Post-exertional malaise (PEM): a defining feature of long covid
While the number of fatal acute SARS-CoV-2 infections has declined since 2020, the proportion of these infections that result in persisting symptoms has not reduced significantly.1 The continuity or development of new symptoms longer than 3 months after an acute SARS-CoV-2 infection is clinically defined as long covid.2 PEM, a hallmark and debilitating feature, is recognised as one of the most frequent manifestations of long covid and is present in ~80% of patients with the condition.3 PEM is a delayed exacerbation (or new onset) of symptoms after physical or cognitive activity above a patient- and time-dependent threshold, which may persist for days, weeks or months or even result in a permanent change in a patient’s baseline.2 The need to screen for PEM in suspected long covid before initiating a rehabilitation strategy has already been recognised by major health authorities, including the WHO, who heavily cautioned against graded exercise therapies for patients experiencing PEM.2
PEM in long covid: cardiac alterations and pathological mechanisms
Historically, and without physiological evidence, deconditioning has been proposed as a driver of physiological alterations in both long covid and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).4 ME/CFS is a related disease in which patients experience profound fatigue as well as PEM. The aetiology of ME/CFS is unclear, but it often starts with a viral infection, similar to SARS-CoV-2-induced long covid. Indeed, in a 2025 statement, the American Heart Association proposed that cardiac alterations in long covid may be attributed to deconditioning.5 Perhaps this may apply in long-term ME/CFS; however, the peripheral adaptations seen in long covid patients cannot solely be explained by physical inactivity itself.6 There is considerable heterogeneity of cardiac abnormalities in these patients. Studies on cardiopulmonary function and structure reveal significant cardiovascular alterations in patients with long covid, including scarring, inflammatory changes and residual myocardial alterations in a subset of patients with long covid.7 With invasive cardiopulmonary exercise test measurements, patients commonly exhibit preload failure, such that there is insufficient cardiac filling.6 While some long covid patients exhibit reductions in cardiac volumes that may be indicative of deconditioning, other notable alterations, such as the preload failure and inflammation-mediated scarring, are not typical of deconditioning, and thus deconditioning alone is not sufficient to explain cardiac alterations in all long covid patients.
The pathophysiology of these cardiac alterations is currently unknown. Mitochondrial and endothelial dysfunction, autoimmunity and electrophysiological alterations have been proposed to contribute to the pathophysiology of long covid and ME/CFS.3 In multiple tissues of long covid patients, mitochondrial dysfunction, including deranged mitochondria, has been shown.3 There is further evidence accumulating of endothelial damage and dysfunction in these patients,8 who may exhibit ‘leaky vessels’ or impaired vasomechanical regulation. Both endothelial dysfunction and impaired mitochondrial function may also be implicated in the poor oxygen extraction in patients.6 Whether these cellular and molecular alterations are also observed in cardiac muscle is currently unknown. The absence of validated animal models and the inability to obtain longitudinal cardiac biopsy data constrain the development of a clear pathophysiological theory for post-viral diseases. Cardiac deconditioning may indeed contribute to a subset of long covid patients, particularly in home- or bed-bound patients or as the disease progresses.
Incorporating PEM evaluation and monitoring in patient care
As no single factor has been elucidated as the main driver of long covid symptoms, it is of the utmost importance that patient-specific strategies are considered for clinical care. Rehabilitation that focuses solely on one symptom may not be beneficial for the patient’s long-term care if other symptoms worsen at the same time. Healthcare providers should systematically screen for long covid aetiology, exclude other pathologies, and quantify postural orthostatic tachycardia syndrome (POTS) and PEM severity (eg, via the functional capacity questionnaire).2 PEM is also the core symptom and key diagnostic aspect of the Canadian Consensus Criteria for ME/CFS and can be diagnosed via the DePaul Symptom Questionnaire.9 Stratification of patients by POTS or PEM status allows for tailored rehabilitation plans, prioritising breathing exercises, low-intensity activities and pacing strategies for those experiencing PEM.
While prolonged rest may initially seem beneficial for symptom management, extended periods of daytime lying or bed rest can induce cardiovascular and skeletal muscle deconditioning. Lying down during the day can be minimised by supported sitting or gentle upright postures and compression garments—provided the patient’s symptoms allow for such a strategy. Encouraging light, tolerance-based activity and postural variation is essential to prevent further functional decline while respecting post-exertional symptom thresholds.10
The repetitive exposure to PEM events may perpetuate the worsening of patient health. Thus, monitoring patient response to various activities can aid in the reduction of PEM episodes, overall improving patient outcomes. Wearable heart rate monitors may be a practical method to monitor patient activity levels;11 however, we acknowledge that their use may not be feasible in less-resourced settings. Using first ventilatory threshold-guided heart rate pacing enables patients to remain within their individual energy envelope, minimising PEM exacerbations while supporting gradual, safe reconditioning. This personalised, data-driven method contrasts with traditional graded exercise therapy, which remains contraindicated for patients with PEM. Activity recommendations must be adjusted in real time to prevent symptom exacerbations.2
Incorporating PEM into a new conceptual model of long covid cardiac rehabilitation programmes is essential to clinically distinguish it from cardiovascular deconditioning and to safeguard patients from unintended harm. New programmes should deviate from historical guidelines for ME/CFS and include the latest insights into the pathophysiology of long covid. We emphasise the heterogeneous nature of the disease and the need for targeted pharmacotherapy for PEM and POTS (including low-dose naltrexone, beta-blockers or pyridostigmine) to reduce symptom burden.10 12 Such an interdisciplinary approach will assist in personalised exercise and recovery prescriptions to avoid relapses or worsening of symptoms.
In conclusion, PEM and cardiac alterations in long covid patients can occur, but these findings are largely independent of cardiac deconditioning. Thus, an individually tailored management strategy, guided by exercise physiology data, for patients with long covid and PEM is recommended.
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Acknowledgments
We would like to extend our sincerest thanks to the following who contributed to the development of the present text: Brent Appelman, Yaneer Bar-Yam, Jonas Bergquist, Svetlana Blitshteyn, Danilo Buonsenso, Wolfam Doehner, Rae Duncan, Andrew Ewing, Mark A Faghy, Amine Ghram, Andréa Lúcia Gonçalves da Silva, Stephanie L Grach, Merel Hellemons, Jelle Y Huijts, Binita Kane, Amos Lal, Raina MacIntyre, Alexios-Fotios A Mentis, Javaid Nauman, Simone Porcelli, Ethresia Pretorius, Christian Puta, Alfonso J Rodríguez-Morales, Carmen Scheibenbogen, Anouk Slaghekke, Ioakim Spyridopoulos, Jürgen M Steinacker, Karl J Tronstad, Amber L Vermeesch, Azfar Zaman and Koen AE Zwetsloot.
