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Physician to Physician: Candid Talk on the Use of Convalescent Plasma to Treat Hospitalized Patients

In today’s blog, we have the opportunity to get advice from a national expert in the use of COVID-19 convalescent plasma (CCP): Arturo Casadevall, MD, PhD, Bloomberg Distinguished Professor of Molecular Microbiology & Immunology and Infectious Diseases at the Johns Hopkins Bloomberg School of Public Health and Johns Hopkins School. Interviewer,  Francis X. Campion, MD, FACP is an internal medicine physician at Harvard Vanguard Medical Services and Principal Lead for Digital Health at The MITRE Corporation. 

Early Intervention is Best 

Dr. Campion: We’ve gained a great deal of knowledge about SARS-CoV-2 over the past year and the role of CCP in the treatment of patients with the infection. Based on what we know today, what kinds of patients will benefit the most from CCP? 

Dr. Casadevall: I encourage patients to ask their healthcare providers about plasma as soon as they are told they will be admitted to the hospital. Plasma’s power is in the early stages, interrupting the virus’ destructive work by limiting its ability to replicate in the body and avoiding lung-damaging inflammation. The American Association of Blood Banks (AABB) recommends that plasma should be used as close as possible to the onset of symptoms. When a patient is hospitalized, physicians should arrange for plasma infusion as early as possible, preferably within the first few days. If a patient is already critically ill, particularly those on mechanical ventilation, plasma is unlikely to provide any benefit. Every patient is unique and there are many factors that go into decision making. But that’s why it’s so important to consider use of plasma as an important treatment option.  

Dr. Campion:  The FDA clarified the Emergency Use Authorization in February 2021. What was the evidence base that led to this update? I know you were one of the co-authors on the large registry-based study sponsored by Mayo Clinic. 

Dr. Casadevall: In January 2021, two studies that appeared in The New England Journal of Medicine (NEJM) helped advance our understanding of plasma. The studies showed that when CCP is given early, treating patients with plasma containing a high concentration of virus-fighting antibodies can reduce the risk of serious illness and improve a patient’s chances of survival. The first study was a randomized controlled trial conducted in Argentina, which examined the use of convalescent plasma in older adults, early in illness. Researchers found a significant benefit. For every four patients treated with medium- or high-antibody plasma, one patient was able to avoid serious respiratory illness. In the second study led by the Mayo Clinic, we examined how early use of plasma affected the risk of death 30 days after treatment. We found that using high-antibody plasma in patients who were well enough to breathe without mechanical ventilation reduced their relative risk of death by one-third. Both studies confirmed that plasma did not improve the survival for patients who had already developed advanced illness or were on mechanical ventilation, underscoring the need for early conversations about treatment.  

Plasma for the Immunocompromised 

Dr. Campion:  The EUA indicated that CCP may be particularly helpful for patients who are immunocompromised. This seems consistent with findings from a related study by Dr. Joyner and colleagues on a group of patients with hematologic malignancies who received CCP. Can you explain the role of CCP in treating this special category of patients?   

Dr. Casadevall: Some patients who are immunocompromised, in particular those with leukemias and lymphomas, often have problem clearing the virus that causes COVID-19 because they don’t make strong antibody responses. Consequently, when these patients get COVID-19 the disease can be severe and become chronic. Numerous publications in the literature support the use of convalescent plasma in this group since the plasma provides the antibodies that they are unable to make themselves. 

Dr. Campion:  The preprint report from the large UK RECOVERY Trial on hospitalized patients found no overall mortality benefit at 28 days. What advice do you have for physicians as they try to determine which patients should be selected for treatment with CCP? 

Dr. Casadevall: The RECOVERY results are disappointing but explainable. Basically, they found that CCP administration had no effect on mortality in a large study carried out in the United Kingdom. Mortality was 24% in both groups, which is significantly higher than in other studies and suggests that this was a population with advanced disease where CCP is less likely to be effective. CCP works best when administered early, such that it can neutralize virus and reduce the likelihood that progressive inflammation would lead to respiratory failure. Once respiratory failure begins one cannot expect that antibody can reverse this process. However, there was reason for encouragement in their subgroup analysis, which showed that those treated early were less likely to die than those treated late, a finding that just missed statistical significance at the 0.05 level. Furthermore, there is concern that 93% of their patients were concomitantly treated with corticosteroids, which can interfere with antibody function and perhaps negate beneficial effects from CCP. 

Effectiveness of CCP with Variants

Dr. Campion:  Regarding the emerging SARS CoV-2 variants that are quickly spreading in the US, do you expect CCP to be more or less helpful?

Dr. Casadevall: There are multiple variants of concern already circulating in the US including the UK and the South African and the Brazilian variants. Additionally, there are new variants emerging in the US including the California and the New York variants. Variants are worrisome because they can express new properties such as increased transmission, greater lethality, and ability to escape from the immunity elicited by vaccines or prior COVID. If variants become a major problem, CCP would be helpful in countering them, for unlike vaccines, monoclonal antibodies and anti-viral drugs, plasma needs no development. As soon as we have recently infected patients willing to donate plasma, we can help those who are newly infected.  Hence, variant CCP can be used to treat variant COVID-19. We expect that high titer CCP which has been collected recently and from a recovered patient in the same community has the best chance for containing neutralizing antibodies effective against the currently circulating virus in that community. 

Recruit More Recovered Patients

Dr. Campion:  There is good evidence that patient who have recovered from COVID-19 infection and then received the vaccine, have particularly high levels of neutralizing antibody. What advice to you have for plasma donors, particularly now that we are so focused on collecting and administering high-titer convalescent plasma? 

Dr. Casadevall: Indeed, patients who had COVID-19 infection and later receive the vaccine have an “exponential” increase in neutralizing antibodies. This has now been shown in a few studies. Dr. Stamatatos and team at the University of Washington showed that COVID-19 patients who later received the Pfizer or Moderna mRNA vaccines generated anamnestic B and CD4+ T cell responses and a 1000-fold increase in neutralizing antibody titers. Remember, the supply of convalescent plasma doesn’t depend on manufacturing capacity in a factory. It depends on people who have survived COVID-19 to step forward and make a potentially lifesaving donation. I am very proud and grateful for The Fight Is In Us campaign which is making the donation process easy. I think The Fight is in Us Campaign has been a remarkable altruistic effort that has made a major difference against COVID-19 by ensuring a steady supply of plasma and this is a remarkable accomplishment given the disruptions of the pandemic. I encourage physicians to send their recovered patients to the website so they can find their closest donation center.  

Closing

Dr. Campion: Thank you, Arturo, for taking the time for our conversation today. This certainly has been a year of learning together. The clinical and research communities have collaborated to generate and apply the science of convalescent plasma under great public scrutiny, in a very compressed timeframe. Plenty of challenges lay ahead as we navigate the emergence of SARS-CoV-2 variants. Thank you again for all you are doing to advance the science and save lives. 

Authors

  • FX Campion, MD, FACP, The MITRE Corporation
  • Arturo Casadevall, MD, PhD, Johns Hopkins Bloomberg School of Public Health and Johns Hopkins School

Photo Credit: Coolpicture/Moment via Getty Images

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