Safety and efficacy of convalescent plasma for severe COVID-19: a randomized, single blinded, parallel, controlled clinical study
Manuel Rojas, Yhojan Rodríguez, Juan Carlos Hernández, Juan C Díaz-Coronado, José Alejandro Daza Vergara, Verónica Posada Vélez, Jessica Porras Mancilla, Iván Araujo, Jairo Torres Yepes, Oscar Briceño Ricaurte, Juan Mauricio Pardo-Oviedo, Diana M Monsalve, Yeny Acosta-Ampudia, Carolina Ramírez-Santana, Paula Gaviria García, Lina Acevedo Landinez, Luisa Duarte Correales, Jeser Santiago Grass, Cristian Ricaurte Pérez, Gustavo Salguero López, Nataly Mateus, Laura Mancera, Ronald Rengifo Devia, Juan Esteban Orjuela, Christian R Parra-Moreno, Andrés Alfonso Buitrago, Inés Elvira Ordoñez, Claudia Fabra Osorio, Nathalia Ballesteros, Luz H Patiño, Sergio Castañeda, Marina Muñoz, Juan David Ramírez, Paul Bastard, Adrian Gervais, Lucy Bizien, Jean-Laurent Casanova, Bernardo Camacho, Juan Esteban Gallo, Oscar Gómez, Adriana Rojas-Villarraga, Carlos E Pérez, Rubén Manrique, Rubén D Mantilla, Juan-Manuel Anaya
BMC Infectious Diseases, doi:10.1186/s12879-022-07560-7
Background: Convalescent plasma (CP) has been widely used to treat COVID-19 and is under study. However, the variability in the current clinical trials has averted its wide use in the current pandemic. We aimed to evaluate the safety and efficacy of CP in severe coronavirus disease 2019 (COVID-19) in the early stages of the disease.
Methods: A randomized controlled clinical study was conducted on 101 patients admitted to the hospital with confirmed severe COVID-19. Most participants had less than 14 days from symptoms onset and less than seven days from hospitalization. Fifty patients were assigned to receive CP plus standard therapy (ST), and 51 were assigned to receive ST alone. Participants in the CP arm received two doses of 250 mL each, transfused 24 h apart. All transfused plasma was obtained from "super donors" that fulfilled the following criteria: titers of anti-SARS-CoV-2 S1 IgG ≥ 1:3200 and IgA ≥ 1:800 antibodies. The effect of transfused anti-IFN antibodies and the SARS-CoV-2 variants at the entry of the study on the overall CP efficacy was evaluated. The primary outcomes were the reduction in viral load and the increase in IgG and IgA antibodies at 28 days of follow-up. The per-protocol analysis included 91 patients. Results: An early but transient increase in IgG anti-S1-SARS-CoV-2 antibody levels at day 4 post-transfusion was observed (Estimated difference [ED], − 1.36; 95% CI, − 2.33 to − 0.39; P = 0.04). However, CP was not associated with viral load reduction in any of the points evaluated. Analysis of secondary outcomes revealed that those patients in the CP arm disclosed a shorter time to discharge (ED adjusted for mortality, 3.1 days; 95% CI, 0.20 to 5.94; P = 0.0361) or a reduction of 2 points on the WHO scale when compared with the ST group (HR adjusted for mortality, 1.6; 95% CI, 1.03
Abbreviations
Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s12879-022-07560-7. Additional file 1. Lineages and mutations of interest in the studied population.
Author contributions
Declarations Ethics approval and consent to participate The institutional review board of the Universidad del Rosario approved the study design (Act. 421 CEI-UR). Written informed consent was obtained from all participants, and the trial was conducted following the principles stated in the Declaration of Helsinki and Good Clinical Practice guidelines.
Consent for publication All participants provided consent to publish.
Competing interests None.
Author contributions Conceptualization: JMA, JEG, RM; Acquisition of data: YR, JCH, JCD, JAD, VPV, JPM, IA, JTY, OBR, JMPO, DMM, YAA, CRS, PGG JSG, CRP, GSL, NM, LM, RRD, JEO, CRPM, AAB, ARV, CEP; Methodology: JMA, ARV, RM, GSL, JEG, BC; Statistical Analysis: MR, RM, JMA; Funding acquisition: JMA, BC, RM; Procurement of convalescent plasma: PGG, LAL, LDC, JSG, CRP, GSL, BC; Center Coordination: CF; Monitoring: IEO; Variants analysis: NB, LHP, SC, MM, JDR; Anti-IFN antibodies: PB, AG, LB, J-LC; Writing and editing: MR, JMA. All authors read and approved the final manuscript. • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data..
References
Acosta-Ampudia, Monsalve, Rojas, Rodríguez, Gallo et al., COVID-19 convalescent plasma composition and immunological effects in severe patients, J Autoimmun
Acosta-Ampudia, Rojas, Monsalve, Rodríguez, Ramírez-Santana et al., Comment on: nature and dimensions of the systemic hyper-inflammation and its attenuation by convalescent plasma in severe COVID-19, J Infect Dis
Agarwal, Mukherjee, Kumar, Chatterjee, Bhatnagar et al., Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial), BMJ,
doi:10.1136/bmj.m4232Alqahtani, Abdulrahman, Almadani, Alali, Zamrooni et al., Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease, Sci Rep,
doi:10.1038/s41598-021-89444-5Anaya, Monsalve, Rojas, Rodríguez, Montoya-García et al., Latent rheumatic, thyroid and phospholipid autoimmunity in hospitalized patients with COVID-19, J Transl Autoimmun
Avendaño-Solá, Ramos-Martínez, Muñez-Rubio, Ruiz-Antorán, Molina et al., A multicenter randomized open-label clinical trial for convalescent plasma in patients hospitalized with COVID-19 pneumonia, J Clin Invest,
doi:10.1172/JCI152740Axfors, Janiaud, Schmitt, Hooft, Smith et al., Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials, BMC Infect Dis
Bajpai, Kumar, Maheshwari, Chhabra, Gupta, Efficacy of Convalescent Plasma Therapy compared to Fresh Frozen Plasma in Severely ill COVID-19 Patients: A Pilot Randomized Controlled Trial, medRxiv
Bajpai, Maheshwari, Dogra, Kumar, Gupta et al., Efficacy of convalescent plasma therapy in the patient with COVID-19: a randomised control trial (COPLA-II trial), BMJ Open,
doi:10.1136/bmjopen-2021-055189Balcells, Rojas, Corre, Martínez-Valdebenito, Ceballos et al., Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial, PLoS Med,
doi:10.1371/journal.pmed.1003415Bandopadhyay, 'rozario, Lahiri, Sarif, Ray et al., Nature and dimensions of systemic hyperinflammation and its attenuation by convalescent plasma in severe COVID-19, J Infect Dis
Bastard, Gervais, Voyer, Rosain, Philippot et al., Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths, Sci Immunol
Casadevall, Dragotakes, Johnson, Senefeld, Klassen et al., Convalescent plasma use in the USA was inversely correlated with COVID-19 mortality, Elife,
doi:10.7554/eLife.69866Castañeda, Patiño, Muñoz, Ballesteros, Guerrero-Araya et al., Evolution and epidemic spread of SARS-CoV-2 in Colombia: a year into the pandemic, Vaccines
Cepeda-Cuervo, Beta regression models: Joint mean and variance modeling, J Stat Theory Pract
Chang, Feng, Meng, Apostolidis, Mack et al., Newonset IgG autoantibodies in hospitalized patients with COVID-19, Nat Commun
Cárdenas-Turanzas, Ensor, Wakefield, Zhang, Wallace et al., Cross-validation of a Sequential Organ Failure Assessment scorebased model to predict mortality in patients with cancer admitted to the intensive care unit, J Crit Care
Diggle, Liang, Zeger, Longitudinal data analysis
Duan, Liu, Li, Zhang, Yu et al., Effectiveness of convalescent plasma therapy in severe COVID-19 patients, Proc Natl Acad Sci
Esmaeili, Esmaeili, Pourpak, Immunological effects of convalescent plasma therapy for coronavirus: a scoping review, BMC Infect Dis
Fitzmaurice, Davidian, Verbeke, Molenberghs, Longitudinal data analysis
Fitzmaurice, Laird, Ware, Applied longitudinal analysis
Foix, López, Díez-Fuertes, Mcconnell, Aj, Predicted impact of the viral mutational landscape on the cytotoxic response against SARS-CoV-2, PLoS Comput Biol
Fung, Nambiar, Pandey, Aldrich, Teraoka et al., Treatment of immunocompromised COVID-19 patients with convalescent plasma, Transpl Infect Dis,
doi:10.1111/tid.13477Gharbharan, Jordans, Geurtsvankessel, Hollander, Karim et al., Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection, Nat Commun,
doi:10.1038/s41467-021-23469-2Goldstein, Multilevel mixed linear model analysis using iterative generalized least squares, Biometrika
Harvey, Carabelli, Jackson, Gupta, Thomson et al., SARS-CoV-2 variants, spike mutations and immune escape, Nat Rev Microbiol
Joyner, Carter, Senefeld, Klassen, Mills et al., Convalescent plasma antibody levels and the risk of death from Covid-19
Li, Wu, Nie, Zhang, Hao et al., The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity, Cell
Li, Zhang, Hu, Tong, Zheng et al., Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial, JAMA
Libster, Marc, Wappner, Coviello, Bianchi et al., Early high-titer plasma therapy to prevent severe covid-19 in older adults, N Engl J Med,
doi:10.1056/NEJMoa2033700Naveca, Nascimento, De Souza, Corado, Nascimento et al., COVID-19 in Amazonas, Brazil, was driven by the persistence of endemic lineages and P1 emergence, Nat Med
O'toole, Hill, Pybus, Watts, Bogoch et al., Tracking the international spread of SARS-CoV-2 lineages B.1.1.7 and B.1.351/501Y-V2 with grinch, Wellcome Open Res,
doi:10.12688/wellcomeopenres.16661.2Okba, Müller, Wang, Geurtsvankessel, Corman, Severe acute respiratory syndrome coronavirus 2−specific antibody responses in coronavirus disease patients, Emerg Infect Dis
Park, Tarpey, Liu, Goldfeld, Wu et al., Development and validation of a treatment benefit index to identify hospitalized patients with COVID-19 who may benefit from convalescent plasma, JAMA Netw open
Raadsen, Gharbharan, Jordans, Mykytyn, Lamers et al., Interferon-α2 auto-antibodies in convalescent plasma therapy for COVID-19, J Clin Immunol
Rambaut, Holmes, 'toole, Hill, Mccrone et al., A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology, Nat Microbiol
Rao, Estimation of variance and covariance components-MINQUE theory, J Multivar Anal
Ray, Paul, Bandopadhyay, 'rozario, Sarif et al., A phase 2 single center open label randomised control trial for convalescent plasma therapy in patients with severe COVID-19, Nat Commun,
doi:10.1038/s41467-022-28064-7Rodionov, Biener, Spieth, Achleitner, Hölig et al., Potential benefit of convalescent plasma transfusions in immunocompromised patients with COVID-19, The Lancet Microbe
Rojas, Anaya, Why will it never be known if convalescent plasma is effective for COVID-19, J Transl Autoimmun
Rojas, Rodríguez, Monsalve, Acosta-Ampudia, Camacho et al., Convalescent plasma in Covid-19: Possible mechanisms of action, Autoimmun Rev
Rs, RStudio: Integrated Development for R. RStudio
Savvateeva, Filippova, Valuev-Elliston, Nuralieva, Yukina et al., Microarray-based detection of antibodies against SARS-CoV-2 proteins, common respiratory viruses and type i interferons, Viruses
Shen, Wang, Zhao, Yang, Li et al., Treatment of 5 critically ill patients with COVID-19 with convalescent plasma, JAMA
Simonovich, Pratx, Scibona, Beruto, Vallone et al., A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia, N Engl J Med
Sullivan, Gebo, Shoham, Bloch, Lau et al., Early outpatient treatment for covid-19 with convalescent plasma, N Engl J Med,
doi:10.1056/NEJMoa2119657Theel, Harring, Hilgart, Granger, Performance characteristics of four high-throughput immunoassays for detection of IgG antibodies against SARS-CoV-2, J Clin Microbiol
Tonn, Corman, Johnsen, Richter, Rodionov et al., Stability and neutralising capacity of SARS-CoV-2-specific antibodies in convalescent plasma, Lancet Microbe
Trujillo, Consenso colombiano de atención, diagnóstico y manejo de la infección por SARS-COV-2/COVID 19 en establecimientos de atención de la salud Recomendaciones basadas en consenso de expertos e informadas en la evidencia, Infect
Verbeke, Linear mixed models for longitudinal data
Weidner, Gänsdorfer, Unterweger, Weseslindtner, Drexler et al., Quantification of SARS-CoV-2 antibodies with eight commercially available immunoassays, J Clin Virol Off Publ Pan Am Soc Clin Virol
