Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis

Abstract

BACKGROUNDElevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare with those observed in critically ill patients with acute respiratory distress syndrome (ARDS) or sepsis due to other causes.METHODSWe used a Luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1β, IL-1RA, IL-6, IL-8, IL-18, and TNF-α) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTSFifteen hospitalized COVID-19 patients, 9 of whom were critically ill, were compared with critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1β, IL-1RA, IL-6, IL-8, IL-18, and TNF-α between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONLevels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDINGFunding was received from NHLBI K23 HL125663 (AJR); The Bill and Melinda Gates Foundation OPP1113682 (AJR and CAB); Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687 NIH/NIAID U19AI057229-16; Stanford Maternal Child Health Research Institute; and Chan Zuckerberg Biohub (CAB).

Keywords: COVID-19; Cytokines; Inflammation.

Figure 1. Expression of inflammatory cytokines does not differ between COVID-19 and non-COVID sepsis and ARDS.

Cytokine expression levels of 2 replicates per sample were measured in plasma using Luminex and normalized for nonspecific binding, resulting in the mean of plate-detrended median fluorescence intensity (dpMFI) values for each cytokine per sample. Moderate COVID-19 (COV-noICU, orange), n = 6. Severe COVID-19 (COV-ICU, purple), n = 9. ARDS (pink), n = 12. Sepsis (green), n = 16. Circles represent subjects with COVID-19, triangles represent subjects with ARDS, and squares represent subjects with sepsis. The box plot visualizes the following summary statistics: the middle line represents the median; the lower hinge corresponds to the first quartile (25th); the upper hinge corresponds to the third quartile (75th); upper and lower whiskers extend from the hinge respectively to the largest value and smallest value or no further than 1.5 × interquartile range; data beyond the whiskers are outliers. Wilcoxon rank sum tests were performed for each cytokine, observing COV-ICU compared with COV-noICU, ARDS, and sepsis. P values were adjusted for multiple comparisons using the Benjamini-Hochberg correction method. No cytokines had adjusted P < 0.05. P values for comparison between COV-noICU and COV-ICU: IL-1β, P = 0.53, adjusted P = 0.79; IL-1RA, P = 0.036, adjusted P = 0.22; IL-6, P = 0.018, adjusted P = 0.16; IL-8, P = 0.46, adjusted P = 0.79; IL-18, P = 0.27, adjusted P = 0.70; TNF-α, P = 0.86, adjusted P = 0.99. P values for comparison between COV-ICU and ARDS: IL-1β, P = 0.65, adjusted P = 0.84; IL-1RA, P = 0.92, adjusted P = 0.99; IL-6, P = 0.51, adjusted P = 0.79; IL-8, P = 0.60, adjusted P = 0.83; IL-18, P = 0.095, adjusted P = 0.32; TNF-α, P = 0.069, adjusted P = 0.31. P values for comparison between COV-ICU and sepsis: IL-1β, P = 0.36, adjusted P = 0.79; IL-1RA, P = 0.11, adjusted P = 0.32; IL-6, P = 0.45, adjusted P = 0.79; IL-8, P = 0.93, adjusted P = 0.99; IL-18, P = 0.0043, adjusted P = 0.078; TNF-α, P = 1, adjusted P = 1.