Convalescent plasma use in the USA was inversely correlated with COVID-19 mortality
Curation statements for this article:-
Curated by eLife
Evaluation Summary:
This work is of interest to clinicians, epidemiologists and policy makers as it raises concerns about under-utilization of convalescent plasma (CCP) therapy during the Covid-19 pandemic, which in turn led to an increased number of preventable patient deaths. The authors demonstrate an inverse correlation between CCP use and mortality per admission in the US. They estimate that reduced use of CCP may have resulted in 29,000 to 36,000 excess deaths over the past year in the US.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
The US Food and Drug Administration authorized COVID-19 convalescent plasma (CCP) therapy for hospitalized COVID-19 patients via the Expanded Access Program (EAP) and the Emergency Use Authorization (EUA), leading to use in about 500,000 patients during the first year of the pandemic for the USA.
Methods:
We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data.
Results:
CCP usage per admission peaked in Fall 2020, with more than 40% of inpatients estimated to have received CCP between late September and early November 2020. However, after randomized controlled trials failed to show a reduction in mortality, CCP usage per admission declined steadily to a nadir of less than 10% in March 2021. We found a strong inverse correlation (r = −0.52, p=0.002) between CCP usage per hospital admission and deaths occurring 2 weeks after admission, and this finding was robust to examination of deaths taking place 1, 2, or 3 weeks after admission. Changes in the number of hospital admissions, SARS-CoV-2 variants, and age of patients could not explain these findings. The retreat from CCP usage might have resulted in as many as 29,000 excess deaths from mid-November 2020 to February 2021.
Conclusions:
A strong inverse correlation between CCP use and mortality per admission in the USA provides population-level evidence consistent with the notion that CCP reduces mortality in COVID-19 and suggests that the recent decline in usage could have resulted in excess deaths.
Funding:
There was no specific funding for this study. AC was supported in part by RO1 HL059842 and R01 AI1520789; MJJ was supported in part by 5R35HL139854. This project has been funded in whole or in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority under Contract No. 75A50120C00096.
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Author Response:
Reviewer #1:
In the early days of the pandemic there was unqualified enthusiasm for convalescent plasma therapy. This enthusiasm shifted dramatically as several trials showed no apparent benefit. Although this manuscript does not show a causal relationship between convalescent plasma therapy and prognosis it is provocative and suggests that further work is needed to assess its utility.
Strengths of the manuscript include the comprehensive review of existing datasets and the use of state-of-the-art statistical methods for examining potential confounders such as patient age, seasonal variation in hospital admissions that might have impacted quality of care, and the emergence of SARS-CoV-2 variants. Weaknesses include lack of data that might have enabled identification of patients who are likely to benefit from …
Author Response:
Reviewer #1:
In the early days of the pandemic there was unqualified enthusiasm for convalescent plasma therapy. This enthusiasm shifted dramatically as several trials showed no apparent benefit. Although this manuscript does not show a causal relationship between convalescent plasma therapy and prognosis it is provocative and suggests that further work is needed to assess its utility.
Strengths of the manuscript include the comprehensive review of existing datasets and the use of state-of-the-art statistical methods for examining potential confounders such as patient age, seasonal variation in hospital admissions that might have impacted quality of care, and the emergence of SARS-CoV-2 variants. Weaknesses include lack of data that might have enabled identification of patients who are likely to benefit from convalescent plasma and characteristics of plasma (such as neutralization titers) that may be associated with efficacy. These weaknesses do not indicate a lack of effort on the part of the team; there is simply no way to obtain the data.
We appreciate the reviewer kind words. We are aware of efforts by others who are doing extensive electronic health record analysis and are expected to have data on plasma characteristics and outcome.
Reviewer #2:
The use of convalescent plasma (CCP) to treat patients with Covid-19 has changed over the course of the pandemic (from rates as high as 40% of hospitalized patients in October, 2020 to a low of less than 10% by March 2021). To explore the efficacy of CCP therapy and the impact of the drop in CCP use, the authors assess whether there was a link between CCP use and patient mortality rates over time in the U.S. Using information from blood centers to estimate CCP usage and population level information on deaths from public databases, they found a strong inverse correlation between CCP usage per hospital admission and deaths due to Covid-19 after admission. The model estimates that the case fatality rate decreased by 1.8 percentage points for every 10 percentage point increase in the rate of CCP use. The detailed analysis suggests that the observed effect could not be attributed to changes in patient ages over time or the emergence of variant viruses. Other cofounders such as changes in the use of additional therapeutic agents or clinical interventions were not analyzed. The authors acknowledge the main limitation of this type of analysis i.e. that establishing a correlation does not prove a causal role. With that caveat, they conclude that the decline in usage may have resulted in excess deaths, possibly 29,000 to 36,000 over the past year in the U.S. Because the decreased usage of CCP occurred during the time that several randomized clinical trials and some media coverage reported no benefit of CCP, the authors suggest that resultant "plasma hesitancy" may have contributed to increased mortality. These findings add an important perspective to future considerations for clinical care, treatment guidelines and regulatory approvals of CCP. Emphasizing the importance of using high-titer units and administering CCP early in the disease course, the authors urge a more nuanced interpretation of the available evidence and a holistic approach to decisions about the use of CCP in individual patients.
Reviewer #3:
This is an important manuscript on COVID-19 convalescent plasma (CCP) that challenges the findings of the larger Mayo Clinic CCP study demonstrating a lack of efficacy. Their main findings are that there is a strong inverse correlation between CCP use and mortality for admitted patients in the USA. Overall this is a well written manuscript without any overt weaknesses.
We appreciate the kind words.
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Reviewer #3 (Public Review):
This is an important manuscript on COVID-19 convalescent plasma (CCP) that challenges the findings of the larger Mayo Clinic CCP study demonstrating a lack of efficacy. Their main findings are that there is a strong inverse correlation between CCP use and mortality for admitted patients in the USA. Overall this is a well written manuscript without any overt weaknesses.
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Reviewer #2 (Public Review):
The use of convalescent plasma (CCP) to treat patients with Covid-19 has changed over the course of the pandemic (from rates as high as 40% of hospitalized patients in October, 2020 to a low of less than 10% by March 2021). To explore the efficacy of CCP therapy and the impact of the drop in CCP use, the authors assess whether there was a link between CCP use and patient mortality rates over time in the U.S. Using information from blood centers to estimate CCP usage and population level information on deaths from public databases, they found a strong inverse correlation between CCP usage per hospital admission and deaths due to Covid-19 after admission. The model estimates that the case fatality rate decreased by 1.8 percentage points for every 10 percentage point increase in the rate of CCP use. The …
Reviewer #2 (Public Review):
The use of convalescent plasma (CCP) to treat patients with Covid-19 has changed over the course of the pandemic (from rates as high as 40% of hospitalized patients in October, 2020 to a low of less than 10% by March 2021). To explore the efficacy of CCP therapy and the impact of the drop in CCP use, the authors assess whether there was a link between CCP use and patient mortality rates over time in the U.S. Using information from blood centers to estimate CCP usage and population level information on deaths from public databases, they found a strong inverse correlation between CCP usage per hospital admission and deaths due to Covid-19 after admission. The model estimates that the case fatality rate decreased by 1.8 percentage points for every 10 percentage point increase in the rate of CCP use. The detailed analysis suggests that the observed effect could not be attributed to changes in patient ages over time or the emergence of variant viruses. Other cofounders such as changes in the use of additional therapeutic agents or clinical interventions were not analyzed. The authors acknowledge the main limitation of this type of analysis i.e. that establishing a correlation does not prove a causal role. With that caveat, they conclude that the decline in usage may have resulted in excess deaths, possibly 29,000 to 36,000 over the past year in the U.S. Because the decreased usage of CCP occurred during the time that several randomized clinical trials and some media coverage reported no benefit of CCP, the authors suggest that resultant "plasma hesitancy" may have contributed to increased mortality. These findings add an important perspective to future considerations for clinical care, treatment guidelines and regulatory approvals of CCP. Emphasizing the importance of using high-titer units and administering CCP early in the disease course, the authors urge a more nuanced interpretation of the available evidence and a holistic approach to decisions about the use of CCP in individual patients.
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Reviewer #1 (Public Review):
In the early days of the pandemic there was unqualified enthusiasm for convalescent plasma therapy. This enthusiasm shifted dramatically as several trials showed no apparent benefit. Although this manuscript does not show a causal relationship between convalescent plasma therapy and prognosis it is provocative and suggests that further work is needed to assess its utility.
Strengths of the manuscript include the comprehensive review of existing datasets and the use of state-of-the-art statistical methods for examining potential confounders such as patient age, seasonal variation in hospital admissions that might have impacted quality of care, and the emergence of SARS-CoV-2 variants. Weaknesses include lack of data that might have enabled identification of patients who are likely to benefit from convalescent …
Reviewer #1 (Public Review):
In the early days of the pandemic there was unqualified enthusiasm for convalescent plasma therapy. This enthusiasm shifted dramatically as several trials showed no apparent benefit. Although this manuscript does not show a causal relationship between convalescent plasma therapy and prognosis it is provocative and suggests that further work is needed to assess its utility.
Strengths of the manuscript include the comprehensive review of existing datasets and the use of state-of-the-art statistical methods for examining potential confounders such as patient age, seasonal variation in hospital admissions that might have impacted quality of care, and the emergence of SARS-CoV-2 variants. Weaknesses include lack of data that might have enabled identification of patients who are likely to benefit from convalescent plasma and characteristics of plasma (such as neutralization titers) that may be associated with efficacy. These weaknesses do not indicate a lack of effort on the part of the team; there is simply no way to obtain the data.
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Evaluation Summary:
This work is of interest to clinicians, epidemiologists and policy makers as it raises concerns about under-utilization of convalescent plasma (CCP) therapy during the Covid-19 pandemic, which in turn led to an increased number of preventable patient deaths. The authors demonstrate an inverse correlation between CCP use and mortality per admission in the US. They estimate that reduced use of CCP may have resulted in 29,000 to 36,000 excess deaths over the past year in the US.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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SciScore for 10.1101/2021.04.07.21255089: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
No key resources detected.
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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
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…
SciScore for 10.1101/2021.04.07.21255089: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
No key resources detected.
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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
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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