Baker, Owen R.

BACKGROUND COVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined. METHODS This secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization–equivalent anti–Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis. RESULTS SARS-CoV-2 anti–S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01). CONCLUSION In unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors’ antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use. TRIAL REGISTRATION ClinicalTrials.gov NCT04373460. FUNDING Department of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

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.

Abstract Background Post-COVID conditions (PCC) are common, and risk factors include older age and female sex. While high interleukin (IL)-6 and C-reactive protein are associated with more severe disease, it is unclear whether other cytokines are associated with PCC. This study was performed to identify factors associated with PCC development. Methods The Convalescent Plasma to Limit SARS-CoV-2 Associated Complications (CSSC-004) trial was a double-blind, multi-center, randomized, controlled trial comparing the use of COVID-19 convalescent plasma (CCP) to control plasma for the prevention of hospitalization among COVID-19 outpatients. Among 882 individuals participating in the trial with available biospecimens and symptom data, the association between early COVID-19 treatment, cytokine levels and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14 and day 90 using a multiplexed sandwich immuosassay. Presence of any PCC symptom was assessed at day 90. Associations between COVID-19 treatment, cytokine levels and PCC were examined using multivariate logistic regression models. Results Baseline characteristics were similar by trial treatment group (Figure 1). At day 90, 292 (33.1%) participants had PCC. The most common symptoms were fatigue (14.5%), anosmia (14.5%), and ageusia (10.0%). Levels of most cytokines decreased over time (Figure 2). Six pro-inflammatory cytokines especially IL-6 were elevated at baseline among those with PCC (Figure 3). In multivariable analysis, female sex (adjusted odds ratio [AOR]=2.70[1.93-3.81]), age 50 or greater (AOR=1.32[1.17-1.50]), and elevated baseline IL-6 (AOR=1.59[1.02-2.47]) were associated with development of PCC, whereas race, obesity, vaccine status and diabetes were not. Those who received early CCP treatment (&lt;5 days after symptom onset) compared to late CCP treatment had statistically significant lower odds of PCC (AOR=0.60 [0.38-0.95]). Conclusion This study showed high prevalence of PCC symptoms at day 90, particularly among those with higher baseline levels of IL-6 or who did not receive early CCP treatment. The potential utility of IL-6 modulation as a therapeutic intervention among individuals as higher risk for PCC should be studied. Disclosures Kelly Gebo, MD, MPH, Pfizer: Advisor/Consultant|Spark HealthCare: Advisor/Consultant Sonya L. Heath, MD, Pfizer: Data Monitoring Committee/DSMB Shmuel Shoham, MD, adagio: Advisor/Consultant|Adamis: Advisor/Consultant|ansun: Grant/Research Support|Avir Pharma: Honoraria|cidara: Grant/Research Support|F2G: Grant/Research Support|Immunome: Advisor/Consultant|Karius: Honoraria|Scynexis: Advisor/Consultant|zeteo: Grant/Research Support Judith S. Currier, M.D., MSc, Merck and Company: Advisor/Consultant|Merck and Company: Honoraria Moises A. Huaman, MD, MSc, AN2 Therapeutics Inc: Grant/Research Support|Gilead Sciences Inc: Grant/Research Support|Insmed Inc: Grant/Research Support Jay S. Raval, MD, Sanofi Genzyme: Advisor/Consultant Arturo Casadevall, MD, PhD, Ortho Diagnostics: Speakers Bureau|Sabtherapeutics: Advisor/Consultant

Post-COVID conditions (PCCs) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about treatment, inflammation, and PCC. Among 882 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of COVID-19 convalescent plasma (CCP) vs control plasma with available biospecimens and symptom data, the association between early CCP treatment, cytokine levels, and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14, and day 90 using a multiplexed sandwich immunoassay (Meso Scale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. Associations between CCP treatment, cytokine levels, and PCC were examined using multivariate logistic regression models. One third of the 882 participants had day 90 PCC symptoms, with fatigue (14.5%) and anosmia (14.5%) being most common. Cytokine levels decreased from baseline to day 90. In a multivariable analysis, female sex (adjusted odds ratio [AOR] = 2.69 [1.93–3.81]), older age (AOR = 1.32 [1.17–1.50]), and elevated baseline levels of IL-6 (AOR = 1.59 [1.02–2.47]) were independently associated with development of PCC. Those who received early CCP treatment (≤5 days after symptom onset) compared to late CCP treatment had statistically significant lower odds of PCC. IMPORTANCE Approximately 20% of individuals infected with SARS-CoV-2 experienced long-term health effects, as defined PCC. However, it is unknown if there are any early biomarkers associated with PCC or whether early intervention treatments may decrease the risk of PCC. In a secondary analysis of a randomized clinical trial, this study demonstrates that among outpatients with SARS-CoV-2, increased IL-6 at time of infection is associated with increased odds of PCC. In addition, among individuals treated early, within 5 days of symptom onset, with COVID-19 convalescent plasma, there was a trend for decreased odds of PCC after adjusting for other demographic and clinical characteristics. Future treatment studies should be considered to evaluate the effect of early treatment and anti-IL-6 therapies on PCC development.