Plasma from recovered COVID-19 patients with high levels of antibodies appeared to delay or stop progression of illness in mildly ill older adults infected with the novel coronavirus, a small randomised, controlled, double-blind Argentine trial concluded. “This simple and inexpensive intervention can reduce demands on the health care system and may save lives,” the authors write.
Plasma from recovered COVID-19 patients with high levels of antibodies appeared to delay or stop progression of illness in mildly ill older adults infected with the novel coronavirus, a study has concluded. Researchers at Fundacion INFANT in Buenos Aires, Argentina, led the small randomised, controlled, double-blind trial of the effects of infusing convalescent plasma in 160 older adults within 72 hours of symptom onset from 4 June to 25 October, 2020, half of whom received the treatment. The patients were either 75 years and older (88 [55%]), with or without underlying illnesses, or 65 to 74 years with at least one underlying condition (72 [45%]).
The trial was stopped early, at 76% of target enrolment, because COVID-19 cases substantially declined in Buenos Aires, precluding continued recruitment. Of the 80 patients in the intention-to-treat population given convalescent plasma, 13 (16%) developed severe COVID-19, compared with 25 of 80 (31%) given a placebo (relative risk [RR], 0.52; RR reduction, 48%). Two participants in the convalescent plasma group (2.5%) and four in the placebo group (5%) died.
A modified intention-to-treat analysis that excluded six patients who developed severe illness before plasma or placebo infusion demonstrated a larger intervention effect size (RR, 0.40) and efficacy of 60%.
Nine of 76 patients (12%) who received convalescent plasma and 23 of 78 (29%) who received placebo became severely ill. Patients in the convalescent plasma group in this analysis also took longer to develop serious respiratory disease than those in the placebo group.
Seven patients had to be treated with convalescent plasma to prevent one case of severe respiratory disease (95% confidence interval, 4 to 50). Median time to development of severe respiratory disease was shorter in the convalescent plasma group than in the placebo group (15 days for each, but the interquartile range was 15 to 15 in the treatment group and 9 to 15 in the placebo group.
Of the 80 patients given convalescent plasma, 4 (5%) progressed to a life-threatening respiratory illness, compared with 10 of 80 (12%) given placebo. Five patients in the convalescent plasma group (6%) had a critical systemic illness, versus 6 (8%) in the placebo group.
Twenty-four hours after infusion, participants in the convalescent plasma group had significantly higher concentrations of antibodies against SARS-CoV-2, the virus that causes COVID-19, than placebo group patients.
While no immunoglobulin G (IgG) correlate of protection for anti-coronavirus antibodies was found between mild and severe cases, the researchers saw a dose-dependent effect for IgG concentrations in plasma bags. Selection of donor plasma with higher-than-the-median antibody levels demonstrated a relative risk reduction of 73.3%, with a need to treat four patients to avert clinical worsening.
By day 25 of follow-up, only two patients were still receiving supplemental oxygen, but both recovered within the next 2 days. No adverse events were reported.
The authors said that while their study wasn't statistically powered to measure long-term outcomes, patients who received convalescent plasma seemed to do better than those who received a placebo in terms of developing life-threatening respiratory disease, critical systemic illness, and death.
"Our findings underscore the need to return to the classic approach of treating acute viral infections early," the researchers said.
Indeed, they said, their trial design was fundamentally different from those of randomised trials of convalescent plasma with poor or mixed results in that it involved older adults treated within 3 days of symptom onset rather than the 8 to 30 days in other trials.
With relatively easy access to convalescent plasma in many low- and middle-income countries and relatively low cost, the treatment may be a good alternative to other, more expensive treatments such as administration of monoclonal antibodies, the researchers said.
"This simple and inexpensive intervention can reduce demands on the health care system and may save lives," the authors concluded. "Early infusions of convalescent plasma can provide a bridge to recovery for at-risk patients until vaccines become widely available."
Study Details
Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults
Romina Libster, Gonzalo Pérez Marc, Diego Wappner, Silvina Coviello, Alejandra Bianchi, Virginia Braem, Ignacio Esteban, Mauricio T Caballero, Cristian Wood, Mabel Berrueta, Aníbal Rondan, Gabriela Lescano, Pablo Cruz, Yvonne Ritou, Valeria Fernández Viña, Damián Álvarez Paggi, Sebastián Esperante, Adrián Ferreti, Gastón Ofman, Álvaro Ciganda, Rocío Rodriguez, Jorge Lantos, Ricardo Valentini, Nicolás Itcovici, Alejandra Hintze, M Laura Oyarvide, Candela Etchegaray, Alejandra Neira, Ivonne Name, Julieta Alfonso, Rocío López Castelo, Gisela Caruso, Sofía Rapelius, Fernando Alvez, Federico Etchenique, Federico Dimase, Darío Alvarez, Sofía S Aranda, Clara Sánchez Yanotti, Julián De Luca, Sofía Jares Baglivo, Sofía Laudanno, Florencia Nowogrodzki,
Ramiro Larrea, María Silveyra, Gabriel Leberzstein, Alejandra Debonis, Juan Molinos, Miguel González, Eduardo Perez, Nicolás Kreplak, Susana Pastor Argüello, Luz Gibbons, Fernando Althabe, Eduardo Bergel, Fernando P Polack for the Fundación INFANT–COVID-19 Group
Published in NEJM on 6 January, 2021
Abstract
Background
Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness.
Methods
We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible.
Results
A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P=0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed.
Conclusions
Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19.
[link url="https://www.cidrap.umn.edu/news-perspective/2021/01/early-convalescent-plasma-may-lower-risk-severe-covid-seniors"]CIDRAP material[/link]
[link url="https://www.nejm.org/doi/full/10.1056/NEJMoa2033700"]NEJM study[/link]
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