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Convalescent plasma may benefit some COVID-19 patients with comorbidities

Transfusions of blood plasma donated by people who have already recovered from infection with the pandemic virus may help other patients hospitalised with COVID-19, a recent international study shows.

The treatment, known as convalescent plasma, is still considered experimental by the US Food and Drug Administration (FDA). Plasma contains antibodies, blood proteins that are part of the immune system. Shaped so they can attach to the virus that causes COVID-19, SARS-CoV- 2, antibodies glom on to and tag it for removal from the body, researchers say.

Led by researchers at NYU Grossman School of Medicine, the study showed that among 2,341 men and women, those who received an injection of convalescent plasma soon after hospitalisation were 15% less likely to die within a month from COVID-19 than those who did not receive convalescent plasma or those who received an inactive saline placebo.

Notably, the researchers found that the biggest benefits for the therapy were among patients most at risk for severe complications because of pre-existing conditions, such as diabetes or heart disease. The treatment, which contains antibodies and other immune cells needed to fight the infection, also appears to benefit those with type A or AB blood.

“Our results show that, overall, patients hospitalised with COVID-19 may derive modest benefit from convalescent plasma, with some patient subgroups benefiting more than others,” says study lead investigator and biostatistician Andrea Troxel, ScD. With respect to the groups most likely to benefit, on 28 December 2021, the FDA revised the Emergency Use Authorization for convalescent plasma, limiting its use to patients with diseases that suppress their immune systems, or who receive medical treatments with the same effect.

“Patients with co-existing disease were most likely to show improvement from convalescent plasma, probably because they have the most difficulty producing antibodies to fight their infection,” adds Troxel. “The infused plasma boosts their body’s ability to fight the virus, but only in the early stage of the disease and before the illness overwhelms their body.”

The current study findings, published in the journal JAMA Network Open, come from the pooling of patient information from eight recently completed studies in the United States, Belgium, Brazil, India, The Netherlands, and Spain on the effects of convalescent plasma for COVID- 19.

These benefits of the treatment are only likely to become clear as more data from the trials become available, says Troxel, a professor in the Department of Population Health at NYU Langone. This is because the data from individual trials are too small to show the treatment’s overall impact on subsets of patients, she says. Some individual studies have showed the therapy to be ineffective or of limited value.

Study co-investigator Eva Petkova, PhD, says the team is using its study data to create a scoring system of patient descriptors, including age, stage of COVID-19, and co-existing diseases, making it easier for clinicians to calculate who stands to benefit most from use of convalescent plasma.

“Our treatment benefit index is designed to serve as a quick and effective tool for physicians to use in deciding when to administer convalescent plasma for COVID-19,” says Petkova, a professor in the Departments of Population Health and Child and Adolescent Psychiatry at NYU Langone.

For the study, researchers grouped all patient information from smaller, separate clinical investigations about convalescent plasma therapy, including trials at NYU Langone, Albert Einstein College of Medicine and Montefiore Medical Center, Zuckerberg San Francisco General Hospital, and the University of Pennsylvania in Philadelphia. Researchers hoped any benefits or disadvantages in treatment would be easier to spot among the largest possible sample of patients. All trials were randomised and controlled, meaning that the patient had a random chance of being assigned to receive convalescent plasma or not to receive it.

Included in the analysis were data from another multicentre US study published separately in December 2021 in JAMA Internal Medicine. That study in 941 patients hospitalised with COVID-19 showed that patients receiving high doses of convalescent plasma therapy and not on other medications, such as remdesivir or corticosteroids, were likely to benefit from the blood plasma treatment.

Study co-primary investigator Dr Mila Ortigoza, PhD, an assistant professor in the Departments of Medicine and Microbiology at NYU Langone, says these initial results supported the idea that convalescent plasma could be a feasible treatment option, especially when other therapies are not yet available, as at the beginning of a pandemic.

In addition, convalescent plasma collected from previously infected and subsequently vaccinated donors (VaxPlasma) would contain antibodies in high enough quantities and diversity that could provide added protection against emerging viral variants, says Ortigoza. Viruses typically mutate genetically (acquire random changes in their DNA or RNA codes) over the course of any pandemic. For this reason, convalescent plasma has the potential to offer effective treatment more quickly after such mutations than treatment types that tend to become less effective with time and must undergo a re-design process to address a new variant, such as monoclonal antibody treatments.

Study details

Development and Validation of a Treatment Benefit Index to Identify Hospitalized Patients With COVID-19 Who May Benefit From Convalescent Plasma.

Hyung Park, Thaddeus Tarpey, Mengling Liu, Keith Goldfeld, Yinxiang Wu, Danni Wu, Yi Li, Jinchun Zhang, Dipyaman Ganguly, Yogiraj Ray, Shekhar Ranjan Paul, Prasun Bhattacharya, Artur Belov, Yin Huang, Carlos Villa, Richard Forshee, Nicole C. Verdun, Hyun ah Yoon, Anup Agarwal, Ventura Alejandro Simonovich, Paula Scibona, Leandro Burgos Pratx, Waldo Belloso, Cristina Avendaño-Solá, Katharine J Bar, Rafael F. Duarte, Priscilla Y. Hsue, Anne F. Luetkemeyer, Geert Meyfroidt, André M. Nicola, Aparna Mukherjee, Mila B. Ortigoza, Liise-anne Pirofski, Bart J. A. Rijnders, Andrea Troxel, Elliott M. Antman, Eva Petkova.

Published in JAMA Network Open on 13 December 2022

Key Points

Question Does COVID-19 convalescent plasma (CCP), compared with placebo, improve the clinical status of hospitalised patients with COVID-19 requiring noninvasive supplemental oxygen?
Findings In this randomised clinical trial including 941 patients, based on the World Health Organization 11-point Ordinal Scale for Clinical Improvement, CCP did not benefit 468 participants randomised to CCP compared with 473 randomised to placebo from April 2020 to March 2021. However, in exploratory analyses, CCP appeared to benefit those enrolled from April to June 2020, the period when most participants received high-titer CCP and were not receiving remdesivir and corticosteroids at randomisation.
Meaning In this trial, CCP did not meet prespecified outcomes for efficacy, but high-titer CCP may have benefited hospitalised patients with COVID-19 early in the pandemic when other treatments were not in use, suggesting a heterogenous treatment effect over time.

Abstract

Importance There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalised with COVID-19.
Objective To determine the safety and efficacy of CCP compared with placebo in hospitalised patients with COVID-19 receiving noninvasive supplemental oxygen.
Design, Setting, and Participants CONTAIN COVID-19, a randomised, double-blind, placebo-controlled trial of CCP in hospitalised adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalised for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation.

Interventions
A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline).

Main Outcomes and Measures
The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomisation; the secondary outcome was WHO scores determined on day 28. Subgroups were analysed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analysed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8.

Results
Of 941 participants randomised (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR<1] = 72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; P[cOR<1] = 76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; P[cOR<1] = 93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; P[cOR<1] = 97%) for those not receiving remdesivir and not receiving corticosteroids at randomisation. Median CCP SARS-CoV-2 neutralising titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (P = .57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (P = .06).

Conclusions and Relevance
In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use.

 

JAMA article – Development and Validation of a Treatment Benefit Index to Identify Hospitalized Patients With COVID-19 Who May Benefit From Convalescent Plasma (Open access)

 

See more from MedicalBrief archives:

 

Convalescent plasma fails to improve outcomes in critically ill COVID-19 patients

 

Early convalescent plasma for high-risk outpatients with COVID-19 — Trial stopped

 

Convalescent plasma may improve survival with severe COVID-19 — US/Brazil trial

 

Convalescent plasma: Optimal timeframe and donor profile

 

Cross-neutralisation of variants in convalescent plasma — small SA study

 

 

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