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.

Outcome of SARS-CoV-2 infection is linked to MAIT cell activation and cytotoxicity.

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.

CGRP inhibits SARS-CoV-2 infection of bronchial epithelial cells, and its pulmonary levels correlate with viral clearance in critical COVID-19 patients.

Upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with critical coronavirus disease 2019 (COVID-19) present with life-threatening respiratory distress, pulmonary damage, and cytokine storm. One unexplored component in COVID-19 is the neuropeptide calcitonin gene-related peptide (CGRP), which is highly abundant in the airways and could converge in multiple aspects of COVID-19-related pulmonary pathophysiology. Whether CGRP affects SARS-CoV-2 infection directly remains elusive. We show that in critical COVID-19 patients, CGRP is increased in both plasma and lungs. Importantly, CGRP pulmonary levels are elevated in early SARS-CoV-2-positive patients and restored to baseline upon subsequent viral clearance in SARS-CoV-2-negative patients. We further show that CGRP and its stable analog SAX directly inhibit infection of bronchial Calu-3 epithelial cells with SARS-CoV-2 Omicron and Alpha variants in a dose-dependent manner. Both pre- and post-infection treatments with CGRP and/or SAX are enough to block SARS-CoV-2 productive infection of Calu-3 cells. CGRP-mediated inhibition occurs via activation of the CGRP receptor and involves down-regulation of both SARS-CoV-2 entry receptors at the surface of Calu-3 cells. Together, we propose that increased pulmonary CGRP mediates beneficial viral clearance in critical COVID-19 patients by directly inhibiting SARS-CoV-2 propagation. Hence, CGRP-based interventions could be harnessed for management of COVID-19.IMPORTANCEThe neuropeptide CGRP is highly abundant in the airways. Due to its immunomodulatory, vasodilatory, and anti-viral functions, CGRP could affect multiple aspects of COVID-19-related pulmonary pathophysiology. Yet, the interplay between CGRP and SARS-CoV-2 during COVID-19 remains elusive. Herein, we show that pulmonary levels of CGRP are increased in critical COVID-19 patients, at an early stage of their disease when patients are SARS-CoV-2-positive. Upon subsequent viral clearance, CGRP levels are restored to baseline in SARS-CoV-2-negative patients. We further show that pre- and post-infection treatments with CGRP directly inhibit infection of Calu-3 bronchial epithelial cells with SARS -CoV-2, via activation of the CGRP receptor leading to decreased expression of both SARS-CoV-2 entry receptors. Together, we propose that increased pulmonary CGRP is beneficial in COVID-19, as CGRP-mediated inhibition of SARS-CoV-2 infection could contribute to viral clearance in critical COVID-19 patients. Accordingly, CGRP-based formulations could be useful for COVID-19 management.

Outcomes in Critically Ill Allogeneic Hematopoietic Stem-Cell Transplantation Recipients.

Rationale: Allogeneic hematopoietic stem-cell transplantation (Allo-HSCT) recipients are still believed to be poor candidates for ICU management. Methods: We investigated outcomes and determinants of mortality in a large multicenter retrospective cohort of Allo-HSCT patients admitted between January 1, 2015, and December 31, 2020, to 14 French ICUs. The primary endpoint was 90-day mortality. Measurements and Main Results: In total, 1,164 patients were admitted throughout the study period. At the time of ICU admission, 765 (66%) patients presented with multiple organ dysfunction, including acute respiratory failure in 40% (n = 461). The median sepsis-related organ failure assessment score was 6 (interquartile range, 4-8). Invasive mechanical ventilation, renal replacement therapy, and vasopressors were required in 438 (38%), 221 (19%), and 468 (41%) patients, respectively. ICU mortality was 26% (302 deaths). Ninety-day, 1-year, and 3-year mortality rates were 48%, 63%, and 70%, respectively. By multivariable analysis, age > 56 years (odds ratio [OR], 2.0 [95% confidence interval (CI), 1.53-2.60]; P < 0.001), time from Allo-HSCT to ICU admission between 30 and 90 days (OR, 1.68 [95% CI, 1.17-2.40]; P = 0.005), corticosteroid-refractory acute graft-versus-host disease (OR, 1.63 [95% CI, 1.38-1.93]; P < 0.001), need for vasopressors (OR, 1.9 [95% CI, 1.42-2.55]; P < 0.001), and mechanical ventilation (OR, 3.1 [95% CI, 2.29-4.18]; P < 0.001) were independently associated with 90-day mortality. In patients requiring mechanical ventilation, mortality rates ranged from 39% (no other risk factors for mortality) to 100% (four associated risk factors for mortality). Conclusions: Most critically ill Allo-HSCT recipients survive their ICU stays, including those requiring mechanical ventilation, with an overall 90-day survival rate reaching 51.8%. A careful assessment of goals of care is required in patients with two or more risk factors for mortality.

Multicenter Retrospective Study of Invasive Fusariosis in Intensive Care Units, France.

Invasive fusariosis can be life-threatening, especially in immunocompromised patients who require intensive care unit (ICU) admission. We conducted a multicenter retrospective study to describe clinical and biologic characteristics, patient outcomes, and factors associated with death and response to antifungal therapy. We identified 55 patients with invasive fusariosis from 16 ICUs in France during 2002----2020. The mortality rate was high (56%). Fusariosis-related pneumonia occurred in 76% of patients, often leading to acute respiratory failure. Factors associated with death included elevated sequential organ failure assessment score at ICU admission or history of allogeneic hematopoietic stem cell transplantation or hematologic malignancies. Neither voriconazole treatment nor disseminated fusariosis were strongly associated with response to therapy. Invasive fusariosis can lead to multiorgan failure and is associated with high mortality rates in ICUs. Clinicians should closely monitor ICU patients with a history of hematologic malignancies or stem cell transplantation because of higher risk for death.

Septic shock in the immunocompromised cancer patient: a narrative review.

Immunosuppressed patients, particularly those with cancer, represent a momentous and increasing portion of the population, especially as cancer incidence rises with population growth and aging. These patients are at a heightened risk of developing severe infections, including sepsis and septic shock, due to multiple immunologic defects such as neutropenia, lymphopenia, and T and B-cell impairment. The diverse and complex nature of these immunologic profiles, compounded by the concomitant use of immunosuppressive therapies (e.g., corticosteroids, cytotoxic drugs, and immunotherapy), superimposed by the breakage of natural protective barriers (e.g., mucosal damage, chronic indwelling catheters, and alterations of anatomical structures), increases the risk of various infections. These and other conditions that mimic sepsis pose substantial diagnostic and therapeutic challenges. Factors that elevate the risk of progression to septic shock in these patients include advanced age, pre-existing comorbidities, frailty, type of cancer, the severity of immunosuppression, hypoalbuminemia, hypophosphatemia, Gram-negative bacteremia, and type and timing of responses to initial treatment. The management of vulnerable cancer patients with sepsis or septic shock varies due to biased clinical practices that may result in delayed access to intensive care and worse outcomes. While septic shock is typically associated with poor outcomes in patients with malignancies, survival has significantly improved over time. Therefore, understanding and addressing the unique needs of cancer patients through a new paradigm, which includes the integration of innovative technologies into our healthcare system (e.g., wireless technologies, medical informatics, precision medicine), targeted management strategies, and robust clinical practices, including early identification and diagnosis, coupled with prompt admission to high-level care facilities that promote a multidisciplinary approach, is crucial for improving their prognosis and overall survival rates.

Platelet transfusions in adult thrombocytopenic ICU patients: Protocol for a sub-study of the PLOT-ICU cohort.

INTRODUCTION: Platelet transfusions are frequently used in intensive care unit (ICU) patients, but contemporary epidemiological data are sparse. We aim to present contemporary international data on the use of platelet transfusions in adult ICU patients with thrombocytopenia. METHODS: This is a protocol and statistical analysis plan for a post hoc sub-study of 504 thrombocytopenic patients from the 'Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU)'. The primary outcome will be the number of patients receiving platelet transfusion in the ICU reported according to the type of product received (apheresis-derived versus pooled whole-blood-derived transfusions). Secondary platelet transfusion outcomes will include platelet transfusion volumes; timing of platelet transfusion; approach to platelet transfusion dosing (fixed dosing versus weight-based dosing) and platelet count increments for prophylactic transfusions. Secondary clinical outcomes will include the number of patients receiving red blood cell- and plasma transfusions during ICU stay; the number of patients who bled in the ICU, the number of patients who had a new thrombosis in the ICU, and the number of patients who died. The duration of follow-up was 90 days. Baseline characteristics and secondary clinical outcomes will be stratified according to platelet transfusion status in the ICU and severity of thrombocytopenia. Data will be presented descriptively. CONCLUSIONS: The outlined study will provide detailed epidemiological data on the use of platelet transfusions in adult ICU patients with thrombocytopenia using data from the large international PLOT-ICU cohort study. The findings will inform the design of future randomised trials evaluating platelet transfusions in ICU patients.

Platelet transfusions in adult ICU patients with thrombocytopenia: A sub-study of the PLOT-ICU inception cohort study.

BACKGROUND: Platelet transfusions are frequently used in the intensive care unit (ICU), but current practices including used product types, volumes, doses and effects are unknown. STUDY DESIGN AND METHODS: Sub-study of the inception cohort study 'Thrombocytopenia and Platelet Transfusions in the ICU (PLOT-ICU)', including acutely admitted, adult ICU patients with thrombocytopenia (platelet count <150 × 109/L). The primary outcome was the number of patients receiving platelet transfusion in ICU by product type. Secondary outcomes included platelet transfusion details, platelet increments, bleeding, other transfusions and mortality. RESULTS: Amongst 504 patients with thrombocytopenia from 43 hospitals in 10 countries in Europe and the United States, 20.8% received 565 platelet transfusions; 61.0% received pooled products, 21.9% received apheresis products and 17.1% received both with a median of 2 (interquartile range 1-4) days from admission to first transfusion. The median volume per transfusion was 253 mL (180-308 mL) and pooled products accounted for 59.1% of transfusions, however, this varied across countries. Most centres (73.8%) used fixed dosing (medians ranging from 2.0 to 3.5 × 1011 platelets/transfusion) whilst some (mainly in France) used weight-based dosing (ranging from 0.5 to 0.7 × 1011 platelets per 10 kg body weight). The median platelet count increment for a single prophylactic platelet transfusion was 2 (-1 to 8) × 109/L. Outcomes of patients with thrombocytopenia who did and did not receive platelet transfusions varied. CONCLUSIONS: Among acutely admitted, adult ICU patients with thrombocytopenia, 20.8% received platelet transfusions in ICU of whom most received pooled products, but considerable variation was observed in product type, volumes and doses across countries. Prophylactic platelet transfusions were associated with limited increases in platelet counts.

Pulmonary and Nonpulmonary Sepsis Differentially Modulate Lung Immunity toward Secondary Bacterial Pneumonia: A Critical Role for Alveolar Macrophages.

Clinical observations suggest that the source of primary infection accounts for a major determinant of further nosocomial pneumonia in critically ill patients with sepsis. Here we addressed the impact of primary nonpulmonary or pulmonary septic insults on lung immunity using relevant double-hit animal models. C57BL/6J mice were first subjected to polymicrobial peritonitis induced by cecal ligation and puncture (CLP) or bacterial pneumonia induced by intratracheal challenge with Escherichia coli. Seven days later, postseptic mice received ab intratracheal challenge with Pseudomonas aeruginosa. Compared with controls, post-CLP mice became highly susceptible to P. aeruginosa pneumonia, as demonstrated by defective lung bacterial clearance and increased mortality rate. In contrast, all postpneumonia mice survived the P. aeruginosa challenge and even exhibited improved bacterial clearance. Nonpulmonary and pulmonary sepsis differentially modulated the amounts and some important immune functions of alveolar macrophages. Additionally, we observed a Toll-like receptor 2 (TLR2)-dependent increase in regulatory T cells (Tregs) in lungs from post-CLP mice. Antibody-mediated Treg depletion restored the numbers and functions of alveolar macrophages in post-CLP mice. Furthermore, post-CLP TLR2-deficient mice were found resistant to secondary P. aeruginosa pneumonia. In conclusion, polymicrobial peritonitis and bacterial pneumonia conferred susceptibility or resistance to secondary gram-negative pulmonary infection, respectively. Immune patterns in post-CLP lungs argue for a TLR2-dependent cross-talk between Tregs and alveolar macrophages as an important regulatory mechanism in postseptic lung defense.

Impact of sex differences on cardiac injury in critically ill patients with COVID-19.

BACKGROUND: COVID-19 infections are associated with accrued inflammatory responses which may result in cardiac injury. Immune response to infection appears different between men and women, suggesting that COVID-19 patients' outcomes may differ according to biological sex. However, the impact of biological sex on the occurrence of cardiac injury during intensive care unit (ICU) stay in COVID-19 patients remain unclear. METHODS: In this multicenter and prospective study, we included consecutive patients admitted to ICU for severe COVID-19 pneumonia, during the first two pandemic waves. Biological, electrocardiogram (ECG) and echocardiographic variables were collected on ICU admission. Cardiac injury was defined by increased troponin above 99th percentile of upper norm value and newly diagnosed ECG and/or echocardiographic abnormalities. The primary endpoint was the proportion of patients with cardiac injury during ICU stay according to biological sex. The impact of biological sex on other subsequent clinical outcomes was also evaluated. RESULTS: We included 198 patients with a median age of 66 (56-73) years, 147 (74%) patients were men and 51 (26%) were women. Overall, 119 (60%) patients had cardiac injury during ICU stay and the proportion of patients with cardiac injury during ICU stay was not different between men and women (60% vs. 61%, p = 1.00). Patients with cardiac injury during ICU stay showed more cardiovascular risk factors and chronic cardiac disease and had a higher ICU mortality rate. On ICU admission, they had a more marked lymphopenia (0.70 (0.40-0.80) vs. 0.80 (0.50-1.10) × 109/L, p < 0.01) and inflammation (C-Reactive Protein (155 (88-246) vs. 111 (62-192) mg/L, p = 0.03); D-Dimers (1293 (709-2523) vs. 900 (560-1813) µg/L, p = 0.03)). Plasmatic levels of inflammatory biomarkers on ICU admission correlated with SAPS-2 and SOFA scores but not with the different echocardiographic variables. Multivariate analysis confirmed cardiovascular risk factors (OR = 2.31; 95%CI (1.06-5.02), p = 0.03) and chronic cardiac disease (OR = 8.58; 95%CI (1.01-73.17), p = 0.04) were independently associated with the occurrence of cardiac injury during ICU stay, whereas biological sex (OR = 0.88; 95%CI (0.42-1.84), p = 0.73) was not. Biological sex had no impact on the occurrence during ICU stay of other clinical outcomes. CONCLUSIONS: Most critically ill patients with COVID-19 were men and experienced cardiac injury during ICU stay. Nevertheless, biological sex had no impact on the occurrence of cardiac injury during ICU stay or on other clinical outcomes. Clinical trial registration NCT04335162.

Early shoulder-girdle MRI findings in severe COVID-19-related intensive care unit-acquired weakness: a prospective cohort study.

OBJECTIVE: To describe clinical and early shoulder-girdle MR imaging findings in severe COVID-19-related intensive care unit-acquired weakness (ICU-AW) after ICU discharge. METHODS: A single-center prospective cohort study of all consecutive patients with COVID-19-related ICU-AW from November 2020 to June 2021. All patients underwent similar clinical evaluations and shoulder-girdle MRI within the first month and then 3 months (± 1 month) after ICU discharge. RESULTS: We included 25 patients (14 males; mean [SD] age 62.4 [12.5]). Within the first month after ICU discharge, all patients showed severe proximal predominant bilateral muscular weakness (mean Medical Research Council total score = 46.5/60 [10.1]) associated with bilateral, peripheral muscular edema-like MRI signals of the shoulder girdle in 23/25 (92%) patients. At 3 months, 21/25 (84%) patients showed complete or quasi-complete resolution of proximal muscular weakness (mean Medical Research Council total score > 48/60) and 23/25 (92%) complete resolution of MRI signals of the shoulder girdle, but 12/20 (60%) patients experienced shoulder pain and/or shoulder dysfunction. CONCLUSIONS: Early shoulder-girdle MRI findings in COVID-19-related ICU-AW included muscular edema-like peripheral signal intensities, without fatty muscle involution or muscle necrosis, with favorable evolution at 3 months. Precocious MRI can help clinicians distinguish critical illness myopathy from alternative, more severe diagnoses and can be useful in the care of patients discharged from intensive care with ICU-AW. KEY POINTS: • We describe the clinical and shoulder-girdle MRI findings of COVID-19-related severe intensive care unit-acquired weakness. • This information can be used by clinicians to achieve a nearly specific diagnosis, distinguish alternative diagnoses, assess functional prognosis, and select the more appropriate health care rehabilitation and shoulder impairment treatment.

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.

When breast cancer comes to the ICU: outcomes and prognostic factors.

BACKGROUND: Breast cancer is the most prevalent neoplasm in women in North American and European countries. Data about intensive care unit (ICU) requirements and the related outcomes are scarce. Furthermore, long-term outcome after ICU discharge has not been described. MATERIAL AND METHODS: We conducted a retrospective monocenter study including patients with breast cancer requiring unplanned ICU admission over a 14-year period (2007-2020). RESULTS: 177 patients (age = 65[57-75] years) were analyzed. Breast cancer was at a metastatic stage for 122 (68.9%) patients, recently diagnosed in 25 (14.1%) patients or in progression under treatment in 76 (42.9%) patients. Admissions were related to sepsis in 56 (31.6%) patients, to iatrogenic/procedural complication in 19 (10.7%) patients and to specific oncological complications in 47 (26.6%) patients. Seventy-two (40.7%) patients required invasive mechanical ventilation, 57 (32.2%) vasopressors/inotropes, and 26 (14.7%) renal replacement therapy. In-ICU and one-year mortality rates were 20.9% and 57.1%, respectively. Independent factors associated with in-ICU mortality were invasive mechanical ventilation and impaired performance status. One-year mortality in ICU survivors was independently associated with specific complications, triple negative cancer, and impaired performance status. After hospital discharge, most patients (77.4%) were able to continue or initiate antitumoral treatment. CONCLUSION: ICU admission was linked to the underlying malignancy in one-quarter of breast cancer patients. Despite the low in-ICU mortality rate (20.9%) and thereafter continuation of cancer treatment in most survivors (77.4%), one-year mortality reached 57.1%. Impaired performance status prior to the acute complication was a potent predictor of both short-term and long-term outcomes.

Severe COVID-19 is associated with hyperactivation of the alternative complement pathway.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) is characterized by impaired type I interferon activity and a state of hyperinflammation leading to acute respiratory distress syndrome. The complement system has recently emerged as a key player in triggering and maintaining the inflammatory state, but the role of this molecular cascade in severe COVID-19 is still poorly characterized. OBJECTIVE: We aimed at assessing the contribution of complement pathways at both the protein and transcriptomic levels. METHODS: To this end, we systematically assessed the RNA levels of 28 complement genes in the circulating whole blood of patients with COVID-19 and healthy controls, including genes of the alternative pathway, for which data remain scarce. RESULTS: We found differential expression of genes involved in the complement system, yet with various expression patterns: whereas patients displaying moderate disease had elevated expression of classical pathway genes, severe disease was associated with increased lectin and alternative pathway activation, which correlated with inflammation and coagulopathy markers. Additionally, properdin, a pivotal positive regulator of the alternative pathway, showed high RNA expression but was found at low protein concentrations in patients with a severe and critical disease, suggesting its deposition at the sites of complement activation. Notably, low properdin levels were significantly associated with the use of mechanical ventilation (area under the curve = 0.82; P = .002). CONCLUSION: This study sheds light on the role of the alternative pathway in severe COVID-19 and provides additional rationale for the testing of drugs inhibiting the alternative pathway of the complement system.

Early Clinical and Electrophysiological Brain Dysfunction Is Associated With ICU Outcomes in COVID-19 Critically Ill Patients With Acute Respiratory Distress Syndrome: A Prospective Bicentric Observational Study.

OBJECTIVES: Describe the prevalence of acute cerebral dysfunction and assess the prognostic value of an early clinical and electroencephalography (EEG) assessment in ICU COVID-19 patients. DESIGN: Prospective observational study. SETTING: Two tertiary critical care units in Paris, France, between April and December 2020. PATIENTS: Adult critically ill patients with COVID-19 acute respiratory distress syndrome. INTERVENTIONS: Neurologic examination and EEG at two time points during the ICU stay, first under sedation and second 4-7 days after sedation discontinuation. MEASUREMENTS AND MAIN RESULTS: Association of EEG abnormalities (background reactivity, continuity, dominant frequency, and presence of paroxystic discharges) with day-28 mortality and neurologic outcomes (coma and delirium recovery). Fifty-two patients were included, mostly male (81%), median (interquartile range) age 68 years (56-74 yr). Delayed awakening was present in 68% of patients (median awakening time of 5 d [2-16 d]) and delirium in 74% of patients who awoke from coma (62% of mixed delirium, median duration of 5 d [3-8 d]). First, EEG background was slowed in the theta-delta range in 48 (93%) patients, discontinuous in 25 patients (48%), and nonreactive in 17 patients (33%). Bifrontal slow waves were observed in 17 patients (33%). Early nonreactive EEG was associated with lower day-28 ventilator-free days (0 vs 16; p = 0.025), coma-free days (6 vs 22; p = 0.006), delirium-free days (0 vs 17; p = 0.006), and higher mortality (41% vs 11%; p = 0.027), whereas discontinuous background was associated with lower ventilator-free days (0 vs 17; p = 0.010), coma-free days (1 vs 22; p < 0.001), delirium-free days (0 vs 17; p = 0.001), and higher mortality (40% vs 4%; p = 0.001), independently of sedation and analgesia. CONCLUSIONS: Clinical and neurophysiologic cerebral dysfunction is frequent in COVID-19 ARDS patients. Early severe EEG abnormalities with nonreactive and/or discontinuous background activity are associated with delayed awakening, delirium, and day-28 mortality.

Prevalence, characteristics and outcome of cardiac manifestations in critically-ill antiphospholipid syndrome patients.

AIMS: Antiphospholipid syndrome (APS) is a rare autoimmune disease defined by thrombotic events occurring in patients with persistent antiphospholipid antibodies. Cardiac manifestations in critically-ill APS patients are poorly investigated. We conducted a study to assess the prevalence, the characteristics and the prognosis of cardiac manifestations in thrombotic APS patients admitted to intensive care unit (ICU). METHODS AND RESULTS: A French, national, multicentre, retrospective study, conducted, from January 2000 to September 2018, including all APS patients admitted to 24 participating centres' ICUs with any new thrombotic (arterial, venous or microvascular) manifestation. Cardiac manifestations were defined as any new cardiac abnormalities relying on clinical examination, cardiac biomarkers, echocardiography, cardiac magnetic resonance (CMR) and coronarography. One hundred and thirty-six patients (female 72%) were included. Mean age at ICU admission was 46 ± 15years. Cardiac manifestations were present in 71 patients (53%). In patients with cardiac involvement, median left ventricular ejection fraction (LVEF) was 40% [28-55], troponin was elevated in 93% patients, coronary angiogram (n = 19, 27%) disclosing a coronary obstruction in 21%. CMR (n = 21) was abnormal in all cases, with late gadolinium enhancement in 62% of cases. Cardiac manifestations were associated with a non-significant increase of mortality (32% vs. 19%, p = 0.08). After 1-year follow-up, median LVEF was 57% [44-60] in patients with cardiac involvement. CONCLUSION: Cardiac involvement is frequent in critically-ill thrombotic APS patients and may be associated to more severe outcome. Increased awareness on this rare cause of myocardial infarction with or without obstructive coronary artery is urgently needed.

Management of thrombotic microangiopathy in pregnancy and postpartum: report from an international working group.

Pregnancy and postpartum are high-risk periods for different forms of thrombotic microangiopathy (TMA). However, the management of pregnancy-associated TMA remains ill defined. This report, by an international multidisciplinary working group of obstetricians, nephrologists, hematologists, intensivists, neonatologists, and complement biologists, summarizes the current knowledge of these potentially severe disorders and proposes a practical clinical approach to diagnose and manage an episode of pregnancy-associated TMA. This approach takes into account the timing of TMA in pregnancy or postpartum, coexisting symptoms, first-line laboratory workup, and probability-based assessment of possible causes of pregnancy-associated TMA. Its aims are: to rule thrombotic thrombocytopenic purpura (TTP) in or out, with urgency, using ADAMTS13 activity testing; to consider alternative disorders with features of TMA (preeclampsia/eclampsia; hemolysis elevated liver enzymes low platelets syndrome; antiphospholipid syndrome); or, ultimately, to diagnose complement-mediated atypical hemolytic uremic syndrome (aHUS; a diagnosis of exclusion). Although they are rare, diagnosing TTP and aHUS associated with pregnancy, and postpartum, is paramount as both require urgent specific treatment.

Post-cardiac arrest myoclonus and in ICU mortality: insights from the Parisian Registry of Cardiac Arrest (PROCAT).

BACKGROUND: Post-cardiac arrest myoclonus (PCAM) is a frequent finding in resuscitated patients after cardiac arrest (CA), with rather poor prognostic significance. In this study, we evaluated the association of PCAM within intensive care unit (ICU) mortality from a university hospital CA patients' registry. METHODS: Clinical data of consecutive CA survivors admitted in the intensive care unit (ICU) between January and December 2016 at the Paris Cochin University Hospital were assessed from the Parisian registry of cardiac arrest (PROCAT) and analyzed. Neurologic outcome was assessed using the Cerebral Performance Categories (CPC) scale at ICU discharge. Prevalence of PCAM and their association with mortality at ICU discharge were computed. RESULTS: One hundred thirty-two (132) patients were included (73.5% males), median age of 66 years. Among them, 37 (28%) developed PCAM during their ICU stay. Only two patients with PCAM survived (5.4%). PCAM was strongly associated with mortality at ICU discharge (odds ratio 17.5 [4.2-123.2]). Sensitivity, specificity, PPV, and NPV of PCAM for prediction of death were 41%, 96%, 95%, and 46%, respectively. CONCLUSION: PCAM was observed in nearly one-third of CA patients admitted in ICU. Patients with PCAM had a significantly higher likelihood of ICU mortality and a low likelihood of a good outcome. The prognostic value of PCAM seems rather bleak but remains nuanced and merits study in larger-scale prospective studies taking into account confounding factors.

Platelet transfusions and thrombocytopenia in intensive care units: Protocol for an international inception cohort study (PLOT-ICU).

INTRODUCTION: Thrombocytopenia is frequent in intensive care unit (ICU) patients and has been associated with worse outcome. Platelet transfusions are often used in the management of ICU patients with severe thrombocytopenia. However, the reported frequencies of thrombocytopenia and platelet transfusion practices in the ICU vary considerably. Therefore, we aim to provide contemporary epidemiological data on thrombocytopenia and platelet transfusion practices in the ICU. METHODS: We will conduct an international inception cohort, including at least 1000 acutely admitted adult ICU patients. Routinely available data will be collected at baseline (ICU admission), and daily during ICU stay up to a maximum of 90 days. The primary outcome will be the number of patients with thrombocytopenia (a recorded platelet count < 150 × 109 /L) at baseline and/or during ICU stay. Secondary outcomes include mortality, days alive and out of hospital, days alive without life-support, the number of patients with at least one bleeding episode, at least one thromboembolic event and at least one platelet transfusion in the ICU, the number of platelet transfusions and the indications for transfusion. The primary and secondary outcomes will be presented descriptively. In addition, we will assess risk factors for developing thrombocytopenia during ICU stay and the association between thrombocytopenia at baseline and 90-day mortality using logistic regression analyses. CONCLUSION: The outlined international PLOT-ICU cohort study will provide contemporary epidemiological data on the burden and clinical significance of thrombocytopenia in adult ICU patients and describe the current platelet transfusion practice.

Survival in Immunocompromised Patients Ultimately Requiring Invasive Mechanical Ventilation: A Pooled Individual Patient Data Analysis.

Rationale: Acute respiratory failure (ARF) is associated with high mortality in immunocompromised patients, particularly when invasive mechanical ventilation is needed. Therefore, noninvasive oxygenation/ventilation strategies have been developed to avoid intubation, with uncertain impact on mortality, especially when intubation is delayed. Objectives: We sought to report trends of survival over time in immunocompromised patients receiving invasive mechanical ventilation. The impact of delayed intubation after failure of noninvasive strategies was also assessed. Methods: Systematic review and meta-analysis using individual patient data of studies that focused on immunocompromised adult patients with ARF requiring invasive mechanical ventilation. Studies published in English were identified through PubMed, Web of Science, and Cochrane Central (2008-2018). Individual patient data were requested from corresponding authors for all identified studies. We used mixed-effect models to estimate the effect of delayed intubation on hospital mortality and described mortality rates over time. Measurements and Main Results: A total of 11,087 patients were included (24 studies, three controlled trials, and 21 cohorts), of whom 7,736 (74%) were intubated within 24 hours of ICU admission (early intubation). The crude mortality rate was 53.2%. Adjusted survivals improved over time (from 1995 to 2017, odds ratio [OR] for hospital mortality per year, 0.96 [0.95-0.97]). For each elapsed day between ICU admission and intubation, mortality was higher (OR, 1.38 [1.26-1.52]; P < 0.001). Early intubation was significantly associated with lower mortality (OR, 0.83 [0.72-0.96]), regardless of initial oxygenation strategy. These results persisted after propensity score analysis (matched OR associated with delayed intubation, 1.56 [1.44-1.70]). Conclusions: In immunocompromised intubated patients, survival has improved over time. Time between ICU admission and intubation is a strong predictor of mortality, suggesting a detrimental effect of late initial oxygenation failure.