Publication Date
3-1-2022
Journal
Critical Care Medicine
DOI
10.1097/CCM.0000000000005229
PMID
34612846
PMCID
PMC8855771
PubMedCentral® Posted Date
10-12-2021
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Antibodies, Monoclonal, Humanized, Biomarkers, COVID-19, Double-Blind Method, Female, Humans, Inflammation Mediators, Length of Stay, Male, Patient Discharge, Prognosis, Respiration, Artificial, SARS-CoV-2, COVID-19 Drug Treatment
Abstract
OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia.
DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial.
SETTING: Hospitals in North America and Europe.
PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care.
INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo.
MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo.
CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.
Included in
Biochemistry, Biophysics, and Structural Biology Commons, COVID-19 Commons, Epidemiology Commons, Medical Sciences Commons, Medical Specialties Commons
