“Millions of people continue to suffer from exhaustion, cognitive problems and other long-lasting symptoms after a coronavirus infection. The exact causes of the illness, known as long Covid, are not known. But new research offers clues, describing the toll the illness takes on the body and why it can be so debilitating.” Josh Keller
The New York Times recently published a superb and beautifully illustrated article, “How Long COVID Exhausts the Body“, by Josh Keller that it featured prominently on its website. Keller, who obviously did his homework, noted a possible chronic fatigue syndrome (ME/CFS) connection several times in the article. The full connection between the two was not explored.
Maybe it should be. Some groups, after all, don’t seem to believe these diseases have much in common. After the National Institutes of Health (NIH), for instance, received over a billion dollars to investigate and find treatments for long COVID, it has continued to dismiss and, in some cases, even cut ME/CFS funding. Its refusal to allow even a small number of people with ME/CFS to participate in its massive long-COVID studies, its decision to delay research center funding for 7 months, and then continue them at their paltry levels, it’s early termination of perhaps the most important study in the ME/CFS field’s history, and its removal of a mention of ME/CFS from its long-COVID website suggests that, if anything, the NIH may be moving backward on ME/CFS.
A major article by one of the biggest media outlets in the world on long COVID provides an opportunity to clarify where ME/CFS stands in relation to long COVID. (Thanks to Lisa White for the suggestion.)
How Long COVID and ME/CFS Exhaust the Body
“Researchers have also found evidence that Covid may trigger a lasting and damaging autoimmune response. Studies have found surprisingly high levels of autoantibodies, which mistakenly attack a patient’s own tissues, many months after an initial infection.” KellerStill, Autoimmunity provides a tantalizing way to explain the remarkable diversity of symptoms, the gender imbalance, and the infectious trigger found in ME/CFS.
The autoantibody explorations in long COVID already surpass those in ME/CFS in their size and complexity and suggest that a broad range of autoantibodies are unleashed by the coronavirus infection. Several ME/CFS studies have found evidence of increased levels of autoantibodies to receptors (beta-adrenergic (AdR), muscarinic acetylcholine receptors (M-AChR)) which, among other things, affect sympathetic nervous system functioning and the blood vessels. Small studies suggest that targeted therapies that remove those autoantibodies may be helpful as well and at least one is under investigation in long COVID.
Some researchers have proposed that the combination of autoimmune tendencies, dysautonomia, and small fiber neuropathy in ME/CFS, POTS, and some other diseases calls for a new disease designation called “autoimmune neurosensory dysautonomia“. (As we’ll see that combination is also found in long COVID). Several hypotheses as well as exercise studies suggest that autoimmunity plays a major role in ME/CFS
The Virus That Never Left?
“One possibility is that the body is still fighting remnants of the coronavirus. Researchers found that the virus spreads widely during an initial infection, and that viral genetic material can remain embedded in tissues — in the intestines, lymph nodes and elsewhere — for many months.” Keller
As ME/CFS, or a very similar state to it, has been shown to be triggered by many pathogens (Epstein-Barr virus, HHV-6, Coxsackie, Giardia, etc.) the idea that a virus, in some form, is still, even after it’s mostly been fought off, continuing to tweak the immune system has triggered some of the most creative explorations in ME/CFS.
Enterovirus – Several early studies found evidence of enteroviral RNA remaining in the muscles of some people with ME/CFS. Since 2005, Dr. John Chia has presented evidence of a “smoldering” enterovirus infection in ME/CFS including increased antibody levels, the presence of enteroviral RNA in the plasma and in stomach biopsies, usually following what Chia called “a severe flulike illness” of unknown origin. Chia believes that enteroviral RNA in the muscles may be responsible for the exertion problems in ME/CFS.
Epstein-Barr Virus – With studies now proclaiming that EBV is the cause of multiple sclerosis, EBV is getting more attention than ever. EBV was the first virus associated with ME/CFS and is still being studied almost 40 years later. In a long-running NIH grant, for instance, Ohio State researchers have found evidence that a strange, smoldering EBV infection that is unable to fully replicate itself, is nevertheless pumping proteins out that the immune system is reacting to in ME/CFS. A recent Norwegian study that found evidence of a continuing inflammatory response 6 months after an EBV infection suggested that the virus had triggered a long-running immune response in ME/CFS.
HHV-6 – In perhaps the most creative pathogenic hypothesis yet, Prusty and Naviaux propose that an HHV-6/7 reactivation may be triggering a cell danger response that ends up fragmenting the mitochondria and impairing energy production in ME/CFS.
“Many long Covid patients struggle with physical activity long after their initial infection, and experience a relapse of symptoms if they exercise. Initial studies suggest that dysfunction in the circulatory system might impair the flow of oxygen to muscles and other tissues, limiting aerobic capacity and causing severe fatigue.
In one study, patients with long-lasting Covid symptoms had unexpected responses to riding a bike. Despite having apparently normal hearts and lungs, their muscles were only able to extract a portion of the normal amount of oxygen from small blood vessels as they pedaled, markedly reducing their exercise capacity.
One possible culprit: Chronic inflammation may damage nerve fibers that help control circulation, a condition called small fiber neuropathy. The damaged fibers, seen in skin biopsies, are associated with dysautonomia, a malfunction of automatic functions like heart rate, breathing and digestion that is very common in long Covid patients.” Keller
While autoimmunity and viral persistence/reactivation are possibilities in ME/CFS, they remain just that – possibilities. The evidence that some sort of circulatory problem exists in ME/CFS, on the other hand, is quite strong. The first evidence showed up over 20 years ago when McCully/Natelson found reduced oxygen flows to the muscles. Problems with the microcirculation and endothelial cell functioning – two major concerns in both long COVID and ME/CFS/FM – subsequently appeared in three ME Research UK funding studies/papers in 2000, 2003, and 2005.
Blood flows to the muscles and the brain have seen the most study.
Blood Flows to the Brain
“Another research group found that long Covid may significantly reduce the amount of blood that reaches the brain, a finding that has was also seen in patients with a related chronic condition, ME/CFS, before the pandemic.” Keller
The evidence for reduced blood flows to the brain first surfaced in 1996 and has waxed and waned over the years. The brain blood flow question was largely resolved when Visser/Van Campen/Rowe, using a newer, more accurate technique, found reduced brain blood flows in virtually everyone with ME/CFS, including people who did not meet the criteria for orthostatic intolerance.
Further studies indicated that after tilt table testing, blood flows to the brain take much longer to return to normal in ME/CFS, that blood volume – a crucial aspect of circulatory function – is low, that in severe ME/CFS even sitting or mild “tilting” can result in significantly reduced brain blood flows, and that tilt-table testing produces similar effects in long-COVID patients.
Medow’s eye-opening 2014 study demonstrated the dramatic impact reduced oxygen flows to the brain may be having in ME/CFS. When Medow used phenylephrine in ME/CFS patients with orthostatic intolerance to increase blood flows to their brains, their cognitive issues and symptoms completely disappeared during the dreaded tilt table test.
“Many long Covid patients struggle with physical activity long after their initial infection, and experience a relapse of symptoms if they exercise. Initial studies suggest that dysfunction in the circulatory system might impair the flow of oxygen to muscles and other tissues, limiting aerobic capacity and causing severe fatigue.” Keller
Exercise studies have been amongst the most illuminating in what is probably the most exertion intolerant disease on the planet. (The symptom post-exertional malaise – which is now being used in long COVID studies – grew out of the ME/CFS field and experts proposed that ME/CFS be called Systemic Exertion Intolerant Disease (SEID).
Many studies have demonstrated problems with aerobic capacity in ME/CFS. Workwell’s novel 2-day exercise studies, which have become well-validated over time, demonstrate a feature that, until a recent long COVID study found it – had been documented only in ME/CFS: that exercise one day damages one’s ability to produce energy the next day.
David Systrom’s invasive exercise work suggests that two types of circulatory problems crop up in ME/CFS during exercise: a shunt appears to be preventing sufficient oxygen delivery to the muscles and leaky veins are preventing sufficient blood flows to the heart (and ultimately the heart). Vermeulen and others have also found evidence of reduced oxygen delivery to the muscles during exercise in ME/CFS.
Systrom’s and Mancini’s invasive and two-day exercise studies, respectively, may have – because they directly address the exertion issues in long COVID – produced the most significant findings to date. Both have found similar exercise issues in long-COVID patients and ME/CFS.
“South African researchers found another circulation problem: Microscopic blood clots. Tiny clots that form during an initial Covid infection will typically break down naturally, but might persist in long Covid patients. These clots could block the tiny capillaries that carry oxygen to tissues throughout the body.” Keller
Small Fiber Neuropathy (SFN) and Dysautonomia
“Chronic inflammation may damage nerve fibers that help control circulation, a condition called small fiber neuropathy. The damaged fibers, seen in skin biopsies, are associated with dysautonomia, a malfunction of automatic functions like heart rate, breathing, and digestion that is very common in long Covid patients.” Keller
Just one small study provides evidence of small fiber neuropathy in long COVID, but many studies indicate it’s present in ME/CFS/FM. Keller, interestingly, embraces Systrom’s and others’ hypothesis that the SFN found in the skin is the most obvious but least troubling manifestation of an issue that has body-wide consequences and which includes the diversion of blood away from the muscles.
Dysautonomia, of course, is a common theme in ME/CFS, fibromyalgia, and postural orthostatic tachycardia syndrome (POTS) and appears to be present in long COVID as well. Lower heart rate variability ratings that are indicative of sympathetic nervous system dominance, are found in ME/CFS, FM, POTS, and long COVID. A simple standing test that stresses the autonomic nervous system has been proposed as a diagnostic test by ME/CFS practitioners, and reduced heart rate variability measures were predictive of poor sleep.
An Inflamed Brain?
“Although it is unclear how often the virus directly penetrates the brain, even mild infections appear to cause significant brain inflammation, according to the researchers, who included Dr. Nath, Dr. Iwasaki and Dr. Michelle Monje, a neurologist at Stanford. Infections may trigger the over-activation of immune cells called microglia in a way that appears similar to the process that can contribute to cognitive problems in aging and some neurodegenerative diseases.” Keller
The degree to which neuroinflammation plays in ME/CFS is unclear, but several small studies have found evidence of widespread neuroinflammation. The high cost of brain imaging studies and the low support given ME/CFS means the neuroinflammation findings – suspected to be amongst the most potentially important in the field – have come slowly indeed with just three small studies published over the past 8 years. Studies that have displayed a similar brain signature in ME/CFS’s sister diseases – fibromyalgia and Gulf War Illness – cry out for more neuroinflammation studies . Those studies will, thankfully, surely come in long COVID.
“Millions of people continue to suffer from exhaustion, cognitive problems, and other long-lasting symptoms after an infection. The exact causes of these illnesses, known as long COVID and chronic fatigue syndrome (ME/CFS), are not known. But new research offers clues, describing the toll the illness takes on the body and why it can be so debilitating.” Takeoff on Keller
The overlaps are remarkable but maybe even more remarkable is how quickly the same themes have emerged in long COVID and ME/CFS. That isn’t because long-COVID researchers are piggybacking on ME/CFS/FM research. Only a few have had anything to do with ME/CFS. Rather they’re assessing long-COVID patients based on what they see before them; i.e. Long COVID itself is pushing the research in the same direction it’s taken in ME/CFS. In almost every case, the findings Keller laid out in long COVID match up closely with those seen in ME/CFS.
We’re still very early in the game but the results are promising for both people with long COVID and people with ME/CFS. People with long COVID will benefit from the long years of study into ME/CFS, and people with ME/CFS will benefit from the enormous funding being poured into long COVID.
They also bring up an interesting question: if long COVID is worth $1.15 billion in research funding, how much is ME/CFS, which affects up to 2 million people in the U.S. and currently gets $15 million/year, worth?
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