Two-day cardiopulmonary exercise test

Two-day cardiopulmonary exercise test or 2-day CPET is an accepted, reliable test for post-exertional malaise (PEM), one of the cardinal symptoms that distinguishes individuals with and without ME/CFS. The hypothesis is that ME/CFS patients are almost unique in having a severe deterioration in the second of the two cardiopulmonary exercise tests performed on consecutive days.

The cardiopulmonary exercise test (CPET) is the same non-invasive test given to measure the fitness levels of athletes, as well as people with cardiopulmonary illness. However, if the test is repeated 24 hours later, ME/CFS patients will fare significantly worst than they did on the first day. The Institute of Medicine report states that: "ME/CFS patients have significantly lower results on CPET [day] 2 than on CPET [day] 1 on one or more of the following parameters: VO2max (Keller et al., 2014; VanNess et al., 2007; Vermeulen et al., 2010), VO2 at ventilatory threshold (Keller et al., 2014), and maximal workload or workload at ventilatory threshold (Keller et al., 2014; Snell et al., 2013)."

Although the Institute of Medicine report states that 2-day CPET is very reliable to objectively measure PEM, the IOM committee emphasized "that the CPET is not required to diagnose patients with ME/CFS. Further, this test carries substantial risk for these patients as it may worsen their condition (Nijs et al., 2010; VanNess et al., 2010)."

Evidence
Mark VanNess, Christopher Snell and Staci Stevens of the University of the Pacific, were the first to study the two-day CPET procedure in patients with ME/CFS. In a 2007 study published in the Journal of Chronic Fatigue Syndrome, they compared six ME/CFS patients with six controls. At the first CPET there were no major differences between the two groups. At the second CPET however, ME/CFS patients reached significantly lower peak oxygen consumption and oxygen consumption at aerobic threshold.

In 2010 a Dutch research group including Ruud Vermeulen and Frans Visser used the 2-day CPET in a study with 15 female ME/CFS and 15 healthy controls. Patients reached the aerobic threshold and the maximal exercise at much lower oxygen consumption than controls, an effect that was magnified during the second-day exercise test. Since levels of creatinine kinase in the blood and oxidative phosphorylation in mononuclear cells were normal in patients before and after exercise, Vermeulen et al. speculated that the lowered anaerobic threshold was not so much a result of mitochondrial insufficiency, but of impaired oxygen transport to the muscles.

In 2013 Snell, Stevens and VanNess tested the 2-day CPET procedure in a larger sample of 51 ME/CFS patients and 10 heathy controls. Once again, there were no sufficient differences between the groups at the first CPET. During the exercise test on the second day however, ME/CFS patients showed much lower oxygen consumption and workload at peak exercise and at aerobic threshold. Group differences were not due to lack of effort since most participants attained the ventilatory threshold and achieved a respiratory exchange ratio of greater than or equal to 1,1.

In 2014 the research group of Betsy Keller used the 2-day CPET protocol in a study involving 22 ME/CVS patient. A decline on several physiological measures was found (see table), while the respiratory exchange ratio indicated maximum efforts by participants during both exercise tests.

This group followed this research up with a study of a single pair of monozygotic twins in 2016. In 2017, a research team form New Zealand compared the physiological responses during a 2-day CPET, in ten patients with ME/CFS, seven patients with MS and seventeen healthy controls. Curiously peak oxygen increased at the second exercise test in ME/CFS patients, but there was a significant reduction noticeable in workload at aerobic threshold, a decline that was not seen in MS-patients or healthy controls. According to the authors: "“differences between MS and CFS/ME responses only became evident after a second maximal exercise test, thus suggesting that a repeated protocol is required to not only distinguish CFS/ME from HC, but also from other fatigue-related conditions, who may not suffer from postexertional malaise and have a differing delayed fatigue profile.”"In a 2019 the 2-day CPET procedure was tested by an Australian research team of Nelson and colleagues. They found a significant larger reduction in workload at the ventilatory treshold in patients with ME/CFS compared to healthy controls. A percentage change of −6.3% to −9.8% provided good sensitivity and specificity, indicating this test has the potential to become a biomarker for ME/CFS. However, the sample size of this study was small (16 ME/CFS paitients), the control group consisted only of healthy persons (instead of patients with other chronic illnesses) and no significant difference was found in VO2 at the ventilatory threshold.

A small Norwegian study also reported a significant larger reduction in workload at the ventilatory treshold in 18 patients with ME/CFS compared to healthy controls, although this was not the case for peak values or VO2 measurement at the ventilatory threshold. The authors also measured arterial lactate concentrations, every 30 seconds during the exercise tests. Lactate was higher per power output per kg in patients than controls and the differences increased significantly at the second exercise test. In the healthy controls lactate concentration at the ventilatory threshold decreased while this was not the case in ME/CFS patients,suggesting a problem in lactate clearance ability.

Unpublished studies have reported negative results for the repeated CPET procedure. A thesis by Nielsen TM at the Massey University, New-Zealand, performed the second exercise test 48 hours and 72 hours later, instead of the usual 24 hours. The study did not find significant reductions of workload at the ventilatory threshold in ME/CFS patients compared to controls. The 8 ME/CFS patients in the 72 hours group had a workload at ventilatory threshold that was slightly higher instead of lower than during the first test. In a 2018 presentation Ruud Vermeulen reported to have data on approximately 500 ME/CFS patients who performed the repeated CPET procedure and that the second test did not show any significant difference compared to the first. It is unclear which outcome measures Vermeulen was referring to.

Use as a Biomarker
Snell et al. suggested 2-day CPET could be used "diagnostically as an objective indicator of an abnormal postexertion response and possibly even a biomarker for the condition". Using the data from the two exercise tests, their research team was able to correctly classify 95% of the total sample, as a patient or healthy control.

While a unique reduction in physiological capacity was observed in ME/CFS by several studies and different research groups, sample sizes were rather small and disagreement exists on which physiological measure accurately displayed ME/CFS patients’ abnormal exertional response.

Another objection to the 2-day CPET as a biomarker for ME/CFS was raised by Snell et al themselves. They suggested it might be unethical to use this method to detect ME/CFS patients since many of these patients might suffer relapse as a result of exercise testing. In their 2010 study, 60% of ME/CFS patients reported that it took them more than 5 days to recover from a single (maximal) CPET. It is therefore possible that in some ME/CFS patients a 2-day CPET might cause a long-lasting relapse. Science-reporter and ME/CFS patient Simon McGrath for example wrote: “You couldn’t pay me enough money to take even one max test. My last relapse, which took me nearly 2 years to get over, happened after way less than maximal exertion – a 2-day test is not for everyone."

Others have noted that the CPET-procedure is not very practical. It cannot be used in patients with severe ME/CFS (thus excluding these patients from study) and because of cost and expertise, it may not be available to most clinicians. CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars. For these reasons PEM is commmonly assessed using self-reporting questionnaires.

Brian Vastag was able to prove his PEM was a severe symptom causing disability with CPET winning his long term disability (LTD) claim.

Cost and availability

 * Workwell Foundation (United States, CA)
 * Betsy Keller at Ithaca College (United States, NY) Cost is $2200. Because they are based in a college setting (not healthcare setting), they cannot process insurance (including Medicare or Medicaid), so the patient would need to work directly with their insurer about reimbursement. (private email)
 * Laura Black at Hunter-Hopkins Center, Charlotte, NC
 * Open Medicine Institute Clinic
 * Physiologic 334 Scottsdale Drive, Robina, Gold Coast, Australia
 * Many UK universities offer standard CPETs which can be adapted for patients with ME.

Talks and interviews

 * 2013, CPET Presentation by Dr. Christopher Snell, Part ICPET Presentation by Dr. Christopher Snell, Part II
 * 2014, Mark VanNess 'Exercise and ME/CFS' at Bristol Watershed. Part One

Learn more

 * The Workwell Foundation: Testing for Disability
 * 2007, Legal and Scientific Considerations of the Exercise Stress Test
 * 2013, Busted! Exercise Study Finds Energy Production System is Broken in Chronic Fatigue Syndrome
 * 2013, Repeat Test Reveals Dramatic Drop in ME/CFS Exercise Capacity
 * 2018, Victory For ME Disability Claim – U.S. Court Upholds Plaintiff's Lawsuit After Being Denied Disability
 * 2019, Decoding the 2-day Cardiopulmonary Exercise Test (CPET) in Chronic Fatigue Syndrome (ME/CFS) by C. Christian