Safety and effectiveness of RBD-specific polyclonal equine F(ab´)2 fragments for the treatment of hospitalized patients with severe Covid-19 disease: A retrospective cohort study

  1. Diego H. Farizano Salazar
  2. Fernando Achinelli
  3. Mariana Colonna
  4. Lucía Pérez
  5. Analía A. Giménez
  6. Maria Alejandra Ojeda
  7. Susana N. Miranda Puente
  8. Lía Sánchez Negrette
  9. Florencia Cañete
  10. Ornela I. Martelotte Ibarra
  11. Santiago Sanguineti
  12. Linus Spatz
  13. Fernando A. Goldbaum
  14. Carolina Massa
  15. Marta Rivas
  16. Mariana Pichel
  17. Yanina Hiriart
  18. Vanesa Zylberman
  19. Sandra Gallego
  20. Brenda Konigheim
  21. Francisco Fernández
  22. Matías Deprati
  23. Ian Roubicek
  24. Diego H. Giunta
  25. Esteban Nannini
  26. Gustavo Lopardo
  27. Waldo H. Belloso
  28. on behalf of EPIC Study Group

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

Passive immunotherapy has been evaluated as a therapeutic alternative for patients with COVID-19 disease. Equine polyclonal immunotherapy for COVID-19 (EPIC) showed adequate safety and potential efficacy in a clinical trial setting and obtained emergency use authorization in Argentina. We studied its utility in a real world setting with a larger population.

Methods

We conducted a retrospective cohort study at “Hospital de Campaña Escuela-Hogar" (HCEH) in Corrientes, Argentina, to assess safety and effectiveness of EPIC in hospitalized adults with severe COVID-19 pneumonia. Primary endpoints were 28-days all-cause mortality and safety. Mortality and improvement in modified WHO clinical scale at 14 and 21 days were secondary endpoints. Potential confounder adjustment was made by logistic regression weighted by the inverse of the probability of receiving the treatment (IPTW) and doubly robust approach.

Findings

Subsequent clinical records of 446 non-exposed (Controls) and 395 exposed (EPIC) patients admitted between November 2020 and April 2021 were analyzed. Median age was 58 years and 56.8% were males. Mortality at 28 days was 15.7% (EPIC) vs. 21.5% (Control). After IPTW adjustment the OR was 0.66 (95% CI: 0.46–0.96) P = 0.03. The effect was more evident in the subgroup who received two EPIC doses (complete treatment, n = 379), OR 0.58 (95% CI 0.39 to 0.85) P = 0.005. Overall and serious adverse events were not significantly different between groups.

Conclusions

In this retrospective cohort study, EPIC showed adequate safety and effectiveness in the treatment of hospitalized patients with severe SARS-CoV-2 disease.

Article activity feed

  1. Version published to 10.1371/journal.pone.0274796
  2. ScreenIT

    SciScore for 10.1101/2022.04.07.22273558: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Patients from the exposed group provided written informed consent for the administration of EPIC.
    Sex as a biological variableExclusion criteria were: SARS-CoV-2 disease other than severe (asymptomatic, mild, moderate or critical), pregnant women or during lactation period, patients already admitted to intensive care unit (ICU), confirmation of microbiological cause of pneumonia other than SARS-CoV-2, patients with therapeutic limitation or patients with history of anaphylaxis or severe allergic reaction to equine sera or to contact or exposure to horse proteins.
    RandomizationThis method, which is an extension of the propensity score, is particularly helpful in the estimation of causal associations when a randomized clinical trial is unfeasible.
    Blindingnot detected.
    Power AnalysisWith these assumptions, a minimal inclusion of 392 exposed and 392 non-exposed patients (784 patients in total) was required for a two-tailed test with an a error of 5% and 80% of statistical power.

    Table 2: Resources

    Antibodies
    SentencesResources
    Selection criteria: Patients were included in the study if had between 18 and 79 years old, COVID-19 diagnosis confirmed by SARS-CoV-2 antigen test or reverse-transcriptase-polymerase-chain reaction (qRT-PCR -GeneDX Co, Ltd or similar) or positive anti SARS-CoV-2 IgM antibodies, had severe disease defined as: respiratory rate of more than 30/min, or oxygen saturation <94% on room air at sea level, or a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, or lung compromise of more than 50%.
    antigen test or reverse-transcriptase-polymerase-chain reaction (qRT-PCR -GeneDX Co, Ltd or similar)
    suggested: None
    anti SARS-CoV-2 IgM
    suggested: None
    Software and Algorithms
    SentencesResources
    All statistical analysis was performed using STATA statistical software version 15.1
    STATA
    suggested: (Stata, RRID:SCR_012763)

    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:
    The main limitation of the study is the non-randomized design; however, data collection included structured forms applied for subjects enrolled in both cohort groups and at the same Hospital. Even more, all hospitalized subjects with COVID-19 were evaluated and enrolled in the study in a consecutive manner. Another existing limitation is that patients were included in one clinical site, missing the generalizability observed in multicenter trials. Of note, the results shown here should not be extrapolated to the vaccinated population nor to those with prior COVID-19 disease since only one participant had received a COVID-19 vaccine and a history of SARS-CoV-2 infection was an exclusion criterion. Although this was not fully studied, it can be speculated that most of the patients enrolled in this study were probably infected with the Gamma or P.1 variant due to the epidemiological situation of Argentina at the time of study. Nevertheless, being of polyclonal nature, EPIC has a broader recognition of epitopes on RBD Spike protein than mAbs, making this immunotherapy more robust against viral scape mutations. Interestingly, EPIC showed high neutralizing activity against Gamma and Delta variants of concern and was also capable of neutralizing Omicron, although with less efficiency (Gallego S. et al., unpublished data). Therefore, the clinical benefit observed in this study could be extrapolated to patients infected with any of the above-mentioned variants of concern.

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

    IdentifierStatusTitle
    NCT04954235CompletedEffectiveness and Safety Study of Specific Hyperimmune Equin…

    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.

    Results from scite Reference Check: We found no unreliable references.

    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.

  3. Version published to 10.1101/2022.04.07.22273558 on medRxiv