A Solve M.E.-funded project to uncover and assess the latest Long-COVID research findings made these blogs possible
The coronavirus was only a trigger. The question is what did it trigger?
The goal of these continuing research reviews is to find out what researchers are learning about long COVID and how it might apply to chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), postural orthostatic intolerance syndrome (POTS), and related diseases.
With long COVID becoming a thing last summer, and many studies taking years to create, complete, and get published, we’re probably still getting only a taste of the work underway to understand long COVID. Several things are already clear, however. The work on long COVID is very broad-based, with researchers all over the world participating, very few of whom have any connection with ME/CFS. That’s excellent news for ME/CFS as people with ME/CFS make a natural control group that some of these researchers will want to employ in future studies.
First, though, a look at what the big research funder in the long COVID field – the National Institutes of Health – is doing to support both long COVID and its sister disease, ME/CFS.
The NIH, Long COVID and ME/CFS/FM
One negative note to report: while the NIH is talking a good game about ME/CFS and long COVID it’s not doing anything to include ME/CFS in its studies. The NIH grants are not allowing ME/CFS patients (or other disease groups) to be used as controls. Nor is it clear if the NIH is even asking researchers to assess if long COVID patients meet the criteria for ME/CFS (or fibromyalgia for that matter).
This certainly doesn’t mean that long COVID research won’t lead to breakthroughs for these diseases – it will and a future blog later will demonstrate how. It does indicate, though, that despite the close connection between the two conditions, the NIH is not doing anything to integrate ME/CFS into its huge long COVID funding opportunities. (Check out questions ME Action and Solve ME submitted to the NIH regarding integrating ME/CFS into long-COVID research)
Advocacy efforts directed at the US Congress are crucial. We almost achieved a monster win last year.
This highlights the fact that we’re going to continue to have to fight for what we get and how crucial effective advocacy. It was Congressional advocacy, after all, that got the NIH the $1.15 billion to spend on long COVID. Despite Dr. Collin’s public concerns about long COVID, despite all the publicity long COVID has received, it’s very important to note that NIH didn’t do anything to specifically support long COVID until it got money from Congress. So far as the NIH was concerned it was almost as if long COVID didn’t exist. If Congress hadn’t acted, the NIH probably wouldn’t be doing anything specific for long COVID now. There would certainly be no huge studies, no biobanks, no data collection centers, no consistent methodological approaches. Instead, the small amounts of long COVID research that did get funded would have been done in a haphazard and inefficient manner.
All sorts of advocacy opportunities exist – and they are all helpful – but legislative efforts directed at Congress potentially bring the most bang for the buck. While not easy to achieve they have the potential to literally change the landscape of ME/CFS funding overnight. We actually came close to doing that last year.
An Opportunity Missed
Passing HR 7057 last year could have provided a breakthrough in NIH funding for ME/CFS this year.
Our failure to come together and pass HR 7057 (the U.C.S. ME/CFS Act) last year to have Congress directly oversee MECFS funding at the NIH had real consequences. If it had passed Congress would have taken control of the $15 million in funding ME/CFS got last year. The real purpose of the bill, though, was for Congress to determine if NIH funding for ME/CFS was adequate the next year, the year after that, and the year after that.
The Solve ME Initiative and the advocates who supported its work during Lobby Day and afterwards made sure Congress well knew the long COVID-ME/CFS connection. Given that it would have been surprising, indeed, if Congress had not told the NIH to dramatically increase its funding for ME/CFS this year – finally fulfilling decades of effort to increase funding for this disease.
Two Other Major NIH Initiatives Underway
This is the second major research opportunity into which ME/CS seemingly fit like a glove and has, at least thus far, been excluded. The first was the $170 million NIH-funded exercise initiative seeking to get at the molecular roots of exercise. As that effort specifically did not include any other disease groups it was no surprise that ME/CFS wasn’t included.
That was the bad news. The good news is that both these two huge efforts are aimed directly at core issues in ME/CFS and long COVID and will undoubtedly help them greatly. The NIH’s HEAL initiative on chronic pain makes it three large NIH initiatives underway that are focused on the key symptoms in these diseases.
That is great news. They underscore, though, the need to make sure that the ME/CFS/FM research fields are in position to quickly take advantage of the insights that will surely flood in over the next couple of years.
The other good news is that the long COVID research results continue to suggest that it is indeed closely related to ME/CFS/FM and that findings from long COVID will likely translate to these conditions and vice versa. With that onto the research review…
Long-COVID Study Research Review
T-cell exhaustion has been proposed in ME/CFS, and interest in the role T-cells play in fibromyalgia is growing. One study suggests T-helper cells that help drive the immune response are reduced in long COVID – perhaps indicating a role in the immune response that allowed the coronavirus to be active longer and produce more long-term damage. A similar finding has been found in multiple sclerosis and helper T-cells have been targeted in fibromyalgia.
Another long-COVID study found that cognitive deficits and reduced quality of life was associated with reduced expression of memory T cells. Plus, in a really intriguing finding which could perhaps explain some of the negative responses to the COVID vaccines in ME/CFS/FM, the study found “aberrantly elevated” T cell responses to SARS-CoV-2 mRNA vaccines in the long-COVID patients.
Neutrophils appear to be having problems in both long COVID and ME/CFS
Another study found that neutrophil dysfunction appears to be causing long-term immune suppression in long-COVID patients. That was interesting given that neutrophils appeared to be kicking the bucket in larger numbers than usual in ME/CFS and that abnormal neutrophil counts were found as well. The long COVID study also suggested that histamine producing or triggering cells may be upregulated in long COVID – suggesting that mast cell activation may be occurring. On that note, a long-COVID mast cell study didn’t have much to say about biology, but it did note that the symptoms found in mast cell and long-COVID patients were virtually identical.
We don’t know if ME/CFS or long COVID are autoimmune diseases and no studies have assessed ME/CFS patients response to the coronavirus, but the fact that people with autoimmune diseases appeared twice as likely to come down with long COVID, and have more severe long-COVID symptoms, suggested some type of connection is present.
Mayo Clinic researchers looked for a condition called autoimmune encephalitis – which is about as nasty as it sounds – and found it in long COVID – but only it in a very small percentage of patients.
An ACE-2 / Gut / Dopamine / Brain Connection?
The ACE-2 receptor that the coronavirus binds to in order to enter cells potentially presents a fascinating connection as ACE-2 problems have also been found in ME/CFS. ACE-2 receptor problems, for instance, could play a role in the low blood volume found in ME/CFS. A French group took it upon themselves to look for the receptor in gut tissues and found that a coronavirus infection of those cells reduced dopamine production, and given the role that gut-produced dopamine plays in the brain, could produce “prolonged brain alterations.”
That’s a pretty nice connection given that Miller’s ME/CFS studies suggest that a key dopamine-producing area in the brain (the basal ganglia) may be dysfunctional in ME/CFS.
On the subject of dopamine, no less than three 2021 studies found that different dopamine agonists (enhancers) (Daphnetin, Ropinirole, Pramipexole) reduced symptoms in fibromyalgia mouse models. Dopaminergic drugs have not been used much in chronic pain, but a recent review suggests more trials will be coming.
A deranged ACE-2 receptor may not be the only potential microbiome connection between ME/CFS, fibromyalgia, and long COVID. Several studies suggest that a bad bloom of gut flora plays a role in both ME/CFS and fibromyalgia. Not only did a study of the oral microbiome (in the mouth) in long COVID find evidence that more pro-inflammatory bacteria were present, but the authors specifically stated that the bacteria found were similar to those found in ME/CFS.
Blood Vessel Connections Rising
Endothelial cells are of interest in long COVID, ME/CFS and fibromyalgia
Aortic hypermetabolism – presumably associated with inflammation – or a virus- was detected about 20% of long-COVID patients. The possibility that inflamed endothelial cells lining the blood vessels are present has been suggested in both ME/CFS and fibromyalgia. A 2019 study, in fact, proposed that a marker of endothelial cell dysfunction might prove to be a diagnostic biomarker for FM.
As has been found in cardiac studies in ME/CFS, no heart structural abnormalities that could explain the fatigue/exertion problems in long COVID were found in a Turkish study. Increased i18F-FDG uptake was found, also suggesting that a hypermetabolic state associated with inflammation was present. Plus, low NO (nitric oxice) levels suggested that endothelial dysfunction was present and was impeding blood flows. (The endothelial cells lining our blood vessels dilate them using NO.
An Italian study also found evidence of endothelial cell dysfunction and reduced blood flows. The two twists in this study were that the blood flow reductions were associated with pulmonary problems – which have not been found in ME/CFS – and were found in men but not women with long COVID.
Exercise testing is a crucial test for long COVID, ME/CFS and FM because of the potential for the role that energy production plays in these diseases. Exercise comes easier to people with FM than to people with ME/CFS, but that doesn’t mean it’s a walk in the park. Studies suggest that people with FM have trouble raising their heart rates to optimal levels during exercise, that peak energy production may be reduced, and that oxygen delivery to the muscles may be impaired. Plus, a recent review of the role pain plays in post-exertional malaise confirmed “pain as a component of PEM” and emphasized “its debilitating impact in ME/CFS and FM”.
The first long-COVID exercise test did show similarities to ME/CFS. Find out more about that here
The long-COVID exercise study appears to have recruited Donna Mancini, an exercise physiologist, to work on ME/CFS. That’s a very good thing – the more exercise physiologists poking into ME/CFS, the better.
The Mancini-Natelson Exercise Study is Now Open
An NIH-funded 2-day exercise study – called “A Cardiovascular Analysis of Post-exertional Malaise” – aims to dig deeper into the exercise problems found in ME/CFS than has been done before.
The question they’re trying to answer is a central one: why do people with ME/CFS tend to blow through their aerobic energy production systems so quickly during exercise – leaving them trying to squeeze little bits of energy out of their anaerobic energy production system?
This several million-dollar, 120-person study is going to have severe and non-severe ME/CFS patients, and healthy controls. It’s taking place at the Icahn School of Medicine at Mount Sinai University In New York City. They have funds to help participants with travel expenses and time spent (but not airfare). To find out more, call the Pain & Fatigue Study Center research staff at 212-844-6665.
- The NIH is not including ME/CFS patients in its long COVID studies and, indeed, is not doing anything specifically for ME/CFS in its long COVID work.
- While ME/CFS still stands to benefit enormously from the long COVID work it highlights how important advocacy is. The NIH wasn’t going to do anything for long COVID until advocates got Congress to pass money to study it. Likewise, it’s not going to specifically do anything for ME/CFS unless advocates get Congress to push it to do that.
- Immune findings remain pretty sparse but neutrophil dysfunction has been found in both ME/CFS and long COVID. Gut studies suggest that dopamine production problems could reach all the way up to the brain. That’s intriguing as several studies in both FM and ME/CFS suggest dopamine problems in the brain may be present.
- Endothelial cell dysfunction in the blood cells has quickly become a topic in long COVID and has been a topic in fibromyalgia and ME/CFS for quite some time. As blood vessels problems could explain much – reduced energy production, reduced blood flows to the brain, microcirculation problems – in all three diseases it’s good to see long COVID researchers concentrating on them so early – and coming up with similar results.
- Similarly, it’s very good to see exercise studies crop up in long COVID so quickly – and for those studies to display some similar findings to those found in ME/CFS. Hopefully, it’s only a matter of time before the 2-day exercise studies Workwell has championed in ME/CFS, get underway, and long COVID researchers begin using exercise to stress their patients’ systems.
- Findings suggesting that a hypercoagulable state is present in long COVID are intriguing given similar findings which showed up in ME/CFS/FM about 20 years ago. They present another way to explain reduced blood flows to the muscles, reduced cellular energy production, etc.
- A finding that a hypercatabolic state appears to exist where people with long COVID are breaking down their muscles to produce energy is eerily reminiscent of similar findings in ME/CFS. The metabolomic studies sure to show up in long COVID will be fascinating indeed.
The most recent small (18 patients) long-COVID exercise study – done a hearty 9 months after the initial infection – employed a one-day exercise test. Given that, it was not surprising that it did not find as many abnormalities (most were in the low normal range) as the 2-day tests done in ME/CFS. The finding, though, that, “The most notable finding in our study is the remarkable similarity of CPET across patients with PASC and those presenting with unexplained dyspnea in the pre-COVID-19 era.”, by itself, suggests that long-COVID and ME/CFS patients may have similar CPET findings as it was “unexplained dyspnea” which first led Systrom to work on ME/CFS; the unexplained dyspnea patients may have had ME/CFS.
Another finding suggesting that the blood is having trouble getting to the muscles in some long-COVID patients is reminiscent of Systrom’s findings as well. It was interesting and encouraging as well that these authors – hailing like Systrom does from Harvard – suggested that non-traditional (i.e. more in depth) exercise testing is needed. Let’s hope that they’re in touch with Systrom.
Next came an Israeli exercise study which found reduced peak V02 and other findings lower in long-COVID patients. Chronotropic incompetence – the inability to raise the heart rate to high enough levels during exercise – was the believed cause. The study also found reduced stroke volume, which was believed due to a reduction in diastolic volume. Chronotropic incompetence has also been found in ME/CFS, and, if I’m reading them correctly, the Isreali findings like a match for Systrom’s finding of reduced preload, which is likely caused by microcirculatory leaks that are reducing blood flows to the heart.
That long-COVID researchers have so quickly turned to exercise studies to attempt to explain long COVID is a surprising, at least to me, and very welcome development. That, fingers crossed, should lead to employing Workwell’s 2-day exercise tests in long COVID, and hopefully in fibromyalgia as well.
The 2-day exercise results – which have found that exercise one day damages one’s ability to exercise the next day – are apparently so unusual that some exercise physiologists explain them by assuming that Workwell must be doing something wrong. Similar results showing up consistently in long COVID would present the medical world with a real problem – how to explain something they don’t believe should exist.
A Hypercoagulable State?
Thick, clotty blood could presumably impair oxygen delivery to the muscles and it was thick, clotty blood that the next long-COVID study found. The study found “a significant failure in the fibrinolytic process. Of particular interest was the presence of persistent anomalous (amyloid) microclots and a pathological fibrinolytic system”.
In fibrinolysis, fibrin clots – which are found in coagulated states – are broken down. Hypercoagulation was quite a thing in both ME/CFS and fibromyalgia about 20 years ago, but after a quite small study – which noted that it was too small to be definitive – found no evidence of it in ME/CFS, that was pretty much it for that idea. Dr. Holtorf, though, apparently still uses heparin to good effect in some of his ME/CFS/FM patients.
Muscle Breakdown in Long COVID and ME/CFS?
It looks like hypercoagulation may be a big subject in long COVID as an Italian study also found high markers of coagulation, suggesting that an inflammatory/hypercatabolic state was present.
It was really intriguing to hear hypercatabolism mentioned given that it implies “a breakdown of muscle and adipose tissue… as a result of injury, metabolic stress, or sepsis or an unduly rapid breakdown of body tissues”. As was just noted in the Chris Armstrong interview, the ME/CFS metabolomic studies suggest that people with ME/CFS are indeed in a hypercatabolic state and are breaking down their muscle tissues for energy.
Health Rising hasn’t dug into fibromyalgia metabolomic studies as much, but recent studies have also highlighted metabolites associated with energy production and amino acid metabolism. One study – which mimicked findings in ME/CFS – highlighted energy, lipid, and amino acid metabolites, which suggested that heightened oxidative stress, inflammation, and tryptophan degradation play a key role in FM.
Metabolomics is often touted as an excellent diagnostic tool for diseases with unknown origins. As the metabolomics field has become more and more settled, over time we can expect many long-COVID metabolomics studies to show up. One such study found distinct metabolic differences between long-COVID patients and people who’d completely recovered from COVID-19.
Explaining the musculoskeletal problems in fibromyalgia (FM) and ME/CFS – including the evidence of things like cranocervica instability (CCI) and tethered cord syndrome – has presented a problem. A two-person case series may have an answer. This report from Italian researchers of two patients who developed an inflammatory condition called sacroiliitis after a mild coronavirus infection suggests that a systemic inflammatory response triggered by the virus may have produced it. This area clearly needs a lot more research and we may get it as the massive NIH-funded studies follow long COVID patients over time and start to pick up the musculoskeletal problems that show up.
Will gender bias inhibit long COVID efforts?
An Italian review found, interestingly enough, that women experience less severe short-term complications from COVID-19 but more severe long-term complications; i.e. are more likely to come down with long COVID. It almost seems as if women are better equipped to fight off the virus (a stronger Immune response?) but that doing so is more apt to destabilize them. This may make sense with regard to autoimmunity. Infections can trigger autoimmune diseases – which women are also more susceptible to.
Another paper tackled the gender question head-on, calling gender disparity “a black hole for long COVID”. The paper stated, “Unfortunately, there is also “a school of thought” sustaining that the Long COVID gender skew could simply represent an artefact: it could just be conceived by “hysterical, middle-aged women”, and then noted that females have stronger innate and acquired immunological and hormonal responses than males and have a higher incidence of autoimmune diseases.
The Long-COVID ME/CFS Connection
Finally, with some long-COVID patient groups reportedly shying away from being associated with ME/CFS, it was good to see a spanish group take the bull by the horns and explicitly ask: “Long COVID: Is it really myalgic encephalomyelitis?”. They concluded “that persistent COVID syndrome does not constitute a new entity but is, in fact, in some cases, a myalgic encephalomyelitis.”
That’s an interesting conclusion given that while many studies assess long-COVID symptoms, I’ve only found one which assessed how many ex-COVID patients met the criteria for ME/CFS. That study found that symptoms such as fatigue were common six months after infection and that 13% met criteria produced for “systemic exertion intolerance disease” – the term developed by the IOM panel for ME/CFS. Those findings suggest that COVID-19 is indeed very good at producing ME/CFS – and that it’s also producing distress in people who don’t meet the criteria.
The NIH may not be specifically supporting ME/CFS in its long COVID studies but the long COVID research studies thus far provide plenty of room for encouragement for ME/CFS and fibromyalgia patients as similar immune, blood vessel, exercise, metabolomic and other findings suggest that the diseases are quite similar. The fact that long COVID researchers have already jumped on exercise studies is surprising and encouraging and suggests it’s only a matter of time before the crucial two-day exercise studies are mounted in the long COVID field. The fact that many researchers from outside the ME/CFS/FM fields are studying long COVID suggests that the ME/CFS/FM research fields are due to expand as some of them gravitate to it.
We’re still at the very beginning of learning about long COVID, with many more studies likely to come. The NIH, for instance, has yet to announce the recipients of roughly $500 million in grant funding. So far, though, so good.
Check out the first long COVID research review.
This content was originally published here.