Search

Background: Sarcoidosis is a chronic, multisystem inflammatory disorder characterized by non-caseating epithelioid granulomas; infiltration of mononuclear cells; and destruction of microarchitecture in the skin, eye, heart, and central nervous system, and the lung in >90% of cases. XTMAB-16 is a chimeric anti-tumor necrosis factor alpha (TNFα) antibody, distinct from other anti-TNF antibodies based on its molecular structure. The efficacy of XTMAB-16 has not been clinically demonstrated, and it is still undergoing clinical development as a potential treatment for sarcoidosis. The current study demonstrates the activity of XTMAB-16 in a well-established in vitro sarcoidosis granuloma model, although XTMAB-16 is not yet approved by the United States Food and Drug Administration (FDA) for treatment of sarcoidosis, or any other disease.Objective: To provide data to guide safe and efficacious dose selection for the ongoing clinical development of XTMAB-16 as a potential treatment for sarcoidosis.Methods: First, XTMAB-16 activity was evaluated in an established in vitro model of granuloma formation using peripheral blood mononuclear cells from patients with active pulmonary sarcoidosis to determine a potentially efficacious dose range. Second, data obtained from the first-in-human study of XTMAB-16 (NCT04971395) were used to develop a population pharmacokinetic (PPK) model to characterize the pharmacokinetics (PK) of XTMAB-16. Model simulations were performed to evaluate the sources of PK variability and to predict interstitial lung exposure based on concentrations in the in vitro granuloma model.Results: XTMAB-16 dose levels of 2 and 4 mg/kg, once every 2 weeks (Q2W) or once every 4 weeks (Q4W) for up to 12 weeks, were supported by data from the non-clinical, in vitro secondary pharmacology; the Phase 1 clinical study; and the PPK model developed to guide dose level and frequency assumptions. XTMAB-16 inhibited granuloma formation and suppressed interleukin-1β (IL-1β) secretion in the in vitro granuloma model with a half maximal inhibitory concentration (IC50) of 5.2 and 3.5 μg/mL, respectively. Interstitial lung concentrations on average, following 2 or 4 mg/kg administered Q2W or Q4W, are anticipated to exceed the in vitro IC50 concentrations.Conclusion: The data presented in this report provide a rationale for dose selection and support the continued clinical development of XTMAB-16 for patients with pulmonary sarcoidosis.

BACKGROUND: Devastating cases of sepsis in previously healthy patients have received widespread attention and have helped to catalyze state and national mandates to improve sepsis detection and care. However, it is unclear what proportion of patients hospitalized with sepsis previously were healthy and how their outcomes compare with those of patients with comorbidities. RESEARCH QUESTION: Among adults hospitalized with community-onset sepsis, how many previously were healthy and how do their outcomes compare with those of patients with comorbidities? STUDY DESIGN AND METHODS: We retrospectively identified all adults with community-onset sepsis hospitalized in 373 US hospitals from 2009 through 2015 using clinical indicators of presumed infection and organ dysfunction (Centers for Disease Control and Prevention’s Adult Sepsis Event criteria). Comorbidities were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes. We applied generalized linear mixed models to measure the associations between the presence or absence of comorbidities and short-term mortality (in-hospital death or discharge to hospice), adjusting for severity of illness on admission. RESULTS: Of 6,715,286 hospitalized patients, 337,983 (5.0%) were hospitalized with community-onset sepsis. Most patients with sepsis (329,052 [97.4%]) had received a diagnosis of at least one comorbidity; only 2.6% previously were healthy. Patients with sepsis who previously were healthy were younger than those with comorbidities (mean age, 58.0 ± 19.8 years vs 67.0 ± 16.5 years), were less likely to require ICU care on admission (37.9% vs 50.5%), and were more likely to be discharged home (57.9% vs 45.6%), rather than to subacute facilities (16.3% vs 30.8%), but showed higher short-term mortality rates (22.8% vs 20.8%; P < .001 for all). The association between previously healthy status and higher short-term mortality persisted after risk adjustment (adjusted OR, 1.99; 95% CI, 1.87-2.13). INTERPRETATION: The vast majority of patients hospitalized with community-onset sepsis harbor pre-existing comorbidities. However, previously healthy patients may be more likely to die when they seek treatment at the hospital with sepsis compared with patients with comorbidities. These findings underscore the importance of early sepsis recognition and treatment for all patients.

Sarcoidosis Sarcoidosis is a lung disease of unknown cause characterized by noncaseating granulomas; the heart and nervous system may also be involved. It is often misdiagnosed; tissue biopsy is needed for a definitive diagnosis. Glucocorticoids are recommended as initial treatment, when needed, but not for long-term care.

Sarcoidosis is an autoimmune disorder in which granulomatous inflammation leads to multiorgan dysfunction. Cardiac involvement in particular is associated with substantial morbidity and mortality.1 Potential cardiac manifestations include atrioventricular block, ventricular tachycardia (VT), heart failure, and sudden death. Steroids are recommended for pulmonary sarcoidosis and may be effective for cardiac involvement as well. For instance, steroid therapy is reported to be associated with improvement in atrioventricular block and left ventricular (LV) function.2,3 Based on this sort of observational data, the Heart Rhythm Society recommends immunosuppression for active cardiac sarcoidosis.4 Key Teaching Points • Cardiac sarcoidosis is a disease in which granulomatous inflammation in the heart leads to cardiac dysfunction. Cardiac sarcoidosis most commonly manifests with left ventricular dysfunction, heart block, and/or atrial or ventricular arrhythmias. • Ventricular tachycardia (VT) is a particularly devastating complication of cardiac sarcoidosis and is associated with increased morbidity and mortality. Despite optimal treatment, patients often have recurrence of VT and are at increased risk of sudden cardiac death. • VT in cardiac sarcoidosis may occur as a result of either inflammation or scar. Scar-mediated VT is generally caused by re-entry around sites of scar, whereas inflammatory VT is generally a result of increased automaticity. • VT in cardiac sarcoidosis may be treated with immunosuppression, antiarrhythmic drugs, or catheter ablation. Immunosuppression seems to be most useful for patients with automaticity-mediated VT secondary to inflammation. • In our case series, high-dose intravenous (IV) glucocorticoids were an effective treatment for malignant ventricular arrhythmias in cardiac sarcoidosis patients with active myocardial inflammation. The use of high-dose IV glucocorticoids has previously been validated in other systemic rheumatologic diseases, including rheumatoid arthritis, lupus, and organ transplant rejection.

Background The initial presentation of sepsis in the emergency department (ED) is difficult to distinguish from other acute illnesses based upon similar clinical presentations. A new blood parameter, a measurement of increased monocyte volume distribution width (MDW), may be used in combination with other clinical parameters to improve early sepsis detection. We sought to determine if MDW, when combined with other available clinical parameters at the time of ED presentation, improves the early detection of sepsis. Methods A retrospective analysis of prospectively collected clinical data available during the initial ED encounter of 2158 adult patients who were enrolled from emergency departments of three major academic centers, of which 385 fulfilled Sepsis-2 criteria, and 243 fulfilled Sepsis-3 criteria within 12 h of admission. Sepsis probabilities were determined based on MDW values, alone or in combination with components of systemic inflammatory response syndrome (SIRS) or quick sepsis-related organ failure assessment (qSOFA) score obtained during the initial patient presentation (i.e., within 2 h of ED admission). Results Abnormal MDW (> 20.0) consistently increased sepsis probability, and normal MDW consistently reduced sepsis probability when used in combination with SIRS criteria (tachycardia, tachypnea, abnormal white blood count, or body temperature) or qSOFA criteria (tachypnea, altered mental status, but not hypotension). Overall, and regardless of other SIRS or qSOFA variables, MDW > 20.0 (vs. MDW ≤ 20.0) at the time of the initial ED encounter was associated with an approximately 6-fold increase in the odds of Sepsis-2, and an approximately 4-fold increase in the odds of Sepsis-3. Conclusions MDW improves the early detection of sepsis during the initial ED encounter and is complementary to SIRS and qSOFA parameters that are currently used for this purpose. This study supports the incorporation of MDW with other readily available clinical parameters during the initial ED encounter for the early detection of sepsis. Trial registration ClinicalTrials.gov, NCT03145428. First posted May 9, 2017. The first subjects were enrolled June 19, 2017, and the study completion date was January 26, 2018.

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.

This review aims to describe how the clinical manifestations of sarcoidosis may be shaped by the effects of sex hormones and by age dependent changes in immune functions and physiology This review is intended to highlight the need to consider the effects of sex and sex in future studies of sarcoidosis.The clinical manifestations of sarcoidosis differ based on sex and gender There is emerging evidence that female and male hormones and X-linked genes are important determinants of immune responses to environmental antigens, which has important implications for granuloma formation in the context of sarcoidosis Furthermore, sex hormone levels predictably change throughout adolescence and adulthood, and this occurs in parallel with the onset immune senescence and changes in physiology with advanced age.Recent studies indicate that sex and age are important variables shaping the immune response of humans to environmental antigens We posit herein that sex and age are important determinants of sarcoidosis clinical phenotypes Many gaps in our understanding of the roles played by sex and gender in sarcoidosis, and these need to be considered in future studies.

Timely regulation of oxygen (FioOpen-labeled, randomized control pilot trial.Medical ICU.Adults requiring mechanical ventilation.Protocolized oxygen titration was initiated one hour after initiation of mechanical ventilation. When SpoThe primary end point was to determine if early FioOur pilot study indicates that early Fio

Both hyperoxemia and hypoxemia are deleterious in critically ill patients. Targeted oxygenation is recommended to prevent both of these extremes, however this has not translated to the bedside. Hyperoxemia likely persists more than hypoxemia due to absence of immediate discernible adverse effects, cognitive biases and delay in prioritization of titration.We present the methodology for the Titration Of Oxygen Levels (TOOL) trial, an open label, randomized controlled trial of an algorithm-based FiOThis study is designed to evaluate the efficacy of a high fidelity, bioinformatics-based, electronic medical record derived electronic alert system to improve targeted oxygenation in mechanically ventilated patients by reducing excessive FiO

OBJECTIVES: Increased monocyte distribution width (MDW) has recently been shown to be a reliable indicator of early sepsis detection. This study therefore sought to determine if inflammasome activation can be linked to monocyte size changes in sepsis. DESIGN: An in vitro sepsis model using bacterial endotoxin (lipopolysaccharide [LPS]) to study the effect of inflammasome activation on monocyte cell size distribution by microscopy and MDW measurements using a standard clinical hematology analyzer. SETTING: University research laboratory. SUBJECTS: Healthy adult volunteers and cultured human monocyte cells in wild-type state and after clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 knockout of key inflammasome components (apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, gasdermin-D). INTERVENTIONS: In vitro treatment of specimens with bacterial LPS. MEASUREMENTS AND MAIN RESULTS: Wild-type THP1 cells demonstrated a significant increase in cell area (207 μm2 [159–400 μm2] vs 160 μm2 [134–198 μm2]; p < 0.001) and distribution width (198 vs 55 μm2; p < 0.0001) by microscopy following treatment with LPS. Increased MDW correlated with inflammasome activation as demonstrated by release of interleukin (IL)-1β and with the presence of large distended pyroptotic cells by microscopy. All of these effects were blocked in the inflammasome knockout cells. Whole blood samples treated similarly also demonstrated IL-1β release and increased MDW (median 24.7 U [22.2–27.2 U] vs 16.3 U [15.1–17.6 U]; p = 0.008) as measured using the Beckman-Coulter Unicel DxH900 analyzer. When peripheral blood mononuclear cells were isolated prior to treatment with LPS, microscopy confirmed the presence of large pyroptotic cells correlating to IL-1β release in the human subject samples as well. CONCLUSIONS: The increased MDW seen in patients with sepsis can be reproduced in an in vitro sepsis model and blocked using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 technology to inactivate the inflammasome. These findings suggest that pyroptotic cellular swelling underlies changes in MDW in septic patients and connect MDW to early events in the inflammatory cascade of sepsis.

Sarcoidosis is a systemic disease, and the gene/protein expression patterns may be different among different tissues, particularly based on the presence or absence of granulomas and also based on subphenotypes with progressive or non-progressive disease manifestations. There is a growing body of data evaluating global transcriptomic changes across multiple tissue compartments in sarcoidosis. However, whether similar biological pathways are emerging is unknown. Furthermore, the transcriptional impact on the proteome is required to validate molecular pathways driving heterogeneity in sarcoidosis. The purpose of this study is to compare biological inferences from published datasets and explore the compartment specificity of these responses in sarcoidosis. Common pathways identified across datasets or tissue types may serve as convenient biomarkers and could lead to the discovery of novel therapeutic targets. Footnotes This manuscript has recently been accepted for publication in the ERJ Open Research . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article. Conflict of interests: Dr. Bhargava has nothing to disclose. Conflict of interests: Dr. Liao has nothing to disclose. Conflict of interests: Dr. Crouser has nothing to disclose. Conflict of interests: Dr. Maier has nothing to disclose. Conflict of interests: Dr. Leach has nothing to disclose.

Sepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis. Randomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 103 cells/μL. Participants received one nivolumab dose [480 mg (n = 15) or 960 mg (n = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters. Twelve deaths occurred [n = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [n = 1, 6.7% (480 mg); n = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [n = 2, 13.3% (480 mg); n = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase. In this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any ‘cytokine storm’. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted. NCT02960854.

Supplemental Digital Content is available in the text., Objectives: Most septic patients are initially encountered in the emergency department where sepsis recognition is often delayed, in part due to the lack of effective biomarkers. This study evaluated the diagnostic accuracy of peripheral blood monocyte distribution width alone and in combination with WBC count for early sepsis detection in the emergency department. Design: An Institutional Review Board approved, blinded, observational, prospective cohort study conducted between April 2017 and January 2018. Setting: Subjects were enrolled from emergency departments at three U.S. academic centers. Patients: Adult patients, 18–89 years, with complete blood count performed upon presentation to the emergency department, and who remained hospitalized for at least 12 hours. A total of 2,212 patients were screened, of whom 2,158 subjects were enrolled and categorized per Sepsis-2 criteria, such as controls (n = 1,088), systemic inflammatory response syndrome (n = 441), infection (n = 244), and sepsis (n = 385), and Sepsis-3 criteria, such as control (n = 1,529), infection (n = 386), and sepsis (n = 243). Interventions: The primary outcome determined whether an monocyte distribution width of greater than 20.0 U, alone or in combination with WBC, improves early sepsis detection by Sepsis-2 criteria. Secondary endpoints determined monocyte distribution width performance for Sepsis-3 detection. Measurements and Main Results: Monocyte distribution width greater than 20.0 U distinguished sepsis from all other conditions based on either Sepsis-2 criteria (area under the curve, 0.79; 95% CI, 0.76–0.82) or Sepsis-3 criteria (area under the curve, 0.73; 95% CI, 0.69–0.76). The negative predictive values for monocyte distribution width less than or equal to 20 U for Sepsis-2 and Sepsis-3 were 93% and 94%, respectively. Monocyte distribution width greater than 20.0 U combined with an abnormal WBC further improved Sepsis-2 detection (area under the curve, 0.85; 95% CI, 0.83–0.88) and as reflected by likelihood ratio and added value analyses. Normal WBC and monocyte distribution width inferred a six-fold lower sepsis probability. Conclusions: An monocyte distribution width value of greater than 20.0 U is effective for sepsis detection, based on either Sepsis-2 criteria or Sepsis-3 criteria, during the initial emergency department encounter. In tandem with WBC, monocyte distribution width is further predicted to enhance medical decision making during early sepsis management in the emergency department.

Objectives:To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559; Bristol-Myers Squibb, Princeton, NJ) and its effect on immune biomarkers in participants with sepsis-associated immunosuppression.Design:Randomize

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, FEV1, 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. FEV1 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 .

Introduction Sarcoidosis is a systemic granulomatous disease of unknown cause afflicting young to middle-aged adults. The majority of patients with active pulmonary sarcoidosis complain of overwhelming fatigue, which often persists despite administration of immune-modulating drugs typically used to treat sarcoidosis. Nicotine offers an alternative to conventional treatments, which are associated with a spectrum of serious untoward effects, including diabetes mellitus, osteoporosis, bone marrow suppression, severe infections, cirrhosis. The described pilot randomized trial aims to provide preliminary data required to design subsequent Phase II/III trials to formally evaluate nicotine as a novel low-cost and highly-effective, safe treatment option for patients with active pulmonary sarcoidosis. Methods and Design: This is a randomized double-blind controlled trial of adults with confirmed pulmonary sarcoidosis, allocated in equal proportion to sustained release transdermal nicotine or placebo patch. The primary objective outcome is the improvement in forced vital capacity at study week 26 from baseline measurement. Secondary measures include lung texture score, and self-reported outcomes including the Fatigue Assessment Scale, the St George's Respiratory Questionnaire, and the Sarcoidosis Assessment Tool. Discussion Current therapies for active pulmonary sarcoidosis, remain either expensive and often with numerous side-effects, as with novel industry developed therapies, or with reduced quality of life, as with corticosteroids. Nicotine therapy provides promise as a safe, available, and cost-effective intervention strategy, which we expect to be acceptable to patients. ClinicalTrials.gov NCT02265874.

ObjectiveCardiac sarcoidosis is difficult to diagnose, often requiring expensive and inconvenient advanced imaging techniques. Circulating exosomes contain genetic material, such as microRNA (miRNA), that are derived from diseased tissues and may serve as potential disease-specific biomarkers. We thus sought to determine whether circulating exosome-derived miRNA expression patterns would distinguish cardiac sarcoidosis (CS) from acute myocardial infarction (AMI).MethodsPlasma and serum samples conforming to CS, AMI or disease-free controls were procured from the Biologic Specimen and Data Repository Information Coordinating Center repository and National Jewish Health. Next generation sequencing (NGS) was performed on exosome-derived total RNA (n = 10 for each group), and miRNA expression levels were compared after normalization using housekeeping miRNA. Quality assurance measures excluded poor quality RNA samples. Differentially expressed (DE) miRNA patterns, based upon >2-fold change (p< 0.01), were established in CS compared to controls, and in CS compared to AMI. Relative expression of several DE-miRNA were validated by qRT-PCR.ResultsDespite the advanced age of the stored samples (~5–30 years), the quality of the exosome-derived miRNA was intact in ~88% of samples. Comparing plasma exosomal miRNA in CS versus controls, NGS yielded 18 DE transcripts (12 up-regulated, 6 down-regulated), including miRNA previously implicated in mechanisms of myocardial injury (miR-92, miR-21) and immune responses (miR-618, miR-27a). NGS further yielded 52 DE miRNA in serum exosomes from CS versus AMI: 5 up-regulated in CS; 47 up-regulated in AMI, including transcripts previously detected in AMI patients (miR-1-1, miR-133a, miR-208b, miR-423, miR-499). Five miRNAs with increased DE in CS included two isoforms of miR-624 and miR-144, previously reported as markers of cardiomyopathy.ConclusionsMiRNA patterns of exosomes derived from CS and AMI patients are distinct, suggesting that circulating exosomal miRNA patterns could serve as disease biomarkers. Further studies are required to establish their specificity relative to other cardiac disorders.

Rationale Despite the availability of multi-“omics” strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures. Objective To facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis). Methods Transcriptomic profiles of immune-related gene from micro-dissected sarcoidosis granulomas within lung and mediastinal lymph node tissues and compared to infectious granulomas from paraffin-embedded blocks. Differentially-expressed genes (DEGs) were profiled, compared among the three granulomatous diseases and analyzed for functional enrichment pathways. Results Despite histologic similarities, DEGs and pathway enrichment markedly differed in sarcoidosis granulomas from lymph nodes and lung. Lymph nodes showed a clear immunological response, whereas a structural regenerative response was observed in lung. Sarcoidosis granuloma gene expression data corroborated previously reported genomic biomarkers (STAB1, HBEGF, and NOTCH4), excluded others and identified new genomic markers present in lung and lymph nodes, ADAMTS1, NPR1 and CXCL2. Comparisons between sarcoidosis and pathogen granulomas identified pathway divergences and commonalities at gene expression level. Conclusion These findings suggest the importance of tissue and disease-specificity evaluation when exploring sarcoidosis genomic markers. This relevant translational information in sarcoidosis and other two histopathological similar infections provides meaningful specific genomic-derived biomarkers for sarcoidosis diagnosis and prognosis.

The mechanisms underlying abnormal granuloma formation in patients with sarcoidosis are complex and remain poorly understood. A novel in vitro human granuloma model was used to determine the molecu...

Background A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort. Research Question The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis. Study Design and Methods In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George’s Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses. Results The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (–8.0 for placebo vs –1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (–2.3 vs –7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24). Interpretation Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis.

Objectives: To characterize the current burden, outcomes, and costs of managing sepsis patients in U.S. hospitals. Design: A retrospective observational study was conducted using the Premier Healthcare Database, which represents ~20% of U.S. inpatient discharges among private and academic hospitals. Hospital costs were obtained from billing records per the cost accounting method used by each hospital. Descriptive statistics were performed on patient demographics, characteristics, and clinical and economic outcomes for the index hospitalization and 30-day readmissions. Setting: Sepsis patient hospitalizations, including inpatient, general ward, and ICU (intermediate and/or step-down). Patients: Adults over 18 years old with a hospital discharge diagnosis code of sepsis from January 1, 2010, to September 30, 2016. Interventions: None. This was a retrospective observational study of deidentified data. Measurements and Main Results: The final study cohort consisted of 2,566,689 sepsis cases, representing patients with a mean age of 65 years (50.8% female). Overall mortality was 12.5% but varied greatly by severity (5.6%, 14.9%, and 34.2%) for sepsis without organ dysfunction, severe sepsis, and septic shock, respectively. Costs followed a similar pattern increasing by severity level: $16,324, $24,638, and $38,298 and varied widely by sepsis present at admission ($18,023) and not present at admission ($51,022). Conclusions: The highest burden of incidence and total costs occurred in the lowest severity sepsis cohort population. Sepsis cases not diagnosed until after admission, and those with increasing severity had a higher economic burden and mortality on a case-by-case basis. Methods to improve early identification of sepsis may provide opportunities for reducing the severity and economic burden of sepsis in the United States.

INTRODUCTION: Sarcoidosis is a chronic granulomatous inflammatory disease that commonly causes lung disease, but can affect other vital organs and tissues. The cause of sarcoidosis is unknown, and current therapies are commonly limited by lack of efficacy, adverse side effects, and excessive cost. AREAS COVERED: The manuscript will provide a review of current concepts relating to the pathogenesis of sarcoidosis, and how these disease mechanisms may be leveraged to develop more effective treatments for sarcoidosis. It provides only a brief summary of currently accepted therapy, while focusing more extensively on potential novel therapies. EXPERT OPINION: Current sarcoidosis therapeutic agents primarily target the M1 or pro-inflammatory pathways. Agents that prevent M2 polarization, a regulatory phenotype favoring fibrosis, are attractive treatment alternatives that could potentially prevent fibrosis and associated life threatening complications. Effective treatment of sarcoidosis potentially requires simultaneous modulation both M1/M2 polarization instead of suppressing one pathway over the other to restore immune competent and inactive (M0) macrophages.

TOPIC: Critical Care TYPE: Original Investigations PURPOSE: Gasdermin-D (GSDMD) is a pore-forming molecule that serves as the final effector of pyroptosis (a form of inflammatory cell death) following activation of the cellular inflammasome in monocytes. Disulfiram (DSM), a drug used in the treatment of alcohol abuse, has recently been shown to inhibit GSDMD via disruption of pore formation after its cleavage by the inflammatory caspases (1, 4, and 5). The aim of this study was to elucidate the inhibitory effects of DSM on GSDMD-mediated pyroptosis and explore its role as a potential therapeutic agent in sepsis. METHODS: A series of experiments was conducted using THP1 cells (a human monocytic cell line) or purified human monocytes from the blood of healthy donors. Samples were pretreated with DSM in various concentrations 30 minutes prior to inflammasome activation with bacterial lipopolysaccharide (LPS). Cells were then assessed under light microscopy for swelling and fluorescent microscopy for the formation of ASC specks (activated oligomers of the adaptor protein required for caspase activation). Cell death was assessed using a lactate dehydrogenase (LDH) cytotoxicity assay. Interleukin-1-beta (IL1s) release was measured by ELISA. GSDMD cleavage, pro-IL1s synthesis, and caspase-1 cleavage were assessed using immunoblots. RESULTS: Unexpectedly, low dose DSM accentuated inflammasome activation. Dramatic inflammasome induction was observed at a concentration of 10uM, a dose associated with near peak inhibition in the prior study. However, higher doses of 50 to 100 uM suppressed pyroptosis as evidenced by loss of cell swelling and ASC speck formation, as well as LDH and IL-1s release. The DSM effect occurred downstream of caspase-1 activation as evidenced by preserved intracellular pro-IL1s synthesis and caspase-1 cleavage in the presence of DSM. Contrary to the prior report, GSDMD cleavage appeared to be inhibited at these higher doses. CONCLUSIONS: DSM unexpectedly exhibits upstream activation of the inflammasome at low doses but downstream inhibition at high doses. CLINICAL IMPLICATIONS: Although DSM's inhibitory effects on inflammasome function make it a promising agent for the future treatment of acute inflammatory conditions such as sepsis and covid-19, our results indicate that further study is needed to better characterize its possible activating effects at lower concentrations. DISCLOSURES: Collaboration via BARDA grant funding relationship with Beckman Coulter, Inc. Please note: 9/19/2019-8/31/2014 Added 04/27/2021 by Elliott Crouser, source=Web Response, value=Grant/Research Support No relevant relationships by Gregory Eisinger, source=Web Response No relevant relationships by Mikhail Gavrilin, source=Web Response No relevant relationships by Wissam Osman, source=Web Response No relevant relationships by Evan Prather, source=Web Response No relevant relationships by Mark Wewers, source=Web Response

Many aspects of pathogenic granuloma formation are poorly understood, requiring new relevant laboratory models that represent the complexity (genetics and diversity) of human disease. To address this need, we developed an in vitro model of granuloma formation using human peripheral blood mononuclear cells (PBMCs) derived from patients with active sarcoidosis, latent tuberculosis (TB) infection (LTBI), or normal healthy control subjects. PBMCs were incubated for 7 days with uncoated polystyrene beads or beads coated with purified protein derivative (PPD) or human serum albumin. In response to PPD-coated beads, PBMCs from donors with sarcoidosis and LTBI formed robust multicellular aggregates resembling granulomas, displaying a typical T-helper cell type 1 immune response, as assessed by cytokine analyses. In contrast, minimal PBMC aggregation occurred when control PBMCs were incubated with PPD-coated beads, whereas the response to uncoated beads was negligible in all groups. Sarcoidosis PBMCs responded to human serum albumin-coated beads with modest cellular aggregation and inflammatory cytokine release. Whereas the granuloma-like aggregates formed in response to PPD-coated beads were similar for sarcoidosis and LTBI, molecular profiles differed significantly. mRNA expression patterns revealed distinct pathways engaged in early granuloma formation in sarcoidosis and LTBI, and they resemble molecular patterns reported in diseased human tissues. This novel in vitro human granuloma model is proposed as a tool to investigate mechanisms of early granuloma formation and for preclinical drug discovery research of human granulomatous disorders. Clinical trial registered with www.clinicaltrials.gov (NCT01857401).

Supplemental Digital Content is available in the text., Objective: To explain the paradigm of significant renal functional impairment despite preserved hemodynamics and histology in sepsis-induced acute kidney injury. Design: Prospective observational animal study. Setting: University research laboratory. Subjects: Male Wistar rats. Intervention: Using a fluid-resuscitated sublethal rat model of fecal peritonitis, changes in renal function were characterized in relation to global and renal hemodynamics, and histology at 6 and 24 hours (n = 6–10). Sham-operated animals were used as comparison (n = 8). Tubular cell mitochondrial function was assessed using multiphoton confocal imaging of live kidney slices incubated in septic serum. Measurements and Main Results: By 24 hours, serum creatinine was significantly elevated with a concurrent decrease in renal lactate clearance in septic animals compared with sham-operated and 6-hour septic animals. Renal uncoupling protein-2 was elevated in septic animals at 24 hours although tubular cell injury was minimal and mitochondrial ultrastructure in renal proximal tubular cells preserved. There was no significant change in global or renal hemodynamics and oxygen delivery/consumption between sham-operated and septic animals at both 6- and 24-hour timepoints. In the live kidney slice model, mitochondrial dysfunction was seen in proximal tubular epithelial cells incubated with septic serum with increased production of reactive oxygen species, and decreases in nicotinamide adenine dinucleotide and mitochondrial membrane potential. These effects were prevented by coincubation with the reactive oxygen species scavenger, 4-hydroxy-2,2,6,6-tetramethyl-piperidin-1-oxyl. Conclusions: Renal dysfunction in sepsis occurs independently of hemodynamic instability or structural damage. Mitochondrial dysfunction mediated by circulating mediators that induce local oxidative stress may represent an important pathophysiologic mechanism.

This multicenter cohort study of adults who have survived hospitalization for sepsis assesses whether abnormalities in the host immune response during hospitalization for sepsis persist after discharge., Key Points Question Does sepsis have immune sequelae, and are these sequelae associated with poor long-term outcomes? Findings In this cohort study of 483 patients who survived hospitalization with sepsis at 12 US hospitals, 25.8% had elevated high-sensitivity C-reactive protein levels (a marker of inflammation) at 3 months, 30.2% at 6 months, and 25.6% at 12 months and 46.4% had elevated soluble programmed death ligand 1 levels (a marker of immunosuppression) at 3 months, 44.9% at 6 months, and 49.4% at 12 months. Two common phenotypes were identified based on these markers, and patients with hyperinflammation and immunosuppression had a higher risk of readmission or death. Meaning Persistent elevation of inflammation and immunosuppression markers is common up to a year in patients who survive hospitalization for sepsis and may be associated with poor long-term outcomes., Importance Long-term immune sequelae after sepsis are poorly understood. Objective To assess whether abnormalities in the host immune response during hospitalization for sepsis persist after discharge. Design, Settings, and Participants This prospective, multicenter cohort study enrolled and followed up for 1 year adults who survived a hospitalization for sepsis from January 10, 2012, to May 25, 2017, at 12 US hospitals. Exposures Circulating levels of inflammation (interleukin 6 and high-sensitivity C-reactive protein [hs-CRP]), immunosuppression (soluble programmed death ligand 1 [sPD-L1]), hemostasis (plasminogen activator inhibitor 1 and D-dimer), endothelial dysfunction (E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1), and oxidative stress biomarkers were measured at 5 time points during and after hospitalization for sepsis for 1 year. Individual biomarker trajectories and patterns of trajectories across biomarkers (phenotypes) were identified. Main Outcomes and Measures Outcomes were adjudicated centrally and included all-cause and cause-specific readmissions and mortality. Results A total of 483 patients (mean [SD] age, 60.5 [15.2] years; 265 [54.9%] male) who survived hospitalization for sepsis were included in the study. A total of 376 patients (77.8%) had at least 1 chronic disease, and their mean (SD) Sequential Organ Failure Assessment score was 4.2 (3.0). Readmissions were common (485 readmissions in 205 patients [42.5%]), and 43 patients (8.9%) died by 3 months, 56 patients (11.6%) died by 6 months, and 85 patients (17.6%) died by 12 months. Elevated hs-CRP levels were observed in 23 patients (25.8%) at 3 months, 26 patients (30.2%) at 6 months, and 23 patients (25.6%) at 12 months, and elevated sPD-L1 levels were observed in 45 patients (46.4%) at 3 months, 40 patients (44.9%) at 6 months, and 44 patients (49.4%) at 12 months. Two common phenotypes were identified based on hs-CRP and sPDL1 trajectories: high hs-CRP and sPDL1 levels (hyperinflammation and immunosuppression phenotype [326 of 477 (68.3%)]) and normal hs-CRP and sPDL1 levels (normal phenotype [143 of 477 (30.0%)]). These phenotypes had similar clinical characteristics and clinical course during hospitalization for sepsis. Compared with normal phenotype, those with the hyperinflammation and immunosuppression phenotype had higher 1-year mortality (odds ratio, 8.26; 95% CI, 3.45-21.69; P

Objectives: To estimate the potential clinical and health economic value of earlier sepsis identification in the emergency department using a novel diagnostic marker, monocyte distribution width. Design: The analysis was conducted in two phases: 1) an analysis of the pivotal registration trial evidence to estimate the potential benefit of monocyte distribution width for early sepsis identification and (2) a cost-consequence analysis to estimate the potential economic and clinical benefits that could have resulted from earlier administration of antibiotics for those patients. Setting: Sepsis identified in the emergency department which led to inpatient hospitalizations. Patients: Adult sepsis patients admitted through the emergency department. Interventions: None. This was a model simulation of clinical and economic outcomes of monocyte distribution width based on results from a noninterventional, multicenter clinical trial. Measurements and Main Results: Among the 385 patients with sepsis, a total of 349 were eligible for inclusion. Sixty-seven percent of patients were predicted to benefit from monocyte distribution width results, resulting in an estimated mean reduction in time to antibiotics administration from 3.98 hours using standard of care to 2.07 hours using monocyte distribution width + standard of care. Based on this simulated reduction in time to antibiotics, monocyte distribution width + standard of care could have resulted in a less than or equal to 14.2% reduction (27.9% vs 32.5%) in mortality, a mean reduction of 1.48 days (10.0 vs 11.5 d) in length of stay, and $3,460 ($23,466 vs $26,926) savings per hospitalization. At the hospital level, based on an established national mean of 206 sepsis hospitalizations per hospital per year, earlier identification with monocyte distribution width is predicted to result in a total of $712,783 in annual cost savings per hospital. Conclusions: Improved early identification of sepsis using monocyte distribution width along with current standard of care is estimated to improve both clinical and economic outcomes of sepsis patients presenting in the emergency department. Further research is warranted to confirm these model projections.

IntroductionSarcoidosis and tuberculosis are granulomatous pulmonary diseases characterised by heightened immune reactivity toMycobacterium tuberculosisantigens. We hypothesised that an unsupervised analysis comparing the molecular characteristics of granulomas formed in response toM. tuberculosisantigens in patients with sarcoidosis or latent tuberculosis infection (LTBI) would provide novel insights into the pathogenesis of sarcoidosis.MethodsA genomic analysis identified differentially expressed genes in granuloma-like cell aggregates formed by sarcoidosis (n=12) or LTBI patients (n=5) in an establishedin vitrohuman granuloma model wherein peripheral blood mononuclear cells were exposed toM. tuberculosisantigens (beads coated with purified protein derivative) and cultured for 7 days. Pathway analysis of differentially expressed genes identified canonical pathways, most notably antigen processing and presentationviaphagolysosomes, as a prominent pathway in sarcoidosis granuloma formation. The phagolysosomal pathway promoted mechanistic target of rapamycin complex 1 (mTORc1)/STAT3 signal transduction. Thus, granuloma formation and related immune mediators were evaluated in the absence or presence of various pre-treatments known to prevent phagolysosome formation (chloroquine) or phagosome acidification (bafilomycin A1) or directly inhibit mTORc1 activation (rapamycin).ResultsIn keeping with genomic analyses indicating enhanced phagolysosomal activation and predicted mTORc1 signalling, it was determined that sarcoidosis granuloma formation and related inflammatory mediator release was dependent upon phagolysosome assembly and acidification and mTORc1/S6/STAT3 signal transduction.ConclusionsSarcoidosis granulomas exhibit enhanced and sustained intracellular antigen processing and presentation capacities, and related phagolysosome assembly and acidification are required to support mTORc1 signalling to promote sarcoidosis granuloma formation.

A relatively new class of CD4 expressing T cells that also express and release interleukin-17 (Th17 cells) is gaining attention based on their capacity to regulate inflammatory responses in a spectrum of chronic autoimmune diseases. The purpose of this review is to consider recent studies relating to the critical role played by Th17 cells in the pathogenesis of sarcoidosis.Th17 cells are unique in their capacity to adapt to local molecular cues to variably promote or suppress inflammation. On the basis of knowledge established originally in the context of autoimmune disorders, recent investigations indicate that Th17 cells are instrumental in all stages of granuloma evolution, including granuloma formation, maintenance and resolution. Recent research shed light on the mechanisms regulating Th17 cell plasticity and the implications for sarcoidosis disease progression, such as the mechanisms by which regulatory T cells (Tregs) promote resolution of Th17-mediated inflammation.The balance between Th17 cells and Tregs in sarcoidosis patients has important implications for clinicians and clinical researchers seeking more reliable prognostic markers and more targeted therapeutic agents.

RATIONALE: Observational studies suggest obesity is associated with sepsis survival, but these studies are small, fail to adjust for key confounders, measure body mass index (BMI) at inconsistent time points, and/or use administrative data to define sepsis. OBJECTIVE: To estimate the relationship between BMI and sepsis mortality using detailed clinical data for case detection and risk-adjustment. DESIGN: Retrospective cohort analysis of a large clinical data repository SETTING: 139 hospitals in the United States of America PATIENTS: Adult inpatients with sepsis meeting Sepsis-3 criteria EXPOSURE: BMI in six categories: underweight (BMI

Sarcoidosis is a complex, polygenic disease of unknown cause with diverse clinical phenotypes, ranging from self-limited, asymptomatic disease to life-altering symptoms and early disease-related mortality. It is unlikely that a single common environmental exposure (e.g., infection, antigen) entirely explains the disease, and numerous genetic mutations are associated with the disease. As such, it is reasonable to assume, as with other phenotypically diverse diseases, that distinct genetic mechanisms and related biological biomarkers will serve to further define sarcoidosis subphenotypes, mechanisms, and possibly etiology, thus guiding personalized care. The fields of “omics” and systems biology research are widely applied to understand polygenic and phenotypically diverse diseases, such as sarcoidosis. “Omics” refers to technologies that allow comprehensive profiling of sets of molecules in an organism. Systems biology applies advanced computational approaches to make sense of the enormous data sets that are typically generated from “omics” platforms. The primary objectives of this article are to review the available “omics” tools, assess the current status of “omics” and systems biology research in the field of sarcoidosis, and consider how this technology could be applied to advance our understanding of the mechanistic underpinnings of disease and to develop novel treatments.