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We report a longitudinal analysis of the immune response associated with a fatal case of COVID-19 in Europe. This patient exhibited a rapid evolution towards multiorgan failure. SARS-CoV-2 was detected in multiple nasopharyngeal, blood, and pleural samples, despite antiviral and immunomodulator treatment. Clinical evolution in the blood was marked by an increase (2-3-fold) in differentiated effector T cells expressing exhaustion (PD-1) and senescence (CD57) markers, an expansion of antibody-secreting cells, a 15-fold increase in γδ T cell and proliferating NK-cell populations, and the total disappearance of monocytes, suggesting lung trafficking. In the serum, waves of a pro-inflammatory cytokine storm, Th1 and Th2 activation, and markers of T cell exhaustion, apoptosis, cell cytotoxicity, and endothelial activation were observed until the fatal outcome. This case underscores the need for well-designed studies to investigate complementary approaches to control viral replication, the source of the hyperinflammatory status, and immunomodulation to target the pathophysiological response. The investigation was conducted as part of an overall French clinical cohort assessing patients with COVID-19 and registered in clinicaltrials.gov under the following number: NCT04262921.

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial., Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock., Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8)., Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial., Trial Registration: ClinicalTrials.gov, NCT02393781 . Registered on March 19, 2015.

Background: Classic mortality prediction models in intensive care units (ICUs) are based on clinical scores, which do not contain any coagulation test (SAPS-II or SOFA scores)., Objectives: To determine whether coagulation tests can improve mortality prediction in patients with septic shock., Patients and Methods: One hundred fifty-eight consecutive patients with septic shock entering our institution's ICU were investigated on the first day of admission, and deaths were registered during the first month., Results: Among all the coagulation tests performed, only the fibrinogen (Fg) plasma level, together with the SAPS-II score and the age, were included in our simplified mortality score [area under the receiver operating curve (AUC) 0.927, standard deviation (SD) 0.030], which was more efficient than SAPS-II and SOFA scores themselves in predicting first-week mortality, its optimized cut-off having a very high negative predictive value (NPV) [0.989; 95% confidence interval (CI) 0.967-1.000)]. A simplified score predicting first-month mortality, containing the prothrombin ratio and the antithrombin activity values in addition to the age, the hemoglobin concentration, and the SAPS-II and SOFA scores (AUC 0.889, SD 0.026), was found to be superior to the SAPS-II and SOFA scores, the optimized cut-off value having a high NPV (0.952; 95% CI 0.888-1.000)., Conclusions: In patients admitted to an ICU with septic shock, some initial coagulation test values can help identify those who will survive in the first week and then in the first month.