A brief, comprehensive measure of post-exertional malaise

Abstract

Aim:Post-exertional malaise (PEM) has been a challenging construct to measure, particularly with self-report instruments, which have the benefits of being less expensive and less invasive than cardiopulmonary exercise tests. Existing PEM questionnaires have often been used for diagnostic purposes and less frequently as outcome measures. Few self-report PEM measures address comprehensive PEM domains, including types of triggers, duration of symptoms, delayed symptom onset, number of symptoms, frequency and severity of symptoms, as well as whether pacing or other strategies reduce or eliminate PEM. Without characterizing these features, salient aspects of PEM would be overlooked. However, efforts to assess all these domains can be time-consuming and potentially burdensome.
Methods:The current study offers investigators a brief but comprehensive instrument of critical PEM domains, called the DePaul Symptom Questionnaire (DSQ)-PEM-2, to assess PEM. Validation data were derived from a large sample of individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Results:The DSQ-PEM-2 was developed using an existing dataset of individuals with ME, CFS, or both ME and CFS, allowing comprehensive coverage of key PEM domains.
Conclusions:The DSQ-PEM-2 can be used either for diagnostic purposes or as an outcome measure. The instrument’s time frames for symptom manifestation can be adapted to suit a variety of research or clinical contexts. Future validation studies need to include a healthy control group.

Keywords

myalgic encephalomyelitis/chronic fatigue syndrome / post-exertional malaise / DePaul Symptom Questionnaire-PEM-2

References

[1] Appelman B, Charlton BT, Goulding RP, Kerkhoff TJ, Breedveld EA, Noort W, et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat Commun. 2024; 15: 17.

[2] Cortes Rivera M, Mastronardi C, Silva-Aldana CT, Arcos-Burgos M, Lidbury BA. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review. Diagnostics (Basel). 2019; 9: 91.

[3] Lim E, Kang E, Jang E, Son C. The Prospects of the Two-Day Cardiopulmonary Exercise Test (CPET) in ME/CFS Patients: A Meta-Analysis. J Clin Med. 2020; 9: 4040.

[4] Nacul LC, Mudie K, Kingdon CC, Clark TG, Lacerda EM. Hand Grip Strength as a Clinical Biomarker for ME/CFS and Disease Severity. Front Neurol. 2018; 9: 992.

[5] Paffrath A, Kim L, Kedor C, Stein E, Rust R, Freitag H, et al. Impaired Hand Grip Strength Correlates with Greater Disability and Symptom Severity in Post-COVID Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Clin Med. 2024; 13: 2153.

[6] Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [Internet]. [cited 2025 Apr 20]. Available from: https://www.commondataelements.ninds.nih.gov/Myalgic%20Encephalomyelitis/Chronic%20Fatigue%20Syndrome

[7] Brown A, Jason LA. Meta-analysis investigating post-exertional malaise between patients and controls. J Health Psychol. 2020; 25: 2053-71.

[8] Jason LA, Evans M, So S, Scott J, Brown A. Problems in defining post-exertional malaise. J Prev Interv Community. 2015; 43: 20-31.

[9] Jason LA, Choi M. Dimensions and Assessment of Fatigue. In: Watanabe Y, Evengård B, Natelson BH, Jason LA, Kuratsune H, editors. Fatigue Science for Human Health. Tokyo: Springer Japan; 2008. pp. 1-16. [DOI]

[10] Jason LA, King CP, Richman JA, Taylor RR, Torres SR, Song S. U.S. Case Definition of Chronic Fatigue Syndrome: Diagnostic and Theoretical Issues. J Chronic Fatigue Syndr. 1999; 5: 3-33. [DOI]

[11] Hawk C, Jason LA, Torres-Harding S. Differential diagnosis of chronic fatigue syndrome and major depressive disorder. Int J Behav Med. 2006; 13: 244-51.

[12] Mateo LJ, Chu L, Stevens S, Stevens J, Snell CR, Davenport T, et al. Post-exertional symptoms distinguish Myalgic Encephalomyelitis/Chronic Fatigue Syndrome subjects from healthy controls. Work. 2020; 66: 265-75.

[13] Stussman B, Calco B, Norato G, Gavin A, Chigurupati S, Nath A, et al. Mixed methods system for the assessment of post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: an exploratory study. BMJ Neurol Open. 2024; 6: e000529.

[14] Davenport TE, Stevens SR, Stevens J, Snell CR, Ness JMV. Development and measurement properties of the PEM/PESE activity questionnaire (PAQ). Work. 2023; 74: 1187-97.

[15] Sivan M, Preston N, Parkin A, Makower S, Gee J, Ross D, et al. The modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm) patient-reported outcome measure for Long Covid or Post-COVID-19 syndrome. J Med Virol. 2022; 94: 4253-64.

[16] Vernon SD, Hartle M, Sullivan K, Bell J, Abbaszadeh S, Unutmaz D, et al. Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Work. 2023; 74: 1179-86.

[17] Sommerfelt K, Schei T, Seton KA, Carding SR. Assessing Functional Capacity in Myalgic Encephalopathy/Chronic Fatigue Syndrome: A Patient-Informed Questionnaire. J Clin Med. 2024; 13: 3486.

[18] Jason LA, Evans M, Porter N, Brown M, Brown A, Hunnell J, et al. The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition. Am J Biochem Biotechnol. 2010; 6: 120-35. [DOI]

[19] Jason LA, Sunnquist M. The Development of the DePaul Symptom Questionnaire: Original, Expanded, Brief, and Pediatric Versions. Front Pediatr. 2018; 6: 330.

[20] Jason LA. Measuring Post-Exertional Malaise with DePaul Symptom Questionnaires: Challenges and Opportunities. OBM Neurobiol. 2025; 9: 267.

[21] Twomey R, DeMars J, Franklin K, Culos-Reed SN, Weatherald J, Wrightson JG. Chronic Fatigue and Postexertional Malaise in People Living With Long COVID: An Observational Study. Phys Ther. 2022; 102: pzac005.

[22] Cotler J, Holtzman C, Dudun C, Jason LA. A Brief Questionnaire to Assess Post-Exertional Malaise. Diagnostics (Basel). 2018; 8: 66.

[23] Jason LA, So S, Brown AA, Sunnquist M, Evans M. Test-Retest Reliability of the DePaul Symptom Questionnaire. Fatigue. 2015; 3: 16-32.

[24] Jason LA, Holtzman CS, Sunnquist M, Cotler J. The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome. J Health Psychol. 2021; 26: 238-48.

[25] Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009; 42: 377-81.

[26] Holtzman CS, Bhatia S, Cotler J, Jason LA. Assessment of Post-Exertional Malaise (PEM) in Patients with Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS): A Patient-Driven Survey. Diagnostics (Basel). 2019; 9: 26.

[27] Ramsay AM. Myalgic Encephalomyelitis and PostViral Fatigue States: The saga of Royal Free disease. Gower Medical for the Myalgic Encephalomyelitis Association; 1988.

[28] Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011; 270: 327-38.

[29] Jason LA, McManimen SL, Sunnquist M, Holtzman CS. Patient perceptions of post exertional malaise. Fatigue: Biomed, Health Behav. 2018; 6: 92-105. [DOI]

[30] Jason LA, Sunnquist M, Brown A, Furst J, Cid M, Farietta J, et al. Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains. J Neurol Neurobiol. 2015; 1: 10.16966/2379-7150.114. [DOI] [PubMed] [PMC]

[31] Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992; 30: 473-83. [PubMed]

[32] McHorney CA, Ware JE Jr, Lu JF, Sherbourne CD. The MOS 36-item Short-Form Health Survey (SF-36): III. Tests of data quality, scaling assumptions, and reliability across diverse patient groups. Med Care. 1994; 32: 40-66.

[33] Sunnquist M, Lazarus S, Jason LA. The development of a short form of the DePaul Symptom Questionnaire. Rehabil Psychol. 2019; 64: 453-62.

[34] Oliveira CR, Jason LA, Unutmaz D, Bateman L, Vernon SD. Improvement of Long COVID symptoms over one year. Front Med (Lausanne). 2023; 9: 1065620.

[35] Jason LA, Dorri JA. ME/CFS and Post-Exertional Malaise among Patients with Long COVID. Neurol Int. 2022; 15: 1-11.

[36] RECOVER-VITAL: A Platform Protocol for Evaluation of Interventions for Viral Persistence, Viral Reactivation, and Immune Dysregulation in Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) [Internet]. [cited 2025 Apr 20]. Available from: https://trials.recovercovid.org/documents/RECOVER-VITAL_Protocol_V4.0.pdf

[37] RECOVER-ENERGIZE: A Platform Protocol for Evaluation of Interventions for Exercise Intolerance in Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) [Internet]. [cited 2025 Apr 20]. Available from: https://trials.recovercovid.org/documents/RECOVER_ENERGIZE_Protocol_v.2.0.pdf

[38] Wold BKG, Tveito K, Angelsen A, Bringsli G, Berglund F, Gustavsen M, et al. Symptom-based survey diagnoses may serve to identify more homogenous sub-groups of fatigue and postviral diseases. Fatigue: Biomed, Health Behav. 2024; 12: 261-77. [DOI]

[39] Sanal-Hayes NEM, Mclaughlin M, Hayes LD, Mair JL, Ormerod J, Carless D, et al. A scoping review of 'Pacing' for management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): lessons learned for the long COVID pandemic. J Transl Med. 2023; 21: 720.

[40] Haffke M, Freitag H, Rudolf G, Seifert M, Doehner W, Scherbakov N, et al. Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS). J Transl Med. 2022; 20: 138.

[41] Klein J, Wood J, Jaycox JR, Dhodapkar RM, Lu P, Gehlhausen JR, et al. Distinguishing features of long COVID identified through immune profiling. Nature. 2023; 623: 139-48.

[42] Pagen DME, Van Herck M, van Bilsen CJA, Brinkhues S, Konings K, den Heijer CDJ, et al. High proportions of post-exertional malaise and orthostatic intolerance in people living with post-COVID-19 condition: the PRIME post-COVID study. Front Med (Lausanne). 2023; 10: 1292446.

[43] Rathgeb C, Pawellek M, Behrends U, Alberer M, Kabesch M, Gerling S, et al. The Evaluation of Health Care Services for Children and Adolescents With Post-COVID-19 Condition: Protocol for a Prospective Longitudinal Study. JMIR Res Protoc. 2023; 12: e41010.

[44] Taenzer M, Löffler-Ragg J, Schroll A, Monfort-Lanzas P, Engl S, Weiss G, et al. Urine Metabolite Analysis to Identify Pathomechanisms of Long COVID: A Pilot Study. Int J Tryptophan Res. 2023; 16: 11786469231220781.

[45] Tanguay P, Gaboury I, Daigle F, Bhéreur A, Dubois O, Lagueux É, et al. Post-exertional malaise may persist in Long COVID despite learning STOP-REST-PACE. Fatigue: Biomed, Health Behav. 2023; 11: 113-28. [DOI]

[46] Toepfner N, Brinkmann F, Augustin S, Stojanov S, Behrends U. Long COVID in pediatrics-epidemiology, diagnosis, and management. Eur J Pediatr. 2024; 183: 1543-53.

[47] Twomey R, Yeung ST, Wrightson JG, Millet GY, Culos-Reed SN. Post-exertional Malaise in People With Chronic Cancer-Related Fatigue. J Pain Symptom Manage. 2020; 60: 407-16.

[48] Wernhart S, Weihe E, Totzeck M, Balcer B, Rassaf T, Luedike P. Cardiopulmonary Profiling of Athletes with Post-Exertional Malaise after COVID-19 Infection-A Single-Center Experience. J Clin Med. 2023; 12: 4348.

[49] Shaheen A, Shaheen N; Collaborative Group; Shoib S, Saeed F, Buhari M, Flouty O. Analysis of COVID-19 Patientsʼ Symptoms and Vaccine Impact Using Deep Learning Approach, and Development Machine Learning Based Risk Calculator: A Multicentric Collaborative Study. Research Square [Preprint]. 2023 [cited 2025 Apr 20]. Available from: https://www.researchsquare.com/article/rs-3739801/v1

[50] Summary of Core/Supplemental - Highly Recommended Recommendations: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) CDEs [Internet]. [cited 2025 Apr 20]. Available from: https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/CDEStartupResource_MECFS.pdf

[51] Carnes MU, Brown LM, Enger M. Common data elements to advance ME/CFS research. Open Access Gov. 2025: 164-7.

[52] Sculthorpe NF, McLaughlin M, Cerexhe L, Macdonald E, Iacono AD, Sanal-Hayes NEM, et al. Tracking Persistent Symptoms in Scotland (TraPSS): a longitudinal prospective cohort study of COVID-19 recovery after mild acute infection. BMJ Open. 2025; 15: e086646.

[53] Huang K, Lidbury BA, Thomas N, Gooley PR, Armstrong CW. Machine learning and multi-omics in precision medicine for ME/CFS. J Transl Med. 2025; 23: 68.