COVID-19 convalescent plasma therapy decreases inflammatory cytokines: a randomized controlled trial
Authors: Habtehyimer Feben , Zhu Xianming , Redd Andrew D. , Gebo Kelly A. , Abraham Alison G. , Patel Eshan U. , Laeyendecker Oliver , Gniadek Thomas J. , Fernandez Reinaldo E. , Baker Owen R. , Ram Malathi , Cachay Edward R. , Currier Judith S. , Fukuta Yuriko , Gerber Jonathan M. , Heath Sonya L. , Meisenberg Barry , Huaman Moises A. , Levine Adam C. , Shenoy Aarthi , Anjan Shweta , Blair Janis E. , Cruser Daniel , Forthal Donald N. , Hammitt Laura L. , Kassaye Seble , Mosnaim Giselle S. , Patel Bela , Paxton James H. , Raval Jay S. , Sutcliffe Catherine G. , Abinante Matthew , Oei Kevin S. , Cluzet Valerie , Cordisco Marie Elena , Greenblatt Benjamin , Rausch William , Shade David , Gawad Amy L. , Klein Sabra L. , Pekosz Andrew , Shoham Shmuel , Casadevall Arturo , Bloch Evan M. , Hanley Daniel , Tobian Aaron A. R. , Sullivan David J. 
Published: November 2023

ABSTRACT

Early COVID-19 convalescent plasma (CCP) transfusion to outpatients with COVID-19 decreases progression to hospitalization, but the mechanism of how CCP reduces severity is unknown. Among 882 COVID-19 participants transfused with CCP or control plasma in a randomized controlled trial, 21 cytokines and chemokines were measured using electrochemiluminescence assays. Wilcoxon rank sum tests were used to evaluate the difference between early (transfused within 5 days of symptom onset) CCP vs early control plasma and late (transfused 6–9 days after symptom onset) CCP vs late control plasma at each visit. Linear mixed-effect models were used to assess the difference in the slope of cytokine change. Median cytokine and chemokine levels were similar between the early CCP and early control groups pre-transfusion. At the day 14 visit, only the median IL-6 (
P
= 0.014) and IL-16 (
P
= 0.036) levels were lower in the early CCP group compared to the early control group, but these differences were not statistically significant after correcting for multiple comparisons (requiring
P
< 0.0024). IL-6 levels decreased significantly faster in the early CCP group from screening to the day 14 visit compared to the early control group (
P
< 0.001). No difference was observed in the slope of cytokine change from screening to day 90 between early CCP and early control groups. Late control and late CCP arms showed similar cytokine and chemokine levels through study follow-up. One mechanism by which early CCP transfusion reduces hospitalization may be by decreasing IL-6 levels, as the reduction is associated with better recovery from COVID-19.

IMPORTANCE
This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.