Post-exertional malaise in Long COVID: subjective reporting versus objective assessment

Abstract

Background: Post-exertional malaise (PEM) is a central feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and has emerged as a prominent feature of Long COVID. The optimal clinical approach to PEM is inconclusive, and studies of the impact of exercise have yielded contradictory results.

Objective: The objective of this study was to examine PEM in Long COVID by assessing the prevalence of self-reported PEM across study cohorts and symptom responses of Long COVID patients to a standardized exercise stressor. Secondarily, Long COVID symptom responses to exercise were compared to those of ME/CFS and healthy volunteers.

Methods: Data from three registered clinical trials comprised four cohorts in this study: Long COVID Questionnaire Cohort (QC; n = 244), Long COVID Exercise Cohort (EC; n = 34), ME/CFS cohort (n = 9), and healthy volunteers (HV; n = 9). All cohorts completed questionnaires related to physical function, fatigue, and/or PEM symptoms. EC also performed a standardized exercise test (cardiopulmonary exercise test, CPET), and the PEM response to CPET was assessed using visual analog scales and qualitative interviews (QIs) administered serially over 72 h. EC PEM measures were compared to ME/CFS and HV cohorts. A secondary analysis of QI explored positive responses to CPET among EC, ME/CFS and HV.

Results: Self-reported PEM was 67% in QC and estimated at 27% in EC. Only 2 of 34 EC patients (5.9%) were observed to develop PEM after a CPET. In addition, PEM responses after CPET in Long COVID were not as severe and prolonged as those assessed in ME/CFS. Twenty-two of 34 EC patients (64.7%) expressed at least one of 7 positive themes after the CPET.

Conclusion: Self-report of PEM is common in Long COVID. However, observable PEM following an exercise stressor was not frequent in this small cohort. When present, PEM descriptions during QI were less severe in Long COVID than in ME/CFS. Positive responses after an exercise stressor were common in Long COVID. Exercise testing to determine the presence of PEM may have utility for guiding clinical management of Long COVID.

Keywords: cardiopulmonary exercise test (CPET); myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); post acute sequelae of SARS-CoV-2; post-COVID condition; post-exertional symptom exacerbation.

Figure 1

Patient flow and cohort by clinical trial study.

Figure 2

The VAS for CFS Symptom Questionnaire.

Figure 3

Graphical view of the QI among sample patients from (A) HV, (B) Long COVID EC, and (C) ME/CFS. Symbols denote severity of overall symptoms at specified timepoints in relation to the CPET. Red symbols denote patients meeting criteria for PEM. Dashed line indicates usual baseline levels. Two different patients are shown in (B) for EC.

Figure 4

Three severity levels of PEM based on distribution of SF-36 PCS scores among Long COVID QC patients. As described in the methods, means were used to categorize Long COVID EC patients into PEM severity categories based on SF-36 PCS scores.

Figure 5

Proportion of patients by self-reported PEM severity for Long COVID QC, Long COVID EC, and ME/CFS. PEM categories represented for “No PEM” (blue), “Moderate PEM” (orange), and “Severe PEM” (red). Refer to methods for determination of PEM categories for each cohort.

Figure 6

VAS scores before and after CPET for (A) physical fatigue, (B) mental fatigue, (C) muscle aches, and (D) headache for ME/CFS (purple), Long COVID EC (blue), and HV (green). Dashed line denotes when the CPET was performed. Symbols are mean ± one standard deviation.

Figure 7

Heatmaps for change in VAS scores after CPET for (A) physical fatigue, (B) mental fatigue, (C) muscle aches, and (D) headache for ME/CFS (top section), Long COVID EC (middle section), and HV (bottom section). Time categories (x-axis) with individual patients (y-axis) are arranged in ascending order within respective group cohorts. Lighter pigments indicate minimal changes in VAS scores, with darker pigments depicting more (orange) or reduced (green) symptom severity from pre-CPET. Subject IDs in red met criteria for PEM by QI. Subject IDs denoted with (†) were in both EC and QC. Asterisks (*) denote data removed due to confounding variables.

Figure 8

Heatmaps of (A) PEM based on QI and (B) change in symptom severity after CPET for ME/CFS (top section), Long COVID EC (middle section), and HV (bottom section). Time categories (x-axis) with individual patients (y-axis) are arranged in ascending order within respective group cohorts. Subject IDs in red met criteria for PEM by QI. Subject IDs denoted with (†) were in both EC and QC. Asterisks (*) denote data removed due to confounding variables.

Figure 9

CPET outcomes for HV, Long COVID EC, and ME/CFS. Violin plots with distribution of individual data points for (A) RER, (B) peak VO₂ as percent predicted, and (C) peak HR as percent of age-predicted maximal heart rate. Data points in red indicates patients meeting criteria for PEM by QI. Dashed line demarcates targets for (A) sufficient effort, (B) normal exercise capacity, and (C) expected peak HR on the CPET.

Figure 10

Word clouds of most bothersome symptoms from the QI for (A) Long COVID EC and (B) ME/CFS.

Figure 11

(A) Proportion of patients expressing a positive response after the CPET by cohort. (B) Number of patients by (B) number of positive themes and (C) theme category by cohort.