COVID-19: What We Have Learned and Still Need to Discover

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Dan Simon, MD: Hello everyone. My name is Dr. Daniel Simon. I am your host of the Science@UH podcast sponsored by the University Hospitals Research and Education Institute. This podcast series feature University Hospitals’ cutting edge research and innovations. Thank you for listening to another episode. Today, I am happy to be joined by Dr. Grace McComsey, Vice President of Research and Associate Chief Scientific Officer at University Hospitals. Dr. McComsey is also the principal investigator of the Case Western Reserve University, CTSC [Clinical & Translational Science Unit]. She is here today to talk about her latest research findings in the area of Covid-19. Welcome, Grace.

Dr. Grace McComsey: Thank you, Dan. Good to be with you today.

Dan Simon, MD: Grace, you are known internationally as an infectious disease expert related to cardiovascular and metabolic complications of HIV. Can you share with us your career journey? What inspires you to be a physician scientist, and how did you choose to study infectious disease as your main research focus?

Dr. Grace McComsey: Yeah, actually, interestingly I was born in Lebanon. You can tell from my accent, I'm sure. Over there I always wanted to be an engineer. In fact, I submitted to the engineering school, got accepted, everything was ready for me, and then I changed my mind, a lot of pressure from my parents. They wanted me to be a doctor and I was 17 then. This is when you go to med school in Lebanon, you decide at 17 and I went for it. And now honestly, I don't regret it.

So I was in med school, I knew I liked it very quickly and, interestingly, every time I got to the clinical side and did infectious disease, I was fascinated with it because you look at the entire patient, you look at every organ instead of looking at a specific organ. So I was very fascinated with it.

I came in to the United States because my mentor in Lebanon, who made me actually so passionate about I.D. [Infectious Disease], had trained in the United States. So I came in to train in I.D. I wanted to see kids and adults, didn't know what to do, found that there is a Med-Peds, Medicine Pediatrics.

So this is how I ended up with Med-Peds and I knew before residency that I wanted to be in infectious disease so I did that kind of in reverse. I knew my fellowship before I knew what residency I wanted to be, and I think now I made the exact good choice for me because I love it.

Dan Simon, MD: Well, you know, it's interesting. You've seen really an absolute transformation in the care of patients with HIV. I remember when I was an intern and medical student, actually in 1985, taking care of the very first patients with HIV who all obviously passed away for an opportunistic infections. Now, I guess you would say it's we've converted into a chronic disease living with HIV and that really is your area, because now we have cardiovascular and metabolic complications. Can you tell us a little bit about that? What did your, what were your research discoveries in the past decade?

Dr. Grace McComsey: Yeah, so HIV is fascinating and you're right, when I was training, it was kind of the tail end of people dying from HIV. But I do recall having an entire floor, all HIV patients and my worst months on service, I was in pediatric infectious disease. I was a fellow. We lost five kids from HIV. But I think this is what made me so attracted and passionate about that area…so I decided during fellowship that I'm going to make HIV my career, and I started doing research. Initially, when I started my research, people were living, we had good cocktails. It wasn't the most convenient, but at least people were alive. And then we started seeing that there is something called lipodystrophy, where people, fat well made them look bad, made it a stigma issue because I would go on the street and I can tell you who has HIV just from the way they look. So this is awful to live with. And then we started to realize looking at some cardiovascular complications that this excess fat, that's maldistributed. So they would have significant amount of visceral fat in their abdomen, but their arms and leg look very thin as well as their face. So the face and limbs look like they're malnourished, but then they have a huge abdomen. So that's what we call lipodystrophy.

Then we started to see diabetes and cardiovascular disease. So one of my prior, my first two NIH grants were looking at mitochondrial toxicity. And in fact, my work found that there were significant subcutaneous fat mitochondrial toxicity, which was directly linked to why they were losing fat in the limbs. So my work actually connected it to different HIV drugs that now we don't use.

And we started to see less and less lipoatrophy. The ectopic issue, unfortunately, with HIV, the reason I still do this area after more than a decade and a half is because we went from lipoatrophy to people straight, having weight gain. We were talking a lot of weight gain more than the general population. And that weight is all in the places that fat shouldn't be there, and the liver and the pancreas and the visceral fat. So now we're seeing a lot of diabetes. We're seeing a lot of cardiovascular disease.

This area is booming now because our patients are living a long life. The only thing that's making them die earlier are these complications. Cardiovascular disease being number one.

So it's still very pertinent area that continues to be very interesting and there's always a lot to do so. So it went from lipodystrophy to plain weight gain and ectopic fat accumulation.

Dan Simon, MD: Wow, that's an amazing story. And of course, as a cardiologist I can tell you it always comes back to the heart. We like to think it's the most important organ.

So Grace, let's transition for a second, and obviously, since the beginning of the pandemic in March of 2020 the, UH Clinical Research Center under your leadership, has really played a critical role leading Covid-19 related clinical trials of vaccines, antivirals, and anti-inflammatories, really to bring a range of options for our patients..for both the prevention and the treatments of the disease as well as its complications. The pandemic has been going on now for, two and a half years. What have you learned about Covid and what still remains unknown from your perspective.

Dr. Grace McComsey: Yeah, it was amazing actually when the pandemic came in, resource centers took one of two attitudes, either, yeah, we're, we're research, we're not clinical, so go home, work virtual or some people like us were very aggressive and said this is the time where research will shine if we're aggressive and do a good job.

So from day one we were able to get the first interventional studies. Starting with Remdesivir as the antiviral… with all the initial vaccine studies. So we were, were very aggressive even contacting sponsors and, saying, we do want to do your studies…and not only Covid studies, we didn't forget about the other diseases that could still kill people during Covid.

So cancer is an example. We never shut down our cancer unit in fact, we had people from 10 different states come in during the Covid pandemic for cancer studies because their cancer units had closed, at least the research part. So we were really happy that we were able to preserve the important interventional non-Covid studies at the same time that we were able to do some of the most important studies.

We built a biorepository that has more than 25,000 specimens. That's very important because it's so hard to be able to collect specimens, even blood on patients with Covid, everybody was scared of them, nobody wanted to get Covid early on so we built this biorepository and collected samples so that investigators can get grants and can use them for preliminary studies. And it helped, I would say about at least 50 different grants, and we had a lot of studies come out… and as well as some of the interventional studies that we did, for example, one that I led It's called upamostat. It's a, serum inhibitor, a protease inhibitor that we found actually very good success with. It's now under minor revision, it's almost accepted. And it's really interesting that the repurposing of drugs turned out to be a very good thing. This is a drug that we use for cancers for other reasons. It's an oral drug, easy to use, not toxic. So we tried it and UH was at the forefront of that upamostat study. We enrolled the most and I was the main academic lead. So we're going to publish that.

And with some other interesting studies that people don't even think about, we found that there is a vitamin called vitamin K2 that is notorious actually for being like lacking from American diet. So Americans actually, unlike Europeans, don't take vitamin K2 and it's lacking from our bad diet. So what happened is most of us, about 75% of Americans have K2 deficiency. So we found, and it was replicated by two other European groups, that having poor vitamin K2 at presentation with Covid independently predicted your outcome. So that was one of the studies that we did that came out of that and was published. So we tried to do a lot of studies. We did one with zinc deficiency as well as we did multiomic studies. So we went from kind of the most simpler but clinically relevant to some of the very sophisticated, very complicated studies trying to find predictors of Covid.

And interestingly at the start we were thinking about acute Covid, right? We just wanted people to survive it. We never thought initially that that's going to be a much bigger problem, the follow up of these people. But the biorepository had followed people for up to a year, which became very, very important in our future investigations of long Covid.

Dan Simon, MD: Grace, I think one of the things, you know, congratulations to you and your team. You displayed an agility and a nimbleness during Covid, which, was one of the reasons for your success in doing over 300 Covid related research studies. As you pointed out, you were pushing the envelope for video consent, video follow up, and of course, the rest of the industry, so to speak, followed because it was the only way that we could, really do these studies.

I think that, you had over 175 people enroll, in the Pfizer vaccine trial alone and one of the things that University Hospitals brought was a great population of diversity to the vaccine trial. And that was very important, obviously to manufacturers to make sure that all Americans were enrolled in the trial.

So last year you received a very, very large grant from NIH. Over 17 million dollars establishing a large northeast Ohio cohort named NEOCURE that seeks to understand why some people have prolonged symptoms, what we call now long Covid or developed new or recurring symptoms after the acute phase of Covid infection.

NEOCURE is part of the NIH researching Covid to enhance RECOVER Initiative. Can you tell us a little bit about this? We know now that 10 to 15% of men, 20 to 30% of women have persistent symptoms after 30 days and as you pointed out, that means there are millions and millions of Americans with long Covid. What exactly is it and what are you trying to do and discover?

Dr. Grace McComsey: Sure, so RECOVER is an initiative, very interesting initiative actually, came from the Congress realizing that there are a lot of Americans now on disability because of this long Covid. So they knew something was wrong and they needed to put money into an initiative that brings the whole country together to investigate this new problem.

In my opinion, this is the new pandemic, actually, people are not scared of acute Covid anymore, but they're really scared of having long Covid. So they gave 1.2 billion dollar and it started this huge initiative called RECOVER it's Trans-NIH Institute. And they selected 15 hubs nationally to be the adult cohort and we are one of 15 in the nation. Lucky for us, we were along with Chicago, the only Midwest and the only site in Ohio. So we're really proud of that to bring it to our community.

So what it is, is RECOVER one, phase one, is the one that you are referring to. We're collecting and following people for four years after either their acute infection, so a large proportion of patients are followed from the start, from their acute Covid infection…as well as some of them after they had long Covid.

So the idea is to build this huge infrastructure of not only blood and biologic specimen, but a lot of clinical data as well as a central biorepository that will be used by the PIs of RECOVER for a lot of studies, as you can imagine, we still don't know the mechanism of these symptoms that people have. And I would say more interesting and more concerning that the persistent symptoms that people have are these new health conditions like diabetes that are happening after Covid. So whether in adults or kids, diabetes is being recognized as something that's frequently triggered by Covid. So a lot of people in fact, we looked at that in a large global network called TriNetX a paper under review now that showed that the incidents after Covid was much higher than the incidents after flu, for example. So people who say, well, during an infection, you get a lot of stress, Covid time was very stressful. Maybe that's why it's triggering diabetes. It's not just that, even compared to other viral illnesses, compared to the background population at the same time who lived through the Covid pandemic, there is something that seemed to trigger diabetes in patients after Covid and sadly not even the serious Covid. So when people have mild Covid they could still be at risk for long Covid and even asymptomatic.

There have been people who just had a test because they were having a procedure. They knew they had Covid, but they never felt anything and still developed diabetes or developed persistent symptoms that came, I shouldn't say persistent because the symptoms are new after Covid. So the Covid, the acute phase recovered, they didn't feel it and then a months or two later they started to have very, very severe symptoms of long Covid. So it's real, it's not, a reason to get disability. Like some people made it, political. It's people who just want to get disability and sit home. It is as real as it could be for a syndrome.

Dan Simon, MD: Grace, I think one of the things that we think about obviously are the shortness of breath and persistent cough. But there are a lot of very, very other troublesome long Covid problems. And those of course include brain fog, a troubling increase in heart attack and stroke, 50 to a 100 % increase, 100 to a 200% increase in blood clots in the legs and pulmonary emboli or blood clots to the lungs.

And so this has really, led us, I think and many other investigators to be concerned that there is really widespread in ongoing inflammation that's playing a role in this process. You and I talked just this week, a very important study, not yet published, but the pre-print has been released from The Veteran Affairs system of, 10,000 people with long Covid compared to 40 over 42,000 without. And it appears that the treatment with Paxlovid not only reduces long Covid but importantly reduces re-hospitalization and death following Covid in follow up out to 6 to 12 months. So, I guess the disappointing thing is we don't have any proven therapies for long Covid. Where do you think that's sitting right now?

Dr. Grace McComsey: Yeah, well at sitting with RECOVER actually we're about to start phase two of RECOVER and one of the first agents that we are going to try and there is a protocol already that's almost finalized is Paxlovid. So I think antivirals make sense because more and more we have evidence of persistent virus, whether in autopsy tissues of people who died…after Covid and some of them died not because of Covid, just after Covid several months, nine months after, they found some virus hidden in different reservoirs. And the Harvard group actually recently published a very interesting study showing circulating levels of spike protein as, as long as 12 months after the infection and those level of protein in the blood correlated with symptoms so they're meaningful clinically.

So this is why antivirals, I think, make a lot of sense. The only difference is, you can't just give five days. Everybody think it's very short. So five days, as you know, this is what we give for acute infections. So for long Covid, we are going to give 15 days because that's as long as Pfizer have safety data on. And then we'll see what happened. But there are a lot of interventional studies that will common immunomodulators, as you mentioned, I know my group and others have data on bunch of circulated cytokines that are very increased TNF receptor 12IL6, I mean you name it. Actually, they're all increased in people with Pax and interestingly, they correlate with symptoms. Even people who are more symptomatic than others have higher levels than the past, than the milder past. So they definitely mean something but we'll see what happen if you try to block inflammation. Right? Is the inflammation really just the last phase kind of and you may not be able to change that by just giving immunomodulators.

Another thing just I want to mention is more and more data, including data we have is showing that the gut has a lot to do with Pax. If you take people with Pax, they have increased markers of gut permeability, of alteration in gut and of microbial translocation, whether it's bacterial or fungal. So the gut actually, like HIV, interestingly, long Covid is turning out to be a gut dysfunction leading to microbial translocation leading to increase inflammation. So in the short time, I would say there's a lot that we learned, but there's a lot more to.

Dan Simon, MD: So Grace, let me ask you this. If you're a patient with Long Covid and Dr. David Rosenberg runs a multidisciplinary long Covid clinic at Ahuja, which is booking appointments out three to six months. I mean, we're just flooded. We have neurologists, rheumatologists, psychologists, behavioral health specialists, I mean, it's really a, team effort infectious disease experts, of course, pulmonologists, all focused on these patients. If you are a patient, how do you get into one of these trials? Do they contact recover sites? How exactly could they reach out to you?

Dr. Grace McComsey: Yeah, we, built actually locally, UH, is the number one enrolling site currently in the nation. We're the second enrolling hub because we have MetroHealth with us enrolling. But the first site, and the reason is we built a lot of campaign whether through, UH, social media, just so people understand that Ohio does have a site. And I can tell you that we have close to 900 patients now only from, UH, and we have patients from West Virginia, from Michigan, from Pennsylvania. It is amazing how long people are willing to drive to be on the study because not only they want to help science, they want to know why they have these symptoms.

If somebody comes with exercise intolerance or shortness of breath, while we do a lot of different tests, whether it's cardiac MRI, CT chest, pulmonary function tests, we have a lot of tests within the RECOVER because we do want to define phenotypes, not just by self-report of symptoms. So, I think we're going to learn like an enormous amount because we'll be able to match some mechanistic studies with some clinical phenotypes that are defined not only by self-report of symptoms but by real objective tests that we're doing within RECOVER. So people are contacting us from, everywhere. It's very easy to reach us. Actually at UH, if you go to the UH main page actually scroll down to research. You will find long Covid, or you can just search, put in the search either my name or you can put RECOVER or long Covid, you will get to the study. And we're happy that, they gave us actually more slots than initially planned because we did so well. So we still have couple hundred slots available.

Dan Simon, MD: Well, that's really terrific. Thank you so much for taking time to speak with us today. Grace, this has been really very inspiring to me. For our listeners interested in learning more about research at University Hospitals, please visit uhhospitals.org. Thank you very much.

Dr. Grace McComsey: Thank you.