Response to B. Walitt et al. Nature Communications https://doi.org/10.1038/s41467-024-45107-3 (2024)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, systemic disease with significant pathophysiological uncertainties and variable presentations¹. Here, we challenge Walitt et al.’s² conclusion that post-infectious (PI) ME/CFS is a disorder defined by altered effort preference, leading to activity avoidance and subsequent deconditioning. We believe this interpretation risks reinforcing skepticism about the serious biological nature of ME/CFS and its hallmark of post-exertional malaise (PEM), as well as its potential misclassification as a mental health condition.

Walitt et al.² utilized a single CPET to evaluate systems-level physiological responses to exercise. However, this methodology does not allow for measuring responses after an initial exertion, which is critically important for fully understanding PEM³. Over the past two decades, 2-day CPET has been used to characterize the systems-level metabolism of ME/CFS³. This paradigm uses an initial maximal CPET to establish the individual’s baseline performance and as a participant-referenced method to induce PEM⁴. A second maximal CPET is then conducted 24 h later to measure physiological and perceptual responses to exercise during the post-exertional state⁴. Standard objective criteria to evaluate effort are used to ensure maximal testing, including the respiratory exchange ratio at peak exertion⁴. This removes uncertainty related to effort. Meta-analyses involving participants with ME/CFS who have completed 2-day CPET indicate characteristic declines in the volume of oxygen consumed, work rate, and heart rate (HR) at submaximal exertion on the second CPET. These findings are reliably observed in people with ME/CFS but not deconditioned individuals^5,6,7. Accordingly, the Institute of Medicine (IOM) cautioned that “a single CPET may be insufficient to document the abnormal response of ME/CFS patients to exercise.”^{1 (p. 106)}

Using a single CPET introduces a threat to validity in Walitt et al.’s study², as it did not allow for the measurement of submaximal performance decrement in the post-exertional state^1,3,4,5,6. This is important because deconditioning and PEM are not mutually exclusive. Special care must be taken when applying and interpreting CPET results¹. Failure to use 2-day CPET prevented the authors from adequately testing their conclusion that PEM is related to participants’ effort preference, as they did not evaluate physiological performance under conditions involving objective, standardized criteria for maximal exertion. Unfortunately, the use of a single CPET in this study contributed to the authors’ misinterpretation that PEM is synonymous with reduced effort and deconditioning.

Read the rest of this letter here: https://www.nature.com/articles/s41467-025-64538-0

Source: Davenport, T.E., Scheibenbogen, C., Zinn, M.A. et al. Altered effort and deconditioning are not valid explanations of myalgic encephalomyelitis/chronic fatigue syndrome. Nat Commun 16, 9176 (2025). https://doi.org/10.1038/s41467-025-64538-0 https://www.nature.com/articles/s41467-025-64538-0 (Full text)