Preprint Safety of Cardiopulmonary Exercise Testing in Patients with Severe Post- COVID-19 Condition: A Matched Case- Control Study, 2026, Weber et al

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Safety of Cardiopulmonary Exercise Testing in Patients with Severe Post- COVID-19 Condition: A Matched Case- Control Study

Weber, Vincent; Tomaskovic, Aleksandar; Ochmann, David T.; Hillen, Barlo; Zentgraf, Severin; Enger, Mirjam S.; Lachtermann, Ella; Neuberger, Elmo W. I.; Simon, Perikles

Abstract
Patients severely affected by post-COVID-19 condition (PCC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) exhibit reduced physical capacity, hyperventilation, and a high susceptibility to post-exertional malaise (PEM).

Cardiopulmonary exercise testing (CPET) is considered the gold standard for objectively assessing physical capacity and for exploring underlying physiological limitations. However, evidence regarding the safety and PEM-associated symptoms following CPET remains limited. This study aims to objectively assess physical capacity using CPET, and to systematically investigate changes in PEM-associated symptom duration and severity before and after CPET.

18 PCC patients and 18 healthy controls (matched for sex, age, and body-mass-index) completed a single maximal symptom-limited CPET on a bicycle ergometer. Ten PEM-specific symptoms were assessed daily for 7 days before and 14 days after CPET (scale 0-10). For clinical characterization, the Canadian Consensus Criteria (CCC), Bell Disability Scale, and DePaul Symptom Questionnaire Short-Form-PEM (DSQ-PEM) questionnaires were completed once before the CPET.

Among PCC patients, 61% fulfilled ME/CFS criteria, 67% screened positive for DSQ-PEM, and the mean Bell-Score was 37.8 ± 19.3.

Physical capacity was markedly reduced compared with healthy controls (Peak power output: 1.1 vs. 2.4 W/kg, p < 0.001; VO 2peak 16.0 vs. 26.5 mL/min/kg; p < 0.001).

In the PCC group, a significant increase in mean symptom severity was observed across all measured symptoms from baseline to the acute period (1-3 days after the CPET; Δ = 0.56, p = 0.002) but after 4-7 days, levels returned to baseline. Two out of ten symptoms increased significantly after the CPET: general fatigue (Δ = 0.99, p = 0.018) and joint pain (Δ = 0.69, p = 0.036). However, after 4 to 7 days no significant differences remained.

No significant group-by-timepoint interaction was found when stratifying PCC patients by DSQ-PEM status (p = 0.187), Bell-Scores (≤30 vs. >30, p = 0.276), or ME/CFS status (p = 0.523). Severely affected PCC patients showed markedly reduced physical capacity compared with matched controls.

A single maximal but symptom-limited CPET induced only a transient, clinically non-relevant symptom increase (1-3 days) without prolonged exacerbation. Furthermore, the results of the CPET can be used to provide individualized objective cut-off values aimed at minimizing PEM during exercise therapy and/or activities of daily living.

Trial registration: DRKS, DRKS00032394. Registered 28 July 2023, https://drks.de/search/de/trial/DRKS00032394

Web | DOI | PDF | Research Square | Preprint
 
the mean Bell-Score was 37.8 ± 19.3.
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That is the entire scale of mild to severe:
60: Mild to moderate symptoms at rest; daily activity limitation clearly noted. Overall functioning 70%-90%. Unable to work full-time in jobs requiring physical labor, but able to work full-time in light activity if hours flexible.

50: Moderate symptoms at rest. Moderate to severe symptoms with exercise or activity; overall activity level reduced to 70% of expected. Unable to perform strenuous duties, but able to perform light duty or desk work 4-5 hours a day, but requires rest periods.

40: Moderate symptoms at rest. Moderate to severe symptoms with exercise or activity; overall activity level reduced to 50%-70% of expected. Not confined to house. Unable to perform strenuous duties; able to perform light duty or desk work 3-4 hours a day, but requires rest periods.

30: Moderate to severe symptoms at rest. Severe symptoms with any exercise; overall activity level reduced to 50% of expected. Usually confined to house. Unable to perform any strenuous tasks. Able to perform desk work 2-3 hours a day, but requires rest periods.

20: Moderate to severe symptoms at rest. Unable to perform strenuous activity; overall activity 30%-50% of expected. Unable to leave house except rarely; confined to bed most of day; unable to concentrate for more than 1 hour a day.

I don’t understand the rationale for doing this. What’s the benefit?
 
Utsikt said:
That is the entire scale of mild to severe:
60: Mild to moderate symptoms at rest; daily activity limitation clearly noted. Overall functioning 70%-90%. Unable to work full-time in jobs requiring physical labor, but able to work full-time in light activity if hours flexible.

50: Moderate symptoms at rest. Moderate to severe symptoms with exercise or activity; overall activity level reduced to 70% of expected. Unable to perform strenuous duties, but able to perform light duty or desk work 4-5 hours a day, but requires rest periods.

40: Moderate symptoms at rest. Moderate to severe symptoms with exercise or activity; overall activity level reduced to 50%-70% of expected. Not confined to house. Unable to perform strenuous duties; able to perform light duty or desk work 3-4 hours a day, but requires rest periods.

30: Moderate to severe symptoms at rest. Severe symptoms with any exercise; overall activity level reduced to 50% of expected. Usually confined to house. Unable to perform any strenuous tasks. Able to perform desk work 2-3 hours a day, but requires rest periods.

20: Moderate to severe symptoms at rest. Unable to perform strenuous activity; overall activity 30%-50% of expected. Unable to leave house except rarely; confined to bed most of day; unable to concentrate for more than 1 hour a day.

I don’t understand the rationale for doing this. What’s the benefit?
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I was meaning to post that and ask if there's more separation in the paper apart from what they mentioned in the abstract ("No significant group-by-timepoint interaction was found when stratifying PCC patients by DSQ-PEM status (p = 0.187), Bell-Scores (≤30 vs. >30, p = 0.276)").

It's seems misleading to put "severe" in the title.
 
I am not an ME/CFS patient, so I cannot personally feel what PEM is like. But in a situation where reliable static biomarkers for ME/CFS have not been found, and where that path may not be very promising, PEM induced after CPET may be a very valuable “dynamic biomarker.”
It is not just another symptom. It is a state change after exertion that can reveal the abnormal physiology of ME/CFS. In my view, researchers have not made full use of this tool. Of course, because CPET can worsen patients’ symptoms, it should only be used very carefully in research settings.
 
Shiqiru said:
It is a state change after exertion that can reveal the abnormal physiology of ME/CFS.
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It can, but not necessarily easily. If there's a measurable physical difference, such as elevated blood lactate, there are still too many possibilities for what's causing that. Mitochondrial? Vascular? Neurological? There would also be "experts" claiming that it's psychological. All those theories, without significant evidence supporting them.

Back when I had a reliable PEM blocker, I thought it would be valuable to do a wide array of tests on me, after exertion, with or without the blocker, to see what is different. No one was interested, but I'm wondering what the chance of them looking for the right factors in the right place and at the right time would actually have been. If, for example, the difference was astrocyte process lengths, or neuron-neuron vesicle transfer in a small part of the brain, all the blood tests available wouldn't reveal that. We still don't know where to look or what to look for. Also, measurable differences during PEM might be far downstream from the root cause, and vary greatly with the individual. You might, for example, measure measure elevated lactate in some subjects, and reduced ones in others. Is that a direct result of PEM, or just a result of feeling lousy, which affects how you move, and how you breathe, etc, which depends on the individual?
 
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