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Purpose of Review: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a poor prognosis and limited therapeutic options. A multitude of promising compounds are currently being investigated; however, the design and conductance of late-phase clinical trials in IPF has proven particularly challenging., Recent Findings: Despite promising phase 2 data, ziritaxestat, an autotaxin inhibitor, pentraxin-2, an endogenous protein that regulates wound healing and fibrosis, and pamrevlumab, a human monoclonal antibody against connective tissue growth factor, failed to show efficacy in phase 3 trials. Endpoint selection is critical for the design, execution, and success of clinical trials; recently, attention has been paid to the assessment of how patients feel, function, and survive with the aim of aligning scientific objectives and patient needs in IPF. External control arms are control patients that derive from historical randomized controlled trials, registries, or electronic health records. They are increasingly used to assess treatment efficacy in clinical trials owing to their potential to reduce study duration and cost and increase generalizability of findings., Summary: Advances in study design, end point selection and statistical analysis, and innovative strategies for more efficient enrolment of study participants have the potential to increase the likelihood of success of late-phase clinical trials in IPF., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Depending on local cues, macrophages can polarize into classically activated (M1) or alternatively activated (M2) phenotypes. This study investigates the impact of polarized macrophage-derived Extracellular Vesicles (EVs) (M1 and M2) and their cargo of miRNA-19a-3p and miRNA-425-5p on TGF-β production in lung fibroblasts. EVs were isolated from supernatants of M0, M1, and M2 macrophages and quantified using nanoscale flow cytometry prior to fibroblast stimulation. The concentration of TGF-β in fibroblast supernatants was measured using ELISA assays. The expression levels of miRNA-19a-3p and miRNA-425-5p were assessed via TaqMan-qPCR. TGF-β production after stimulation with M0-derived EVs and with M1-derived EVs increased significantly compared to untreated fibroblasts. miRNA-425-5p, but not miRNA-19a-3p, was significantly upregulated in M2-derived EVs compared to M0- and M1-derived EVs. This study demonstrates that EVs derived from both M0 and M1 polarized macrophages induce the production of TGF-β in fibroblasts, with potential regulation by miRNA-425-5p.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease of unknown cause with a dismal prognosis. Nintedanib and Pirfenidone are approved worldwide for the treatment of IPF, but they only slow the rate of functional decline and disease progression. Therefore, there is an urgent need for more efficacious and better tolerated drugs., Areas Covered: αvβ6 and αvβ1 are two integrins overexpressed in fibrotic tissue, which play a critical role in the development of lung fibrosis. They act by converting transforming growth factor (TGF)-β, one of the most important profibrotic cytokine, in its active form. Here, we summarize and critically discuss the potential of a dual αvβ6/αvβ1 integrin inhibitor for the treatment of IPF., Expert Opinion: Bexotegrast, a dual αvβ6/αvβ1 integrin inhibitor, has the potential to slow or even halt disease progression in IPF. Indeed, the strong pre-clinical rationale and promising early phase clinical trial data have raised expectations.

The present review provides a comprehensive examination of the intricate dynamics between α-synuclein, a protein crucially involved in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease and multiple system atrophy, and endogenously-produced bioactive lipids, which play a pivotal role in neuroinflammation and neurodegeneration. The interaction of α-synuclein with bioactive lipids is emerging as a critical factor in the development and progression of neurodegenerative and neuroinflammatory diseases, offering new insights into disease mechanisms and novel perspectives in the identification of potential biomarkers and therapeutic targets. We delve into the molecular pathways through which α-synuclein interacts with biological membranes and bioactive lipids, influencing the aggregation of α-synuclein and triggering neuroinflammatory responses, highlighting the potential of bioactive lipids as biomarkers for early disease detection and progression monitoring. Moreover, we explore innovative therapeutic strategies aimed at modulating the interaction between α-synuclein and bioactive lipids, including the development of small molecules and nutritional interventions. Finally, the review addresses the significance of the gut-to-brain axis in mediating the effects of bioactive lipids on α-synuclein pathology and discusses the role of altered gut lipid metabolism and microbiota composition in neuroinflammation and neurodegeneration. The present review aims to underscore the potential of targeting α-synuclein-lipid interactions as a multifaceted approach for the detection and treatment of neurodegenerative and neuroinflammatory diseases.

Sarcoidosis is a granulomatous multiorgan disease, thought to result from exposure to yet unidentified antigens in genetically susceptible individuals. The exaggerated inflammatory response that leads to granuloma formation is highly complex and involves the innate and adaptive immune system. Consecutive immunological studies using advanced technology have increased our understanding of aberrantly activated immune cells, mediators and pathways that influence the formation, maintenance and resolution of granulomas. Over the years, it has become increasingly clear that disease immunopathogenesis can only be understood if the clinical heterogeneity of sarcoidosis is taken into consideration, along with the distribution of immune cells in peripheral blood and involved organs. Most studies offer an immunological snapshot during disease course, while the cellular composition of both the circulation and tissue microenvironment may change over time. Despite these challenges, novel insights on the role of the immune system are continuously published, thus bringing the field forward. This review highlights current knowledge on the innate and adaptive immune responses involved in sarcoidosis pathogenesis, as well as the pathways involved in non-resolving disease and fibrosis development. Additionally, we describe proposed immunological mechanisms responsible for drug-induced sarcoid like reactions. Although many aspects of disease immunopathogenesis remain to be unraveled, the identification of crucial immune reactions in sarcoidosis may help identify new treatment targets. We therefore also discuss potential therapies and future strategies based on the latest immunological findings., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

One view of sarcoidosis is that the term covers many different diseases. However, no classification framework exists for the future exploration of pathogenetic pathways, genetic or trigger predilections, patterns of lung function impairment, or treatment separations, or for the development of diagnostic algorithms or relevant outcome measures. We aimed to establish agreement on high-resolution CT (HRCT) phenotypic separations in sarcoidosis to anchor future CT research through a multinational two-round Delphi consensus process. Delphi participants included members of the Fleischner Society and the World Association of Sarcoidosis and other Granulomatous Disorders, as well as members' nominees. 146 individuals (98 chest physicians, 48 thoracic radiologists) from 28 countries took part, 144 of whom completed both Delphi rounds. After rating of 35 Delphi statements on a five-point Likert scale, consensus was achieved for 22 (63%) statements. There was 97% agreement on the existence of distinct HRCT phenotypes, with seven HRCT phenotypes that were categorised by participants as non-fibrotic or likely to be fibrotic. The international consensus reached in this Delphi exercise justifies the formulation of a CT classification as a basis for the possible definition of separate diseases. Further refinement of phenotypes with rapidly achievable CT studies is now needed to underpin the development of a formal classification of sarcoidosis., Competing Interests: Declaration of interests SRD has received consulting fees for participation as an external expert steering committee member for a phase 3b/4 trial of trastuzumab deruxtecan in stage IV breast cancer from AstraZeneca and honoraria for travel expenses and for tutoring on radiology masterclasses in interstitial lung disease (ILD) from Boehringer Ingelheim; he is a co-founder and clinical director of, and holds shares in, DMC Radiology Reporting (an outsourcing, teleradiology company with no research or commercial interest in sarcoidosis). NSi has received honoraria for lectures from the World Association of Sarcoidosis and other Granulomatous Disorders (WASOG), Associazione Polo Italia-Cina, and Boehringer Ingelheim. KAJ has received grants from Three Lakes Foundation, the Chest Foundation, the University of Calgary Cumming School of Medicine, and the University Hospital Foundation (affiliated with the University of Alberta), consulting fees from Boehringer Ingelheim, Hoffman-La Roche, Pliant Therapeutics, Three Lakes Foundation, and Thyron SAB, and honoraria for lectures from Boehringer Ingelheim and Hoffman-La Roche; she has participated on the data safety monitoring board (DSMB) for the Ambulatory Oxygen for Treatment of Exertional Hypoxaemia in Pulmonary Fibrosis (PFOX) trial (no payment received). PMG has received grants from Boehringer Ingelheim, speaker's fees from Boehringer Ingelheim, Roche, Teva, Cipla, and Brainomix, and travel support from Boehringer Ingelheim and Roche; he is a medical director of, and holds stock options in, Brainomix (a company that develops artificial intelligence-powered imaging technologies unrelated to the submitted work). DAC has received grants from Boehringer Ingelheim, the Ann Theodore Foundation, the Foundation for Sarcoidosis Research, and aTyr, consulting fees from Kinevant and CSL Behring, and travel support from Roche. AD has received consulting fees from Boehringer Ingelheim, Roche, Brainomix, and Vicore; he is a medical director of, and holds stock options in, Brainomix. DAL has received consulting fees from Calyx and has participated on the advisory board for Boehringer Ingelheim. ER has received grants from Boehringer Ingelheim, honoraria for lectures from Boehringer Ingelheim and Chiesi, and travel support from Boehringer Ingelheim; she has participated on advisory boards for Boehringer Ingelheim and Roche. PS has received grants from PPM Services, Boehringer Ingelheim, and Roche, consulting fees from Novartis, Behring, PPM Services, Pieris, and GlycoCore, honoraria for lectures from Chiesi, Boehringer Ingelheim, and Menarini, support for attending meetings from PPM Services and Boehringer Ingelheim, and fees for participation on a DSMB or advisory board from Galapagos, Pieris, Boehringer Ingelheim, and Novartis, all outside of the submitted work. RPB has received grants from aTyr, Mallinckroft, Bellephron, Genentech, Actelion, and the Foundation for Sarcoidosis Research, consulting fees from aTyr, Kinevent, Bellephron, and the Millikin Center, and speaker's fees for lectures on sarcoidosis and other ILDs from Boehringer Ingelheim, Mallinckrodt, and United Therapeutics. SLFW has received grants from Boehringer Ingelheim and Galapagos, consulting fees from Boehringer Ingelheim, Roche, Galapagos, the Open Source Imaging Consortium, Puretech, Pliant, Oncorendi Therapeutics, and FLUIDDA, and honoraria for lectures and for developing educational material from Boehringer Ingelheim; he has participated on advisory boards for Boehringer Ingelheim and Roche. VK has received speaker's fees from Boehringer Ingelheim and Novartis. AUW has received consulting fees from Roche and Veracyte, and honoraria for lectures and presentations from Boehringer Ingelheim, Roche, and Veracyte; he is the president of the WASOG. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The pathologic diagnosis of pleural mesothelioma is generally based on international guidelines, but no compulsory points based on different drugs approvals in different European countries are required to be reported. According to the last (2021) edition of the World Health Organization classification of pleural tumors, the nuclear grade of epithelioid-type mesothelioma should be always inserted in the pathologic report, while the presence of BRCA-associated protein-1 (BAP1) (clone C4) loss and a statement on the presence of the sarcomatoid/nonepithelioid component are fundamental for both a screening of patients with suspected BAP1 tumor predisposition syndrome and the eligibility to perform first-line immunotherapy at least in some countries. Several Italian experts on pleural mesothelioma who are deeply involved in national scientific societies or dedicated working groups supported by patient associations agreed that the pathology report of mesothelioma of the pleura should always include the nuclear grade in the epithelioid histology, which is an overt statement on the presence of sarcomatoid components (at least 1%, in agreement with the last classification of pleural mesothelioma) and the presence of BAP1 loss (BAP1-deficient mesothelioma) or not (BAP1-retained mesothelioma) in order to screen patients possibly harboring BAP1 tumor predisposition syndrome. This review aims to summarize the most recent data on these three important elements to provide evidence regarding the possible precision needs for mesothelioma.

This article summarises a selection of scientific highlights in the field of interstitial lung diseases (ILDs) presented at the International Congress of the European Respiratory Society in 2023. Translational and clinical studies focused on the whole spectrum of ILDs, from (ultra)rare ILDs to sarcoidosis, ILDs associated with connective tissue disease and idiopathic pulmonary fibrosis. The main topics of the 2023 Congress presentations were improving the diagnostic process of ILDs, better prediction of disease course and investigation of novel treatment options., Competing Interests: Conflict of interest: L. Fabbri, J. Guiot and E. Bargagli have nothing to disclose. Conflict of interest: M. Vermant reports travel fees from Sanofi, outside the submitted work. Conflict of interest: E. Miądlikowska reports travel fees from Boehringer Ingelheim, outside the submitted work. Conflict of interest: D. Estrella reports travel fees from Sanofi and Roche/Genentech outside the submitted work. Conflict of interest: M.S. Wijsenbeek reports grants from Boehringer Ingelheim and Hoffmann la Roche, and fees from Bristol Myers Squibb, Boehringer Ingelheim, Galapagos, Galecto, Hoffman la Roche, Horizon Therapeutics, Kinevant Sciences, Molecure, Nerre Therapeutics, Novartis, PureTech Health, Respivant and CSL Behring, outside the submitted work, paid to her institution. Conflict of interest: W. Wuyts reports grants and fees from Boehringer Ingelheim, Hoffman la Roche, Galapagos and Sanofi, outside the submitted work, paid to his institution. Conflict of interest: A. Froidure reports grants and fees from Boehringer Ingelheim. Conflict of interest: P. Spagnolo reports grants from PPM Services, Roche and Boehringer Ingelheim, outside the submitted work, paid to his institution; and fees from PPM Services, Novartis, Pieris, Glycocore Pharma, Galapagos, Boehringer Ingelheim and Menarini outside the submitted work. Conflict of interest: M. Veltkamp reports fees from Boehringer Ingelheim and Chiesi outside the submitted work. Conflict of interest: M. Molina-Molina reports grants and fees from Boehringer Ingelheim, Roche, Chiesi and Ferrer, outside the submitted work. Conflict of interest: C. McCarthy reports grants and fees from Boehringer Ingelheim, Savara Inc., AI Therapeutics and Theravance Inc., outside the submitted work. Conflict of interest: K. Antoniou reports grants and fees from Boehringer Ingelheim, Hoffmann la Roche, GlaxoSmithKline, AstraZeneca, Chiesi and Menarini outside the submitted work. Conflict of interest: M. Kreuter reports grants and fees from Boehringer Ingelheim, Hoffman la Roche and Nichtraucherhelden/Sanero outside the submitted work. Conflict of interest: C.C. Moor reports grants and fees from Boehringer Ingelheim, Hoffmann la Roche, AstraZeneca and Daiichi Sankyo, outside the submitted work, paid to her institution., (Copyright ©The authors 2024.)

Background: The family of Suppressor of Cytokine Signaling (SOCS) acts as a controller of the duration and intensity of cytokine function by negatively regulating the JAK-STAT signaling pathway. SOCS' role in inflammatory diseases in animal models is well demonstrated. However, its role in the development of human disease is still under investigation. SOCS3 plays an important role in tumor development where its downregulation has been implicated in the pathogenesis of various solid tumors such as triple-negative breast cancer., Aim: The aim of this work was to study (1) the expression of SOCS3 in smokers' lungs and its relation to the degree of inflammation and (2) SOCS3 regulation by microRNA (miRNA) in alveolar-macrophage (AM)-derived extracellular vesicles (EVs) in bronchoalveolar lavage (BAL)., Methods: Group A: 35 smokers' [19 with COPD (SC) and 16 without COPD (S)] and 9 nonsmokers (NS); SOCS3, TNFα in AM, and CD8 + T cells were quantified by immunohistochemistry, in lung tissue. Group B: additional 9 SC, 11 S, and 5 NS; AM-EVs expressing SOCS3 (CD14 + SOCS3 + ) and SOCS3 suppressors miRNA-19a-3p and 221-3p in EVs were quantified by flow cytometry and PCR, in BAL., Results: The percentage of SOCS3 + AM was higher in SC [68 (6.6-99)%] and S [48 (8-100)%] than in NS [9.6 (1.9-61)%; p = 0.002; p = 0.03] and correlated with % of TNFα + AM ( r = 0.48; p = 0.0009) and CD8 + T cells ( r = 0.44; p = 0.0029). In BAL, the CD14 + SOCS3 + EVs/μL were increased in SC [33 (21-74)] compared to S [16 (8-37); p = 0.03] and NS [9 (7-21); p = 0.003]. Conversely, miRNA-19a-3p and miRNA-221-3p expression were increased in S when compared to SC [19 (2-53) vs . 3 (0.6-8); p = 0.03 and 3 (0.005-9.6) vs . 0.2 (0.08-0.7); p = 0.05]., Conclusions: The suppressor function of SOCS3 in COPD seems to be overridden by other factors and does not follow the animal-model paradigm. Expression of SOCS3 in BAL macrophage-derived EVs might be useful to assess the degree of inflammation and possible progression of COPD. Downregulation of SOCS3, by miRNA, in smokers without COPD might contribute to the risk of developing cancer in these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tinè, Balestro, Carpi, Neri, Biondini, Conti, Casara, Bernardinello, Cocconcelli, Turato, Baraldo, Celi, Spagnolo, Cosio, Saetta and Bazzan.)

Although sarcoidosis is generally regarded as a benign condition, approximately 20-30% of patients will develop a chronic and progressive disease. Advanced pulmonary fibrotic sarcoidosis and cardiac involvement are the main contributors to sarcoidosis morbidity and mortality, with failure of the liver and/or kidneys representing additional life-threatening situations. In this review, we discuss diagnosis and treatment of each of these complications and highlight how the integration of clinical, pathological and radiological features may help predict the development of such high-risk situations in sarcoid patients.

Background: There is no standard definition of respiratory-related hospitalisation, a common end-point in idiopathic pulmonary fibrosis (IPF) clinical trials. As diverse aetiologies and complicating comorbidities can present similarly, external adjudication is sometimes employed to achieve standardisation of these events., Methods: An algorithm for respiratory-related hospitalisation was developed through a literature review of IPF clinical trials with respiratory-related hospitalisation as an end-point. Experts reviewed the algorithm until a consensus was reached. The algorithm was validated using data from the phase 3 ISABELA trials (clinicaltrials.gov identifiers NCT03711162 and NCT03733444), by assessing concordance between nonadjudicated, investigator-defined, respiratory-related hospitalisations and those defined by the adjudication committee using the algorithm., Results: The algorithm classifies respiratory-related hospitalisation according to cause: extraparenchymal (worsening respiratory symptoms due to left heart failure, volume overload, pulmonary embolism, pneumothorax or trauma); other (respiratory tract infection, right heart failure or exacerbation of COPD); "definite" acute exacerbation of IPF (AEIPF) (worsening respiratory symptoms within 1 month, with radiological or histological evidence of diffuse alveolar damage); or "suspected" AEIPF (as for "definite" AEIPF, but with no radiological or histological evidence of diffuse alveolar damage). Exacerbations ("definite" or "suspected") with identified triggers (infective, post-procedural or traumatic, drug toxicity- or aspiration-related) are classed as "known AEIPF"; "idiopathic AEIPF" refers to exacerbations with no identified trigger. In the ISABELA programme, there was 94% concordance between investigator- and adjudication committee-determined causes of respiratory-related hospitalisation., Conclusion: The algorithm could help to ensure consistency in the reporting of respiratory-related hospitalisation in IPF trials, optimising its utility as an end-point., Competing Interests: Conflict of interest: P. Ford and N. Prasad are former employees of, and have received warrants from, Galapagos. Conflict of interest: M. Kreuter reports grants and personal fees from Galapagos during the conduct of the study, and grants and personal fees from Boehringer Ingelheim and Roche outside the submitted work. Conflict of interest: K.K. Brown reports support from the National Heart, Lung, and Blood Institute; participation on a Scientific Advisory Board/work as an external science advisor for Blade Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, DevPro Biopharma, Eleven P15, Galapagos, Galecto, Huitai Biomedicine, Open Source Imaging, Pliant, RedxPharma and Sanofi; participation on a data monitoring committee for Biogen and Humanetics; and work in a leadership or fiduciary role for the Fleischner Society and the Open Source Imaging Consortium. Conflict of interest: W.A. Wuyts reports no personal fees; the University Hospitals Leuven received consultancy fees from Galapagos during the conduct of the study, and grants from Boehringer Ingelheim and Roche outside the submitted work. Conflict of interest: M. Wijsenbeek reports no personal fees; the Erasmus MC received consultancy fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Galapagos, Galecto, Hoffmann-La Roche, Horizon Therapeutics, Kinevant Sciences, Molecure, NeRRe Therapeutics, Novartis, PureTech Health, Thyron and Vicore; and grants from AstraZeneca/Daiichi Sankyo, Boehringer Ingelheim and Hoffmann-La Roche outside the submitted work. The Erasmus MC received speaker fees from Boehringer Ingelheim, CSL Behring and Hoffmann-La Roche outside the submitted work. Conflict of interest: D. Israël-Biet reports speaker and advisory board fees from Boehringer Ingelheim. Conflict of interest: R. Hubbard reports consulting fees from Galapagos. Conflict of interest: S.D. Nathan reports consulting fees from Bellerophon, Boehringer Ingelheim, Galapagos, Roche-Genentech and United Therapeutics. He is on the speakers’ bureau for Boehringer Ingelheim, Roche-Genentech and United Therapeutics. Conflict of interest: H. Nunes reports consulting fees from Galapagos during the conduct of the study, and consulting fees from Boehringer Ingelheim and Roche-Genentech. Conflict of interest: B. Penninckx is a former consultant to Galapagos. Conflict of interest: I. Seghers is a former employee of Galapagos. Conflict of interest: N. Verbruggen is an employee of Galapagos. Conflict of interest: P. Spagnolo reports consulting fees from Behring, Chiesi, Galapagos (during the conduct of this study), Glycocore, Lupin, Novartis, Pieris and PPM services, and institutional grants from Boehringer Ingelheim, PPM services and Roche outside the submitted work. Conflict of interest: N. Hirani reports no personal fees; the University of Edinburgh received fees from Boehringer Ingelheim, Galapagos, Guidepoint Global and Roche for consultancy and advisory work on behalf of Dr Hirani. The University of Edinburgh and NHS Lothian R&D have received grants and donations from Boehringer Ingelheim, Galecto, Indalo, Roche and UCB on behalf of Dr Hirani. No consultancies or grants are directly related to the submitted work. Conflict of interest: J. Behr reports personal fees from Galapagos during the conduct of the study, and consultation or advisory fees from AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Pliant, Roche and Sanofi/Genzyme; funding or grants from Boehringer Ingelheim; speaking and lecture fees from AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Ferrer, Novartis, Pliant, Roche and Sanofi/Genzyme; and travel reimbursement from Boehringer Ingelheim, Ferrer and Roche outside the submitted work. Conflict of interest: R.J. Kaner reports personal fees from Galapagos during the conduct of the study, and grants from Afferent, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi Pillar, CSL Behring, Genentech, National Institutes of Health, Pulmonary Fibrosis Foundation, Respivant and Toray, and personal fees from Boehringer Ingelheim, Genentech, Gilead, Medimmune, The France Foundation and United Therapeutics outside the submitted work. Conflict of interest: T.M. Maher, via his institution, has received industry-academic funding from AstraZeneca and GlaxoSmithKline R&D, and consultation or advisory fees from AstraZeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Fibrogen, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Pliant, Roche, Trevi and Veracyte., (Copyright ©The authors 2024.)

Systemic sclerosis (SSc) is a heterogeneous autoimmune disease, where a significant proportion of patients develop interstitial lung disease (ILD), which is the major cause of mortality. In recent years, the diagnosis of SSc-ILD has improved a lot, and caring rheumatologists, together with pulmonologists, regularly screen and follow the development and course of ILD. Considerable progress has also been made in the treatment of SSc-ILD based on several clinical trials. The recommendations for immunosuppressive treatment have been modified and supplemented with targeted agents (tocilizumab, rituximab), and antifibrotic drugs such as nintedanib registered as a new treatment for SSc-ILD. However, there are no clear recommendations regarding the start and timing of nintedanib treatment. A debate on the early introduction of nintenadib or not took place on the 7th edition of the International Congress on Controversies in Rheumatology and Autoimmunity (CORA) in March/2023, and this review summarizes the main arguments that were discussed in this session., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paolo Spagnolo reports a relationship with Boehringer Ingelheim Pharmaceuticals Inc. that includes: board membership, consulting or advisory, funding grants, and speaking and lecture fees. Paolo Spagnolo reports a relationship with PPM Services SA that includes: consulting or advisory, funding grants, and travel reimbursement. Paolo Spagnolo reports a relationship with Novartis that includes: board membership and consulting or advisory. Paolo Spagnolo reports a relationship with Roche that includes: funding grants. Paolo Spagnolo reports a relationship with CSL Behring LLC that includes: board membership. Paolo Spagnolo reports a relationship with Pieris Pharmaceuticals Inc. that includes: consulting or advisory. Paolo Spagnolo reports a relationship with A Menarini International Pharmaceutics that includes: speaking and lecture fees. Paolo Spagnolo reports a relationship with Galapagos that includes: board membership and consulting or advisory. Paolo Spagnolo reports a relationship with Chiesi Pharmaceuticals Inc. that includes: speaking and lecture fees. Elisabetta Zanatta reports a relationship with Boehringer Ingelheim Pharmaceuticals Inc. that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Gabriella Szucs reports a relationship with Boehringer Ingelheim Pharmaceuticals Inc. that includes: speaking and lecture fees., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Childhood interstitial lung disease (chILD) is a large and heterogeneous group of disorders characterized by diffuse lung parenchymal markings on chest imaging and clinical signs such as dyspnea and hypoxemia from functional impairment. While some children already present in the neonatal period with interstitial lung disease (ILD), others develop ILD during their childhood and adolescence. A timely and accurate diagnosis is essential to gauge treatment and improve prognosis. Supportive care can reduce symptoms and positively influence patients' quality of life; however, there is no cure for many of the chILDs. Current therapeutic options include anti-inflammatory or immunosuppressive drugs. Due to the rarity of the conditions and paucity of research in this field, most treatments are empirical and based on case series, and less than a handful of small, randomized trials have been conducted thus far. A trial on hydroxychloroquine yielded good safety but a much smaller effect size than anticipated. A trial in fibrotic disease with the multitargeted tyrosine kinase inhibitor nintedanib showed similar pharmacokinetics and safety as in adults. The unmet need for the treatment of chILDs remains high. This article summarizes current treatments and explores potential therapeutic options for patients suffering from chILD., (© 2023. The Author(s).)

Millions of workers are exposed to substances known to cause occupational interstitial lung diseases (ILDs), particularly in developing countries. However, the burden of the disease is likely to be underestimated due to under-recognition, under-reporting or both. The diagnosis of occupational ILD requires a high level of suspicion and a thorough occupational history, as occupational and non-occupational ILDs may be clinically, functionally and radiologically indistinguishable, leading to delayed diagnosis and inappropriate management. A potential occupational aetiology should always be considered in the differential diagnosis of ILD, as removal from the workplace exposure, with or without treatment, is a key therapeutic intervention and may lead to significant improvement. In this article, we provide an overview of the 'traditional' inorganic dust-related ILDs but also address idiopathic pulmonary fibrosis and the immunologically mediated chronic beryllium disease, sarcoidosis and hypersensitivity pneumonitis, with emphasis on the importance of surveillance and prevention for reducing the burden of these conditions. To this end, health-care professionals should be specifically trained about the importance of occupational exposures as a potential cause of ILD., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Idiopathic pulmonary fibrosis (IPF), the most common and severe of the idiopathic interstitial pneumonias, is a chronic and relentlessly progressive disease, which occurs mostly in middle-aged and elderly males. Although IPF is by definition "idiopathic", multiple factors have been reported to increase disease risk, aging being the most prominent one. Several occupational and environmental exposures, including metal dust, wood dust and air pollution, as well as various lifestyle variables, including smoking and diet, have also been associated with an increased risk of IPF, probably through interaction with genetic factors. Many of the predisposing factors appear to act also as trigger for acute exacerbations of the disease, which herald a poor prognosis. The more recent literature on inhalation injuries has focused on the first responders in the World Trade Center attacks and military exposure. In this review, we present an overview of the environmental and occupational causes of IPF and its pathogenesis. While our list is not comprehensive, we have selected specific exposures to highlight based on their overall disease burden.

Competing Interests: Declaration of Competing Interest Authors declare no conflict of interest.

Idiopathic pulmonary fibrosis (IPF) remains a disease with poor survival. The pathogenesis is complex and encompasses multiple molecular pathways. The first-generation antifibrotics pirfenidone and nintedanib, approved more than 10 years ago, have been shown to reduce the rate of progression, increase the length of life for patients with IPF, and work for other fibrotic lung diseases. In the last two decades, most clinical trials on IPF have failed to meet the primary endpoint and an urgent unmet need remains to identify agents or treatment strategies that can stop disease progression. The pharmacotherapeutic landscape for IPF is moving forward with a number of new drugs currently in clinical development, mostly in phase I and II trials, while only a few phase III trials are running. Since our understanding of IPF pathogenesis is still limited, we should keep focusing our efforts to deeper understand the mechanisms underlying this complex disease and their reflection on clinical phenotypes. This review discusses the key pathogenetic concepts for the development of new antifibrotic agents, presents the newest data on approved therapies, and summarizes new compounds currently in clinical development. Finally, future directions in antifibrotics development are discussed., (© 2023. The Author(s).)

Thoracic ultrasound (TUS) has become an essential procedure in respiratory medicine. Due to its intrinsic safety and versatility, it has been applied in patients affected by several respiratory diseases both in intensive care and outpatient settings. TUS can complement and often exceed stethoscope and radiological findings, especially in managing pleural diseases. We hereby aimed to describe the establishment, development, and optimization in a large, tertiary care hospital of a pleural clinic, which is dedicated to the evaluation and monitoring of patients with pleural diseases, including, among others, pleural effusion and/or thickening, pneumothorax and subpleural consolidation. The clinic was initially meant to follow outpatients undergoing medical thoracoscopy. In this scenario, TUS allowed rapid and regular assessment of these patients, promptly diagnosing recurrence of pleural effusion and other complications that could be appropriately managed. Over time, our clinic has rapidly expanded its initial indications thus becoming the place to handle more complex respiratory patients in collaboration with, among others, thoracic surgeons and oncologists. In this article, we critically describe the strengths and pitfalls of our "pleural clinic" and propose an organizational model that results from a synergy between respiratory physicians and other professionals. This model can inspire other healthcare professionals to develop a similar organization based on their local setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Tinè, Daverio, Semenzato, Cocconcelli, Bernardinello, Damin, Saetta, Spagnolo and Balestro.)

Purpose of Review: Genetics contributes substantially to the susceptibility to idiopathic pulmonary fibrosis (IPF). Genetic studies in sporadic and familial disease have identified several IPF-associated variants, mainly in telomere-related and surfactant protein genes.Here, we review the most recent literature on genetics of IPF and discuss how it may contribute to disease pathogenesis., Recent Findings: Recent studies implicate genes involved in telomere maintenance, host defence, cell growth, mammalian target of rapamycin signalling, cell-cell adhesion, regulation of TGF-β signalling and spindle assembly as biological processes involved in the pathogenesis of IPF. Both common and rare genetic variants contribute to the overall risk of IPF; however, while common variants (i.e. polymorphisms) account for most of the heritability of sporadic disease, rare variants (i.e. mutations), mainly in telomere-related genes, are the main contributors to the heritability of familial disease. Genetic factors are likely to also influence disease behaviour and prognosis. Finally, recent data suggest that IPF shares genetic associations - and probably some pathogenetic mechanisms - with other fibrotic lung diseases., Summary: Common and rare genetic variants are associated with susceptibility and prognosis of IPF. However, many of the reported variants fall in noncoding regions of the genome and their relevance to disease pathobiology remains to be elucidated., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Diaphragm ultrasound (DUS) has been extensively used in critically ill patients while data on outpatients with interstitial lung disease (ILD) are limited. We hypothesized that diaphragm function, assessed by ultrasound, could be impaired in patients with ILD, considering both Idiopathic Pulmonary Fibrosis (IPF) and Connective Tissue Disease (CTD-ILD), compared to healthy subjects. Moreover, this impairment could impact clinical and functional parameters., Methods: All consecutive CTD-ILD and IPF patients followed in our center (March-October 2020) were screened. Diaphragm displacement (DD), inspiratory thickness (Ti), expiratory thickness (Te), thickening fraction (TF), and respiratory functional parameters were collected. The prevalence of diaphragmatic dysfunction (TF <30%) was then recorded., Results: Eighty-two consecutive patients (41 CTD-ILD, 41 IPF) and 15 age- and sex-matched controls were enrolled. In the overall population, 24 out of 82 (29%) presented diaphragmatic dysfunction. In CTD-ILD, DD and Ti were lower as compared to IPF (p = 0.021 and p = 0.036, respectively); while diaphragmatic dysfunction was more prevalent compared to controls (37% vs 7%, p = 0.043). TF positively correlated to patients' functional parameters in the CTD-ILD group (FVC%pred: p = 0.003; r = 0.45), while not in the IPF group. Diaphragmatic dysfunction was associated with moderate/severe dyspnea in both CTD-ILD and IPF (p = 0.021)., Conclusion: The prevalence of diaphragmatic dysfunction was 29% in patients with ILD and was associated with moderate/severe dyspnea. CTD-ILD presented lower DD compared with IPF and a higher prevalence of diaphragmatic dysfunction (TF<30%) compared with controls. TF was associated with lung function only in CTD-ILD patients, suggesting its potential role in the comprehensive patient assessment., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Patients with connective tissue diseases can develop interstitial lung disease (ILD), leading to a progressive fibrosing ILD (PF-ILD) phenotype in some cases. We aimed to investigate the occurrence of PF-ILD in idiopathic inflammatory myopathies (IIMs), and factors potentially predicting this phenotype. Secondary aims were to assess the radiological pattern and factors associated with IIMs-ILD., Methods: Patients with IIMs from our multicentric prospective cohort were retrospectively evaluated. Data were recorded at IIMs and ILD diagnosis, and during follow-up. Patients with ILD were classified according to the predominant high-resolution CT (HRCT) pattern: non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP) and organising pneumonia (OP). PF-ILD was defined according to the 2022 American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS) and Latin American Thoracic Society (ALAT) guidelines. Univariate and multivariate analyses were performed to identify factors associated to ILD and to PF-ILD., Results: Of 253 patients with IIMs, 125 (49%) had ILD: 99 (78%) at IIMs diagnosis and 26 (22%) during follow-up (21/26 within 5 years). Multivariate analysis identified anti-Jo-1, anti-MDA5, anti-Ro52, high score on manual muscle test, mechanic's hands and Raynaud's phenomenon as independently associated with ILD. The predominant HRCT pattern was NSIP (50% of patients), followed by UIP (28%) and OP (22%). At 1-year follow-up, PF-ILD occurred in 18% of IIMs-ILD. PF-ILD was predicted by anti-MDA5, heliotropic rash, xerostomia and xerophthalmia at univariate but not at multivariate analysis., Conclusion: Patients with IIM should be carefully screened for ILD at IIMs diagnosis and yearly during follow-up. All patients with IIMs-ILD should be carefully monitored to capture ILD progression since a consistent proportion of them are expected to develop PF-ILD., Competing Interests: Competing interests: EZ and EB report personal and consulting fees from Boehringer Ingelheim. JA and YA report consulting fees from Boehringer Ingelheim. PS reports institutional grants and personal fees from PPM Services, Boehringer Ingelheim and Roche; consulting fees from Boehringer Ingelheim; non-financial support from PPM Services and Boehringer Ingelheim, and personal fees from Galapagos, Chiesi, Novartis, Lupin, Pieris and Santhera Pharmaceuticals., (© 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.)

Endobronchial Ultrasound (EBUS) has been widely used to stage lung tumors and to diagnose mediastinal diseases. In the last decade, this procedure has evolved in several technical aspects, with new tools available to optimize tissue sampling and to increase its diagnostic yield, like elastography, different types of needles and, most recently, miniforceps and cryobiopsy. Accordingly, the indications for the use of the EBUS scope into the airways to perform the Endobronchial Ultrasound-TransBronchial Needle Aspiration (EBUS-TBNA) has also extended beyond the endobronchial and thoracic boundaries to sample lesions from the liver, left adrenal gland and retroperitoneal lymph nodes via the gastroesophageal tract, performing the Endoscopic UltraSound with Bronchoscope-guided Fine Needle Aspiration (EUS-B-FNA). In this review, we summarize and critically discuss the main indication for the use of the EBUS scope, even the more uncommon, to underline its utility and versatility in clinical practice.

Sarcoidosis is a multisystemic disease of unknown etiology characterized by the formation of granulomas in various organs, especially lung and mediastinal hilar lymph nodes. The clinical course and manifestations are unpredictable: spontaneous remission can occur in approximately two thirds of patients; up to 20% of patients have chronic course of the lung disease (called advanced pulmonary sarcoidosis, APS) resulting in progressive loss of lung function, sometimes life-threatening that can lead to respiratory failure and death. The immunopathology mechanism leading from granuloma formation to the fibrosis in APS still remains elusive. Recent studies have provided new insights into the genetic factors and immune components involved in the clinical manifestation of the disease. In this review we aim to summarize the clinical-prognostic characteristics and molecular pathways which are believed to be associated with the development of APS.

Background: Real-world data regarding health-care resource use (HCRU) and costs of idiopathic pulmonary fibrosis (IPF) are scarce. In France, at the time of the study, pirfenidone and nintedanib were reimbursed for documented IPF only, with similar reimbursement criteria with regard to disease characteristics, prescription through a dedicated form, and IPF diagnosis established in a multidisciplinary setting. The objective of this study was to evaluate costs related to HCRU in patients newly treated with pirfenidone or nintedanib in 2015-2016, in France, using the exhaustive claims data of the French National Health System., Methods: Patients aged <50 years or who had pulmonary fibrosis secondary to an identified cause were excluded. HCRU-related costs up to 31 December 2017 were compared using generalized linear models adjusted for age, sex, year of treatment initiation, time to treatment initiation and proxies of disease severity identified during a pre-treatment period., Results: During the study period, a treatment with pirfenidone or nintedanib was newly initiated in 804 and 509 patients, respectively. No difference was found between groups for age, sex, time to treatment initiation, Charlson comorbidity score, and number of hospitalisations or medical visits prior to treatment initiation. As compared to pirfenidone, nintedanib was associated with higher costs for medications (1.2; 95% CI, 1.1-1.3) and medical visits (1.3; 95% CI, 1.2-1.4), as well as a higher global cost (1.1; 95% CI, 1.0-1.2). The costs of medical procedures, hospitalizations and indirect HCRU did not statistically differ between the two cohorts., Conclusions: This observational study identified potential differences in HCRU-related costs under newly prescribed antifibrotic drugs, deserving further explorations., Competing Interests: Declaration of Competing Interest F. Dalon, M. Nolin and M. Belhassen are full-time employees of PELyon. E. Van Ganse is the scientific advisor of PELyon. K.-U. Kirchgässler is an employee and shareholder of F. Hoffmann-La Roche, Ltd. V. Cottin reports personal fees and non-financial support from Actelion, Bayer/MSD and Roche; grants, personal fees and non-financial support from Boehringer Ingelheim; personal fees from Novartis, Sanofi, Promedior, Celgene, Galapagos and Galecto, outside the submitted work. P. Spagnolo reports institutional grants, consulting fees and non-financial support from PPM Services; institutional grants, personal fees and non-financial support from Roche and Boehringer Ingelheim; personal fees from Chiesi, Galapagos, Lupin, Pieris and REDX Pharma, outside the submitted work. P. Bonniaud reports personal fees and non-financial support from Roche, Boehringer Ingelheim, Novartis, Sanofi, Chiesi, AstraZeneca, Stallergenes and GSK, outside the submitted work., (Copyright © 2022 SPLF and Elsevier Masson SAS. All rights reserved.)

Sarcoidosis is a disease of unknown cause characterized by granulomatous inflammation. Although the lung is almost universally involved, any organ can be affected. Complex pathogenesis and protean clinical manifestations are additional features of the disease. The diagnosis is one of exclusion, although the presence of noncaseating granulomas at disease sites is a prerequisite in most cases. The management of sarcoidosis requires a multidisciplinary approach, particularly when the heart, the brain, or the eyes are involved. The paucity of effective therapies and the lack of reliable predictors of disease behavior greatly contribute to making sarcoidosis a challenging disease to manage., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The local, extravascular, activation of the coagulation system in response to injury is a key factor mediating the resulting inflammatory response. Coagulation Factor XIIIA (FXIIIA) found in alveolar macrophages (AM) and dendritic cells (DC), by influencing fibrin stability, might be an inflammatory modifier in COPD., Aims: To study the expression of FXIIIA in AM and Langerin+DC (DC-1) and their relation to the inflammatory response and disease progression in COPD., Methods: In 47 surgical lungs, 36 from smokers (22 COPD and 14 no-COPD) and 11 from non-smokers we quantified by immunohistochemistry FXIIIA expression in AM and DC-1 along with numbers of CD8+Tcells and CXCR3 expression in lung parenchyma and airways. Lung function was measured prior to surgery., Results: The percentage of AM expressing FXIII (%FXIII+AM) was higher in COPD than no-COPD and non-smokers. DC-1 expressed FXIIIA and their numbers were higher in COPD than no-COPD and non-smokers. DC-1 positively correlated with %FXIII+AM (r=0.43; p<0.018). CD8+Tcells, which were higher in COPD than in no-COPD, were correlated with DC-1 (p<0.01) and %FXIII+AM. CXCR3+ cells were increased in COPD and correlated with %FXIII+AM (p<0.05). Both %FXIII+AM (r=-0.6; p=0.001) and DC-1 (r=-0.7; p=0.001) correlated inversely with FEV 1 ., Conclusion: FXIIIA, an important link between the extravascular coagulation cascade and inflammatory response, is significantly expressed in alveolar macrophages and dendritic cells of smokers with COPD, suggesting that it could play an important role in the adaptive inflammatory reaction characteristic of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bazzan, Casara, Radu, Tinè, Biondini, Faccioli, Pezzuto, Bernardinello, Conti, Balestro, Calabrese, Simioni, Rea, Turato, Spagnolo, Cosio and Saetta.)

This article contains a selection of scientific highlights in the field of interstitial lung diseases (ILDs) presented at the hybrid European Respiratory Society International Congress 2022. Early Career Members of Assembly 12 summarise recent advances in translational and clinical research in idiopathic interstitial pneumonias, ILDs of known origin, sarcoidosis and other granulomatous diseases, and rare ILDs. Many studies focused on evaluation of diagnostic and prognostic (bio)markers, and novel pharmacological and nonpharmacological treatment options for different ILDs. In addition, new insights in clinical, physiological and radiological features of various rare ILDs were presented., Competing Interests: Conflict of interest: K.M. Antoniou has received consulting fees from BI, GSK and Roche, outside the submitted work; payment or honoraria from BI, Roche, Chiesi, Menarini, GSK and AstraZeneca, outside the submitted work. C. McCarthy has received grants or contracts from Health Research Board, Ireland, Enterprise Ireland and The LAM Foundation, outside the submitted work; consulting fees from Savara Inc., AI Therapeutics and Theravance Inc., outside the submitted work; support for attending meetings and/or travel from Boehringer Ingelheim, outside the submitted work; participation on a Data Safety Monitoring Board or Advisory Board for Savara Inc., outside the submitted work; and is a Breathe (published by ERS) editorial board member. M. Veltkamp has received consulting fees from Boehringer Ingelheim and Chiesi, outside the submitted work; payment or honoraria from Boehringer Ingelheim, outside the submitted work; participation on a data safety monitoring or advisory board for COLD study (Kalverda and Annema) on cryobiopsy in ILD, outside the submitted work. A. Froidure has received consulting fees from Boehringer Ingelheim and GlaxoSmithKline, outside the submitted work; payment or honoraria from Boehringer Ingelheim, outside the submitted work; and support for attending meetings and/or travel from Sanofi, outside the submitted work. M. Molina-Molina received grants or contracts from Boehringer Ingelheim, Roche, outside the submitted work; consulting fees from Ferrer, Boehringer Ingelheim, Roche, outside the submitted work; payment or honoraria from Chiesi, Roche, Boehringer Ingelheim outside the submitted work; and support for attending meetings and/or travel from Boehringer Ingelheim, outside the submitted work. W.A. Wuyts has received grants or contracts from Roche, Boehringer Ingelheim and Galapagos, outside the submitted work; consulting fees from Roche, Boehringer Ingelheim, Galapagos and Sanofi, outside the submitted work; participation on a data safety monitoring or advisory board for Roche, Boehringer Ingelheim and Sanofi, outside the submitted work; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: working group Belgian respiratory society (unpaid) and ERS group 12.1 (unpaid), outside the submitted work. D.W. Loth has received payment or honoraria from Boehringer Ingelheim B.V., outside the submitted work; support for attending meetings and/or travel from Boehringer Ingelheim B.V., outside the submitted work. E. Khurtsidze has received grants or contracts from Erasmus, outside the submitted work. M. Kreuter has received grants or contracts from Boehringer and Roche, outside the submitted work; consulting fees from Boehringer and Roche, outside the submitted work; payment or honoraria from Boehringer, Novartis, and Roche, outside the submitted work. P. Spagnolo has received grants or contracts from Roche, Boehringer Ingelheim and PPM Services, outside the submitted work; consulting fees from PPM Services, Chiesi, Galapagos, Behring, Santhera Pharmaceuticals and Novartis, outside the submitted work; payment or honoraria from Chiesi, Boehringer Ingelheim, outside the submitted work; participation on a data safety monitoring or advisory board for Galapagos, outside the submitted work; leadership or fiduciary role in other board, society, committee or advocacy group for ERS group 12.03 (Group chair, unpaid), outside the submitted work. P.P. Diep received payment or honoraria from Boehringer Ingelheim Norway, honoraria for presentations, outside the submitted work; support for attending the Nordic ILD-congress in Stockholm 2021, outside the submitted work. C.C. Moor has received grants or contracts from Boehringer Ingelheim, AstraZeneca and Daiichi-Sankyo, outside the submitted work; payment or honoraria from Boehringer Ingelheim, Hoffman–la Roche, outside the submitted work; ERS Early Career Member Committee, outside the submitted work. M.S. Wijsenbeek has received grants or contracts from Boehringer Ingelheim; Hoffman la Roche; The Netherlands Organisation for Health Research and Development; The Dutch Lung Foundation; The Dutch Pulmonary Fibrosis, outside the submitted work; consulting fees from Bristol Myers Squibb, Boehringer Ingelheim, Galapagos, Galecto, Hoffman la Roche, Horizon therapeutics, Kinevant Sciences, Molecure, Nerre Therapeutics, Novartis, PureTech Health, and Respivant, outside the submitted work; payment or honoraria from Boehringer Ingelheim, CSL Behring, Hoffman la Roche and Novartis, outside the submitted work; support for attending meetings and/or travel from Boehringer Ingelheim and Hoffman la Roche Galapagos, outside the submitted work; participation on a data safety monitoring or advisory board for Savara, Galapagos, outside the submitted work; leadership or fiduciary role in other board, society, committee or advocacy group for Chair of the Idiopathic Interstitial Pneumonia group of the European Respiratory Society; member of the board of the Netherlands Respiratory Society; member of the scientific advisory board of the European Idiopathic Pulmonary Fibrosis and Related Disorders Federation; Chair of the educational committee of the European Reference Network for Rare Lung Diseases; advisory board of the Dutch Lungfibrosis and Sarcoidosis patient associations (unpaid), outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: Sarcoidosis is a multisystem disease, characterised by the infiltration of various organs by non-necrotising granulomas. The disease's heterogeneity complicates the study of patients' experiences., Objective: To gather insight into life experiences, unmet needs and views on hypothetically emerging treatment options among patients living with sarcoidosis., Methods: Multinational, virtual, interactive, moderated discussion of specific questions between people with sarcoidosis, with experienced clinicians participating., Results: Nine patients with sarcoidosis from Australia, Denmark, Germany, Italy, Japan and the US, and three clinicians took part. All patients had pulmonary sarcoidosis, self-assessed as mild by five patients. The path to diagnosis was convoluted, with up to four physicians and a large number of tests involved. There was agreement that the process would be improved by earlier referral to specialists. The patients made a clear distinction between 'living with a condition' (adapting to the disease) and 'being ill'. The concept of remission was viewed sceptically as disease might develop in multiple organs. Panellists had a pragmatic attitude to therapies: side effects during a treatment course were accepted if overall symptoms improved. When considering hypothetical new therapies, improved quality of life (QoL) was the most important need; improved tolerability had lower priority. New therapies should be targeted on reducing disease progression and improving symptoms and QoL rather than corticosteroid withdrawal., Conclusions: The interactive exchange provided insights into the need for earlier specialist referrals, distrust of the concept of remission in sarcoidosis, and the need for therapies targeted on reducing disease progression and improving symptoms and QoL., Competing Interests: Competing interest MAJ reports consulting fees from Bohringer-Ingelheim and receipt of grants for his institution from aTyr, Kinevant, Mallinckrodt, and Star Therapeutics. PS reports personal fees from Novartis during the conduct of the study and personal fees from Behring and Chiesi outside the submitted work. RS has no conflicts to disclose. GF reports personal fees from Foundation for Sarcoidosis Research - Industry Patient Roundtable, outside the submitted work. FP and AMT are employees of Novartis. RPB reports consulting fees from ATYR, Actelion, Bellephron, Kinevant, Novartis and Xentria, and research grants from ATYR, Actelion, Bellephron and Genentech., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Since the beginning of the SARS-CoV-2 pandemic, over 550 million people have been infected worldwide. Despite these large numbers, the long-term pulmonary consequences of COVID-19 remain unclear., Aims: The aim of this single-center observational cohort study was to identify and characterize pulmonary sequelae of COVID-19 at 12 months from hospitalization and to reveal possible predictors for the persistence of long-term lung consequences., Methods: Based on the persistence or absence of radiological changes after 12 months from hospitalization, the whole population was categorized into NOT-RECOVERED (NOT-REC) and RECOVERED (REC) groups, respectively. Clinical and pulmonary function data tests and clinical data were also collected and compared in the two groups. In the NOT-REC group, high resolution computed tomography (HRCT) images were semiquantitatively scored analyzing ground-glass opacities (GGO), interstitial thickening (IT), consolidations (CO), linear and curvilinear band opacities, and bronchiectasis for each lung lobe. Logistic regression analyses served to detect the factors associated with 12-month radiological consequences., Results: Out of the 421 patients followed after hospitalization for SARS-CoV-2 pneumonia, 347 met inclusion and exclusion criteria and were enrolled in the study. The NOT-REC patients ( n = 24; 6.9%) were significantly older [67 (62-76) years vs. 63 (53-71) years; p = 0.02], more frequently current smokers [4 (17%) vs. 12 (4%); p = 0.02], and with more severe respiratory failure at the time of hospitalization [PaO 2 /FiO 2 at admission: 201 (101-314) vs. 295 (223-343); p = 0.01] compared to REC group ( n = 323; 93.1%). On multivariable analysis, being a current smoker resulted in an independent predictor for lung sequelae after 12 months from hospitalization [5.6 OR; 95% CI (1.41-22.12); p = 0.01]., Conclusion: After 12 months from hospital admission, a limited number of patients displayed persistent pulmonary sequelae with minimal extension. Being a current smoker at the time of SARS-CoV-2 infection is an independent predictive factor to lung consequences, regardless of the disease severity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bernardinello, Cocconcelli, Giraudo, Daverio, Castelli, Petrarulo, Bovo, Fichera, Cavinato, Cattelan, Saetta, Spagnolo and Balestro.)

Competing Interests: JMO reports grants from the US National Institutes of Health; grants and personal fees from Boehringer Ingelheim; and personal fees from Genentech, AmMax Bio, Gatehouse Bio, United Therapeutics, and Lupin pharmaceuticals, outside of the submitted work. CJR reports grants and personal fees from Boehringer Ingelheim, Hoffmann-La Roche, Pliant Therapeutics, and Veracyte, outside of the submitted work. AS reports reimbursement for travel and participation in conferences from Boehringer Ingelheim and Roche, outside of the submitted work. DL reports personal fees from Roche and Boehringer Ingelheim, outside of the submitted work. LR reports grants and personal fees from Biogen, Roche, ImmuneWorks, Boehringer Ingelheim, Celgene, Nitto, FibroGen, Promedior, Pliant Therapeutics, Asahi Kasei, Toray, BMS, RespiVant, and CSL Behring, outside of the submitted work. FB reports grants and personal fees from AstraZeneca, Bayer, Chiesi, GlaxoSmithKline, Guidotti, Grifols, Insmed, Menarini, Mundipharma, Novartis, Pfizer, and Zambon, outside of the submitted work. SA reports grants and personal fees from Bayer, Grifols, AstraZeneca, Zambon, Chiesi, Insmed, GlaxoSmithKline, Menarini, ZetaCube Srl, and Fisher & Paykel, outside of the submitted work. All other authors declare no competing interests.

Background and Objective: There remains a paucity of large databases for patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. We aimed to create a European registry., Methods: This was a multicentre, retrospective study across seven European countries between 1 January 2010 and 18 May 2021., Results: We identified 324 patients with lung cancer among 3178 patients with IPF (prevalence = 10.2%). By the end of the 10 year-period following IPF diagnosis, 26.6% of alive patients with IPF had been diagnosed with lung cancer. Patients with IPF and lung cancer experienced increased risk of all-cause mortality than IPF patients without lung cancer (HR: 1.51, [95% CI: 1.22-1.86], p < 0.0001). All-cause mortality was significantly lower for patients with IPF and lung cancer with a monocyte count of either <0.60 or 0.60-<0.95 K/μl than patients with monocyte count ≥0.95 K/μl (HR [<0.60 vs. ≥0.95 K/μl]: 0.35, [95% CI: 0.17-0.72], HR [0.60-<0.95 vs. ≥0.95 K/μl]: 0.42, [95% CI: 0.21-0.82], p = 0.003). Patients with IPF and lung cancer that received antifibrotics presented with decreased all cause-mortality compared to those who did not receive antifibrotics (HR: 0.61, [95% CI: 0.42-0.87], p = 0.006). In the adjusted model, a significantly lower proportion of surgically treated patients with IPF and otherwise technically operable lung cancer experienced all-cause mortality compared to non-surgically treated patients (HR: 0.30 [95% CI: 0.11-0.86], p = 0.02)., Conclusion: Lung cancer exerts a dramatic impact on patients with IPF. A consensus statement for the management of patients with IPF and lung cancer is sorely needed., (© 2022 Asian Pacific Society of Respirology.)

The MUC5B rs35705950 mutant T allele is the strongest genetic risk factor for familial and sporadic IPF. We sought to determine whether MUC5B genotype influences radiological patterns of IPF at diagnosis, as well as their change over time, in patients on antifibrotic therapy. Among eighty-eight IPF patients, previously genotyped for MUC5B rs35705950, we considered seventy-eight patients who were evaluated for radiological quantification of the following features both at treatment initiation (HRCT1) and after 1 year (HRCT2): ground glass opacities (AS), reticulations (IS) and honeycombing (HC). Of the evaluated patients, 69% carried at least one copy of the T allele (TT/TG). Carriers of the T allele displayed similar FVC loss in the first year of treatment as GG carriers, but overall survival at the end of follow-up was longer in the TT/TG group, compared to the GG group. In the GG group, both the AS and HC increased significantly, whereas in the TT/TG group only HC increased over the first year of treatment. MUC5B rs35705950 GG carriers are associated with increased ground glass and honeycombing extent over time and worse survival than T allele carriers. Longitudinal HRCT may help define the prognostic role of the MUC5B rs35705950 genotype.

Thoracic involvement is one of the main determinants of morbidity and mortality in patients with autoimmune rheumatic diseases (ARDs), with different prevalence and manifestations according to the underlying disease. Interstitial lung disease (ILD) is the most common pulmonary complication, particularly in patients with systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIMs) and rheumatoid arthritis (RA). Other thoracic manifestations include pulmonary arterial hypertension (PAH), mostly in patients with SSc, airway disease, mainly in RA, and pleural involvement, which is common in systemic lupus erythematosus and RA, but rare in other ARDs.In this review, we summarize and critically discuss the current knowledge on thoracic involvement in ARDs, with emphasis on disease pathogenesis and management. Immunosuppression is the mainstay of therapy, particularly for ARDs-ILD, but it should be reserved to patients with clinically significant disease or at risk of progressive disease. Therefore, a thorough, multidisciplinary assessment to determine disease activity and degree of impairment is required to optimize patient management. Nevertheless, the management of thoracic involvement-particularly ILD-is challenging due to the heterogeneity of disease pathogenesis, the variety of patterns of interstitial pneumonia and the paucity of randomized controlled clinical trials of pharmacological intervention. Further studies are needed to better understand the pathogenesis of these conditions, which in turn is instrumental to the development of more efficacious therapies., (© 2022. The Author(s).)

Sarcoidosis is a heterogeneous disease, which can affect virtually every body organ, even though lungs and intra thoracic lymph nodes are almost universally affected. The presence of noncaseating granulomas is the histopathological hallmark of the disease, and clinical picture depends on the organs affected. Data about interaction between sarcoidosis and comorbidities, such as cardiovascular and pulmonary diseases, autoimmune disorders, malignancy and drug-related adverse events are limited. Several lung conditions can be associated with sarcoidosis, such as pulmonary hypertension and fibrosis, making it difficult sometimes the differentiation between complications and distinctive pathologies. Their coexistence may complicate the diagnosis of sarcoidosis and contribute to the highly variable and unpredictable natural history, particularly if several diseases are recognised. A thorough assessment of specific disorders that can be associated with sarcoidosis should always be carried out, and future studies will need to evaluate sarcoidosis not only as a single disorder, but also in the light of possible concomitant conditions.Key messagesComorbidities in sarcoidosis are common, especially cardiovascular and pulmonary diseases.In the diagnostic workup, a distinction must be made between sarcoidosis-related complaints and complaints caused by other separate disorders. It can be very difficult to distinguish between complications of sarcoidosis and other concomitant conditions.The coexistence of multiple conditions may complicate the diagnosis of sarcoidosis, affect its natural course and response to treatment.

Interstitial lung disease (ILD) secondary to drug-induced lung injury is an increasingly common cause of morbidity and mortality. The number of drugs associated with the development of ILD continues to rise, mainly due to the use of novel monoclonal antibodies and biologicals for neoplastic and rheumatological diseases, and includes, among others, chemotherapeutics, molecular targeting agents, immune checkpoint inhibitors, antibiotics, antiarrhythmics and conventional or biological disease-modifying antirheumatic drugs. Drug-induced ILD (DI-ILD) manifests with a variety of clinical patterns, ranging from mild respiratory symptoms to rapidly progressive respiratory failure and death. In most cases, there are no pathognomonic clinical, laboratory, radiological or pathological features and the diagnosis of DI-ILD is suspected in the presence of exposure to a drug known to cause lung toxicity and after exclusion of alternative causes of ILD. Early identification and permanent discontinuation of the culprit drug are the cornerstones of treatment with systemic glucocorticoids being used in patients with disabling or progressive disease. However, for certain drugs, such as checkpoint inhibitors, the frequency of lung toxicity is such that mitigation strategies are put in place to prevent this complication, and occurrence of DI-ILD is not necessarily synonymous with permanent drug discontinuation, particularly in the absence of valid therapeutic alternatives., Competing Interests: Conflict of interest: P. Bonniaud reports research grants (paid to his institution) from AstraZeneca, personal fees for participation to advisory board meetings from Roche, Boehringer Ingelheim, AstraZeneca and Novartis, and support for attending medical/research meetings from Roche, Boehringer Ingelheim, AstraZeneca, Novartis, Chiesi, Sanofi and Stallergenes. P. Spagnolo, G. Rossi, N. Sverzellati and V. Cottin have nothing to disclose., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Coronavirus disease 2019 (COVID-19) has been associated with dysregulation of the immune system featuring inappropriate immune responses, exacerbation of inflammatory responses, and multiple organ dysfunction syndrome in patients with severe disease. Sarcoidosis, also known as Besnier-Boeck-Schaumann disease, is an idiopathic granulomatous multisystem disease characterized by dense epithelioid non-necrotizing lesions with varying degrees of lymphocytic inflammation. These two diseases have similar clinical manifestations and may influence each other at multiple levels, eventually affecting their clinical courses and prognosis. Notably, sarcoidosis patients are at high risk of severe COVID-19 pneumonia because of the underlying lung disease and chronic immunosuppressive treatment. In this narrative review, we will discuss interactions between sarcoidosis and COVID-19 in terms of clinical manifestations, treatment, and pathogenesis, including the role of the dysregulated renin-angiotensin system, altered immune responses involving increased cytokine levels and immune system hyperactivation, and cellular death pathways.

Introduction: Regardless corticosteroids are recommended for the treatment of organizing pneumonia there is limited evidence supporting this practice. Thus, we performed a systematic review of the literature on systemic corticosteroid treatment for organizing pneumonia., Methods: A search was implemented in the PubMed database (Medline) for articles published in the last 20 years. Those studies with incomplete or insufficient data and case reports were excluded. We collected data including: demographics, clinical data, diagnostic procedures, aetiology, treatment regimen (drug, posology, duration, response) and evolution., Results: A total of 135 publications were selected and finally 13 studies with 849 patients were included in the review: 12 retrospective observational studies and a single prospective observational study. Most of the patients were started on treatment with systemic corticosteroids - a total of 627 (30-100% depending on the series), but there was a great heterogeneity regarding drug, doses and duration. On those that started treatment, 226 (36%) presented a relapse of the disease during follow-up. Only one study provided information regarding treatment side-effects., Conclusion: The findings of this systematic review show the low quality data supporting the use of corticosteroids for the treatment of organizing pneumonia. This highlights a need to undertake appropriately designed studies to investigate which is the most appropriate treatment regimen that trades off benefits and risks of prolonged corticosteroid administration., (© 2022 Sociedad Española de Neumología y Cirugía Torácica (SEPAR). Published by Elsevier España, S.L.U.)

Purpose of Review: Immune checkpoint inhibitors (ICIs) have rapidly become a mainstay of cancer treatment. However, immune modulation resulting from checkpoint inhibition can cause inflammation in any organ system, with pneumonitis being one of the most severe immune-related adverse events (irAEs). Here, we review the most recent literature on pulmonary adverse events following ICIs., Recent Findings: Several systematic reviews and meta-analyses of data from trials of antiprogrammed death-1 (PD-1; nivolumab, pembrolizumab), anti-PD-ligand-1 (PD-L1; atezolizumab, avelumab, durvalumab) and anticytotoxic T lymphocyte antigen-4 (CTLA-4; ipilimumab or tremelimumab) in patients with advanced cancer have explored the relative risk and incidence of lung toxicity among different tumor types and therapeutic regimens. They have showed that the incidence of all-grade (1-4) and high-grade (3-4) pneumonitis is significantly higher in nonsmall cell lung cancer (NSCLC) compared with other tumor types. In addition, they have demonstrated that immunotherapy, especially monoimmunotherapy, has a significantly lower risk of irAEs compared to immune-chemotherapy. Treatment for lung cancer, preexisting interstitial lung disease, smoking history and male sex appear to increase the risk for ICI-related pneumonitis., Summary: Lung toxicity is an uncommon but potentially severe and even fatal complication of ICIs. Timely recognition is critically important but challenging, particularly in patients with lung cancer wherein drug toxicity can mimic disease progression or recurrence., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Chronic bronchitis (CB) importantly affects outcomes in smokers with COPD, but the effects on smokers without COPD are less well known and less emphasized. The aim of our study was to investigate the possible effects of CB on clinical outcomes in smokers without COPD (noCOPD) and compare them with the effects in smokers with COPD (COPD)., Methods: For that purpose, we studied 511 smokers, 302 with and 209 without COPD, followed for 10 years in an academic COPD ambulatory setting. Chronic bronchitis was defined as the presence of cough and sputum production for at least 3 months in each of two consecutive years. All subjects underwent clinical and functional examination with spirometry, diffusion capacity (DLco), 6-min walking test (6MWT), mMRC Dyspnoea Scale, COPD Assessment Test (CAT), and recording of annual frequency of exacerbations. All-cause mortality during follow-up was recorded., Results: 27% of noCOPD and 45% of COPD had CB. noCOPD with CB had lower FEV 1 and DLco, worse 6MWT, more dyspnoea, a higher number of exacerbations and lower survival than noCOPD without CB. CB did not affect FEV 1 decline in noCOPD but it significantly did in COPD., Conclusions: The presence of chronic bronchitis in smokers without COPD will significantly affect symptoms, quality of life, and survival, underlining the importance of recognizing the condition and managing it accordingly.

Background: When considering the diagnosis of idiopathic pulmonary fibrosis (IPF), experienced clinicians integrate clinical features that help to differentiate IPF from other fibrosing interstitial lung diseases, thus generating a "pre-test" probability of IPF. The aim of this international working group perspective was to summarize these features using a tabulated approach similar to chest HRCT and histopathologic patterns reported in the international guidelines for the diagnosis of IPF, and to help formally incorporate these clinical likelihoods into diagnostic reasoning to facilitate the diagnosis of IPF. Methods: The committee group identified factors that influence the clinical likelihood of a diagnosis of IPF, which was categorized as a pre-test clinical probability of IPF into "high" (70-100%), "intermediate" (30-70%), or "low" (0-30%). After integration of radiological and histopathological features, the post-test probability of diagnosis was categorized into "definite" (90-100%), "high confidence" (70-89%), "low confidence" (51-69%), or "low" (0-50%) probability of IPF. Findings: A conceptual Bayesian framework was created, integrating the clinical likelihood of IPF ("pre-test probability of IPF") with the HRCT pattern, the histopathology pattern when available, and/or the pattern of observed disease behavior, into a "post-test probability of IPF." The diagnostic probability of IPF was expressed using an adapted diagnostic ontology for fibrotic interstitial lung diseases. Interpretation: The present approach will help incorporate the clinical judgment into the diagnosis of IPF, thus facilitating the application of IPF diagnostic guidelines and, ultimately improving diagnostic confidence and reducing the need for invasive diagnostic techniques.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unknown origin characterized by progressive scarring of the lung leading to irreversible loss of function. Despite the availability of two drugs that are able to slow down disease progression, IPF remains a deadly disease. The pathogenesis of IPF is poorly understood, but a dysregulated wound healing response following recurrent alveolar epithelial injury is thought to be crucial., Areas Covered: In the last few years, the role of the immune system in IPF pathobiology has been reconsidered; indeed, recent data suggest that a dysfunctional immune system may promote and unfavorable interplay with pro-fibrotic pathways thus acting as a cofactor in disease development and progression. In this article, we review and critically discuss the role of T cells in the pathogenesis and progression of IPF in the attempt to highlight ways in which further research in this area may enable the development of targeted immunomodulatory therapies for this dreadful disease., Expert Opinion: A better understanding of T cell interactions has the potential to facilitate the development of immune modulators targeting multiple T cell-mediated pathways, thus halting disease initiation and progression.

Purpose of Review: Growing evidence suggests that ageing-associated alterations occur in both idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Here, we review the most recent literature on dysregulated ageing pathways in IPF and COPD and discuss how they may contribute to disease pathogenesis., Recent Findings: Recent studies have shown that alveolar epithelial type II (ATII) cells undergo premature senescence under stress and that senescent ATII cells promote lung fibrogenesis. Some studies have explored the role of mitochondrial dysfunction in IPF. They have provided evidence that dysfunctional mitochondria are important contributors to fibrogenesis through release of damaged DNA and excessive formation of reactive oxygen species, whereas restoration of mitochondrial homeostasis may attenuate lung fibrosis. Insufficient autophagy has been shown to promote epithelial-to-mesenchymal transition and aberrant epithelial-fibroblast crosstalk, suggesting that autophagy augmentation may represent a potential therapeutic strategy. A number of studies have also explored the role of cellular senescence, mitochondrial homeostasis and autophagy in COPD., Summary: Several ageing mechanisms are dysregulated in the lungs of patients with IPF and COPD, although how they contribute to disease development and progression remains elusive. Genetic or pharmacologic attenuation of senescence-related pathways and elimination of senescent cells may represent a promising therapeutic strategy., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved .)