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Elevated Rate of HLA Antibodies in Male COVID-19 Convalescent Plasma Donors

A Risk Factor for Transfusion-Related Acute Lung Injury
Published:November 23, 2020DOI:https://doi.org/10.1016/j.mayocp.2020.11.007
      To The Editor:
      The FDA-approved Expanded Access Program provided an exception to collect coronavirus disease-2019 (COVID-19) convalescent plasma (CCP) from recovered patients. Convalescent plasma has become a treatment for patients with severe or life-threatening severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection under the Expanded Access Program. To date, CCP has been reported to be as safe as standard plasma transfusion.
      • Joyner M.J.
      • Wright R.S.
      • Fairweather D.
      • et al.
      Early safety indicators of COVID-19 convalescent plasma in 5000 patients.
      Unlike regular blood donors, CCP donors have recently recovered from a potentially serious viral infection. Although transmission of coronaviruses has never been reported from transfusion, other plasma-borne factors related to recent coronavirus infection potentially could. Donor human leukocyte antigen antibodies (HLA-Ab) are a primary cause of transfusion-related acute lung injury (TRALI), which is one of the top causes of transfusion-related mortality. Although donor HLA-Ab are usually caused by previous pregnancies, transfusions, or transplantations, viral infections can also trigger the formation and rise of HLA-Ab.
      • D'Orsogna L.
      • van den Heuvel H.
      • van Kooten C.
      • Heidt S.
      • Claas F.H.J.
      Infectious pathogens may trigger specific allo-HLA reactivity via multiple mechanisms.
      ,
      • Russell M.R.
      • Halnon N.J.
      • Alejos J.C.
      • Salem M.M.
      • Reardon L.C.
      COVID-19 in a pediatric heart transplant recipient: emergence of donor-specific antibodies.
      As part of national TRALI mitigation strategies, blood banks currently only use plasma from male donors, never pregnant female donors or previously pregnant female donors who screen negative for HLA-Ab.
      Given that patients with severe or life-threatening SARS-CoV-2 infection already have significant acute lung injury, CCP recipients would be at a greater mortality risk if TRALI occurred. Moreover, TRALI in CCP recipients could be misattributed to progression of the recipient’s underlying SARS-CoV-2 infection. For all of these reasons, we implemented universal screening of all CCP donors for HLA-Ab, regardless of sex, at our institution.
      All CCP donors collected from April 3, 2020, through July 31, 2020, were screened for HLA-Ab (LabScreen Mixed Class I & II, One Lambda, West Hills, California). Positive screening cutoff ratios were previously established at the +5 standard deviation threshold in a population of never-transfused male standard blood donors (class I ratio >30; class II ratio >18) so that <0.01% of male blood donors would screen positive.
      • Triulzi D.J.
      • Kleinman S.
      • Kakaiya R.M.
      • et al.
      The effect of previous pregnancy and transfusion on HLA alloimmunization in blood donors: implications for a transfusion-related acute lung injury risk reduction strategy.
      ,
      • Carrick D.M.
      • Norris P.J.
      • Endres R.O.
      • et al.
      Establishing assay cutoffs for HLA antibody screening of apheresis donors.
      HLA-Ab specificities of positive screens were confirmed using a single-antigen bead (SAB) assay (LabScreen Single Antigen Class I or II). Additional testing with acid-treated single antigen beads was also performed on those donors with class I HLA-Ab to confirm that the reactivity observed was to intact HLA.
      • Jacob E.K.
      • De Goey S.R.
      • Gandhi M.J.
      Positive virtual crossmatch with negative flow crossmatch results in two cases.
      During the collection period, 157 unique CCP donors underwent HLA-Ab screening, and 16 CCP donors (10.1%) were deferred for a positive HLA-Ab screen. Of 69 unique male CCP donors, 5 screened positive for HLA-Ab (7.2%; Table); HLA-Ab specificities of all 5 male positive HLA antibody screens were confirmed and identified by SAB. Additional testing against acid-treated HLA beads for the 4 donors with class I HLA-Ab revealed that those with detected HLA-Ab essentially did not have reactivity against denatured HLA targets and are thus clinically relevant (Figure). None of these 5 male CCP donors had a history of transfusion, transplantation, or pregnancy. This male HLA-Ab screening positivity rate was significantly higher than expected for this donor population (P<.0001; χ2 test). In all, male donors represented 31% of all CCP donors who have screened positive for HLA-Ab (5 of 16).
      TableDemographic and HLA Antibody Results for 5 Male COVID-19 Convalescent Plasma Donors With Positive HLA Antibody Screens
      Donor numberSexAge (years)Days since reported COVID-19 symptom resolutionMixed class I HLA antibody ratioMixed class II HLA antibody ratioSingle antigen HLA antibody specificity [mean fluorescence intensity]
      1M47510.1618.52DR8[1188], DR13[1072], DR17[1070], DR14[966], DR11[716], DR18[635], DR12[309]

      DRw52[370]

      DQ6[534], DQ5[300]
      2M494131.423.36A25 [513], A11[444], A80[409], A23[391], A43[345], A34[305]

      B61[813], B46[585], B60[543], B63[453], B75[409], B54 [385], B64[378], B75[373], B41[349], B77[340], B55[313], B78[312]

      Cw12[1137], Cw7[1039], Cw8[964], Cw5[684], Cw17[665], Cw6[612], Cw9[590], Cw4[551], Cw10[551], Cw15[530], Cw16[483], Cw14[474], Cw18[435], Cw1[415], Cw2[383]
      3M5211656.9611.85A25[16404], A66[1339], A33[800]
      4M538334.536.32B46[1349], B76[322]
      5M3210831.080B46[811], B60[459], B62[304]
      Figure thumbnail gr1
      FigureDonor #3 class I HLA antibody testing using native and acid-treated single-antigen beads.
      Given these findings in this unique donor population, further studies are needed to better understand the association of HLA-Ab with SARS-CoV-2 infection. Confirmation of these findings could have significant implications on CCP donor screening to help mitigate the risk of TRALI, especially now that use of CCP has broadened to any hospitalized patient with COVID-19 under an FDA Emergency-Use Authorization. Confirmation of these findings would also add to the growing body of literature on the role of viral infection in development of HLA-Ab, which could have broader implications for persons prone to chronic infections (eg, patients with cystic fibrosis who need lung transplantation).

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        Early safety indicators of COVID-19 convalescent plasma in 5000 patients.
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      Linked Article

      • In Reply — Safety of Convalescent Plasma Transfusion
        Mayo Clinic ProceedingsVol. 96Issue 5
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          We thank Drs Franchini and Glingani for their letter in response to our recent Letter to the Editor entitled “Elevated Rate of HLA Antibodies in Male COVID-19 Convalescent Plasma Donors: A Risk Factor for Transfusion-Related Acute Lung Injury” and the safety data on COVID-19 convalescent plasma (CCP) transfusions they provided from their institution.1 As they noted, all of their CCP units were collected from recovered men or nulliparous women without a history of blood transfusion. Among the 516 CCP units administered, only a handful of mild allergic transfusion reactions occurred without any reported cases of transfusion-related acute lung injury (TRALI).
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      • Safety of Convalescent Plasma Transfusion
        Mayo Clinic ProceedingsVol. 96Issue 5
        • Preview
          We read with interest the Letter to the Editor by Juskewitch and colleagues,1 recently published in Mayo Clinic Proceedings, in which the investigators observed an unusually high rate (16/157 [10.1%]) of positivity in screens for human leukocyte antigen antibody (HLA-Ab), implicated in transfusion-related acute lung injury (TRALI), in donors of coronavirus disease 2019 (COVID-19) convalescent plasma (CCP). As 5 of them (5/157 [3.1%]) were male donors without a previous known risk factor for the development of HLA-Ab, the authors raised concerns about the safety of CCP.
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