Avdoralimab (Anti-C5aR1 mAb) Versus Placebo in Patients With Severe COVID-19: Results From a Randomized Controlled Trial (FOR COVID Elimination [FORCE]).

OBJECTIVES: Severe COVID-19 is associated with exaggerated complement activation. We assessed the efficacy and safety of avdoralimab (an anti-C5aR1 mAb) in severe COVID-19. DESIGN: FOR COVID Elimination (FORCE) was a double-blind, placebo-controlled study. SETTING: Twelve clinical sites in France (ICU and general hospitals). PATIENTS: Patients receiving greater than or equal to 5 L oxygen/min to maintain Sp o2 greater than 93% (World Health Organization scale ≥ 5). Patients received conventional oxygen therapy or high-flow oxygen (HFO)/noninvasive ventilation (NIV) in cohort 1; HFO, NIV, or invasive mechanical ventilation (IMV) in cohort 2; and IMV in cohort 3. INTERVENTIONS: Patients were randomly assigned, in a 1:1 ratio, to receive avdoralimab or placebo. The primary outcome was clinical status on the World Health Organization ordinal scale at days 14 and 28 for cohorts 1 and 3, and the number of ventilator-free days at day 28 (VFD28) for cohort 2. MEASUREMENTS AND MAIN RESULTS: We randomized 207 patients: 99 in cohort 1, 49 in cohort 2, and 59 in cohort 3. During hospitalization, 95% of patients received glucocorticoids. Avdoralimab did not improve World Health Organization clinical scale score on days 14 and 28 (between-group difference on day 28 of -0.26 (95% CI, -1.2 to 0.7; p = 0.7) in cohort 1 and -0.28 (95% CI, -1.8 to 1.2; p = 0.6) in cohort 3). Avdoralimab did not improve VFD28 in cohort 2 (between-group difference of -6.3 (95% CI, -13.2 to 0.7; p = 0.96) or secondary outcomes in any cohort. No subgroup of interest was identified. CONCLUSIONS: In this randomized trial in hospitalized patients with severe COVID-19 pneumonia, avdoralimab did not significantly improve clinical status at days 14 and 28 (funded by Innate Pharma, ClinicalTrials.gov number, NCT04371367).

Lung Abscess in Critically Ill Coronavirus Disease 2019 Patients With Ventilator-Associated Pneumonia: A French Monocenter Retrospective Study.

The pulmonary vascular endothelialitis together with the high rate of distal pulmonary embolism or thrombosis extensively reported in critically ill coronavirus disease 2019 patients may impair antibiotic diffusion in the lung parenchyma of coronavirus disease 2019 patients with ventilator-associated pneumonia leading to insufficient antibiotic concentration, thus promoting lung abscess formation. We report that 17 of 119 coronavirus disease 2019 patients (14%) with ventilator-associated pneumonia developed a lung abscess. Proportion of patients receiving corticosteroids did not differ between patients with and without lung abscess. Most of lung abscess were polymicrobial. Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus were the leading causative bacteria. Most of lung abscesses involved the right lower lobe. Three patients had concomitant pulmonary embolism or thrombosis in the territory of lung abscess. Lung abscess was retrospectively visible on chest radiograph in 29% of the patients. As the occurrence of lung abscess impacts the duration of antibiotics therapy, chest CT scan should be easily performed in case of treatment failure of ventilator-associated pneumonia despite adequate antimicrobial therapy.

Bacterial and viral co-infections in patients with severe SARS-CoV-2 pneumonia admitted to a French ICU.

BACKGROUND: Data on the prevalence of bacterial and viral co-infections among patients admitted to the ICU for acute respiratory failure related to SARS-CoV-2 pneumonia are lacking. We aimed to assess the rate of bacterial and viral co-infections, as well as to report the most common micro-organisms involved in patients admitted to the ICU for severe SARS-CoV-2 pneumonia. PATIENTS AND METHODS: In this monocenter retrospective study, we reviewed all the respiratory microbiological investigations performed within the first 48 h of ICU admission of COVID-19 patients (RT-PCR positive for SARS-CoV-2) admitted for acute respiratory failure. RESULTS: From March 13th to April 16th 2020, a total of 92 adult patients (median age: 61 years, 1st-3rd quartiles [55-70]; males: n = 73/92, 79%; baseline SOFA: 4 [3-7] and SAPS II: 31 [21-40]; invasive mechanical ventilation: n = 83/92, 90%; ICU mortality: n = 45/92, 49%) were admitted to our 40-bed ICU for acute respiratory failure due to SARS-CoV-2 pneumonia. Among them, 26 (28%) were considered as co-infected with a pathogenic bacterium at ICU admission with no co-infection related to atypical bacteria or viruses. The distribution of the 32 bacteria isolated from culture and/or respiratory PCRs was as follows: methicillin-sensitive Staphylococcus aureus (n = 10/32, 31%), Haemophilus influenzae (n = 7/32, 22%), Streptococcus pneumoniae (n = 6/32, 19%), Enterobacteriaceae (n = 5/32, 16%), Pseudomonas aeruginosa (n = 2/32, 6%), Moraxella catarrhalis (n = 1/32, 3%) and Acinetobacter baumannii (n = 1/32, 3%). Among the 24 pathogenic bacteria isolated from culture, 2 (8%) and 5 (21%) were resistant to 3rd generation cephalosporin and to amoxicillin-clavulanate combination, respectively. CONCLUSIONS: We report on a 28% rate of bacterial co-infection at ICU admission of patients with severe SARSCoV-2 pneumonia, mostly related to Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae and Enterobacteriaceae. In French patients with confirmed severe SARSCoV-2 pneumonia requiring ICU admission, our results encourage the systematic administration of an empiric antibiotic monotherapy with a 3rd generation cephalosporin, with a prompt de-escalation as soon as possible. Further larger studies are needed to assess the real prevalence and the predictors of co-infection together with its prognostic impact on critically ill patients with severe SARS-CoV-2 pneumonia.

Pulmonary embolism or thrombosis in ARDS COVID-19 patients: A French monocenter retrospective study.

Hypercoagulability and endotheliopathy reported in patients with coronavirus disease 2019 (COVID-19) combined with strict and prolonged immobilization inherent to deep sedation and administration of neuromuscular blockers for Acute Respiratory Distress Syndrome (ARDS) may expose critically ill COVID-19 patients to an increased risk of venous thrombosis and pulmonary embolism (PE). We aimed to assess the rate and to describe the clinical features and the outcomes of ARDS COVID-19 patients diagnosed with PE during ICU stay. From March 13th to April 24th 2020, a total of 92 patients (median age: 61 years, 1st-3rd quartiles [55-70]; males: n = 73/92, 79%; baseline SOFA: 4 [3-7] and SAPS II: 31 [21-40]; invasive mechanical ventilation: n = 83/92, 90%; ICU mortality: n = 45/92, 49%) were admitted to our 41-bed COVID-19 ICU for ARDS due to COVID-19. Among them, 26 patients (n = 26/92, 28%) underwent a Computed Tomography Pulmonary Angiography which revealed PE in 16 (n = 16/26, 62%) of them, accounting for 17% (n = 16/92) of the whole cohort. PE was bilateral in 3 (19%) patients and unilateral in 13 (81%) patients. The most proximal thrombus was localized in main (n = 4, 25%), lobar (n = 2, 12%) or segmental (n = 10, 63%) pulmonary artery. Most of the thrombi (n = 13/16, 81%) were located in a parenchymatous condensation. Only three of the 16 patients (19%) had lower limb venous thrombosis on Doppler ultrasound. Three patients were treated with alteplase and anticoagulation (n = 3/16, 19%) while the 13 others (n = 13/16, 81%) were treated with anticoagulation alone. ICU mortality was higher in patients with PE compared to that of patients without PE (n = 11/16, 69% vs. n = 2/10, 20%; p = 0.04). The low rate of lower limb venous thrombosis together with the high rate of distal pulmonary thrombus argue for a local immuno-thrombotic process associated with the classic embolic process. Further larger studies are needed to assess the real prevalence and the risk factors of pulmonary embolism/thrombosis together with its prognostic impact on critically ill patients with COVID-19.