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Is the RECOVER Initiative listening to 30 years of experience? Time will tell. 

RECOVER Initiative listening to ME/CFS

Does the RECOVER Initiative believe that 30 years of work on post-infectious illnesses has something to offer it? Time will tell.

The RECOVER Initiative is not just a big deal for long COVID; it’s potentially a very big deal for chronic fatigue syndrome (ME/CFS), post-treatment Lyme disease syndrome, fibromyalgia, and many other diseases that are often triggered by an infection. With so much money going into the RECOVER Initiative, it’s important for every post-infectious disease that the RECOVER Initiative get it right.

More money will be spent on the Initiative over the next couple of years than has been spent on ME/CFS in 30 years, but there’s no substitute for hard-won experience. With the ME/CFS research field having a several-decade head start on studying post-infectious diseases, it can provide something of a road map – if the Initiative will listen.

Whether it’s been listening – whether it felt the small ME/CFS field had something to offer it – was a central theme in the list of questions I sent to the RECOVER Initiative several months ago. You can decide for yourself whether Initiative is or isn’t. For me, I think it will take time to know that.

The Interview

In or Out? The ME/CFS RECOVER Cohort Question

The first question was rather long-winded, but basically, it was a request to include an ME/CFS cohort in the RECOVER Initiative in order to learn about ME/CFS and inform long COVID. For the long version, see below.

RECOVER ME/CFS

Was the RECOVER Initiative willing to include an ME/CFS cohort? For the first time, I understood why it answered the way it did.

Chronic fatigue syndrome (ME/CFS) is a small research field – receiving about $15 million/year in funding from the NIH. The RECOVER Initiative, on the other hand, received $1.15 billion from Congress to study long COVID. To all indications, ME/CFS is very similar to the most prominent form of long COVID. It will be impossible, though, for the small ME/CFS field to integrate the many findings that the RECOVER Initiative and other long-COVID projects will unearth as well as the results from the numerous treatment trials. (The ME/CFS study section at the NIH does not allow for treatment trials).

There is an effective and efficient way out of this: take advantage of the infrastructure already built and enroll a cohort of people with ME/CFS into the RECOVER Initiative. The NIH would save lots of money that it would otherwise have to spend reinventing the wheel with ME/CFS, and the million-plus really long haulers in the ME/CFS community – which has been vastly underserved by the NIH over the years – would finally benefit.

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My first question is – is the RECOVER Initiative or the NIH willing to add an ME/CFS cohort, and if not, why not?)

“ME/CFS is one of several conditions with symptoms that overlap significantly with Long COVID and creating cohorts for each of those conditions will decrease the rigor and statistical significance of the results. Focusing on individuals who were infected by the same virus, albeit with different variants, at the same time, increases our chances of gaining a comprehensive understanding of the recovery process for this infection. RECOVER will have data to assess the epidemiology of those who meet criteria for ME/CFS in the cohort studies and is likely to generate data applicable to understanding ME/CFS.  

Researchers can also apply for NIH funding for “ancillary studies” focused on the relationship between ME/CFS (and other overlapping conditions) and Long COVID utilizing RECOVER data.”

RECOVER’S answer was a disappointing “no”, but in truth, the light bulb finally came on for me. I realized that if I was the RECOVER Initiative, I would probably concentrate my forces and exclude chronic fatigue syndrome (ME/CFS) as well (!).

Would it really hurt this enormous Initiative to plug in a couple of hundred people with ME/CFS and perhaps post-treatment Lyme disease? I don’t think so. Would it possibly help them understand the long-term effects of post-infectious illnesses? I think it would but faced with its big and uncertain task – to solve a kind of disease that the medical profession has ignored for years and has little idea what to do with – I can understand RECOVER’s answer.

Avindra Nath spoke to the benefit of focus when he proposed that if you solve one of the mystery diseases like long COVID, ME/CFS/FM, you’ll probably solve the rest of them, and the best way to do that is to have a stringent focus.

Avindra Nath on ME/CFS and Long COVID – “We’re Going to Learn a Lot”

Plus, many people with long COVID who meet the criteria for ME/CFS will, of course, inevitably be in the study and be thoroughly assessed – so the long-COVID form of ME/CFS is going to be in there. If things stand as they are now with long COVID and ME/CFS so closely linked together,  they will be a nice stand-in for the rest of us.

I get the RECOVER Initiative’s side of this, but what about the NIH? Wouldn’t the NIH benefit from the economies of scale, the RECOVER infrastructure, and the opportunity to compare the really long haulers with the shorter haulers? Shouldn’t it fund and put an ME/CFS cohort through the RECOVER Initiative? Of course, It should. The RECOVER Initiative could surely handle a 500-person ME/CFS cohort. That would be huge by our standards but would be a small blip amongst the tens of thousands of long-COVID and healthy controls that are already participating in the study.

Making a Difference: Is Forty Years of Work Enough?

ME/CFS experts and the RECOVER Initiative

RECOVER has brought in some ME/CFS experts. Time will tell how much of a difference they’ll be allowed to make.

ME/CFS may be a small field, but it’s also the only field with almost 40 years of research dedicated to understanding a post-infectious illness such as long COVID (that is – the subset of long-COVID patients with similar symptoms). The effects of exertion, for instance, have likely been explored with greater depth than in any other illnesses.

Is the RECOVER Initiative being informed by the findings from the ME/CFS field and similar fields like postural orthostatic tachycardia syndrome (POTS) and post-treatment Lyme disease, and if so – how is that happening?

“Investigators and clinicians with research expertise and clinical experience with post-infection syndromes, including ME/CFS and POTS, are contributing their expertise and knowledge to the RECOVER Initiative, participating in oversight committees and working groups that determine what assessments and tests are incorporated into the protocols, and helping design ancillary protocols to complement studies in this area.

In addition, patient representatives either affected by these conditions or advocating for research on them are contributing alongside as members of these structures.  Please see the link below for a current list of post-infection illness experts. The list is likely to expand as others confirm and as the Initiative continues and will be updated periodically.

That’s an interesting list that is indeed chock-full of ME/CFS experts. Eighteen of the 28 people on the NIH’s Post-Infection Illness Expert List have experience in ME/CFS and/or POTS/dysautonomia. They include Dr. Bateman, Dr. Bonilla, Leonard Jason, David Systrom, Nancy Klimas, Peter Novak, Anthony Komaroff, Galen Marshall, Janet Mullington, Benjamin Natelson, Dane Cook, Suzanne Vernon, and others.

The expert list, though, is not part of the formal RECOVER structure; i.e. it’s not one of the committees, task forces or groups that are tasked with guiding the Initiative. In fact, so far as the page indicates, it’s not tasked with anything and only shows up in the FAQ section. Other than existing as a list, it’s not clear at all what, if anything, it does.

The Commonalities with other Post Viral Syndromes Task Force (see Pathobiology Task Forces), on the other hand, is part of the RECOVER infrastructure and contains 6 well-known ME/CFS experts (David Systrom (co-chair), Leonard Jason, Suzanne Vernon, Benjamin Natelson, Hector Bonilla, Emily Taylor). Hector Bonilla. Lucinda Bateman and Janet Mullington are also members of other committees/groups. Aside from that and the Executive Committee (see below), ME/CFS experts are sparse indeed in the Initiative. That’s probably to be expected, though, given how small the ME/CFS research field is.

Interestingly, three of the five voting members (Dr. Koroshetz, Anthony Fauci, and Joesph Breen) of the Executive Committee that directs the overall strategy are actually well acquainted with ME/CFS – so ME/CFS is actually well represented at the top.

Conclusion: ME/CFS experts are abundant in the “other post-viral syndrome” group but are rarely found in the task forces, group and committees that are guiding the Initiative. Except that is in the Executive Committee where three of the five members have considerable knowledge of ME/CFS.

To Stress or Not to Stress: That is Indeed the Question

General Question – is the RECOVER Initiative going to use exercise or other stressors to help it learn about long COVID?

Exercise stressors are ubiquitous in ME/CFS research for a reason - they work!

Exercise stressors are ubiquitous in ME/CFS research for a reason – they work! (An ME/CFS patient at Workwell).

The ME/CFS field has found that using physical or mental stressors to provoke issues that are undetected at baseline, but which clearly affect functioning, critical to understanding the disease. For instance, exercise studies are regularly used not just to understand how the cardiovascular system or the energy production systems are functioning but also to explore the effects of physical or mental exertion on immune functioning, the brain and cognition, the gut, metabolism, protein production and others.

Study after study after study has found normal results at baseline which become quite abnormal after a stressor is added. If long COVID is similar to ME/CFS, it will likely take much longer to ferret out its secrets if these stressors are not included. Is the RECOVER Initiative: A) incorporating exercise – whether physical or mental – stressors into its studies; and B) if so – how?

Also, given how helpful adding a physical or mental stressor to a study has been in understanding diseases like ME/CFS and POTS – and how much is missed when one does not do that – and how unusual it is for other fields to employ them – has the RECOVER Initiative explicitly encouraged its investigators to include them?

“RECOVER includes patient-reported questionnaires, data extraction from electronic health records and claims data, basic clinical examinations, blood draws, and radiology studies as well as provocative testing.

The RECOVER protocol also monitors participants during testing to make sure they are able to tolerate testing with stressors. Among the various tests are:

  •      A 6-minute walk test
  •      Pulmonary function tests
  •      A cardiopulmonary exercise test which includes a 30 second sit-to-stand test and an active standing test.

The RECOVER protocol is online:  https://recovercovid.org/protocols.”

RECOVER stated there will be provocative testing but did not state how. Three tiers of testing will occur in RECOVER.

  • Tier One – Everyone will go through Tier I. PEM as a symptom is followed throughout. No exercise testing is done. A 30-second “Sit to Stand” and an “Active Standing Test” is done. These tests simply appear to be assessing the ability to stand.
  • Tier Two – about 30% of the participants will go through Tier II, which includes  6-minute walk test but how its being used is not clear.
  • Tier Three – about 20% of the participants will go through Tier III which includes “full cardiopulmonary exercise testing”, as well as a tilt table test. (It does not state whether the test is invasive or non-invasive. I assume it’s non-invasive). (I assume that whoever answered this question got his answer wrong and the “full cardiopulmonary exercise test” is not simply a combination of a sit-to-stand and an active stand test.)

Preliminary Conclusion: It appears that exercise tests are being used to assess a person’s ability to exercise and produce energy but it’s not clear how they are being used as a provocation as the RECOVER protocol does not clarify this. (Exercise also didn’t appear to be used as a stressor in any of the extramural studies funded by RECOVER.) Given how effective these stressors are in ME/CFS, it was surprising that RECOVER wouldn’t explicitly state they’re using them in their protocols.

I had to ask about 2-day CPET tests, which show that exercise on one day depletes the ability to engage in exercise the next day in ME/CFS.

Two day exercise tests

Two-day exercise tests are the only tests that have definitively shown that exercise one day reduces the amount of energy available the next. It doesn’t appear that the Initiative is going to use them.

On the subject of exercise – two-day CPET studies – one done the day after the other – have revealed an inability to reproduce energy output the next day in ME/CFS. This is apparently unheard of in the medical world. Not only has this been revealing regarding post-exertional malaise – a term created by the ME/CFS field – but they have been used many times to assist in disability claims. Will the RECOVER Initiative be using this type of test to help understand why exercise leaves people with long COVID so functionally impaired?

“The schedule for all tests, including the walking test and the cardiopulmonary exercise test are included in the RECOVER protocol Appendix:  https://recovercovid.org/protocols.”

The answer again was “no” – 2-day exercise tests are not being used.

It made total sense to use exercise to understand ME/CFS given the post-exertional malaise that ME/CFS is famous for, but it still took years to get exercise installed as a standard provocation measure. Whether or not RECOVER is going to do that is unclear.

Of course, there’s much we don’t know about RECOVER. At this point, we just have access to the standard testing protocols, and there must be much, much more to the Initiative than them. My guess is that they provide the baseline data that the researchers will work off of. The studies that they produce will be a different deal. We won’t know about them and what the Initiative is actually doing until they come out.

The Gist

  • More money will be spent on the RECOVER Initiative over the next couple of years than has been spent on ME/CFS in 30 years, but there’s no substitute for hard-won experience. With the ME/CFS research field having a several-decade head start on studying post-infectious diseases, it can provide something of a road map – if the Initiative will listen. Much of this interview with the RECOVER Initiative was about that question. 
  • When asked about that, RECOVER pointed to a list of ME/CFS experts. It was a nice, hearty list for sure, but it appeared to be just a list; i.e. the experts weren’t tasked with doing anything and weren’t part of the leadership team for RECOVER.  Several ME/CFS experts are embedded in the post-infectious disease committee, however, and several members of the Executive Committee have quite a bit of experience with it.  Otherwise, the participation of ME/CFS experts is quite low. 
  • When asked whether the Initiative is going to include exercise or cognitive stressors, RECOVER pointed to the protocol page which indicates that cardiopulmonary exercise tests and other exercise tests will be employed at some points but does not make clear if they will be used as a provocation. 
  • The 2-day exercise tests that show exercise one day reduces the amount of energy available the next do not appear to be being used. Once again, though, we don’t know how the studies will proceed. Will they include these tests? Time will tell. 
  • RECOVER expects to launch clinical trials aimed at improving immune functioning, batting down viral persistence, and enhancing autonomic nervous system functioning, cognition, sleep and exercise tolerance over the next year. 🙂

 

 

 

MoTrPAC Collaboration – This question was basically meant to, if they weren’t clued into the MoTrPAC initiative that’s studying the effects of exercise on the body, clue them in on it.

Again on the subject of exercise. The NIH is currently in, I believe the 3rd year of its $170 “Molecular Transducers of Physical Activity Consortium” (MoTrPAC) project to understand the effects of exercise on the body. Given the exercise findings thus far in long COVID and the many exercise findings in ME/CFS, is the RECOVER project being informed in any way by the MoTrPAC findings, and if so, how?

“While there is knowledge of the potential information to be shared across the programs, there have not yet been any known formal collaborations.”

I was surprised to see only 40 funded individual grant applications. Did the NIH not get many applications? Do you expect more to be funded? Will another grant opportunity open up, and if so, do you know when?

“All applications to RECOVER for funding in response to the pathobiology NOSI and ROA, and clinical trials ROA were carefully reviewed and selected based on merit in accordance with the published review criteria. Notices for open funding opportunities and Notices of Intent to Publish a Funding Opportunity will be posted and made available on the RECOVER website:  https://recovercovid.org/funding.”

Conclusion: The RECOVER Initiative is going to stick firmly to its plan of having an almost entirely in-house directed effort. Koroshetz said they wanted to avoid the kind of scattershot approach that pervades medical research which tends to produce many findings but results in few conclusions. Let’s hope they have the right crew working on this and the right plan – a lot is riding on it.

The Future

Looking forward to a year from now, what do you expect to have happened in the RECOVER Initiative?

“Within the coming year, the adult cohort will complete enrollment. There will be additional information and publications emerging from the observational RECOVER protocols. RECOVER publications will be accessible from the website.

In addition, it is expected that a number of clinical trials will have been launched focusing on possible disease mechanisms and potential treatments for key symptoms/symptom clusters, such as:

  • Viral persistence and reactivation and immune dysregulation: whether the virus stays in some people’s bodies, or if other viruses are subsequently activated, or if the immune response triggers other disorders.

  •  Autonomic dysfunction: Changes in the ability to regulate heart rate, body temperature, breathing, digestion, and sensation.

  •  Sleep disorders: Changes to sleep patterns or ability to sleep.

  •  Neurologic/Cognitive Dysfunction: Trouble thinking clearly or brain fog.

  •  Exercise intolerance/fatigue: Changes in a person’s ability to be active and/or low energy level.”

It was good to see RECOVER move quickly on treatment trials and it’ll be fascinating – and tell us much about the direction of the Initiative itself – to see what treatments they plan to test. Will they be conservative or will they be willing to assess treatments that don’t have a lot of hard data (e.g. LDN) on them but might be helpful.

Will they be daring in ways the ME/CFS field has not been? Their Paxlovid trial suggests they may be willing to try more heavy-duty immune and antiviral drugs that the ME/CFS field has had trouble getting its handle on. They may be more comfortable trying biologics, for instance, than something like oxaloacetate or dextro-naltrexone.

I would hope that a drug like Mestinon, which has been around for a long time and did well in a shortie trial to improve aerobic functioning in ME/CFS, would be on their list.

It’ll be fascinating to see what they will do to improve immune functioning (IVIG, biologics) or improve autonomic functioning (hoping for Mestinon), sleep (I would bet good money we’ll see a big cognitive behavioral therapy for insomnia trial, cognitive dysfunction (stimulants, rTMS, HBOT), and finally, exercise intolerance (low dose naltrexone, Ampligen, oxaloacetate, HBOT, Mestinon).

In any case, it’s good to see the NIH will apparently shortly begin trying to address some major components of long COVID.

BIG (Little) Donation Drive Update

light bulb piggy

We’re keeping an eye on RECOVER and the other groups that make a difference in these diseases.

With as important an initiative as the RECOVER Initiative is to ME/CFS/FM and long COVID, we had to try to get some answers.

While they might not have been as forthcoming as we would want (lol), they did give us some insights into what’s going on over there – and we’re not done. We’re going to keep hawkeyed on that $1 billion-plus project.

If that’s the kind of work you want from a website, please support us in the last week of our drive. 🙂

 

 

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