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Is the NIH’s RECOVER program recovering?
Money, Money, Money
Why has Health Rising spent so much time on the RECOVER Initiative for long COVID? It’s simple – money. Let’s not even think about the $1.15 billion Congress gave RECOVER over 4 years ago. That’s largely gone. In February 2024, however, RECOVER received a $515 million infusion from the Biden administration to support clinical trials.
Nobody else has anywhere close to that kind of money. If we want to more or less quickly get good treatments to the primary care doctors that most of us rely on, we need convincing clinical trials and, in that concern, RECOVER is unique. It alone has the funding to comprehensively explore multiple treatments and quickly get them into doctors’ offices. As ME/CFS researcher Al Aly asserted during the conference, “We need RECOVER to succeed”.
Something recently appears to have changed with the Initiative. It received its new money seven months ago, yet Dr. Marrazzo, the new Director of NIAID (which put on the conference), stated that the conference was quickly put together in the last month. Someone (Director Bertagnolli, Director Marrazzo?) decided it was time for RECOVER to open its doors and bring in some new viewpoints.
It was good they did. In her interview with Betsy Ladyzhets, Bertagnolli said the 2 1/2 day RECOVER TLC meeting – designed to open RECOVER up to new viewpoints – was “crucial” for the success of the Initiative. She’s likely right.
The (Missing) Hunt for Biomarkers
The GIST
- Why has Health Rising spent so much time on the RECOVER Initiative for long COVID? It’s simple – money. In February 2024, RECOVER received a $515 million infusion from the Biden administration to support clinical trials.
- Nobody else has anywhere close to that kind of money. If we want to more or less quickly get good treatments to the primary care doctors that most of us rely on, we need convincing clinical trials and, in that concern, RECOVER is unique. As long COVID researcher Al Aly asserted during the conference, “We need RECOVER to succeed”.
- In her interview with Lady Bezyhats, Bertagnolli said the 2 1/2 day RECOVER TLC meeting – designed to open RECOVER up to new viewpoints regarding its clinical trial efforts – was “crucial” for the success of the Initiative. She’s likely right.
- RECOVER has put itself in a hole. Presenter after presenter acknowledged that the long-COVID field desperately needs biomarkers (“Biomarkers should be a holy grail”) RECOVER put most of its money into investigative studies that are characterizing long-COVID patients – not digging into their pathophysiology.
- The only avenue RECOVER appears to have left to generate strong biological data is by tweaking patients’ systems with treatments and then analyzing how their systems respond. Indeed, in a new field like long COVID, one might have expected RECOVER to use clinical trials to ferret how what was happening with it. In a recent interview, Bertagnolli emphasized how much she expected RECOVER to learn from these kinds of “exploratory” clinical trials.
- We learned, though, that RECOVER is only gathering biological data in its Paxlovid study. Given that it was very good to hear NIAID Director Marrazzo declare that RECOVER would, for the first time, embrace small exploratory treatment trials that are designed not just to see if a drug works but what impact it has on the body as well. Using this approach even a negative clinical trial can provide important insights into what’s going on in long COVID.
- Urgency was the theme of the day but RECOVER has seemed anything but urgent. Most of its clinical trials only opened up over the last year. From day one, RECOVER knew it needed a good long COVID definition but only funded one about 18 months ago and that definition was vague. One consequence is that RECOVER is using very general criteria in its clinical trial studies. Whether you have ME/CFS-like long COVID or pulmonary or kidney-long COVID, RECOVER is treating them as one in its trials.
- While neither RECOVER nor the NIH has provided much of the biological data RECOVER needs to effectively design its clinical trials, Amy Proal of Polybio asserted that “clear leads” are already present and that “we can design really good trials” right now. Monoclonal antibodies that have proved effective in small trials are wasting away on drug company’s shelves unused.
- Avindra Nath stated that he thought it was time to stratify patients on the kind of immune dysfunction present and target it in treatment trials. These are the kinds of exciting approaches being done outside of RECOVER which has focused its large trials on mostly conservative treatments (brain retraining, sleep hygiene, melatonin, exercise, Ivabradine).
- The use of “Platform trials” was widely agreed on (Stephen Deeks (UCSF), Lisa McCorkell, Avindra Nath, NINDS representative). Because these trials use one control group to test multiple treatments, they are considerably cheaper and faster than using different control groups for each study – as RECOVER is doing now. Other suggestions such as using a “playoffs” model where treatments vie against each other in small studies before the winners move on to bigger studies, combination, and remote trials.
- The Paxlovid trials underway are an example of what NOT to do. Four very similar trials were underway. Because Paxlovid hasn’t been assessed for safety beyond 2 weeks, the trials appear to have lasted all of 15 days (!) – probably far too short a time period to make a dent in as complex a disease as long COVID.
- Several presenters asserted that LC patients need to be given a risk/benefit choice and that noted many LC would rather take some risk (say in a longer Paxlovid trial) than remain in their present state. Others asked why anyone thinks one drug is going to do the trick when multiple drugs are commonly needed for infections and chronic illnesses.
- It was clear that a major stumbling block for the long-COVID field (and for ME/CFS, POTS, etc.) has been a lack of industry engagement. Avindra Nath, for instance, tried but failed to interest pharma in exploring checkpoint inhibitors in LC. One industry rep said pharma is perplexed by long COVID and is unclear which drugs to try.
- Stephen Deeks (UCSF, LIINC), though, provided a blast of fresh air when he bluntly said that he didn’t believe that repurposed drugs would do the trick. In a recent article, Deeks called long COVID’s effects on the body as “chaos and mayhem” 🙂 and said what the field needs, above all, are objective markers.
- There’s no mystery to beating LC, Deeks said. We simply have to do what we did with HIV/AIDS; that is, embark on a massive effort to understand the mechanisms that are driving it and develop the biomarkers that drug companies need to enter the LC space.
- We also need good “endpoints” – the symptom markers by which drug companies can tell if the drug is working. Seth Lederman of Tonix, the company that developed the Tomnya drug that is under approval at the FDA for fibromyalgia, asserted that if FDA would PUBLICLY declare that the Patient Global Assessment of Change (PGIC) is a valid assessment for long COVID, drug companies would move in.
- Not many people are excited about RECOVER’s clinical trials, but that may be changing. Meighan Stone, the founder and executive director of “The Long COVID Campaign” and co-author of “Awakening: #MeToo and the Global Fight for Women’s Rights” said she was hopeful for the first time in a long time.
- Time will tell how this all sorts out, but the panels of speakers RECOVER brought in suggested it’s making a sincere effort to move forward. We need to give RECOVER a chance
- RECOVER is staffed by people new to the field, who had to build a big project on the fly, and mistakes were probably bound to happen. If RECOVER self-corrects, this wouldn’t be the first time that a large endeavor at the NIH got off to a slow start but successfully rebooted itself.
- NIAID Director Dr. Marrazzo pointed to a new, more open and creative RECOVER. She promised: small mechanistic/exploratory clinical trials and platform clinical trials will be done; that RECOVER will employ the same processes the ACCT/ACTIV network used to identify long COVID drugs; that RECOVER will work with the FDA to define endpoints to use in drug approvals; that the larger trials will be done in such a way to lead to FDA approval; that communication and collaboration, especially with patients groups, will increase and that monthly progress reports will be provided.
- For RECOVER’s arguably most important challenge – its clinical trials effort – to succeed, it needs biological data to guide it, and that’s an even bigger challenge. Stephen Deeks asserted that a massive effort akin to what was done in HIV/AIDS is needed to uncover the biomarkers and mechanisms driving long COVID. Once those are discovered, the pharmaceutical companies – as they did with HIV/AIDS – will jump in.
- The NIH, thus far, though, has not embraced long COVID (or ME/CFS or post-infectious diseases, in general) and no massive effort to uncover biomarkers is underway. One could be underway, though, and very quickly, if the Long COVID Moonshot Bill is passed. Get that bill passed and the circle is complete: we have a robust research effort that informs the search for good treatments. That’s where we want to be and that’s where we must put our efforts. Find out more here.
Both NIH Director Bertagnolli and NIAID Director Marrazzo (pictured) are new to their jobs – and both appear to be interested in long COVID and ME/CFS.
The start of the first day kind of encapsulated the concerns regarding RECOVER: nothing worked! The Zoom link originally sent out was incorrect, leaving dozens of us staring at a mostly blank screen for 40 minutes. Eventually, someone remembered to tell us a new Zoom link had been sent out. NIH Director Bertagnolli’s opening talk was missed. (She reportedly hung around the conference for the rest of the day.)
Once the link was restored, the news was good. NIAID Director Marrazzo – who reportedly is very interested in both long COVID and ME/CFS – quickly uttered some words many of us wanted to hear: “exploratory clinical trials”.
RECOVER has put itself in a hole. Presenter after presenter acknowledged that the long-COVID field desperately needs biomarkers (“Biomarkers should be a holy grail”).
RECOVER, though, put most of its money into investigative studies that are simply characterizing long-COVID patients. (When Clint Wright, the NINDS representative, exclaimed about the urgent need for biomarkers, he might have looked into the mirror and asked himself how much long-COVID research NINDS is funding? (Answer: not much).
Right now neither RECOVER nor the NIH has produced the biological data it needs to guide it. RECOVER has created a huge biorepository of samples – a real strength – but appears to lack the money to assess them.
RECOVER did not do itself any favors when one representative said, with a straight face, “Thanks to RECOVER, we know much about the biology of long COVID”. A review of RECOVER’s publications uncovered just 9 pathobiology studies, 3 of which did not apply to the ME/CFS-like subset, and most of which were quite small, (and which RECOVER only partially funded). That’s a pretty paltry result.
The fact that RECOVER used Michael VanElzakker’s fascinating study as a showcase of what it’s done for long-COVID (LC) pathophysiology was emblematic of the problem. VanElzakker’s study linked neuroinflammation to vascular problems – a potentially key finding – but employed just 12 LC patients!
Time will tell what’s coming down the pike, but the only avenue RECOVER appears to have left to generate strong biological data is by tweaking patients’ systems with treatments and then measuring how their systems respond. Indeed, in her Ladyzhets interview, Bertagnolli emphasized how much she expected RECOVER to learn from these kinds of “exploratory” clinical trials.
Thanks to an alert questioner, though, we learned RECOVER only gathered biological data in the”Vital Paxlovid” trial. It’s true that many of the trials (brain retraining, exercise, goal setting, sleep hygiene) probably wouldn’t have provided much information but the IVIG, modafinil, and rTMS trial might have. With the exception of IVIG, though, these aren’t the kind of treatments that could be used to provide relief and deeply probe long-COVID pathophysiology.
In the end, RECOVER chose a conservative clinical trial approach to assess a conservative set of treatments. (RECOVER has never, to my knowledge, publicly acknowledged their rationale for choosing the treatments they did.)
The lack of initiative RECOVER showed on the clinical trial front was puzzling because if any disease seemed to call for a creative approach, it seemed like long COVID did. Given that LC is a new and complex disease, one would have thought RECOVER would have found ways to take a poke at it, so to speak, with exploratory clinical trials.
Exploratory Clinical Trials
These trials have been happening at a small scale outside of RECOVER with the LIINC Initiative at UCSF, at PolyBio Research Foundation (whose motto is “Science in Action”, and at the REVERSE long COVID baritcinib trial. Amy Proal reported that PolyBio will not put on any clinical trials until it also has the funding to also explore LC patients’ biology. Steven Deeks said he knows of 4 or 5 drugs that could effectively probe LC’ patients biology.
With Marrazzo immediately supporting these exciting projects, it appears RECOVER is about to change. With its $515 million infusion, RECOVER has the funding to dramatically expand these efforts. Let’s hope it fully embraces this opportunity.
Urgency!?
Urgency, ironically, given that RECOVER has not begun its exercise trial, has only recently begun its sleep trial, and only opened its autonomic nervous trial in March of this year, and its Neuro trial in October of last year, was a key theme. One RECOVER presenter said, “We have no time to waste”, and indeed, we don’t. On the one hand, it’s good to see RECOVER acknowledge that “we have no time to waste”; on the other, it’s a little jarring given how long RECOVER has taken to get its initial trials going. It took six months after RECOVER received its funding for it to decide to put this conference on!
We learned that it was only about 18 months ago, or 2 and 1/2 years after long COVID came on the scene, that RECOVER tasked the National Academy of Sciences (NASEM) to create criteria for long COVID. Given the critical need to define the illness for its studies and trials, one wonders what took RECOVER so long.
NASEM then took about 18 months to produce the criteria. While the criteria have been lauded, they are intentionally inclusive and not precise enough to define subtypes. (Note that the NASEM reported that the biggest problem with defining #longCOVID is a lack of a biomarker.)
We’ll see that the lack of a biomarker doesn’t necessarily stop the clinical trials – there are ways around that – but finding one would propel the field forward tremendously. Finding a biomarker, though, will surely require that RECOVER uncover the distinct subsets in the long-COVID population and explore them deeply.
RECOVER’s Broad Brush
I would have thought uncovering these subsets would have been one of RECOVER’s first tasks, but that hasn’t happened. As a consequence, RECOVER is taking a broad brush in its current clinical trials.
Participants must have had an “acute onset of fever AND cough (influenza-like illness)” OR “acute onset of ANY THREE OR MORE of the following signs or symptoms: fever, cough, general, weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, nausea, diarrhea, anorexia”, as well as cognitive dysfunction (for the Neuro trial), sleep issues (for the sleep trial), etc.
RECOVER, then, is investigating very general symptoms (sleep/cognitive problems/fatigue”) – any of which could be caused in any number of ways – across a wide variety of unidentified subsets. Surely the pulmonary subset, for instance, could be experiencing cognitive problems for different reasons than the ME/CFS-like subset. (Notice that post-exertional malaise is not mentioned.)
That’s one reason we need biological data to guide the clinical trials.
Infrastructure Needed
Thankfully, there are no illusions about the scope of the task ahead. Despite the fact that long COVID is produced by a single pathogen, I don’t think anyone hasn’t been surprised by how complex the disease is. (HIV/AIDS is looking like a cakewalk compared to long COVID right now.) Given that, it was good to see a speaker acknowledging the need to “plan for infrastructure because this is going to go on for a long time”.
Infrastructure, or more specifically, the lack of it in the NIH (outside of the RECOVER program), is a crucial point. I could find no evidence of an organized effort at the NIH to combat long COVID. The fact is that few grant opportunities can account for the low levels of funding and a scattershot approach to the disease as a whole. The NIH has clearly not gotten behind long COVID.
Treatment Approaches
While what’s ultimately causing LC is unclear, there are no lack of potential treatments to explore. Amy Proal of PolyBio declared, “we can design really good trials” right now, and she referenced the “clear leads” that were already present.
She noted the success that monoclonal antibody drugs have had with some LC patients, plugged Michael Peluso’s and Stephen Deeks’s small exploratory mAb trial (no NIH funding), and decried the fact that monoclonal antibodies are sitting unused on drug company shelves – and are about to expire. (One article stated that “gallons of monoclonal antibodies” are losing efficacy over time). Some think that monoclonal antibodies will be more effective than antivirals at bottling up the coronavirus (or other pathogens).
Nancy Klimas found dramatic success with some older mAbs, and received funding from the state of Florida for another which should be underway now.
(At Mt. Sinai, David Putrino, who was not at the conference, is assessing the effects of two broad-spectrum antivirals, monoclonal antibodies, immune modulators, and anti-clotting drugs this year. He hopes to launch a major multi-treatment platform in 2026).
Avindra Nath – who believes that problems with B-cell maturation is driving ME/CFS and LC, said it was time to stratify patients on the kind of immune dysfunction present and target that in treatment trials. That’s the kind of biological approach that’s needed.
In that vein, one commenter noted that the remarkable hepatitis C treatment success came about largely because of government support but that the NIH is currently providing no funding for direct long-COVID drug trials.
Platform Trials
Some time ago, Nath introduced the idea of “platform trials“; indeed, he suggested that the ME/CFS and LC fields would be lost without them. Stephen Deeks (UCSF), Lisa McCorkell, and the NINDS representative also endorsed the platform trial concept.
Platform trials compare “multiple, simultaneous…interventions against a single … control group. They attempt to answer the question: “which therapy will best treat this disease”. Because these trials use one control group to test multiple treatments, they are considerably cheaper and faster than using different control groups for each study – as RECOVER is doing now. Again and again, speakers urged RECOVER to incorporate platform trials into their program.
Other suggestions such as using a “playoffs” model where treatments vie against each other in small studies before the winners move on to bigger studies, combination, and remote trials.
The Paxlovid Predicament
The Paxlovid trials underway are an example of what NOT to do. With limited funding available, there’s no reason that we needed 4 Paxlovid trials. Even Dr. Marrazzo appeared to think that was too much.
Plus, because Paxlovid hasn’t been assessed for safety beyond 2 weeks, the trials appear to have lasted all of 15 days (!) – probably far too short a time period to make a dent in as complex a disease as long COVID. The NIH’s Paxlovid trial was 900 persons strong and probably cost tens of millions of dollars to bring off.
Several presenters asserted that LC patients need to be given a risk/benefit choice and that noted many LC would rather take some risk (say in a longer Paxlovid trial) than remain in their present state. Others asked why anyone thinks one drug is going to do the trick when multiple drugs are commonly needed for infections and chronic illnesses.
That brought to mind Skip Pridgen’s early success with adding Paxlovid to his 2-antiviral regimen to treat herpesviruses.
The Big Stumbling Block – Getting Industry Engaged
It was clear that a major stumbling block for the long-COVID field (and for ME/CFS, POTS, etc.) has been a lack of industry engagement. Avindra Nath, for instance, tried but failed to interest pharma in exploring checkpoint inhibitors in LC. I missed the industry talk on the last day but an industry rep said that pharma is perplexed by long COVID and unclear which drugs to try.
That provided a nice entry for Stephen Deeks (UCSF, LIINC), though, who provided a blast of fresh air when he bluntly said that he didn’t believe that repurposed drugs will do the trick. In a recent article, Deeks called long COVID’s effects on the body as “chaos and mayhem” 🙂 and said what the field needs, above all, are objective markers.
There’s no mystery to beating LC, Deeks said. We simply have to do what we did with HIV/AIDS; that is, embark on a massive effort to understand the mechanisms that are driving it and develop the biomarkers that drug companies need to enter the LC space.
(That kind of effort is not even close to happening at the NIH. The massive research effort that Deeks believes will win the day for long COVID – and could do so rather quickly – could happen in a flash, though, if we pass the Long COVID Moonshot bill currently making its way through Congress. The bill provides $10 billion over ten years for long COVID, ME/CFS, POTS, and post-infectious disease research.)
Our future is in our hands! Please support the Moonshot bill!
It’s not just the lack of biomarkers that’s scaring drug companies off. Absent them, they need good clinical endpoints (symptom assessments) they can trust to tell them if their drug is working or not, and they don’t feel they have them. Seth Lederman of Tonix, the company that developed the Tomnya drug that is under approval at the FDA for fibromyalgia, had some ideas around that.
Lederman asserted that if the FDA PUBLICLY declared that the Patient Global Assessment of Change (PGIC) is a valid assessment for long COVID, drug companies would feel secure enough to enter the field. Lederman noted that early on, using the PGIC in cancer dramatically accelerated the number of cancer drugs under investigation.
Todd Davenport (Workwell Foundation) asserted that we do actually have objective measures, such as reduced blood flows to the brain, that could readily be established to assess treatment effectiveness. Plus, the ME/CFS field, in collaboration with the CDC, produced a set of Common Data Elements that could be helpful in standardizing research efforts and assessing clinical trial effectiveness.
In other words, there are ways to move forward with clinical trials while the work to uncover biomarkers goes forward.
Others
Jaime Seltzer (#MEAction) aptly noted that every long-COVID patient who testified had gotten better after learning what helped with ME/CFS. She argued for the inclusion of ME/CFS patients in clinical trials. She (and Todd Davenport after her) also noted the strange disappearance of PEM from the discussion thus far. Davenport reported that PEM is uniquely disabling, highly individual, dramatically effects functioning, and assessing it must be part of any long-COVID clinical trial regimen.
In a nice analogy, Davenport reported that the long-COVID field “is now rushing to catch a flight without packing a suitcase”. I took that to mean that it and RECOVER still has much to learn from both the ME/CFS field and the historical underfunding and marginalization of ME/CFS research.
We need to understand why, even after decades of demonstrating the great needs of the ME/CFS community and the field itself, ME/CFS remains stuck with low and even declining funding at the NIH. Something in the way the NIH operates not only prevents it from embracing “outsider” diseases like ME/CFS, fibromyalgia, POTS, ME/CFS, long COVID etc. but seems to actively work against them.
Until the reasons for that are made clear and rectified, all these disease are at risk.
Conclusions
Not many people are excited about RECOVER’s clinical trials, but that may be changing. Meighan Stone, the founder and executive director of “The Long COVID Campaign” and co-author of “Awakening: #MeToo and the Global Fight for Women’s Rights” said she was hopeful for the first time in a long time.
Time will tell how this all sorts out, but the panels of speakers RECOVER brought in suggested that it’s making a sincere effort to move forward. From Ziyad Al Aly to Michael VanElzakker to Amy Proal to Jaime Seltzer to Hannah Davis to Peter Rowe to Ian Lipkin to Micheal Peluso to Avindra Nath to Steven Deeks and Paul Utz, RECOVER included panelists it must have known would push it to move forward in new ways.
Giving RECOVER a Chance
The post-infectious disease field is essentially a new one. RECOVER is staffed by people new to the field, who had to build a big project on the fly, and mistakes were probably bound to happen. If RECOVER self-corrects, this wouldn’t be the first time that a large endeavor at the NIH got off to a slow start but successfully rebooted itself.
RECOVER has going for it a large infrastructure (too large?) (157 clinical sites, 243 principal investors) that can track patients over time, and produce clinical trials that use the same endpoints, as well as a huge sample biorepository (about 1,000,000 samples that includes over 200 (unlucky) participants in its autopsy program).
Now, a new way forward has been provided that RECOVER appears to be embracing. Time will tell how much, ultimately, that RECOVER will take on board, but NIAID Director Dr. Marrazzo seems to be committed to dramatically changing its course. She promised:
- While outlining it in red, Marrazzo made a special point that addressing “mechanistic questions” (i.e. what’s causing the disease) would inform RECOVER’s priorities in the next trials. (Instead of treating symptoms, RECOVER will focus more on getting at the heart of the disease in the next trials).
- RECOVER will employ the same process that worked in ACCT/ACTIV network to assess COVID-19 drugs to help identify LC drugs to test.
- Small mechanistic/exploratory clinical trials to get at long COVID’s underlying pathophysiology will be done.
- Platform drug trials to more quickly and cheaply assess multiple treatment possibilities will be included.
- RECOVER will work with the FDA to define endpoints that RECOVER and industry can use to get drug approvals.
- The larger trials that are done will be done in such a way so that, if they are successful, they will help lead to FDA approval.
- Communication and collaboration, especially with patients groups, will increase. New working groups with the appropriate expertise will be produced.
- Monthly progress reports will be provided.
Ziyad Al Aly is right: failure is not an option for RECOVER. RECOVER’s clinical trials program appears to be moving in the right direction, but it is only one piece of the puzzle. For RECOVER’s arguably most important challenge – its clinical trials effort – to succeed, it needs biological data to guide it, and that’s an even bigger challenge.
Stephen Deeks asserted that a massive effort akin to what was done in HIV/AIDS is needed to uncover the biomarkers and mechanisms driving long COVID. Once those are discovered, the pharmaceutical companies – as they did with HIV/AIDS – will jump in.
The NIH, thus far, though, has not embraced long COVID (or ME/CFS or post-infectious diseases, in general) and no massive effort to uncover biomarkers is underway. One could be underway, though, and very quickly, if the Long COVID Moonshot Bill is passed. Get that bill passed and the circle is complete: we have a robust research effort that informs the search for good treatments. That’s where we want to be and that’s where we must put our efforts.
‘Nancy Klimas found dramatic success’
great! So what’s she doing to follow that up? ‘Dramatic success’ is a huge claim. It implies a treatment is a no-brainer and should move forward at pace as a treatment
As the blog states “Nancy Klimas found dramatic success with some older mAbs, and received funding from the state of Florida for another which should be underway now.”
Hi Matthias, After reading your comment on the last post about a lot of important research that we are not hearing about, I decided to do some research on the ME Association site and found a goldmine of provocative studies including this one.
“Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/anti-pathogen agent in a retrospective case series”
Nancy Klimas is one of the authors of this study published in March of this year. I am very interested in the nebulized treatment that was so successful in relieving symptoms of both ME/CFS and Long Covid.
This study was funded by NIH
R01 AI159314-01
(LKS), Ramsey Award (SolveME, Inc.) (LKS), private donations (LKS) and Patient -Led Research Collaborative (LSK).
If you want to know more about the nebulized agent used in this study, go to https://inspiritol.com/
Thanks Betty. Will look at it.
Despite NIH’s uselessness, fortunately there’s a lot of great research happening.
In a recent YouTube video, Jarred Younger seemed very excited by some research he had heard of that (he couldn’t reveal) will apparently be published in the near future.
There’s hope!
Actually, the study I referenced on CD8 T cell dysfunction and treatment with Inspiritol was funded by the NIH. The problem with research today
is that each researcher is working on their own hypothesis, but without confirmatory studies by others, these just result in “teasers” that is, interesting diagnostic or treatment concepts that never become available to the ME/CFS or Long Covid populations.
Research is extremely competitive both for the scientist(s) and the university they work for which takes 30-60% of the grant off the top for overhead.
Let’s look at it this way, if the billion dollar Moonshot is funded, at a minimum $300,000,000 will go to overhead costs, not research.
In an ideal world, three studies on the same concept would be conducted at three different universities or agencies using the same protocol. Then, it would be easy to determine if the hypothesis is correct or just another blind alley.
Although very interesting, with apparently very significant efficacy, it was a small group of patients. It would be interesting to hear what clinical trials might be planned. Perhaps since Cort knows Dr Klimas he might be able to ask.
I presume there could be massive commercial benefit for Salerno if a trial was successful.
These promising leads need follow up!
Reading the study it seems like they are looking at clinical trials
Betty, that is such a good point about small studies not being followed up with larger studies, or larger studies not being repeated by different groups to see whether the results can be replicated.
This is what has struck me over and over again in reading about ME/CFS research.
Perhaps the one area in which we do have some replication (thanks to the overlap with autonomic research) is the low blood flow to the brain.
I thought Nath thought the problems lie in the brain/CNS
I believe that the brain/CNS finding of Nath’s study may not be the cause of ME/CFS, but rather a protective (fatigue-inducing) mechanism to prevent running into PEM. So I think it’s encouraging he’s looking for the problem elsewhere.
While a lot of discussion focused on the CNS from the very beginning Nath focused on the immune system – it was kind of lost!
Hi Cort, I notice that lately articles are more often posted without The Gist.
As I am at the beginning of severe scale, and often read only the much-appreciated Gist box, I’d prefer if The Gist wasn’t added later, but rather the article posted later but including The Gist. (to avoid the energy expenditure of scrolling in vain down the article in search of the Gist, which has been the case a couple of times now). Thank you very much!
“If I had more time, I would have written a shorter letter”
– Mark Twain (and others)
🙂 Yes! It’s surprisingly hard to pick out the main points and summarize an article. Usually, in truth, it goes pretty well.
I always admire your ability of doing exactly that. I hope I have often enough expressed I’m grateful for you doing so. It is a great accessibility service to those not able to digest the whole thing, so I hope at least you know the extra work is appreciated! 🙂
Thanks! Yes, I know the GIST is really appreciated! 🙂
Well yes I know that, but the movements related to navigating a page are particularly draning to me (typing is better because I can do them piano-style with less muscular repetition). I have problems with hand movements in particular (like cleaning movements, or similar to what Whitney once reported how pressing with fingertip will quickly overexert him, while pressing with elbow will not.
I do hope you were not criticizing my post, because this site is my window to the world of ME/CFS science and I really appreciate the gist providing the accessibility for me to continue doing so as I’m mostly not cognitively able to take in the full article.
Just jumping in here to explain that the reason I do the narrations is because when I was more severe it took too many spoons to read articles and the only way I could take them in was when narration was provided, as it takes less neurological energy to listen than to read and scroll as you pointed out (I totally get that). So the idea is to be more inclusive of people with more severe ME. One idea is that you could wait for the e-mail to come out, at which point most of the time both the GIST and main article have been narrated. I usually aim to do both within 24 hours of the article first being posted.
Yes the narration feature is a great new accessibility feature, it’s a great service that you’re doing this! We’re all a bit different, aren’t we? 🙂 I have about zero ability of auditory intake of narration, probably relating to hypersensitivity to noises. I don’t get any email notifications (and would really not like to have more of them in my overflowing inbox). I’m used to just checking the website for new blogs.
Maybe there’s a way Cort could send the article text to you other than posting it publicly? so everything (article, narration and the gist) could be posted all together, once everything is ready? Or, I don’t know, maybe the blog has some sort of joint working or limited access setting so Cort could share it with you for narration and then make it public once everything is in place? G avoid misunderstanding, I’m definitely NOT suggesting to do the gist earlier, but rather to wait-up with pulishing everything until all the parts are in place.
With low energy, I don’t feel good about something being in limbo and having to come back to a blog more than once to see if the gist is there. I had been thinking the Gist could also be important to get more scientists to read and follow the blog, who may not have more than a couple of minutes to spare for reading (I had intentend to recommend the blog and particularly the gist to the scientists I sometimes write to, and I guess it would be confusing if it’s not there). I suppose there’s some potential for confusion when an article is posted sort-of “incomplete” and parts added later, because that’s not what most people are used to from the internet.
If it’s too much trouble doing it differently I understand and will definitely survive :-), just saying I’d prefer and would find it clearer if everything were posted together. I also understand there may also be articles too short to warrant a gist or of the urgent type like informing on a petition as early as possible, or times when Cort our hero’s battery runs low ..
The blogs first get edited and then are posted online so that Geoff can provide narration for them. I want to have the GIST done by then but often do not. Writing the GIST usually comes at the end of a long day of writing and believe me, I am usually not a happy camper at that point! There’s something about summarizing an article that seems particularly daunting at that point.
My main goal is to get the GIST in BEFORE the email and social media blasts are sent out. It’s basically a matter of how much energy I have.
Sorry about the inconvenience. I’m working on the GIST now and it should be up soon!
Thanks Cort for explaining that the change is related to the new narration feature. I could never do all that you do 🙂 Maybe there’s a way to get the blog to Geoff other than posting, so all can be published as one? I don’t use social media, just check your website every couple of days for updates.
I see! How about subscribing to the blog? That way once you see the blog in your inbox you can be pretty sure that the GIST will be in there. 🙂
Just want to say you day an amazing job and we are grateful for you!
Thanks!
You can bet as soon as a treatment or cure is found that GREED will step in and take over…many people will profit from us sick people
As for Paxlovid: It took a strenuous feat of self-advocacy to obtain it but I’m very glad I did. Not only did it wipe out my fairly severe case of covid in 2022, but it also seems to have put my ME/CFS into temporary remission, for about a month (a very enjoyable one!). I followed up by reporting this experience to my ME Dr and asking for more antiviral treatment but was denied and told there is no evidence viruses have anything to do ME/CFS.
holy crow!!
I have yet to read this blog post, but look forward to it.
I was given an opportunity to offer a public comment at the RECOVER TLC meeting. Here is the 3 minute video I made in advance that aired as part of the meeting: https://www.youtube.com/watch?v=4KvZw07hlcU
Nothing has changed. Research money keeps pouring into a leaky bucket. Prof. Scheibenbogen admitted there’s still no biomarker for Long COVID or ME/CFS.
https://mecfs-research.org/researchfunding-charite-details/
You’d expect RECOVER to have made progress by now, but it remains aimless, poking in the same direction without results.
No serious studies have focused on brain inflammation (meningitis), the endocrine system, or the hypothalamus. What about the lungs—has anyone looked into the possibility of cystic fibrosis? What about the kidneys or adrenal glands? Has muscle weakness been investigated for potential SMN1 or SMN2 impairment? Where are the CSF tests for lingering or reactivated viruses, bacteria, or fungi?
The only real winners seem to be the pharmaceutical companies, which sell medications and supplements that often have more side effects.
I’m absolutely convinced that Dr Clare Craig is right: https://x.com/i/status/1839239471515967856
Some reasons why ME (and other similar diseases) has been downplayed are that they are not cancer, not stroke, not HIV (though I believe HIV had a rough start too), heart attack etc.
Hart failure is lesser ranked than heart attack, lung cancer is lesser than breast cancer, geriatric less than pediatric, acute lesser than chronic.
Neuro is mystic to most peop, even amongst medicine, espescially diffuse neurological symtoms (and the not so diffuse are truly scary!).
Accidents (broken bones, wounds, cuts etc) are easier than internal medicine and diseases. Often you can fixs the patient right there and then, while diseases are more diffuse.
There are more status in working in an emergency dept than in rehab which is still fancier than dementia or lung diseases caused mainly by smoking.
And then, when you add all these symtoms that are oh so disabling, but still somewhere between physiological psychological, some very measurable if recognized as mesurable and not “just” mood, like dysautonomia.
I live in Europe, but NIH probably work about the same as our institutions. Problems that are acute (causing death if nothing is done – like Covid, like fancy diseases (heart, internal organs …), diseases with high status. And that are measurable and treatable or persived as a lagre threat. That is what they are concentrating on.
Other diseases get more “words” about how important they are, like psychological health among our young, depression and lonliness among our elder, the wave of overweight/obesity, but are less funded in reality and left for the individual to cope with being some kind of fault of your own. Lifestyle changes to cure everything.
Lifestyle changes etc are important, but implying that it is the only thing, or that one is doing to little to get well is truly damaging.
I do believe that these things are still hampering our “medical leadership” in really understanding and adressing the needs. Sadly.
It’s not fancy …
Sorry, I’m in THAT mood today.
Shouldn’t we gradually conclude that this disease is invisible with the current medical state and techniques? Or are the doctors not looking properly enough? I think we’ve reached a dead end. And what do we actually know about this disease?
I’m on the opposite end.I recently talked with an ME/CFS expert who said she could be retiring now but wanted to stick around because it was so exciting. So many more people are looking at these diseases now. Just the fact the PolyBio and others are already, and RECOVER is going to start, probing LC patients with experimental treatment is really exciting. We have a whole slew of researchers looking at these diseases now.
Just think what we could do if we passed the Moonshot bill (!)
I agree. There’s lots of research happening, as per a previous post from me lots of interesting stuff that hasn’t even been covered on this amazing website, and that’s saying something!
I am very interested in the University of Oxford’s long covid study that was published earlier this year. They found ongoing inflammation, raised IL-6 and high levels of hepcidin. I am especially interested in the high levels of hepcidin, as this affects how iron is used by the body, and can contribute to PEM, fatigue etc.
High hepcidin also impairs immunity, so could be contributing to lower immunity, higher inflammation etc which then leads to higher hepcidin etc etc. round and round in circles
Perpetuating a chronic disease state
Cort it’s not a mystery why ME/CFS is suddenly being included in the RECOVER Initiative. #NotJustFatigue and their lobbying firm have been working all year for it to be included. And they were successful in getting a Senate L-HHS Directive to include ME/CFS in the RECOVER Initiative early this summer. The NIH is aware of this and knows it’s coming. That’s how these things work.
I would love to hear more about this 🙂
Hi Cort,
I am always deeply consterned about how stupid we are as a human specie.
We (mainly politicians and totally greedy immoral and corrupted leaders running all businesses including medical research) are never able to learn from past events in history and always having to keep doing stupid things all the time (like wasting 1.15 Billion) until the pockets of everybody are full. Then we turn around and ask for more money to do the things we should have done right away at first. And the wheel keeps spinning on and on.
The leaders running the cigarette industry did the same stupid things and caused so many cancers to naive people trusting the honeyed pubs saying that cigarette was not nocive for health.
The leaders running the oil industry are doing exactly the same stupid things actually with climate change causing so many dammage to environment while naive people are trusting the honeyed pubs and false studies saying that oil industry has absolutely nothing to do with it.
Damn we are stupid…
“RECOVER has put itself in a hole. Presenter after presenter acknowledged that the long-COVID field desperately needs biomarkers (“Biomarkers should be a holy grail”).”
This is the most important sentence you wrote.
I wish ME/CFS and LongCovid advocates would concentrate their entire resources on advocating for legislation, and funding for ME/CFS and LongCovid diagnostic biomarkers from bench to bedside. They are literally the only thing that will save us and the NIH is blocking them deliberately and maliciously.
In 2012, the FDA turned down Ampligen as a treatment for ME/CFS because “there is no diagnostic blood test for ME/CFS.” and the NIH has never called for funding of ME/CFS diagnostic biomarkers and has denied funding for potential ME/CFS diagnostic biomarkers like the Nanoneedle. That is not a bug. It’s a feature. Bertagnolli and Marazzano do not appear to be willing to adopt the one policy that would make RECOVER-TLC successful.
I fight for ME/CFS diagnostic biomarkers because I’m fighting for a FDA-approved treatment.
There is no way forward for RECOVER-TLC unless the NIH calls for direct funding for LongCovid and ME/CFS diagnostic and prognostic biomarkers.
The HIV blood test that was invented as a blood screen and it came before the AZT.
If you want a treatment for LongCovid and/or ME/CFS fight everyday for diagnostic biomarkers.
Dr. Alain Moreau, Ph.D. has 11 MicroRNAs that can identify and Stratify LongCovid patients into 6 clusters by provoking PEM through a Cuff and objectively measuring them through something called Hexoskin. More importantly, these MicroRNAs can identify Drug Responders, and we need Drug companies like Aim Immunotech et al to adopt their use so we can get this show on the road.
MicroRNAs are the easiest to translate into the clinical lab from the research lab because it’s already been once before. There’s an explosion of MicroRNA biomarkers coming down the pipe for various diseases.
Dr. Alain Moreau should have been at RECOVER TLC conference to inform researchers, clinicians, and Industry people of that. But he wasn’t. So who didn’t want him there? Why was he absent?
Hi Andrea,
Here is the link for the studies you are talking about. This is in Montreal.
https://www.omfcanada.ngo/collaborative-research-center-montreal/
I already gave Cort this link about two months ago.
Here is also an interesting paper (in french) about the diagnostic test itself but I guess you can pass it through google translate.
https://lemedecinduquebec.org/archives/2023/5/encephalomyelite-myalgique-et-fibromyalgie-un-premier-test-moleculaire-pour-poser-le-diagnostic/#:~:text=Le%20P%20r%20Alain%20Moreau,pi%C3%A8ce%20d%27un%20puzzle%20complexe.
The COVID studies to date seemed to just be duplicating tests already done on ME/CFS. So disappointed. The NIH long-term study was also a big disappointment. So many exploratory studies are small and never followed up. This one says “small mechanistic/exploratory clinical trials and platform clinical trials will be done.” How about some 2nd and 3rd studies?
To me, we need to start from Dr. Naviaux’s Cell Danger Response study that showed cells were not properly energy because glucose and oxygen are not generating mitochondrial energy. A follow-up showed excess sodium in the cells inhibits the ejection of potassium. There was also info from a theoretical bio-chemist (maybe bio-physicist) that started with Naviaux’s cellular level and followed it thru the myriad of symptoms generated (i.e. if this does that, it would lead to the next group of symptoms). Personally, I believe this all leads to cortisol dysfunction from the danger constantly reporting to cortisol’s alarm system. When it doesn’t self-correct, it keeps trying to constantly throw more adrenaline at it, which is the main source of our adrenal fatigue. The old Light studies showed adrenaline fully on 3 days after the trigger. Further, I believe that internal and external factors keep pushing us over the top. Whether it is the autonomic body problems being reported to cortisol, or the problems with external factors such as dealing with problem people, hot sun, loud noises, pushing ourselves too far mentally, physically, emotionally or environmentally – they all trigger the cortisol alarm system which then tries to correct with adrenaline. When it doesn’t fix itself, the whole process goes down the rabbit hole. Dealing with the cell not producing energy keeps cortisol on the edge of the fence, anything more pushes us back into a dauer state. The only way to stop the downward spiral is to sleep. Oxygen not being in the cells is very bad for the brain (and all of its functions), the digestive system, heart and liver, the biggest users of oxygen in the body. “The liver, brain, and heart consume the most oxygen in the body.
“The liver consumes 20.4%, the brain 18.4%, and the heart 11.6%. All of the skeletal muscle combined consumes 20%, the kidneys 7.2%, and the skin 4.8%. Everything else in the body uses the remaining 17.6%.”
Is it possible that there isn’t a biomarker for Long COVID, or for ME/CFS? Many diseases and syndromes don’t have biomarkers and are still diagnosed and researched.
While it would be good to find a biomarker (or a group of them), I agree with Todd Davenport that we don’t need to wait. There are other things that can be measured right now.
Cort, did you see the nifty proof of concept that Workwell did with a Lumia (formerly Stat) earpiece and some exercise testing?
Also, there was some interesting “big data” research on brain fog recently:
https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2024.1409250/full
I’m afraid it glaringly misses some opportunities on asking about comorbidities/other diagnoses, but it still has value, I think.
Thank you for another great article.