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Komaroff

Komaroff has been working on ME/CFS for almost 40 years

What a timely meeting. Mass ME/CFS and FM was celebrating its 40th anniversary, and so probably was Tony Komaroff MD and his long history of treating, researching, and advocating for chronic fatigue syndrome (ME/CFS) – we are facing the most exciting and potentially fruitful period that ME/CFS has ever seen.

Komaroff noted that 40 years ago – only a small number of doctors/researchers were interested in ME/CFS and that the constant refrain from doctors and their unrevealing tests was that “there doesn’t seem to be anything wrong with them”.

Thankfully, he felt differently. His first two papers on ME/CFS on the Epstein-Barr virus and infectious mononucleosis date all way back to 1987. In November of that year, Komaroff – with a cast of co-authors that included Dan Peterson and Paul Cheney – published the first natural killer cell paper. From 1987 to 2002, Komaroff published every year – often multiple times – on ME/CFS.

His most memorable paper in my mind – and one of the most impactful papers in ME/CFS history, I would guess – came in 1996 when Komaroff led a study that showed that people with chronic fatigue syndrome (ME/CFS) were significantly more functionally impaired than people with heart failure, heart attack, multiple sclerosis, type II diabetes, and depression.

In 2019, though, he wrote an article, “Advances in Understanding the Pathophysiology of Chronic Fatigue Syndrome”, in the Journal of the American Medical Association (JAMA) that really got around. Reportedly “the most widely circulated general medical journal in the world”, JAMA is not a specialty journal; it doesn’t focus on neurology or immunology – it’s aimed primarily at doctors and medical students. JAMA states that its Impact Factor (51.3) is one of the highest in medicine and science.

According to an analysis of the articles appearing in JAMA in 2018, Komaroff’s article – just two weeks after its publication – already had enough page views (57,000) to put it in the top ten most viewed articles of that year.

Chronic Fatigue Syndrome (ME/CFS) Article Rocks Top Medical Journal

Komaroff has a history of support for ME/CFS that can be matched by few. Likewise, the Mass ME/CFS Association which, as virtually every other regional ME/CFS organization fell by the wayside, remains a strong and active organization.

The Talk – ME/CFS and Long COVID: Emerging Similarities and Why it Matters

Komaroff’s talk on “MECFS and Long COVID: Emerging Similarities and Why it Matters” cemented the relationship between ME/CFS and long COVID as it underscored the tremendous effect long COVID has already had.

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First, Komaroff cited a study that laid out the remarkable devastation the SARS CoV-2 coronavirus has left in its wake since it first appeared in Wuhan, China in late 2019. The study compared 73,000 people who had had COVID-19 to 5 million people who had not. While we tend to think of post-COVID-19 problems in terms of an ME/CFS-like illness, the virus has had many other post-infectious impacts: the rate of heart attacks doubled, the rates of lung failure quadrupled, and the rates of diabetes climbed 1.5x’s. Overall, simply getting infected with the coronavirus left a person with a risk of death that was 1.6x’s higher. (Recently, the CDC also reported that the coronavirus pandemic was responsible for raising maternal mortality rates by 25%.)

Close Connections

Two of the big questions I had regarding long COVID and ME/CFS were answered with Komaroff’s next slide: I wondered whether the scientific community would really embrace long COVID and would long COVID really be very similar to ME/CFS. Dr. Komaroff’s next slide made it crystal clear that the answer to both those questions was yes.

Coronavirus

Getting COVID-19 dramatically increased one’s chances of coming down with another serious disease.

Komaroff referred to a systematic review of 57 studies (57!) that followed 250,000 COVID patients (of whom 80% had been hospitalized) over time. It concluded that 38% of them still suffered from fatigue, 31% from pain, 27% from sleep problems and 24% from difficulty concentrating, and 16% from exercise intolerance six months later. Another study found that from 13-25% of formerly hospitalized patients met the criteria for ME/CFS 6-9 months later. While the focus was on people who had been hospitalized, these are far higher numbers than other studies of post-infectious illnesses have found and they speak to the particular virulence of the SARS-CoV-2 coronavirus.

We’ve also worried about whether long COVID is going to leave ME/CFS in the dust; whether the research world, in its eagerness to go after long COVID, was going to forget its elder relation. Of course, long COVID has gotten the lion’s share of attention, but Komaroff’s next slide indicated that ME/CFS has not been forgotten at all.

Another systematic review – published once again back in 2021 – of 21 studies, no less, that compared the symptoms of ME/CFS with those of long COVID – found that with a few exceptions like loss of smell/taste loss and rash, symptomatically, the two seemed identical.

But what about where the rubber really meets the road – the biology?  ME/CFS won’t benefit much from long COVID unless it’s biologically similar. Komaroff next posted a remarkable list of biological dysfunctions that have been found in both diseases:

  • Dysautonomia
  • The generation of large numbers of autoantibodies
  • A switch from generating energy efficiently (from glucose and fats to amino acids)
  • A low energy/hypometabolic state
  • Increased oxidative stress
  • Mast cell activation
  • Abnormal exercise test results
  • Blood vessel/coagulation problems
  • EBV and other herpesvirus reactivation
  • Small fiber neuropathy
  • Cognitive problems
  • HPA axis problems
  • Neuroinflammation
  • Gut microbiome changes.

Komaroff listed only 3 things found in ME/CFS (ion channelopathy, exhausted NK/T-cells, craniocervical instability) that have not been found yet in long COVID – perhaps for lack of looking.

The news was good indeed. So far, ME/CFS and long COVID are looking like mirror images of each other. Citing Bindu Paul’s and Marian Lemle’s recent paper on ME/CFS, Komaroff noted it’s going to be fascinating to see how all these different components fit together, but hey, we know how far fascinating can get you in the medical world. ME/CFS, after all, has been fascinating for decades. Being fascinating and fifty cents (make it $2 now) will buy you a cup of coffee and not much more. Long COVID will need more than fascinating to get the powers that be engaged, and Komaroff reported on four studies that should do the trick.

Dramatic Economic Consequences

long COVID costs

Several prestigious studies have found long COVID is prevalent and may be producing enormous economic costs.

Four studies from distinguished institutions and figures (Brookings Institution, CDC, National Bureau of Economic Research, David Cutler/Larry Summers) all published in 2022, and three in the last couple of months, suggest they darn well should.

The January 2022 Brookings report, “Is ‘long Covid’ worsening the labor shortage?“, reported that 16 million adults in the U.S. likely have long COVID – putting 2-4 million of them out of work and suggesting that the labor shortage in the U.S. may be due more to long COVID than to other factors that are frequently cited (poor pay, lack of access to childcare, increased savings, etc.). Stating that the economic cost of lost wages is probably from $170-230 billion a year, the report warned that “If long COVID patients don’t begin recovering at greater rates, the economic burden will continue to rise”.

The report, by the way, used the 2021 Mayo Clinic publication “ME/CFS: Essentials of Diagnosis and Management” produced by ME/CFS experts to validate that other post-viral illnesses have a similar impact.

In a result that jived well with the earlier Brookings Report, the CDC recently found that over 18 million adult Americans are currently experiencing symptoms of long COVID, and 15 million Americans have problems performing daily activities because of it.

That was bad, but then comes the shocking summary: Cutler and Summers believe the total economic cost to the U.S. over five years from long COVID ($3.7 trillion) will be about the same as the great recession of 2008-10 caused. Plus, it’s possible that people with long COVID seeking disability could double the number of people receiving disability overall.

Although Komaroff didn’t mention it our own Art Mirin published an analysis which found the total annual economic impact (not including costs of disability services, social services, and lost income on the part of caretakers) will range from roughly $140 billion to $600 billion.

Suddenly the $1.15 billion Congress gave to the NIH to study long COVID over five years in the RECOVER project looks rather puny.

The Gist

  • Tony Komaroff and the Mass ME/CFS and FM share something special – about 40 years of working on ME/CFS. Komaroff’s talk to celebrate the 40th anniversary of Mass ME/CFS and FM focused on – what else – ME/CFS and long COVID and the similarities between them. 
  • First, he reported on the remarkable devastation the SARS-CoV-2 coronavirus has left behind those who have survived it: dramatic increases in the rates of heart attacks, lung failure quadrupled, diabetes, early death, and, of course, what we know of as long COVID. 
  • Dozens of studies as of last year had documented the high rates of long COVID left behind by the virus, particularly in hospitalized patients. Similarly, almost 2 dozen studies – as of last year again – had documented nearly identical symptoms in long COVID and ME/CFS. 
  • That was all to the good for ME/CFS but if its going to benefit from long COVID the biology is where the rubber meets the road. ME/CFS must be found to be biologically similar to long COVID if it’s going to really benefit.
  • Here the news was good indeed as Komaroff rattled off over a dozen biological abnormalities that have been found in both diseases. They included: dysautonomia, autoantibodies, hypometabolic state, inefficient energy generation,  abnormal exercise test results, mast cell activation, herpesvirus reactivation, neuroinflammation, gut microbiome changes, and others. 
  • It will be fascinating seeing how all those factors fit together but as we all know fascinating and a couple of bucks will buy you a cup of coffee in the medical world and that’s about all.  Long COVID, though, has some aces up its sleeve that would seem to guarantee that it will continue to get a great deal of funding and attention. 
  • Recent studies from prestigious institutions suggest that 15 million or so Americans may have long COVID, that it’s already producing hundreds of billions of dollars of economic losses yearly, that it may be so prevalent that it’s affecting the labor force, and that the long-term costs may reach trillions of dollars.  
  • Komaroff then presented a possible ground zero for long COVID and ME/CFS. He proposed that inflammation in the body or brain could be impacting a small number of nuclei in the hypothalamus  that are largely responsible for the flu-like symptoms found in ME/CFS. 
  • Komaroff didn’t name which nuclei they are but Angus Mackay has recently proposed in two papers on ME/CFS and long COVID that a key stress integrator in the hypothalamus called the periventricular nucleus is getting overwhelmed by inflammation.  
  • Those kinds of costs make the $1.15 billion RECOVER Initiative look rather puny in comparison. While lauding the Initiative’s structure, Komaroff bemoaned the fact that it took 9 months after long COVID was present to get it launched and almost a year later for it to begin accepting patients.

  • Komaroff did not vote to approve Ampligen and he explained why. The lack of long-term data (the company cut its first trial short) and, in particular, the inaccurate data produced by the company at the FDA hearing made him doubt the veracity of its published data.  Komaroff, of course, was not alone in not trusting a company that had run afoul of regulators, was frequently battling lawsuits, was known for overstating its results, and had a dodgy reputation. After firing its longtime President the company has made a dramatic turnaround and now seems set to begin a long COVID trial next year. Komaroff said he welcomed the study.

  • While Komaroff would not predict what would happen, he effectively laid out why this time is so exciting.  The huge numbers of long-COVID patients, the influx of vast amounts of money into long-COVID research, the close similarities between ME/CFS and long COVID, and the immense amount of economic stress long COVID appears to be causing should set up long COVID for years of intense study which ME/CFS should benefit from.

The NIH’s RECOVER Initiative

Komaroff is one of the ME/CFS experts advising the RECOVER Initiative.

Case Definition – Who Needs a Case Definition? The one thing researchers seem, above all, to call for in long COVID is a case definition. As someone who helped create case definitions that didn’t exactly work out in the past, and who has also been involved in efforts to correct them, Komaroff gave some sage advice to the RECOVER Initiative – don’t worry about the case definition right now. Instead, gather all the data you can and then derive the definition from that. You’re inevitably going to get it wrong if you produce one now. He said it appeared the Initiative was following that path.

Komaroff lauded the standardized databases being compiled in the RECOVER project and seemed to think the project was well-conceived, but he bemoaned its slowness. One of his slides incorrectly stated that the NIH was investing $1.15 billion into long COVID – a frequent mistake. The NIH itself actually distinguished itself among major medical funders by investing virtually nothing into long COVID until the $1.15 billion was given to it by Congress in a December 2020 bill.

Komaroff thought it was embarrassing that it took 9 months after it was clear that long COVID was present for the U.S. to commit to doing a study and then took almost a year to get the study going. He didn’t want to want to minimize how hard it was to create the protocols, and get the researchers, doctors, etc. who were needed for a study of that size – but still. We clearly weren’t prepared for the pandemic either. We knew one was coming and should have been much better prepared and we’re still not doing the things we need to be ready for the next one.

The Cause (???)

Komaroff then presented his idea of what’s happened with long COVID and ME/CFS. First, he asked – what do you feel like when you have the flu? (Something very much like ME/CFS.) The symptoms produce something called “sickness behavior” which is designed to make us immobile (stop spreading the infection) and cause us to conserve our energy to fight off the infection. It’s a (usually) temporary response from the central nervous system in which neuroinflammation is prominently featured.

Komaroff then got specific – he proposed that a small number of neurons in the hypothalamus had gotten hammered by the innate immune system (the one responsible for inflammation). Interestingly, it’s now clear that inflammation outside the brain – such as in the gut – can result in inflammation in the brain. A virus in or outside of the brain, or a virus-induced alteration of the gut microbiome, could all end up as inflammation in the brain.

In one swoop, Komaroff presented a way different pathogens could cause the same illness: any pathogen (coronavirus, EBV, Ross-River virus, Ebola, Giardia, etc.), or inflammation in the gut, could ultimately whack the hypothalamus, causing the symptoms of ME/CFS, long COVID and any other post-infectious illness.

Komaroff reported that several recent papers produced in prestigious journals have found evidence reporting that nuclei in the brainstem/hypothalamus in mice can produce these symptoms. Unfortunately, Komaroff didn’t name what nuclei he was so interested in.

Angus Mackay, though, has published two papers proposing that the paraventricular nucleus (PVN) in the hypothalamus – which he calls the central stress integrator in the brain – is ground zero for ME/CFS and long COVID. In his 2021 long-COVID paper, Mackay reported that:

“incoming stress-signals from all types of infections (via inflammatory mediators, such as cytokines and chemokines)” as well as “pain (signals), emotional distress and cardiovascular changes from physical exertion, all converge upon this nucleus – which regulates both neuroendocrine and autonomic nervous system activity.”

He believes that the paraventricular nucleus gets overwhelmed and switched to a dysfunctional state in people with post-infectious illnesses. Another recent review, which proposed that ME/CFS is, at heart, a neurological illness, also fingered the hypothalamus and the PVN in ME/CFS.

Treatment

Finally, there were some questions about Ampligen and Abilify.

Ampligen – Komaroff rather notoriously voted not to approve Ampligen for ME/CFS when it came up for FDA approval. Here he reported that Ampligen has been subjected to randomized, controlled trials – those published trials have shown some benefits in CPET test results but haven’t persuasively shown improvements in symptoms. Almost as an afterthought, he added that although it may be upsetting for some, he didn’t vote for FDA approval because some of the evidence presented at the FDA hearing was incorrect and that made him question the veracity of Hemispherx’s published data. Plus, the company (after cutting short its first trial) had precious little long-term data.

Well, welcome to the club. I don’t know why anyone would question Komaroff’s reasoning. I don’t think that even Hemispherx supporters totally trusted them.

An NIH official rather memorably said, “no professional drug company with any degree of professionalism would ever develop Ampligen the way it was developed by HEM.” The company was seemingly besieged by lawsuits for a while and got its knuckles rapped by the FDA several times. Even Kim McCleary, then head of the CFIDS Association of America, who above all wanted to find a drug for ME/CFS, steered clear of Hemispherx, calling Ampligen “a good drug in the wrong hands”.

Thankfully, after the departure of its longtime head (he was fired), the company – now AIM Immunotech – has made a remarkable turnaround over the past few years, and a long-COVID trial is apparently looming. Komaroff said he was delighted that Ampligen was being trialed in long COVID.

Longtime ME/CFS Drug Ampligen Gets Its Shot with Long COVID

Komaroff hoped that Abilify’s manufacturer would pick up the tabs for a large Abilify ME/CFS trial.

Conclusion

Without a doubt, this is an exciting time for ME/CFS and Komaroff effectively laid out why that’s so: the huge numbers of long-COVID patients, the influx of vast amounts of money into long-COVID research, the close similarities between ME/CFS and long COVID, and the immense amount of economic stress long COVID appears to be causing should set up long COVID for years of intense study which ME/CFS should benefit from.

Komaroff has been around too long to state that ME/CFS or long COVID is necessarily going be solved – too many chronic diseases that have been well-studied are, of course, still around – but perhaps for the first time, there is not just the hope but the expectation that major changes are coming to the ME/CFS field and the field of post-infectious illnesses in general – the outcome of which we can hardly tell.

Check out what Mass ME/CFS and FM has been up to in the last year.

 

 

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