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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.

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 .

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.

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

Sepsis most often presents to the ED, and delayed detection is harmful. WBC count is often used to detect sepsis, but changes in WBC count size also correspond to sepsis. We sought to determine if volume increases of circulating immune cells add value to the WBC count for early sepsis detection in the ED.A blinded, prospective cohort study was conducted in two different ED populations within a large academic hospital.Neutrophil and monocyte volume parameters were measured in conjunction with routine CBC testing on a UniCel DxH 800 analyzer at the time of ED admission and were evaluated for the detection of sepsis. There were 1,320 subjects in the ED consecutively enrolled and categorized as control subjects (n = 879) and those with systemic inflammatory response syndrome (SIRS) (n = 203), infection (n = 140), or sepsis (n = 98). Compared with other parameters, monocyte distribution width (MDW) best discriminated sepsis from all other conditions (area under the curve [AUC], 0.79; 95% CI, 0.73-0.84; sensitivity, 0.77; specificity, 0.73; MDW threshold, 20.50), sepsis from SIRS (AUC, 0.74; 95% CI, 0.67-0.84), and severe sepsis from noninfected patients in the ED (AUC, 0.88; 95% CI, 0.75-0.99; negative predictive value, 99%). The added value of MDW to WBC count was statistically significant (AUC, 0.89 for MDW + WBC vs 0.81 for WBC alone; P .01); a decision curve analysis also showed improved performance compared with WBC count alone.The incorporation of MDW with WBC count is shown in this prospective cohort study to improve detection of sepsis compared with WBC count alone at the time of admission in the ED.ClinicalTrials.gov; No.: NCT02232750; URL: www.clinicaltrials.gov.

Background New evidence links nicotine to the regulation of T cell-mediated inflammation via α7 nicotinic cholinergic receptor activation, and chronic nicotine exposure (smoking) reduces the incidence of granulomatous diseases. We sought to determine whether nicotine treatment was well tolerated while effectively normalizing immune responses in patients with active pulmonary sarcoidosis. Methods Consenting adults with symptomatic sarcoidosis (n = 13) were randomly assigned to receive 12 weeks of nicotine treatment plus conventional therapy or conventional therapy alone. Obtained blood cells were evaluated for their responsiveness to selected Toll-like receptor (TLR) and nucleotide oligomerization domain-like receptor ligands and T cell surface marker expression before and after nicotine treatment. Asymptomatic patients (n = 6) and disease-free subjects (n = 6) served as comparative control subjects. Adverse events were monitored for the duration of the study. Results Compared with the asymptomatic group, symptomatic patients had impaired peripheral responses to TLR2, TLR4, and TLR9 ligands (anergy) and reduced peripheral populations of CD4 + FoxP3 + regulatory T cells (Tregs). Nicotine treatment was associated with restoration of TLR2 and TLR9 responsiveness, and expansion of Tregs, including the CD4 + CD25 − FoxP3 + phenotype. There were no serious adverse events or signs of nicotine dependency. Conclusions Nicotine treatment in active pulmonary sarcoidosis was well tolerated and restored peripheral immune responsiveness to TLR2 and TLR9 agonists and expansion of FoxP3 + Tregs, including a specific “preactivated” (CD25 − ) phenotype. The immune phenotype of patients with symptomatic sarcoidosis treated with nicotine closely resembled that of asymptomatic patients, supporting the notion that nicotine treatment may be beneficial in this patient population. Trial registry ClinicalTrials.gov ; No.: NCT00701207; URL: www.clinicaltrials.gov

Chest CT scans are commonly used to clinically assess disease severity in patients presenting with pulmonary sarcoidosis. Despite their ability to reliably detect subtle changes in lung disease, the utility of chest CT scans for guiding therapy is limited by the fact that image interpretation by radiologists is qualitative and highly variable. We sought to create a computerized CT image analysis tool that would provide quantitative and clinically relevant information.We established that a two-point correlation analysis approach reduced the background signal attendant to normal lung structures, such as blood vessels, airways, and lymphatics while highlighting diseased tissue. This approach was applied to multiple lung fields to generate an overall lung texture score (LTS) representing the quantity of diseased lung parenchyma. Using deidentified lung CT scan and pulmonary function test (PFT) data from The Ohio State University Medical Center's Information Warehouse, we analyzed 71 consecutive CT scans from patients with sarcoidosis for whom simultaneous matching PFTs were available to determine whether the LTS correlated with standard PFT results.We found a high correlation between LTS and FVC, total lung capacity, and diffusing capacity of the lung for carbon monoxide (Plt; .0001 for all comparisons). Moreover, LTS was equivalent to PFTs for the detection of active lung disease. The image analysis protocol was conducted quickly (lt; 1 min per study) on a standard laptop computer connected to a publicly available National Institutes of Health ImageJ toolkit.The two-point image analysis tool is highly practical and appears to reliably assess lung disease severity. We predict that this tool will be useful for clinical and research applications.

The treatment options for patients with sarcoidosis are presently limited, and it is unclear which treatments are most effective for any given patient. We have identified a sarcoidosis phenotype characterized by CD4(+) lymphopenia and resistance to conventional immunosuppressants, such as corticosteroids and methotrexate. Based on recent reports linking tumor necrosis factor (TNF)-alpha to regulatory T-cell (Treg) dysfunction, we hypothesized that sarcoidosis-associated CD4(+) lymphopenia would resolve with anti-TNFalpha treatment. Five consecutive patients with CD4(+) lymphopenia were treated with a chimeric anti-TNFalpha antibody (infliximab). Clinical disease manifestations and peripheral blood T-cell subsets were assessed before and after infliximab treatment. All patients experienced significant increases in absolute peripheral blood lymphocyte and CD4(+) T-cell counts and demonstrated improvement in clinical disease manifestations in response to infliximab. No change in the distribution of T-cell subsets was noted. The presence of CD4(+) lymphopenia identifies a distinct sarcoidosis phenotype that is particularly responsive to anti-TNFalpha therapy.

Food Drug and Cosmetic Blue No. 1 dye (FD&C Blue No. 1) is commonly added to enteral nutrition formulations in order to facilitate the detection of gastric aspirate in tracheal secretions of critically ill patients. However, reports of systemic blue dye absorption and associated adverse outcomes are emerging. We report two cases of abnormal systemic absorption of FD&C Blue No. 1 in critically ill patients who subsequently died of refractory shock and metabolic acidosis. Risk factors and mechanisms of FD&C Blue No. 1 toxicity are discussed, and alternate approaches to gastric aspiration detection in critically ill patients are considered.