Early Use of High-Titer Plasma May Prevent Severe COVID-19

Damian McNamara

January 06, 2021

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Administering convalescent plasma that has high levels of antibodies against SARS-CoV-2 within the first 3 days of symptoms was associated with significantly lower chances of progression to severe COVID-19, new evidence demonstrates.

In a trial of 160 older adults with COVID-19, half of whom were randomly assigned to receive plasma and half to receive placebo infusion, treatment with high-titer plasma lowered the relative risk for severe disease by 48% in an intent-to-treat analysis.

Dr Fernando Polack

"We now have evidence, in the context of a small but well-designed study, that convalescent plasma with high titers of antibody against SARS-CoV-2 administered in the first 3 days of mild symptoms to infected elderly reduces progression of illness and the rate of severe presentations," senior author Fernando Polack, MD, told Medscape Medical News.

"Not any plasma, not any time," added Polack, who is an infectious disease specialist and scientific director at Fundacion INFANT and professor of pediatrics at the University of Buenos Aires School of Medicine, Buenos Aires, Argentina. The key, he said, is to select plasma in the upper 28th percentile of IgG antibody concentrations and to administer therapy prior to disease progression.

The study was published online January 6 in The New England Journal of Medicine.

"It's a very good study and approaches a different population from the PlasmAr study," Ventura Simonovich, MD, chief of the Clinical Pharmacology Section, Medical Clinic Service, Hospital Italiano de Buenos Aires, told Medscape Medical News. "This is the first published randomized controlled trial that shows real benefit in this [older adult] population, the most vulnerable in this disease," he said.

Simonovich, who was not affiliated with the current study, was lead author of the PlasmAr trial, which was published in The New England Journal of Medicine November 24, 2020. In that trial, the researchers evaluated adults aged 18 years and older and found no significant benefit with convalescent plasma treatment over placebo for patients with COVID-19 and severe pneumonia.

"We know antibodies work best when given early and in high dose. This is one of the rare reports that validates it in the outpatient setting," David Sullivan, MD, professor of molecular biology and immunology at Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, told Medscape Medical News when asked to comment.

Sullivan pointed out that most previous studies on convalescent plasma focused on patients with COVID-19 who had severe cases late in the disease course.

Regarding the current study, he said, "The striking thing is treating people within 3 days of illness."

A more cautious interpretation may be warranted, one expert said. "The study demonstrates the benefit of early intervention. There was a dose-dependent effect, with higher titers providing a greater benefit," Manoj Menon, MD, MPH, a hematologist and oncologist at the University of Washington School of Medicine, in Seattle, Washington, told Medscape Medical News.

"Taken together, the findings have biologic plausibility and produce more data on the role of convalescent plasma to a relevant age cohort," he added.

However, Menon said, "Given the limited sample size, I do not think this study, although well conducted, definitively addresses the role of convalescent plasma for COVID-19. But it does merit additional study."

A Search for Clear Answers

Treatments that target the early stages of COVID-19 "remain elusive. Few strategies provide benefit, several have failed, and others are being evaluated," the researchers note. "In hospitalized patients with COVID-19, the infusion of convalescent plasma against SARS-CoV-2 late in the course of illness has not shown clear benefits and, consequently, the most appropriate antibody concentrations for effective treatment are unclear."

To learn more, Polack and colleagues included patients with PCR-confirmed COVID-19 who were aged 75 years or older, regardless of comorbidities. They also included patients aged 65 to 74 years of age who had at least one underlying condition. Participants were enrolled at clinical sites or geriatric units in Argentina. The mean age was 77 years, and 62% were women.

In an intent-to-treat analysis, the primary outcome ― severe respiratory disease ― occurred in 16% of the plasma recipients, vs 31% of the group that received placebo. The relative risk was 0.52 (95% CI, 0.29 – 0.94; P = .03).

The number needed to treat to avoid a severe respiratory disease episode was 7 (95% CI, 4 – 50).

Life-threatening respiratory disease, a secondary outcome, occurred in four people in the plasma group, compared with 10 in the placebo group. Two patients in the treatment group and four patients in the placebo group died.

The researchers also ran a modified intent-to-treat analysis that excluded six participants who experienced severe respiratory disease prior to receiving plasma or placebo. In this analysis, efficacy of plasma therapy increased to 60%.

"Again, this finding suggests that early intervention is critical for efficacy," the investigators note.

The investigators, who are based in Argentina, defined their primary endpoint as a respiratory rate of 30 or more breaths per minute and/or an oxygen saturation of less than 93% while breathing ambient air.

Sullivan pointed out that this is equivalent to the threshold commonly used for hospitalizing people with COVID-19 in the United States. "So it's equivalent to avoiding hospitalizations. The take-home is high-titer plasma prevents respiratory distress, which equals hospitalization for us."

Sullivan is conducting similar research in the United States regarding the use of plasma for treatment or prevention. He and colleagues are evaluating adults aged 18 to 90 years, "not just the ones at highest risk for going to the hospital," he said. Enrollment is ongoing.

An Inexpensive Therapy With Global Potential?

"Although our trial lacked the statistical power to discern long-term outcomes, the convalescent plasma group appeared to have better outcomes than the placebo group with respect to all secondary endpoints," the researchers write. "Our findings underscore the need to return to the classic approach of treating acute viral infections early, and they define IgG targets that facilitate donor selection."

Polack said, "This is an inexpensive solution to mitigate the burden of severe illness in the population most vulnerable to the virus: the elderly. And it has the attraction of being applicable not only in industrialized countries but in many areas of the developing world."

Convalescent plasma "is a potentially inexpensive alternative to monoclonal antibodies," the researchers add. Furthermore, "early infusions of convalescent plasma can provide a bridge to recovery for at-risk patients until vaccines become widely available."

Polack said the study findings did not surprise him. "We always thought that, as it has been the case in the past with many therapeutic strategies against respiratory and other viral infections, the earlier you treat, the better.

"We just hoped that within 72 hours of symptoms we would be treating early enough ― remember that there is a 4- to 5-day incubation period that the virus leverages before the first symptom ― and with enough antibody," he added.

"We are glad it worked," he said.

The study was supported by the Bill and Melinda Gates Foundation and by the Fundación INFANT Pandemic Fund. Polack, Simonovich, and Sullivan have disclosed various financial relationships industry.

N Engl J Med. Published online January 6, 2021. Full text

Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology and neurology. Follow Damian on Twitter: @MedReporter.


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