Search

Purpose: 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.Methods: 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.Results: 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.Conclusions: 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. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT02960854. [ABSTRACT FROM AUTHOR]

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: Randomized, placebo-controlled, dose-escalation.Setting: Seven U.S. hospital ICUs.Study Population: Twenty-four participants with sepsis, organ dysfunction (hypotension, acute respiratory failure, and/or acute renal injury), and absolute lymphocyte count less than or equal to 1,100 cells/μL.Interventions: Participants received single-dose BMS-936559 (10-900 mg; n = 20) or placebo (n = 4) infusions. Primary endpoints were death and adverse events; key secondary endpoints included receptor occupancy and monocyte human leukocyte antigen-DR levels.Measurements and Main Results: The treated group was older (median 62 yr treated pooled vs 46 yr placebo), and a greater percentage had more than 2 organ dysfunctions (55% treated pooled vs 25% placebo); other baseline characteristics were comparable. Overall mortality was 25% (10 mg dose: 2/4; 30 mg: 2/4; 100 mg: 1/4; 300 mg: 1/4; 900 mg: 0/4; placebo: 0/4). All participants had adverse events (75% grade 1-2). Seventeen percent had a serious adverse event (3/20 treated pooled, 1/4 placebo), with none deemed drug-related. Adverse events that were potentially immune-related occurred in 54% of participants; most were grade 1-2, none required corticosteroids, and none were deemed drug-related. No significant changes in cytokine levels were observed. Full receptor occupancy was achieved for 28 days after BMS-936559 (900 mg). At the two highest doses, an apparent increase in monocyte human leukocyte antigen-DR expression (> 5,000 monoclonal antibodies/cell) was observed and persisted beyond 28 days.Conclusions: In this first clinical evaluation of programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition in sepsis, BMS-936559 was well tolerated, with no evidence of drug-induced hypercytokinemia or cytokine storm, and at higher doses, some indication of restored immune status over 28 days. Further randomized trials on programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition are needed to evaluate its clinical safety and efficacy in patients with sepsis. [ABSTRACT FROM AUTHOR]

The article offers information on the development of drugs that boost immunity in patients with life-threatening infections. It further discusses decrease in deaths due to advances in supportive therapies during the early phases of septic shock; effect of immunosuppression manifested by the incidence of new secondary infections; and also mentions about the immunoadjuvants that activate early-responding immune effector cells.

Sepsis is a global health priority, yet effective host‐directed targeted therapies have not been identified outside of the setting of coronavirus disease 2019 (COVID‐19). Lymphopenia occurs in up to ~52% of patients with sepsis and is associated with a higher mortality at both 30 and 100 days. In COVID‐19, the presence of lymphopenia correlates with intensive care unit admission, acute respiratory distress syndrome and death. The mechanisms underpinning lymphopenic sepsis remain unknown, and while high rates of lymphocyte apoptosis have been implicated, the relative contributions of cellular trafficking to inflamed tissues and reduction in lymphopoiesis require investigation. Further delineation of these underlying mechanisms holds the potential to open new avenues for the development of host‐directed therapies in lymphopenic sepsis. These may include recombinant cytokines (e.g. interleukin‐7), monoclonal antibodies (e.g. anti‐interleukin‐1, anti‐programmed cell death protein 1) and small interfering RNA (e.g. targeting interleukin‐10, transforming growth factor beta). Applying the frontier tools of translational cellular and genomic medicine to understand lymphopenia in the setting of critical infections holds the potential to significantly reduce the excessive global burden of sepsis. [ABSTRACT FROM AUTHOR]

The authors reflects on the study which examines the role played by autophagy in the altered function and depletion of T cells during severe experimental sepsis. They mention that the rate of autophagosome formation, reflected through mean fluorescence index in green fluorescent protein (GFP)-LC3 transgenic mice, significantly increased over time in the CD4 T cells of septic mice equated with sham-operated controls.

The article discusses the relevance of some immunity molecular mechanisms to both cancer and chronic infection. Topics addressed include the inducement of similar immunologic responses, ways to improve host immunity without experiencing side effects associated with an overreactive immune system, clinical trials of granulocyte-macrophage colony-stimulating factor (GM-CSF), and the need for greater collaboration among oncologists, translational immunologists and infectious-disease specialists.

Sepsis - which is a severe life-threatening infection with organ dysfunction - initiates a complex interplay of host pro-inflammatory and anti-inflammatory processes. Sepsis can be considered a race to the death between the pathogens and the host immune system, and it is the proper balance between the often competing pro- and anti-inflammatory pathways that determines the fate of the individual. Although the field of sepsis research has witnessed the failure of many highly touted clinical trials, a better understanding of the pathophysiological basis of the disorder and the mechanisms responsible for the associated pro- and anti-inflammatory responses provides a novel approach for treating this highly lethal condition. Biomarker-guided immunotherapy that is administered to patients at the proper immune phase of sepsis is potentially a major advance in the treatment of sepsis and in the field of infectious disease. [ABSTRACT FROM AUTHOR]

The authors express their belief that antipyretic therapy should not be given routinely to febrile patients in septic shock. They argue that there are few well-designed clinical trials examining the effects of antipyretic therapy in critically ill patients and few have specifically addressed the role of antipyretic therapy in septic patients. They added that although external cooling was found to decrease vasopressor requirements and 14-day mortality, it had no effect on long-term mortality.

Summary: Failures of highly touted trials have caused experts to call for re-evaluation of the current approach toward sepsis. New research has revealed key pathogenic mechanisms; autopsy results have shown that most patients admitted to intensive care units for treatment of sepsis had unresolved septic foci at post mortem, suggesting that patients were unable to eradicate invading pathogens and were more susceptible to nosocomial organisms, or both. These results suggest that therapies that improve host immunity might increase survival. Additional work showed that cytokine production by splenocytes taken post mortem from patients who died of sepsis is profoundly suppressed, possibly because of so-called T-cell exhaustion—a newly recognised immunosuppressive mechanism that occurs with chronic antigenic stimulation. Results from two clinical trials of biomarker-guided therapeutic drugs that boosted immunity showed promising findings in sepsis. Collectively, these studies emphasise the degree of immunosuppression that occurs in sepsis, and explain why many previous sepsis trials which were directed at blocking inflammatory mediators or pathogen recognition signalling pathways failed. Finally, highly encouraging results from use of the new immunomodulatory molecules interleukin 7 and anti-programmed cell death 1 in infectious disease point the way for possible use in sepsis. We hypothesise that immunoadjuvant therapy represents the next major advance in sepsis. [ABSTRACT FROM AUTHOR]

The article discusses apoptosis and its impact on programmed cell death and on the treatment of various diseases. Two types of mammalian cell death are widely recognized, namely, necrosis and apoptosis. However, there is a third type of cell death being proposed which is called autophagy. Genetically controlled cell death is considered as programmed cell death and it consists of two basic types, namely, apoptosis and autophagy-associated cell death. Information on the impact of apoptosis on autoimmune diseases is also presented.

The author focuses on the use of imaging modality to detect apoptotic cell death in septic patients. He relates the study "Imaging Lymphoid Cell Death In Vivo During Polymicrobial Sepsis," by L. Zou and colleagues in the November 2015 issue. He notes that the authors of the study develop a novel noninvasive method to monitor apoptotic cell death in sepsis, but the annexin-V imaging has a number of issues limiting its usage in septic patients.

Some labile cell types whose numbers are normally controlled through programmed cell death are subject to markedly increased destruction during some severe infections. Lymphocytes, in particular, undergo massive and apparently unregulated apoptosis in human patients and laboratory animals with sepsis, potentially playing a major role in the severe immunosuppression that characterizes the terminal phase of fatal illness. Extensive lymphocyte apoptosis has also occurred in humans and animals infected with several exotic agents, including Bacillus anthracis, the cause of anthrax; Yersinia pestis, the cause of plague; and Ebola virus. Prevention of lymphocyte apoptosis, through either genetic modification of the host or treatment with specific inhibitors, markedly improves survival in murine sepsis models. These findings suggest that interventions aimed at reducing the extent of immune cell apoptosis could improve outcomes for a variety of severe human infections, including those caused by emerging pathogens and bioterrorism agents. [ABSTRACT FROM AUTHOR]

Although the prevailing concept has been that mortality in sepsis results from an unbridled hyper-inflammatory cytokine-mediated response, the failure of more than 30 clinical trials to treat sepsis by controlling this cytokine response requires a 'rethink' of the molecular mechanism underpinning the development of sepsis. As we discuss here, remarkable new studies indicate that most deaths from sepsis are actually the result of a substantially impaired immune response that is due to extensive death of immune effector cells. Rectification of this apoptotic–inflammatory imbalance using modulators of caspases and other components of the cell-death pathway have shown striking efficacy in stringent animal models of sepsis, indicating an entirely novel path forward for the clinical treatment of human sepsis. [ABSTRACT FROM AUTHOR]

We agree that autoimmune pulmonary toxicity is a potential serious adverse effect of checkpoint inhibitor therapy in patients with sepsis and that it may be difficult to recognize in patients who are being mechanically ventilated. Importantly, we also believe that the frequency of autoimmune adverse effects of checkpoint inhibitors in patients with sepsis would be reduced compared with most other patient groups because of the effect of sepsis to naturally decrease host immune competence ([4]). 1 Suresh K D'Alessio F. Immune Checkpoint Inhibitor Use in Sepsis: Monitoring Immune Checkpoint Inhibitor Toxicity. [Extracted from the article]

Sepsis is the leading cause of death in surgical intensive care units and is a major cause of morbidity and mortality in neonatal and medical intensive care units. The Centers for Disease Control and Prevention estimates that, in the United States alone, ∼500,000 people develop sepsis and 175,000 people die each year. Sepsis is a growing problem; its incidence has tripled from 1972 to 1992. Recently, apoptosis has been identified as an important mechanism of cell death in animal models of sepsis and endotoxemia. During sepsis, there is extensive apoptotic death of lymphocytes and gastrointestinal epithelial cells. The extensive apoptotic death of lymphocytes is likely an important cause of the profound immunosuppression that is a hallmark of patients with sepsis. The apoptosis of gastrointestinal epithelial cells may compromise the integrity of the bowel wall, resulting in translocation of bacteria or endotoxins into the systemic circulation. The potential importance of apoptosis in the pathophysiology of sepsis is illustrated by results from animal models that demonstrate that blocking lymphocyte apoptosis improves survival in sepsis. A variety of strategies to inhibit apoptosis may ultimately provide an effective therapy for this highly lethal disorder. [ABSTRACT FROM AUTHOR]

Sepsis is the leading cause of morbidity and mortality in critically ill patients in many intensive care units. The pathophysiology of organ failure and death in patients with sepsis remain elusive. This review focuses on recent advances in our understanding of the mechanisms of cell death in sepsis, the types of cells that are dying and the consequences on immunity. Extensive apoptotic death results in immune cell depletion and may compromise the ability of the patient to eradicate the primary infection and predispose to secondary nosocomial infections. Peripheral circulating lymphocyte apoptosis is also increased in patients with sepsis and correlates with the severity of the disease. In addition, recent evidence indicates that uptake of apoptotic cells impairs the immune function of surviving cells and contributes to immunosuppression. This new understanding of sepsis may lead to novel therapeutic approaches including pharmacological agents that block apoptosis. [ABSTRACT FROM AUTHOR]

Lymphocyte rolling velocity is determined largely by interactions between leukocyte α[sub 4]-integrin (CD49d) and L-selectin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in mesentric postcapillary venules and Peyer's patch high endothelial tissue sites of lymphocyte emigration is not known. With the use of real-time intravital confocal microscopy, we found that rolling velocities of T lymphocytes in the murine mesentric lymph node (MLN) HEV also depend on L-selectin and CD49d. However, in the murine spleen, rolling velocities of T lymphocytes are not influenced by the loss of L-selectin and CD49d. With the use of FITC-dextran and TIE2-GFP mice, we further defined the microvascular compartments of the spleen and showed that adherence of T cells is localized to regions in the white pulp that are not lined by endothelial cells and have shear rates similar to bone marrow sinusoids. These results establish that T cell trafficking to the spleen differs from trafficking to other secondary lymphoid organs and suggest that the mechanical properties of the blood-filtering role of the spleen are important in T cell accumulation in the organ. [ABSTRACT FROM AUTHOR]

In sepsis, both necrotic and apoptotic cell death can occur. Apoptotic cells induce anergy that could impair the host response, whereas necrotic cells cause immune activation that might result in enhanced antimicrobial defenses, We determined whether adoptive transfer of apoptotic or necrotic cells impacted survival in a clinically relevant sepsis model. We also evaluated the effects of adoptive transfer of apoptotic or necrotic cells on the prototypical TH1 and TH2 cytokines IFN-γ and IL-4, respectively. C57BL6/J mice had adoptive transfer of apoptotic (irradiated) or necrotic (freeze thaw) splenocytes. Controls received saline. Apoptotic cells greatly increased mortality, whereas necrotic splenocytes markedly improved survival, P ≤ 0.05. The contrasting effects that apoptotic or necrotic cells exerted on survival were mirrored by opposite effects on splenocyte IFN-γ production with greatly decreased and increased production, respectively. Importantly, either administration of anti-IFN-γ antibodies or use of IFN-γ knockout mice prevented the survival benefit occurring with necrotic cells. This study demonstrates that the type of cell death impacts survival in a clinically relevant model and identifies a mechanism for the immune suppression that is a hallmark of sepsis. [ABSTRACT FROM AUTHOR]

The article discusses research on the use of systemic inflammatory response syndrome (SIRS) criteria in defining severe sepsis. It references a study by K. M. Kaukonen and colleagues, published in the "New England Journal of Medicine." Topics discussed include the emergence of sepsis as one of the most common causes of death in critically ill patients, how researchers redefined severe sepsis, and the definition of sepsis in the Surviving Sepsis Campaign guidelines published in 2013.

Demonstrates the feasibility of determining intracellular calcium in vivo and in situ using fluorine-19 nuclear magnetic resonance spectroscopy (19 F-NMR) and 5-fluro-1,2-bis(2-aminophenoxy)ethane-N ,N ,N' ,N' -tetraacetic acid (5F-BAPTA). Effects of 5F-BAPTA intravenous infusion on rats.

Current surgical guidelines for the treatment of intra-abdominal sepsis recommend interventional source control as the key element of therapy, alongside resuscitation and antibiotic administration. Past trials attempted to predict the success of interventional source control to assess whether further interventional therapy is needed. However, no predictive score could be developed. We utilized an established murine abdominal sepsis model, the cecal ligation and puncture (CLP), and performed a successful surgical source control intervention after full development of sepsis, the CLP-excision (CLP/E). We then sought to evaluate the success of the source control by characterizing circulating neutrophil phenotype and functionality 24 h postintervention. We showed a significant relative increase of neutrophils and a significant absolute and relative increase of activated neutrophils in septic mice. Source control with CLP/E restored these numbers back to baseline. Moreover, main neutrophil functions, the acidification of cell compartments, such as lysosomes, and the production of Tumor Necrosis Factor-alpha (TNF-α), were impaired in septic mice but restored after CLP/E intervention. Neutrophil characterization by phenotyping and evaluating their functionality indicates successful source control in septic mice and can serve as a prognostic tool. These findings provide a rationale for the phenotypic and functional characterization of neutrophils in human patients with infection. Further studies will be needed to determine whether a predictive score for the assessment of successful surgical source control can be established. • Successful surgical source control in abdominal sepsis can be modeled with the murine CLP-excision model (CLP/E). • Sepsis leads to a relative increase of neutrophils in whole blood and a relative and absolute increase of activated neutrophils, both of which return to that of the healthy control after source control (CLP/E). • Sepsis also leads to functional impairment of neutrophils (acidification of cell compartments and TNF-α production) from septic mice but not those mice with source control (CLP/E). • The phenotypic and functional characterization of neutrophils in mice can provide a rationale to develop a predictive scoring system to evaluate the success of source control in infected human patients. [ABSTRACT FROM AUTHOR]

These results demonstrate a potential mechanism for improved sepsis survival in patients taking prophylactic aspirin and suggest that aspirin may be effective as immunomodulatory treatment for septic patients. Understanding the mechanisms of aspirin as a sepsis therapy will set the stage for the next iteration of clinical studies to identify the septic patients that will benefit most from treatment with aspirin. Establishing these mechanisms of action of aspirin in sepsis moves aspirin treatment toward the long-term goal of a precision therapy for sepsis. [Extracted from the article]

The article discusses the result of a study suggesting the use of immunotherapy for sepsis. In this study, a new mechanism by which the interaction between a monocyte, a macrophage protein known as programmed death 1 (PD-1), and PD-L1 induces immunosuppression in patients with HIV is described. Findings revealed that microbial mediators translocate across the intestinal epithelium in chronic human immunodeficiency virus (HIV)-induced inflammation and are recognized by toll-like receptors. The researchers also found an increase in the production of interleukin-10 by monocytes from persons infected with HIV resulting from PD-1 activation. Analysis shows the potential improvement of the prognosis of patients with any of a variety of chronic infections by blocking PD-1.

The authors look at research on preventing and reducing mortality from sepsis, which they note is a complication from infections that is a frequent cause of death in hospitals. They cite a study by medical researcher Georg F. Weber and colleagues, reported in the current issue, showing that blocking the cytokine interleukin-3 may be an effective treatment for sepsis, and express caution about this anti-inflammatory treatment approach.

The authors comment on a counterpoint editorial which is in favor of giving antipyretic therapy routinely to febrile patients in septic shock. They find that although the editorial presented a well-constructed argument, the authors maintain their position that fever should not routinely be treated in all patients with septic shock adding that antipyretic therapy prevents fever-related augmentation of the immune system and impairs the clinical recognition of new infections.

The article presents the findings of the two studies on the pathogenic mechanisms of sepsis immunopathology. It says that the studies feature the impact of sustained critical illness on immune function and induce basic research and development of methods to enhance immunity. It reflects on the report that the inactive viruses cytomegalovirus (CMV) and herpes simplex virus (HSV) are reactivated in severely ill individuals, saying that the key aspect of critical illness is immunosuppression.

A letter to the editor is presented in response to an article by Petros and colleagues in the December 21/28, 1992 issue, which discusses the inhibition of nitric oxide (NO) synthesis in restoring the blood pressure in septic shock patients.

A response by Richard S. Hotchkiss and Irene E. Karl to a letter to the editor about their article "The pathophysiology and treatment of sepsis," in the January 9, 2003 issue is presented.

Reports on the pathophysiology and treatment of sepsis. How sepsis is the leading cause of death in critically ill patients; View that new therapies have been developed to treat sepsis; View that sepsis represents an uncontrolled inflammatory response; Suggestion that sepsis is consistent with the failure of the immune system; Treatments of sepsis including insulin therapy and activated protein C.

Objectives: To test the hypothesis that forced-air warming of critically ill afebrile sepsis patients improves immune function compared to standard temperature management.Design: Single-center, prospective, open-label, randomized controlled trial.Setting: One thousand two hundred-bed academic medical center.Patients: Eligible patients were mechanically ventilated septic adults with: 1) a diagnosis of sepsis within 48 hours of enrollment; 2) anticipated need for mechanical ventilation of greater than 48 hours; and 3) a maximum temperature less than 38.3°C within the 24 hours prior to enrollment. Primary exclusion criteria included: immunologic diseases, immune-suppressing medications, and any existing condition sensitive to therapeutic hyperthermia (e.g., brain injury). The primary outcome was monocyte human leukocyte antigen (HLA)-DR expression, with secondary outcomes of CD3/CD28-induced interferon gamma (IFN-γ) production, mortality, and 28-day hospital-free days.Interventions: External warming using a forced-air warming blanket for 48 hours, with a goal temperature 1.5°C above the lowest temperature documented in the previous 24 hours.Measurements and Main Results: We enrolled 56 participants in the study. No differences were observed between the groups in HLA-DR expression (692 vs 2,002; p = 0.396) or IFN-γ production (31 vs 69; p = 0.678). Participants allocated to external warming had lower 28-day mortality (18% vs 43%; absolute risk reduction, 25%; 95% CI, 2-48%) and more 28-day hospital-free days (difference, 2.6 d; 95% CI, 0-11.6).Conclusions: Participants randomized to external forced-air warming did not have a difference in HLA-DR expression or IFN-γ production. In this pilot study, however, 28-day mortality was lower in the intervention group. Future research should seek to better elucidate the impact of temperature modulation on immune and nonimmune organ failure pathways in sepsis. [ABSTRACT FROM AUTHOR]

The global COVID-19 pandemic has claimed the lives of more than 750,000 US citizens. Dysregulation of the immune system underlies the pathogenesis of COVID-19, with inflammation mediated tissue injury to the lung in the setting of suppressed systemic immune function. To define the molecular mechanisms of immune dysfunction in COVID-19 we utilized a systems immunology approach centered on the circulating leukocyte phosphoproteome measured by mass cytometry. We find that although COVID-19 is associated with wholesale activation of a broad set of signaling pathways across myeloid and lymphoid cell populations, STAT3 phosphorylation predominated in both monocytes and T cells. STAT3 phosphorylation was tightly correlated with circulating IL-6 levels and high levels of phospho-STAT3 was associated with decreased markers of myeloid cell maturation/activation and decreased ex-vivo T cell IFN-γ production, demonstrating that during COVID-19 dysregulated cellular activation is associated with suppression of immune effector cell function. Collectively, these data reconcile the systemic inflammatory response and functional immunosuppression induced by COVID-19 and suggest STAT3 signaling may be the central pathophysiologic mechanism driving immune dysfunction in COVID-19. [ABSTRACT FROM AUTHOR]

Highlights: [•] Sepsis is the leading cause of death in critically ill patients and novel therapies are necessary. [•] Immune suppression is frequently associated with sepsis-related deaths. [•] Therapies or immunomodulatory agents that enhance the immune response should be considered. [•] Cytokines and co-inhibitory receptors represent potential immunomodulatory agents. [ABSTRACT FROM AUTHOR]

Sepsis remains the leading cause of death in most intensive care units. Advances in understanding the immune response to sepsis provide the opportunity to develop more effective therapies. The immune response in sepsis can be characterized by a cytokine-mediated hyper-inflammatory phase, which most patients survive, and a subsequent immune-suppressive phase. Patients fail to eradicate invading pathogens and are susceptible to opportunistic organisms in the hypo-inflammatory phase. Many mechanisms are responsible for sepsisinduced immuno-suppression, including apoptotic depletion of immune cells, increased T regulatory and myeloid-derived suppressor cells, and cellular exhaustion. Currently in clinical trial for sepsis are granulocyte macrophage colony stimulating factor and interferon gamma, immune-therapeutic agents that boost patient immunity. Immuno-adjuvants with promise in clinically-relevant animal models of sepsis include anti-programmed cell death-1 and interleukin-7. The future of immune-therapy in sepsis will necessitate identification of the immunologic phase using clinical and laboratory parameters as well as biomarkers of innate and adaptive immunity. [ABSTRACT FROM AUTHOR]

A nonimmunocompromised patient developed life-threatening soft tissue infection with Trichosporon asahii , Fusarium , and Saksenaea that progressed despite maximum antifungal therapies and aggressive debridement. Interleukin-7 immunotherapy resulted in clinical improvement, fungal clearance, reversal of lymphopenia, and improved T-cell function. Immunoadjuvant therapies to boost host immunity may be efficacious in life-threatening fungal infections. [ABSTRACT FROM AUTHOR]

What Is the Skinny on Obesity During Sepsis? The latter seemed to be supported by observations linking certain diets to higher sepsis risk ([3]), and morbid obesity to increased sepsis mortality ([4], [5]). Another limitation was the reliance solely on sepsis mortality, without knowing the sepsis denominator within the obese and nonobese cohorts. Regardless of the mechanisms explaining the "obesity sepsis paradox", the large, well-designed retrospective study by Pepper et al ([9]) provides the strongest evidence to date linking lower sepsis mortality to obesity. [Extracted from the article]

Sepsis initiates simultaneous pro- and anti-inflammatory processes, the pattern and intensity of which vary over time. The inability to evaluate the immune status of patients with sepsis in a rapid and quantifiable manner has undoubtedly been a major reason for the failure of many therapeutic trials. Although there has been considerable effort to immunophenotype septic patients, these methods have often not accurately assessed the functional state of host immunity, lack dynamic range, and are more reflective of molecular processes rather than host immunity. In contrast, ELISpot assay measures the number and intensity of cytokine-secreting cells and has excellent dynamic range with rapid turnaround. We investigated the ability of a (to our knowledge) novel whole blood ELISpot assay and compared it with a more traditional ELISpot assay using PBMCs in sepsis. IFN-g and TNF-a ELISpot assays on whole blood and PBMCs were undertaken in control, critically ill nonseptic, and septic patients. Whole blood ELISpot was easy to perform, and results were generally comparable to PBMC-based ELISpot. However, the whole blood ELISpot assay revealed that nonmonocyte, myeloid populations are a significant source of ex vivo TNF-a production. Septic patients who died had early, profound, and sustained suppression of innate and adaptive immunity. A cohort of septic patients had increased cytokine production compared with controls consistent with either an appropriate or excessive immune response. IL-7 restored ex vivo IFN-g production in septic patients. The whole blood ELISpot assay offers a significant advance in the ability to immunophenotype patients with sepsis and to guide potential new immunotherapies. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the immune responses of influenza and coronavirus disease 2019 (COVID-19) patients. The patients' lymphocytes, monocytes, and surface human leukocyte antigen (HLA)-class II expressions were compared. Based on the results, COVID-19 patients have lower cytokine levels than those of influenza patients.

Headache disorders are highly prevalent and debilitating, with limited treatment options. Previous studies indicate that many proinflammatory immune cells contribute to headache pathophysiology. Given the well-recognized role of regulatory T (Treg) cells in maintaining immune homeostasis, we hypothesized that enhancing Treg function may be effective to treat multiple headache disorders. In a mouse model of chronic migraine, we observed that repeated nitroglycerin (NTG, a reliable trigger of migraine in patients) administration doubled the number of CD3 T cells in the trigeminal ganglia without altering the number of Treg cells, suggesting a deficiency in Treg-mediated immune homeostasis. We treated mice with low-dose interleukin-2 (ld-IL2) to preferentially expand and activate endogenous Treg cells. This not only prevented the development of NTG-induced persistent sensitization but also completely reversed the established facial skin hypersensitivity resulting from repeated NTG administration. The effect of ld-IL2 was independent of mouse sex and/or strain. Importantly, ld-IL2 treatment did not alter basal nociceptive responses, and repeated usage did not induce tolerance. The therapeutic effect of ld-IL2 was abolished by Treg depletion and was recapitulated by Treg adoptive transfer. Furthermore, treating mice with ld-IL2 1 to 7 days after mild traumatic brain injury effectively prevented as well as reversed the development of behaviors related to acute and chronic post-traumatic headache. In a model of medication overuse headache, Ld-IL2 completely reversed the cutaneous hypersensitivity induced by repeated administration of sumatriptan. Collectively, this study identifies ld-IL2 as a promising prophylactic for multiple headache disorders with a mechanism distinct from the existing treatment options. [ABSTRACT FROM AUTHOR]

Sepsis is characterized as life-threatening organ dysfunction caused by a dysregulated host immune response to infection. The purpose of this investigation was to determine the differential effect of sepsis on innate versus adaptive immunity, in humans, by examining RNA expression in specific immune cell subsets, including monocytes/macrophages and CD4 and CD8 T cells. A second aim was to determine immunosuppressive mechanisms operative in sepsis that might be amenable to immunotherapy. Finally, we examined RNA expression in peripheral cells from critically ill nonseptic patients and from cancer patients to compare the unique immune response in these disorders with that occurring in sepsis. Monocytes, CD4 T cells, and CD8 T cells from septic patients, critically ill nonseptic patients, patients with metastatic colon cancer, and healthy controls were analyzed by RNA sequencing. Sepsis induced a marked phenotypic shift toward downregulation of multiple immune response pathways in monocytes suggesting that impaired innate immunity may be fundamental to the immunosuppression that characterizes the disorder. In the sepsis cohort, there was a much more pronounced effect on gene transcription in CD4 T cells than in CD8 T cells. Potential mediators of sepsis-induced immunosuppression included Arg-1, SOCS-1, and SOCS-3, which were highly upregulated in multiple cell types. Multiple negative costimulatory molecules, including TIGIT, Lag-3, PD-1, and CTLA-4, were also highly upregulated in sepsis. Although cancer had much more profound effects on gene transcription in CD8 T cells, common immunosuppressive mechanisms were present in all disorders, suggesting that immunoadjuvant therapies that are effective in one disease may also be efficacious in the others. [ABSTRACT FROM AUTHOR]

The article focuses on a cohort study published within the issue of the periodical which used a single-cell mass cytometry approach to characterize the phenotype and function of major innate and adaptive immune responses in patients who suffered from traumatic injury. It mentions individualized risk stratification based on the deep immune profiling of critically ill patients and characterization of intracellular expression of over 20 cytokines at the single-cell level.

Background: Multidrug resistant (MDR) bacterial pathogens are a serious problem of increasing importance facing the medical community. MDR bacteria typically infect the most immunologically vulnerable: patients in intensive care units, patients with extensive comorbidities, oncology patients, hemodialysis patients, and other immune suppressed individuals are likely to fall victim to these pathogens. One promising novel approach to treatment of MDR bacteria is immuno-adjuvant therapy to boost patient immunity. Success with this strategy would have the major benefit of providing protection against a number of MDR pathogens. Objectives: This study had two main objectives. First, immunophenotyping of peripheral blood mononuclear cells from patients with sepsis associated with MDR bacteria was performed to examine for findings indicative of immunosuppression. Second, the ability of three immuno-adjuvants with distinct mechanisms of action to reverse CD4 and CD8 T cell dysfunction, a pathophysiological hallmark of sepsis, was evaluated. Results: Septic patients with MDR bacteria had increased expression of the inhibitory receptor PD-1 and its ligand PD-L1 and decreased monocyte HLA-DR expression compared to non-septic patients. All three immuno-adjuvants, IL-7, anti-PD-L1, and OX-40L, increased T cell production of IFN-γ in a subset of septic patients with MDR bacteria: IL-7 was most efficacious. There was a strong trend toward increased mortality in patients whose T cells failed to increase IFN-γ production in response to the three treatments. Conclusion: Immuno-adjuvant therapy reversed T cell dysfunction, a key pathophysiological mechanism in septic patients with MDR bacteria. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the impact of an emergency department mechanical ventilation protocol on clinical outcomes and adherence to lung-protective ventilation in patients with acute respiratory distress syndrome.Design: Quasi-experimental, before-after trial.Setting: Emergency department and ICUs of an academic center.Patients: Mechanically ventilated emergency department patients experiencing acute respiratory distress syndrome while in the emergency department or after admission to the ICU.Interventions: An emergency department ventilator protocol which targeted variables in need of quality improvement, as identified by prior work: 1) lung-protective tidal volume, 2) appropriate setting of positive end-expiratory pressure, 3) oxygen weaning, and 4) head-of-bed elevation.Measurements and Main Results: A total of 229 patients (186 preintervention group, 43 intervention group) were studied. In the emergency department, the intervention was associated with significant changes (p < 0.01 for all) in tidal volume, positive end-expiratory pressure, respiratory rate, oxygen administration, and head-of-bed elevation. There was a reduction in emergency department tidal volume from 8.1 mL/kg predicted body weight (7.0-9.1) to 6.4 mL/kg predicted body weight (6.1-6.7) and an increase in lung-protective ventilation from 11.1% to 61.5%, p value of less than 0.01. The intervention was associated with a reduction in mortality from 54.8% to 39.5% (odds ratio, 0.38; 95% CI, 0.17-0.83; p = 0.02) and a 3.9 day increase in ventilator-free days, p value equals to 0.01.Conclusions: This before-after study of mechanically ventilated patients with acute respiratory distress syndrome demonstrates that implementing a mechanical ventilator protocol in the emergency department is feasible and associated with improved clinical outcomes. [ABSTRACT FROM AUTHOR]

Objectives: The mechanism(s) for septic cardiomyopathy in humans is not known. To address this, we measured messenger RNA alterations in hearts from patients who died from systemic sepsis, in comparison to changed messenger RNA expression in nonfailing and failing human hearts.Design: Identification of genes with altered abundance in septic cardiomyopathy, ischemic heart disease, or dilated cardiomyopathy, in comparison to nonfailing hearts.Setting: ICUs at Barnes-Jewish Hospital, St. Louis, MO.Patients: Twenty sepsis patients, 11 ischemic heart disease, nine dilated cardiomyopathy, and 11 nonfailing donors.Interventions: None other than those performed as part of patient care.Measurements and Main Results: Messenger RNA expression levels for 198 mitochondrially localized energy production components, including Krebs cycle and electron transport genes, decreased by 43% ± 5% (mean ± SD). Messenger RNAs for nine genes responsible for sarcomere contraction and excitation-contraction coupling decreased by 43% ± 4% in septic hearts. Surprisingly, the alterations in messenger RNA levels in septic cardiomyopathy were both distinct from and more profound than changes in messenger RNA levels in the hearts of patients with end-stage heart failure.Conclusions: The expression profile of messenger RNAs in the heart of septic patients reveals striking decreases in expression levels of messenger RNAs that encode proteins involved in cardiac energy production and cardiac contractility and is distinct from that observed in patients with heart failure. Although speculative, the global nature of the decreases in messenger RNA expression for genes involved in cardiac energy production and contractility suggests that these changes may represent a short-term adaptive response of the heart in response to acute change in cardiovascular homeostasis. [ABSTRACT FROM AUTHOR]

Background Sepsis remains a leading cause of death in most intensive care units. Many deaths in sepsis are due to nosocomial infections in patients who have entered the immunosuppressive phase of the disorder. One cause of immunosuppression in sepsis is T-cell exhaustion mediated by programmed cell death-1 (PD-1) interaction with its ligand (PD-L1). Studies demonstrated that blocking the interaction of PD-1 with PD-L1 with knockout mice or inhibitory antibodies reversed T-cell dysfunction and improved sepsis survival. This study assessed the efficacy of a novel short-acting peptide (compound 8) that inhibits PD-1:PD-L1 signaling in a clinically relevant second-hit fungal sepsis model. Methods Mice underwent cecal ligation and puncture to induce peritonitis. Three days later, mice received intravenous injection of Candida albicans . Forty-eight hours after Candida infection, mice were treated with compound 8 or inactive peptide. The effect of Candida infection on expression of coinhibitory molecules, PD-1, and PD-L1 were quantitated by flow cytometry on CD4 + cells, CD8 + cells, natural killer (NK) cells, and natural killer T-cells (NKT). The effect of compound 8 on survival was also examined. Results Four days after fungal infection, PD-1 and PD-L1 expressions were markedly increased on CD4 + , NK, and NKT cells in septic versus sham-operated mice (%PD-1 on CD4 + , 11.9% versus 2.8%; and %PD-L1 on NKT, 14.8% versus 0.5%). Compared with control, compound 8 caused a 2-fold increase in survival from 30% to 60%, P < 0.05. Conclusions Compound 8 significantly improved survival in a clinically relevant immunosuppressive model of sepsis. These results support immunoadjuvant therapy targeting T-cell exhaustion in this lethal disease. [ABSTRACT FROM AUTHOR]

The article focuses on the development of sepsis, blood poisoning, to ill patients. Topics mentioned include the importance of patients care management, the effects of immunosuppressive drugs, and the septic patients medical care. Also mentioned are the effectiveness of immunotherapy in cancer patients and the immunoparalysis.