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The feasibility of multiple units of convalescent plasma in mechanically ventilated patients with COVID-19: A pilot study

      Keywords

      To the Editor:
      A renewed interest in convalescent plasma (CP) was triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Based on the historical use of CP during prior viral outbreaks, a small number of case series and observational studies were conducted early in the pandemic to evaluate the therapeutic role of CP in coronavirus disease 2019 (COVID-19) [
      • Wooding D.J.
      • Bach H.
      Treatment of COVID-19 with convalescent plasma: lessons from past coronavirus outbreaks.
      ]. Though the results were mixed, in April 2020, the Mayo Clinic received permission from the US Food and Drug Administration (FDA) to start an Expanded Access Program (EAP) for the use of CP as treatment for COVID-19. The EAP increased access to CP and facilitated investigation of its safety and efficacy [
      • Joyner M.J.
      • Carter R.E.
      • Senefeld J.W.
      • Klassen S.A.
      • Mills J.R.
      • Johnson P.W.
      • et al.
      Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19.
      ]. In August of 2020, the FDA granted an emergency use authorization (EUA) for CP [

      Hinton DM. Emergency Use Authroization of Convalescent Plasma for COVID-19, Letter of Authorization, 2020. 〈http://www.wellspanlabs.org/media/15813/FDA_-EUA_Convalescent-PlasmaLOA_FINAL_web_82320.pdf〉.

      ]. When the EUA was granted, the efficacy of CP in COVID-19 was still unknown, and important questions about timing of treatment, patient selection, dosing, and antibody testing remained unanswered. There is now a better understanding of the serological response to SARS-CoV-2, “high-titer” thresholds for different anti-SARS-CoV-2 antibody assays have been defined [

      Hinton DM. Emergency Use Authroization of Convalescent Plasma for COVID-19, Letter of Authorization, 2020. 〈http://www.wellspanlabs.org/media/15813/FDA_-EUA_Convalescent-PlasmaLOA_FINAL_web_82320.pdf〉.

      ], and a large cohort study suggests that “high-titer” CP may be effective in reducing progression of COVID-19 in some hospitalized patients [
      • Joyner M.J.
      • Carter R.E.
      • Senefeld J.W.
      • Klassen S.A.
      • Mills J.R.
      • Johnson P.W.
      • et al.
      Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19.
      ].
      Early in the pandemic, we were interested in strategies that would increase a patient’s chances of receiving the quantity (i.e.; titer) and type (i.e.; neutralizing) of antibodies needed to suppress SARS-CoV-2 viral injury. We anticipated this could be done safely via serial transfusions of CP given the low risk of plasma transfusion [
      • Bloch E.M.
      • Shoham S.
      • Casadevall A.
      • Sachais B.S.
      • Shaz B.
      • Winters J.L.
      • et al.
      Deployment of convalescent plasma for the prevention and treatment of COVID-19.
      ]. Based on this premise, we conducted a pilot study to evaluate the feasibility of repeated dosing of anti-SARS-CoV-2 CP in critically ill mechanically ventilated patients. Key parameters included access to CP and provider willingness to transfuse multiple units of CP to profoundly hypoxemic, mechanically ventilated patients. Additional areas of interest included the antibody content of the transfused CP and measures of safety.
      In this single-arm, open-label, pilot study conducted at two academic medical centers (NCT04353206), 10 hypoxemic (PaO2/FiO2 < 300) mechanically ventilated adults (age > 18 years) with acute respiratory failure due to COVID-19 were enrolled within 72 h of intubation. Patients were transfused with up to six units of CP (2 units of CP on day 0, 3, and 6), or until significant clinical improvement (PaO2/FiO2 > 300), extubation, futility (i.e., as determined by the treating physician), or death (whichever occurred first). Plasma transfused to enrolled patients at Cedars Sinai was sourced from donors via the Blood Donor Service of the Cedars Sinai Transfusion Medicine Program. These units were then screened using a lateral flow assay to detect the presence or absence anti-SARS-CoV-2 antibodies (Haelgen COVID-19 IgG/IgM Rapid Test). By contrast, at Johns Hopkins, CP was sourced via an expanded access resource to which individuals donate after recovery from COVID-19, but no assessments for antibody presence were made before use. Vital signs, laboratory studies, and assessment of clinical status (including ventilatory requirements) were performed on days 0, 3, and 6 of plasma administration. Additional follow-up was performed on days 14, 28, and 60, which included assessments of respiratory and overall clinical status. Antibody levels of the transfused units of CP were measured retrospectively at both sites using commercially available enzyme-linked immunosorbent assays (ELISAs).
      The baseline demographics and clinical outcomes of the 10 patients are reported in Table 1. The median age was 59 years; 7 patients were male, and 8 met criteria for obesity (BMI > 30). The median time between date of onset of respiratory symptoms and mechanical ventilation and first CP infusion was 11 and 12.5 days, respectively. All patients received concomitant SARS-COVID-2 therapy with remdesivir and dexamethasone. Six patients were extubated by day 60. Among the eight patients who were discharged alive, the median time on mechanical ventilation was 22.5 days. The median length of stay for these survivors was 35 days. Two patients died before discharge. Neither death was attributed to the use of CP. In fact, none of the 10 patients in the pilot had any adverse events attributable to CP.
      Table 1Baseline demographics and clinical outcomes of enrolled patients with COVID-19 who received multiple doses of CP.
      Patient Number12345678910
      Age (years)51656949403374537072
      Sex (M/F)FMMMMMMMFF
      Race/EthnicityHispanicAfrican-AmericanCaucasianHispanicHispanicCaucasianCaucasianHispanicAfrican-AmericanAfrican-American
      BMI38333336283028384046
      ComorbidityObesity, HLD, pre-diabetesCAD, DM, CKD, HLD, HTN, ObesityCAD, HTN, ObesityObesityNoneHIV/AIDS, ObesityHLD, HTN, OSADM, HLD, HTNDM, GERD, HTN, Obesity, OSAAsthma, CKD, Obesity
      Time to MV1151216113211159
      Time to CP2161318135241269
      Other TherapyDex, RemdesivirDex, RemdesivirAzithro, Dex, RemdesivirDex, RemdesivirDex, RemdesivirDex, RemdesivirAzithro, Dex, Remdesivir, Vit CDex, RemdesivirDex, RemdesivirDex, Remdesivir
      ExtubatedNYYNYYNYNY
      MV Days7321821274643675
      Adverse Events0000000000
      Discharged AliveNYYNYYYYYY
      Hospital Days8443523711364 *108022
      Azithro = Azithromycin, BMI = body mass index, CAD = coronary artery disease, CKD = chronic kidney disease, CP = convalescent plasma, Dex = Dexamethasone, DM = diabetes mellites, GERD = gastroesophageal reflux disease, HLD = hyperlipidemia, HTN = hypertension, MV = mechanical ventilation, OSA = obstructive sleep apnea, Vit C = Vitamin. *Discharged alive to vent rehabilitation unit
      Table 2 shows severity of disease based on APACHE II and SOFA Scores [
      • Knaus W.A.
      • Draper E.A.
      • Wagner D.P.
      • Zimmerman J.E.
      APACHE II: a severity of disease classification system.
      ,
      • Vincent J.L.
      • Moreno R.
      • Takala J.
      • Willatts S.
      • De Mendonca A.
      • Bruining H.
      • Reinhart C.K.
      • Suter P.M.
      • Thijs L.G.
      The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.
      ]. The median APACHE II score was 22 on day 0, which correlates to an approximated 40% likelihood of in-hospital death [
      • Knaus W.A.
      • Draper E.A.
      • Wagner D.P.
      • Zimmerman J.E.
      APACHE II: a severity of disease classification system.
      ]. The median SOFA score on day 0 was 9, and for those who remained alive and in hospital at day 28 (n = 5), the median SOFA score was 8.
      Table 2Severity of disease based on APACHE II and Modified SOFA.
      Patient number12345678910
      APACHE II
      Day 019413424162428201818
      mSOFA
      Day 0813117107108710
      Day 391210811311368
      Day 6N/A1798838274
      Day 14N/A12794212DC62
      Day 28N/A81N/A6DC9DC9DC
      Note: Patient 4 expired by Day 28. Patient 6 did not follow-up on Day 28.
      DC: patient discharged alive and SOFA not calculated.
      Table 3 displays the antibody content of each plasma unit administered to the 10 patients enrolled at the two sites. Antibodies were measured using the Abbott Architect or the Euroimmun anti-SARS-CoV-2 IgG assays at site 1 (patients 1 – 6; Cedars Sinai) and site 2 (patients 7−10; Johns Hopkins), respectively [
      • Klein S.L.
      • Pekosz A.
      • Park H.S.
      • Ursin R.L.
      • Shapiro J.R.
      • Benner S.E.
      • et al.
      Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population.
      ,
      • Patel E.U.
      • Bloch E.M.
      • Clarke W.
      • Hsieh Y.H.
      • Boon D.
      • Eby Y.
      • Fernandez R.E.
      • Baker O.R.
      • Keruly M.
      • Kirby C.S.
      • Klock E.
      • Littlefield K.
      • Miller J.
      • Schmidt H.A.
      • Sullivan P.
      • Piwowar-Manning E.
      • Shrestha R.
      • Redd A.D.
      • Rothman R.E.
      • Sullivan D.
      • Shoham S.
      • Casadevall A.
      • Quinn T.C.
      • Pekosz A.
      • Tobian A.A.R.
      • Laeyendecker O.
      Comparative Performance of Five Commercially Available Serologic Assays To Detect Antibodies to SARS-CoV-2 and Identify Individuals with High Neutralizing Titers.
      ]. Antibodies were measured in the plasma of all but one donor; one patient did not receive CP on day 3, and four patients did not did not receive CP on day 6. Based on the EUA-defined thresholds for high-titer using the Abbott Architect assay (specimen/calibrator [S/C] > 4.5) or Euroimmun assay (Arbitrary Unit [AC] > 3.5), all patients at Cedars Sinai and one patient at Johns Hopkins received at least 1 unit of high-titer CP. Overall, 20 of the 50 (40%) CP units administered met criteria for high-titer. Notably, review of transfusion records demonstrated that some patients received more than one unit of CP from the same donor (e.g. units 1–2 in patient 2, units 1, 3, and 5 in patient 7). This had the potential to provide serial doses of high-titer CP to some patients (patient 2), while in others it resulted in serial transfusions of non-high-titer CP (patient 7). Moreover, 53% of units administered at Cedars Sinai met criteria for high-titer CP compared to only 11% of units at Johns Hopkins. Indeed, it appears that the practice at Cedars Sinai of using a lateral flow assay to identify units as having some detectable anti-SARS-CoV-2 antibodies was of value in identifying units with a higher likelihood of being high-titer. Notably, lateral flow assays are easy to use, portable, provide a rapid result, and do not require the laboratory infrastructure and technical expertise necessary to conduct ELISA assays [
      • Conklin S.E.
      • Martin K.
      • Manabe Y.C.
      • Schmidt H.A.
      • Miller J.
      • Keruly M.
      • et al.
      Evaluation of serological SARS-CoV-2 lateral flow assays for rapid point-of-care testing.
      ].
      Table 3Abbott and Euroimmun anti-SARS-CoV-2 IgG Serum/Calibrator per unit of plasma administered.
      IgG S/CPatient 1Patient 2Patient 3Patient 4Patient 5Patient 6Patient 7Patient 8Patient 9Patient 10
      AssayAbbottAbbottAbbottAbbottAbbottAbbottEuroimmunEuroimmunEuroimmunEuroimmun
      Day 0
      Unit 14.637.385.263.077.184.330.20.190.841.03
      Unit 22.467.38Not tested9.176.267.50.321.61.063.59
      Day 3
      Unit 10.615.267.744.27.031.660.2N/A0.843.17
      Unit 22.637.950.572.8121.660.32N/A1.068.37
      Day 6
      Unit 1N/A7.746.886.887.46N/A0.2N/A0.38N/A
      Unit 2N/A0.576.883.118.03N/A0.32N/A0.38N/A
      Sum of Titer10.3336.28> 27.3329.2437.7615.551.561.794.5616.16
      S/C = specimen/calibrator
      Note: EUA-defined high-titer CP is an index (S/C) > 4.5 for the Abbott assay & > 3.5 for Euroimmun
      N/A = Not applicable because not transfused on this day
      Our study also suggests that administering multiple units of CP is feasible. Among patients receiving units pre-screened with a lateral flow assay, the cumulative antibody delivered overall was much greater than had a single unit been transfused. CP was readily accessible and clinical providers were supportive of a multi-dosing strategy, whereby concerns related to volume overload and the potential for transfusion associated lung injury did not impact enrollment. Further, no adverse events were attributed to CP infusion.
      There are limitations of this study. First, while we did not observe any transfusion associated adverse events, the small sample size and non-randomized design limit this observation. Second, we did not measure pre- and post-infusion anti-SARS-CoV-2 endogenous antibody titers, so whether the infusion of the convalescent plasma changed antibody levels in the recipients is unknown.
      In conclusion, a strategy that employs a qualitative assay and transfusion of multiple units can be used to increase the amount of antigen specific antibody transfused overall. This strategy may be especially valuable in resource-limited settings where ELISA assays and monoclonal antibodies are scarce. We encourage continued enrollment into clinical trials to better understand CP as treatment, both for COVID-19 as well as to inform the response to emerging infectious diseases.

      Acknowledgments

      NM’s effort is supported in part by NCI (1U54CA260591–01, sub-project ID 8248). EMB’s effort is supported in part by the NHLBI (1K23HL151826). The study also had support from Bloomberg Philanthropies and the State of Maryland.

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