Identification of natural killer markers associated with fatal outcome in COVID-19 patients.

Introduction: Increasing evidence has shown that coronavirus disease 19 (COVID-19) severity is driven by a dysregulated immunological response. Previous studies have demonstrated that natural killer (NK) cell dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of NK cell markers as a driver of death in the most critically ill patients. Methods: We enrolled 50 non-vaccinated hospitalized patients infected with the initial virus or the alpha variant of SARS-CoV-2 with moderate or severe illness, to evaluate phenotypic and functional features of NK cells. Results: Here, we show that, consistent with previous studies, evolution NK cells from COVID-19 patients are more activated, with the decreased activation of natural cytotoxicity receptors and impaired cytotoxicity and IFN-γ production, in association with disease regardless of the SARS-CoV-2 strain. Fatality was observed in 6 of 17 patients with severe disease; NK cells from all of these patients displayed a peculiar phenotype of an activated memory-like phenotype associated with massive TNF-α production. Discussion: These data suggest that fatal COVID-19 infection is driven by an uncoordinated inflammatory response in part mediated by a specific subset of activated NK cells.

Cumulative incidence of SARS-CoV-2 infection and associated risk factors among frontline health care workers in Paris: the SEROCOV cohort study.

With the COVID-19 pandemic, documenting whether health care workers (HCWs) are at increased risk of SARS-CoV-2 contamination and identifying risk factors is of major concern. In this multicenter prospective cohort study, HCWs from frontline departments were included in March and April 2020 and followed for 3 months. SARS-CoV-2 serology was performed at month 0 (M0), M1, and M3 and RT-PCR in case of symptoms. The primary outcome was laboratory-confirmed SARS-CoV-2 infection at M3. Risk factors of laboratory-confirmed SARS-CoV-2 infection at M3 were identified by multivariate logistic regression. Among 1062 HCWs (median [interquartile range] age, 33 [28-42] years; 758 [71.4%] women; 321 [30.2%] physicians), the cumulative incidence of SARS-CoV-2 infection at M3 was 14.6% (95% confidence interval [CI] [12.5; 16.9]). Risk factors were the working department specialty, with increased risk for intensive care units (odds ratio 1.80, 95% CI [0.38; 8.58]), emergency departments (3.91 [0.83; 18.43]) and infectious diseases departments (4.22 [0.92; 18.28]); current smoking was associated with reduced risk (0.36 [0.21; 0.63]). Age, sex, professional category, number of years of experience in the job or department, and public transportation use were not significantly associated with laboratory-confirmed SARS-CoV-2 infection at M3. The rate of SARS-CoV-2 infection in frontline HCWs was 14.6% at the end of the first COVID-19 wave in Paris and occurred mainly early. The study argues for an origin of professional in addition to private life contamination and therefore including HCWs in the first-line vaccination target population. It also highlights that smokers were at lower risk.Trial registration The study has been registered on ClinicalTrials.gov: NCT04304690 first registered on 11/03/2020.

Increased mortality in patients with severe SARS-CoV-2 infection admitted within seven days of disease onset.

PURPOSE: Coronavirus disease 2019 (COVID-19) is creating an unprecedented healthcare crisis. Understanding the determinants of mortality is crucial to optimise intensive care unit (ICU) resource use and to identify targets for improving survival. METHODS: In a multicentre retrospective study, we included 379 COVID-19 patients admitted to four ICUs between 20 February and 24 April 2020 and categorised according to time from disease onset to ICU admission. A Cox proportional-hazards model identified factors associated with 28-day mortality. RESULTS: Median age was 66 years (53-68) and 292 (77%) were men. The main comorbidities included obesity and overweight (67%), hypertension (49.6%) and diabetes (30.1%). Median time from disease onset (i.e., viral symptoms) to ICU admission was 8 (6-11) days (missing for three); 161 (42.5%) patients were admitted within a week of disease onset, 173 (45.6%) between 8 and 14 days, and 42 (11.1%) > 14 days after disease onset; day 28 mortality was 26.4% (22-31) and decreased as time from disease onset to ICU admission increased, from 37 to 21% and 12%, respectively. Patients admitted within the first week had higher SOFA scores, more often had thrombocytopenia or acute kidney injury, had more limited radiographic involvement, and had significantly higher blood IL-6 levels. Age, COPD, immunocompromised status, time from disease onset, troponin concentration, and acute kidney injury were independently associated with mortality. CONCLUSION: The excess mortality in patients admitted within a week of disease onset reflected greater non-respiratory severity. Therapeutic interventions against SARS-CoV-2 might impact different clinical endpoints according to time since disease onset.

Transpulmonary thermodilution detects rapid and reversible increases in lung water induced by positive end-expiratory pressure in acute respiratory distress syndrome.

PURPOSE: It has been suggested that, by recruiting lung regions and enlarging the distribution volume of the cold indicator, increasing the positive end-expiratory pressure (PEEP) may lead to an artefactual overestimation of extravascular lung water (EVLW) by transpulmonary thermodilution (TPTD). METHODS: In 60 ARDS patients, we measured EVLW (PiCCO2 device) at a PEEP level set to reach a plateau pressure of 30 cmH2O (HighPEEPstart) and 15 and 45 min after decreasing PEEP to 5 cmH2O (LowPEEP15' and LowPEEP45', respectively). Then, we increased PEEP back to the baseline level (HighPEEPend). Between HighPEEPstart and LowPEEP15', we estimated the degree of lung derecruitment either by measuring changes in the compliance of the respiratory system (Crs) in the whole population, or by measuring the lung derecruited volume in 30 patients. We defined patients with a large derecruitment from the other ones as patients in whom the Crs changes and the measured derecruited volume were larger than the median of these variables observed in the whole population. RESULTS: Reducing PEEP from HighPEEPstart (14 ± 2 cmH2O) to LowPEEP15' significantly decreased EVLW from 20 ± 4 to 18 ± 4 mL/kg, central venous pressure (CVP) from 15 ± 4 to 12 ± 4 mmHg, the arterial oxygen tension over inspired oxygen fraction (PaO2/FiO2) ratio from 184 ± 76 to 150 ± 69 mmHg and lung volume by 144 [68-420] mL. The EVLW decrease was similar in "large derecruiters" and the other patients. When PEEP was re-increased to HighPEEPend, CVP, PaO2/FiO2 and EVLW significantly re-increased. At linear mixed effect model, EVLW changes were significantly determined only by changes in PEEP and CVP (p < 0.001 and p = 0.03, respectively, n = 60). When the same analysis was performed by estimating recruitment according to lung volume changes (n = 30), CVP remained significantly associated to the changes in EVLW (p < 0.001). CONCLUSIONS: In ARDS patients, changing the PEEP level induced parallel, small and reversible changes in EVLW. These changes were not due to an artefact of the TPTD technique and were likely due to the PEEP-induced changes in CVP, which is the backward pressure of the lung lymphatic drainage. Trial registration ID RCB: 2015-A01654-45. Registered 23 October 2015.