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RationaleFollowing acute respiratory distress syndrome (ARDS), joblessness is common but poorly understood.ObjectivesTo evaluate the timing of return to work after ARDS, and associated risk factors, lost earnings, and changes in healthcare coverage Methods: Over 12-month longitudinal follow-up, ARDS survivors from 43 U.S. ARDSNet hospitals provided employment and healthcare coverage data via structured telephone interviews. Factors associated with the timing of return to work were assessed using Fine and Gray regression analysis. Lost earnings were estimated using Bureau of Labor Statistics data.Measurements and main resultsOf 922 consenting survivors, 386 (42%) were employed before ARDS (56% male; mean ± SD age, 45 ± 13 yr), with seven dying by 12-month follow-up. Of 379 previously employed 12-month survivors, 166 (44%) were jobless at 12-month follow-up. Accounting for competing risks of death and retirement, half of enrolled and previously employed survivors returned to work by 13 weeks after hospital discharge, with 68% ever returning by 12 months. Delays in return to work were associated with longer hospitalization and older age among nonwhite survivors. Over 12-month follow-up, 274 (71%) survivors accrued lost earnings, averaging $26,949 ± $22,447 (60% of pre-ARDS annual earnings). Jobless survivors experienced a 14% (95% confidence interval, 5-22%; P = 0.002) absolute decrease in private health insurance (from 44% pre-ARDS) and a 16% (95% confidence interval, 7-24%; P

Rationale: Little is known about the genetic regulation of granulomatous inflammation in sarcoidosis.Objectives: To determine if tissue gene array analysis would identify novel genes engaged in inflammation and lung remodeling in patients with sarcoidosis.Methods: Gene expression analysis was performed on tissues obtained from patients with sarcoidosis at the time of diagnosis (untreated) (n = 6) compared with normal lung tissue (n = 6). Expression of select genes was further confirmed in lung tissue from a second series of patients with sarcoidosis and disease-free control subjects (n = 11 per group) by semi-quantitative RT-PCR. Interactive gene networks were identified in patients with sarcoidosis using Ingenuity Pathway Analysis (Ingenuity Systems, Inc., Redwood, CA) software. The expression of proteins corresponding to selected overexpressed genes was determined using fluorokine multiplex analysis, and immunohistochemistry. Selected genes and proteins were then analyzed in bronchoalveolar lavage fluid in an independent series of patients with sarcoidosis (n = 36) and control subjects (n = 12).Measurements and Main Results: A gene network engaged in Th1-type responses was most significantly overexpressed in the sarcoidosis lung tissues, including genes not previously reported in the context of sarcoidosis (e.g., IL-7). MMP-12 and ADAMDEC1 transcripts were most highly expressed (> 25-fold) in sarcoidosis lung tissues, corresponding with increased protein expression by immunohistochemistry. MMP-12 and ADAMDEC1 gene and protein expression were increased in bronchoalveolar lavage samples from patients with sarcoidosis, correlating with disease severity.Conclusions: Tissue gene expression analyses provide novel insights into the pathogenesis of pulmonary sarcoidosis. MMP-12 and ADAMDEC1 emerge as likely mediators of lung damage and/or remodeling and may serve as markers of disease activity. [ABSTRACT FROM AUTHOR]

Bronchial stenosis (BS) consequent to iron pill aspiration (IPA) has been observed in few reported cases. This condition is often irreversible and may necessitate lobectomy in severe cases. Unlike most foreign bodies (FBs), the iron pill disintegrates in the airway and cannot be detected on bronchoscopy. However, bronchial biopsy and lung tissue may reveal iron deposits along with airway inflammation months after the aspiration. Thus, IPA can be diagnosed by a triad of aspiration, airway inflammation, and iron deposits on histology even in the absence of an FB. We report a case of IPA with BS in which the diagnosis was established by bronchial biopsy and was successfully managed with balloon bronchoplasty and therapy with topical mitomycin C. [ABSTRACT FROM AUTHOR]

Abstract Introduction Sarcoidosis is a multisystem granulomatous disease for which the association with mycobacteria continues to strengthen. It is hypothesized that a single, poorly degradable antigen is responsible for sarcoidosis pathogenesis. Several reports from independent groups support mycobacterial antigens having a role in sarcoidosis pathogenesis. To identify other microbial targets of the adaptive immune response, we tested the ability of CD4+ and CD8+ T cells to recognize multiple mycobacterial antigens. Methods Fifty-four subjects were enrolled in this study: 31 sarcoidosis patients, nine non-tuberculosis mycobacterial (NTM) infection controls, and 14 PPD- controls. Using flow cytometry, we assessed for Th1 immune responses to ESAT-6, katG, Ag85A, sodA, and HSP. Results Alveolar T-cells from twenty-two of the 31 sarcoidosis patients produced a CD4+ response to at least one of ESAT-6, katG, Ag85A, sodA, or HSP, compared to two of 14 PPD- controls (p = 0.0008) and five of nine NTM controls (p = 0.44), while eighteen of the 31 sarcoidosis subjects tested produced a CD8+ response to at least one of the mycobacterial antigens compared to two of 14 PPD- controls (p = 0.009) and three of nine NTM controls (0.26). Not only did the BAL-derived T cells respond to multiple virulence factors, but also to multiple, distinct epitopes within a given protein. The detection of proliferation upon stimulation with the mycobacterial virulence factors demonstrates that these responses are initiated by antigen specific recognition. Conclusions Together these results reveal that antigen-specific CD4+ and CD8+ T cells responses to multiple mycobacterial epitopes are present within sites of active sarcoidosis involvement, and that these antigen-specific responses are present at the time of diagnosis.

Background: Community advisory boards (CABs) are increasingly recognized as a means of incorporating patient experience into clinical practice and research. The power of CABs is derived from engaging with community members as equals throughout the research process. Despite this, little is known of community member experience and views on best practices for running a CAB in a rare pulmonary disease., Research Question: What are CAB members' views on the best practices for CAB formation and maintenance in a rare pulmonary disease?, Study Design and Methods: In August 2021, we formed the Cleveland Clinic Sarcoidosis Health Partners (CC-HP) as a CAB to direct research and clinic improvement initiatives at a quaternary sarcoidosis center. We collaboratively evaluated our process for formation and maintenance of the CC-HP with the patient members of the group. Through the series of reflection/debriefing discussions, CAB patient members developed a consensus account of salient obstacles and facilitators of forming and maintaining a CAB in a rare pulmonary disease., Results: Clinician and community members of the CC-HP found published guidelines to be an effective tool for structuring formation of a CAB in a rare pulmonary disease. Facilitators included a dedicated coordinator, collaborative development of projects, and a focus on improving clinical care. Obstacles to CAB functioning were formal structure, focus on projects with academic merit but no immediate impact to patients, and overreliance on digital resources., Interpretation: By centering our evaluation of our CAB on community member experience, we were able to both identify facilitators and impediments to CAB as well as improve our own processes., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: D. A. C. receives support from Boehringer-Ingelheim (steering committee); aTyr, AI Therapeutics, and Mallinckrodt (clinical trials); Foresee Pharmaceuticals, Molecure, and Kinevant (consulting); and Pliant and FibroGen (committee honoraria). None declared (L. B., S. H., L. M., J. R., K. S., R. J., K. A. B., J. D. T., M. L. R. N., L. J. H.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Sarcoidosis is a multisystem granulomatous syndrome that arises from a persistent immune response to a triggering antigen(s). There is no "gold standard" test or algorithm for the diagnosis of sarcoidosis, making the diagnosis one of exclusion. The presentation of the disease varies substantially between individuals, in both the number of organs involved, and the manifestations seen in individual organs. These qualities dictate that health care providers diagnosing sarcoidosis must consider a wide range of possible alternative diagnoses, from across a range of presentations and medical specialties (infectious, inflammatory, cardiac, neurologic). Current guideline-based diagnosis of sarcoidosis recommends fulfillment of three criteria: 1) compatible clinical presentation and/or imaging 2) demonstration of granulomatous inflammation by biopsy (when possible) and, 3) exclusion of alternative causes, but do not provide guidance on standardized strategies for exclusion of alternative diagnoses. In this review, we provide a summary of the most common differential diagnoses for sarcoidosis involvement of lung, eye, skin, central nervous system, heart, liver, and kidney. We then propose a framework for testing to exclude alternative diagnoses based on pretest probability of sarcoidosis, defined as high (typical findings with sarcoidosis involvement confirmed in another organ), moderate (typical findings in a single organ), or low (atypical/findings suggesting of an alternative diagnosis). This work highlights the need for informed and careful exclusion of alternative diagnoses in sarcoidosis., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: The proportion of patients who develop progressive pulmonary fibrosis (PPF), along with risk factors for progression remain poorly understood., Objectives: To examine factors associated with an increased risk of developing PPF among patients at a referral center., Methods: We identified patients with a diagnosis of interstitial lung disease (ILD) seen within the Cleveland Clinic Health System. Utilizing a retrospective observational approach we estimated the risk of developing progression by diagnosis group and identified key clinical predictors using the FVC component of both the original progressive fibrotic interstitial lung disease (PFILD) and the proposed PPF (ATS) criteria., Results: We identified 5934 patients with a diagnosis of ILD. The cumulative incidence of progression over the 24 months was similar when assessed with the PFILD and PPF criteria (33.1 % and 37.9 % respectively). Of those who met the ATS criteria, 9.5 % did not meet the PFILD criteria. Conversely, 4.3 % of patients who met PFILD thresholds did not achieve the 5 % absolute FVC decline criteria. Significant differences in the rate of progression were seen based on underlying diagnosis. Steroid therapy (HR 1.46, CI 1.31-1.62) was associated with an increased risk of progressive fibrosis by both PFILD and PPF criteria., Conclusion: Regardless of the definition used, the cumulative incidence of progressive disease is high in patients with ILD in the 24 months following diagnosis. Some differences are seen in the risk of progression when assessed by PFILD and PPF criteria. Further work is needed to identify modifiable risk factors for the development of progressive fibrosis., Competing Interests: Declaration of competing interest The study is funded by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). Maeve Macmurdo, Xinge Ji, Alex Milinovich, Blaine Martyn-Dow, Aman Pande, Alex Zajichek, Janine Bauman, David Sugano, Michael W. Kattan and Daniel A. Culver are employed by the Cleveland Clinic which received research support from BIPI to collaborate on this project. Pratik Pimple, Amy L. Olson, Shaun Bender, and Craig Conoscenti are employees of BIPI. Daniel Culver received honoraria from BIPI for his participation in a Steering Committee, from Pliant for his participation in an Adjudication Committee and coverage for travel costs from Roche. All other members of the Cleveland Clinic study team cited no other disclosures., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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

Background: Due to the heterogeneity of sarcoidosis, there is a need to define clinical phenotypes to allow for tailoring of clinical care and identification of more homogenous populations to facilitate research., Methods: We utilized data from a prospectively collected registry of sarcoidosis patients seen at a single quaternary referral center between January 2019 and February 2021. We used multiple correspondence analysis (MCA) and k-means clustering to investigate if the clusters previously identified in the GenPhenReSa study were reproducible in a US population. We also investigated if these clusters were stable when the population was stratified by race., Results: We replicated 3 of the 5 clusters seen in the GenPhenReSa study in our cohort. We likewise identified similar clusters between White and Black patients with sarcoidosis. Differences in organ manifestations associations between White and Black patients were seen primarily in relation to cardiac, neurologic, and ocular involvement., Conclusions: The organ clusters of liver-spleen, isolated pulmonary, and musculoskeletal-skin were reproducible in a US cohort, and in both Black and White patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LJH, AT, SH, XW have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.JCS:Lecture honoraria - Kinevant, Boehringer IngelheimRB:Research Grants - Celgene, Actelion, aTyr, Genentech, Gilead, Bellerophon, Bayer, Mallinckrodt, Foundation for Sarcoidosis Research.Scientific Advisor - Astra Zeneca, Actelion, aTyr, Kinevant, Xentria, Mallinckrodt, Boehringer Ingelheim, Foresee Pharmaceuticals, Ann Theodore Foundation.Speaker's Bureau - Mallinckrodt, United Therapeutics, Boehringer IngelheimDAC:Steering Committee - Boehringer-IngelheimClinical Trials – Atyr, AI Therapeutics, MallinckrodtConsulting – Foresee Pharmaceuticals, Molecure, KinevantCommittee Honoraria – Pliant, FibroGen., (Copyright © 2024. Published by Elsevier Ltd.)

Background: An effective HIV vaccine will most likely need to have potent immunogenicity and broad cross-subtype coverage. The aim of the HIV Vaccine Trials Network (HVTN) 124 was to evaluate safety and immunogenicity of a unique polyvalent DNA-protein HIV vaccine with matching envelope (Env) immunogens., Methods: HVTN 124 was a randomised, phase 1, placebo-controlled, double-blind study, including participants who were HIV seronegative and aged 18-50 years at low risk for infection. The DNA vaccine comprised five plasmids: four copies expressing Env gp120 (clades A, B, C, and AE) and one gag p55 (clade C). The protein vaccine included four DNA vaccine-matched GLA-SE-adjuvanted recombinant gp120 proteins. Participants were enrolled across six clinical sites in the USA and were randomly assigned to placebo or one of two vaccine groups (ie, prime-boost or coadministration) in a 5:1 ratio in part A and a 7:1 ratio in part B. Vaccines were delivered via intramuscular needle injection. The primary outcomes were safety and tolerability, assessed via frequency, severity, and attributability of local and systemic reactogenicity and adverse events, laboratory safety measures, and early discontinuations. Part A evaluated safety. Part B evaluated safety and immunogenicity of two regimens: DNA prime (administered at months 0, 1, and 3) with protein boost (months 6 and 8), and DNA-protein coadministration (months 0, 1, 3, 6, and 8). All randomly assigned participants who received at least one dose were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT03409276) and is closed to new participants., Findings: Between April 19, 2018 and Feb 13, 2019, 60 participants (12 in part A [five men and seven women] and 48 in part B [21 men and 27 women]) were enrolled. All 60 participants received at least one dose, and 14 did not complete follow-up (six of 21 in the prime-boost group and eight of 21 in the coadminstration group). 11 clinical adverse events deemed by investigators as study-related occurred in seven of 48 participants in part B (eight of 21 in the prime-boost group and three of 21 in the coadministration group). Local reactogenicity in the vaccine groups was common, but the frequency and severity of reactogenicity signs or symptoms did not differ between the prime-boost and coadministration groups (eg, 20 [95%] of 21 in the prime-boost group vs 21 [100%] of 21 in the coadministration group had either local pain or tenderness of any severity [p=1·00], and seven [33%] vs nine [43%] had either erythema or induration [p=0·97]), nor did laboratory safety measures. There were no delayed-type hypersensitivity reactions or vasculitis or any severe clinical adverse events related to vaccination. The most frequently reported systemic reactogenicity symptoms in the active vaccine groups were malaise or fatigue (five [50%] of ten in part A and 17 [81%] of 21 in the prime-boost group vs 15 [71%] of 21 in the coadministration group in part B), headache (five [50%] and 18 [86%] vs 12 [57%]), and myalgia (four [40%] and 13 [62%] vs ten [48%]), mostly of mild or moderate severity., Interpretation: Both vaccine regimens were safe, warranting evaluation in larger trials., Funding: US National Institutes of Health and US National Institute of Allergy and Infectious Diseases., Competing Interests: Declaration of interests IF, NG, KES, JRH, SE, SCDR, DEM, DCM, GDT, LC, and SL report support for the present manuscript from National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS, and the HIV Vaccine Trials Network (HVTN) paid to their institutions. SCDR and DEM report support for the present manuscript from the Bill & Melinda Gates Foundation, and grants or contracts outside of the submitted work from Janssen, Sanofi, and Moderna. IF reports grants or contracts outside of the submitted work from Janssen, Gilead, Moderna, Pfizer, and Sanofi paid to his institution, consulting fees from Gilead and ViiV, and participation or payment from Janssen for participation on a data safety monitoring board or advisory board. JRH reports support for attending meetings or travel from the HVTN. MCK reports grants or contracts from NIAID outside of the submitted work and participation on a data safety monitoring board or advisory board for the Worcester HIV Vaccine. SL reports royalties or licences from Cosmic Bliss Sciences related to polyvalent DNA–protein HIV vaccine IP from the University of Massachusetts Medical School, Worcester, MA, USA, and reports stock ownership of Cosmic Bliss Sciences since 2023. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cardiac involvement is a major cause of morbidity and mortality in patients with sarcoidosis. It is important to distinguish between clinical manifest diseases from clinically silent diseases. Advanced cardiac imaging studies are crucial in the diagnostic pathway. In suspected isolated cardiac sarcoidosis, it's key to rule out alternative diagnoses. Therapeutic options can be divided into immunosuppressive agents, guideline-directed medical therapy, antiarrhythmic medications, device/ablation therapy, and heart transplantation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To investigate the response to Acthar Gel® in patients with moderate to severe sarcoidosis uveitis., Methods: This is a prospective open-label study that enrolled patients with moderate to severe sarcoidosis uveitis to receive 80 units daily of Acthar Gel for ten days followed by maintenance treatment with 80 units twice weekly. The primary outcome was the proportion of patients meeting at least one of the following variables 1) improved visual acuity, 2) resolution of intraocular inflammation, 3) ability to taper ocular or oral steroids by at least 50% or 4) reduction of cystoid macular edema, with no worsening of any single measure and no need for additional sarcoidosis therapies at 24 weeks., Results: A total of nine patients were enrolled in the study. Four patients completed the full 24-week course of Acthar Gel, and three of these met the primary endpoint. Among the five patients who did not complete the 24-week course of treatment, four discontinued the treatment due to worsening ocular inflammation. One patient discontinued treatment due to severe adverse effects. The most common adverse effects were fluid retention (77%), insomnia (44%), hypertension (44%) and hyperglycemia (44%)., Conclusions: We observed a clinical response to Acthar Gel in some patients with moderate to severe sarcoidosis uveitis, but a substantial proportion either failed to respond or did not tolerate the therapy. These observations may serve as preliminary data for controlled trials of Acthar Gel, but they do not support its role prior to failure of other agents., Competing Interests: Declaration of Competing interest None, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Pulmonary hypertension (PH) is a risk factor for mortality in patients with sarcoidosis. Severe PH in chronic lung disease has previously been defined as mean pulmonary arterial pressure (mPAP) ≥ 35 mmHg or mPAP 25 ≥ mmHg with cardiac index (CI) ≤ 2 L/min/m 2 . However, there is no clear definition denoting severity of sarcoidosis-associated PH (SAPH). We aimed to determine pulmonary hemodynamic cut-off values where transplant-free survival was worse among patients with SAPH. This was a retrospective cohort analysis of the Registry of SAPH database focusing on pulmonary hemodynamic predictors of transplant-free survival among patients with precapillary SAPH. Cox regression was performed to determine which pulmonary hemodynamic values predicted death or lung transplantation. Kaplan-Meier survival analysis was performed on statistically significant predictors to determine pulmonary hemodynamic cut-off values where transplant-free survival was decreased. Decreased transplant-free survival occurred among SAPH patients with mPAP ≥ 40 mmHg and SAPH patients with pulmonary vascular resistance (PVR) ≥ 5 Woods units (WU). Transplant-free survival was not decreased in patients who fulfilled prior criteria of severe PH in chronic lung disease. We identified new cut-offs with decreased transplant-free survival in the SAPH population. Neither cut-off of mPAP ≥ 40 mmHg nor PVR ≥ 5 WU has previously been shown to be associated with decreased transplant-free survival in SAPH. These values could suggest a new definition of severe SAPH. Our PVR findings are in line with the most recent European Society of Cardiology/European Respiratory Society guideline definition of severe PH in chronic lung disease., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S. J. W. has received honoraria for lectures and advisory boards from Janssen (previously known as Actelion), Bayer, MSD and GSK. He has received travel grants from Janssen and GSK. He has received research grants from Bayer and Janssen. RPB has grant support from Gilead, Bayer, Actelion, Genentech, aTyr, Novartis, and Bellephron for studies in sarcoidosis. O. A. S. consults for and is a speaker for Bayer, United Therapeutics, and Janssen & Janssen. She also consults for Altavant. L. C. P. declares personal fees from Janssen Pharmaceuticals, outside the submitted work. SB has received consultancy fees from aTy and Kinevant. S. D. N. is a consultant for Boehringer‐Ingelheim, Roche, United Therapeutics, Bellerophon, Third Pole, and Merck. He is on the speakers bureau for Boehringer‐Ingelheim and United Therapeutics. R. G. has received consultancy fees from Mallinckrodt. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors. The remaining author declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Cardiac sarcoidosis (CS) is a potentially serious form of infiltrative cardiomyopathy. Despite scarce evidence, immunosuppressive treatment is generally recommended, but local routines may vary significantly. We sought to survey the clinical practices in the treatment of CS, with the aim that the results may suggest future research priorities. We conducted a web-based survey focused on treatment-naive patients with CS. We subclassified CS according to the presence/absence of overt cardiac presentation (clinically manifest/silent) and to the presence/absence of active inflammation (metabolically active/inactive by fluorodeoxyglucose positron emission tomography). The survey was developed jointly by the authors and administered to expert clinicians (n = 79) involved in CS treatment. An agreement threshold was set at 70%. A total of 62 of 79 respondents (78.5%) from 12 countries completed the survey. The agreement threshold was reached for: (1) always treating clinically manifest, metabolically active CS, 57 of 62 (91.9%), (2) never treating clinically silent, metabolically inactive CS, 44 of 62 (71.0%), (3) not requiring histopathologic confirmation of sarcoidosis before treatment initiation, (49 of 62, 79.0%), (4) using fluorodeoxyglucose positron emission tomography for assessing treatment indication (44 of 62, 71.0%) and treatment response (44 of 62, 71.0%), and (5) using prednisone as a first-line agent (100%), although respondents were divided on monotherapy (69.4%) or combination with methotrexate 25.8%. The approach to particular scenarios, tapering, and duration of treatment showed the greatest variation in response. In conclusion, in this survey of clinical practice, important aspects of CS treatment reached the agreement threshold, whereas others showed a great degree of clinical equipoise., Competing Interests: Declaration of Competing Interest Dr. Birnie discloses being on the advisory board for Star Therapeutics and Kinevant/Roivant Sciences. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Sarcoidosis is a complex systemic disease. Our study aimed to (1) identify novel alleles associated with sarcoidosis susceptibility; (2) provide an in-depth evaluation of HLA alleles and sarcoidosis susceptibility and (3) integrate genetic and transcription data to identify risk loci that may more directly impact disease pathogenesis. We report a genome-wide association study of 1335 sarcoidosis cases and 1264 controls of European descent (EA) and investigate associated alleles in a study of African Americans (AA: 1487 cases and 1504 controls). The EA and AA cohort was recruited from multiple United States sites. HLA alleles were imputed and tested for association with sarcoidosis susceptibility. Expression quantitative locus and colocalization analysis were performed using a subset of subjects with transcriptome data. Forty-nine SNPs in the HLA region in HLA-DRA, -DRB9, -DRB5, -DQA1 and BRD2 genes were significantly associated with sarcoidosis susceptibility in EA, rs3129888 was also a risk variant for sarcoidosis in AA. Classical HLA alleles DRB1*0101, DQA1*0101 and DQB1*0501, which are highly correlated, were also associated with sarcoidosis. rs3135287 near HLA-DRA was associated with HLA-DRA expression in peripheral blood mononuclear cells and bronchoalveolar lavage from subjects and lung tissue and whole blood from GTEx. We identified six novel SNPs (out of the seven SNPs representing the 49 significant SNPs) and nine HLA alleles associated with sarcoidosis susceptibility in the largest EA population. We also replicated our findings in an AA population. Our study reiterates the potential role of antigen recognition and/or presentation HLA class II genes in sarcoidosis pathogenesis., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

There is expansive literature documenting the presence of health disparities, but there are disproportionately few studies describing interventions to reduce disparity. In this narrative review, we categorize interventions to reduce health disparity in pulmonary disease within the US health care system to support future initiatives to reduce disparity. We identified 211 articles describing interventions to reduce disparity in pulmonary disease related to race, income, or sex. We grouped the studies into the following four categories: biologic, educational, behavioral, and structural. We identified the following five main themes: (1) there were few interventional trials compared with the breadth of studies describing health disparities, and trials involving patients with asthma who were Black, low income, and living in an urban setting were overrepresented; (2) race or socioeconomic status was not an effective marker of individual pharmacologic treatment response; (3) telehealth enabled scaling of care, but more work is needed to understand how to leverage telehealth to improve outcomes in marginalized communities; (4) future interventions must explicitly target societal drivers of disparity, rather than focusing on individual behavior alone; and (5) individual interventions will only be maximally effective when specifically tailored to local needs. Much work has been done to catalog health disparities in pulmonary disease. Notable gaps in the identified literature include few interventional trials, the need for research in diseases outside of asthma, the need for high quality effectiveness trials, and an understanding of how to implement proven interventions balancing fidelity to the original protocol and the need to adapt to local barriers to care., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary sarcoidosis is characterized by the accumulation of immune cells that form granulomas affecting the lungs. Efzofitimod (ATYR1923), a novel immunomodulator, selectively binds neuropilin 2, which is upregulated on immune cells in response to lung inflammation., Research Question: What is the tolerability, safety, and effect on outcomes of efzofitimod in pulmonary sarcoidosis?, Study Design and Methods: In this randomized, double-blind, placebo-controlled study evaluating multiple ascending doses of efzofitimod administered intravenously every 4 weeks for 24 weeks, randomized patients (2:1) underwent a steroid taper to 5 mg/d by week 8 or < 5 mg/d after week 16. The primary end point was the incidence of adverse events (AEs); secondary end points included steroid reduction, change in lung function, and patient-reported outcomes on health-related quality-of-life scales., Results: Thirty-seven patients received at least one dose of study medication. Efzofitimod was well tolerated at all doses, with no new or unexpected AEs and no dose-dependent AE incidence. Average daily steroid doses through end of study were 6.8 mg, 6.5 mg, and 5.6 mg for the 1 mg/kg, 3 mg/kg, and 5 mg/kg groups compared with 7.2 mg for placebo, resulting in a baseline-adjusted relative steroid reduction of 5%, 9%, and 22%, respectively. Clinically meaningful improvements were achieved across several patient-reported outcomes, several of which reached statistical significance in the 5 mg/kg dose arm. A dose-dependent but nonsignificant trend toward improved lung function also was observed for 3 and 5 mg/kg., Interpretation: Efzofitimod was safe and well tolerated and was associated with dose-dependent improvements of several clinically relevant end points compared with placebo. The results of this study support further evaluation of efzofitimod in pulmonary sarcoidosis., Trial Registry: ClinicalTrials.gov; No.: NCT03824392; URL: www., Clinicaltrials: gov., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Real-world studies have reported reduced mortality in patients with idiopathic pulmonary fibrosis (IPF) treated with antifibrotic therapy; however, the initiation or discontinuation of therapy during these studies may have introduced bias. This study investigated the effect of antifibrotic therapy on mortality and other outcomes in patients with IPF using causal inference methodology., Methods: Data from a multicenter US registry of patients with IPF were used to assess the effect of antifibrotic therapy (nintedanib or pirfenidone) on death, death or lung transplant, respiratory-related hospitalization, and acute worsening of IPF (defined as any health care encounter deemed due to acute worsening of IPF). This study used the Gran method, which accounts for differences in patient characteristics and for treatment initiations and discontinuations during follow-up. The analysis cohort was limited to patients who started antifibrotic therapy on or after the day of enrollment or had never taken it., Findings: Among the 499 patients analyzed, 352 (70.5%) received antifibrotic therapy. Estimated event rates of death at 1 year were 6.6% (95% CI, 6.1-7.1) for treated patients and 10.2% (95% CI, 9.5-10.9) for control patients. There was a numerical reduction in the risk of death (hazard ratio [HR], 0.53; 95% CI, 0.28-1.03; P = 0.060) but numerical increases in risks of respiratory-related hospitalization (HR, 1.88; 95% CI, 0.90-3.92; P = 0.091) and acute worsening of IPF (HR, 1.71; 95% CI, 0.36-8.09; P = 0.496) in treated versus control patients., Implications: Analyses based on causal inference methodology suggest that patients with IPF who receive antifibrotic therapy have improved survival., Competing Interests: Declaration of Interest JAdeA is a member of the Steering Committee for the IPF-PRO/ILD-PRO Registry; has received speaker fees from Boehringer Ingelheim (BI); has served on a Data Safety Monitoring Board for Respivant Sciences, Roche/Genentech, the National Institutes of Health; and is a Scientific Advisory Committee member for the Pulmonary Fibrosis Foundation. MLN, ASH, LS and SMP are employees of DCRI, which receives funding support from BIPI to coordinate the IPF-PRO/ILD-PRO Registry. In addition, SMP has received research funding paid to Duke/DCRI from AstraZeneca, Bristol Myers Squibb, CareDx; royalties from UpToDate; and speaker fees from Altavant Sciences and Bristol Myers Squibb. DAC is a member of the Steering Committee and Publication Committee for the IPF-PRO/ILD-PRO Registry and reports consulting and speaker fees from BI and Genentech. HJK is a member of the Publication Committee for the IPF-PRO/ILD-PRO Registry and has received a grant for a Patient Education Day from Roche/Genentech. TL, LJL, MR have no disclosures. ZS reports consulting fees and honoraria for lectures from BI and Genentech. SB was an employee of BIPI at the time that this study was conducted. TBL and CSC are employees of BIPI., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Efzofitimod is a first-in-class biologic based on a naturally occurring splice variant of histidyl-tRNA synthetase (HARS) that downregulates immune responses via selective modulation of neuropilin-2 (NRP2). Preclinical data found high expression of NRP2 in sarcoidosis granulomas. Treatment with efzofitimod reduced the granulomatous inflammation induced by P. acnes in an animal model of sarcoidosis. A dose escalating trial of efzofitimod in sarcoidosis with chronic symptomatic pulmonary disease found that treatment with efzofitimod was associated with improved quality of life with a trend towards reduced glucocorticoid use and stable to improved pulmonary function. These studies have led to a large Phase 3 trial of efzofitimod in symptomatic pulmonary sarcoidosis.

Purpose of Review: The treatment of sarcoidosis remains uncertain, despite 70 years of study. The conventional approach is to initiate corticosteroids in individuals who require treatment. The position of more aggressive regimes is unknown., Recent Findings: Recent recognition that many patients will require prolonged therapy, and the observation that corticosteroids lead to overt and insidious toxicities, have led to suggestions that steroid-sparing medications be used earlier in the management of sarcoidosis. Individuals with poor prognostic features, designated as 'high-risk' sarcoidosis may, especially benefit from a broader palette of therapeutic options in the initial treatment regimen. An even more aggressive approach, known as 'top-down' or 'hit-hard and early' therapy has emerged in the fields of gastroenterology and rheumatology in the past 15 years, on the premise that highly effective early control of inflammation leads to better outcomes. These regimens typically involve early initiation of biologic therapies., Summary: For certain subpopulations of sarcoidosis patients, 'top-down' therapy could be helpful. Severe pulmonary sarcoidosis, neurosarcoidosis, cardiac sarcoidosis and multiorgan sarcoidosis are phenotypes that may be most relevant for revised therapeutic algorithms. Precision medicine approaches and randomized trials will be necessary to confirm a role for top-down therapy in the routine management of sarcoidosis., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Clinically overt granulomatous involvement of the nervous system (i.e. neurosarcoidosis) can be seen in up to 10% of patients with sarcoidosis. Establishing a diagnosis of neurosarcoidosis is often challenging due to the heterogeneity of clinical presentations that are sometimes nonspecific, and inaccessibility of tissue confirmation. Recommended treatments are based on expert opinions that are derived from clinical experience and limited data from retrospective studies, as data from randomized controlled studies are limited., Area Covered: In this article, we comprehensively review all available literature on epidemiology, clinical presentations, diagnosis, treatment, and outcomes of neurosarcoidosis. We also offer our opinions on diagnostic approach and treatment strategy., Expert Opinion: Given the invasive nature and the limited sensitivity of biopsy of the nervous system, diagnosis of neurosarcoidosis is usually made when ancillary tests (such as magnetic resonance imaging and cerebrospinal fluid analysis) are compatible, and alternative diagnoses are reasonably excluded in patients with established extraneural sarcoidosis. Several factors must be taken into consideration to formulate the initial treatment strategy, including the extent of the disease, severity, functional impairment, comorbidities, and patient's preference. In addition, treatment regimen of neurosarcoidosis should be formulated with an emphasis on long-term strategy.

Rationale: Transbronchial cryobiopsy has been increasingly used to diagnose interstitial lung diseases. However, there is uncertainty regarding its accuracy and risks, mainly due to a paucity of prospective or randomized trials comparing cryobiopsy to surgical biopsy., Objectives: To evaluate the diagnostic yield and complications of cryobiopsy in patients selected by multidisciplinary discussion., Methods: This was a prospective cohort from 2017 to 2019. We included consecutive patients with suspected interstitial lung diseases being considered for lung biopsy presented at our multidisciplinary meeting., Measurements and Main Results: Of 112 patients, we recommended no biopsy in 31, transbronchial forceps biopsy in 16, cryobiopsy in 54 and surgical biopsy in 11. By the end of the study, 34 patients had had cryobiopsy and 24 patients, surgical biopsy. Overall pathologic and multidisciplinary diagnostic yield of cryobiopsy was 47.1% and 61.8%, respectively. The yield increased over time for both pathologic (year 1: 28.6%, year 2: 54.5%, year 3: 66.7%, p = 0.161) and multidisciplinary (year 1: 50%, year 2: 63.6%, year 3: 77.8%, p = 0.412) diagnosis. Overall rate of grade 4 bleeding after cryobiopsy was 11.8%. Cryobiopsy required less chest tube placement (11.8% vs 100%, p < 0.001) and less hospitalizations compared to surgical biopsy (26.5% vs 95.7%, p < 0.001), but hospitalized patients had a longer median hospital stay (2 days vs 1 day, p = 0.004)., Conclusions: Diagnostic yield of cryobiopsy increased over time but the overall grade 4 bleeding rate was 11.8%., (© 2022. The Author(s).)

Individuals experiencing homelessness represent a growing population in the United States. Air pollution exposure among individuals experiencing homelessness has not been quantified. Utilizing local knowledge mapping, we generated activity spaces for 62 individuals experiencing homelessness residing in a semi-rural county within the United States. Satellite derived measurements of fine particulate matter (PM2.5) were utilized to estimate annual exposure to air pollution experienced by our participants, as well as differences in the variation in estimated PM2.5 at the local scale compared with stationary monitor data and point location estimates for the same period. Spatial variation in exposure to PM2.5 was detected between participants at both the point and activity space level. Among all participants, annual median PM2.5 exposure was 16.22 μg/m 3 , exceeding the National Air Quality Standard. Local knowledge mapping represents a novel mechanism to capture mobility patterns and investigate exposure to air pollution within vulnerable populations. Reliance on stationary monitor data to estimate air pollution exposure may lead to exposure misclassification, particularly in rural and semirural regions where monitoring is limited.

Introduction: Sarcoidosis associated pulmonary hypertension (SAPH) is a leading contributor to sarcoidosis-related mortality. The 6-min walk test (6MWT) is widely used in assessment of cardiorespiratory conditions. A reduced 6-min walk distance (6MWD) has been associated with increased mortality in SAPH. We examined patients from the Registry of Sarcoidosis Associated Pulmonary Hypertension (ReSAPH) who had performed 6MWT at enrollment to identify variables that affect 6MWD, and the prognostic value of 6MWT variables regarding death or lung transplantation., Material and Methods: ReSAPH patients with available 6MWT were included. Variables analyzed using pre-defined cutoffs included 6MWD, initial and end of test Borg dyspnea score, oxygen saturation, and heart rate at beginning, end, and after 1-min recovery, absolute change in oxygen saturation, modified distance-saturation product (mDSP), and the heart rate recovery at 1-min (HRR)., Findings: 174 patients met inclusion criteria; 48 patients died and 8 underwent lung transplantation. Patients with 6MWD<300 m had a higher chance of dying or undergoing transplantation compared to those with 6MWD>300 m (p = 0.012). No associations with outcome were observed with mDSP cutoff 200 m%, desaturation≥5% and oxygen saturation<88% at end of 6MWT, or multiple HRR cutoffs (13,14,16). 6MWD correlated with initial Borg score, (p = 0.001), DLCO% (p = 0.0001) and sPAP (p = 0.031) on multivariate analysis. These variables were significant for both pre- and post-capillary PH subgroups. 6MWD also correlated with fatigue assessment scale (FAS) (p = 0.015)., Conclusion: Of the parameters evaluated, 6MWD had the greatest prognostic value in SAPH which correlated with other physiologic and hemodynamic variables. 6MWT captures the multidimensional effects of sarcoidosis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: The impact of common measures to assess sarcoidosis have not been compared longitudinally to outcomes that are meaningful to patients. We prospectively examined the relationship of baseline measurements of sarcoidosis status to outcomes of interest to patients longitudinally over 6 months., Methods: Sarcoidosis patients cared for at 6 US medical centers were "phenotyped" at baseline with measurements of pulmonary function, organ involvement, health related quality of life (HRQoL) instruments, and their anti-sarcoidosis treatment history. These patients were followed for 6 months by monitoring outcomes of interest to patients (OIPs) including steps walked, calories expended, sleep, HRQoL measures, workdays missed and health care utilization. For each baseline phenotypic measurement, patients were dichotomized into two groups above and below a specified cutoff value. The area under the OIP versus time curve was compared between these two groups., Results: The cutoff values for many baseline phenotypic measures distinguished the patients into groups with significantly different 6-month OIPs. The chosen cutoff for the patient global estimate of health status distinguished the most OIPs (13/15). The 6-min walk distance cutoff was associated with more OIPs than spirometric measures. All of the HRQOL measure cutoffs were associated with many OIPs, although most of them were other HRQOL measures., Interpretation: Cutoffs for most of the phenotypic measures used to assess sarcoidosis distinguished groups of sarcoidosis patients with differing OIPs over the subsequent 6 months. The patients' global assessment of their disease was the most accurate of these measures., Clinical Trial Registration Number: NCT04342403., (Copyright © 2022. Published by Elsevier Ltd.)

Sarcoidosis-associated pulmonary hypertension (SAPH) is an important complication of advanced sarcoidosis. Over the past few years, there have been several studies dealing with screening, diagnosis and treatment of SAPH. This includes the results of two large SAPH-specific registries. A task force was established by the World Association of Sarcoidosis and Other Granulomatous disease (WASOG) to summarise the current level of knowledge in the area and provide guidance for the management of patients. A group of sarcoidosis and pulmonary hypertension experts participated in this task force. The committee developed a consensus regarding initial screening including who should undergo more specific testing with echocardiogram. Based on the results, the committee agreed upon who should undergo right-heart catheterisation and how to interpret the results. The committee felt there was no specific phenotype of a SAPH patient in whom pulmonary hypertension-specific therapy could be definitively recommended. They recommended that treatment decisions be made jointly with a sarcoidosis and pulmonary hypertension expert. The committee recognised that there were significant defects in the current knowledge regarding SAPH, but felt the statement would be useful in directing future studies., Competing Interests: Conflict of interest: L. Savale reports support for the present manuscript from Janssen and Janssen, and MSD. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events received from Janssen and Janssen, and MSD, outside the submitted work. Support for attending meetings and/or travel received from Janssen and Janssen, and MSD, outside the submitted work. Conflict of interest: O. Shlobin reports participation on a Data Safety Monitoring Board or Advisory Board for Bayer, United Therapeutics, Johnson and Johnson, and Altavant, outside the submitted work. Conflict of interest: V. Kouranos reports receiving payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, and Roche, outside the submitted work. Conflict of interest: S.D. Nathan reports receiving consulting fees from United Therapeutics, Bellerophon, Merck, Bayer, Roche, and Boehringer Ingelheim, outside the submitted work. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from United Therapeutics, Bayer, Roche, and Boehringer Ingelheim, outside the submitted work. Payment for expert testimony received from Roche. Conflict of interest: H. Nunes reports receiving consulting fees from Actelion (now Janssen), outside the submitted work. Conflict of interest: R. Gupta reports receiving grants of contracts from Bayer, outside the submitted work. Conflict of interest: J.C. Grutters reports receiving grants or contracts from SPHINX trial (Actelion) outside the submitted work. J.C. Grutters also reports to be member of the SPHINX trial steering committee. Conflict of interest: D.A. Culver reports participation on a Data Safety Monitoring Board or Advisory Board for Actelion (Janssen), and United Therapeutics, outside the submitted work. Conflict of interest: D. Ouellette reports receiving grants or contracts from US Federal Government/PICORI, and Sanofi, outside the submitted work. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Sunrise 2019, India, outside the submitted work. Payment for expert testimony received from Adam & McGrevey Law Firm, and Spangenberg, Shibley & Liber, outside the submitted work. Unpaid Incoming chair Critical Care Network; CHEST. Conflict of interest: E.E. Lower reports receiving grants or contracts from Bayer, Bellephron, Actelion, Genentech, Mallinckrodt, aTyr, Novartis, and Gilead, outside the submitted work. Conflict of interest: T. Al-Hakim reports support for the present manuscript from Foundation for Sarcoidosis Research, and Bayer Pharmaceuticals. Conflict of interest: A.U. Wells reports participation on a Data Safety Monitoring Board or Advisory Board for Roche, outside the submitted work. A.U. Wells also reports to be President Elect of the World Association of Sarcoidosis and Other Granulomatous Diseases. Conflict of interest: M. Humbert reports receiving grants or contracts from Acceleron, Janssen, and Merck, outside the submitted work. Consulting fees received from Acceleron, Janssen, and Merck, outside the submitted work. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events received from AOP, Janssen, and Merck, outside the submitted work. Participation on a Data Safety Monitoring Board or Advisory Board for Acceleron, Janssen, and Merck. Conflict of interest: R.P. Baughman reports support for the present manuscript from Foundation for Sarcoidosis Research. Grants or contracts received from Bayer, Bellephron, Actelion, Genentech, Mallinckrodt, aTyr, Novartis, and Gilead, outside the submitted work. Consulting fees received from Mallinckrodt. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events received from Mallinckrodt, Boehringer Ingelheim, and United Therapeutics. Participation on a Data Safety Monitoring Board or Advisory Board for Bellephron, United Therapeutics, Mallinckrodt, and Actelion. Conflict of interest: M. Huitema and M.C. Post have nothing to disclose., (Copyright ©The authors 2022.)

Purpose: To assess the impact of concomitant emphysema on outcomes in patients with idiopathic pulmonary fibrosis (IPF)., Methods: The IPF-PRO Registry is a US registry of patients with IPF. The presence of combined pulmonary fibrosis and emphysema (CPFE) at enrollment was determined by investigators' review of an HRCT scan. Associations between emphysema and clinical outcomes were analyzed using Cox proportional hazards models., Results: Of 934 patients, 119 (12.7%) had CPFE. Compared with patients with IPF alone, patients with CPFE were older (median 72 vs 70 years); higher proportions were current/former smokers (88.2% vs 63.7%), used oxygen with activity (49.6% vs 31.9%) or at rest (30.8% vs 18.4%), had congestive heart failure (13.6% vs 4.8%) and had prior respiratory hospitalization (25.0% vs 16.7%); they had higher FVC (median 71.8 vs 69.4% predicted) and lower DLco (median 35.3 vs 43.6% predicted). In patients with CPFE and IPF alone, respectively, at 1 year, rates of death or lung transplant were 17.5% (95% CI: 11.7, 25.8) and 11.2% (9.2, 13.6) and rates of hospitalization were 21.6% (14.6, 29.6) and 20.6% (17.9, 23.5). There were no significant associations between emphysema and any outcome after adjustment for baseline variables. No baseline variable predicted outcomes better in IPF alone than in CPFE., Conclusion: Approximately 13% of patients in the IPF-PRO Registry had CPFE. Physiologic characteristics and comorbidities of patients with CPFE differed from those of patients with IPF alone, but the presence of emphysema did not drive outcomes after adjustment for baseline covariates., Trial Registration: ClinicalTrials.gov, NCT01915511; registered August 5, 2013., (© 2022. The Author(s).)

Background: Performance benchmarks for the management of idiopathic pulmonary fibrosis (IPF) have not been established. We used data from the IPF-PRO Registry, an observational registry of patients with IPF managed at sites across the US, to examine associations between the characteristics of the enrolling sites and patient outcomes., Methods: An online survey was used to collect information on the resources, operations, and self-assessment practices of IPF-PRO Registry sites that enrolled ≥ 10 patients. Site variability in 1-year event rates of clinically relevant outcomes, including death, death or lung transplant, and hospitalization, was assessed. Models were adjusted for differences in patient case mix by adjusting for known predictors of each outcome. We assessed whether site-level heterogeneity existed for each patient-level outcome, and if so, we investigated potential drivers of the heterogeneity., Results: All 27 sites that enrolled ≥ 10 patients returned the questionnaire. Most sites were actively following > 100 patients with IPF (70.4%), had a lung transplant program (66.7%), and had a dedicated ILD nurse leader (77.8%). Substantial heterogeneity was observed in the event rates of clinically relevant outcomes across the sites. After controlling for patient case mix, there were no outcomes for which the site variance component was significantly different from 0, but the p-value for hospitalization was 0.052. Starting/completing an ILD-related quality improvement project in the previous 2 years was associated with a lower risk of hospitalization (HR 0.60 [95% CI 0.44, 0.82]; p = 0.001)., Conclusions: Analyses of data from patients with IPF managed at sites across the US found no site-specific characteristics or practices that were significantly associated with clinically relevant outcomes after adjusting for patient case mix. Trial registration ClinicalTrials.gov, NCT01915511. Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511., (© 2022. The Author(s).)

Background: There are no validated clinical outcome assessments (COAs) used in neurosarcoidosis., Objective: We surveyed clinicians who treat patients with neurosarcoidosis to determine: 1) current approaches to assessment of neurologic impairment, and 2) clinicians' needs regarding future COA development., Methods: Physician contacts from the Foundation for Sarcoidosis Research and Neurosarcoidosis Consortium Group were sent an online survey., Results: For 43/143 responders, COAs were used in a minority of settings. Apart from time for administration, the biggest barriers to implementation were lack of validated, disease-specific measures., Conclusions: Lack of validated, disease-specific measures is a barrier to monitoring neurological impairment in neurosarcoidosis., (Copyright © 2021. Published by Elsevier B.V.)

Background: Pulmonary sarcoidosis is a rare granulomatous disease of unknown aetiology. Heterogeneity in the outcomes measured in trials of treatment for pulmonary sarcoidosis has impacted on the ability to systematically compare findings, contributing to research inefficiency. The FSR-SCOUT study has aimed to address this heterogeneity by developing a core outcome set that represents a patient and health professional consensus on the most important outcomes to measure in future research for the treatment of pulmonary sarcoidosis., Research Design and Methods: systematic review of trial registries, narrative synthesis of published qualitative literature on the patient experience and results of a patient survey contributed to the development of a comprehensive list of outcomes that were rated in a two round online Delphi survey. The Delphi survey was completed by patients/carers and health professionals and the results discussed and ratified at an online consensus meeting., Results: 259 patients/carers and 51 health professionals completed both rounds of the Delphi survey. A pre-agreed definition of consensus was applied and the results discussed at an online consensus meeting attended by 17 patients and 7 health professionals). Fifteen outcomes, across five domains (physiological/clinical, treatment, resource use, quality of life, and death), reached the definition of consensus and were included in the core outcome set., Conclusions: The core outcome set represents a patient and health professional consensus on the most important outcomes for pulmonary sarcoidosis research. The use of the core outcome set in future trials, and efforts to validate its components, will enhance the relevance of trials to stakeholders and will increase the opportunity for the research to contribute to evidence synthesis., Competing Interests: NLH, SLG, PRW, RPB, MAJ, NAK, DEV, JCG, DAC have no competing interests. ESB is an employee of Janssen Research and Development, LLC, who has sponsored research studies in Sarcoidosis. EJS is an employee of Insmed Incorporated. MW employee of Janssen Research & Development. HJ is a sarcoidosis patient. TA-H, HN and NS were employed by the funder (The Foundation for Sarcoidosis Research) during the research., (Copyright: © 2021 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

Introduction: Echocardiographic measurement of the right ventricular systolic pressure (RVSP) is commonly used for estimating systolic pulmonary artery pressure (PASP) measured during right heart catheterization (RHC) in patients suspected for pulmonary hypertension (PH). Generally, there seems to be a strong correlation. However, this has been reported as less robust in sarcoidosis. We aim to investigate the correlation between RVSP and RHC measurements using real world data and analyzed factors influencing the relationship between RVSP and PASP in sarcoidosis., Methods & Results: Data of patients with and without sarcoidosis associated PH who had both a measurable echocardiographic RVSP and invasive PASP were collected from the RESAPH registry, PULSAR study and Cincinnati Sarcoidosis Clinic database (n=173, 60.1% female, mean age 56.0±9.5 years). Among them, 124 had PH confirmed by RHC. There was a strong correlation between RVSP and PASP (r=0.640). This correlation was significant in both male and female, white or non-white, forced vital capacity (FVC) >60%, and presence of fibrosis (p<0.001). However, it was less robust in patients with FVC of 50% or less. RVSP was considered inaccurate if the difference with PASP was > 10mmHg. Inaccurate echocardiographic estimation of the invasive PASP occurred in 50.8%, with overestimation mostly in patients without PH, and underestimation in patients with severe PH. An RVSP>50mmHg was associated with worse survival., Conclusions: In this real world multicenter cohort of sarcoidosis patients, we found a significant correlation between RVSP as determined by echocardiography and invasive PASP. Over- or underestimation of PASP occurred frequently. Therefore, echocardiographic RVSP measurement alone to screen for PH in sarcoidosis should be used with caution., (Copyright: © 2021 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

Background: The major reasons to treat sarcoidosis are to lower the morbidity and mortality risk or to improve quality of life (QoL). The indication for treatment varies depending on which manifestation is the cause of symptoms: lungs, heart, brain, skin or other manifestations. While glucocorticoids remain the first choice for initial treatment of symptomatic disease, prolonged use is associated with significant toxicity. Glucocorticoid-sparing alternatives are available. The presented treatment guidelines aim to provide guidance to physicians treating the very heterogenous sarcoidosis manifestations., Methods: A European Respiratory Society Task Force committee composed of clinicians, methodologists and patients with experience in sarcoidosis developed recommendations based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology. The committee developed eight PICO (Patients, Intervention, Comparison, Outcomes) questions and these were used to make specific evidence-based recommendations., Results: The Task Force committee delivered 12 recommendations for seven PICOs. These included treatment of pulmonary, cutaneous, cardiac and neurologic disease as well as fatigue. One PICO question regarding small-fibre neuropathy had insufficient evidence to support a recommendation. In addition to the recommendations, the committee provided information on how they use alternative treatments, when there was insufficient evidence to support a recommendation., Conclusions: There are many treatments available to treat sarcoidosis. Given the diverse nature of the disease, treatment decisions require an assessment of organ involvement, risk for significant morbidity, and impact on QoL of the disease and treatment., Competing Interests: Conflict of interest: R.P. Baughman reports grants from Gilead, Genentech, Bayer, aTyr and Bellephron, grants and personal fees for consultancy from Novartis, personal fees for consultancy from Methial, grants and personal fees for consultancy and lectures from Mallinckrodt, grants and personal fees for lectures from Boehringer Ingelheim, outside the submitted work. Conflict of interest: D. Valeyre reports personal fees for advisory board work from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: P. Korsten reports grants and personal fees from GlaxoSmithKline, personal fees from AbbVie, Pfizer, Chugai, Novartis Pharma, Sanofi-Aventis, Lilly and Gilead, outside the submitted work. Conflict of interest: A.G. Mathioudakis reports grants from Boehringer Ingelheim, outside the submitted work. Conflict of interest: W.A. Wuyts has nothing to disclose. Conflict of interest: A. Wells reports personal fees for lectures and advisory board work from Boehringer Ingelheim and Roche, during the conduct of the study. Conflict of interest: P. Rottoli has nothing to disclose. Conflict of interest: H. Nunes has nothing to disclose. Conflict of interest: E.E. Lower reports grants from Gilead, Genentech, Bayer and aTYR, grants and personal fees for consultancy from Novartis, outside the submitted work. Conflict of interest: M.A. Judson received grant support for his institution from Mallickrodt. Conflict of interest: D. Israël-Biet has nothing to disclose. Conflict of interest: J.C. Grutters has nothing to disclose. Conflict of interest: M. Drent has nothing to disclose. Conflict of interest: D.A. Culver reports grants and personal fees from aTyr, Mallinckrodt, Boehringer Ingelheim and Foundation for Sarcoidosis Research, personal fees from Roche, outside the submitted work. Conflict of interest: F. Bonella reports personal fees and non-financial support from Boehringer Ingelheim, Roche, Galapagos, BMS and Savara Pharma, outside the submitted work. Conflict of interest: K. Antoniou has nothing to disclose. Conflict of interest: F. Martone has nothing to disclose. Conflict of interest: B. Quadder has nothing to disclose. Conflict of interest: G. Spitzer has nothing to disclose. Conflict of interest: B. Nagavci acts as an ERS methodologist. Conflict of interest: T. Tonia acts as an ERS methodologist. Conflict of interest: D. Rigau acts as an ERS methodologist. Conflict of interest: D.R. Oullette reports grants from PCORI (Patient-Centred Outcomes Research Institute, US Federal) and Sanofi, outside the submitted work; and has provided expert witness work for venous thromboembolic disease., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Rationale: Lower-income patients with sarcoidosis experience worse outcomes than those with higher incomes. The reasons for these disparities are not well understood. Objectives: To identify patient-reported barriers to and facilitators of self-empowered care among patients with sarcoidosis residing in high- and low-median-income zip-code areas. Methods: Patients with biopsy-proven sarcoidosis who had received pharmacologic treatment within the past year and who were cared for in a sarcoidosis clinic of a large, urban medical system were included. Focus groups were stratified by high- and low-median-income zip-code areas. Transcriptions were analyzed using grounded theory. Results: Five focus groups were created; two included patients living in zip-code areas with high median incomes ($84,263; interquartile range [IQR], $79,334-$89,795), and three included patients living in zip-code areas with low median incomes ($27,470; IQR, $22,412-27,597). Patients with sarcoidosis from low-income and high-income zip-code areas reported remarkably similar experiences. Patients reported that sarcoidosis was a burden owing to its disease manifestations and the adverse effects of treatment, which led to a compromised ability to perform their activities of daily living at home or at work. Reported barriers to care included perceived inadequate knowledge about sarcoidosis among providers, communication barriers with providers, and the high cost of treatment. Patients from low-income zip-code areas experienced discrimination related to race and income, which served to compound their mistrust. Patients sought to overcome these barriers through self-empowerment, including independent learning, self-advocacy, medication nonadherence, and use of alternative therapies. Conclusions: Patients with sarcoidosis who lived in high- and low-income zip-code areas expressed similar overall concerns regarding sarcoidosis care. However, patients from low-income zip-code areas more frequently expressed concerns about racial and income-based discrimination. Patients from both groups addressed these barriers through self-empowerment, which included not adhering to prescribed therapies. Future work should focus on the effects of culturally and socioeconomically congruent, community-engaged interventions for quality of life of patients with sarcoidosis.

Background: Tobacco smoking is associated with a reduced risk of developing sarcoidosis, and we previously reported that nicotine normalizes immune responses to environmental antigens in patients with active pulmonary sarcoidosis. The effects of nicotine on the progression of pulmonary sarcoidosis are unknown., Research Question: Is nicotine treatment well tolerated, and will it improve lung function in patients with active pulmonary sarcoidosis?, Study Design and Methods: With local institutional review board approval, a randomized, double-blind, controlled pilot trial was conducted of daily nicotine transdermal patch treatment (21 mg daily) or placebo patch use for 24 weeks. The Ohio State University Wexner Medical Center and Cleveland Clinic enrolled 50 consecutive subjects aged ≥ 18 years with active pulmonary sarcoidosis, based on symptoms (ie, dyspnea, cough) and objective radiographic evidence of infiltrates consistent with nonfibrotic lung disease. Each study group was compared at 26 weeks based on repeated measures of FVC, FEV 1 , quantitative lung texture score based on CT texture analysis, Fatigue Assessment Score (FAS), St. George's Respiratory Questionnaire (SGRQ), and the Sarcoidosis Assessment Tool., Results: Nicotine treatment was associated with a clinically significant, approximately 2.1% (70 mL) improvement in FVC from baseline to 26 weeks. FVC decreased by a similar amount (2.2%) in the placebo group, with a net increase of 140 mL (95% CI, 10-260) when comparing nicotine vs placebo groups at 26 weeks. FEV 1 and FAS improved marginally in the nicotine-treated group, compared with those on placebo. No improvement was observed in lung texture score, FAS, St. George's Respiratory Questionnaire score, or the Sarcoidosis Assessment Tool. There were no reported serious adverse events or evidence of nicotine addiction., Interpretation: Nicotine treatment was well tolerated in patients with active pulmonary sarcoidosis, and the preliminary findings of this pilot study suggest that it may reduce disease progression, based on FVC., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT02265874; URL: www.clinicaltrials.gov., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Aims: In coronavirus disease 2019 (COVID-19), myocardial injury is associated with systemic inflammation and higher mortality. Our aim was to perform a proof of concept trial with canakinumab, a monoclonal antibody to interleukin-1β, in patients with COVID-19, myocardial injury, and heightened inflammation., Methods and Results: This trial required hospitalization due to COVID-19, elevated troponin, and a C-reactive protein concentration more than 50 mg/L. The primary endpoint was time to clinical improvement at Day 14, defined as either an improvement of two points on a seven-category ordinal scale or discharge from the hospital. The secondary endpoint was mortality at Day 28. Forty-five patients were randomly assigned to canakinumab 600 mg ( n  = 15), canakinumab 300 mg ( n  = 14), or placebo ( n  = 16). There was no difference in time to clinical improvement compared to placebo [recovery rate ratio (RRR) for canakinumab 600 mg 1.15, 95% confidence interval (CI) 0.46-2.91; RRR for canakinumab 300 mg 0.61, 95% CI 0.23-1.64]. At Day 28, 3 (18.8%) of 15 patients had died in the placebo group, compared with 3 (21.4%) of 14 patients with 300 mg canakinumab, and 1 (6.7%) of 15 patients with 600 mg canakinumab. There were no treatment-related deaths, and adverse events were similar between groups., Conclusion: There was no difference in time to clinical improvement at Day 14 in patients treated with canakinumab, and no safety concerns were identified. Future studies could focus on high dose canakinumab in the treatment arm and assess efficacy outcomes at Day 28., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)