Association of Convalescent Plasma Treatment with Reduced Mortality and Improved Clinical Trajectory in Patients Hospitalized with COVID-19 in the Community Setting
Authors: Egloff Shanna A. Arnold , Junglen Angela , Restivo Joseph S.A. , Wongskhaluang Marjorie , Martin Casey , Doshi Pratik , Schlauch Daniel , Fromell Gregg , Sears Lindsay E. , Correll Mick , Burris Howard A. , LeMaistre Charles F. 
Published: June 2021

Background

Convalescent plasma (CP) quickly emerged as one of the first investigational treatment options for COVID-19. Evidence supporting CP for treating patients hospitalized with COVID-19 has been inconclusive, leading to conflicting recommendations regarding its use. The primary objective was to perform a comparative effectiveness study of CP for all-cause, in-hospital mortality in patients with COVID-19.

Methods

The matched, multicenter, electronic health records-based, retrospective cohort study included 44,770 patients hospitalized with COVID-19 in one of 176 HCA Healthcare-affiliated community hospitals across the United States from March 2 to October 7, 2020. Coarsened exact matching (1:k) was employed resulting in a sample of 3,774 CP and 10,687 comparison patients.

Results

Examining mortality using a shared frailty model and controlling for concomitant medications, calendar date of admission, and days from admission to transfusion demonstrated a significant association of CP with lower risk of mortality compared to the comparison group (aHR = 0.71, 95% CI 0.59-0.86,p<0.001). Examination of patient risk trajectories, represented by 400 clinico-demographic features from our Real-Time Risk Model (RTRM), indicated that patients who received CP recovered more quickly. The time from admission to CP transfusion was significantly associated with risk of mortality and stratification revealed that CP within 3 days after admission, but not 4-7 days, was associated with a significant reduction in mortality risk (aHR = 0.53, 95% CI 0.47-0.60,p<0.001). CP serology level was inversely associated with mortality when controlling for interaction with days to transfusion (HR = 0.998, 95% CI 0.997-0.999,p= 0.013) but was not significant in a univariable analysis.

Conclusion

Utilizing this large, diverse, multicenter cohort, we demonstrate that CP is significantly associated with reduced risk of in-hospital mortality. These observations demonstrate the utility of real-world evidence and suggest the need for further evaluation prior to abandoning CP as a viable therapy for COVID-19.

Funding

This research was supported, in whole, by HCA Healthcare and/or an HCA Healthcare affiliated entity including Sarah Cannon and Genospace.

Research in Context

Evidence before this study

Discrepant reports of the efficacy of various treatments for COVID-19, including convalescent plasma (CP), emerged from a rapidly evolving political and interventional landscape of the pandemic. Furthermore, clinical interpretations of this discordant data led to underuse, overuse and misuse of certain interventions, often ignoring mechanistic context altogether. CP has been utilized in prior pandemics/epidemics to introduce antibodies to elicit an immune response during the viral phase of infection. Thus, CP received early priority for emergency use and randomized trial engagement. Initially, the United States had issued individual emergency investigational new drug (eIND) use for CP and initiated its expanded access protocol (EAP) to monitor its safety profile and to allow broader access. This effectively restricted access to those with severe disease, which is not mechanistically aligned with targeting the viral phase. Many randomized control trials (RCTs) were being setup for testing efficacy of CP in the inpatient setting and, to a lesser extent, the outpatient setting. Some trial designs focused on severe disease and others on less severe. United States RCTs had additional enrollment challenges due to competing patient access to EAP. All studies were limited by supply and demand due to regional outbreaks and to the shear operational effort of coordinating donations, sampling, serology testing, ordering, and distribution.

To date, most matched studies and RCTs around the globe have shown a trend of CP providing survival benefit, but all had relatively small cohorts except the RECOVERY trial, which failed to show a benefit with CP. Results ranged from no significant effect to 56% reduction in mortality with the latter coming out of a multisite RCT based in New York and Rio De Janeiro. There has been a minimum of nine matched control studies and seven randomized control trials evaluating convalescent plasma.

We frequently assessed World Health Organization (WHO), United Stated Food and Drug Administration (FDA), BARDA/Mayo Clinic led EAP, and the United States Center for Disease Control and Prevention (CDC) resources as well as queried both preprint archives (MedRXIV & SSRN) and PubMed with the search terms “retrospective”, “convalescent plasma”, “randomized”, “trial”, “comparative effect”, “COVID”, “hospital”, “in-hospital”, “hospitalized” and “mortality” to ensure we were considering the most recent methodology and results generated for CP. The last search was performed on May 14, 2021. No date restrictions or language filters were applied.

Added value of this study

To our knowledge, this study is the largest and most geographically diverse of its kind to comprehensively evaluate and confirm the beneficial association of CP with all-cause mortality in patients hospitalized with COVID-19. Our data provides context to optimal delivery and validates recent trends in the literature showing CP benefit. There is a dose-response effect with CP antibody levels and we demonstrate that sooner really is better in accordance with the mechanisms of viral clearance and immune regulation. Finally, this is all done in the context of a diverse community setting in one of the largest hospital systems in the United States.

Implications of all the available evidence

As novel, more virulent and transmissible SARS-CoV-2 variants emerge around the globe and as reports of post-vaccine “breakthrough” infections and vaccine hesitancy increase, there is a renewed motivation to identify effective treatments for hospitalized patients. The data presented here, along with a growing body of evidence from matched-control studies and RCTs, demonstrate that further evaluation is required prior to abandoning CP as an effective intervention in the treatment of hospitalized COVID-19 patients.