Two New Neutrophil Subsets Define a Discriminating Sepsis Signature.

Rationale: Sepsis is the leading cause of death in adult ICUs. At present, sepsis diagnosis relies on nonspecific clinical features. It could transform clinical care to have immune-cell biomarkers that could predict sepsis diagnosis and guide treatment. For decades, neutrophil phenotypes have been studied in sepsis, but a diagnostic cell subset has yet to be identified. Objectives: To identify an early, specific immune signature of sepsis severity that does not overlap with other inflammatory biomarkers and that distinguishes patients with sepsis from those with noninfectious inflammatory syndrome. Methods: Mass cytometry combined with computational high-dimensional data analysis was used to measure 42 markers on whole-blood immune cells from patients with sepsis and control subjects and to automatically and comprehensively characterize circulating immune cells, which enables identification of novel, disease-specific cellular signatures. Measurements and Main Results: Unsupervised analysis of high-dimensional mass cytometry data characterized previously unappreciated heterogeneity within the CD64+ immature neutrophils and revealed two new subsets distinguished by CD123 and PD-L1 (programmed death ligand 1) expression. These immature neutrophils exhibited diminished activation and phagocytosis functions. The proportion of CD123-expressing neutrophils correlated with clinical severity. Conclusions: This study showed that these two new neutrophil subsets were specific to sepsis and detectable through routine flow cytometry by using seven markers. The demonstration here that a simple blood test distinguishes sepsis from other inflammatory conditions represents a key biological milestone that can be immediately translated into improvements in patient care.

Comparison of Circulating Immune Cells Profiles and Kinetics Between Coronavirus Disease 2019 and Bacterial Sepsis.

OBJECTIVES: Although clinical presentation of coronavirus disease 2019 has been extensively described, immune response to severe acute respiratory syndrome coronavirus 2 remains yet not fully understood. Similarities with bacterial sepsis were observed; however, few studies specifically addressed differences of immune response between both conditions. Here, we report a longitudinal analysis of the immune response in coronavirus disease 2019 patients, its correlation with outcome, and comparison between severe coronavirus disease 2019 patients and septic patients. DESIGN: Longitudinal, retrospective observational study. SETTING: Tertiary-care hospital during the first 2020 coronavirus disease 2019 outbreak in France. PATIENTS: All successive patients with confirmed severe acute respiratory syndrome coronavirus 2 infection admitted to the emergency department, medical ward, and ICU with at least one available immunophenotyping performed during hospital stay. MEASUREMENTS AND MAIN RESULTS: Between March and April 2020, 247 patients with coronavirus disease 2019 were included and compared with a historical cohort of 108 severe septic patients. Nonsevere coronavirus disease 2019 patients (n = 153) presented normal or slightly altered immune profiles. Severe coronavirus disease 2019 (n = 94) immune profile differed from sepsis. Coronavirus disease 2019 exhibited profound and prolonged lymphopenia (mostly on CD3, CD4, CD8, and NK cells), neutrophilia, and human leukocyte antigen D receptor expression on CD14+ monocytes down-regulation. Surprisingly, coronavirus disease 2019 patients presented a unique profile of B cells expansion, basophilia, and eosinophilia. Lymphopenia, human leukocyte antigen D receptor expression on CD14+ monocytes down-regulation, and neutrophilia were associated with a worsened outcome, whereas basophilia and eosinophilia were associated with survival. Circulating immune cell kinetics differed between severe coronavirus disease 2019 and sepsis, lack of correction of immune alterations in coronavirus disease 2019 patients during the first 2 weeks of ICU admission was associated with death and nosocomial infections. CONCLUSIONS: Circulating immune cells profile differs between mild and severe coronavirus disease 2019 patients. Severe coronavirus disease 2019 is associated with a unique immune profile as compared with sepsis. Several immune features are associated with outcome. Thus, immune monitoring of coronavirus disease 2019 might be of help for patient management.

Timing and causes of death in severe COVID-19 patients.

BACKGROUND: Previous studies reporting the causes of death in patients with severe COVID-19 have provided conflicting results. The objective of this study was to describe the causes and timing of death in patients with severe COVID-19 admitted to the intensive care unit (ICU). METHODS: We performed a retrospective study in eight ICUs across seven French hospitals. All consecutive adult patients (aged ≥ 18 years) admitted to the ICU with PCR-confirmed SARS-CoV-2 infection and acute respiratory failure were included in the analysis. The causes and timing of ICU deaths were reported based on medical records. RESULTS: From March 1, 2020, to April 28, 287 patients were admitted to the ICU for SARS-CoV-2 related acute respiratory failure. Among them, 93 patients died in the ICU (32%). COVID-19-related multiple organ dysfunction syndrome (MODS) was the leading cause of death (37%). Secondary infection-related MODS accounted for 26% of ICU deaths, with a majority of ventilator-associated pneumonia. Refractory hypoxemia/pulmonary fibrosis was responsible for death in 19% of the cases. Fatal ischemic events (venous or arterial) occurred in 13% of the cases. The median time from ICU admission to death was 15 days (25th-75th IQR, 7-27 days). COVID-19-related MODS had a median time from ICU admission to death of 14 days (25th-75th IQR: 7-19 days), while only one death had occurred during the first 3 days since ICU admission. CONCLUSIONS: In our multicenter observational study, COVID-19-related MODS and secondary infections were the two leading causes of death, among severe COVID-19 patients admitted to the ICU.

IL-7 and Its Beneficial Role in Sepsis-Induced T Lymphocyte Dysfunction.

Sepsis, defined as life-threatening organ dysfunction caused by dysregulated host response to infection, has recently been acknowledged as a worldwide health priority. Sepsis remains the leading cause of mortality in intensive care units and accounts for 6 million deaths every year. Few therapeutic options targeting host immune response in sepsis have demonstrated their efficacy so far. Increasing evidence suggests that a profound immune suppression develops following sepsis, affecting innate and adaptive immune response, of which intensity and duration is associated with increased risk of death and nosocomial infection. Immunostimulant treatments are thus now evaluated in sepsis, and recombinant human IL-7 (rhIL-7) represents a promising candidate. rhIL-7 has been evaluated in several clinical trials in patients with altered lymphocytic responses (HIV infection, hematopoietic stem cell transplantation, and cancer). Recent studies in animal models and in patients' samples ex vivo demonstrated its efficacy in improving sepsis-induced T cell alterations. Finally, the first clinical trial evaluating rhIL-7 in septic shock patients has just been published. This review will discuss the use of rhIL-7 to treat sepsis-induced T cell dysfunction by introducing the pathophysiology of sepsis and sepsis-related lymphocyte alterations before focusing on rhIL-7 and its potential use of as a therapeutic intervention in patients.

Systematic review with meta-analysis of mid-regional pro-adrenomedullin (MR-proadm) as a prognostic marker in Covid-19-hospitalized patients.

BACKGROUND: Mid-regional pro-adrenomedullin (MR-proADM) is useful for risk stratification in patients with sepsis and respiratory infections. The study's purpose was to assess the available data and determine the association between MR-proADM levels and mortality in COVID-19 participants. METHODS: A comprehensive literature search of medical electronic databases was performed including PubMed, Web of Science, Scopus, Cochrane, and grey literature for relevant data published from 1 January 2020, to 20 November 2022. Mean differences (MD) with 95% confidence intervals (CI) were calculated. RESULTS: Fourteen studies reported MR-proADM levels in survivors vs. non-survivors of COVID-19 patients. Pooled analysis showed that MR-proADM level in the survivor group was 0.841 ± 0.295 nmol/L for patients who survive COVID-19, compared to 1.692 ± 0.761 nmol/L for non-survivors (MD = -0.78; 95%CI: -0.92 to -0.64; p < 0.001). CONCLUSIONS: The main finding of this study is that mortality of COVID-19 is linked to MR-proADM levels, according to this meta-analysis. The use of MR-proADM might be extremely beneficial in triaging, assessing probable therapy escalation, predicting potential complications during therapy or significant clinical deterioration of patients, and avoiding admission which may not be necessary. Nevertheless, in order to confirm the obtained data, it is necessary to conduct large prospective studies that will address the potential diagnostic role of MR-proADM as a marker of COVID-19 severity.KEY MESSAGESSeverity of COVID-19 seems to be linked to MR-proADM levels and can be used as a potential marker for predicting a patient's clinical course.The use of MR-proADM might be beneficial in triaging, assessing probable therapy escalation, predicting potential complications during therapy or significant clinical deterioration of patients, and avoiding admission which may not be necessary.For patients with COVID-19, MR-proADM may be an excellent prognostic indicator because it is a marker of endothelial function that may predict the precise impact on the equilibrium between vascular relaxation and contraction and lowers platelet aggregation inhibitors, coagulation inhibitors, and fibrinolysis activators in favor of clotting factors.

Impact of Early Out-of-Bed Mobilization on Functional Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage: A Retrospective Cohort Study.

BACKGROUND: Effects of early mobilization are not well documented in patients with aneurysmal subarachnoid hemorrhage (aSAH). Only a few studies have investigated it through progressive mobilization protocols and suggested that it is safe and feasible. This study aimed to determine the impact of early out-of-bed mobilization (EOM) on 3-month functional outcome and cerebral vasospasm (CVS) occurrence in patients with aSAH. METHODS: A retrospective review of consecutive patients admitted to the intensive care unit with a diagnosis of aSAH was performed. EOM was defined as out-of-bed (OOB) mobilization performed before or on day 4 after aSAH onset. The primary outcome was 3-month functional independence (i.e., a modified Rankin Scale below 3) and the occurrence of CVS. RESULTS: A total of 179 patients with aSAH met the inclusion criteria. Thirty-one patients constituted the EOM group, and 148 patients were in the delayed out-of-bed mobilization group. Functional independence was more frequent in the EOM group than in the delayed out-of-bed mobilization group (n = 26 [84%] vs. n = 83 [56%], P = 0.004). In a multivariable analysis, EOM was an independent predictor of functional independence (adjusted odds ratio = 3.11; 95% confidence interval, 1.11-10.36; P < 0.05). The delay between bleeding and first OOB mobilization was also identified as an independent risk factor for the occurrence of CVS (adjusted odds ratio = 1.12; 95% confidence interval = 1.06-1.18, P < 0.001). CONCLUSIONS: EOM was independently associated with favorable functional outcome after aSAH. The delay between bleeding and OOB mobilization was an independent risk factor for reduced functional independence and CVS occurrence. Prospective randomized trials are necessary to confirm these results and improve clinical practice.

Efficacy of almitrine as a rescue therapy for refractory hypoxemia in COVID and non-COVID acute respiratory distress syndrome. A retrospective monocenter study.

BACKGROUND: Almitrine, a drug enhancing hypoxic pulmonary vasoconstriction, has been proposed as a rescue therapy for refractory hypoxemia in COVID related acute respiratory distress syndrome (C-ARDS). We aimed at investigating the response to almitrine depending on the cause of ARDS (COVID vs. non-COVID). METHODS: Monocenter retrospective study from 2014 to 2021. All patients diagnosed with moderate to severe ARDS and treated with almitrine as rescue therapy for refractory hypoxemia were studied. Factor independently associated with oxygenation response to almitrine infusion were determined. RESULTS: Sixty patients with ARDS and treated with almitrine were analyzed, 36 (60%) due to SARS-CoV-2 infection and 24 (40%) due to other causes. Baseline PaO2/FiO2 was 78 [61-101] mmHg, 76% had at least one prone positioning before the start of almitrine infusion. Median PaO2/FiO2 increased by +38 [7-142] mmHg (+61% [10-151]) after almitrine infusion. PaO2/FiO2 increased by +134 [12-186] mmHg in non-COVID ARDS (NC-ARDS) and by +19 [8-87] mmHg in C-ARDS. The increase in PaO2/FiO2 was lower in C-ARDS than in NC-ARDS (P=0.013). In multivariable analysis, C-ARDS, non-invasive ventilation and concomitant use of norepinephrine were independently associated with a decreased oxygenation response to almitrine infusion. CONCLUSIONS: Our study reports a highly variable response to almitrine infusion in ARDS patients with refractory hypoxemia. Independent factors associated with a reduced oxygenation response to almitrine infusion were: COVID ARDS, concomitant use of norepinephrine, and non-invasive ventilatory strategy.

Cytokine profiles in adults with imported malaria.

The increase in worldwide travel is making imported malaria a growing health concern in non-endemic countries. Most data on the pathophysiology of malaria come from endemic areas. Little is known about cytokine profiles during imported malaria. This study aimed at deciphering the relationship between cytokine host response and malaria severity among imported cases in France. This study reports cytokine profiles in adults with Plasmodium falciparum malaria included in the PALUREA prospective study conducted between 2006 and 2010. The patients were classified as having uncomplicated malaria (UM) or severe malaria (SM), with this last further categorized as very severe malaria (VSM) or less severe malaria (LSM). At hospital admission, eight blood cytokines were assayed in duplicate using Luminex® technology: interleukin (IL)-1α, IL-1ß, IL-2, IL-4, IL-10, tumor necrosis factor (TNF)α, interferon (IFN)γ, and macrophage migration inhibitory factor (MIF). These assays were repeated on days 1 and 2 in the SM group. Of the 278 patients, 134 had UM and 144 SM. At hospital admission, over half the patients had undetectable levels of IL-1α, IL-1ß, IL-2, IL-4, IFNγ, and TNFα, while IL-10 and MIF were significantly higher in the SM vs. the UM group. Higher IL-10 was significantly associated with higher parasitemia (R = 0.32 [0.16-0.46]; P = 0.0001). In the SM group, IL-10 elevation persisting from admission to day 2 was significantly associated with subsequent nosocomial infection. Of eight tested cytokines, only MIF and IL-10 were associated with disease severity in adults with imported P. falciparum malaria. At admission, many patients had undetectable cytokine levels, suggesting that circulating cytokine assays may not be helpful as part of the routine evaluation of adults with imported malaria. Persisting high IL-10 concentration was associated with subsequent nosocomial infection, suggesting its possible interest in immune monitoring of most severe patients.

Immunotherapy to treat sepsis induced-immunosuppression: Immune eligibility or outcome criteria, a systematic review.

Sepsis-induced immunosuppression (SIS) is the target of multiple clinical studies testing immunotherapies. To date, most trials are performed on a heterogeneous and unselected population. Without any consensual definition of immunosuppression and therapeutic goals, results from these trials remain poorly transposable. In this perspective, we conducted a systematic review aiming at 1/registering the inclusion criteria, 2/ report the outcomes evaluated in this literature. We searched Pubmed, Embase, and ClinicalTrials.gov for studies using an immunotherapy to reverse SIS. This review collected for each study: design, intervention, immune inclusion criteria, outcome, definition of sepsis, and source of infection. From the 80 studies assessed for eligibility, 29 were included: 17 RCT, 6 observational prospective studies, 6 ongoing RCT. Sepsis was defined based upon current recommendations at the time, with most patients presenting at least one organ failure. We found important heterogeneity regarding the use of immune parameters, both as inclusion and as outcome criteria. Only 13 studies selected patients suffering from immunosuppression based on immune biomarkers. Two immune criterias were commonly used: lymphocyte count and monocytic HLA-DR expression. This heterogeneity criteria in studies targeting SIS justify the conduct of a consensus process to define criteria to diagnose SIS and identify relevant outcomes markers.

Systemic Inflammation Evaluated by Interleukin-6 or C-Reactive Protein in Critically Ill Patients: Results From the FROG-ICU Study.

Background: The prognostic impact of high concentration of interleukin-6 (IL-6) or C-reactive protein (CRP), two routinely available markers of systemic inflammation in the general population of critically ill patients, remains unclear. In a large cohort of critically ill patients including septic and non-septic patients, we assessed the relationship between baseline IL-6 or CRP and mortality, organ dysfunction, and the need for organ support. Methods: This was an ancillary analysis of the prospective French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study including patients with a requirement for invasive mechanical ventilation and/or vasoactive drug support for more than 24 h following intensive care unit (ICU) admission. The primary objective was to determine the association between baseline IL-6 or CRP concentration and survival until day 90. Secondary outcomes included organ dysfunction as evaluated by the Sequential Organ Failure Assessment (SOFA) score, and the need for organ support, including vasopressors/inotropes and/or renal replacement therapy (RRT). Results: Median IL-6 and CRP concentrations (n = 2,076) at baseline were 100.9 pg/ml (IQR 43.5-261.7) and 143.7 mg/L (IQR 78.6-219.8), respectively. Day-90 mortality was 30%. High IL-6 or CRP was associated with worse 90-day survival (hazard ratios 1.92 [1.63-2.26] and 1.21 [1.03-1.41], respectively), after adjustment on the Simplified Acute Physiology Score II (SAPS-II). High IL-6 was also associated with the need for organ-support therapies, such as vasopressors/inotropes (OR 2.67 [2.15-3.31]) and RRT (OR 1.55 [1.26-1.91]), including when considering only patients independent from those supports at the time of IL-6 measurement. Associations between high CRP and organ support were inconsistent. Conclusion: IL-6 appears to be preferred over CRP to evaluate critically ill patients' prognoses.

Outcomes of Patients With Active Cancer and COVID-19 in the Intensive-Care Unit: A Multicenter Ambispective Study.

Background: Several studies report an increased susceptibility to SARS-CoV-2 infection in cancer patients. However, data in the intensive care unit (ICU) are scarce. Research Question: We aimed to investigate the association between active cancer and mortality among patients requiring organ support in the ICU. Study Design and Methods: In this ambispective study encompassing 17 hospitals in France, we included all adult active cancer patients with SARS-CoV-2 infection requiring organ support and admitted in ICU. For each cancer patient, we included 3 non cancer patients as controls. Patients were matched at the same ratio using the inverse probability weighting approach based on a propensity score assessing the probability of cancer at admission. Mortality at day 60 after ICU admission was compared between cancer patients and non-cancer patients using primary logistic regression analysis and secondary multivariable analyses. Results: Between March 12, 2020 and March 8, 2021, 2608 patients were admitted with SARS-CoV-2 infection in our study, accounting for 2.8% of the total population of patients with SARS-CoV-2 admitted in all French ICUs within the same period. Among them, 105 (n=4%) presented with cancer (51 patients had hematological malignancy and 54 patients had solid tumors). 409 of 420 patients were included in the propensity score matching process, of whom 307 patients in the non-cancer group and 102 patients in the cancer group. 145 patients (35%) died in the ICU at day 60, 59 (56%) with cancer and 86 (27%) without cancer. In the primary logistic regression analysis, the odds ratio for death associated to cancer was 2.3 (95%CI 1.24 - 4.28, p=0.0082) higher for cancer patients than for a non-cancer patient at ICU admission. Exploratory multivariable analyses showed that solid tumor (OR: 2.344 (0.87-6.31), p=0.062) and hematological malignancies (OR: 4.144 (1.24-13.83), p=0.062) were independently associated with mortality. Interpretation: Patients with cancer and requiring ICU admission for SARS-CoV-2 infection had an increased mortality, hematological malignancy harboring the higher risk in comparison to solid tumors.

Role of Damage-Associated Molecular Patterns in Septic Acute Kidney Injury, From Injury to Recovery.

Damage-associated molecular patterns (DAMPs) are a group of immunostimulatory molecules, which take part in inflammatory response after tissue injury. Kidney-specific DAMPs include Tamm-Horsfall glycoprotein, crystals, and uromodulin, released by tubular damage for example. Non-kidney-specific DAMPs include intracellular particles such as nucleus [histones, high-mobility group box 1 protein (HMGB1)] and cytosol parts. DAMPs trigger innate immunity by activating the NRLP3 inflammasome, G-protein coupled class receptors or the Toll-like receptor. Tubular necrosis leads to acute kidney injury (AKI) in either septic, ischemic or toxic conditions. Tubular necrosis releases DAMPs such as histones and HMGB1 and increases vascular permeability, which perpetuates shock and hypoperfusion via Toll Like Receptors. In acute tubular necrosis, intracellular abundance of NADPH may explain a chain reaction where necrosis spreads from cell to cell. The nature AKI in intensive care units does not have preclinical models that meet a variation of blood perfusion or a variation of glomerular filtration within hours before catecholamine infusion. However, the dampening of several DAMPs in AKI could provide organ protection. Research should be focused on the numerous pathophysiological pathways to identify the relative contribution to renal dysfunction. The therapeutic perspectives could be strategies to suppress side effect of DAMPs and to promote renal function regeneration.

Hemodynamic Impact of Cardiovascular Antihypertensive Medications in Patients With Sepsis-Related Acute Circulatory Failure.

BACKGROUND: Impact of prior cardiovascular antihypertensive medication during the initial phase of septic shock in terms of catecholamine requirements and mortality has been poorly investigated and remains unclear. OBJECTIVES: To investigate the association between chronic prescription of cardiovascular antihypertensive medication prior to intensive care unit (ICU) admission, catecholamine requirement, and mortality in patients with septic shock. METHODS: We included all consecutive patients diagnosed with septic shock within the first 24 h of ICU admission, defined as a microbiologically proven or clinically suspected infection, associated with acute circulatory failure requiring vasopressors despite adequate fluid filling. Prior cardiovascular antihypertensive medication was defined as the chronic use of betablockers (BB), calcium channel blockers (CCB), angiotensin converting enzyme inhibitor (ACEi)/angiotensin receptor blockers (ARB). ICU mortality was investigated using multivariate competitive risk analysis. RESULTS: Among 735 patients admitted for septic shock between 2008 and 2016, 46.9% received prior cardiovascular antihypertensive medication. Prior cardiovascular antihypertensive therapy was not associated with increased norepinephrine requirements during the first 24 h (median = 0.28 µg/kg/min in patients previously treated vs. 0.26 µg/kg/min). Prior cardiovascular antihypertensive medication was not associated with a higher risk of ICU mortality after adjustment (cause-specific hazard = 1.28, 95% confidence interval [0.98-1.66], P = 0.06). Subgroups analyses for BB, CCB, and ACEi/ARB using propensity score analyses retrieved similar results. CONCLUSION: In patients admitted with septic shock, prior cardiovascular antihypertensive medication seems to have limited impact on initial hemodynamic failure and catecholamine requirement.

Pulmonary infections prime the development of subsequent ICU-acquired pneumonia in septic shock.

PURPOSE: To investigate the determinants and the prognosis of intensive care unit (ICU)-acquired pneumonia in patients with septic shock. METHODS: This single-center retrospective study was conducted in a medical ICU in a tertiary care center from January 2008 to December 2016. All consecutive patients diagnosed for septic shock within the first 48 h of ICU admission were included. Patients were classified in three groups: no ICU-acquired infections (no ICU-AI), ICU-acquired pneumonia and non-pulmonary ICU-AI. The determinants of ICU-acquired pneumonia and death were investigated by multivariate competitive risk analysis. RESULTS: A total of 1021 patients were admitted for septic shock, and 797 patients were alive in the ICU after 48 h of management. The incidence of a first episode of ICU-AI was 31%, distributed into pulmonary (17%) and non-pulmonary ICU-AI (14%). Patients with septic shock caused by pneumonia were at increased risk of further pulmonary ICU-AI with a cumulated incidence of 34.4%. A pulmonary source of the initial septic shock was an independent risk factor for subsequent ICU-acquired pneumonia (cause-specific hazard 2.33, 95% confidence interval [1.55-3.52], p < 0.001). ICU-AI were not associated with a higher risk of ICU mortality after adjustment in a multivariate-adjusted cause-specific proportional hazard model. CONCLUSION: Septic shock of pulmonary origin may represent a risk factor for subsequent ICU-acquired pneumonia without affecting mortality.