Category: Exercise

Multimodal Web-Based Telerehabilitation for Patients With Post-COVID-19 Condition: Protocol for a Randomized Controlled Trial

Abstract:

Background: Patients with post-COVID-19 condition (PCC) experience persistent, long-term health consequences following SARS-CoV-2 infection, including fatigue, hyperventilation, cognitive impairment, and limitations in daily activities. There is emerging evidence suggesting that exercise and respiratory therapy-based telerehabilitation is safe and could potentially improve physical capacity while reducing health care costs.

Objective: This study aims to evaluate the superiority of a multimodal, symptom-titrated telerehabilitation program over standard care in patients with PCC who are severely affected, using the highest oxygen uptake rate (VO2peak [mL/min/kg]) achieved during the cardiopulmonary exercise test (CPET) and minute ventilation/carbon dioxide production slope (VE/VCO2 [full slope]) as primary outcomes. In addition, this study seeks to provide novel insights into the clinical and physiological adaptations associated with PCC, informing future rehabilitation strategies.

Methods: This prospective, randomized, waitlist-controlled trial was approved by the Rhineland-Palatinate Medical Association ethics committee. All procedures comply with the Declaration of Helsinki. This study comprises 3 examination time points, which include patient-reported outcomes, clinical assessments, and a CPET. It is structured into an 8-week intervention phase followed by an 8-week follow-up phase. Following baseline assessment, patients will be randomly assigned to either the intervention group (IG) or the control group (CG). During the intervention phase, IG participants will receive a web-based, multimodal, symptom-titrated telerehabilitation program consisting of sports medicine consultations, weekly teleconsultations, a structured pacing approach, and exercise and respiratory therapy. In contrast, CG participants will receive treatment as usual, which includes a single sports medicine consultation on healthy habits and a self-directed pacing approach for managing symptoms and daily activities. During the follow-up phase, IG participants will continue training independently without teleconsultations, whereas CG participants will undergo the same telerehabilitation intervention as the IG. A follow-up assessment will be conducted for both groups to evaluate long-term effects. This study adheres to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines and follows the Consensus on Exercise Reporting Template.

Results: Recruitment began in August 2023 and was extended until March 2025. As of March 2025, 80 participants have been recruited, and data analysis is ongoing. Final results are expected by December 2025, with a cross-sectional analysis of baseline data anticipated by July 2025.

Conclusions: This study is the first randomized controlled trial investigating the effectiveness of multimodal and symptom-titrated telerehabilitation in patients with PCC who are severely affected. The integration of various objective diagnostic systems will provide valuable insights into emerging postviral fatigue syndromes, supporting the development of CPET-based diagnostics, personalized rehabilitation strategies, and future research on long-term telerehabilitation effectiveness. The findings will be disseminated through peer-reviewed publications, professional networks, and patient advocacy groups to ensure scientific, clinical, and public impact.

Trial registration: German Clinical Trials Register (DRKS) DRKS00032394; https://drks.de/search/de/trial/DRKS00032394.

Source: Tomaskovic A, Weber V, Ochmann DT, Neuberger EW, Lachtermann E, Brahmer A, Haller N, Hillen B, Enders K, Eggert V, Zeier P, Lieb K, Simon P. Multimodal Web-Based Telerehabilitation for Patients With Post-COVID-19 Condition: Protocol for a Randomized Controlled Trial. JMIR Res Protoc. 2025 May 21;14:e65044. doi: 10.2196/65044. PMID: 40397936. https://www.researchprotocols.org/2025/1/e65044 (Full text)

Ignorance about post-exertional malaise and continued conflation of ME/CFS with chronic fatigue harms patients and stymies research progress

Dear Editor,

There are numerous issues with the opinion piece by Miller and coauthors. Most concern longstanding fallacies about the nature of ME/CFS and what patients believe about their illness, which — again — need to be corrected. I’d like to focus on just one: The defining and cardinal feature of ME/CFS is not fatigue, but rather post-exertional malaise (PEM).

PEM, sometimes referred to as post-exertional symptom exacerbation (PESE), can be defined as episodes during which people with ME/CFS experience significant worsening of existing symptoms and/or onset of new symptoms following amounts of physical or mental exertion or sensory stimuli that they could easily tolerate before the illness [1]. The length and severity of an episode of PEM are out of proportion to the amount of exertion or stimulus that triggered it; in severe or very severe ME/CFS patients, PEM may be triggered by, for example, short conversations with their carers or brief exposure to bright light, and these episodes may last week, months, or longer.

PEM remains poorly understood, but the concept and terminology have over recent years become much more mainstream, owing to the high prevalence of PEM in long covid [2]. The consensus opinion among ME/CFS patients is that daily activities and sensory input should be managed in such a way as to minimise PEM, because PEM severely impacts quality of life and can in some cases lead to further long-term deterioration in patients’ health and functional capacity. This concept forms the basis of pacing, an energy management strategy recommended by NICE [3].

In their opinion piece, Miller and coauthors ignore PEM when listing common symptoms of ME/CFS. This is an attempt to continue framing this illness as belonging to a family of ‘fatiguing conditions’, which, along with other ‘medically unexplained symptoms’, they argue can be treated with psychological interventions and rehabilitation.

Read the rest of this letter here: https://www.bmj.com/content/389/bmj.r977/rr-6

The risk of blaming patients for their lack of recovery

Dear Editor,

In their article on the management of patients with severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Miller et al. propose a biopsychosocial model in which “a gradual, controlled approach to increasing activity is an important part of rehabilitation.” This approach, however, is far from new and has been tested in randomized trials with limited success.

The PACE study, for example, examined fourteen sessions of cognitive behaviour therapy (CBT) or graded exercise therapy (GET), each combined with specialist medical care. Treatment aimed to help ME/CFS patients gradually resume physical activities, address unhelpful cognitions, and reverse deconditioning. Recovery rates for GET and CBT were low and did not differ significantly from the control group, with rates of 4%, 7%, and 3%, respectively, as defined by the study’s pre-registered recovery criteria. [1] Employment and fitness data also showed no clinically significant improvement. [2]

Read the full letter by Michiel Tack here: https://www.bmj.com/content/389/bmj.r977/rr-3

Stress-Induced Changes in Immune Signatures in ME/CFS Patients Determined by Transcriptome Analysis

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM). We evaluated transcriptomic changes in peripheral blood mononuclear cells (PBMC) of ME/CFS patients undergoing an exercise challenge and explored the transcriptomic response to exercise and recovery in PBMC of ME/CFS patients, as compared to healthy controls using RNA sequencing technology. As transcriptomic changes in ME/CFS patients are still in the phase of discovery, analysis of data has to be stringent, and the most important results have to be validated by a different technology, such as real-time PCR or NanoString.

Source: Gamer J, Van Booven D, Zarnowski O, Perez M, Frank J, Pangeni RP, Collado F, Klimas NG, Oltra E, Nathanson L. Stress-Induced Changes in Immune Signatures in ME/CFS Patients Determined by Transcriptome Analysis. Methods Mol Biol. 2025;2920:103-112. doi: 10.1007/978-1-0716-4498-0_7. PMID: 40372680. https://link.springer.com/protocol/10.1007/978-1-0716-4498-0_7

Repeated Cardiopulmonary Exercise Testing of ME/CFS Patients

Abstract:

Post-exertional malaise is a cardinal symptom present in 95% of individuals with myalgic encephalomyelitis (ME/CFS). Repeated cardiopulmonary exercise testing has been momentous in revealing that the physiological systems of those with ME/CFS are impaired or damaged and do not respond to exercise/physical activity like those without the condition. The 24-h repeated exercise test may demonstrate a reduction in peak oxygen consumption (VO2 peak), VO2 at ventilatory threshold, power output at both peak and ventilatory threshold, along with a reduction/diminished maximal heart rate commensurate with chronotropic intolerance. In this chapter, I describe the process and methods of repeated cardiopulmonary exercise testing, used to assess exercise tolerance in individuals with ME/CFS.

Source: Hodges L. Repeated Cardiopulmonary Exercise Testing of ME/CFS Patients. Methods Mol Biol. 2025;2920:163-172. doi: 10.1007/978-1-0716-4498-0_10. PMID: 40372683. https://link.springer.com/protocol/10.1007/978-1-0716-4498-0_10

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.

Source: Stussman B, Camarillo N, McCrossin G, Stockman M, Norato G, Vetter CS, Ferrufino A, Adedamola A, Grayson N, Nath A, Chan L, Walitt B, Chin LMK. Post-exertional malaise in Long COVID: subjective reporting versus objective assessment. Front Neurol. 2025 Apr 23;16:1534352. doi: 10.3389/fneur.2025.1534352. PMID: 40337174; PMCID: PMC12055772. https://pmc.ncbi.nlm.nih.gov/articles/PMC12055772/ (Full text)

Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID: Commonalities Detected by Invasive Cardiopulmonary Exercise Testing

Abstract:

Rationale: There is substantial overlap of exertional symptoms in Long COVID (LC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) including intractable fatigue, post-exertional malaise (PEM), and orthostatic intolerance, but very little objective data liking the two. This study compares exercise pathophysiology in the two disorders and normal controls using invasive cardiopulmonary exercise testing (iCPET).

Methods: Between January 2019 and December 2024, 1,518 patients underwent a clinical iCPET at Brigham and Women’s Hospital. Exclusion criteria included morbid obesity (BMI>40 kg/m2), severe anemia ([Hb]<9.0 g/dL), elite athletes (peak VO2 (pVO2)>120% predicted), sub-maximum effort (RER<1.05), a primary pulmonary mechanical limit (VE @ AT/MVV>0.7), and comorbidities such as active/treated cancer, interstitial lung disease, or other respiratory related diseases. iCPET results from 438 ME/CFS patients, 73 LC patients, and 43 symptomatic but otherwise normal controls were analyzed. pV02, peak cardiac output (pQc), peak right atrial pressure (pRAP), peak systemic oxygen extraction (pSOE; Ca-vO2/[Hb]), and ventilatory inefficiency (VE/VCO2 slope) were compared among groups. Statistical significance was determined using Kruskal-Wallis tests for global comparisons, with post-hoc Dunn tests for pairwise group comparisons. Holm-Bonferroni adjustments were applied to control for multiple comparisons.

Results: LC and ME/CFS displayed reduced pVO2 % predicted compared to controls (LC: 78.4 ± 18%, ME/CFS: 78.1 ± 17%, Controls: 97.5 ± 10%, P≤0.0001). Reduced pQc % predicted was also observed compared to controls (LC: 91.1 ± 18%, ME/CFS: 96.3%, Controls: 101 ± 11%, P≤0.001). pRAP were significantly less compared to controls (LC: 1.1 ± 3.1 mmHg, ME/CFS: 1.3 ± 2.8 mmHg, Controls: 3.6 ± 3.4 mmHg, P≤0.001). Significant reductions in pSOE were seen for LC and ME/CFS (LC: 0.81 ± 0.1, ME/CFS: 0.81 ± 0.1, Controls, 0.91 ± 0.1, P≤0.0001). The only measure with no significant difference between disease and control was VE/VCO2 slope (LC: 31.4 ± 8.4, ME/CFS: 31.6 ± 6.9, Controls: 32.0 ± 6.7, P≥0.261). Most interestingly, no significant differences were seen between the two diseases for any of the analyzed measures (P≥0.245).

Conclusions: We report the largest cohort of ME/CFS and LC investigated with iCPET to date. ME/CFS and LC share symptomatic, reduced aerobic capacity at peak exercise, which is driven by preload insufficiency and impaired systemic O2 extraction, the latter compatible with peripheral left-to-right shunting and/or limb skeletal muscle dysfunction. These findings should drive future diagnostics and personalized medicine in both diseases. We hope these data inform the pending prospective NIH RECOVER iCPET study of LC.

Source: J. Squires, S. Palwayi, P. Li, W. Xiao, K. LeWine, S.W. Johnson, D. Felsenstein, A.B. Waxman, and D.M. Systrom. Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID: Commonalities Detected by Invasive Cardiopulmonary Exercise Testing [abstract]. Am J Respir Crit Care Med 2025;211:A7881. https://www.atsjournals.org/doi/​10.1164/ajrccm.2025.211.Abstracts.A7881

Wearable heart rate variability monitoring identifies autonomic dysfunction and thresholds for post-exertional malaise in Long COVID

Abstract:

Objectives Patients with Long COVID experience disabling fatigue, autonomic dysfunction, reduced exercise capacity, and post-exertional malaise (PEM). Heart rate variability (HRV) can evaluate autonomic function and monitor overexertion, potentially helping to mitigate PEM. This study aimed to use continuous multi-day HRV recordings to monitor overexertion and study autonomic function in Long COVID.

Method Heart rate and HRV were continuously measured in 127 patients with long COVID (43±11 years, 32% male) and 21 healthy controls (42±13 years, 48% male), and daily life activities tracked in a logbook. Participants underwent a (sub)maximal cardiopulmonary exercise test to determine heart rate at the first ventilatory threshold (VT1) to study HRV responses to exercise at different intensities.

Results HRV was lower in patients with long COVID compared to healthy controls during various daily activities and sleep (p<0.027). HRV remained lower for 24 hours after exercise below, at or above VT1 in patients, but not in healthy controls (p=0.010). Nighttime HRV decreased with intense exercise and longer durations in patients with long COVID (p=0.018), indicative of exercise-induced diurnal disturbances of the autonomic nervous system in long COVID.

Conclusion Heart rate variability, assessed by wearables, confirms autonomic dysfunction in patients with long COVID. The delayed recovery of the sympathovagal balance after exercise close and above to VT1 suggests that VT1 can be practically interpreted as a PEM threshold.

Application These results confirm the applicability of wearables to assess autonomic function and manage overexertion in long COVID patients.

What is already known on this topic Patients with long COVID often experience fatigue, autonomic dysfunction, and post-exertional malaise (PEM). HRV can be used as a non-invasive tool to measure autonomic function and recovery. Anecdotal evidence suggests lower HRV in patients with long COVID, but measurements are usually very short.

What this study adds This study demonstrates that continuous HRV monitoring through wearables can effectively identify overexertion and autonomic dysfunction during daily activities in patients with long COVID. Patients with long COVID have a lower heart rate variability during sleep and HRV remained significantly lower for a longer period after moderate-to-heavy exercise, that is generally associated with the induction of post-exertional malaise.

How this study might affect research, practice, or policy This study supports the use of wearables for assessing autonomic function and overexertion in daily life, helping patients with long COVID in pacing daily activities to mitigate symptoms of post-exertional malaise. HRV tracking after exercise shows that VT1 is a potential threshold for PEM. Sports physicians and physiotherapists can incorporate HRV biofeedback measures into pacing advice to patients. Additional research is needed to further investigate the effect of such an intervention.

Source: Twan Ruijgt, Anouk Slaghekke, Anneke Ellens, Kasper W. Janssen, Rob C.I. Wüst.. Wearable heart rate variability monitoring identifies autonomic dysfunction and thresholds for post-exertional malaise in Long COVID. medRxiv 2025.03.18.25320115; doi: https://doi.org/10.1101/2025.03.18.25320115 https://www.medrxiv.org/content/10.1101/2025.03.18.25320115v1.full-text (Full text)

Physical function and psychosocial outcomes after a 6-month self-paced aquatic exercise program for individuals with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Purpose: A randomized-controlled trial to investigate the efficacy of a 6-month self-paced aquatic exercise intervention on physical function, symptoms and psychosocial measures in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Methods: Thirty-two individuals diagnosed with ME/CFS (55.0 ± 13.9 yr) were randomized into an intervention group (INT, n = 17) or control group (CON, n = 15) for a 6-month trial of two 20-min sessions per week of self-paced aquatic movements and stretches. Pre- and post-intervention outcomes included physiological measures, 6-min walk test, hand-grip strength, Sit-to-Stand, Apley’s shoulder test, Sit-Reach test, perceived exertion, fatigue (FACIT), anxiety/depression (HADS) questionnaires, and tiredness and pain scores (VAS 0-10 scale).

Results: The INT group significantly increased walk test distance (13.7%, P < 0.001), Sit-to-Stand scores (33.7%, P < 0.001) and peak expiratory pulmonary flow (12.9%, P = 0.028) post-intervention. Fatigue (29.5%, P = 0.005), depression (21.7%, P = 0.010), combined anxiety/depression scores (16.9%, P = 0.047) and resting diastolic blood pressure (4.8%, P < 0.001) also significantly improved for the INT group. Sit-Reach scores were significantly lower for the INT group compared to CON post-intervention (- 4.0 ± 10.4 vs + 4.3 ± 10.7 cm, P = 0.034). There were no adverse events or worsening of symptoms during the trial.

Conclusions: Self-paced, low-moderate-intensity aquatic exercise improved walk distance, lower limb strength, fatigue, depression and peak expiratory flow without worsening ME/CFS symptoms. This mode of low-intensity physical activity may confer mental health and physical benefits provided the activity is self-paced and within patient energy limits.

Source: Broadbent S, Coetzee S, Calder A, Beavers R. Physical function and psychosocial outcomes after a 6-month self-paced aquatic exercise program for individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Eur J Appl Physiol. 2025 Apr 5. doi: 10.1007/s00421-025-05759-5. Epub ahead of print. PMID: 40186656. https://link.springer.com/article/10.1007/s00421-025-05759-5 (Full text)

The metabolic and physiologic impairments underlying long COVID associated exercise intolerance

Abstract:

Data from invasive CPET (iCPET) revealed long COVID patients have impaired systemic oxygen extraction (EO2), suggesting impaired mitochondrial ATP production. However, it remains uncertain whether the initial severity of SARS-CoV-2 infection has implications on EO2 and exercise capacity (VO2) nor has there been assessment of anerobic ATP generation in long COVID patients. iCPET was performed on 47 long COVID patients (i.e., full cohort; n = 8 with severe SARS-CoV-2 infection). ‘

In a subset of patients (i.e., metabolomic cohort; n = 26) metabolomics on venous and arterial blood samples during iCPET was performed. In the full cohort, long COVID patients exhibited reduced peak EO2 with reduced peak VO2 (90 ± 17% predicted) relative to cardiac output (118 ± 23% predicted). Peak VO2 [88% predicted (IQR 81% – 108%) vs. 70% predicted (IQR 64% – 89%); p = 0.02] and EO2 [0.59(IQR 0.53-0.62) vs. 0.53(IQR 0.50-0.48); p = 0.01) were lower in severe versus mild infection.

In the metabolomic cohort, 12 metabolites were significantly consumed, and 41 metabolites were significantly released (p-values < 0.05). Quantitative metabolomics demonstrated significant increases in inosine and succinate arteriovenous gradients during exercise. Peak VO2 was significantly correlated with peak venous succinate (r = 0.68; p = 0.0008) and peak venous lactate (r = 0.49; p = 0.0004). Peak EO2 and consequently peak VO2 impact long COVID patients in a severity dependent manner.

Exercise intolerance associated with long COVID is defined by impaired aerobic and anaerobic energy production. Peak venous succinate may serve as a potential biomarker in long COVID.

Source: Leitner BP, Joseph P, Quast AF, Ramirez MA, Heerdt PM, Villalobos JG, Singh I. The metabolic and physiologic impairments underlying long COVID associated exercise intolerance. Pulm Circ. 2024 Nov 13;14(4):e70009. doi: 10.1002/pul2.70009. PMID: 39544193; PMCID: PMC11560803. https://pmc.ncbi.nlm.nih.gov/articles/PMC11560803/ (Full text)