Nature and Dimensions of Systemic Hyperinflammation and its Attenuation by Convalescent Plasma in Severe COVID-19

  1. Purbita Bandopadhyay
  2. Ranit D’Rozario
  3. Abhishake Lahiri
  4. Jafar Sarif
  5. Yogiraj Ray
  6. Shekhar Ranjan Paul
  7. Rammohan Roy
  8. Rajshekhar Maiti
  9. Kausik Chaudhuri
  10. Saugata Bagchi
  11. Ayan Maiti
  12. Mohammed Masoom Perwez
  13. Biswanath Sharma Sarkar
  14. Devlina Roy
  15. Rahul Chakraborty
  16. Janani Srinivasa Vasudevan
  17. Sachin Sharma
  18. Durba Biswas
  19. Chikam Maiti
  20. Bibhuti Saha
  21. Prasun Bhattacharya
  22. Rajesh Pandey
  23. Shilpak Chatterjee
  24. Sandip Paul
  25. Dipyaman Ganguly

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Abstract

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), has led to significant morbidity and mortality. While most suffer from mild symptoms, some patients progress to severe disease with acute respiratory distress syndrome (ARDS) and associated systemic hyperinflammation.

Methods

First, to characterize key cytokines and their dynamics in this hyperinflammatory condition, we assessed abundance and correlative expression of a panel of 48 cytokines in patients progressing to ARDS as compared to patients with mild disease. Then, in an ongoing randomized controlled trial of convalescent plasma therapy (CPT), we analyzed rapid effects of CPT on the systemic cytokine dynamics as a correlate for the level of hypoxia experienced by the patients.

Results

We identified an anti-inflammatory role of CPT independent of its neutralizing antibody content.

Conclusions

Neutralizing antibodies, as well as reductions in circulating interleukin-6 and interferon-γ–inducible protein 10, contributed to marked rapid reductions in hypoxia in response to CPT.

Clinical Trial Registry of India

CTRI/2020/05/025209. http://www.ctri.nic.in/

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  1. ScreenIT

    SciScore for 10.1101/2020.09.21.20199109: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: Ethical approval: The randomized control trial (RCT) on convalescent plasma therapy and all associated studies and the human sampling needed for them were done with informed consent from the patients as per recommendation and ethical approval from the Institutional Review Boards of CSIR-Indian Institute of Chemical Biology, Kolkata, India (IICB/IRB/2020/3P), Institutional Review Boards of Medical College Hospital, Kolkata (MC/KOL/IEC/NON-SPON/710/04/2020), India and Infectious Disease & Beleghata General Hospital (ID & BG Hospital), Kolkata, India (IDBGH/Ethics/2429).
    IRB: Ethical approval: The randomized control trial (RCT) on convalescent plasma therapy and all associated studies and the human sampling needed for them were done with informed consent from the patients as per recommendation and ethical approval from the Institutional Review Boards of CSIR-Indian Institute of Chemical Biology, Kolkata, India (IICB/IRB/2020/3P), Institutional Review Boards of Medical College Hospital, Kolkata (MC/KOL/IEC/NON-SPON/710/04/2020), India and Infectious Disease & Beleghata General Hospital (ID & BG Hospital), Kolkata, India (IDBGH/Ethics/2429).
    RandomizationEthical approval: The randomized control trial (RCT) on convalescent plasma therapy and all associated studies and the human sampling needed for them were done with informed consent from the patients as per recommendation and ethical approval from the Institutional Review Boards of CSIR-Indian Institute of Chemical Biology, Kolkata, India (IICB/IRB/2020/3P), Institutional Review Boards of Medical College Hospital, Kolkata (MC/KOL/IEC/NON-SPON/710/04/2020), India and Infectious Disease & Beleghata General Hospital (ID & BG Hospital), Kolkata, India (IDBGH/Ethics/2429).
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Presence of SARS-CoV-2 neutralizing antibodies in the plasma samples block interaction between HRP-RBD and hACE2, which is detected through colorimetry.
    hACE2
    suggested: None
    Since presence of SARS-CoV-2 neutralizing antibodies in the plasma samples will result in inhibition of interaction between HRP-RBD and plate-bound human ACE2 protein, and subsequent development of color, assay results are interpreted as inhibition rate of assay reaction.
    human ACE2 protein,
    suggested: None
    In case of recipient patients the amount of neutralizing antibodies was calculated considering the amount (ml) of plasma transfused to them. ELISA for anti SARS-CoV-2 IgG: Levels of Immunoglobulin G (IgG) specific for SARS-CoV-2 in the plasma isolated from peripheral blood of recovered patients were detected using EUROIMMUN Anti-SARS-CoV-2 (IgG) Elisa kit (Cat No-EI 2606-9601 G).
    anti SARS-CoV-2 IgG: Levels of Immunoglobulin G (IgG
    suggested: None
    Anti-SARS-CoV-2 (IgG
    suggested: None
    The two reaction steps in this ELISA involves the incubation of diluted patient samples in pre-coated wells following which bound antibodies are detected using enzyme labeled anti human IgG.
    anti human IgG
    suggested: None
    Presence of anti SARS-CoV-2 IgG antibodies in the plasma was measured using the following formula: Ratio = Extinction of the control or patient samples/Extinction of calibrator (Ratio ≥ 1.1 is interpreted as positive).
    anti SARS-CoV-2 IgG
    suggested: None
    Similar tests were performed between neutralizing antibody content and IgG antibody content for plasma recipient patients.
    IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    Visualisation of the network was performed using Cytoscape.
    Cytoscape
    suggested: (Cytoscape, RRID:SCR_003032)

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1093/infdis/jiab010
  3. Version published to 10.1101/2020.09.21.20199109v2 on medRxiv
  4. Version published to 10.1101/2020.09.21.20199109v1 on medRxiv