C reactive protein utilisation, a biomarker for early COVID-19 treatment, improves lenzilumab efficacy: results from the randomised phase 3 'LIVE-AIR' trial.

OBJECTIVE: COVID-19 severity is correlated with granulocyte macrophage colony-stimulating factor (GM-CSF) and C reactive protein (CRP) levels. In the phase three LIVE-AIR trial, lenzilumab an anti-GM-CSF monoclonal antibody, improved the likelihood of survival without ventilation (SWOV) in COVID-19, with the greatest effect in participants having baseline CRP below a median of 79 mg/L. Herein, the utility of baseline CRP to guide lenzilumab treatment was assessed. DESIGN: A subanalysis of the randomised, blinded, controlled, LIVE-AIR trial in which lenzilumab or placebo was administered on day 0 and participants were followed through Day 28. PARTICIPANTS: Hospitalised COVID-19 participants (N=520) with SpO2 ≤94% on room air or requiring supplemental oxygen but not invasive mechanical ventilation. INTERVENTIONS: Lenzilumab (1800 mg; three divided doses, q8h, within 24 hours) or placebo infusion alongside corticosteroid and remdesivir treatments. MAIN OUTCOME MEASURES: The primary endpoint was the time-to-event analysis difference in SWOV through day 28 between lenzilumab and placebo treatments, stratified by baseline CRP. RESULTS: SWOV was achieved in 152 (90%; 95% CI 85 to 94) lenzilumab and 144 (79%; 72 to 84) placebo-treated participants with baseline CRP <150 mg/L (HR: 2.54; 95% CI 1.46 to 4.41; p=0.0009) but not with CRP ≥150 mg/L (HR: 1.04; 95% CI 0.51 to 2.14; p=0.9058). A statistically significant interaction between CRP and lenzilumab treatment was observed (p=0.044). Grade ≥3 adverse events with lenzilumab were comparable to placebo in both CRP strata. No treatment-emergent serious adverse events were attributed to lenzilumab. CONCLUSION: Hospitalised hypoxemic patients with COVID-19 with baseline CRP <150 mg/L derived the greatest clinical benefit from treatment with lenzilumab. TRIAL REGISTRATION NUMBER: NCT04351152; ClinicalTrials.gov.

Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a phase 3, randomised, placebo-controlled trial.

BACKGROUND: The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. METHODS: In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04351152, and is completed. FINDINGS: Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41-137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79-89) participants in the lenzilumab group and in 190 (78%; 72-83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02-2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. INTERPRETATION: Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown. FUNDING: Humanigen.

Severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infections occurring in healthcare workers after booster vaccination: A comparison of delta versus omicron variants.

In this study, we used genomic sequencing to identify variants of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) in healthcare workers with coronavirus disease 2019 (COVID-19) after receiving a booster vaccination. We compared symptoms, comorbidities, exposure risks, and vaccine history between the variants. Postbooster COVID-19 cases increased as the SARS-CoV-2 omicron variant predominated.

Outcomes and antibiotic use in patients with coronavirus disease 2019 (COVID-19) admitted to an intensive care unit.

Antibiotic overuse is high in patients hospitalized with coronavirus disease 2019 (COVID-19) despite a low documented prevalence of bacterial infections in many studies. In this study evaluating 65 COVID-19 patients in the intensive care unit, empiric broad-spectrum antibiotics were often overutilized with an inertia to de-escalate despite negative culture results.

Outcomes and Antibiotic Use in Patients with COVID-19 Admitted to an Intensive Care Unit

Background Studies have shown the proportion of critically ill patients with COVID-19 receiving empiric antibiotics (ABX) greatly exceeds those with culture-proven bacterial co-infections. However, the benefits of continuing ABX in culture-negative (CxN) cases is unknown;this practice may increase the risks associated with ABX overuse. The purpose of this study was to evaluate outcomes and antibiotic use (AU) in intensive care unit (ICU) patients with COVID-19 based on culture results. Methods This was a multicenter, retrospective cohort study evaluating adults in an ICU for the first episode of ABX initiated following a confirmed COVID-19 diagnosis between September to December 2020. Blood and/or respiratory cultures must have been obtained within 24 hours (h) of ABX initiation. Patients were categorized into three groups: 1) CxN, ABX discontinued ≤ 72 h, 2) CxN, ABX continued > 72 h, or 3) Culture-positive (CxP). Data on AU was obtained from electronic medication administration records. The primary outcome was clinical success, defined as being discharged alive or > 2-point decrease in the World Health Organization Clinical Progression Scale score from day of ABX initiation to day 30. Results A total of 65 patients were included with 35.4% being CxP. ABX were discontinued ≤ 72 h in 23.8% of CxN patients. Methicillin-susceptible Staphylococcus aureus was the most common organism in 52.2% of CxP patients (66.7% respiratory;16.7% blood;16.7% both). Anti-methicillin-resistant Staphylococcus aureus and anti-pseudomonal antibiotics were the most prescribed for the initial regimen (Table 1). ABX de-escalation occurred in 58.5% of patients. Initial ABX duration was significantly longer in the CxP group (P < 0.01). No significant difference in clinical success was observed (Table 2). Although not significantly different, the highest rate of adverse events occurred in the CxN and ABX continued > 72 h group (40.6%). Table 1. Antibiotic Use in ICU Patients with COVID-19 Table 2. Clinical Outcomes and Adverse Events in ICU Patients with COVID-19 Conclusion In ICU patients with COVID-19, empiric broad-spectrum ABX are often overutilized with an inertia to de-escalate despite negative culture results, potentially increasing the risk of adverse events. This remains an important area for focused antimicrobial stewardship efforts to mitigate the development of multidrug resistance. Disclosures Christopher Polk, MD, Atea (Research Grant or Support)Gilead (Advisor or Review Panel member, Research Grant or Support)Humanigen (Research Grant or Support)Regeneron (Research Grant or Support)

Ripples into waves: Trade networks, economic activity, and asset prices⟡

We exploit information in sovereign CDS spreads and the international trade network to provide causal evidence of the propagation of global economic shocks. We show that trade links are an important source of shock transmission using the natural experiments of the Japanese tsunami and the COVID-19 lockdown in China. We then confirm more general and gradual information flows along the trade network by showing extensive country-level credit/equity cross-sectional return predictability. News about country fundamentals flows primarily from importers to exporters, depends on both direct and indirect links in the trade network, and is magnified by the exporting country's financial vulnerability.