Drs Alfred Kim and Leonard Calabrese on Long COVID Among Immunosuppressed Patients

In this podcast, Alfred Kim, MD, PhD, and Leonard Calabrese, DO, provide updates on the rapidly changing dynamics of long COVID. They also discuss current strategies in managing the lingering effects after COVID-19 infection among the immunosuppressed population.

Leonard Calabrese, DO, is vice chairman of the Department of Rheumatic and Immunologic Diseases and head of the Section of Clinical Immunology at the Cleveland Clinic Foundation in Cleveland, Ohio. Alfred H. Kim, MD, PhD, is an assistant professor, Division of Rheumatology, School of Medicine, at Washington University in St. Louis. There, he is the founder and director of the Lupus Clinic.

--

TRANSCRIPT:

Al Kim:
Hello, everyone. My name's Al Kim. I'm an adult rheumatologist at Barnes Jewish Hospital in St. Louis, Missouri, where I'm also on faculty at Washington University School of Medicine. I direct the Lupus Center here. And today we have the honor of having a guest that we've had before here, Dr. Len Calabrese. Len, do you mind introducing yourself?

Dr. Len Calabrese:
I'm a clinical immunologist and rheumatologist with an appointment in infectious disease. I run an immunology center at the Cleveland Clinic. Al, nice to be with you.

Al Kim:
Yeah, the pleasure is all mine, Len. Today we're going to be covering two relatively broad and obviously dynamic topics. One is going to be updates on long Covid, a space that has been very rapidly growing due to some recent research done by numerous groups internationally. Then we're going to pivot over to current strategies to be able to manage Covid in our immunosuppressed populations.
Let's start off with long Covid. There's been clearer definitions clinically about what long Covid is. And so, I know, Len, you've been writing about this profusely, trying to be the voice of reason for many people. Can you give us what your impressions are right now of what long Covid is and how do we recognize it?

Dr. Len Calabrese:
Well, thank you, Al. I would say to start out that it is still a highly contentious area, and that long Covid falls under the overall umbrella of a sequelae, which is some event that is a consequence of a previous event. That previous event is having being infected with SARS-CoV-2 and experiencing COVID-19 illness. And then it starts to get a little looser as to what constitutes normal recovery, because that's what we aspire to, right? You have this illness. You're sick for days or a week or weeks. And then at some point in time it becomes out of the two standard deviations of what we think that recovery from a respiratory virus should be.

These states of health that are either new and onset or previously exacerbated then fall into two large categories. One, are these pathologically defined events? I had COVID-19, three months ago. I had an MI 13 weeks from now. Is that a sequelae or is it part of life's journey? So those are pathologically defined. We put them over here. The far larger group that everyone is most interested in focusing on are those conditions, which we use the rubric, not pathologically defined. That's really not a fair assessment of them, but they're far less well understood.

And these are patients that following COVID-19, either developed new onset or have persistent fatigueability, often with post-exertional features, neurocognitive complaints, pain that can be diffuse, sleep disturbances and a number of other conditions. This is where the intense focus is, in trying to define it. Yet at the same time, while most people are setting the benchmark at three months for the onset of it, we don't really have universally accepted classification criteria like we have for so many conditions in RA. So, you might be studying the people with neurocognitive complaints. I might be studying the people with diffuse somatic pain. Are they the same thing or are they not? So, that's where we're at. What's your take?

Al Kim:
Yeah. I agree, but I do think that at least in terms of what's been published in the literature, we don't obviously have the classification criteria that you have mentioned before. But people have taken a broad based approach in terms of being able to at least report outcomes in various groups, immunosuppressed, non-immunosuppressed, et cetera, in order to be able to be as inclusive as possible, with the hopes that we can better define specific features, right, that are going to be more attributable to the sequelae.

I'm just looking at the CDC website on long Covid or post-Covid conditions. They literally have a heading that says Symptoms That are Hard to Explain and Manage, which is a huge source of frustration for a lot of the patients that are going on social media to describe their experiences. If you look on Twitter for example, there are ample descriptions of patients extremely frustrated with the inability for the system to really help them out. I think at ACR, Len, you brought up a really important point. We really have to be deep empaths. We have to be listening to these patients. The second we don't validate their experience poor things ensue. Could you expand on that a little bit more? Because I think what you said at ACR was very, very poignant.

Dr. Len Calabrese:
Thank you for the comment. I phrased this because despite this being contentious, of what is under the umbrella and what is not under the umbrella, the person in the room at a healthcare encounter that counts is the patient and it's the patient's voice. Regardless of what we know or don't know about immunopathogenesis, it's they who are suffering. So, I think it's important to treat them as we would want to be treated, to be validated, to be heard. Also, to be candid that we're in the process of trying to understand this and that we can provide guidance and a path ahead without totally understanding this or having any approved treatments for this.
So, empathy is a paramount, particularly when there is such uncertainty that surrounds this condition. On social media, this is very contentious. And people that even intimate that there is a psychological component pilloried for this. And at the same time, there's strong evidence that there is a neuropathologic basis for much of this.

Al Kim:
True.

Dr. Len Calabrese:
Functional imaging, deep profiling of CSF and examinations of tissues. So I think that we're learning a lot about many unexplained sequelae, post-infectious sequelae and that is a positive.

People have been complaining about MECFS from a myriad of infectious conditions for decades and decades. Very unheard in terms of their own voice. And now they're being validated. And that's where the future is. The other thing I just segue, because we could talk about this forever, is that the other very hot area now is trying to look at these discreet areas of pathogenesis. And the observation that autoimmunity ensues after Covid-19 is incontrovertible. Whether it's the driver of the bus or the passenger in the bus, we don't know.
The fact that there are orthogonal data that suggests that for many, persistence of viral elements, whether that's from productive infection or some other mechanism that we don't yet understand. And then, this emerging area of micro clots that everyone is talking about. You can see with the naked eye and are now being quantified by more standard techniques like flow. As always, Alfred North Whitehead said, "Seek simplicity but distrust it." So we have all these pathogenic mechanisms, plus microbiome dysfunction that persists for years. Is that responsible for everything or maybe one tiny thing in this? And this is where the heavy lifting is coming.

Al Kim:
Yeah. As terrible as Covid's been for everyone, the few glimmers of hope is going to be the ability for us to be able to have samples pre and post-Covid, longitudinally for years, is going to be incredibly valuable for multiple disease processes.

You previously mentioned an immunologic signature of Covid is going to be autoimmunity. You're obviously referring to a substantial amount of incredible work by Ignacio Sanz, who is the Chief of Rheumatology down at Emory and a B-cell Biologist extraordinaire, who has shown that there's a B-cell activation pathway called the extrafollicular pathway that is the genesis of a lot of the autoantibodies that are observed in people with COVID-19.

And interestingly enough, it is this pathway that generates autoreactive B-cells, there's eventually making autoantibodies in lupus, right?

And I think the question I have in that particular space is going to be, will the extrafollicular pathway kind of predominance in Covid be as durable as something like observed in lupus?
Because if it is, there are lessons learned in terms of how mechanistically this occurs. The data from Georg Schett with the CAR T-cells in lupus targeting CD19 where auto-antibodies that don't go away with standard [inaudible 00:09:09] therapies are going away indicates that this could potentially be reset.

Dr. Len Calabrese:
Yeah.

Al Kim:
And so I think there's going to be really interesting 2, 3, 4 year data about the durability of both serologic autoimmunity, but that could translate to clinical autoimmunity that's going to be incredibly helpful for rheumatologists downstream.

Dr. Len Calabrese:
Just a final comment countervailing to that is from a very interesting work by PJ Utz and the Stanford group showing that the development of autoimmunity and the signature of autoimmunity is not unique to Covid-19 and can be seen not only after other respiratory and non-respiratory infections, but also after critical illness. And so an autoimmune response that we're getting this totally different glimpse of right now we're used to seeing patients with an autoimmune disease and then looking for autoantibodies. These are people that have had insults to many, at least to me it suggests that an autoimmune response, this auto anti- [inaudible 00:10:140 type of response may be part of a network of homeostatic regulation that we have yet to even start to figure out. So are those auto-antibodies causing this? I don't know. There are some evidence very recent in the last month I think it's PLOS One article showing a fading of the auto-antibody response at one year. So anyway, we'll come back in three months and we'll have a totally different story.

Al Kim:
Right, exactly. This is just relevant for February 2023 that these comments are being made today. So I guess let's pivot to the impact of long Covid or, or even kind of the risk factors of long Covid in patients with rheumatic diseases. The state literature that are starting to emerge. I think some of the best one is coming from the Mass Gen Brigham effort by Jeff Sparks and Zach Wallace and their entire extraordinary group there. They published the late November and Annals Rheumatic Disease looking at the impact of vaccination and the acquisition of long Covid or the other term would be post-acute sequelae of Covid-19. And it does appear that people who are fully vaccinated, although it's not 100%, there's definitely a strong trend to having reduced acquisition of long Covid in these people, which is I think consistent with the observations made in the immunocompetent population also. There are some data also with the use of antivirals as associating with reduced acquisition long Covid. Although I'm not sure. I don't know if you've seen any literature in the immunosuppressed population regarding this.

Dr. Len Calabrese:
With you on all of these that early and aggressive therapy has also been shown in other observational cohort analysis, and there are also data from non-immunosuppressive vaccines of protective effect. And there's also some epidemiologic evidence that this is probably going to be less impactful in the Omicron era versus pre-Omicron variants. Having said that, all of these studies are observational, and you have to look at it looking for more robust data to demonstrate that. But not getting infected, having a mild infection, being treated early on, I'm all for it.

Al Kim:
I think this is actually a good way to segue into the current strategies of managing Covid in the immunosuppressed population. We continue to see issues in our own system, particularly with B cell depleted patients and those in a substantial burden of immunosuppressive therapies. We are seeing them somewhat disproportionately represented in hospitalized Covid patients at Barnes.

And I'm sure you're seeing similar observations in Cleveland. The arsenal that we have has changed a bit, and that one change in particular has been quite dramatic in terms of the use of monoclonal antibodies, both for pre-exposure prophylaxis but also post-exposure prophylaxis. It's pretty clear that the newer variants that have emerged, the Omicron subvariants that are really immune evasive variants have really caused problems for the current monoclonal arsenal. You've obviously have published very nice observations pre late Omicron stage of the use of products like Tixagevimab/cilgavimab known as Evusheld in these populations. If you don't mind just at least from a proof of principle that this PrEP or preexposure prophylaxis with monoclonal antibodies is effective. Do you just mind sharing some of the experiences you've had at Cleveland Clinic?

Dr. Len Calabrese:
Sure. Back this all up. Monoclonal antibodies were a very prominent part of our armamentarium, not only for treatment in patients, particularly those that can't mount humeral immune responses, both early treatment and also some data in patients with advanced disease, but ultimately went through phases of post-exposure prophylaxis. For a time we had activity that could prevent progression in people who were exposed. And then gleefully, we saw the introduction of pre-exposure prophylaxis, particularly designed as you point out for those people who can't respond to vaccines. And I'll just add, I think we've done a lot to understand who is really immunocompromised. And we're very actually pleased and we love to talk to our patients that people on a single biologic monotherapy, if it's not a B-cell depleting agent, these people are doing quite well with this, and people on low dose methotrexate and beyond. But those people who are on high dose immunosuppression, B-cell depleting agents, this was a tremendous comfort to them.

It was a highly effective form of prevention. And then add to that, all the oncology patients, primary immunodeficiency patients, transplant patients, et cetera, and not surprisingly understanding what viruses do in a Darwinian fashion, they escape from pressure of the integrated immune response. And a monoclonal is really a one trick pony. Its paratope is just directed at one single thing, and Omicron nearly a third of the T-cell epitopes are mutated. Nearly a third of the B-cell epitopes are mutated. So we don't have one now, but they're new ones on the way. And I'm going to throw this at you. The technology is there to produce these very rapidly. But these clinical trials, as we've discussed in other settings, are kind of insufferable right now. It can take a long time and a lot of people are going to pay a price for this.

Al Kim:
Yeah.

Dr. Len Calabrese:
You want to embellish on that?

Al Kim:
Yeah. So we're not in the business of pissing off the FDA, but the thing is that I agree with you is that I think some of the audience will know AstraZeneca is developing an Evusheld 2.0, so to speak. The antibody that's going to be the thing that is going to be likely effective in the current environment today, February 2023. It doesn't actually have a name name, it has a code AZD1061. But it can neutralize all the newer variants, the BA.4.6, BQ.1.1, BXX and it's subvariants. But the issue here is that a trial is needed to be able to demonstrate safety and so it's called supernova. We are for full disclosure of sites for this and we're trying to rapidly get the contracts and then regulatory stuff in line so we can recruit people. But this takes time, right?

And the issue then becomes by the time data is ready to be presented to the FDA at whatever time point that may be, is the relevance of Evusheld 2.0 going to be irrelevant, right? Has the virus then found a secondary escape from current immune responses? And I think we have to anticipate that, right? The BXX for example, that subvariant came from Singapore, which was 90% double vaccinated. And again, that's double vaccinated to common variant. We definitely diversify our antibody repertoire to be able to try to anticipate other variants.

But nevertheless, the real issue here is that the virus does have that capacity to be able to find weaknesses in adaptive immunity through our vaccination approaches and try to survive through those new channels. Unfortunately, more and more people are going to be infected by these new variants, or potentially more fortunately they're going to be boosted by the bivalent or certainly the BA.5 vaccines. Then we're going to have increasing pressure on the virus to try to evade those responses, right? And it's going to be interesting to see in retrospect whether or not the strategies that we have right now to really protect the public from harm. Is it the right way of doing it in a particularly vulnerable situation for an important population of our patients? It's a discussion that's going to be intense.

Dr. Len Calabrese:
Yeah. And the sub rosa is that we have the technology to appraise the neutralization capacity ex vivo very well. It's very standardized. And the antibody itself, the framework is virtually the same. It's just the idiotypic areas that are governed by that that have changed. So anyway, we'll say some months from now we'll be seeing something new hopefully to protect these patients. Let me ask you, a lot has been said here about who warrants antiviral therapy. We have several antivirals available to us. Several more look like they're in late stage development. They seem to be highly underutilized, at least based on national data with a lot of social determinants of health playing a role in this. In a practice of rheumatologists, immunologists who take care of immunocompromised patients, who are high on your list to get this and who are plus minus or how do you make those decisions?

Al Kim:
So it's a very complicated nuanced topic as you brought up before because disparities play a major role in the utilization of a lot of the antivirals. I think a blanket statement that antivirals are effective still remains in effect. I think we're very fortunate that SARS CoV-2 does not have the RNA polymerase has proofreading capacity, so it can't mutate as quickly as other viruses and try to evade antiviral pharmaceutical intervention. But we have had continuing trouble, particularly with our lupus patients who are predominantly minority, and at least in our center, about 40% of them live in the 30% most vulnerable neighborhoods using the social vulnerability index by the CDC. And we've had trouble accessing that population whenever they feel like they're sick with Covid. We don't understand those root causes. On the other hand, for the patients who have have better access, we have been using antivirals pretty freely, not just in the most vulnerable, the B-cell depleted people in cyclophosphamide, let's say mycophenolate high-dose prednisone.

We've been using it much more liberally in these people. And generally I think a lot of these people do quite well afterwards with a pocket full. And I can't tell you a specific number that do have rebound, and we've talked about this before, Len, about where the hell is the virus harboring itself that eludes both innate, the immune responses generated, and of course in some of the more immunosuppressed people, who knows what immune responses they have. But certainly the antivirals aren't accessing these niches. And I'm fascinated by where these are. But overall, I think if you took a population level look at this, antivirals still have a major role to play in attenuating both disease severity, symptom duration, and certainly potentially as data will come out hopefully long Covid.

Dr. Len Calabrese:
I hope so too. And I think that the time will tell. The issue of rebound has been now well-documented, but now we're also seeing that even in the course of natural infection resolution, a somewhat similar size of population clears virus and then rebound. So we've got a lot to understand about this. I think we'll be talking about this for quite a while.

Al Kim:
Yeah, so this is just a chapter in a multi-volume story on the impact of Covid on our patients with rheumatic diseases on immunosuppression. So with that, Len, obviously wonderful to chat with you.

Al Kim:
These discussions always remind us of where we need to go in terms of research in the future and improving overall care for our rheumatic disease patients. So with that, I'll wrap up here. Again, my name is Al Kim, and again, thank you Len, and I hope everyone has a great day. Take care.