Abstract: The American Journal of Pathology, Vol. 191, No. 1, January 2021 ajp.amjpathol.org IMMUNOPATHOLOGY AND INFECTIOUS DISEASES Significantly Decreased Mortality in a Large Cohort of Coronavirus Disease 2019 (COVID-19) Patients Transfused Early with Convalescent Plasma Containing High-Titer AntieSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein IgG Eric Salazar,*y Paul A. Christensen,* Edward A. Graviss,*z Duc T. Nguyen,z Brian Castillo,* Jian Chen,* Bevin V. Lopez,x Todd N. Eagar,*y Xin Yi,*y Picheng Zhao,* John Rogers,* Ahmed Shehabeldin,* David Joseph,* Faisal Masud,{ Christopher Leveque,* Randall J. Olsen,*yz David W. Bernard,*y Jimmy Gollihar,k and James M. Musser*yz From the Departments of Pathology and Genomic Medicine* and Anesthesiology and Critical Care,{ Houston Methodist Hospital, Houston, Texas; the Department of Pathology and Laboratory Medicine,y Weill Cornell Medical College, New York, New York; the Center for Molecular and Translational Human Infectious Diseasesz and the Academic Office of Clinical Trials,x Houston Methodist Research Institute, Houston, Texas; and the The Combat Capabilities Development Command Army Research Laboratory-South,k University of Texas at Austin, Austin, Texas Accepted for publication October 28, 2020. Address correspondence to James M. Musser, M.D., Ph.D., 6565 Fannin St., Suite B490, Houston, TX 77030. E-mail: jmmusser@ houstonmethodist.org. 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. (Am J Pathol 2021, 191: 90e107; https://doi.org/10.1016/ j.ajpath.2020.10.008) Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused massive societal disruption and death globally. As of September 27, 2020, there have been >33 million COVID-19 cases, causing in excess of 1,000,000 deaths worldwide.1 The United States has many areas where rising case rates continue to threaten multiple populations. Few effective treatments exist (https://www.covid19treatmentguidelines.nih.gov, last accessed September 24, 2020), in spite of hundreds of ongoing..