Trial By Error: Now a Scottish Long Covid Study Fails to Mention the Risk of Post-Exertional Malaise

By David Tuller, DrPH

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And here’s another major trial designed by investigators who think that an exercise program might be the optimal strategy for treating the complex grab-bag of conditions known as long Covid. As with other long Covid research, these investigators seem either unaware of or unconcerned about the core ME/CFS symptom known as post-exertional malaise (PEM)–also called post-exertional symptom exacerbation (PESE) or, in the ME-ICC case definition, post-exertional neuroimmune exhaustion (PENE).

The study in question is called “Prevention and Early Treatment of the Long-term Physical Effects of Coronarvirus-19 (COVID-19): a Randomised Clinical Trial of Resistance Exercise.” Conducted by the University of Glasgow, in conjunction with NHS Greater Glasgow and Clyde, it is funded by Scotland’s Chief Scientist Office, which two decades ago also kicked in some of the funding for the now-discredited PACE trial.

The projected sample size is 220. Recruitment began last May and is expected to continue into next year. A twitter thread critiquing the study caught my attention.

The investigators are recruiting patients still experiencing symptoms four weeks or more after the onset of infection, including both those who were hospitalized for Covid-19 and those who weren’t. Another group of hospitalized patients is being tracked from shortly after infection to determine if the exercise intervention can prevent prolonged symptoms. All participants also receive standard care. Those in the comparison arm get only standard care—a typical feature of many such behavioral intervention studies.

Unlike key members of the GET/CBT ideological brigades, the Glasgow investigators seem to recognize that measures of function, and not just self-reported measures like fatigue and physical function, are critical. While the multiple assessments include a range of subjective questionnaires, the primary outcome is something called the Shuttle Walk Test. Here is how it is described in a version of the patient information sheet from March, 2021:

“This will involve you being asked to walk around two cones set 9 metres apart…in time to a set of electronic beeps. Initially, the walking speed is very slow, but each minute the walking speed increases. We ask you to walk for as long as you can until you are either too breathless or can’t keep up with the beeps, and then the test ends.”

Hm. Sounds like a great way to generate a crash! In fact, PEM has emerged as a key feature in a significant number of long Covid cases, although certainly many patients do not experience it. For those who do, it could be contra-indicated not just to perform the Shuttle Walk Test but to engage in an exercise program implicitly framed around the notion that covid-related deconditioning is a cause of patients’ ongoing symptoms.

At the least, the investigators should be screening prospective participants for PEM, but the trial registration on the clinicaltrials.gov website makes no mention of this. Nor does a page of basic information on the NHS site. The criteria for exclusion listed in the trial protocol do not include the presence of PEM. And in a section on possible risks to participants, the protocol asserts only that the “complications of exercise intervention may be soft tissue strain, falls or exhaustion”—none of which is a description of PEM.

In a trial like this, prospective participants should be warned in the process of consenting that prolonged relapses triggered by excess exertion are a potential risk of taking part. But the patient information sheet only notes that “the exercises and the Shuttle Walk Test may make you feel tired and fatigued, but as you are in control of the amount of exercise you do, this should only last a short time.” As anyone familiar with PEM knows, this assurance that the consequences of taking the Shuttle Walk Test or engaging in excess exertion will only last a “short time” is unwarranted.

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As the trial registration explains, the study was prompted by the deficit of non-pharmacological interventions available for long Covid:

“To address this gap, the investigators have set out to develop a lifestyle intervention that may be helpful to patients with persisting symptoms in the recovery (or convalescence) phase after COVID-19. Specifically, the investigators will train participants to undertake a pragmatic resistance-based exercise intervention that they can learn and apply according to their circumstances in-hospital or in the community. The rationale is predicated on providing patients with a personalised therapy option and empowering them in the self-management of their recovery following illness due to COVID-19 infection.”

But the investigators and those who reviewed and approved the study do not seem to have fully consulted the relevant literature—or at least that’s my assumption from the omission of any apparent recognition or understanding of the role of PEM. Perhaps they should read an opinion piece published earlier this month in The New York Times titled “Pushing ‘Long Covid’ Sufferers Too Hard Could Cause Them to Crash.” Here’s how it starts:

“Most of us were brought up with the folk wisdom that exercise is the best medicine, and often it’s true. But not for people who are suffering from long Covid and other post-viral syndromes. For them, overexertion can severely aggravate their conditions, whose symptoms may include fatigue and brain fog.”

The writer, Peter Coy, is an economics writer, not a scientific researcher. But it seems like the Glasgow investigators have bought into the folk wisdom mentioned by Coy rather than fully grasping that many long Covid patients experience serious relapses—and need to carefully monitor their activity levels.

The trial appears to presume that “empowering” participants in the “self-management of their recovery” is a key to recovery itself. But most patients recover naturally from the short-term consequences of viral illness without any rehabilitation, as will many of those still experiencing symptoms during the first four weeks after a bout of Covid-19. These patients will be unlikely to need any “empowerment” at all.

For those with physiological deficits resulting in PEM, however, such “empowerment” could encourage them to push themselves beyond their body’s limits to a potentially harmful degree. The investigators do not seem to have sufficiently considered this possibility.