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“It’s the first real solid attempt to come up with some biologic mechanisms for long Covid,” said Dr. Steven Deeks.

A large and complex long-COVID study was recently published. It’s one of the first major studies to follow large numbers of long-COVID patients and test the heck out of them as they become ill. This study is just the beginning – we will see many more of its ilk – but it provides a view into a different magnitude of study than we’ve seen before.

moving parts long COVID study

This large long COVID study had many moving parts. Even bigger ones will follow.

The ME/CFS studies that attempted to get at ME/CFS as it was being produced were limited by funding constraints. It was frustrating to see Leonard Jason, for instance, struggle to get funding from the NIH to dig into the hundreds of samples of college students who came down with ME/CFS in order to try to get at the disease at its earliest stages.

Some of the long-COVID studies coming down the pike are of another world entirely. Huge patient sets combined with ample funding will give them the opportunity to understand long COVID in a way that was impossible with ME/CFS.

For the people with chronic fatigue syndrome (ME/CFS), the biological similarities in key biological areas (exercise physiology, gut) thus far, between long COVID and ME/CFS are closer than I would have expected. This study simply adds to them, and in a new and very intriguing way, as it reaches back into some of the very first findings in ME/CFS.

The Study

The new study, “Multiple Early Factors Anticipate Post-Acute COVID-19“, involved researchers from over a dozen universities, pharmaceutical, and other companies. The fact that Gilead and Merck were amongst the funders suggested the drug companies, in a way they never have been in ME/CFS, are interested in finding treatments for long-COVID patients.

The study assessed autoantibodies, proteomics, and metabolomics in the blood and guts of 209 COVID-19 patients from infection to 2-3 months later, with 457 healthy controls. They then corroborated their findings in a group of 100 long-COVID patients.

One strike against the study for people with ME/CFS – only about 30% of the patients had not been hospitalized.

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Results

Autoantibodies to the Fore

With autoantibodies appearing to contribute to long COVID in about 2/3rds of patients, autoantibodies won the prize for the biggest potential factor.

This isn’t the first-time autoantibodies took center stage in long COVID. An earlier paper suggested that a massive production of unusual autoantibodies occurred early in the infection.

Is “Friendly Fire” Causing Long COVID, ME/CFS and POTS? The Autoantibody Question

This study did not survey as wide a number of autoantibodies but found that, of the 4 factors identified, autoantibodies appeared to play the biggest role in most patients. Autoantibodies – antibodies with the potential to attack or affect the body – were common both during the initial infection and when long COVID had taken hold.

The fact that the long-COVID patients tended to have mature (class-switched) autoantibodies at the onset of infection suggested the long-COVID patients’ immune systems had become activated before they were infected with COVID-19. In fact, the authors noted that a specific class of hyperactivated B-cells (AtM) was reminiscent of what’s seen in lupus – an autoimmune condition.

One wonders if a similar kind of incipient autoimmune state is present in those who later come down with ME/CFS or another post-infectious disease. The case has been made that ME/CFS, with its female prevalence, heritable component, and infectious onset, is an autoimmune disease.

Sex, Autoimmunity and Chronic Fatigue Syndrome … or Why More Women Than Men Get ME/CFS

A recent Japanese ME/CFS B -cell study may be suggesting something similar when it states, “B-cell responses in ME/CFS are directed against infectious agents or priming antigens induced before disease onset.”

The authors also proposed that anti-interferon a2 autoantibodies may have opened the door for long COVID by inhibiting the production of antibodies against the coronavirus – thus giving the virus more time to wreak havoc. These antibodies may have also exacerbated the illness by ramping up inflammation.

Back to the Future I: Cortisol Takes an Early Hit

It was remarkable to see two factors – cortisol and Epstein-Barr Virus (which dominated the early research efforts in ME/CFS) – show up in one of the first really large long-COVID studies.

The study found reduced cortisol levels in COVID-19 patients still suffering from viral/respiratory symptoms. The low cortisol levels were associated with steroid treatment – which suppresses inflammation – at the first two time points, but not at the third time point, suggesting that longer-term cortisol suppression was a function of the virus – not the steroid treatment.

Many studies have assessed cortisol in different ways in ME/CFS and FM (fibromyalgia) without, it should be noted, resulting in a standard treatment protocol. Interestingly, different kinds of reduced cortisol levels have been found in fibromyalgia and ME/CFS. Problems with cortisol clearance that produces higher cortisol residues in FM appears to inhibit the production of cortisol, overall. People with ME/CFS, on the other hand, tend to produce lower cortisol levels in the early morning hours.

Could Neuroinflammation Be Triggering the Cortisol Issues in ME/CFS and Fibromyalgia?

Dr. Klimas’s modeling studies suggest the HPA axis plays a predominant role in ME/CFS and Gulf War Illness and the treatment protocol which came out of them employs a drug (mifepristone) designed to reset that system.

Dr. Klimas’s Big Win and What it Means for Chronic Fatigue Syndrome (ME/CFS)

Let’s hope that this finding holds up in future studies and researchers finally really dig into what’s kind of been a black box for ME/CFS – the HPA (hypothalamic-pituitary-adrenal) axis. It makes total sense given its connections to the stress response, the immune system, and the metabolism that it’s involved, and many studies cite irregularities, but the field has never been able to: a) either capture and explain what’s going on in a satisfactory way; or b) provide any real treatment options.

Back to the Future II: Epstein-Barr Virus (EBV) Shows Up Again

Thirty-five years later Epstein-Barr virus is still being studied in ME/CFS.

Maybe you thought the coronavirus was going to be the whole show? Not at all. If any virus knows how to exploit a weakness it’s Epstein-Barr virus (EBV). EBV is one of those herpes viruses that just hangs around and around.  Bruce Patterson said the coronavirus is the most complex virus he’s seen, but I suspect many pathologists would nominate EBV. This huge and complex virus has been linked to over a dozen diseases, including several cancers, and is probably the chief trigger of adolescent-associated ME/CFS. Almost 35 years after the EBV connection showed up in ME/CFS, research into it continues.

One of the authors reported that EBV reactivation appears to play a role in about a third of long-COVID patients, and was associated with the later development of fatigue and memory problems.

EBV is another factor that’s kind of shrouded in mystery. It’s too enticing a possibility to give up, and EBV ME/CFS studies, in particular, fairly regularly emerge, but there’s no consensus on the role EBV reactivation plays in this disease. Should this study’s findings hold up, a deep dive into EBV’s effects in long COVID could produce tremendous results in ME/CFS.

On the EBV note, Solve ME recently reported that a landmark study published in Science suggested that EBV may now be considered “the leading cause of multiple sclerosis” (!). Solve ME also noted that Moderna will soon begin Phase I trials of an mRNA EBV vaccine.

The Gut

T-cell

Cytotoxic T-cells in the gut got excited about something as long COVID emerged.

The study suggested that the gut gets involved early as well. The most intriguing finding was an expansion of cytotoxic (killer) T-cells that showed up – not at the infection – but months later as long COVID took root.

The authors suggested that a latter viral shedding of the coronavirus in the gut had woken up the T-cells but noted that the T-cells primed to attack the cytomegalovirus had also woken up.

The Gist

  • A large study examined immune functioning in COVID-19 patients as they came down with long COVID over 2-3 months. Note, though, that only 30% had not been hospitalized.
  • The study found four factors found early in the infection which appeared to push people towards having long COVID. Three of those factors have shown up in ME/CFS, and two of them dominated ME/CFS research early on.
  • Having high levels of activated autoantibodies during the early stage of the infection appeared to put the most people in danger of coming down with long COVID.  Most interestingly, the high levels of activated autoantibodies don’t appear to have been caused by the infection but were there before the infection started – suggesting the long COVID patients may have had an incipient autoimmune reaction going.
  • Epstein-Barr virus (EBV) reactivation appeared to push about 30% of the participants toward long COVID. EBV has been studied in ME/CFS since the mid-1980’s.
  • Low cortisol levels – another early avenue of study in ME/CFS – were also associated with the appearance of long COVID.
  • The activation of killer T-cells in the gut as long COVID set in indicated that gut changes occur early as well.
  • Four distinct pathways – all originating early in the infection – that lead to long COVID were found. The authors proposed that small immune alterations early in the illness morphed into major changes as the illness proceeded – making the origins of the ill obscure – unless it was studied in its earliest phases.
  • Even though this study included 300 long COVID patients, the authors noted that bigger studies are needed. With the NIH following 900 plus long COVID cohorts across a dozen or more institutions, those studies are coming.
  • Given that many things could have popped out of this study, it was remarkable to see two old ME/CFS themes (EBV reactivation, low cortisol) and one recent one (autoantibodies) quickly pop out in one of the largest longitudinal long COVID studies to date.

Bystander Activation

While the gut PASC patient had high levels of undifferentiated but activated T-cells early in the illness, other PASC patients demonstrated early specialized activation of the T-cell. All those undifferentiated but activated T-cells caused the investigators to ask if a “bystander” pathogen had become activated as well.

It turned out that cytomegalovirus (CMV)-specific T-cells had become activated as well. Somehow, the coronavirus had turned on T-cells specifically designed to take on CMV! As no actual CMV upregulation had occurred, the authors proposed that the CMV-specific T-cells were involved in the gut problems found in long COVID (PASC).

Four Roads to Long COVID

Next, the authors attempted to correlate symptoms with the gene expression of the immune cells as long COVID appeared to assert itself. They uncovered 4 quite distinct immune signatures indicating different biological types of long COVID were present:

  • pro-inflammatory signatures in monocytes, cytotoxic effector signatures in CD8+ T cells and NK cells, and memory signatures in B cells.
  • CD4+ T cell signatures, M2-like (anti-inflammatory) monocyte signatures, and a plasma B cell signature.
  • Intermediate type.
  • naïve-like T- and B-cell signatures, and resting NK cell signatures.

The germs of those activations stretched all the way back to the infection; i.e. the authors could chart how a person’s immune status at an infection pushed them towards a specific long-COVID endpoint. People with EBV reactivation, for instance, tended to end up in the intermediate group. Interestingly, they could not do the opposite; that is, they could not infer from end-state what the original immune state of the patients was – they needed to have that initial data to do that.

This is often what happens, though, when you perturb a very complex system. Small changes in the beginning that can produce enormous impacts over time get lost as the system evolves. One silver lining to the seemingly never-ending pandemic, though, is that researchers should have no trouble following patients from the murky beginnings of their illness’s conception.

The authors proposed it’s essential to do so, and noted how important it is for other “long” conditions such as Lyme Disease and post-ICU syndrome (but no mention of ME/CFS (???)) be exhaustively studied from their early beginnings. (That’s a very nice recommendation and let’s hope that the NIH decides to provide the funds necessary to do that.)

Most of the focus was on ways to hopefully stop long COVID in its tracks by using antivirals, boosting cortisol, and immunotherapy. Dr. Deeks, who was not part of the study, though, sounded as if they could go further.

One of the authors reported that EBV reactivation appears to play a role in about a third of long-COVID patients and was associated with the later development of fatigue and memory problems.

Dr. Deeks offered some hope for the future.

“If these pathways get confirmed, we as clinicians can actually design interventions to make people better. That is the take-home message.”

Conclusion

This large and complex study was packed with formerly hospitalized COVID-19 patients making it remarkable, indeed, to see several longstanding areas of interest in ME/CFS (cortisol, EBV reactivation), as well as some “shortstanding” ones (autoantibodies), pop out.

This is the kind of large study that we hardly ever see in chronic fatigue syndrome (ME/CFS) or fibromyalgia (FM) but even this study with its 309 long-COVID patients is going to seem like a piker compared to the NIH-funded studies that are underway.  The NIH is currently funding over a dozen centers, each of which may be following as many 900 long-COVID patients over 4 years.

That’s a good thing as even this very large study, which followed over 200 patients (and then corroborated its results in another 100 patients), wasn’t, the authors said, nearly large enough. That’s apparently because the authors captured only a small part of the condition’s complexity.

These huge studies and the rigor with which they are being produced, though, means they should, as this study did, pretty quickly produce some nice, juicy leads. With the NIH sitting on about $600 million – that’s $600 million dollars – of unspent long-COVID funds, it has ample resources to build on the findings its initial studies produce.

As the last blog noted, the fact that we know the trigger and can precisely measure what happened when the gun, so to speak, when off, and that massive amounts of funding are available, suggests that long COVID – as complex as it surely is – may be a disease that’s just waiting to be solved.

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