Towards an understanding of physical activity-induced post-exertional malaise: Insights into microvascular alterations and immunometabolic interactions in post-COVID condition and myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: A considerable number of patients who contracted SARS-CoV-2 are affected by persistent multi-systemic symptoms, referred to as Post-COVID Condition (PCC). Post-exertional malaise (PEM) has been recognized as one of the most frequent manifestations of PCC and is a diagnostic criterion of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Yet, its underlying pathomechanisms remain poorly elucidated. PURPOSE AND METHODS: In this review, we describe current evidence indicating that key pathophysiological features of PCC and ME/CFS are involved in physical activity-induced PEM. RESULTS: Upon physical activity, affected patients exhibit a reduced systemic oxygen extraction and oxidative phosphorylation capacity. Accumulating evidence suggests that these are mediated by dysfunctions in mitochondrial capacities and microcirculation that are maintained by latent immune activation, conjointly impairing peripheral bioenergetics. Aggravating deficits in tissue perfusion and oxygen utilization during activities cause exertional intolerance that are frequently accompanied by tachycardia, dyspnea, early cessation of activity and elicit downstream metabolic effects. The accumulation of molecules such as lactate, reactive oxygen species or prostaglandins might trigger local and systemic immune activation. Subsequent intensification of bioenergetic inflexibilities, muscular ionic disturbances and modulation of central nervous system functions can lead to an exacerbation of existing pathologies and symptoms.

["The idea of rehabilitation will have to be completely rethought for this illness" - Qualitative results of an online survey on patients' experiences with inpatient rehabilitation for post COVID-19 condition (long COVID)]. / "Der Reha-Gedanke muss bei dieser Erkrankung völlig neu gedacht werden" ­ Qualitative Ergebnisse einer Online-Befragung zu Erfahrungen Betroffener mit stationärer Rehabilitation bei Long/Post-COVID.

BACKGROUND: In Germany, an estimated number of 70,000 people diagnosed with long COVID or post-COVID syndrome (PCS) had received inpatient medical rehabilitation by the end of 2022. Due to the heterogeneity of the clinical picture, the variability of interventions and inconsistent endpoints, previous studies on the effectiveness of rehabilitation are of limited value. It therefore remains unclear whether and to what extent rehabilitation measures established for, e.g., pulmonary, cardiovascular, or neurological diseases are suitable for patients with PCS. OBJECTIVES: To identify the experiences and perspectives of those affected by PCS, in relation to inpatient rehabilitation and to describe patients' values and wishes with respect to evidence-based medicine. METHODS: In January/February 2023, the German initiative "Long COVID Deutschland" conducted a retrospective online survey (39 closed items, two open answer fields) among adult PCS sufferers on their experiences with inpatient rehabilitation. Recruitment was carried out via social media and websites of patient initiatives. The open answers were analyzed using a structuring and summarizing qualitative content analysis according to Mayring, supplemented by descriptive representations of the distribution of standardized information. RESULTS: Of 1,191 participants in the survey, 733 used open response formats to additionally explain their experiences and the effects of individual measures on their general condition. 366 (50%) reported that their state of health deteriorated, mainly because of strength or endurance training and too extensive treatment plans. The presence of a post-exertional malaise (PEM) or its insufficient consideration during rehabilitation was described as the main barrier. Recognition and acceptance of individual performance limits, flexible and coordinated individual treatment plans tailored to the patient's limitations, and support in coping with the disease were described as supportive factors. From the participants' perspective, learning strategies to avoid deterioration in their state of health due to overexertion, the so-called pacing, should be the core treatment goal for patients affected by PEM. DISCUSSION: The results are not statistically representative but ensure systematic insights into the subjective perspectives of those affected, the consideration of which represents one of the three principles of evidence-based medicine. The results show that for PCS patients with PEM, even minimum requirements for rehabilitation measures can lead to overexertion and aggravation. CONCLUSIONS: Common subject-specific rehabilitation concepts appear to be only partially suitable for dealing with the symptoms and the heterogeneity of the disease. Aims and interventions should be individually adapted, and the focus should be on pacing, disease coping and management. A reliable test for PEM and rehabilitation ability before the start of rehabilitation is needed to ensure safety for those affected. To adequately classify studies on the effectiveness of rehabilitation, risks and side effects should be disclosed.

Long COVID: a narrative review of the clinical aftermaths of COVID-19 with a focus on the putative pathophysiology and aspects of physical activity.

The pandemic coronavirus disease 2019 (COVID-19) can cause multi-systemic symptoms that can persist beyond the acute symptomatic phase. The post-acute sequelae of COVID-19 (PASC), also referred to as long COVID, describe the persistence of symptoms and/or long-term complications beyond 4 weeks from the onset of the acute symptoms and are estimated to affect at least 20% of the individuals infected with SARS-CoV-2 regardless of their acute disease severity. The multi-faceted clinical picture of long COVID encompasses a plethora of undulating clinical manifestations impacting various body systems such as fatigue, headache, attention disorder, hair loss and exercise intolerance. The physiological response to exercise testing is characterized by a reduced aerobic capacity, cardiocirculatory limitations, dysfunctional breathing patterns and an impaired ability to extract and use oxygen. Still, to this day, the causative pathophysiological mechanisms of long COVID remain to be elucidated, with long-term organ damage, immune system dysregulation and endotheliopathy being among the hypotheses discussed. Likewise, there is still a paucity of treatment options and evidence-based strategies for the management of the symptoms. In sum, this review explores different aspects of long COVID and maps the literature on what is known about its clinical manifestations, potential pathophysiological mechanisms, and treatment options.