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. Author manuscript; available in PMC: 2026 Sep 12.
Published in final edited form as: Med Sci Sports Exerc. 2025 Nov 4;58(4):637–649. doi: 10.1249/MSS.0000000000003891

Post-Exertional Symptom Exacerbation After Sub-Maximal Exercise in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of COVID-19

Giovanni Berardi 1, Adam Janowski 1, Samuel McNally 1, Andrew Post 1, Alpana Garg 2, Kathleen A Sluka 1
PMCID: PMC13565752  NIHMSID: NIHMS2205791  PMID: 41185151

Abstract

Purpose:

In individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC), physical activity can exacerbate symptoms for days-to-weeks, referred to as post-exertional symptom exacerbation (PESE). This study characterized the trajectory of PESE symptoms before and for 7 days after a sub-maximal exercise task in individuals with ME/CFS or PASC.

Methods:

Individuals with ME/CFS (n=30) or PASC (n=30) and matched controls (n=30) were recruited from a university hospital and the community setting. Participants completed a 25-minute moderate intensity exercise on a whole-body cycle ergometer. The trajectory of 8 commonly reported PESE symptoms (physical fatigue, mental fatigue, pain, physical function, flu-like symptoms, gastrointestinal symptoms, sleep dysfunction, anxiety) before and for 7 days after exercise.

Results:

There was variability in the proportion of those who experienced increased symptoms ranging from 46/60 reporting physical fatigue to only 18/30 reporting anxiety. There was no change in any of the symptoms across the 7-day period when analyzed individually. An aggregate score of 4-5 symptoms that includes physical fatigue, mental fatigue, physical function and flu-like symptoms, with or without pain, was more comprehensive in capturing maximal changes in PESE. Changes were greatest during the 72h post-exercise and for those with ME/CFS. The aggregate score shows 8/30 of individuals with ME/CFS and 12/30 with PASC show minimal-to-no increase in PESE, while 6-7/30 show increases greater than 3/10 points.

Conclusion:

PESE to a clinically relevant exercise task is variable in individuals with ME/CFS and PASC as submaximal exercise does not exacerbate symptoms for some, while modifications of intensity may be necessary to minimize PESE in others.

Keywords: fatigue, pain, exercise, Chronic Fatigue Syndrome, Post-Acute COVID-19 Syndrome

Introduction

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC) are complex syndromes characterized by persistent fatigue.(1-5) Both syndromes have a similar symptom presentation that includes physical and mental fatigue, localized joint pain and widespread pain, sleep dysfunction, and general malaise, all of which impact function.(6-8) A hallmark feature of ME/CFS is the exacerbation of symptoms by physical activity, referred to as post-exertional symptom exacerbation (PESE);(2, 9) exacerbation of symptoms by physical activity is also reported in individuals with PASC.(9, 10)

PESE occurs during and after an exercise task, lasts for hours to weeks, and is a barrier to participation in daily activities and exercise.(11-22) The use of exercise in these populations is controversial, primarily due to PESE.(23-30) Systematic reviews show that routine exercise improved symptoms in PASC and possibly ME/CFS.(26, 28, 31, 32) Qualitative studies report long-lasting exacerbation of symptoms, while quantitative studies show differing reports for both ME/CFS and PASC that depend on intensity of exercise, symptoms examined, and time of assessment after exercise.(15, 16, 19, 33, 34) For example, a recent study showed PESE symptoms lasting for 7 days following two serial maximal intensity exercise tests in individuals with ME/CFS.(21) In contrast, a low intensity walking task shows minimal PESE in individuals with ME/CFS.(19) Together, these data suggest intensity of exercise is critical to the PESE response.

The majority of studies examining PESE after exercise focus on fatigue, with a few expanding to examine other symptoms such as pain and physical function.(35-38) As PESE is multidimensional, examining multiple symptoms could increase sensitivity of the measure and more accurately reflect an individualized response, as recently shown for individuals with ME/CFS in response to a maximal intensity exercise.(21) Currently validated self-report measures of PESE rely on self-reported recall of symptoms in response to exercise,(35-38) and thus may not reflect the actual day-to-day variability during exercise recovery.(9, 12, 15, 37, 39-41) Using ecological momentary assessment to examine symptoms of PESE would minimize recall bias and capture a more detailed and nuanced understanding of the daily response. Understanding PESE following a clinically relevant therapeutic dose of exercise is pivotal to improve symptom management in both ME/CFS and PASC. Therefore, the purpose of the current study was to characterize PESE using a daily trajectory rating of 8 commonly reported symptoms, before and for 7 days after, a moderate intensity exercise task in individuals with ME/CFS and PASC, when compared to matched controls.

Methods

Study Design

Individuals meeting diagnostic criteria for PASC (n=10 M, 20 F) or ME/CFS (n=1 M, 29 F), and age, sex, and BMI matched controls (n=7 M, 23 F), were recruited to participate (Supplemental Methods: Enrollment Criteria & Recruitment Details). During the baseline visit, participants completed measures to characterize pain, fatigue and PESE (Supplemental Methods: Baseline Measures). Before, immediately after, and daily for 1-week following exercise participants completed the PESE trajectory survey. Study participants were also invited to complete the PESE survey daily for 8 days without exercise exposure to understand natural fluctuation in symptoms; this was collected a posteriori 9 to 20 months after the exercise task (HC: 6 M, 15 F; ME/CFS: 10 M, 20 F; PASC: 7 M, 15 F). The research protocol was approved by the Institutional Review Board of the University of Iowa, conducted in accordance with the Declaration of Helsinki and participants provided written informed consent prior to enrollment.

Exercise Task

Participants completed a whole-body exercise task on a seated arm-leg cycle ergometer (Airdyne AD7, Schwinn, USA). Heart rate was monitored with a Polar H6 sensor (Polar Electro Oy, Finland). After a 5 min warm up, moderate intensity exercise was maintained for 20 minutes using 60-70% age-predicted maximal heart rate as a target. Individuals who were unable to achieve 60% of age-predicted maximal heart rate were encouraged to continue exercising as able. Perceived exertion, fatigue, and pain were reported every 5 minutes during the exercise task and immediately after completion (Supplemental Methods: Exercise Measures).

Post-Exertional Symptom Exacerbation (PESE) Trajectory

PESE was evaluated using a series of 0-10 numerical rating scales (NRS), higher values indicating worse symptoms, before and for 7 days after exercise for the following symptoms: physical fatigue, mental fatigue, pain, physical function, flu-like symptoms, gastrointestinal symptoms, sleep quality, and anxiety. The survey was sent to participants daily through REDCap (Supplemental Methods: PESE Trajectory). All participants received follow-up surveys at the same time in which they completed their baseline (pre-exercise) survey. Each participant was encouraged to respond to the survey promptly, however, were provided reminders at 2 and 4 hours after the initial survey delivery if the survey was not completed. A 0-10 NRS was chosen since this is considered a valid method to assess symptoms in a short time period and are quick and easy to use for participants,(42-48) and multiple NRS scores have been used previously to assess the response fo some symptoms to maximal exercise.(22, 41, 49)

Statistical Analysis

All data were analyzed using IBM SPSS Statistics (Version 29, IBM, Armonk, NY) and R Statistical Software (v4.2.1; R Core Team 2024). The analysis was pre-planned and included descriptive statistics, measurement of individual responses, and analysis of aggregate scores. Self-report baseline measures and PESE trajectory items were assessed for normality and linearity with the Shapiro-Wilk test and visual inspection of Q-Q plots. Data were reported as mean (SD) for continuous variables and percentages for categorical variables in text and tables and mean (SEM) in figures. Differences in baseline participant characteristics and parameters measured during exercise were assessed using one-way Analysis of Variance (ANOVA) followed by Bonferroni-adjusted multiple comparisons. Change in individual PESE trajectory symptoms over time was assessed with mixed-model ANOVA with factors of time and group. Assessment of symptom trajectories without exercise exposure were considered independent and analyzed separately to show the natural variability in symptoms. The Greenhouse-Geisser adjustment was used when sphericity was not met and post-hoc tests were applied where appropriate with paired t-tests. There was a low level of missing data with the PESE trajectory survey (1.5% for the post-exercise trajectory and 0.5% for the non-exercise trajectory). Missing values were imputed as the mean of adjacent days however, missing values for day 1 and day 7 were imputed with day 2 and day 6 values, respectively. Chi-square or Fisher Exact Test were performed when appropriate for categorical data.

Due to the significant variability in each symptom, we analyzed which symptom combinations best differentiated PESE among groups: 1) ME/CFS and PASC versus controls after exercise and 2) ME/CFS and PASC after exercise versus ME/CFS and PASC without exercise to determine if symptoms changes were above normal variation. Change scores were calculated for each post-exercise day from baseline (Day 0). Aggregate scores were summed using all 255 symptom combinations across days 1-7 after exercise. Between group differences were assessed using effect size (Cohen’s D) and ranked from highest to lowest. Effect size calculation did not involve formal hypothesis testing therefore adjustment for multiple comparisons was not warranted. To determine the relative importance of each trajectory item in measuring PESE, the frequency of each item in the top 20% highest effect sizes of 255 combinations was determined. ME/CFS and PASC were analyzed separately throughout all analyses.

Results

Individuals with ME/CFS and PASC reported greater fatigue, pain, and PESE on self-report questionnaires at baseline compared to HC; individuals with ME/CFS reported greater pain compared to PASC (Table 1). There were more males (men) in the PASC and HC groups.

Table 1.

Participant Characteristics

HC ME/CFS PASC
Age 44.1 ± 16.1 43.2 ± 13.4 44.1 ± 15.2
Sex (male / female) 7 / 23 1 / 29 10 / 20
Gender (man / woman) 7 / 23 1 / 29 10 / 20
BMI 25.9 ± 4.2 28.8 ± 7.4 29.0 ± 7.7
Fatigue Severity Scale Total Score 19.2 ± 6.4 51.8 ± 8.3a 47.3 ± 11.2a
Brief Fatigue Inventory - Fatigue Severity Score 1.1 ± 1.1 5.1 ± 1.5a 4.7 ± 1.6a
Brief Pain Inventory - Pain Severity Score 0.3 ± 0.5 3.3 ± 1.6a 2.2 ± 1.4a,b
Brief Pain Inventory - Pain Interference Score 0.2 ± 0.5 4.2 ± 2.7a 2.3 ± 2.3a, b
DePaul Symptom Questionnaire – Post-Exertional Malaise Short Form
 Symptom Frequency Sum Score 0.8 ± 1.4 11.1 ± 3.5a 7.3 ± 4.6a, b
 Symptom Severity Sum Score 0.7 ± 1.4 10.7 ± 3.6a 7.2 ± 3.8a, b
 Threshold for Self-Reported PEM (n) 2 28 20
Condition Duration
 3 to < 6 months --- 0 4
 6 to < 12 months --- 0 7
 1 year --- 1 2
 2 years --- 2 12
 3 years --- 0 5
 4 to 10 years --- 20 0
 11 to 20 years --- 2 0
 > 20 years --- 5 0
Number of Comorbidities 1.0 ± 1.2 7.3 ± 3.6 4.1 ± 3.4
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HC = healthy control, ME/CFS = myalgic encephalomyelitis/chronic fatigue syndrome, PASC = post-acute sequelae of SARS-CoV-2 infection, PEM = post-exertional malaise. ME/CFS or PASC compared to HC:

a =

p<.001. ME/CFS compared to PASC:

b =

p <.05

The exercise task was completed by all HC, 27/30 ME/CFS, and 29/30 PASC. Similar mean and maximal heart rate were achieved among groups while the HC group performed the exercise task at a greater RPM (Supplemental Table 1). The ME/CFS and PASC group reported greater fatigue, pain, and exertion during the exercise task and individuals with ME/CFS reported greater fatigue compared to PASC (Supplemental Table 1).

PESE Trajectory

Prior to exercise, average intensity of all 8 symptoms was greater in individuals with ME/CFS and PASC compared to HC, while physical fatigue, pain, physical dysfunction, and flu-like symptoms was greater in ME/CFS compared to PASC (Table 2). The trajectory data before and after exercise was highly variable with ratings ranging from 0-10 for most symptoms (Figure 1-2, Supplemental Figure 1-3). To examine effects in response to exercise, we analyzed the change in symptoms after exercise compared to before exercise – these data showed that the response to exercise was highly variable with some showing increases, some decreases and others no change in symptoms (Figure 2). Changes in mental fatigue and flu-like symptoms were greater on Day 1 in individuals with ME/CFS compared to HC; there were no changes in other individual symptoms between groups (Supplemental Material: Results).

Table 2.

PESE Symptom Survey Responses from Pre-Exercise to 7-days Following Exercise

Symptom Group Pre-Exercise
Day 0		 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Group
(p)		 Time
(p)		 Group x Time
(p)
Physical Fatigue HC 1.3 ± 1.5 1.4 ± 1.6 1.1 ± 1.7 1.3 ± 1.6 1.7 ± 1.8 1.4 ± 1.6 1.1 ± 1.5 1.4 ± 1.7 <.001 <.001 <.001d
ME/CFS 5.9 ± 2a 7.1 ± 1.5 6.8 ± 1.6 6.4 ± 2.3 5.9 ± 2.4 5.6 ± 1.7 5.5 ± 2 5.3 ± 1.8
PASC 5.2 ± 2.5a 5.9 ± 2.3 5.5 ± 2.5 5.2 ± 2.8 4.4 ± 2.2 4.2 ± 2.2 4.1 ± 2.3 4.2 ± 2.4
Mental Fatigue HC 1.5 ± 1.6 1.5 ± 1.9 1.3 ± 2 1.4 ± 2.1 1.4 ± 1.9 1.3 ± 2.1 1.3 ± 2.1 1.4 ± 1.8 <.001 <.001 <.001
ME/CFS 5.6 ± 2.5a 6.9 ± 2.3c 6.5 ± 2.3 6 ± 2.4 5.1 ± 2.3 4.9 ± 2.1 5.1 ± 2.3 4.9 ± 2
PASC 5 ± 2.5a 5.5 ± 2.5 5 ± 3.2 4.9 ± 2.9 4.2 ± 2.5 4 ± 2.2 3.8 ± 2.3 4.5 ± 2.4
Pain HC 0.7 ± 1 0.8 ± 1 0.6 ± 0.8 0.5 ± 0.7 0.9 ± 1.1 0.7 ± 1.3 0.5 ± 0.8 0.7 ± 1 <.001 <.001 .044d
ME/CFS 4.9 ± 2.3a 5.9 ± 2.1 5.1 ± 2.1 4.8 ± 2 5.1 ± 2.1 4.7 ± 2 4.1 ± 2 3.9 ± 2.2
PASC 3.8 ± 2.5a 4.1 ± 2.6 3.7 ± 2.8 3.8 ± 2.7 3.4 ± 2.5 3.4 ± 2.5 3.2 ± 2.4 3.3 ± 2.3
Physical Function HC 0.2 ± 0.5 0.3 ± 0.8 0.2 ± 0.5 0.3 ± 0.5 0.3 ± 0.5 0.4 ± 0.9 0.3 ± 0.7 0.3 ± 0.5 <.001 <.001 .007d
ME/CFS 5.1 ± 2.1a 6.3 ± 2 5.6 ± 2.2 5.3 ± 2.4 5 ± 2.4 5 ± 2.2 4.9 ± 2.2 4.5 ± 2.2
PASC 4.2 ± 2.8a 4.4 ± 2.6 3.8 ± 2.9 4 ± 3 3.2 ± 2.4 3 ± 2.4 3.2 ± 2.3 3.2 ± 2.3
Flu-like Symptoms HC 0.1 ± 0.4 0 ± 0 0 ± 0 0 ± 0 0.3 ± 1.5 0 ± 0.2 0 ± 0 0 ± 0.2 <.001 <.001 .011d
ME/CFS 1.9 ± 2.6a,b 2.9 ± 2.9c 2.9 ± 3.1 2.8 ± 2.6 2.2 ± 2.1 2.2 ± 2.3 1.7 ± 2.1 1.5 ± 2.1
PASC 0.5 ± 1.5a 0.9 ± 1.8 1.4 ± 2.7 1.2 ± 2.3 1.4 ± 2.6 1.3 ± 2.6 0.8 ± 2 0.8 ± 1.7
Gastrointestinal Symptoms HC 0.3 ± 0.8 0.3 ± 0.7 0.2 ± 0.6 0.3 ± 1 0.6 ± 1.6 0.4 ± 1 0.4 ± 0.7 0.5 ± 1.3 <.001 .357 .632
ME/CFS 3.8 ± 2.8a 3.3 ± 2.9 3.4 ± 2.6 3.4 ± 2.8 3.1 ± 2.8 2.7 ± 2.8 3 ± 2.8 2.8 ± 2.9
PASC 2.5 ± 2.9a 2.3 ± 2.8 2.2 ± 3.2 2 ± 2.9 2.3 ± 3.2 1.9 ± 2.8 2.1 ± 2.9 2.4 ± 2.8
Sleep Dysfunction HC 2.9 ± 2.2 2.7 ± 2.1 2 ± 2 2.1 ± 2 1.9 ± 1.7 2.1 ± 2.2 2.1 ± 2.1 2.3 ± 2.2 <.001 <.001 .136
ME/CFS 5.9 ± 2.8a 6.6 ± 2.9 5.7 ± 2.7 5 ± 2 5 ± 2.2 4.7 ± 2.2 4.7 ± 2.4 4.8 ± 2.4
PASC 5.7 ± 2.8a 5.3 ± 2.7 3.8 ± 2.4 4.6 ± 2.2 4.2 ± 2.6 4 ± 2.4 4.2 ± 2.3 4.4 ± 2.3
Anxiety HC 1.3 ± 1.7 1.1 ± 1.7 0.9 ± 1.7 1.2 ± 1.9 1.2 ± 1.9 1 ± 1.9 1 ± 2.1 1.1 ± 2 <.001 .020 .788
ME/CFS 4.2 ± 3.1a 3.6 ± 2.9 3.4 ± 2.8 3.6 ± 3.2 3.6 ± 2.9 3.2 ± 3 3.5 ± 3 3.7 ± 2.9
PASC 3.5 ± 2.8a 3.2 ± 2.9 2.8 ± 2.7 2.7 ± 2.9 2.9 ± 2.3 3.2 ± 2.7 3.1 ± 2.7 3.4 ± 3.1
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HC = healthy control, ME/CFS = myalgic encephalomyelitis/chronic fatigue syndrome, PASC = post-acute sequelae of SARS-CoV-2 infection. ME/CFS or PASC compared to HC:

a =

p<.001. ME/CFS compared to PASC:

b =

p <.05. ME/CFs compared to HC:

c =

p < .05.

d =

post-hoc analysis not significant.

Figure 1.

Figure 1.

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Self-reported Post-Exertional Symptom Exacerbation following exercise in HC (gray), ME/CFS (blue), PASC (red) for a) physical fatigue, b) mental fatigue, c) pain, d) physical function, e) flu-like symptoms, f) GI-symptoms, g) sleep dysfunction, h) anxiety. HC = healthy control, ME/CFS = myalgic encephalomyelitis, PASC = post-acute sequelae of SARS-CoV-2 infection, GI = gastrointestinal, NRS = numerical rating scale.

Figure 2.

Figure 2.

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Peak Change in Self-reported Post-Exertional Symptom Exacerbation following exercise in HC (gray), ME/CFS (blue), PASC (red) for a) physical fatigue, b) mental fatigue, c) pain, d) physical function, e) flu-like symptoms, f) GI-symptoms, g) sleep dysfunction, h) anxiety. HC = healthy control, ME/CFS = myalgic encephalomyelitis, PASC = post-acute sequelae of SARS-CoV-2 infection, GI = gastrointestinal, NRS = numerical rating scale.

To better examine variability, we compared the frequency of individuals that reported increases in each symptom. More individuals with ME/CFS or PASC reported increases in physical fatigue, mental fatigue, pain, physical function, flu-like symptoms and GI symptoms, but not sleep dysfunction or anxiety, when compared to controls (Supplemental Table 3). The peak change of each symptom occurred within the first 3 days following exercise (Supplemental Figure 3). Further the total number of symptoms that increased by at least 1/10 points during the 3-day period after exercise was greater in those with ME/CFS and PASC compared to controls (Supplemental Figure 4, Supplemental Results).

PESE Survey Aggregate Score

We next asked if combining symptoms improved the ability to detect PESE in those with ME/CFS and PASC when compared to controls. We used this aggregate score to determine the time course for PESE changes in response to the exercise task. Effect sizes for all combinations (255 total) of the 8 PESE symptom change scores were increased across all days, peaking on Days 2 and 3, and were greater in individuals with ME/CFS (Figure 3a). To examine if the exercise task increased PESE, we compared effect sizes of the trajectories after completion of the exercise task to trajectories when individuals did not exercise. When compared to no exercise, effect sizes of all combinations (255 total) of the 8 PESE symptom change scores were highest on Day 1, plateaued on Day 3, and were greater in those with ME/CFS (Figure 3b). Thus, subsequent analysis compared combinations based on the first 3 days after exercise.

Figure 3.

Figure 3.

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Effect Size for Change Score Combinations Across Each Post-Exertional Symptom Domain from baseline to Day 7 following exercise in ME/CFS (blue), PASC (red) when comparing a) Exercising ME/CFS (blue) & PASC (red) to Exercising HC, and b) Exercising vs non-exercising ME/CFS (blue) & PASC (red). ME/CFS = myalgic encephalomyelitis, PASC = post-acute sequelae of SARS-CoV-2 infection, GI = gastrointestinal.

The top symptom combinations (of 255) that yielded the greatest effect size for ME/CFS and PASC throughout the first 24, 48, and 72 hours were similar between ME/CFS and PASC (Figure 4, Supplemental Table 4 & 5, Supplemental Figure 5). Both ME/CFS and PASC symptom combinations included physical fatigue, mental fatigue, pain, physical function and flu-like symptoms. Additionally, ME/CFS also included GI symptoms and sleep dysfunction while PASC symptom combinations also included anxiety.

Figure 4.

Figure 4.

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Percent prevalence of individual PESE item combinations in the top 10 of generated effect sizes throughout the 2 effect size analyses (ME/CFS & PASC exercise vs HC exercise; ME/CFS & PASC exercise vs non-exercise) across days 1 through 3 in individuals with a) ME/CFS and b) PASC. ME/CFS = myalgic encephalomyelitis, PASC = post-acute sequelae of SARS-CoV-2 infection, GI = gastrointestinal.

Next, we examined symptom profiles using 5 different aggregate score scenarios using data over the first 3 days after exercise. Combining multiple symptoms including physical fatigue, mental fatigue, physical function and flu-like symptoms, with or without pain, showed the greatest effect sizes and greatest change in symptoms compared to symptom combinations of ≤2 or all 8 (Table 2; Scenario 3 and 4). Interestingly, 8/30 of individuals with ME/CFS and 12/30 of individuals with PASC showed minimal to no response (<1/10 aggregate score) to the exercise task, while 6-7/30 of individuals with ME/CFS and PASC showed a relatively large response (>3/10 aggregate score)(Table 2). Half of individuals with ME/CFS (15/30) and 12/30 of individuals with PASC, compared to 7/30 of controls, responded with a moderate change (1-3/10 points). Thus, these data highlight the variability in PESE to a standardized moderate intensity exercise.

Discussion

The current study provides novel insights into the variability of PESE in response to a moderate-intensity exercise task in individuals with ME/CFS and PASC. Analysis of single-symptom domains did not reveal consistent changes due to the inherent variability across individuals. A more comprehensive assessment of PESE that combined multiple symptoms including physical fatigue, mental fatigue, physical function and flu-like symptoms, with or without pain, over a 3-day period after exercise more accurately captured the response to exercise. Importantly, there was significant variability in PESE with some individuals showing minimal responses to sub-maximal exercise while others showed a stronger response.

These data highlight the variability in response to a single bout of exercise in individuals with ME/CFS and PASC. Importantly, this was in response to a submaximal exercise task performed at 60-70% of age-predicted maximal heart rate. This agrees with prior studies in ME/CFS showing variability in PESE following exercise tasks and daily activities using open-ended qualitative approaches,(12, 21, 50) as well as more quantitative approaches after a standardized exercise task.(22, 51) Our single-symptom domain analysis suggests no significant symptom intensity change occurred following a submaximal exercise task. However, this was likely due to symptom variability as we present evidence that the majority of individuals with ME/CFS and PASC experience some PESE (>1 point) over the first 3 days after exercise. In contrast, the PESE response to two maximal exercise tasks produced symptoms in nearly all individuals with ME/CFS that lasted through 7 days.(21) Variability in the response to exercise is expected as both ME/CFS and PASC are heterogeneous conditions with multiple contributing mechanisms including dysfunction in energy metabolism, immune, and autonomic function.(52-58) Therefore, individuals within each population may have different magnitude and duration of exercise-induced PESE.

While assessment of individual PESE symptoms is informative, it may be insufficient to adequately characterize the multidimensional nature of PESE following an exercise task. Our data suggest an aggregate score which combines 4-5 symptoms for three days following submaximal exercise may best characterize the magnitude of PESE in both ME/CFS and PASC. Symptom domains of fatigue, pain, and physical function were reported in several prior studies for both ME/CFS and PASC.(21, 38, 49) Similar to the current study, Davenport et al. show that symptom clusters after a maximal exercise task most accurately discriminate between individuals with ME/CFS to controls.(21) However, they showed an aggregate score of two symptoms was optimal, while the current study showing 4-5 symptoms was optimal. This could be related to methodological differences in measuring PESE as the prior study assessed symptom responses as a binomial variable while the current study examined the magnitude of the response which may provide greater sensitivity. The combination of multiple symptoms is the foundation of standardized questionnaires including those for PESE,(59-61) thus an aggregate score is likely to better reflect the multidimensional nature of PESE.

Multiple comparisons have been made regarding the similarities in symptom presentation and pathophysiology of ME/CFS and PASC.(9) The current study is the first to directly compare PESE using real-time daily assessment among individuals with ME/CFS and PASC following a standardized submaximal exercise. We showed a greater PESE effect in ME/CFS compared to PASC. Measures of fatigue, pain, physical function, and flu-like symptoms were common between both cohorts, agreeing with a prior study that also showed fatigue and pain were similar between ME/CFS and PASC.(9) On the other hand, in ME/CFS GI symptoms and disturbed sleep were more frequently represented in the highest effect size combinations suggesting a greater impact compared to those with PASC. However, anxiety was more frequently represented in those with PASC which may be associated with the shorter disease duration (<2 years). Further those with ME/CFS were more likely to experience PESE than those with PASC, which also could be related to disease duration, or unique mechanisms underlying the two conditions.

Unique to our study, we not only compared the trajectory to controls, but we also compared to the same individuals over a week without an exercise exposure to account for the inherent variability in symptoms. This showed peak PESE at 24h and lower effect sizes. Previous research testing a single bout of exercise has exclusively used a comparison group consisting of controls who exercised.(15, 41, 62-64) Despite lower effect sizes, likely due to daily variability in symptom presentation, we were still able to detect differences between groups within the first 3 days and thus the response to exercise is beyond normal symptom variability.

The magnitude and duration of symptom exacerbation was less in the current study than prior reports examining the response to a maximal exercise task, suggesting lower-intensity exercises have the potential to be more tolerable in ME/CFS and PASC.(65, 66) This has clinical implications for implementation of exercise in these conditions. It is important to assess multiple symptoms to determine the magnitude of PESE as some individuals will have minimal to no PESE. In those with PESE, avoidance of a daily exercise routine and allowing adequate recovery time may be necessary. It also may be necessary to individualize the exercise task using lower intensities or shorter duration to prevent PESE, yet still promote increased activity. Indeed, a recent report provided exercise recommendations for PASC that are based on the presence of no, mild/moderate, and severe PESE, thus supporting an individualized approach.(67) Future studies will need to assess effectiveness of this approach.

The CDC suggests that standard exercise protocols for ME/CFS could be harmful, despite several clinical trials showing low-intensity exercise improving outcomes.(68) For PASC, recent clinical trials show improvement in symptoms, function, and quality of life with regular exercise.(69-73) Several reports show alterations in muscle function and pathology in ME/CFS including hypoperfusion, leukocyte infiltration, and mitochondrial dysfunction, while in PASC mitochondrial dysfunction and increased amyloid deposits occur in muscle after a maximal exercise.(74-76) It is unclear if these muscle pathologies would occur with a lower intensity exercise similar to that performed in the current study, or if lower-intensity regular exercise will reduce the pathology. A prior report shows a walking task produced minimal to no PESE in ME/CFS,(66) similar to many individuals in the current study. Further, multiple studies show that individuals with ME/CFS who are able to engage in routine light intensity exercise, achieve reductions in fatigue and improved function.(26) The current study showed 20-23% of those with ME/CFS or PASC showed a likely clinically significant change, greater than 3-point increase, in symptoms to a moderate intensity task suggesting for some a modified approach may be necessary. On the other hand, 27-43% of individuals showed no change, less than 1 point increase in symptoms after the exercise task, suggesting for these individuals exercise was likely not harmful. The majority (40-50%) of individuals showed a small change, between 1-3 points, in symptoms and may need modification. While for pain, the clinically significant difference is thought to be greater than 2 or 30%, for other symptoms the MCID is less clear, and may be less like it is for fatigue. Future studies will need to determine the clinically relevant changes in the symptom change, determine if modification of the exercise task can reduce PESE acutely, and determine if regular exercise can reduce PESE.

Limitations

The PESE experienced in this study is specific to the exercise task performed and may not be generalizable to other tasks. While we verbally encouraged study participants to not partake in additional exercise, we were not able to control for all physical, cognitive, or emotional stressors which may have confounded PESE following exercise. Individuals who volunteered in this study were willing to participate in an exercise task and those with more severe PESE may not have been willing or able to participate in our study. One limitation of the study is that we used a simple numerical rating scale to capture each individual symptom. While we did capture 8 symptoms, we recognize that this may not fully capture the full PESE experience. Future studies will need to further validate PESE using both the simple multi-symptom NRS surveys, as well as more complex surveys to comprehensively capture the PESE experience.

Conclusion

PESE following a single exercise task is variable among individuals with ME/CFS and PASC. A more comprehensive assessment of PESE was captured using an aggregate score across multiple symptom domains. Additionally, due to variability in peak symptom change, assessment of PESE over multiple days may provide a more complete picture of each individual’s experience. Future research should investigate whether the use of a task-specific measure of PESE improves assessment and management of PESE with daily activities and acute exercise in clinical and research settings.

Supplementary Material

supplemental

Supplemental Digital Content 1 – Supplemental Methods, Results, Tables, and Figures

Supplemental Digital Content 2 – Strobe Checklist

Table 3.

PESE Presentation According to Symptom Assessment Scenarios of Varying Symptom Combinations within the first 3 days after exercise. Aggregate scores for PESE were converted to a 0-10 scale for direct comparison between scenarios.

Group Scenario 1
(Physical
Fatigue)		 Scenario 2
(Physical
Fatigue, Mental
Fatigue)		 Scenario 3
(Physical Fatigue,
Mental Fatigue,
Physical Function,
Flu-like
Symptoms)		 Scenario 4
(Physical Fatigue,
Mental Fatigue,
Pain, Physical
Function, Flu-like
Symptoms)		 Scenario 5
(All Symptoms)
Effect Size (relative to HC) ME/CFS 0.71 0.82 1.33 1.28 1.15
PASC 0.45 0.50 0.65 0.66 0.47
Change score Peak Single Symptom (0-10) HC 0.6 ± 1.8 1.1 ± 1.9 1.3 ± 1.8 1.4 ± 1.7 1.9 ± 1.7
ME/CFS 1.8 ± 1.9 2.3 ± 1.6 3.5 ± 2.0 3.7 ± 2.1 4.2 ± 1.9
PASC 1.7 ± 2.9 2.3 ± 2.7 3.3 ± 2.4 3.5 ± 2.5 3.8 ± 2.5
Average Change Score Aggregate Score (0 – 10x n symptoms) HC 0.6 ± 1.8 1.0 ± 3.4 1.2 ± 4.2 1.4 ± 4.8 2.2 ± 6.5
ME/CFS 1.8 ± 1.9 3.5 ± 3.3 7.7 ± 5.7 9.3 ± 7.3 11.2 ± 8.9
PASC 1.7 ± 2.9 3.1 ± 4.8 5.5 ± 8.2 6.9 ± 10.2 7.7 ± 14.4
Average Change Score Normalized (0-10) HC 0.6 ± 1.8 0.5 ± 1.7 0.3 ± 1.0 0.3 ± 1.0 0.3 ± 0.8
ME/CFS 1.8 ± 1.9 1.8 ± 1.6 1.9 ± 1.4 1.9 ± 1.5 1.4 ± 1.1
PASC 1.7 ± 2.9 1.6 ± 2.4 1.4 ± 2.1 1.4 ± 2.0 1.0 ± 1.8
Symptom Change <1 Aggregate Score (n / %) HC 17 / 56.7 21 / 70.0 23 / 76.7 23 / 76.7 24 / 80.0
ME/CFS 7 / 23.3 8 / 26.7 8 / 26.7 8 / 26.7 9 / 30.0
PASC 8 / 26.7 11 / 36.7 13 / 43.3 12 / 40.0 16 / 53.3
Symptom Change 1-3 Aggregate Score (n / %) HC 11 / 36.7 6 / 20.0 7 / 23.3 7 / 23.3 6 / 20.0
ME/CFS 19 / 63.3 17 / 56.7 15 / 50.0 15 / 50.0 20 / 66.7
PASC 15 / 50.0 12 / 40.0 11 / 36.7 12 / 40.0 11 / 36.7
Symptom Change >3 Aggregate Score (n / %) HC 2 / 6.7 3 / 10.0 0 / 0 0 / 0 0 / 0
ME/CFS 4 / 13.3 5 / 16.7 7 / 23.3 7 / 23.3 1 / 3.3
PASC 7 / 23.3 7 / 23.3 6 / 20.0 6 / 20.0 3 / 10.0
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Acknowledgements / Funding Sources

TriNetX, REDCap, and the Clinical Research Unit is supported by the Institute for Clinical and Translational Science at the University of Iowa under the National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program, grant UM1TR004403. Supported by the National Institutes of Health under award number: R01AR077418, R01AR077418-S1. Postdoctoral support for GB provided by the National Institutes of Neurological Disease and Stroke (U24NS112873-03S2). Predoctoral support for AJ provided by Foundation for Physical Therapy Research Promotion of Doctoral Studies I & II and postdoctoral support for AJ provided by T32 NS045549. Predoctoral support for AP provided by PODS I & II and NIAMS UH3 AR076387-02S1. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Abbreviations

ME/CFS

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

PASC

Post-acute Sequelae of SARS-CoV-2 infection

PESE

post-exertional symptom exacerbation

BMI

body mass index

Footnotes

Conflict of Interest

The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. All authors declare no support, relationships, or activities that could have influenced the submitted work. The results of the present study do not constitute endorsement by the American College of Sports Medicine.

Data Availability

The datasets generated during and/or analyzed during the current study are not publicly available in a public repository but are available from the corresponding author [kathleen-sluka@uiowa.edu].

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supplemental
NIHMS2205791-supplement-supplemental.docx (2.2MB, docx)

Data Availability Statement

The datasets generated during and/or analyzed during the current study are not publicly available in a public repository but are available from the corresponding author [kathleen-sluka@uiowa.edu].

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