Leonard Calabrese, DO, on Long COVID for the Rheumatologist

Leonard Calabrese, DO, discusses the symptoms and phenotypes of long COVID and where rheumatologists fit into the treatment of these patients.

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.

TRANSCRIPT:

Hi, this is Dr. Len Calabrese coming at you from the Cleveland Clinic. I want to take a few minutes to discuss and kind of conceptualize long COVID, a disorder that is now front and center in modern medicine, but it still lacks a definition, diagnostic test, and the field of rheumatology and the personal perspective of rheumatologists. I'll be giving a plenary talk on this at EULAR this year, and I've been thinking about it for many months, and we're now starting to do some work in this.

So what is long COVID? I think everyone knows that it's either the continuation of symptoms that have developed during COVID-19 or the development of symptoms in the wake of COVID-19. Exactly what is the timeframe that defines it as a condition, whether it's 4 weeks, 8 weeks, 12 weeks, or 6 months is not universally agreed upon. But I will tell you that most epidemiologic studies suggest that by 3 months, as many as 1 in 3 people have persistent symptoms.

Over 50 symptoms have been identified in long COVID. The most frequent are fatigue, brain fog, postexertional exacerbation of these complaints. Also, viscerosomatic pain, breathlessness, chest pain, tachycardia, postural intolerance. The range of severity ranges from mild to disabling. At the present time, we do not have diagnostic tests for this but we're learning a lot. There is an unprecedented research effort underway supported by NIH, but it's going to be a long time until we reap the fruits of this initiative.

Let me give you my perspective of this condition. I think there are multiple endotypes and I like to divide it into 2 large groups. One, those people that have had severe COVID in the hospital, in the unit, who may have suffered PTSD and beyond who have end organ dysfunction from strokes, scarring in the lungs, et cetera. We'll put those aside. The vast majority of people go through diligent workups and have no evidence of end organ involvement, yet still have prominent symptoms.

The second point that I would like to make is that within there, there are different clinical endotypes, one dominated by this chronic fatigue, which has features of ME/CFS, postexertional fatigue, orthostatic intolerance, exacerbated by exercise, psychologic, or emotional stressors, and looks just like ME/CFS that I've studied for over 3 decades. A second phenotype is dominated by autonomic dysfunction. And there's overlap, of course. These are people that have unequivocal tachycardic syndromes that persist after COVID-19. They have decreased in heart rate variability, suggesting vagal nerve insufficiency with or without syncope, but can be quite disabling. The third phenotype is the neurocognitive phenotype. There have been scores and scores of studies that have documented the presence of this. There can be declines of IQ that are equivalent of 10 years of aging that have been identified. And by and large, these people have normal neuro imaging. And the mechanism of this is unclear.

The potential etiopathogenic mechanisms of this include exacerbation of a pre-existing, but perhaps subclinical, autoimmune disease, where people may walk around with asymptomatic autoimmunity and generate this. And it is due to aberrant immune and persistent immune activation. I'll talk about evidence in a second. A second theory is that it is due to new onset auto immunity, and that is supported by multiple studies that have identified autoantibodies starting from the acute phase and persisting. A third and very rising theory is that this is from persistent viral infection, or at least the presence of structural viral particles that persist for many months after the acute infection. And a fourth theory is that this is a culmination of multiple factors, including psychosocial factors that have emanated from the clinical disease. And lastly is remaining unknown factors that we have not studied.

I think we have a long way to go to understand this. It requires careful study of well curated clinical populations with appropriate controls and detailed studies of immune, virologic, neuropsychologic domains within these populations, and I think we're getting there. I'm most impressed with the unequivocal data showing new onset autoantibodies, whether these are drivers or passive, that remains to be identified.

The last point that I'll make is that some of the best data or most intriguing data is a persistent interferon in immune activation syndrome in those people that are complaining of these long COVID symptoms, and this is after controlling for other viral infections, past non-SARS coronavirus infection. Some of these were coming out of Australia. And that has made many of us start to think, well, does this share clinical features with other diseases that bear an interferon signature? What comes to mind in our world obviously is lupus, but there's also an interferon signature in Sjogren's. There's an interferon signature in ILD, PMDM, a modest interferon signature associated with RA. All of this needs to be unpackaged. I've had some very interesting conversations with some leaders in the interferon world just trying to think about this.

I'll wind up by saying, how would a rheumatologist see a patient with long COVID? I think for several reasons. Number one, our patients with immune-mediated diseases will develop long COVID. And do we know they do it more or less? I don't know but we have studies underway to address this as well as many others. Secondly, there may be patients who generate new onset autoantibodies with or without symptoms after COVID who may come to see us and we need to be knowledgeable about this evolving database on this.

Thirdly, and I think rheumatologists have figured this out, patients with onset fatigue, viscerosomatic pain, and brain fog may come to us as central pain amplification syndromes and we need to be able to sort this out. What is the relationship to COVID? Is this just idiopathic fibromyalgia or beyond? And then finally, unexplained multiorgan system dysfunction is the life of rheumatologists. Add to that a few autoantibodies that may or may not be related. I think we will seeing these patients.

The last point I want to make is that what are the therapies moving ahead? The pipeline is rather shallow right now and yet, there are studies being launched with targeted therapies and immune-based therapies already. I know some rheumatologists are already engaged in these. There are studies going on of vagal nerve tone, and this immuno-autonomic world and rheumatology are one. I'm seeing these patients in my practice and they're challenging. And I tell them all, "Your maladies are real. They're not in your head and they're not your fault. Right now, maybe all I can give you is my ear, my time, and my voice."

I'm interested in moving ahead with both clinical and therapeutic research studies. And I think that we have a place at this table and we will have a place at this table. So keep us in mind of what's going on. We just posted a CME talk on the Cleveland Clinic site on long COVID. Easy to check out. And I'm looking for doing a lot more programming in this area and I'm looking forward to my EULAR talk. This is Len Calabrese coming at you with some thoughts on long COVID for the rheumatologist.