Challenges in interpreting cytokine data in COVID-19 affect patient care and management

Abstract

The disease caused by the coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARSAU -CoV-2) (Coronavirus Disease - CoV 2019. (COVID-19)) has resulted in significant morbidity and mortality worldwide. Severe disease is thought to be mediated by a variant of cytokine storm syndrome (CSS), where a hyperinflammatory state characterized by elevated levels of circulating cytokines and chemokines is thought to portend a poor prognosis. The likely significant contribution of CSS in severe COVID-19 infection is supported by demonstrated efficacies of broad immunomodulatory agents, including corticosteroids and Janus kinase (JAKAU ): Pl inhibitors, in improving clinical outcomes in hospitalized patients with COVID-19 [1-3]. While multiple studies have described elevated levels of pro-inflammatory cytokines in severely ill patients hospitalized with COVID-19 [4], a subset of studies have questioned whether CSS is indeed an important mechanistic driver of COVID-19 based on the observation that cytokine elevation in COVID-19 may be more muted compared to conditions such as acute respiratory distress syndrome (ARDS), sepsis, and cytokine release syndrome related to chimeric antigen receptor T-cell therapy [5,6]. The lack of a gold standard for measuring cytokines using multiplexed approaches and significant variation in measurements among different assays raises the concern that the discrepancies among studies in COVID-19 and other diseases may be related to differences in the laboratory vendors or specific assays used for measurement. We experienced this discrepancy in cytokine measurements firsthand in our health system, where cytokine panels were routinely ordered for many of over 4,000 patients hospitalized with COVID-19, and a quantitative multiplex bead assay for a panel of 12 cytokines was conducted by an off-site Clinical Laboratory Improvement Amendments (CLIA)-accredited vendor (Lab A). Peak cytokine levels from 1,328 patients, from whom serial cytokine levels were obtained throughout their hospitalization, were extracted from the electronic medical records and the recently established Yale DOM-CovX database [7] (Table 1). In parallel, plasma was collected from a subset of 247 patients hospitalized with COVID-19 and was enrolled in research studies, and multiplex cytokine levels were measured by a secondary laboratory (Lab B), which used a different type of multiplex assay, and these patients were categorized into intensive care unit (ICU) and non-ICU, based on their hospitalization status at the time of sample collection [7,8]. While many of the cytokines measured by Lab B were found to be elevated and correlated with disease severity.