key: cord-0852221-so9uy899 authors: Joyner, M. J.; Senefeld, J. W.; Klassen, S. A.; Mills, J. R.; Johnson, P. W.; Theel, E. S.; Wiggins, C. C.; Bruno, K. A.; Klompas, A. M.; Lesser, E. R.; Kunze, K. L.; Sexton, M. A.; Diaz Soto, J. C.; Baker, S. E.; Shepherd, J. R. A.; van Helmond, N.; van Buskirk, C. M.; Winters, J. L.; Stubbs, J. R.; Rea, R. F.; Hodge, D. O.; Herasevich, V.; Whelan, E. R.; Clayburn, A. J.; Larson, K. F.; Ripoll, J. G.; Andersen, K. J.; Buras, M. R.; Vogt, M. N. P.; Dennis, J. J.; Regimbal, R. J.; Bauer, P. R.; Blair, J. E.; Paneth, N. S.; Fairweather, D.; Wright, R. S.; Carter, R. E.; Casadevall, A. title: Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience date: 2020-08-12 journal: medRxiv : the preprint server for health sciences DOI: 10.1101/2020.08.12.20169359 sha: 72e9d895bf641913f5acc9255e9f04c80cd5f3e5 doc_id: 852221 cord_uid: so9uy899 Importance: Passive antibody transfer is a longstanding treatment strategy for infectious diseases that involve the respiratory system. In this context, human convalescent plasma has been used to treat coronavirus disease 2019 (COVID-19), but the efficacy remains uncertain. Objective: To explore potential signals of efficacy of COVID-19 convalescent plasma. Design: Open-label, Expanded Access Program (EAP) for the treatment of COVID-19 patients with human convalescent plasma. Setting: Multicenter, including 2,807 acute care facilities in the US and territories. Participants: Adult participants enrolled and transfused under the purview of the US Convalescent Plasma EAP program between April 4 and July 4, 2020 who were hospitalized with (or at risk of) severe or life threatening acute COVID-19 respiratory syndrome. Intervention: Transfusion of at least one unit of human COVID-19 convalescent plasma using standard transfusion guidelines at any time during hospitalization. Convalescent plasma was donated by recently-recovered COVID-19 survivors, and the antibody levels in the units collected were unknown at the time of transfusion. Main Outcomes and Measures: Seven and thirty-day mortality. Results: The 35,322 transfused patients had heterogeneous demographic and clinical characteristics. This cohort included a high proportion of critically-ill patients, with 52.3% in the intensive care unit (ICU) and 27.5% receiving mechanical ventilation at the time of plasma transfusion. The seven-day mortality rate was 8.7% [95% CI 8.3%-9.2%] in patients transfused within 3 days of COVID-19 diagnosis but 11.9% [11.4%-12.2%] in patients transfused 4 or more days after diagnosis (p<0.001). Similar findings were observed in 30-day mortality (21.6% vs. 26.7%, p<0.0001). Importantly, a gradient of mortality was seen in relation to IgG antibody levels in the transfused plasma. For patients who received high IgG plasma (>18.45 S/Co), seven-day mortality was 8.9% (6.8%, 11.7%); for recipients of medium IgG plasma (4.62 to 18.45 S/Co) mortality was 11.6% (10.3%, 13.1%); and for recipients of low IgG plasma (<4.62 S/Co) mortality was 13.7% (11.1%, 16.8%) (p=0.048). This unadjusted dose-response relationship with IgG was also observed in thirty-day mortality (p=0.021). The pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days compared to low antibody level plasma units. Conclusions and Relevance: The relationships between reduced mortality and both earlier time to transfusion and higher antibody levels provide signatures of efficacy for convalescent plasma in the treatment of hospitalized COVID-19 patients. This information may be informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma. Trial Registration: ClinicalTrials.gov Identifier: NCT04338360 13.7% (11.1%, 16.8%) (p=0.048). This unadjusted dose-response relationship with IgG 83 was also observed in thirty-day mortality (p=0.021). The pooled relative risk of mortality Passive antibody transfer, including convalescent plasma or serum, has 95 previously been used to treat infectious diseases that involve the respiratory system 1-3 . 96 This therapeutic approach was established early in the last century and included 97 widespread use of convalescent plasma for treatment of the 1918 influenza 4 . In this 98 context, the coronavirus disease 2019 pandemic has revived interest in the 99 use of convalescent plasma for the treatment of hospitalized patients with COVID-19. 100 Although there is substantial interest in the use of COVID-19 convalescent plasma, the 101 efficacy signals are preliminary 5,6 . 102 In response to the global COVID-19 pandemic and need for access to treatments (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020 . . https://doi.org/10.1101 Methods 119 Design and Oversight 120 As described previously 7,8 , the EAP was a US national, 121 pragmatic intervention conducted as a multicenter, open-label protocol in hospitalized 122 adults with COVID-19. All hospitals or acute care facilities in the US and any physician 123 licensed in the US were eligible to participate provided they agreed to adhere to the 124 treatment protocol, FDA, and state regulations. 125 Mayo Clinic served as the academic research organization conducting the study. The laboratory test whom were symptom free for 14 days, or more according to standard 145 blood center procedures 9 . An aliquot of plasma or serum was shipped from a subset of 146 blood collection centers for later antibody testing. At the time of collection, each plasma 147 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020 . . https://doi.org/10.1101 Statistics 175 The sample size for the EAP was not determined a priori and patient accrual has not 176 concluded at the time of this writing. The sample sizes for these analyses varied by the 177 availability of linked antibody data, and in some cases, missing data. For the analyses 178 not associated with antibody data, all transfusions on or before July 4, 2020 were 179 included (i.e., three months after the first confirmed transfusion in the EAP). The 180 database was locked for this study report on August 5, 2020 to allow all included analysis did not adjust for the potential clustering that may have occurred in doing so. 203 For the semi-quantitative Ortho-Clinical IgG assay, low, medium and high relative 204 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint binding antibody levels were established by setting thresholds for low and high based 205 on the ~20 th and ~80 th percentiles of the distribution for the S/Co ratios, respectively. 206 Accordingly, the thresholds were set at 4.62 S/Co and 18.45 S/Co. Table 1 ), gender, race, age at enrollment (as categories), and indicator variables for 234 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint having already developed one or more severe COVID-19 conditions (as shown in Table 235 1), being on a ventilator, use of hydroxychloroquine, use of remdesivir, and use of 236 steroids prior to transfusion. 237 Descriptive statistics are presented as frequencies and percentages. Analytic data are 238 presented as point estimates and 95% confidence intervals. P-values less than 0.05 239 were considered statistically significant and no correction for multiple testing has been 240 applied to reported p-values. All statistical analyses were completed using R version 241 3.6.2. 242 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint Table 1 , stratified into three groups delineating the time 250 period of the study and COVID-19 pandemic. The data set represented a non-251 probability sample of hospitalized COVID-19 patients with diverse representation of 252 gender, age, weight status, race, and ethnicity. As shown in Table 1 , the patients 253 transfused early in the study period (before May 01) were more critically-ill (higher rates 254 of mechanical ventilation, ICU admissions and septic shock), had higher concomitant 255 treatment with hydroxychloroquine and azithromycin, and lower concomitant treatment 256 with remdesivir compared with groups transfused later in the study period. Since the initiation of the EAP, there has been a reduction in both the seven-day crude 259 mortality rate and a pronounced shift of the time to transfusion towards more rapid 260 transfusion of convalescent plasma. The crude seven-day mortality rate was reduced in 261 patients transfused within 3 days (8.7%, 8.3%-9.2%) of COVID-19 diagnosis compared 262 to patients transfused 4 or more days after COVID-19 diagnosis (11.9%, 11.4%-12.3%; 263 P<0.001), Table 2 . Similar trends were seen for unadjusted 30-day mortality. Table 2 264 presents several additional analyses by risk modifiers (e.g., age and ventilation status at 265 time of transfusion). As a means for controlling for study epoch, the time to transfusion 266 association is presented further stratified by study period. More favorable estimates for 267 mortality were found for all early transfusions (3 or fewer days) across both 7-and 30-268 day mortality for all three study months (P<0.001; Table 2 ). 270 In a subset of 3,082 transfused patients who received only a single unit of plasma (150 271 -250 mL), the unadjusted antibody association with mortality is presented in Table 2. 272 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint Supplemental Table 2 presents the key demographic data by antibody groups (low, 273 medium and high) for these patients. While there were some statistically significant 274 differences among the antibody level groupings, this table shows that patients were well 275 balanced across the antibody level groupings as a whole. The associations of mortality 276 with antibody levels was found at both 7-and 30-days (p<0.05 for both) and when 277 antibody levels were stratified by time to transfusion, a pronounced separation in 278 mortality was found between the extremes of the classification (early transfusion, high 279 antibody levels vs. late transfusion, low antibody levels) albeit the associations for 7-day 280 mortality was at the threshold for statistical significance (p=0.05). Supplemental Table 281 2 presents additional estimates of crude mortality on the subset of patients with 282 matched antibody data. 283 Figure 2A presents the adjusted analyses with antibody groupings alone whereas 284 Figure 2B presents these same data allowing for the timing of the transfusion to be 285 integrated directly into the analysis. These data demonstrate a clear "dose" dependent 286 relationship of reduced 7-day mortality with the higher antibody levels. Figure 2C and 287 2D replicate these findings using 30-day mortality data. While some confidence intervals 288 include the null value of relative risk of 1.0, the magnitude of relative risks, particularly 289 after adjustment, is an important finding of the study. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint Discussion 300 In our cohort of over 35,000 hospitalized patients with COVID-19, several signals 301 consistent with effectiveness for convalescent plasma were observed in a broad sample 302 of acute care facilities across the US. Earlier use of convalescent plasma was 303 associated with lower observed rates of 7-day and 30-day mortality. The use of 304 convalescent plasma with higher antibody levels was associated with reduced 7-day 305 and 30-day mortality. These findings were supported by two different analytical methods 306 used to control for confounding. The finding of a dose response between antibody levels 307 and reduction in mortality provides strong evidence that specific antibody is the active 308 agent in convalescent plasma for treatment of COVID-19. All data considered as a 309 whole, these findings are consistent with the notion that the quality and manner in which week-to-week trends in crude mortality (as previously observed 7 ) were temporally 328 associated with more rapid treatment. Prior to the antibiotic era, treatment of respiratory 329 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint infections with antibody therapy was most effective if initiated within three days of 330 hospitalization. Thus, we used a similar timeframe, relative to date of diagnosis rather 331 than hospitalization, for stratifying the current data. Along similar lines, 7 and 30 day 332 survivors received on average higher volumes of plasma in unadjusted analyses. This is 333 of interest because we had no knowledge of the volume of plasma which might 334 constitute an efficacious dose prior to beginning this study. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint The design of the EAP has been criticized because it was not a randomized placebo, 360 controlled trial (RCT) 18 . We started the EAP in late March 2020. It was designed to 361 provide access to convalescent plasma largely at hospitals and acute care facilities that 362 were not already part of a RCT or did not have the infrastructure to support complex 363 RCTs. We also envisioned modest total enrollment and our original IRB approval was 364 for 5,000 patients. In this context, our primary goal was to report on the safety of 365 convalescent plasma and to perform an exploratory analysis for potential signals of 366 efficacy. As described earlier, the EAP was a pragmatic study design, organized to 367 allow routine clinical care to dictate the timing and administration of plasma with the 368 collection of real world data. We did not prespecify which medications patients should 369 be on to participate. The enrollment and data collection forms were streamlined to make 370 participation easy for sites engulfed in the work of a pandemic. The use of a central, 371 academic IRB allowed for consistent data evaluation and oversight. We streamlined PI 372 credentialing and IRB reliance processes. All forms were web-based at a time when 373 some believed that SARS-CoV-2 might be transmitted via paper contaminated with the 374 virus. We did not randomly assign treatment strategies or use of adjunctive medications. 375 Nonetheless, there were some elements of randomization or pseudo-randomization in 376 our study. Physicians could choose the timing of convalescent plasma, the number of 377 units administered, any repeat therapies and whether ICU or mechanically ventilated 378 patients were included. Furthermore, the degree of immune activity within the units of 379 convalescent plasma (i.e. specific IgG levels) was not known. It was assumed that 380 patients would receive plasma with low, medium and high antibody levels in a pseudo-381 randomized manner and that would enable assessment of efficacy. 382 We acknowledge that RCTs produce evidence of the highest quality in most but not all (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint pandemic has migrated across different US regions every few weeks, making it 390 challenging to predict where sites should be selected and prepared for a RCT. Third, 391 sites must be validated and activated. This work requires training of the investigators 392 and study team members as well as typically on-site visits. The crises of the COVID-19 393 pandemic were not compatible with these site training and activation activities; travel 394 within the US has been restricted and staff sent to activate sites would likely have been 395 quarantined for two weeks before being able to go to another region to activate sites. 396 Fourth, the very nature of a RCT requires subject willingness to be randomized to active 397 treatment or placebo or a comparator agent. There was no consensus in April nor is The relationships between mortality and both time to plasma transfusion, and antibody 415 levels provide a signature that is consistent with efficacy for the use of convalescent 416 plasma in the treatment of hospitalized COVID-19 patients. 417 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020 . . https://doi.org/10.1101 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020 . . https://doi.org/10.1101 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. Harmony. JAMA. 2020. 505 506 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint including daily counts (blue bars) and 7-day average (blue line). The dashed vertical reference 517 lines delineate the three study epochs. 518 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020 . . https://doi.org/10.1101 Refer to the methods for the variables in the adjustment and the calculation of the relative risks. 528 categorized as none (n=0), limited (n=1 -4) or many (5 or more), as defined in Table 1 . 539 540 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020 . . https://doi.org/10.1101 Compatible COVID-19 convalescent plasma was administered intravenously according 569 to accepted transfusion guidelines used for fresh frozen plasma. 570 For practical purposes in the current outbreak, one -two units of compatible COVID-19 572 convalescent plasma were administered. Convalescent plasma was obtained from a 573 registered or licensed blood collector and was collected preferably by apheresis or, if 574 necessary, by conventional methods. Individual institutional guidelines for the 575 administration of plasma were followed, including the use of any premedications, such 576 as acetaminophen or diphenhydramine. 577 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint Compatible convalescent plasma units were obtained from a registered or licensed 579 blood collector following registration of a patient under the auspices of the Expanded 580 Access Program. COVID-19 convalescent plasma was supplied as an investigational 581 blood product for the treatment of COVID-19. The plasma container label of the COVID-582 19 convalescent plasma unit included the following statement, "Caution: New Drug -583 Limited by Federal (or United States) law to investigational use." (21 CFR 312.6(a)). Eligible patients for this Expanded Access Program were identified by their treating 586 providers. The patient inclusion criteria were specific to hospitalized patients, these 587 criteria were exceptionally broad. Age at least 18 years 2. Laboratory confirmed diagnosis of infection with SARS-CoV-2 3. Admitted to an acute care facility for the treatment of COVID-19 complications Severe or life threatening COVID-19, or judged by the treating provider to be at high risk of progression to severe or life-threatening disease 5. Informed consent provided by the patient or healthcare proxy Severe or Life-threatening COVID-19 is defined by one or more of the following: · dyspnea · respiratory frequency ≥ 30 · min -1 · blood oxygen saturation ≤ 93% · partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300 · lung infiltrates > 50% within 24 to 48 hours · respiratory failure · septic shock · multiple organ failure 590 None. 592 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint Supplemental These data include a subset of the sample (n = 2,009), only those patients that currently have severe or lifethreatening COVID-19 Data was not available for Gender (n=6), Weight Status (n=190) and Mechanical Ventilation prior to infusion (n=61). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint Supplemental Table 3 . Crude Mortality (7 and 30 day) of patients with IgG transfused with COVID-10 Convalescent Plasma. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 12, 2020. . https://doi.org/10.1101/2020.08.12.20169359 doi: medRxiv preprint Hark back: 462 passive immunotherapy for influenza and other serious infections Serum therapy revisited: animal models of infection and 465 development of passive antibody therapy Return to the past: the case for antibody-based therapies in 468 infectious diseases Meta-analysis: convalescent blood 470 products for Spanish influenza pneumonia: a future H5N1 treatment? Effect of Convalescent Plasma Therapy on Time to Clinical 473 Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized 474 Clinical Trial Treatment of Coronavirus Disease 2019 (COVID-476 19) Patients with Convalescent Plasma Safety Update: COVID-19 Convalescent 478 Plasma in 20,000 Hospitalized Patients Deployment of convalescent plasma for the 482 prevention and treatment of COVID-19 The REDCap consortium: Building an international 484 community of software platform partners Research electronic 486 data capture (REDCap)--a metadata-driven methodology and workflow process for 487 providing translational research informatics support Throughput Immunoassays for Detection of IgG Antibodies against SARS-CoV-2 The Results of the Serum Treatment in Thirteen Hundred Cases of Epidemic 493 Meningitis Serum Therapy" revisited: Animal models of infection and 496 the development of passive antibody therapy Return to the past: the case for antibody-based therapies in Age at Enrollment (years) 424 (34.7%) 4,938 (33.3%) 4,806 (35.6%) 12,168 (34.4%) 60 to 69 2 6%) 13,563 (38.4%) Not Hispanic/Latino 4,599 (65.8%) 9,549 (64.3%) 7,611 (56.4%) 21,759 (61.6%) Clinical Status Current severe or lifethreatening COVID-19 .7%) 1,130 (7.6%) 1,023 (7.6%) 736 (53.4%) 6,137 (41.3%) 7,735 (57.4%)