Kinetics of SARS-CoV-2 antibody responses pre-COVID-19 and post-COVID-19 convalescent plasma transfusion in patients with severe respiratory failure: an observational case–control study

  1. Matthew N Klein
  2. Elizabeth Wenqian Wang
  3. Paul Zimand
  4. Heather Beauchamp
  5. Caitlin Donis
  6. Matthew D Ward
  7. Aidaelis Martinez-Hernandez
  8. Ali Tabatabai
  9. John W Baddley
  10. Evan M Bloch
  11. Kristin E Mullins
  12. Magali J Fontaine

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Abstract

While the SARS-CoV-2 pandemic may be contained through vaccination, transfusion of convalescent plasma (CCP) from individuals who recovered from COVID-19 (CCP) is considered an alternative treatment. We investigate if CCP transfusion in patients with severe respiratory failure increases plasma titres of SARS-CoV-2 antibodies and improves clinical outcomes.

Methods

Patients with COVID-19 (n=34) were consented for CCP transfusion and serial blood draws pretransfusion and post-transfusion. Plasma SARS-CoV-2 antireceptor binding domain (RBD) IgG and IgM titres were measured by ELISA serially, and compared with serial plasma titre levels from control patients (n=68). The primary outcome was survival at 30 days, and secondary outcomes were length of ventilator and/or extracorporeal membrane oxygenation (ECMO) support, length of stay (LOS) in the hospital and in the intensive care unit (ICU). Outcomes were compared with matched control patients (n=34). Kinetics of antibodies and clinical outcomes were compared using LOess regression and ORs, respectively.

Results

Prior to CCP transfusion, 74% of patients were anti-RBD seropositive for IgG (median 1:3200), and 81% were anti-RBD IgM seropositive (median 1:320), while 16% were seronegative. The kinetics of antibody titres in CCP recipients were similar to controls. CCP recipients presented with similar survival, duration on ventilatory and/or ECMO support, as well as ICU and hospital LOS compared with controls.

Conclusions

CCP transfusion did not increase the kinetics of SARS-CoV2 antibodies and did not result in improved clinical outcomes in patients with COVID-19 with severe respiratory failure, suggesting that CCP may not be indicated in this category of patients.

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  1. Version published to 10.1136/jclinpath-2020-207356
  2. ScreenIT

    SciScore for 10.1101/2020.12.10.20247007: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: This study was approved by the University of Maryland Baltimore Institutional Review Board (HP-00092606).
    Consent: Informed consent was obtained, and CCP was transfused following FDA authorization through either the eIND pathway or the Mayo Clinic EAP.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The wells were then washed, incubated for one hour with either Horseradish Peroxidase conjugated goat-anti-human IgG or IgM detection antibody (1:12000) (Invitrogen), washed, incubated with 3,3′,5,5′-Tetramethylbenzidine (TMB) substrate (Seracare; Milford, MA) for 10 minutes in the dark, and quenched with 1N sulfuric acid (Thermo Fisher Scientific).
    IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    In brief, plasmids containing the SARS-CoV-2 spike protein RBD (provided by the Krammer Laboratory, Icahn School of Medicine at Mount Sinai, NY) were transformed into competent E. coli (New England BioLabs; Ipswich, MA) and grown in Luria-Bertani broth with ampicillin overnight in shaker flasks.
    New England BioLabs
    suggested: (New England Biolabs, RRID:SCR_013517)
    Protein concentration was measured by NanoDrop (Thermo Fisher Scientific; Waltham, MA), and SDS-PAGE assessed purity.
    Thermo Fisher Scientific
    suggested: (Thermo Fisher Scientific, RRID:SCR_008452)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Strengths and limitations of this study: This study adds to the current literature on CCP efficacy by characterizing the kinetics of SARS-CoV-2 antibodies following CCP transfusion, which has not been previously described longitudinally in comparison to control plasma samples from non-transfused COVID-19 patients. Furthermore, the study reports on CCP therapeutic responses in specific subgroups of patients who require either solely ventilatory support and/or ECMO support. Our institution is a referral center for those most severe cases of COVID-19 in the state of Maryland. Thus, we believe that the data presented can provide generalizability on the effect of CCP transfusion in subgroups of critically ill patients presenting with different levels of respiratory support. To strengthen the study, we compared the antibody titer measurements by ELISA to those obtained on a commercially available instrument, the Ortho VITROS total anti-SARS-CoV-2 Ig platform, which had been previously validated against a SARS-CoV-2 neutralizing live-cell assay(20, 21). The median IgG titers prior to CCP transfusion were high (>1:3200). Interestingly, Salazar et al. showed that anti-RBD IgG titers greater than 1:1350 correlated with SARS-CoV-2 neutralization (VN) titers greater than 1:160 at 80% probability(20). VN titer > 1:160 is the recommended level by the FDA in CCP products using the Ortho VITROS IgG platform at a signal to a cut-off ratio (S/C) of 12. While we were not able to compare our tit...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2020.12.10.20247007v1 on medRxiv