Is There a Role for Hematopoietic Growth Factors During Sepsis?

Sepsis is a complex syndrome characterized by simultaneous activation of pro- and anti-inflammatory processes. After an inflammatory phase, patients present signs of immunosuppression and possibly persistent inflammation. Hematopoietic growth factors (HGFs) are glycoproteins that cause immune cells to mature and/or proliferate. HGFs also have a profound effect on cell functions and behavior. HGFs play crucial role in sepsis pathophysiology and were tested in several clinical trials without success to date. This review summarizes the role played by HGFs during sepsis and their potential therapeutic role in the Management of sepsis-related immune disturbances

Rôle des récepteurs monocytaires aux chimiokines dans la physiopathologie du sepsis

Sepsis is the generalized inflammatory response secondary to an infection. This is a common and serious condition that involves the immune system. The action of innate immunity in sepsis is mediated by the activation and recruitment of monocytes, which are mononuclear circulating cells, which modulate the inflammatory process. The mobilization of monocytes involves chemotactic cytokines (chemokines) and their receptors. This work was specifically focused on the role of monocyte expression of chemokine receptors CCR2 and CX3CR1 in sepsis. To this end, we used mouse models of sepsis and analyzed the role of a common genetic polymorphism of CX3CR1 in a cohort of patients with sepsis.We have shown that in sepsis, monocytes’ motility was modified with an increase of their adhesion to vascular walls that was controlled in part by CX3CR1. We have also shown that inflammatory monocytes play a key role in the regulation of the inflammatory phenomenon in sepsis and that they protected the kidney from septic lesions via a CX3CR1 mediated adhesion mechanism. The I249 allele of CX3CR1, confering increased adhesive properties to monocytes, is a protective factor regarding the occurrence of acute kidney injury in septic patients. Collectively, these data confirm a a regulatory role for inflammatory monocytes during sepsis and identify potential new therapeutic targets.Le sepsis est la réaction inflammatoire généralisée secondaire à une infection. C’est une pathologie fréquente et grave qui fait intervenir le système immunitaire. L’action de l’immunité innée se fait par l’activation et le recrutement des monocytes, des cellules mononuclées circulantes qui modulent le phénomène inflammatoire. La mobilisation des monocytes fait intervenir les cytokines chimiotactiques (chimiokines) et leurs récepteurs. Nous nous sommes spécifiquement intéressé dans ce travail au rôle de l’expression monocytaire des récepteurs aux chimiokines CCR2 et CX3CR1 au cours du sepsis. Pour ce faire, nous avons utilisé des modèles murins de sepsis et analysé le rôle d’un polymorphisme génétique de CX3CR1 dans une cohorte de malades atteints de sepsis. Nous avons montré qu’au cours du sepsis, les monocytes présentaient une augmentation de l’adhérence aux parois vasculaire contrôlée par le récepteur CX3CR1. Nous avons également montré que les monocytes inflammatoires jouaient un rôle essentiel dans la régulation du phénomène inflammatoire au cours du sepsis en protégeant le rein des lésions septiques. Cette protection est médiée par l’expression de CX3CR1. L’allèle I249 du gène Cx3cr1, à l’origine d’une augmentation des propriétés adhésives du couple CX3CR1/CX3CL1, est un facteur protecteur dans la survenue d’insuffisance rénale aiguë chez le malade atteint de sepsis. Collectivement, ces travaux confirment un rôle régulateur des monocytes inflammatoires au cours du sepsis et identifient de potentielles nouvelles cibles thérapeutiques

Subphenotypes in patients with acute respiratory distress syndrome treated with high-flow oxygen

Acute respiratory distress syndrome; Biomarkers; High-flow nasal oxygenSíndrome de dificultat respiratòria aguda; Biomarcadors; Oxigen nasal d'alt fluxSíndrome de dificultad respiratoria aguda; Biomarcadores; Oxígeno nasal de alto flujoBackground Acute respiratory distress syndrome (ARDS) subphenotypes differ in outcomes and treatment responses. Subphenotypes in high-flow nasal oxygen (HFNO)-treated ARDS patients have not been investigated. Objectives To identify biological subphenotypes in HFNO-treated ARDS patients. Methods Secondary analysis of a prospective multicenter observational study including ARDS patients supported with HFNO. Plasma inflammation markers (interleukin [IL]-6, IL-8, and IL-33 and soluble suppression of tumorigenicity-2 [sST2]) and lung epithelial (receptor for advanced glycation end products [RAGE] and surfactant protein D [SP-D]) and endothelial (angiopoietin-2 [Ang-2]) injury were measured. These biomarkers and bicarbonate were used in K-means cluster analysis to identify subphenotypes. Logistic regression was performed on biomarker combinations to predict clustering. We chose the model with the best AUROC and the lowest number of variables. This model was used to describe the HAIS (High-flow ARDS Inflammatory Subphenotype) score. Results Among 41 HFNO patients, two subphenotypes were identified. Hyperinflammatory subphenotype (n = 17) showed higher biomarker levels than hypoinflammatory (n = 24). Despite similar baseline characteristics, the hyperinflammatory subphenotype had higher 60-day mortality (47 vs 8.3% p = 0.014) and longer ICU length of stay (22.0 days [18.0–30.0] vs 39.5 [25.5–60.0], p = 0.034). The HAIS score, based on IL-8 and sST2, accurately distinguished subphenotypes (AUROC 0.96 [95%CI: 0.90–1.00]). A HAIS score ≥ 7.45 was predictor of hyperinflammatory subphenotype. Conclusion ARDS patients treated with HFNO exhibit two biological subphenotypes that have similar clinical characteristics, but hyperinflammatory patients have worse outcomes. The HAIS score may identify patients with hyperinflammatory subphenotype and might be used for enrichment strategies in future clinical trials.The princeps study was supported, in part, by a grant from Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (FEDER) (PI14/01420) and a grant from Federación Española del Enfermo Crítico (FEEC) 2015. No specific support was done for this re-analysis

A network meta-analysis of therapeutic and prophylactic management of vasospasm on aneurysmal subarachnoid hemorrhage outcomes

BackgroundVasospasm and cerebral ischemia after aneurysmal subarachnoid hemorrhage are associated with mortality and poor neurological outcomes. We studied the efficacy of all available strategies targeting vasospasm and cerebral ischemia on outcomes in a network meta-analysis.MethodsWe searched EMBASE and MEDLINE databases from 1 January 1990 and 28 November 2021 according to PRISMA guidelines. Randomized controlled trials and longitudinal studies were included. All curative or preventive strategies targeting vasospasm and/or cerebral ischemia were eligible. A network meta-analysis was performed to compare all interventions with one another in a primary (randomized controlled trials only) and a secondary analysis (both trials and longitudinal studies). Mortality by 3 months was the primary outcome. Secondary outcomes were vasospasm, neurological outcome by 3 months, and dichotomized as “good” or “poor” recovery according to each study definition.ResultsA total of 2,382 studies were screened which resulted in the selection of 192 clinical trials (92 (47.9%) and 100 cohorts (52.1%) and the inclusion of 41,299 patients. In randomized controlled studies, no strategy decreased mortality by 3 months. Statins (0.79 [0.62–1]), tirilazad (0.82 [0.69–0.97]), CSF drainage (0.47 [0.29–0.77]), and clazosentan (0.51 [0.36–0.71]) significantly decreased the incidence of vasospasm. Cilostazol was the only treatment associated with improved neurological outcomes by 3 months in the primary (OR 1.16, 95% CI [1.05–1.28]) and secondary analyses (OR 2.97, 95% CI [1.39–6.32]).DiscussionIn the modern era of subarachnoid hemorrhage, all strategies targeting vasospasm failed to decrease mortality. Cilostazol should be confirmed as a treatment to improve neurological outcomes. The link between vasospasm and neurological outcome appears questionable.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=116073, identifier: PROSPERO CRD42018116073

Relationship between positive end-expiratory pressure levels, central venous pressure, systemic inflammation and acute renal failure in critically ill ventilated COVID-19 patients: a monocenter retrospective study in France

Background The role of positive pressure ventilation, central venous pressure (CVP) and inflammation on the occurrence of acute kidney injury (AKI) have been poorly described in mechanically ventilated patient secondary to coronavirus disease 2019 (COVID-19). Methods This was a monocenter retrospective cohort study of consecutive ventilated COVID-19 patients admitted in a French surgical intensive care unit between March 2020 and July 2020. Worsening renal function (WRF) was defined as development of a new AKI or a persistent AKI during the 5 days after mechanical ventilation initiation. We studied the association between WRF and ventilatory parameters including positive end-expiratory pressure (PEEP), CVP, and leukocytes count. Results Fifty-seven patients were included, 12 (21%) presented WRF. Daily PEEP, 5 days mean PEEP and daily CVP values were not associated with occurrence of WRF. 5 days mean CVP was higher in the WRF group compared to patients without WRF (median [IQR], 12 mm Hg [11-13] vs. 10 mm Hg [9–12]; P=0.03). Multivariate models with adjustment on leukocytes and Simplified Acute Physiology Score (SAPS) II confirmed the association between CVP value and risk of WRF (odd ratio, 1.97; 95% confidence interval, 1.12–4.33). Leukocytes count was also associated with occurrence of WRF in the WRF group (14 G/L [11–18]) and the no-WRF group (9 G/L [8–11]) (P=0.002). Conclusions In mechanically ventilated COVID-19 patients, PEEP levels did not appear to influence occurrence of WRF. High CVP levels and leukocytes count are associated with risk of WRF

Radiomic analysis of abdominal organs during sepsis of digestive origin in a French intensive care unit

Background Sepsis is a severe and common cause of admission to the intensive care unit (ICU). Radiomic analysis (RA) may predict organ failure and patient outcomes. The objective of this study was to assess a model of RA and to evaluate its performance in predicting in-ICU mortality and acute kidney injury (AKI) during abdominal sepsis. Methods This single-center, retrospective study included patients admitted to the ICU for abdominal sepsis. To predict in-ICU mortality or AKI, elastic net regularized logistic regression and the random forest algorithm were used in a five-fold cross-validation set repeated 10 times. Results Fifty-five patients were included. In-ICU mortality was 25.5%, and 76.4% of patients developed AKI. To predict in-ICU mortality, elastic net and random forest models, respectively, achieved areas under the curve (AUCs) of 0.48 (95% confidence interval [CI], 0.43–0.54) and 0.51 (95% CI, 0.46–0.57) and were not improved combined with Simplified Acute Physiology Score (SAPS) II. To predict AKI with RA, the AUC was 0.71 (95% CI, 0.66–0.77) for elastic net and 0.69 (95% CI, 0.64–0.74) for random forest, and these were improved combined with SAPS II, respectively; AUC of 0.94 (95% CI, 0.91–0.96) and 0.75 (95% CI, 0.70–0.80) for elastic net and random forest, respectively. Conclusions This study suggests that RA has poor predictive performance for in-ICU mortality but good predictive performance for AKI in patients with abdominal sepsis. A secondary validation cohort is needed to confirm these results and the assessed model

Pleural innate response activator B cells protect against pneumonia via a GM-CSF-IgM axis

Pneumonia is a major cause of mortality worldwide and a serious problem in critical care medicine, but the immunophysiological processes that confer either protection or morbidity are not completely understood. We show that in response to lung infection, B1a B cells migrate from the pleural space to the lung parenchyma to secrete polyreactive emergency immunoglobulin M (IgM). The process requires innate response activator (IRA) B cells, a transitional B1a-derived inflammatory subset which controls IgM production via autocrine granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. The strategic location of these cells, coupled with the capacity to produce GM-CSF–dependent IgM, ensures effective early frontline defense against bacteria invading the lungs. The study describes a previously unrecognized GM-CSF-IgM axis and positions IRA B cells as orchestrators of protective IgM immunity

Lp-PLA 2 Antagonizes Left Ventricular Healing After Myocardial Infarction by Impairing the Appearance of Reparative MacrophagesCLINICAL PERSPECTIVE

Background—Healing after myocardial infarction (MI) involves the biphasic accumulation of inflammatory Ly-6Chigh and reparative Ly-6Clow monocytes/macrophages. Excessive inflammation disrupts the balance between the 2 phases, impairs infarct healing, and contributes to left ventricle remodeling and heart failure. Lipoprotein-associated phospholipase A2 (Lp-PLA2), a member of the phospholipase A2 family of enzymes, produced predominantly by leukocytes, participates in host defenses and disease. Elevated Lp-PLA2 levels associate with increased risk of cardiovascular events across diverse patient populations, but the mechanisms by which the enzyme elicits its effects remain unclear. This study tested the role of Lp-PLA2 in healing after MI. Methods and Results—In response to MI, Lp-PLA2 levels markedly increased in the circulation. To test the functional importance of Lp-PLA2, we generated chimeric mice whose bone marrow–derived leukocytes were Lp-PLA2–deficient (bmLp-PLA2−/−). Compared with wild-type controls, bmLp-PLA2−/− mice subjected to MI had lower serum levels of inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, and decreased number of circulating inflammatory myeloid cells. Accordingly, bmLp-PLA2−/− mice developed smaller and less inflamed infarcts with reduced numbers of infiltrating neutrophils and inflammatory Ly-6Chigh monocytes. During the later, reparative phase, infarcts of bmLp-PLA2−/− mice contained Ly-6Clow macrophages with a skewed M2-prone gene expression signature, increased collagen deposition, fewer inflammatory cells, and improved indices of angiogenesis. Consequently, the hearts of bmLp-PLA2−/− mice healed more efficiently, as determined by improved left ventricle remodeling and ejection fraction. Conclusions—Lp-PLA2 augments the inflammatory response after MI and antagonizes healing by disrupting the balance between inflammation and repair, providing a rationale for focused study of ventricular function and heart failure after targeting this enzyme acutely in MI

On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver

Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal1. In various pathophysiological conditions, however, erythrocyte life span is severely compromised, which threatens the organism with anemia and iron toxicity2,3. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that Ly-6Chigh monocytes ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate to ferroportin 1 (FPN1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+ Tim-4neg macrophages are transient, reside alongside embryonically-derived Tim-4high Kupffer cells, and depend on Csf1 and Nrf2. The spleen likewise recruits iron-loaded Ly-6Chigh monocytes, but these do not differentiate into iron-recycling macrophages due to the suppressive action of Csf2. Inhibiting monocyte recruitment to the liver leads to kidney and liver damage. These observations identify the liver as the primary organ supporting rapid erythrocyte removal and iron recycling and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)