key: cord-0925165-xmxa95r2
authors: Rogers, Ralph; Shehadeh, Fadi; Mylona, Evangelia K; Rich, Josiah; Neill, Marguerite; Touzard-Romo, Francine; Geffert, Sara; Larkin, Jerome; Bailey, Jeffrey A; Lu, Shaolei; Sweeney, Joseph; Mylonakis, Eleftherios
title: Convalescent plasma for patients with severe COVID-19: a matched cohort study
date: 2020-10-10
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa1548
sha: 87510af5aee08027f6b534f6a6052957f630e81f
doc_id: 925165
cord_uid: xmxa95r2

BACKGROUND: The efficacy of convalescent plasma (CP) for the treatment of COVID-19 remains unclear. METHODS: In a matched cohort analysis of hospitalized patients with severe COVID-19, the impact of CP treatment on in-hospital mortality was evaluated using univariate and multivariate Cox proportional-hazards models, and the impact of CP treatment on time to hospital discharge was assessed using a stratified log-rank analysis. RESULTS: 64 patients who received CP a median of 7 days after symptom onset were compared to a matched control group of 177 patients. The incidence of in-hospital mortality was 12.5% and 15.8% in the CP and control groups, respectively (p = 0.52). There was no significant difference in the risk of in-hospital mortality between the two groups (adjusted hazard ratio [aHR] 0.93, 95% confidence interval [CI] 0.39 – 2.20). The overall rate of hospital discharge was not significantly different between the two groups (rate ratio [RR] 1.28, 95% CI 0.91 – 1.81), although there was a significantly increased rate of hospital discharge among patients 65-years-old or greater who received CP (RR 1.86, 95% CI 1.03 – 3.36). There was a greater than expected frequency of transfusion reactions in the CP group (2.8% reaction rate observed per unit transfused). CONCLUSIONS: We did not demonstrate a significant difference in risk of mortality or rate of hospital discharge between the CP and control groups. There was a signal for improved outcomes among the elderly, and further adequately powered randomized studies should target this subgroup when assessing the efficacy of CP treatment.

M a n u s c r i p t M a n u s c r i p t 4

The emergence of SARS-CoV-2 has led to a global pandemic with millions of infections reported across over 200 countries less than 6 months after the first case was reported [1] [2] [3] . Many therapeutic agents are being evaluated, some of which are already in clinical use despite varying levels of evidence to support their efficacy [4] . One such widely used agent is convalescent plasma (CP), the transfusion of plasma collected from individuals who have recovered from COVID-19 to currently infected patients, in an attempt to provide some degree of passive humoral immunity to the recipient via the transfer of antibodies directed against SARS-CoV-2 [5] . This approach has been used to treat infections for centuries, and more recent experiences with CP for other emerging viral infections suggest that CP may also be an effective therapy for SARS-CoV-2 [6, 7] .

Clinical evidence describing the efficacy of CP for patients with COVID-19 remains limited.

Early clinical reports from China were encouraging [8] [9] [10] [11] , while another report suggests limited efficacy when used late in the course of disease [12] . Multiple randomized clinical trials are ongoing [13] . A report of early safety data from 20,000 patients given CP through a large expanded access protocol is reassuring [14] .

This study describes the clinical outcomes of a cohort of hospitalized patients with severe COVID-19 who received CP. Notably, the study is one of the first to analyze the clinical outcomes of a large group of patients who received CP in comparison to a closely matched group receiving standard of care treatment.

We studied adult patients admitted to three hospitals within the Lifespan health system, Rhode

Island Hospital and The Miriam Hospital, both in Providence, Rhode Island, USA, and Newport

Hospital, in Newport, Rhode Island, USA. This matched cohort study was an electronic chart review A c c e p t e d M a n u s c r i p t 5 approved by the Institutional Review Board of RIH. All data were extracted from the electronic health record.

All patients who received CP at our institution did so through the expanded access protocol [15] .

Due to limitations in locally available serologic testing at the time, CP was given to patients prior to knowing the SARS-CoV-2 antibody content. Instead, SARS-CoV-2 antibody content was assessed retrospectively on thawed segments (if available) using the Abbott Architect SARS-CoV-2 IgG assay (Abbott, Abbott Park, IL). All patients were prescribed 2 units of plasma and patients were included even if they only received one of the units.

In addition to the broad eligibility requirements set out in the CP expanded access protocol [16] , patients were eligible to receive CP treatment if they also fulfilled the following local inclusion criteria: 1) symptom onset ≤ 10 days prior, 2) requiring supplemental oxygen (but not invasive ventilation), 3) no evidence of current hypercoagulability (D-dimer > 1000 µg/L, clinical signs of thrombosis).

All adult patients with a positive molecular test for COVID-19 admitted to the hospital prior to May 31, 2020 who did not receive CP were reviewed for potential inclusion in the control group. To capture a similar case mix to those patients eligible for CP (see above), additional inclusion criteria for the control group included the following: 1) symptom onset ≤ 10 days prior to admission, 2) hospital admission ≥ 48 hours, 3) required supplemental oxygen (but not invasive ventilation) within 48 hours of hospitalization, 4) D-dimer obtained within 48 hours of hospitalization and < 1000 µg/L. M a n u s c r i p t 6 CP group patient selection All patients who received CP prior to May 31, 2020 were considered for potential inclusion in the CP group. Of note, our local practice regarding CP use (including implementation of our local inclusion criteria and increasing the dose of CP from 1 to 2 units) changed quickly after we first began using CP. The initial 10 patients given CP before this change were not included in this analysis. Several other patients who received CP were also excluded from the analysis after applying the control group inclusion criteria to the CP group. The decision to exclude these CP recipients was an effort to preserve uniformity within the CP group and between the CP and control groups and was made prior to any further data analysis.

The primary outcome of this study was the impact of CP treatment on all cause in-hospital mortality;

the secondary outcome was the impact of CP treatment on the time to hospital discharge. All outcomes were censored at day 28.

We compared patient's characteristics between the two groups using 

Of the 82 consecutive patients who received CP during the study period, 64 were included in the analysis. Excluded patients either received CP prior to the implementation of our local inclusion criteria or (in retrospect) did not meet the structured inclusion criteria for the matched control group [ Figure 1 ]. Three patients included in the CP group received only 1 unit of CP (one withdrew due to clinical improvement and hospital discharge, two had transfusion-related acute lung injury

[TRALI] reactions associated with the first unit). The remainder of the patients received 2 units of CP.

The control group included 177 patients who did not receive CP [ Table 1 ].

Patients received CP at a median of 7 days after symptom onset. SARS-CoV-2 antibody testing was retrospectively performed on 97 (89.0%) of the 109 CP units which were transfused, 13

(13%) of these units had an antibody index (AI) below the cutoff for a positive result (AI < 1.4) [ Figure   2+ . All patients in the CP group except 3 received at least 1 unit of CP with an AI ≥ 1.4 and 18 patients received 2 units of CP both with AI ≥ 5 * Table 2+ .

The demographics and summative pre-existing comorbidities score of the patients in the CP group and control groups were generally similar, although there were 3 patients with HIV/AIDS in the CP group (all virally suppressed with baseline CD4 > 700) and none in the control group [ There were no other documented adverse events associated with CP use for the patients included in this study.

This matched cohort study examined the use of CP in hospitalized patients with severe COVID-19

and found no significant difference in overall in-hospital mortality or time to hospital discharge as compared to a control group who did not receive CP. The CP group and control groups in this study were drawn from a well-defined population, were similar in baseline characteristics and severity of illness, and were followed long enough to allow for adequate analysis of clinical outcomes. We found a signal for efficacy of CP in elderly patients, a signal for a larger effect of CP with a higher quantity of measured SARS-CoV-2 antibody, and a greater than expected frequency of transfusion reactions.

Importantly, a subgroup analysis examining only patients 65-years-old or greater who received CP showed a significantly increased rate of hospital discharge as compared to the control group. An effect specific to this age group is not entirely surprising given the increase in morbidity among the elderly with COVID-19, the waning of humoral immunity with age, and the importance of the humoral compartment of the overall immune response in combating this infection [17] [18] [19] . A subgroup analysis examining only those patients who received 2 units of CP with AI ≥ 5

showed an even larger increase in the rate of hospital discharge among the elderly as compared to the control group. There was also a statistically significant increase in the rate of hospital discharge among White/Caucasian patients of all ages, although this may have been primarily driven by the relative increased age of the White/Caucasian patients in our study as compared patients of other races or ethnicities (data not shown). The semi-quantitative description of the amount of SARS-CoV-2 anti-nucleocapsid IgG provided by the assay's antibody index (AI) that was used in this study has been shown to have similar positivity rate as a recombinant neutralizing assay, although the correlation between neutralizing titers and AI was demonstrated to be poor [20] . In a more recent study using a SARS-CoV-2 neutralizing assay, a different SARS-CoV-2 anti-spike IgG assay was very well correlated with the neutralizing titer [21] . Although we cannot draw any direct conclusions about the neutralizing titers of the CP used in our study, the increase in the rate of hospital discharge across multiple stratifications seen in the subgroup with AI ≥ 5 as compared to the entire CP group aligns well with the expected and recently demonstrated dose-dependent effect of CP [22] .

There was a greater than expected frequency of transfusion reactions in the CP group. The observed per unit reaction rate of 3/109 (2.8%) is consistent with the 2.5% reported by Li et al [23] and higher than that reported to our blood banks (<1%, data not shown). We classified two cases as TRALI reactions. We are aware that CP is manufactured from never transfused male donors and never pregnant females or the CP is tested for anti-HLA antibodies. Hence, neither product (donor) was investigated for anti-HLA antibodies. However, the pathophysiology of Type 2 TRALI in hospitalized patients is not related to donor alloantibodies, but to other compounds with inflammatory evoking properties in the context of an activated pulmonary endothelium, which clearly pertains to COVID-19 patients [24] . Our elevated frequency of transfusion reactions does not A c c e p t e d M a n u s c r i p t 11 align with data reported from the large safety study associated with the expanded access protocol (TRALI 0.10%, TACO 0.18%, severe allergic transfusion reaction 0.13%) [14] . This difference may highlight the difficulty of accurately detecting transfusion reactions in critically ill patients.

Studying the efficacy of CP in an adequately powered prospective randomized fashion has historically been difficult. Retrospective or non-randomized assessments of efficacy cannot provide the same quality of evidence, as highlighted by the contrasting data provided by a non-randomized cohort study of CP for severe pandemic influenza A (H1N1) 2009 which suggested a mortality benefit of adding CP to the local standard of care [25] , and two more recent well powered randomized controlled trials (RCTs) examining the use of high-titer anti-influenza plasma as compared to placebo [26] or low-titer plasma [27] for the treatment of seasonal influenza infection, neither of which showed a significant difference in the primary outcome studied (clinical status at day 7). Considering these findings, a critical analysis of any non-randomized study assessing the efficacy of CP is imperative.

While our study does demonstrate a lower incidence of in-hospital mortality in the CP group as compared to the control group, this difference was not statistically significant, and a multivariate analysis also showed no significant difference in the risk for mortality between the groups. Two other propensity-matched cohort studies suggest a mortality benefit of CP for COVID-19 [28, 29] . In contrast, three RCTS (each with their own limitations) were unable to demonstrate any mortality benefit [23, 30, 31] . Among other factors, the timing of CP transfusion in relation to symptom onset, the antibody titer of the CP transfused, and the quantity of plasma transfused all varied widely among these studies, making it difficult to analyze their outcomes collectively, a topic explored in several recent meta-analyses [32] [33] [34] . The initial outcomes data from over 35,000 patients who received CP under the expanded access protocol reemphasizes the importance of these factors, with a high antibody titer and earlier transfusion corresponding to decreased mortality, as compared to a lower titer or later transfusion [22] .

A c c e p t e d M a n u s c r i p t 12 The findings of this study should be generalized with caution. There is the possibility of a known or unknown confounder biasing the composition of the CP group and the control group and thus obscuring (or amplifying) the measured effect of CP treatment. Many of the patients in the control group were hospitalized either before CP was locally available or during the peak of local COVID-19 hospitalizations when logistical constraints may have prevented them from being offered CP. The CP and control groups were generally well matched among all variables examined except corticosteroid use (significantly higher in the CP group), but both the multivariate mortality analysis and stratified rate of hospital discharge analysis adjusted for this difference. Many patients were given multiple potentially efficacious therapies (e.g. remdesivir, corticosteroids, convalescent plasma) and this study is not powered to deconvolute any potential synergistic or antagonistic effects of these various therapies. The single center nature of the study allows for a comparison with a well-matched controlled group but also limits enrollment, and thus the study may have been underpowered to show a significant difference in the outcomes studied. To assess the effect that the timing of CP transfusion had on efficacy, rather than use a measure of time from hospital admission to CP transfusion (which does not account for duration of symptoms prior to hospitalization or allow for a comparison to the control group), we instead used a measure of duration of symptoms prior to hospital admission (since most patients received CP within 1-2 days after admission) [Supplementary Table 1 ]. We also did not specifically analyze an outcome examining time to clinical improvement and using hospital discharge as a surrogate for this measure may be misleading since some patients may have remained hospitalized for unrelated reasons.

In conclusion, this is one of the first analyses comparing CP to standard of care for the treatment of COVID-19. Though our study had several limitations, we found no significant overall difference in the risk for in-hospital mortality or in the rate of hospital discharge for those patients who received CP as compared to those who did not. A secondary analysis showed a significantly increased rate of hospital discharge for CP given to patients 65-years-old or greater. While M a n u s c r i p t 22 A c c e p t e d M a n u s c r i p t 23 

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