Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19.

Blood myeloid cells are known to be dysregulated in coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2. It is unknown whether the innate myeloid response differs with disease severity and whether markers of innate immunity discriminate high-risk patients. Thus, we performed high-dimensional flow cytometry and single-cell RNA sequencing of COVID-19 patient peripheral blood cells and detected disappearance of non-classical CD14LowCD16High monocytes, accumulation of HLA-DRLow classical monocytes (Human Leukocyte Antigen - DR isotype), and release of massive amounts of calprotectin (S100A8/S100A9) in severe cases. Immature CD10LowCD101-CXCR4+/- neutrophils with an immunosuppressive profile accumulated in the blood and lungs, suggesting emergency myelopoiesis. Finally, we show that calprotectin plasma level and a routine flow cytometry assay detecting decreased frequencies of non-classical monocytes could discriminate patients who develop a severe form of COVID-19, suggesting a predictive value that deserves prospective evaluation.

Erythropoietin downregulates red blood cell clearance, increasing transfusion efficacy in severely anemic recipients.

Red blood cells (RBC) transfusion is used to alleviate symptoms and prevent complications in anemic patients by restoring oxygen delivery to tissues. RBC transfusion efficacy, that can be measured by a rise in hemoglobin (Hb) concentration, is influenced by donor-, product-, and recipient-related characteristics. In some studies, severe pre-transfusion anemia is associated with a greater than expected Hb increment following transfusion but the biological mechanism underpinning this relationship remains poorly understood. We conducted a prospective study in critically ill patients and quantified Hb increment following one RBC transfusion. In a murine model, we investigated the possibility that, in conjunction with the host erythropoietic response, the persistence of transfused donor RBC is improved to maintain a highest RBC biomass. We confirmed a correlation between a greater Hb increment and a deeper pre-transfusion anemia in a cohort of 17 patients. In the mouse model, Hb increment and post-transfusion recovery were increased in anemic recipients. Post-transfusion RBC recovery was improved in hypoxic mice or those receiving an erythropoiesis-stimulating agent and decreased in those treated with erythropoietin (EPO)-neutralizing antibodies, suggesting that EPO signaling is necessary to observe this effect. Irradiated recipients also showed decreased post-transfusion RBC recovery. The EPO-induced post-transfusion RBC recovery improvement was abrogated in irradiated or in macrophage-depleted recipients, but maintained in splenectomized recipients, suggesting a mechanism requiring erythroid progenitors and macrophages, but which is not spleen-specific. Our study highlights a physiological role of EPO in downregulating post-transfusion RBC clearance, contributing to maintain a vital RBC biomass to rapidly cope with hypoxemia.

Impact of Blood Product Transfusions on the Risk of ICU-Acquired Infections in Septic Shock.

OBJECTIVES: Transfusions of blood products are common in critically ill patients and have a potential for immunomodulation. The aim of this study is to address the impact of transfusion of blood products on the susceptibility to ICU-acquired infections in the high-risk patients with septic shock. DESIGN: A single-center retrospective study over a 10-year period (2008-2017). SETTING: A medical ICU of a tertiary-care center. PATIENTS: All consecutive patients diagnosed for septic shock within the first 48 hours of ICU admission were included. Patients who were discharged or died within the first 48 hours were excluded. INTERVENTIONS: RBC, platelet, and fresh frozen plasma transfusions collected up to 24 hours prior to the onset of ICU-acquired infection. MEASUREMENTS AND MAIN RESULTS: During the study period, 1,152 patients were admitted for septic shock, with 893 patients remaining alive in the ICU after 48 hours of management. A first episode of ICU-acquired infection occurred in 28.3% of the 48-hour survivors, with a predominance of pulmonary infections (57%). Patients with ICU-acquired infections were more likely to have received RBC, platelet, and fresh frozen plasma transfusions. In a multivariate Cox cause-specific analysis, transfusions of platelets (cause-specific hazard ratio = 1.55 [1.09-2.20]; p = 0.01) and fresh frozen plasma (cause-specific hazard ratio = 1.38 [0.98-1.92]; p = 0.05) were independently associated with the further occurrence of ICU-acquired infections. CONCLUSIONS: Transfusions of platelets and fresh frozen plasma account for risk factors of ICU-acquired infections in patients recovering from septic shock. The occurrence of ICU-acquired infections should be considered as a relevant endpoint in future studies addressing the indications of transfusions in critically ill patients.

Time Course of Septic Shock in Immunocompromised and Nonimmunocompromised Patients.

OBJECTIVES: To address the impact of underlying immune conditions on the course of septic shock with respect to both mortality and the development of acute infectious and noninfectious complications. DESIGN: An 8-year (2008-2015) monocenter retrospective study. SETTING: A medical ICU in a tertiary care center. PATIENTS: Patients diagnosed for septic shock within the first 48 hours of ICU admission were included. Patients were classified in four subgroups with respect to their immune status: nonimmunocompromised and immunocompromised distributed into hematologic or solid malignancies and nonmalignant immunosuppression. Outcomes were in-hospital death and the development of ischemic and hemorrhagic complications and ICU-acquired infections. The determinants of death and complications were addressed by multivariate competing risk analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eight hundred one patients were included. Among them, 305 (38%) were immunocompromised, distributed into solid tumors (122), hematologic malignancies (106), and nonmalignant immunosuppression (77). The overall 3-day, in-ICU, and in-hospital mortality rates were 14.1%, 37.3%, and 41.3%, respectively. Patients with solid tumors displayed increased in-hospital mortality (cause-specific hazard, 2.20 [95% CI, 1.64-2.96]; p < 0.001). ICU-acquired infections occurred in 211 of the 3-day survivors (33%). In addition, 95 (11.8%) and 70 (8.7%) patients exhibited severe ischemic or hemorrhagic complications during the ICU stay. There was no association between the immune status and the occurrence of ICU-acquired infections. Nonmalignant immunosuppression and hematologic malignancies were independently associated with increased risks of severe ischemic events (cause-specific hazard, 2.12 [1.14-3.96]; p = 0.02) and hemorrhage (cause-specific hazard, 3.17 [1.41-7.13]; p = 0.005), respectively. CONCLUSIONS: The underlying immune status impacts on the course of septic shock and on the susceptibility to ICU-acquired complications. This emphasizes the complexity of sepsis syndromes in relation with comorbid conditions and raises the question of the relevant endpoints in clinical studies.

Return to work after out of hospital cardiac arrest, insights from a prospective multicentric French cohort.

RATIONALE: About 60 to 70% of out-of-hospital cardiac arrest (OHCA) survivors who worked before cardiac arrest return to work within one year but the precise conditions for this resumption of professional activity remain little known. The objective of this study was to assess components of return to work among OHCA survivors. PATIENTS AND METHODS: We used the French national multicentric cohort AfterRosc to include OHCA survivors admitted between April 1st 2021 and March 31st 2022, discharged alive from the Intensive Care Unit (ICU), and who were less than 65 years old. A phone-call interview was performed one year after OHCA to assess return to work, level of education, former level of occupation as well as neurological recovery. Geographic and socio-economic data from the patient's residential neighborhoods were also collected. Comparisons were performed between patients who returned to work and those who did not, using non-parametric tests. RESULTS: Of the 251 patients included in the registry, 86 were alive at ICU discharge and 31 patients that worked prior to the OHCA were included for analysis. Seventeen survivors returned to work after a median delay of 112 days [92-157] Among them, nine (53%) had required initial work adjustments. Overall, only 6 patients (19%) had returned to work ad integrum. Higher educational level, work which required higher competence-level, higher income, living in a better socio-economical neighborhood, as well as better scores on all three standardized MPAI-4 score components (abilities, adjustment and participation) were significantly associated with return to work. Participants that had not returned to work had a significant drop of income (p = 0.0025). CONCLUSION: In this prospective study regarding French OHCA survivors, return to work is associated with better socio-economical individual and environmental status, as well as better scores on all MPAI-4 components.

Plasma thioredoxin levels during post-cardiac arrest syndrome: relationship with severity and outcome.

INTRODUCTION: Despite experimental evidence, clinical demonstration of acute state of oxidative stress and inflammation during post-cardiac arrest syndrome is lacking. Plasma level of thioredoxin (TRX), a redox-active protein induced under conditions of oxidative stress and inflammation, is increased in various critical care conditions. We determined plasma TRX concentrations after cardiac arrest and assessed relationships with severity and outcome. METHODS: Retrospective study of consecutive patients admitted to a single academic intensive care unit (ICU) for out-of-hospital cardiac arrest (between July 2006 and March 2008). Plasma levels of TRX were measured at admission, day (D) 1, 2 and 3. RESULTS: Of 176 patients included, median TRX values measured in ICU survivors and non-survivors were, respectively: 22 ng/mL (7.8 to 77) vs. 72.4 (21.9 to 117.9) at admission (P < 0.001); 5.9 (3.5 to 25.5) vs. 23.2 (5.8 to 81.4) at D1 (P = 0.003); 10.8 (3.6 to 50.8) vs. 11.7 (4.5 to 66.4) at D2 (P = 0.22); and 16.7 (5.3 to 68.3) vs. 17 (4.3 to 62.9) at D3 (P = 0.96). Patients dying within 24 hours had significantly (P < 0.001) higher TRX levels (118.6 ng/mL (94.8 to 280)) than those who died after 24 hours or survived (50.8 (13.9 to 95.7) and 22 (7.8 to 77)). The area under the ROC curve to predict early death was 0.84 (0.76 to 0.91). CONCLUSIONS: Our data show for the first time that TRX levels were elevated early following cardiac arrest, suggestive of oxidative stress and inflammation occurring with this condition. Highest values were found in the most severe patients. TRX could be a useful tool for further exploration and comprehension of post-cardiac arrest syndrome.

Catheter dysfunction and dialysis performance according to vascular access among 736 critically ill adults requiring renal replacement therapy: a randomized controlled study.

OBJECTIVE: To compare dialysis catheter function according to catheter site. DESIGN: Multicenter, open, randomized controlled trial. SETTING: Nine university-affiliated hospitals and three general hospitals in France. PATIENTS: Seven hundred thirty-six patients in intensive care units who required a first venous catheterization to perform either intermittent hemodialysis (470 patients with 1275 sessions) or continuous renal replacement therapy (266 patients with 1003 days). INTERVENTION: Patients randomly received either femoral (n = 370) or jugular (n = 366) catheterization. For the jugular site, right-side position (n = 252) was recommended. MEASUREMENTS AND MAIN RESULTS: Time to catheter ablation for dysfunction, urea reduction ratio (intermittent hemodialysis), and downtime (continuous renal replacement therapy) were assessed for all participants and evaluated by randomly assigned catheterization site (femoral or jugular). Baseline demography and dialysis prescriptions were similar between the site arms. In modified intent-to-treat, catheter dysfunction occurred in 36 of 348 (10.3%) and 38 of 342 (11.1%) patients in the femoral and jugular groups, respectively. The risk of catheter dysfunction did not significantly differ between randomized groups (hazard ratio, 1.06; 95% confidence interval, 0.67-1.68; p = .80). Compared to the femoral site, the observed risk of dysfunction decreased in the right jugular position (15 of 226; 6.6%; adjusted hazard ratio, 0.58; 95% confidence interval, 0.31-1.07; p = .09) and significantly increased in the left jugular position (23 of 118; 19.5%; adjusted hazard ratio, 1.89; 95% confidence interval, 1.12-3.21; p < .02). The postintermittent hemodialysis mean urea reduction ratio per session was 50.8% (standard deviation, 16.1) for femoral vs. 52.8% (standard deviation, 15.8) for jugular (p = .30) sites, and the median continuous renal replacement therapy downtime per patient-day was 1.17 hrs (interquartile range, 0.75-1.50) for both sites (p = .98). CONCLUSIONS: In terms of catheter dysfunction and dialysis performance among critically ill adults requiring acute renal replacement therapy, jugular site did not significantly outperform femoral site placement.

Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-ß and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor-κB and characterized by increased tumor necrosis factor-α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.

Hemodynamic efficiency of hemodialysis treatment with high cut-off membrane during the early period of post-resuscitation shock: The HYPERDIA trial.

BACKGROUND: After resuscitation of cardiac arrest (CA), an acute circulatory failure occurs in about 50% of cases, which shares many characteristics with septic shock. Most frequently, supportive treatments are poorly efficient to prevent multiple organ failure and death. We evaluated whether an early plasma removal of inflammatory mediators using high cut-off continuous veno-venous hemodialysis (HCO-CVVHD) could improve hemodynamic status and outcome of these patients. PATIENTS AND METHODS: We performed a randomized open-label trial. Patients with post-cardiac arrest shock (defined as requirement of norepinephrine or epinephrine infusion > 1 mg/h) were included. The experimental group received 2 distinct sessions of HCO-CVVHD during the first 48 h following ICU admission. The control group received continuous veno-venous hemofiltration (CVVH) with standard membranes if needed. The primary endpoint was the delay to shock resolution asssessed by the length of catecholamine infusion. Number of vasopressors-free days at day 28, arterial blood pressure measures every 6-hours, daily fluid balance and mortality (ICU and day-28) were evaluated as secondary endpoints. RESULTS: 35 patients were included: 17 (median age 68.4, 59% male) in the HCO-CVVHD group and 18 (median age 66.3, 83% male) in the control group. Baseline characteristics did not differ between the two groups. Day-28 mortality rate was 64.7% and 72.2% in the HCO-CVVHD and control group, respectively (p = 0.72). Probability of vasopressors discontinuation over time was similar in the two groups (p for logrank test = 0.67). Number of day-28 catecholamine-free days was 25.1 [0, 26.5] and 24.5 [0, 26.2] in the HCO-CVVHD and control group, respectively (p = 0.65). No difference was observed regarding the daily-dose of vasopressors, arterial pressure profile and fluid balance. CONCLUSION: In cardiac arrest patients, HCO-CVVHD did not decrease the lenght of post-resuscitation shock and had no significant effect on hemodynamic profile. REGISTRATION: NCT00780299.

Usefulness of early plasma S-100B protein and Neuron-Specific Enolase measurements to identify cerebrovascular etiology of out-of-hospital cardiac arrest.

BACKGROUND: While S-100B protein and Neuron-Specific Enolase (NSE) dosages have been extensively investigated for neurological prognostication after cardiac arrest (CA), there is no data about their ability to detect a cerebrovascular cause of CA. We assessed the utility of plasma S-100B protein and NSE measurements for early diagnosis of primary neurological cause in resuscitated CA patients. PATIENTS AND METHODS: Case control study based on two prospectively acquired CA databases. Patients with a primary cerebrovascular etiology were compared with randomly selected CA of non-neurological cause. S-100B protein and NSE were measured at ICU admission in all patients. RESULTS: CA was due to a cerebrovascular etiology in 18 patients (subarachnoid hemorrhage, n = 15; ischemic stroke, n = 3), with an ICU mortality of 100%. Comparative group was constituted with 66 patients (cardiac etiology n = 45, respiratory etiology n = 21), with an ICU mortality of 71%. Admission S-100B protein concentration was 2.0 [0.63-7.15] µg/L in the cerebrovascular group and 0.45 [0.24-1.95] in the non-cerebrovascular group (p < 0.001). In contrast, NSE concentration was similar in cerebrovascular and non-cerebrovascular etiologies (35 [25-103] µg/L vs. 27 [19-47] respectively, p = 0.16). Area under ROC curves for S-100B protein and NSE to predict cerebrovascular cause of CA was 0.75 [95% CI: 0.64-0.87] and 0.61 [95% CI: 0.45-0.76], respectively. CONCLUSIONS: Even if S-100B protein dosage performs slightly better than NSE, early dosages of these biomarkers are poorly predictive of a cerebrovascular etiology of CA. Our results suggest that early measurement of brain biomarkers should not be recommended to tailor the imaging strategy employed to investigate the CA cause.

Association of REL polymorphisms and outcome of patients with septic shock.

BACKGROUND: cRel, a subunit of NF-κB, is implicated in the inflammatory response observed in autoimmune disease. Hence, knocked-out mice for cRel had a significantly higher mortality, providing new and important functions of cRel in the physiopathology of septic shock. Whether genetic variants in the human REL gene are associated with severity of septic shock is unknown. METHODS: We genotyped a population of 1040 ICU patients with septic shock and 855 ICU controls for two known polymorphisms of REL; REL rs842647 and REL rs13031237. Outcome of patients according to the presence of REL variant alleles was compared. RESULTS: The distribution of REL variant alleles was not significantly different between patients and controls. Among the septic shock group, REL rs13031237*T minor allele was not associated with worse outcome. In contrast, REL rs842647*G minor allele was significantly associated with more multi-organ failure and early death [OR 1.4; 95 % CI (1.02-1.8)]. CONCLUSION: In a large ICU population, we report a significant clinical association between a variation in the human REL gene and severity and mortality of septic shock, suggesting for the first time a new insight into the role of cRel in response to infection in humans.

Timing and causes of death in septic shock.

BACKGROUND: Most studies about septic shock report a crude mortality rate that neither distinguishes between early and late deaths nor addresses the direct causes of death. We herein aimed to determine the modalities of death in septic shock. METHODS: This was a 6-year (2008-2013) monocenter retrospective study. All consecutive patients diagnosed for septic shock within the first 48 h of intensive care unit (ICU) admission were included. Early and late deaths were defined as occurring within or after 3 days following ICU admission, respectively. The main cause of death in the ICU was determined from medical files. A multinomial logistic regression analysis using the status alive as the reference category was performed to identify the prognostic factors associated with early and late deaths. RESULTS: Five hundred forty-three patients were included, with a mean age of 66 ± 15 years and a high proportion (67 %) of comorbidities. The in-ICU and in-hospital mortality rates were 37.2 and 45 %, respectively. Deaths occurred early for 78 (32 %) and later on for 166 (68 %) patients in the ICU (n = 124) or in the hospital (n = 42). Early deaths were mainly attributable to intractable multiple organ failure related to the primary infection (82 %) and to mesenteric ischemia (6.4 %). In-ICU late deaths were directly related to end-of-life decisions in 29 % of patients and otherwise mostly related to ICU-acquired complications, including nosocomial infections (20.4 %) and mesenteric ischemia (16.6 %). Independent determinants of early death were age, malignancy, diabetes mellitus, no pathogen identification, and initial severity. Among 3-day survivors, independent risk factors for late death were age, cirrhosis, no pathogen identification, and previous corticosteroid treatment. CONCLUSIONS: Our study provides a comprehensive assessment of septic shock-related deaths. Identification of risk factors of early and late deaths may determine differential prognostic patterns.