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Competing Interests: Declaration of competing interest All authors have nothing to disclose related to this work

Background: Computational advances in artificial intelligence have led to the recent emergence of U-Net convolutional neural networks (CNNs) applied to medical imaging. Our objectives were to assess the progression of fibrotic interstitial lung disease (ILD) using routine CT scans processed by a U-Net CNN developed by our research team, and to identify a progression threshold indicative of poor prognosis., Methods: CT scans and clinical history of 32 patients with idiopathic fibrotic ILDs were retrospectively reviewed. Successive CT scans were processed by the U-Net CNN and ILD quantification was obtained. Correlation between ILD and FVC changes was assessed. ROC curve was used to define a threshold of ILD progression rate (PR) to predict poor prognostic (mortality or lung transplantation). The PR threshold was used to compare the cohort survival with Kaplan Mayer curves and log-rank test., Results: The follow-up was 3.8 ± 1.5 years encompassing 105 CT scans, with 3.3 ± 1.1 CT scans per patient. A significant correlation between ILD and FVC changes was obtained (p = 0.004, ρ = -0.30 [95% CI: -0.16 to -0.45]). Sixteen patients (50%) experienced unfavorable outcome including 13 deaths and 3 lung transplantations. ROC curve analysis showed an aera under curve of 0.83 (p < 0.001), with an optimal cut-off PR value of 4%/year. Patients exhibiting a PR ≥ 4%/year during the first two years had a poorer prognosis (p = 0.001)., Conclusions: Applying a U-Net CNN to routine CT scan allowed identifying patients with a rapid progression and unfavorable outcome., Competing Interests: Declaration of Competing Interest XG, SR, CF, MB, DIBI, JFB, DV, JCj, JMN, PYB have no conflicts of interest. MPD received fees (presentations or participation in expert groups) from Boehringer-Ingelheim. HN received fees from Roche/Genentech, Boehringer-Ingelheim, Galapagos., (Copyright © 2023 SPLF and Elsevier Masson SAS. All rights reserved.)

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

In this review, the infectious complications observed in sarcoidosis are considered from a practical point of view to help the clinician not to overlook them in a difficult context, as pulmonary sarcoidosis makes the recognition of superinfections more difficult. An increased incidence of community-acquired pneumonia and of opportunistic pneumonia has been reported, especially in immunosuppressed patients. Pulmonary destructive lesions of advanced sarcoidosis increase the incidence of chronic pulmonary aspergillosis and infection by other agents. Screening and treatment of latent tuberculosis infection are crucial to prevent severe tuberculosis. Severity in COVID-19 appears to be increased by comorbidities rather than by sarcoidosis per se. The diagnosis of infectious complications can be challenging and should be considered as a potential differential diagnosis when the exacerbation of sarcoidosis is suspected. These complications not only increase the need for hospitalizations, but also increase the risk of death. This aspect must be carefully considered when assessing the overall health burden associated with sarcoidosis. The impact of immune dysregulation on infectious risk is unclear except in exceptional cases. In the absence of evidence-based studies on immunosuppressants in the specific context of pulmonary sarcoidosis, it is recommended to apply guidelines used in areas outside sarcoidosis. Preventive measures are essential, beginning with an appropriate use of immunosuppressants and the avoidance of unjustified treatments and doses. This approach should take into account the risk of tuberculosis, especially in highly endemic countries. Additionally, parallel emphasis should be placed on vaccinations, especially against COVID-19.

Computerised processing of images from routine noncontrast HRCT could be an efficient, costless and safe tool to investigate the vascular remodelling that occurs in the months after COVID-19 in a large number of patients https://bit.ly/3qAQZDW., Competing Interests: Conflict of interest: The authors have no personal conflicts of interest to disclose., (Copyright ©The authors 2023.)

Interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF) or post-COVID-19 pulmonary fibrosis, are progressive and severe diseases characterized by an irreversible scarring of interstitial tissues that affects lung function. Despite many efforts, these diseases remain poorly understood and poorly treated. In this paper, we propose an automated method for the estimation of personalized regional lung compliances based on a poromechanical model of the lung. The model is personalized by integrating routine clinical imaging data - namely computed tomography images taken at two breathing levels in order to reproduce the breathing kinematic-notably through an inverse problem with fully personalized boundary conditions that is solved to estimate patient-specific regional lung compliances. A new parametrization of the inverse problem is introduced in this paper, based on the combined estimation of a personalized breathing pressure in addition to material parameters, improving the robustness and consistency of estimation results. The method is applied to three IPF patients and one post-COVID-19 patient. This personalized model could help better understand the role of mechanics in pulmonary remodeling due to fibrosis; moreover, patient-specific regional lung compliances could be used as an objective and quantitative biomarker for improved diagnosis and treatment follow up for various interstitial lung diseases., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The pathophysiology of high-altitude pulmonary edema is currently attributed to exacerbated heterogeneous hypoxic pulmonary vasoconstriction. However, although other cellular mechanisms have been hypothesized, they are still poorly understood. In this review, we focused on cells of the pulmonary acinus, the distal unit for gas exchange, known to be responders to acute hypoxia, notably through many humoral or tissue factors that connect this intercellular network constituting the alveolo-capillary barrier. Hypoxia could drive alveolar edema by: 1 ) damaging the fluid reabsorption capacity of alveolar epithelial cells, 2 ) increasing the endothelial and epithelial permeability, especially by alteration of occluding junctions, 3 ) triggering the inflammation mainly led by alveolar macrophages, 4 ) increasing interstitial water accumulation by disruption of extracellular matrix architecture and tight junctions, 5 ) inducing pulmonary vasoconstriction through an orchestrated response of pulmonary arterial endothelial and smooth muscle cells. Hypoxia may also alter the function of fibroblasts and pericytes that contribute to the interconnection of the cells of the alveolar-capillary barrier. Due to its complex intercellular network and delicate pressure gradient equilibrium, the alveolar-capillary barrier is simultaneously affected by acute hypoxia in all its components, leading to rapid accumulation of water in the alveoli.

Some patients with idiopathic pulmonary fibrosis present impaired ventilatory variables characterised by low forced vital capacity values associated with an increase in respiratory rate and a decrease in tidal volume which could be related to the increased pulmonary stiffness. The lung stiffness observed in pulmonary fibrosis may also have an effect on the functioning of the brainstem respiratory neural network, which could ultimately reinforce or accentuate ventilatory alterations. To this end, we sought to uncover the consequences of pulmonary fibrosis on ventilatory variables and how the modification of pulmonary rigidity could influence the functioning of the respiratory neuronal network. In a mouse model of pulmonary fibrosis obtained by 6 repeated intratracheal instillations of bleomycin (BLM), we first observed an increase in minute ventilation characterised by an increase in respiratory rate and tidal volume, a desaturation and a decrease in lung compliance. The changes in these ventilatory variables were correlated with the severity of the lung injury. The impact of lung fibrosis was also evaluated on the functioning of the medullary areas involved in the elaboration of the central respiratory drive. Thus, BLM-induced pulmonary fibrosis led to a change in the long-term activity of the medullary neuronal respiratory network, especially at the level of the nucleus of the solitary tract, the first central relay of the peripheral afferents, and the Pre-Bötzinger complex, the inspiratory rhythm generator. Our results showed that pulmonary fibrosis induced modifications not only of pulmonary architecture but also of central control of the respiratory neural network., 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 Yegen, Marchant, Bernaudin, Planes, Boncoeur and Voituron.)

Diagnosing pulmonary sarcoidosis raises challenges due to both the absence of a specific diagnostic criterion and the varied presentations capable of mimicking many other conditions. The aim of this review is to help non-sarcoidosis experts establish optimal differential-diagnosis strategies tailored to each situation. Alternative granulomatous diseases that must be ruled out include infections (notably tuberculosis, nontuberculous mycobacterial infections, and histoplasmosis), chronic beryllium disease, hypersensitivity pneumonitis, granulomatous talcosis, drug-induced granulomatosis (notably due to TNF-a antagonists, immune checkpoint inhibitors, targeted therapies, and interferons), immune deficiencies, genetic disorders (Blau syndrome), Crohn's disease, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and malignancy-associated granulomatosis. Ruling out lymphoproliferative disorders may also be very challenging before obtaining typical biopsy specimen. The first step is an assessment of epidemiological factors, notably the incidence of sarcoidosis and of alternative diagnoses; exposure to risk factors (e.g., infectious, occupational, and environmental agents); and exposure to drugs taken for therapeutic or recreational purposes. The clinical history, physical examination and, above all, chest computed tomography indicate which differential diagnoses are most likely, thereby guiding the choice of subsequent investigations (e.g., microbiological investigations, lymphocyte proliferation tests with metals, autoantibody assays, and genetic tests). The goal is to rule out all diagnoses other than sarcoidosis that are consistent with the clinical situation. Chest computed tomography findings, from common to rare and from typical to atypical, are described for sarcoidosis and the alternatives. The pathology of granulomas and associated lesions is discussed and diagnostically helpful stains specified. In some patients, the definite diagnosis may require the continuous gathering of information during follow-up. Diseases that often closely mimic sarcoidosis include chronic beryllium disease and drug-induced granulomatosis. Tuberculosis rarely resembles sarcoidosis but is a leading differential diagnosis in regions of high tuberculosis endemicity., Competing Interests: The authors declare that this review was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Valeyre, Brauner, Bernaudin, Carbonnelle, Duchemann, Rotenberg, Berger, Martin, Nunes, Naccache and Jeny.)

Intimal granulomatous angiitis is a facet of pulmonary sarcoidosis vasculitis that has almost been forgotten. Its observation may offer new understanding of the various patterns of pulmonary hypertension associated with sarcoidosis. https://bit.ly/3g6Ms76., Competing Interests: Conflict of interest: F. Jeny has received payment or honoraria from Boehringer Ingelheim, outside the submitted work; and support for attending meetings from Oxyvie, outside the submitted work. D. Valeyre has received payment or honoraria from Roche, Boehringer Ingelheim and AstraZeneca, outside the submitted work; and support to attend meetings from Boehringer Ingelheim, outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Rationale: idiopathic pulmonary fibrosis (IPF) is the most severe form of fibrosing interstitial lung disease, characterized by progressive respiratory failure leading to death. IPF's natural history is heterogeneous, and its progression unpredictable. Most patients develop a progressive decline of respiratory function over years; some remain stable, but others present a fast-respiratory deterioration without identifiable cause, classified as acute exacerbation (AE)., Objectives: to develop and characterize an experimental mice model of lung fibrosis AE, mimicking IPF-AE at the functional, histopathological, cellular and molecular levels., Methods: we established in C57BL/6 male mice a chronic pulmonary fibrosis using a repetitive low-dose bleomycin (BLM) intratracheal (IT) instillation regimen (four instillations of BLM every 2 weeks), followed by two IT instillations of a simple or double-dose BLM challenge to induce AE. Clinical follow-up and histological and molecular analyses were done for fibrotic and inflammatory lung remodeling analysis., Measurements and Main Results: as compared with a low-dose BLM regimen, this AE model induced a late burst of animal mortality, worsened lung fibrosis and remodeling, and superadded histopathological features as observed in humans IPF-AE. This was associated with stronger inflammation, increased macrophage infiltration of lung tissue and increased levels of pro-inflammatory cytokines in lung homogenates. Finally, it induced in the remodeled lung a diffuse expression of hypoxia-inducible factor 1α, a hallmark of tissular hypoxia response and a major player in the progression of IPF., Conclusion: this new model is a promising model of AE in chronic pulmonary fibrosis that could be relevant to mimic IPF-AE in preclinical trials.

Pulmonary function is tightly linked to the lung mechanical behavior, especially large deformation during breathing. Interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF), have an impact on the pulmonary mechanics and consequently alter lung function. However, IPF remains poorly understood, poorly diagnosed, and poorly treated. Currently, the mechanical impact of such diseases is assessed by pressure-volume curves, giving only global information. We developed a poromechanical model of the lung that can be personalized to a patient based on routine clinical data. The personalization pipeline uses clinical data, mainly computed tomography (CT) images at two time steps and involves the formulation of an inverse problem to estimate regional compliances. The estimation problem can be formulated both in terms of "effective", i.e., without considering the mixture porosity, or "rescaled," i.e., where the first-order effect of the porosity has been taken into account, compliances. Regional compliances are estimated for one control subject and three IPF patients, allowing to quantify the IPF-induced tissue stiffening. This personalized model could be used in the clinic as an objective and quantitative tool for IPF diagnosis., (Copyright © 2022 by ASME.)

Background: High prevalence of obstructive sleep apnea (OSA) is reported in incident and prevalent forms of idiopathic pulmonary fibrosis (IPF). We previously reported that Intermittent Hypoxia (IH), the major pathogenic element of OSA, worsens experimental lung fibrosis. Our objective was to investigate the molecular mechanisms involved., Methods: Impact of IH was evaluated on C57BL/6J mice developing lung fibrosis after intratracheal instillation of Bleomycin (BLM). Mice were Pre-exposed 14 days to IH before induction of lung fibrosis or Co-challenged with IH and BLM for 14 days. Weight loss and survival were daily monitored. After experimentations, lungs were sampled for histology, and protein and RNA were extracted., Results: Co-challenge or Pre-exposure of IH and BLM induced weight loss, increased tissue injury and collagen deposition, and pro-fibrotic markers. Major worsening effects of IH exposure on lung fibrosis were observed when mice were Pre-exposed to IH before developing lung fibrosis with a strong increase in sXBP1 and ATF6N ER stress markers., Conclusion: Our results showed that IH exacerbates BLM-induced lung fibrosis more markedly when IH precedes lung fibrosis induction, and that this is associated with an enhancement of ER stress markers.

Extrapulmonary sarcoidosis occurs in 30-50% of cases of sarcoidosis, most often in association with pulmonary involvement, and virtually any organ can be involved. Its incidence depends according to the organs considered, clinical phenotype, and history of sarcoidosis, but also on epidemiological factors like age, sex, geographic ancestry, and socio-professional factors. The presentation, symptomatology, organ dysfunction, severity, and lethal risk vary from and to patient even at the level of the same organ. The presentation may be specific or not, and its occurrence is at variable times in the history of sarcoidosis from initial to delayed. There are schematically two types of presentation, one when pulmonary sarcoidosis is first discovered, the problem is then to detect extrapulmonary localizations and to assess their link with sarcoidosis, while the other presentation is when extrapulmonary manifestations are indicative of the disease with the need to promptly make the diagnosis of sarcoidosis. To improve diagnosis accuracy, extrapulmonary manifestations need to be known and a medical strategy is warranted to avoid both under- and over-diagnosis. An accurate estimation of impairment and risk linked to extrapulmonary sarcoidosis is essential to offer the best treatment. Most frequent extrapulmonary localizations are skin lesions, arthritis, uveitis, peripheral lymphadenopathy, and hepatic involvement. Potentially severe involvement may stem from the heart, nervous system, kidney, eye and larynx. There is a lack of randomized trials to support recommendations which are often derived from what is known for lung sarcoidosis and from the natural history of the disease at the level of the respective organ. The treatment needs to be holistic and personalized, taking into account not only extrapulmonary localizations but also lung involvement, parasarcoidosis syndrome if any, symptoms, quality of life, medical history, drugs contra-indications, and potential adverse events and patient preferences. The treatment is based on the use of anti-sarcoidosis drugs, on treatments related to organ dysfunction and supportive treatments. Multidisciplinary discussions and referral to sarcoidosis centers of excellence may be helpful for difficult diagnosis and treatment decisions., (© 2021. The Author(s).)

Background: Macrophages are pivotal cells in sarcoidosis. Monocytes-derived (MD) macrophages have recently been demonstrated to play a major role especially in pulmonary sarcoidosis. From inflammatory tissues to granulomas, they may be exposed to low oxygen tension environments. As hypoxia impact on sarcoidosis immune cells has never been addressed, we designed the present study to investigate MD-macrophages from sarcoidosis patients in this context. We hypothesized that hypoxia may induce functional changes on MD-macrophages which could have a potential impact on the course of sarcoidosis., Methods: We studied MD-macrophages, from high active sarcoidosis (AS) (n=26), low active or inactive sarcoidosis (IS) (n=24) and healthy controls (n=34) exposed 24 hours to normoxia (21% O 2 ) or hypoxia (1.5% O 2 ). Different macrophage functions were explored: hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-κB) activation, cytokines secretion, phagocytosis, CD80/CD86/HLA-DR expression, profibrotic response., Results: We observed that hypoxia, with a significantly more pronounced effect in AS compared with controls and IS, increased the HIF-1α trans-activity, promoted a proinflammatory response (TNFα, IL1ß) without activating NF-κB pathway and a profibrotic response (TGFß1, PDGF-BB) with PAI-1 secretion associated with human lung fibroblast migration inhibition. These results were confirmed by immunodetection of HIF-1α and PAI-1 in granulomas observed in pulmonary biopsies from patients with sarcoidosis. Hypoxia also decreased the expression of CD80/CD86 and HLA-DR on MD-macrophages in the three groups while it did not impair phagocytosis and the expression of CD36 expression on cells in AS and IS at variance with controls., Conclusions: Hypoxia had a significant impact on MD-macrophages from sarcoidosis patients, with the strongest effect seen in patients with high active disease. Therefore, hypoxia could play a significant role in sarcoidosis pathogenesis by increasing the macrophage proinflammatory response, maintaining phagocytosis and reducing antigen presentation, leading to a deficient T cell response. In addition, hypoxia could favor fibrosis by promoting profibrotic cytokines response and by sequestering fibroblasts in the vicinity of granulomas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jeny, Bernaudin, Valeyre, Kambouchner, Pretolani, Nunes, Planès and Besnard.)

Study Question: In patients with sarcoidosis, past and ongoing immunosuppressive regimens, recurrent disease in the transplant and extrapulmonary involvement may affect outcomes of lung transplantation. We asked whether sarcoidosis lung phenotypes can be differentiated and, if so, how they relate to outcomes in patients with pulmonary sarcoidosis treated by lung transplantation., Patients and Methods: We retrospectively reviewed data from 112 patients who met international diagnostic criteria for sarcoidosis and underwent lung or heart-lung transplantation between 2006 and 2019 at 16 European centres., Results: Patient survival was the main outcome measure. At transplantation, median (interaquartile range (IQR)) age was 52 (46-59) years; 71 (64%) were male. Lung phenotypes were individualised as follows: 1) extended fibrosis only; 2) airflow obstruction; 3) severe pulmonary hypertension (sPH) and airflow obstruction; 4) sPH, airflow obstruction and fibrosis; 5) sPH and fibrosis; 6) airflow obstruction and fibrosis; 7) sPH; and 8) none of these criteria, in 17%, 16%, 17%, 14%, 11%, 9%, 5% and 11% of patients, respectively. Post-transplant survival rates after 1, 3, and 5 years were 86%, 76% and 69%, respectively. During follow-up (median (IQR) 46 (16-89) months), 31% of patients developed chronic lung allograft dysfunction. Age and extended lung fibrosis were associated with increased mortality. Pulmonary fibrosis predominating peripherally was associated with short-term complications., Answer to the Study Question: Post-transplant survival in patients with pulmonary sarcoidosis was similar to that in patients with other indications for lung transplantation. The main factors associated with worse survival were older age and extensive pre-operative lung fibrosis., Competing Interests: Conflict of interest: J. Le Pavec has nothing to disclose. Conflict of interest: D. Valeyre has nothing to disclose. Conflict of interest: P. Gazengel has nothing to disclose. Conflict of interest: A.M. Holm has nothing to disclose. Conflict of interest: H.H. Schultz has nothing to disclose. Conflict of interest: M. Perch has nothing to disclose. Conflict of interest: A. Le Borgne has nothing to disclose. Conflict of interest: M. Reynaud-Gaubert has nothing to disclose. Conflict of interest: C. Knoop has nothing to disclose. Conflict of interest: L. Godinas has nothing to disclose. Conflict of interest: S. Hirschi has nothing to disclose. Conflict of interest: V. Bunel has nothing to disclose. Conflict of interest: R. Laporta has nothing to disclose. Conflict of interest: S. Harari has nothing to disclose. Conflict of interest: E. Blanchard has nothing to disclose. Conflict of interest: J.M. Magnusson has nothing to disclose. Conflict of interest: A. Tissot has nothing to disclose. Conflict of interest: J-F. Mornex has nothing to disclose. Conflict of interest: C. Picard has nothing to disclose. Conflict of interest: L. Savale has nothing to disclose. Conflict of interest: J-F. Bernaudin has nothing to disclose. Conflict of interest: P-Y. Brillet has nothing to disclose. Conflict of interest: H. Nunes has nothing to disclose. Conflict of interest: M. Humbert has nothing to disclose. Conflict of interest: E. Fadel has nothing to disclose. Conflict of interest: J. Gottlieb has nothing to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Low income, a known prognostic indicator of various chronic respiratory diseases, has not been properly studied in idiopathic pulmonary fibrosis (IPF). We hypothesize that a low income has an adverse prognostic impact on IPF., Methods: Patients were selected from the French national prospective cohort COFI. Patients' income was assessed through the median city-level income provided by the French National Institute of Statistics and Economic Studies according to their residential address. Patients were classified in two groups as "low income" vs. "higher income" depending on whether their annual income was estimated to be < or ≥18 170 €/year (the first quartile of the income distribution in the study population). The survival and progression-free survival (PFS) of the groups were compared by a log-rank test and a Cox model in multivariate analysis., Results: 200 patients were included. The average follow-up was 33.8 ± 22.7 months. Patients in the low income group were significantly more likely to be of non-European origin (p < 0.006), and to have at least one occupational exposure (p < 0.0001), and they tended to have a higher cumulative exposure to fine particles PM 2.5 (p = 0.057). After adjusting for age, gender, forced vital capacity at inclusion, geographical origin, and occupational exposure having a low-income level was a factor associated with a worse PFS (HR: 1.81; CI 95% : 1.24-2.62, p = 0.001) and overall survival (HR: 1.49; CI 95% : 1.0006-2.23, p = 0.049)., Conclusions: Low income appears to be a prognostic factor in IPF. IPF patients with low incomes may also be exposed more frequently to occupational exposures., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

(1) Background: Pediatric sarcoidosis is a rare and mostly severe disease. Very few pediatric series with a prolonged follow-up are reported. We aimed to evaluate the evolution of pediatric sarcoidosis in adulthood. (2) Material and methods: Patients over 18-years-old with a pediatric-onset sarcoidosis (≤15-year-old) who completed at least a three-year follow-up in French expert centers were included. Clinical information at presentation and outcome in adulthood were studied. (3) Results: A total of 52 patients were included (34 prospectively in childhood and 18 retrospectively in adulthood), with a mean age of 12 (±2.7) at diagnosis. The median duration time of follow-up was 11.5 years (range 3-44.5). Relapses mostly occurred during treatment decrease (84.5%), others within the three years after treatment interruption (9.1%), and rarely when the disease was stable for more than three years (6.4%). Sarcoidosis was severe in 11 (21.2%) in adulthood. Patients received a high corticosteroid cumulative dose (median 17,900 mg) for a median duration of five years (range 0-32), resulting in mostly mild (18; 35.3%) and rarely severe (2; 3.8%) adverse events. (4) Conclusions: Pediatric-onset sarcoidosis needed a long-term treatment in almost half of the patients. Around one fifth of pediatric-onset sarcoidosis patients had severe sarcoidosis consequences in adulthood., Competing Interests: F.C.-A. is the PI of an academic study of the efficacy of infliximab in extrapulmonary sarcoidosis. T.A. reports personal fees from Chiesi, other from Vital Aire, other from Astrazeneca, other from Boehringer Ingelheim, outside the submitted work. D.V. reports personal fees from Roche, personal fees from Boehringer Ingelheim, outside the submitted work. N.N. reports grants from Société de pneumologie pédiatrique et d’allergologie (France), outside the submitted work. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. All others authors declared no direct conflict of interest related to the present work.

Few studies have examined the effects of air pollution in diffuse interstitial lung disease and they have focused on small numbers of patients. Most data are available in idiopathic pulmonary fibrosis and studies suggest that the level of exposure to pollutants may influence the development of acute exacerbations (ozone and NO 2 ), their incidence (NO 2 ), decline in respiratory function (PM 10 ) and death (PM 10 and PM 2.5 ). Several studies show an increase in the incidence of rheumatoid arthritis in people living near busy roads. In systemic scleroderma, hypersensitivity pneumonitis and sarcoidosis although negative effects of pollution have been reported the data are insufficient to be conclusive. Nevertheless, the observed effects of air pollution are consistent with those described for other chronic respiratory diseases. Exposure to pollution induces oxidative stress, chronic inflammation and shortening of telomeres, which are all mechanisms described in fibrogenesis. New epidemiological studies are needed with individual measurements of exposure to outdoor and indoor pollution, as well as fundamental studies to clarify the effect of pollution on fibrogenesis., (Copyright © 2020. Published by Elsevier Masson SAS.)

Sarcoidosis is a systemic granulomatous disease that can reduce life expectancy mainly due to pulmonary fibrosis resulting from granulomatous inflammation The lack of vascularization within pulmonary granulomas suggests that macrophages localized in the center of these structures are hypoxic. Hypoxia signaling pathways are known to be pro-inflammatory and pro-fibrotic in various pathological conditions. Recent data suggest an involvement of the transcription factor hypoxia-inducible factor (HIF) in the pathogenesis of sarcoidosis. This could represent a new research approach for the understanding and therapeutic management of sarcoidosis., (Copyright © 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Multiple problems may be encountered during the diagnosis of sarcoidosis: at first diagnose sarcoidosis in an appropriate clinical setting, secondly, identify any manifestation to be linked to sarcoidosis at diagnosis work-up and during evolution; thirdly, recognize "danger" in sarcoidosis and parasarcoidosis syndromes, and finally, diagnose sarcoidosis recovery. Diagnosis is often delayed as presentation may be diverse, non-specific, or atypical. Diagnosis of sarcoidosis is based on three criteria: a compatible presentation; evidence of non-caseating granulomas and exclusion of any alternative diagnosis. However, even when all criteria are fulfilled, the probability of sarcoidosis diagnosis varies from definite to only possible depending upon the presence of more or less characteristic radio-clinical and histopathological findings and on the epidemiological context. Bilateral hilar lymphadenopathy and/or diffuse lung micronodules mainly along lymphatics are the most frequent highly suggestive findings. Evidence of granulomas relies on superficial biopsies of clinically suspected lesion when present or most often by bronchial endoscopy. The diagnosis of sarcoidosis may be difficult in absence of thoracic or skin manifestations and may require the benefit of hindsight before being definitive. Differential diagnoses, mainly tuberculosis, must be considered. The diagnosis of events during evolution relies on serial clinical, pulmonary function, radiographic evaluation and on extrapulmonary manifestations work-up, including electrocardiogram and blood biology. Affected organs need to be related to sarcoidosis using an appropriate diagnostic assessment instrument. To declare the recovery of sarcoidosis, all manifestations must have disappeared spontaneously or after 3-5 years post-treatment without relapse., (Copyright © 2019 SPLF and Elsevier Masson SAS. All rights reserved.)

Purpose: To design and validate a preprocessing procedure dedicated to T2-weighted MR images of lung cancers so as to improve the ability of radiomic features to distinguish between adenocarcinoma and other histological types. Materials and Methods: A discovery set of 52 patients with advanced lung cancer who underwent T2-weighted MR imaging at 3 Tesla in a single center study from August 2017 to May 2019 was used. Findings were then validated using a validation set of 19 additional patients included from May to October 2019. Tumor type was obtained from the pathology report after trans-thoracic needle biopsy, metastatic lymph node or metastasis samples, or surgical excisions. MR images were preprocessed using N4ITK bias field correction and by normalizing voxel intensities with fat as a reference region. Segmentation and extraction of radiomic features were performed with LIFEx software on the raw images, on the N4ITK-corrected images and on the fully preprocessed images. Two analyses were conducted where radiomic features were extracted: (1) from the whole tumor volume (3D analysis); (2) from all slices encompassing the tumor (2D analysis). Receiver operating characteristic (ROC) analysis was used to identify features that could distinguish between adenocarcinoma and other histological types. Sham experiments were also designed to control the number of false positive findings. Results: There were 31 (12) adenocarcinomas and 21 (7) other histological types in the discovery (validation) set. In 2D, preprocessing increased the number of discriminant radiomic features from 8 without preprocessing to 22 with preprocessing. 2D analysis yielded more features able to identify adenocarcinoma than 3D analysis (12 discriminant radiomic features after preprocessing in 3D). Preprocessing did not increase false positive findings as no discriminant features were identified in any of the sham experiments. The greatest sensitivity of the 2D analysis applied to preprocessed data was confirmed in the validation set. Conclusion: Correction for magnetic field inhomogeneities and normalization of voxel values are essential to reveal the full potential of radiomic features to identify the tumor histological type from MR T2-weighted images, with classification performance similar to those reported in PET/CT and in multiphase CT in lung cancers., (Copyright © 2020 Lacroix, Frouin, Dirand, Nioche, Orlhac, Bernaudin, Brillet and Buvat.)

Childhood pulmonary Langerhans cell histiocytosis (PLCH) is a rare disease. Its pulmonary histopathology, according to comprehensive clinical-radiological findings and BRAF V600E mutation status, has not yet been thoroughly documented. From the 167 childhood PLCH cases entered in the French National Histiocytosis Registry (1983-2016), we retrieved lung biopsies from a consecutive retrospective series of 17 patients, diagnosed when they were 2 weeks to 16 years old (median, 9.4 years), and report the clinical and histopathological findings herein. Histological analyses of biopsies (16 surgical and 1 postmortem) found the following features, alone or associated: Langerhans cell (LC) nodules with cavitation (9/17), cysts (14/17), fibrotic scars (2/17), peribronchiolar topographic distribution of the lesions (10/17), and accessory changes, like stretch emphysema (7/17). Those characteristics closely resemble those describing adult PLCH. However, unusual findings observed were 2 large nodules and a diffuse interstitial LC infiltrate. BRAF V600E mutation was detected in 4 of 12 samples tested, notably in the 3 with unusual features. In conclusion, childhood PLCH mostly shares the common histology features already described in adult PLCH, regardless of age. Because smoking is considered the major trigger in PLCH pathogenesis, the findings based on this series suggest other inducers of bronchiolar LC recruitment, especially in very young patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Circulating serum amyloid A (SAA) is increased in various inflammatory conditions. The human SAA protein family comprises the acute phase SAA1/SAA2, known to activate a large set of innate and adaptive immune cells, and the constitutive SAA4. The liver synthesis of SAA1/SAA2 is well-established but there is still an open debate on extrahepatic SAA expression especially in macrophages. We aimed to investigate the ability of human primary monocytes and monocyte-derived macrophages to express SAA1, SAA2 and SAA4 at both the transcriptional and protein levels, as previous studies almost exclusively dealt with monocytic cell lines. Monocytes and derived macrophages from healthy donors were stimulated under various conditions. In parallel with SAA, pro-inflammatory IL1A, IL1B and IL6 cytokine expression was assessed. While LPS alone was non-effective, a combined LPS/dexamethasone treatment induced SAA1 and to a lesser extent SAA2 transcription in human monocytes and macrophages. In contrast, as expected, pro-inflammatory cytokine expression was strongly induced following stimulation with LPS, an effect which was dampened in the presence of dexamethasone. Furthermore, in monocytes polarized towards a pro-inflammatory M1 phenotype, SAA expression in response to LPS/dexamethasone was potentiated; a result mainly seen for SAA1. However, a major discrepancy was observed between SAA mRNA and intracellular protein levels under the experimental conditions used. Our results demonstrate that human monocytes and macrophages can express SAA genes, mainly SAA1 in response to an inflammatory environment. While SAA is considered as a member of a large cytokine network, its expression in the monocytes-macrophages in response to LPS-dexamethasone is strikingly different from that observed for classic pro-inflammatory cytokines. As monocytes-macrophages are major players in chronic inflammatory diseases, it may be hypothesized that SAA production from macrophages may contribute to the local inflammatory microenvironment, especially when macrophages are compactly organized in granulomas as in sarcoidosis., Competing Interests: Pr. Dominique Valeyre reports personal fees as a member of scientific advisory board from Roche and Boehringer Ingelheim and from Astra Zenecca unrelated to the work submitted. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors declare no conflict of interest.

Background: Sarcoidosis, characterized by epithelioid granulomas, is considered to be caused by a complex interplay between genetics and environmental agents. It has been hypothesized that exogenous inorganic particles as crystalline silica could be a causal or adjuvant agent in sarcoidosis onset., Objectives: To investigate the location, frequency and physicochemical characteristics of foreign materials and mineral tissue deposits in the granulomatous area of cutaneous sarcoidosis., Methods: Skin biopsies (n = 14) from patients diagnosed with cutaneous sarcoidosis (mean age 43 years; 11 patients with extracutaneous involvement) were investigated using polarized light examination (PLE), μFourier Transform Infra-Red (μFT-IR) spectroscopy and Field Emission Scanning Electron Microscopy coupled with Energy Dispersive X-ray Spectroscopy (FE-SEM/EDX)., Results: Combined PLE, μFT-IR, FE-SEM/EDX analysis allowed to characterize mineral deposits in 7/14 biopsies (50%). It identified crystalline silica (SiO 2 ) inside granulomas in three biopsies and calcite (CaCO 3 ) at their periphery in 4., Conclusion: This study emphasizes the need of using combined methods for assessment of mineral deposits in granulomatous diseases. According to the location and characteristics of deposits, we can hypothesize that SiO 2 particles contribute to the granuloma formation, whereas CaCO 3 deposits are related to the granuloma biology. However, the significance of the association between SiO 2 deposits and sarcoidosis is still disputed., (© 2018 European Academy of Dermatology and Venereology.)

Endoplasmic Reticulum (ER) stress of alveolar epithelial cells (AECs) is recognized as a key event of cell dysfunction in pulmonary fibrosis (PF). However, the mechanisms leading to AECs ER stress and ensuing unfolded protein response (UPR) pathways in idiopathic PF (IPF) remain unclear. We hypothesized that alveolar hypoxic microenvironment would generate ER stress and AECs apoptosis through the hypoxia-inducible factor-1α (HIF-1α). Combining ex vivo, in vivo and in vitro experiments, we investigated the effects of hypoxia on the UPR pathways and ER stress-mediated apoptosis, and consecutively the mechanisms linking hypoxia, HIF-1α, UPR and apoptosis. HIF-1α and the pro-apoptotic ER stress marker C/EBP homologous protein (CHOP) were co-expressed in hyperplastic AECs from bleomycin-treated mice and IPF lungs, not in controls. Hypoxic exposure of rat lungs or primary rat AECs induced HIF-1α, CHOP and apoptosis markers expression. In primary AECs, hypoxia activated UPR pathways. Pharmacological ER stress inhibitors and pharmacological inhibition or silencing of HIF-1α both prevented hypoxia-induced upregulation of CHOP and apoptosis. Interestingly, overexpression of HIF-1α in normoxic AECs increased UPR pathways transcription factors activities, and CHOP expression. These results indicate that hypoxia and HIF-1α can trigger ER stress and CHOP-mediated apoptosis in AECs, suggesting their potential contribution to the development of IPF.

Background: Severe obstructive sleep apnea (OSA) with chronic intermittent hypoxia (IH) is common in idiopathic pulmonary fibrosis (IPF). Here, we evaluated the impact of IH on bleomycin- (BLM-) induced pulmonary fibrosis in mice., Methods: C57BL/6J mice received intratracheal BLM or saline and were exposed to IH (40 cycles/hour; FiO 2 nadir: 6%; 8 hours/day) or intermittent air (IA). In the four experimental groups, we evaluated (i) survival; (ii) alveolar inflammation, pulmonary edema, lung oxidative stress, and antioxidant enzymes; (iii) lung cell apoptosis; and (iv) pulmonary fibrosis., Results: Survival at day 21 was lower in the BLM-IH group ( p < 0.05). Pulmonary fibrosis was more severe at day 21 in BLM-IH mice, as assessed by lung collagen content ( p = 0.02) and histology. At day 4, BLM-IH mice developed a more severe neutrophilic alveolitis, ( p < 0.001). Lung oxidative stress was observed, and superoxide dismutase and glutathione peroxidase expression was decreased in BLM-IH mice ( p < 0.05 versus BLM-IA group). At day 8, pulmonary edema was observed and lung cell apoptosis was increased in the BLM-IH group., Conclusion: These results show that exposure to chronic IH increases mortality, lung inflammation, and lung fibrosis in BLM-treated mice. This study raises the question of the worsening impact of severe OSA in IPF patients.