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The Recover Initiative produced an important paper! So, it is possible… 🙂 That’s a bit tongue-in-cheek. As RECOVER has started to move out of its electronic health care studies – which are not very helpful for its ME/CFS-like long-COVID cohort – it’s begun producing some interesting studies.

Still, for the chronic fatigue syndrome (ME/CFS) community, in particular, the “Incidence and Prevalence of Post-COVID-19 Myalgic Encephalomyelitis: A Report from the Observational RECOVER-Adult Study” is something of a landmark. The study was led by Suzanne Vernon, PhD, a long-time ME/CFS researcher and Research Director for the Bateman Horne Center, and that was notable in itself.

The only reason we probably have this study is that early in the pandemic, Suzanne Vernon, on behalf of the Bateman Horne Center, reached out to the University of Utah and told them they were interested in collaborating on long-term COVID research.

Subsequently, the University of Utah included the BHC in its RECOVER application, and when the application was approved, the BHC became the recruiting center for what is now called the Mountain States PASC Consortium (MSPC). That’s how we got an ME/CFS center right in the heart of the RECOVER project.

As Dr. Vernon wrote in her blog, “COVID-19 Triggers ME/CFS,” the RECOVER project’s size provides researchers an “unprecedented opportunity” to understand the long-term effects of COVID-19. This also means that RECOVER’s results should be pretty unassailable – something we don’t see in ME/CFS. In this case, the results were good news, indeed, for the ME/CFS community.

The Study

4,515 people in the study entered the RECOVER project within 30 days of coming down with COVID-19. Six months later, they were assessed, using the Institute of Medicine (IOM) criteria, to see if they met the criteria for ME/CFS, were ME/CFS-like (at least 1 ME/CFS symptom), or had no symptoms.

Note that this study was not designed to catch the subset of people who had been hospitalized with COVID-19 because it did not include them.

ME/CFS Explodes in the U.S. 

As expected, most people who came down with COVID-19 completely recovered (56%). However, a large percentage (40%) still had some problems (were ME/CFS-like; had at least one ME/CFS symptom), and a small number (4.5%) met the Institute of Medicine criteria for ME/CFS.

Four and a half percent may seem like a small number, but given how many people came down with COVID-19, it suggests that an unexpectedly large number of people have one of the most severe types of long COVID. Indeed, despite using more restrictive criteria (IOM criteria) than other studies, the RECOVER study found a significantly higher percentage of long-term COVID patients have ME/CFS than other studies.

Overall, the study found that the coronavirus pandemic has caused a 15fold increase in ME/CFS in the U.S. – and that’s likely an undercount. The RECOVER Initiative got going so late in the pandemic that it missed people who came down with the more severe Delta variant. (An earlier study found these patients tended to be sicker than people who got the later variants.) Because vaccination decreases the risk of coming down with ME/CFS – and most people in this study were vaccinated – people exposed to the coronavirus before the development of the vaccines probably had higher rates of ME/CFS as well. Because more severely ill patients were less likely to enroll in the study, it also missed those.

The risk of coming down with ME/CFS after COVID-19 mostly fits with what we know. People who were white, female, between 46 to 65 years of age, who lived in a rural area, were less likely to have been vaccinated or to have completed college, were at higher risk of ME/CFS. The white prevalence was surprising given that RECOVER has gone to great lengths to be representative, and most ME/CFS surveys have found greater ME/CFS prevalence in minority groups.

The study found that the ME/CFS group of long-COVID patients were: a) far worse off than the ME/CFS-like group, and b) quite distinct.

The Severe Group

Forty-five percent of the people who met the criteria for ME/CFS clustered in the most severe long-COVID symptom category as defined by a prior study. That 2023 study is intriguing because it seemed to suggest that most long-COVID patients have, if not ME/CFS, at least a form of it.

Note that three of the four symptom clusters defined below featured post-exertional malaise and appear to be ME/CFS-based – suggesting that the RECOVER researchers were actually measuring clusters of ME/CFS patients.

Long-COVID Symptom Clusters 

• Cluster 1 was characterized primarily by loss/change in smell or taste. Those participants had the lowest symptom burden and quality of life impairment.
• Cluster 2 had PEM (99%); half had dizziness and gastrointestinal symptoms; none had brain fog (!).
• Cluster 3 was defined by the presence of brain fog (100%), PEM (99%), and other symptoms.
• Cluster 4 participants had high levels of all symptoms, including PEM, dizziness, gastrointestinal symptoms, and brain fog, and overall had the worst quality of life.

Note that most of the ME/CFS-like patients (who did not meet the IOM criteria for ME/CFS) made up a whopping 40% of the RECOVER cohort – and didn’t fit into any of the PASC categories – suggesting they may be something like a nothing burger. They were not symptomatically distinct – as one would expect a group with a severe illness to be. If that’s true, this study suggests the ME/CFS group is the one to focus on.

More than anything else, the new study reports that when a (non-hospitalized) long-COVID patient gets really ill, they essentially have ME/CFS.

Wake-Up Call for the Medical Community

Dr. Vernon wrote that the dramatic “rise in ME/CFS cases the study found” is a “wake-up call for the medical community”, and that providers will encounter ME/CFS “far more frequently”. She noted, though, that “the knowledge and tools … doctors need to identify and manage symptoms in both ME/CFS and Long COVID patients” are readily available.

Talking about definitions, a movement in afoot to produce a new, critical one for ME/CFS.

Support a New ME/CFS Research Definition

ME/CFS has been using a broad-based clinical definition for its research studies for decades—and that’s a no-no. Diseases typically use a narrower research definition to ensure their research studies contain only the disease in question.

After Lenny Jason and Carolyn Kingdon presented almost identical posters calling for new research criteria at the IACFS/ME conference in 2023, they’ve been working with Adam Lowe to fill that big hole in ME/CFS research and have created a petition to support that.

You can support the effort to produce more effective ME/CFS research studies by signing a petition here being circulated by the ME Association and MEAction.

The RECOVER Initiative and ME/CFS

Now that a RECOVER Initiative study has highlighted how serious the ME/CFS portion of long COVID is, what is next for the ME/CFS group of long-COVID patients – and for people with ME/CFS?

I admit that I am, on many levels, obsessed with RECOVER. The huge amount of funding it’s received, what it’s chosen to do with it, what it’s accomplishing, and what we can expect from it are never far from my mind. With President Biden and the NIH contributing another $662 million to RECOVER over the past year, RECOVER is funded through 2029. Total funding stands at a whopping $1.81 billion.

You know what they say: when you get to a billion dollars, you start talking about some real money. You know what they also say: when you’re given much, much is asked of you in return. Let’s see what RECOVER has been doing with that money.

It’s surprisingly difficult to get hard figures, but RECOVER appears to be pouring most of its funding (@$1 billion) into its immense observational studies involving about 40,000 people. Three hundred million dollars are going to its clinical trials, $58 million to fund pathobiology work, and the rest to fund its huge biospecimen (822,000 samples from the adults alone), data centers, and autopsy work.

With RECOVER devoting about 3% of its funding to pathobiology studies, RECOVER is clearly not interested right now in getting at the source of long COVID. Instead, its main goal is to characterize this big and messy condition. Because RECOVER was tasked with assessing all forms of long COVID-19, its observational testing protocols had to cast a wide enough net to pluck out every type of long COVID found.

That brings us to the ME/CFS subset. RECOVER needed to find tests that would make its long-COVID subsets stand out like a sore thumb – not an easy job. Most people with ME/CFS/long COVID know the frustration of getting negative test result after test result. Indeed, ME/CFS seems almost immune to standard testing procedures. ME/CFS researchers, on the other hand, have shown that ME/CFS will show its face when the right tests are used – and that’s the big question … did RECOVER use tests that will illuminate its ME/CFS subset?

RECOVER’s Observational Protocols

RECOVER provided a list of its observational testing protocols in September 2021. Three testing tiers are present: the first tier includes many symptom assessments and is pretty rudimentary, the second tier has more involved tests, and the third tier is the most specialized. Well over 100 symptom assessments and tests are being given.

Here’s an important part. RECOVER estimated that about 30% of the cohort will get tier 2 tests, and 20% of participants will get tier 3 tests; i.e., about 5,000 and 3,000 people in its adult cohort will get the tier 2 and 3 tests, respectively. Because different clinical centers are offering different tests, the actual numbers will probably be smaller, but the gist is that RECOVER is looking at some very large sample sizes.

Tier 1 –  Basic Testing

A recent study indicated that the Tier 1 testing was completely unilluminating.

Tier 2

It seems likely that most of the tests in Tier 2 will not reveal much about the ME/CFS-like cohort, either.

Unrevealing Tests –  include pulmonary function, electrocardiogram, echocardiography, two chest CT scans, fecal white blood stool (diarrhea), fibroscan (fatty liver disease), a variety of autoimmune tests (RNP antibody (scleroderma), smooth muscle antibody (autoimmune hepatitis), LA antibody (lupus), RO antibody (good to see Sjogren’s in there, but the test is not very accurate), anti-dsDNA antibody (lupus), anti-nuclear antibody (general autoimmunity), anti-CCP (rheumatoid arthritis), rheumatoid factor (RA, Sjogren’s), ICAM-1 (inflammation), oral glucose tolerance test (OGTT), insulin, and c-peptide test.

Possibly Revealing Tests – Some tests that may be revealing include the limited cytokine panel (IL2 receptor; IL 1beta, 2, 4-6, 8, 10, 13, 17; interferon-gamma, TNF alpha), the ICAM-1+, and the EBV+  tests. (No information is given on what the EBV+ test is testing for.)

Tier 3

Things get more interesting at Tier 3. If 20%, 10%, or even 5% of the 15,000 adults in the RECOVER project get Tier 3 testing, RECOVER should have plenty of room to dig out specific subsets.

Serum protein immunofixation electrophoresis+ – measures proteins – particularly immunoglobulins – in the blood. Significant changes in blood serum proteins associated with immune system activation, altered coagulation, and tissue damage have been found in long COVID. This test has not been assessed in ME/CFS.

Complete neurocognitive testing+  – specific cognitive tests have been needed in ME/CFS … will RECOVER use them?

EndoPAT testing (Endothelial Peripheral Arterial Tonometry) – assesses blood vessel functioning – could be very revealing.

Serum B12/Methylmalonic acid+  – B12 status – low B12 can produce unexplained fatigue or weakness, tingling, numbness, or memory issues. One ME/CFS study found high B12 – perhaps because of sedimentation. Probably not very revealing (?)

CPK, Aldolase, and Myositis Panel Tests – evaluate muscle inflammation, damage, or autoimmune myopathies. It would be surprising if these tests captured much, but one study did find increased CK levels in ME/CFS. (Is a muscle inflammation subset out there?)

The Brain and Central Nervous System

Cerebral Spinal Fluid

Things get moving with cerebral spinal fluid (CSF) tests. CSF test results have been quite variable in ME/CFS and long COVID, but with perhaps 1000s of patients assessed, these tests could pluck out some intriguing subsets.

• Protein levels – assess the integrity of the blood-brain barrier (BBB), detect inflammation, and identify conditions affecting the central nervous system. Abnormal CSF protein levels have been associated with a variety of neurological diseases. Test results in long COVID and ME/CFS have been variable. Mildly elevated protein levels in both conditions suggest subtle blood-brain-barrier problems or mild inflammation. Elevated levels of specific proteins (e.g., IL-6, IL-8, or other inflammatory markers) in some patients suggest neuroinflammation is present.
• GFAP – demonstrates astrocyte damage in the brain. Two studies have found increased GFAP levels in ME/CFS or long-COVID patients.
• Neurofilament light chain – a biomarker for neurological damage. One study found increased NFL levels in long COVID and borderline increased levels in ME/CFS.
• AB40, AB42, and pTau – are cerebrospinal fluid (CSF) biomarkers primarily used to assess Alzheimer’s disease (AD) and other neurodegenerative conditions. Reduced Aβ42 levels in some ME/CFS and long-COVID patients could reflect neuroinflammation and/or increased amyloid deposition. Similarly, elevated pTau levels in long COVID could indicate neuroinflammation and early neurodegenerative changes.

Other Brain Tests

• Lumbar puncture (overlaps with brain CSF findings): In addition to finding subtle immune abnormalities, lumbar punctures have found increased CSF pressure in ME/CFS, a potentially major finding.
• Brain MRI with and without gadolinium – A brain MRI without gadolinium will probably be uninformative as it assesses structural issues that, to my knowledge, have not been found. The brain MRI with gadolinium, however, can uncover blood-brain-barrier disruption, active inflammation, and vascular abnormalities—exactly what we’re looking for. Without going into the many brain MRI findings in ME/CFS, FM, and long COVID, it suffices to say that numerous abnormalities have been found, and these tests done in large numbers could be very informative.

Others

• Cardiac MRI with and without gadolinium – reduced preload and small hearts have been found in ME/CFS and/or long COVID. Cardiac MRIs don’t do a great job of showing preload failure caused by reduced blood volume – which is what is found in ME/CFS and long COVID – but can infer it. MRIs are good, however, at uncovering small hearts, which have been found.
• Nerve Conduction – probably not illuminating as it assesses large nerve functioning and the small nerve fibers are more affected in ME/CFS and long COVID.
• Skin Biopsy – will uncover small fiber neuropathy – which we already know is present.
• Muscle Biopsy – How helpful these will be depends on how thorough the assessment is. Muscle biopsies in both ME/CFS and long COVID have found evidence of mitochondrial dysfunction, oxidative stress, and muscle fiber atrophy.
• Facility-based polysomnography (sleep test) – Results depend on the type of sleep study done. Nothing particularly novel is expected of this, but it should illuminate basic sleep problems.
• Autonomic testing – Tilt table testing, including supine and upright plasma catecholamine levels, heart rate variability (cardiovagal innervation testing), and the Valsalva test. Again, there is nothing novel about this quite limited testing regimen. It will help establish rates of postural orthostatic tachycardia syndrome (POTS), neurally mediated hypotension, and others.

Invasive CPET

Including the iCPET in the Tier 3 tests in 2023 was a big shock. This test can illuminate what’s happening in ME/CFS and long COVID like few others can. Coming straight out of David Systrom’s work with ME/CFS, the iCPET is ME/CFS’s gift to long COVID. It was great—and surprising—to see the RECOVER project take it on.

The iCPET hits at the heart of ME/CFS and long COVID—the inability to produce energy. Possible mitochondrial and oxygen utilization problems, blood vessel problems (blood loss), cardiac abnormalities (not due to the heart) such as reduced stroke volume and preload (reduced amounts of blood leaving and/or entering the heart), and breathing abnormalities (reduced CO2, breathing patterns) can all show up.

Not only should the iCPET test rapidly distinguish between the long-COVID ME/CFS patients and the others, but it will also  point the finger at energy production, oxygen utilization, blood flows, and breathing patterns. Its presence is a big win for long COVID.

Gut

• Stool Microbiome – Gut dysbiosis (dysfunctional gut microbiome) has consistently been found in both ME/CFS and long COVID. Both conditions show reduced diversity, increased pro-inflammatory bacteria, and reduced short-chain fatty acids (SCFAs, such as butyrate). Altered gut bacteria could contribute to neuroinflammation and problems with energy production.
• Gastric emptying—delayed gastric emptying ( movement through the GI tract) has been found in some long-COVID and ME/CFS patients. Because gastric emptying problems can reflect autonomic nervous system and microbiome problems, this is potentially a valuable test.
• Fecal calprotectin – assesses intestinal inflammation; studies are sparse, and results are mixed.
• Anti-Mullerian hormone – an interesting choice. Anti-mullerian hormone reflects reproductive health. It has not been assessed in ME/CFS or long COVID but could be impacted given the gynecological issues found.

The Missed Tests

Unfortunately, RECOVER missed many potentially valuable tests. Not using provocation (exertion) stressors in at least some participants to illuminate this exertion-challenged disease was a big miss. Employing transcranial Doppler tests to assess blood flows to the brain would have been eye-opening. Given how helpful they’ve been in ME/CFS, the fact that RECOVER is not employing metabolic tests in any fashion seems bizarre. Ditto with immune tests; besides the cytokine panels, I didn’t see any immune tests.

The list of potentially valuable tests goes on: SPECT, PET, magnetic resonance spectroscopy (MRS), functional near-infrared spectroscopy (fNIRS), blood volume, mitochondria, oxidative stress, microclots, EBV duTPase, HHV6, and probably many others have been helpful in ME/CFS and would surely have illuminated the ME/CFS subset of long COVID and produced fascinating results. The loss is major. Check out what some of these studies have found

• Transcranial Doppler – reduced blood flows to the brain when upright in virtually everyone with ME/CFS
• Metabolic Findings – reduced fatty acid oxidation, altered amino acid metabolism, impaired tryptophan-kynurenine pathways, impaired energy production in several cells.
• SPECT scan – reduced blood flows and reduced oxygen uptake in parts of the brain
• Magnetic resonance spectroscopy (MRS) – elevated lactate levels, impaired energy metabolism in the brain and muscle
• PET scan – neuroinflammation, hypometabolism
• Functional near-infrared spectroscopy (fNIRS) – reduced cerebral blood flows and reduced oxygenation in the brain and muscles
• Mitochondria – reduced ATP production, reduced respiratory chain efficiency, reduced aerobic energy production, reduced mitochondrial production, increased levels of oxidative stress

The Mysterious Missing Molecular Investigation

Surprisingly, aside from the microbiome assessment, none of the ‘omics’ tests (genomics, transcriptomics, metabolomics, proteomics) were included. These may be expensive tests, but they have “revolutionized” diagnostics and are producing much of the progress in the ME/CFS field. Getting at the molecular heart of long COVID will require using these tests.

Nisha Viswanathan, MD, the director of the Long COVID Program at UCLA Health, believes so. Speaking to Medscape, she asserted:

“We need to have large-scale research at the molecular level to find treatments that could lead to long-term sustained remission of long COVID rather than just managing symptoms … If we don’t develop a better understanding of the disease’s mechanism and how to diagnose it at a molecular level, we’re never going to truly be able to treat it”.

A Backwards Approach?

For me, RECOVER got it backwards… Faced with a puzzling new disease, I expected RECOVER to employ one of the biggest “omics’ explorations in the history of medicine. With all the omics and data mining tools now available, long COVID-19 seemed like the perfect test case for how to get at the beating molecular heart of a new disease as quickly as possible. Once you get there, as Dr. Viswanathan noted, the diagnostics and treatment possibilities should open up.

If it worked, RECOVER might be on the road to uncovering diagnostic biomarkers for its subsets, new research avenues, and new treatment options. Instead, RECOVER has relied on a very large observational program and a testing regimen that, at least at this point, doesn’t seem to fit the ME/CFS-like portion of its cohort all that well.

The observational component of the program will certainly produce results. The benefits of large-scale invasive exercise studies are large and obvious. So, too, the brain MRI, gut microbiome, and endothelial functioning studies. Many of the others (cerebral spinal fluid components, CPK, aldolase, and myositis panel, fecal, serum protein immunofixation electrophoresis+) seem more like stabs in the dark, which may or may not work out.

Instead of putting all its eggs in one big and very expensive testing basket, RECOVER could and should have created a smaller, side experimental testing regimen that examined more unorthodox tests, intending to incorporate successful ones into the larger testing protocols. Doesn’t a new disease entity call for something like that?

Likewise, instead of producing smaller rounds of experimental clinical trials, which could have progressed to larger rounds, or using a more efficient approach like platform trials, RECOVER put all its eggs into producing 15 large, very expensive, mostly uninspiring trials. (Note that RECOVER now embraces a more nimble approach to clinical trials.)

RECOVER’s sheer size potentially confers real benefits. Its strategy was apparently to build the foundation of a field; that is, to create a broad database of results that will feed researcher interest for years.

How well RECOVER accomplishes its aim, though, depends entirely on how wisely it chose its testing regimen. Note that RECOVER severely limited its testing options by following so many participants (40,000) – and one wonders if some sort of statistical prerogative drove its decisions. Note that the $763 million RECOVER originally allocated to its observational cohort was insufficient, and it needed to add over $300 million more to finish that part of the study.

Questions will continue to be asked about RECOVER’s return on its enormous investment ($1 billion+) in its large observational cohort. Does more evidence that POTS, sleep problems, cognitive difficulties, HRV abnormalities, and small fiber neuropathy are present move the field forward? Since we already know that long COVID increases the risk of autoimmune diseases, did RECOVER really need to do its autoimmune tests?

Time will tell what RECOVER’s return on investment will be. If RECOVER’s tests illuminate the ME/CFS-like group of long-COVID patients well, they will provide the field with a strong base. Over the next year or two, RECOVER should be done assessing its Tier 2 and 3 results, and we’ll know more.

A Big Help?

Even with its rather paltry testing regimen, I think RECOVER, with its big cohorts, may ultimately help a lot. Over the next few years, RECOVER should validate and extend what we know about exercise intolerance, brain issues, gut and blood vessel issues, and, importantly, uncover subsets in each area.

The invasive exercise studies will jumpstart more studies that attempt to understand the roles blood flows, oxygen uptake, mitochondrial problems, shunting, CO2 levels, etc., play in the exercise intolerance found in these illnesses. Studies exploring the role that energy production problems play in these diseases will boom.

Because the Nath intramural study’s limited examination did not reveal significant structural abnormalities in the ME/CFS patients’ muscles, while other, more extensive muscle biopsy studies have, everything depends on how detailed RECOVER’s muscle biopsy studies are. If they’re extensive enough, these studies will spur studies into mitochondrial problems, oxidative stress, inflammation, and impaired energy metabolism. That would be a huge boon.

We’ll have a better idea of where the broken connections in the brain are, how they affect symptoms, and in which patients they occur. While blood flows into the brain and in the brain itself are not being assessed, blood vessels in the brain are. If we get lucky—if getting lucky means uncovering evidence of misfolded proteins, neurological damage, and neuroinflammation—those results will spur more interest in the brain. While limited, the autonomic nervous system results will spur more interest in dysautonomia. With its large studies, RECOVER should be able to tell us pretty conclusively about what’s gone wrong with the gut microbiome, in which patients, and how it affects symptoms.

The identification of subsets will enable deep dives into their molecular underpinnings, allowing for the development of biosignatures. The huge amounts of data that RECOVER is making publicly available will help computational biologists understand long COVID on a systemic level. Plus, the enormous biorepositories of samples RECOVER is collecting should prove invaluable in the long run.

Time will tell!

Health Rising’s End of the Year (Beginning of the Year) Donation Drive is Done!

Thanks to the hundreds of people who supported us! After I thank everyone and collate all the results, I’ll let you know the totals. I think we did just fine! 🙂