Early outpatient administration of high-titre SARS-CoV-2 convalescent plasma reduced hospitalisations by more than 50%, according to a US nationwide multicentre study.
The research, led by researchers at Johns Hopkins Medicine and the Johns Hopkins Bloomberg School of Public Health and which appeared in The New England Journal of Medicine (NEJM), shows that high-titre (antibody-rich) COVID convalescent plasma – when administered to COVID-19 outpatients within nine days after testing positive – reduced the need for hospitalisation for more than half of the study’s predominantly unvaccinated outpatients. The US Food and Drug Administration (FDA) currently authorises this plasma as a treatment option for outpatients with immune-compromising diseases or receiving immune-compromising medications, and for all patients hospitalised with early-stage COVID-19.
The findings were first presented in a preprint posted to MedRxiv on 21 December, 2021.
“Based on our findings and conclusions, which are now validated through the peer-review process, 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,” said study co-lead author Dr David Sullivan, professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health, with a joint appointment in infectious diseases at the Johns Hopkins University School of Medicine.
“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,” he added.
In the outpatient early-treatment study conducted between June 2020 and October 2021, the researchers provided 1,181 randomised patients with one dose each of either polyclonal high-titre convalescent plasma (containing a concentrated mixture of antibodies specific to SARS-CoV-2) or placebo control plasma (with no SARS-CoV-2 antibodies). The patients were 18 and older, and had tested positive for SARS-CoV-2 within eight days prior to transfusion. A successful therapy was defined as a patient not requiring hospitalisation within 28 days after plasma transfusion.
The study found that 17 patients out of 592 (2.9%) who received the convalescent plasma required hospitalisation within 28 days of their transfusion, compared with 37 out of 589 (6.3%) who received placebo control plasma. This translated to a relative risk reduction for hospitalisation of 54%.
Timing of the convalescent plasma transfusion also is critical: “The earlier the better,” the researchers said.
“Based on the findings of an analysis in the new paper that wasn’t available when the preprint was posted, we found that if convalescent plasma is given within five days after diagnosis, the effectiveness at reducing hospitalisation approximated 80%,” Sullivan said.
“We concluded that these results strongly support high-titer SARS-CoV-2 convalescent plasma as an effective early treatment for COVID-19 with advantages like low cost, wide availability and rapid resilience to the virus’s evolving variants,” said study co-lead author Dr Kelly Gebo, professor of medicine at the Johns Hopkins University School of Medicine.
The next step, the researchers said, was to make convalescent plasma for the outpatient treatment of COVID-19 easier to use, more efficiently administered and more accessible to those who might need it. As part of that effort, they have provided clinicians with a guide for implementing a plasma transfusion centre for outpatients with COVID-19, including logistical, staffing and blood banking requirements. The guide appears in a paper published last month in the journal Transfusion.
The team also continues to seek more understanding of what else convalescent plasma can do for outpatients with COVID-19. A soon-to-be published study will look at the ability of plasma to neutralise SARS-CoV-2 variants, including delta and omicron, despite no previous donor exposure to those viruses.
Since the study findings were first announced last December, there have been three developments supporting the use of convalescent plasma for early-stage COVID-19:
On 28 December, the FDA expanded the authorised emergency use of convalescent plasma with high titers of anti-SARS-CoV-2 antibodies “for the treatment of COVID-19 in patients with immunosuppressive disease or receiving immunosuppressive treatment, in either the outpatient or inpatient setting”.
On 2 February, the Infectious Disease Society of America updated its “Guidelines on the Treatment and Management of Patients with COVID-19” to include the “use of convalescent plasma in ambulatory patients with mild-to-moderate COVID-19 at high risk for progression to severe disease with no other treatment options”.
On 7 March, the American Red Cross announced that it was “temporarily testing all blood donations for COVID-19 antibodies to help identify donations that could be processed into convalescent plasma”.
The organisation said this was being done “to help support immunocompromised patients battling COVID-19”.
“These recent acknowledgements of high-titre convalescent plasma’s benefit in treating early-stage COVID-19 – in conjunction with our peer-reviewed findings and our new guide for more effective administration of the treatment – provide clinicians with an additional option for outpatients,” Gebo said.
Study details
Early Outpatient Treatment for Covid-19 with Convalescent Plasma
David Sullivan, Kelly Gebo, Shmuel Shoham, Evan Bloch, Bryan Lau, Aarthi Shenoy, Giselle Mosnaim, Thomas Gniadek, Yuriko Fukuta, Bela Patel, Sonya Heath, Adam Levine, Barry Meisenberg, Emily Spivak, Shweta Anjan, Moises Huaman, Janis Blair, Judith Currier, James Paxton, Jonathan Gerber, Joann Petrini, Patrick Broderick, William Rausch, Marie-Elena Cordisco, Jean Hammel, Benjamin Greenblatt, Valerie Cluzet, Daniel Cruser, Kevin Oei, Matthew Abinante, Laura Hammitt, Catherine Sutcliffe, Donald N. Forthal, Martin Zand, Edward Cachay, Jay Raval, Seble Kassaye, Colin Foster, Michael Roth, Christi Marshall, Anusha Yarava, Karen Lane, Nichol McBee, Amy Gawad, Nicky Karlen, Atika Singh, Daniel Ford, Douglas Jabs, Lawrence Appel, David Shade, Stephan Ehrhardt, Sheriza Baksh, Oliver Laeyendecker, Andrew Pekosz, Sabra Klein, Arturo Casadevall, Aaron Tobian, Daniel Hanley.
Published in The New England Journal of Medicine on 30 March 2022.
Background
Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (COVID-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset COVID-19 is uncertain.
Methods
In this multicentre double-blind, randomised, controlled trial, we evaluated the efficacy and safety of COVID-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomisation. The primary outcome was COVID-19–related hospitalisation within 28 days after transfusion.
Results
Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomisation, and 1181 received a transfusion. In the pre-specified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P=0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with COVID-19 who were hospitalised were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalised.
Conclusions
In participants with COVID-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalisation.
Original MedRXiv preprint article
Randomised Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma
David Sullivan, Kelly Gebo et al
Abstract
Background
The efficacy of polyclonal high titer convalescent plasma to prevent serious complications of COVID-19 in outpatients with recent onset of illness is uncertain.
Methods
This multicentre double-blind randomised controlled trial compared the efficacy and safety of SARS-CoV-2 high titer convalescent plasma to placebo control plasma in symptomatic adults ≥18 years positive for SARS-CoV-2 regardless of risk factors for disease progression or vaccine status. Participants with symptom onset within 8 days were enrolled, then transfused within the subsequent day. The measured primary outcome was COVID-19-related hospitalisation within 28 days of plasma transfusion. The enrolment period was June 3, 2020 to October 1, 2021.
Results
A total of 1225 participants were randomised and 1181 transfused. In the pre-specified modified intention-to-treat analysis that excluded those not transfused, the primary endpoint occurred in 37 of 589 (6.3%) who received placebo control plasma and in 17 of 592 (2.9%) participants who received convalescent plasma (relative risk, 0.46; one-sided 95% upper bound confidence interval 0.733; P=0.004) corresponding to a 54% risk reduction. Examination with a model adjusting for covariates related to the outcome did not change the conclusions.
Conclusion
Early administration of high titer SARS-CoV-2 convalescent plasma reduced outpatient hospitalisations by more than 50%. High titer convalescent plasma is an effective early outpatient COVID-19 treatment with the advantages of low cost, wide availability, and rapid resilience to variant emergence from viral genetic drift in the face of a changing pandemic.
Infectious Disease Society of America Guidelines (Open access)
Transfusion journal article – Guide for implementing plasma transfusion centre (Open access)
See more from MedicalBrief archives:
Convalescent plasma may benefit some COVID-19 patients with comorbidities
Convalescent plasma fails to improve outcomes in critically ill COVID-19 patients
Drop in convalescent plasma use in US hospitals linked to higher COVID-19 mortality
Cross-neutralisation of variants in convalescent plasma — small SA study