Search

Background: Sarcoidosis is a heterogeneous granulomatous disease with no accurate biomarkers of disease progression. Therefore, we profiled and integrated the DNA methylome, mRNAs, and microRNAs to identify molecular changes associated with sarcoidosis and disease progression that might illuminate underlying mechanisms of disease and potential biomarkers., Methods: Bronchoalveolar lavage cells from 64 sarcoidosis subjects and 16 healthy controls were used. DNA methylation was profiled on Illumina HumanMethylationEPIC arrays, mRNA by RNA-sequencing, and miRNAs by small RNA-sequencing. Linear models were fit to test for effect of sarcoidosis diagnosis and progression phenotype, adjusting for age, sex, smoking, and principal components of the data. We built a supervised multi-omics model using a subset of features from each dataset., Results: We identified 1,459 CpGs, 64 mRNAs, and five miRNAs associated with sarcoidosis versus controls and four mRNAs associated with disease progression. Our integrated model emphasized the prominence of the PI3K/AKT1 pathway, which is important in T cell and mTOR function. Novel immune related genes and miRNAs including LYST, RGS14, SLFN12L, and hsa-miR-199b-5p, distinguished sarcoidosis from controls. Our integrated model also demonstrated differential expression/methylation of IL20RB, ABCC11, SFSWAP, AGBL4, miR-146a-3p, and miR-378b between non-progressive and progressive sarcoidosis., Conclusions: Leveraging the DNA methylome, transcriptome, and miRNA-sequencing in sarcoidosis BAL cells, we detected widespread molecular changes associated with disease, many which are involved in immune response. These molecules may serve as diagnostic/prognostic biomarkers and/or drug targets, although future testing is required for confirmation., (© 2024. The Author(s).)

Granulomas are frequently encountered by pathologists in all types of lung specimens and arise from diverse etiologies. They should always be reported as necrotizing or non-necrotizing, with microorganism stains performed to evaluate for infection. With attention to distribution, quality (poorly vs well-formed), associated features, and correlation with clinical, radiologic, and laboratory data, the differential diagnosis for granulomatous lung disease can usually be narrowed to a clinically helpful "short list." This review describes a practical approach to pulmonary granulomas and reviews the clinicopathological aspects of common entities, including infectious (mycobacteria, fungi) and noninfectious (hypersensitivity pneumonitis, sarcoid, and vasculitis) causes., Competing Interests: Disclosure No disclosures or conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Different patterns of fibrosis on high-resolution CT scans (HRCT) have been associated with reduced survival in some interstitial lung diseases. Nothing is known about HRCT scan patterns and survival in sarcoidosis., Research Question: Will a detailed description of the extent and pattern of HRCT scan fibrosis in patients with stage IV pulmonary sarcoidosis impact pulmonary function and survival?, Study Design and Methods: Two hundred forty patients with stage IV sarcoidosis at two large tertiary institutions were studied. The earliest HRCT scan with fibrosis was reviewed for extent of fibrosis (< 10%, 10%-20%, and > 20%) and presence of bronchiectasis, upper lobe fibrocystic changes, basal subpleural honeycombing, ground-glass opacities (GGOs), large bullae, and mycetomas. Presence of sarcoidosis-associated pulmonary hypertension (SAPH) and pulmonary function testing performed within 1 year of HRCT were recorded. Patients were followed up until last clinic visit, death, or lung transplantation., Results: The mean age was 58.4 years. Seventy-four percent were Black, 63% were female, and mean follow-up was 7.4 years. Death or LT occurred in 53 patients (22%). Thirty-one percent had > 20% fibrosis, 25% had 10%-20% fibrosis, and 44% had < 10% fibrosis. The most common HRCT abnormalities were bronchiectasis (76%), upper lobe fibrocystic changes (36%), and GGOs (28%). Twelve percent had basal subpleural honeycombing, and 32% had SAPH. Patients with > 20% fibrosis had more severe pulmonary impairment, were more likely to have SAPH (53%), and had worse survival (44% mortality; P < .001). Upper lobe fibrocystic changes, basal subpleural honeycombing, and large bullae were associated with worse pulmonary function and worse survival. Patients with basal subpleural honeycombing had the worst pulmonary function and survival (55% mortality; P < .001). GGOs were associated with worse pulmonary function but not worse survival, and mycetomas were associated with worse survival but not worse pulmonary function. A Cox proportional hazards model indicated that basal subpleural honeycombing (hazard ratio, 7.95), diffusion capacity for carbon monoxide < 40% (HR, 5.67) and White race (hazard ratio, 2.61) were independent predictors of reduced survival., Interpretation: HRCT scan features of fibrotic pulmonary sarcoidosis had an impact on pulmonary function and survival. Presence of >20% fibrosis and basal subpleural honeycombing are predictive of worse pulmonary function and worse survival in patients with stage IV pulmonary sarcoidosis., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: O. N. O. has received consulting fees from CSL-Behring and received research assistance/served as principal investigator (PI) for sarcoidosis industry sponsored studies conducted by aTYR, Novartis, Kinevant, and Xentria. E. E. L. and R. P. B. have received research grants and/or served as consultants for Janssen, Mallinckrodt, aTyr, Novartis, Xentria, Actelion, Genentech and Gilead. R. P. B. has been a speaker for Mallinckrodt. V. M. has received research assistance from United Therapeutics. There were no potential conflicts of interests with respect to the research, authorship, and/or publication of this paper. None declared (S. A.)., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Sarcoidosis is a multisystem inflammatory disorder with unclear etiology and can often pose a diagnostic challenge. A tissue diagnosis is often necessary to illustrate the non-caseating granulomas on histopathology. This review aims to synthesize current evidence related to tissue diagnosis of sarcoidosis using various bronchoscopic techniques. We start by discussing standard bronchoscopic techniques which have remained the cornerstone of diagnostic workup such as bronchoalveolar lavage (BAL), endobronchial biopsy (EBB), conventional transbronchial needle aspiration (cTBNA) and transbronchial lung biopsy (TBLB) followed by newer modalities that incorporate real-time image guidance using endobronchial and endoscopic ultrasound. Although BAL, EBB, and TBLB have been employed as a diagnostic tool for several decades, their sensitivity and diagnostic yield is inferior to ultrasound-based endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). More recently, convincing evidence has also emerged to support the diagnostic accuracy and tissue yield of transbronchial lung cryobiopsy which will also be discussed in this review. These advances in bronchoscopic equipment and techniques over the last 2 decades have made it possible to obtain tissue samples using minimally invasive techniques thus avoiding invasive open lung biopsy and the risks that inherently follow. Up-to-date knowledge of these modalities is imperative for ensuring evidence-based medicine and improving patient-centric outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Diagnosis of sarcoidosis depends on a compatible clinical and imaging presentation, histologic finding of non-necrotizing granulomatous inflammation, and exclusion of alternative causes of granulomatous diseases. This study has reviewed the diagnostic algorithms and approaches of sarcoidosis., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Tuberculosis (TB) and sarcoidosis are both granulomatous diseases. Here, we compared the immunological microenvironments of granulomas from TB and sarcoidosis patients using in situ sequencing (ISS) transcriptomic analysis and multiplexed immunolabeling of tissue sections. TB lesions consisted of large necrotic and cellular granulomas, whereas "multifocal" granulomas with macrophages or epitheloid cell core and a T-cell rim were observed in sarcoidosis samples. The necrotic core in TB lesions was surrounded by macrophages and encircled by a dense T-cell layer. Within the T-cell layer, compact B-cell aggregates were observed in most TB samples. These B-cell clusters were vascularized and could contain defined B-/T-cell and macrophage-rich areas. The ISS of 40-60 immune transcripts revealed the enriched expression of transcripts involved in homing or migration to lymph nodes, which formed networks at single-cell distances in lymphoid areas of the TB lesions. Instead, myeloid-annotated regions were enriched in CD68 , CD14 , ITGAM , ITGAX , and CD4 mRNA. CXCL8 and IL1B mRNA were observed in granulocytic areas in which M. tuberculosis was also detected. In line with ISS data indicating tertiary lymphoid structures, immune labeling of TB sections expressed markers of high endothelial venules, follicular dendritic cells, follicular helper T cells, and lymph-node homing receptors on T cells. Neither ISS nor immunolabeling showed evidence of tertiary lymphoid aggregates in sarcoidosis samples. Together, our finding suggests that despite their heterogeneity, the formation of tertiary immune structures is a common feature in granulomas from TB patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Carow, Muliadi, Skålén, Yokota, Kathamuthu, Setiabudiawan, Lange, Scheu, Gaede, Goldmann, Pandita, Masood, Pervez, Grunewald, Hasan, Levin and Rottenberg.)

Introduction: Observational data suggest that the 19-gauge (G) needle for endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) offers a higher diagnostic yield than the 22-G needle in sarcoidosis. No randomized trial has compared the yield of the two needles., Methods: We randomized consecutive subjects with suspected sarcoidosis and enlarged thoracic lymph nodes to undergo EBUS-TBNA with either the 19-G or the 22-G needle. We compared the study groups for diagnostic sensitivity (primary outcome) assessed by the yield of granulomas in subjects finally diagnosed with sarcoidosis. We also compared the sample adequacy, difficulty performing the needle puncture assessed on a visual analog scale (VAS), the subject's cough intensity on an operator-rated VAS, and procedure-related complications (secondary outcomes)., Results: We randomized 150 (mean age, 43.0 years; 55% women) subjects and diagnosed sarcoidosis in 116 subjects. The diagnostic sensitivity of the 19-G needle (45/60, 75.0%) was not higher (p = 0.52) than the 22-G needle (39/56, 69.6%). We obtained adequate aspirates in 90.0% and 85.7% of subjects in the respective groups (p = 0.48). The operators had greater difficulty puncturing lymph nodes with the 19-G needle (p = 0.03), while the operator-assessed cough intensity was similar in the groups (p = 0.41). Transient hypoxemia was the only complication encountered during EBUS-TBNA (two subjects in either group)., Conclusion: We did not find the 19-G needle superior to the 22-G in diagnostic sensitivity, specimen adequacy, or safety of EBUS-TBNA in sarcoidosis. Puncturing the lymph nodes was more difficult with the 19-G needle., (© 2024 S. Karger AG, Basel.)

Background: The ability of high-definition (HD) videobronchoscopy to detect airway involvement in sarcoidosis has not been evaluated previously., Research Question: What is the role of HD videobronchoscopy in the identification of sarcoidosis-associated airway abnormalities (AAs)? What are the patterns of AAs more commonly observed and more frequently associated with the detection of granulomas in endobronchial biopsy (EBB)?, Study Design and Methods: In this prospective international multicenter cohort study, consecutive patients with suspected sarcoidosis underwent airway inspection with an HD videobronchoscope and EBB using a standardized workflow. AAs were classified according to six patterns defined a priori: nodularity, cobblestoning, thickening, plaque, increased vascularity, and miscellaneous. We assessed diagnostic yield of EBB, prevalence of AAs, and interobserver agreement for different patterns of AAs., Results: AAs were identified in 64 of 134 patients with sarcoidosis (47.8%), with nodularity (n = 23 [17.2%]), plaque (n = 19 [14.2%]), and increased vascularity (n = 19 [14.2%]) being the most prevalent. The diagnostic yield of EBB was 36.6%. AAs were significantly more prevalent in patients with than in those without nonnecrotizing granulomas on EBB (67.4% vs 36.5%; P = .001). Likewise, parenchymal disease on CT scan imaging was significantly more common in patients with than in those without nonnecrotizing granulomas on EBB (79.6% vs 54.1%; P = .003). On a per-lesion analysis, nonnecrotizing granulomas were seen especially in EBB samples obtained from areas of cobblestoning (9/10 [90%]) and nodularity (17/29 [58.6%]). The overall diagnostic yield of random EBB was low (31/134 [23.1%]). The interobserver agreement for the different patterns of AA was fair (Fleiss κ = 0.34)., Interpretation: In a population with a large prevalence of White Europeans, HD videobronchoscopy detected AAs in approximately one-half of patients with sarcoidosis. The diagnostic yield of EBB was higher in patients with parenchymal involvement on CT scan imaging and in those with AAs, especially if manifesting as cobblestoning and nodularity., Trial Registry: ClinicalTrials.gov; No.: NCT4743596; URL: www., Clinicaltrials: gov., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: There are few reports on the utility of bronchoscopic narrow-band imaging (NBI) for visualizing endobronchial abnormalities in sarcoidosis. Our primary objective was to compare the sensitivity of finding endobronchial abnormality using NBI versus white light bronchoscopy (WLB) in patients with sarcoidosis. The secondary aim was to evaluate the sensitivity of NBI in diagnosing endobronchial sarcoidosis against a reference standard of positive endobronchial biopsy (EBB)., Methods: We retrospectively included subjects with sarcoidosis, where we sequentially recorded WLB and NBI videos to visualize the endobronchial mucosa. We collected data on the demographic findings, sarcoidosis stage, and the histopathological findings of transbronchial needle aspiration, EBB, and transbronchial lung biopsy. Three experienced bronchoscopists viewed the video recordings and noted the abnormalities of the airway mucosa separately on WLB and NBI., Results: We included 28 subjects (mean age, 42.9 y; 53.6% men; 14 each, stages 1 and 2) with a final diagnosis of sarcoidosis. Granulomas were detected on EBB in 11 (39.3%) subjects. We identified endobronchial nodules in 10 and 15 subjects on WLB and NBI. The sensitivity of finding endobronchial abnormality using WLB and NBI was 35.7% (10/28) and 53.6% (15/28), respectively (χ 2 =1.77, df=1, P =0.18). The sensitivity of NBI in diagnosing endobronchial sarcoidosis against a positive EBB was 63.6% (7/11 subjects). There was excellent agreement (Κ=0.86) for detecting nodules on NBI among the 3 observers., Conclusion: NBI might allow the identification of additional abnormalities not detected on WLB in sarcoidosis. Larger studies are required to confirm our observations., Competing Interests: Disclosure: There is no conflict of interest or other disclosures., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Lung transplantation is the definitive therapy for end-stage pulmonary sarcoidosis. While recurrent sarcoidosis in allografts has been described in several case reports, the incidence and clinicopathologic characteristics remain unclear. In this study, we characterize the clinical and histopathologic features of recurrent sarcoidosis diagnosed in posttransplant lung surveillance transbronchial biopsies (TBBx). We identified 35 patients who underwent lung transplant for pulmonary sarcoidosis during the study period. Among them, 18 patients (51%) experienced recurrent sarcoidosis posttransplant. These included 7 females and 11 males with mean age at recurrence of 51.6 years. The average time interval from transplant to recurrence was 252 days (22 to 984 d). All TBBx contained >4 pieces of alveolated lung tissue with no evidence of International Society for Heart and Lung Transplantation (ISHLT) grade A2, A3, or A4 acute cellular rejection; chronic rejection; or antibody-mediated rejection. There were 33 surveillance TBBx that contained granulomatous inflammation with a mean of 3.6 well-formed granulomas per TBBx (range: 1 to >20). Multinucleated giant cells were identified in 11 TBBx (33.3%), with 1 case containing asteroid bodies. While most of the granulomas were "naked granulomas," 5 cases (15.2%) showed prominent lymphoid cuffing. Two cases showed evidence of fibrosis. One of the granulomas had focal necrosis; however, no infectious organisms were identified by special stains and clinical correlation suggested this case represented recurrent sarcoidosis. Biopsies of recurrent sarcoidosis usually show multiple well-formed granulomas with giant cells in more than half of the cases, while lymphoid cuffing, fibrosis, asteroid bodies, and necrotizing granulomas are uncommon findings. Pathologists should be aware of these features, as recurrence of sarcoidosis following lung transplant occurs in more than half of patients., Competing Interests: Conflicts of Interest and Source of Funding: A portion of this work was supported by the Barnes-Jewish Hospital Foundation (grant number 5192). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Sarcoidosis is a multi-system, idiopathic, inflammatory disorder that affects the lungs in over 90% of patients. The incidence of bone lesions in sarcoidosis is only 1-13%., Case Report: This study describes a 60-year-old woman with a previous history of thyroid cancer, and a more recent diagnosis of lung cancer with suspicious metastatic lesions, which were confirmed to be sarcoidosis., Conclusion: This case suggests that pulmonary neoplasms and pulmonary sarcoidosis can coexist and be easily confused. When lung cancer is accompanied by symmetric hilar lymph node enlargement and multiple lung nodules, sarcoidosis should be considered in addition to metastasis, and a biopsy should be performed for confirmation.

Case Presentation: A 63-year-old man presented with fever, thoracalgia, weight loss, diffuse lymphadenopathy, and a massive pleural effusion. Extensive laboratory and radiologic investigations for possible autoimmune, infectious, hematologic, and neoplastic conditions all resulted negative. A lymph node biopsy showed a granulomatous necrotizing lymphadenitis, suspicious for tuberculosis. Although mycobacterium tuberculosis (MT) was never isolated and tuberculin skin test resulted negative, diagnosis of extrapulmonary tuberculosis was made and anti-tubercular therapy was started. Despite the strict adherence to 5 months of treatment, he returned to the emergency ward complaining of fever, chest pain and pleural effusion; total-body CT and PET scans demonstrated a progression of new disseminated nodular consolidations., Diagnostic Work-Up: Microscopic and cultural search for MT and other micro-organisms resulted again negative on urine, stool, blood, pleural fluid, and spinal lesion biopsy. We therefore started considering alternative diagnosis for necrotizing granulomatosis, including multidrug-resistant tuberculosis, Wegener granulomatosis, Churg Strauss syndrome, necrobiotic nodules of rheumatoid arthritis, lymphomatoid granulomatosis and Necrotizing Sarcoid Granulomatosis (NSG). Having already rejected other autoimmune, hematological, and neoplastic disorders, NSG resulted the most consistent hypothesis. With an expert we thus re-examined histological specimens that were suggestive for an atypical presentation of sarcoidosis. Steroid therapy was initiated, achieving symptoms improvement., Discussion: Sarcoidosis is a rare condition that can be challenging to diagnose, due to its variability in clinical presentation, often mimicking alternative conditions like disseminated tuberculosis. A high degree of suspicion and an experienced lab in anatomical pathology are essential for final diagnosis., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is valuable for diagnosing pulmonary sarcoidosis. We aimed to evaluate the diagnostic yield of EBUS-TBNA and cytology in sarcoidosis during the first 9 years at our institution., Methods: Patients who underwent EBUS-TBNA for suspected sarcoidosis between January 2011 and November 2019 were identified retrospectively. EBUS-TBNA was performed with rapid on-site cytological evaluation of the samples. The final diagnosis was based on the pathology and/or cytology results, radiologic features, and clinical follow-up findings. The yield rate was analyzed annually., Results: Eighty patients underwent 83 EBUS-TBNA procedures for suspected sarcoidosis. In total, 136 lymph nodes were sampled. The mean number of lymph node stations sampled was 2.0 ± 0.6; the mean number of needle passes per lymph node was 3.5 ± 0.8. Sixty-five patients were diagnosed with sarcoidosis, with a total of 68 procedures. Nonnecrotizing granulomatous inflammation was detected in the EBUS-TBNA samples from 49/68 procedures (yield rate: 72.1%). Of 19 patients with sarcoidosis who did not obtain a pathological diagnosis with EBUS-TBNA, epithelioid cells and/or multinuclear giant cells suggestive of granulomatous inflammation were detected in five. The sensitivity, specificity, positive predictive value, and negative predictive value (NPV) for pathological diagnosis of sarcoidosis using EBUS-TBNA were 72.1%, 100%, 100%, and 24.0%, respectively. On using cytology, the sensitivity and NPV increased to 79.4% and 26.3%, respectively. The yield rate did not increase until 2016., Conclusion: EBUS-TBNA is useful for diagnosing sarcoidosis. Cytology resulted in an additional yield rate of 7.3%, which improved as the number of cases increased., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Necrotizing sarcoid granulomatosis (NSG) is a rare disease that shares similarities with pulmonary vasculitides and sarcoidosis. This is a report of two cases of NSG with a review of literature. The first case is a 33-year-old black female with a one-year history of malaise and cough. Lung imaging revealed scattered pulmonary nodules. Histopathology showed multiple necrotizing granulomas without prominent neutrophilic infiltrates. The second case is a 58-year-old white female with a one-year history of fatigue, dyspnea, and ophthalmoplegia on the left eye. Imaging showed multiple pulmonary nodules. Lung biopsy was consistent with NSG. The challenge of the NSG diagnosis is to distinguish it from other mimickers. Pathology often shows necrotizing granulomatous vasculitis, distinguishing it from classical sarcoid. Laboratory markers for vasculitis like neutrophil cytoplasmic antibodies and antibodies against myeloperoxidase and proteinase 3 are negative or only low titers. NSG responds well to immune-suppression, most commonly with glucocorticoids., Competing Interests: Declaration of Competing Interest There is no conflict of interest in this paper., (Copyright © 2022 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: There is little information on the value of different processing methods for samples obtained during endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) in suspected sarcoidosis. We evaluated the role of conventional smears, liquid-based cytology (LBC), cell-blocks and flow cytometric immunophenotyping in the diagnosis of sarcoidosis using EBUS-TBNA samples., Methods: This was a prospective study of consecutive EBUS-TBNA samples from clinically suspected cases of sarcoidosis. In addition to conventional smears, we prepared LBC smears, cell-blocks, and performed flow cytometric evaluation of the CD4:CD8 ratio. The final diagnosis of sarcoidosis was made based on the relevant clinical details and laboratory investigations including the results of transbronchial and endobronchial biopsies (TBLB and endobronchial biopsy)., Results: We included 60 subjects [mean age: 45.2 y; 29 (48.3%) men]. The sensitivity of conventional smears, LBC, and cell-blocks for diagnosing sarcoidosis was found to be 75.5%, 37.8%, 35%, respectively, when used alone. However, on combining conventional and LBC smears, the sensitivity increased to 84.4% and on combining all three techniques, the sensitivity was 86.7%. The CD4:CD8 ratio on flow cytometric immunophenotyping of EBUS-TBNA samples ranged from 0 to 11.5 with a mean of 3.17±2.78 in confirmed cases of sarcoidosis and 70% of these cases had CD4:CD8 ratio of more than 2., Conclusion: Cell-blocks and liquid-based preparations add to the yield of conventional preparation of EBUS-TBNA samples in the diagnosis of sarcoidosis. A combination of conventional and LBC works well in detecting almost 85% of the cases of sarcoidosis. Higher CD4:CD8 ratio favors a diagnosis of sarcoidosis., Competing Interests: Disclosure: There is no conflict of interest or other disclosures., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Sarcoidosis is a multi-system disorder with an increasing propensity to present in older patients. Diagnostic uncertainty is common and understandable given the higher prevalence of co-morbidities in older patients and broad differential for multi-system clinical presentations. Excluding malignancy and infection with a high degree of certainty is challenging and may require repeated confirmatory investigation where the diagnosis remains in doubt., Summary of Main Findings: There are a paucity of studies examining late-onset sarcoidosis. Female predominance, pulmonary, ocular, skin and systemic symptoms are common, while more classical presentations such as Lofgren's syndrome are uncommon. Positivity rates of biopsies vary between studies; however, targeted biopsies of accessible sites with organ involvement are the most successful. Therapeutic management is directed at reducing inflammation, and thereby reducing symptom burden, improving quality of life and avoiding progression of organ damage. While most older patients will require corticosteroid therapy, they are also more prone to developing adverse effects. Most older patients will experience a clinical remission; however, the risk of developing chronic sarcoidosis and organ damage is higher compared with younger counterparts. Patients with evidence of pulmonary fibrosis and pulmonary hypertension are at particular risk., Impact on Clinical Practice: Health care providers who care for older adults should be aware of the increasing prevalence of late-onset sarcoidosis and consider the diagnosis in those who present with otherwise unexplained systemic symptoms, thoracic abnormalities on imaging and/or evidence of other organ involvement. Earlier diagnosis and therapeutic intervention to halt the development of pulmonary fibrosis and pulmonary hypertension and monitoring for treatment-related adverse effects will confer a mortality benefit., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Miliary sarcoidosis is a rare form of sarcoidosis characterized by numerous miliary-like micronodules dispersed throughout the lungs. It has been documented in less than 1% of all sarcoidosis cases. We first described a rare case of miliary sarcoidosis and then conducted a literature review on the subject., Case Presentation: A 51-year-old male complained about a progressive loss of appetite, significant weight loss, occasional night sweats, and fatigue. After a thorough clinical exploration, a differential diagnosis of miliary lung disease was suspected - miliary tuberculosis, fungal infection, metastatic pulmonary carcinoma, or sarcoidosis. High-resolution chest computed tomography revealed bilateral diffuse micronodules with mediastinal lymphadenopathy. Histopathological analysis of transbronchial bioptic tissue identified non-caseating epithelioid granulomas, while no malignant cells were found. Lung tuberculosis and fungal infections were excluded. The levels of angiotensin-converting enzyme in the blood, as well as serum's and 24-hour urine calcium levels, were elevated. After a multidisciplinary discussion, the diagnosis of miliary pulmonary sarcoidosis was established. The patient was treated with prednisone for a total of 9 months, with full clinical and radiological recovery. Using PubMed, we also conducted a review of the literature on this topic and discovered only a few case reports of patients with miliary sarcoidosis, with just one systematic review accessible. The key findings of studies investigating patients diagnosed with miliary sarcoidosis are tabularly displayed., Conclusions: Miliary sarcoidosis is an uncommon type of pulmonary sarcoidosis that can mimic several entities that manifest as miliary nodules. Most patients require treatment since it can have a significant impact on lung function.

Purpose: To explore the clinical significance of anti-rabphillin-3A antibody for the differential diagnosis of lymphocytic panhypophysitis., Methods and Results: A 58-year-old Japanese man developed uveitis of unknown cause in 2017. In 2019, he became aware of polyuria. In August 2020, he noticed transient diplopia and was diagnosed with right abducens nerve palsy. At the same time, he complained of fatigue and loss of appetite. Head magnetic resonance imaging demonstrated enlargement of the pituitary stalk and pituitary gland, corresponding to hypophysitis. Hormone stimulation tests showed blunted responses with respect to all anterior pituitary hormones. Central diabetes insipidus was diagnosed on the basis of a hypertonic saline loading test. Taking these findings together, a diagnosis of panhypopituitarism was made. Computed tomography showed enlargement of hilar lymph nodes. Biopsies of the hilar lymph nodes revealed non-caseating epithelioid cell granulomas that were consistent with sarcoidosis. Biopsy of the anterior pituitary revealed mild lymphocyte infiltration in the absence of IgG4-positive cells, non-caseating granulomas, or neoplasia. Western blotting revealed the presence of anti-rabphilin-3A antibody, supporting a diagnosis of lymphocytic panhypophysitis. Because the patient had no visual impairment or severe uveitis, we continued physiological hormone replacement therapy and topical steroid therapy for the uveitis., Conclusion: To the best of our knowledge, this is the first case of anti-rabphilin 3A antibody positive lymphocytic panhypophysitis comorbid with sarcoidosis, diagnosed by both pituitary and hilar lymph node biopsy. The utility of anti-rabphilin-3A antibody for the differential diagnosis of hypophysitis like this case should be clarified with further case studies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The COVID-19 pandemic has resulted in dramatic loss of life worldwide, but as the large number of acutely ill patients subsides, the emerging group of "COVID-19 long-haulers" present a clinical challenge. Studies have shown that many of these patients suffer long-term pulmonary disease related to residual fibrosis. Prior studies have shown that while many patients have non-specific findings of fibrotic-like changes, others develop specific patterns of interstitial lung disease., Case Report: Here, we present the first case of a patient developing pulmonary sarcoidosis one year after critical illness from COVID-19. He developed numerous non-necrotizing and well-formed granulomas in mediastinal lymph nodes and pulmonary nodules, compatible radiographically and pathologically with sarcoid., Conclusions: While the pathophysiology of sarcoid is incompletely understood, inflammation is mediated through the dysregulation of a number of different cytokines (IFNγ, IL-2, IL-12, IL-17, IL-22). This case provides valuable clues for better understanding of the shared pathophysiology of cytokine dysregulation seen in COVID-19 and other interstitial lung diseases such as sarcoidosis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We herein report the long-term changes in chest computed tomography (CT) findings from early sarcoidosis lesions to pleuroparenchymal fibroelastosis (PPFE)-like lesions in a 30-year-old man with granulomas on a transbronchial lung biopsy. Multiple bilateral micronodular and nodular opacities around the bronchovascular bundle in the upper lobes detected by chest CT in 2004 disappeared, but paradoxically, peripheral consolidations continued to grow at the periphery of the original lesions. Chest CT in 2017 confirmed the progression of bilateral shrinkage of the upper lobe, spread of peripheral consolidations and wedge-shaped opacities below the first rib, and bronchiectatic air bronchograms, confirming PPFE-like lesions.

Necrotizing sarcoid granulomatosis (NSG) is a rare inflammatory disease. Although considered by some to be a subtype of sarcoidosis, this opinion is not universal. NSG is histologically characterized by the presence of necrotizing sarcoid like granuloma and granulomatous vasculitis. The exclusion of potential etiologies for necrotizing granulomatous inflammation is necessary to establish a diagnosis of NSG. A 70-year old female presented to our office after she was incidentally found to have a right lung cavitary lesion on a shoulder X-ray. She had an extensive serologic workup for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, mycobacterial and fungal etiologies, but they were all negative. She subsequently underwent bronchoscopic evaluation and biopsies. The histopathologic analysis revealed sarcoid-like granulomatous inflammation with large necrosis and mild granulomatous vasculitis. The pulmonary function test revealed a restrictive ventilatory defect. The patient was treated with steroid therapy with rapid radiologic and spirometric improvement., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to disclose., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Introduction: Sarcoidosis is a granulomatous inflammatory disease with high chances of reduced quality of life, irreversible organ damage, and reduced life expectancy when vital organs are involved. Any organ system can be affected, and the lungs are most often affected. There is no preventive strategy as the exact etiology is unknown, and complex immunogenetic and environmental factors determine disease susceptibility and phenotype. Present-day treatment options originated from clinical practice and are effective in many patients. However, a substantial percentage of patients suffer from unacceptable side effects or still develop refractory, threatening pulmonary or extrapulmonary disease., Areas Covered: As non-caseating granulomas, the pathological hallmark of disease, are assigned to divergent activation and regulation of the immune system, targets in relation to the possible triggers of granuloma formation and their sequelae were reviewed., Expert Opinion: The immunopathogenesis underlying sarcoidosis has been a dynamic field of study. Several recent new insights give way to promising new therapeutic targets, such as certain antigenic triggers (e.g. from Aspergillus nidulans ), mTOR, JAK-STAT and PPARγ pathways, the NRP2 receptor and MMP-12, which await further exploration. Clinical and trigger related phenotyping, and molecular endotyping will likely hold the key for precision medicine in the future.

Rationale: Pulmonary sarcoidosis is generally presumed to be a T-helper cell type 1- and macrophage-driven disease. However, mouse models have recently revealed that chronically inflamed lung tissue can also comprise T follicular helper (Tfh)-like cells and represents a site of active T-cell/B-cell cooperation. Objectives: To assess the role of pulmonary Tfh- and germinal center-like lymphocytes in sarcoidosis. Methods: BAL fluid, lung tissue, and peripheral blood samples from patients with sarcoidosis were analyzed by flow cytometry, immunohistology, RNA sequencing, and in vitro T-cell/B-cell cooperation assays for phenotypic and functional characterization of germinal center-like reactions in inflamed tissue. Measurements and Main Results: We identified a novel population of Tfh-like cells characterized by high expression of the B helper molecules CD40L and IL-21 in BAL of patients with sarcoidosis. Transcriptome analysis further confirmed a phenotype that was both Tfh-like and tissue resident. BAL T cells provided potent help for B cells to differentiate into antibody-producing cells. In lung tissue, we observed large peribronchial infiltrates with T and B cells in close contact, and many IgA + plasmablasts. Most clusters were nonectopic; that is, they did not contain follicular dendritic cells. Patients with sarcoidosis also showed elevated levels of PD-1 high CXCR5 - CD40L high ICOS high Tfh-like cells, but not classical CXCR5 + Tfh cells, in the blood. Conclusions: Active T-cell/B-cell cooperation and local production of potentially pathogenic antibodies in the inflamed lung represents a novel pathomechanism in sarcoidosis and should be considered from both diagnostic and therapeutic perspectives.

Sarcoidosis (SA) is a systemic granulomatous disorder of unknown etiology with lung and mediastinal lymph nodes (LNs) as the main location. T lymphocytes play important role in the formation of granulomas in SA, but still little is known about the role of maturation profile in the development of inflammatory changes. The aim of this study was to determine the CD4+ and CD8+ T cells maturation profile in LNs and in peripheral blood (PB) and its relation to disease severity expressed by diffusing capacity of the lung for carbon monoxide (DLCO). 29 patients with newly pulmonary SA were studied. Flow cytometry was used for cells evaluation in EBUS-TBNA samples. We observed lower median proportion of T lymphocytes, CD4+ T and CD8+ T cells in patients with DLCO< 80% than in patients with normal diffusion (DLCO > 80%). Patients with DLCO < 80% had lower median proportion of effector and higher median proportion of central memory CD4+ and CD8+ T cells than patients with DLCO > 80%. We reported for the first time that LNs CD4+ and CD8+ T cells maturation differs depending on the DLCO value in sarcoidosis. Lymphocytes profiles in LNs may reflect the immune status of patients with SA and can be analysed by flow cytometry of EBUS-TBNA samples.

Sarcoidosis is a multi-systemic, non-caseating granulomatous disorder with an idiopathic aetiology. We report a 58-year-old Malay woman, with underlying type II diabetes mellitus, hypertension and history of stage II pulmonary sarcoidosis presenting with incidental finding of multiple hypodense liver lesions. Her recent contrasted enhanced computed tomography of the abdomen and pelvis demonstrated multiple intra-abdominal lymphadenopathies with evidence of liver and splenic infiltrations. Her ageappropriate malignancy screening was negative while liver biopsy showed non-caseating granulomatous hepatitis consistent with hepatic sarcoidosis. In view of her normal liver enzymes and normalised serum calcium levels, no immunosuppressive therapy was commenced. She remains asymptomatic and is currently under our close monitoring.

Background: Pulmonary sarcoidosis (PS) is a noncaseating granulomatous disease of unknown origin. Despite conflicting reports, it is considered that the regulatory T (Treg) cells are functionally impaired in PS, but the underlying mechanisms remain unclear. OX40, a pivotal costimulatory molecule, is essential for T-cell functions and memory development, but its impact on Treg cells is ambiguous., Research Question: Does the OX40 pathway influence the suppressive functions of Treg cells in PS?, Study Design and Methods: Fifty treatment-naïve patients with PS and 30 healthy control participants were recruited for this study. Polychromatic flow cytometry-based immunologic assays were performed to enumerate effector T helper (Th) cells and Treg cells along with their functions. Using real-time polymerase chain reaction analysis, small interfering RNA, and pharmacologic inhibitors, the impact of OX40 on Treg cell function was investigated., Results: We observed enrichment of Th-9 cells perhaps for the first time along with Th-1, Th-17, and Treg cells in patients' BAL fluid (BALF) compared with peripheral blood. However, Treg cells were observed to be functionally defective at the pathological site. We observed higher expression of OX40 on both T effector (CD4 + Foxp3 - ) and Treg (CD4 + Foxp3 + ) cells obtained from the BALF of patients with PS. However, OX40 exerted contrasting impact on these T-cell subsets, enhancing effector T-cell functions (interferon γ, tumor necrosis factor α) while inhibiting Treg cell function (IL-10, transforming growth factor β). OX40 silencing or blocking on Treg cells resulted in restoration of their impaired functions., Interpretation: We propose that inhibiting the OX40 pathway may constitute a therapeutic strategy for controlling inflammatory T cells by restoring Treg cell functions in patients with PS., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

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.)

Background: Sarcoidosis is a systemic granulomatous disease that in most patients affects the lung. Pulmonary fibrotic sarcoidosis is clinically, radiologically, and pathologically a heterogeneous condition. Although substantial indirect evidence suggests small airways involvement, direct evidence currently is lacking., Research Question: What is the role of the (small) airways in fibrotic sarcoidosis?, Study Design and Methods: Airway morphologic features were investigated in seven explant lungs with end-stage fibrotic sarcoidosis using a combination of CT scanning (large airways), micro-CT scanning (small airways), and histologic examination and compared with seven unused donor lungs as controls with specific attention focused on different radiologically defined sarcoidosis subtypes., Results: Patients with central bronchial distortion (n = 3), diffuse bronchiectasis (n = 3), and usual interstitial pneumonia pattern (n = 1) were identified based on CT scan, showing a decrease and narrowing of large airways, a similar airway number and increased airway diameter of more distal airways, or an increase in airway number and airway diameter, respectively, compared with control participants. The number of terminal bronchioles per milliliter and the total number of terminal bronchioles were decreased in all forms of fibrotic sarcoidosis. Interestingly, the number of terminal bronchioles was inversely correlated with the degree of fibrosis. Furthermore, we identified granulomatous remodeling as a cause of small airways loss using serial micro-CT scanning and histologic examination., Interpretation: The large airways are involved differentially in subtypes of sarcoidosis, but the terminal bronchioles universally are lost. This suggests that small airways loss forms an important aspect in the pathophysiologic features of fibrotic pulmonary sarcoidosis., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Sarcoidosis is a systemic granulomatous disease predominantly affecting the lungs. The mechanisms promoting disease pathogenesis and progression are unknown, although interleukin-15 (IL-15) has been associated with the immune-mediated inflammation of sarcoidosis. Because the identification of a mechanistically based, clinically relevant biomarker for sarcoidosis remains elusive, we hypothesized this role for IL-15. Pulmonary sarcoidosis granuloma formation was modeled using trehalose 6,6'-dimicolate (TDM), which was administered into wild-type and three lineages of mice: those overexpressing IL-15, deficient in IL-15, and deficient in IL-15 receptor α. The number of granulomas per lung was counted and normalized to the wild type. IL-15 concentrations were measured in the bronchoalveolar lavage (BAL) from healthy controls and subjects with sarcoidosis in our cohort, where associations between IL-15 levels and clinical manifestations were sought. Findings were validated in another independent sarcoidosis cohort. TDM administration resulted in similar granuloma numbers across all lineages of mice. IL-15 concentrations were elevated in the BAL of both human cohorts, irrespective of disease phenotypes. In exploratory analysis, an association with obesity was observed, and various other soluble mediators were identified in the BAL of both cohorts. Although IL-15 is enriched in the sarcoidosis lung, it was independent of disease pathogenesis or clinical manifestations in our mouse model and human cohorts of sarcoidosis. An association with obesity perhaps reflects the ongoing inflammatory processes of these comorbid conditions. Our findings showed that IL-15 is redundant for disease pathogenesis and clinical progression of sarcoidosis.

Background: Video-assisted mediastinoscopy (VAM) is a valuable method in the investigation of diseases with mediastinal lymphadenopathy or those localized in the mediastinum. The aim of this study was to determine the diagnostic value of VAM in the investigation of mediastinal involvement of nonlung cancer diseases and to describe our institutional surgical experience., Methods: Clinical parameters such as age, sex, histological diagnosis, morbidity, and mortality of all patients who underwent VAM for the investigation of mediastinal involvement of diseases except lung cancer between January 2006 and July 2018 were retrospectively reviewed, and the diagnostic efficacy of VAM was determined statistically., Results: During the study period, 388 patients underwent VAM, and 536 lymph nodes were sampled for histopathological evaluation of mediastinum due to mediastinal lymphadenopathy or paratracheal lesions. The most common diagnoses were sarcoidosis ( n  = 178 [45.9%]), tuberculous lymphadenitis ( n  = 108 [27.8%]), lymphadenitis with anthracosis ( n  = 72 [18.6%]), and lymphoma ( n  = 15 [3.9%])., Conclusion: The results of the study show that VAM should be used because of its high diagnostic benefit in mediastinal lymphadenopathies, which are difficult to diagnose, or mediastinal lesions located in the paratracheal region. Despite the increase in the number of new diagnostic modalities, VAM is still the most effective method and a gold standard., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Sarcoidosis is a systemic inflammatory granulomatous disease, frequently affecting the lung. If left untreated, it may end in lung fibrosis. Proangiogenic and profibrotic vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, fibroblast growth factor (FGF)-2 and platelet-derived growth factor (PDGF)-AB are a known therapeutical target in pulmonary fibrosing diseases, e.g. IPF, but there is no targeted therapy option for pulmonary fibrosis in sarcoidosis., Objectives: The aim of our study was to determine the association of these markers' serum levels on lung function and the patients' quality of life in a long-term follow-up of sarcoidosis patients, to provide further information for finding targeted therapy options for pulmonary sarcoidosis., Methods: 54 patients with sarcoidosis underwent blood sampling, pulmonary function testing and answered the King's Brief Interstitial Lung Disease (K-BILD) questionnaire at baseline and at three-years follow-up. Serum levels of profibrotic and angiogenic markers were assessed at baseline by enzyme-linked immunosorbent assay., Results: Between 2015 and 2018, 54 patients with biopsy proven sarcoidosis were enrolled. Throughout the observation period, there was a significant decrease in the diffusion capacity for carbon monoxide (DLCO) [%] (-6.5504 ± 13,39, p = 0.001) and forced expiratory volume in one second predicted (FEV1) [%] (-6.07 ± 12.09, p = 0.001). Patients with greater impairment of forced vital capacity (FVC) did have significantly higher serum levels of VEGF (p = 0.03) and PDGF-AB (p<0.001). The K-BILD questionnaire did not change significantly during follow-up. However, patients with worsening K-BILD scores did have significantly higher serum-levels of PDGF-AB (2.67 pg/ml ± 0.93 vs. 1.88 pg/ml ± 0.60, p = 0.004) at baseline, compared to those with unchanged or increasing K-BILD scores., Conclusions: Among patients with pulmonary sarcoidosis, baseline serum levels of VEGF and PDGF-AB were associated with pulmonary function impairment. Furthermore, PDGF-AB was associated with worsening K-BILD scores. No such association was observed for FGF-2 and TGF-ß1. VEGF and PDGF-AB may be possible prognostic and therapeutic targets in sarcoidosis as a fibrosing ILD beyond IPF., Competing Interests: The authors have declared that no competing interests exist.

Sarcoidosis is a multi-system disorder of granulomatous inflammation which most commonly affects the lungs. Its etiology and pathogenesis are not well defined in part due to the lack of reliable modeling. Here, we present the development of an in vitro three-dimensional lung-on-chip biochip designed to mimic granuloma formation. A lung on chip fluidic macrodevice was developed and added to our previously developed a lung-on-membrane model (LOMM). Granulomas were cultured from blood samples of patients with sarcoidosis and then inserted in the air-lung-interface of the microchip to create a three-dimensional biochip pulmonary sarcoidosis model (3D BSGM). Cytokines were measured after 48 hours. ELISA testing was performed to measure cytokine response difference between LOMM with 3D BSGM. There were statistically significant differences in IL-1ß (P = 0.001953), IL-6 (P = 0.001953), GM-CSF (P = 0.001953), and INF-γ expressions (P = 0.09375) between two groups. The current model represents the first 3D biochip sarcoidosis model created by adding a microfluidics system to a dual-chambered lung on membrane model and introducing developed sarcoid-granuloma to its air-lung-interface., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: BE is a paid employee of Genix-Engineering. MM was awarded a research grant from Mallinckrodt Pharmaceuticals and is an advisory board member of Mallinckrodt Pharmaceuticals. MM has a pending patent for this technology (Provisional patent application UMIP-441 Mirsaeidi 126683-040PV1). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Sarcoidosis is a multisystemic granulomatous disorder that can affect virtually any organ. However, pulmonary and thoracic lymph node involvement predominates; abnormalities on chest radiographs are present in 80 to 90% of patients with sarcoidosis. High-resolution computed tomographic (HRCT) scans are superior to chest X-rays in assessing extent of disease, and some CT features may discriminate an active inflammatory component (which may be amenable to therapy) from fibrosis (for which therapy is not indicated). Typical findings on HRCT include micronodules, perilymphatic and bronchocentric distribution, perihilar opacities, and varying degrees of fibrosis. Less common findings on CT include mass-like or alveolar opacities, miliary opacities, mosaic attenuation, honeycomb cysts, and cavitation. With progressive disease, fibrosis, architectural distortion, upper lobe volume loss with hilar retraction, coarse linear bands, cysts, and bullae may be observed. We discuss the salient CT findings in patients with sarcoidosis (with a major focus on pulmonary features) and present classical radiographic and histopathological images of a few extrapulmonary sites., Competing Interests: None declared., (Thieme. All rights reserved.)

Pulmonary sarcoidosis has unknown etiology, a difficult diagnostic procedure and no curative treatment. Extracellular vesicles including exosomes are nano-sized entities released from all cell types. Previous studies of exosomes from bronchoalveolar lavage fluid (BALF) of sarcoidosis patients have revealed pro-inflammatory components and abilities, but cell sources and mechanisms have not been identified. In the current study, we found that BALF exosomes from sarcoidosis patients, but not from healthy individuals, induced a dose-dependent elevation of intracellular IL-1β in monocytes. Analyses of supernatants showed that patient exosomes also induced release of IL-1β, IL-6 and TNF from both PBMCs and enriched monocytes, suggesting that the observed effect is direct on monocytes. The potently chemotactic chemokine CCL2 was induced by exosomes from a subgroup of patients, and in a blocking assay the exosome-induced CCL2 was reduced for 13 out of 19 patients by the asthma drug Montelukast, a cysteinyl leukotriene receptor antagonist. Further, reactive oxygen species generation by PBMCs was induced to a higher degree by patient exosomes compared to healthy exosomes. These findings add to an emerging picture of exosomes as mediators and disseminators of inflammation, and open for further investigations of the link between CCL2 and exosomal leukotrienes in sarcoidosis.

Background: Sarcoidosis is a chronic inflammatory disease of unknown cause characterized by granuloma formation. Mechanisms for chronic persistence of granulomas are unknown. Matrix Metalloproteinase-12 (MMP12) degrades extracellular matrix elastin and enables infiltration of immune cells responsible for inflammation and granuloma formation. Previous studies report increased MMP12 in sarcoidosis patients and association between MMP12 expression and disease severity. We also observed elevated MMP12 in our multiwall carbon nanotube (MWCNT) murine model of granulomatous inflammation. Here we hypothesized that MMP12 is important to acute and late phases of granuloma pathogenesis. To test this hypothesis, we analyzed granulomatous and inflammatory responses of Mmp12 knock-out (KO) mice at 10 (acute) and 60 days (late) after MWCNT instillation., Methods: C57BL/6 (wildtype) and Mmp12 KO mice underwent oropharyngeal instillation of MWCNT. Lungs were harvested at 3, 10, 20, and 60 days post instillation for evaluation of MMP12 expression and granulomatous changes. Bronchoalveolar lavage (BAL) cells were analyzed 60 days after MWCNT instillation for expression of mediators thought to play a role in sarcoid granulomatosis: peroxisome proliferator-activated receptor-gamma (PPARγ), interferon-gamma (IFN-γ), and CCL2 (MCP-1)., Results: Pulmonary granuloma appearance at 10 days after MWCNT instillation showed no differences between wildtype and Mmp12 KO mice. In contrast, by 60 days after MWCNT instillation, Mmp12 KO mice revealed markedly attenuated granuloma formation together with elevated PPARγ and reduced IFNγ expression in BAL cells compared to wildtype. Unexpectedly, Mmp12 KO mice further demonstrated increased alveolar macrophages with increased CCL2 at 60 days., Conclusions: The striking reduction of granuloma formation at day 60 in Mmp12 KO mice suggests that MMP12 is required to maintain chronic granuloma pathophysiology. The increased PPARγ and decreased IFNγ findings suggest that these mediators also may be involved since previous studies have shown that PPARγ suppresses IFNγ and PPARγ deficiency amplifies granuloma formation. Interestingly, a role of MMP12 in granuloma resolution is also suggested by increases in both macrophage influx and CCL2. Overall, our results strongly implicate MMP12 as a key factor in granuloma persistence and as a possible therapeutic target in chronic pulmonary sarcoidosis., (Copyright © 2020 Mohan, Neequaye, Malur, Soliman, McPeek, Leffler, Ogburn, Tokarz, Knudson, Gharib, Schnapp, Barna and Thomassen.)

Purpose of Review: Mortality in patients with sarcoidosis has primarily been attributed to advanced pulmonary sarcoidosis. This review aims to provide an update on recent clinical studies that help to better phenotype these patients, discuss new treatment options, and suggest areas where additional research is needed., Recent Findings: Diagnosis and management of advanced pulmonary sarcoidosis has changed as new technologies and treatment options have emerged. Clinical phenotypes of advanced disease have evolved to show overlap in presentation with other interstitial lung diseases. Assessment involves more advanced imaging modalities. New promising treatment options are being studied. Pulmonary rehabilitation and lung transplantation are being utilized to improve health-related quality of life and survival., Summary: Patients with advanced pulmonary fibrosis can have variable clinical, radiographic, histopathologic presentation. Given the poor health-related quality of life and high rates of mortality, medical therapy and pulmonary rehabilitation may benefit these patients. Lung transplantation should be considered in those with end-stage disease.

Background: Diagnosis of extra-pulmonary sarcoidosis can be difficult, and a biopsy is usually required. We evaluated the utility of endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) in patients with suspected extra-pulmonary sarcoidosis with thoracic lymph nodes ≤10 mm on chest computed tomography (CT) and no or minimal pulmonary infiltrates., Methods: The Cleveland Clinic bronchoscopy registry was screened. Patients with thoracic lymph nodes >10 mm on short axis or significant pulmonary infiltrates in the chest CT scan were excluded. Two separate analyses using expert consensus (before and after release of bronchoscopy results) were the reference standard., Results: 15 patients met the inclusion criteria. 40% had suspected ocular, 33% cardiac and 27% neurologic sarcoidosis. Six patients (40%) had EBUS-TBNA compatible with sarcoidosis. When the reference standard was the consensus diagnosis blinded to bronchoscopy results, the sensitivity, specificity, positive predictive value and negative predictive value of EBUS-TBNA were 56%, 83%, 83%, and 56% respectively. The combination of a positive EBUS-TBNA and BAL CD4/CD8 improved the specificity from 83 to 100%, but the difference was not statistically significant (p = 0.074). When the reference standard was the consensus diagnosis with the bronchoscopic results, the sensitivity, specificity, positive predictive value and negative predictive value of EBUS-TBNA were 75%, 100%, 100%, and 78% respectively., Conclusions: In patients with suspected extra-pulmonary sarcoidosis, the EBUS-TBNA may be useful in the diagnosis of patients with thoracic lymph nodes ≤10 mm and no or minimal pulmonary infiltrates on chest CT. Larger and prospective studies are needed to validate our findings., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pulmonary involvement occurs in up to 95% of sarcoidosis cases. In this pilot study, we examine lung compartment-specific protein expression to identify pathways linked to development and progression of pulmonary sarcoidosis. We characterized bronchoalveolar lavage (BAL) cells and fluid (BALF) proteins in recently diagnosed sarcoidosis cases. We identified 4,306 proteins in BAL cells, of which 272 proteins were differentially expressed in sarcoidosis compared to controls. These proteins map to novel pathways such as integrin-linked kinase and IL-8 signaling and previously implicated pathways in sarcoidosis, including phagosome maturation, clathrin-mediated endocytic signaling and redox balance. In the BALF, the differentially expressed proteins map to several pathways identified in the BAL cells. The differentially expressed BALF proteins also map to aryl hydrocarbon signaling, communication between innate and adaptive immune response, integrin, PTEN and phospholipase C signaling, serotonin and tryptophan metabolism, autophagy, and B cell receptor signaling. Additional pathways that were different between progressive and non-progressive sarcoidosis in the BALF included CD28 signaling and PFKFB4 signaling. Our studies demonstrate the power of contemporary proteomics to reveal novel mechanisms operational in sarcoidosis. Application of our workflows in well-phenotyped large cohorts maybe beneficial to identify biomarkers for diagnosis and prognosis and therapeutically tenable molecular mechanisms.

The inability to effectively model sarcoidosis in the laboratory or in animals continues to hinder the discovery and translation of new, targeted treatments. The granuloma is the signature pathological hallmark of sarcoidosis, yet there are significant knowledge gaps that exist with regard to how granulomas form. Significant progress toward improved therapeutic and prognostic strategies in sarcoidosis hinges on tractable experimental models that recapitulate the process of granuloma formation in sarcoidosis and allow for mechanistic insights into the molecular events involved. Through its inherent representation of the complex genetics underpinning immune cell dysregulation in sarcoidosis, a recently developed in vitro human granuloma model holds promise in providing detailed mechanistic insight into sarcoidosis-specific disease regulating pathways at play during early stages of granuloma formation. The purpose of this review is to critically evaluate current sarcoidosis models and assess their potential to progress the field toward the goal of improved therapies in this disease. We conclude with the potential integrated use of preclinical models to accelerate progress toward identifying and testing new drugs and drug combinations that can be rapidly brought to clinical trials., (Copyright © 2020 Locke, Schlesinger and Crouser.)

Introduction: Pulmonary fibrosing sarcoidosis is associated with increased mortality. This study was aimed to explore the prognosis value of a panel of parameters for predicting mortality., Methods: This retrospective study included 216 patients with confirmed stage 4 pulmonary sarcoidosis. Stage 4 diagnosis date served as baseline. The following information was systematically present at baseline: epidemiological characteristics; treatments; pulmonary function; composite physiologic index (CPI); systolic pulmonary artery pressure at echocardiography; pulmonary fibrosis extent, main pulmonary artery/ascending aorta diameters ratio (MPAD/AAD) and MPAD/body surface area (BSA) measured and calculated using computed tomography, Walsh's algorithm based on CPI, lung fibrosis extent and MPAD/AAD ratio, and modified Walsh's algorithm with MPAD/BSA replacing MPAD/AAD allowed to estimate good or bad prognosis profiles. The primary outcome of the study was all cause mortality and lung transplantation. The value of baseline parameters was tested as predictors of mortality using univariate and multivariate analyses., Results: Median follow-up was 105 months. There were 41 deaths and 5 transplantations. At multivariate analysis, survival was independently predicted by several parameters including CPI, lung fibrosis extent, pulmonary hypertension at echography or MPAD/BSA ratio, Walsh's algorithm, and geographic origin. The modified Walsh's algorithm was most highly predictive., Conclusion: Survival was best predicted by geographic origin, lung fibrosis extent, PH at echography or MPAD/BSA ratio, as well as by various scores among them the modified Walsh's algorithm had very high predictive value thanks to MPAD/BSA ratio which accurately predicted mortality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pulmonary sarcoidosis is characterized by an exaggerated CD4 + T cell response and formation of non-necrotizing granulomas. Tumour necrosis factor α (TNF-α) is regarded as crucial for granuloma formation and TNF-α inhibitors offer a third-line treatment option for patients not responding to conventional treatment. However, not all patients benefit from treatment, and an optimal dose and treatment duration have not been established. Insight into the influence of TNF-α inhibitors on lung immune cells may provide clues as to what drives inflammation in sarcoidosis and improve our understanding of treatment outcomes. To evaluate the effects of treatment with the TNF-α inhibitor infliximab on lung immune cells and clinical features of the patients, 13 patients with sarcoidosis refractory to conventional treatment were assessed with bronchoalveolar lavage (BAL), spirometry and computerized tomography (CT) scan closely adjacent to the start of infliximab treatment. These investigations were repeated after 6 months of treatment. Treatment with TNF-α inhibitor infliximab was well tolerated with no adverse events, except for one patient who developed a probable adverse event with liver toxicity. Ten patients were classified as responders, having a reduced CD4/CD8 ratio, a decreased percentage of CD4 + T cells expressing the activation marker CD69 and number of mast cells (P < 0·05 for all). The percentage of T regulatory cells (T regs ), defined as forkhead box P3 + CD4 + T cells decreased in most patients. In conclusion, six months of infliximab treatment in patients with sarcoidosis led to signs of decreased CD4 + T cell alveolitis and decreased mastocytosis in the lungs of responders., (© 2020 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)

Background: The diagnosis of sarcoidosis is not standardized but is based on three major criteria: a compatible clinical presentation, finding nonnecrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. There are no universally accepted measures to determine if each diagnostic criterion has been satisfied; therefore, the diagnosis of sarcoidosis is never fully secure. Methods: Systematic reviews and, when appropriate, meta-analyses were performed to summarize the best available evidence. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation approach and then discussed by a multidisciplinary panel. Recommendations for or against various diagnostic tests were formulated and graded after the expert panel weighed desirable and undesirable consequences, certainty of estimates, feasibility, and acceptability. Results: The clinical presentation, histopathology, and exclusion of alternative diagnoses were summarized. On the basis of the available evidence, the expert committee made 1 strong recommendation for baseline serum calcium testing, 13 conditional recommendations, and 1 best practice statement. All evidence was very low quality. Conclusions: The panel used systematic reviews of the evidence to inform clinical recommendations in favor of or against various diagnostic tests in patients with suspected or known sarcoidosis. The evidence and recommendations should be revisited as new evidence becomes available.

Competing Interests: Competing interests: None declared.