2-day CPET

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.^[1][2] PEM is a cardinal symptom of myalgic encephalomyelitis/chronic fatigue syndrome and is common in long COVID as well.^[3]

2-day CPET
A CPET being administered

Background

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]