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2-day CPET
Person on a treadmill wearing a mask connected to a metabolic cart
A CPET being administered

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]

Background

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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

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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]

References

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  1. ^ a b "Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 2: Physiological Characteristics During Acute Exercise Are Abnormal in People With Postexertional Symptom Exacerbation". JOSPT Blog. 2022-02-09. doi:10.2519/jospt.blog.20220209 (inactive 4 June 2025).{{cite journal}}: CS1 maint: DOI inactive as of June 2025 (link)
  2. ^ Joseph, Phillip; Singh, Inderjit; Oliveira, Rudolf; Capone, Christine A.; Mullen, Mary P.; Cook, Dane B.; Stovall, Mary Catherine; Squires, Johanna; Madsen, Kristine; Waxman, Aaron B.; Systrom, David M. (2023). "Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Postacute Sequelae of SARS-CoV-2". Chest. 164 (3): 717–726. doi:10.1016/j.chest.2023.03.049. PMC 10088277. PMID 37054777.
  3. ^ a b c d e Franklin, John Derek; Graham, Michael (2022-07-03). "Repeated maximal exercise tests of peak oxygen consumption in people with myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review and meta-analysis". Fatigue: Biomedicine, Health & Behavior. 10 (3): 119–135. doi:10.1080/21641846.2022.2108628. ISSN 2164-1846. S2CID 251636593.
  4. ^ a b Lim, Eun-Jin; Kang, Eun-Bum; Jang, Eun-Su; Son, Chang-Gue (2020-12-14). "The Prospects of the Two-Day Cardiopulmonary Exercise Test (CPET) in ME/CFS Patients: A Meta-Analysis". Journal of Clinical Medicine. 9 (12): 4040. doi:10.3390/jcm9124040. ISSN 2077-0383. PMC 7765094. PMID 33327624.
  5. ^ Davenport, Todd E.; Lehnen, Mary; Stevens, Staci R.; VanNess, J. Mark; Stevens, Jared; Snell, Christopher R. (2019-03-22). "Chronotropic Intolerance: An Overlooked Determinant of Symptoms and Activity Limitation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?". Frontiers in Pediatrics. 7: 82. doi:10.3389/fped.2019.00082. ISSN 2296-2360. PMC 6439478. PMID 30968005.
  6. ^ Twomey, Rosie; et al. (2022-02-02). "Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID: Postexertional Symptom Exacerbation is an Abnormal Response to Exercise/Activity". JOSPT Blog. doi:10.2519/jospt.blog.20220202 (inactive 4 June 2025).{{cite journal}}: CS1 maint: DOI inactive as of June 2025 (link)
  7. ^ a b c d Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness (PDF). National Academies of Medicine Press. pp. 82–83.
  8. ^ Durstenfeld, Matthew S.; Sun, Kaiwen; Tahir, Peggy; Peluso, Michael J.; Deeks, Steven G.; Aras, Mandar A.; Grandis, Donald J.; Long, Carlin S.; Beatty, Alexis; Hsue, Priscilla Y. (2022-10-12). "Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults: A Systematic Review and Meta-analysis". JAMA Network Open. 5 (10): e2236057. doi:10.1001/jamanetworkopen.2022.36057. ISSN 2574-3805. PMC 9557896. PMID 36223120.
  9. ^ Keller, Betsy; Receno, Candace N.; Franconi, Carl J.; Harenberg, Sebastian; Stevens, Jared; Mao, Xiangling; Stevens, Staci R.; Moore, Geoff; Levine, Susan; Chia, John; Shungu, Dikoma; Hanson, Maureen R. (2024-07-05). "Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations". Journal of Translational Medicine. 22 (1): 627. doi:10.1186/s12967-024-05410-5. ISSN 1479-5876. PMC 11229500. PMID 38965566.
  10. ^ Nijs, Jo; De Meirleir, Kenny; Duquet, William (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. ISSN 0003-9993. PMID 15468015.
  11. ^ Hodges, L. D.; 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. ISSN 1475-097X. PMID 28782878.
  12. ^ Heine, Martin; Akker, Lizanne Eva van den; Verschuren, Olaf; Visser-Meily, Anne; Kwakkel, Gert; Group, TREFAMS-ACE Study (2015-03-19). "Reliability and Responsiveness of Cardiopulmonary Exercise Testing in Fatigued Persons with Multiple Sclerosis and Low to Mild Disability". PLOS ONE. 10 (3): e0122260. Bibcode:2015PLoSO..1022260H. doi:10.1371/journal.pone.0122260. ISSN 1932-6203. PMC 4366200. PMID 25789625. {{cite journal}}: |last6= has generic name (help)
  13. ^ Balady, Gary J.; Arena, Ross; Sietsema, Kathy; Myers, Jonathan; Coke, Lola; Fletcher, Gerald F.; Forman, Daniel; Franklin, Barry; Guazzi, Marco; Gulati, Martha; Keteyian, Steven J.; Lavie, Carl J.; Macko, Richard; Mancini, Donna; Milani, Richard V. (2010-07-13). "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. ISSN 1524-4539. PMID 20585013.
  14. ^ Twomey, Rosie; Yeung, Samuel T.; Wrightson, James G.; Millet, Guillaume Y.; Culos-Reed, S. Nicole (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. ISSN 1873-6513. PMID 32105793.
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