The NIH’s RECOVER Initiative has not exactly been garnering a lot of praise. On the plus side, the NIH has clearly given the project a lot of thought and put together a program designed to produce meaningful results; i.e. results that stick. No more one-and-done studies, no loose ends – just a methodical rigorous approach to understanding long COVID that leaves us with answers. That’s the promise.
It hasn’t been as smooth as all that, though. It took the Initiative a year to start recruiting patients; for some reason, it strangely originally decided to study as many young patients as adults; the few studies that have been produced have been underwhelming in the extreme; and despite stating six or more months ago that it was going to start treatment studies, it’s begun a grand total of one.
Let’s give RECOVER the benefit of the doubt and attribute the misfires to the growing pains that accompany any large initiative. Recently, though, a real head-scratcher has shown up. MEAction got the ball rolling when it reported last week that the RECOVER Initiative was moving forward with an exercise trial in long COVID. Rumors regarding an exercise trial have actually been floating around for a quite a while. In his book, “The Long Haul“, Ryan Prior reported that a $4 million “high-intensity interval” exercise trial had been greenlit but it wasn’t until MEAction reported it that it was clear that the trial was close to happening.
Talk about popping a balloon. The RECOVER Initiative has apparently seeded itself with ME/CFS experts. It says it’s listening to them and yet THIS happens, Interpreted one way, it’s basically potentially the worse news that the ME/CFS community could get: the RECOVER Initiative has gone biopsychosocial. (It almost certainly hasn’t but that’s going to be the interpretation). Another battle seemingly looms.
At the end of February, MEAction sent a detailed letter to the RECOVER Clinical Trials Steering Committee, reporting their concern that the trial would include people with the ME/CFS brand of long COVID. Citing the methodologically flawed PACE trial, and the years of problems it caused, as well as research studies indicating an impaired energy production process is present in ME/CFS, MEAction asked the NIH if they were accounting for the existence of post-exertional malaise (PEM) in their trial, requested that the trial exclude all patients with PEM, and that the particulars of the trial be made public.
Rachel Fairbank, the author of the Nature.com article, put a pin on the PEM question, when she noted that up to 60% of long-COVID patients could be categorized as having ME/CFS and that even more may experience PEM.
Of course, we have to remember that long COVID casts a wide net, and besides, a very prominent ME/CFS subset it also includes people with lung, kidney, and or heart problems and people who’ve been in intensive care and have become deconditioned from lack of activity. As MEAction acknowledged in their letter, other cohorts might benefit from exercise.
MEAction apparently has not gotten a response to its letter, but an article published in Nature.com, “Long COVID exercise trials proposed by NIH raise alarm“, ramped up the heat considerably. If RECOVER was able to at least temporarily blow off MEAction, they apparently felt they had to respond to the queries from a prominent scientific journal. They stated:
“the agency is working with patient representatives in shaping the exercise trial protocol”, and that they would include “inclusion and exclusion criteria to make sure that people who could be harmed by exercise will not be included in that platform trial”.
While the devil is in the details, that’s encouraging. What we don’t know and will probably never know is what effect MEAction’s and other advocacy efforts had on the makeup of the exercise trial. While RECOVER has incorporated ME/CFS experts and long-COVID patients into its decision-making process, it’s not clear how deeply embedded they are or how closely they are being listened to.
Ryan Prior reported that as of November 2021, RECOVER had failed to include patients and their experiences in a meaningful way. That surprised him given the important role that patients played in the last great new condition the NIH was faced with – HIV. One would have thought that the Initiative would have been eager to bring patients on board given how little it knew about long COVID- but not so.
Prior reported that the Body Politic urged the NIH to pay special attention to ME/CFS research. At least at that time, the group felt that the Initiative’s leadership only had “a shallow understanding in the field of post-viral research”, and was probably doomed to reinvent the wheel.
The RECOVER Initiative’s response to my questions asking whether it was employing exercise stressors to help advance its understanding of long COVID more quickly left me with a similar question. Time will tell, of course, what RECOVER will do – we still know very little about their studies, but the Initiative’s answers and its funding of studies that didn’t appear to involve exercise stressors did not seem to bode well.
Beyond that, it seems baffling that the NIH would choose an expensive exercise trial to be one of its first clinical trials. The benefits of exercise, of course, are well-known for people with lung or heart injuries. Breathing exercises can help with lung problems and interval training can help with heart issues. It seems more likely, though, that an exercise trial in long COVID would try to address the deconditioning that resulted from long hospital stays or from a lack of activity in the aftermath.
It’s not as if the medical world, though, doesn’t fully get that absent an ME/CFS-like condition, exercise is good for patients who’ve become deconditioned. That doesn’t require a $4 million study. One hopes that RECOVER is aware that given how vague the term ‘long COVID” is, the results of any exercise study, no matter how carefully the ME/CFS-like long COVID group is excluded, are going to be misconstrued as pertaining to all long COVID patients. Why risk that?
The ME/CFS community, of course had to deal with the fallout from exercise clinical trials for years. The entire history of graduated exercise therapy (GET) in ME/CFS was based on the proposition that people with ME/CFS had become deconditioned, and that once exercise resolved that, they would return to health. Despite the modest results of the cognitive behavioral (CBT) and graded exercise therapy (GET) trials, CBT and GET ended up subsuming the small ME/CFS clinical trial field.
Over time physiological studies poked holes in the deconditioning hypothesis. A large study emphatically showed that while deconditioning is present in ME/CFS, it did not impact the ability to produce energy; i.e. energy production was impaired whether a person was deconditioned or not.
Similarly, David Systrom’s invasive exercise studies showed that people with ME/CFS and/or long COVID exhibit the opposite results expected to occur with deconditioning. Workwell’s two-day exercise protocol definitively showed that exercise one day whacks ME/CFS patients’ ability to produce energy the next. Those kinds of specialized studies pointed to core problems in ME/CFS – something that graded exercise studies could never do.
Importantly, though, the results of one-day CPET studies can be misleading They often indicate that yes, deconditioning is present, leading the authors to propose exercise therapy as a fix. One long COVID study even asserted that the presence of deconditioning indicates that an “organic” condition is not present. A Scottish resistance exercise trial long-COVID study is underway.
Other studies that are more circumspect provide hope that the long-COVID field will not, in the end, have to reinvent the wheel regarding exercise. A University of California San Francisco review of 38 exercise studies published in the Journal of the American Medical Association (JAMA) concluded that deconditioning was common in long COVID but that so were “problems of oxygen extraction” – a key ME/CFS finding from David Systrom. It concluded that:
“Potential mechanisms for exertional intolerance other than deconditioning include altered autonomic function (eg, chronotropic incompetence, dysfunctional breathing), endothelial dysfunction, and muscular or mitochondrial pathology.”
Advocating against graded exercise therapy (GET) can be a bit tricky, though. Perhaps because perhaps many GET studies used the Oxford criteria, they do not, in general, show that harm has been done. A 2017 systematic review, for instance, found that “no evidence suggests that exercise therapy may worsen outcomes”. It may be better to ask, given the limited positive benefits that GET provides, whether it’s worth pursuing at all. That same review’s conclusion that people with ME/CFS “may feel less fatigued” isn’t likely to light a fire under patients or their advocates.
Charles McCone, a long-COVID patient working with the RECOVER Initiative, certainly isn’t excited about the promise of an exercise trial. He told Nature that he found it “baffling and discouraging” that the Initiative is spending money on an exercise trial. Noting that, “Dozens of drugs [for long COVID] have been identified as promising candidates that need immediate further study,” McCone delivered the kicker “Funding is limited”. (Note, though, that Nature reported that the RECOVER Initiative plans to spend $172 million on clinical trials.)
Herein lies the big question. Why spend $4 million on a study that’s pretty much guaranteed to produce modest results? This, after all, would not be a small study – it would be about half the size of the PACE trial in ME/CFS – still easily the largest study ever done on ME/CFS. (My second thought after hearing about the study was that the RECOVER Initiative had too much money… My first thought was “are they serious about long COVID?”; i.e. have they assessed the ME/CFS literature?). Lisa McCorkell, a co-founder of the Patient-Led Research Collaborative for long COVID asked, “Why?”, as well.
“In a world where there’s hundreds of things to trial, why are we choosing this one thing that we know has the potential to cause harm to a substantial portion of patients?”
The RECOVER Initiative, thus far, has one treatment trial underway. Is an exercise trial really going to be second? Is it really worth alienating the biggest long-COVID subset of patients – not to mention the entire ME/CFS community?
The ME/CFS community well knows how even modest results can get translated by journalists and doctors into conclusions that send research efforts, doctors’ protocols, and the public down tunnels with no cheese. Look at what’s happened with fibromyalgia. A few modest results have resulted in the fibromyalgia research field being virtually been overtaken by exercise studies. Dozens of fibromyalgia exercise studies have swamped that small field over the last year.
That won’t happen with the RECOVER Initiative – it’s simply too big but it literally couldn’t have found a better way to alienate its main clientele or attract more negative attention – something it surely doesn’t need – and may only be starting to get. Nature.com is not the only major media outlet digging into this. Stat News is also digging into the exercise trial – and that’s the really good news to come out of this: the media is watching…