Efficacy and safety of convalescent plasma and intravenous immunoglobulin in critically ill COVID-19 patients. A controlled clinical trial

  1. Jose Lenin Beltran Gonzalez
  2. Mario González Gámez
  3. Emmanuel Antonio Mendoza Enciso
  4. Ramiro Josue Esparza Maldonado
  5. Daniel Hernández Palacios
  6. Samuel Dueñas Campos
  7. Itzel Ovalle Robles
  8. Mariana Jocelyn Macías Guzmán
  9. Andrea Lucia García Díaz
  10. César Mauricio Gutiérrez Peña
  11. Ana Lilian Reza-Escalera
  12. Maria Teresa Tiscareño Gutierrez
  13. Elva Galvan-Guerra
  14. Maria del Rocio Dorantes Morales
  15. Lucila Martínez Medina
  16. Victor Antonio Monroy Colin
  17. Arreola Guerra Jose Manuel

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Abstract

Background

The proportion of critically ill COVID-19 patients has collapsed hospital care worldwide. The need for alternative therapies for this group of patients is imperative. This study aims to compare the safety and efficacy of convalescent plasma (CP) compared with human immunoglobulin (IVIg) in patients requiring the administration of high oxygen levels or mechanical ventilation.

Methods

This is a controlled, randomized, open clinical trial of patients with pneumonia secondary to SARS-CoV-2 infection, that fulfilled criteria for severe or critical disease. They were randomized in a 1:2 ratio; group 1 was administered IVIg at a dose of 0.3 grams per kilogram of ideal weight, in an 8-hour infusion every 24 hours, for 5 days. Group 2 was administered 200 ml of CP infused in 2 hours, for 2 days. The primary outcomes were duration of hospitalization and mortality at 28 days.

Results

One hundred and ninety (190) patients were randomized; 130 to the CP group, and 60 to the IVIg group. Their average age was 58 years (IQR 47 – 72), and most were male (n= 119, 62.6 %). On inclusion, 85.2 % of patients (n=162) were on invasive mechanical ventilation therapy. Overall mortality in all included patients was 53 % (n= 102), with a median follow-up of 14 days (IQI 8 – 26). Mortality at 28 days was 45.2 % (n=86). In the intention-to-treat analysis, there was no difference between groups neither in mortality on follow-up (53.8 vs. 53.3, p =1.0) nor at 28 days (46.2 vs 43 %, p=0.75, Log Rank p = 0.83). Per-protocol analysis between treatment groups revealed no difference in mortality throughout hospitalization (51.5 vs 51.4 %, p=1.0) nor after 28 days (42.1 vs 42.87 %, p=0.92 Log Rank p = 0.54). Only 23 patients in the CP group received plasma with detectable anti-SARS-CoV-2 antibodies.

Conclusions

In critically ill patients or on invasive mechanical ventilation for treatment of Covid-19, the use of CP is not superior to IVIg in terms of hospitalization duration or mortality. The use of CP is based on complex logistics and requires an assured level of antibodies if used therapeutically. IVIg does not appear to be useful in this group of patients.

clinicaltrials.gov identifier: NCT04381858 .

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    SciScore for 10.1101/2021.03.28.21254507: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: Patients that were included signed an informed consent form, either personally or if unable due to illness severity, by the responsible relative whose authorization was requested by telephone following hospital safety measures.
    IRB: This study was approved by the ethics committee of the Centenario Hospital Miguel Hidalgo, on April 15, 2020, with the identifier number 2020-R-25.
    RandomizationThis is a controlled, randomized, open clinical trial including patients with secondary pneumonia to SARS-CoV-2 infection, and fulfilling severe or critical disease criteria, to compare the efficacy and safety of CP administration in comparison with the use of IVIg.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Serum aliquots from donor patients were safeguarded to document the presence of anti-SARS-CoV-2 IgG antibodies by immunochemiluminescence (ARCHITECT ABBOTT).
    anti-SARS-CoV-2 IgG
    suggested: None

    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:
    One of our study’s weaknesses is the use of convalescent plasmas in which antibodies were not measured since this is a limited resource in our setting. This occurred at the beginning of the study and later, we were only able to conduct qualitative determinations. But this study underscores the complexity of recruiting optimal plasma donors and the logistics of its administration. This is clearly reflected in the large proportion of patients that did not receive CP. On the other hand, the IVIg group was treated at pre-established times and with established doses, with no relevant deviations from the contemplated protocol. Regardless, it did not prove to be superior to CP which suggests therapeutic futility, at least in terms of the administered dosage and the characteristics of our patient population.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04381858CompletedConvalescent Plasma vs Human Immunoglobulin to Treat COVID-1…
    NCT04391127CompletedHydroxychloroquine and Ivermectin for the Treatment of COVID…

    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 10.1101/2021.03.28.21254507 on medRxiv