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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.

IntroductionSarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures.MethodsAfter obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations.ResultsIn the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement.DiscussionThe observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene–environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.

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.

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by a male predominance. The aim of the study was to explore gender differences in a well-designed French multicentre prospective IPF cohort (COhorte FIbrose, COFI) with a 5-year follow-up.Methods: Between 2007 and 2010, 236 patients with incident IPF were included in COFI. Gender characteristics were compared using a t-test, Chi-squared test and ANOVA, as appropriate. Survival analyses were performed.Results: Fifty-one (22%) females and 185 (78%) males with an average age at diagnosis of 70.1 ± 9.20 and 67.4 ± 10.9 years, respectively, were included in the cohort. Women were significantly less exposed to tobacco smoke [never n = 32 (62.7%) vs. n = 39 (21.1%), p < 0.001] and to occupational exposure [n = 7 (13.7%) vs. n = 63 (34.1%), p = 0.012]. Baseline forced vital capacity, % of predicted (FVC%) was significantly better in women compare to men (83.0% ± 25.0 v. 75.4% ± 18.7 p = 0.046). At presentation honeycombing and emphysema on CT scan were less common in women [n = 40 (78.4%) vs. n = 167 (90.3%) p = 0.041] and [n = 6 (11.8%) vs. n = 48 (25.9%) p = 0.029], respectively. During follow-up fewer women were transplanted compared to men [n = 1 (1.96%) vs. n = 20 (10.8%) p = 0.039]. Medians of survival were comparable by gender [31 months (CI 95%: 28–40) vs. 40 months (CI 95%: 33–72) p = 0.2]. After adjusting for age and FVC at inclusion, being a woman was not associated to a better survival.Conclusions: Women appear to have less advanced disease at diagnosis, maybe due to less exposure history compare to men. Disease progression and overall survival remains comparable regardless gender, but women have less access to lung transplantation.

BackgroundMacrophages 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.MethodsWe 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% O2) or hypoxia (1.5% O2). 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.ResultsWe 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.ConclusionsHypoxia 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.

Background: A computational proteomic analysis suggested that SARS-CoV-2 might bind to hemoglobin (Hb). The authors hypothesized that this phenomenon could result in a decreased oxygen (O2) binding and lead to hemolytic anemia as well. The aim of this work was to investigate whether the affinity of Hb for O2 was altered during COVID-19.Methods: In this retrospective, observational, single-center study, the blood gas analyses of 100 COVID-19 patients were compared to those of 100 non-COVID-19 patients. Fifty-five patients with carboxyhemoglobin (HbCO) ≥8% and 30 with sickle cell disease (SCD) were also included (“positive controls” with abnormal Hb affinity). P50 was corrected for body temperature, pH, and PCO2.Results: Patients did not differ statistically for age or sex ratio in COVID-19 and non-COVID-19 groups. Median P50 at baseline was 26 mmHg [25.2–26.8] vs. 25.9 mmHg [24–27.3], respectively (p = 0.42). As expected, P50 was 22.5 mmHg [21.6–23.8] in the high HbCO group and 29.3 mmHg [27–31.5] in the SCD group (p < 0.0001). Whatever the disease severity, samples from COVID-19 to non-COVID-19 groups were distributed on the standard O2-Hb dissociation curve. When considering the time-course of P50 between days 1 and 18 in both groups, no significant difference was observed. Median Hb concentration at baseline was 14 g.dl–1 [12.6–15.2] in the COVID-19 group vs. 13.2 g.dl–1 [11.4–14.7] in the non-COVID-19 group (p = 0.006). Among the 24 COVID-19 patients displaying anemia, none of them exhibited obvious biological hemolysis.Conclusion: There was no biological argument to support the hypothesis that SARS-CoV-2 could alter O2 binding to Hb.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease, with a median survival of 2–3 years and variable natural history, characterized by gradual and progressive deterioration. Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe complication, associated with poor survival and a mortality > 50%. To date, no treatment has proven effective in AE-IPF, with cyclophosphamide (CYC) the only therapy suggested to be effective on survival, primarily based on retrospective series. Considering the high fatality rates of AE-IPF, evaluating the efficacy of immunosuppressive agents in a randomized controlled trial proves crucial, as the results could significantly impact treatment and prognosis of AE-IPF. Methods The EXAFIP study is a French national multicenter double-blind placebo-controlled randomized trial. Its primary objective is to evaluate the efficacy of CYC compared to placebo on early survival in patients treated with corticosteroids. We hypothesize that adding CYC to high-dose corticosteroids would reduce 3-month mortality in AE-IPF patients. The primary outcome is all-cause mortality rate at Month 3; secondary objectives are to evaluate the efficacy of CYC compared to placebo on overall survival at Months 6 and 12, respiratory disease-specific mortality, respiratory morbidity, and chest high-resolution computed tomography features, and to determine prognostic factors in AE-IPF and compare the safety of the two treatment arms during 6 months’ follow-up. Discussion There is an urgent unmet clinical need for effective AE-IPF treatment. The EXAFIP study is the first large Phase III placebo-controlled randomized trial evaluating the efficacy and safety of CYC added to corticosteroids in treating AE-IPF. The results of this study could significantly impact treatment strategy and prognosis of AE-IPF. Trial registration Clinical trials, NCT02460588; Date: June 2, 2015, prospectively; Issue date: 14/11/2017; Protocole Amendment Number: 03.

Pulmonary sarcoidosis presents substantial management challenges, with limited evidence on effective therapies and phenotypes. In the absence of definitive evidence, expert consensus can supply clinically useful guidance in medicine. An international panel of 26 experts participated in a Delphi process to identify consensus on pharmacological management in sarcoidosis with the development of preliminary recommendations. The modified Delphi process used three rounds. The first round focused on qualitative data collection with open-ended questions to ensure comprehensive inclusion of expert concepts. Rounds 2 and 3 applied quantitative assessments using an 11-point Likert scale to identify consensus. Key consensus points included glucocorticoids as initial therapy for most patients, with non-biologics (immunomodulators), usually methotrexate, considered in severe or extrapulmonary disease requiring prolonged treatment, or as a steroid-sparing intervention in cases with high risk of steroid toxicity. Biologic therapies might be considered as additive therapy if non-biologics are insufficiently effective or are not tolerated with initial biologic therapy, usually with a tumour necrosis factor-α inhibitor, typically infliximab. The Delphi methodology provided a platform to gain potentially valuable insight and interim guidance while awaiting evidenced-based contributions.

Abstract Background Sarcoidosis (OMIM 181000) is a multi-systemic granulomatous disorder of unknown origin. Despite multiple genome-wide association (GWAS) studies, no major pathogenic pathways have been identified to date. To find out relevant sarcoidosis predisposing genes, we searched for de novo and recessive mutations in 3 young probands with sarcoidosis and their healthy parents using a whole-exome sequencing (WES) methodology. Methods From the SARCFAM project based on a national network collecting familial cases of sarcoidosis, we selected three families (trios) in which a child, despite healthy parents, develop the disease before age 15 yr. Each trio was genotyped by WES (Illumina HiSEQ 2500) and we selected the gene variants segregating as 1) new mutations only occurring in affected children and 2) as recessive traits transmitted from each parents. The identified coding variants were compared between the three families. Allelic frequencies and in silico functional results were analyzed using ExAC, SIFT and Polyphenv2 databases. The clinical and genetic studies were registered by the ClinicalTrials.gov - Protocol Registration and Results System (PRS) (https://clinicaltrials.gov) receipt under the reference NCT02829853 and has been approved by the ethical committee (CPP LYON SUD EST – 2 – REF IRB 00009118 – September 21, 2016). Results We identified 37 genes sharing coding variants occurring either as recessive mutations in at least 2 trios or de novo mutations in one of the three affected children. The genes were classified according to their potential roles in immunity related pathways: 9 to autophagy and intracellular trafficking, 6 to G-proteins regulation, 4 to T-cell activation, 4 to cell cycle and immune synapse, 2 to innate immunity. Ten of the 37 genes were studied in a bibliographic way to evaluate the functional link with sarcoidosis. Conclusions Whole exome analysis of case-parent trios is useful for the identification of genes predisposing to complex genetic diseases as sarcoidosis. Our data identified 37 genes that could be putatively linked to a pediatric form of sarcoidosis in three trios. Our in-depth focus on 10 of these 37 genes may suggest that the formation of the characteristic lesion in sarcoidosis, granuloma, results from combined deficits in autophagy and intracellular trafficking (ex: Sec16A, AP5B1 and RREB1), G-proteins regulation (ex: OBSCN, CTTND2 and DNAH11), T-cell activation (ex: IDO2, IGSF3), mitosis and/or immune synapse (ex: SPICE1 and KNL1). The significance of these findings needs to be confirmed by functional tests on selected gene variants.

Abstract Background Sarcoidosis is a systemic disease characterized by the formation of immune granulomas in various organs, mainly the lungs and the lymphatic system. Exaggerated granulomatous reaction might be triggered in response to unidentified antigens in individuals with genetic susceptibility. The present study aimed to determine the genetic variants implicated in a familial case of sarcoidosis. Methods Sarcoidosis presentation and history, NOD2 profile, NF-κB and cytokine production in blood monocytes/macrophages were evaluated in individuals from a family with late appearance of sarcoidosis. Results In the present study, we report a case of familial sarcoidosis with typical thoracic sarcoidosis and carrying the NOD2 2722G > C variant. This variant is associated with the presence of three additional SNPs for the IL17RA, KALRN and EPHA2 genes, which discriminate patients expressing the disease from others. Despite a decrease in NF-κB activity, IL-8 and TNF-A mRNA levels were increased at baseline and in stimulated conditions. Conclusions Combination of polymorphisms in the NOD2, IL17RA, EPHA2 and KALRN genes could play a significant role in the development of sarcoidosis by maintaining a chronic pro-inflammatory status in macrophages.

Sarcoidosis is a multisystem disease characterized by the development and accumulation of granulomas, the hallmark of an inflammatory process induced by environmental and/or infectious and or genetic factors. This auto-inflammatory disease mainly affects the lungs, the gateway to environmental aggressions and viral infections. We have shown previously that genetic predisposition to sarcoidosis occurring in familial cases is related to a large spectrum of pathogenic variants with, however, a clustering around mTOR (mammalian Target Of Rapamycin)-related pathways and autophagy regulation. The context of the COVID-19 pandemic led us to evaluate whether such genetic defects may increase the risk of a severe course of SARS-CoV2 infection in patients with sarcoidosis. We extended a whole exome screening to 13 families predisposed to sarcoidosis and crossed the genes sharing mutations with the list of genes involved in the SARS-CoV2 host-pathogen protein-protein interactome. A similar analysis protocol was applied to a series of 100 healthy individuals. Using ENRICH.R, a comprehensive gene set enrichment web server, we identified the functional pathways represented in the set of genes carrying deleterious mutations and confirmed the overrepresentation of autophagy- and mitophagy-related functions in familial cases of sarcoidosis. The same protocol was applied to the set of genes common to sarcoidosis and the SARS-CoV2-host interactome and found a significant enrichment of genes related to mitochondrial factors involved in autophagy, mitophagy, and RIG-I-like (Retinoic Acid Inducible Gene 1) Receptor antiviral response signaling. From these results, we discuss the hypothesis according to which sarcoidosis is a model for studying genetic abnormalities associated with host response to viral infections as a consequence of defects in autophagy and mitophagy processes.

(1) Background: Systemic granulomatosis developed in a context of malignancy has already been reported. Our objective was to describe the clinical, radiological, functional, biological, and evolutive characteristics of sarcoidosis-like cancer-associated granulomatosis (SLCAG) and to compare them to those of sarcoidosis. (2) Methods: 38 patients with a biopsy-proven SLCAG developed after a diagnostic of malignancy were included. The control group consisted of sarcoidosis patients matched for age, sex, and radiologic stage. Clinical, biological, physiological, radiological, and outcome data were collected. (3) Results: The mean age of SLCAG patients was 51 ± 14 years. They were diagnosed within 15 ± 14 months of the cancer diagnosis (breast cancer most frequently). All SLCAG patients presented a thoracic involvement, extrathoracic locations were observed in 32% of subjects. SLCAG was more often asymptomatic than sarcoidosis (p < 0.0001). During follow-up, systemic treatment was less often required in SLCAG than in sarcoidosis (58% vs. 32%, p = 0.04 respectively) and SLCAG were characterized by a significantly less severe progression profile according to the Sarcoid Clinical Activity Classification, with a complete recovery more frequent at 5 years (p = 0.03). (4) Conclusion: This case-control study shows that SLCAG differs from sarcoidosis with a significantly more benign course. These results might argue for true differences in the physiopathology, which remain to be elucidated.

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.

Real-world studies include a broader patient population for a longer duration than randomised controlled trials (RCTs) and can provide relevant insights for clinical practice. PASSPORT was a multicentre, prospective, post-authorisation study of patients who were newly prescribed pirfenidone and followed for 2 years after initiating treatment. Physicians collected data on adverse drug reactions (ADRs), serious ADRs (SADRs) and ADRs of special interest (ADRSI) at baseline and then every 3 months. Post hoc stepwise logistic regression models were used to identify baseline characteristics associated with discontinuing treatment due to an ADR. Patients (n=1009, 99.7% with idiopathic pulmonary fibrosis) had a median pirfenidone exposure of 442.0 days. Overall, 741 (73.4%) patients experienced ADRs, most commonly nausea (20.6%) and fatigue (18.5%). ADRs led to treatment discontinuation in 290 (28.7%) patients after a median of 99.5 days. Overall, 55 (5.5%) patients experienced SADRs, with a fatal outcome in six patients. ADRSI were reported in 693 patients, most commonly gastrointestinal symptoms (38.3%) and photosensitivity reactions/skin rashes (29.0%). Older age and female sex were associated with early treatment discontinuation due to an ADR. Findings were consistent with the known safety profile of pirfenidone, based on RCT data and other post-marketing experience, with no new safety signals observed.

Sarcoidosis is a multi-system disease of unknown etiology characterized by the formation of granulomas in various organs. It affects people of all ethnic backgrounds and occurs at any time of life but is more frequent in African Americans and Scandinavians and in adults between 30 and 50 years of age. Sarcoidosis can affect any organ with a frequency varying according to ethnicity, sex and age. Intrathoracic involvement occurs in 90% of patients with symmetrical bilateral hilar adenopathy and/or diffuse lung micronodules, mainly along the lymphatic structures which are the most affected system. Among extrapulmonary manifestations, skin lesions, uveitis, liver or splenic involvement, peripheral and abdominal lymphadenopathy and peripheral arthritis are the most frequent with a prevalence of 25–50%. Finally, cardiac and neurological manifestations which can be the initial manifestation of sarcoidosis, as can be bilateral parotitis, nasosinusal or laryngeal signs, hypercalcemia and renal dysfunction, affect less than 10% of patients. The diagnosis is not standardized but is based on three major criteria: a compatible clinical and/or radiological presentation, the histological evidence of non-necrotizing granulomatous inflammation in one or more tissues and the exclusion of alternative causes of granulomatous disease. Certain clinical features are considered to be highly specific of the disease (e.g., Löfgren’s syndrome, lupus pernio, Heerfordt’s syndrome) and do not require histological confirmation. New diagnostic guidelines were recently published. Specific clinical criteria have been developed for the diagnosis of cardiac, neurological and ocular sarcoidosis. This article focuses on the clinical presentation and the common differentials that need to be considered when appropriate.

First of all, we would like to thank all the authors for their contribution and the editorial staff who enabled the achievement of this “Management of Sarcoidosis: Challenges and Solutions” Special Issue [...]

Sarcoidosis is a systemic disease of unknown cause with very diverse presentation, outcome, severity and need for treatments. While some presentations may be very typical, for many patients, the presentation is nonspecific, with shared associations with other diseases at times being by far more frequent or misleading, which can be a cause of significant delay and often several consultations before a diagnosis of sarcoidosis can be confirmed. This is particularly the case when pulmonary manifestations are in the forefront. The diagnosis relies on three well-known criteria. In clinical practice, these criteria are not easily implemented, particularly by physicians without expertise in sarcoidosis, which can lead to a risk of either under- or over-diagnosis. Qualifying the presentation according to sarcoidosis diagnosis is essential. However, it is often not easy to classify the presentation as typical versus compatible or compatible versus inconsistent. Further investigations are needed before any other hypothesis is to be considered. It is important to detect events and to determine whether or not they are indicative of a flare of sarcoidosis. Eventually, treatment needs to be related to the correct indications. The evaluation of the efficacy and safety of treatments is crucial. To address such issues, we present five emblematic cases that illustrate this.

Sarcoidosis is a complex disease that belongs to the vast group of autoinflammatory disorders, but the etiological mechanisms of which are not known. At the crosstalk of environmental, infectious, and genetic factors, sarcoidosis is a multifactorial disease that requires a multidisciplinary approach for which genetic research, in particular, next generation sequencing (NGS) tools, has made it possible to identify new pathways and propose mechanistic hypotheses. Codified treatments for the disease cannot always respond to the most progressive forms and the identification of new genetic and metabolic tracks is a challenge for the future management of the most severe patients. Here, we review the current knowledge regarding the genes identified by both genome wide association studies (GWAS) and whole exome sequencing (WES), as well the connection of these pathways with the current research on sarcoidosis immune-related disorders.

(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.

Idiopathic pulmonary fibrosis (IPF) is the most frequent chronic idiopathic interstitial pneumonia in adults. The management of rare diseases in France has been organised by a national plan for rare diseases, which endorsed a network of expert centres for rare diseases throughout France. This article is an overview of the executive summary of the French guidelines for the management of IPF, an initiative that emanated from the French National Reference Centre and the Network of Regional Competence Centres for Rare Lung Diseases. This review aims at providing pulmonologists with a document that: 1) combines the current available evidence; 2) reviews practical modalities of diagnosis and management of IPF; and 3) is adapted to everyday medical practice. The French practical guidelines result from the combined efforts of a coordination committee, a writing committee and a multidisciplinary review panel, following recommendations from the Haute Autorité de Santé. All recommendations included in this article received at least 90% agreement by the reviewing panel. Herein, we summarise the main conclusions and practical recommendations of the French guidelines.

Idiopathic pulmonary fibrosis (IPF) affects lung parenchyma with progressing fibrosis. In this study, we aimed to replicate MUC5B rs35705950 variants and determine new plausible candidate variants for IPF among four different European populations. We genotyped 26 IPF candidate loci in 165 IPF patients from four European countries: Czech Republic (n = 41), Germany (n = 33), Greece (n = 40), France (n = 51) and performed association study comparing observed variant distribution with this obtained in a genetically similar Czech healthy control population (n = 96) described in our earlier data report. A highly significant association for a promoter variant (rs35705950) of mucin encoding MUC5B gene was observed in all IPF populations, individually and combined [OR (95% CI); p-value as 5.23 (8.94-3.06); 1.80x10-11). Another non-coding variant, rs7934606 in MUC2 was significant among German patients [2.85 (5.05-1.60); 4.03x10-4] and combined European IPF cases [2.18 (3.16-1.50); 3.73x10-5]. The network analysis for these variants indicated gene-gene and gene-phenotype interactions in IPF and lung biology. With replication of MUC5B rs35705950 previously reported in U.S. populations of European descent and indicating other plausible polymorphic variants relevant for IPF, we provide additional reference information for future extended functional and population studies aimed, ideally with inclusion of clinical parameters, at identification of IPF genetic markers.

A new survey coordinated by the French expert centres for rare pulmonary diseases investigated French pulmonologists' diagnostic and therapeutic practice for idiopathic pulmonary fibrosis (IPF) and explored changes since a previous survey in 2011–2012. From May 16 to August 30, 2014, 524 pulmonologists were contacted. Those following at least one patient with IPF were invited to complete a questionnaire administered by telephone or e-mail. 166 (31.7%) pulmonologists, 161 (97%) of whom had participated to the first survey, completed the questionnaire. Of those, 46% and 52%, respectively, discussed the cases with radiologists and pathologists. Out of 144 pulmonologists practicing outside of expert centres, 80% indicated referring patients to those centres. The 2013 French practical guidelines for IPF were known by 92% of pulmonologists involved in IPF, 96% of whom considered them appropriate for practice. The multidisciplinary discussion form for IPF diagnosis was known by 74% and considered appropriate by 94%. Diagnosis and management resulted from multidisciplinary discussion in 50% of the cases. About 58% of patients were diagnosed with “mild to moderate IPF” as defined by forced vital capacity ≥50% of the predicted value and diffusing capacity for carbon monoxide ≥35% of predicted. At the time of the survey, 31% of physicians were using pirfenidone to treat patients with “mild-to-moderately severe IPF” and 30% generally prescribed no treatment. Substantial improvement has occurred since the 2011–2012 survey with regard to knowledge of guidelines and proper management of IPF. Early diagnosis still needs to be improved through the network of expert centres.

A polymorphism on the MUC5B promoter (rs35705950) has been associated with idiopathic pulmonary fibrosis (IPF) but not with systemic sclerosis (SSc) with interstitial lung disease (ILD). We genotyped the MUC5B promoter in the first 142 patients of the French national prospective cohort of IPF, in 981 French patients with SSc (346 ILD), 598 Italian patients with SSc (207 ILD), 1383 French controls and 494 Italian controls. A meta-analysis was performed including all American data available. The T risk allele was present in 41.9% of the IPF patients, 10.8% of the controls (P = 2 × 10(-44)), OR 6.3 [4.6-8.7] for heterozygous patients and OR 21.7 [10.4-45.3] for homozygous patients. Prevalence of the T allele was not modified according to age, gender, smoking in IPF patients. However, none of the black patients with IPF presented the T allele. The prevalence of the T risk allele was similar between French (10%) and Italian (12%) cohorts of SSc whatever the presence of an ILD (11.1% and 13.5%, respectively). Meta-analysis confirmed the similarity between French, Italian and American cohorts of IPF or SSc-ILD. This study confirms 1) an association between the T allele risk and IPF, 2) an absence of association with SSc-ILD, suggesting different pathophysiology.

New approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations.To determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases.We compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations.An Interferon-inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls.Tuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the heterogeneity of their profiles and their transcriptional response to treatment.