Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience
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Abstract
Importance
Passive antibody transfer is a longstanding treatment strategy for infectious diseases that involve the respiratory system. In this context, human convalescent plasma has been used to treat coronavirus disease 2019 (COVID-19), but the efficacy remains uncertain.
Objective
To explore potential signals of efficacy of COVID-19 convalescent plasma.
Design
Open-label, Expanded Access Program (EAP) for the treatment of COVID-19 patients with human convalescent plasma.
Setting
Multicenter, including 2,807 acute care facilities in the US and territories.
Participants
Adult participants enrolled and transfused under the purview of the US Convalescent Plasma EAP program between April 4 and July 4, 2020 who were hospitalized with (or at risk of) severe or life threatening acute COVID-19 respiratory syndrome.
Intervention
Transfusion of at least one unit of human COVID-19 convalescent plasma using standard transfusion guidelines at any time during hospitalization. Convalescent plasma was donated by recently-recovered COVID-19 survivors, and the antibody levels in the units collected were unknown at the time of transfusion.
Main Outcomes and Measures
Seven and thirty-day mortality.
Results
The 35,322 transfused patients had heterogeneous demographic and clinical characteristics. This cohort included a high proportion of critically-ill patients, with 52.3% in the intensive care unit (ICU) and 27.5% receiving mechanical ventilation at the time of plasma transfusion. The seven-day mortality rate was 8.7% [95% CI 8.3%-9.2%] in patients transfused within 3 days of COVID-19 diagnosis but 11.9% [11.4%-12.2%] in patients transfused 4 or more days after diagnosis (p<0.001). Similar findings were observed in 30-day mortality (21.6% vs. 26.7%, p<0.0001). Importantly, a gradient of mortality was seen in relation to IgG antibody levels in the transfused plasma. For patients who received high IgG plasma (>18.45 S/Co), seven-day mortality was 8.9% (6.8%, 11.7%); for recipients of medium IgG plasma (4.62 to 18.45 S/Co) mortality was 11.6% (10.3%, 13.1%); and for recipients of low IgG plasma (<4.62 S/Co) mortality was 13.7% (11.1%, 16.8%) (p=0.048). This unadjusted dose-response relationship with IgG was also observed in thirty-day mortality (p=0.021). The pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days compared to low antibody level plasma units.
Conclusions and Relevance
The relationships between reduced mortality and both earlier time to transfusion and higher antibody levels provide signatures of efficacy for convalescent plasma in the treatment of hospitalized COVID-19 patients. This information may be informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma.
Trial Registration
ClinicalTrials.gov Identifier: NCT04338360
Key Points
Question
Does transfusion of human convalescent plasma reduce mortality among hospitalized COVID-19 patients?
Findings
Transfusion of convalescent plasma with higher antibody levels to hospitalized COVID-19 patients significantly reduced mortality compared to transfusions with low antibody levels. Transfusions within three days of COVID-19 diagnosis yielded greater reductions in mortality.
Meaning
Embedded in an Expanded Access Program providing access to COVID-19 convalescent plasma and designed to assess its safety, several signals consistent with efficacy of convalescent plasma in the treatment of hospitalized COVID-19 patients emerged.
Article activity feed
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SciScore for 10.1101/2020.08.12.20169359: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The Mayo Clinic Institutional Review Board (IRB) was the central IRB, approved the protocol all modifications, and performed regulatory oversight for all sites and investigators.
Consent: Written informed consent was obtained from the participant or a legally-authorized representative prior to enrollment, except for those patients who necessitated use of an emergency consent process defined in collaboration with the US FDA.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources Plasma Collection: Convalescent plasma was obtained from a registered or … SciScore for 10.1101/2020.08.12.20169359: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The Mayo Clinic Institutional Review Board (IRB) was the central IRB, approved the protocol all modifications, and performed regulatory oversight for all sites and investigators.
Consent: Written informed consent was obtained from the participant or a legally-authorized representative prior to enrollment, except for those patients who necessitated use of an emergency consent process defined in collaboration with the US FDA.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources Plasma Collection: Convalescent plasma was obtained from a registered or licensed blood collector, and COVID-19 antibody levels were unknown at the time of plasma collection. COVID-19suggested: NoneResults of this assay are based on the sample signal-to-cut-off (S/Co) ratio, with values <1.0 and ≥1.00 corresponding to negative and positive results, The S/Co values reflect relative levels of anti-SARS-CoV-2 antibodies. anti-SARS-CoV-2suggested: NoneBased on insights from the pre-antibiotic era that antibody therapy was most effective when given early2,13, our cohort was stratified into categories based on the days from COVID-19 diagnosis to plasma transfusion, including: 0, 1-3, 4-10, and 11 or more days and for some graphical presentations and analyses, dichotomized into 0-3 vs. 4 or more days. 1-3suggested: None4-10suggested: NoneSoftware and Algorithms Sentences Resources Data Entry: Web-based, standardized data reporting surveys were completed to assess the clinical status of patients using the Research Electronic Data Capture system (REDCap, v.9.1.15 Vanderbilt University, Nashville, TN)10,11, with FDA authorization, as previously described7,8. REDCapsuggested: (REDCap, RRID:SCR_003445)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Limitations: The design of the EAP has been criticized because it was not a randomized placebo, controlled trial (RCT)18. We started the EAP in late March 2020. It was designed to provide access to convalescent plasma largely at hospitals and acute care facilities that were not already part of a RCT or did not have the infrastructure to support complex RCTs. We also envisioned modest total enrollment and our original IRB approval was for 5,000 patients. In this context, our primary goal was to report on the safety of convalescent plasma and to perform an exploratory analysis for potential signals of efficacy. As described earlier, the EAP was a pragmatic study design, organized to allow routine clinical care to dictate the timing and administration of plasma with the collection of real world data. We did not prespecify which medications patients should be on to participate. The enrollment and data collection forms were streamlined to make participation easy for sites engulfed in the work of a pandemic. The use of a central, academic IRB allowed for consistent data evaluation and oversight. We streamlined PI credentialing and IRB reliance processes. All forms were web-based at a time when some believed that SARS-CoV-2 might be transmitted via paper contaminated with the virus. We did not randomly assign treatment strategies or use of adjunctive medications. Nonetheless, there were some elements of randomization or pseudo-randomization in our study. Physicians could choose the ...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04338360 Approved for marketing Expanded Access to Convalescent Plasma for the Treatment of … Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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SciScore for 10.1101/2020.08.12.20169359: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement The Mayo Clinic Institutional Review Board (IRB) was the central IRB, approved the protocol all modifications, and performed regulatory oversight for all sites and investigators. Randomization Limitations The design of the EAP has been criticized because it was not a randomized placebo, controlled trial (RCT)18. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources Plasma Collection Convalescent plasma was obtained from a registered or licensed blood collector, and COVID-19 antibody levels were unknown at the time of plasma collection. CO…SciScore for 10.1101/2020.08.12.20169359: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement The Mayo Clinic Institutional Review Board (IRB) was the central IRB, approved the protocol all modifications, and performed regulatory oversight for all sites and investigators. Randomization Limitations The design of the EAP has been criticized because it was not a randomized placebo, controlled trial (RCT)18. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources Plasma Collection Convalescent plasma was obtained from a registered or licensed blood collector, and COVID-19 antibody levels were unknown at the time of plasma collection. COVID-19suggested: NoneAntibody testing Binding antibody levels from sera were tested using the Ortho-Clinical Diagnostics VITROS Anti-SARS-CoV-2 IgG chemiluminescent immunoassay (CLIA) in accordance with manufacturer instructions12. Anti-SARS-CoV-2 IgGsuggested: NoneBased on insights from the pre-antibiotic era that antibody therapy was most effective when given early2,13, our cohort was stratified into categories based on the days from COVID-19 diagnosis to plasma transfusion, including: 0, 1-3, 4-10, and 11 or more days and for some graphical presentations and analyses, dichotomized into 0-3 vs. 4 or more days. 1-3suggested: None4-10suggested: NoneSoftware and Algorithms Sentences Resources Data Entry Web-based, standardized data reporting surveys were completed to assess the clinical status of patients using the Research Electronic Data Capture system (REDCap, v.9.1.15 Vanderbilt University, Nashville, TN)10,11, with FDA authorization, as previously described7,8. REDCapsuggested: (REDCap, RRID:SCR_003445)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
Limitations The design of the EAP has been criticized because it was not a randomized placebo, controlled trial (RCT)18. We started the EAP in late March 2020. It was designed to provide access to convalescent plasma largely at hospitals and acute care facilities that were not already part of a RCT or did not have the infrastructure to support complex RCTs. We also envisioned modest total enrollment and our original IRB approval was for 5,000 patients. In this context, our primary goal was to report on the safety of convalescent plasma and to perform an exploratory analysis for potential signals of efficacy. As described earlier, the EAP was a pragmatic study design, organized to allow routine clinical care to dictate the timing and administration of plasma with the collection of real world data. We did not prespecify which medications patients should be on to participate. The enrollment and data collection forms were streamlined to make participation easy for sites engulfed in the work of a pandemic. The use of a central, academic IRB allowed for consistent data evaluation and oversight. We streamlined PI credentialing and IRB reliance processes. All forms were web-based at a time when some believed that SARS-CoV-2 might be transmitted via paper contaminated with the virus. We did not randomly assign treatment strategies or use of adjunctive medications. Nonetheless, there were some elements of randomization or pseudo-randomization in our study. Physicians could choose the timing of convalescent plasma, the number of units administered, any repeat therapies and whether ICU or mechanically ventilated patients were included. Furthermore, the degree of immune activity within the units of convalescent plasma (i.e. specific IgG levels) was not known. It was assumed that patients would receive plasma with low, medium and high antibody levels in a pseudorandomized manner and that would enable assessment of efficacy. We acknowledge that RCTs produce evidence of the highest quality in most but not all clinical situations. RCTs can occur when a number of specific criteria are present which allow their conduct. First, RCTs necessitate a stable supply of investigational product (i.e. convalescent plasma) or placebo/comparator which can be pre-positioned at all participating sites. The supply of convalescent plasma in April was not sufficient for such collection and pre-positioning. Second, RCTs require sufficient numbers of sites pandemic has migrated across different US regions every few weeks, making it challenging to predict where sites should be selected and prepared for a RCT. Third, sites must be validated and activated. This work requires training of the investigators and study team members as well as typically on-site visits. The crises of the COVID-19 pandemic were not compatible with these site training and activation activities; travel within the US has been restricted and staff sent to activate sites would likely have been quarantined for two weeks before being able to go to another region to activate sites. Fourth, the very nature of a RCT requires subject willingness to be randomized to active treatment or placebo or a comparator agent. There was no consensus in April nor is there a global consensus now regarding what would be an appropriate placebo-control to use. Fifth, many COVID-19 patients would likely have been distrustful of being randomized to a placebo based upon historical precedent. Sixth, the number of sites who could have participated in a RCT is limited; who was the appropriate ethical entity to pick those sites and to exclude other sites? Our design allowed any willing hospital, PI and patient to be included in the pragmatic, real-world data study. Finally, there were ongoing small RCTs when we started this program. Physicians, hospitals and patients have the choices of this program versus a RCT. It is clear that over 90,000 patients and over 10,000 physicians elected to participate in the pragmatic, real-world evidence study design. We did not indicate our study would prove efficacy or even offer potential help. It was clear that it was a research investigation and informed consent was obtained in all subjects prior to the transfusion of plasma. Perhaps the current design can inform trialists and RCT advocates of the importance of study designs which are easy and simple to join/enroll and which make the workload of participation as easy and clinically relevant as possible.
Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from JetFighter: We did not find any issues relating to colormaps.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.
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