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What Should Clinicians Know About Using Convalescent Plasma for COVID-19?

Segment Description: In part 2 of the interview, Ryan W. Stevens, PharmD, BCIDP, discusses the risks associated with convalescent plasma and highlights what clinicians should know about using convalescent plasma among patients with COVID-19.

Interview transcript (modified slightly for readability):

Contagion®: Thanks for joining us for another Contagion coronavirus video. Today we're joined by Dr. Ryan Stevens who is a member of the Society of Infectious Diseases Pharmacists and recently presented a webinar on convalescent plasma.

Thanks for those resources. My next question is what are the risks that are associated with convalescent plasma?

Stevens: When we think about the risk of convalescent plasma, we're generally talking about similar risks to the administration of other blood or blood products. Most notably, we can compare the FFP or fresh frozen plasma, given that convalescent plasma is essentially FFP from a COVID-19 patient or patient previously infected with SARS-CoV-2. Some of these risks that we might expect would include a group of infections. So first we'll talk about the fact that administration of any blood or blood product is accompanied by the risk of transmission of blood borne pathogens. This risk is really low with current screening standards, but it's worth mentioning. The second form of infection risk has to do with transmission of the SARS-CoV-2 virus. First, we'll talk about transmission to the recipient. There's a theory or an idea that it's possible that if a donor had not fully recovered from infection at the time they donated, that the virus could be passed to the recipient. This would be extremely uncommon. The rates of viremia in in patients with SARS-CoV-2 or active COVID-19 is around 1%. It would be a pretty rare thing to have circulating virus transmitted and then giving plasma to a patient who is already actively infected with SARS-CoV-2. So, the risk of that is relatively unknown but worth mentioning. The other area of transmission of the virus to talk about is the possibility that if a patient is not fully recovered at the time, they go donate that they could pass that virus to health care workers that are responsible for collecting or processing the convalescent plasma.  The donation criteria around the resolution is really important. The fourth and final sort of infection risk or theoretical concern we should dispense with this idea of antibody dependent enhancement.

What this refers to is that, in some viral infections, the presence of a low or sub neutralizing concentration of antibodies causes the innate immune system to sort of back off a little bit. And as that innate immune system backs off, it actually increased viral entropy and replication, which thereby can cause sort of a paradoxical worsening of infection. This is most notable and has been sort of most both studied in dengue. And though it's not specifically been found with SARS-CoV-2 it is sort of a concern that's been discussed in several publications. And just as we have pursued the idea of convalescent plasma therapy. The other risks of convalescent plasma therapy really had to do with the adverse reaction that we could see to this therapy.

The most common is going to be sort of a non-anaphylactic reaction or allergic reaction to the infusion of blood product. As far as life threatening reactions, so we do worry a little bit about transfusion-related acute lung injury. This can be tied to HLA antibodies and so carefully screening for HLA will help to reduce this risk. It's relatively rare as well, around 1 case for every 5000 units of plasma. But, given the fact that a lung injury in a patient who's already demonstrating the pathophysiology of COVID-19 could be potentially problematic, something worth noting. Transfusion associated circulatory overload is another possibility. This is typically more associated with than large volume administration of blood products and given the current convalescent plasma administration protocols are somewhere between a unit and 2 units, it's not likely to be a huge issue. But one noteworthy factor is that the risk factors for transfusion associated circulatory overload sort of mirror that as those same risk factors for severe COVID-19; being advanced age or cardiopulmonary comorbidities. Something worth noting that there's a little bit of overlap between those. And then the final life-threatening adverse effects would be anaphylaxis and the possibility with blood or blood product administration, at which point the infusions terminated, if that were to be observed.

Contagion®: Now, my last question for you is, based on all of this, what are the most important things for clinicians to know right now about use of convalescent plasma for COVID-19?

Stevens: Well, I think one of the most common question is, well, how do I get it? How would I get access to convalescent plasma for my patients? This is accomplished really in 3 ways. So the first is by enrollment in a clinical trial and there's several clinical trial protocols out there right now, ranging from everything from post exposure prophylaxis, asymptomatic individuals to severe cases. The protocols vary and are available through this national COVID-19 Convalescent Plasma Project website. The second way that somebody could get access to convalescent plasma for their patients is through the national expanded access program. The program that was put together by the FDA, but it's being coordinated by Mayo Clinic.

This requires the facility to register with the national expanded access program. It is run through the Mayo Clinic's IRB, and patients that are enrolled for administration through the program still have to be enrolled with the program and consented. That's an important thing to note. The program is really intended for patients that are 18 years of age or older with lab confirmed SARS-CoV-2 infection, and severe or life-threatening disease. They define severe disease as the presence of dyspnea, arrest rate greater than 30, oxygen saturation plus 93% room air, PaO2/FiO2 ratio of less than 300, or the demonstrate lung infiltrates, consuming about 50% of the lung In the last 24 to 48 hours. Life threatening disease is defined as respiratory failure or septic shock or multi organ dysfunction. Interestingly, I checked just before our call, and as of the 21st of April, the expanded access program had enrolled 2803 patients across 1808 sites, and 933 patients have already completed their transfusions, so I think the program is greatly increasing access to the product. The third and final way you could get access is through a single patient emergency IND and this is done through the FDA. It's also intended for patients with severe life-threatening disease, and specifically those who wouldn't have access to the product through clinical trials or the expanded access program.

There are 2 mechanisms by which to obtain that. The first is that if it's a non-emergency situation, you could just fill out the FDA form 3926 and send that in. The turnaround time is somewhere on the 48 hours on the FDA website and they maybe train him around a little bit faster than that. And then the second way is it's an emergency situation, there's a toll-free number you can find on the FDA website and call, where the turnaround time is listed as less than four hours. If that was actually the method by which one chose. It's important to note you start to fill out that form 3926 and send that in within 15 days of the approval of the therapy. One of the other common questions that comes up with regards to convalescent plasmas, is how we dose it. How much convalescent plasma is one getting? Again, this is somewhat of a moving target and it's a moving target because our understanding of how neutralizing antibody titers correlate with immunity is still evolving with regards to COVID-19.

Typically, regimens have been designed considering a typical human plasma volume and correlating that with a presumed recipient neutralizing antibody titer zero and then trying to determine how much plasma with what titer would it take to get a patient with specific thresholds and that's where that threshold is not super well defined yet and will continue to evolve over time. At this point in time, most protocols are recommending between 1 unit and 2 units. Again, ideally, if we can test a neutralizing antibody titer prior to this patient. The post exposure prophylaxis protocol is recommending 1 unit, whereas the treatment protocols are recommending between 1 and 2 units, but the second unit being administered at the discretion of the treating physician. The last thing again that I just want to emphasize is that our understanding of antibody titers and how IgG or neutralizing antibody titers may correlate to a patient's immunity is still evolving at this point in time. And our understanding of typical conversion is even still continuing to evolve at this point in time. As we better understand neutralizing antibody thresholds that are appropriate for both recipients and donors, I think that our understanding of complex plasma and the design of the regimen may be subject to change over time.

The last thing that I want to note is that there's a ton of references out there around convalescent plasma, and a few that are great. The FDA release has great information about ways to get more information on convalescent plasma and or how you might obtain it or information for donors. Again, I've already mentioned the National COVID-19 Convalescent Plasma Project from Michigan State University is fantastic with information from everything from protocols for healthcare workers to donor criteria and registration. And then lastly, if you're looking for information on the national expanded access program, if you're considering enrolling or even if you're just curious how many patients have already been enrolled and treated, you can visit, which is the website for that program. And so lots of exciting stuff out there. Again, I think this is going to continue to evolve relatively rapidly as we understand it more through the use of clinical trials and the national access program.

Contagion®: Fantastic. Well, thank you so much, Dr. Stevens for joining us today. And for any viewers that are interested in reviewing his webinar, you can do so on the SIDP website and a link will be included below this video. Thanks again for joining us.

The SIDP webinar is available here.
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