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

IntroductionIncreasing 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.MethodsWe 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.ResultsHere, 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.DiscussionThese 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

Relationship between ventilator-associated pneumonia and mortality in COVID-19 patients: a planned ancillary analysis of the coVAPid cohort

Background Patients with SARS-CoV-2 infection are at higher risk for ventilator-associated pneumonia (VAP). No study has evaluated the relationship between VAP and mortality in this population, or compared this relationship between SARS-CoV-2 patients and other populations. The main objective of our study was to determine the relationship between VAP and mortality in SARS-CoV-2 patients. Methods Planned ancillary analysis of a multicenter retrospective European cohort. VAP was diagnosed using clinical, radiological and quantitative microbiological criteria. Univariable and multivariable marginal Cox's regression models, with cause-specific hazard for duration of mechanical ventilation and ICU stay, were used to compare outcomes between study groups. Extubation, and ICU discharge alive were considered as events of interest, and mortality as competing event. Findings Of 1576 included patients, 568 were SARS-CoV-2 pneumonia, 482 influenza pneumonia, and 526 no evidence of viral infection at ICU admission. VAP was associated with significantly higher risk for 28-day mortality in SARS-CoV-2 group (adjusted HR 1.65 (95% CI 1.11-2.46), p = 0.013), but not in influenza (1.74 (0.99-3.06), p = 0.052), or no viral infection groups (1.13 (0.68-1.86), p = 0.63). VAP was associated with significantly longer duration of mechanical ventilation in the SARS-CoV-2 group, but not in the influenza or no viral infection groups. VAP was associated with significantly longer duration of ICU stay in the 3 study groups. No significant difference was found in heterogeneity of outcomes related to VAP between the 3 groups, suggesting that the impact of VAP on mortality was not different between study groups. Interpretation VAP was associated with significantly increased 28-day mortality rate in SARS-CoV-2 patients. However, SARS-CoV-2 pneumonia, as compared to influenza pneumonia or no viral infection, did not significantly modify the relationship between VAP and 28-day mortality

a planned ancillary analysis of the coVAPid cohort

Funding: This study was supported in part by a grant from the French government through the «Programme Investissement d’Avenir» (I-SITE ULNE) managed by the Agence Nationale de la Recherche (coVAPid project). The funders of the study had no role in the study design, data collection, analysis, or interpreta tion, writing of the report, or decision to submit for publication.BACKGROUND: Patients with SARS-CoV-2 infection are at higher risk for ventilator-associated pneumonia (VAP). No study has evaluated the relationship between VAP and mortality in this population, or compared this relationship between SARS-CoV-2 patients and other populations. The main objective of our study was to determine the relationship between VAP and mortality in SARS-CoV-2 patients. METHODS: Planned ancillary analysis of a multicenter retrospective European cohort. VAP was diagnosed using clinical, radiological and quantitative microbiological criteria. Univariable and multivariable marginal Cox's regression models, with cause-specific hazard for duration of mechanical ventilation and ICU stay, were used to compare outcomes between study groups. Extubation, and ICU discharge alive were considered as events of interest, and mortality as competing event. FINDINGS: Of 1576 included patients, 568 were SARS-CoV-2 pneumonia, 482 influenza pneumonia, and 526 no evidence of viral infection at ICU admission. VAP was associated with significantly higher risk for 28-day mortality in SARS-CoV-2 (adjusted HR 1.70 (95% CI 1.16-2.47), p = 0.006), and influenza groups (1.75 (1.03-3.02), p = 0.045), but not in the no viral infection group (1.07 (0.64-1.78), p = 0.79). VAP was associated with significantly longer duration of mechanical ventilation in the SARS-CoV-2 group, but not in the influenza or no viral infection groups. VAP was associated with significantly longer duration of ICU stay in the 3 study groups. No significant difference was found in heterogeneity of outcomes related to VAP between the 3 groups, suggesting that the impact of VAP on mortality was not different between study groups. INTERPRETATION: VAP was associated with significantly increased 28-day mortality rate in SARS-CoV-2 patients. However, SARS-CoV-2 pneumonia, as compared to influenza pneumonia or no viral infection, did not significantly modify the relationship between VAP and 28-day mortality. CLINICAL TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov, number NCT04359693.publishersversionpublishe

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/)

Prediction of fluid responsiveness : new methods, new limits

L’expansion volémique est le traitement de première intention de l’insuffisance circulatoire aiguë dans presque tous les cas. Cependant, son efficacité très inconstante et ses effets secondaires incitent à en prédire les effets avant de l’entreprendre. Plusieurs tests ont été développés pour détecter cet état de précharge dépendance, et nous nous sommes intéressés au perfectionnement de certains d’entre eux et à la description de leurs limites.Le test de passive leg raising (PLR) repose sur le transfert de sang veineux depuis le territoire veineux splanchnique et les membres inférieurs vers le thorax. Nous avons démontré qu’en cas d’hypertension intra-abdominale, la valeur diagnostique du test était plus faible, avec l’apparition de nombreux cas de faux négatifs. Cette limite du PLR test est importante en raison de la prévalence de l’hypertension intra-abdominale chez les patients de soins intensifs.Les effets de ce test doivent être appréciés sur le débit cardiaque, et plusieurs méthodes ont déjà été décrites pour cela. Nous avons d’abord pu montrer que celle qui consiste à mesurer les effets du test sur les débits artériels carotidien et fémoral n’était pas fiable, avec une très mauvaise corrélation entre les changements de débit cardiaque et ceux de ces deux débits artériels. En revanche, nous avons décrit une méthode originale et fiable pour mesurer les effets du test, qui consiste en la mesure de l’indice de perfusion (IP), rapport entre la portion pulsatile et non pulsatile du signal de saturation pulsée en oxygène. Même si le signal ne pouvait pas être recueilli de façon stable chez tous les patients, les changements de cet indice lors du PLR permettaient de mesurer ses effets et de détecter la précharge dépendance. Ces résultats ouvrent la possibilité de mesurer les effets du test grâce à un outil non-invasif et pouvant être utilisé chez tous les patients en réanimation et au bloc opératoire.Enfin, nous avons appliqué la mesure de l’IP à un autre test détectant la précharge dépendance, le test d’occlusion télé-expiratoire. Il consiste à interrompre la ventilation mécanique pendant quelques secondes et à observer les changements simultanés du débit cardiaque. Même s’ils sont de plus faible amplitude que ceux induits par le PLR, ces changements étaient correctement suivis par les modifications de l’IP et ils détectaient de façon fiable la précharge dépendance.Volume expansion is the first-line treatment of acute circulatory failure in almost all cases. However, its inconsistent effectiveness and side effects encourage to predict its effects before undertaking it. Several tests have been developed to detect preload responsiveness and we have sought to improve some of them and describe their limits.The passive leg raising (PLR) test is based on the transfer of some venous blood from the venous compartment of the splanchnic compartment and the lower limbs toward the thorax. We have shown that, in case of intra-abdominal hypertension, the diagnostic value of the test was lower, with many cases false negatives cases. This limitation of the PLR test is of importance because of the prevalence of intra-abdominal hypertension in critically ill patients.The effects of this test should be evaluated on cardiac output, and several methods have already been described for this evaluation. First, we have shown that measuring the effects of the test on carotid and femoral arterial flows was unreliable, with a very poor correlation between changes in cardiac output and those in these two arterial flows. Second, we have described an original and reliable method for measuring the effects of the test, which consists in measuring the perfusion index (PI), the ratio between the pulsatile and non-pulsatile portions of the pulse oximetry signal. Although a stable signal could not be obtained in all patients, changes in this index during PLR allowed the measurement of its effects and the detection of preload responsiveness. These results open up the possibility of measuring the effects of the test with a non-invasive tool that can be used in all patients in the intensive care unit and the operating room.Finally, we applied the PI measurement to another test of preload responsiveness, the end-expiratory occlusion test. It consists in interrupting mechanical ventilation for a few seconds and observing simultaneous changes in cardiac output. Although the changes are smaller than those induced by PLR, these changes were well tracked by PI changes and reliably detected preload dependence

Prédiction de la réponse à l’expansion volémique : Nouvelles limites, nouvelles méthodes

Volume expansion is the first-line treatment of acute circulatory failure in almost all cases. However, its inconsistent effectiveness and side effects encourage to predict its effects before undertaking it. Several tests have been developed to detect preload responsiveness and we have sought to improve some of them and describe their limits.The passive leg raising (PLR) test is based on the transfer of some venous blood from the venous compartment of the splanchnic compartment and the lower limbs toward the thorax. We have shown that, in case of intra-abdominal hypertension, the diagnostic value of the test was lower, with many cases false negatives cases. This limitation of the PLR test is of importance because of the prevalence of intra-abdominal hypertension in critically ill patients.The effects of this test should be evaluated on cardiac output, and several methods have already been described for this evaluation. First, we have shown that measuring the effects of the test on carotid and femoral arterial flows was unreliable, with a very poor correlation between changes in cardiac output and those in these two arterial flows. Second, we have described an original and reliable method for measuring the effects of the test, which consists in measuring the perfusion index (PI), the ratio between the pulsatile and non-pulsatile portions of the pulse oximetry signal. Although a stable signal could not be obtained in all patients, changes in this index during PLR allowed the measurement of its effects and the detection of preload responsiveness. These results open up the possibility of measuring the effects of the test with a non-invasive tool that can be used in all patients in the intensive care unit and the operating room.Finally, we applied the PI measurement to another test of preload responsiveness, the end-expiratory occlusion test. It consists in interrupting mechanical ventilation for a few seconds and observing simultaneous changes in cardiac output. Although the changes are smaller than those induced by PLR, these changes were well tracked by PI changes and reliably detected preload dependence.L’expansion volémique est le traitement de première intention de l’insuffisance circulatoire aiguë dans presque tous les cas. Cependant, son efficacité très inconstante et ses effets secondaires incitent à en prédire les effets avant de l’entreprendre. Plusieurs tests ont été développés pour détecter cet état de précharge dépendance, et nous nous sommes intéressés au perfectionnement de certains d’entre eux et à la description de leurs limites.Le test de passive leg raising (PLR) repose sur le transfert de sang veineux depuis le territoire veineux splanchnique et les membres inférieurs vers le thorax. Nous avons démontré qu’en cas d’hypertension intra-abdominale, la valeur diagnostique du test était plus faible, avec l’apparition de nombreux cas de faux négatifs. Cette limite du PLR test est importante en raison de la prévalence de l’hypertension intra-abdominale chez les patients de soins intensifs.Les effets de ce test doivent être appréciés sur le débit cardiaque, et plusieurs méthodes ont déjà été décrites pour cela. Nous avons d’abord pu montrer que celle qui consiste à mesurer les effets du test sur les débits artériels carotidien et fémoral n’était pas fiable, avec une très mauvaise corrélation entre les changements de débit cardiaque et ceux de ces deux débits artériels. En revanche, nous avons décrit une méthode originale et fiable pour mesurer les effets du test, qui consiste en la mesure de l’indice de perfusion (IP), rapport entre la portion pulsatile et non pulsatile du signal de saturation pulsée en oxygène. Même si le signal ne pouvait pas être recueilli de façon stable chez tous les patients, les changements de cet indice lors du PLR permettaient de mesurer ses effets et de détecter la précharge dépendance. Ces résultats ouvrent la possibilité de mesurer les effets du test grâce à un outil non-invasif et pouvant être utilisé chez tous les patients en réanimation et au bloc opératoire.Enfin, nous avons appliqué la mesure de l’IP à un autre test détectant la précharge dépendance, le test d’occlusion télé-expiratoire. Il consiste à interrompre la ventilation mécanique pendant quelques secondes et à observer les changements simultanés du débit cardiaque. Même s’ils sont de plus faible amplitude que ceux induits par le PLR, ces changements étaient correctement suivis par les modifications de l’IP et ils détectaient de façon fiable la précharge dépendance

Limiting positive end-expiratory pressure to protect renal function in SARS-CoV-2 critically ill patients

International audienceNo abstract availabl

The effects of passive leg raising may be detected by the plethysmographic oxygen saturation signal in critically ill patients

Abstract Background A passive leg raising (PLR) test is positive if the cardiac index (CI) increased by > 10%, but it requires a direct measurement of CI. On the oxygen saturation plethysmographic signal, the perfusion index (PI) is the ratio between the pulsatile and the non-pulsatile portions. We hypothesised that the changes in PI could predict a positive PLR test and thus preload responsiveness in a totally non-invasive way. Methods In patients with acute circulatory failure, we measured PI (Radical-7) and CI (PiCCO2) before and during a PLR test and, if decided, before and after volume expansion (500-mL saline). Results Three patients were excluded because the plethysmography signal was absent and 3 other ones because it was unstable. Eventually, 72 patients were analysed. In 34 patients with a positive PLR test (increase in CI ≥ 10%), CI and PI increased during PLR by 21 ± 10% and 54 ± 53%, respectively. In the 38 patients with a negative PLR test, PI did not significantly change during PLR. In 26 patients in whom volume expansion was performed, CI and PI increased by 28 ± 14% and 53 ± 63%, respectively. The correlation between the PI and CI changes for all interventions was significant (r = 0.64, p  9%, a positive response of CI (≥ 10%) was diagnosed with a sensitivity of 91 (76–98%) and a specificity of 79 (63–90%) (area under the receiver operating characteristics curve 0.89 (0.80–0.95), p < 0.0001). Conclusion An increase in PI during PLR by 9% accurately detects a positive response of the PLR test. Trial registration ID RCB 2016-A00959-42. Registered 27 June 2016

Beneficial Effects of Norepinephrine Alone on Cardiovascular Function and Tissue Oxygenation in a Pig Model of Cardiogenic Shock

International audienceINTRODUCTION:The present study was developed to investigate the effects of norepinephrine alone on hemodynamics and intrinsic cardiac function in a pig model of cardiogenic shock mimicking the clinical setting.METHODS:Cardiogenic shock was induced by 1-h ligation of the left anterior descending (LAD) artery followed by reperfusion. Pigs were monitored with a Swan-Ganz catheter, a transpulmonary thermodilution catheter, and a conductance catheter placed in the left ventricle for pressure-loop measurements. Measurements were performed before LAD occlusion, 1 h after LAD occlusion, and 4 h after myocardial reperfusion.RESULTS:Myocardial infarction and reperfusion was followed by cardiogenic shock characterized by a significant increase in heart rate and significant decreases in mean arterial pressure (MAP), mixed venous oxygen saturation (SVO2), left ventricular end-diastolic pressure (LVEDP), prerecruitable stroke work (PRSW), and cardiac power index (CPI). Lactate levels were significantly increased. The systemic vascular resistance index (SVRI) and global end-diastolic volume index (GEDVI) remained unchanged. When compared with the control group (n = 6), norepinephrine infusion (n = 6) was associated with no changes in heart rate, a significant increase in MAP, SVO2, left ventricular ejection fraction, pressure development during isovolumic contraction, SVRI, and CPI and a decrease in lactate level. Cardiac index tended to increase (P = 0.059), whereas PRSW did not change in the norepinephrine group. LVEDP and GEDVI remained unchanged.CONCLUSIONS:Norepinephrine alone is able to improve hemodynamics, cardiac function, and tissue oxygenation in a pig model of ischemic cardiogenic shock

MOESM1 of Carotid and femoral Doppler do not allow the assessment of passive leg raising effects

Additional file 1: Table S1. Ability of different Doppler variable to detect a positive passive leg raising test. Table S2. Diagnostic ability of changes in carotid and femoral blood flows to detect changes in cardiacindex ≥ 10% and ≥ 15%. Figure S1. Study design. Figure S2. Correlation between absolute values of carotid blood flow (measured by TAMEAN) and of cardiac index, n = 135 (n = 38 before PLR, 38 during passive leg raising (PLR), 38 after PLR and 21 after volume expansion = 135 in total). Figure S3. Correlation between absolute values of femoral blood flow and of cardiac index, n = 45 ( n = 14 before PLR, 14 during passive leg raising (PLR), 14 after PLR and 3 after volume expansion = 45 in total)