key: cord-274860-7ec2jcoq
authors: Salazar, Eric; Christensen, Paul A.; Graviss, Edward A.; Nguyen, Duc T.; Castillo, Brian; Chen, Jian; Lopez, Bevin Valdez; Eagar, Todd N.; Yi, Xin; Zhao, Picheng; Rogers, John; Shehabeldin, Ahmed; Joseph, David; Masud, Faisal; Leveque, Christopher; Olsen, Randall J.; Bernard, David W.; Gollihar, Jimmy; Musser, James M.
title: Significantly decreased mortality in a large cohort of COVID-19 patients transfused early with convalescent plasma containing high titer anti-SARS-CoV-2 spike protein IgG
date: 2020-11-04
journal: Am J Pathol
DOI: 10.1016/j.ajpath.2020.10.008
sha: 
doc_id: 274860
cord_uid: 7ec2jcoq

Coronavirus disease 2019 (COVID-19) convalescent plasma has emerged as a promising therapy and has been granted emergency use authorization by the U.S. Food and Drug Administration (FDA) for hospitalized COVID-19 patients. We recently reported results from interim analysis of a propensity-score matched study suggesting that early treatment of COVID-19 patients with convalescent plasma containing high titer anti-spike protein receptor binding domain (RBD) IgG significantly decreases mortality. We here present results from 60-day follow up of our cohort of 351 transfused hospitalized patients. Prospective determination of ELISA 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 (S/C) ratio of 24.0 for transfused units, a value far exceeding the recently FDA-required 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 post-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.

Coronavirus disease 2019 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 more than 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. Very few effective treatments exist (https://www.covid19treatmentguidelines.nih.gov/, both links last accessed September 24, 2020), although hundreds of registered clinical trials are ongoing, including several phase 3 vaccine trials (https://www.nytimes.com/interactive/2020/science/coronavirusvaccine-tracker.html, subscription required).

We and others have published safety and efficacy outcomes in patients who were transfused with COVID-19 convalescent plasma. [2] [3] [4] Aggregated available evidence stimulated the U.S. Food and Drug Administration (FDA) in late August 2020 to grant Emergency Use Authorization (EUA) for COVID-19 convalescent plasma therapy (https://www.fda.gov/media/141477/download, last accessed September 24, 2020). In our previous study, interim analysis revealed that, relative to matched controls, patients transfused with convalescent plasma containing high titer anti-spike protein receptor binding domain (RBD) IgG within 72 hrs of hospital admission had significantly reduced mortality at 28 days post-transfusion. 3 To further investigate these observations, and to address limitations inherent in an interim analysis, we here present results from 60-day follow up of our entire cohort of 351 transfused patients.

The data confirm our previous findings that transfusion of patients soon after hospital admission with high titer anti-spike protein RBD IgG present in convalescent plasma significantly decreases mortality.

We analyzed data from patients cared for in all eight Houston Methodist hospitals from March 28, 2020, through September 14, 2020 , with the approval of the Houston Methodist Research Institute ethics J o u r n a l P r e -p r o o f review board and with written informed consent of the patient or legally authorized representative.

Details of the study, including inclusion and exclusion criteria, and criteria for the transfusion of multiple units have been described. 3 

Detailed protocols for convalescent plasma collection and anti-spike protein titer assessment have been described. 3, 5, 6 COVID-19 convalescent plasma units were selected for transfusion based on antispike ectodomain and RBD IgG ELISA titers available on donor units obtained from April 7, 2020 onward. We previously published that plasma with an anti-RBD IgG titer of ≥1:1350 corresponds to an ~80% probability of a live virus in vitro neutralization titer of ≥1:160. 7 This titer is the value initially recommended by the FDA for transfusing COVID-19 patients. 8 To facilitate the need for increased donor unit assessment, we standardized our ELISA to four plasma dilutions: 1:50, 1:150, 1:450, and 1:1350. To select the highest titer unit available, ELISA results were ranked based on highest titer and, subsequently by highest optical density at dilution 1:50. Patients were transfused with the ABOcompatible convalescent plasma unit with the highest titer and highest optical density at dilution 1:50 available. Frozen serum samples were assessed retrospectively with the Ortho VITROS IgG assay (Raritan, NJ) according to manufacturer's instructions.

We analyzed patients who met a 60-day outcome defined as having outcome data available 60 days post-transfusion (cases) and 60 days post-hospitalization (controls). Control patients enrolled in other clinical trials were excluded from the analysis. Patients discharged before Day 60 were presumed to be on room air after discharge unless otherwise noted in the electronic medical record. Baseline characteristics for COVID-19 patients who met the 60-day outcome definition are shown in Supplemental Table S1 .

We conducted a one-to-many nearest neighbor propensity score matching analysis without replacement using an initial ratio of case:control=1:3 and caliper of ≤1 between patients having plasma J o u r n a l P r e -p r o o f transfusion (cases) versus patients who did not have plasma transfusion (controls). The primary matching criteria included age (categorical, <30, 30-39, 40-49, 50-59, 60-69, 70-79, ≥80) , sex, BMI (+/-30), diabetes, hypertension, chronic pulmonary disease, chronic kidney disease, hyperlipidemia, coronary disease, and baseline ventilation requirement within 48 hrs of admission, use of any steroid, azithromycin, hydroxychloroquine, remdesivir, ribavirin, and tocilizumab. A secondary propensity score matching was conducted based on the ventilation status at Day 0, defined as the day of transfusion for cases and the corresponding day in the hospitalization course for controls, using a case:control ratio of either 1:2 or 1:1 and caliper ≤1. 9 Propensity score matching adjusts for the influences of potential confounding factors and minimizes bias in estimating outcome effect. 10 The approach has particular advantage in lieu of randomized controlled trials.

The primary outcome (mortality within 60 days post-Day 0) was displayed by Kaplan-Meier curves. Differences between groups were compared with the log-rank test. Cox proportional hazards modeling (with clustered sandwich estimator option for the matched cluster in the propensity-matched cohorts) was performed to determine the characteristics associated with the overall mortality within 28 days and 60 days. Variables for the multivariable models were selected based on potential clinical relevance and using Stata's Lasso technique with cross-validation. 11, 12 Receiver operating characteristic (ROC) curve analysis with Youden index was used to identify the optimal time (in hours) from admission-to-transfusion of first unit that discriminates 60-day mortality in patients that received COVID-19 convalescent plasma. 13 ROC analysis with Youden index allows for the determination of the optimal cut point for continuous variables, at which the combination of the sensitivity and specificity of the evaluated variable is maximized.

Generalized linear modeling (GLM) and multinomial logistic regression with a cluster variance estimator were also used to evaluate several exploratory endpoints. The evaluated covariates included supplemental oxygen requirements (room air, low-flow oxygen delivery, high-flow oxygen delivery, noninvasive positive pressure ventilation, mechanical ventilation, extracorporeal membrane oxygenation (ECMO), or death) at Day 7, Day 14, Day 28, and Day 60 post-transfusion; clinical improvement relative to Day 0; intensive care unit (ICU) stay requirement; ICU length of stay; mechanical ventilation J o u r n a l P r e -p r o o f requirement; length of mechanical ventilation requirement; length of supplemental oxygen requirement; and inflammatory marker levels (interleukin-6, C-reactive protein, ferritin, fibrinogen, D-dimer) at Day 7.

Clinical improvement relative to Day 0 was defined as a 1 point improvement in ordinal scale [1, discharged (alive) ; 2, hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (for COVID-19 or otherwise); 3, hospitalized, requiring low-flow supplemental oxygen; 4, hospitalized, on non-invasive ventilation or high-flow oxygen devices; 5, hospitalized and on invasive mechanical ventilation or ECMO; 6, death]. All analyses were performed with Stata version 16.1 (StataCorp LLC, College Station, TX, USA) or the R Statistical Computing environment (http://www.Rproject.org/, last accessed September 24, 2020). A p-value of ≤0.05 was considered significant.

We had 5,297 hospitalized COVID-19 patients available for analysis, 353 of whom were transfused with COVID-19 convalescent plasma. Two of the 353 patients received plasma without a titer assessment prior to transfusion, and these patients were excluded from the overall analysis, resulting in a cohort of 351 transfused evaluable patients. Relative to non-transfused patients, transfused patients were significantly younger, predominantly male, predominantly Hispanic, had a higher BMI, lower rates of comorbidities (specifically, chronic pulmonary disease, chronic kidney disease, hyperlipidemia, and coronary disease, but not hypertension and diabetes), a higher requirement for supplemental oxygen, and higher inflammatory biomarker concentrations. D-dimer was significantly lower in the transfused cohort at baseline by 0.2 fibrinogen equivalent units. Use of steroids, azithromycin, remdesivir, and tocilizumab was more common among the transfused cohort (Supplemental Table S1 ).

Among 351 transfused patients included in the study, only seven (2.0%) had adverse events deemed related to plasma transfusion. Six events were classified as allergic transfusion reactions and five of these six were mild and included only a transient rash. One patient developed transient worsening of J o u r n a l P r e -p r o o f shortness of breath that resolved with diphenhydramine. One case of possible transfusion-associated circulatory overload occurred, with associated transient worsening of dyspnea that improved with furosemide. These two events were deemed to be significant adverse events. Thus, among the 351 transfused study patients, only two (0.6%) significant adverse events were deemed related to plasma transfusion.

Univariate and multivariate Cox proportional hazards modeling assessing factors associated with a higher risk of death within 60 days post-transfusion Day 0 was performed for all COVID-19 patients admitted to our eight hospitals during the study period for whom data were available (Supplemental Tables S2 and S3). Factors associated with a higher risk of death in the multivariate analysis included age, male sex, diabetes, chronic kidney disease, worst ventilation status within 48 hrs of admission, and/or administration of any steroids or tocilizumab. Neither ABO blood type, race, nor ethnicity were associated with higher risk of death in the multivariate analysis. Importantly, the covariates that had a significant association with risk of death were included in the propensity score matching algorithm. We did not include baseline inflammatory concentrations in the multivariate analysis and in the propensity score matching algorithm because of the high proportion of missing data.

Most transfused patients (278/351; 79%) received only one ~300 mL unit of COVID-19 convalescent plasma. The great majority of patients received an initial or sole unit of convalescent plasma with anti-RBD IgG titer of ≥1:1350 (321/351; 91%); 24 patients received an initial or sole unit of convalescent plasma with an anti-RBD IgG titer >1:150 but <1:1350; six patients received an initial or sole unit of convalescent plasma with anti-RBD IgG titer of <1:150. For patients who received a second unit of convalescent plasma, 71 (71/75; 95%) received a second unit with an anti-RBD IgG titer ≥1:1350, and four (4/75; 5%) patients received a second unit with an anti-RBD IgG titer >1:150 but <1:1350.

The FDA issued an EUA for convalescent plasma transfusion of COVID-19 patients on August 23, 2020. The agency's guidance is to use convalescent plasma units with a signal/cutoff (S/C) level of >12, as defined by the Ortho VITROS IgG test (https://www.fda.gov/media/141477/download, last accessed September 24, 2020). For 278 of the 351 (79%) initial plasma units transfused, a sample was available for retrospective assessment of anti-SARS-CoV-2 IgG titer by the Ortho VITROS IgG test.

The median IgG S/C ratio was 24.0 (range=0.01-35) and only seven units (3%) had a corresponding S/C ratio of <12. In addition, we found a very strong positive correlation between the ELISA anti-RBD IgG optical density at dilution 1:50 and the Ortho VITROS IgG test for 1,142 samples with parallel assessment (R=0.88; P<0.001). The distribution of Ortho VITROS IgG S/C ratios and anti-RBD IgG ELISA optical density for transfused plasma units confirms that high anti-spike protein IgG titer units were being given to the enrolled COVID-19 patients (Figure 1 ).

Propensity score matching yielded a study population of 341 transfused patients and 594 matched controls, which were balanced across all matching criteria (Figure 2 and Supplemental Table S4 ).

Kaplan-Meier curves showed significantly decreased mortality within 60 days post-Day 0 in the transfused cohort relative to propensity score-matched controls (P=0.02) (data not shown). Statistical significance increased to P=0.003 when the matching algorithm and analysis were restricted to patients transfused with plasma with an anti-RBD IgG titer of ≥1:1350 (Figure 3 ). Mortality was not significantly different within 60 days post-Day 0 between cases and controls in patients who were intubated at Day 0 or in patients who were transfused more than 72 hrs after admission, even when the analysis was restricted to patients who received plasma with an anti-RBD IgG titer of ≥1:1350. There was no significant difference in mortality between cases and controls when the analysis was restricted to patients who received plasma with an anti-RBD IgG titer of <1:1350. In contrast, mortality was significantly decreased in patients who received plasma with an anti-RBD IgG titer of ≥1:1350 within 72 hrs of admission (Figure 4 ). Point estimates of the outcomes when the analysis was restricted to transfusion of high titer plasma confirm these findings ( Table 1) .

Consistent with these observations, the unadjusted HR and adjusted HR in the univariate and multivariate Cox proportional hazards models for mortality within 60 days was significant when the analysis was restricted to patients who received plasma with an anti-RBD IgG titer of ≥1:1350 ( Table   2) . Due to small sample sizes, multivariate analysis could not be performed for patients who received plasma with a titer ≥1:1350 and were intubated at Day 0, or who were transfused more than 72 hrs after hospitalization. In these two cohorts, the unadjusted HR in univariate analyses for mortality within 60 days post-Day 0 was not significant (HR=1.61 for controls; P=0.44 and HR=1.93 for controls; P=0. 16, respectively) . Similarly, the unadjusted HR for mortality within 60 days in the analysis restricted to patients who received plasma with a titer <1:1350 was not significant (HR=1.57 for controls, P=0.36).

However, the unadjusted HR for mortality within 60 days was significant (HR=1.93 for controls, P=0.02) when the analysis was restricted to patients who received plasma with a titer ≥1:1350 within 72 hrs of hospital admission. For this cohort, the adjusted HR for mortality within 60 days was significant when assessed for a 28-day outcome (aHR=2.09 for controls; P=0.047) and approached significance when assessed for a 60-day outcome (aHR=1.82 for controls; P=0.051).

We sought to identify the optimal window after hospitalization within which transfusion of convalescent plasma was most useful with respect to altering mortality. ROC curve analysis with Youden index revealed an optimal cut point of transfusion within 44 hrs of hospital admission for discriminating mortality within 60 days post-transfusion in all patients transfused with COVID-19 convalescent plasma ( Figure 5A ). The analysis identified the same cut point when restricted to patients transfused with convalescent plasma with an anti-RBD IgG titer ≥1:1350. Therefore, we performed the propensity score-matched analysis using this cut point as a restrictor. Cohorts were again balanced across all matching criteria (data not shown). The resulting Kaplan-Meier curves showed significantly decreased mortality within 60 days post-Day 0 in the cohort transfused with convalescent plasma with an anti-RBD IgG ≥1:1350 within 44 hrs of admission relative to propensity score-matched controls (P=0.004) ( Figure 5B ). Point estimates of the outcomes for the analysis restricted to transfusion of high titer convalescent plasma within 44 hrs confirm these findings ( Table 3) . Univariate Cox regression in this cohort revealed a significant unadjusted HR for mortality within 60 days (HR=3.26 for controls, J o u r n a l P r e -p r o o f P=0.01). Likewise, multivariate Cox regression showed a significant adjusted HR for mortality within 28 days (aHR=2.63 for controls, P=0.04) and within 60 days post-Day 0 (aHR = 2.90 for controls, P=0.02) ( Table 4 ).

Transfusion of convalescent plasma has emerged in the last six months as a promising therapy for COVID-19 patients and has been granted emergency use authorization for hospitalized patients by the FDA. Because of the logistical challenges of planning and executing a study during a rapidly changing pandemic involving very complex medical patients, the results of few completed controlled studies assessing convalescent plasma efficacy have been published. Here, we provide an analysis of a propensity score-matched study from a large cohort of hospitalized COVID-19 patients who were transfused in one healthcare system with high-titer convalescent plasma qualified in one laboratory. In the aggregate, the data confirm and extend findings from our interim analysis suggesting that transfusion of convalescent plasma with high titer anti-RBD IgG is safe and significantly decreases COVID-19 mortality. 3 Transfusion later in hospitalization or later in the disease course (e.g., postintubation) had no significant benefit on mortality, regardless of plasma titer. Several lines of evidence support our findings, including survival analyses of specific cohorts of transfused patients relative to matched controls, point estimates from the generalized linear model and multinomial logistic regression, and univariate and multivariate analyses.

The current analysis addressed several limitations we identified in our interim analysis. 3 First, the patient sample size is almost three times as large as that included in our interim analysis. Second, we included additional covariates in the propensity score matching algorithm, including relevant concomitant medications (any steroid, azithromycin, hydroxychloroquine, remdesivir, ribavirin, and tocilizumab). Importantly, factors identified as having a significant adjusted HR for mortality for all hospitalized COVID-19 patients were included in the propensity match. Third, because a large proportion of deaths occurred after 28 days post-Day 0, we assessed a 60-day outcome. Fourth, control patients enrolled in other clinical trials involving alternative experimental therapies were J o u r n a l P r e -p r o o f excluded. Fifth, when possible, we performed multivariate analyses assessing factors associated with mortality within 60 days. Finally, we used ROC analysis with Youden index to identify the optimal cut point at which transfusion of convalescent plasma is most useful with respect to altering mortality.

Our results bear on other recent studies treating patients with convalescent plasma. 4, 9, [14] [15] [16] [17] For example, a recent fixed-effect meta-analysis model assessing 12 controlled studies of COVID-19 convalescent plasma found that the aggregate mortality rate of transfused COVID-19 patients was significantly lower than that of non-transfused patients. 4 Results from three randomized controlled studies and one large observational study have recently been released. 2, [18] [19] [20] The PLACID trial found convalescent plasma was not associated with significantly reduced mortality or progression to severe disease. 18 However, resolution of shortness of breath, fatigue, and negative conversion of SARS-CoV-2 viral RNA at Day 7 was higher in the transfused study arm. The authors acknowledged several limitations of their study. For example, the proportion of patients with comorbidities, especially diabetes, was higher in the transfused study arm. Importantly, most of the convalescent plasma donors were young with mild disease and their median titer of neutralizing antibody was 1:40, a value considerably lower than the FDA-recommended neutralizing antibody titer of 1:160. In addition, neutralizing antibody titers were not determined before transfusion, which means the highest titer units were not used for transfusion. Similar results were reported for a randomized controlled trial conducted in Chile in which neutralizing antibody titers in donor plasma were not determined prior to transfusion. 20 In contrast, interim analysis of a randomized controlled trial from Spain with 81 randomized patients, reported that no patients progressed to mechanical ventilation or death among the 38 patients receiving convalescent plasma (0%), whereas six of 43 patients (14%) in the control arm did. 19 Mortality rates were 0% versus 9.3% at Days 15 and 29 for the active and control groups, respectively. All transfused convalescent plasma units had neutralizing antibodies with a titer >1:80 with a median titer of 1:292.

Unfortunately, the trial was stopped after the first interim analysis due to decreased recruitment related to better control of the pandemic. In contrast to several of the studies cited above, we methodically selected units for transfusion based on the ELISA data identifying the highest level of IgG antibody directed against spike ectodomain and RBD. We transfused compatible donor units determined to have J o u r n a l P r e -p r o o f the highest antibody titer available, an approach confirmed by our retrospective assessment of anti-SARS-CoV-2 IgG by the Ortho VITROS assay (Figure 1) . Thus, the vast majority of our patients were transfused with convalescent plasma units with very high titer anti-spike protein IgG. We think it reasonable to speculate that this strategy contributed to differences in outcomes observed between our study and several others that did not transfuse patients with plasma units specifically chosen to have very high IgG antibody levels against spike protein. Overall, the results from various published studies highlight the difficulty in drawing definitive conclusions for convalescent plasma efficacy from multiple studies with variable design, a problem that can extend to and thereby hobble randomized controlled trials with different study designs.

Substantial efforts to collect, use, and study COVID-19 convalescent plasma continue worldwide. Our study has several implications for these efforts. The data presented here may inform the design and conduct of ongoing or future studies. For example, we conclude that transfusing plasma units with low or no antibody titer against spike protein is unlikely to be beneficial. Our data support the concept that identification of units contain high antibody titer by either a viral neutralization assay or a surrogate thereof prior to transfusion is essential, regardless of the type of trial being conducted.

COVID-19 convalescent plasma is now being administered widely in the United States under an EUA, with an Ortho VITROS IgG cutoff of >12 required by the FDA for the designation of a high titer unit. In our study, we prospectively selected units based on anti-RBD IgG ELISA data. Assessment of transfused units by the Ortho VITROS assay was done retrospectively. The relative lack of data from an adequate number of patients we transfused with convalescent plasma units near or below the S/C cutoff of 12 precludes evaluation of this cutoff value with respect to outcome. However, we conclude that prospective selection and transfusion of very high titer units likely contributed to the significantly decreased mortality we observed. In addition, transfusing soon after hospitalization will be more beneficial than the alternative. Similarly, transfusion in patients that have progressed to the need for mechanical ventilation or otherwise have further deteriorated clinically likely confers no clear benefit.

These findings support the notion that virus neutralizing antibodies present in COVID-19 convalescent plasma impart therapeutic benefit when patients are in the relatively early viral infection/replication J o u r n a l P r e -p r o o f phase of COVID-19 disease, but not after patients have progressed to manifest disease mechanisms such as a pathogenic severe inflammatory host response. 21, 22 Prioritizing studies targeted toward early disease patients is, therefore, important. Our finding that a large proportion of deaths in COVID-19 patients occurs after Day 28 may also have implications for study design, as findings at Day 28 may not apply over a longer follow-up period.

Importantly, our study has several limitations. First, it is a propensity score-matched study rather than a randomized controlled trial. Although we made every effort to control for all important covariates, potentially relevant covariates may have been omitted unintentionally from the matching algorithm.

Second, the background standard of care for COVID-19 has evolved as new data emerged. Thus, we may not have completely addressed the potential for variations over time in background standard of care and period effect as sources of confounding in our dataset. Third, there was heterogeneity in the transfusion of two units versus one based on inventory limitations early in the study and on patient enrollment in other trials that specifically excluded redosing of convalescent plasma. Fourth, our analysis was based on patient data available in the electronic medical record. Fifth, we note that the results reflect the experience of one system of eight hospitals in the Houston metropolitan region that have a fairly uniform approach to COVID-19 patient care. Our findings may not apply to all hospitalized COVID-19 patients because of inter-institutional and/or regional heterogeneity in medical care. Sixth, baseline inflammatory marker measurements were not included in the matching algorithm due to the high proportion of missing data points. Our study approach facilitated rapid assessment of safety and efficacy of high-titer anti-SARS-CoV-2 convalescent plasma transfusion during early phases of a rapidly evolving pandemic with uncertain trajectory. The data presented here may help to inform the science and logistics of ongoing and future studies that address the use of convalescent plasma for other emerging and rapidly disseminating infectious diseases.

To summarize, this propensity score-matched analysis of a large patient cohort confirms and extends our previous findings and suggests that transfusion of convalescent plasma containing very high titer anti-RBD IgG early in hospitalization reduces mortality in COVID-19 patients.

We thank Terumo BCT for continuously and rapidly supplying blood collection devices and supplies.

We also thank Shmuel Shoham, MD for graciously sharing a draft study protocol for adaptation early in the study planning phase.

Statement of ethical assurance: JMM 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. Interleukin - Steroids and tocilizumab were treated as time-varying covariates in the multivariate model. 

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