A 2-day CPET is a cardiopulmonary exercise test given on two successive days to measure the effect of post-exertional malaise (PEM) on a patient's ability to exercise. PEM is a cardinal symptom of myalgic encephalomyelitis/chronic fatigue syndrome and is common in long COVID as well.
Background
Most Recent Research
According to a new study by Mancini, Cook, Brunjes, Soto, Blate, Quan, Yamazaki, Norweg, and Natelson (2026), consecutive two-day cardiopulmonary exercise test results do not change between testing days, as initially thought, for patients with chronic fatigue syndrome. The researchers investigated the validity of using a two-day consecutive cardiopulmonary exercise test (CPET) protocol to measure post-exertional malaise (PEM) and disability in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
Methodology: Researchers tested 58 ME/CFS patients and 25 age- and sex-matched sedentary controls using maximal bicycle ergometer tests over two sequential days (24 hours apart). They tracked peak oxygen consumption (VO2), ventilatory threshold (VT), heart rate, and perceived exertion.
Key Findings:
ME/CFS patients demonstrated a lower maximum heart rate compared to controls.
ME/CFS patients reported a significantly higher level of perceived exertion at all stages of exercise across both days compared to controls.
Conclusion: The researchers concluded that the 2-day CPET protocol yields identical exercise-capacity metrics on consecutive days for both ME/CFS patients and healthy controls. Therefore, the data does not support using consecutive 2-day CPETs as a reliable diagnostic tool to define PEM or disability in ME/CFS patients.
Prior Research
In a past study, several differences were found 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 exhibited lower performance and heart rate, and on the second test, performance was even lower, while for controls, it was the same or slightly better. The largest decrease was in anaerobic threshold, which signifies a shift from aerobic to anaerobic metabolism at a lower level of exertion, and was not influenced by effort. 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. Additionally, healthy people generally recovered from a CPET within 24 hours while people with ME/CFS do not.
A 2-day CPET was hypothesized to measure PEM and its effect on physical functioning. (Objective indicators of maximal effort during both tests control for effort.) However, its utility has not been completely confirmed, as many studies of it have been small. 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. Because PEM is also a symptom of long COVID, the 2-day CPET may be useful in evaluating exercise intolerance there as well.
The cause of decreased performance was not understood. Proposals include impaired oxygen transport, impaired aerobic metabolism, impaired microvascular blood flow, loss of passive microvascular filtration and mitochondrial dysfunction.
This original test provoked symptoms by design, and recovery oulsbe prolonged. In some cases, it may worsen the illness long-term, as such it should only be applied to patients when absolutely necessary.
Criticisms 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. On top of that PEM itself has been claimed to exist in cancer-related fatigue, however this study did not differentiate between PEM and exercise intolerance.
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