Several differences have been found between people with and without ME/CFS, including people with other diseases or who are sedentary. On the first test, people with ME/CFS exhibit lower performance and heart rate, and on the second test, performance is even lower, while for controls, it is the same or slightly better. The largest decrease is in anaerobic threshold, which signifies a shift from aerobic to anaerobic metabolism at a lower level of exertion, and is not influenced by effort.[3][1][4] Peak power output, heart rate, and VO2max also decrease, and in ME/CFS, but effort and familiarity with the test may affect VO2max and power.[5][3] Additionally, healthy people generally recover from a CPET within 24 hours while people with ME/CFS do not.[6]
A 2-day CPET is hypothesized to measure PEM and its effect on physical functioning.[7] (Objective indicators of maximal effort during both tests control for effort.)[7] However, its utility has not been completely confirmed, as many studies of it have been small.[4] While it should not be required for a diagnosis, a 2-day CPET can show that symptoms are not due to deconditioning and provide evidence for obtaining disability benefits.[7] Because PEM is also a symptom of long COVID, the 2-day CPET may be useful in evaluating exercise intolerance there as well.[8]
The cause of decreased performance is not understood. Proposals include impaired oxygen transport, impaired aerobic metabolism, impaired microvascular blood flow, loss of passive microvascular filtration and mitochondrial dysfunction.[3]
The test provokes symptoms by design, and recovery may be prolonged. In some cases, it may worsen the illness long-term, as such it should only be applied to patients when absolutely necessary.[3][7]
Criticisms
At the same time, the allegation that 2-day CPET proves CFS has received criticism. Because the test cannot be blinded, patients know day 2 is the “make you crash” day. In the 2024 study perceived exertion (RPE) was already higher at ventilatory threshold on day 1 in ME/CFS and climbed further on day 2 despite lower workloads—classic anticipatory pacing. Psychological factors linked to exercise avoidance (kinesiophobia, catastrophizing) are well-documented in CFS and correlate with slower functional tasks even when aerobic capacity is unchanged, showing that motivation can depress output independently of physiology. High RER (>1.1) only proves a maximal bout at the end of the test; it does not exclude deliberate early throttling that drags VO₂-peak down.[9][10]
Meanwhile, the test is not very specific to CFS either. A pilot comparison using the same 24 h repeat protocol found multiple-sclerosis patients showed day-2 VO₂ and workload shifts that overlapped CFS, undermining “uniqueness.” Repeat-CPET reliability studies in cardiac, pulmonary and multiple sclerosis cohorts report intra-individual variation of 4-7 % for VO₂-peak; several CFS papers cite falls in the 7-12 % range—just outside that noise band and within confidence limits of small samples. A 2015 PLoS One analysis explicitly questioned the sensitivity of CPET change-scores in fatiguing illness.[11][12][13] On top of that PEM itself has been found to exist in other disorders as well, such as cancer-related fatigue.[14]
^Nijs J, De Meirleir K, Duquet W (October 2004). "Kinesiophobia in chronic fatigue syndrome: assessment and associations with disability". Archives of Physical Medicine and Rehabilitation. 85 (10): 1586–1592. doi:10.1016/j.apmr.2003.12.033. ISSN0003-9993. PMID15468015.
^Hodges LD, Nielsen T, Baken D (July 2018). "Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study". Clinical Physiology and Functional Imaging. 38 (4): 639–644. doi:10.1111/cpf.12460. ISSN1475-097X. PMID28782878.
^Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, et al. (13 July 2010). "Clinician's Guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association". Circulation. 122 (2): 191–225. doi:10.1161/CIR.0b013e3181e52e69. ISSN1524-4539. PMID20585013.
^Twomey R, Yeung ST, Wrightson JG, Millet GY, Culos-Reed SN (August 2020). "Post-exertional Malaise in People With Chronic Cancer-Related Fatigue". Journal of Pain and Symptom Management. 60 (2): 407–416. doi:10.1016/j.jpainsymman.2020.02.012. ISSN1873-6513. PMID32105793.
