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Effect of High-Titer Convalescent Plasma on Progression to Severe Respiratory Failure or Death in Hospitalized Patients With COVID-19 PneumoniaA Randomized Clinical Trial

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To identify the key insights or developments described in this article
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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 (Pao2/Fio2) ratio between 350 and 200 mm Hg at enrollment, the rate of the primary clinical end point (need for mechanical ventilation, defined as Pao2/Fio2 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.

Abstract

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 (Pao2/Fio2) ratio between 350 and 200 mm Hg were eligible.

Interventions  Patients in the experimental group received intravenous high-titer CP (≥1:160, 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 (Pao2/Fio2 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, high-titer anti–SARS-CoV-2 CP did not reduce the progression to severe respiratory failure or death within 30 days.

Trial Registration  ClinicalTrials.gov Identifier: NCT04716556

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: September 28, 2021.

Published: November 29, 2021. doi:10.1001/jamanetworkopen.2021.36246

Correction: This article was corrected on December 21, 2021, to fix errors in the Results section, Figure 1, Table 1, and the Article Information section, and on January 18, 2022, to fix errors in the Article Information section.

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Menichetti F et al. JAMA Network Open.

Corresponding Author: Francesco Menichetti, MD, Infectious Diseases Unit, Department of Clinical and Experimental Medicine, Azienda Ospedaliera Universitaria Pisana, Via Paradisa 2, 56124 Pisa, Italy (menichettifrancesco@gmail.com).

Author Contributions: Dr Popoli had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Menichetti, Popoli, Puopolo, Spila Alegiani, Tiseo, Toschi, Massari, Palmisano, Marano, Piconi, Beccastrini, Lanza, Focosi, Mazzoni, Pistello, Falcone.

Acquisition, analysis, or interpretation of data: Menichetti, Popoli, Puopolo, Spila Alegiani, Tiseo, Bartoloni, De Socio, Luchi, Blanc, Puoti, Toschi, Massari, Palmisano, Marano, Chiamenti, Martinelli, Franchi, Pallotto, Suardi, Luciani Pasqua, Merli, Fabiani, Bertolucci, Borchi, Modica, Moneta, Marchetti, d'Arminio Monforte, Stoppini, Ferracchiato, Fabbri, Beccastrini, Saccardi, Giacometti, Esperti, Pierotti, Bernini, Bianco, Benedetti, Lanzi, Bonfanti, Massari, Sani, Saracino, Castagna, Trabace, Pistello, Falcone.

Drafting of the manuscript: Menichetti, Popoli, Puopolo, Tiseo, Toschi, Palmisano, Marano, Martinelli, Franchi, Suardi, Luciani Pasqua, Borchi, Moneta, Fabbri, Beccastrini, Esperti, Pierotti, Trabace, Lanza, Falcone.

Critical revision of the manuscript for important intellectual content: Menichetti, Popoli, Spila Alegiani, Bartoloni, De Socio, Luchi, Blanc, Puoti, Toschi, Massari, Palmisano, Marano, Chiamenti, Pallotto, Merli, Fabiani, Bertolucci, Modica, Marchetti, d'Arminio Monforte, Stoppini, Ferracchiato, Piconi, Saccardi, Giacometti, Bernini, Bianco, Benedetti, Lanzi, Bonfanti, Massari, Sani, Saracino, Castagna, Focosi, Mazzoni, Pistello, Falcone.

Statistical analysis: Puopolo, Spila Alegiani, Massari, Borchi, Saccardi, Esperti.

Obtained funding: Popoli, Moneta.

Administrative, technical, or material support: Tiseo, De Socio, Pallotto, Fabiani, Piconi, Benedetti, Lanzi, Saracino, Lanza, Focosi, Mazzoni, Pistello, Falcone.

Supervision: Menichetti, Popoli, Spila Alegiani, Bartoloni, De Socio, Luchi, Toschi, Massari, Palmisano, Marano, Marchetti, d'Arminio Monforte, Giacometti, Bernini, Bianco, Castagna, Trabace.

Conflict of Interest Disclosures: Dr Menichetti reported serving as the principal investigator for an AstraZeneca-sponsored 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 Saracino reported receiving grants for research and/or educational purposes from Gilead, ViiV, MSD, Abbvie, Janssen, Shionogi, and Pfizer in the last 3 years outside the submitted work. Dr Castagna reported receiving personal fees from ViiV, MSD, Gilead, Janssen, and Theratecnologies in the last 3 years outside the submitted work. Dr Falcone reported receiving grants and speaker honoraria from Angelini, Shionogi, MSD, Pfizer, Gilead, Menarini, and Nordic Pharma in the last 3 years outside the submitted work. No other disclosures were reported.

Funding/Support: This study was sponsored by the Italian National Institute of Health, Istituto Superiore di Sanità (ISS) and the Italian Medicines Agency, Agenzia Italiana del Farmaco (AIFA).

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: A complete list of the members of the TSUNAMI Study group appears in Supplement 3.

Data Sharing Statement: See Supplement 4.

Additional Contributions: The authors are grateful to the scientific committee of the TSUNAMI Trial, constituted by Franco Locatelli, MD (Department of Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Sapienza, University of Rome), Giuseppe Ippolito, MD (National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS), Nicola Magrini, MD (Agenzia Italiana del Farmaco), Renato Bernardini, MD (Agenzia Italiana del Farmaco), Silvio Brusaferro, MD (Istituto Superiore di Sanità), Vincenzo De Angelis, MD (Centro Nazionale Sangue), Cesare Perotti, MD (Policlinico San Matteo), Giuseppe Remuzzi, MD (Istituto Mario Negri), Giustina De Silvestro, MD (Centro Trasfusionale Padova), Massimo Costantini, MD (IRCCS Reggio Emilia), and Manuela Bocchino, MD (Agenzia Italiana del Farmaco), for their support to the TSUNAMI Trial. The authors are also grateful to Giuseppe De Donno, MD (Carlo Poma Hospital), pioneer in the clinical use of convalescent plasma in Italy, who passed away. No compensation was received for these contributors. We confirm to have obtained written permission by each individual in the acknowledgment section.

Additional Information: The TsuStat Group, composed by Drs Puopolo, Massari Marco, Spila, and Alegiani of the National Institute of Health, conducted and are responsible for the data analysis.

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