Effect of High-Titer Convalescent Plasma on Progression to Severe Respiratory Failure or Death in Hospitalized Patients With COVID-19 Pneumonia
JAMA Network Open, doi:10.1001/jamanetworkopen.2021.36246
IMPORTANCE Convalescent plasma (CP) has been generally unsuccessful in preventing worsening of respiratory failure or death in hospitalized patients with COVID-19 pneumonia. OBJECTIVE To evaluate the efficacy of CP plus standard therapy (ST) vs ST alone in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia. DESIGN, SETTING, AND PARTICIPANTS This prospective, open-label, randomized clinical trial enrolled (1:1 ratio) hospitalized patients with COVID-19 pneumonia to receive CP plus ST or ST alone between July 15 and December 8, 2020, at 27 clinical sites in Italy. Hospitalized adults with COVID-19 pneumonia and a partial pressure of oxygen-to-fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio between 350 and 200 mm Hg were eligible. INTERVENTIONS Patients in the experimental group received intravenous high-titer CP (Ն1:160, by microneutralization test) plus ST. The volume of infused CP was 200 mL given from 1 to a maximum of 3 infusions. Patients in the control group received ST, represented by remdesivir, glucocorticoids, and low-molecular weight heparin, according to the Agenzia Italiana del Farmaco recommendations.
MAIN OUTCOMES AND MEASURES The primary outcome was a composite of worsening respiratory failure (PaO 2 /FiO 2 ratio <150 mm Hg) or death within 30 days from randomization.
RESULTS Of the 487 randomized patients (241 to CP plus ST; 246 to ST alone), 312 (64.1%) were men; the median (IQR) age was 64 (54.0-74.0) years. The modified intention-to-treat population included 473 patients. The primary end point occurred in 59 of 231 patients (25.5%) treated with CP and ST and in 67 of 239 patients (28.0%) who received ST (odds ratio, 0.88; 95% CI, 0.59-1.33; P = .54). Adverse events occurred more frequently in the CP group (12 of 241 [5.0%]) compared with the control group (4 of 246 [1.6%]; P = .04).
CONCLUSIONS AND RELEVANCE In patients with moderate to severe COVID-19 pneumonia, hightiter anti-SARS-CoV-2 CP did not reduce the progression to severe respiratory failure or death within 30 days. (continued) Key Points Question Is convalescent plasma useful in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia? Findings In this randomized clinical trial of 487 patients with COVID-19 pneumonia and a partial pressure of arterial oxygen-to-fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio between 350 and 200 mm Hg at enrollment, the rate of the primary clinical end point (need for mechanical ventilation, defined as PaO 2 /FiO 2 ratio <150 mm Hg, or death) was not significantly different between the convalescent plasma group and the control group. Meaning In this trial, convalescent plasma did not reduce the progression to severe respiratory failure or death within 30 days.
Conflict of Interest Disclosures: Dr Menichetti reported serving as the principal investigator for an AstraZenecasponsored trial and a Toscana Life Science-sponsored trial evaluating monoclonal antibodies for SARS-CoV-2 (for which no personal fees were received), and receiving speaker honoraria or advisory board or support for meetings from Angelini, Menarini, Correvio, MSD, Pfizer, Astellas, Gilead, BMS, Janssen, ViiV, BioMerieux, Biotest, Becton-Dickinson, Pfizer, Shionogi, Roche, GSK, Advanz Pharma, and ThermoFisher in the last 3 years outside the submitted work. Dr Bartoloni reported receiving study grants from MSD, ViiV Healthcare, and Nordic Pharma and receiving fees for presentations at local congress or expert meetings from Pfizer and MSD in the last 3 years outside the submitted work; Dr Puoti reported receiving personal fees and nonfinancial support from Abbvie, grants and nonfinancial support from Gilead Science, and personal fees from Merck and Theratechnologies outside the submitted work. Dr Marchetti reported receiving grants for lectures, advisory board, or conferences by Gilead, ViiV, and Janssen in the last 3 years outside the submitted work. Dr d'Arminio Monforte reported receiving grants for lectures, advisory board, or conferences by Gilead, ViiV, MSD, Angelini, and Janssen in the last 3 years outside the submitted work; Dr Bonfanti reported receiving personal fees from Viiv, Gilead, Jannsen Pharmaceuticals, Merck, and Pfizer outside the submitted work. Dr..
Acquisition, Menichetti, Popoli, Puopolo, Alegiani et al., Critical revision of the manuscript for important intellectual content
Administrative, Tiseo, Socio, Pallotto, Fabiani et al., None
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.m3939
Alegria, Sud, Steinberg, Gai, Siddiqui, Reporting of participant race, sex, and socioeconomic status in randomized clinical trials in general medical journals, 2015 vs 2019, JAMA Netw Open, doi:https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2021.11516&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2021.36246
Alqahtani, Abdulrahman, Almadani, Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease, Sci Rep, doi:10.1038/s41598-021-89444-5
Amanat, White, Miorin, An in vitro microneutralization assay for SARS-CoV-2 Serology and drug screening, Curr Protoc Microbiol, doi:10.1002/cpmc.108
Avendaño-Solà, Ramos-Martinez, Muñez-Rubio, Convalescent plasma for COVID-19: a multicenter, randomized clinical trial. medRxiv, doi:10.1101/2020.08.26.20182444
Bajpai, Kumar, Maheshwari, Efficacy of convalescent plasma therapy compared to fresh frozen plasma in severely ill COVID-19 patients: a pilot randomized controlled trial. medRxiv, doi:10.1101/2020.10.25.20219337
Balcells, Rojas, Corre, 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.1003415
Bellan, Patti, Hayden, Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients, Sci Rep, doi:10.1038/s41598-020-77698-4
Gharbharan, Jordans, Geurtsvankessel, Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection, Nat Commun, doi:10.1038/s41467-021-23469-2
Harris, Taylor, Thielke, Payne, Gonzalez et al., Research electronic data capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support, J Biomed Inform, doi:10.1016/j.jbi.2008.08.010
Horby, Estcourt, Peto, Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial, Lancet, doi:10.1016/S0140-6736(21)00897-7
Hubbard, Backholer, Wiltshire, Cardigan, Ariëns, Effects of riboflavin and amotosalen photoactivation systems for pathogen inactivation of fresh-frozen plasma on fibrin clot structure, Transfusion, doi:10.1111/trf.13261
Joyner, Carter, Senefeld, Convalescent plasma antibody levels and the risk of death from COVID-19, N Engl J Med, doi:10.1056/NEJMoa2031893
Korley, Durkalski-Mauldin, Yeatts, Early convalescent plasma for highrisk outpatients with COVID-19, N Engl J Med. Published online, doi:10.1056/NEJMoa2103784
Körper, Weiss, Zickler, Results of the CAPSID randomized trial for high-dose convalescent plasma in severe COVID-19 patients, J Clin Invest. Published online, doi:10.1172/JCI152264
Libster, Marc, Wappner, Fundación INFANT-COVID-19 Group. Early high-titer plasma therapy to prevent severe COVID-19 in older adults, N Engl J Med, doi:10.1056/NEJMoa2033700
Menichetti, Puopolo, Alegiani, Tiseo, Toschi et al., data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis
Nazionale, Ai Responsibili delle Strutture di Coordinamento per la Attività Trasfusionali delle Regioni e Province Autonome
O'donnell, Grinsztejn, Cummings, A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19, J Clin Invest, doi:10.1172/JCI150646
Ray, Paul, Bandopadhyay, Clinical and immunological benefits of convalescent plasmatherapy in severe COVID-19: insights from a single center open label randomised control trial. medRxiv, doi:10.1101/2020.11.25.20237883
Rome, Bocchino, Md, National Institute for Infectious Diseases
Simonovich, Pratx, Scibona, A randomized trial of convalescent plasma in COVID-19 Severe Pneumonia, N Engl J Med, doi:10.1056/NEJMoa2031304
Wang, Lagakos, Ware, Hunter, Drazen, Statistics in medicine-reporting of subgroup analyses in clinical trials, N Engl J Med, doi:10.1056/NEJMsr077003