Thesis Comparison of Clinical and Pathophysiological Characteristics of ME/CFS and Chronic Fatigue Associated with Post-COVID-19 Syndrome, 2024, RIABKOVA

Dolphin · Jan 2, 2025

https://disser.spbu.ru/files/2024/disser_en_riabkova_varvara.pdf

SAINT PETERSBURG STATE UNIVERSITY
As a manuscript
RIABKOVA Varvara Aleksandrovna

COMPARISON OF CLINICAL AND PATHOPHYSIOLOGICAL CHARACTERISTICS OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME AND CHRONIC FATIGUE ASSOCIATED WITH POST-COVID-19 SYNDROME

Scientific specialities
3.3.3. Pathological physiology
3.1.18. Internal medicine

DISSERTATION for an academic degree candidate of medical sciences.

Translation from Russian

Scientific supervisors:
Churilov Leonid Pavlovich candidate of medical sciences, associate professor
Shoenfeld Yehuda (Israel) Doctor of Medicine, member of The Israeli Academy of Sciences and Humanities, professor Saint-Petersburg – 2024

Yann04 · Jan 2, 2025

Table of Contents:

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Hutan · Jan 2, 2025

Research objectives

1. To study the prevalence of ME/CFS according to its diagnostic criteria among patients with chronic fatigue associated with PCS.

2. To determine the signs of dysautonomia based on the analysis of heart rate variability (HRV), blood pressure variability (BPV), and baroreflex function during spontaneous breathing and paced breathing in patients with chronic fatigue associated with PCS and in patients with ME/CFS not related to COVID-19.

3. To evaluate hypothalamic-pituitary-adrenal (HPA) axis activity with the measurement of the cortisol awakening response (CAR) in patients with chronic fatigue associated with PCS and in patients with ME/CFS not related to COVID-19.

4. To investigate microvascular endothelial function based on the analysis of post- occlusive reactive hyperemia (PORH) measured by Laser-Doppler flowmetry (LDF) in patients with chronic fatigue associated with PCS and in patients with ME/CFS not related to COVID-19.

5. To characterize the state of regulatory function of the immune system according to the data on the spectrum and intensity of autoreactive processes reflecting its interaction with cells of different organs and tissues in patients with chronic fatigue associated with PCS and in patients with ME/CFS not related to COVID-19.

6. To assess microbiome composition according to the data obtained by gas chromatography-mass spectrometry of microbial markers in venous blood of patients with chronic fatigue associated with PCS and in patients with ME/CFS not related to COVID-19.

7. On the basis of the study results, to assess the degree of similarity and the presence of differences in the pathogenesis of ME/CFS and chronic fatigue associated with PCS.

The work was performed within the framework of the grant from the Government of the Russian Federation (contract No 14.W03.31.0009 of 13.02. 2017) for state support of scientific research conducted under the supervision of leading scientists and grant of the Russian Scientific Foundation of the Russian Academy of Sciences No. 22-15- 00113 dated 13.05.2022, https://rscf.ru/project/22-15-00113/
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Hutan · Jan 2, 2025

The findings from these studies have certainly been widely shared and may well have been influential for the care of people with ME/CFS in Russia

16 journal articles were published on the topic of the study, 13 of which were published in journals indexed in the international reference databases Web of Science and Scopus, including:

- 8 articles describing the scientific results obtained during the work, some of which were included in the thesis:

1. Ryabkova VA, Gavrilova NY, Fedotkina TV, Churilov LP, Shoenfeld Y. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-COVID Syndrome: A Common Neuroimmune Ground? // Diagnostics (Basel). 2022;13(1):66. doi: 10.3390/diagnostics13010066.

2. Ryabkova VA, Gavrilova NY, Poletaeva AA, Pukhalenko AI, Koshkina IA, Churilov LP, Shoenfeld Y. Autoantibody Correlation Signatures in Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Association with Symptom Severity // Biomedicines. 2023;11(2):257. doi: 10.3390/biomedicines11020257.

3. Ryabkova VA, Rubinskiy AV, Marchenko VN, Trofimov VI, Churilov LP. Similar Patterns of Dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue and Post- COVID-19 Syndromes // Pathophysiology. 2024;31(1):1-17. doi: 10.3390/pathophysiology31010001.

4. Ryabkova VA, Gavrilova NY, Kanduc D, Churilov LP, Shoenfeld Y. Post-COVID syndrome and its immunopathological mechanisms. The role of autoimmunity // Russian Biomedical Research. 2021; 6(3):7-11.

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5. Churilov LP, Kanduc D, Ryabkova VA. COVID-19: adrenal response and

molecular mimicry // Isr Med Assoc J. 2021;23(10):618-619.
6. Gavrilova NY, Soprun LA, Lukashenko MV, Ryabkova VA, Fedotkina TV,

Churilov LP, Shoenfeld Y. New Clinical Phenotype of the Post-Covid Syndrome: Fibromyalgia and Joint Hypermobility Condition. // Pathophysiology. 2022;29(1):24-29. https://doi.org/10.3390/pathophysiology29010003

7. Normatov M.G., Karev V.E., Kolobov A.V., Maevskaya V.A., Ryabkova V.A., Utekhin V.I., Churilov L.P. Post-COVID Endocrine Disorders: Putative Role Of Molecular Mimicry And Some Pathomorphological Correlates // Diagnostics. 2023;13(3):522.DOI: 10.3390/diagnostics13030522

8. Yevsyutina Y.V., Danilov A.B., Simonova A.V., Ryabkova V.A. Psychoneuroimmunological Markers of Post-COVID Syndrome // Clinical Pathophysiology. 2023; 29(3):43-50.

- 8 review articles:

1. Ryabkova VA, Churilov LP, Shoenfeld Y. Influenza infection, SARS, MERS and COVID-19: Cytokine storm – The common denominator and the lessons to be learned.// Clin Immunol. 2021;223:108652. doi: 10.1016/j.clim.2020.108652.

2. Ryabkova VA, Churilov LP, Shoenfeld Y. Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination? //Int J Mol Sci. 2019;20(20):5164. doi: 10.3390/ijms20205164.

3. Shoenfeld Y, Ryabkova VA, Scheibenbogen C, Brinth L, Martinez-Lavin M, Ikeda S, Heidecke H, Watad A, Bragazzi NL, Chapman J, Churilov LP, Amital H. Complex syndromes of chronic pain, fatigue and cognitive impairment linked to autoimmune dysautonomia and small fiber neuropathy.// Clin Immunol. 2020;214:108384. doi: 10.1016/j.clim.2020.108384.

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4. Makarova YA, Ryabkova VA, Salukhov VV, Sagun BV, Korovin AE, Churilov LP.

Atherosclerosis, Cardiovascular Disorders and COVID-19: Comorbid Pathogenesis. // Diagnostics (Basel). 2023;13(3):478. doi: 10.3390/diagnostics13030478.

5. Shcherbak S. G., Anisenkova A. Yu., Mosenko S. V., Puzankova E. V., Mamaeva O. P., Vologzhanin D. A., Gavrilova N. Yu., Ryabkova V. A., Churilov L. P., Golota A. S., Kamilova T. A. “Long COVID”. Current state of the problem and prospects for study and treatment. Part 1. Clinical Pathophуsiology, 2022; 28(3):3-21

6. Ryabkova VA, Churilov LP, Shoenfeld Y. COVID-19 and ABO blood groups. // Isr Med Assoc J. 2021;23(3):140-142.

7. Ryabkova VA, Churilov LP, Shoenfeld Y. Hyperstimulation of the immune system as a cause of autoimmune diseases. Annals of the Russian Academy of Medical Sciences.

2020;75(3):204-213.
8. Ryabkova VA, Bregovskaya AA, Soprun LA, Gavrilova NY, Churilov LP.

Autoimmune manifestations of the post-COVID-19 condition. // Immunopathol Persa. 2022:e31339. doi:10.34172/ ipp.2022.31339.

- 4 chapters in book:

1. Ryabkova V.A., Churilov L.P. Disease course and pathogenesis of post-COVID-19 condition / in book: Autoimmunity, COVID-19, Post-COVID-19 Syndrome and COVID- 19 Vaccination (Eds: Y. Shoenfeld & A. Dotan). – Amsterdam: Academic Press, 2023. – P. 759-771. – doi 10.1016/B978-0-443-18566-3.00006-2.

2. Soprun L., Gavrilova N., Ryabkova V.A., Lukashenko M., Kamaeva E. The post- COVID syndrome / in book: Autoimmunity, COVID-19, Post-COVID-19 Syndrome and COVID-19 Vaccination (Eds: Y. Shoenfeld & A. Dotan). – Amsterdam: Academic Press, 2023. – P. 747-758

3. Gavrilova N., Malkova A., Soprun L., Ryabkova V.A., Kamaeva E. Long-term assessment of autoantibodies in post-COVID syndrome. / in book: Autoimmunity, COVID-19, Post-COVID-19 Syndrome and COVID-19 Vaccination (Eds: Y. Shoenfeld & A. Dotan). – Amsterdam: Academic Press, 2023. – P. 772-779

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4. Gavrilova N., Soprun L., Ryabkova V.A., Lukashenko M., Kamaeva E. The post-

COVID syndrome / in book: Autoimmunity, COVID-19, Post-COVID-19 Syndrome and COVID-19 Vaccination (Eds: Y. Shoenfeld & A. Dotan). – Amsterdam: Academic Press, 2023. – P. 784-787

The main results of the study were reported and discussed at international and national scientific conferences with international participation. In particular:

- 11 papers were published in the proceedings of international and national scientific conferences:

1. Churilov, L. P., Ryabkova, V. A., Gavrilova, N. Yu., Poletaeva, A. A., The spectrum and intensity of natural autoimmunity in fibromyalgia and chronic fatigue syndrome – a potential key to therapy? // XVII International Scientific Congress "Rational Pharmacotherapy – Golden Autumn": Proceedings of the Congress / Edited by: Professor Hadjidis, A. K. St. Petersburg: Publishing House of St. Petersburg State Economic University, 2022. – 195-197 p.

2. Ryabkova, V. A., Gavrilova, N. Y., Poletaeva, A. A., Churilov, L. P. (2022). Abnormalities of the spectrum and intensity of autoimmunity in post-COVID-19 syndrome. // Proceedings of the Russian Scientific and Practical Conference "COVID-19: results and prospects" (Sestroretsk, 14 October 2022)/ University Therapeutic Bulletin, 2022, 4:32-33.

3. Ryabkova V.A., Poletaeva A.A., Koshkina I.A., Yevsyutina Y.V., Marchenko V.N., Trofimov V.I., Churilov L.P. Abnormalities in the levels of natural autoantibodies in post- COVID-19 syndrome and ongoing symptomatic COVID-19// All-Russian therapeutic congress with international participation Botkin readings Collection of abstracts. / Edited by: Mazurov V.I., Trofimov E.A. St. Petersburg: 2023. – с. 233-234.

4. Ryabkova VA, Churilov LP "Similar changes of microcirculation in post-COVID19 syndrome and myalgic encephalomyelitis/chronic fatigue syndrome". // 9th International Congress of Pathophysiology and 5th Congress of Physiological Sciences of Serbia with International Participation: final Program and Abstract Book, 04–06 July 2023, Belgrade,

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Serbia / eds I. Srejović, I. Milosavljević; International Society of Pathophysiology. –

Kragujevac: Fakultet medicinskih nauka Univerziteta u Kraguievcu, 2023. – P. 41
5. Ryabkova VA, Churilov LP, Gavrilova NY, Fedotkina TV, Poletaeva AA, Rodionova SV, Shoenfeld Y. Study of Human Microecology by Mass Spectrometry of Microbial Markers in the Blood of Patients with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome and Post-COVID-19-Condition // Eur J Rheumatol 2024;11(suppl

2):S133
6. Ryabkova V.A., Rubinsky A.V., Marchenko V.N., Trofimov V.I., Churilov L.P.

Dysautonomia as a mechanism of pathogenesis of post-COVID-19 syndrome and chronic fatigue syndrome: the possibility of objectification of asthenia and a potential target of therapy// All-Russian therapeutic congress with international participation: Botkin readings. Collection of abstracts. Edited by: Mazurov V.I., Trofimov E.A. – St. Petersburg: 2024 – P. 194-195.

7. Ryabkova VA, Rubinsky AV, Marchenko VN, Trofimov VI, Churilov LP Features of autonomous dysfunction in patients with post-COVID-19 syndrome // New concepts of mechanisms of inflammation, autoimmunity and infections: Proceedings of IX International Scientific and Practical Conference (Kazan, 26-27 October 2023). Edited by R.Sh. Khasanov – Kazan: RIO KGMA, 2023. – с. 52-57.

8. Gavrilova N.Yu., Ryabkova V.A., Fedotkina T.V., Korovin A.E., Churilov L.P. Pathogenesis of disorders of autonomic regulation of systemic circulation in patients with chronic fatigue syndrome, postural tachycardia and fibromyalgia // State and prospects of development of modern science in the direction of "Biotechnical systems and technologies". Collection of articles of the III All-Russian scientific and technical conference. Anapa: Military-Innovation Technopolis "Era", 2021. – P. 192-195.

9. Ryabkova VA, Gavrilova NY, Korovin AE, Churilov LP, Schoenfeld I. Clinical and pathophysiological characteristics of chronic fatigue syndrome as a neuroimmune disease// State and prospects of development of modern science in the direction of "Biotechnical systems and technologies". Collection of articles of the III All-Russian scientific and technical conference. Anapa: VIT "Era", 2021. – P. 72-78.

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10. Churilov L.P., Fedotkina T.V., Nikolaev A.V., Normatov M.G., Novitskaya T.A.,

Ryabkova V.A., Starshinova A.A. Infection and Autoimmunity: Triggering of Somatic Diseases // Immunology-2024. Abstract book of Conference (Harbin, 27 July 2024). Harbin, HMU Publisher, 2024. – P. 14

11. Ryabkova VA, Churilov LP. Chronic fatigue syndrome and post-covid syndrome: stressor adaptation disorders and approaches to their correction. In Proceedings of the XIX International Scientific Congress “Rational Pharmacotherapy - ‘Golden Autumn’. Edited by Professor Hadjidis, A. K. Spb: SpbGEU, 2024. – P. 183-186.

- the obtained results were also presented at the All-Russian conference in the form of an oral report (without publishing abstracts):

1. Ryabkova V.A., Poletaeva A.A., Sobolevskaya P.A., Korovin A.E., Churilov L.P. Abnormalities of natural autoimmunity in post-COVID-19 syndrome. Report at the XIII All-Russian School on Clinical Immunology "Immunology for Doctors", 29 January – 4 February 2023, Pushkin Mountains, Pskov region
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The obtained new knowledge about the pathogenesis of ME/CFS and PCS, as well as the results of the analysis of modern international consensus recommendations on the diagnosis and therapy of these conditions (published in 2021) were introduced into the educational process and used in teaching at the Medical Institute of St. Petersburg State University in the elective course "Autoimmunology" (speciality "General medicine", 5th year). In this course for the first time modern ideas about ME/CFS and PCS were included in the training programme for medical doctors.
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I really hope the studies were done well.

Hutan · Jan 2, 2025

Reported main findings

1. “Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-COVID Syndrome: A Common Neuroimmune Ground?” [212], pages 1-17
Some characteristics of ME/CFS and PCS as neuroimmune diseases are described and compared; high prevalence of dysautonomia and microcirculatory dysfunction in these conditions is shown; lack of correlation of fatigue severity with depression/anxiety and the presence of correlation between fatigue severity and neuroimmune disturbances in ME/CFS and PCS are noted. Author's contribution is 100%.

2. “Autoantibody Correlation Signatures in Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Association with Symptom Severity” [73], pages 1-15
We described the methodology for the assessment of the regulatory function of the immune system, according to the data on the spectrum of natural AAb (as it reflects the interaction of the immune system with cells of different organs and tissues); we showed the presence of some shifts of the natural AAb serum levels in patients with ME/CFS, in particular, shifts in the level of AAb to gamma-aminobutyric acid (GABA) receptors were the most pronounced in this group of patients. Author's contribution is 100%.

3. “Similar Patterns of Dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue and Post-COVID-19 Syndromes” [276], pages 1-17 – The use of paced breathing at 12 breaths per minute was justified for the more accurate characterization of the separate contribution of disorders of the sympathetic and parasympathetic parts of the autonomic nervous system in the studies of HRV; the presence of a similar pattern of autonomic nervous system dysfunction in ME/CFS and PCS, its relationship to the clinical manifestations of these conditions and the potential therapeutic role of paced breathing were proved. Author's contribution 100%.

4. “Post-COVID syndrome and its immunopathological mechanisms. The role of autoimmunity” [249], pages 7-11 – Based on the analysis of the registry of patients with PCS, which we have established, we reported that the most common phenotype of PCS is chronic-fatigue-like one; high prevalence of ME/CFS among PCS patients, according to the diagnostic criteria of ME/CFS, was shown; the potential role of autoimmune mechanisms of the PCS pathogenesis and the need for a specialized center for dynamic observation and rehabilitation of such patients were substantiated. Author's contribution is 100%.

5. “COVID-19: adrenal response and molecular mimicry” [96], pages 618-619 – The hypothesis of autoimmune nature of the HPA axis dysfunction in post-infectious fatigue syndromes was substantiated. Author’s contribution 30%.
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"The main provisions for defence

1. The prevalence of ME/CFS, according to its diagnostic criteria, among patients with chronic fatigue associated with PCS is 45.7%, necessitating increased awareness among physicians about ME/CFS, modern approaches to its diagnosis and therapy.

2. Patients with ME/CFS not related to COVID-19 and with the chronic fatigue associated with PCS exhibit a similar pattern of dysautonomia, characterized by reduced HRV, increased BPV, and decreased baroreflex sensitivity, and the severity of these signs correlates with the fatigue level.

3. Microcirculation disorders are characteristic of both groups of patients, but in ME/CFS not related to COVID-19 there is impairment in endothelium-dependent vasodilation, while patients with chronic fatigue associated with PCS shows a decrease in the minimum perfusion value during occlusion, which may indicate microcirculatory stasis.

4. Decreased reactivity of the HPA axis is typical for the group of patients with ME/CFS not related to COVID-19, in which it is closely linked to sleep disturbances. At the same time HPA reactivity does not appear to be a significant factor in the pathogenesis of chronic fatigue associated with PCS.

5. Both groups of patients exhibit signs of polyclonal activation of the adaptive immune system, and the analysis of natural autoantibody (AAb) serum profiles, according to the concept of the regulatory function of the immune system, suggests new pathomechanisms of ME/CFS and PCS.

6. The analysis of the microbiome composition in patients with chronic fatigue associated with PCS and in patients with ME/CFS not related to COVID-19 suggests alterations in the small intestinal microbiota composition, increased mucosal permeability, and immune system dysfunction at the mucosal level, more pronounced in ME/CFS.

7. Thus, the comparison of findings characterizing the regulatory functions of the nervous, endocrine, and immune systems as well as microcirculation disorders in chronic fatigue associated with PCS, in patients with ME/CFS not related to COVID-19, and in healthy individuals revealed significant similarities in the pathomechanisms of PCS and ME/CFS, as well as some features more typical for each of these syndromes."

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