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Some researchers have proposed that long COVID is a subset of fibromyalgia

Some researchers have proposed that long COVID is a subtype of long COVID.

I think people are pretty familiar with the idea that long COVID could be a subtype of chronic fatigue syndrome (ME/CFS) but fibromyalgia? Not so much. In fact, we’ve hardly heard anything about a possible connection between FM and long COVID. The third most common musculoskeletal condition, FM reportedly affects from 2–3% of the world’s population – making it a huge cause of pain and suffering – yet despite its considerable symptom overlap with long COVID, it’s largely been absent from the discussion around long COVID.

This may be partially due to the fact that FM is not often associated with a triggering infection. As we’ll see, though, FM can be triggered by an infection, and it’s so similar in other ways that disregarding it is just, well, lazy science.

That’s hopefully changing. In, “Could the fibromyalgia syndrome be triggered or enhanced by COVID-19?”, the authors answer their question with a clear yes.

First, they cite numerous studies indicating that the SARS-CoV-2 virus can infect the muscles and produce a rather familiar “triangle of myalgia, physical fatigue, and muscle weakness”.

The major symptoms (fatigue/muscle weakness (70.6%), headaches (68%), and muscle pain (55%) associated with long COVID seem to set up well to mimic fibromyalgia. Interestingly, it appears that some symptoms – possibly associated with small fiber neuropathy – tingling (60%), burning sensations (43%) take longer to show up.

The high rates of neurological symptoms (altered mental status, confusion, dizziness, nausea, headache, burning pain, numbness or tingling, allodynia (sensitivity to light touch)) found in long COVID suggest that it, too, is a central sensitivity syndrome – otherwise known as a nociplastic condition. In fact, one study, “Is Central Sensitisation the Missing Link of Persisting Symptoms after COVID-19 Infection?”, found symptoms of central sensitization in over 70% of post-COVID patients.

Besides the chronic pain found in FM, the suite of other symptoms found in long COVID (physical or mental fatigue (70%), sleep problems, cognitive dysfunction, gut problems, problems with stimuli) are common in the ME/CFS-like suite of diseases (chronic fatigue syndrome, postural orthostatic tachycardia syndrome (POTS), Post-treatment Lyme Disease Syndrome (PTLDS) and long COVID.  A web-based survey found that 30% of post-COVID patients met the criteria for FM.

While we don’t tend to think of FM as a post-infectious disorder, numerous cases of it developing in conjunction in with a pathogen (Giardia, hepatitis C virus, human immunodeficiency virus (HIV), parvovirus, or Epstein–Barr virus) have been reported.

Study Shows That Fibromyalgia is a Post-infectious Disease Too

 

Similar Mechanisms Behind Long COVID and Fibromyalgia (?)

Mechanisms fibromyalgia and long COVID

The same mechanisms could be driving FM and long COVID.

If a significant subset of long-COVID patients essentially have FM, the next question is how? What mechanisms are causing these two diseases? Now it gets really interesting.

Not long after the pandemic started, Widyadharma’s literature review of the intersection between viral infections and pain noted that viruses can cause pain by directly invading the tissues, by triggering immune activation, or by inducing autoimmunity.

The idea that the coronavirus or other viruses may be directly invading the tissues is intriguing given the many aberrant muscle findings in FM (not to mention its name, which was focused on pain in the muscles).

A Workout Without Working (Much): Fibromyalgia Study Suggests Muscles Are ‘Wired and Tired’ As Well: Implications for ME/CFS

Indeed, parvovirus – which has been associated with ME/CFS – is widespread in the population and causes long-term arthritis-like symptoms in a subset of patients. Hepatitis B and C, HIV, several mosquito-borne viruses, varicella zoster virus (shingles), and other coronaviruses have all been shown to trigger chronic pain conditions.

While we don’t usually think of them in this way, some viruses can also induce mitochondrial dysfunctions, which in turn can cause chronic pain. Besides the fatigue they experience, about 70% of people with mitochondrial diseases also experience chronic pain. It’s perhaps no surprise that mitochondrial problems in the sensory neurons can mess up sensory signaling and produce pain hypersensitivity.

The idea that inflammation triggered by the coronavirus might be taking a hammer to the mitochondria showed up early in the pandemic. Besides hampering ATP production, the coronavirus itself could also be causing the mitochondria to pound out inflammatory factors that alter the gut flora (microbiome), trigger coagulation and fuel more inflammation. The reversion to more glycolytically produced energy that the coronavirus can cause itself is inflammatory and has even been suggested to produce the central sensitization found in FM.

Dorsal Root Ganglia - from Wikimedia

IgG antibodies attacked the glial cells surrounding the dorsal root ganglia (pictured – Image from Wikimedia- Ganglia Category).

The dorsal root ganglia present another fascinating possibility. These nerve centers located just outside the spinal cord send pain and sensory signals to the central nervous system. They’re known to be disrupted in FM and could, in effect, present a kind of ground zero for the disease that destabilizes the central nervous system.

Nobody had bothered to look for the ACE-2 receptor that the coronavirus uses to gain entry into the cell in the dorsal root ganglion before the coronavirus showed up, but when they did, it showed up in spades. In fact, the authors suggested that coronavirus may even be gaining access to the nervous system through them and other pain-sensing neurons.

Goebel’s striking DRG study shone a bright light on this critical sensory switchboard. Goebel found that giving mice IgG antibodies from FM patients resulted in an FM-like mouse. (Goebel was able to do something similar with complex regional pain syndrome, chronic post-traumatic limb pain, and rheumatoid arthritis).

Study Suggests Something in the Blood is Causing Fibromyalgia

Goebel found that the antibodies had clustered themselves in the dorsal root ganglia and other peripheral pain-sensing nerves of the mice. In a recent small laboratory study, Goebel found that antibodies from long-COVID patients or from fibromyalgia patients attacked the glial cells cultured from the dorsal root ganglia. They even proposed that long COVID is a subtype of FM and ME/CFS.

“Our results lend credence to the hypothesis that long-COVID is an infection-triggered subtype of FMS and chronic fatigue syndrome.”

Something in the Blood II: Long-COVID / Fibromyalgia Autoimmune Connection Found

Interestingly, early in the pandemic, Oaklander speculated that the SARS-CoV-2 virus might be impacting the small fiber neurons that transmit sensory signals. (These nerve fibers are damaged in long COVID, FM, POTS, and ME/CFS.) Two years later in a small study, she and Avindra Nath found that “prolonged, often disabling, small-fiber neuropathy after mild SARS-CoV-2 was most common” in the long-COVID patients. Another study documented the loss of nerve fibers in the corneas of long-COVID patients’ eyes.

Other commonalities include blood vessel problems, microbiome alterations, autonomic nervous system issues, and the possibility of neuroinflammation.

Are Stiffened Arteries Increasing Cardiovascular Risk in ME/CFS and Fibromyalgia?

 

The Musculoskeletal (FM?) Long-COVID Subtype

Using electronic health records (EHC), the RECOVER Initiative used diagnostic categories in about 33,000 patient records to identify four long-COVID subtypes.

While the  “Data-driven identification of post-acute SARS-CoV-2 infection subphenotypes” study clearly has its flaws, it did point to an FM-like subset. The authors noted that many conditions such as musculoskeletal pain, “nervous system pain” and abdominal pain don’t lend themselves to clear diagnoses. Fatigue, of course, is another condition that many doctors hardly consider in their diagnoses, and post-exertional malaise would not show up in these records either. The authors noted that these conditions are more likely to be seen in “functional disorders” (fibromyalgia, ME/CFS, etc.) than in “clearly defined disease etiologies”.

This study, then, exposed a failure of the medical system to account for these disorders, and attempted to study a condition – long COVID – using factors (clear disease diagnoses) that aren’t suited for them. Still, the results were interesting.

For one, it showed that a prominent subset of long-COVID patients – older patients with more cardiac symptoms, who had more comorbid diseases – don’t fit the ME/CFS/FM subtype at all.

These were people with cardiac, kidney, and circulation problems who made up about a third of patients. They tended to be older, were more likely to be male (almost 50%) than the other subsets, and were more likely to have been hospitalized during the pandemic. They were also more likely to have been diagnosed with other diseases prior to the infection.

The second subtype – respiratory, sleep, and anxiety – also included about a third of patients and was dominated by respiratory problems, sleep disorders, anxiety, and symptoms such as headache and chest pain. They were more likely to have had asthma and allergies and other respiratory problems prior to infection. Note how common some of these symptoms (headaches, sleep disorders, chest pain, anxiety) are in ME/CFS/FM.

The Gist

  • Whatever keeps a disease hidden is happening with regard to fibromyalgia and long COVID. Despite the fact that fibromyalgia has similar symptoms as long COVID, it has rarely been associated with it. 
  • It appears likely, though, that many people with long COVID have – as do FM patients – a central sensitivity syndrome; i.e. their nervous systems overreact to painful stimuli and even sometimes innocuous stimuli like touch, light, and sounds.
  • Studies show that numerous pathogens other than the coronavirus can trigger fibromyalgia and other pain disorders.
  • Invasion of the muscle tissue has not been highlighted with long COVID, but because the coronavirus can directly invade muscle tissues, it could be triggering an inflammatory reaction in them and producing an FM-like condition. 
  • Similarly, the coronavirus could produce a pain hypersensitivity state by attacking the mitochondria.
  • The discovery that the ACE-2 receptors that the virus uses to enter the cells riddle the dorsal root ganglia opens another possibility. The virus could be disrupting this central sensory processing point – causing it to slam the central nervous system with pain and other sensory signals in FM.
  • Indeed, one researcher has found that antibodies from FM and long-COVID patients appear to be attacking the microglial (immune cells) in these important nerve centers. 
  • Other studies have found that the same small nerve fiber damage present in FM and ME/CFS is present in long COVID as well.
  • An electronics health data records study identified a common musculoskeletal cohort that looks like FM. 
  • The fact that FM-like ME/CFS is associated with long COVID should bring hope to the long-suffering and poorly supported FM population. Fibromyalgia on a per-person basis is more poorly funded at the NIH than ME/CFS is. If Avindra Nath is right – and understanding one of the mystery diseases like FM, ME/CFS and long COVID will lead to an understanding of them all – then help may be on the way. 
  • Stay tuned!

The third subtype – musculoskeletal and nervous – showed up in about a quarter of the patients.  They experienced musculoskeletal pain, headaches, and sleep-wake disorders. About 60% were female. They had visited the doctor more prior to the infection than the other subtypes, and had a greater incidence of rheumatoid arthritis, asthma, and soft tissue, bone, and sleep disorders. The high rates of pain, headaches, and sleep-wake problems, as well as the high rates of doctor visits, clearly showcased this group as the FM-like group.

More symptoms associated with FM showed up in the fourth subtype (10%) – which was characterized by digestive and respiratory conditions.

All in all, FM, and diseases like ME/CFS appear to supersede these categories. It would take combining categories 2-4 – which make up about 2/3rds of the long-COVID cohort – to adequately describe people with diseases like FM and ME/CFS. It’ll be interesting, as the studies evolve, to see if musculoskeletal or FM-long COVID, fatigue and PEM-long COVID – or ME/CFS-Long COVID, or gut-long COVID or IBS-long COVID subcategories emerge.

Takeaways

  • Whatever keeps a disease hidden is happening with regard to fibromyalgia and long COVID. Despite the fact that fibromyalgia has similar symptoms and possibly similar mechanisms as long COVID, it has rarely been associated with it.
  • It appears likely, though, that many people with long COVID have – as do FM patients – a central sensitivity syndrome; i.e. their nervous systems overreact to painful stimuli and even sometimes innocuous stimuli like touch, light, and sounds.
  • Studies also show that numerous pathogens other than the coronavirus can trigger fibromyalgia and other pain disorders.
  • Invasion of the muscle tissue has not been highlighted with long COVID, but because the coronavirus can directly invade muscle tissues, it could be triggering an inflammatory reaction in them and producing an FM-like condition.
  • Similarly, the coronavirus could produce a pain hypersensitivity state by attacking the mitochondria.
  • The discovery that the ACE-2 receptors that the virus uses to enter the cells riddle the dorsal root ganglia opens another possibility. The virus could be disrupting this central sensory processing point – causing it to slam the central nervous system with pain and other sensory signals in FM.
  • Indeed, one researcher has found that antibodies from FM and long-COVID patients appear to be attacking the microglial (immune cells) in these important nerve centers.
  • Other studies have found that the same small nerve fiber damage present in FM and ME/CFS is present in long COVID as well.
  • An electronic health data records study identified a common musculoskeletal cohort that looks like FM.
  • Fibromyalgia on a per-person basis is more poorly funded at the NIH than ME/CFS is. The fact that FM-like ME/CFS is associated with long COVID should bring hope to the long-suffering and poorly supported FM population. If Avindra Nath is right – and understanding one of the mystery diseases like FM, ME/CFS and long COVID will lead to an understanding of them all – then help may be on the way.
  • Stay tuned!
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