Excited by a renewed focus on viruses, Dr. Klimas hopes to open a Center of Excellence to study and treat viral reactivation.
The Dr. Klimas interview is the next in a series of “What’s Up, Doc?” video interviews where I ask experts in the ME/CFS/FM and long-COVID fields what’s exciting them right now.
You can watch the video here. (I forgot to turn off the recording, leaving the last five minutes of it scanning the ceiling of my trailer… Whoops! I could not edit that part because the video sits on the Nova Southeastern University website.)
The blog below goes over the talk and adds in things here and there…
You’re always guaranteed a stimulating conversation with Nancy Klimas. It’s not just that she’s a researcher – she’s also a doctor and longtime chronic fatigue syndrome (ME/CFS) advocate. From the IACFS/ME to CFSAC – the former federal ME/CFS Advisory Panel – to many working groups, she’s participated in just about everything possible. It came as no surprise that when I asked her about what’s exciting now in the ME/CFS/long COVID field, she focused not on her work but on the field at large.
Taking the long-range view, she returned to her first ME/CFS paper from 34 years ago (at the time of the interview), “Immunologic abnormalities in chronic fatigue syndrome”. Chronic immune activation, NK cell defects, viral reactivation – we’re still talking about all of those (and have now added immune senescence – a new term).
THE GIST
From researcher to doctor, to serving on many ME/CFS panels and working groups, Dr. Nancy Klimas has been in the thick of things for decades. Given that, it wasn’t all that surprising that when asked about what’s exciting her now in the ME/CFS field, she focused not on her work but on the field at large.
Taking a long-range view, she returned to her first ME/CFS paper from 34 years ago, which found chronic immune activation, immune cell exhaustion, and viral reactivation – all of which researchers are still studying but in much greater depth now.
As Nancy talked, the failure of the NIH, in particular, to provide sufficient funding came into focus. Stephen Strauss’s determination, after his small trial of acyclovir – which is not particularly effective against the Epstein-Barr virus – failed, that the Epstein-Barr virus (EBV) was not involved in ME/CFS effectively shut down research into viral reactivation for years at the NIH.
Consistent findings of EBV reactivation during the early stages of a coronavirus infection, and its consistent emergence in long COVID, have changed the picture dramatically, however. EBV is now a big deal, and that’s good, but Dr. Klimas also pointed out that HHV-6 – which is reactivated as much, if not more, in her patients – is hardly being studied.
Chronic viral reactivation means chronic immune overdrive, and Dr. Klimas said that if any diseases exhibited chronic immune overdrive, they were ME/CFS and long COVID. That chronic immune activation comes at a cost, and that’s immune senescence – a steady degradation of the immune system’s ability to cope.
So, what makes Dr. Klimas excited is the renewed focus on viruses and the immune system as treatment targets. She hopes to create a “Center of Excellence for Viral Reactivation and Human Disease” that can research viral reactivation and treat it and that brings us to Dr. Klimas’s biggest need for ME/CFS – a clinical trials network for ME/CFS.
A clinical trials network for ME/CFS is Dr. Klimas’s top choice in her “Desperately Needed” category. It would fit in the “let’s finally get serious about treating ME/CFS approach” category.
Clinical trial networks are designed to produce an optimal blend of rigor and efficiency. They are the antidote to the small, underpowered, disorganized clinical trials that have pervaded ME/CFS research and have not provided much help. The benefits are voluminous: improved patient recruitment, a streamlined approach, the need for only one placebo group, better data quality, centralized databases, and shared best practices mean reduced costs and more reliable outcomes.
A clinical trials network would mean “smart trials”: trials that target subsets instead of ME/CFS patients at large – something Dr. Klimas believes is the key to success in this disease. A Rituximab trial, for instance, would focus on ME/CFS patients with signs of autoimmunity instead of taking all comers.
Dr. Klimas said that if she had a great benefactor, she “would slam some serious dollars” into creating a clinical trials network. 🙂
With that, we turned to her long-delayed ME/CFS trial and found out that it isn’t a duplicate of her GWI trial. First, note that the trial is designed to be curative; i.e., it was what supercomputer modeling suggested could return people with ME/CFS to homeostasis or health.
With the high rates of testosterone deficiency she sees in men with ME/CFS, she will first normalize the sex hormones, then attempt to stop brain inflammation with etanercept (Enbrel), then reset the HPA axis and stop the inflammation using mifepristone. The trial either has begun or will begin soon.
Dr. Klimas is taking a staggered three-drug approach to ME/CFS, but she’s leaving open the possibility that the right antiviral could do the trick…
If ME/CFS is like HIV, caused by a pathogen that persists in the body, theoretically, it could simply be cured by eliminating the virus. Antiviral trials have been few and far between, but Martin Lerner’s and Jose Montoya’s work suggests antivirals can be helpful. Despite all the interest in herpesviruses, the past 30 or 40 years have not brought us any randomized, placebo-controlled clinical trials.
While the current crop of antiherpesvirus drugs is not particularly effective, some drug candidates are being tested for other diseases. Dr. Klimas’s monoclonal antibody (mAB) case series produced incredible results with long COVID – and at least 10 mAB studies targeting EBV are underway. Another drug Dr. Klimas finds particularly enticing is Moderna’s anti-EBV vaccine, which is in phase I testing now – and which she hopes, at some point, to try testing in her patients.
A model produced by Dr. Klimas’s chief computational biologist, Travis Craddock, found that combining Rituximab with a herpesvirus drug was able to knock down EBV for long periods of time. Attempts to use antivirals alone allowed EBV to quickly roar back.
Dr. Klimas also looks forward to the breakthroughs she believes artificial intelligence and other means of complex data analysis will bring. Her team’s supercomputer assesses data randomly and in every direction possible using chaos theory so that no possibility escapes it.
An email today indicated that the Institute for Neuro-Immune Medicine has teamed up with Conquer CFS to provide people with ME/CFS with two months of free access to the Conquer CFS Emergency Reset course created by Max Kennedy – a former person with ME/CFS – in conjunction with Dr. Jenny Jin, an CFS/Fibromyalgia and Pain Management Expert. Find out how at the bottom of the blog.
(Yes, 35 years later, we’re talking about a similar paradigm, but look how far this still very small field has come. NK cells are no longer the big focus, but now the really heavy hitters of the adaptive immune response—T and B cells—are. Researchers now believe that the failure of these cells may have caused the innate and more inflammatory arm of the immune system to step in and attempt to compensate.
(Why these immune cells have failed is no longer such a mystery, either. Studies suggest that an inability to produce sufficient amounts of energy may be the cause—a nice finding given the overall energy production problems in ME/CFS. Plus, there’s a new player in town. Immune senescence/exhaustion wasn’t a thing back in the 90s, but it is now and has been found in NK, T, and B cells in ME/CFS.)
As Nancy talked, the failure of the NIH, in particular, to provide sufficient funding came into focus. Anthony Fauci played a prominent role in that when he cast the small ME/CFS research program out into the wilderness and closed down its three small centers—one of which was led by Nancy.
While Stephen Strauss was one of the first researchers to push for a serious study of ME/CFS, Strauss’s determination, after his small acyclovir trial failed, that Epstein-Barr virus was not involved in ME/CFS effectively shut down research into viral reactivation for years at the NIH. (At one point, the NIH flat-out stated it would not support any research into pathogens in ME/CFS.)
Dr. Klimas noted that acyclovir is not particularly effective against EBV but that more effective drugs have more safety issues. (The current crop of EBV drugs (acyclovir, valacyclovir, and ganciclovir) only affect the virus when it is replicating; i.e. when it’s in its “lytic phase”. Even in its latent phase, however, EBV can cause cancer and autoimmune disease.)
Consistent findings of EBV reactivation during the early stages of a coronavirus infection and its consistent emergence in long COVID have changed the picture dramatically. EBV is now a bigger focus. With the big bug’s ability to mess up immune functioning, induce autoimmunity, and cause cancer, and its long history in ME/CFS, Dr. Klimas wondered why its reactivation in long COVID has come as a surprise.
Dr. Klimas finds that HHV-6 is as often reactivated in her patients as EBV. It has only rarely been studied…
HHV-6 is another matter. Dr. Klimas finds a lot of HHV-6 reactivation in ME/CFS – perhaps more than EBV – yet it has been virtually ignored in both ME/CFS and long COVID. (My lab tests showed high levels of HHV-6 but no EBV reactivation.) In the past year, several studies have linked HHV-6 to ME/CFS and a couple to long COVID. John Chia’s enterovirus findings present another intriguing pathogen possibility that has not received its due.
Noting that our immune systems have backup upon backup systems, Dr. Klimas said anytime you see a virus escape, you know things are broken. We’re learning more about viral reactivation all the time. The coronavirus was never thought to produce a latent infection, but gut studies suggest that in some people, the coronavirus is indeed still present.
A broken immune system doesn’t mean the immune system stops trying to get at the virus. In fact, at least for a time, it may be trying harder than ever. Dr. Klimas said if there were ever illnesses in chronic immune overdrive, they were ME/CFS and long COVID. That chronic immune activation comes at a cost, and that’s immune senescence.
Immune senescence has typically been associated with aging, but some findings (T, B, and NK cell dysregulation, viral reactivation, chronic inflammation, telomere shortening) suggest that the immune systems in people with ME/CFS are aging more rapidly than normal as well.
So, what makes Dr. Klimas excited is the renewed focus on viruses and the immune system as treatment targets. She hopes to create a “Center of Excellence for Viral Reactivation and Human Disease” that can research viral reactivation and treat it – which brings us to Dr. Klimas’s biggest need for ME/CFS.
“Desperately Needed”- A Clinical Trials Network
A clinical trials network for ME/CFS is Dr. Klimas’s top choice in her “Desperately Needed” category. It would fit in the “let’s finally get serious about treating ME/CFS approach” category.
Clinical trial networks are designed to produce an optimal blend of rigor and efficiency. They’re not easy to build – it took Klimas and company three years to produce the protocols, criteria, primary/secondary outcomes, etc., needed for the Gulf War Illness clinical trials network. Once they were done, though, the trials could move forward effectively and efficiently.
Improved patient recruitment, a streamlined approach, the need for only one placebo group, better data quality, centralized databases, and shared best practices mean reduced costs and more reliable outcomes. With that comes more funding opportunities, as public institutions, private foundations, and pharmaceutical companies are more likely to fund trials in that setting.
They are the antidote to the small, underpowered, disorganized clinical trials that have pervaded ME/CFS research and have not provided much help. No one can count on – or knows what to make of – a small clinical trial that uses different criteria from other trials to choose its patients, different outcome measures to assess them, and is underpowered to boot.
In a clinical trials network, antiviral trials would target people with signs of viral reactivation.
A clinical trials network for ME/CFS would, Dr. Klimas said, design smart trials – i.e., trials that target subsets instead of ME/CFS patients at large – something that Dr. Klimas believes will be the key to success in this disease.
Instead of taking all comers, as the past Rituximab trial did, a new Rituximab trial would target ME/CFS patients with signs of autoimmunity. Similarly, an antiviral trial would target patients with signs of viral reactivation, etc.
Dr. Klimas said that if she had a great benefactor, she “would slam some serious dollars” into creating a clinical trials network. It could use the infrastructure produced in the Gulf War Illness clinical trials network that was funded by the DOD.
When asked, “If a clinical trials network had been recommended for ME/CFS,” ChatGPT stated one has been “strongly recommended” by “advocacy groups, researchers, and governmental advisory bodies.” While ME/CFS is “severely underfunded,” a “clinical trials network could dramatically improve the pace of ME/CFS research and potentially lead to the discovery of effective treatments.”
Dr. Klimas’s 2-Stage – No, Make That 3-Stage – ME/CFS Clinical Trial
For now, we have what we have, and I had to ask Dr. Klimas about her long-delayed ME/CFS clinical trial, and when she answered, something new popped up – the ME/CFS trial is not a duplicate of the GWI illness trial. Given the testosterone deficiency she often sees in men with ME/CFS, it wasn’t surprising to see the model say first normalize the sex hormones, then stop brain inflammation with etanercept (Enbrel), then reset the HPA axis and stop the inflammation using mifepristone.
With her model showing that testosterone is protective in men and often deficient, Dr. Klimas added testosterone to her ME/CFS clinical trial.
We’ll see how the trial turns out, but note that it’s one of the few trials designed to be curative, i.e., to return ME/CFS patients’ systems to homeostasis, or normalcy. I suspect it won’t be – that’s a lot to ask (!) – but since Dr. Klimas will feed the data from the trial back into the computer to strengthen the next model, it should move the needle forward.
The testosterone issue illuminates the sometimes shocking holes found in ME/CFS research. Even though sex hormones must, it seems, play a role in the female predominance seen in ME/CFS (and fibromyalgia and long COVID), the role testosterone may be playing in men has been almost completely ignored. Dr. Klimas’s 2014 study was the first to mention it at all (the study found testosterone was protective against ME/CFS), and only one other paper – published last year – has.
Speaking of her staggered three-drug approach to ME/CFS – Dr. Klimas said you’re probably not going to cure this illness by touching one target – you’re going to have to touch several. There was a proviso to that, though. She’s leaving open the possibility that the right antiviral could do the trick…
An Antiviral Approach
If ME/CFS is like HIV, caused by a pathogen that persists in the body, theoretically, it could simply be cured by eliminating the virus, but antiviral trials have been few and far between.
Martin Lerner, whom she called “a beautiful man” and who cured his own ME/CFS, “worked like hell to get EBV out of ME/CFS patients’ systems,” she said. Instead of relying solely on less effective but safer antivirals, Lerner used some big-gun antivirals, rotated his antivirals – and had some good treatment results to boot.
If ME/CFS and long COVID are caused by persistent viruses, then antivirals could be curative.
(Lerner’s published studies produced good results but were, I was told, wanting statistically. Lerner often used long-duration treatments – up to a year or more – and required his patients to pay close attention to pacing. Health Rising has several Lerner recovery stories on its website. In a video interview coming up, Dr. Henderson in Denver told me that antivirals took a minimum of three months to work in ME/CFS.)
Jose Montoya at Stanford, in what Dr. Klimas called a very underpowered prospective chart review study, found that 81% of patients responded cognitively and, importantly, that the longer a person was treated – the better the response he/she had. An earlier, very small (n=12) study found that 9/12 patients experienced a near resolution of their symptoms. Note that both of these trials used a drug – valganciclovir (Valcyte) – which Dr. Klimas characterized as being not particularly effective with EBV.
Despite some promising results, a larger, placebo-controlled phase II trial was never done – something Dr. Klimas found shocking. Halting EBV reactivation would not have been able to die on the vine, she thought, if ME/CFS had a clinical trials network and a way to get phase II trials (n=50-500 people) funded. (Phase II trials test both the efficacy and the optimum dose of a drug.)
The long and the short of it is that despite all the interest in EBV and other herpesviruses in ME/CFS, we’ve hardly begun to start assessing the role antivirals could play.
Knocking EBV Down with a 2-Drug Combo
Another question is: why would we expect one drug to knock out such a complex and persistent virus? Dr. Pridgen’s two-drug approach to herpesviruses in fibromyalgia is in stage three trials, and Pridgen’s early data suggested that adding Paxlovid to it could do well in long COVID.
Dr. Klimas did not mention Travis Craddock’s model of EBV reduction, but it was fascinating. Craddock found that if EBV was present in both epithelial and B-cells (it’s latent in both), that while Rituximab could knock down EBV-infected B-cells, the virus would soon re-emerge from EBV-infected epithelial cells. The only way to get long-term EBV suppression with one drug was to use such high doses that it would be toxic.
Adding a timed B-cell treatment to an antiviral drug was different – it flatlined the virus for quite a while. Craddock was continuing to refine the approach but said, theoretically, it could produce a long-term reduction in viral load.
Future EBV Drugs
Given Dr. Klimas’s rather spectacular early success with monoclonal antibodies (mAB) for long COVID (another trial should have begun by now), I had to ask if mABs exist for Epstein-Barr virus. Monoclonal antibodies can be effective against viruses because they can lock onto a virus, target it for the immune system, and keep it from entering cells. mWhile no mABs have, at least ten trials assessing EBV mAB effectiveness against cancer are underway.
Dr. Klimas was interested in trying out a new mRNA vaccine for EBV.
Dr. Klimas was particularly interested in Moderna’s mRNA vaccine for EBV, that is in phase I (safety) trials right now. Moderna is using the same technology it used in its coronavirus vaccine to alert the immune system to the presence of EBV and attack it: that is, it triggers the cell to produce proteins associated with EBV so that the immune system will quickly recognize EBV when it shows up and attack it. Both the mRNA and the proteins produced by the vaccine are quickly broken down, leaving the immune system on the lookout for any viral reactivation.
Dr. Klimas said that as soon as the trial was done, she would be knocking on Moderna’s door to see if they’re interested in working with her.
N of I trials – the Personalized Medicine Approach and the AI Juggernaut
Dr. Klimas wants to see big, well-organized clinical trials in ME/CFS, but she also wants to do big, comprehensive N=1 studies. Since every person is different, if you gather enough data, artificial intelligence can provide treatment plans – first fix this, then do this, and then do that – for individuals.
Speaking of artificial intelligence, data mining and computational biology – it will only get more effective. The sky is the limit with regard to data. The 3 million bits of data per timepoint she and her team gave the computational biologists during the exercise study didn’t impress them at all – they wanted more (and if I have the right study, that was ten years ago).
Dr. Klimas’s team uses chaos theory to look at data from every possible angle.
Klimas’s team uses chaos theory in their supercomputer to come up with answers. The program assesses the data randomly and in every direction possible so that no possibility escapes it – and then provides models her team can assess and test.
One reason we need more NIH-funded studies is that about ten years ago, the NIH required that if they paid for a study, the raw data had to be made public – so Dr. Klimas is pouring NIH-funded ME/CFS study data into her dataset. Since Nath’s intramural study assessed things no one else has done, the data from that study will be quite helpful.
Dr. Klimas said she tried to become a long-COVID RECOVER clinical center but apparently failed because her plans included comparing long COVID and ME/CFS – and that was a no-no. She is in the midst, though, of a large CDC-funded study comparing long COVID and ME/CFS. (If you are in South Florida and have long COVID, please contact her – she needs more participants.)
Institute of Neuro-Immune Medicine Embraces Mind/Body Approach
Lastly, Dr. Klimas didn’t mention it, but an email today indicated that the Institute for Neuro-Immune Medicine is branching out and has teamed up with Conquer CFS to provide people with ME/CFS two months of free access to the Conquer CFS Emergency Reset course created by Max Kennedy – a former person with ME/CFS – in conjunction with Dr. Jenny Jin, an CFS/Fibromyalgia and Pain Management Expert.
More and more ME/CFS experts are including mind/body/neuroplasticity practices in their treatment protocols. To get 2 months of free access:
- Click this link: https://conquercfs.com/courses.
- Select “Emergency Reset Course.”
- Please fill out the form details (including the ‘payment method’ section). Note that the link above provides you with two months of free access. A credit card is needed in case you decide to subscribe for longer.
- Please email mcarr1@nova.edu if you’d like to receive an email reminder at the two-month mark. At this time, you can decide whether to continue with a paid subscription or cancel once the free access expires.
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Thus far, our “What’s Up, Doc?” series has included interviews with Lauren Stiles (Dysautonomia International), Eleanor Stein MD, Wenzhong Xiao (Open Medicine Foundation), and Nancy Klimas (Institute for Neuroimmune Medicine). Talks with Dr. Natelson (neurologist) and Dr. Thomas Henderson will be up shortly, and more are planned. If there’s anyone you want Health Rising to talk to, please let us know. 🙂
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Thanks Cort for a great article.
It’s depressing and disturbing that we knew immune exhaustion is a central fatigue in ME/CFS 35 years ago.
Looking forward positively, let’s hope / pray that PolyBio’s antiviral trials are a success:
https://polybio.org/projects/a-clinical-trial-of-repurposed-hiv-antivirals-in-longcovid/
Also that the rapamycin trials are successful. It could well be that at least part of rapamycin’s value is antiviral
It’s interesting how some treatments seem to work well for certain subsets. It seems pretty clear that ME/CFS comprises either several diseases, or at least several very different manifestations.
Latest results from Carmen S. et al:
https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(24)00330-2/fulltext?uuid=uuid%3Afa264381-5db2-447d-87ab-4fc7bcca6ccf