Leonard Calabrese, DO, on the Nosology of Long COVID
Dr Leonard Calabrese discusses the similarities and differences of fibromyalgia, chronic fatigue syndrome, and long COVID, and why classifying these diseases properly is important to accurate diagnosis and effective treatment.
Leonard Calabrese, DO, is the director of RJ Fasenmyer Center for Clinical Immunology and a professor of medicine at Cleveland Clinic in Cleveland, Ohio.
Welcome to this podcast from the Rheumatology and Arthritis Learning Network. I'm your host, Rebecca Mashaw, and I'm delighted to be here today with Dr. Leonard Calabrese, who is a professor of medicine and director of the RJ Fasenmyer Center for Immunology at Cleveland Clinic. He's going to talk to us about a piece he and Dr. Philip Mease cooperated on, speaking about the need to revise the noseology of Long COVID. So let's start with that.
Would you define noseology for us?
Dr Calabrese:
Noseology is basically the classification and naming of diseases.
This all came about, uh, in the late fall, early winter, when Professor Xavier Mariette, one of the smartest guys that I know, wrote a piece as a viewpoint in the Annals of the Rheumatic Disease, which was entitled “Long COVID, A new word for naming fibromyalgia?” And Xavier raised a lot of good points in there. And basically— this is now online and you can easily access it, open access—said that, you know, when you really look at this issue of long COVID, we lack a crisp definition of it. And estimates by our own CDC say it occurs either in 7% of people or 40% of people. And that's because we don't really have, universally accepted classification criteria, let alone diagnostic criteria. And he pointed out that most patients, most patients with long COVID —and we're not talking about people who have been in the hospital, that were in the intensive care unit, that have pulmonary scarring or strokes or things—talking about people that generally had mild to moderate covid.
And then after 1, 2, 3 months, say, “I just don't feel right.” And when you look at those people, they have a constellation of numerous symptoms dominated by fatiguability, neurocognitive complaints or brain fog, poor quality sleep, and often accompanied by some type of pain, headache, visceral, somatic pain, et cetera. He said, you know, this has been a familiar phenotype to rheumatologists for a long time, and it looks very much like fibromyalgia. Furthermore, he emphasizes in this literature that this picture is not specific to long COVID, and that many patients who have this have been associated with psychologic stressors, though, and suggested that much of this symptomatology was related to what he refers to. And many people kind of think about as psychosomatic illnesses that are more in your brain than your body.
So with that out there, and it's a very wonderful piece and it's really thought out, and I'm summarizing it very crisply. I feel very strongly that it's not as simple as that. And, we wrote—with Philip Mease, who really knows so much about rheumatic diseases, including fibromyalgia—a rebuttal saying, indeed, the phenotype that you described does sound very much like fibromyalgia. But in the first place, there is so much more to long COVID than that. This is one large piece of the pie. There are other people, particularly at the extreme ends of the long COVID spectrum, and we don't know how many that well represents. These are people that are highly debilitated that you read articles in the New York Times and the Atlantic about, and I see these patients from all over the world.
It's, it's horrendous. And they look very much like ME/CFS, chronic fatigue syndrome, which there is a strong overlap with the fibromyalgia phenotype, but the differences to me are several fold. Number one people that at the extreme end of long COVID, this is not fibromyalgia. They're stricken and often debilitated by dysautonomia. They have rich immunologic signatures. And while we still don't know the mechanism of action, distinctive elements of it that really separate it from what we recognize in our offices as fibromyalgia. Secondly, I think that his emphasis on the neuropsychiatric aspects of fibromyalgia is kind of reductionist. This was kind of our old thinking, that the pathophysiology was poorly understood and was thought to be psychological in nature. And in the past, you know, 5 years in particular, we've been bolstered by the pain community that now considers fibromyalgia under the umbrella of what is currently referred to as nociplastic pain syndromes. That's pain that is, uh, not nociceptive. It's not from injury of tissues. It is not necessarily neuropathic. It is a final common pathway and the mechanism is central sensitization of those pathways. And that there are biomarkers for that microglial activation and other glial cell activation. It's not just pain. And it is a CNS process that is independent from classical psychologic factors. Not that they're not complicit in this, but there's more to it than that.
So that's where we started this discussion. And then I kind of finished this with Philip and said that, you know, long COVID is a work in progress. There are more questions than answers. We're closer to the beginning than the end of it, but I will say this unequivocally, that I don't believe by and large in these psychosomatic paradigms of a generation ago. When we say psychosomatic, I say the brain, the immune system are one organ, and that there are psychologic inputs to this. But the final common pathway is a central neurologic activation pathway that, you know, can't always be solved by counseling or just feeling better. It's, it's far more complicated than that. And saying that it's psychosomatic is offensive to a lot of people who have it. And you know, patient organizations, because it's often equated with a state of weakness. You know, you're not psychologically fit enough to, you know, buffer yourself from the slings and arrows that the rest of us had when we had our COVID. You know, there's something psychologically wrong with you. I think that that's very, very reductionist.
Finally I said that while we're figuring this out, we can do a lot of things. And probably the best is to listen to these people and reassure them that their condition, their disorder, their problems, they're, real, they're not in their head and they're not their fault. To create an empathic working relationship, which I think can be helpful to begin with. So that's, that's the nutshell of it.
This is really a much bigger topic than this. And I'll say a couple things. Number one, at EULAR this year in Vienna, in June, just like the ACR, every year there is a topic that is the great debate and, you know, it's a huge draw. So this year the great debate is long COVID, a new word for naming fibromyalgia. And on one side of the podium is Professor Marriette. And I guess I'm on the other side of the podium, so I'm really looking forward to it.
And I’ll close by saying we're here at the beginning of February, that's June, that's in COVID terms, that's like a hundred years. So I have no idea what the data will be. And as I always like to say, I'll be interested to hear what I have to say about it at the time.
Rebecca Mashaw:
Well, I think we all will be. One of the things that you mentioned in your article in, I believe it was also in the Annals of Rheumatic Diseases, was that you had some suggestions about future research. What would those be?
Dr Calabrese:
Well, there are so many things on this agenda. First of all, something that we don't know robustly, what percentage of patients meeting some of the current long COVID definitions, CDC, NICE, international definitions, how many of them meet fibromyalgia diagnostic criteria? And how do these patients differ from patients who meet the Institute of Medicine criteria for ME/CFS —are they overlapping? Are they the same? Are they different? And then one thing that we didn't have time to talk about on this interview here is the whole issue of post-exertional malaise. This is a physiologic response that is characteristic of chronic fatigue syndrome, where patients are intolerant to a variety of stressors. It refers to a worsening of their symptoms, or the appearance of new symptoms after physical or cognitive exertion.
And it's often delayed 24, 40, 72 hours after they've experienced; this is a phenomena that is widely talked about now in the long COVID world and the Me/CFS world. And I will tell you that the rheumatology world is devoid of any robust dialogue of this. And we don't know how our fibromyalgia patients stack up to this. We're currently launching a study on that at the present time.
And then finally, what about all these biomarkers that abound in long COVID signs of viral persistence, immune activation, immunosenescence, reactivation of latent viruses, microbiome changes, CNS changes? Are they merely epiphenomena? Are they the passengers on the bus or are they causing these symptoms? Are they drivers of the bus? So lots to be done.
Rebecca Mashaw:
And as you mentioned, there's been a lot more history with fibromyalgia and probably even with ME/CFS than there has been with long COVID. So that's part of the picture. Is it not that we just need more data? You mentioned more data coming out between now and EULAR.
Dr Calabrese:
Up until long COVID, anyone that said they're studying ME/ CFS was considered, you know, on the periphery of biomedical science. Nobody wanted to hear about it. It was marginalized, very hard to do research in the area, very hard to get funded. And this is like a wake-up call for medicine and health in general. What is being described right now is within that spectrum. And I think a lot of people are being validated that they've been doing good quality work, but now I think there's going to be a lot more resources put forward for that.
Rebecca Mashaw:
A study in one area could very likely have impacts on the other conditions as well, and what we know about those?
Dr Calabrese:
And Professor Mariette is right--why isn't anyone talking about fibromyalgia in the long COVID world? And I think that actually, and I'll say this publicly, I think that the long COVID community actually perjoratizes the fibromyalgia community. They say, oh, we don't have that. That's a psychosomatic illness. The very thing that they are riled up about when people say that long COVID is a psychosomatic illness. This is just not a useful dialogue. But we've been studying fibromyalgia for decades. There's a lot of useful biology here that may help explain long COVID as well. So, we need to start talking to each other better.
Rebecca Mashaw
Well, we will look forward to hearing about the debate at EULAR and hopefully we'll be able to talk to you after that and see what was discussed.
Dr Calabrese:
Yeah, well, it's an interesting ride. It's like drinking from a fire hydrant. The data comes out so fast. It's not like that in the world of rheumatology.
Rebecca Mashaw:
Alright, well thank you very much for spending this time with us.
Dr Calabrese:
My privilege. Thank you.
Reference: Calabrese LH, Mease PJ. Improving the nosology of Long COVID: it is not so simple. Ann Rheum Dis. 2024;83(1):9-11.
Connect with Dr Calabrese on Twitter @LCalabreseDO
