibrosis. We assessed the efficacy and safety of nintedanib versus placebo in patients with progressive RA-ILD in the INBUILD trial., Methods: The INBUILD trial enrolled patients with fibrosing ILD (reticular abnormality with traction bronchiectasis, with or without honeycombing) on high-resolution computed tomography of >10% extent. Patients had shown progression of pulmonary fibrosis within the prior 24 months, despite management in clinical practice. Subjects were randomised to receive nintedanib or placebo., Results: In the subgroup of 89 patients with RA-ILD, the rate of decline in FVC over 52 weeks was -82.6 mL/year in the nintedanib group versus -199.3 mL/year in the placebo group (difference 116.7 mL/year [95% CI 7.4, 226.1]; nominal p = 0.037). The most frequent adverse event was diarrhoea, which was reported in 61.9% and 27.7% of patients in the nintedanib and placebo groups, respectively, over the whole trial (median exposure: 17.4 months). Adverse events led to permanent discontinuation of trial drug in 23.8% and 17.0% of subjects in the nintedanib and placebo groups, respectively., Conclusions: In the INBUILD trial, nintedanib slowed the decline in FVC in patients with progressive fibrosing RA-ILD, with adverse events that were largely manageable. The efficacy and safety of nintedanib in these patients were consistent with the overall trial population. A graphical abstract is available at: https://www.globalmedcomms.com/respiratory/INBUILD&#95;RA-ILD . Key Points • In patients with rheumatoid arthritis and progressive pulmonary fibrosis, nintedanib reduced the rate of decline in forced vital capacity (mL/year) over 52 weeks by 59% compared with placebo. • The adverse event profile of nintedanib was consistent with that previously observed in patients with pulmonary fibrosis, characterised mainly by diarrhoea. • The effect of nintedanib on slowing decline in forced vital capacity, and its safety profile, appeared to be consistent between patients who were taking DMARDs and/or glucocorticoids at baseline and the overall population of patients with rheumatoid arthritis and progressive pulmonary fibrosis., (© 2023. The Author(s).)

Objectives: The clinical course of coronavirus disease 2019 (COVID-19) infection is often aggressive, with unfavorable outcomes for those with comorbidities such as type 2 diabetes mellitus (T2DM). We aimed to assess the prevalence and risk factors of COVID-19 infection, mortality, and post-infection lung fibrosis in patients with COVID-19 infection who had T2DM., Methods: In this cross-sectional study, we included adult patients with T2DM who attended an endocrinology clinic and underwent testing for COVID-19 infection., Results: Among 1039 included patients, the mean age was 59.5 ± 11.0 years and 429 (41.3%) were men. Overall, 87.1% of patients had received COVID-19 vaccination and 32.3% had confirmed COVID-19 infection. The COVID-19-related mortality was 3.0% and rate of post-COVID-19 lung fibrosis was 19.1%. Vaccination was associated with lower COVID-19-related mortality (odds ratio [OR]: 0.03, 95% confidence interval [CI]: 0.0-0.3) and post-COVID-19 lung fibrosis risk (OR: 0.3, 95% CI: 0.1-0.9)., Conclusion: Patients with T2DM exhibited a high prevalence of COVID-19 infection and associated mortality. However, COVID-19 vaccines were beneficial in reducing the risks of COVID-19-related mortality and post-infection lung fibrosis in these patients. COVID-19 vaccines and boosters are recommended for patients with T2DM. Further studies involving larger study populations are necessary to validate these findings.

Background: Interstitial lung disease (ILD) is a significant cause of disability and mortality in systemic sclerosis (SSc), where lung fibrosis stems from the interaction of cells within the epithelial, endothelial, interstitial, and immune cell compartments. Extracellular vesicles (EVs) are particles released by cells capable of transferring functionally active molecules, playing a crucial role in intercellular communication. This scoping review aims to identify and map existing evidence about the role of EVs as biomarkers or pathophysiological actors in SSc-ILD. It also retrospectively assesses the compliance of published articles with the current reporting guidelines established by the International Society of Extracellular Vesicles (ISEV)., Methods: This scoping review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. The searches were conducted up until 31 May 2023, with no restrictions on the starting year., Results: Out of 778 publications identified and screened, 9 references were selected. The eligible studies collectively involved a total of 539 SSc patients, with 220 patients presenting with ILD, as demonstrated by high-resolution computed tomography. The studies largely focused on the quantitative assessment of EVs through flow cytometry, primarily concerning larger EVs. The studies primarily focused on the association of EV features with vascular complications, with fibrotic pulmonary involvement typically explored as a secondary finding. The evaluated patients' clinical characteristics were significantly heterogeneous across the studies as well as the association of EV features with the evidence of ILD but none of them longitudinally investigated the relationships with SSc-ILD prognosis. Adherence of these exploratory studies to ISEV reporting guidelines in terms of EV nomenclature, reporting of pre-analytic variables, and qualitative verification of EV separation products was incomplete., Conclusions: The evidence concerning the clinical association of EV features is limited and conflicting. The interpretation of available data is substantially biased due to patient selection tailored for vascular complications, heterogeneity of separation methodology, and a lack of validation procedures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate whether symptoms of gastroesophageal reflux disease and radiographic measures of esophageal dilation are associated with radiographic progression of systemic sclerosis-related interstitial lung disease (SSc-ILD)., Methods: Participants of the Scleroderma Lung Study II, which compared mycophenolate versus cyclophosphamide for SSc-ILD, completed the reflux domain of the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 at baseline. The diameter and area of the esophagus in the region of maximum dilation was measured by quantitative image analysis. Univariate and multivariable linear regression analyses were created to evaluate the relationship between these measures of esophageal involvement and progression of SSc-ILD over 2 years, based on the radiologic quantitative interstitial lung disease (QILD) and quantitative lung fibrosis (QLF) in the lobe of maximum involvement (LM). All multivariable models controlled for the treatment arm, baseline ILD severity, and proton-pump inhibitor use., Results: The baseline mean patient-reported reflux score was 0.57, indicating moderate reflux (n = 141). Baseline mean maximal esophageal diameter and area were 22 mm and 242 mm 2 , respectively. Baseline reflux scores were significantly associated with the change in QLF-LM and QILD-LM in the univariate and multivariable models. Neither radiographic measure of esophageal dilation was associated with the change in radiographic measures of lung involvement., Conclusion: Severity of reflux symptoms as measured by an SSc-specific questionnaire was independently associated with the change in the radiographic extent of ILD and fibrosis over 2 years in patients with SSc-ILD. Two objective measures of esophageal dilation were not associated with radiographic progression of ILD, highlighting the need for improved objective measures of esophageal dysfunction in SSc., (© 2022 American College of Rheumatology.)

Objectives: Almost all patients with systemic sclerosis (SSc) harbour autoantibodies. Anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent and associate with distinct clinical phenotypes. B cell responses underlying these phenotypes are ill-defined. To understand how B cell autoreactivity and disease pathology connect, we determined phenotypic and functional characteristics of autoreactive B cells in ATA-positive and ACA-positive patients., Methods: Levels and isotypes of autoantibodies secreted by ex vivo cultured peripheral blood mononuclear cells from patients with ATA-positive (n=22) and ACA-positive (n=20) SSc were determined. Antibody secreting cells (ASCs) were isolated by cell sorting and cultured separately. Correlations were studied between the degree of spontaneous autoantibody production and the presence and degree of interstitial lung disease (ILD)., Results: Circulating B cells secreting either ATA-immunoglobulin G (IgG) or ACA-IgG on stimulation was readily detectable in patients. The ATA response, but not the ACA response, showed additional secretion of autoreactive IgA. ATA-IgG and ATA-IgA were also secreted spontaneously. Additional cell sorting confirmed the presence of ATA-secreting plasmablasts. The degree of spontaneous ATA-secretion was higher in patients with ILD than in those without (p<0.001) and correlated with the degree of pulmonary fibrosis (p<0.001)., Conclusion: In contrast to ACA-positive patients, ATA-positive patients show signs of recent activation of the B cell response that hallmarks this disease. The degree of activation correlates with the presence and severity of ILD, the most deleterious disease manifestation. This could explain differential responsiveness to B cell depleting therapy. The abundant and spontaneous secretion of ATA-IgG and ATA-IgA may point toward a continuously activating trigger., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Interstitial lung disease (ILD) is a common extramuscular manifestation of the anti-synthetase syndrome (ASS). Patients with ASS-ILD are at risk in developing a progressive fibrosing phenotype despite appropriate treatments. This study investigated the risk factors and the predictive value of multiple risk factors for progressive pulmonary fibrosis (PPF) in patients with ASS-ILD., Methods: Ninety patients with a diagnosis of ASS and evidence of ILD on high-resolution computed tomography (HRCT) were recruited. Among them, 72 participants completed follow-up for more than 12 months. These patients were further divided into a PPF-ASS group (n = 18) and a non-PPF-ASS group (n = 54). Logistic regression analysis was performed to investigate the risk factors for PPF. The predictive value of the combined risk factors for predicting PPF were analyzed by a ROC curve., Results: The PPF-ASS group had a higher rate of positive non-Jo-1 antibodies, a significantly higher neutrophil-to-lymphocyte ratio (NLR) and serum lactate dehydrogenase (LDH), and a significantly lower PaO 2 /FiO 2 ratio and diffusing capacity for carbon monoxide (DLCO%pred) than the non-PPF-ASS group. In addition, elevated serum Krebs von den Lungen-6 (KL-6) level and reticular opacities were significantly more common, and corticosteroid monotherapy at onset was administered more frequently in the PPF-ASS group. The median duration of follow-up was 37.4 months, survival was poorer in the PPF-ASS group, and the overall survival was 88.9%. Multivariate regression analysis further revealed that positive non-Jo-1 antibodies, NLR, and KL-6 were independent risk factors for PPF. These combined indexes had good accuracy (area under the curve = 0.874) in predicting PPF in patients with ASS-ILD., Conclusion: Positive non-Jo-1 antibodies, NLR, and serum KL-6 are independent risk factors for PPF in patients with ASS-ILD. Monitoring these markers can potentially predict PPF in this group of patients. Key Points • Positive non-Jo-1 antibodies, NLR, and serum KL-6 are independent risk factors associated with PPF in patients with ASS-ILD. • Monitoring non-Jo-1 antibodies, NLR, and serum KL-6 can potentially predict PPF in patients with ASS-ILD., (© 2023. The Author(s).)

Introduction: Coronavirus disease 2019 (COVID-19) pneumonia is a heterogeneous disease with variable effects on lung parenchyma, airways, and vasculature, leading to long-term effects on lung functions., Materials and Methods: This multicentric, prospective, observational, and interventional study included 1000 COVID-19 cases confirmed with reverse transcription-polymerase chain reaction. All cases were assessed with high-resolution computed tomography thorax, oxygen saturation, inflammatory marker as D-dimer at the entry point, and follow-up. Age, gender, comorbidity, use of bilevel positive airway pressure/noninvasive ventilation (BiPAP/NIV), and outcome as with or without lung fibrosis as per CT severity were key observations. In selected cases, we have performed lower limb venous Doppler and computed tomography (CT) pulmonary angiography to rule out deep-vein thrombosis (DVT) or pulmonary thromboembolism (PTE) respectively. Statistical analysis is performed by using Chi-square test., Observations and Analysis: Age (<50 and >50 years) and gender (male vs. female) has a significant association with D-dimer level (P < 0.00001 and P < 0.010, respectively). CT severity score at the entry point with the D-dimer level has a significant correlation (P < 0.00001). The D-dimer level has a significant association with the duration of illness before hospitalization (P < 0.00001). Comorbidities have a significant association with D-dimer levels (P < 0.00001). D-dimer level has a significant association with oxygen saturation (P < 0.00001). BIPAP/NIV requirement has a significant association with the D-dimer level (P < 0.00001). Timing of BIPAP/NIV requirement during hospitalization has a significant association with D-dimer level (P < 0.00001). Follow-up D-dimer titer during hospitalization as compared to normal and abnormal to entry point level has a significant association with post-COVID lung fibrosis, DVT, and PTE (P < 0.00001)., Conclusions: D-dimer has documented a very crucial role in COVID-19 pneumonia in predicting the severity of illness and assessing response to treatment during hospitalization, and follow-up titers have a significant role in step-up or step-down interventions in a critical care setting., Competing Interests: None

Background and Aim: Pulmonary hypertension (PH) is a common complication of combined pulmonary fibrosis and emphysema (CPFE). Whether the incidence of PH is increased in CPFE compared with pure pulmonary fibrosis or emphysema remains unclear. This meta-analysis aimed to evaluate the risk of PH in patients with CPFE compared to those with IPF or COPD/emphysema., Methods: We searched the PubMed, Embase, Cochrane Library, and CNKI databases for relevant studies focusing on the incidence of PH in patients with CPFE and IPF or emphysema. Pooled odds ratios (ORs) and standard mean differences (SMD) with 95% confidence intervals (95% CIs) were used to evaluate the differences in the clinical characteristics presence and severity of PH between patients with CPFE, IPF, or emphysema. The survival impact of PH in patients with CPFE was assessed using hazard ratios (HRs)., Results: A total of 13 eligible studies were included in the meta-analysis, involving 560, 720, and 316 patients with CPFE, IPF, and emphysema, respectively. Patients with CPFE had an increased PH risk with a higher frequency of pulmonary hypertension and higher estimated systolic pulmonary artery pressure (esPAP), compared with those with IPF (OR: 2.66; 95% CI: 1.55-4.57; P < 0.01; SMD: 0.86; 95% CI: 0.52-1.19; P < 0.01) or emphysema (OR: 3.19; 95% CI: 1.42-7.14; P < 0.01; SMD: 0.73; 95% CI: 0.50-0.96; P < 0.01). In addition, the patients with CPFE combined with PH had a poor prognosis than patients with CPFE without PH (HR: 6.16; 95% CI: 2.53-15.03; P < 0.01)., Conclusions: Our meta-analysis showed that patients with CPFE were associated with a significantly higher risk of PH compared with those with IPF or emphysema alone. The presence of PH was a poor predictor of mortality., (© 2023. The Author(s).)

Objective: Acute lung injury (ALI) is a common complication of critical diseases with high morbidity and mortality. This study explored the regulatory role and mechanism of high mobility histone box 1 protein (HMGB1) on pulmonary fibrosis (PF) after ALI in rats through nucleotide oligomerization domain-like receptor protein-3 (NLRP3) inflammasome., Methods: PF rat models after ALI were established by induction of bleomycin. Degree of fibrosis was assessed by Masson staining and Ashcroft scoring. Hydroxyproline (Hyp) contents in lung tissues and rat lung tissue morphology were detected by enzyme-linked-immunosorbent serologic assay (ELISA) and hematoxylin and eosin staining. The levels of NLRP3, major proteins of NLRP3 inflammasome (NLRP3/ASC/caspase-1), and downstream inflammatory cytokines interleukin (IL)-1 and IL-18 were determined using immunohistochemistry, Western blotting analysis, and ELISA. The nuclear/cytoplasmic nuclear factor erythroid 2-related factor 2 (Nrf2) levels and HO-1 levels were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting analysis. Rats was injected with lentivirus carrying short hairpin (sh)-HMGB1 and zinc protoporphyria (ZNPP) (HO-1 inhibitor) to assess the effects of HMGB1 and HO-1 on PF and NLRP3 inflammasome activation., Results: Bleomycin induced PF after ALI in rats, manifested as patchy fibrosis, atelectasis, and excessive expansion, and increased Aschcroft score and Hyp content. Bleomycin treatment enhanced levels of NLRP3, ASC, caspase-1, IL-1, and IL-18 in rat lung tissues, which promoted activation of NLRP3 inflammasome. HMGB1 was up-regulated in bleomycin-induced rats. HMGB1 knockdown partially reversed NLRP3 inflammasome activation and PF progression. HMGB1 knockdown promoted Nrf2 nuclear translocation and up-regulated HO-1. Suppression of HO-1 partially reversed inhibition of HMGB1 knockdown on NLRP3 inflammasome activation and PF., Conclusion: HMGB1 can activate NLRP3 inflammasomes and promote PF by inhibiting the Nrf2/HO-1 pathway., Competing Interests: The authors declared that they had no competing interests to assert.