Significantly Decreased Mortality in a Large Cohort of Coronavirus Disease 2019 (COVID-19) Patients Transfused Early with Convalescent Plasma Containing High-Titer Anti–Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein IgG
Eric Salazar, Paul A Christensen, Edward A Graviss, Duc T Nguyen, Brian Castillo, Jian Chen, Bevin V Lopez, Todd N Eagar, Xin Yi, Picheng Zhao, John Rogers, Ahmed Shehabeldin, David Joseph, Faisal Masud, Christopher Leveque, Randall J Olsen, David W Bernard, Jimmy Gollihar, M.D James M Musser
The American Journal of Pathology, doi:10.1016/j.ajpath.2020.10.008
Coronavirus disease 2019 (COVID-19) convalescent plasma has emerged as a promising therapy and has been granted Emergency Use Authorization by the US Food and Drug Administration for hospitalized COVID-19 patients. We recently reported results from interim analysis of a propensity scoreematched study suggesting that early treatment of COVID-19 patients with convalescent plasma containing hightiter anti-spike protein receptor binding domain (RBD) IgG significantly decreases mortality. We herein present results from a 60-day follow-up of a cohort of 351 transfused hospitalized patients. Prospective determination of enzyme-linked immunosorbent assay anti-RBD IgG titer facilitated selection and transfusion of the highest titer units available. Retrospective analysis by the Ortho VITROS IgG assay revealed a median signal/cutoff ratio of 24.0 for transfused units, a value far exceeding the recent US Food and Drug Administrationerequired cutoff of 12.0 for designation of high-titer convalescent plasma. With respect to altering mortality, our analysis identified an optimal window of 44 hours after hospitalization for transfusing COVID-19 patients with high-titer convalescent plasma. In the aggregate, the analysis confirms and extends our previous preliminary finding that transfusion of COVID-19 patients soon after hospitalization with high-titer anti-spike protein RBD IgG present in convalescent plasma significantly reduces mortality.
Author Contributions E.S. and J.M.M. conceived the project; E.S., P.A.C., E.A.G., D.T.N., B.C., J.C., B.V.L., T.N.E., X.Y., P.Z., J.R., A.S., D.J., and J.G. acquired data; E.S., P.A.C., E.A.G., D.T.N., B.C., J.C., and J.M.M. analyzed data; E.S., P.A.C., E.A.G., D.T.N., and J.M.M. wrote the manuscript; E.S., P.A.C., E.A.G., D.T.N., and J.M.M. prepared figures; C.L., R.J.O., D.W.B., F.M., and J.G. provided scholarly advice; all authors revised the manuscript and gave final approval for publication. J.M.M. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Supplemental Data Supplemental material for this article can be found at http://doi.org/10.1016/j.ajpath.2020.10.008.
References
Agarwal, Mukherjee, Kumar, Chatterjee, Bhatnagar et al., Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial), BMJ
Avendano-Sola, Ramos-Martinez, Munez-Rubio, Ruiz-Antoran, De Molina et al., Convalescent plasma for COVID-19: a multicenter, randomized clinical trial, medRxiv,
doi:10.1101/2020.08.26.20182444Balcells, Rojas, Corre, Martínez-Valdebenito, Ceballos et al., Early anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: a randomized phase II clinical trial, medRxiv,
doi:10.1101/2020.09.17.20196212Barone, Desimone, Convalescent plasma to treat coronavirus disease 2019 (COVID-19): considerations for clinical trial design, Transfusion
Bohn, Hall, Sepiashvili, Jung, Steele et al., Pathophysiology of COVID-19: mechanisms underlying disease severity and progression, Physiology
Casadevall, Pirofski, The convalescent sera option for containing COVID-19, J Clin Invest
Eckhardt, Cummings, Rajagopalan, Borden, Bitan et al., Evaluating the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in severely ill adults with COVID-19: a structured summary of a study protocol for a randomized controlled trial, Trials
Gharbharan, Jordans, Geurtsvankessel, Hollander, Karim et al., Convalescent plasma for COVID-19: a randomized clinical trial, medRxiv,
doi:10.1101/2020.07.01.20139857Hastie, Tibshirani, Wainwright, Statistical Learning with Sparsity: The Lasso and Generalizations
Hegerova, Gooley, Sweerus, Maree, Bailey et al., Use of convalescent plasma in hospitalized patients with Covid-19: case series, Blood
Joyner, Senefeld, Klassen, Mills, Johnson et al., Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience, medRxiv,
doi:10.1101/2020.08.12.20169359Klassen, Senefeld, Johnson, Carter, Wiggins et al., Evidence favouring the efficacy of convalescent plasma for COVID-19 therapy, medRxiv,
doi:10.1101/2020.07.29.20162917Lasso, Stata Reference Manual: Release 16
Li, Zhang, Hu, Tong, Zheng et al., Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial, JAMA
Liu, Lin, Baine, Wajnberg, Gumprecht et al., Convalescent plasma treatment of severe COVID-19: a matched control study, Nat Med
Rosenbaum, Db, The central role of the propensity score in observational studies for causal effects, Biometrika
Salazar, Christensen, Graviss, Nguyen, Castillo et al., Treatment of coronavirus disease 2019 patients with convalescent plasma reveals a signal of significantly decreased mortality, Am J Pathol
Salazar, Kuchipudi, Christensen, Eagar, Yi et al., Convalescent plasma anti-SARS-CoV-2 spike protein ectodomain and receptor binding domain IgG correlate with virus neutralization, J Clin Invest
Salazar, Kuchipudi, Christensen, Eagar, Yi et al., Relationship between anti-spike protein antibody titers and SARS-CoV-2 in vitro virus neutralization in convalescent plasma, bioRxiv,
doi:10.1101/2020.06.08.138990Salazar, Perez, Ashraf, Chen, Castillo et al., Treatment of coronavirus disease 2019 (COVID-19) patients with convalescent plasma, Am J Pathol
Youden, Index for rating diagnostic tests, Cancer
DOI record:
{
"DOI": "10.1016/j.ajpath.2020.10.008",
"ISSN": [
"0002-9440"
],
"URL": "http://dx.doi.org/10.1016/j.ajpath.2020.10.008",
"alternative-id": [
"S0002944020304892"
],
"assertion": [
{
"label": "This article is maintained by",
"name": "publisher",
"value": "Elsevier"
},
{
"label": "Article Title",
"name": "articletitle",
"value": "Significantly Decreased Mortality in a Large Cohort of Coronavirus Disease 2019 (COVID-19) Patients Transfused Early with Convalescent Plasma Containing High-Titer Anti–Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein IgG"
},
{
"label": "Journal Title",
"name": "journaltitle",
"value": "The American Journal of Pathology"
},
{
"label": "CrossRef DOI link to publisher maintained version",
"name": "articlelink",
"value": "https://doi.org/10.1016/j.ajpath.2020.10.008"
},
{
"label": "Content Type",
"name": "content_type",
"value": "article"
},
{
"label": "Copyright",
"name": "copyright",
"value": "© 2021 American Society for Investigative Pathology. Published by Elsevier Inc."
}
],
"author": [
{
"ORCID": "http://orcid.org/0000-0003-1961-3125",
"affiliation": [],
"authenticated-orcid": false,
"family": "Salazar",
"given": "Eric",
"sequence": "first"
},
{
"affiliation": [],
"family": "Christensen",
"given": "Paul A.",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0003-1024-5813",
"affiliation": [],
"authenticated-orcid": false,
"family": "Graviss",
"given": "Edward A.",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0002-5059-4404",
"affiliation": [],
"authenticated-orcid": false,
"family": "Nguyen",
"given": "Duc T.",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0001-5392-2373",
"affiliation": [],
"authenticated-orcid": false,
"family": "Castillo",
"given": "Brian",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Chen",
"given": "Jian",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Lopez",
"given": "Bevin V.",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Eagar",
"given": "Todd N.",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Yi",
"given": "Xin",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Zhao",
"given": "Picheng",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Rogers",
"given": "John",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Shehabeldin",
"given": "Ahmed",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0002-0848-5423",
"affiliation": [],
"authenticated-orcid": false,
"family": "Joseph",
"given": "David",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Masud",
"given": "Faisal",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Leveque",
"given": "Christopher",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Olsen",
"given": "Randall J.",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0002-7276-1197",
"affiliation": [],
"authenticated-orcid": false,
"family": "Bernard",
"given": "David W.",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Gollihar",
"given": "Jimmy",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Musser",
"given": "James M.",
"sequence": "additional"
}
],
"container-title": "The American Journal of Pathology",
"container-title-short": "The American Journal of Pathology",
"content-domain": {
"crossmark-restriction": true,
"domain": [
"clinicalkey.jp",
"clinicalkey.com",
"ajp.amjpathol.org",
"clinicalkey.es",
"clinicalkey.com.au",
"clinicalkey.fr",
"elsevier.com",
"sciencedirect.com"
]
},
"created": {
"date-parts": [
[
2020,
11,
4
]
],
"date-time": "2020-11-04T03:34:35Z",
"timestamp": 1604460875000
},
"deposited": {
"date-parts": [
[
2022,
1,
1
]
],
"date-time": "2022-01-01T17:55:10Z",
"timestamp": 1641059710000
},
"funder": [
{
"DOI": "10.13039/100015158",
"doi-asserted-by": "publisher",
"name": "Fondren Foundation"
},
{
"DOI": "10.13039/100015190",
"doi-asserted-by": "publisher",
"name": "Houston Methodist Hospital"
},
{
"DOI": "10.13039/100015581",
"doi-asserted-by": "publisher",
"name": "Houston Methodist Research Institute"
}
],
"indexed": {
"date-parts": [
[
2024,
3,
29
]
],
"date-time": "2024-03-29T06:36:12Z",
"timestamp": 1711694172880
},
"is-referenced-by-count": 118,
"issue": "1",
"issued": {
"date-parts": [
[
2021,
1
]
]
},
"journal-issue": {
"issue": "1",
"published-print": {
"date-parts": [
[
2021,
1
]
]
}
},
"language": "en",
"license": [
{
"URL": "https://www.elsevier.com/tdm/userlicense/1.0/",
"content-version": "tdm",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2021,
1,
1
]
],
"date-time": "2021-01-01T00:00:00Z",
"timestamp": 1609459200000
}
},
{
"URL": "http://www.elsevier.com/open-access/userlicense/1.0/",
"content-version": "vor",
"delay-in-days": 365,
"start": {
"date-parts": [
[
2022,
1,
1
]
],
"date-time": "2022-01-01T00:00:00Z",
"timestamp": 1640995200000
}
}
],
"link": [
{
"URL": "https://api.elsevier.com/content/article/PII:S0002944020304892?httpAccept=text/xml",
"content-type": "text/xml",
"content-version": "vor",
"intended-application": "text-mining"
},
{
"URL": "https://api.elsevier.com/content/article/PII:S0002944020304892?httpAccept=text/plain",
"content-type": "text/plain",
"content-version": "vor",
"intended-application": "text-mining"
}
],
"member": "78",
"original-title": [],
"page": "90-107",
"prefix": "10.1016",
"published": {
"date-parts": [
[
2021,
1
]
]
},
"published-print": {
"date-parts": [
[
2021,
1
]
]
},
"publisher": "Elsevier BV",
"reference": [
{
"key": "10.1016/j.ajpath.2020.10.008_bib1",
"series-title": "COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU)",
"year": "2020"
},
{
"article-title": "Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience",
"author": "Joyner",
"journal-title": "medRxiv",
"key": "10.1016/j.ajpath.2020.10.008_bib2",
"year": "2020"
},
{
"DOI": "10.1016/j.ajpath.2020.08.001",
"article-title": "Treatment of coronavirus disease 2019 patients with convalescent plasma reveals a signal of significantly decreased mortality",
"author": "Salazar",
"doi-asserted-by": "crossref",
"first-page": "2290",
"journal-title": "Am J Pathol",
"key": "10.1016/j.ajpath.2020.10.008_bib3",
"volume": "190",
"year": "2020"
},
{
"article-title": "Evidence favouring the efficacy of convalescent plasma for COVID-19 therapy",
"author": "Klassen",
"journal-title": "medRxiv",
"key": "10.1016/j.ajpath.2020.10.008_bib4",
"year": "2020"
},
{
"article-title": "Relationship between anti-spike protein antibody titers and SARS-CoV-2 in vitro virus neutralization in convalescent plasma",
"author": "Salazar",
"journal-title": "bioRxiv",
"key": "10.1016/j.ajpath.2020.10.008_bib5",
"year": "2020"
},
{
"DOI": "10.1016/j.ajpath.2020.05.014",
"article-title": "Treatment of coronavirus disease 2019 (COVID-19) patients with convalescent plasma",
"author": "Salazar",
"doi-asserted-by": "crossref",
"first-page": "1680",
"journal-title": "Am J Pathol",
"key": "10.1016/j.ajpath.2020.10.008_bib6",
"volume": "190",
"year": "2020"
},
{
"DOI": "10.1172/JCI141206",
"article-title": "Convalescent plasma anti-SARS-CoV-2 spike protein ectodomain and receptor binding domain IgG correlate with virus neutralization",
"author": "Salazar",
"doi-asserted-by": "crossref",
"first-page": "6728",
"journal-title": "J Clin Invest",
"key": "10.1016/j.ajpath.2020.10.008_bib7",
"volume": "130",
"year": "2020"
},
{
"DOI": "10.1111/trf.15843",
"article-title": "Convalescent plasma to treat coronavirus disease 2019 (COVID-19): considerations for clinical trial design",
"author": "Barone",
"doi-asserted-by": "crossref",
"first-page": "1123",
"journal-title": "Transfusion",
"key": "10.1016/j.ajpath.2020.10.008_bib8",
"volume": "60",
"year": "2020"
},
{
"DOI": "10.1038/s41591-020-1088-9",
"article-title": "Convalescent plasma treatment of severe COVID-19: a matched control study",
"author": "Liu",
"doi-asserted-by": "crossref",
"first-page": "1708",
"journal-title": "Nat Med",
"key": "10.1016/j.ajpath.2020.10.008_bib9",
"volume": "26",
"year": "2020"
},
{
"DOI": "10.1093/biomet/70.1.41",
"article-title": "The central role of the propensity score in observational studies for causal effects",
"author": "Rosenbaum",
"doi-asserted-by": "crossref",
"first-page": "41",
"journal-title": "Biometrika",
"key": "10.1016/j.ajpath.2020.10.008_bib10",
"volume": "70",
"year": "1983"
},
{
"author": "Hastie",
"key": "10.1016/j.ajpath.2020.10.008_bib11",
"series-title": "Statistical Learning with Sparsity: The Lasso and Generalizations",
"year": "2015"
},
{
"author": "Lasso",
"key": "10.1016/j.ajpath.2020.10.008_bib12",
"series-title": "Stata Reference Manual: Release 16",
"year": "2020"
},
{
"DOI": "10.1002/1097-0142(1950)3:1<32::AID-CNCR2820030106>3.0.CO;2-3",
"article-title": "Index for rating diagnostic tests",
"author": "Youden",
"doi-asserted-by": "crossref",
"first-page": "32",
"journal-title": "Cancer",
"key": "10.1016/j.ajpath.2020.10.008_bib13",
"volume": "3",
"year": "1950"
},
{
"DOI": "10.1186/s13063-020-04422-y",
"article-title": "Evaluating the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in severely ill adults with COVID-19: a structured summary of a study protocol for a randomized controlled trial",
"author": "Eckhardt",
"doi-asserted-by": "crossref",
"first-page": "499",
"journal-title": "Trials",
"key": "10.1016/j.ajpath.2020.10.008_bib14",
"volume": "21",
"year": "2020"
},
{
"article-title": "Convalescent plasma for COVID-19: a randomized clinical trial",
"author": "Gharbharan",
"journal-title": "medRxiv",
"key": "10.1016/j.ajpath.2020.10.008_bib15",
"year": "2020"
},
{
"DOI": "10.1182/blood.2020006964",
"article-title": "Use of convalescent plasma in hospitalized patients with Covid-19: case series",
"author": "Hegerova",
"doi-asserted-by": "crossref",
"first-page": "759",
"journal-title": "Blood",
"key": "10.1016/j.ajpath.2020.10.008_bib16",
"volume": "136",
"year": "2020"
},
{
"DOI": "10.1001/jama.2020.10044",
"article-title": "Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial",
"author": "Li",
"doi-asserted-by": "crossref",
"first-page": "460",
"journal-title": "JAMA",
"key": "10.1016/j.ajpath.2020.10.008_bib17",
"volume": "324",
"year": "2020"
},
{
"DOI": "10.1136/bmj.m3939",
"article-title": "Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial)",
"author": "Agarwal",
"doi-asserted-by": "crossref",
"first-page": "m3939",
"journal-title": "BMJ",
"key": "10.1016/j.ajpath.2020.10.008_bib18",
"volume": "371",
"year": "2020"
},
{
"article-title": "Convalescent plasma for COVID-19: a multicenter, randomized clinical trial",
"author": "Avendano-Sola",
"journal-title": "medRxiv",
"key": "10.1016/j.ajpath.2020.10.008_bib19",
"year": "2020"
},
{
"article-title": "Early anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: a randomized phase II clinical trial",
"author": "Balcells",
"journal-title": "medRxiv",
"key": "10.1016/j.ajpath.2020.10.008_bib20",
"year": "2020"
},
{
"article-title": "Pathophysiology of COVID-19: mechanisms underlying disease severity and progression",
"author": "Bohn",
"first-page": "288",
"journal-title": "Physiology (Bethesda)",
"key": "10.1016/j.ajpath.2020.10.008_bib21",
"volume": "35",
"year": "2020"
},
{
"DOI": "10.1172/JCI138003",
"article-title": "The convalescent sera option for containing COVID-19",
"author": "Casadevall",
"doi-asserted-by": "crossref",
"first-page": "1545",
"journal-title": "J Clin Invest",
"key": "10.1016/j.ajpath.2020.10.008_bib22",
"volume": "130",
"year": "2020"
}
],
"reference-count": 22,
"references-count": 22,
"relation": {
"has-preprint": [
{
"asserted-by": "object",
"id": "10.1101/2020.10.02.20206029",
"id-type": "doi"
}
]
},
"resource": {
"primary": {
"URL": "https://linkinghub.elsevier.com/retrieve/pii/S0002944020304892"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [
"Pathology and Forensic Medicine"
],
"subtitle": [],
"title": "Significantly Decreased Mortality in a Large Cohort of Coronavirus Disease 2019 (COVID-19) Patients Transfused Early with Convalescent Plasma Containing High-Titer Anti–Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein IgG",
"type": "journal-article",
"update-policy": "http://dx.doi.org/10.1016/elsevier_cm_policy",
"volume": "191"
}
