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Safety Update

COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients

      Abstract

      Objective

      To provide an update on key safety metrics after transfusion of convalescent plasma in hospitalized coronavirus 2019 (COVID-19) patients, having previously demonstrated safety in 5000 hospitalized patients.

      Patients and Methods

      From April 3 to June 2, 2020, the US Food and Drug Administration Expanded Access Program for COVID-19 convalescent plasma transfused a convenience sample of 20,000 hospitalized patients with COVID-19 convalescent plasma.

      Results

      The incidence of all serious adverse events was low; these included transfusion reactions (n=78; <1%), thromboembolic or thrombotic events (n=113; <1%), and cardiac events (n=677, ~3%). Notably, the vast majority of the thromboembolic or thrombotic events (n=75) and cardiac events (n=597) were judged to be unrelated to the plasma transfusion per se. The 7-day mortality rate was 13.0% (12.5%, 13.4%), and was higher among more critically ill patients relative to less ill counterparts, including patients admitted to the intensive care unit versus those not admitted (15.6 vs 9.3%), mechanically ventilated versus not ventilated (18.3% vs 9.9%), and with septic shock or multiple organ dysfunction/failure versus those without dysfunction/failure (21.7% vs 11.5%).

      Conclusion

      These updated data provide robust evidence that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19, and support the notion that earlier administration of plasma within the clinical course of COVID-19 is more likely to reduce mortality.

      Abbreviations and Acronyms:

      COVID-19 (coronavirus disease 2019), EAP (Expanded Access Program), FDA (Food and Drug Administration), ICU (intensive care unit), IRB (Institutional Review Board), SAE (serious adverse event), TACO (transfusion-associated circulatory overload), TRALI (transfusion-related acute lung injury)
      Coronavirus disease 2019 (COVID-19) continues to be a worldwide pandemic, and the number of deaths attributed to COVID-19 in the United States at the time of this writing (~150,000) exceeds that of any other nation in the world.

      Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): cases in US. CDC website. https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html. Accessed August 4, 2020.

      The overall case fatality rate for diagnosed COVID-19 ranges from approximately 4% to greater than 50%,
      • Rajgor D.D.
      • Lee M.H.
      • Archuleta S.
      • Bagdasarian N.
      • Quek S.C.
      The many estimates of the COVID-19 case fatality rate.
      • Wang K.
      • Zhang Z.
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      • Tao Y.
      • Xie M.
      15-day mortality and associated risk factors for hospitalized patients with COVID-19 in Wuhan, China: an ambispective observational cohort study.
      • Yang X.
      • Yu Y.
      • Xu J.
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      • Bhatraju P.K.
      • Ghassemieh B.J.
      • Nichols M.
      • et al.
      Covid-19 in critically ill patients in the Seattle region — case series.
      with higher mortality rates observed in more critically ill patients. In response to the COVID-19 outbreak in the United States and reportedly high case-fatality rates, the US Food and Drug Administration (FDA) in collaboration with the Mayo Clinic and national blood banking community developed a national Expanded Access Program (EAP) to collect and distribute COVID-19 convalescent plasma. Historical precedent indicates that human convalescent plasma is a viable option for mitigation and treatment of COVID-19.
      • Casadevall A.
      • Pirofski L.A.
      The convalescent sera option for containing COVID-19.
      ,
      • Zhang J.S.
      • Chen J.T.
      • Liu Y.X.
      • et al.
      A serological survey on neutralizing antibody titer of SARS convalescent sera.
      The premise of human convalescent plasma therapy is that plasma of recently infected and currently recovered COVID-19 patients contains antiviral antibodies and other bioactive elements that can be used to treat patients with COVID-19. Convalescent plasma has a strong historical record of some efficacy during acute infectious pandemics.
      • Casadevall A.
      • Pirofski L.A.
      The convalescent sera option for containing COVID-19.
      ,
      • Luke T.C.
      • Kilbane E.M.
      • Jackson J.L.
      • Hoffman S.L.
      Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment?.
      As recently summarized,
      • Casadevall A.
      • Pirofski L.A.
      The convalescent sera option for containing COVID-19.
      convalescent plasma represents a promising treatment strategy with strong historical precedence, biological plausibility, and limited barriers for rapid development and deployment of this investigational therapy.
      Recently, our investigation of key safety indicators in 5000 patients transfused with COVID-19 convalescent plasma showed an incidence of transfusion-related serious adverse events (SAEs) of less than 1% and a mortality rate of 14.9%.
      • Joyner M.J.
      • et al.
      Early Safety Indicators of COVID-19 Convalescent Plasma in 5,000 Patients.
      These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized adults with COVID-19. Because an additional 15,000 hospitalized patients have been transfused with convalescent plasma under the purview of the EAP, a subsequent safety update is warranted. These new data may provide novel insights into the incidence of emerging adverse events associated with COVID-19, including thromboembolic
      • Wright F.L.
      • Vogler T.O.
      • Moore E.E.
      • et al.
      Fibrinolysis shutdown correlates to thromboembolic events in severe COVID-19 infection.
      ,
      • Wichmann D.
      • Sperhake J.P.
      • Lutgehetmann M.
      • et al.
      Autopsy findings and venous thromboembolism in patients with COVID-19.
      and cardiac events.
      • Inciardi R.M.
      • Lupi L.
      • Zaccone G.
      • et al.
      Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19).
      Further, these data may provide better understanding of the clinical features contributing to the 7-day mortality rate among transfused patients with COVID-19.
      Thus, we analyzed key safety metrics following transfusion of convalescent plasma in 20,000 hospitalized adults with severe or life-threatening COVID-19. These data represent a deeper and larger analysis relative to our initial report of 5000 transfused patients under the EAP. We hypothesized that both the 7-day mortality rate and the number of SAEs related to the transfusion of convalescent plasma would continue to be low. Additionally, we hypothesized that higher mortality rates would be observed in more critically ill patients.

      Patients and Methods

      As described previously,
      • Joyner M.J.
      • et al.
      Early Safety Indicators of COVID-19 Convalescent Plasma in 5,000 Patients.
      the program is a FDA-initiated, national, multicenter, open-label EAP in hospitalized adults who had (or were judged to have high risk of progression to) severe or life-threatening COVID-19. The US COVID-19 Convalescent Plasma EAP was conducted as a pragmatic treatment study, empowering local acute care facilities to use the emerging best evidence for care while allowing for administration of convalescent plasma. It was conducted within a modified clinical trial framework: All participants were allowed access to convalescent plasma per the discretion of the treating physician/principal investigator given the nature of the pandemic and the lack of any effective therapies at the time of design. It was the intent a priori to create a control comparator group to determine potential efficacy using patients hospitalized with COVID-19 infections during the same period. This decision was made after collaboration with the US FDA. This report is only on safety of the convalescent plasma for the initial 20,000 subjects. A future publication will discuss potential efficacy.
      Between the date of initial Institutional Review Board (IRB) approval of the EAP (April 1, 2020) and June 11, 2020, more than 20,000 patients were transfused with COVID-19 convalescent plasma (Figure 1). The Mayo Clinic IRB served as the central IRB and empaneled an independent Data and Safety Monitoring Board to oversee the safety analyses. Written informed consent was obtained from the participant or a legally authorized representative before enrollment or with use of emergency consent procedures recommended by the US FDA and approved by the Mayo Clinic IRB. The protocol was modified to allow inclusion of incarcerated participants once it became clear that this group was especially vulnerable and at risk.
      Figure thumbnail gr1
      Figure 1Participation in the US COVID-19 Convalescent Plasma Expanded Access Program (EAP) including data extracted on June 11, 2020. Choropleth map displaying the number of cumulatively enrolled patients in the EAP within each state, with lower enrollment values displayed in a lighter hue of green and higher enrollment values displayed in a darker hue of green. Registered acute care facilities are represented as filled yellow circles, with larger circles indicating greater number of registered facilities within the metropolitan area of a city. The choropleth map does not display data from US territories, including registered facilities in Puerto Rico, Guam, and Northern Mariana Islands.
      Eligible patients were aged 18 years or older, hospitalized with a laboratory-confirmed diagnosis of infection with severe acute respiratory syndrome coronavirus 2, and had (or were judged by a health care provider to be at high risk of progression to) severe or life-threatening COVID-19. The clinical symptoms defining severe or life-threatening COVID-19 are outlined in Table 1.
      Table 1Patient Characteristics Stratified by Month of COVID-19 Convalescent Plasma Transfusion
      Values shown are n (%).
      AprilMayTotal
      Characteristic
       N621413,78620,000
      Age, y
       18-39449 (7.2)1083 (7.9)1,532 (7.7)
       40-592056 (33.1)4320 (31.3)6,376 (31.9)
       60-691798 (28.9)3611 (26.2)5,409 (27.0)
       70-791260 (20.3)2859 (20.7)4,119 (20.6)
       ≥80651 (10.5)1913 (13.9)2,564 (12.8)
      Sex
       Female2262 (36.4)5499 (39.9)7761 (38.8)
       Male3924 (63.2)8241 (59.8)12,165 (60.8)
       Intersex or transgender22 (0.4)35 (0.3)57 (0.3)
       Undisclosed6 (0.1)11 (0.1)17 (0.1)
      Weight status
      These data include a subset of the sample (n=18,689).
       Underweight61 (1.2)249 (1.8)310 (1.7)
       Normal weight868 (17.3)2454 (18.0)3322 (17.8)
       Overweight1502 (30.0)3802 (27.8)5304 (28.4)
       Obese2587 (51.6)7166 (52.4)9753 (52.2)
      Race
       Asian408 (6.6)591 (4.3)999 (5.0)
       Black1132 (18.2)2784 (20.2)3916 (19.6)
       White2993 (48.2)6741 (48.9)9734 (48.7)
       Other or unknown1681 (27.1)3670 (26.6)5351 (26.8)
      Ethnicity
       Hispanic or Latino2142 (34.5)4794 (34.8)6936 (34.7)
       Not Hispanic or Latino4072 (65.5)8992 (65.2)13,064 (65.3)
      Clinical status
       Current severe or life-threatening COVID-194963 (79.9)9274 (67.3)14,237 (71.2)
       High risk of severe or life-threatening COVID-191251 (20.1)4512 (32.7)5763 (28.8)
       Intensive care unit admission4038 (65.0)7522 (55.0)11,560 (58.1)
       Mechanical ventilation
      These data include a subset of the sample (n=19,256).
      2709 (48.5)4155 (30.4)6864 (35.6)
      Clinical symptoms
      These data include a subset of the sample (n=14,237), only those patients that currently have severe or life-threatening COVID-19.
       Respiratory failure3574 (72.0)6155 (66.4)9729 (68.3)
       Dyspnea3152 (63.5)6561 (70.7)9713 (68.2)
       Blood oxygen saturation ≤93%3092 (62.3)6663 (71.8)9755 (68.5)
       Lung infiltrates >50% within 24 to 48 h2105 (42.4)4021 (43.4)6126 (43.0)
       Respiratory frequency ≥30/min1937 (39.0)4014 (43.3)5951 (41.8)
       PaO2:FiO2
      PaO2:FiO2 the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ratio.
      <300
      1642 (33.1)3014 (32.5)4656 (32.7)
       Multiple organ dysfunction or failure936 (18.9)1212 (13.1)2148 (15.1)
       Septic shock734 (14.8)987 (10.6)1721 (12.1)
      a Values shown are n (%).
      b These data include a subset of the sample (n=18,689).
      c These data include a subset of the sample (n=19,256).
      d These data include a subset of the sample (n=14,237), only those patients that currently have severe or life-threatening COVID-19.
      e PaO2:FiO2 the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ratio.

      Procedures

      As described previously,
      • Joyner M.J.
      • et al.
      Early Safety Indicators of COVID-19 Convalescent Plasma in 5,000 Patients.
      ABO-compatible COVID-19 convalescent plasma had no minimum neutralizing-antibody titer level and was donated by recently recovered COVID-19 survivors. Approximately 200 to 500 mL of convalescent plasma was administered intravenously according to institutional transfusion guidelines. Web-based, standardized data reporting surveys were completed to assess clinical status of patients at regular time intervals (4-hours and 7-days after convalescent plasma transfusion) using the Research Electronic Data Capture system (REDCap, v.9.1.15 Vanderbilt University, Nashville, TN).
      • Harris P.A.
      • Taylor R.
      • Thielke R.
      • Payne J.
      • Gonzalez N.
      • Conde J.G.
      Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support.
      ,
      • Harris P.A.
      • Taylor R.
      • Minor B.L.
      • et al.
      The REDCap consortium: building an international community of software platform partners.

      Serious Adverse Event Reporting

      Separate REDCap data collection forms were used to report each SAE that occurred within 7 days following the convalescent plasma transfusion. Two primary data capture forms were used to report SAEs: a transfusion form and a SAE form. Serious adverse events which occurred during the time window beginning at the onset of the plasma transfusion and including the 4-hour period following the transfusion were reported on the transfusion form. By definition, the primary SAEs related to transfusion (including transfusion associated circulatory overload [TACO] and transfusion-related acute lung injury [TRALI]) occurred within 6 hours of the transfusion. All transfusion-related SAEs occurred within 4 hours of the transfusion and thus, were all reported on the transfusion form. All other SAEs were reported on the SAE form. The attribution scale used by treating physicians for evaluating SAE relatedness to convalescent plasma transfusion included unrelated, possibility related, probably related, or definitely related. All transfusion-related SAEs were independently adjudicated over the course of the study by the Investigational New Drug sponsor (M.J.J.) and trained designee (A.M.K.) using the National Healthcare Safety Network Biovigilance Component Hemovigilance Module Surveillance Protocol as a conceptual framework.
      US Centers for Disease Control and Prevention. The National Healthcare Safety Network (NHSN) Manual

      Statistics

      Data presented in this safety report may undergo additional data quality control measures as the study continues. The proportion of each of a series of SAEs was summarized using a point estimate and 95% score CI as outlined in Table 2. The point estimates for mortality were estimated at day 7 based on the crude mortality and Wilson confidence interval calculation for binomial proportions. All analyses and graphics were produced with R version 3.6.2 (Vienna, Austria).
      Table 2SAE Characteristics in Patients Transfused With COVID-19 Convalescent Plasma (N=20,000)
      ICU = intensive care unit; MOF = multiple organ failure or dysfunction; SAE = severe adverse event; TACO = transfusion-associated circulatory overload; TRALI = transfusion-related acute lung injury.
      SAE: Transfusion reactionsReportedRelated% Estimate
      Point estimate of related serious adverse event incidence relative to 20,000 transfusions.
      (95% CI)
      Mortality within four hours of transfusion63100.05 (0.03-0.09)
      TACO36360.18 (0.13-0.25)
      TRALI21210.10 (0.07-0.16)
      Severe allergic transfusion reaction21210.10 (0.07-0.16)
      7-day SAE reports
       Thrombolic or thromboembolic complication113380.19 (0.14-0.26)
       Sustained hypotension
      Sustained hypotension included events requiring intravenous pressor support.
      457540.27 (0.21-0.35)
       Cardiac events
      Cardiac events included ventricular or atrial fibrillation or arrhythmia requiring treatment, and cardiac arrest.
      677800.40 (0.32-0.50)
      7-day mortalityReported
      Crude Estimate259212.96 (12.50-13.44)
      Clinical status
       No ICU admission (n=8323)7729.28 (8.67-9.92)
       ICU admission (n=11,560)180615.62 (14.97-16.30)
       No mechanical ventilation (n=12,147)12209.85 (9.34-10.38)
       Mechanical ventilation (n=6864)125818.33 (17.43-19.26)
      Clinical symptoms
       No MOF or septic shock (n=17,081)195211.45 (10.98-11.94)
       MOF or septic shock (n=2919)64021.72 (20.27-23.24)
      a ICU = intensive care unit; MOF = multiple organ failure or dysfunction; SAE = severe adverse event; TACO = transfusion-associated circulatory overload; TRALI = transfusion-related acute lung injury.
      b Point estimate of related serious adverse event incidence relative to 20,000 transfusions.
      c Sustained hypotension included events requiring intravenous pressor support.
      d Cardiac events included ventricular or atrial fibrillation or arrhythmia requiring treatment, and cardiac arrest.

      Results

      From April 3 to June 11, 2020, a total of 30,117 patients were enrolled in the EAP and a total of 21,987 enrolled patients received a COVID-19 convalescent plasma transfusion (Figure 1). Data from the first 5000 transfused patients have been reported previously.
      • Joyner M.J.
      • et al.
      Early Safety Indicators of COVID-19 Convalescent Plasma in 5,000 Patients.
      This update reports data from 20,000 patients including the initial 5000 and subsequent 15,000 transfused patients. By June 2, 2020, a total of 20,000 patients had been transfused with COVID-19 convalescent plasma, thus, 7-day mortality data are presented for all 20,000 patients.

      Patient Characteristics

      Key patient characteristics at the time of enrollment are presented in Table 1. The patient enrollment indicates a wide age range of hospitalized patients with COVID-19, consistent with prior Centers for Disease Control and Prevention published data.
      • Garg S.
      Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019—COVID-NET, 14 States, March 1–30, 2020.
      The study population was diverse, with 20% of patients being African American, nearly 35% Hispanic, and 5% Asian. The recruitment of a diverse population has improved over the course of the study. Nearly 40% of our subjects were women. Most of the patients enrolled were overweight or obese, consistent with early reports of risk.
      • Goyal P.
      • Choi J.J.
      • Pinheiro L.C.
      • et al.
      Clinical characteristics of COVID-19 in New York City.
      Nearly all of the patients had severe or life-threatening COVID-19 by design of the investigational protocol. Nearly two-thirds had respiratory failure as well as dyspnea as a primary symptom. Most were hypoxic and nearly half had pulmonary infiltrates. At least one-third had severe respiratory compromise. Equal numbers appeared to have multiorgan failure or septic shock, but these were a small percentage of the total population.

      Serious Adverse Events

      Key SAEs related to the transfusion of convalescent plasma are reported in Table 2. Our report is not a comprehensive summary of all risks associated with hospitalization of COVID-19, but it did assume that convalescent plasma potentially could cause life-threatening cardiac events and thrombotic events, so these were collected with an underlying assumption of attribution. Within 4 hours of completion of the COVID-19 convalescent plasma transfusion, 141 SAEs classified as transfusion reactions were reported (<1% of all transfusions). Of these SAEs, there were 78 non-mortality events reported, with 36 reports of TACO, 21 reports of TRALI, and 21 reports of severe allergic transfusion reaction. Of the SAEs reported within 4 hours of plasma transfusion, there were 63 mortalities (0.3% of all transfusions) and 10 of these mortalities were judged as related (possibly, n=10; probably, n=0; definitely, n=0) to the transfusion of COVID-19 convalescent plasma.
      Within 7 days of completion of the COVID-19 convalescent plasma transfusion, 1247 other SAEs were reported. Of these SAEs, 113 thromboembolic or thrombotic events were reported, 457 sustained hypotensive events requiring intravenous pressor support were reported, and 677 patients suffered a cardiac event. Notably, the vast majority of the thromboembolic or thrombotic complications (n=75) and cardiac events (n=597) were judged to be unrelated to the plasma transfusion.

      Seven-Day Mortality

      Seven-day mortality rates stratified by key clinical status indicators are presented in Table 2. Over the first 7 days after the COVID-19 convalescent plasma transfusion, a total of 2592 deaths were observed. The overall 7-day mortality rate was 12.96% (95% CI, 12.50% to 13.44%) (Figure 2). The 7-day mortality rate was higher among the sickest of our critically ill patients, including patients admitted to the intensive care unit (ICU) versus those not admitted to the ICU (15.6% vs 9.3%), mechanically ventilated versus not mechanically ventilated (18.3% vs 9.9%), and those with septic shock or multiple organ dysfunction/failure versus without septic shock or multiple organ dysfunction/failure (21.7% vs 11.5%).
      Figure thumbnail gr2
      Figure 2Seven-day mortality rate in patients transfused with COVID-19 convalescent plasma stratified by week since initiation of the US COVID-19 Convalescent Plasma Expanded Access Program (EAP). Each green bar indicates the 7-day mortality rate stratified by the patients enrolled during a given week since the initiation of the EAP.

      Discussion

      In this safety update of the US Convalescent Plasma Expanded Access Program of 20,000 hospitalized patients in the United States with severe or life-threatening COVID-19, the overall frequency of SAEs classified as attributable or likely secondary to convalescent plasma transfusion continued to be low (<1% of all transfusions) and the 7-day mortality rate in this extremely high-risk cohort was 13.0%. Despite the potential risks associated with plasma transfusion in critically ill patients,
      US Centers for Disease Control and Prevention. The National Healthcare Safety Network (NHSN) Manual
      ,
      • Dzik S.
      COVID-19 Convalescent Plasma: Now Is the Time for Better Science.
      these data provide continued optimism for the safety of COVID-19 convalescent plasma.

      Emerging COVID-19 Clinical Complications

      Although thrombotic and thromboembolic events are emerging clinical complications of COVID-19,
      • Wright F.L.
      • Vogler T.O.
      • Moore E.E.
      • et al.
      Fibrinolysis shutdown correlates to thromboembolic events in severe COVID-19 infection.
      ,
      • Wichmann D.
      • Sperhake J.P.
      • Lutgehetmann M.
      • et al.
      Autopsy findings and venous thromboembolism in patients with COVID-19.
      ,
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.M.
      • et al.
      Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.
      our data show a low rate (<1%) of these events within the first 7 days after COVID-19 convalescent plasma transfusion. Cardiac events represent another novel clinical concern of COVID-19,
      • Inciardi R.M.
      • Lupi L.
      • Zaccone G.
      • et al.
      Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19).
      particularly in the context of open-label use of experimental treatments such as hydroxychloroquine.
      • Giudicessi J.R.
      • Noseworthy P.A.
      • Friedman P.A.
      • Ackerman M.J.
      Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19).
      In aggregate, adverse cardiac events occurred in ~3% of patients transfused with COVID-19 convalescent plasma. The vast majority of adverse cardiac events of interest were deemed unrelated to the plasma transfusion (88%) by the treating physicians. Collectively, these data suggest that transfusion of COVID-19 convalescent plasma per se does not demonstrably increase the risk of adverse cardiac events. We note that the incidence of TRALI and TACO reported in this study of 0.10% and 0.10%, respectively, is significantly lower than those reported in previous studies, which ranged from 5% to 8% and 1% to 4%, respectively,
      • Roubinian N.
      TACO and TRALI: biology, risk factors, and prevention strategies.
      despite the fact that many of the COVID-19 patients receiving plasma were critically ill and likely at risk for clinical conditions which mimic TACO.

      Study Limitations

      Although this study was not designed to evaluate efficacy of convalescent plasma, we note with optimism that after 20,000 transfused patients, the 7-day mortality rate (13.0%) is low (Table 2). Although the mortality rate has decreased (Figure 2), we note that the clinical characteristics of the transfused patients in the EAP have shifted toward less critically ill patients and lower proportions of apparent “rescue therapy.” No therapy has been introduced into clinical use during this period which reduces (to our knowledge) mortality in hospitalized patients with COVID-19. We postulate that several potential explanations may explain the observed decline in mortality. The ability and success of the US health care community at managing hospitalized COVID-19 patients is likely improving. Second, the blood banking communities have enhanced the availability of convalescent plasma such that more patients received plasma earlier in their hospital course. The more expeditious delivery of plasma to patients reflects improved logistics for the collection, deployment, and use of convalescent plasma, and a larger COVID-19 recovered population that may be potential plasma donors. In this regard it is remarkable that there was no system in place for convalescent plasma use in March 2020 and yet within months the nation is now able to meet most of the demand, despite complex logistics.
      • Bloch E.M.
      • Shoham S.
      • Casadevall A.
      • et al.
      Deployment of convalescent plasma for the prevention and treatment of COVID-19.
      Given the historical experience that antibody therapies are most effective when given earlier and that convalescent plasma has reduced mortality in prior epidemics,
      • Casadevall A.
      • Pirofski L.A.
      The convalescent sera option for containing COVID-19.
      the lower mortality in more recently treated patients would be consistent with greater efficacy from earlier use. Finally, as recovered COVID-19 patients were more quickly recruited for convalescent plasma donation, the plasma may contain higher levels of neutralizing antibodies or other bioactive elements. However, additional data are required to evaluate these potential explanations for the observed trends.

      Conclusion

      Data from the first 20,000 patients transfused with COVID-19 convalescent plasma show that use of convalescent plasma is safe and carries no excess risk of complications. Indeed, convalescent plasma may be associated with improvement in survival; however, this report does not establish efficacy. Additionally, our data show that the US health care system is improving in its care for those hospitalized for COVID-19 including managing those critically ill patients with multiple comorbidities included in these analyses. Overall, the mortality observed has decreased with our observations and continued use of convalescent plasma. Given the accelerating deployment of this therapy, these emerging data provide early safety indicators of convalescent plasma for COVID-19 treatment and suggest research should shift focus from safety toward determining the efficacy of convalescent plasma.

      Acknowledgments

      The authors thank the dedicated members of the US Convalescent Plasma Expanded Access Program team — Machiko Anderson, Supriya Behl, Lori Bergstrom, Brian Butterfield, Grant Dubbels, Adam Eggert, Ree Erickson, Rebekah Frost, Daniel Gaz, Winston Guo, Starr Guzman, Karina Hex, Vidhu Joshi, Megan Knudson, Tessa Kroeninger, Frances Lynch, Tim Miksch, Lisa Muenkel, Ryan Oldenburg, Amy Olofson, Laura Pacheco-Spann, Dr Kelly Paulson, Dr Sumedha Penheiter, Melanie Peterson, Katrina Pierce, Nicloas Saikali, Jeffrey Schmoll, Pamela Skaran, Lindsay Stromback, Edward Swaray, Morgan Swope, Kristine Tree, Joe Wick, and Janelle Worthington; the members of the Mayo Clinic Institutional Review Board; the Mayo Clinic Office of Human Research Protection; the Mayo Clinic Office of Research Regulatory Support, and in particular Mark Wentworth . The authors thank the Executive Dean of Research at Mayo Clinic , Dr Gregory Gores, and the CEO of Mayo Clinic, Dr Gianrico Farrugia, for their support and assistance; the independent Data and Safety Monitoring Board for their work and oversight of the Expanded Access Program — Drs Allan S. Jaffe (chair), David O. Warner, William G. Morice II, Paula J. Santrach, Robert L. Frye, Lawrence J Appel, and Taimur Sher; the members of the National COVID-19 Convalescent Plasma Project (http://ccpp19.org) for their intellectual contributions and support; the participating medical centers and medical teams and blood centers for their rigorous efforts necessary to make this program possible; the donors for providing COVID-19 convalescent plasma; Drs Joyner, Bruno, Klassen, Kunze, Johnson, Lesser, Wiggins, Senefeld, and Klompas are co-first authors. Drs Paneth, Verdun, Marks, Casadevall, Fairweather, Carter, and Wright are co-senior authors.

      Supplemental Online Material

      References

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      Linked Article

      • Micro-Thrombosis, Perfusion Defects, and Worsening Oxygenation in COVID-19 Patients: A Word of Caution on the Use of Convalescent Plasma
        Mayo Clinic ProceedingsVol. 96Issue 1
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          Joyner et al1 recently provided a safety update on the use of convalescent plasma (CP) in a population of 20,000 patients with coronavirus disease-19 (COVID-19). The results on the safety aspects, elegantly presented by the authors, may seem encouraging from many perspectives. However, we would like to comment on an extremely important aspect when considering the use of CP.
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      • Limitations of Safety Update on Convalescent Plasma Transfusion in COVID-19 Patients
        Mayo Clinic ProceedingsVol. 95Issue 12
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          Joyner et al1 have reported a safety update on the use of convalescent plasma transfusion in a convenience sample of 20,000 hospitalized patients with coronavirus disease 2019 (COVID-19). The authors should be applauded for undertaking this monumental effort in providing the medical community with this valuable data in a timely manner amid the pandemic. Upon reflecting on the methods and results, I would like to express reservation on some of the methods used and how the findings were interpreted.
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      • In Reply — Micro-Thrombosis, Perfusion Defects, and Worsening Oxygenation in COVID-19 Patients: A Word of Caution on the Use of Convalescent Plasma
        Mayo Clinic ProceedingsVol. 96Issue 1
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          We would like to thank our colleagues for their letter in response to our manuscript. The letter raises important theoretical concerns about the impact of procoagulant factors in plasma on the coagulation cascade in the context of patients with severe COVID-19.1 Generally, we agree with the word of caution regarding the use of convalescent plasma in the context of patients with severe COVID-19 and evidence of dysregulated hemostasis, as observed among patients who required extracorporeal membrane oxygenation (ECMO) support.
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      • In Reply — Limitations of Safety Update on Convalescent Plasma Transfusion in COVID-19 Patients
        Mayo Clinic ProceedingsVol. 95Issue 12
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          The authors thank Dr Farag for his letter in response to our manuscript “Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients.”1 The letter raises important questions about the presentation of our updated safety report from the Convalescent Plasma Expanded Access Program (EAP). The fundamental element of our response to all of the questions raised by Dr Farag is the need to frame the context of the paper. Establishing clinical efficacy for a potential therapeutic agent deployed during a public health crisis involves a climb through an epistemic ladder, and the comments from Dr Farag primarily highlight future rungs of that ladder.
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      • In the Limelight: September 2020
        Mayo Clinic ProceedingsVol. 95Issue 9
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          This month’s feature highlights five articles on COVID-19 that appear in the current print and online issue of Mayo Clinic Proceedings. These articles are also featured on the Mayo Clinic Proceedings’ YouTube Channel ( https://youtu.be/MT3ZFDAOKYU ).
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