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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: Pleuroparenchymal fibroelastosis (PPFE) has no currently available specific treatment. Benefits of lung transplantation (LT) for PPFE are poorly documented., Methods: We conducted a nation-wide multicentric retrospective study in patients who underwent lung or heart-lung transplantation for chronic end-stage lung disease secondary to PPFE between 2012 and 2022 in France., Results: Thirty-one patients were included. At transplantation, median age was 48 years [IQR 35-55]. About 64.5% were women. Twenty-one (67.7%) had idiopathic PFFE. Sixteen (52%) had bilateral LT, 10 (32%) had single LT, 4 (13%) had lobar transplantation and one (3%) had heart-lung transplantation. Operative mortality was 3.2%. Early mortality (<90 days or during the first hospitalization) was 32%. Eleven patients (35.5%) underwent reoperation for hemostasis. Eight (30.8%) experienced bronchial complications. Mechanical ventilation time was 10 days [IQR 2-55]. Length of stay in intensive care unit and hospital were 34 [IQR 18-73] and 64 [IQR 36-103] days, respectively. Median survival was 21 months. Post-transplant survival rates after 1, 2, and 5 years were 57.9%, 42.6% and 38.3% respectively. Low albuminemia (p = 0.046), FVC (p = 0.021), FEV1 (p = 0.009) and high emergency lung transplantation (p = 0.04) were associated with increased early mortality. Oversized graft tended to be correlated to a higher mortality (p = 0.07)., Conclusion: LT for PPFE is associated with high post-operative morbi-mortality rates. Patients requiring high emergency lung transplantation with advanced disease, malnutrition, or critical clinical status experienced worse outcomes., Gov Identifier: NCT05044390., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Progressive pulmonary fibrosis (PPF) is a general term for a class of interstitial lung diseases (ILDs) characterized by a progressive fibrosing (PF) phenotype. Patients with PPF have decreased lung function, exercise ability, and quality of life. The purpose of this study was to investigate the clinical characteristics, potential associated factors for disease progression, and survival outcomes of patients in the PPF population., Methods: This study retrospectively reviewed the data of patients diagnosed with ILD between January 2011 and December 2022 at The First Affiliated Hospital of Ningbo University. A PF phenotype was defined based on the criteria that were used in the PPF clinical practice guidelines, which led to the identification of 92 patients with a PF phenotype among the 177 patients with fibrotic ILD. Baseline clinical information and laboratory parameters were collected and analysed in our cohort., Results: Patients in the PPF group had higher tumour marker levels and lower pulmonary function test results at baseline than did those in the non-PPF group. According to the multivariate logistic regression analysis, age >65 years (OR 2.71, 95% CI 1.26-5.89; p  = 0.011), LDH >245 U/L (OR 3.07, 95% CI 1.39-6.78; p  = 0.006), CA-153 > 35 U/mL (OR 3.16, 95% CI 1.25-7.97; p  = 0.015), FVC <60% predicted (OR 4.82, 95% CI 1.60-14.51; p  = 0.005), DLCO <50% predicted (OR 3.21, 95% CI 1.43-7.21; p  = 0.005), and the UIP-like pattern on chest HRCT (OR 3.65, 95% CI 1.33-10.07; p  = 0.012) were potentially associated with the progression of fibrotic interstitial lung diseases (f-ILDs) to PPF. Furthermore, the PPF group had a poorer survival rate than the non-PPF group ( p  = 0.0045). According to the multivariate Cox regression analysis, an SPAP ≥ 37 mmHg (HR 2.33, 95% CI 1.09-5.00; p  = 0.030) and acute exacerbation (HR 2.88, 95% CI 1.26-6.59; p  = 0.012) were identified as significant prognostic factors for mortality in patients with PPFs., Conclusions: Patients who were older, had high CA-153 and LDH levels, had poor pulmonary function test results, or had a UIP-like pattern on chest HRCT were more likely to have indications for the progression of f-ILD to PPF. Increased SPAP and AE are independent risk factors for the prognosis of PPF patients, so additional attention should be given to such patients.

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).)

Acute respiratory distress syndrome (ARDS) has a fibroproliferative phase that may be followed by pulmonary fibrosis. Pulmonary fibrosis following COVID-19 pneumonia has been described at autopsy and following lung transplantation. We hypothesized that protein mediators of tissue remodeling and monocyte chemotaxis are elevated in the plasma and endotracheal aspirates of critically ill patients with COVID-19 who subsequently develop features of pulmonary fibroproliferation. We enrolled COVID-19 patients admitted to the ICU with hypoxemic respiratory failure. (n = 195). Plasma was collected within 24h of ICU admission and at 7d. In mechanically ventilated patients, endotracheal aspirates (ETA) were collected. Protein concentrations were measured by immunoassay. We tested for associations between protein concentrations and respiratory outcomes using logistic regression adjusting for age, sex, treatment with steroids, and APACHE III score. In a subset of patients who had CT scans during hospitalization (n = 75), we tested for associations between protein concentrations and radiographic features of fibroproliferation. Among the entire cohort, plasma IL-6, TNF-α, CCL2, and Amphiregulin levels were significantly associated with in-hospital mortality. In addition, higher plasma concentrations of CCL2, IL-6, TNF-α, Amphiregulin, and CXCL12 were associated with fewer ventilator-free days. We identified 20/75 patients (26%) with features of fibroproliferation. Within 24h of ICU admission, no measured plasma proteins were associated with a fibroproliferative response. However, when measured 96h-128h after admission, Amphiregulin was elevated in those that developed fibroproliferation. ETAs were not correlated with plasma measurements and did not show any association with mortality, ventilator-free days (VFDs), or fibroproliferative response. This cohort study identifies proteins of tissue remodeling and monocyte recruitment are associated with in-hospital mortality, fewer VFDs, and radiographic fibroproliferative response. Measuring changes in these proteins over time may allow for early identification of patients with severe COVID-19 at risk for fibroproliferation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Holton 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.)

Objective: To describe the frequency of progressive pulmonary fibrosis (PPF) in an incident cohort of systemic sclerosis (SSc)-related interstitial lung disease (ILD) and its impact on survival., Methods: Incident ILD was defined as the new development of characteristic fibrotic changes on chest HRCT scan. PPF was defined as per the 2022 American Thoracic Society. Determinants of PPF were identified using generalised estimating equations. Impact on survival was analysed using accelerated failure time regression modelling., Results: Of our incident SSc-ILD cases, 38.8% (n = 180) experienced PPF within a 12-month period after ILD diagnosis. Determinants of PPF included older age (OR 1.02, 95%CI 1.00-1.03, P = 0.011), dcSSc (OR 1.54, 95% CI 1.06-2.25, P = 0.024) and SSc-specific antibodies (anticentomere antibody OR 0.51, 95%CI 0.29-0.91, P = 0.021 and anti-Scl-70 antibody OR 1.46, 95%CI 1.01-2.09, P = 0.043). Raised CRP was numerically associated with PPF but did not reach statistical significance (OR 1.29, 95%CI 0.99-1.68, P = 0.064) nor did GORD or dysphagia (OR 1.18, 95%CI 0.57-2.42, P = 0.658 and OR 1.17, 95%CI 0.57-2.40, P = 0.664, respectively). The presence of PPF significantly impacted survival in SSc-ILD (hazard ratio 2.66, 95%CI 1.59-4.41, P < 0.001)., Conclusions: PPF occurred in a third of our incident SSc-ILD cohort; however, its occurrence was significantly associated with mortality indicating an at-risk group who may be suitable for earlier introduction of immunosuppressive and/or antifibrotic therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 diffuse parenchymal lung diseases with various clinical courses. Disease progression is one of the most important prognostic factors, and, the definition of progressive pulmonary fibrosis (PPF) has recently been established. This study aimed to estimate the prevalence, risk factors, and prognosis of PPF among patients with non-idiopathic pulmonary fibrosis (IPF) in real-world practice. A total of 215 patients were retrospectively analyzed between January 2010 and June 2023 at the Haeundae Paik Hospital in the Republic of Korea. According to the criteria proposed in 2022 by Raghu et al, PPF defined as a condition that satisfies 2 or more of the following in the past year: worsening of respiratory symptoms, physiological evidence of disease progression, and radiological evidence of disease progression. The median age of the subjects was 67 years and 63.7% were female. A total of 40% was diagnosed with PPF and connective tissue disease-associated ILD (52.3%) was the most common type, followed by nonspecific interstitial pneumonitis (NSIP) (25.6%) and cryptogenic organizing pneumonitis (16.3%). In multivariate logistic regression for predicting PPF, both the use of steroids and immunosuppressants (OR: 2.57, 95% CI: 1.41-4.67, P = .002) and home oxygen use (OR: 25.17, 95% CI: 3.21-197.24, P = .002) were independent risk factors. During the follow-up period, the mortality rate was significantly higher in the PPF group than in the non-PPF group (24.4% vs 2.3%, P < .001). In the survival analysis using the Cox proportional hazard regression model, disease progression, older age and lower forced vital capacity (FVC) were independent risk factors for mortality. Our study demonstrated that the prevalence of PPF was 40%. Concomitant therapy of steroids with an immunosuppressants and home oxygen use are risk factors for PPF. PPF itself was significantly associated with high mortality rates. Risk factors for mortality were disease progression, older age, and lower FVC., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Molecular pathways found to be important in pulmonary fibrosis are also involved in cancer pathogenesis, suggesting common pathways in the development of pulmonary fibrosis and lung cancer., Research Question: Is pulmonary fibrosis from exposure to occupational carcinogens an independent risk factor for lung cancer?, Study Design and Methods: A comprehensive search of PubMed, Embase, Web of Science and Cochrane databases with over 100 search terms regarding occupational hazards causing pulmonary fibrosis was conducted. After screening and extraction, quality of evidence and eligibility criteria for meta-analysis were assessed. Meta-analysis was performed using a random-effects model., Results: 52 studies were identified for systematic review. Meta-analysis of subgroups identified silicosis as a risk factor for lung cancer when investigating odds ratios for silicosis in autopsy studies (OR 1.47, 95% CI 1.13-1.90) and for lung cancer mortality in patients with silicosis (OR 3.21, 95% CI 2.67-3.87). Only considering studies with an adjustment for smoking as a confounder identified a significant increase in lung cancer risk (OR 1.58, 95% CI 1.34-1.87). However, due to a lack of studies including cumulative exposure, no adjustments could be included. In a qualitative review, no definitive conclusion could be reached for asbestosis and silicosis as independent risk factors for lung cancer, partly because the studies did not take cumulative exposure into account., Interpretation: This systematic review confirms the current knowledge regarding asbestosis and silicosis, indicating a higher risk of lung cancer in exposed individuals compared to exposed workers without fibrosis. These individuals should be monitored for lung cancer, especially when asbestosis or silicosis is present., Competing Interests: Conflict of interest: T. Kraus and J. Krabbe give talks on this topic at workshops, seminars, and conferences for which have been paid for by the organisers including travel and accommodation. J. Krabbe, S. Drießen and T. Kraus have done research in the past funded by German institutions for statutory accident insurance and prevention with unrestricted grants to the University Hospital RWTH Aachen. K.M. Steffens has nothing to disclose., (Copyright ©The authors 2024.)

Background: Acute exacerbation (AE) refers to rapidly progressive respiratory deterioration in the clinical course of interstitial lung disease (ILD). Progressive pulmonary fibrosis (PPF) is the chronic progressive phenotype of ILD. No study has investigated the relationship between AE and PPF in ILD., Objectives: We aimed to determine the association between AE and PPF in ILD patients., Design: A retrospective cohort study., Methods: A total of 414 patients hospitalised for ILD were included in our study. The clinical presentations, radiographic features and laboratory findings of the patients were reviewed., Results: AE was present in 120 (29.0%) ILD patients and was associated with a higher risk of death than non-AE patients in the whole cohort (HR 2.893; 95% CI, 1.847-4.529; p  < 0.001). However, the significant difference disappeared when stratified by PPF (HR 1.192; 95% CI, 0.633-2.247; p  = 0.586) and non-PPF (HR 1.113; 95% CI, 0.384-3.223; p  = 0.844). In addition, the adverse effect of PPF on prognosis remained consistent in both AE and non-AE patients. Multivariable logistic regression analysis showed that compared with non-PPF patients, only age was a risk factor for PPF in AE-ILD, while the risk factors for PPF in the non-AE group were age, definite usual interstitial pneumonia and mediastinal lymph node enlargement., Conclusion: In the context of ILD, both AE and PPF were found to be associated with poor prognosis. However, the adverse effect of AE on prognosis disappeared when PPF was considered as a stratification feature, whereas the adverse effect of PPF on prognosis persisted in both AE and non-AE individuals. Therefore, it is important to investigate effective strategies to prevent disease progression after AE. Increased recognition and attention to PPF and early antifibrotic therapy at the appropriate time is also warranted.

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.

In this study, sulfated polysaccharides extracted from Laminaria japonica were degraded by free radicals to obtain low molecular weight fucoidan (LMWF). The in vivo and in vitro effects of LMWF on bleomycin-treated pulmonary fibrosis mice and TGF-treated A549 cells, respectively, were evaluated, and the role of antioxidant activity was assessed. H&E, Masson's trichrome, and Sirius red staining results showed that bleomycin induced obvious pathological changes and collagen deposition in the lung tissue of mice. However, LMWF effectively inhibited collagen deposition, and based on immunohistochemistry analyses, LMWF can also inhibit the expression of fibrosis markers. At the same time, LMWF could regulate related antioxidant factors in the lung tissue of pulmonary fibrosis mice and reduce the pressure of oxidative stress. Moreover, LMWF could improve the morphology of cells induced with TGF, which confirmed that LMWF could inhibit fibrosis via antioxidant activity modulation., Competing Interests: There are no conflicts to declare., (Copyright © 2022 Huidan Dong et al.)

Background: Research questions To compare the efficacy of nintedanib and pirfenidone in the treatment of progressive pulmonary fibrosis; and to compare the efficacy of anti-fibrotic therapy (grouping nintedanib and pirfenidone together) in patients with IPF versus patients with progressive lung fibrosis not classified as IPF., Study Design and Methods: A search of databases including MEDLINE, EMBASE, PubMed, and clinicaltrials.gov was conducted. Studies were included if they were randomised controlled trials of pirfenidone or nintedanib in adult patients with IPF or non-IPF patients, and with extractable data on mortality or decline in forced vital capacity (FVC). Random effects meta-analyses were performed on changes in FVC and where possible on mortality in the selected studies., Results: 13 trials of antifibrotic therapy were pooled in a meta-analysis (with pirfenidone and nintedanib considered together as anti-fibrotic therapy). The change in FVC was expressed as a standardised difference to allow pooling of percentage and absolute changes. The mean effect size in the IPF studies was - 0.305 (SE 0.043) (p < 0.001) and in the non-IPF studies the figures were - 0.307 (SE 0.063) (p < 0.001). There was no evidence of any difference between the two groups for standardised rate of FVC decline (p = 0.979). Pooling IPF and non-IPF showed a significant reduction in mortality, with mean risk ratio of 07.01 in favour of antifibrotic therapy (p = 0.008). A separate analysis restricted to non-IPF did not show a significant reduction in mortality (risk ratio 0.908 (0.547 to 1.508), p = 0.71., Interpretation: Anti-fibrotic therapy offers protection against the rate of decline in FVC in progressive lung fibrosis, with similar efficacy shown between the two anti-fibrotic agents currently in clinical use. There was no significant difference in efficacy of antifibrotic therapy whether the underlying condition was IPF or non-IPF with progressive fibrosis, supporting the hypothesis of a common pathogenesis. The data in this analysis was insufficient to be confident about a reduction in mortality in non-IPF with anti-fibrotic therapy. Trial Registration PROSPERO, registration number CRD42021266046., (© 2021. The Author(s).)

Background: The bronchiectasis severity index (BSI) and FACED score are currently used in predicting outcomes of non-cystic fibrosis bronchiectasis (NCFB). Distance-saturation product (DSP), the product of distance walked, and lowest oxygen saturation during the 6-min walk test showed strong predictive power of mortality in non-CF bronchiectasis patients. This study aimed to compare the efficacy of these scores and DSP in predicting mortality., Methods and Patients: Our retrospective study included NCFB patients from January 2004 to December 2017. We recorded the basic data, pulmonary function, radiologic studies, sputum culture results, acute exacerbations (AE), emergency department (ED) visits, hospitalization, and mortality., Results: A total 130 NCFB patients were analysed. The mean BSI score, FACED score, and DSP were 8.8 ± 4.9, 3.4 ± 1.7, and 413.1 ± 101.5 m%, respectively. BSI and FACED scores had comparable predictive power for AE ( p =.011; p =.010, respectively). The BSI score demonstrated a significant correlation with ED visits ( p =.0003). There were 12 deaths. Patients were stratified using a DSP cut-off value of 345 m% according to the best area under receiver operator characteristic curve (AUC) value in mortality. DSP was not correlated with AE and ED visits. BSI, FACED scores, and DSP demonstrated statistically significant correlations with hospitalization ( p <.0001; p <.0001; p =.0007, respectively). The AUC for overall mortality was similar for BSI, FACED score, and DSP (0.80 versus 0.85, p =.491; 0.85 versus 0.83, p =.831)., Conclusion: DSP had comparable predictive power for mortality as the well-validated BSI and FACED scores and is relatively easy to use in clinical practice.KEY MESSAGEDistance-saturation product (DSP) comprised with the product of distance walked, and lowest oxygen saturation during the 6-min walk test, which is common used in clinical practice.DSP demonstrated strong and comparable predictive power of mortality as the well-validated BSI and FACED scores in non-CF bronchiectasis patients.

Diffuse alveolar injury and pulmonary fibrosis (PF) are the main causes of death of Covid-19 cases. In this study a low molecular weight fucoidan (LMWF) with unique structural was obtained from Laminaria japonica, and its anti- PF and anti-epithelial-mesenchymal transition (EMT) bioactivity were investigated both in vivo and in vitro. After LWMF treatment the fibrosis and inflammatory factors stimulated by Bleomycin (BLM) were in lung tissue. Immunohistochemical and Western-blot results found the expression of COL2A1, β-catenin, TGF-β, TNF-α and IL-6 were declined in mice lung tissue. Besides, the phosphorylation of PI3K and Akt were inhibited by LMWF. In addition, the progression of EMT induced by TGF-β1 was inhibited by LMWF through down-regulated both TGF-β/Smad and PI3K/AKT signaling pathways. These data indicate that unique LMWF can protect the lung from fibrosis by weakening the process of inflammation and EMT, and it is a promising therapeutic option for the treatment of PF., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Combined pulmonary fibrosis and emphysema (CPFE) is recognized as a characteristic syndrome of smoking-related interstitial lung disease that has a worse prognosis than idiopathic pulmonary fibrosis (IPF). However, outcomes after lung transplantation for CPFE have not been reported. The aim of this study is to describe the clinical features and outcomes of CPFE after lung transplantation., Research Question: What are the clinical features and outcomes of CPFE after lung transplantation?, Study Design and Methods: This is a single-center retrospective cohort study of patients with CPFE and IPF who underwent lung transplantation at our center between January 2011 and December 2016. We defined CPFE as ≥10% emphysema in the upper lung fields combined with fibrosis on high-resolution CT scan. We characterized the clinical features of patients with CPFE and compared their outcomes after lung transplantation with those with IPF., Results: Twenty-seven of 172 (16%) patients with IPF met criteria for CPFE. Severe pulmonary hypertension was present in 16 of 27 (59%) patients with CPFE. On logistic regression analysis, CPFE was significantly associated with primary graft dysfunction (PGD) grade 3 (OR, 3.14; 95% CI, 1.18-8.37; P = .02). On competing risk regression analysis, CPFE was associated with acute cellular rejection (ACR) grade ≥ A2, and chronic lung allograft dysfunction (CLAD) (hazard ratio [HR], 1.89; 95% CI, 1.10-3.25; P = .02; HR, 1.96; 95% CI, 1.02-3.77; P = .04, respectively). Five-year survival was 79.0% for the CPFE group and 75.4% for the IPF group (log-rank P = .684)., Interpretation: After transplantation, patients with CPFE were more likely to develop PGD, ACR, and CLAD compared with those with IPF. However, survival was not significantly different between the two groups., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Recent studies suggest that the mortality rate of pulmonary fibrosis (PF) in the U.S. is decreasing. However, the mortality trends and demographic differences of PF among the states have not been evaluated., Objective: To evaluate PF-related mortality rates and trends in the nine most populated states in the U.S., Methods: Population-based study using the Multiple Cause of Death Database available through the Centers for Disease Control and Prevention website. PF-related deaths were identified using ICD codes., Results: From 2004 to 2018, average annual mortality rates ranged from being the lowest in New York (110.8 per 1,000,000) to the highest in North Carolina (195.3 per 1,000,000). The mortality rates showed a decline in the majority of the states and were stable in the other states. The most significant declines were in California and Michigan. The average mortality rates in males were higher than females in all the states (rate ratio ranged from 1.56 in Texas to 1.81 in New York) and the decline in the mortality rates was more pronounced compared to males in most states. The mortality rates in Blacks were lower compared to Whites in all the states (rate ratio ranged from 0.47 in New York to 0.69 in Ohio) and the decline in the mortality rates over the period was more significant than in Whites., Conclusions: There is substantial variation in mortality rates and mortality trends between states and different demographics. Further studies are needed to evaluate the environmental factors, diagnostic accuracy, and coding practices contributing to these differences., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Lung cancer patients with interstitial lung disease (ILD) are prone for higher morbidity and mortality and their treatment is challenging. The purpose of this study is to investigate whether the survival of lung cancer patients is affected by the presence of ILD documented on CT., Materials and Methods: 146 patients with ILD at initial chest CT were retrospectively included in the study. 146 lung cancer controls without ILD were selected. Chest CTs were evaluated for the presence of pulmonary fibrosis which was classified in 4 categories. Presence and type of emphysema, extent of ILD and emphysema, location and histologic type of cancer, clinical staging and treatment were evaluated. Kaplan-Meier estimates and Cox regression models were used to assess survival probability and hazard of death of different groups. P value < 0.05 was considered significant., Results: 5-year survival for the study group was 41% versus 48% for the control group (log-rank test p = 0.0092). No significant difference in survival rate was found between the four different categories of ILD (log-rank test, p = 0.195) and the different histologic types (log-rank test, p = 0.4005). A cox proportional hazard model was used including presence of ILD, clinical stage and age. The hazard of death among patients with ILD was 1.522 times that among patients without ILD (95%CI, p = 0.029)., Conclusion: Patients with lung cancer and CT evidence of ILD have a significantly shorter survival compared to patients with lung cancer only. Documenting the type and grading the severity of ILD in lung cancer patients will significantly contribute to their challenging management., Competing Interests: The authors have declared that no competing interests exist.

Background: Previous studies reporting the causes of death in patients with severe COVID-19 have provided conflicting results. The objective of this study was to describe the causes and timing of death in patients with severe COVID-19 admitted to the intensive care unit (ICU)., Methods: We performed a retrospective study in eight ICUs across seven French hospitals. All consecutive adult patients (aged ≥ 18 years) admitted to the ICU with PCR-confirmed SARS-CoV-2 infection and acute respiratory failure were included in the analysis. The causes and timing of ICU deaths were reported based on medical records., Results: From March 1, 2020, to April 28, 287 patients were admitted to the ICU for SARS-CoV-2 related acute respiratory failure. Among them, 93 patients died in the ICU (32%). COVID-19-related multiple organ dysfunction syndrome (MODS) was the leading cause of death (37%). Secondary infection-related MODS accounted for 26% of ICU deaths, with a majority of ventilator-associated pneumonia. Refractory hypoxemia/pulmonary fibrosis was responsible for death in 19% of the cases. Fatal ischemic events (venous or arterial) occurred in 13% of the cases. The median time from ICU admission to death was 15 days (25th-75th IQR, 7-27 days). COVID-19-related MODS had a median time from ICU admission to death of 14 days (25th-75th IQR: 7-19 days), while only one death had occurred during the first 3 days since ICU admission., Conclusions: In our multicenter observational study, COVID-19-related MODS and secondary infections were the two leading causes of death, among severe COVID-19 patients admitted to the ICU.

Background: This an update of a Cochrane Review. Paraquat is a widely used herbicide, but is also a lethal poison. In some low- and middle-income countries (LMICs) paraquat is commonly available and inexpensive, making poisoning prevention difficult. Most of the people poisoned by paraquat have taken it as a means of self-poisoning. Standard treatment for paraquat poisoning prevents further absorption and reduces the load of paraquat in the blood through haemoperfusion or haemodialysis. The effectiveness of standard treatments is extremely limited. The immune system plays an important role in exacerbating paraquat-induced lung fibrosis. Immunosuppressive treatment using glucocorticoid and cyclophosphamide in combination has been developed and studied as an intervention for paraquat poisoning., Objectives: To assess the effects of glucocorticoid with cyclophosphamide for moderate to severe oral paraquat poisoning., Search Methods: The most recent searches were run in September 2020. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Injuries Trials Register), Ovid MEDLINE(R), Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid OLDMEDLINE, Embase Classic + Embase (Ovid), ISI WOS (SCI-EXPANDED, SSCI, CPCI-S, and CPSI-SSH), and trials registries. We also searched the following three resources: China National Knowledge Infrastructure database (CNKI ); Wanfang Data (); and VIP () on 12 November 2020. We examined the reference lists of included studies and review papers., Selection Criteria: We included randomised controlled trials (RCTs). For this update, in accordance with Cochrane Injuries' Group policy (2015), we included only prospectively registered RCTs for trials published after 2010. We included trials which assessed the effects of glucocorticoid with cyclophosphamide delivered in combination. Eligible comparators were standard care (with or without a placebo), or any other therapy in addition to standard care. Outcomes of interest included mortality and infections., Data Collection and Analysis: We calculated the mortality risk ratio (RR) and 95% confidence interval (CI). Where possible, we summarised data for all-cause mortality at relevant time periods (from hospital discharge to three months after discharge) in meta-analysis, using a fixed-effect model. We conducted sensitivity analyses based on factors including whether participants were assessed at baseline for plasma paraquat levels. We also reported data on infections within one week after initiation of treatment., Main Results: We included four trials with a total of 463 participants. The included studies were conducted in Taiwan (Republic of China), Iran, and Sri Lanka. Most participants were male. The mean age of participants was 28 years. We judged two of the four included studies, including the largest and most recently conducted study (n = 299), to be at low risk of bias for key domains including sequence generation. We assessed one study to be at high risk of selection bias and another at unclear risk, since allocation concealment was either not mentioned in the trial report or explicitly not undertaken. We assessed three of the four studies to be at unclear risk of selective reporting, as no protocols could be identified. An important source of heterogeneity amongst the included studies was the method of assessment of participants' baseline severity using analysis of plasma levels (two studies employed this method, whilst the other two did not). No studies assessed the outcome of mortality at 30 days following ingestion of paraquat. Low-certainty evidence from two studies indicates that glucocorticoids with cyclophosphamide in addition to standard care may slightly reduce the risk of death in hospital compared to standard care alone ((RR 0.82, 95% CI 0.68 to 0.99; participants = 322); results come from sensitivity analysis excluding studies not assessing plasma at baseline). However, we have limited confidence in this finding as heterogeneity was high (I 2 = 77%) and studies varied in terms of size and comparators. A single large study provided data showing that there may be little or no effect of treatment at three months post discharge from hospital (RR 0.98, 95% CI 0.85 to 1.13; 1 study, 293 participants; low-certainty evidence); however, analysis of long-term results amongst participants whose injuries arose from self-poisoning must be interpreted with caution. We remain uncertain of the effect of glucocorticoids with cyclophosphamide on infection within one week after initiation of the treatment; this outcome was assessed by two small studies only (31 participants, very low-certainty evidence) that considered leukopenia as a proxy or risk factor for infection. Neither study reported infections in any participants., Authors' Conclusions: Low-certainly evidence suggests that glucocorticoids with cyclophosphamide in addition to standard care may slightly reduce mortality in hospitalised people with oral paraquat poisoning. However, we have limited confidence in this finding because of substantial heterogeneity and concerns about imprecision. Glucocorticoids with cyclophosphamide in addition to standard care may have little or no effect on mortality at three months after hospital discharge. We are uncertain whether glucocorticoid with cyclophosphamide puts patients at an increased risk of infection due to the limited evidence available for this outcome. Future research should be prospectively registered and CONSORT-compliant. Investigators should attempt to ensure an adequate sample size, screen participants for inclusion rigorously, and seek long-term follow-up of participants. Investigators may wish to research the effects of glucocorticoid in combination with other treatments., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: There is a paucity of data on the epidemiology, survival estimates and healthcare resource utilisation and associated costs of patients with progressive fibrosing interstitial lung disease (PF-ILD) in France. An algorithm for extracting claims data was developed to indirectly identify and describe patients with PF-ILD in the French national administrative healthcare database., Methods: The French healthcare database, the Système National des Données de Santé (SNDS), includes data related to ambulatory care, hospitalisations and death for 98.8% of the population. In this study, algorithms based on age, diagnosis and healthcare consumption were created to identify adult patients with PF-ILD other than idiopathic pulmonary fibrosis between 2010 and 2017. Incidence, prevalence, survival estimates, clinical features and healthcare resource usage and costs were described among patients with PF-ILD., Results: We identified a total of 14,413 patients with PF-ILD. Almost half of them (48.1%) were female and the mean (± standard deviation) age was 68.4 (± 15.0) years. Between 2010 and 2017, the estimated incidence of PF-ILD ranged from 4.0 to 4.7/100,000 person-years and the estimated prevalence from 6.6 to 19.4/100,000 persons. The main diagnostic categories represented were exposure-related ILD other than hypersensitivity pneumonitis (n = 3486; 24.2%), idiopathic interstitial pneumonia (n = 3113; 21.6%) and rheumatoid arthritis-associated ILD (n = 2521; 17.5%). Median overall survival using Kaplan-Meier estimation was 3.7 years from the start of progression. During the study, 95.2% of patients had ≥ 1 hospitalisation for respiratory care and 34.3% were hospitalised in an intensive care unit. The median (interquartile range) total specific cost per patient during the follow-up period was €25,613 (10,622-54,287) and the median annual cost per patient was €18,362 (6856-52,026), of which €11,784 (3003-42,097) was related to hospitalisations. Limitations included the retrospective design and identification of cases through an algorithm in the absence of chest high-resolution computed tomography scans and pulmonary function tests., Conclusions: This large, real-world, longitudinal study provides important insights into the characteristics, epidemiology and healthcare resource utilisation and costs associated with PF-ILD in France using a comprehensive and exhaustive database, and provides vital evidence that PF-ILD represents a high burden on both patients and healthcare services. Trial registration ClinicalTrials.gov, NCT03858842. ISRCTN, ISRCTN12345678. Registered 3 January 2019-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03858842.

Background: Patients with fibrotic hypersensitivity pneumonitis (HP) show variable clinical courses, and some experience rapid deterioration (RD), including acute exacerbation (AE). However, little is known about AE in fibrotic HP. Here, we retrospectively examined the incidence, risk factors, and outcomes of AE in fibrotic HP., Methods: The incidence rates of AE were calculated in 101 patients with biopsy-proven HP. AE was defined as the worsening of dyspnoea within 30 days, with new bilateral lung infiltration and no evidence of infection or other causes of dyspnoea., Results: During follow-up (median: 30 months), 18 (17.8%) patients experienced AE. The 1, 3, and 5 year incidence rates of AE were 6.0, 13.6, and 22.8%, respectively. Lower diffusing capacity of the lung for carbon monoxide (DL CO ) and a radiologic usual interstitial pneumonia (UIP)-like pattern were risk factors for AE. In-hospital mortality after AE was 44.4%. Median survival from diagnosis was significantly shorter in patients with AE (26.0 months) than in those with no-AE RD (55.0 months; p = 0.008) or no RD (not reached; p < 0.001). AE remained a significant predictor of all-cause mortality (hazard ratio, 8.641; 95% confidence interval, 3.388-22.040; p < 0.001) after adjustment for age, body mass index, lung function, lymphocyte levels in bronchoalveolar lavage fluid, and the presence of a UIP-like pattern., Conclusions: AE was not uncommon among patients with fibrotic HP and significantly affected prognosis. A lower DL CO value and radiologic UIP-like pattern at diagnosis were associated with the development AE in patients with fibrotic HP.

Competing Interests: The authors have no funding and conflicts of interests to disclose.

The objective of this study was to investigate the effects of nationwide lockdown during the Novel Coronavirus Disease 2019 (COVID-19) pandemic on an average volume of alcohol consumption and drinking patterns. A survey was conducted with a random sample of 4072 people. The authors found a significant influence of the pandemic period on alcohol consumption compared to the pre-pandemic period. The vast majority of respondents reduced the frequency of consumption of all types of alcohol. However, when the population was divided into subgroups, this differentiation demonstrated that particular groups are more vulnerable to alcohol misuse. Higher frequency of alcohol consumption during the COVID-19 pandemic lockdown was most often found in the group of men, people aged 18-24 years, inhabitants of big cities, and remote workers. Besides, significant differences were observed in subpopulations concerning different types of alcohol. Results emphasized the importance of monitoring and implementation of actions aimed at reducing the potential psychosocial impact of COVID-19, including alcohol-related disorders.

Pulmonary fibrosis is a progressive scarring disease of the lungs, characterized by inflammation, fibroblast activation, and deposition of extracellular matrix. The long pentraxin 3 (PTX3) is a member of the pentraxin family with non-redundant functions in innate immune responses, tissue repair, and haemostasis. The role played in the lungs by PTX3 during the fibrotic process has not been elucidated. In this study, the impact of PTX3 expression on lung fibrosis was assessed in an intratracheal bleomycin (BLM)-induced murine model of the disease applied to wild type animals, transgenic mice characterized by endothelial overexpression and stromal accumulation of PTX3 (Tie2-PTX3 mice), and genetically deficient Ptx3 -/- animals. Our data demonstrate that PTX3 is produced during BLM-induced fibrosis in wild type mice, and that PTX3 accumulation in the stroma compartment of Tie2-PTX3 mice limits the formation of fibrotic tissue in the lungs, with reduced fibroblast activation and collagen deposition, and a decrease in the recruitment of the immune infiltrate. Conversely, Ptx3 -null mice showed an exacerbated fibrotic response and decreased survival in response to BLM treatment. These results underline the protective role of endogenous PTX3 during lung fibrosis and pave the way for the study of novel PTX3-derived therapeutic approaches to the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Maccarinelli, Bugatti, Churruca Schuind, Ganzerla, Vermi, Presta and Ronca.)

Introduction: Pulmonary fibrosing sarcoidosis is associated with increased mortality. This study was aimed to explore the prognosis value of a panel of parameters for predicting mortality., Methods: This retrospective study included 216 patients with confirmed stage 4 pulmonary sarcoidosis. Stage 4 diagnosis date served as baseline. The following information was systematically present at baseline: epidemiological characteristics; treatments; pulmonary function; composite physiologic index (CPI); systolic pulmonary artery pressure at echocardiography; pulmonary fibrosis extent, main pulmonary artery/ascending aorta diameters ratio (MPAD/AAD) and MPAD/body surface area (BSA) measured and calculated using computed tomography, Walsh's algorithm based on CPI, lung fibrosis extent and MPAD/AAD ratio, and modified Walsh's algorithm with MPAD/BSA replacing MPAD/AAD allowed to estimate good or bad prognosis profiles. The primary outcome of the study was all cause mortality and lung transplantation. The value of baseline parameters was tested as predictors of mortality using univariate and multivariate analyses., Results: Median follow-up was 105 months. There were 41 deaths and 5 transplantations. At multivariate analysis, survival was independently predicted by several parameters including CPI, lung fibrosis extent, pulmonary hypertension at echography or MPAD/BSA ratio, Walsh's algorithm, and geographic origin. The modified Walsh's algorithm was most highly predictive., Conclusion: Survival was best predicted by geographic origin, lung fibrosis extent, PH at echography or MPAD/BSA ratio, as well as by various scores among them the modified Walsh's algorithm had very high predictive value thanks to MPAD/BSA ratio which accurately predicted mortality., 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 © 2020 Elsevier Ltd. All rights reserved.)

Background: Most Thai patients with systemic sclerosis (SSc) have diffuse cutaneous SSc (dcSSc) unlike most Caucasians and some Asians. A longitudinal cohort study among Thai dcSSc is needed., Objectives: We aimed to determine the overall clinical characteristics, define the clinical difference between limited cutaneous SSc (lcSSc) and dcSSc, and ascertain the mortality rate and the factors associated with mortality., Method: We conducted a cohort study including 566 Thai adult SSc patients between January 2013 and June 2019. Clinical difference between lcSSc and dcSSc was investigated using generalized estimating equations (GEE)., Results: Females presented more than males (356 vs 210 cases). The majority of cases were dcSSc (411; 72.6%). The median duration of disease at the time of pulmonary fibrosis (PF) detection was 2.5 years, pulmonary arterial hypertension 8.1 years, and renal crisis 4.1 years. By GEE analysis, dcSSc was significantly associated with salt-and-pepper skin, hand deformity, and every 1-point increase in modified Rodnan skin score (mRSS). A greater mortality risk was associated with age at onset >60 years (hazards ratio [HR] 5.5), a World Health Organization functional class (FC) III (HR 5.1), FC IV (HR 34.8), edematous skin (HR 11.4), early onset of PF (HR 1.7), each 5-point increase in the mRSS (HR 4.5), and ≥2 internal organ involvements (HR 10.1)., Conclusion: dcSSc is a common SSc subset among Thais. PF was an early complication in SSc and earlier PF detection was associated with a poorer prognosis. Elderly onset, high FC, severe skin tightness, and multiple organ involvements were associated with a greater mortality risk., (© 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Critical patients with the coronavirus disease 2019 (COVID-19), even those whose nucleic acid test results had turned negative and those receiving maximal medical support, have been noted to progress to irreversible fatal respiratory failure. Lung transplantation (LT) as the sole therapy for end-stage pulmonary fibrosis related to acute respiratory distress syndrome has been considered as the ultimate rescue therapy for these patients., Methods: From February 10 to March 10, 2020, three male patients were urgently assessed and listed for transplantation. After conducting a full ethical review and after obtaining assent from the family of the patients, we performed three LT procedures for COVID-19 patients with illness durations of more than one month and extremely high sequential organ failure assessment scores., Results: Two of the three recipients survived post-LT and started participating in a rehabilitation program. Pearls of the LT team collaboration and perioperative logistics were summarized and continually improved. The pathological results of the explanted lungs were concordant with the critical clinical manifestation, and provided insight towards better understanding of the disease. Government health affair systems, virology detection tools, and modern communication technology all play key roles towards the survival of the patients and their rehabilitation., Conclusions: LT can be performed in end-stage patients with respiratory failure due to COVID-19-related pulmonary fibrosis. If confirmed positive-turned-negative virology status without organ dysfunction that could contraindicate LT, LT provided the final option for these patients to avoid certain death, with proper protection of transplant surgeons and medical staffs. By ensuring instant seamless care for both patients and medical teams, the goal of reducing the mortality rate and salvaging the lives of patients with COVID-19 can be attained.

Pulmonary fibrosis (PF) is a kind of interstitial lung disease with the features of progressive and often fatal dyspnea. Tetrandrine (TET) is the major active constituent of Chinese herbal Stephania tetrandra S. Moore , which has already applied clinically to treat rheumatism, lung cancer, and silicosis. In this work, a tetrandrine-hydroxypropyl-β-cyclodextrin inclusion compound (TET-HP-β-CD) was developed for the treatment of pulmonary fibrosis via inhalation administration. TET-HP-β-CD was prepared by the freeze-drying method and identified using the cascade impactor, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectrum (FT-IR). A bleomycin-induced pulmonary fibrosis rat model was used to assess the effects of inhaled TET and TET-HP-β-CD. Animal survival, hydroxyproline content in the lungs, and lung histology were detected. The results showed that inhalation of TET-HP-β-CD alleviated inflammation and fibrosis, limited the accumulation of hydroxyproline in the lungs, regulated protein expression in PF development, and improved postoperative survival. Moreover, nebulized delivery of TET-HP-β-CD accumulated chiefly in the lungs and limited systemic distribution compared with intravenous administration. The present results indicated that inhalation of TET-HP-β-CD is an attractive candidate for the treatment of pulmonary fibrosis.

Objective: To investigate the value of ultrasound in the dynamic assessment of lung injury after acute paraquat poisoning., Methods: A prospective observational study was performed on patients with paraquat poisoning from admission to day 28 or discharge. Ultrasound assessment of the lungs was performtyed every 48 hours. The correlation of the lung ultrasound score (LUS) with other indicators was analyzed., Results: Twenty-six patients were enrolled, with an average age of 46 ± 16 years. The average toxic dose was 95 ± 51 mL. The intensive care unit (ICU) stay averaged 9 ± 8 days, and the 28-day mortality was 88.5%. There was a significant negative correlation between LUS and oxygenation index (rho = -0.896) and a significant positive correlation between LUS and carbon dioxide concentration (rho = 0.567). Lung ultrasound and computed tomography imaging correlated closely., Conclusion: Lung ultrasound can reflect changes in lung status in patients with paraquat poisoning and can be used to evaluate lung injury in these patients. Trial registration: ChiCTR, ChiCTR-DDD-16010211. Registered 21 December 2016, http://www.chictr.org.cn/listbycreater.aspx .

Objective: To describe the associations between autoantibodies, clinical presentation, and outcomes among patients with systemic sclerosis (SSc) in order to develop a novel SSc classification scheme that would incorporate both antibodies and the cutaneous disease subset as criteria., Methods: Demographic and clinical characteristics, including cutaneous subset, time of disease and organ complication onset, and autoantibody specificities, were determined in a cohort of SSc subjects. Survival analysis was used to assess the effect of the autoantibodies on organ disease and death., Results: The study included 1,325 subjects. Among the antibody/skin disease subsets, anticentromere antibody-positive patients with limited cutaneous SSc (lcSSc) (n = 374) had the highest 20-year survival (65.3%), lowest incidence of clinically significant pulmonary fibrosis (PF) (8.5%) and scleroderma renal crisis (SRC) (0.3%), and lowest incidence of cardiac SSc (4.9%), whereas the frequency of pulmonary hypertension (PH) was similar to the mean value in the SSc cohort overall. The anti-Scl-70+ groups of patients with lcSSc (n = 138) and patients with diffuse cutaneous SSc (dcSSc) (n = 149) had the highest incidence of clinically significant PF (86.1% and 84%, respectively, at 15 years). Anti-Scl-70+ patients with dcSSc had the lowest survival (32.4%) and the second highest incidence of cardiac SSc (12.9%) at 20 years. In contrast, in anti-Scl-70+ patients with lcSSc, other complications were rare, and these patients demonstrated the lowest incidence of PH (6.9%) and second highest survival (61.8%) at 20 years. Anti-RNA polymerase antibody-positive SSc patients (n = 147) had the highest incidence of SRC (28.1%) at 20 years. The anti-U3 RNP+ SSc group (n = 56) had the highest incidence of PH (33.8%) and cardiac SSc (13.2%) at 20 years. Among lcSSc patients with other autoantibodies (n = 295), the risk of SRC and cardiac SSc was low at 20 years (2.7% and 2.4%, respectively), while the frequencies of other outcomes were similar to the mean values in the full SSc cohort. Patients with dcSSc who were positive for other autoantibodies (n = 166) had a poor prognosis, demonstrating the second lowest survival (33.6%) and frequent organ complications., Conclusion: These findings highlight the importance of autoantibodies, cutaneous subset, and disease duration when assessing morbidity and mortality in patients with SSc. Our novel classification scheme may improve disease monitoring and benefit future clinical trial designs in SSc., (© 2019, American College of Rheumatology.)

Background: At present, no approved pharmacotherapies are available for unclassifiable interstitial lung disease (ILD), which is characterised by progressive fibrosis of the lung. We aimed to assess the efficacy and safety of pirfenidone in patients with progressive fibrosing unclassifiable ILD., Methods: We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 70 centres in Australia, Belgium, Canada, Czech Republic, Denmark, Germany, Greece, Ireland, Israel, Italy, Poland, Portugal, Spain, and the UK. Eligible patients (aged ≥18-85 years) had progressive fibrosing unclassifiable ILD, a percent predicted forced vital capacity (FVC) of 45% or higher and percent predicted carbon monoxide diffusing capacity (DLco) of 30% or higher, more than 10% fibrosis on high-resolution CT, and a high-resolution CT from the previous 12 months. Patients were randomly assigned (1:1) to 2403 mg oral pirfenidone daily or placebo using a central validated interactive voice or web-based response system, stratified by concomitant mycophenolate mofetil use and presence or absence of interstitial pneumonia with autoimmune features. Investigators, site personnel, and patients were masked to treatment assignment. The primary endpoint was mean predicted change in FVC from baseline over 24 weeks, measured by daily home spirometry. Secondary endpoints were change in FVC measured by site spirometry, proportion of patients who had a more than 5% or more than 10% absolute or relative decline in percent predicted FVC measured by clinic-based spirometry, change in percent predicted DLco, change in 6-min walk distance (6MWD), change in University of California San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) score, change in Leicester Cough Questionnaire score, change in cough visual analogue scale, and changes in total and subscores of the St George's Respiratory Questionnaire (SGRQ), all of which were compared with baseline. Additional secondary endpoints included proportion of patients who had non-elective hospitalisation (respiratory and all-cause) and acute exacerbations, and progression-free survival. Efficacy was analysed in the intention-to-treat (ITT) population, which included all randomly assigned patients. Safety was assessed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03099187, and is no longer recruiting., Findings: Between May 15, 2017, and June 5, 2018, 253 patients were randomly assigned to receive 2403 mg pirfenidone (n=127) or placebo (n=126) and were included in the ITT analysis set. Analysis of the primary endpoint was affected by intraindividual variability in home spirometry values, which prevented application of the prespecified statistical model. Over 24 weeks, predicted median change in FVC measured by home spirometry was -87·7 mL (Q1-Q3 -338·1 to 148·6) in the pirfenidone group versus -157·1 mL (-370·9 to 70·1) in the placebo group. Over 24 weeks, predicted mean change in FVC measured by site spirometry was lower in patients given pirfenidone than placebo (treatment difference 95·3 mL [95% CI 35·9 to 154·6], p=0·002). Compared with the placebo group, patients in the pirfenidone group were less likely to have a decline in FVC of more than 5% (odds ratio [OR] 0·42 [95% CI 0·25 to 0·69], p=0·001) or more than 10% (OR 0·44 [0·23 to 0·84], p=0·011). At week 24, mean change in DLco from baseline was -0·7% (SD 7·1) for the pirfenidone group and -2·5% (8·8) for the placebo group, and mean change in 6MWD from baseline was -2·0 m (68·1) for the pirfenidone group and -26·7 m (79·3) for the placebo group. Changes from baseline in UCSD-SOBQ, Leicester Cough Questionnaire score, cough visual analogue scale, and SGRQ scores were similar between the pirfenidone and placebo groups at week 24. Analysis of acute exacerbations, hospital admissions, and time to death from respiratory causes during the study yielded no meaningful results due to a small number of events. No differences in progression-free survival were identified between the pirfenidone and placebo groups, irrespective of the definition of progression-free survival used. Treatment-emergent adverse events were reported in 120 (94%) of 127 patients in the pirfenidone group and 101 (81%) of 124 patients in the placebo group. Serious treatment-emergent adverse events were reported in 18 (14%) patients in the pirfenidone group and 20 (16%) patients in the placebo group. The most common treatment-related treatment-emergent adverse events were gastrointestinal disorders (60 [47%] in the pirfenidone group vs 32 [26%] in the placebo group), fatigue (16 [13%] vs 12 [10%]), and rash (13 [10%] vs nine [7%])., Interpretation: Although the planned statistical model could not be applied to the primary endpoint data, analysis of key secondary endpoints suggests that patients with progressive fibrosing unclassifiable ILD could benefit from pirfenidone treatment, which has an acceptable safety and tolerability profile. These findings support further investigation of pirfenidone as an effective treatment for patients with progressive fibrotic unclassifiable ILD., Funding: F Hoffmann-La Roche., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Myeloperoxidase anti-neutrophil cytoplasmic antibody-related nephritis (MPO-ANCA nephritis) is occasionally accompanied by lung abnormalities such as pulmonary fibrosis. However, the clinical features of pulmonary fibrosis in patients with MPO-ANCA nephritis have not been well documented. This study was performed to compare the prognosis of a usual interstitial pneumonia (UIP) pattern of lung fibrosis in patients with MPO-ANCA nephritis with the prognosis of idiopathic pulmonary fibrosis (IPF)., Methods: We retrospectively reviewed the medical records of 126 patients with MPO-ANCA nephritis and identified 31 with a UIP pattern of lung fibrosis on high-resolution or thin-slice computed tomography (CT). We compared the characteristics and prognosis of these patients with those of 32 patients with IPF. In 18 patients from both groups, we assessed and compared the decline in lung volume over time using three-dimensional (3D) CT images reconstructed from thin-section CT data., Results: The numbers of male and female patients were nearly equal among patients with MPO-ANCA nephritis exhibiting a UIP pattern; in contrast, significant male dominancy was observed among patients with IPF (p = 0.0021). Significantly fewer smokers were present among the patients with MPO-ANCA nephritis with a UIP pattern than among those with IPF (p = 0.0062). There was no significant difference in the median survival time between patients with MPO-ANCA nephritis with a UIP pattern (50.8 months) and IPF (55.8 months; p = 0.65). All patients with IPF in this cohort received antifibrotic therapy (pirfenidone or nintedanib). Almost half of the deaths that occurred in patients with MPO-ANCA nephritis with a UIP pattern were caused by non-respiratory-related events, whereas most deaths in patients with IPF were caused by respiratory failure such as acute exacerbation. In the 3D CT lung volume analyses, the rate of decline in lung volume was equivalent in both groups., Conclusions: MPO-ANCA nephritis with a UIP pattern on CT may have an unfavorable prognosis equivalent to that of IPF with a UIP pattern treated with antifibrotic agents.

Sarcoidosis is a highly variable granulomatous multisystem syndrome. It affects individuals in the prime years of life; both the frequency and severity of sarcoidosis are greater in economically disadvantaged populations. The diagnosis, assessment, and management of pulmonary sarcoidosis have evolved as new technologies and therapies have been adopted. Transbronchial needle aspiration guided by endobronchial ultrasound has replaced mediastinoscopy in many centers. Advanced imaging modalities, such as fluorodeoxyglucose positron emission tomography scanning, and the widespread availability of magnetic resonance imaging have led to more sensitive assessment of organ involvement and disease activity. Although several new insights about the pathogenesis of sarcoidosis exist, no new therapies have been specifically developed for use in the disease. The current or proposed use of immunosuppressive medications for sarcoidosis has been extrapolated from other disease states; various novel pathways are currently under investigation as therapeutic targets. Coupled with the growing recognition of corticosteroid toxicities for managing sarcoidosis, the use of corticosteroid sparing anti-sarcoidosis medications is likely to increase. Besides treatment of granulomatous inflammation, recognition and management of the non-granulomatous complications of pulmonary sarcoidosis are needed for optimal outcomes in patients with advanced disease., Competing Interests: Competing interests We have read and understood the BMJ policy on declaration interests and declare the following interests: DAC received honorariums from Johnson and Johnson, aTyr, Gilead, Mallinckrodt, Boehringer Ingelheim, and Genentech for participation in advisory boards and consulting. MAJ has received grants for his institution from Mallinckrodt, aTyr, and Novartis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose: Combined pulmonary fibrosis and emphysema (CPFE) has emerged as a new syndrome with characteristics of both fibrosis and emphysema. We determined the impacts of radiologic emphysema severity on pulmonary function tests (PFTs), exercise capacity and mortality., Patients and Methods: IPF patients (n = 110) diagnosed at the Chest Diseases Clinic between September 2013 and January 2016 were enrolled in the study and followed up until June 2017. Visual and digital emphysema scores, PFTs, pulmonary artery pressure (sPAP), 6-minute walking test, composite physiologic index (CPI), and survival status were recorded. Patients with emphysema and those with pure IPF were compared., Results: The CPFE-group had a significantly greater ratio of men(p < 0.001), lower BMI (p < 0.001), lower mean PaO 2 (p = 0.005), higher mean sPAP (p = 0.014), and higher exercise desaturation (p < 0.001). The CPFE group had a significantly higher FVC(L)(p = 0.016), and lower FEV1/FVC ratio (p = 0.002), DLCO, and DLCO/VA ratio(p = 0.03 and p = 0.005, respectively). Lung volumes of the CPFE group had significantly higher VC(p = 0.017), FRC (p < 0.001), RV(p < 0.001), RV/TLC(p < 0.001), and TLC(p < 0.001). There were significant correlations between emphysema scores and FVC (L)(p = 0.01), FEV1/FVC(p = 0.001), DLCO (p = 0.003), VC(p = 0.014), FRC (L)(p < 0.001), RV(p < 0.001), TLC(p < 0.001), and RV/TLC (p < 0.001). Mortality rates were comparable between the two groups. CPI (p = 0.02) and sPAP (p = 0.01) were independent predictors of mortality in patients with CPFE., Conclusions: The presence and severity of emphysema affects pulmonary function in IPF. Patients with CPFE have reduced diffusion capacity, more severe air trapping, worse muscle weakness, more severe exercise desaturation, and pulmonary hypertension. CPI and pulmonary hypertension are two independent risk factors for mortality in subjects with CPFE., (Copyright © 2019 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Background: Pulmonary fibrosis (PF) is the most common disease indication for lung transplantation. Our recent work implicated an excess of rare genetic variants in the telomere-related genes TERT, RTEL1, and PARN in PF disease risk. The impact of such variants on posttransplant outcomes is uncertain. The objective of this study was to determine if patients with these PF-associated variants have altered rates of posttransplant acute rejection (AR), chronic lung allograft dysfunction (CLAD), and survival., Methods: The study cohort consisted of 262 PF lung transplant recipients previously genetically characterized by whole exome sequencing. Thirty-one patients (11.8%) had variants in TERT, RTEL1, or PARN, whereas 231 (88.2%) did not. Multivariate Cox proportional hazards models adjusted for relevant clinical variables were used to assess the outcomes of death and CLAD. The AR burden was quantified and compared over the first posttransplant year., Results: Patients with PF with disease-associated variants in TERT, RTEL1, or PARN had a significantly higher risk of death (adjusted hazard ratio [HR], 1.82; 95% CI, 1.07-3.08; P = .03) and CLAD (adjusted HR, 2.88; 95% CI, 1.42-5.87; P = .004) than patients without these variants. There was no difference in AR burden or rates of grade 3 primary graft dysfunction between the two groups., Conclusions: Rare variants in the telomere-related genes TERT, RTEL1, or PARN are associated with poor posttransplant outcomes among PF lung transplant recipients. Further research is needed to understand the biological mechanisms by which telomere-related variants increase the risk for death and CLAD., (Published by Elsevier Inc.)

To observe whether edaravone can protect organs and inhibit pulmonary fibrosis in patients with paraquat poisoning and to provide a method for clinical intervention for paraquat poisoning.Forty-four cases of paraquat poisoning were collected from March 2011 to December 2017 in our hospital. Eighteen cases from March 2011 to November 2013 did not receive edaravone treatment and were considered the control group, and 26 cases from January 2014 to December 2017 were treated with edaravone and were considered the observation group. Injuries to the central nervous system, heart, liver, kidney, and digestive system were evaluated on at 24 hours, 3 days, and 7 days after hospitalization. The expression of serum inflammatory factors (interleukin [IL]-6, IL-10, tumor necrosis factor-α [TNF-α]) and oxidative stress correlation (superoxide dismutase [SOD] and malondialdehyde [MDA]) were assayed at 24 hours, 3 days, and 7 days after being hospitalized. After 7, 14, and 30 days, the changes in pathological lung characteristics in the 2 groups were assessed, and survival rates were calculated.Edaravone significantly increased the serum levels of SOD and obviously markedly reduce the serum levels of IL-6, IL-10, TNF-α, and MDA in patients poisoned with paraquat (P < .05). Edaravone significantly protected the liver (P = .021), cardiovascular (P = .031), and renal (P = .028) organs of patients from paraquat poisoning-induced injury after 7 days but had no significant protection or improvement on respiratory and digestive tract damage. Edaravone delayed the occurrence of pulmonary fibrosis and increase the survival time of patients at 7 and 14 days (P < .05). However, the 1-month follow-up found that edaravone did not reduce pulmonary fibrosis (77.8% vs 73.1%, P = .615) and did not increase the survival rate of the patients (61.1% vs 65.3%, P = .853).Edaravone is beneficial for protecting the kidneys and liver from paraquat poisoning through reducing oxidative stress and inhibiting inflammatory response. It can also inhibit the pulmonary fibrosis process and prolong the survival time of the patients. However, no significant improvements were seen in the probability of pulmonary fibrosis and the survival rate.

Patients with certain types of fibrosing interstitial lung disease (ILD) are at risk of developing a progressive phenotype characterised by self-sustaining fibrosis, decline in lung function, worsening quality of life, and early mortality. It has been proposed that such progressive fibrosing ILDs, which show commonalities in clinical behaviour and in the pathogenetic mechanisms that drive progressive fibrosis, may be "lumped" together for the purposes of clinical research and, potentially, for treatment. At present, no drugs are approved for the treatment of ILDs other than nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis. For other progressive fibrosing ILDs, the mainstay of drug therapy is immunosuppression. However, it is postulated that, once the response to lung injury in fibrosing ILDs has reached the stage at which fibrosis has become progressive and self-sustaining, targeted antifibrotic therapy would be required to slow disease progression. Nintedanib, an intracellular inhibitor of tyrosine kinases, has shown antifibrotic, anti-inflammatory and vascular remodelling effects in several non-clinical models of fibrosis, irrespective of the trigger for the injury. Ongoing clinical trials will provide insight into the role of antifibrotic treatment with nintedanib or pirfenidone in the management of fibrosing ILDs with a progressive phenotype., Competing Interests: Conflict of interest: V. Cottin reports personal fees from Actelion (for consultancy, lectures and travel to medical meetings), Boehringer Ingelheim (for development of educational presentations, consultancy, lectures and travel to medical meetings), Bayer (for consultancy), Gilead (as a member of an adjudication committee), MSD (for consultancy and travel to medical meetings), Novartis (for consultancy and lectures), Roche (for consultancy, lectures and travel to medical meetings), Sanofi (for consultancy and lectures), Promedior (as chair of the Data and Safety Monitoring Board (DSMB)), Celgene (for the DSMB) and Galapagos (for consultancy and as chair of the DSMB), as well as grants from Boehringer Ingelheim and Roche to his institution, all outside the submitted work. Conflict of interest: L. Wollin is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: A. Fischer reports grants and consultancy fees from Boehringer Ingelheim, and consultancy fees from F. Hoffman La Roche, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer and Genentech, during the conduct of the study. Conflict of interest: M. Quaresma is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: S. Stowasser is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: S. Harari reports grants and personal fees from Roche, Actelion and Boehringer Ingelheim, outside the submitted work. In addition to being investigator in trials involving these companies, relationships include lectures and membership of scientific advisory boards, and grants for research., (Copyright ©ERS 2019.)

Objectives: This multicentre study aimed to investigate the overall mortality of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) and to compare CPFE-SSc characteristics with those of other SSc subtypes (with interstitial lung disease-ILD, emphysema or neither)., Methods: Chest CTs, anamnestic data, immunological profile and pulmonary function tests of patients with SSc were retrospectively collected. Each chest CT underwent a semiquantitative assessment blindly performed by three radiologists. Patients were clustered in four groups: SSc-CPFE, SSc-ILD, SSc-emphysema and other-SSc (without ILD nor emphysema). The overall mortality of these groups was calculated by Kaplan-Meier method and compared with the stratified log-rank test; Kruskal-Wallis test, t-Student test and χ² test assessed the differences between groups. P<0.05 was considered statistically significant., Results: We enrolled 470 patients (1959 patient-year); 15.5 % (73/470) died during the follow-up. Compared with the SSc-ILD and other-SSc, in SSc-CPFE there was a higher prevalence of males, lower anticentromere antibodies prevalence and a more reduced pulmonary function (p<0.05). The Kaplan-Meier survival analysis demonstrates a significantly worse survival in patients with SSc-CPFE (HR vs SSc-ILD, vs SSc-emphysema and vs other-SSc, respectively 1.6 (CI 0.5 to 5.2), 1.6 (CI 0.7 to 3.8) and 2.8 (CI 1.2 to 6.6)., Conclusions: CPFE increases the mortality risk in SSc along with a highly impaired lung function. These findings strengthen the importance to take into account emphysema in patients with SSc with ILD., Competing Interests: Competing interests: None declared.

Background: The United States lung allocation system prioritizes allocation based on medical urgency and benefit but does not address a federal mandate for broader geographic organ sharing. It is unknown whether broader geographic sharing of donor lungs would improve lung transplant waitlist outcomes., Methods: A discrete event microsimulation model simulated donor lung allocation according to different geographic lung-sharing policies, including the historic local donor service area (DSA)-based policy and hypothetical policies that prioritize candidates to donors within 500-mile or 1,000-mile geographic radii. Candidate waitlist mortality, number of transplants, and 1-year survival were compared across organ allocation policies. Waitlist mortality rates were further stratified by diagnosis, Lung Allocation Score (LAS) threshold, ABO blood type, and region., Results: Under broader geographic lung sharing, the proportion of chronic obstructive pulmonary disease transplant recipients decreased, whereas the proportion of pulmonary fibrosis recipients increased. Waitlist mortality decreased with broader geographic lung sharing with a 21.3% decrease in waitlist mortality with 500-mile lung sharing and a 31.8% decrease in waitlist mortality with 1,000-mile lung sharing. The decrease in waitlist deaths occured across all U.S. geographic regions and was greatest in candidates with pulmonary fibrosis and/or high medical urgency., Conclusions: Broader geographic sharing of donor lungs could reduce waitlist mortality, particularly among pulmonary fibrosis and high-medical-urgency candidates., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Collectins such as mannose-binding lectin (MBL) and surfactant protein D (SP-D) become temporarily deposited in extravascular compartments after tissue injury and perform immune-stimulatory or inflammation-limiting functions. However, their turnover mechanisms, necessary to prevent excessive tissue damage, are virtually unknown. In this study, we show that fibroblasts in injured tissues undertake the clearance of collectins by using the endocytic collagen receptor uPARAP. In cellular assays, several types of collectins were endocytosed in a highly specific uPARAP-dependent process, not shared by the closely related receptor MR/CD206. When introduced into dermis or bleomycin-injured lungs of mice, collectins MBL and SP-D were endocytosed and routed for lysosomal degradation by uPARAP-positive fibroblasts. Fibroblast-specific expression of uPARAP governed endogenous SP-D levels and overall survival after lung injury. In lung tissue from idiopathic pulmonary fibrosis patients, a strong up-regulation of uPARAP was observed in fibroblasts adjacent to regions with SP-D secretion. This study demonstrates a novel immune-regulatory function of fibroblasts and identifies uPARAP as an endocytic receptor in immunity., (© 2018 Jürgensen et al.)

Background: The prevalence of classifiable and unclassifiable causes of lung fibrosis and its implications for survival are mostly unknown in combined pulmonary fibrosis and emphysema (CPFE)., Materials and Methods: Patients with >10% involvement of both emphysema and lung fibrosis seen over 11 years at our institution were reviewed independently by expert radiologists for fibrotic and emphysematous findings and overall fibrotic CT pattern. Underlying interstitial lung disease (ILD) diagnoses and baseline demographic and clinical characteristics were collated and assessed for predictors of comparative survival., Results: In this retrospective cohort, 179 CPFE patients were identified and categorized as 58 usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) (32%), 42 secondary ILD (23%), and 79 unclassifiable ILD (44%). The most prevalent (47%) radiologic pattern was 'unclassifiable', followed by 'consistent' and 'possible' UIP pattern in 38%. Adjusted predictors of mortality for the cohort as a whole included age (HR 1.03[1.01-1.06], P = 0.002), percent predicted diffusing capacity for carbon monoxide (unit HR 0.97 [0.96-0.99], P = 0.001), honeycombing (HR 1.58 [1.02-2.43], P = 0.04), and right ventricular dysfunction (HR 2.28 [1.39-3.97], P = 0.002). Survival was similar between CPFE with secondary ILD and CPFE with UIP/IPF, while CPFE with unclassifiable ILD had better comparative survival (Log rank = 0.026)., Conclusions: Our findings suggest only about a third of CPFE patients represent suspected UIP/IPF; the majority were clinically and radiologically unclassifiable ILD whose survival was comparatively better. Identifiable or secondary causes of lung fibrosis in CPFE occurred in about a fifth of presenting patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Although these conditions are rare, a proportion of patients with interstitial lung diseases (ILDs) may develop a progressive-fibrosing phenotype. Progressive fibrosis is associated with worsening respiratory symptoms, lung function decline, limited response to immunomodulatory therapies, decreased quality of life and, potentially, early death. Idiopathic pulmonary fibrosis may be regarded as a model for other progressive-fibrosing ILDs. Here we focus on other ILDs that may present a progressive-fibrosing phenotype, namely idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, connective tissue disease-associated ILDs ( e.g. rheumatoid arthritis-related ILD), fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis and ILDs related to other occupational exposures. Differential diagnosis of these ILDs can be challenging, and requires detailed consideration of clinical, radiological and histopathological features. Accurate and early diagnosis is crucial to ensure that patients are treated optimally., Competing Interests: Conflict of interest: V. Cottin reports receiving the following, outside the submitted work: personal fees from Actelion for consultancy, lectures and travel to medical meetings; personal fees from Boehringer Ingelheim for the development of educational presentations, consultancy, lectures and travel to medical meetings; personal fees from Bayer for consultancy; personal fees from Gilead for acting as a member of an adjudication committee; personal fees from GSK for consultancy; personal fees from MSD for consultancy and travel to medical meetings; personal fees from Novartis for consultancy and lectures; personal fees from Roche for consultancy, lecture fees and travel to medical meetings; personal fees from Sanofi for consultancy and lectures; a grant to his institution from Boehringer Ingelheim; a grant to his institution from Roche; personal fees from Promedior for acting as Chair of the DSMB; personal fees from Celgene for the DSMB; and personal fees from Galapagos for consultancy and for acting as Chair of the DSMB. Conflict of interest: N.A. Hirani has nothing to disclose. Conflict of interest: D.L. Hotchkin has nothing to disclose. Conflict of interest: A.M. Nambiar reports receiving the following, outside the submitted work: grants, personal fees, non-financial support and other support from Boehringer Ingelheim; and grants from Genentech-Roche. Conflict of interest: T. Ogura reports receiving the following, outside the submitted work: grants and personal fees from Boehringer Ingelheim, Japan; grants from the Ministry of Health, Labour and Welfare, Japan; personal fees from Astellas Pharma Inc., Shionogi & Co. Ltd, Toray Industries Inc., AstraZeneca K.K. and Kyorin Inc. Conflict of interest: M. Otaola has nothing to disclose. Conflict of interest: D. Skowasch reports receiving the following, outside the submitted work: personal fees/honoraria for consulting and speaking from Boehringer Ingelheim and Roche. Conflict of interest: J.S. Park has nothing to disclose. Conflict of interest: H.K. Poonyagariyagorn has nothing to disclose. Conflict of interest: W. Wuyts reports receiving the following, outside the submitted work: grants paid to his university from Boehringer Ingelheim and Hoffmann La Roche; and travel fees from Galapagos. Conflict of interest: A.U. Wells reports receiving the following, outside the submitted work: personal fees for speaking and for acting on advisory boards from Boehringer Ingelheim, Roche and Bayer., (Copyright ©ERS 2018.)

There are over 200 interstitial lung diseases (ILDs). In addition to patients with idiopathic pulmonary fibrosis (IPF), a percentage of patients with other ILDs also develop progressive fibrosis of the lung during their disease course. Patients with progressive-fibrosing ILDs may show limited response to immunomodulatory therapy, worsening symptoms and lung function and, ultimately, early mortality. There are few data for ILDs that may present a progressive fibrosing phenotype specifically, but we believe the burden and healthcare costs associated with these conditions may be comparable to those reported in IPF. This review discusses the burden of ILDs that may present a progressive fibrosing phenotype and the factors impacting healthcare utilisation., Competing Interests: Conflict of interest: C. Holtze reports non-financial support from Boehringer Ingelheim (writing assistance), during the conduct of the study. Conflict of interest: K. Flaherty reports personal fees from Boehringer Ingelheim (consultancy – IPF 2016), Genentech (consultancy – IPF 2015), Veracyte (consultancy – IPF 2017), Roche (consultancy – IPF 2017), France Foundation (IPF CME content and presentations), Fibrogen (consultancy – IPF 2016) and Sanofi-Genzyme (consultancy – IPF 2017), outside the submitted work. Conflict of interest: M. Kreuter reports grants and personal fees from Roche and Boehringer Ingelheim, during the conduct of the study. Conflict of interest: F. Luppi reports personal fees from Boehringer Ingelheim, grants and personal fees from Roche, during the conduct of the study. Conflict of interest: T. Moua has nothing to disclose. Conflict of interest: C. Vancheri reports grants and personal fees from Roche and Boehringer Ingelheim, outside the submitted work. Conflict of interest: M.B. Scholand reports other from Boehringer Ingelheim (advisory board and investigator in clinical trials), Genentech (advisory board and investigator in a clinical trial), Fibrogen (investigator in a clinical trial), and Global Blood Therapeutics (investigator in a clinical trial), outside the submitted work. In addition, M.B. Scholand has a patent “Apparatus, compositions and methods for assessment of chronic obstructive pulmonary disease progression among rapid and slow decline conditions” issued., (Copyright ©ERS 2018.)

Acute exacerbation of interstitial lung disease (ILD) is associated with a poor prognosis and high mortality. Numerous studies have documented acute exacerbation in idiopathic pulmonary fibrosis (IPF), but less is known about these events in other ILDs that may present a progressive-fibrosing phenotype. We propose defining acute exacerbation as an acute, clinically significant respiratory deterioration, typically less than 1 month in duration, together with computerised tomography imaging showing new bilateral glass opacity and/or consolidation superimposed on a background pattern consistent with fibrosing ILDs. Drawing on observations in IPF, it is suspected that epithelial injury or proliferation and autoimmunity are risk factors for acute exacerbation in ILDs that may present a progressive-fibrosing phenotype, but further studies are required. Current acute exacerbation management strategies are based on recommendations in IPF, but no randomised controlled trials of acute exacerbation management have been performed. Although there are no formal strategies to prevent the development of acute exacerbation, possible approaches include antifibrotic drugs (such as nintedanib and pirfenidone), and minimising exposure to infection, airborne irritants and pollutants. This review discusses the current knowledge of acute exacerbation of ILDs that may present a progressive-fibrosing phenotype and acknowledges limitations of the data available., Competing Interests: Conflict of interest: M. Kolb reports grants and personal fees from Roche, Boehringer Ingelheim and Prometic, personal fees from Gilead and Genoa, and grants from Actelion, Respivert, Alkermes and Pharmaxis, outside the submitted work. Conflict of interest: B. Bondue reports grants and personal fees from Boehringer Ingelheim and Le Roche-Hoffmann-La Roche, outside the submitted work. Conflict of interest: A. Pesci has nothing to disclose. Conflict of interest: Y. Miyazaki reports grants and personal fees from Nippon Boehringer Ingelheim and grants from Shionogi, outside the submitted work. Conflict of interest: J.W. Song has nothing to disclose. Conflict of interest: N.Y. Bhatt has nothing to disclose. Conflict of interest: J.T. Huggins reports grants and other fees from Roche/Genentech and Boehringer Ingelheim, during the conduct of the study. Conflict of interest: J.M. Oldham reports other support from Boehringer Ingelheim for writing fees, during the conduct of the study; and personal fees (for speakers fees and advisory board fees) from Boehringer Ingelheim and Genentech, outside the submitted work. Conflict of interest: M.L. Padilla reports personal fees from Boehringer Ingelheim and Genentech, outside the submitted work. Conflict of interest: J. Roman reports grants and personal fees from Boehringer Ingelheim and is a member of the Medical Advisory Board of Pulmonary Fibrosis Foundation. Conflict of interest: S. Shapera reports personal fees from AstraZeneca, grants, personal fees (participation in clinical trials) and other from Boehringer Ingelheim, Canada and Hoffman La-Roche, Canada, and other (participation in clinical trials) from Medimmune, ProMetic Canada and Sanofi-Aventis, outside the submitted work., (Copyright ©ERS 2018.)

Background: Serum hemeoxygenase-1 (HO-1) has been proposed to be a biomarker of lung disease activity and prognosis. The present study aimed at evaluating whether HO-1 could be a useful marker for evaluating disease activity and predicting prognosis in patients with interstitial pneumonia (IP)., Materials and Methods: Serum HO-1 levels of newly diagnosed or untreated patients with IP were measured at hospitalization. We evaluated the relationships between serum HO-1 and other serum biomarkers, high resolution CT (HRCT) findings, and hospital mortality., Results: Twenty-eight patients with IP, including 14 having an acute exacerbation (AE) and 14 not having an AE, were evaluated. The patients having an AE had significantly higher HO-1 levels than those not having an AE (53.5 ng/mL vs. 24.1 ng/mL; p < 0.001), and the best cut-off level to discriminate between having an AE or not having an AE was 41.6 ng/mL. Serum HO-1 levels were positively correlated with serum levels of surfactant protein-D ( r =0.66, p < 0.001) and the ground glass opacity score (calculated from HRCT; r =0.40, p =0.036). Patients who subsequently died in hospital had presented with significantly higher HO-1 levels than those who did not die in hospital (64.8 ng/mL vs. 32.0 ng/mL; p =0.009)., Conclusion: Serum HO-1 may serve as a useful biomarker for detecting AE or predicting hospital mortality in patients with IP.

Systemic sclerosis (SSc) is associated with high mortality owing to internal organ complications, and lung disease is the leading cause of SSc-associated death. The most notable lung complications in SSc are fibrosis and pulmonary arterial hypertension (PAH). A major challenge for the management of lung disease in SSc is detecting those patients with severe pathology and those patients who are likely to benefit from available treatments. In the past few years, strategies for managing lung fibrosis and pulmonary hypertension, including PAH, have greatly progressed. For lung fibrosis, the tools to assess risk of progression and severity of the disease have been refined. Clinical trial results support the use of immunosuppression, including high-intensity regimens with autologous stem cell transplantation. New trials are underway to test other potential therapies including treatments that are approved for use in idiopathic lung fibrosis. For PAH, identifying individuals at high risk of disease development is critical. In addition, individuals who have borderline elevation of pulmonary arterial pressure need to be appropriately managed and followed up. Many approved drugs targeting PAH are now available, and results from large-scale clinical trials provide robust evidence that various treatments for SSc-associated PAH are associated with good long-term outcomes.

Background: Double-lung transplantation (DLT) has better long-term outcomes compared with single-lung transplantation (SLT) in pulmonary fibrosis. However, controversy persists about whether older patients or patients with high lung allocation scores would benefit from DLT. Moreover, the degree of pulmonary hypertension in which SLT should be avoided is unknown., Methods: A retrospective analysis using the United Network for Organ Sharing database was performed in all recipients of lung transplants for pulmonary fibrosis. Kaplan-Meier survival for SLT versus DLT was compared and stratified by age, allocation score, and mean pulmonary artery pressure. Cox regression and propensity-matching analyses were performed., Results: Between 1987 and 2015; 9,191 of 29,779 lung transplants were performed in pulmonary fibrosis. Ten-year survival rates were 55% for DLT and 32% for SLT (p < 0.001). When stratified by age, DLT recipients had improved survival at all age cutoffs, except age ≥70 years. In addition, DLT recipients had improved survival across all lung allocation scores (<45, ≥45, ≥60, ≥75) and all pulmonary artery pressure categories (<25, ≥25, ≥30, ≥40 mm Hg). Among DLT recipients, pulmonary artery pressure and allocation score did not affect survival. Among SLT recipients, a pressure ≥25 mm Hg did not influence survival. Conversely, patients with a pressure ≥30 mm Hg and an allocation score ≥45 had decreased survival. On Cox regression and on propensity matching, DLT had improved survival compared with SLT., Conclusions: In pulmonary fibrosis, DLT has improved survival compared with SLT and should be considered the procedure of choice in patients younger than 70 years of age. SLT in patients with mean pulmonary artery pressure ≥30 mm Hg and an allocation score ≥45 should be discouraged., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)