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Blair G Fulton,1 Christopher J Ryerson1,2 1Department of Medicine, 2Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada Abstract: Major risk factors for idiopathic pulmonary fibrosis (IPF) include older age and a history of smoking, which predispose to several pulmonary and extra-pulmonary diseases. IPF can be associated with additional comorbidities through other mechanisms as either a cause or a consequence of these diseases. We review the literature regarding the management of common pulmonary and extra-pulmonary comorbidities, including chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, venous thromboembolism, sleep-disordered breathing, gastroesophageal reflux disease, coronary artery disease, depression and anxiety, and deconditioning. Recent studies have provided some guidance on the management of these diseases in IPF; however, most treatment recommendations are extrapolated from studies of non-IPF patients. Additional studies are required to more accurately determine the clinical features of these comorbidities in patients with IPF and to evaluate conventional treatments and management strategies that are beneficial in non-IPF populations. Keywords: interstitial lung disease, management, idiopathic pulmonary fibrosis, comorbidities

Background: Stress of the endoplasmic reticulum (ER) leading to activation of the unfolded protein response (UPR) and alveolar epithelial cell (AEC) apoptosis may play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our objectives were to determine whether circulating caspase-cleaved cytokeratin-18 (cCK-18) is a marker of AEC apoptosis in IPF, define the relationship of cCK-18 with activation of the UPR, and assess its utility as a diagnostic biomarker.Methods: IPF and normal lung tissues were stained with the antibody (M30) that specifically binds cCK-18. The relationship between markers of the UPR and cCK-18 was determined in AECs exposed in vitro to thapsigargin to induce ER stress. cCK-18 was measured in serum from subjects with IPF, hypersensitivity pneumonitis (HP), nonspecific interstitial pneumonia (NSIP), and control subjects.Results: cCK-18 immunoreactivity was present in AECs of IPF lung, but not in control subjects. Markers of the UPR (phosphorylated IRE-1α and spliced XBP-1) were more highly expressed in IPF type II AECs than in normal type II AECs. Phosphorylated IRE-1α and cCK-18 increased following thapsigargin-induced ER stress. Serum cCK-18 level distinguished IPF from diseased and control subjects. Serum cCK-18 was not associated with disease severity or outcome.Conclusions: cCK-18 may be a marker of AEC apoptosis and UPR activation in patients with IPF. Circulating levels of cCK-18 are increased in patients with IPF and cCK-18 may be a useful diagnostic biomarker. © 2012 Cha et al.; licensee BioMed Central Ltd.

CONTEXT: Little is known about the treatment and correlates of dyspnea in idiopathic pulmonary fibrosis (IPF). OBJECTIVES: The objective of this systematic review was to summarize the literature regarding the treatment and correlates of dyspnea in IPF. METHODS: MEDLINE, EMBASE, and all Evidence-Based Medicine Reviews were searched for publications that evaluated treatment or correlates of dyspnea in IPF. Reference lists and recent review articles also were searched. RESULTS: The heterogeneity of included studies did not permit meta-analysis. Dyspnea improved in studies of sildenafil, pulmonary rehabilitation, and prednisone with colchicine. Additional studies of these three treatments, however, found discordant results. One study suggested that assisted ventilation delivered by facemask improved exertional dyspnea. Oxygen and opioids improve dyspnea in other chronic lung diseases, but data in IPF are limited. Correlates of dyspnea included functional and physiological measures and comorbid diseases. CONCLUSION: Sildenafil and pulmonary rehabilitation should be considered as potential therapies for dyspnea in selected patients with IPF. Supplemental oxygen and opioids may be additional potential therapies; however, the evidence supporting their use is weak. Additional research should focus on the management of functional status and comorbidities as potential treatments for dyspnea. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing and progressive interstitial lung disease of unknown aetiology with a pathogenesis still partly unknown. Several microvascular and macrovascular abnormalities have been demonstrated in the pathogenesis of IPF and related pulmonary hypertension (PH), a complication of the disease., Methods: We carried out a non-systematic, narrative literature review aimed at describing the role of the vasculature in the natural history of IPF., Results: The main molecular pathogenetic mechanisms involving vasculature ( i.e. endothelial-to-mesenchymal transition, vascular remodelling, endothelial permeability, occult alveolar haemorrhage, vasoconstriction and hypoxia) and the genetic basis of vascular remodelling are described. The prevalence and clinical relevance of associated PH are highlighted with focus on the vasculature as a prognostic marker. The vascular effects of current antifibrotic therapies, the role of pulmonary vasodilators in the treatment of disease, and new pharmacological options with vascular-targeted activity are described., Conclusions: The vasculature plays a key role in the natural history of IPF from the early phases of disease until development of PH in a subgroup of patients, a complication related to a worse prognosis. Pulmonary vascular volume has emerged as a novel computed tomography finding and a predictor of mortality, independent of PH. New pharmacological options with concomitant vascular-directed activity might be promising in the treatment of IPF., Competing Interests: Conflict of interest: G. Sotgiu is an associate editor of this journal. The other authors have nothing to disclose., (Copyright ©The authors 2024.)

The use of steroids in fibrotic interstitial lung diseases is founded on limited evidence. This modified Delphi survey sheds light on current clinical practices. Given the risks of steroids, clinical trials are needed to evaluate efficacy and harm. https://bit.ly/3VkgvbS., Competing Interests: Conflicts of interest: M. Funke-Chambour declares grants or contracts from Boehringer Ingelheim, consultancy and speaker's fees from Boehringer Ingelheim, Roche, MSD, AstraZeneca, Pfizer, GSK and Sanofi, outside this project. P. Suter has nothing to disclose. G.R. Jenkins declares grants to his institution from AstraZeneca, Biogen, Galecto, GlaxoSmithKline, Nordic Biosciences, RedX and Pliant, consultancy fees from AbbVie, Apollo Therapeutics, AstraZeneca, Brainomix, Bristol Myers Squibb, Chiesi, Cohbar, Daewoong, GlaxoSmithKline, Resolution Therapeutics and Pliant, honoraria from Boehringer Ingelheim, Chiesi, Roche, PatientMPower and AstraZeneca, payment for expert testimony from Pinsent Masons LLP, and participation on data safety or advisory board for Boehringer Ingelheim, Galapagos and Vicore, outside this project. L. Kawano-Dourado declares grants paid to their institution from Boehringer Ingelheim and Bristol Myers Squibb, and consultancy fees from Boehringer Ingelheim, outside this project. C.J. Ryerson declares grants from Boehringer Ingelheim paid to his institution, consultancy fees from Boehringer Ingelheim, Pliant Therapeutics, AstraZeneca, Trevi Therapeutics and Veracyte, payment or honoraria for lectures or presentations from Hoffmann-La Roche and Boehringer Ingelheim, and payment for expert testimony and travel support from Boehringer Ingelheim, outside this project. A.U. Wells reports consultancy fees from Roche, and payment or honoraria for lectures or presentations from Boehringer Ingelheim and Veracyte, and is President of the World Association of Sarcoidosis and Other Granulomatous Diseases, outside of the submitted work. M. Kreuter declares grants or contracts and royalties or licenses from Boehringer Ingelheim and Roche, consulting fees from Nichtraucherhelden/Sanero, Boehringer Ingelheim, Roche, BMS, GSK and AstraZeneca, and a leadership or fiduciary role for the European Respiratory Society, outside this project. K.A. Johannson declares grants paid to her institution from the University Hospital Foundation and the Three Lakes Foundation, consulting fees from Boehringer Ingelheim, Roche, Pliant Therapeutics and Brainomix, payment or honoraria for lectures or presentations and travel support from Boehringer Ingelheim, participation on a Data Safety Monitoring Board for the PFOX trial, and a stock option from Thyron SAB, outside this project., (Copyright ©The authors 2024.)

Background: The internet is a common source of health information for patients and caregivers. To date, content and information quality of YouTube videos on sarcoidosis has not been studied. The aim of our study was to investigate the content and quality of information on sarcoidosis provided by YouTube videos., Methods: Of the first 200 results under the search term "sarcoidosis," all English-language videos with content directed at patients were included. Two independent investigators assessed the content of the videos based on 25 predefined key features (content score with 0-25 points), as well as reliability and quality (HONCode score with 0-8 points, DISCERN score with 1-5 points). Misinformation contained in the videos was described qualitatively., Results: The majority of the 85 included videos were from an academic or governmental source (n = 63, 74%), and median time since upload was 33 months (IQR 10-55). Median video duration was 8 min (IQR 3-13) and had a median of 2,044 views (IQR 504 - 13,203). Quality assessment suggested partially sufficient information: mean HONCode score was 4.4 (SD 0.9) with 91% of videos having a medium quality HONCode evaluation. Mean DISCERN score was 2.3 (SD 0.5). Video content was generally poor with a mean of 10.5 points (SD 0.6). Frequently absent key features included information on the course of disease (6%), presence of substantial geographical variation (7%), and importance of screening for extrapulmonary manifestations (11%). HONCode scores were higher in videos from academic or governmental sources (p = 0.003), particularly regarding "transparency of sponsorship" (p < 0.001). DISCERN and content scores did not differ by video category., Conclusions: Most YouTube videos present incomplete information reflected in a poor content score, especially regarding screening for extrapulmonary manifestations. Quality was partially sufficient with higher scores in videos from academic or governmental sources, but often missing references and citing specific evidence. Improving patient access to trustworthy and up to date information is needed., (© 2024. The Author(s).)

Background: Fibrotic interstitial lung disease (ILD) is frequently associated with abnormal oxygenation; however, little is known about the accuracy of oxygen saturation by pulse oximetry (SpO 2 ) compared with arterial blood gas (ABG) saturation (SaO 2 ), the factors that influence the partial pressure of carbon dioxide (PaCO 2 ) and the impact of PaCO 2 on outcomes in patients with fibrotic ILD., Study Design and Methods: Patients with fibrotic ILD enrolled in a large prospective registry with a room air ABG were included. Prespecified analyses included testing the correlation between SaO 2 and SpO 2 , the difference between SaO 2 and SpO 2 , the association of baseline characteristics with both the difference between SaO 2 and SpO 2 and the PaCO 2 , the association of baseline characteristics with acid-base category, and the association of PaCO 2 and acid-base category with time to death or transplant., Results: A total of 532 patients with fibrotic ILD were included. Mean resting SaO 2 was 92±4% and SpO 2 was 95±3%. Mean PaCO 2 was 38±6 mmHg, with 135 patients having PaCO 2 <35 mmHg and 62 having PaCO 2 >45 mmHg. Correlation between SaO 2 and SpO 2 was mild to moderate (r=0.39), with SpO 2 on average 3.0% higher than SaO 2 . No baseline characteristics were associated with the difference in SaO 2 and SpO 2 . Variables associated with either elevated or abnormal (elevated or low) PaCO 2 included higher smoking pack-years and lower baseline forced vital capacity (FVC). Lower baseline lung function was associated with an increased risk of chronic respiratory acidosis. PaCO 2 and acid-base status were not associated with time to death or transplant., Interpretation: SaO 2 and SpO 2 are weakly-to-moderately correlated in fibrotic ILD, with limited ability to accurately predict this difference. Abnormal PaCO 2 was associated with baseline FVC but was not associated with outcomes., Competing Interests: Competing interests: MAD reports no conflicts of interest relevant to this manuscript. KD reports no conflicts of interest relevant to this manuscript. DA reports grants and personal fees from Boehringer Ingelheim, grants from Canadian Institute for Health Research and from Fonds de Recherche du Quebec en Santé. CD reports no conflicts of interest relevant to this manuscript. JHF reports personal fees from AstraZeneca and Boehringer Ingelheim. KJ reports grants from Boehringer Ingelheim, Pulmonary Fibrosis Society of Calgary, University of Calgary School of Medicine; personal fees from Boehringer Ingelheim, Roche, Three Lakes Foundation, Pliant Therapeutics, Theravance, Blade Therapeutics. MK reports grants from Canadian Institute for Health Research, Roche, Boehringer Ingelheim, Pieris, Prometic; personal fees from Boehringer Ingelheim, Roche, European Respiratory Journal, Belerophon, United Therapeutics, Nitto Denko, MitoImmune, Pieris, AbbVie, DevPro Biopharma, Horizon, Algernon, CSL Behring. SDL reports consulting/personal fees and moderator honoraria from Boehringer-Ingelheim, honoraria from Hoffman-La Roche Ltd, grants from AstraZeneca and the University of Saskatchewan. HM reports grants from Boehringer Ingelheim and Gilead. VM reports grants from Boehringer Ingelheim, AstraZeneca, and Roche; personal fees from Boehringer Ingelheim and Roche. BM reports no conflicts of interest relevant to this manuscript. JM reports personal fees from Boehringer Ingelheim and Roche. D-CM reports personal fees from Boehringer Ingelheim. CJR reports grants from Boehringer Ingelheim; personal fees from AstraZeneca, Boehringer Ingelheim, Roche, Pliant Therapeutics, Cipla, Veracyte., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD., Design: Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only., Eligibility Criteria: Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded., Data Synthesis: The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I 2 evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design., Results: A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI -4.00 to 9.88, I 2 =79.3%; %DLco -2.03, 95% CI -4.38 to 0.32, I 2 =0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I 2 =0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DL CO (95% CI 2.05 to 6.79, I 2 =0.0%). AZA studies were limited. All estimates were considered very low certainty evidence., Conclusions: There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD., Prospero Registration Number: CRD42023423223., Competing Interests: Competing interests: GJ is supported by a National Institute for Health Research (NIHR) Research Professorship (NIHR reference RP-2017-08-ST2-014). GJ is a trustee of Action for Pulmonary Fibrosis and reports personal fees from Astra Zeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daewoong, Galapagos, Galecto, GlaxoSmithKline, Heptares, NuMedii, PatientMPower, Pliant, Promedior, Redx, Resolution Therapeutics, Roche, Veracyte and Vicore. CJR reports grants from Boehringer Ingelheim, and honoraria or consulting fees from Boehringer Ingelheim, Pliant Therapeutics, Astra Zeneca, Trevi Therapeutics, Veracyte, Hoffmann-La Roche, Cipla. FL, IS, LF, WA and LK-D report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

What is this summary about? This plain language summary shares results from a clinical study called INTEGRIS-IPF that was published in the American Journal of Respiratory and Critical Care Medicine in 2024. This study looked at a medicine called bexotegrast (beck-so-teh-grast) as a possible treatment for idiopathic pulmonary fibrosis (i-dee-uh-pa-thick pul-muh-ner-ee fie-bro-sis; IPF). Bexotegrast is an investigational medicine, which means that it is being studied and has not yet been approved by the US Food and Drug Administration (FDA), for people with IPF to take as a treatment. IPF is a chronic, progressive lung disease that makes it hard to breathe and gets worse over time. There is no cure for IPF, treatment includes symptom management and consideration for the use of nintedanib or pirfenidone , which may decrease the pace of disease progression.The study compared bexotegrast to a placebo (a treatment that looks identical to the medicine but has no medicinal effect) to look at how well it works and how safe it is in treating people with IPF. Most people in the study also took one of two medicines that are already approved by the FDA for IPF, pirfenidone or nintedanib .

Objectives: We aimed to assess the available evidence for corticosteroids in fibrotic interstitial lung disease (fILD) to inform the randomised embedded multifactorial adaptive platform ILD., Design: Systematic review and meta-analysis., Data Sources: We searched Embase, Medline, Cochrane CENTRAL and Web of Science databases from inception to April 17 2023., Eligibility Criteria: We included studies that compared corticosteroids with standard care, placebo or no treatment in adult patients with fILD., Data Extraction and Synthesis: We report on the change in forced vital capacity (FVC) and mortality. We used random-effects meta-analysis to estimate relative risk (RR) for dichotomous outcomes, and mean difference (MD) and standardised MDs for continuous outcomes, with 95% CIs., Results: Of the 13 229 unique citations identified, we included 10 observational studies comprising 1639 patients. Corticosteroids had an uncertain effect on mortality compared with no treatment (RR 1.03 (95% CI 0.85 to 1.25); very low certainty evidence). The effect of corticosteroids on the rate of decline in FVC (% predicted) was uncertain when compared with no treatment (MD 4.29% (95% CI -8.26% to 16.83%); very low certainty evidence). However, corticosteroids might reduce the rate of decline in FVC in patients with non-idiopathic pulmonary fibrosis (IPF) fILD (MD 10.89% (95% CI 5.25% to 16.53%); low certainty evidence), while an uncertain effect was observed in patients with IPF (MD -3.80% (95% CI -8.94% to 1.34%); very low certainty evidence)., Conclusions: The current evidence on the efficacy and safety of corticosteroids in fILD is limited and of low certainty. Randomised trials are needed to address this significant research gap., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Many patients use the internet as a source of health information. Sarcoidosis is a complex disease, and internet resources have not yet been analyzed for reliability and content on sarcoidosis., Aims: Our study aimed to investigate the content and the quality of information on sarcoidosis provided by internet resources., Methods: Google, Yahoo, and Bing were searched for the term "sarcoidosis," and the first 200 hits were saved in each case. Those websites that met the inclusion criteria (English language, no registration fees, and relevant to sarcoidosis) were then analyzed by two independent investigators for readability, quality (HON, JAMA, and DISCERN), and content (25 predefined key facts) of the provided information., Results: The websites were most commonly scientific or governmental ( n = 57, 46%), and the median time since the last update was 24 months. Quality was rated with a median JAMA score of 2 (1; 4) and a median overall DISCERN score of 2.4 (1.1; 4.1), both scores represent partially sufficient information. In total, 15% of websites had a HON certificate. Website content measured by the median key fact score was 19 (ranging from 2.5 to 25) with the lowest scores for acute vs. chronic course of the disease, screening for extrapulmonary disease, and diffuse body pain. Poor results were achieved in industry websites and blogs ( p = 0.047) with significant differences regarding definition ( p = 0.004) and evaluation ( p = 0.021)., Discussion: Sarcoidosis-related content of internet resources is partially sufficient; however, several important aspects are frequently not addressed, and the quality of information is moderate. Future directions should focus on providing reliable and comprehensive information on sarcoidosis; physicians from different disciplines and patients including self-support groups should collaborate on achieving this., Competing Interests: KB received payment for lectures from Boehringer Ingelheim and a grant from Sarkoidose-Netzwerk e.V. JF has received grant funding from the University of Toronto and the Canadian Pulmonary Fibrosis Foundation and has received honoraria from Boehringer Ingelheim and AstraZeneca. CR reports grants from Boehringer Ingelheim and Hoffman la Roche; consulting fees from Boehringer Ingelheim, Hoffman la Roche, Astra Zeneca, Veracyte, Ensho, and Pliant Therapeutics; payment for lectures from Boehringer Ingelheim, Hoffman la Roche, and Cipla Ltd.; and support for attending meetings from Cipla Ltd., and Boehringer Ingelheim (unrelated to this submission). FH reports payment for lectures from Astra Zeneca, GSK, and Chiesi and is a part of the Data Safety Monitoring Board from Apogenix. MK reports grants, consulting fees, and payment for lectures from Boehringer Ingelheim and Roche. KK was employed by Limbach Gruppe SE. The remaining 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 © 2023 Buschulte, Höger, Ganter, Wijsenbeek, Kahn, Kriegsmann, Wilkens, Fisher, Ryerson, Herth and Kreuter.)

Objectives: We sought to 1) identify long COVID phenotypes based on patient reported outcome measures (PROMs) and 2) determine whether the phenotypes were associated with quality of life (QoL) and/or lung function., Methods: This was a longitudinal cohort study of hospitalized and non-hospitalized patients from March 2020 to January 2022 that was conducted across 4 Post-COVID Recovery Clinics in British Columbia, Canada. Latent class analysis was used to identify long COVID phenotypes using baseline PROMs (fatigue, dyspnea, cough, anxiety, depression, and post-traumatic stress disorder). We then explored the association between the phenotypes and QoL (using the EuroQoL 5 dimensions visual analogue scale [EQ5D VAS]) and lung function (using the diffusing capacity of the lung for carbon monoxide [DLCO])., Results: There were 1,344 patients enrolled in the study (mean age 51 ±15 years; 780 [58%] were females; 769 (57%) were of a non-White race). Three distinct long COVID phenotypes were identified: Class 1) fatigue and dyspnea, Class 2) anxiety and depression, and Class 3) fatigue, dyspnea, anxiety, and depression. Class 3 had a significantly lower EQ5D VAS at 3 (50±19) and 6 months (54 ± 22) compared to Classes 1 and 2 (p<0.001). The EQ5D VAS significantly improved between 3 and 6 months for Class 1 (median difference of 6.0 [95% CI, 4.0 to 8.0]) and Class 3 (median difference of 5.0 [95% CI, 0 to 8.5]). There were no differences in DLCO between the classes., Conclusions: There were 3 distinct long COVID phenotypes with different outcomes in QoL between 3 and 6 months after symptom onset. These phenotypes suggest that long COVID is a heterogeneous condition with distinct subpopulations who may have different outcomes and warrant tailored therapeutic approaches., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Wong 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.)

Background: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is challenging to manage, with a paucity of robust data to guide treatment. Our aim was to characterize the pharmacologic treatment of RA-ILD utilizing a retrospective design in a national multi-center prospective cohort, and to identify associations between treatment and change in lung function and survival., Methods: Patients with RA-ILD and a radiological pattern of non-specific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) were included. Unadjusted and adjusted linear mixed models and Cox proportional hazards models were used to compare lung function change and risk of death or lung transplant by radiologic patterns and treatment., Results: Of 161 patients with RA-ILD, UIP pattern was more common than NSIP (55.9% vs. 44.1%). Only 44/161 (27%) patients were treated over median follow-up of 4 years with medication choice appearing unrelated to patient-specific variables. Decline in forced vital capacity (FVC) was not associated with treatment. Patients with NSIP had lower risk of death or transplant, compared to UIP (P=0.0042). In patients with NSIP, there was no difference in time to death or transplant comparing treated to untreated in adjusted models [hazard ratio (HR) =0.73; 95% confidence interval (CI): 0.15-3.62; P=0.70]. Similarly, in patients with UIP, there was no difference in time to death or lung transplant between treated and untreated in adjusted models (HR =1.06; 95% CI: 0.49-2.28; P=0.89)., Conclusions: Treatment of RA-ILD is heterogeneous, with most patients in this cohort not receiving treatment. Patients with UIP had worse outcomes compared to NSIP, similar to other cohorts. Randomized clinical trials are needed to inform pharmacologic therapy in this patient population., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1820/coif). All authors report that Canadian Registry for Pulmonary Fibrosis is sponsored by Boehringer Ingelheim Canada but it has had no influence on this study design/manuscript. VM reports personal fees from Boehringer Ingelheim Canada and Hoffman-La Roche Ltd., and Astra Zeneca, grants from the University of Saskatchewan, Royal University Hospital Foundation, Boehringer Ingelheim, Astra Zeneca and Hoffman-La Roche. SL reports consulting fees and moderator honoraria from Boehringer-Ingelheim and a grant from the University of Saskatchewan. SL has served on prior advisory boards of Boehringer-Ingelheim. DA reports consulting fees from Boehringer-Ingelheim and Hoffman-La Roche, payments for a lecture from Boehringer-Ingelheim, and research grants from Boehringer Ingelheim. JHF reports grants from the Canadian Pulmonary Fibrosis Foundation and the University of Toronto, and personal fees from Boehringer-Ingelheim and AstraZeneca, outside the submitted work. JHF serves as an unpaid medical advisory board member of Canadian Pulmonary Fibrosis Foundation. SS reports advisory board participation and personal fees from Boehringer-Ingelheim, Hoffman-La Roche, and AstraZeneca. JM reports personal fees from Boehringer-Ingelheim and Hoffman-La Roche. HM reports research grants from Boehringer-Ingelheim, Galapagos, BMS and Hoffman-La Roche, personal fees from Boehringer-Ingelheim, and participates on an advisory board for Boehringer Ingelheim. CDF reports educational grants and research grants from Boehringer-Ingelheim, Roche and the Canadian Pulmonary Fibrosis Foundation; personal fees from Roche and Boehringer Ingelheim; Chair of the Board for the Canadian Pulmonary Fibrosis Foundation. NH reports research grants from Boehringer-Ingelheim and Janssen, and personal fees from Boehringer-Ingelheim, Janssen, and Hoffman-La Roche. MK serves as an unpaid editorial board member of Journal of Thoracic Disease. MK reports grants from Boehringer-Ingelheim, Hoffman-La Roche and Pieris, personal fees from Boehringer Ingelheim, Hoffman-La Roche, Horizon, Cipla, Abbvie, Bellerophon, Algernon, CSL Behring, United Therapeutics Novartis and LabCorp, participation on the advisory board of United Therapeutics Novartis and LabCorp, and allowance for serving as Chief Editor of the European Respiratory Journal. MS reports honoraria for attending symposia from Boehringer-Ingelheim. AWW reports speaker’s honoraria from Boehringer-Ingelheim and AstraZeneca. PGW reports payment for presentation from Vertex. PGW is a member of the Cystic Fibrosis Foundation Drug Safety Monitoring Board. CJR reports personal fees from Boehringer-Ingelheim, Hoffman-La Roche, Veracyte, AstraZeneca, Pliant Therapeutics, Cipla Ltd., and Ensho Health. KAJ reports grants from University Hospital Foundation, Three Lakes Foundation and University oof Calgary CSM, and personal fees from Boehringer-Ingelheim, Hoffman-La Roche, Pliant Therapeutics and Three Lakes Foundation. KAJ is a member of the board for PFOX Trial. The authors have no other conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Background: Little is known about generalisability of randomised controlled trials (RCTs) for idiopathic pulmonary fibrosis (IPF). We evaluated eligibility criteria for phase III IPF RCTs to determine their representativeness in clinical registries, and calculated forced vital capacity (FVC) changes according to eligibility criteria., Methods: Common eligibility criteria used in >60% of IPF RCTs were identified from a literature search and applied to patients with IPF from prospective Australian and Canadian registries. Additional pre-specified criteria of 6-min walk distance (6MWD) and different measures of preceding disease progression were also evaluated. Joint longitudinal-survival modelling was used to compare FVC decline according to eligibility for individual and composite criteria., Results: Out of 990 patients with IPF, 527 (53%) met all common RCT eligibility criteria at the first clinic visit, including 343 with definite IPF and 184 with radiological probable usual interstitial pneumonia pattern without histological confirmation ( i.e. provisional IPF). The percentages of eligible patients for landmark RCTs of nintedanib and pirfenidone were 19-50%. Adding 6MWD ≥150 m and different measures of preceding disease progression to the composite common criteria reduced the percentages of patients meeting eligibility to 52% (n=516) and 4-18% (n=12-61), respectively. Patients meeting the composite common criteria had less-rapid 1-year FVC decline than those who did not (-90 versus -103 mL, p=0.01). Definite IPF generally had more-rapid 1-year FVC decline compared to provisional IPF., Conclusions: Eligibility criteria of previous IPF RCTs have limited generalisability to clinical IPF populations, with FVC decline differing between eligible and ineligible populations., Competing Interests: Conflict of interest: Y.H. Khor reports fellowship support from NHMRC Investigator Grant, and support for the CARE-PF registry (with no influence on this study) from Boehringer Ingelheim, during the conduct of the study. K.A. Johannson reports personal fees, non-financial support and other from Boehringer Ingelheim, personal fees from Hoffman-La Roche Ltd, Pliant Therapeutics and Thyron, grants from University Hospital Foundation, Pulmonary Fibrosis Society of Calgary and University of Calgary Cumming School of Medicine, and personal fees and non-financial support from Three Lakes Foundation, outside the submitted work. V. Marcoux reports grants from Boehringer Ingelheim, during the conduct of the study; grants from University of British Columbia and Boehringer Ingelheim, outside the submitted work. J.H. Fisher reports grants from Boehringer Ingelheim, during the conduct of the study; grants from Canadian Pulmonary Fibrosis Foundation and University of Toronto, and personal fees from Boehringer Ingelheim and AstraZeneca, outside the submitted work. D. Assayag reports grants from Boehringer Ingelheim Canada, and lecture honoraria from Boehringer Ingelheim and Hoffman La Roche, outside the submitted work. H. Manganas reports support for the present manuscript from University of British Columbia; grants from Boehringer Ingelheim Canada, Hoffmann La Roche, Galapagos and BMS, honoraria for educational events from Boehringer Ingelheim Canada, and advisory board membership for Boehringer Ingelheim Canada, outside the submitted work. M. Kolb reports grants from Boehringer Ingelheim, Pieris and Roche, consulting fees from Boehringer Ingelheim, Roche, Horizon, Cipla, Abbvie, Bellerophon, Algernon, CSL Behring, United Therapeutics and LabCorp, lecture honoraria from Roche, Novartis and Boehringer Ingelheim, payment for expert testimony from Roche, advisory board participation with United Therapeutics and LabCorp, and reports an editorial allowance from ERJ, outside the submitted work. C.J. Ryerson reports grants from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from Boehringer Ingelheim and Hoffmann-La Roche, and personal fees from Veracyte, Pliant Therapeutics, AstraZeneca and Cipla Ltd, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Exploration of cytokine levels in systemic sclerosis-associated interstitial lung disease (SSc-ILD) and idiopathic pulmonary fibrosis (IPF) is needed to find common and diverse biomolecular pathways. Circulating levels of 87 cytokines were compared amongst 19 healthy controls and consecutive patients with SSc-ILD (n = 39), SSc without ILD (n = 29), and IPF (n = 17) recruited from a Canadian centre using a log-linear model adjusted for age, sex, baseline forced vital capacity (FVC), and immunosuppressive or anti-fibrotic treatment at time of sampling. Also examined was annualized change in FVC. Four cytokines had Holm's corrected p-values less than 0.05. Eotaxin-1 levels were increased approximately two-fold in all patient categories compared to healthy controls. Interleukin-6 levels were eight-fold higher in all ILD categories compared to healthy controls. MIG/CXCL9 levels increased two-fold more in all but one patient category compared to healthy controls. Levels of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13, (ADAMTS13) were lower for all categories of patients compared to controls. No substantial association was found for any of the cytokines with FVC change. Observed cytokine differences suggest both common and diverse pathways leading to pulmonary fibrosis. Further studies evaluating longitudinal change of these molecules would be informative., (© 2023. The Author(s).)

Objectives: Fibrotic interstitial lung disease (ILD) includes a large group of conditions that lead to scarring of the lungs. The lack of available 5-level EuroQol 5D (EQ5D) data has limited the ability to conduct economic evaluations in ILD. The purpose of this study was to develop and validate a mapping algorithm that predicts EQ5D utilities from commonly collected pulmonary function measurements (forced vital capacity [FVC] and diffusing capacity of the lung for carbon monoxide [DLCO]) in fibrotic ILDs., Methods: EQ5D utility and pulmonary function measurements from the Canadian Registry for Pulmonary Fibrosis were included. Ordinary least squares (OLS), beta regression, two-part, and tobit models were used to map EQ5D utilities from FVC or DLCO. Model performance was assessed by comparing the predicted and observed utilities. Subgroup analyses were also conducted to test how well models performed across different patient characteristics. The models were then externally validated in the Australian Idiopathic Pulmonary Fibrosis Registry., Results: The OLS model performed as well as other more complex models (root mean squared error: 0.17 for FVC and 0.16 for DLCO). As with the other models, the OLS algorithm performed well across the different subgroups (except for EQ5D utilities < 0.5) and in the external validation cohort., Conclusion: We developed a mapping algorithm that predicts EQ5D utilities from FVC and DLCO, with the intent that this algorithm can be applied to clinical trial populations and real-world cohorts that have not prioritized collection of health-related utilities. The mapping algorithm can be used in future economic evaluations of potential ILD therapies., Competing Interests: Drs. Wong, Johannson, Marcoux, Assayag, Manganas, Kolb, Ryerson report personal fees and/or grants from Boehringer Ingelheim, outside the submitted work. Drs. Marcoux, Assayag, Kolb, and Ryerson report grants and/or personal fees from Roche Canada, outside the submitted work. Dr. Marcoux reports grants from AstraZeneca, outside the submitted work. Drs. Wong and Assayag report personal fees from AstraZeneca, outside the submitted work. Dr. Johannson reports grants from The Chest Foundation, University of Calgary Cumming School of Medicine, Pulmonary Fibrosis Society of Calgary, UCB Biopharma SPRL and personal fees from Blade Therapeutics, Theravance, Three Lakes Foundation, Pliant Therapeutics, and Hoffman-La Roche Ltd., outside the submitted work. Dr. Manganas reports grants from Galapagos, outside the submitted work. Dr. Kolb reports grants from Canadian Pulmonary Fibrosis Foundation, grants from Canadian Institute for Health Research, grants and personal fees from Prometic, other from European Respiratory Journal, personal fees from Third Pole, MitoImmune, Abbvie, DevPro Biopharma, Horizon, Algernon, CSL Behring, and grants and personal fees from Pieris, outside the submitted work. Dr. Ryerson reports personal fees from Pliant Therapeutics and Veracyte, outside the submitted work;. Drs. Sun, Cox, Fisher, Khalil, Palmer, de Graaff, Walters, Hopkins, Zappala, Goh, Moodley, Navaratnam, Corte, and Zhang report nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Wong 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.)

Background: The pathophysiology, evolution, and associated outcomes of post-COVID dyspnea remain unknown. The aim of this study was to determine the prevalence, severity, and predictors of dyspnea 12 months following hospitalization for COVID-19, and to describe the respiratory, cardiac, and patient-reported outcomes in patients with post-COVID dyspnea., Methods: We enrolled a prospective cohort of all adult patients admitted to 2 academic hospitals in Vancouver, Canada with PCR-confirmed SARS-CoV-2 during the first wave of COVID between March and June 2020. Dyspnea was measured 3, 6, and 12 months after initial symptom onset using the University of California San Diego Shortness of Breath Questionnaire., Results: A total of 76 patients were included. Clinically meaningful dyspnea (baseline score > 10 points) was present in 49% of patients at 3 months and 46% at 12 months following COVID-19. Between 3 and 12 months post-COVID-19, 24% patients had a clinically meaningful worsening in their dyspnea, 49% had no meaningful change, and 28% had a clinically meaningful improvement in their dyspnea. There was worse sleep, mood, quality of life, and frailty in patients with clinically meaningful dyspnea at 12 months post-COVID infection compared to patients without dyspnea. There was no difference in PFT findings, troponin, or BNP comparing patients with and without clinically meaningful dyspnea at 12 months. Severity of dyspnea and depressive symptoms at 3 months predicted severity of dyspnea at 12 months., Conclusions: Post-COVID dyspnea is common, persistent, and negatively impacts quality of life. Mood abnormalities may play a causative role in post-COVID dyspnea in addition to potential cardiorespiratory abnormalities. Dyspnea and depression at initial follow-up predict longer-term post-COVID dyspnea, emphasizing that standardized dyspnea and mood assessment following COVID-19 may identify patients at high risk of post-COVID dyspnea and facilitating early and effective management., (© 2023. The Author(s).)

Introduction: Interstitial lung disease (ILD) is a frequent manifestation of connective tissue disease (CTD) with substantial variability in prevalence and outcomes reported across CTD subtypes. This systematic review summarises the prevalence, risk factors and ILD patterns on chest computed tomography of CTD-ILD., Methods: A comprehensive search was performed in Medline and Embase to identify eligible studies. Meta-analyses were completed using a random effects model to determine the pooled prevalence of CTD-ILD and ILD patterns., Results: 11 582 unique citations were identified with 237 articles included. Pooled prevalence of ILD was 11% in rheumatoid arthritis (95% CI 7-15%), 47% in systemic sclerosis (44-50%), 41% in idiopathic inflammatory myositis (33-50%), 17% in primary Sjögren's syndrome (12-21%), 56% in mixed connective tissue disease (39-72%) and 6% in systemic lupus erythematosus (3-10%). Usual interstitial pneumonia was the most prevalent ILD pattern in rheumatoid arthritis (pooled prevalence of 46%), while nonspecific interstitial pneumonia was the most common ILD pattern in all other CTD subtypes (pooled prevalence range 27-76%). Across all CTDs with available data, positive serology and higher inflammatory markers were risk factors for development of ILD., Discussion: We identified substantial variability in ILD across CTD subtypes suggesting that CTD-ILD is too heterogenous to be considered a single entity., Competing Interests: Conflict of interest: G.M. Joy has nothing to disclose. Conflict of interest: O.A. Arbiv has nothing to disclose. Conflict of interest: C.K. Wong has nothing to disclose. Conflict of interest: S.D. Lok has received fees, honoraria, or contracts from University of Saskatchewan CoM, Boehringer Ingelheim, Roche, and AstraZeneca unrelated to this work. Conflict of interest: N.A. Adderley has nothing to disclose. Conflict of interest: K.M. Dobosz has nothing to disclose. Conflict of interest: K.A. Johannson has received fees, honoraria, or contracts from Three Lakes Foundation, Chest Foundation, University of Calgary CSM, University Hospital Foundation, Boehringer Ingelheim, Hoffman-La Roche Ltd, Pliant Therapeutics, Thyron SAB, and PFOX trial all unrelated to this work. Conflict of interest: C.J. Ryerson has received fees, honoraria, or contracts from Boehringer Ingelheim, Hoffman-La Roche Ltd, Pliant Therapeutics, AstraZeneca, Veracyte, Ensho, Cipla Ltd, all unrelated to this work., (Copyright ©The authors 2023.)

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) whose outcomes are worsened with air pollution exposures. DNA methylation (DNAm) patterns are altered in lungs and blood from patients with IPF, but the relationship between air pollution exposures and DNAm patterns in IPF remains unexplored. This study aimed to evaluate the association of PM 2.5 and constituent components with global DNAm in patients with IPF. Patients enrolled in either the University of Pittsburgh Simmons Center for ILD Registry (Simmons) or the U.S.-wide Pulmonary Fibrosis Foundation (PFF) Patient Registry with peripheral blood DNA samples were included. The averages of monthly exposures to PM 2.5 and constituents over 1-year and 3-months pre-blood collection were matched to patient residential coordinates using satellite-derived hybrid models. Global DNAm percentage (%5 mC) was determined using the ELISA-based MethylFlash assay. Associations of pollutants with %5 mC were assessed using beta-regression, Cox models for mortality, and linear regression for baseline lung function. Mediation proportion was determined for models where pollutant-mortality and pollutant-%5 mC associations were significant. Inclusion criteria were met by 313 Simmons and 746 PFF patients with IPF. Higher PM 2.5 3-month exposures prior to blood collection were associated with higher %5 mC in Simmons (β = 0.02, 95%CI 0.0003-0.05, p = 0.047), with trends in the same direction in the 1-year period in both cohorts. Higher exposures to sulfate, nitrate, ammonium, and black carbon constituents were associated with higher %5 mC in multiple models. Percent 5 mC was not associated with IPF mortality or lung function, but was found to mediate between 2 and 5% of the associations of PM 2.5 , sulfate, and ammonium with mortality. In conclusion, we found that higher global DNAm is a novel biomarker for increased PM 2.5 and anthropogenic constituent exposure in patients with IPF. Mechanistic research is needed to determine if DNAm has pathogenic relevance in mediating associations between pollutants and mortality in IPF., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gillian C. Goobie reports financial support was provided by Pulmonary Fibrosis Foundation. Gillian C. Goobie reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. Kathleen O. Lindell reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. Daniel J. Kass reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. S. Mehdi Nouraie reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. Christopher J. Ryerson reports a relationship with Boehringer Ingelheim Canada Ltd that includes: funding grants. Christopher J. Ryerson reports a relationship with Hoffmann-La Roche Limited that includes:. Kerri A. Johannson reports a relationship with Boehringer Ingelheim Canada Ltd that includes: consulting or advisory and funding grants. Kerri A. Johannson reports a relationship with Three Lakes Foundation that includes: consulting or advisory and funding grants. Kerri A. Johannson reports a relationship with Hoffmann-La Roche Limited that includes: consulting or advisory. James P. Fabisiak reports a relationship with Heinz Endowments that includes: funding grants. Daniel J. Kass reports a relationship with National Institutes of Health that includes: funding grants. Yingze Zhang reports a relationship with National Institutes of Health that includes: funding grants., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Autoimmunity has been reported in patients with severe coronavirus disease 2019 (COVID-19). We investigated whether anti-nuclear/extractable-nuclear antibodies (ANAs/ENAs) were present up to a year after infection, and if they were associated with the development of clinically relevant post-acute sequalae of COVID-19 (PASC) symptoms., Methods: A rapid-assessment line immunoassay was used to measure circulating levels of ANAs/ENAs in 106 convalescent COVID-19 patients with varying acute phase severities at 3, 6 and 12 months post-recovery. Patient-reported fatigue, cough and dyspnoea were recorded at each time point. Multivariable logistic regression model and receiver operating curves were used to test the association of autoantibodies with patient-reported outcomes and pro-inflammatory cytokines., Results: Compared to age- and sex-matched healthy controls (n=22) and those who had other respiratory infections (n=34), patients with COVID-19 had higher detectable ANAs at 3 months post-recovery (p<0.001). The mean number of ANA autoreactivities per individual decreased between 3 and 12 months (from 3.99 to 1.55) with persistent positive titres associated with fatigue, dyspnoea and cough severity. Antibodies to U1-snRNP and anti-SS-B/La were both positively associated with persistent symptoms of fatigue (p<0.028, area under the curve (AUC) 0.86) and dyspnoea (p<0.003, AUC=0.81). Pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α and C-reactive protein predicted the elevated ANAs at 12 months. TNF-α, D-dimer and interleukin-1β had the strongest association with symptoms at 12 months. Regression analysis showed that TNF-α predicted fatigue (β=4.65, p=0.004) and general symptomaticity (β=2.40, p=0.03) at 12 months., Interpretation: Persistently positive ANAs at 12 months post-COVID are associated with persisting symptoms and inflammation (TNF-α) in a subset of COVID-19 survivors. This finding indicates the need for further investigation into the role of autoimmunity in PASC., Competing Interests: Conflict of interest: Manali Mukherjee is supported by early investigator award from Canadian Institutes of Health Research (CIHR) and Canadian Asthma Allergy and Immunology Foundation (CAAIF); and reports grants from CIHR and Methapharm Specialty Pharmaceuticals, personal fees from AstraZeneca and GlaxoSmithKline, consultant fees from Novartis, outside the submitted work. S. Svenningsen reports grants from Cyclomedica, personal fees from Arrowhead Pharmaceuticals, honorarium for lectures from AZ, Novartis and Polarean, outside the submitted work. S. Waserman reports grants and consulting fees from Alk Abello and CSL Behring, grants from Canadian Allergy, Asthma, and Immunology Foundation, Aimmune and Takeda, personal and consulting fees from AZ, GSK, Sanofi, Medexus, Miravo Health and Bausch Lomb, consulting fees from Novartis, Pfizer and AbbVie, outside of the submitted work; and is chairperson of an advisory board for Siolta, president for CAAIF, board of directors for Asthma Canada, and medical advisor for Food Allergy Canada. P. Nair reports grants and personal fees from AZ, Teva and Sanofi, personal fees from GSK, Equillium and Arrowhead pharma, grants from Foresee and Cyclomedica, outside the submitted work. N. Balakrishnan reports grants from Natural Sciences and Engineering Research Council of Canada, outside the submitted work. D.M.E. Bowdish reports grants from COVID-19 Immunity Task Force/Public Health Agency of Canada, grants from National Science and Engineering Research Council (NSERC), grants from Canadian Institutes of Health Research, personal fees from AZ Mexico, personal fees for invited presentations from academic institutions, outside the submitted work; and is on the board of directors for Lung Health Foundation, and has been an expert testimony witness for the Government of Canada. K. Son, R. Jamil, A. Chowdhury, Manan Mukherjee, C. Venegas, K. Miyasaki, K. Zhang, Z. Patel, B. Salter, A.C.Y. Yuen, K.S-K. Lau, B. Cowbrough, K. Radford, C. Huang, M. Kjarsgaard, A. Dvorkin-Gheva, J. Smith, Q-Z. Li, C.J. Ryerson, T. Ho, I. Nazy and C. Carlsten have nothing to report., (Copyright ©The authors 2023.)

Background: Individuals with lung disease commonly use the internet as a source of health information on pulmonary rehabilitation (PR). The objective of this study was to characterize internet resources on PR, and to assess the content, readability, and quality of patient-directed PR resources., Methods: The first 200 websites for the search term 'pulmonary rehabilitation resources and exercise' were analyzed on Google, Yahoo, and Bing. Website content was assessed based on 30 key components of PR from the 2013 and 2021 international consensus statements. Website quality was determined using DISCERN, JAMA benchmarks, and Global Quality Scale (GQS)., Results: 66 unique PR websites were identified with the two most common categories being scientific resources (39%) and foundation/advocacy organizations (33%). The average reading level of websites was 11 ± 3. PR content varied significantly across websites (mean range 13.4-21.5). Median DISCERN total score and GQS score were 4 (IQR 3-4) and 3.5 (IQR 2-4), respectively, representing moderate-good quality. Foundation/advocacy websites had higher DISCERN and GQS scores compared to other websites., Conclusion: Foundation/advocacy websites had the highest quality and reliability metrics; however, the higher-than-recommended reading levels may compromise patient comprehension and utilization. This study provides critical insight on the current state of online PR health-related information.

Background: Fatigue is a common symptom in hospitalized and non-hospitalized patients recovering from COVID-19, but no fatigue measurement scales or questions have been validated in these populations. The objective of this study was to perform validity assessments of the fatigue severity scale (FSS) and two single-item screening questions (SISQs) for fatigue in patients recovering from COVID-19., Methods: We examined patients ≥ 28 days after their first SARS-CoV-2 infection who were hospitalized for their acute illness, as well as non-hospitalized patients referred for persistent symptoms. Patients completed questionnaires through 1 of 4 Post COVID-19 Recovery Clinics in British Columbia, Canada. Construct validity was assessed by comparing FSS scores to quality of life and depression measures. Two SISQs were evaluated based on the ability to classify fatigue (FSS score ≥ 4)., Results: Questionnaires were returned in 548 hospitalized and 546 non-hospitalized patients, with scores computable in 96.4% and 98.2% of patients respectively. Cronbach's alpha was 0.96 in both groups. The mean ± SD FSS score was 4.4 ± 1.8 in the hospitalized and 5.2 ± 1.6 in the non-hospitalized group, with 62.5% hospitalized and 78.9% non-hospitalized patients classified as fatigued. Ceiling effects were 7.6% in the hospitalized and 16.1% in non-hospitalized patients. FSS scores negatively correlated with EQ-5D scores in both groups (Spearman's rho - 0.6 in both hospitalized and non-hospitalized; p < 0.001) and were higher among patients with a positive PHQ-2 depression screen (5.4 vs. 4.0 in hospitalized and 5.9 vs. 4.9 in non-hospitalized; p < 0.001). An SISQ asking whether there was "fatigue present" had a sensitivity of 70.6% in hospitalized and 83.2% in non-hospitalized patients; the "always feeling tired" SISQ, had a sensitivity of 70.5% and 89.6% respectively., Conclusions: Fatigue was common and severe in patients referred for post COVID-19 assessment. Overall, the FSS is suitable for measuring fatigue in these patients, as there was excellent data quality, strong internal consistency, and construct validity. However, ceiling effects may be a limitation in the non-hospitalized group. SISQs had good sensitivity for identifying clinically relevant fatigue in non-hospitalized patients but only moderate sensitivity in the hospitalized group, indicating that there were more false negatives., (© 2022. The Author(s).)

Background: Information regarding idiopathic pulmonary fibrosis (IPF) on the internet is often outdated, inaccurate, and potentially harmful. Twitter is a social media platform that allows users to post content in the form of "tweets"., Objective: We sought to assess the prevalence of inaccurate information regarding IPF on Twitter. We hypothesized that foundations and medical organizations would be the least likely to post inaccurate information and that inaccurate tweets would have higher user engagement., Methods: All tweets posted between 2011 and 2019 were gathered using "snscrape" on Python 3.8 while searching for the phrase "idiopathic pulmonary fibrosis". Quantitative analysis was performed to describe trends in IPF-related tweet frequency over time. A subset of tweets made between 2018 and 2019 was screened for verifiable medical statements, which were then analyzed for accuracy compared with contemporary clinical practice guidelines, with descriptive statistics reported. Logistic regression was used to compare tweet accuracy and recommendation of nonindicated therapies across sources, with adjustment for tweet age and character count. Wilcoxon rank-sum tests were used to determine if user engagement (favorites, retweets, and replies) differed between accurate and inaccurate tweets., Results: A total of 16,787 tweets were identified between 2011 and 2019. Between 2018 and 2019, 4,861 tweets were included, of which 1,612 (33%) contained verifiable medical statements. Tweets from sources other than foundations or medical organizations were more likely to contain inaccurate information and to recommend nonindicated therapies in both unadjusted and adjusted analyses. News and media sources had the highest odds of communicating potentially harmful information in both adjusted (odds ratio [OR], 12.00; 95% confidence interval [CI], 5.87-27.16) and unadjusted (OR, 11.62; 95% CI, 5.70-26.21) analyses when compared with foundations and medical organizations. Tweets containing inaccurate information had significantly lower numbers of favorites and retweets ( P  < 0.001 for both)., Conclusion: Misinformation regarding IPF is present on Twitter and is more often presented by news and media sources. Medically inaccurate tweets displayed less user engagement than accurate tweets. This differs from findings on IPF-related information on YouTube and Facebook, which may reflect differences in both author and consumer qualities across social media platforms., (Copyright © 2022 by the American Thoracic Society.)

Background: This multicentre, international, prospective cohort study evaluated whether patients with pulmonary sarcoidosis living in neighbourhoods with greater material and social disadvantage experience worse clinical outcomes., Methods: The area deprivation index and the Canadian Index of Multiple Deprivation evaluate neighbourhood-level disadvantage in the US and Canada, with higher scores reflecting greater disadvantage. Multivariable linear regression evaluated associations of disadvantage with baseline forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide ( D LCO ) and linear mixed effects models for associations with rate of FVC or D LCO decline, and competing hazards models were used for survival analyses in the US cohort, evaluating competing outcomes of death or lung transplantation. Adjustments were made for age at diagnosis, sex, race and smoking history., Results: We included 477 US and 122 Canadian patients with sarcoidosis. Higher disadvantage was not associated with survival or baseline FVC. The highest disadvantage quartile was associated with lower baseline D LCO in the US cohort (β = -6.80, 95% CI -13.16 to -0.44, p=0.04), with similar findings in the Canadian cohort (β = -7.47, 95% CI -20.28 to 5.33, p=0.25); with more rapid decline in FVC and D LCO in the US cohort (FVC β = -0.40, 95% CI -0.70 to -0.11, p=0.007; D LCO β = -0.59, 95% CI -0.95 to -0.23, p=0.001); and with more rapid FVC decline in the Canadian cohort (FVC β = -0.80, 95% CI -1.37 to -0.24, p=0.003)., Conclusion: Patients with sarcoidosis living in high disadvantage neighbourhoods experience worse baseline lung function and more rapid lung function decline, highlighting the need for better understanding of how neighbourhood-level factors impact individual patient outcomes., Competing Interests: Conflict of interest: G.C. Goobie receives research funding and support through the Pulmonary Fibrosis Foundation Scholars Award Program and the University of British Columbia Clinician Investigator Program. C.J. Ryerson, D. Assayag and M.R.J. Kolb report personal fees and grants from Boehringer Ingelheim and Hoffman La Roche outside the submitted work. K.A. Johannson reports personal fees, nonfinancial support and other support from Boehringer Ingelheim and the Three Lakes Foundation, personal fees from Hoffman-La Roche Ltd, and grants from the University Hospital Foundation, the University of Calgary Cumming School of Medicine, and the Pulmonary Fibrosis Society of Calgary. V. Marcoux reports grants and personal fees from Boehringer Ingelheim Canada, Hoffman La-Roche Ltd and AstraZeneca, and grants from the University of Saskatchewan and the Royal University Hospital Foundation. M.R.J. Kolb also reports personal fees and grants from GSK, Gilead, Actelion, Respivert, Genoa, Alkermes, Pharmaxis, Prometric, Indalo and Third Pole. H. Manganas reports grants from Hoffman-La Roche Ltd, Galapagos and BMS, and personal fees and research grants from Boehringer Ingelheim. D. Assayag also reports personal fees and grants from Novartis. J.H. Fisher reports grants from the Canadian Pulmonary Fibrosis Foundation, and personal fees from Boehringer Ingelheim and AstraZeneca, outside of the submitted work. D.J. Kass is supported in part by AR060780, HL133232, UL1 TR001857 and AR076024 (NIH grants), Boehringer Ingelheim grants, and receives collaborative research funding from Regeneron Pharmaceuticals, outside of the submitted work. Y. Zhang is supported in part by AR076024 (NIH grant). S. Keil, E. Schikowski, N. Khalil, X. Chen, K.F. Gibson and K.O. Lindell report no competing interests. S.M. Nouraie receives grant support from Boehringer Ingelheim USA., (Copyright ©The authors 2022.)

Background: Progressive fibrosing interstitial lung disease (PF-ILD) is characterised by progressive physiological, symptomatic and/or radiographic worsening. The real-world prevalence and characteristics of PF-ILD remain uncertain., Methods: Patients were enrolled from the Canadian Registry for Pulmonary Fibrosis between 2015 and 2020. PF-ILD was defined as a relative forced vital capacity (FVC) decline ≥10%, death, lung transplantation or any two of: relative FVC decline ≥5% and <10%, worsening respiratory symptoms or worsening fibrosis on computed tomography of the chest, all within 24 months of diagnosis. Time-to-event analysis compared progression between key diagnostic subgroups. Characteristics associated with progression were determined by multivariable regression., Results: Of 2746 patients with fibrotic ILD (mean±sd age 65±12 years; 51% female), 1376 (50%) met PF-ILD criteria in the first 24 months of follow-up. PF-ILD occurred in 427 (59%) patients with idiopathic pulmonary fibrosis (IPF), 125 (58%) with fibrotic hypersensitivity pneumonitis (HP), 281 (51%) with unclassifiable ILD (U-ILD) and 402 (45%) with connective tissue disease-associated ILD (CTD-ILD). Compared with IPF, time to progression was similar in patients with HP (hazard ratio (HR) 0.96, 95% CI 0.79-1.17), but was delayed in patients with U-ILD (HR 0.82, 95% CI 0.71-0.96) and CTD-ILD (HR 0.65, 95% CI 0.56-0.74). Background treatment varied across diagnostic subtypes, with 66% of IPF patients receiving antifibrotic therapy, while immunomodulatory therapy was utilised in 49%, 61% and 37% of patients with CHP, CTD-ILD and U-ILD, respectively. Increasing age, male sex, gastro-oesophageal reflux disease and lower baseline pulmonary function were independently associated with progression., Conclusions: Progression is common in patients with fibrotic ILD, and is similarly prevalent in HP and IPF. Routinely collected variables help identify patients at risk for progression and may guide therapeutic strategies., Competing Interests: Conflict of interest: M.M. Farooqi reports no conflicts of interest relevant to this manuscript. Conflict of interest: A. Dvorkin-Gheva reports no conflicts of interest relevant to this manuscript. Conflict of interest: K. Donohoe reports no conflicts of interest relevant to this manuscript. Conflict of interest: K. Garlick was an employee for the medical department of Boehringer Ingelheim at the time of the preparation of this manuscript. Conflict of interest: C. Scallan reports personal fees from Boehringer Ingelheim. Conflict of interest: S.G. Chong reports no conflicts of interest relevant to this manuscript. Conflict of interest: S. MacIsaac reports no conflicts of interest relevant to this manuscript. Conflict of interest: D. Assayag reports personal fees from Roche and Boehringer Ingelheim. Conflict of interest: K.A. Johannson reports grants from Boehringer Ingelheim, Pulmonary Fibrosis Society of Calgary and University of Calgary School of Medicine; personal fees from Boehringer Ingelheim, Roche, Three Lakes Foundation, Pliant Therapeutics, Theravance and Blade Therapeutics. Conflict of interest: C.D. Fell reports educational grants and research grants from Boehringer Ingelheim, Roche and the Canadian Pulmonary Fibrosis Foundation; personal fees from Roche and Boehringer Ingelheim; Chair of the Boards for the Canadian Pulmonary Fibrosis Foundation. Conflict of interest: V. Marcoux reports grants from Boehringer Ingelheim, AstraZeneca and Roche; personal fees from Boehringer Ingelheim and Roche. Conflict of interest: H. Manganas reports grants from Boehringer Ingelheim and Gilead. Conflict of interest: J. Morisset reports personal fees from Boehringer Ingelheim and Roche. Conflict of interest: A. Comes reports no conflicts of interest relevant to this manuscript. Conflict of interest: J.H. Fisher reports no conflicts of interest relevant to this manuscript. Conflict of interest: S. Shapera reports educational grants and research grants from Boehringer Ingelheim, Roche and the Canadian Pulmonary Fibrosis Foundation; personal fees from AstraZeneca, Boehringer Ingelheim Canada and Hoffman La-Roche Canada; served on the medical advisory board for the Canadian Pulmonary Fibrosis Foundation. Conflict of interest: A.S. Gershon reports a research grant from the Canadian Pulmonary Fibrosis Foundation. Conflict of interest: T. To reports no conflicts of interest relevant to this manuscript. Conflict of interest: A.W. Wong reports personal fees from AstraZeneca and Boehringer Ingelheim. Conflict of interest: M. Sadatsafavi reports grants from Boehringer Ingelheim; personal fees from Boehringer Ingelheim. Conflict of interest: P.G. Wilcox reports personal fees from Boehringer Ingelheim. Conflict of interest: A.J. Halayko reports no conflicts of interest relevant to this manuscript. Conflict of interest: N. Khalil reports no conflicts of interest relevant to this manuscript. Conflict of interest: G. Cox reports personal fees from Boehringer Ingelheim and Roche. Conflict of interest: L. Richeldi reports grants and personal fees from Boehringer Ingelheim; personal fees from Biogen, Sanofi-Aventis, Celgene, RespiVant, CSL Behring, Nitto, Pliant Therapeutics, Cipla, Zambon, Promedior, Boehringer Ingelheim, Roche and Fibrogen. Conflict of interest: C.J. Ryerson reports grants from Boehringer Ingelheim; personal fees from Boehringer Ingelheim, Roche, Pliant Therapeutics, Cipla and Veracyte. Conflict of interest: M. Kolb reports grants from the Canadian Institute for Health Research, Roche, Boehringer Ingelheim, Pieris and Prometic; personal fees from Boehringer Ingelheim, Roche, European Respiratory Journal, Belerophon, United Therapeutics, Nitto Denko, MitoImmune, Pieris, AbbVie, DevPro Biopharma, Horizon, Algernon and CSL Behring. Conflict of interest: N. Hambly reports grants from Roche and Boehringer Ingelheim; personal fees from Roche, Boehringer Ingelheim and Janssen., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Dehydroepiandrosterone (DHEA) is a precursor sex hormone with antifibrotic properties. The aims of this study were to investigate antifibrotic mechanisms of DHEA, and to determine the relationship between DHEA-sulfate (DHEAS) plasma levels, disease severity and survival in patients with fibrotic interstitial lung diseases (ILDs)., Methods: Human precision cut lung slices (PCLS) and normal human lung fibroblasts were treated with DHEA and/or transforming growth factor (TGF)-β1 before analysis of pro-fibrotic genes and signal proteins. Cell proliferation, cytotoxicity, cell cycle and glucose-6-phosphate dehydrogenase (G6PD) activity were assessed. DHEAS plasma levels were correlated with pulmonary function, the composite physiologic index (CPI), and time to death or lung transplantation in a derivation cohort of 31 men with idiopathic pulmonary fibrosis (IPF) and in an independent validation cohort of 238 men and women with fibrotic ILDs., Results: DHEA decreased the expression of pro-fibrotic markers in-vitro and ex-vivo. There was no cytotoxic effect for the applied concentrations, but DHEA interfered in proliferation by modulating the cell cycle through reduction of G6PD activity. In men with IPF (derivation cohort) DHEAS plasma levels in the lowest quartile were associated with poor lung function and higher CPI (adjusted OR 1.15 [95% CI 1.03-1.38], p = 0.04), which was confirmed in the fibrotic ILD validation cohort (adjusted OR 1.03 [95% CI 1.00-1.06], p = 0.01). In both cohorts the risk of early mortality was higher in patients with low DHEAS levels, after accounting for potential confounding by age in men with IPF (HR 3.84, 95% CI 1.25-11.7, p = 0.02), and for age, sex, IPF diagnosis and prednisone treatment in men and women with fibrotic ILDs (HR 3.17, 95% CI 1.35-7.44, p = 0.008)., Conclusions: DHEA reduces lung fibrosis and cell proliferation by inducing cell cycle arrest and inhibition of G6PD activity. The association between low DHEAS levels and disease severity suggests a potential prognostic and therapeutic role of DHEAS in fibrotic ILD., (© 2022. The Author(s).)

Introduction: Coronavirus Disease-2019 (COVID-19) affects multiple organ systems in the acute phase and also has long-term sequelae. Research on the long-term impacts of COVID-19 is limited. The Post COVID-19 Interdisciplinary Clinical Care Network (PC-ICCN), conceived in July 2020, is a provincially funded resource that is modelled as a Learning Health System (LHS), focused on those people with persistent symptoms post COVID-19 infection., Methods: The PC-ICCN emerged through collaboration among over 60 clinical specialists, researchers, patients, and health administrators. At the core of the network are the post COVID-19 Recovery Clinics (PCRCs), which provide direct patient care that includes standardized testing and education at regular follow-up intervals for a minimum of 12 months post enrolment. The PC-ICCN patient registry captures data on all COVID-19 patients with confirmed infection, by laboratory testing or epi-linkage, who have been referred to one of five post COVID-19 Recovery Clinics at the time of referral, with data stored in a fully encrypted Oracle-based provincial database. The PC-ICCN has centralized administrative and operational oversight, multi-stakeholder governance, purpose built data collection supported through clinical operations geographically dispersed across the province, and research operations including data analytics., Results: To date, 5364 patients have been referred, with an increasing number and capacity of these clinics, and 2354 people have had at least one clinic visit. Since inception, the PC-ICCN has received over 30 research proposal requests. This is aligned with the goal of creating infrastructure to support a wide variety of research to improve care and outcomes for patients experiencing long-term symptoms following COVID-19 infection., Conclusions: The PC-ICCN is a first-in-kind initiative in British Columbia to enhance knowledge and understanding of the sequelae of COVID-19 infection over time. This provincial initiative serves as a model for other national and international endeavors to enable care as research and research as care., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. Learning Health Systems published by Wiley Periodicals LLC on behalf of University of Michigan.)

Background: The Internet is commonly used by patients to acquire health information. To date, no studies have evaluated the quality of information available on YouTube regarding lymphangioleiomyomatosis (LAM). Our aim was to determine the quality and content of YouTube videos regarding LAM and to compare the information provided with current knowledge and guidelines about the disease., Methods: The first 200 video hits on YouTube in English for the search term "lymphangioleiomyomatosis" were recorded. All videos suitable for patient education on LAM were included. Video quality was analyzed independently by two investigators utilizing the Health on the Net (HONcode) score, which assesses whether websites provide understandable, accessible, and trustworthy health information; the DISCERN score, which evaluates the quality of information about treatment decisions; and a newly developed LAM-related content score (LRCS) with 31 guideline elements., Results: The search identified 64 eligible videos. The "engagement rate" of 0.3 was low, with a median number of views of 408 (range 42-73,943), a median of 4 likes (range 0-2082), and the majority (53%) receiving a low HONcode score (≤ 2) and only 10% of videos achieving a high score (> 5). The median DISCERN score was 28 (range 15-61, maximum possible score 80), indicating poor video quality and reliability. The median LRCS was 8 (range 0-29, maximum possible score 31) and videos frequently failed to provide sources of information., Conclusions: Online resources could contribute to the limited and often inaccurate information available to patients with LAM, with only a few YouTube videos providing high-quality patient-relevant information., (© 2022. The Author(s).)

Background: The economic burden of interstitial lung disease (ILD) is unknown, limiting informed resource allocation and planning. We sought to conduct the first systematic review on the direct, indirect, and overall costs associated with ILD and to evaluate the cost-effectiveness of current therapies globally., Methods: We conducted systematic reviews of ILD disease cost studies and cost-effectiveness analyses (CEAs) using MEDLINE, Embase, and Web of Science databases between 2000 and 2020. We compared ILD costs between countries according to the share of costs towards each country's respective gross domestic product (GDP) per capita. Costs are reported in 2020 USD., Results: We identified 25 disease cost studies and 7 CEAs. The direct medical costs ranged between $1824 and $116,927 annually per patient (median $32,834; 14-180% of GDP per capita in Western countries). The leading drivers of direct costs were inpatient (55%), outpatient (22%), and medication costs (18%), based on pooled estimates. Annual indirect costs ranged from $7149 to $10,902 per employed patient (median $9607; 12-23% of GDP per capita). Among the 7 CEAs, only 1 study (14%) showed an ILD therapy (ambulatory oxygen) was cost-effective compared to best supportive care., Conclusion: The direct and indirect costs associated with ILD are consistently high in all countries with available data, with cost-effectiveness profiles of new therapies generally undesirable. Globally, the median total direct cost for ILD equates to 51% of a country's GDP per capita and has been increasing over time., (© 2022. The Author(s).)

Surgical lung biopsy remains the standard procedure for the subset of patients with fibrosing interstitial lung disease (F-ILD) who require a lung biopsy to secure a confident diagnosis. Little is known about the pathologic features of samples obtained via non-intubated/"awake" surgical lung biopsy and the diagnostic accuracy of awake biopsy in patients with F-ILD. Two expert thoracic pathologists blinded to the type of lung biopsy compared the clinical-pathologic features of 120 conventional VATS biopsies with those of 21 consecutive non-intubated/"awake" VATS biopsies. No statistically significant differences between the two procedures were observed with regard to identification of histopathological features. Biopsy length, average of sampled lobes and mean number of slides were similar with the two procedures, while the width of the biopsies was significantly deeper with conventional VATS (31.5 mm versus 25.6 mm; p = 0.01). By contrast, the mean age of patients (69.5 versus 64.5 years; p = 0.02) and the level of diagnostic confidence (100% versus 75%; p = 0.007) were significantly higher among patients undergoing the "awake" procedure. Diagnostic yield was 100% in both groups, with a similar distribution of ILD diagnoses. Non-intubated/"awake" biopsy has the potential to become the standard surgical procedure in patients with F-ILD requiring a histological confirmation of their diagnosis. However, larger prospective studies are needed to validate the safety and diagnostic yield of "awake" compared to conventional VATS., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Obesity is a health epidemic associated with greater morbidity and mortality in the general population. Mass loading of the thorax from obesity leads to a restrictive pulmonary defect that reduces lung capacity in obese individuals without pulmonary disease, and may exacerbate the restrictive pulmonary physiology that is characteristic of interstitial lung disease (ILD). The purpose of this study was to test the association of body mass index (BMI) with pulmonary function, functional capacity, and patient-reported outcomes (dyspnea and quality of life) in patients with ILD. We analyzed 3169 patients with fibrotic ILD from the Canadian Registry for Pulmonary Fibrosis. Patients were subcategorized as underweight (BMI<18.5 kg/m 2 ), normal weight (18.5≤BMI<25), overweight (25≤BMI<30), obese I (30≤BMI<35), obese II (35≤BMI<40), and obese III (BMI>40). Analysis was performed using a linear regression with adjustment for common prognostic variables. Overweight and obese BMI categories were associated with worse pulmonary function, functional capacity, dyspnea, and quality of life compared to normal weight. This is likely a result of mass loading on the thorax, and we speculate that intentional weight-loss may improve lung function and functional capacity in obese patients with fibrotic ILD. The underweight BMI category was also associated with worse functional capacity compared to normal weight, which may reflect greater disease severity or the presence of other comorbidities. Future work should explore the clinical utility of BMI to improve patient outcomes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Rationale: Longitudinal data on the impact of continued, switched or discontinued antifibrotic therapy in patients with idiopathic pulmonary fibrosis (IPF) who have disease progression is needed., Objective: We hypothesized that ongoing antifibrotic use (versus discontinuation) in the setting of forced vital capacity (FVC) decline would be associated with less future decline and lower likelihood of a composite outcome of FVC decline, lung transplant, or death., Methods: We performed a multicenter cohort study using data from the Canadian Registry for Pulmonary Fibrosis in patients with IPF with FVC decline ≥10% over 6 months on antifibrotic therapy. The association of continued, switched or discontinued therapy with (1) further change in FVC and (2) a composite of FVC decline ≥10%, transplant, or death, in the subsequent 6 months, was assessed using adjusted linear and logistic regression modelling, respectively. Generalized estimating equations accounted for repeated observations per patient., Results: 165 patients had a decline in FVC ≥10% over 6 months while receiving antifibrotic therapy. Compared to continued use, antifibrotic discontinuation after FVC decline was associated with greater additional FVC decline (-207 mL 95%CI -353 to -62, p = 0.005) and higher odds of FVC decline ≥10%, transplant, or death (odds ratio 12.2 95%CI 1.2 to 130.5, p = 0.04). There was no difference between continued versus switched antifibrotic therapy., Conclusions: Ongoing antifibrotic therapy in the setting of FVC decline is associated with less future FVC decline and lower odds of FVC decline ≥10%, transplant, or death in a real-world cohort of IPF., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Fibrotic interstitial lung diseases (ILDs) frequently have nonspecific and overlapping clinical and radiological features, resulting in ∼10-20% of patients with ILD lacking a clear diagnosis and thus being labelled with unclassifiable ILD. The objective of this review is to describe how patients with unclassifiable ILD should be evaluated, and what impact specific clinical, radiological and histopathological features may have on management decisions, focusing on patients with a predominantly fibrotic phenotype. We highlight recent data that have suggested an increasing role for antifibrotic medications in a variety of fibrotic ILDs, but justify the ongoing importance of making an accurate ILD diagnosis given the benefit of immunomodulatory therapies in many patient populations. We provide a practical approach to support management decisions that can be used by clinicians and tested by clinical researchers, and further identify the need for additional research to support a rational and standardised approach to the management of patients with unclassifiable ILD., Competing Interests: Conflict of interest: C.J. Ryerson reports personal fees from Veracyte, research funding, grant support, and speaking honoraria from Boehringer Ingelheim and Hoffmann-La Roche, speaking honoraria from Cipla Ltd, and consultancy fees from Pliant Therapeutics, outside the submitted work. Conflict of interest: T.J. Corte reports grant support, consultancy fees, and speaking honoraria from Boehringer Ingelheim and Hoffman-La Roche; grant support from Gilead, Biogen, Bayer, InterMune, Actelion, Galapagos and Avalyn Pharma; and consultancy fees from AstraZeneca, Bristol-Myers Squibb, Promedior and Ad Alta, outside the submitted work. Conflict of interest: J.L. Myers has nothing to disclose. Conflict of interest: S.L.F. Walsh reports research funding from the National Institute of Health and Research; research funding, consultancy fees, and speaking honoraria from Boehringer Ingelheim, Hoffmann-La Roche and Galapagos; consultancy fees from The Open Source Imaging Consortium, FLUIDDA, Medscape, Verocyte and Sanofi-Genzyme; speaking honoraria from Bracco, outside the submitted work. Conflict of interest: S.A. Guler reports grant support and speaking honoraria from Boehringer Ingelheim and Hoffmann-La Roche, outside the submitted work., (Copyright ©The authors 2021.)

Social media is an increasingly popular source of health information, and the rarity and complexity of interstitial lung disease (ILD) may particularly draw patients with ILD to social media for information and support. The objective of this viewpoint is to provide an overview of social media, explore the benefits and limitations of ILD-related social media use, and discuss future development of healthcare information on social media. We describe the value of integrating social media into the practice of ILD health professionals, including its role in information dissemination, patient engagement, knowledge generation, and formation of health policy. We also describe major challenges to expanded social media use in ILD, including limited access for some individuals and populations, abundance of misinformation, and concerns about patient privacy. Finally, for healthcare professionals looking to join social media, we provide practical guidance and considerations to optimize the potential benefits and minimize the potential pitfalls of social media., (© 2021. The Author(s).)

Objectives: The aim of this study was to compare respiratory and patient-reported outcome measures (PROMs) between 3 and 6 months after symptom onset and to identify features that predict these changes., Methods: This was a consecutive prospective cohort of 73 patients who were hospitalised with coronavirus disease 2019 (COVID-19). We evaluated the changes in pulmonary function tests and PROMs between 3 and 6 months and then investigated the associations between outcomes (change in diffusing capacity of the lung for carbon monoxide ( D LCO ), dyspnoea and quality of life (QoL)) and clinical and radiological features., Results: There was improvement in forced vital capacity, total lung capacity and D LCO between 3 and 6 months by 3.25%, 3.82% and 5.69%, respectively; however, there was no difference in PROMs. Reticulation and total computed tomography (CT) scores were associated with lower D LCO % predicted at 6 months (coefficients; -8.7 and -5.3, respectively). The association between radiological scores and D LCO were modified by time, with the degree of association between ground glass and D LCO having decreased markedly over time. There was no association between other predictors and change in dyspnoea or QoL over time., Conclusions: There is improvement in pulmonary function measurements between 3 and 6 months after COVID-19 symptom onset; however, PROMs did not improve. A higher reticulation and total CT score are negatively associated with D LCO , but this association is attenuated over time. Lastly, there is a considerable proportion of patients with unexplained dyspnoea at 6 months, motivating further research to identify the underlying mechanisms., Competing Interests: Conflict of interest: A.S. Shah has nothing to disclose. Conflict of interest: M.H. Ryu has nothing to disclose. Conflict of interest: C.J. Hague has nothing to disclose. Conflict of interest: D.T. Murphy has nothing to disclose. Conflict of interest: J.C. Johnston has nothing to disclose. Conflict of interest: C.J. Ryerson has nothing to disclose. Conflict of interest: C. Carlsten has nothing to disclose. Conflict of interest: A.W. Wong has nothing to disclose., (Copyright ©The authors 2021.)

Introduction: For the management of patients referred to respiratory triage during the early stages of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, either chest radiography or computed tomography (CT) were used as first-line diagnostic tools. The aim of this study was to compare the impact on the triage, diagnosis and prognosis of patients with suspected COVID-19 when clinical decisions are derived from reconstructed chest radiography or from CT., Methods: We reconstructed chest radiographs from high-resolution CT (HRCT) scans. Five clinical observers independently reviewed clinical charts of 300 subjects with suspected COVID-19 pneumonia, integrated with either a reconstructed chest radiography or HRCT report in two consecutive blinded and randomised sessions: clinical decisions were recorded for each session. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and prognostic value were compared between reconstructed chest radiography and HRCT. The best radiological integration was also examined to develop an optimised respiratory triage algorithm., Results: Interobserver agreement was fair (Kendall's W =0.365, p<0.001) by the reconstructed chest radiography-based protocol and good (Kendall's W =0.654, p<0.001) by the CT-based protocol. NPV assisted by reconstructed chest radiography (31.4%) was lower than that of HRCT (77.9%). In case of indeterminate or typical radiological appearance for COVID-19 pneumonia, extent of disease on reconstructed chest radiography or HRCT were the only two imaging variables that were similarly linked to mortality by adjusted multivariable models CONCLUSIONS: The present findings suggest that clinical triage is safely assisted by chest radiography. An integrated algorithm using first-line chest radiography and contingent use of HRCT can help optimise management and prognostication of COVID-19., Competing Interests: Conflict of interests: N. Sverzellati has nothing to disclose. Conflict of interests: C.J. Ryerson has nothing to disclose. Conflict of interests: G. Milanese has nothing to disclose. Conflict of interests: E.A. Renzoni has nothing to disclose. Conflict of interests: A. Volpi has nothing to disclose. Conflict of interests: P. Spagnolo reports grants, personal fees and nonfinancial support from Roche, PPM Services and Boehringer Ingelheim, personal fees from Red X Pharma, Galapagos and Chiesi, outside the submitted work; and the author's spouse is an employee of Novartis. Conflict of interests: F. Bonella reports personal fees and nonfinancial support from Boehringer Ingelheim, Roche, Galapagos, Savara Pharma and Bristol Myers Squibb, outside the submitted work. Conflict of interests: I. Comelli has nothing to disclose. Conflict of interests: P. Affanni has nothing to disclose. Conflict of interests: L. Veronesi has nothing to disclose. Conflict of interests: C. Manna has nothing to disclose. Conflict of interests: A. Ciuni has nothing to disclose. Conflict of interests: C. Sartorio has nothing to disclose. Conflict of interests: G. Tringali has nothing to disclose. Conflict of interests: M. Silva has nothing to disclose. Conflict of interests: E. Michieletti has nothing to disclose. Conflict of interests: D. Colombi has nothing to disclose. Conflict of interests: A.U. Wells reports personal fees and other from Roche, Boehringer Ingelheim and Bayer, outside the submitted work., (Copyright ©The authors 2021.)

Rationale: The pathophysiology of interstitial lung disease (ILD) impacts body composition, whereby ILD severity is linked to lower lean mass., Objectives: To determine i) if pectoralis muscle area (PMA) is a surrogate for whole-body lean mass in ILD, ii) whether PMA is associated with ILD severity, and iii) if the longitudinal change in PMA is associated with pulmonary function and mortality in ILD., Methods: Patients with ILD (n = 164) were analyzed retrospectively. PMA was quantified from a chest computed tomography scan. Peripheral oxygen saturation (SpO 2 ), 6-min walk distance (6MWD), and pulmonary function were obtained as part of routine clinical care. Dyspnea and quality of life were assessed using the UCSD Shortness of Breath Questionnaire and European Quality of Life 5 Dimensions questionnaire, respectively., Results: PMA was associated with whole-body lean mass (p < 0.001). After adjusting for age, sex, height, body mass, and prednisone status, PMA was associated with %-predicted forced vital capacity (FVC), %-predicted diffusion capacity (DL CO ), resting and exertional SpO 2 , and dyspnea (all p < 0.05), but not forced expiratory volume in 1 s (FEV 1 ), FEV 1 /FVC, 6MWD, or quality of life (all p > 0.05). The annual negative PMA slope was associated with annual negative slopes in FVC, FEV 1 , and DL CO (all p < 0.05), but not FEV 1 /FVC (p = 0.46). Annual slope in PMA was associated with all-cause mortality (hazard ratio = -0.80, 95% CI:0.889-0.959; p < 0.001)., Conclusion: In patients with ILD, PMA is a suitable surrogate for whole-body lean mass. A lower PMA is associated with indices of ILD severity, which supports the notion that ILD progression may involve sarcopenia., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Rationale: The University of California, San Diego Shortness of Breath Questionnaire (UCSDSOBQ) is a frequently used domain-specific dyspnea questionnaire; however, there is little information available regarding its use and minimum important difference (MID) in fibrotic interstitial lung disease (ILD). We aimed to describe the key performance characteristics of the UCSDSOBQ in this population., Methods: UCSDSOBQ scores and selected anchors were measured in 1933 patients from the prospective multi-center Canadian Registry for Pulmonary Fibrosis. Anchors included the St. George's Respiratory Questionnaire (SGRQ), European Quality of Life 5 Dimensions 5 Levels questionnaire (EQ-5D-5L) and EQ visual analogue scale (EQ-VAS), percent-predicted forced vital capacity (FVC%), diffusing capacity of the lung for carbon monoxide (DLCO%), and 6-min walk distance (6MWD). Concurrent validity, internal consistency, ceiling and floor effects, and responsiveness were assessed, followed by estimation of the MID by anchor-based (linear regression) and distribution-based methods (standard error of measurement)., Results: The UCSDSOBQ had a high level of internal consistency (Cronbach's alpha = 0.97), no obvious floor or ceiling effect, strong correlations with SGRQ, EQ-5D-5L, and EQ-VAS (|r| > 0.5), and moderate correlations with FVC%, DLCO%, and 6MWD (0.3 < |r| < 0.5). The MID estimate for UCSDSOBQ was 5 points (1-8) for the anchor-based method, and 4.5 points for the distribution-based method., Conclusion: This study demonstrates the validity of UCSDSOBQ in a large and heterogeneous population of patients with fibrotic ILD, and provides a robust MID estimate of 5-8 points.

Background: Patients use Facebook as a resource for medical information. We analyzed posts on idiopathic pulmonary fibrosis (IPF)-related Facebook groups and pages for the presence of guideline content, user engagement, and usefulness., Objective: The objective of this study was to describe and analyze posts from Facebook groups and pages that primarily focus on IPF-related content., Methods: Cross-sectional analysis was performed on a single date, identifying Facebook groups and pages resulting from separately searching "IPF" and "idiopathic pulmonary fibrosis." For inclusion, groups and pages needed to meet either search term and be in English, publicly available, and relevant to IPF. Every 10th post was assessed for general characteristics, source, focus, and user engagement metrics. Posts were analyzed for presence of IPF guideline content, useful scientific information (eg, scientific publications), useful support information (eg, information about support groups), and potentially harmful information., Results: Eligibility criteria were met by 12 groups and 27 pages, leading to analysis of 523 posts. Of these, 42% contained guideline content, 24% provided useful support, 20% provided useful scientific information, and 5% contained potentially harmful information. The most common post source was nonmedical users (85%). Posts most frequently focused on IPF-related news (29%). Posts containing any guideline content had fewer likes or comments and a higher likelihood of containing potentially harmful content. Posts containing useful supportive information had more likes, shares, and comments., Conclusions: Facebook contains useful information about IPF, but posts with misinformation and less guideline content have higher user engagement, making them more visible. Identifying ways to help patients with IPF discriminate between useful and harmful information on Facebook and other social media platforms is an important task for health care professionals., (©Andrew Kochan, Shaun Ong, Sabina Guler, Kerri A Johannson, Christopher J Ryerson, Gillian C Goobie. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 31.05.2021.)

Background: The transition from normal lung anatomy to minimal and established fibrosis is an important feature of the pathology of idiopathic pulmonary fibrosis (IPF). The purpose of this report is to examine the molecular and cellular mechanisms associated with this transition., Methods: Pre-operative thoracic Multidetector Computed Tomography (MDCT) scans of patients with severe IPF (n = 9) were used to identify regions of minimal(n = 27) and established fibrosis(n = 27). MDCT, Micro-CT, quantitative histology, and next-generation sequencing were used to compare 24 samples from donor controls (n = 4) to minimal and established fibrosis samples., Findings: The present results extended earlier reports about the transition from normal lung anatomy to minimal and established fibrosis by showing that there are activations of TGFBI, T cell co-stimulatory genes, and the down-regulation of inhibitory immune-checkpoint genes compared to controls. The expression patterns of these genes indicated activation of a field immune response, which is further supported by the increased infiltration of inflammatory immune cells dominated by lymphocytes that are capable of forming lymphoid follicles. Moreover, fibrosis pathways, mucin secretion, surfactant, TLRs, and cytokine storm-related genes also participate in the transitions from normal lung anatomy to minimal and established fibrosis., Interpretation: The transition from normal lung anatomy to minimal and established fibrosis is associated with genes that are involved in the tissue repair processes, the activation of immune responses as well as the increased infiltration of CD4, CD8, B cell lymphocytes, and macrophages. These molecular and cellular events correlate with the development of structural abnormality of IPF and probably contribute to its pathogenesis., Competing Interests: Declaration of Competing Interest All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Dyspnoea is a cardinal symptom of fibrotic interstitial lung disease (ILD), with a lack of proven effective therapies. With emerging evidence of the role of facial and nasal airflow for relieving breathlessness, this pilot study was conducted to examine the feasibility of conducting a clinical trial of a handheld fan (HHF) for dyspnoea management in patients with fibrotic ILD. In this mixed-methods, randomised, assessor-blinded, controlled trial, 30 participants with fibrotic ILD who were dyspnoeic with a modified Medical Research Council Dyspnoea grade ≥ 2 were randomised to a HHF for symptom control or no intervention for 2 weeks. Primary outcomes were trial feasibility, change in Dyspnoea-12 scores at Week 2, and participants' perspectives on using a HHF for dyspnoea management. Study recruitment was completed within nine months at a single site. Successful assessor blinding was achieved in the fan group [Bang's Blinding Index - 0.08 (95% CI - 0.45, 0.30)] but not the control group [0.47 (0.12, 0.81)]. There were no significant between-group differences for the change in Dyspnoea-12 or secondary efficacy outcomes. During qualitative interviews, participants reported that using the HHF relieved breathlessness and provided relaxation, despite initial scepticism about its therapeutic benefit. Oxygen-experienced participants described the HHF being easier to use, but not as effective for symptomatic relief, compared to oxygen therapy. Our results confirmed the feasibility of a clinical trial of a HHF in fibrotic ILD. There was a high level of patient acceptance of a HHF for managing dyspnoea, with patients reporting both symptomatic benefits and ease of use.

Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure greater than 20 mm Hg and classified into five different groups sharing similar pathophysiologic mechanisms, hemodynamic characteristics, and therapeutic management. Radiologists play a key role in the multidisciplinary assessment and management of PH. A working group was formed from within the Fleischner Society based on expertise in the imaging and/or management of patients with PH, as well as experience with methodologies of systematic reviews. The working group identified key questions focusing on the utility of CT, MRI, and nuclear medicine in the evaluation of PH: (a) Is noninvasive imaging capable of identifying PH? (b) What is the role of imaging in establishing the cause of PH? (c) How does imaging determine the severity and complications of PH? (d) How should imaging be used to assess chronic thromboembolic PH before treatment? (e) Should imaging be performed after treatment of PH? This systematic review and position paper highlights the key role of imaging in the recognition, work-up, treatment planning, and follow-up of PH. This article is a simultaneous joint publication in Radiology and European Respiratory Journal . The articles are identical except for stylistic changes in keeping with each journal's style. Either version may be used in citing this article. © 2021 RSNA and the European Respiratory Society. Online supplemental material is available for this article.

Use of molecular targeting agents and immune checkpoint inhibitors (ICIs) has increased the frequency and broadened the spectrum of lung toxicity, particularly in patients with cancer. The diagnosis of drug-related pneumonitis (DRP) is usually achieved by excluding other potential known causes. Awareness of the incidence and risk factors for DRP is becoming increasingly important. The severity of symptoms associated with DRP may range from mild or none to life-threatening with rapid progression to death. Imaging features of DRP should be assessed in consideration of the distribution of lung parenchymal abnormalities (radiologic pattern approach). The CT patterns reflect acute (diffuse alveolar damage) interstitial pneumonia and transient (simple pulmonary eosinophilia) lung abnormality, subacute interstitial disease (organizing pneumonia and hypersensitivity pneumonitis), and chronic interstitial disease (nonspecific interstitial pneumonia). A single drug can be associated with multiple radiologic patterns. Treatment of a patient suspected of having DRP generally consists of drug discontinuation, immunosuppressive therapy, or both, along with supportive measures eventually including supplemental oxygen and intensive care. In this position paper, the authors provide diagnostic criteria and management recommendations for DRP that should be of interest to radiologists, clinicians, clinical trialists, and trial sponsors, among others. This article is a simultaneous joint publication in Radiology and CHEST . The articles are identical except for stylistic changes in keeping with each journal's style. Either version may be used in citing this article. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Background: Frailty is a state of increased vulnerability to various health stressors but little information is summarized about frailty in patients with specific chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and asthma., Objective: We aimed to describe the burden of frailty on patients with chronic respiratory disorders and to discuss the need for multidisciplinary care services., Methods: PubMed and Cochrane Central databases were systematically reviewed for studies reporting outcomes associated with frailty in COPD, IPF, and asthma. Electronic databases were searched for relevant articles published in English from 2010 up to July 2020. Appraisal was carried out based on the Hierarchy of Evidence Rating System and the GRADE guidelines., Results: A total of 31 articles met all inclusion criteria with 24 of them at level IV, 1 at level V, and 6 at level VI. Frailty is likely to negatively affect quality of life and to increase the risk of mortality, especially in elderly with COPD, IPF and asthma. Each disease has a particular effect on the balance between health status, respiratory impairment and frailty. A greater understanding of frailty phenotype across different ages, as well as in a range of long-term conditions, is of great necessity in both clinical and research settings. Limited conformity was observed between different methodologies and nature of chronic diseases studied, leading to a further difficulty to extract homogeneous information., Conclusion: Literature shows that frailty is prevalent in COPD, IPF, and asthma, after adjusting for shared risk factors. Our findings suggest that frailty should be approached as an entity per se', in order to assess real mortality risk, alongside respiratory disease severity and the presence of comorbidities. Health care professionals need knowledge, skills and multidisciplinary collaboration to buffer the impact of frailty on everyday practice., Competing Interests: EKS conceived the study idea, invited team members and offered a guidance to search topic. AK performed the literature search and composed results section by appraising findings for the studies included. AK and EKS cross-checked the emerged literature information. KA critically reviewed literature information and offered clinical input when this was necessary. AK, EKS and KA contributed to the first draft preparation. ED and CJR offered intellectual input and contributed in the draft writing and revision based on the field of their expertise. All authors read and approved final manuscriptWe would like to thank Professor Jeffrey J. Swigris for his intellectual input and advice during writing the first draft.Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article., (Copyright: © 2021 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)