 Welcome to the Texas Heart Institute educational programs featuring cardiology in the time of COVID-19 pandemic. The topic of today's presentation is testing, treatments, and vaccines for COVID-19. I'm Zvonber Kreyser, I'm a traditional cardiologist at Texas Heart Institute and CHI Health Baylor St. Luke's. Joining me today for this program is Dr. Stephanie Coulter, she's an assistant medical director at Texas Heart Institute and also director at the Center for Women's Heart and Vascular Health as well as a program director of cardiology disease fellowship and also director of cardiology education. Welcome Dr. Coulter. Thank you so much and Dr. Kreyser, thank you for hosting and agreeing to participate and helping us stay on track through all these cardiology in the time of COVID videos that we've started recently. Today we have the, we're very fortunate because today we have with us Dr. Gallant Chan who's the director of medical education and internal medicine here at Baylor St. Luke's Medical Center. She's also an assistant professor of medicine and is an infectious disease specialist and has been quite involved in the preparation for our hospital for COVID specific developments and we're so pleased to have her today to talk to us about testing, treatment options and vaccine development where the Baylor College of Medicine is really playing a vital role and so we're just really thankful that you're here with us today Gallant. I know you're quite busy and you're needed in the hospital a lot but we're actually interested in because the great question out there is if you watch any of the news programs is everybody's talking about the testing, what's available, how useful are these tests and what tests are we using and what are available in our hospital and our medical center at the current time. Well thank you so much Dr. Coulter and Dr. Kreyser for having me here to talk with you guys. I'm looking forward to our discussion but that's an excellent question. Right now the majority of tests that are available are, sorry, reverse transcription polymer strain reaction tests. They're RT-PCR tests and right now the CDC is recommending that nasopharyngeal swabs are collected in order to run the RT-PCR. Other acceptable options include oral pharyngeal swab and nasal mid-terminant swabs as well. And then for patients who have a productive cough, expectorated sputum is another option, although they emphasize that induction of sputum is not recommended because of safety for the collector and the risk of aerosolization with induction of sputum. We do know that for patients where a lower respiratory tract aspirin or a BAL sample is possible, we can also run the RT-PCR tests on those samples. So Dr. Chen, can you tell us how accurate are those tests from the information that we have currently available? Yes, so we know that in general the test is relatively specific. There is the possibility of false positives in the laboratory tests, mostly contamination of samples that are run in the lab, but in general relatively specific. Now in regards to false negatives, we do know that that varies significantly depending on the quality and the type of specimen and depending on the test. Right now there's a large number commercially available tests via the public sector and individual labs at academic institutions. And so depending on the test and depending on the quality and the type of sample, you may see a different negative predictive value. We were speaking earlier about the negative predictive value and how much that depends on our pre-test probability. And so for our patients who where we are seeing clinical COVID and have a high pre-test probability, we will sometimes see negative RT-PCR tests and opt to repeat the test in order to increase the sensitivity of the test. So when we look at the different types of specimens, here this table is from a Chinese study, but looks at the positive percentage from various types of specimens. And you can see that from Bronco aviolar lavage, 93% of samples were positive. This is looking at over a thousand samples in over 200 COVID positive patients. Whereas compared to sputum, you have about 72% positive. Nasopharyngeal swabs being about 63% positive and the oral swabs were much less likely to be positive at about 32%. We also looked at other specimens, urine, blood, BCs, depending on the patient. So you can see clearly here that depending on the type of specimen that's collected and the quality of that specimen. So remember that nasopharyngeal swabs are not always the most comfortable. It does require some training in order for the patient and for the collector to obtain a high quality swab. And so we know that the sensitivity is affected by those factors. So if I may ask you just an additional question related to this, most of the testing particularly in our region or in our country is a nasal swab and also pharyngeal swab and we can see that we can certainly miss a lot of those patients that definitely have COVID-19. And of course we cannot do a Bronco aviolar lavage on everybody actually very few will get that. So that could give us a false hope that the patient might not have infection and actually there might be an infection. Yeah, so it is true that the CDC recommends nasopharyngeal swabs. Oral pharyngeal swab is a possibility although they recommend nasal swabs because they have seen that the viral loads are higher in nasopharyngeal swabs and sensitivity is higher. Having said that, as you can see sensitivity is nowhere close to 100%. So we are likely missing infections by only using RTPCR. So that brings me to testing by serology. It is a test that's approved by the FDA now looking at IgM and IgG antibodies via ELISA. So there are studies looking at improvement of sensitivity for diagnosis combining the PCR along with an IgM test. Those are studies data mostly out from China but if you look at both IgM and PCR together we're looking closer to 95% sensitivity. So you're catching a much larger proportion of those who are infected. These studies also looked at the timing so we're able to see that PCR, viral loads by PCR are much higher in the first seven days of illness and that in general IgM becomes positive. Seroconversion happens in about half of all patients after seven days and all patients after 14 days. So combining those two will likely boost that sensitivity of the diagnosis. Well that would certainly be helpful in helping to take care of our patients where testing is incomplete and it's not really available. So in our hospital at the current time we are doing PCR and we're hopeful that we'll have serology tests soon. Is that right Galen? Yes so right now it's approved for very select the serology tests are approved very select labs. Our hospital right now as most hospitals are using the PCR tests we're looking at more rapid PCR tests along with rapid serology tests. So I think on the horizon are those developments rapid tests with quicker turnaround time for both PCR and also for antibody but for right now PCR is the most widespread way of diagnosing COVID in our country and being in our hospital. And Galen how long are we waiting currently to get a test back by PCR? Is it a day? Is it done in hospital yet? So the exciting thing is that we should have something online within the next week or so to do in-house so that turnaround time would be closer to a couple of hours as opposed to a day or two. The rapid tests are essentially automated versions of the PCR tests so that a lot of the steps can be done in an automated efficient way in cartridges that are packaged together and distributed to different labs across the country. So we're hoping to get some of that online within the next week or so. Well that would be super helpful because we're blowing through the PPE on patients that are presumed COVID that made me wouldn't require so much protective gear so we could save it up for the patients who need it you know and extend our our half-life of our supplies. I'm worried about that. Right it is a couple of issues it's it's the turnaround time but it's also the sensitivity so having something like a serology test along with the PCR tests would help boost that sensitivity rapidity of the results are key as well as you mentioned regarding conservation of PPE and isolation resources. We also know that looking at looking at serologies including IgG can help us determine who potentially could be immune to COVID to the coronavirus so that could help us in terms of deploying workforce or even things like using convalescent plasma for therapy. So tell me Galen what are the other important testing tips for us that are ordering those tests other than you who are an expert in that? Yeah so I mentioned already that PCR is really our primary way of testing right now serology hopefully to come on board soon. Viral culture is something that's done for research but in terms of clinical specimens really should not be submitted for viral culture for safety reasons and then I already mentioned this but because pretest probability is so important in terms of our negative predictive values for the test that if you have a high clinical suspicion for COVID-19 in a patient repeat testing is something to consider knowing that right now our PCR tests are not a hundred percent sensitive and that depending on when you are testing in that disease progression viral loads may be higher or lower so higher at the beginning of the infection and lower as you progress in general. But Galen currently so sorry to interrupt you but currently we have a lot of interest in having people ask us I'm asymptomatic can I have a test to prove that if I've had it or not and we're not currently recommending PCR tests for asymptomatic individuals because the viral load in that group would may just be too low to detect if it's not symptomatic am I right so I think the jury is out on that we don't know honestly we don't have a lot of great data on testing of asymptomatic patients so we don't know presumably their viral loads would be lower but we don't know that for sure and we don't know the sensitivity of our tests for PCR tests for that population and so I worry that if we have constraints on our testing capabilities currently if we were to use those tests for asymptomatic patients that potentially we are not again we are we wouldn't necessarily be gaining valuable information but I think that if serology tests come online that that would be an interesting option to look at for asymptomatic patients to see who potentially has mounted immune response to coronavirus okay can you tell us about some of the treatments that we're advocating for or the treatment of coronavirus yeah absolutely I did want to mention just one last thing about testing that it is important to test for other pathogens because we do know co-infection with other viruses including influenza and other bacteria has been reported and so it's important even if your clinical suspicion for COVID-19 is high to still check for the other pathogens that could be causing lower respiratory infection but in regards to the other treatments this is a nice figure from science highlighting some of the possible therapies and where they work in the replication cycle of SARS-CoV-2 I'm going to use this really to illustrate some of the different treatment options so for example Remdesivir is an antiviral that was initially developed for therapy of Ebola and other related viruses it is a nucleotide analog that inhibits the viral RNA polymerase and prevents viral replication that way it's already demonstrated activity against MERS and SARS-CoV-1 in vitro and in animal studies and there are case reports of success with Remdesivir for COVID-19 right now our hospital is part of a multicenter trial to determine efficacy for COVID-19 so we're excited to be part of that trial is it just Remdesivir that's in this trial or is it in combination with anything else it's an adaptive it's a randomized controlled trial and it's an adaptive study that potentially could allow for the addition of other arms depending on what therapies seem promising so then I wanted to also address hydroxychloroquine which has been we know in the media a lot lately it works in a more general way its antiviral activity is in decreasing the acidity in endosomes but I would start by saying that the data supporting hydroxychloroquine is pretty thin at this point we know that SARS-CoV-2 actually the primary route of entry for that virus is via a different route through binding of that ACE2 receptor on the cell membrane of host tissues like lung epithelial cells or alveolar cells and so hydroxychloroquine is really targeting a different route of entry this endocytosis that cells can use to ingest things like viruses but in vitro studies in cell culture have shown some activity against SARS-CoV-2 but it's really important that we remember that in those studies they used pretty high doses and of course in the in vitro studies you have the luxury of not worrying about any adverse effects and things like ventricular arrhythmias or prolonged QT intervals and other cardiac toxicities which we have seen in patients who are being treated with hydroxychloroquine so it's important to remember that part of it but also that in vitro studies don't always translate to effects in humans so we know that for example in the past in vitro studies showed that hydroxychloroquine worked against viruses like dengue but then when they went to randomized clinical trials in humans it didn't really pan out in terms of efficacy for for those other viruses so I think it's important to to think about that before we make recommendations for its use in treatment of COVID-19. Calvin I have one word of caution in that we set up a lot of guidelines to limit um telemetry monitoring in COVID or COVID presumed patients and such that you know the patients that may be at greatest risk for COVID or those that have underlying cardiovascular disease may actually be at some increased risk for the development of long QT syndrome particularly when given in combination with the azithromycin we actually had a case in our hospital that was being presumptively treated who did develop torsad and and had to be cardioverted or you know intervened which is actually concerning because it requires a lot of people running in and out of the room so if you're going to put the patient on these drugs that prolong the QT we recommend that you you do monitor the heart rhythm and make sure that it's safe to do so. Absolutely and I think that really highlights that all medications really have potential adverse effects and none of these treatments right now have strong randomized clinical trial data to support their use in COVID-19 and so when we you know in in thinking about what's out there in the media we really have to think about our patients what their underlying comorbidities are what their risks for arrhythmias and other cardiac issues are and and be cautious in using some of these medications. That's why we have clinical trials and we won't talk a little bit more about it later. Yeah so to add to that the hydroxychloroquine is one of the four agents that will be studied in the WHO solidarity trial. Interestingly they didn't initially include hydroxychloroquine but I think because of the media interest they ended up including it as one of the one of its one of the four agents that that they'll study. So hopefully we will get some data soon about whether it is actually effective. We know from observational studies out of France that hydroxychloroquine with zyphromycin potentially led to faster viral clearance and some improved clinical outcomes but in that situation because of the observational design you really don't know if it's a causative issue and if you don't really know without a control whether those patients would have gotten better anyway. And so I think it's hard to say there are some small randomized trials now coming out of China. There was one small study with 30 patients that showed no effect and then another one with about 60 patients that did show maybe a day's worth of difference in terms of resolution of fever and resolution of cough. But again underpowered without a placebo. So it's really hard to to say that that is a strong support for the use of this medication. What about some other antiviral treatments? Can you mention some information? Yeah so another medication that people had been thinking about was lupinevier-ratonovir which has really been used for the past 20 years or so to treat HIV. Lupinevier is a protease inhibitor which means that it inhibits that HIV protease enzyme which cleaves the long protein chain into peptides in order to assemble the viral particles. Ratonovir is also a protease inhibitor and is used to really boost the effect and the duration of the effect of lupinevier so that's not degraded in the patient. So it works well for HIV and it had been shown in animal studies to be effective against coronaviruses like MERS. However, there was a recently published randomized trial from China that showed no effect in COVID-19 although the authors cautioned that the patients they were looking at were very critically ill. About a fifth of them died in the study and so the thought was that potentially this therapy was given late in the disease course and maybe too late to really have an effect in terms of its antiviral activity. So this is also one of the four agents included in the WHO solidarity trial so again hoping for some stronger high quality data. Or maybe just timing the virus when it's replicating to administration of the drug may be much more beneficial than waiting until the virus is enacted a cytokine storm. So yeah and that you know Dr. Kulture that brings me to another therapeutic option. Tosalizumab is an IL-6 receptor inhibitor. We know that patients with severe COVID do experience something like a clinical cytokine release syndrome with elevated IL-6 levels. So the idea is that Tosalizumab would help to blunt that inflammatory response and help blunt that cytokine storm and potentially lead to better clinical outcomes. And that's really right now we've only seen anecdotal reports, case reports of good outcomes with Tosalizumab but there's really again no high quality randomized control trial yet. At our institution we do have an industry sponsored multi-center trial. We are part of that multi-center trial for Tosalizumab. What about a convalescent plasma? We have heard recently there are several institutions in the United States and one here in Houston that's actually advocating the use of this modality of treatment in patients with COVID-19. Yeah so I think that's an exciting option as well. We know that convalescent plasma was reported to have worked in a case series of five critically ill patients in China but again it's a small number of patients. I think the real challenges will be finding appropriate donors and testing to confirm that there is neutralizing activity of the plasma but that is also something that our institution is involved in now. A small convalescent plasma trial underway. So let me ask you and this might be a little bit difficult to answer but when is the most appropriate time to consider this mod of treatment early or could it work in more advanced cases or what is a current understanding when the plasma should work in the best way? Yeah so it seems to me you know looking at the different agents that we've just talked about none again none of which have really been supported by strong randomized clinical trial data but it seems to me that a specific antiviral medication would work in mild to moderate cases earlier in the disease course when you're trying to stop viral rapid viral replication and that the IL-6 inhibitors like tussilizumab or other agents that work on the IL-6 pathway would work in order to blunt that cladokine storm and that inflammatory response that happens in more severe COVID cases. For convalescent plasma we really only have anecdotal data in very critically ill patients it has not been used for mild cases and or at least I haven't seen any data on that so all we have is the scant data in very critically ill patients. But Gowan the fact that there's some pretty I mean that those five patients got much improved and they were pretty much dying so you know of all the things that I've seen so far I mean this looks the most entertaining and promising so far so I'm assuming there's a lot of logistical hurdles to find the appropriate donors but is it mechanically difficult to you know prepare the specimens in a hospital setting is it cumbersome? Yeah so that's I really depends on the capabilities of your pathology lab I think in a large academic center like ours we have some of the finest pathology departments in pathologists so you know if anyone can do it we can but it is a logistical challenge to find the appropriate donors screen the appropriate donors because you're not only when you're talking about plasma you're not only looking at one antibody there are any other antigens to consider and so and you have to be careful about other antigenic stimulation so you have to be in the right ABO blood type compatibility am I right? That's a given yeah so that as well but but really I think we're looking we're hopeful about this but it is it's something that I'm not sure I could imagine to be given in I guess to large numbers of because of the logistical challenges exactly but for those that are really sick it could be a possibility right so Gallant you mentioned already several clinical trials that are going to be started or they're ongoing at the time but let's give us a perspective and overview where we are how many trials are there ongoing currently and what are your expectations? So this was weeks ago this is a list of selected clinical trials for treating COVID-19 from weeks ago but honestly you know that number grows by the day and so it's quite exciting in addition to therapies vaccines are really what's next on the horizon and everyone is looking towards vaccines because that is really hopefully what can get us back to get us to some level of protection to allow us to really get back to how maybe our normal life used to be. Interesting so let me ask you I recently read that there this will be a challenge because and I don't know how important it is but at least at the present time they identified eight different strains of COVID-19 and so is this going to be a challenge because we have so many strains or are those strains maybe less important because there are a lot of similarities between those strains and the vaccine will cover all of them or most of them. Yeah so there are a large number of potential vaccines in development right now the last I checked there were approximately 40 or more potential vaccines in development. SARS you know some of the work really had been done years before we ever knew of the existence of SARS-CoV-2 and that work done on SARS-CoV-1 and MERS has really helped to to bolster the effort now because there is a high degree of genetic similarity between those two viruses SARS-CoV-1 and CoV-2 we know that their genomes are almost 90 percent identical and that because of that what researchers you know researchers aren't really starting from where one at this point that they're using their previous experience and be focusing the technologies that they developed before to try to potentially develop the vaccines for SARS-CoV-2 in regards to different strains we hope that it is not a virus that is mutating quickly and that really the targets I'll talk a little bit more about potential vaccine strategies but really that the targets would be conserved across those strains so that vaccines would work against against the viruses but really one major hurdle I would say that has been identified in the work on SARS-CoV-1 vaccines is this undesired immunopotentiation so an enhancement of an immune response that is a safety issue really for people receiving the vaccine I wanted to highlight a few different vaccine strategies whole virus vaccines recombinant protein subunit vaccines and then also the nucleic acid vaccines which are currently they just started in enrolling patients in a phase one clinical trial for that for the last one so whole virus vaccines are really the classic strategy for vaccines and when we think about viruses the live attenuated or inactivated whole virus and really the major advantage is that you know that the whole virus tends to be very immunogenic so it will give you that immune response it has an inherent ability to stimulate that immune response in the toll receptors that are necessary to recognize those viral pathogens but really it's important to make sure that these vaccines are safe because we do know that live vaccines you know they're we do know that we have to make sure that they're safe for use before they're approved so it potentially could take longer to go through the process of clinical trials and safety trials to make sure that we have that data to support it then recombinant protein subunit vaccines are something that our institution is working hard on and the idea is to elicit an immune response against that spike protein which is the protein that binds to that ACE2 receptor on the human tissue cell membrane and it prevents it would potentially prevent docking with that ACE2 receptor in lung epithelial cells and so in that situation that you would have high levels of protective immunity but that you would be minimizing that immuno potentiation that I was talking about earlier that immune enhancement issue that could cause a safety problem so this is work that's been led by the Texas Children's Hospital Center for Vaccine Development the National School of Tropical Medicine at Baylor College of Medicine along with UTMD and the New York Blood Center but and Dr. Hotez's group of course that has been working on this and then finally the nucleic acid vaccines are promising they've entered now phase one clinical trials with 45 healthy volunteers in the Seattle area so they this really highlights the rapidity with which vaccines are being developed so the company that produces vaccines sequenced the the virus genome about two months ago and then already has a vaccine in trials so the because of the pandemic they really pushed vaccine development through quickly and that's good in some ways because we know it is obviously a time sensitive issue but then we do have to think about the the drawbacks being that we have to be very careful about safety data and and think about whether these vaccines are safe in humans so this is just a table from an overview of the vaccine pipelines put out by our group with Dr. Hotez and Dr. Hotez at the National School of Tropical Medicine at Baylor but it highlights just some of the top candidates for coronavirus vaccines but really I think that's the you know right now there's there's many more this list is not exhaustive or complete in any way but it really highlights that there are a lot of public and private partnerships at work to produce these vaccines that each vaccine strategy here has different advantages and disadvantages and really only time will tell you know which one of these ends up being shown to be safe and efficacious and moving on to actually be used for prevention of COVID-19. It's interesting I heard that there are private foundations for example the Gates Foundation which is moving forward in terms of production capabilities and factories for multiple vaccine strategies and multiple vaccine products. It concomitantly while these are being developed in order to try to facilitate the production of whichever vaccine ends up meeting approval standards. How long are we taking how long do you think it is before a vaccine would be ready to be implemented in a population? Dr. Fauci has cited 12 to 18 months. I think that he and many others would likely say that that is an optimistic estimate but at the same time having said that I've also never heard of a vaccine moving to clinical trials within two months of having the viral genome sequence. So that is already a record and so I think we are moving things more rapidly than we have ever before. It's amazing how a little bitty single-strand RNA virus can hold the world completely hostage. At this point whoever comes up with the strategy is going to hit a massive home run for mankind but they're financials so I could see why you would double down on whatever potential sources there and hope for the best so we're going to hope for them all because otherwise we're in for a very long run. So Gallant I have one of the important questions before we complete with this program close to if not over 60 physicians in Italy died on the front treating patients with COVID-19 and of course there are a lot of physicians that are on the front lines that are exposed to COVID-19 on daily basis particularly emergency room physicians and I have seen among those that died abroad and also in the United States the largest number among emergency room physicians they're gynecologists they're urologists but they're basically and nurses of course a lot of a lot of a paramedical personnel as well that's in direct contact with COVID-19 exposed or disease patient. So do you think that from your professional point of view the viral load and repetitive viral load plays a significant importance as far as the severity of the disease because we see that a lot of those individuals that were on front lines that died were not old they were young some of them were very young so what is your opinion on it from the infectious disease point of view? Yeah so I do think that the inoculum effect is something that may be playing a role so the idea that a higher inoculum of virus potentially can lead to more severe disease but you know that is I think for a lot of the front line healthcare workers that's the main concern not the minni-fuel amount on your you know grocery bags that you accidentally touch one time but really that you are in for example an ICU where a large number of ventilated patients with aerosolizing viral particles who are very sick themselves and potentially have high viral loads themselves right so ICU physicians ED physicians and staff nursing staff of course who are exposed to those COVID patients are really exposed to much higher viral loads than the average person walking around outside of you know in the community so that inoculum effect that you're speaking about you think is something that is real and unfortunately something that hit close to home for us yeah interesting so that is very important and I believe that we all share the view that proper PPEs should be used in individuals medical personnel and physicians that are exposed to most type of patients absolutely and you know that's really what's worrisome is hearing some of the accounts from front line you know from the front lines in areas that have been hard to hit by the pandemic is hearing about the lack of PPE um we are in we are using conservation PPE conservation strategies in our own institution but we have fortunately thus far not experienced the overwhelming volume that some of the other areas in our country in the world have experienced and so um you know I think that absolutely it's very uh worrisome and disturbing to hear about physicians and nurses and other staff who don't have access to the appropriate PPE when they're really in the um really on the front lines and in those areas with the with the highest enough going interesting I think those are really have any questions uh before we complete the program no but I'm really appreciative Gallin of your your intellect and your knowledge of this subject and you've educated the cardiology community quite a lot I'm hopeful that the warm weather and the moist weather that's about to return to Houston affords us some protection I can't believe I'm saying that being a lifelong Texan basically that I'm looking forward to the warm and smuggy air that we're so famous for but do you think that the warm air has any benefit to us down here I think we're still out on that question um there has been uh evidence that uh this virus does just fine in uh warm uh and humid climates but I think that um hopefully that uh you know time will tell um there are mitigation measures will uh start to work around the same time that that warm weather is uh ramping up and maybe the combination of multiple factors uh can hopefully uh bring this epidemic under control but you know nothing replaces the mitigation measures that our public health officials are recommending um social distancing and uh what we're doing now talking over uh zoom is um all of it I think it contributes uh to hopefully flattening that curve and and making sure that our epidemic uh does not overwhelm our healthcare system and uh hopefully you know I I can say comes to an end but when from what I've seen of viruses it they never truly end uh they just they give us a little break maybe um and uh you know we'll we'll be around for the next battle hopefully thank you again gallant appreciate it so much thank you gallant and uh thank you stephanie for your very valuable contribution to the texas heart institute program on treatment testing and vaccine the time of COVID-19 and then thank you all thank you so much for having me