Leonard Calabrese, DO, on Long COVID Similarities to Fibromyalgia, ME/CFS
Dr Calabrese discusses the similarities between long COVID, fibromyalgia, and in its most severe form, myalgic encephalomyelitis/chronic fatigue syndrome, and the importance of reassuring patients that their symptoms and conditions are real.
Leonard Calabrese, DO, is a professor of medicine and vice chair of rheumatic and immunologic diseases at the Cleveland Clinic in Cleveland, Ohio.
Welcome to this podcast from the Rheumatology and Arthritis Learning Network. I'm your moderator, Rebecca Mashaw, and I'm very pleased to be speaking today with Dr. Leonard Calabrese from Cleveland Clinic, who's a professor of medicine and vice chair of rheumatic and immunologic diseases there. He's one of the leaders in healthcare calling for the recognition of similarities between what we're calling long COVID and other conditions, including fibromyalgia and ME/CFS. So we're going to be talking today about some of those similarities and what that means in terms of clinical implications for patients with these problems.
Thank you for your time today, Dr. Calabrese.
Dr Calabrese: Sure.
RALN: Let's start by talking about what we know today about fibromyalgia and myalgic encephalomyelitis or chronic fatigue syndrome, which mercifully we can shorten to ME/CFS. It wasn't too long ago that many clinicians didn't even think these conditions were real. What can you tell us about this now? Where do we stand with these conditions?
Dr Calabrese:
Well, as you said, this is a complicated topic, but fibromyalgia is a disease that rheumatologists are familiar with. It's also referred to as a nociplastic pain disorder, and that conjures up mechanisms of central sensitization, and this is part of the jargon of rheumatology. We understand that this is overrepresented women, overrepresented in patients with immune diseases, and it's characterized by pain, fatigue, disability, neurocognitive dysfunction, and importantly, the majority of people who have this respond to wellness and individually prescribed exercise regimen. So it's a big disease and it is something that we deal with.
Now, on the other hand, there's another condition that known as myalgic encephalomyelitis/chronic fatigue syndrome, long name, ME/CFS, that has been recognized for a century but only codified in this past generation, and it is surrounded by controversy because we don't understand the etiology of it, and up until recently has been prioritized by many as something that does not have clinical gravitas.
Yet at the same time, the Center for Disease Control recognize that there are a million to 2 million people who have this, and I've been studying this and seeing patients with this for over 30 years. In its extreme form, it’s one of the most debilitating and unremitting conditions that I've ever seen that is not fatal.
Now, having said that, I'll add one more point before we go on. In the past few years with the advent or an introduction of the COVID pandemic, we've seen a percentage of people who go on to develop what is called long COVID, which still lacks a crisp definition, but many of these patients have a phenotype that is very similar to fibromyalgia and at the extreme end, many of them have a phenotype that is very similar to ME/CFS. It carries all the poor prognosis that we're talking about. In the past year, the National Institutes of Health have released their results of an intense study of a cohort of patients with ME/CFS involving 15 institutes, 75 scientists, and have demonstrated unequivocally that this is a disease of neural dysregulation, immune dysfunction with immune exhaustion, that is not in people's heads, but is a real disease that we are closer to the beginning than the end of really understanding, but is really validated.
Finally, if you look at people with ME/CFS, about 70% of them would meet criteria for fibromyalgia. So as we have it, we have a spectrum of illnesses. I say that most people in rheumatologic practice fit more in the fibromyalgia picture, more treatable and responsive to therapy, and people with extreme manifestations of ME/CFS have a much more formidable disease.
RALN:
You wrote an article earlier this year, coauthored an article with Dr. Daniel Clauw, mentioning that third classification of pain that you referred to earlier, nociplastic pain. Can you tell us what sets this apart from the more traditional definitions of neuropathic and nociceptive pain?
Dr Calabrese:
Yes. We think of neuropathic pain as being a disease of peripheral nerves, diabetic neuropathy, vasculitic neuropathy, et cetera. Nociceptive pain is the pain that we all understand: hit yourself with a ballpeen hammer and your hand hurts. Neuroplastic pain is probably mediated in large part by central neurologic dysfunction. People do have accentuated tenderness of their tissues, but it's really a family of diseases. Chronic daily headache, fibromyalgia, TMJ syndrome, facial pain, chronic low back pain without an anatomic explanation. This is a huge swatch of disorders and bears a strong resemblance to being a component of both fibromyalgia and ME/CFS and fits very much into the long covid picture.
RALN:
Also, irritable bowel syndrome…?
Dr Calabrese:
Yes, absolutely
RALN:
In the gastro world, those are called disorders of gut brain interaction. So this is central nervous system that we're talking about, right?
Dr Calabrese:
The brain, I tell my patients, the brain and the immune system are one organ, and the brain is the connections between the brain- gut, brain-bowel, brain-skin, brain-tumor, all now coming to the fore. And I think that ME/CFS epitomizes that because this is where we think that most of the pathology is being driven by.
RALN:
You noted that long COVID, in the article, is the highly clinically heterogeneous disorder with multiple clinical endotypes. So that has to present some big challenges to the rheumatologist.
Dr Calabrese:
Well, to all people who are seeing patients, you have to recognize that the term long COVID has undergone many definitions, and we don't have time to get into all of them, but this is a person that has, in its most understandable form, has a good state of health, is infected with SARS-CoV-2 infection, and then following the acute infection, either fails to recover or develops new onset symptoms that are not readily explainable on the basis of some pathologic disease, that they have pulmonary scarring or had a stroke or an MI or developed diabetes.
This is a disorder that has a myriad of symptoms associated with it, and most of us believe that it is probably not a single disease. It is many different syndromes. And then what I didn't emphasize enough is that we also know that there are a list of candidate mechanisms—persistent viral particles, persistent immune activation, neuropathic central sensitization, dysbiosis, microbiome problems, hypercoagulability mitochondrial dysfunction—and it may be that all of these different clinical manifestations may have different disease pathogenic mechanisms, either singly or in a combinatorial fashion.
So I mean, I know that this sounds extraordinarily complex, but we're closer to the beginning than the end of understanding this, and I think that we should be humbled by what we don't know, and at the same time, working diligently to make progress because in its fully developed form, long COVID is indistinguishable from ME/CFS: disabling fatigue, postexertional malaise, which means that even all these activities that they used to be able to do puts them into a tailspin that may be delayed in onset, central sensitization pain, neurocognitive dysfunction, dysautonomia in its fully developed form, POTS. All of this can be seen, and these patients are not showing dramatic improvement. Fortunately, we think that that is the tip of an iceberg in a small segment of these. The last thing I'll say is that for most people who fit more in the neuroplastic pain, fibromyalgia picture who don't have the totally disabling fatigue and dysautonomia, these people have a much better prognosis, and I think that they can be helped with holistic care, very individualized rehabilitation techniques.
There's a lot of different therapies that are being tried, but we don't have any evidence for these, but they need to be reassured that this disease is real. It's not in their head and it's not their fault. And a lot of practitioners, physicians and advanced practitioners, know we don't like to see things that we're not confident about either in terms of diagnosing or knowing what to do, but that's what life is, and we've been dealt a new pandemic. It has a large spectrum. There's a lot of anxiety, doubt, and hard feelings that surround, you don't believe I have this, or There's no room for that type of conversation.
RALN:
How do you help these patients? What sorts of therapies are successful? Your article mentioned some things like yoga and tai chi and some of those kinds of interventions.
Dr Calabrese:
Let me break this down into a few things. First of all, I think that the most important thing is validating a person's symptoms, and I mean this seriously. If a person is not validated, they're never going to get better because they're always going to be looking for something else. And empathic communication, understanding both their complaints and their concerns is the first thing. Secondly, for those people in the mild to moderate end of this, we treat them very much like fibromyalgia. We use very holistic care, exercise, mind-body techniques that have been demonstrated in fibromyalgia, very important, depending upon what their chief complaint is. Is it pain, neurocognitive, breathlessness, et cetera? We tailor that for the patients over here with the ME/CFS, severe disabling, upper 1 percentile, we don't have any specific therapies to offer them. We treat them like ME/CFS, which was energy conservation, a lot of understanding, and I like to see if we can get these people into clinical trials for whatever's going on. NIH has an IVIG trial going on for POTS associated with long COVID, et cetera. Fortunately, this is the tip of the iceberg, not the whole iceberg. Where does integrative therapy? There's interest in everything from metformin to low-dose naltrexone and other therapies, but we don't have control data on this, but many of us will offer this with appropriate monitoring.
RALN:
I read in your piece that you're not looking at opioids. That's not the answer. Those kinds of pain medications.
Dr Calabrese:
That's not the answer to anything that resembles nociplastic pain or fibromyalgia or chronic fatigue. That is the antitherapy.
RALN:
But gabapentin was mentioned. Has that been successful at all?
Dr Calabrese:
Gabapentin is used very pervasively for numerous pain syndromes. I'm not a big fan of gabapentin unless there's a neuropathic pain component to it. I think there's a lot of downsides to it, and I try to avoid it if possible.
RALN:
Alright. Any final thoughts you'd like to share with your clinician colleagues about how they can help these patients and what may be coming down the road?
Dr Calabrese:
I think that this is a turning point for the study of this spectrum of diseases, whether it's under the long COVID umbrella, whether it's under the fibromyalgia umbrella, whether it's under the ME/CFS umbrella. I mean, they're all so highly interrelated. I think the work of the NIH is just a touchpoint in validating this disease and providing an infrastructure for future investigation, including clinical trials. I don't expect any quick fix to be coming along soon, but I think that we have to end the controversy. We need to have open minds. This toxic social media stuff over this disease, patients versus practitioners and disbelief needs to go out the window. So that's how I think.
RALN:
All right. Well, thank you very much for spending the time with us to talk about this today. I'm sure there's a lot more to be said in the future and we look forward to getting back with you.
Dr Calabrese:
This is a snapshot. Thank you very much.
