by Jeffrey Lubell 1
1 Independent Patient-Researcher
Cite as: Lubell, J. (2023). Hypothesis: Could vascular damage caused by massive inflammatory events underlie a relapse/recovery phenotype of ME/CFS and Long COVID? Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 1, 30-35
Abstract
I hypothesize that there is a relapse/recovery type of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID in which a massive inflammatory event—like the inflammatory cascade prompted by the restoration of blood flow (reperfusion) to tissue that had been deprived of blood (ischemia) or an allergic or pseudoallergic reaction—causes substantial damage to blood vessels, launching a more severe phase of ME/CFS. People with Ehlers-Danlos syndrome and other connective tissue disorders may be at particular risk of this phenotype due to having connective tissue (a key component of blood vessels) that is more easily and severely injured during inflammatory events and slower to heal, causing a much longer recovery.
Hypothesis
My daughter has experienced two major “relapse events” in the five years of her myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) illness. The active phase of the first event, in October 2017, lasted only 15 minutes, but left her so weak she could barely walk. The active phase of the second event, in July 2020, lasted about two hours, and initiated a period of very severe disease. Both events were biphasic, with an initial period of feeling very hot (and in one case red all over) followed, several hours later, by whole body shaking/chills and, during the second episode, electric-like zaps and wave-like cascades up her torso.
In my daughter’s experience, these baseline-lowering events are distinct phenomena from day-to-day post-exertional malaise. Unlike the symptoms of post-exertional malaise, which are very impactful but temporary, the relapse events led to major degradations in her condition that have persisted for many months. In the two and half years since the last relapse event, my daughter has made substantial progress toward recovery, but still has not yet regained her June 2020 level of functioning.
As I have worked to better understand my daughter’s various interrelated chronic conditions—which include ME/CFS, hypermobile Ehlers-Danlos syndrome, craniocervical instability, Chiari malformation, tethered cord syndrome, and suspected mast cell activation syndrome—I have connected with many other individuals that have experienced a similar relapse/recovery pattern to their illness. Despite this lived experience, there is very little focus on this pattern in the existing research literature on ME/CFS and Long COVID. A notable exception is a recent preprint that documents epigenetic changes that occur following relapses in two patients with ME/CFS1 and a subsequent paper that incorporates this analysis into a model of chronic neuroinflammation in ME/CFS2.
Drawing on my daughter’s experience and a review of the research literature, I hypothesize that there is a relapse/recovery phenotype of ME/CFS and Long COVID in which susceptible individuals experience massive “relapse events” that cause substantial vascular damage, launching a more severe phase of ME/CFS or Long COVID. Since many of the most prominent symptoms experienced by people with ME/CFS and ME/CFS-type presentations of Long COVID are systemic, the vascular injury is most likely caused by a systemic inflammatory process. I propose that the inflammatory events can be triggered through a range of different mechanisms, including thrombotic events that lead to ischemia/reperfusion injury, anaphylactic or anaphylactoid mast cell activations, or the inflammatory cascade of an acute infection.
Ischemia-reperfusion injury is one likely cause of systemic vascular injury given the heightened risk of thrombotic events after even mild cases of COVID-193 or other viruses,4 and the triggering of powerful and often injurious inflammatory processes during reperfusion, including “TLR-mediated pathways, chemoattractants, the complement cascade,” and reactive oxygen species (ROS)5. Kell and Pretorius have written about the possibility that ischemia-reperfusion injury plays an important role in Long COVID and ME/CFS6. An alternative pathway for vascular injury is mast cell activation during an anaphylactic or anaphylactoid event in response to a pharmaceutical or chemical irritant, which similarly involves the complement system and other powerful inflammatory processes7,8. Vascular injury could also result from a cytokine storm prompted by an acute COVID-19 infection.
This hypothesis is consistent with a recent paper that found evidence of a unique signature of vascular transformation factors in people with Long COVID associated with the process of repairing damaged blood vessels9. It is also consistent with the findings of endothelial dysfunction in people with ME/CFS and Long COVID10,11. In a series of hypothesis papers12,13, Wirth and Scheibenbogen (2021) and Wirth and Scheibenbogen (2022) explore how endothelial dysfunction, microvascular permeability, and the resulting leakage of protein-rich fluid can give rise to many commonly reported ME/CFS symptoms. However, their proposed mechanism does not explain why some individuals experience major relapses followed by periods of slow recovery.
I propose that the vascular hyperpermeability (characterized by the excessive leakage of protein-rich fluid from blood vessels) that prompts many symptoms in ME/CFS—and likely, ME/CFS-type presentations of Long COVID—can arise from several additional mechanisms beyond the one noted by Wirth and Scheibenbogen, including through direct injury to the vascular endothelium14. A significant vascular injury, prompting the degradation of an individual’s condition and the start of a more severe phase of illness, followed by the healing of that injury over time, could help explain the relapse/recovery pattern experienced by some individuals with ME/CFS and Long COVID.
A study in Sweden of 229 individuals with ME/CFS found that half had generalized joint hypermobility, a marker of connective tissue disorders like Ehlers-Danlos syndrome (EDS)15. Another study similarly found a much higher rate of hypermobility among people with ME/CFS and fibromyalgia than among comparison households16. People with EDS and other connective tissue disorders may be at particular risk of this relapse/recovery phenotype due to defective connective tissue that is more easily and severely injured during inflammatory events. As the rheumatologists Esther Jiménez-Encarnación and Luis M Vilá noted in a case study of recurrent venous thrombosis in an individual with hypermobile EDS, “In all types of EDS, the collagen that supports blood vessels is unusually weak and elastic, making blood vessels more prone to injury”17. This is consistent with the findings in several prior studies of a higher incidence of neurovascular incidents among people with a range of connective tissue disorders.18. People with EDS similarly experience poor and delayed wound healing19, which may explain the long length of the recovery phase.
In people with a connective tissue disorder, the connective tissue degradation initiated by the inflammatory event can also cause or exacerbate craniocervical instability and other spinal problems, as well as vascular compression syndromes. These complications could potentially cause additional symptoms in affected individuals.
Whether an individual’s susceptibility to a relapse/recovery phenotype of ME/CFS or Long COVID is related to a connective tissue disorder or another factor, I would expect that, after healing, susceptible individuals remain at risk of future inflammatory events that could trigger another relapse.
Unanswered questions
Could some massive inflammatory events stem from vertebrobasilar ischemia or autonomic dysreflexia secondary to the spinal complications of severe hypermobility?
Is the lymphatic vasculature also injured in massive inflammatory events, exacerbating symptoms during the severe phase?
During the severe phase of a relapse/recovery phenotype of ME/CFS and Long COVID, do chronic inflammation and platelet activation slow recovery of the vasculature by preventing healing and/or exacerbating the injury?
How does the relapse/recovery cycle relate to microclots, autoantibodies, and other less cyclical disease components; are they alternative phenotypes, or do they coexist?
References
1 Helliwell, A., Stockwell, P., Edgar, T., Chatterjee, A., & Tate, W. P. (2022). Dynamic epigenetic changes during a relapse and recovery cycle in myalgic encephalomyelitis/chronic fatigue syndrome. medRxiv, 1-33. https://doi.org/10.1101/2022.02.24.22270912
2 Tate, W. P., Walker, M., Sweetman, E., Helliwell, A., Peppercorn, K., Edgar, C. D., Blair, A., & Chatterjee, A. (2022). Molecular mechanisms of neuroinflammation in ME/CFS and Long COVID to sustain disease and promote relapses. Frontiers in Neurology, 13, 877772. https://doi.org/10.3389/fneur.2022.877772
3 Katsoularis, I., Fonseca-Rodríguez, O., Farrington, P., Jerndal, H., Lundevaller, E. H., Sund, M., Lindmark, K., & Connolly, A. F. (2022). Risks of deep vein thrombosis, pulmonary embolism, and bleeding after COVID-19: Nationwide self-controlled cases series and matched cohort study. BMJ, 377, e069590. https://doi.org/10.1136/bmj-2021-069590
4 Elkind, M. S., Boehme, A. K., Smith, C. R., Meisel, A., & Buckwalter, M. S. (2020). Infection as a stroke risk factor and
determinant of outcome after stroke. Stroke, 51(10), 3156–3168. https://doi.org/10.1161/strokeaha.120.030429
5 Pluijmert, N. J., Atsma, D. E., & Quax, P. H. (2021). Post-ischemic myocardial inflammatory response: A complex and dynamic process susceptible to immunomodulatory therapies. Frontiers in Cardiovascular Medicine, 8. https://doi.org/10.3389/fcvm.2021.647785
6 Kell, D. B., & Pretorius, E. (2022). The potential role of ischaemia–reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: Evidence, mechanisms, and therapeutic implications. Biochemical Journal, 479(16), 1653–1708. https://doi.org/10.1042/bcj20220154
7 Szebeni, J. (2014). Complement activation-related pseudoallergy: A stress reaction in blood triggered by nanomedicines and biologicals. Molecular Immunology, 61(2), 163–173. https://doi.org/10.1016/j.molimm.2014.06.038
8 Nguyen, S., Rupprecht, C. P., Haque, A., Pattanaik, D., Yusin, J. S., & Krishnaswamy, G. (2021). Mechanisms governing anaphylaxis: Inflammatory cells, mediators, endothelial gap junctions and beyond. International Journal of Molecular Sciences, 22(15), 7785. https://doi.org/10.3390/ijms22157785
9 Patel, M. A., Knauer, M. J., Nicholson, M., Daley, M., Van Nynatten, L. R., Martin, C., Patterson, E. L., Cepinskas, G., Seney, S. L., Dobretzberger, V., Miholits, M., Webb, B., & Fraser, D. D. (2022). Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism. Molecular Medicine, 28(1). https://doi.org/10.1186/s10020-022-00548-8
10 Charfeddine, S., Amor, H. I. H., Jdidi, J., Torjmen, S., Kraiem, S., Hammami, R., Bahloul, A., Kallel, N., Moussa, N., Touil, I., Ghrab, A., Elghoul, J., Meddeb, Z., Thabet, Y., Kammoun, S., Bouslama, K., Milouchi, S., Abdessalem, S., & Abid, L. (2021). Long COVID 19 syndrome: Is it related to microcirculation and endothelial dysfunction? Insights from TUN-EndCOV study. Frontiers in Cardiovascular Medicine, 8. https://doi.org/10.3389/fcvm.2021.745758
11 Sørland, K., Sandvik, M. K., Rekeland, I. G., Ribu, L., Småstuen, M. C., Mella, O., & Fluge, Ø. (2021). Reduced endothelial function in myalgic encephalomyelitis/chronic fatigue syndrome—results from open-label cyclophosphamide intervention study. Frontiers in Medicine, 8, 642710. https://doi.org/10.3389/fmed.2021.642710
12 Wirth, K., Scheibenbogen, C., & Paul, F. (2021). An attempt to explain the neurological symptoms of myalgic encephalomyelitis/chronic fatigue syndrome. Journal of Translational Medicine, 19(1), 471. https://doi.org/10.1186/s12967-021-03143-3
13 Wirth, K., & Scheibenbogen, C. (2020). A unifying hypothesis of the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors. Autoimmunity Reviews, 19(6), 102527. https://doi.org/10.1016/j.autrev.2020.102527
14 Kumar, P., Shen, Q., Pivetti, C. D., Lee, E. S., Wu, M. H., & Yuan, S. Y. (2009). Molecular mechanisms of endothelial hyperpermeability: Implications in inflammation. Expert Reviews in Molecular Medicine, 11, e19. https://doi.org/10.1017/s1462399409001112
15 Bragée B., Michos, A., Drum, B., Fahlgren, M., Szulkin, R., & Bertilson, B. C. (2020). Signs of intracranial hypertension, hypermobility, and craniocervical obstructions in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Neurology, 11. https://doi.org/10.3389/fneur.2020.00828
16 Eccles, J. A., Thompson, B. E., Themelis, K., Amato, M. C. M., Stocks, R., Pound, A., Jones, A., Cipinova, Z., Shah-Goodwin, L., Timeyin, J., Thompson, C., Batty, T., Harrison, N. A., Critchley, H. D., & Davies, K. M. (2021). Beyond bones: The relevance of variants of connective tissue (hypermobility) to fibromyalgia, ME/CFS and controversies surrounding diagnostic classification: An observational study. Clinical Medicine, 21(1), 53–58. https://doi.org/10.7861/clinmed.2020-0743
17 Jiménez-Encarnación, E., & Vilá, L. M. (2013). Recurrent venous thrombosis in Ehlers-Danlos syndrome type III: An atypical manifestation. BMJ Case Reports, 2013, bcr2013008922. https://doi.org/10.1136/bcr-2013-008922
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19 Baik, B. S., Lee, W. C., Park, K. H., Yang, W., & Ji, S. Y. (2019). Treatment of the wide open wound in the Ehlers-Danlos syndrome. Archives of Craniofacial Surgery, 20(2), 130–133. https://doi.org/10.7181/acfs.2018.0233