Haunhorst et al. (2024)
- Authors: Simon Haunhorst, Diana Dudziak, Carmen Scheibenbogen, Martina Seifert, Franziska Sotzny, Carsten Finke, Uta Behrends, Konrad Aden, Stefan Schreiber, Dirk Brockmann, Paul Burggraf, Wilhelm Bloch, Claudia Ellert, Anuradha Ramoji, Juergen Popp, Philipp Reuken, Martin Walter, Andreas Stallmach, Christian Puta.
- Institutes: Department of Sports Medicine and Health Promotion, Friedrich-Schiller-University Jena, Jena, Germany; Center for Interdisciplinary Prevention of Diseases Related to Professional Activities, Jena, Germany; Institute of Immunology, Jena University Hospital/ Friedrich-Schiller-University Jena, Jena, Germany; Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Children’s Hospital, School of Medicine, Technical University of Munich, Munich, Germany; German Center for Infection Research (DZIF), Berlin, Germany; AGV Research Unit Gene Vectors, Helmholtz Munich (HMGU), Munich, Germany; Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Internal Medicine I, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Center Synergy of Systems, TU Dresden University of Technology, Dresden, Germany; mHealth Pioneers GmbH, Berlin, Germany; Department for Molecular and Cellular Sports Medicine, Institute for Cardiovascular Research and Sports Medicine, German Sport University Cologne, Cologne, Germany; Landarztnetz Lahn-Dill, Wetzlar, Germany; Initiative Long COVID Deutschland, Lemgo, Germany; Institute of Physical Chemistry (IPC) and Abbe Center of Photonics (ACP), Member of the Leibniz Centre for Photonics in Infection Research (LPI), Friedrich-Schiller-University Jena, Jena, Germany; Leibniz Institute of Photonic Technology, Member of Leibniz Health Technologies, Member of the Leibniz Centre for Photonics in Infection Research (LPI), Jena, Germany; Department for Internal Medicine IV (Gastroenterology, Hepatology and Infectious Diseases), Jena University Hospital, Jena, Germany; Department of Psychiatry and Psychotherapy, Jena Center for Mental Health, Jena University Hospital, Jena, Germany; German Center for Mental Health (DZPG), Partner Site Jena, Jena, Germany; Center for Sepsis Control and Care (CSCC), Jena University Hospital/Friedrich-Schiller-University Jena, Jena, Germany.
- Publisher: Infection
- Link: DOI
Summary
This comprehensive review connects numerous strands of research to build a coherent biological model for post-exertional malaise (PEM). It posits that a combination of impaired microcirculation (poor blood flow in small vessels), damaged mitochondria (cellular energy factories), and a persistently activated immune system creates a vicious cycle where even minimal exertion can lead to a severe crash. This model helps explain the systemic nature of symptoms and why recovery is so prolonged. For patients, this work validates their experience by providing a multi-systemic, biological explanation and points towards specific future therapeutic targets, such as improving endothelial function with supplements like L-arginine 💊, clearing viral reservoirs, or using immunomodulatory drugs, although these remain investigational.
What was researched?
This review article synthesizes current scientific evidence to explain the underlying mechanisms of physical activity-induced post-exertional malaise (PEM). The authors aimed to build a comprehensive model of the pathophysiology by examining microvascular alterations, mitochondrial dysfunction, and immunometabolic interactions in both Post-COVID Condition (PCC) and ME/CFS.
Why was it researched?
PEM is a core diagnostic criterion for ME/CFS and a frequent, debilitating symptom in PCC, yet its biological causes remain poorly understood. Given the significant clinical overlap between PCC and ME/CFS, researchers hypothesize a common etiology might explain PEM in both conditions. This review sought to conceptualize the available evidence to improve the understanding of what triggers PEM episodes.
How was it researched?
This study is a narrative literature review. The authors analyzed and synthesized findings from multiple separate studies focusing on the pathophysiology of PCC and ME/CFS. No new experimental data was generated for this paper.
What has been found?
The review concludes that patients with PEM exhibit reduced systemic oxygen extraction and impaired mitochondrial function upon physical activity. This is driven by several interconnected issues: microvascular dysfunction (including endothelial damage and the formation of fibrinolysis-resistant microclots), mitochondrial damage in muscle cells, and persistent immune activation, possibly due to viral antigen persistence. These problems force a premature switch to anaerobic metabolism, leading to the buildup of substances like lactate and reactive oxygen species, which in turn triggers further immune activation and exacerbates the underlying pathologies in a vicious cycle.
Discussion
The authors acknowledge a primary limitation is that the paper narratively synthesizes findings from many separate studies with different research focuses. They note that no single study has provided conclusive evidence for one overarching disease etiology, meaning the various pathophysiological observations described (e.g., microclots, mitochondrial dysfunction, immune activation) do not necessarily coexist in every patient.
Conclusion & Future Work
The authors conclude that PEM results from dysfunctional physiological adaptation to exercise, creating a self-propagating loop where exertion leads to metabolic and ionic disturbances, secondary muscle and mitochondrial damage, and further immune activation. They recommend that future studies should investigate the connections between the immune system, metabolism, and microcirculation to better understand PEM. They also suggest that activity prescriptions for patients must account for these underlying mechanisms to avoid provoking PEM.