Early Use of High-Titer Plasma Reduced COVID Hospitalizations

News

In a largely unvaccinated population, high-titer convalescent plasma given early after development of COVID-19 reduced hospitalizations, a randomized controlled trial showed.

COVID-19-related hospitalization or death within 28 days occurred in 2.9% of transfusion recipients compared with 6.3% of recipients of control plasma (P=0.005), for a relative 54% risk reduction that was entirely accounted for by hospitalization.

The number needed to treat to prevent one hospitalization was 29.4, reported David J. Sullivan, MD, of Johns Hopkins Bloomberg School of Public Health in Baltimore, and colleagues in the New England Journal of Medicine.

The magnitude of effect was on par with that of monoclonal antibodies against SARS-CoV-2 during the Alpha variant wave, they noted.

“We encourage healthcare professionals to keep SARS-CoV-2 antibody-rich blood plasma available in their blood banks as part of the treatment arsenal against early-stage COVID-19,” Sullivan said in a statement. “We believe that the best role for convalescent plasma is extending its use to early outpatient treatment when other therapies, such as monoclonal antibodies or drugs, are either not readily available — as in low- and middle-income countries — or ineffective, as with SARS-CoV-2 variants that are resistant to certain monoclonal antibodies.”

The FDA authorized convalescent plasma for COVID-19 treatment in mid-2020, but subsequently limited this to high-titer doses for hospitalized patients early in the disease course and those with impaired humoral immunity, before finally restricting it to only immunocompromised patients, albeit allowing outpatient use.

That latest move to allow limited outpatient use was believed to have been based, in part, on a study from Sullivan and colleagues released as a preprint late last year.

The new findings come against a backdrop of decidedly mixed results in prior trials with convalescent plasma:

  • The Argentinian PlasmAr trial yielded no clinical status or overall mortality advantage for hospitalized patients with severe COVID-19
  • RECOVERY showed no mortality, disease progression, or admission duration impact of high-titer doses in COVID-19 inpatients
  • A U.S. registry showed reduced risk of death with high-titer versus low-titer plasma
  • The underpowered Fundación INFANT-COVID-19 trial from Argentina showed reduced risk of progression for older adults with mild COVID-19 if given high-titer convalescent plasma within 72 hours of onset
  • SIREN-C3PO trial results showed no difference in COVID-19 progression with use within a week of onset in high-risk outpatients

“Mixed results with these treatments in previous outbreaks of infectious diseases may have been due to a lack of modern study designs, small sample sizes, a differential viral response to passive antibodies, the inclusion of units with low antibody titers, or administration too long after the onset of disease,” Sullivan’s group wrote.

Their multicenter double-blind trial included 1,225 participants randomized to a single, approximately 250-mL infusion over 1 hour of either a plasma containing at least 1:320 SARS-CoV-2 anti-spike protein antibody levels (>3.5 arbitrary units at 1:101 dilution in accordance with indication change after March 9, 2021) or control plasma. The 1,181 who received a transfusion were included in the prespecified modified intention-to-treat analysis for the primary endpoint.

Analysis of all-cause hospitalizations within 28 days after transfusion yielded similar results to COVID-19-specific hospitalizations in the primary endpoint, with nearly all occurring in the unvaccinated participants (53 of 54). The only three deaths in the trial occurred in the control group.

Prespecified subgroup analyses suggested no differential effects by sex, BMI, age, vaccination status, or presence of hypertension and diabetes.

However, as in earlier studies, sooner appeared to be better: convalescent plasma given within 5 days of symptom onset appeared to have at least a relative 75% reduction in the risk of COVID-19 hospitalization, whereas transfusions at 6 days or beyond held no advantage. That finding was only hypothesis-generating and not corrected for multiplicity, in addition to overlapping confidence intervals.

Study limitations included changing standards of care and available treatments through the course of the trial, which ran from June 3, 2020, through Oct. 1, 2021; lower than typical COVID-19 hospitalization rates; and a relatively young population, with only 35% of the transfused patients ages 50 and older.

In addition, “variants of concern became more prevalent during the trial period, first with the Alpha (B.1.1.7) variant and then with the Delta (B.1.617.2) variant in the summer of 2021,” Sullivan’s group wrote. “The trial plasma was largely obtained in 2020 from donors who had recovered from infection with ancestral forms of SARS-CoV-2.”

The study also used outpatient sites that were often specially constructed and separated from hospital populations, they noted.

“The establishment of infusion centers that can rapidly administer COVID-19 convalescent plasma for outpatients during pandemics may be a consideration for future healthcare systems,” they wrote. “Even in the current pandemic, the continued propagation of SARS-CoV-2 variants with evolving resistance to currently available monoclonal antibodies indicates the potential usefulness of developing capacity for the availability and distribution of COVID-19 convalescent plasma, especially because locally sourced, recently obtained plasma should include antibodies to circulating strains.”

Disclosures

The trial was supported by the Department of Defense, in collaboration with the Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; the National Institute of Allergy and Infectious Diseases; the NIH National Center for Advancing Translational Sciences; the National Heart, Lung, and Blood Institute; the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; and the Shear Family Foundation.

Sullivan reported support from government programs and grants, along with relationships with Bloomberg Philanthropies, Mental Wellness Foundation, Moriah Fund, Healthnetwork Foundation, Octapharma, Shear Family Foundation, AliquantumRx, Masimo, Hemex Health, and Binax (Inverness Medical), as well as legal consulting and patents related to malaria, new angiogenesis inhibitors, and cethromycin.

Leave a Reply

Your email address will not be published. Required fields are marked *