Paradigm Shift for Long COVID Patients (and people with ME/CFS)?
The dramatic announcement that Congress is going to appropriate over a billion dollars (a billion dollars!) to study the COVID-19 long haulers was just one sign that long COVID is being taken seriously. Hopefully, along with that will come a new recognition regarding chronic fatigue syndrome (ME/CFS).
So much of what is being written and done about long COVID, after all, could have been written and done about ME/CFS, but we just didn’t have the sudden, worldwide event to spur the medical profession into action.
We don’t know how many people are usually added to the ME/CFS community every year but we can take a shot. Approximately150,000 people in the U.S. reportedly come down with infectious mononucleosis (IM) every year. If five percent of them come down with an ME/CFS-like condition, IM adds about 7,500 people with ME/CFS to the U.S. every year.
IM, however, is apparently responsible for only about 8% of young people with a sore throat. Tens of millions of people in the U.S. come down with the flu every year. Many more people come down with other colds and infections. Plus, a substantial number of people with ME/CFS do not have an infectious onset. Year after year, then, a lot of people are probably being added – under the medical profession’s radar – to the ME/CFS rolls in the U.S. and elsewhere every year.
The difference with the coronavirus is its sudden impact and its visibility. There’s something about a worldwide “pandemic” that concentrates the mind! One editorial from a leading medical journal wrote:
“Given the scale of the pandemic, if even only a small percentage of the tens of millions of infected people worldwide develop long COVID, a staggeringly large number of people would need long-term follow-up and treatment.”
The pandemic appears to be finally forcing the medical community to acknowledge and grapple with post-infectious illnesses – which, it turns out, are not uncommon at all. Even the really hard cases. Even the most resistant part of the medical profession – the doctors – are starting to change their ways.
They, after all, are getting sick too. Thirty-nine long COVID doctors in the U.K. recently got together to write a “manifesto”, “From doctors as patients: a manifesto for tackling persisting symptoms of covid-19“, to the British Medical Journal (BMJ). If 39 sick doctors in Britain wrote a letter, then hundreds of doctors in the U.S. must be ill.
They weren’t messing around. How often do you see doctors using a term like manifesto. That’s the kind of language that someone uses to try penetrate through the everyday thinking – the tranquilized obliviousness – of a profession. They’re trying to transform the way doctors and the medical profession operate. They are asserting that it’s not feasible anymore to treat only the infection and leave the patient to deal with its long-term consequences. The BMJ letter states:
“death is not the only important negative consequence of SARS-CoV-2 infection. It has become increasingly clear that many patients, even those with mild cases, may go on to develop lasting symptoms that can have disabling consequences for those affected.”
We argue that this means accepting an emerging picture that prolonged symptoms are having a substantial impact on a significant minority of people and acknowledging that death is not the only outcome to measure.
A Nature editorial, “Meeting the Challenge of Long COVID”, felt similarly.
Both editorials pushed for more and more research.
“Failure to understand the underlying biological mechanisms causing these persisting symptoms risks missing opportunities to identify risk factors, prevent chronicity, and find treatment approaches for people affected now and in the future.”
Recognition is also starting to creep in there that ME/CFS has been poorly treated by the medical profession – and some are vowing that history is not going to repeat itself.
Take this Nature editorial, “Long COVID: let patients help define long-lasting COVID symptoms“, which apparently is coming straight from Nature itself – and is going to be widely read. The photo atop the editorial – is from a #Millions Missing patient. The caption below the picture reads:
“Research funders were reluctant to engage with groups representing people with ME/CFS (pictured). The same mistake must not be made with those experiencing long COVID.”
The editorial asserts that:
“researchers and policymakers must take heed of what happened in the case of myalgic encephalomyelitis, also called chronic fatigue syndrome (ME/CFS).”
Unfortunately, the editorial then strangely presents ME/CFS as a kind of problem solved. It states that “It took sustained advocacy from patients’ organizations — who had to organize their own independent science advice — to persuade research funders to listen.” – as if they are listening. It goes on: “And although COVID is well known, long COVID isn’t — at least, not yet. It is crucial that those with the condition are listened to in a way that, tragically, people with ME/CFS were not.” – as if people with ME/CFS are being heard.
Interestingly, it was Peter White (of CBT/GET fame or someone else?), who pointed out that the use of the past tense resulted in a “dangerous misconception”; i.e. that the situation has been solved. “The reality”, White correctly wrote, “is that the tragic situation continues” – that patients still aren’t being listened to, and that funding still sucks.
White asserted that ME/CFS’s causes are unclear, that it’s an intractable illness, and that the “urgent need for high-quality, imaginative and ambitious research should therefore not be undermined by downplaying the current impact of this condition (ME/CFS) on millions of people around the world.”
Even though the editorial got some key facts wrong, it did get a lot right. It brought ME/CFS into the middle of the discussion and used the problems people with ME/CFS encountered in the medical profession to argue for a different response to the long COVID patients. Another silver lining to the COVID-19 catastrophe is surely going to be a recognition of how poorly ME/CFS has been treated.
Even The Lancet – for years the bugaboo of the ME/CFS community for its refusal to address the problems of the PACE trial – has stepped up on the long hauler issue. The recent “Facing up to long Covid” editorial stated that “long COVID is a burgeoning health concern and action…” (and that) “large and long-term cohort studies (which contain both hospitalized and non-hospitalized patients) are urgently needed”.
While it couldn’t bring itself to directly mention myalgic encephalomyelitis, it did acknowledge that “Many patients already feel dismissed or overlooked”, and referred to “poorly understood conditions (such as chronic pain and functional disorders)” as examples of how that has happened in the past. Basically, it said that the mistakes of the past should not be repeated.
When editorials from three major medical journals vow that things will be different this time – maybe they will be. Widespread change is a process that takes place over years, but one wonders if we will look back in five years and say – that was the defining event.
For now, it appears that long COVID is getting attention from major opinion makers in the medical field. While ME/CFS may not be mentioned as much as we might want in connection with long COVID, it’s certainly in the mix.
It was encouraging, for instance, to see ME/CFS experts in abundance in the NIH Post-COVID Sequelae workshop. It was very encouraging to see Emily Taylor and the Solve ME/CFS Initiative get a strong coalition to back a long COVID letter which emphasized the role ME/CFS and allied diseases should play in understanding it. It was even more encouraging to her that Emily Taylor and Solve M.E. played an instrumental role in educating legislators about the dangers of long COVID, which supported the enormous amount of long COVID funding for the NIH.
The next year is going to be very interesting. The time “to strike”, to make our mark, is now when the pandemic is in full force and the attention of the world is on it.
The Autoimmunity or Friendly Fire Hypothesis
An autoimmune process must be high on many researchers’ list of what’s happening to the long haulers. Autoimmune processes are often triggered by infections and can attack virtually any part of the body, and cause diverse symptoms. A recent study not only had some fascinating results but suggests we are going to see some studies the likes of which we’ve rarely seen before. It also demonstrates how important the mountain of work done, not on the long haulers, but on people who are still fighting off the virus, will be to understand the long haulers.
The Diverse Functional Autoantibodies in Patients with COVID-19 study is the kind of big study that we see all too rarely in ME/CFS. Featuring about 30 Yale researchers and almost 200 patients, the authors used the latest technology to look at a specific kind of protein – extracellular and secreted proteins (which are called the “exoproteome”) – which has not been assessed in ME/CFS. The study assessed thousands of these proteins.
The patients ran the gamut from those with mild, or even asymptomatic, infections to the seriously ill.
Right away, the study highlights what an opportunity a raging pandemic presents! It presents the opportunity to catch so much in the act. In typically understated terms, the authors state:
“While pathological innate immune activation is well documented in severe disease, the impact of autoantibodies on disease progression is less defined.”
In other words, medical science well knows how destructive autoantibodies can be in autoimmune diseases, but it doesn’t know all that much about how the immune system gets itself into that fix.
What they found shocked them in a number of ways. First, they found startling autoantibodies present that were able to attack an array of human tissues. The autoantibodies appeared to make a difference: the more “functional” (dangerous) they were, the sicker the person was, and the more tweaked their immune system was. For instance, some of the autoantibodies were blunting the immune response to the virus – not exactly what the immune system was set up to do.
Interestingly, and perhaps importantly, they did not find a specific autoantibody signature in the COVID-19 patients. Instead, they found a complex array of autoantibody responses that were often specific to individual patients. These included many uncommon or rare autoantibodies which appeared to have a big impact on the person they were found.
That’s a very interesting finding given the difficulty thus far in pinning down the autoantibodies at work in ME/CFS. Besides the adrenergic and muscarinic antibodies that Scheibenbogen discovered, I’m not aware of any significant leads. I have a memory, though, of it being reported that lots of antibodies being found in ME/CFS patients, but no specific ones have stood out. Instead, there’s this weird mass of antibody activity.
It appeared that the body’s effort to mount an attack on the coronavirus had let loose a massive escape from the immune mechanisms designed to keep the body from attacking itself. Interestingly, the higher amount of inflammation present and therefore the tissue damage found (in the form of ferritin, CRP, lactate), the more autoantibodies to tissues were found. That made perfect sense. As tissues get damaged during inflammation, they let loose proteins which can then trigger an autoimmune reaction.
Not only were a host of new autoantibodies formed during this process, but the researchers found that old autoantibodies that had been kept in check prior to the infection may have been let loose.
So many autoantibodies were found that the authors asserted that it was critical that future studies employ “unbiased proteome-scale surveys” (i.e. very broad based analyses that could pick up all the unusual autoantibodies floating around).
Finally, they suggested that given the remarkable diversity of autoantibodies which showed up early in the disease process, more studies need to examine this in infectious diseases. The authors suggested that the persistence of these autoantibodies over time could help explain why some people may fail to recover from COVID-19. The senior author of the study stated that:
“Because antibodies can persist for a long time, it’s conceivable that they may contribute to the development of long-Covid diseases”.
This early study, then – as other early studies will do – will be able to inform long COVID studies on what to monitor for – in this cause autoantibodies. They have never, to my knowledge, been studied in post-infectious ME/CFS studies.
Autoimmunity is getting a lot of play in the COVID-19 research literature. In “Autoimmunity as the comet tail of COVID-19 pandemic“, two researchers report that hyper-activation of the immune system – particularly in younger individuals – could be triggering autoimmunity.
That’s an interesting idea, given results from the Dubbo studies which suggested that those individuals with the most severe symptoms were most likely to come down with ME/CFS after an infection.
These researchers believe the atypical forms of COVID-19 which may affect everything from the skin, to the heart and skeletal muscles, blood cells, central and peripheral nervous system, etc., could reflect the diverse autoimmune processes unleashed by the virus.
Another recent review suggested that the wide variety of clinical presentations suggests an overexuberant autoimmune response may have occurred.
Speaking of autoimmunity, a German company called “Berlin Cures” reportedly offered to screen the German long COVID group, “Covid 19 Langzeitbeschwerden”, for their autoantibodies to the adrenergic and muscarinic receptors that Carmen Scheibenbogen first found. In November, a doctor with the group reported that they were finding these antibodies in all long COVID patients tested so far…
Major stakeholders in the medical world have taken up the plight of the long COVID patients. Several editorials doing so have rued the mistakes of the past, where post-infectious patients have not been believed, and some have directly mentioned ME/CFS. Sick doctors are even writing “manifestos” charging the medical profession to change its ways and not consign them and their illness to the wastebasket, as it has in the past.
Meanwhile, COVID-19 studies may be uncovering clues as to what’s happening to the long COVID patients. One large study examining the exoproteome was shocked at how many autoantibodies both to the immune system and to other tissues were found. The fact that the autoantibody levels were correlated with illness severity suggested they were making a difference.
Interestingly, no autoantibody signatures stood out. Instead, the fight against the virus seemed to have triggered the production of a wide array of antibodies that often differed from person to person. Rare autoantibodies which appeared to have functional significance were found. New autoantibodies were formed, and at times, old ones were unleashed. The authors suggested that the persistence of these autoantibodies could help explain long COVID.
One report to a patient group in Germany indicated that the adrenergic and muscarinic antibodies Scheibenbogen found may be turning up frequently in the long COVID patients as well.
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