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1.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-309803

ABSTRACT

Objectives: In severe COVID-19 pneumonia, the appropriate timing and dosing of corticosteroids(CS) is not known. Patient subgroups for which CS could be more beneficial also need appraisal. The aim of this study was to assess the effect of early CS in COVID-19 pneumonia patients admitted to the ICU on the occurrence of 60-day mortality, ICU-acquired-bloodstream infections(ICU-BSI), and hospital-acquired pneumonia and ventilator-associated pneumonia(HAP-VAP). Methods: We included patients with COVID-19 pneumonia admitted to 11 ICUs belonging to the French OutcomeRea TM network from January to May 2020. We used survival models with ponderation with inverse probability of treatment weighting (IPTW). Inflammation was defined as Ferritin >1000 µg/l or D-Dimers >1000 µg/l or C-Reactive Protein >100 mg/dL. Results: The study population comprised 302 patients having a median age of 61.6(53-70) years of whom 78.8% were male and 58.6% had at least one comorbidity. The median SAPS II was 33(25-44). Invasive mechanical ventilation was required in 34.8% of the patients. Sixty-six (21.8%) patients were in the Early-CS-subgroup. Most of them (n=55, 83.3%) received high doses of steroids. Overall, 60-day mortality was 29.4%. The risks of 60-day mortality ( IPTW HR =0.88;95% CI 0.55 to 1.39, p=0.58), ICU-BSI and HAP-VAP were similar in the two groups. Importantly, early CS treatment was associated with a lower mortality rate in patients aged 60 years or more ( IPTW HR, 0.51;95% CI, 0.29 – 0.91;p=0.02). But, CS was associated with an increased risk of death for the patients younger than 60 years without inflammation on admission ( IPTW HR =8.17;95% CI, 1.76, 37.85;p=0.01). Conclusion: For patients with COVID-19 pneumonia, early CS treatment was not associated with patient survival. Interestingly, inflammation and age can significantly influence the effect of CS.

2.
EBioMedicine ; 73: 103622, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1471942

ABSTRACT

BACKGROUND: SARS-CoV-2 has been responsible for considerable mortality worldwide, owing in particular to pulmonary failures such as ARDS, but also to other visceral failures and secondary infections. Recent progress in the characterization of the immunological mechanisms that result in severe organ injury led to the emergence of two successive hypotheses simultaneously tested here: hyperinflammation with cytokine storm syndrome or dysregulation of protective immunity resulting in immunosuppression and unrestrained viral dissemination. METHODS: In a prospective observational monocentric study of 134 patients, we analysed a panel of plasma inflammatory and anti-inflammatory cytokines and measured monocyte dysregulation via their membrane expression of HLA-DR. We first compared the results of patients with moderate forms hospitalized in an infectious disease unit with those of patients with severe forms hospitalized in an intensive care unit. In the latter group of patients, we then analysed the differences between the surviving and non-surviving groups and between the groups with or without secondary infections. FINDINGS: Higher blood IL-6 levels, lower quantitative expression of HLA-DR on blood monocytes and higher IL-6/mHLA-DR ratios were statistically associated with the risk of severe forms of the disease and among the latter with death and the early onset of secondary infections. INTERPRETATION: The unique immunological profile in patients with severe COVID-19 corresponds to a moderate cytokine inflammation associated with severe monocyte dysregulation. Individuals with major CSS were rare in our cohort of hospitalized patients, especially since the use of corticosteroids, but formed a very severe subgroup of the disease. FUNDING: None.


Subject(s)
COVID-19/pathology , Cytokines/blood , Monocytes/metabolism , Aged , COVID-19/complications , COVID-19/virology , Cytokine Release Syndrome/etiology , Female , HLA-DR Antigens/metabolism , Humans , Intensive Care Units , Interleukin-6/blood , Male , Middle Aged , Monocytes/cytology , Monocytes/immunology , Prospective Studies , SARS-CoV-2/isolation & purification , Severity of Illness Index
3.
Trials ; 22(1): 692, 2021 Oct 11.
Article in English | MEDLINE | ID: covidwho-1463262

ABSTRACT

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 pneumonia, with a mortality rate amounting to 34-50% in moderate and severe ARDS, and is associated with prolonged duration of invasive mechanical ventilation. Such as in non-COVID ARDS, harmful mechanical ventilation settings might be associated with worse outcomes. Reducing the tidal volume down to 4 mL kg-1 of predicted body weight (PBW) to provide ultra-low tidal volume ventilation (ULTV) is an appealing technique to minimize ventilator-inducted lung injury. Furthermore, in the context of a worldwide pandemic, it does not require any additional material and consumables and may be applied in low- to middle-income countries. We hypothesized that ULTV without extracorporeal circulation is a credible option to reduce COVID-19-related ARDS mortality and duration of mechanical ventilation. METHODS: The VT4COVID study is a randomized, multi-centric prospective open-labeled, controlled superiority trial. Adult patients admitted in the intensive care unit with COVID-19-related mild to severe ARDS defined by a PaO2/FiO2 ratio ≤ 150 mmHg under invasive mechanical ventilation for less than 48 h, and consent to participate to the study will be eligible. Patients will be randomized into two balanced parallels groups, at a 1:1 ratio. The control group will be ventilated with protective ventilation settings (tidal volume 6 mL kg-1 PBW), and the intervention group will be ventilated with ULTV (tidal volume 4 mL kg-1 PBW). The primary outcome is a composite score based on 90-day all-cause mortality as a prioritized criterion and the number of ventilator-free days at day 60 after inclusion. The randomization list will be stratified by site of recruitment and generated using random blocks of sizes 4 and 6. Data will be analyzed using intention-to-treat principles. DISCUSSION: The purpose of this manuscript is to provide primary publication of study protocol to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Enrollment of patients in the study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT04349618 . Registered on April 16, 2020.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Adult , Extracorporeal Circulation , Humans , Prospective Studies , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/therapy , SARS-CoV-2
4.
PLoS One ; 16(8): e0255644, 2021.
Article in English | MEDLINE | ID: covidwho-1341507

ABSTRACT

OBJECTIVES: In severe COVID-19 pneumonia, the appropriate timing and dosing of corticosteroids (CS) is not known. Patient subgroups for which CS could be more beneficial also need appraisal. The aim of this study was to assess the effect of early CS in COVID-19 pneumonia patients admitted to the ICU on the occurrence of 60-day mortality, ICU-acquired-bloodstream infections(ICU-BSI), and hospital-acquired pneumonia and ventilator-associated pneumonia(HAP-VAP). METHODS: We included patients with COVID-19 pneumonia admitted to 11 ICUs belonging to the French OutcomeReaTM network from January to May 2020. We used survival models with ponderation with inverse probability of treatment weighting (IPTW). RESULTS: The study population comprised 303 patients having a median age of 61.6 (53-70) years of whom 78.8% were male and 58.6% had at least one comorbidity. The median SAPS II was 33 (25-44). Invasive mechanical ventilation was required in 34.8% of the patients. Sixty-six (21.8%) patients were in the Early-C subgroup. Overall, 60-day mortality was 29.4%. The risks of 60-day mortality (IPTWHR = 0.86;95% CI 0.54 to 1.35, p = 0.51), ICU-BSI and HAP-VAP were similar in the two groups. Importantly, early CS treatment was associated with a lower mortality rate in patients aged 60 years or more (IPTWHR, 0.53;95% CI, 0.3-0.93; p = 0.03). In contrast, CS was associated with an increased risk of death in patients younger than 60 years without inflammation on admission (IPTWHR = 5.01;95% CI, 1.05, 23.88; p = 0.04). CONCLUSION: For patients with COVID-19 pneumonia, early CS treatment was not associated with patient survival. Interestingly, inflammation and age can significantly influence the effect of CS.


Subject(s)
Adrenal Cortex Hormones/administration & dosage , COVID-19/drug therapy , COVID-19/mortality , Adult , Aged , COVID-19/therapy , Cohort Studies , Community Networks , Critical Illness/mortality , Critical Illness/therapy , Drug Administration Schedule , Early Medical Intervention/methods , Female , France/epidemiology , Hospital Mortality , Humans , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Respiration, Artificial/mortality , Respiration, Artificial/statistics & numerical data , Time Factors , Treatment Outcome
7.
J Clin Med ; 10(3)2021 Feb 02.
Article in English | MEDLINE | ID: covidwho-1060442

ABSTRACT

The mortality of COVID-19 patients in the intensive care unit (ICU) is influenced by their state at admission. We aimed to model COVID-19 acute respiratory distress syndrome state transitions from ICU admission to day 60 outcome and to evaluate possible prognostic factors. We analyzed a prospective French database that includes critically ill COVID-19 patients. A six-state multistate model was built and 17 transitions were analyzed either using a non-parametric approach or a Cox proportional hazard model. Corticosteroids and IL-antagonists (tocilizumab and anakinra) effects were evaluated using G-computation. We included 382 patients in the analysis: 243 patients were admitted to the ICU with non-invasive ventilation, 116 with invasive mechanical ventilation, and 23 with extracorporeal membrane oxygenation. The predicted 60-day mortality was 25.9% (95% CI: 21.8%-30.0%), 44.7% (95% CI: 48.8%-50.6%), and 59.2% (95% CI: 49.4%-69.0%) for a patient admitted in these three states, respectively. Corticosteroids decreased the risk of being invasively ventilated (hazard ratio (HR) 0.59, 95% CI: 0.39-0.90) and IL-antagonists increased the probability of being successfully extubated (HR 1.8, 95% CI: 1.02-3.17). Antiviral drugs did not impact any transition. In conclusion, we observed that the day-60 outcome in COVID-19 patients is highly dependent on the first ventilation state upon ICU admission. Moreover, we illustrated that corticosteroid and IL-antagonists may influence the intubation duration.

8.
Crit Care Explor ; 3(1): e0329, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1055778

ABSTRACT

OBJECTIVES: About 5% of patients with coronavirus disease-2019 are admitted to the ICU for acute hypoxemic respiratory failure. Opinions differ on whether invasive mechanical ventilation should be used as first-line therapy over noninvasive oxygen support. The aim of the study was to assess the effect of early invasive mechanical ventilation in coronavirus disease-2019 with acute hypoxemic respiratory failure on day-60 mortality. DESIGN: Multicenter prospective French observational study. SETTING: Eleven ICUs of the French OutcomeRea network. PATIENTS: Coronavirus disease-2019 patients with acute hypoxemic respiratory failure (Pao2/Fio2 ≤ 300 mm Hg), without shock or neurologic failure on ICU admission, and not referred from another ICU or intermediate care unit were included. INTERVENTION: We compared day-60 mortality in patients who were on invasive mechanical ventilation within the first 2 calendar days of the ICU stay (early invasive mechanical ventilation group) and those who were not (nonearly invasive mechanical ventilation group). We used a Cox proportional-hazard model weighted by inverse probability of early invasive mechanical ventilation to determine the risk of death at day 60. MEASUREMENT AND MAIN RESULTS: The 245 patients included had a median (interquartile range) age of 61 years (52-69 yr), a Simplified Acute Physiology Score II score of 34 mm Hg (26-44 mm Hg), and a Pao2/Fio2 of 121 mm Hg (90-174 mm Hg). The rates of ICU-acquired pneumonia, bacteremia, and the ICU length of stay were significantly higher in the early (n = 117 [48%]) than in the nonearly invasive mechanical ventilation group (n = 128 [52%]), p < 0.01. Day-60 mortality was 42.7% and 21.9% in the early and nonearly invasive mechanical ventilation groups, respectively. The weighted model showed that early invasive mechanical ventilation increased the risk for day-60 mortality (weighted hazard ratio =1.74; 95% CI, 1.07-2.83, p=0.03). CONCLUSIONS: In ICU patients admitted with coronavirus disease-2019-induced acute hypoxemic respiratory failure, early invasive mechanical ventilation was associated with an increased risk of day-60 mortality. This result needs to be confirmed.

9.
Intensive Care Med ; 47(2): 180-187, 2021 02.
Article in English | MEDLINE | ID: covidwho-1051347

ABSTRACT

PURPOSE: The primary objective of this study was to investigate the risk of ICU bloodstream infection (BSI) in critically ill COVID-19 patients compared to non-COVID-19 patients. Subsequently, we performed secondary analyses in order to explain the observed results. METHODS: We conducted a matched case-cohort study, based on prospectively collected data from a large ICU cohort in France. Critically ill COVID-19 patients were matched with similar non-COVID-19 patients. ICU-BSI was defined by an infection onset occurring > 48 h after ICU admission. We estimated the effect of COVID-19 on the probability to develop an ICU-BSI using proportional subdistribution hazards models. RESULTS: We identified 321 COVID-19 patients and 1029 eligible controls in 6 ICUs. Finally, 235 COVID-19 patients were matched with 235 non-COVID-19 patients. We observed 43 ICU-BSIs, 35 (14.9%) in the COVID-19 group and 8 (3.4%) in the non-COVID-19 group (p ≤ 0.0001), respectively. ICU-BSIs of COVID-19 patients were more frequently of unknown source (47.4%). COVID-19 patients had an increased probability to develop ICU-BSI, especially after 7 days of ICU admission. Using proportional subdistribution hazards models, COVID-19 increased the daily risk to develop ICU-BSI (sHR 4.50, 95% CI 1.82-11.16, p = 0.0012). Among COVID-19 patients (n = 235), a significantly increased risk for ICU-BSI was detected in patients who received tocilizumab or anakinra (sHR 3.20, 95% CI 1.31-7.81, p = 0.011) but not corticosteroids. CONCLUSIONS: Using prospectively collected multicentric data, we showed that the ICU-BSI risk was higher for COVID-19 than non-COVID-19 critically ill patients after seven days of ICU stay. Clinicians should be particularly careful on late ICU-BSIs in COVID-19 patients. Tocilizumab or anakinra may increase the ICU-BSI risk.


Subject(s)
COVID-19/complications , Cross Infection , Sepsis/epidemiology , Aged , Cohort Studies , Cross Infection/epidemiology , Female , France/epidemiology , Humans , Intensive Care Units , Male , Middle Aged , Proportional Hazards Models , Risk Factors
10.
Front Immunol ; 11: 580250, 2020.
Article in English | MEDLINE | ID: covidwho-918140

ABSTRACT

Little is known about the time-dependent immune responses in severe COVID-19. Data of 15 consecutive patients were sequentially recorded from intensive care unit admission. Lymphocyte subsets and total monocyte and subsets counts were monitored as well as the expression of HLA-DR. For 5 patients, SARS-CoV-2-specific T-cell polyfunctionality was assessed against Spike and Nucleoprotein SARS-CoV-2 peptides. Non-specific inflammation markers were increased in all patients. Median monocyte HLA-DR expression was below the 8,000 AB/C threshold defining acquired immunodepression. A "V" trend curve for lymphopenia, monocyte numbers, and HLA-DR expression was observed with a nadir between days 11 and 14 after symptoms' onset. Intermediate CD14++CD16+ monocytes increased early with a reduction in classic CD14++CD16- monocytes. Polyfunctional SARS-Cov-2-specific CD4 T-cells were present and functional, whereas virus-specific CD8 T-cells were less frequent and not efficient. We report a temporal variation of both innate and adaptive immunity in severe COVID-19 patients, helpful in guiding therapeutic decisions (e.g. anti-inflammatory vs. immunostimulatory ones). We describe a defect in virus-specific CD8 T-cells, a potential biomarker of clinical severity. These combined data also provide helpful knowledge for vaccine design. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, identifier NCT04386395.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Monocytes/immunology , SARS-CoV-2/immunology , Severity of Illness Index , Aged , Biomarkers , COVID-19/virology , Female , GPI-Linked Proteins/metabolism , HLA-DR Antigens/immunology , Humans , Immunity, Cellular , Lipopolysaccharide Receptors/metabolism , Longitudinal Studies , Male , Middle Aged , Prospective Studies , Receptors, IgG/metabolism , SARS-CoV-2/genetics
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