August 25, 2023
6 min read
Source/Disclosures
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Disclosures:
Calabrese reports professional relationships with AbbVie, AstraZeneca, Bristol Myers Squibb, Galvani, Genentech, GlaxoSmithKline, Janssen, Novartis, Regeneron, Sanofi and UCB. Laster reports consulting fees from Amgen, Novartis and Pfizer. Putman reports consulting fees from Novartis and clinical trial participation with Abbvie and AstraZeneca, none of which are relevant to the current work.
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Distinguishing between long COVID and fibromyalgia has challenged health care providers across specialties, but rheumatologists may be positioned to clearly define both conditions and offer patients much-needed relief and respect.
Andrew J. Laster
“The symptoms of long COVID share similarities with other post-acute infection syndromes, as well as myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia,” Andrew J. Laster MD, assistant consulting professor of medicine at Duke University, and president of Arthritis & Osteoporosis Consultants of the Carolinas, told Healio. “It may be appropriate to think of all of these illnesses as causing perturbations in central nervous system function at multiple levels and existing in a continuum with more commonality than differences.”
According to Laster, some of the shared traits between long COVID and fibromyalgia, post-acute infectious syndromes (PAIS), and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) include fatigue, sleep disruption and neurocognitive dysfunction.
“Fatigue is often exacerbated by exertion, either physical or mental,” he said. “Non-restorative sleep, neurocognitive dysfunction, viscero-somatic pain and autonomic dysfunction — which can include breathlessness, lightheadedness, tachycardia and sicca symptoms, to name a few — all may be present in any of these four conditions.”
Although these traits cast a shadow long and wide over a swath of specialties, the rheumatology community may actually be best suited to define the boundaries that separate long COVID from other diagnoses, according to Leonard Calabrese, DO, RJ Fasenmyer chair of clinical immunology at the Cleveland Clinic, and chief medical editor of Healio Rheumatology.
Leonard Calabrese
“Rheumatology has been doing this for most of the modern era,” he said. “We have rigorous classification criteria for diseases that are both well-defined and poorly defined. Long COVID researchers should be paying attention to what we have been doing for a living.”
However, at the moment, this may not be happening.
“Long COVID has been an absolute disaster as an area of research,” Michael Putman, MD, MSci, assistant professor of medicine, associate fellowship program director and medical director of the vasculitis program, at the Medical College of Wisconsin, said in an interview. “You can boil it all down to two common problems that afflict all long COVID research — a lack of comparators and a lack of denominators.”
Putman noted that there are plenty of data sets that detail patients with long COVID and their various symptoms, but without comparing them to those with fibromyalgia, or the general population, or to individuals who have never had COVID-19, or those who had COVID-19 but are not experiencing post-infectious syndromes, it is difficult to draw firm conclusions.
“If you do not have a comparator group you are probably just picking up the background malaise from the pandemic,” he said.
Most experts acknowledge that long COVID is still “in search of a proper diagnosis,” according to Putman.
“It can mean a lot of different things to a lot of different people,” he said, adding that the current definition of long COVID is “hopelessly vague and too inclusive.”
According to Putman, nearly any patient who demonstrates some symptoms after COVID illness could qualify as having long COVID.
“With a definition so expansive, it does not really mean anything,” he said. “We need a tighter definition.”
The literature may be a starting point for creating these definitions. Unfortunately, Putman noted, there is still much work to be done in this arena as well.
‘Sparse and a bit conflicting’
“The literature on the effect of fibromyalgia on long COVID is sparse and the data a bit conflicting,” Laster said. “Certainly, the initial stress that COVID had on all of us, coupled with increased isolation and fewer hands-on encounters with therapists and other providers, would be expected to cause flares of disease in patients with fibromyalgia, even in those who did not become infected with SARS-CoV-2.”
Laster suggested that some data may support this hypothesis.
Findings from Lazaridou and colleagues published in BMD Women’s Health investigated 35 patients with fibromyalgia between July 1, 2020, and Nov. 30, 2020. Eligible participants had previously participated in a clinical trial of psychosocial intervention for chronic pain. The results demonstrated a significant increase in pain catastrophizing and fibromyalgia impact during the study period. Anxiety and depression increased, while activity levels and sleep quality decreased, according to the researchers.
Ideally, a data set such as this could begin to describe the similarities and differences between long COVID and fibromyalgia. However, the study lacked two key elements, according to Laster.
“This study did not examine frequency of SARS-CoV-2 infection or whether patients developed long COVID,” he said.
Another study came closer to defining the association between long COVID and fibromyalgia. In a paper published in BMC Musculoskeletal Disorders, Rivera and colleagues retrospectively compared what was then called “post-COVID” in 78 patients with fibromyalgia and 56 patients with rheumatic disease.
“Although entry criteria for post COVID symptoms were not defined, fibromyalgia patients had been symptomatic a mean of 8.5 months, and rheumatic disease patients a mean of 11.5 months, from infection to study entry,” Laster said. “They found a similar prevalence of post-COVID in patients with fibromyalgia vs. rheumatic disease, although severity of symptoms including fatigue, non-restorative sleep and cognitive impairment was greater in patients with fibromyalgia.”
More such data are sure to emerge, eventually allowing clinicians to understand where long COVID and the various conditions it appears to mimic intersect and diverge. However, until those data are mature, it may be beneficial to take Calabrese’s advice and listen to the rheumatologists.
In search of ‘commonalities,’ differences
According to Laster, other commonalities between long COVID and fibromyalgia include a female predominance, low cortisol levels with decreased adrenocorticotropic hormone response — in some studies — as well as abnormalities on functional MRI imaging and volumetric changes in regions of the brain associated with pain.
Calabrese, meanwhile, focused on where the four broad endotypes of long COVID — fatigue, pain, brain fog and sleep — could overlap with other conditions.
“If you take those four clinical domains and start to shuffle them, they could meet criteria for fibromyalgia, or ME/CFS or both,” he said.
Laster agreed that an endotype-based approach could provide some of the answers that researchers are seeking.
“The pain endotype appears quite similar to fibromyalgia, while the fatigue endotype closely mimics ME/CFS, and the autonomic endotype shares features of postural orthostatic tachycardia syndrome (POTS),” he said. “In recent studies of long COVID, up to 30% meet criteria for fibromyalgia and 50% meet criteria for ME/CFS.”
The frequent presence of dysautonomia, as well as the presence of POTS, may be the “richest areas for investigation,” according to Calabrese.
For Laster, a closer look at pain may also yield answers.
“Fibromyalgia is believed to be due to central altered sensitization of pain — nociplastic pain — although a continuum may exist with peripheral nerve abnormalities in some, including findings of small fiber neuropathy,” he said.
Additionally, studies of long COVID have suggested that reactivation of latent viruses, such as Epstein–Barr and herpes, may be a potential cause of chronic disease, according to Laster.
Like Calabrese, Laster is confident that research into the causes of long COVID may shed light on causes of other post-infectious syndromes, along with ME/CFS or fibromyalgia.
“Current theories include persistence of SARS-CoV-2 in tissue potentially remote from the brain, persistent inflammation leading to autoimmunity, dysbiosis and viral reactivation, and tissue damage due to increased oxidative stress,” Laster said.
From these details on genetics and post-infectious syndromes in the context of long COVID and fibromyalgia, the big picture of diagnostic criteria may be emerging, according to Putman.
“From all of this information, we can start to see the domains of pain, fatigue, brain fog and some index of pain and suffering,” he said. “If we add to that a symptom severity score, this could be a useful way to formulate it.”
As researchers continue to wrestle with these details, clinicians everywhere are trying to manage these patients with minimal information and no formal guidance.
‘We are not just checking a box’
The first step to treating these patients has nothing to do with therapeutic choices, according to Putman.
“When you encounter these patients, compassion and respect is of the utmost importance,” he said. “People who have these symptoms have been disrespected, ignored and minimized forever. Whether it is long COVID or fibromyalgia, or something else, you have to acknowledge their suffering, and that what they are experiencing is a real disease.”
Laster agreed that it is essential to acknowledge the fear and frustration these patients may be feeling.
“Importantly, take a careful history and exam,” he said. “The very fact that you are spending time with them in a thoughtful manner will establish a rapport that may have been lacking when were seen by other providers.”
For Calabrese, the natural result of empathy and a careful physical exam will be a robust body of data — something that is badly needed for these patients.
“Gathering detailed clinical data for this purpose is not a small task, and there is no secret that we as rheumatologists hold,” he said. “But don’t just ask the patient if they are tired. Ask if it impacts their quality of life, and, if so, how much. How much is pain impacting their daily activities? We are not just checking a box to say yes or no. This is hard work that is rooted in appreciation of diagnostic criteria, based on rigorous curation of signs and symptoms, using validated measures.”
Although no one believes clear definitions of long COVID — or fibromyalgia — will happen overnight, Calabrese said he believes that using these strategies will ultimately produce results.
“I am optimistic that we will learn a great deal about all of these conditions that have historically been marginalized and under-funded,” he said.
References:
Lazaridou A, et al. BMD Women’s Health. 2022;doi:10.1186/s12905-022-01840-9.
Rivera J, et al. BMC Musculoskeletal Disorders. 2022;doi:10.1186/s12891-022-05436-0.
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