Michaela Fleming

: Michael K. Gusmano, PhD, associate professor and concentration director, health systems and policy, at Rutgers School of Public Health, discusses the importance of maintaining ethical standards in research evaluating potential therapeutics and vaccines for COVID-19.

Interview transcript (modified slightly for readability):

® coronavirus video. Today we're joined by Dr. Michael Gusmano from the Rutgers School of Public Health. Thank you so much for joining us today.

Oh, it's my pleasure. Thanks for inviting me.

Great. So why don't we just get started? The COVID-19 situation is developing very rapidly. Some clinical trials are being approved and begin enrolling what seems like breakneck speed. So what are some important standards that we need to make sure are being maintained during this time?

Well, it's a good question. I think it's incredibly important that we make sure that the trials are well designed. That they can use innovative designs, including complex designs, but that they ought to be using well designed trials with controls. One of my big concerns is that we have rushed, in some cases, into the use of treatment under the Federal Emergency Use Authorization Act without controls. This can be a big problem, because then obviously it far more difficult to evaluate whether any effects are due to the intervention or not, and whether or not there are significant harms associated with that intervention. I think sticking with the usual standards of designing trials well is important. I also think it's important, because one of the things that that we have tried to do in the rush to find vaccines and treatments for COVID-19 is in some instances we skip over animal testing or to do parallel animal testing, and I think we should have a public registry for any of the results from the parallel animal testing that's going on. One of the concerns is that if you begin to see safety problems in the parallel animal testing the phase one human trials should be stopped immediately. It's important for the public to have access to that. Similarly, we are enrolling some healthy people in trials for vaccines, and it's really important from an informed consent point of view to make sure that those people who are being enrolled realize that in some instances, there haven't been animal trials that are going on in parallel, so that they better understand the risks of what they're facing.

So I guess my next question is, how can federal health officials and agencies work to maintain standards and make sure that they're being upheld in COVID-19 research?

Right. Well, I think it's important for the FDA to continue to play its monitoring role, to make sure that it's getting real time information and working in partnership, as it always does with the pharmaceutical industry, university researchers and again to have the political willingness to step in and stop things when there is evidence that the harms are outweighing the benefits.

Now, is it correct to assume that maintaining these ethical standards will require collaboration between researchers and pharmaceutical companies and federal agencies?

Well, I think this is always the case. It's long been the case in our entire regime of developing testing, monitoring, regulating new drugs involve public-private partnerships between the FDA or the European Medicines Agency and pharmaceutical firms, along with the university level researchers. So this has always been a public-private partnership, and that coordination is more important than ever.

COVID-19 mitigation is counting a lot on isolation and social distancing to reduce the burden of COVID on health care systems. So how can protocols for clinical trials not necessarily for COVID, but other disease states be modified to account for this?

Well, again, another good question. I think if you go onto the website, a lot of the IRB is around the country of major universities, including Rutgers, you find information about how they are working with researchers to modify protocols. Some human subjects research, it's simply been stopped because if it's not essential, it shouldn't continue to go on to put people at risk. Some of my research actually is currently on hold because it involved focus groups, for example, that were not related to COVID and just makes absolutely no sense to continue with that when people are at risk. Obviously, for the things we're talking about in terms of clinical trials for vaccines or treatments directly related to COVID, making accommodations but even for other clinical trials, they can make some accommodations. For example, it may be possible in some trials, for the experimental drugs to be delivered to the home, and for people to take those drugs at home and provide appropriate reports back to the researchers and collect data that way. When people have to come into the clinic, obviously, they engage in social distancing when possible, the use of protective equipment, hand washing, and the like. And so in every instance, I think what you're seeing is, IRBs appropriately re-reviewing protocols to make sure that they've been modified to minimize the possible harms that people will face as we're trying to continue to develop new treatments.

Now, if you go on clinicaltrials.gov, you can see that there are thousands of randomized controlled trials already for COVID019 countermeasures. So is there a way to prevent the duplication of effort?

Well, that's what we're trying, and we'll see if it's successful. If you go back last month, the Gates Foundation actually began this before governments did. And so, they started trying to put together a coordinated effort into the agreements of not-for-profits who are helping to fund some of this work, pharmaceutical companies, university researchers. In fact, just last week, Francis Collins, the director of the NIH, announced a new collaborative effort in a public-private partnership to try to coordinate this. So, you have on board the Food and Drug Administration, the EMA, most of the major pharmaceutical companies, university researchers and others who are doing a number of different important things to try to eliminate the unnecessary duplication. Some duplication of effort can be helpful, and you know, with a competition to try to see who can develop the drugs. But what you don't want to be doing is to conduct multiple trials that are not informing each other. Good evidence starts to come in that a promising drug isn't as promising as we hoped. You want to redirect efforts away from that and toward things that seem to be working. The other important thing or one of the other important things that that effort is going to try to do is, to the extent possible, standardize protocols, standardize the use of various outcomes, like different biomarkers that are being used by different trials. That can be valuable because then you can actually compare results from multiple trials that are going on to see if they're consistent with each other. If they're all using different protocols and different markers, it might be more difficult to coordinate that effort. So, whether this will work is something we're going to find out. But I think it's a very good step first by the Gates Foundation and now by the NIH to try to make that work.

Absolutely. Do you have any final thoughts or comments?

Well, I mean, my biggest concern all along, is that we have to not rush the science, there is a completely understandable desire to find a vaccine and/or a cure as soon as humanly possible to get out of suffering and death that is going on. But, it can be incredibly dangerous to try to rush things into the clinic without appropriate evidence. We've seen some of that already with hydroxychloroquine and some of these other things that have come to the fore and then rushed into the clinic. Under the best circumstances, all drugs have some side effects and can produce some harms. There are very few benign interventions in the clinic.

The real question is do the benefits outweigh those harms? And does it make sense we continue to move forward? Frankly, the only way to do that is with good science. I'm afraid that the kinds of clinical trials that we're talking about, particularly the development of vaccines, just take a lot more time than any of us would like to believe. But, I think that's one of the kind of grown up questions that we have to deal with and part of the hard truth people are going to have to accept is that when you try to rush this, you can do some significant damage to people's health. The idea that they have nothing to lose is ridiculous because even when people are facing a life limiting illness, you can induce suffering. You can hasten death, unnecessarily if you are giving them drugs for which we know there are harms and for which we have no evidence that there are benefits. So it's important not to rush this stuff.

Absolutely. Thank you so much for joining us this morning. Dr. Gusmano, we really appreciate hearing your perspective.

Great. Thank you. It was nice speaking with you.

Videos

Michael K. Gusmano, PhD, discusses the importance of maintaining ethical standards in research evaluating potential therapeutics and vaccines for COVID-19.

Don't Rush Science: Maintaining Ethics in Exploring Countermeasures for COVID-19

 Hollis O’Neal, MD, pulmonary-critical care expert, Our Lady of the Lake, and the national primary investigator for the Cytovale early sepsis detection system, discusses sepsis and COVID-19 and provides an overview of his pilot study.

Interview transcript (modified slightly for readability): 

Thanks for joining us today for another coronavirus video with 

. Today we're joined by Dr. Hollis O'Neal, who is a pulmonary and critical care expert at Our Lady of the Lake in Baton Rouge. He is the national primary investigator for the Cytovale early sepsis detection system. Thanks so much for joining us this morning.

Great. So why don't we get started. What is the current burden of sepsis in the United States?

Sepsis has gotten a lot of press over the last several years in United States for a lot of reasons. Number 1, the economic burden is really astronomical. Yearly sepsis costs tens of billions of dollars and rapidly outpaces the other costs of inpatient conditions that we have in the United States, I believe. Osteoarthritis, so hip, knee replacements and things like that would be probably a number 2 and really sepsis massively outpaces that. The other burden that we've seen with sepsis are a couple of things that aren't really captured in monetary cost. One is the intellectual burden it places on emergency medicine providers. It's something that they screen for constantly.

There are sepsis alerts because the government has in place the SEP-1 bundle that requires rapid identification and treatment. It really places a large, I would say intellectual burden, on the emergency department staff to identify the disease. There are frequent notifications from the electronic health record that requires them to intervene. The other burden that it places on us that is also not accounted for in costs--and the Infectious Disease Society of America has made a good point of looking at this-- is the fact that because sepsis is a disease that requires emergent and aggressive intervention, the thought that it requires early and aggressive and almost indiscriminate use of broad spectrum antibiotics. We don't know what the organism are going to be until sometimes several days after the patient's admitted.

It runs the risk of promoting one of the things that we try to prevent, which is antibiotic resistance and now, the development of multidrug resistant organisms because of our indiscriminate use of broad-spectrum antibiotics and the resource utilization that it requires. When we think a patient has sepsis, we often go down a pathway of early and aggressive IV fluid resuscitation, admission to the intensive care unit, and this places yet more burden on the health care system.

So how can sepsis come into play in patients with COVID-19?

COVID-19 has presented to us a little bit of a challenge in that traditionally, we always thought of sepsis as being predominantly a disease caused by bacterial pathogens and then occasionally fungal pathogens in certain populations. What COVID-19 has really shown us is that viral pathogens can also cause a sepsis syndrome as well. It's a little bit different in that there's no great treatment for it. There's no proven therapeutic option for COVID-19 right now, or, for that matter, most forms of viral sepsis. But this is, to my understanding, the first time, probably in history where a viral pathogen has become the overwhelming cause of sepsis, or at least concern for the overwhelming cause of sepsis in our health care system.

It's really provided quite the challenge for us in discerning those patients who do have the disease. I think that one of the things that providers have a hard time understanding sometimes is that COVID-19 tends to be a "plus one" disease not an "instead of" disease. In other words, patients will come in with all of the other things that they typically come in with and they could have COVID-19. It's not a mutually exclusive disease. So, when they come in with a disease, it's not necessarily the only thing they have, they can still have all of their other conditions and complications.

COVID-19 has really provided quite the challenge there. The other thing that it's done to us is really pressed our resource utilization. It was a disease, a pathogen that humans had never seen before, and a disease course in the natural history that was unknown to the treating clinicians. There was a lot of uncertainty upfront in how to treat the patients. There's a lot of concern with communicability of the disease that places a large burden on the use of personal protective equipment, and also disposition. These patients deteriorate rapidly. They often are placed in intensive care units, probably earlier than most patients would be and for good reason, because they do deteriorate and decline so rapidly. For example, an institution like ours, we increased our ICU bed capacity from 80 something beds to over 170 beds within just a week or 2 to accommodate the massive influx of critically ill COVID-19 patients that we have.

Dr. O'Neal, can you tell us a little bit more about the pilot study that you're launching?

One of the things that we've noticed, and through my work with Cytovale over the last 5 to 6 years that we've seen, is that the signature that occurs in viral sepsis does appear to be very similar to the signature that appears in bacterial sepsis. Our largest experience with viral sepsis over the last several years has been influenza, because that does tend to be the viral pathogen that we understand the best with regards to causing multisystem organ failure. We found there are studies that influenza-related sepsis does have a similar signature to other bacteria-related sepsis. As we're thinking through this, one of the important things that we have to do in the emergency department is risk stratify patients and find those patients who are at risk for deterioration for admission to the hospital admission to the ICU versus finding those patients who are at lower risk for deterioration, and those patients can go home and self-quarantine, and treat themselves at home since there is no specific therapy for disease.

We've designed this pilot to be placed very early in the course of an emergency department setting. So most patients who come into the emergency department with some suspicion that they may have COVID-related disease are going to be triaged and at some point, they'll probably have a purple top tube draw for what would be a typical of a CBC. We've designed this pilot to take the remnants of that CBC, and then observe those patients over time, and then determine if they have any infection, including COVID-19. Because remember, COVID-19 is just 1 more of a number of pathogens that these patients could have. But we're looking to see if they have an infection such as COVID-19, and to see if the results of the test will correlate with the severity of illness that the patient has. Where they're admitted to, how long they're in the hospital, do they survive? What kind of treatment do they require? What kind of IV fluids do they require? The goal of this study is to identify those patients rapidly and see if the results of the assay could help in risk stratification of these patients very early in the course of the disease, so that the emergency department can then rapidly work through this massive population of patients that they're seeing every day, and appropriately triage them to treatment.

Now, are there any other goals or objectives that you're looking at in this trial specifically?

Yeah, there are a number. Number 1 is appropriate risk stratification pf these patients. But number 2 is looking at the results of the essay with regards to the severity of illness, predicting certain things like organ dysfunction, organ failures over the first 3 to 4 days of hospitalization in these patients, disposition where they're where they're discharged, to, obviously, length of stay in survival. Those are all secondary end points that we're looking at.

So, you're conducting the study in Louisiana, which is becoming quite a hot spot for COVID-19. How could this rapid diagnostic help hotspot communities in this pandemic that we're seeing right now?

Louisiana really has become one of the hotspots for this disease. If you look at it, per capita, we are probably in the top 3 or so with regards to states in the United States with being affected by this disease. Actually, if you drill down in Louisiana, New Orleans and Baton Rouge are the areas where the predominance of these cases are. One of the things that we're hopeful for is that if we can employ this and in our facilities and see that that this assay, which can be performed in under 10 minutes, can provide our emergency department clinicians with the information they need to appropriately triage these patients, determine who needs more aggressive therapy versus determining who may need to go home, then since we're leading the country in this, as other communities begin to see more and more of this, we could deploy this technology to those communities and help them avoid some of the burden that we've seen with regards to admissions of patients who stay in the hospital for just a day or 2 because we're concerned about what they may or may not have, and then are discharged back resource utilization.

The biggest thing that we see, the biggest problem that we have with regards to resources are really 2. Number 1 nursing and support staff. There just aren't enough nurses and our health care providers do sometimes get sick and so there aren't enough nurses and support staff to take care of the patient. It's much better when we can to have a patient self-quarantine at home. Then, the never-ending shortage of personal protective equipment that we have. Every patient that goes home and is able to self-quarantine is a patient that we don't consume, at least 23 sets of PPE per day as the nurses are going in and out of their rooms to care for the patients. Those are things I think we could help the rest of the country with. If we could use our experience here to educate and help technology and provide technology to help those other locations more efficiently move through their patients in the emergency department. I think that that would be a huge win to the medical community overall.

Absolutely. Is there anything else that you want to add about your study or anything in general?

Yeah, I think the important thing to understand about the Cytovale assay that makes it a little bit unique with regards to this is that a lot of attention has been focused, not only in COVID 19, but in other forms of sepsis that we see is that there's been a lot of attention placed on early pathogen identification. A lot of technology out there and diagnostics [focus on] finding out what the pathogen is. That is not our intent and we should not be not be confused with early pathogen identification. We are a test that assesses the host response. What we say is that we're about the patient not the pathogen. We're looking at how the patient's host response is affecting that patient, and how that immune response might impact that patient's outcome. We'll leave it to the pathogen identification experts to tell us what pathogen that is. We feel that it's our job to appropriately risk stratify these patients because it may be that if you have relatively mild disease and you can go home, it may not be necessary for at least treatment of that specific patient. It may not be necessary to find out what the pathogen is if they're going to be fine at home. Now for epidemiologic purposes, I think that that's a different question. But at least with regards to treatment of the individual patient, we are looking at host response to determine if we can help the patient's outcome.

Fantastic, well Dr. O'Neal, thanks so much for taking the time to join me today. We really appreciate hearing more about your study, and we wish you luck.

Hollis O’Neal, MD, the national primary investigator for the Cytovale early sepsis detection system, discusses sepsis and COVID-19 and provides an overview of his pilot study.

Assessing Host Response for Sepsis Through Early Detection

Is there a link between certain anaerobic bacteria and the risk of developing colorectal cancer?

New research from Danish investigators that was slated to be presented at the 2020 European Congress on Clinical Microbiology and Infectious Diseases (

) this past week suggests there could be. ECCMID’s in person and virtual components were cancelled due to coronavirus disease 2019 (COVID-19), but the congress organizers have released some of the meeting’s abstracts and plan to release more on May 5

Previous research has suggested an association between bacteria from the Bovis group streptococci, 

 and colorectal cancer (CRC). However, recently there have been associations reported between CRC and different 

As such, the investigators, led by Ulrik Stenz Justesen,

Odense University Hospital, Denmark, set out to investigate this association in a large-scale study.

They performed a population-based cohort study which featured blood culture data from more than 2 million individuals in Denmark that was collected from 2007 to 2016.

They combined the data on blood cultures with the national register for CRC and looked for new cases of new cases of CRC that occurred following blood infection with these bacteria. The investigators reported that the risk of incident CRC until 2018 was investigated for 

 spp and was then compared with Bovis group 

 and with controls. Each case was matched by age and sex with 5 controls.

Of 45,760 bacteraemia episodes, 492 (1.1%) were diagnosed with CRC following the bacterial infection. Of these 241 individuals were diagnosed within 1 year.

“Most anaerobic species were associated with a considerable increased risk of CRC (up to 42 times) compared with negative blood cultures,” the investigators wrote.

 was associated with a 42 times increased risk of CRC within a year (0.5% of controls developing CRC vs 20.8%), and a 21-times risk overall (1.1% controls vs 22.6%).

 was linked to a 13 times increased risk of CRC within a year (0.5% of controls vs 6.7%), and a 6-times increased risk overall (1.1% controls vs 6.7%).

 “The discovery of blood infections with certain anaerobic bacteria could potentially result in a recommendation of further evaluation for CRC in selected patients,” the investigators conclude.

However, in a press release Justensen noted that not enough is known about the link right now.

 “At this stage we are not sure if the bacteria are directly causing cases of colorectal cancer, of if the blood infection with these bacteria is itself caused by the cancer. It’s an example of the question ‘is this the chicken or the egg?’”

The abstract, Bacteraemia with anaerobic bacteria and association with colorectal cancer, was slated to be presented at ECCMID 2020.

Articles

Previous research has suggested an association between bacteria from the Bovis group streptococci, Clostridium septicum and colorectal cancer

Is Risk of Colorectal Cancer Linked to Certain Blood Infections?

 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.

 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?

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.

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?

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 USCOVIDplasma.org, 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.

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.

In part 2 of the interview, Ryan W. Stevens, PharmD, BCIDP, discusses the risks associated with convalescent plasma and highlights what clinicians should know.

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

 In part 1 of our interview Ryan W. Stevens, PharmD, BCIDP, infectious diseases and antimicrobial stewardship pharmacist, Mayo Clinic, provides an overview of how convalescent plasma has been used to treat infectious diseases including coronaviruses.

 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 so much for joining us. So let's just get started. Can you describe the mechanism of action of convalescent plasma?

Sure, so, convalescent plasma and the idea of giving it as a therapeutic for viral infections, it really stems from the idea of harvesting the adaptive immune system from 1 patient and then tasking that to the second patient who's in acute viral phase of the illness. So, essentially, you take a patient who's had an infection with the virus and has recovered, that has been presumed or proven to produce antibodies that pathogen. In the case of SARS-CoV-2 this antibody development generally takes place with seroconversion somewhere between 8 and 21 days since the beginning of the infection. After this person has been proven to have the infection and has fully recovered, you take their blood and you harvest plasma from the blood. Then this plasma is then administered the second patient who's in an acute viral phase the illness, thereby passing the adaptive immune system from patient 1 on to patient 2.

So how is convalescent plasma been used for other infectious diseases and specifically for other coronaviruses?

Yeah, so there's a lot out there on this. That would make sense because convalescent plasma is really one of the oldest therapies in infectious disease we have. It dates back into the pre antibiotic era, as far as 1892 when it was used for the treatment of diphtheria, with serum actually being harvested from various animals. Over the years it's been used for a lot of different infections with Spanish flu, measles, and pertussis, but most recently, it's been used in 4 viral illnesses since the year 2000. So, one is influenza A H1N1 one and one in 2009 and one of Ebola in 2015. For the sake of what we're talking about here with SARS-CoV-2 and COVID-19, we should look at it in the context of other coronaviruses. That would include SARS-CoV-1 in 2003, and then the Middle Eastern respiratory syndrome coronavirus in 2012.

So, with regards to SARS-CoV-1 in 2003 outbreak in Hong Kong, there was a study where they administered convalescent plasma to 80 patients with SARS-CoV-1. They look for the primary outcome of discharge from the hospital by day 22. They found that 33 of their 80 patients met this primary outcome, which is about 41%. There were 2 important findings that came out of this study with regards to convalescent plasma. The first is that they found that patients that received convalescent plasma within 14 days of the onset of their symptoms were more likely to reach primary outcome of discharge by day 22.

This would make sense given that we know that coronavirus has 2 immediate phases. The first is the viral phase where the virus is present. The second is more of an immune activation phase. So it makes sense that got the convalescent plasma during the viral phase to have a better outcome. Then the second finding that they found was that patients that were PCR positive by a nasal pharyngeal PCR, but zero negative for antibodies at the time they received the convalescent plasma were actually more likely to reach the primary outcome as well. And again, this makes sense because we're passing the adaptive immunity from one patient onto a second. If the second patient hasn't developed their own active immunity, yet, it would make sense that they would be more likely to potentially experience the outcome of discharge by day 22. If we look at the Middle East respiratory syndrome coronavirus, there's some interesting data that came out of that as well. In 1 very, very small study, they administered convalescent to 3 patients with MERS-CoV. They looked for the rate of earliest seroconversion, so seroconversion to the recipient within a few days. What they found was that there was only 1 of the 3 patients that actually had early seroconversion. That 1 patient was also consequently, the only patient received convalescent plasma with a neutralizing antibody titer of ≥1:80. So the important finding that came out of this study is the idea that the neutralizing antibody titer of the donor may actually impact the seroconversion and thereby potentially the immunity.

What do we know so far about convalescent plasma for COVID-19?

 What we know is relatively limited. Our knowledge of convalescent plasma and its efficacy in SARS-CoV-2 or the treatment of COVID-19 comes from 3 very small studies. Two were small, uncontrolled studies.  This is a cumulative 19 patients across these 2 papers. All patients that received it, all 19 of them, were either severely or critically ill at the time they received the convalescent plasma, and the regimens that they receive varied widely depending on the paper. So 1 used a single unit of convalescent plasma which is about 200 milliliters, with no neutralizing antibody titer of >1:640. That's a very high neutralizing antibody titer. The second used 400 milliliters which was administered in 2 separate 1 unit infusions with a neutralizing antibody titer of >1:40 and an IgG titer of >1:1000. Now, the first study didn't actually check titers with donors, but they administered non-standard volumes. This was more of a safety reason. They administered anywhere between 220 and 2400 milliliters of convalescent plasma.

Another important thing to note is that most of the patients who have received concomitant antiviral therapy, you see that looking at the ritonavir, hydroxychloroquine or other therapies, at the same time or before receiving convalescent plasma, and corticosteroid receipt is also very common in this population.

If we look at the duration symptoms before they presented to the hospital all 19, presented within roughly 2 to 4 days of the development symptoms. They all received convalescent plasma therapy within about 12 to 20 days since the onset of symptoms. All of these papers report various forms of clinical, radiographic, or virologic outcomes. All of them report favorable outcomes. Some of the things that were reported were things like resolution of radiographic infiltrates, or improvement in symptoms and clinical symptoms as defined by various symptom scores, and improvements in inflammatory markers like CRP and IL-6, and increases in antibody titers in recipients. One of the studies specifically reported the rate of conversion of the nasal pharyngeal PCR to a negative result, which also showed favorable outcomes. Most notably is that all 19 of these patients survived at the time that the papers were written. They represent a little bit of reporting bias, but I think it is an encouraging finding. It's important that we note though, that all the papers to date all lack control groups. There was a lot of other confounders that I've mentioned like concurrent antiviral therapies, so the variability in different regimens. We have to interpret the data with caution, but I think when we couple these 19 cases with the data we have from SARS-CoV-1, I'm optimistic about the use of convalescent plasma at this point.

In part 1 of our interview, Ryan W. Stevens, PharmD, BCIDP, provides an overview of how convalescent plasma has been used to treat infectious diseases including coronaviruses.

Examining Convalescent Plasma for SARS, MERS, and SARS-CoV-2

 Live News Network, I’m Michaela Fleming and this is your coronavirus update for Friday, April 24

According to Johns Hopkins, there are now more than 2.7 million cases of COVID-19 and 192,000 associated deaths.

In the United States alone there are more than 870,000 cases and 49,000 deaths. As of this morning more than 4.6 million tests had been administered across the United States. New York, California, Florida, Texas, and New Jersey round out the top 5.

According to Vice President Mike Pence, he is hopeful that the coronavirus epidemic will largely be behind us by Memorial Day — just one month from now. In a radio interview he states that the White House’s recommended “phased approach” is the best way to ensure that there is not a resurgence of the virus.

However, Dr. Anthony Fauci has warned that he is “not overly confident” about the United State’s current testing capacity, which needs to be increased before governors can begin re-opening their states.

Beaches in Sarasota, Florida will reopen Monday for fishing, running, walking, swimming and surfing, their playgrounds, basketball and tennis courts, and beach pavilions will remain closed. On the other hand, Michigan’s governor Gretchen Whitmer announced that the state’s stay at home order will remain in place until at least May 15

The Infectious Diseases Society of America is warning the public that we do not know enough about antibodies to make assumptions about immunity to COVID-19.

Dr. Mary Haden, an IDSA spokesperson and chief of the division of infectious diseases at rush university medical center spoke at a briefing on Friday and said that it is not known if antibodies are protective or what degree of protection they provide. Therefore the IDSA recommends that individuals with antibodies do not change their behavior in any way and continue to practice social distancing.

For other stories relevant to COVID-19 and the latest infectious disease news, visit ContagionLive.com. To track the spread of the pandemic in the United States and abroad, be sure to use the 

 Live News Network, this is Michaela Fleming signing off one last time.

Stay up to date on the latest coronavirus news from Friday, April 24th.

Michaela Fleming

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