Publications by authors named "Steven Opal"

197 Publications

A pilot study of an anti-endotoxin Ig-enriched bovine colostrum to prevent experimental sepsis.

Innate Immun 2021 04;27(3):266-274

Department of Microbial Pathogenesis, University of Maryland School of Dentistry, USA.

Despite the dramatic increase in antimicrobial resistance, there is a dearth of antibiotics in development and few pharmaceutical companies working in the field. Further, any new antibiotics are likely to have a short shelf life. Ab-based interventions offer alternatives that are not likely to be circumvented by the widely prevalent antibiotic resistance genes. Bovine colostrum (BC)-the first milk after parturition, rich in nutrients and immune components-promotes gut integrity and modulates the gut microbiome. We developed a hyperimmune BC (HBC) enriched in Abs to a highly conserved LOS core region of Gram-negative bacteria by immunizing pregnant cows with a vaccine comprised of detoxified LOS from O111 Rc (J5) mutant non-covalently complexed to group B meningococcal outer membrane protein (J5dLOS/OMP). This vaccine generated robust levels of anti-J5 LOS Ab in the colostrum. When given orally to neutropenic rats challenged orally with , administration of HBC improved survival compared to non-immune rats, while both BC preparations improved survival compared to PBS controls. Elevated circulating endotoxin levels correlated with mortality. HBC and to a lesser extent non-immune BC reduced bacterial burden from the liver, lung, and spleen. We conclude that HBC and to a lesser extent BC may be effective supplements that improve outcome from lethal gut-derived disseminated infection and may reduce transmission of Gram-negative bacilli from the gastrointestinal tract.
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http://dx.doi.org/10.1177/17534259211007538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054147PMC
April 2021

Therapeutic Rationale for Endotoxin Removal with Polymyxin B Immobilized Fiber Column (PMX) for Septic Shock.

Int J Mol Sci 2021 Feb 23;22(4). Epub 2021 Feb 23.

Division of Infectious Diseases, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI 02905, USA.

Endotoxin removal therapy with polymyxin B immobilized fiber column (PMX) has been clinically applied for sepsis and septic shock patients since 1994. The effectiveness and usefulness of this therapy have been demonstrated for more than a quarter of a century. However, a documented survival benefit has not yet been demonstrable in a large, multicenter, randomized and controlled trial. Following the findings derived from a large sepsis clinical trial with PMX in North America, a new trial is ongoing to determine if PMX has a long-term survival benefit when administered to septic patients. Another approach to support a survival benefit from intervention with PMX is to utilize a detailed analysis available from a large clinical data base. The endotoxin adsorption capacity of PMX columns in vitro and the effectiveness of PMX columns can be further demonstrable in animal models. The capability of PMX and details of its mechanism of action to intervene in the sepsis cascade and impede organ dysfunction in septic patients is not fully understood. The surface antigen expression in monocytes and neutrophils are improved after PMX therapy. Immunomodulatory effects as a result of endotoxin removal and/or other mechanisms of action have been suggested. These effects and other potential immune effects may explain some of the improved effects upon organ dysfunction of sepsis and septic shock patients. Endotoxemia may be involved in the pathophysiology of other diseases than sepsis. A rapid diagnostic method to detect and target endotoxemia could allow us to practice precision medicine and expand the clinical indications of endotoxin removal therapy.
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http://dx.doi.org/10.3390/ijms22042228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926968PMC
February 2021

Steroids for sepsis and ARDS: this eternal controversy remains with COVID-19.

Lancet 2020 10 9;396(10259):e61-e62. Epub 2020 Oct 9.

Infectious Disease Division, Alpert Medical School of Brown University, Providence, RI, USA.

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http://dx.doi.org/10.1016/S0140-6736(20)32132-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546712PMC
October 2020

Safety and Pharmacokinetics of Recombinant Human Plasma Gelsolin in Patients Hospitalized for Nonsevere Community-Acquired Pneumonia.

Antimicrob Agents Chemother 2020 09 21;64(10). Epub 2020 Sep 21.

BioAegis Therapeutics, North Brunswick, New Jersey, USA.

There remains an unmet need to address the substantial morbidity and mortality associated with severe community-acquired pneumonia (sCAP). Recombinant human plasma gelsolin (rhu-pGSN) improves disease outcomes in diverse animal models of infectious and noninfectious inflammation. This blinded dose-escalation safety study involved non-intensive care unit (ICU) patients admitted for mild CAP and randomized 3:1 to receive adjunctive rhu-pGSN or placebo intravenously. Thirty-three subjects were treated: 8 in the single-dose phase and 25 in the multidose phase. For the single-dose phase, rhu-pGSN at 6 mg/kg of body weight was administered once. For the multidose phase, a daily rhu-pGSN dose of 6, 12, or 24 mg/kg was given on 3 consecutive days. Adverse events (AEs) were generally mild in both treatment groups irrespective of dose. The only serious AE (SAE) in the single-dose phase was a non-drug-related pneumonia in a rhu-pGSN recipient who died after institution of comfort care. One single-dose placebo recipient had a drug-related AE (maculo-papular rash). In the multidose phase, there were 2 SAEs in 1 placebo recipient, including a fatal pulmonary embolism. In the 18 rhu-pGSN recipients in the multidose phase, there were no serious or drug-related AEs, and nausea and increased blood pressure were each reported in 2 patients. The median rhu-pGSN half-life exceeded 17 h with all dosing regimens, and supraphysiologic levels were maintained throughout the 24-h dosing interval in the 2 highest dosing arms. Rhu-pGSN was well tolerated overall in CAP patients admitted to non-ICU beds, justifying a larger proof-of-concept trial in an ICU population admitted with sCAP. (This study has been registered at ClinicalTrials.gov under identifier NCT03466073.).
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http://dx.doi.org/10.1128/AAC.00579-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508610PMC
September 2020

Activating Immunity to Fight a Foe - A New Path.

N Engl J Med 2020 03;382(13):1270-1272

From the Departments of Anesthesiology, Medicine, and Surgery, Washington University School of Medicine, St. Louis (R.S.H.); and the Department of Medicine, Alpert Medical School of Brown University, Providence, RI (S.M.O.).

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http://dx.doi.org/10.1056/NEJMcibr1917242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025910PMC
March 2020

Hiding in Plain Sight: an Approach to Treating Patients with Severe COVID-19 Infection.

mBio 2020 03 20;11(2). Epub 2020 Mar 20.

Fyordgata 59, Trondheim, Norway.

Patients with COVID-19 infection are at risk of acute respiratory disease syndrome (ARDS) and death. The tissue receptor for COVID-19 is ACE2, and higher levels of ACE2 can protect against ARDS. Angiotensin receptor blockers and statins upregulate ACE2. Clinical trials are needed to determine whether this drug combination might be used to treat patients with severe COVID-19 infection.
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http://dx.doi.org/10.1128/mBio.00398-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157814PMC
March 2020

Biomarkers of Infection and Sepsis.

Crit Care Clin 2020 Jan 21;36(1):11-22. Epub 2019 Oct 21.

Critical Care Department, (Pr Laterre), Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium.

The role of biomarkers for detection of sepsis has come a long way. Molecular biomarkers are taking front stage at present, but machine learning and other computational measures using bigdata sets are promising. Clinical research in sepsis is hampered by lack of specificity of the diagnosis; sepsis is a syndrome with no uniformly agreed definition. This lack of diagnostic precision means there is no gold standard for this diagnosis. The final conclusion is expert opinion, which is not bad but not perfect. Perhaps machine learning will displace expert opinion as the final and most accurate definition for sepsis.
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http://dx.doi.org/10.1016/j.ccc.2019.08.002DOI Listing
January 2020

Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial.

JAMA 2019 Oct;322(15):1476-1485

Department of Intensive Care, Rigshospitalet, Copenhagen, Denmark.

Importance: Norepinephrine, the first-line vasopressor for septic shock, is not always effective and has important catecholaminergic adverse effects. Selepressin, a selective vasopressin V1a receptor agonist, is a noncatecholaminergic vasopressor that may mitigate sepsis-induced vasodilatation, vascular leakage, and edema, with fewer adverse effects.

Objective: To test whether selepressin improves outcome in septic shock.

Design, Setting, And Participants: An adaptive phase 2b/3 randomized clinical trial comprising 2 parts that included adult patients (n = 868) with septic shock requiring more than 5 μg/min of norepinephrine. Part 1 used a Bayesian algorithm to adjust randomization probabilities to alternative selepressin dosing regimens and to trigger transition to part 2, which would compare the best-performing regimen with placebo. The trial was conducted between July 2015 and August 2017 in 63 hospitals in Belgium, Denmark, France, the Netherlands, and the United States, and follow-up was completed by May 2018.

Interventions: Random assignment to 1 of 3 dosing regimens of selepressin (starting infusion rates of 1.7, 2.5, and 3.5 ng/kg/min; n = 585) or to placebo (n = 283), all administered as continuous infusions titrated according to hemodynamic parameters.

Main Outcomes And Measures: Primary end point was ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) of commencing study drug. Key secondary end points were 90-day mortality, kidney replacement therapy-free days, and ICU-free days.

Results: Among 868 randomized patients, 828 received study drug (mean age, 66.3 years; 341 [41.2%] women) and comprised the primary analysis cohort, of whom 562 received 1 of 3 selepressin regimens, 266 received placebo, and 817 (98.7%) completed the trial. The trial was stopped for futility at the end of part 1. Median study drug duration was 37.8 hours (IQR, 17.8-72.4). There were no significant differences in the primary end point (ventilator- and vasopressor-free days: 15.0 vs 14.5 in the selepressin and placebo groups; difference, 0.6 [95% CI, -1.3 to 2.4]; P = .30) or key secondary end points (90-day mortality, 40.6% vs 39.4%; difference, 1.1% [95% CI, -6.5% to 8.8%]; P = .77; kidney replacement therapy-free days: 18.5 vs 18.2; difference, 0.3 [95% CI, -2.1 to 2.6]; P = .85; ICU-free days: 12.6 vs 12.2; difference, 0.5 [95% CI, -1.2 to 2.2]; P = .41). Adverse event rates included cardiac arrhythmias (27.9% vs 25.2% of patients), cardiac ischemia (6.6% vs 5.6%), mesenteric ischemia (3.2% vs 2.6%), and peripheral ischemia (2.3% vs 2.3%).

Conclusions And Relevance: Among patients with septic shock receiving norepinephrine, administration of selepressin, compared with placebo, did not result in improvement in vasopressor- and ventilator-free days within 30 days. Further research would be needed to evaluate the potential role of selepressin for other patient-centered outcomes in septic shock.

Trial Registration: ClinicalTrials.gov Identifier: NCT02508649.
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http://dx.doi.org/10.1001/jama.2019.14607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802260PMC
October 2019

An Integrated Safety Summary of Omadacycline, a Novel Aminomethylcycline Antibiotic.

Clin Infect Dis 2019 08;69(Suppl 1):S40-S47

Paratek Pharmaceuticals, Inc., King of Prussia, Pennsylvania.

Omadacycline is a semisynthetic tetracycline antibiotic. Phase III clinical trial results have shown that omadacycline has an acceptable safety profile in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Similar to most tetracyclines, transient nausea and vomiting and low-magnitude increases in liver aminotransferases were the most frequent treatment-emergent adverse events in phase III studies but were not treatment limiting. Package insert warnings and precautions for omadacycline include tooth discoloration; enamel hypoplasia; inhibition of bone growth following use in late pregnancy, infancy, or childhood up to 8 years of age; an imbalance in mortality (2%, compared with 1% in moxifloxacin-treated patients) was observed in the phase III study in patients with community-acquired bacterial pneumonia. Omadacycline has no effect on the QT interval, and its affinity for muscarinic M2 receptors resulted in transient heart rate increases following dosing.
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http://dx.doi.org/10.1093/cid/ciz398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669290PMC
August 2019

Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis.

JAMA 2019 05;321(20):2003-2017

Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Importance: Sepsis is a heterogeneous syndrome. Identification of distinct clinical phenotypes may allow more precise therapy and improve care.

Objective: To derive sepsis phenotypes from clinical data, determine their reproducibility and correlation with host-response biomarkers and clinical outcomes, and assess the potential causal relationship with results from randomized clinical trials (RCTs).

Design, Settings, And Participants: Retrospective analysis of data sets using statistical, machine learning, and simulation tools. Phenotypes were derived among 20 189 total patients (16 552 unique patients) who met Sepsis-3 criteria within 6 hours of hospital presentation at 12 Pennsylvania hospitals (2010-2012) using consensus k means clustering applied to 29 variables. Reproducibility and correlation with biological parameters and clinical outcomes were assessed in a second database (2013-2014; n = 43 086 total patients and n = 31 160 unique patients), in a prospective cohort study of sepsis due to pneumonia (n = 583), and in 3 sepsis RCTs (n = 4737).

Exposures: All clinical and laboratory variables in the electronic health record.

Main Outcomes And Measures: Derived phenotype (α, β, γ, and δ) frequency, host-response biomarkers, 28-day and 365-day mortality, and RCT simulation outputs.

Results: The derivation cohort included 20 189 patients with sepsis (mean age, 64 [SD, 17] years; 10 022 [50%] male; mean maximum 24-hour Sequential Organ Failure Assessment [SOFA] score, 3.9 [SD, 2.4]). The validation cohort included 43 086 patients (mean age, 67 [SD, 17] years; 21 993 [51%] male; mean maximum 24-hour SOFA score, 3.6 [SD, 2.0]). Of the 4 derived phenotypes, the α phenotype was the most common (n = 6625; 33%) and included patients with the lowest administration of a vasopressor; in the β phenotype (n = 5512; 27%), patients were older and had more chronic illness and renal dysfunction; in the γ phenotype (n = 5385; 27%), patients had more inflammation and pulmonary dysfunction; and in the δ phenotype (n = 2667; 13%), patients had more liver dysfunction and septic shock. Phenotype distributions were similar in the validation cohort. There were consistent differences in biomarker patterns by phenotype. In the derivation cohort, cumulative 28-day mortality was 287 deaths of 5691 unique patients (5%) for the α phenotype; 561 of 4420 (13%) for the β phenotype; 1031 of 4318 (24%) for the γ phenotype; and 897 of 2223 (40%) for the δ phenotype. Across all cohorts and trials, 28-day and 365-day mortality were highest among the δ phenotype vs the other 3 phenotypes (P < .001). In simulation models, the proportion of RCTs reporting benefit, harm, or no effect changed considerably (eg, varying the phenotype frequencies within an RCT of early goal-directed therapy changed the results from >33% chance of benefit to >60% chance of harm).

Conclusions And Relevance: In this retrospective analysis of data sets from patients with sepsis, 4 clinical phenotypes were identified that correlated with host-response patterns and clinical outcomes, and simulations suggested these phenotypes may help in understanding heterogeneity of treatment effects. Further research is needed to determine the utility of these phenotypes in clinical care and for informing trial design and interpretation.
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http://dx.doi.org/10.1001/jama.2019.5791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537818PMC
May 2019

Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy: The SCARLET Randomized Clinical Trial.

JAMA 2019 05;321(20):1993-2002

Asahi-Kasei Pharma America Corporation, Waltham, Massachusetts.

Importance: Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy.

Objective: To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy.

Design, Setting, And Participants: The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019.

Interventions: Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days.

Main Outcome And Measures: The primary end point was 28-day all-cause mortality.

Results: Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P = .32). The absolute risk difference was 2.55% (95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group.

Conclusions And Relevance: Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality.

Trial Registration: ClinicalTrials.gov Identifier: NCT01598831.
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http://dx.doi.org/10.1001/jama.2019.5358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547077PMC
May 2019

Inter-α-inhibitor Ameliorates Endothelial Inflammation in Sepsis.

Lung 2019 06 26;197(3):361-369. Epub 2019 Apr 26.

National Institute of Environmental Health Sciences, 111 TW Alexander Dr, Research Triangle Park, NC, 27709, USA.

Purpose: Vascular endothelial cells demonstrate severe injury in sepsis, and a reduction in endothelial inflammation would be beneficial. Inter-α-Inhibitor (IαI) is a family of abundant plasma proteins with anti-inflammatory properties and has been investigated in human and animal sepsis with encouraging results. We hypothesized that IαI may protect endothelia from sepsis-related inflammation.

Methods: IαI-deficient or sufficient mice were treated with endotoxin or underwent complement-induced lung injury. VCAM-1 and ICAM-1 expression was measured in blood and lung as marker of endothelial activation. Human endothelia were exposed to activated complement C5a with or without IαI. Blood from human sepsis patients was examined for VCAM-1 and ICAM-1 and levels were correlated with blood levels of IαI.

Results: IαI-deficient mice showed increased endothelial activation in endotoxin/sepsis- and complement-induced lung injury models. In vitro, levels of endothelial pro-inflammatory cytokines and cell growth factors induced by activated complement C5a were significantly decreased in the presence of IαI. This effect was associated with decreased ERK and NFκB activation. IαI levels were inversely associated with VCAM-1 and ICAM-1 levels in a human sepsis cohort.

Conclusions: IαI ameliorates endothelial inflammation and may be beneficial as a treatment of sepsis.
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http://dx.doi.org/10.1007/s00408-019-00228-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888858PMC
June 2019

Physician agreement on the diagnosis of sepsis in the intensive care unit: estimation of concordance and analysis of underlying factors in a multicenter cohort.

J Intensive Care 2019 21;7:13. Epub 2019 Feb 21.

Immunexpress Inc, 425 Pontius Avenue North, Suite 430, Seattle, WA 98109 USA.

Background: Differentiating sepsis from the systemic inflammatory response syndrome (SIRS) in critical care patients is challenging, especially before serious organ damage is evident, and with variable clinical presentations of patients and variable training and experience of attending physicians. Our objective was to describe and quantify physician agreement in diagnosing SIRS or sepsis in critical care patients as a function of available clinical information, infection site, and hospital setting.

Methods: We conducted a post hoc analysis of previously collected data from a prospective, observational trial ( = 249 subjects) in intensive care units at seven US hospitals, in which physicians at different stages of patient care were asked to make diagnostic calls of either SIRS, sepsis, or indeterminate, based on varying amounts of available clinical information (clinicaltrials.gov identifier: NCT02127502). The overall percent agreement and the free-marginal, inter-observer agreement statistic kappa ( ) were used to quantify agreement between evaluators (attending physicians, site investigators, external expert panelists). Logistic regression and machine learning techniques were used to search for significant variables that could explain heterogeneity within the indeterminate and SIRS patient subgroups.

Results: Free-marginal kappa decreased between the initial impression of the attending physician and (1) the initial impression of the site investigator ( 0.68), (2) the consensus discharge diagnosis of the site investigators ( 0.62), and (3) the consensus diagnosis of the external expert panel ( 0.58). In contrast, agreement was greatest between the consensus discharge impression of site investigators and the consensus diagnosis of the external expert panel ( 0.79). When stratified by infection site, for agreement between initial and later diagnoses had a mean value + 0.24 (range - 0.29 to + 0.39) for respiratory infections, compared to + 0.70 (range + 0.42 to + 0.88) for abdominal + urinary + other infections. Bioinformatics analysis failed to clearly resolve the indeterminate diagnoses and also failed to explain why 60% of SIRS patients were treated with antibiotics.

Conclusions: Considerable uncertainty surrounds the differential clinical diagnosis of sepsis vs. SIRS, especially before organ damage has become highly evident, and for patients presenting with respiratory clinical signs. Our findings underscore the need to provide physicians with accurate, timely diagnostic information in evaluating possible sepsis.
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http://dx.doi.org/10.1186/s40560-019-0368-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383290PMC
February 2019

Novel Chitohexaose Analog Protects Young and Aged mice from CLP Induced Polymicrobial Sepsis.

Sci Rep 2019 02 27;9(1):2904. Epub 2019 Feb 27.

AyuVis Research Inc, 1120 South Freeway, Fort Worth, TX, 76104, USA.

In Gram-negative bacterial sepsis, production of excess pro-inflammatory cytokines results in hyperinflammation and tissue injury. Anti-inflammatory cytokines such as IL-10 inhibit inflammation and enhance tissue healing. Here, we report a novel approach to treat septicemia associated with intra-abdominal infection in a murine model by delicately balancing pro- and anti-inflammatory cytokines. A novel oligosaccharide compound AVR-25 selectively binds to the TLR4 protein (IC = 0.15 µM) in human peripheral blood monocytes and stimulates IL-10 production. Following the cecal ligation and puncture (CLP) procedure, intravenous dosing of AVR-25 (10 mg/kg, 6-12 h post-CLP) alone and in combination with antibiotic imipenem protected both young adult (10-12 week old) and aged (16-18 month old) mice against polymicrobial infection, organ dysfunction, and death. Proinflammatory cytokines (TNF-α, MIP-1, i-NOS) were decreased significantly and restoration of tissue damage was observed in all organs. A decrease in serum C-reactive protein (CRP) and bacterial colony forming unit (CFU) confirmed improved bacterial clearance. Together, these findings demonstrate the therapeutic ability of AVR-25 to mitigate the storm of inflammation and minimize tissue injury with high potential for adjunctive therapy in intra-abdominal sepsis.
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http://dx.doi.org/10.1038/s41598-019-38731-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393422PMC
February 2019

Coinfection With Influenza A Virus and : An Underrecognized Impact on Host Resistance and Tolerance to Pulmonary Infections.

Front Immunol 2018 29;9:2377. Epub 2018 Oct 29.

Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States.

Pneumonia is a world health problem and a leading cause of death, particularly affecting children and the elderly (1, 2). Bacterial pneumonia following infection with influenza A virus (IAV) is associated with increased morbidity and mortality but the mechanisms behind this phenomenon are not yet well-defined (3). Host resistance and tolerance are two processes essential for host survival during infection. Resistance is the host's ability to clear a pathogen while tolerance is the host's ability to overcome the impact of the pathogen as well as the host response to infection (4-8). Some studies have shown that IAV infection suppresses the immune response, leading to overwhelming bacterial loads (9-13). Other studies have shown that some IAV/bacterial coinfections cause alterations in tolerance mechanisms such as tissue resilience (14-16). In a recent analysis of nasopharyngeal swabs from patients hospitalized during the 2013-2014 influenza season, we have found that a significant proportion of IAV-infected patients were also colonized with , a gram-negative bacteria known to be an opportunistic pathogen in a variety of diseases (17). Mice that were infected with following IAV infection demonstrated decreased survival and significant weight loss when compared to mice infected with either single pathogen. Using this model, we found that IAV/ coinfection of the lung is characterized by an exaggerated inflammatory immune response. We observed early inflammatory cytokine and chemokine production, which in turn resulted in massive infiltration of neutrophils and inflammatory monocytes. Despite this swift response, the pulmonary pathogen burden in coinfected mice was similar to singly-infected animals, albeit with a slight delay in bacterial clearance. In addition, during coinfection we observed a shift in pulmonary macrophages toward an inflammatory and away from a tissue reparative phenotype. Interestingly, there was only a small increase in tissue damage in coinfected lungs as compared to either single infection. Our results indicate that during pulmonary coinfection a combination of seemingly modest defects in both host resistance and tolerance may act synergistically to cause worsened outcomes for the host. Given the prevalence of detected in human IAV patients, these dysfunctional tolerance and resistance mechanisms may play an important role in the response of patients to IAV.
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http://dx.doi.org/10.3389/fimmu.2018.02377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217722PMC
October 2019

Whatever happened to the Shwartzman phenomenon?

Innate Immun 2018 11;24(8):466-479

3 The Infectious Disease Division, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, USA.

Ninety years ago, Gregory Shwartzman first reported an unusual discovery following the intradermal injection of sterile culture filtrates from principally Gram-negative strains from bacteria into normal rabbits. If this priming dose was followed in 24 h by a second intravenous challenge (the provocative dose) from same culture filtrate, dermal necrosis at the first injection site would regularly occur. This peculiar, but highly reproducible, event fascinated the microbiologists, hematologists, and immunologists of the time, who set out to determine the mechanisms that underlie the pathogenesis of this reaction. The speed of this reaction seemed to rule out an adaptive, humoral, immune response as its cause. Histopathologic material from within the necrotic center revealed fibrinoid, thrombo-hemorrhagic necrosis within small arterioles and capillaries in the micro-circulation. These pathologic features bore a striking resemblance to a more generalized coagulopathic phenomenon following two repeated endotoxin injections described 4 yr earlier by Sanarelli. This reaction came to be known as the generalized Shwartzman phenomenon, while the dermal reaction was named the localized or dermal Shwartzman reaction. A third category was later added, called the single organ or mono-visceral form of the Shwartzman phenomenon. The occasional occurrence of typical pathological features of the generalized Shwartzman reaction limited to a single organ is notable in many well-known clinical events (e.g., hyper-acute kidney transplant rejection, fulminant hepatic necrosis, or adrenal apoplexy in Waterhouse-Fredrickson syndrome). We will briefly review the history and the significant insights gained from understanding this phenomenon regarding the circuitry and control mechanisms responsible for disseminated intravascular coagulation, the vasculopathy and the immunopathy of sepsis.
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http://dx.doi.org/10.1177/1753425918808008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830869PMC
November 2018

Antibiotic Stewardship: Strategies to Minimize Antibiotic Resistance While Maximizing Antibiotic Effectiveness.

Med Clin North Am 2018 Sep;102(5):831-843

Division of Infectious Disease, Rhode Island Hospital, The Miriam Hospital, Brown University Alpert School of Medicine, 593 Eddy Street, Physicians Office Building, Suite #328, Providence, RI 02903, USA.

Empiric therapy of the septic patient in the hospital is challenging. Antibiotic stewardship is concerned with optimizing antibiotic use and minimizing resistance. Clinicians should avoid overcovering and overtreating colonizing organisms in respiratory secretions and urinary catheters. Empiric therapy should take into account the prevalence of multidrug-resistant organisms in the hospital setting. The most effective resistance prevention strategies is to preferentially select a low resistance potential antibiotic, which should be administered in the highest possible dose without toxicity for the shortest duration to eliminate the infection.
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http://dx.doi.org/10.1016/j.mcna.2018.04.006DOI Listing
September 2018

Soluble programmed cell death protein-1 and programmed cell death ligand-1 in sepsis.

Crit Care 2018 06 7;22(1):146. Epub 2018 Jun 7.

Departments of Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA.

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http://dx.doi.org/10.1186/s13054-018-2064-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991454PMC
June 2018

Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study).

Intensive Care Med 2018 04 9;44(4):438-448. Epub 2018 Apr 9.

Department I of Internal Medicine, Intensive Care Unit and Hemostasis, University Hospital of Cologne, Cologne, Germany.

Purpose: The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP).

Methods: In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L).

Results: Overall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58-78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline.

Conclusions: No significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation.

Trial Registration: NCT01420744.
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http://dx.doi.org/10.1007/s00134-018-5143-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924663PMC
April 2018

Validation of a Host Response Assay, SeptiCyte LAB, for Discriminating Sepsis from Systemic Inflammatory Response Syndrome in the ICU.

Am J Respir Crit Care Med 2018 10;198(7):903-913

11 Immunexpress Inc., Seattle, Washington.

Rationale: A molecular test to distinguish between sepsis and systemic inflammation of noninfectious etiology could potentially have clinical utility.

Objectives: This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte LAB) designed to distinguish between sepsis and noninfectious systemic inflammation in critically ill adults.

Methods: The study employed a prospective, observational, noninterventional design and recruited a heterogeneous cohort of adult critical care patients from seven sites in the United States (n = 249). An additional group of 198 patients, recruited in the large MARS (Molecular Diagnosis and Risk Stratification of Sepsis) consortium trial in the Netherlands ( www.clinicaltrials.gov identifier NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. The performance of SeptiCyte LAB was compared with retrospective physician diagnosis by a panel of three experts.

Measurements And Main Results: In receiver operating characteristic curve analysis, SeptiCyte LAB had an estimated area under the curve of 0.82-0.89 for discriminating sepsis from noninfectious systemic inflammation. The relative likelihood of sepsis versus noninfectious systemic inflammation was found to increase with increasing test score (range, 0-10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables, including procalcitonin. The performance of the assay was not significantly affected by demographic variables, including age, sex, or race/ethnicity.

Conclusions: SeptiCyte LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT01905033 and NCT02127502).
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http://dx.doi.org/10.1164/rccm.201712-2472OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835074PMC
October 2018

Rationale and Design of an Adaptive Phase 2b/3 Clinical Trial of Selepressin for Adults in Septic Shock. Selepressin Evaluation Programme for Sepsis-induced Shock-Adaptive Clinical Trial.

Ann Am Thorac Soc 2018 02;15(2):250-257

4 Berry Consultants, LLC, Austin, Texas.

Septic shock carries substantial morbidity and mortality. The failure of many promising therapies during late-phase clinical trials prompted calls for alternative trial designs. We describe an innovative trial evaluating selepressin, a novel selective vasopressin V receptor agonist, for adults with septic shock. SEPSIS-ACT (Selepressin Evaluation Programme for Sepsis-induced Shock-Adaptive Clinical Trial) is a blinded, randomized, placebo-controlled, two-part, adaptive phase 2b/3 trial, evaluating up to four selepressin dosing strategies. The primary outcome is pressor- and ventilator-free days, with a value of zero assigned for death within 30 days. We calculate Bayesian probabilities of final trial success to guide interim decision-making. Part 1 (dose-finding) has an adaptive sample size based on response-adaptive randomization and prespecified rules to determine stopping for futility or selection of the best dosing regimen for Part 2. Part 2 (confirmation) randomizes a minimum of 1,000 patients equally to the selected dosing regimen or placebo. The final estimate of treatment effect compares all selepressin-treated patients with all placebo-treated patients. The sample size of 1,800 provides 91% power to detect an increase of 1.5 pressor- and ventilator-free days with a reduction in mortality of 1.5%. The trial received a Special Protocol Assessment agreement from the U.S. Food and Drug Administration Center for Drug Evaluation and Research and is underway in Europe and the United States. SEPSIS-ACT is an innovative trial that addresses both optimal dose and confirmation of benefit, accelerating the evaluation of selepressin while mitigating risks to patients and sponsor through use of response-adaptive randomization, a novel registration endpoint, prespecified futility stopping rules, and a large sample size. Clinical Trial registered with www.clinicaltrials.gov (NCT02508649).
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http://dx.doi.org/10.1513/AnnalsATS.201708-669SDDOI Listing
February 2018

Age, exercise, and the outcome of sepsis.

Crit Care 2017 11 23;21(1):286. Epub 2017 Nov 23.

Department of Medicine, Warren Alpert Medical School of Brown University, 593 Eddy St., Providence, RI, 02903, USA.

We report on the increasingly important need to diagnose and care for the elderly with sepsis as a distinct patient population. We share an overview of age-related changes in sepsis physiology and the potential role of exercise.See related research by Tyml et al., https://ccforum.biomedcentral.com/articles/10.1186/s13054-017-1783-1.
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http://dx.doi.org/10.1186/s13054-017-1840-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701382PMC
November 2017

Mortality Benefit of Recombinant Human Interleukin-1 Receptor Antagonist for Sepsis Varies by Initial Interleukin-1 Receptor Antagonist Plasma Concentration.

Crit Care Med 2018 01;46(1):21-28

Infectious Disease Division, Department of Medicine, Memorial Hospital of Rhode Island, the Alpert Medical School of Brown University, Providence, RI.

Objective: Plasma interleukin-1 beta may influence sepsis mortality, yet recombinant human interleukin-1 receptor antagonist did not reduce mortality in randomized trials. We tested for heterogeneity in the treatment effect of recombinant human interleukin-1 receptor antagonist by baseline plasma interleukin-1 beta or interleukin-1 receptor antagonist concentration.

Design: Retrospective subgroup analysis of randomized controlled trial.

Setting: Multicenter North American and European clinical trial.

Patients: Five hundred twenty-nine subjects with sepsis and hypotension or hypoperfusion, representing 59% of the original trial population.

Interventions: Random assignment of placebo or recombinant human interleukin-1 receptor antagonist × 72 hours.

Measurements And Main Results: We measured prerandomization plasma interleukin-1 beta and interleukin-1 receptor antagonist and tested for statistical interaction between recombinant human interleukin-1 receptor antagonist treatment and baseline plasma interleukin-1 receptor antagonist or interleukin-1 beta concentration on 28-day mortality. There was significant heterogeneity in the effect of recombinant human interleukin-1 receptor antagonist treatment by plasma interleukin-1 receptor antagonist concentration whether plasma interleukin-1 receptor antagonist was divided into deciles (interaction p = 0.046) or dichotomized (interaction p = 0.028). Interaction remained present across different predicted mortality levels. Among subjects with baseline plasma interleukin-1 receptor antagonist above 2,071 pg/mL (n = 283), recombinant human interleukin-1 receptor antagonist therapy reduced adjusted mortality from 45.4% to 34.3% (adjusted risk difference, -0.12; 95% CI, -0.23 to -0.01), p = 0.044. Mortality in subjects with plasma interleukin-1 receptor antagonist below 2,071 pg/mL was not reduced by recombinant human interleukin-1 receptor antagonist (adjusted risk difference, +0.07; 95% CI, -0.04 to +0.17), p = 0.230. Interaction between plasma interleukin-1 beta concentration and recombinant human interleukin-1 receptor antagonist treatment was not statistically significant.

Conclusions: We report a heterogeneous effect of recombinant human interleukin-1 receptor antagonist on 28-day sepsis mortality that is potentially predictable by plasma interleukin-1 receptor antagonist in one trial. A precision clinical trial of recombinant human interleukin-1 receptor antagonist targeted to septic patients with high plasma interleukin-1 receptor antagonist may be worthy of consideration.
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http://dx.doi.org/10.1097/CCM.0000000000002749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734955PMC
January 2018

The Role of S1PR3 in Protection from Bacterial Sepsis.

Am J Respir Crit Care Med 2017 12;196(12):1500-1502

2 Infectious Disease Division Rhode Island Hospital and Alpert Medical School of Brown University Providence, Rhode Island.

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http://dx.doi.org/10.1164/rccm.201708-1726EDDOI Listing
December 2017

Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy.

World J Stem Cells 2017 Mar;9(3):45-67

Jorge Zorzopulos, Juan Fló, Ricardo A López, Raul Franco, Immunotech S.A., Ciudad de Buenos Aires C1440FFX, Argentina.

The immune responses of humans and animals to insults (., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.
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http://dx.doi.org/10.4252/wjsc.v9.i3.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368622PMC
March 2017

Should all septic patients be given systemic anticoagulation? No.

Intensive Care Med 2017 Mar 13;43(3):455-457. Epub 2017 Feb 13.

Infectious Disease Division, Warren Alpert Medical School of Brown University, Providence, RI, USA.

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http://dx.doi.org/10.1007/s00134-016-4607-xDOI Listing
March 2017

Severe Pneumonia Caused by Legionella pneumophila: Differential Diagnosis and Therapeutic Considerations.

Infect Dis Clin North Am 2017 03;31(1):111-121

Critical Care Division, Miriam Hospital, Brown University Alpert School of Medicine, Providence, RI, USA; Infectious Disease Division, Rhode Island Hospital, Brown University Alpert School of Medicine, Providence, RI, USA.

Severe legionella pneumonia poses a diagnostic challenge and requires early intervention. Legionnaire's disease can have several presenting signs, symptoms, and laboratory abnormalities that suggest that Legionella pneumophila is the pathogen, but none of these are sufficient to distinguish L pneumophila pneumonia from other respiratory pathogens. L pneumophila is primarily an intracellular pathogen and needs treatment with antibiotics that efficiently enter the intracellular space.
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http://dx.doi.org/10.1016/j.idc.2016.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135102PMC
March 2017

Sepsis: frontiers in supportive care, organisation and research.

Intensive Care Med 2017 Apr 27;43(4):496-508. Epub 2017 Jan 27.

Infectious Diseases Division, The Alpert Medical School of Brown University, Providence, RI, USA.

Because of its high incidence and clinical complexity, sepsis is a major challenge to clinicians and researchers and a global burden to healthcare systems and society. Despite recent progress, short- and long-term morbidity, mortality and costs remain high in both developed and developing countries. Thus, further improvements in supportive interventions and organisation of care are likely to have a substantial impact upon global health. In this narrative review, invited experts describe the challenges and progress to be made in sepsis research and care in the near future. We focus on supportive care (pulmonary, endocrine, renal, and nutritional support, mediator modulation and precision medicine), organisational themes (guidelines, outcome measures and stakeholder involvement) and clinical research as key areas to improving the care and outcomes of patients with sepsis.
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http://dx.doi.org/10.1007/s00134-017-4677-4DOI Listing
April 2017
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