The immunopathogenesis of sarcoidosis.

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.

BAP1 Loss, Nuclear Grading, and Nonepithelioid Features in the Diagnosis of Mesothelioma in Italy: Nevermore without the Pathology Report.

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.

ERS International Congress 2023: highlights from the Interstitial Lung Diseases Assembly.

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.

Suppressor of cytokine signaling-3 expression and its regulation in relation to inflammation in Chronic Obstructive Pulmonary Disease.

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.

High-Risk Sarcoidosis: A Focus on Pulmonary, Cardiac, Hepatic and Renal Advanced Diseases, as Well as on Calcium Metabolism Abnormalities.

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.

An adjudication algorithm for respiratory-related hospitalisation in idiopathic pulmonary fibrosis.

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.

Emerging Treatments for Childhood Interstitial Lung Disease.

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.

Should we use nintedanib as early therapy in patients with SSc-ILD?

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.

High-resolution CT phenotypes in pulmonary sarcoidosis: a multinational Delphi consensus study.

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.

Environmental Causes of Idiopathic Pulmonary Fibrosis.

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.

Walking the path of treatable traits in interstitial lung diseases.

Interstitial lung diseases (ILDs) are complex and heterogeneous diseases. The use of traditional diagnostic classification in ILD can lead to suboptimal management, which is worsened by not considering the molecular pathways, biological complexity, and disease phenotypes. The identification of specific "treatable traits" in ILDs, which are clinically relevant and modifiable disease characteristics, may improve patient's outcomes. Treatable traits in ILDs may be classified into four different domains (pulmonary, aetiological, comorbidities, and lifestyle), which will facilitate identification of related assessment tools, treatment options, and expected benefits. A multidisciplinary care team model is a potential way to implement a "treatable traits" strategy into clinical practice with the aim of improving patients' outcomes. Multidisciplinary models of care, international registries, and the use of artificial intelligence may facilitate the implementation of the "treatable traits" approach into clinical practice. Prospective studies are needed to test potential therapies for a variety of treatable traits to further advance care of patients with ILD.

Pleural clinic: where thoracic ultrasound meets respiratory medicine.

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.

Current and Future Treatment Landscape for Idiopathic Pulmonary Fibrosis.

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.

Occupational interstitial lung diseases.

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.

A complicated case of whole-lung lavage: a case report.

Introduction: We report a life-threatening case of severe respiratory failure due to a pulmonary alveolar proteinosis (PAP) secondary to lysinuric protein intolerance (LPI), complicated by a pre-existing right pneumothorax, which we treated using a rescue whole-lung lavage (WLL). To date, in the literature, there are no cases of WLL performed in this condition. Clinical condition: Patient was referred to our center because of rapidly worsening dyspnea and deterioration of gas exchange, caused by a secondary form of PAP which required an immediate therapeutic option such as the one offered by WLL. On physical examination, bilateral crackles were present, and peripheral blood oxygen saturation was 78% on oxygen with a FiO2 of 40%. Interventions: After stabilizing the clinical conditions with oxygen therapy erogated through a high-flow nasal cannula, shortly after admission, we performed a rescue WLL among two procedures. The procedure was very effective, and the patient was later discharged without oxygen therapy and in good clinical condition. Conclusion: Our case report represents a chance to help fill the gap of knowledge relative to secondary forms of PAP. The patient we presented suffers from a very rare genetic condition (LPI) that only has a few reported cases in the literature and has a very low prevalence which makes it difficult to produce the affected people:newborns ratio. We believe that difficult and rare cases like this one can improve our understanding of the disease and, most importantly, of how much the only therapeutic option we had, a rescue WLL, is effective to improve gas exchange and radiological features, despite being performed in these severe respiratory conditions.

Interstitial lung disease with and without progressive fibrosing phenotype in patients with idiopathic inflammatory myopathies: data from a large multicentric cohort.

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.