Cytokine profiles and neurological manifestations in post-COVID syndrome

Yulia Desheva , Zamira Muruzheva , Olga Tumashova , Tamara Shvedova , Polina Kudar , Georgy Matveev , Irina Koroleva , Galina Leontieva , Anna Lerner , Stanislav Ponkratov , Elvira Firova , Alexander Suvorov

Exploration of Immunology ›› 2025, Vol. 5 ›› Issue (1) : 1003184

PDF (16259KB)
Exploration of Immunology ›› 2025, Vol. 5 ›› Issue (1) :1003184 DOI: 10.37349/ei.2025.1003184
Original Article
research-article
Cytokine profiles and neurological manifestations in post-COVID syndrome
Author information +
History +
PDF (16259KB)

Abstract

Aim: The objectives of our study were to evaluate a range of circulating biomarkers in COVID-19-related long-term neurological dysfunction.

Methods: The study involved 30 patients with post-COVID syndrome (PCS) and 28 patients after COVID-19 without PCS. The third cohort consisted of 29 patients with acute COVID-19 of varying severity. The severity of COVID-19 was classified as mild and moderate to severe. The Montreal Cognitive Assessment (MOCA) and the SAGE test were used to study cognitive functions. The Hospital Anxiety and Depression Scale (HADS), the Sheehan Anxiety Scale, and the Beck Depression Inventory were used to study affective functions. The levels of serum cytokines and IgM, IgG, IgA to the SARS-CoV-2 coronavirus were determined using the Vector-Best test systems (Novosibirsk, Russia). We also studied the IgG subclasses to the spike protein of the SARS-CoV-2.

Results: А mild to moderate COVID-19 infection primarily increases the risk of affective disorders and asthenia and, to a lesser extent, the development of cognitive impairment. The levels of IFN-α, IL-6, as well as serum antibodies to the SARS-CoV-2 among patients with PCS were significantly higher compared to convalescents without PCS. IgM to the SARS-CoV-2 was detected in the blood of patients with PCS during 2–7 months after the disease. After moderate and severe COVID-19, IgG2 and IgG4 were predominant in the blood of patients with PCS and neurological symptoms. The levels of IL-1, IL-4, IL-6, IL-8 in the blood serum of patients with PCS were higher after moderate and severe COVID-19 compared to patients who had mild COVID-19.

Conclusions: The obtained data on an elevated level of cytokines and IFN-α in the blood of PCS patients can suggest the hypothesis about the participation of chronic inflammation in neurological disorders. The main limitation of the study is the relatively small sample size, which limits the statistical analyses.

Keywords

SARS-CoV-2 / COVID-19 / post-COVID syndrome / cytokines / antibodies

Cite this article

Download citation ▾
Yulia Desheva, Zamira Muruzheva, Olga Tumashova, Tamara Shvedova, Polina Kudar, Georgy Matveev, Irina Koroleva, Galina Leontieva, Anna Lerner, Stanislav Ponkratov, Elvira Firova, Alexander Suvorov. Cytokine profiles and neurological manifestations in post-COVID syndrome. Exploration of Immunology, 2025, 5 (1) : 1003184 DOI:10.37349/ei.2025.1003184

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Griffin DE. Why does viral RNA sometimes persist after recovery from acute infections? PLoS Biol. 2022; 20: e3001687.

[2]

Groff D, Sun A, Ssentongo AE, Ba DM, Parsons N, Poudel GR, et al. Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection: A Systematic Review. JAMA Netw Open. 2021; 4: e2128568.

[3]

Batiha GE, Al-Kuraishy HM, Al-Gareeb AI, Welson NN. Pathophysiology of Post-COVID syndromes: a new perspective. Virol J. 2022; 19: 158.

[4]

Mohandas S, Jagannathan P, Henrich TJ, Sherif ZA, Bime C, Quinlan E, et al. RECOVER Mechanistic Pathways Task Force. Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC). Elife. 2023; 12: e86014.

[5]

Varghese PM, Tsolaki AG, Yasmin H, Shastri A, Ferluga J, Vatish M, et al. Host-pathogen interaction in COVID-19: Pathogenesis, potential therapeutics and vaccination strategies. Immunobiology. 2020; 225: 152008.

[6]

Yong SJ. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (Lond). 2021; 53: 737-54.

[7]

Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023; 21: 133-46. Erratum in: Nat Rev Microbiol. 2023; 21:408.

[8]

Castanares-Zapatero D, Chalon P, Kohn L, Dauvrin M, Detollenaere J, Maertens de Noordhout C, et al. Pathophysiology and mechanism of long COVID: a comprehensive review. Ann Med. 2022; 54: 1473-87.

[9]

Rolando LM, Villafañe JH, García SC, Argüello AS, Rosa MV, Romero EAS. Multicomponent Exercise Program to Improve the Immediate Sequelae of COVID-19: A Prospective Study with a Brief Report of 2-Year Follow-Up. Int J Environ Res Public Health. 2022; 19: 12396.

[10]

Taquet M, Sillett R, Zhu L, Mendel J, Camplisson I, Dercon Q, et al. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients. Lancet Psychiatry. 2022; 9: 815-27.

[11]

Alexopoulos H, Magira E, Bitzogli K, Kafasi N, Vlachoyiannopoulos P, Tzioufas A, et al. Anti-SARS-CoV-2 antibodies in the CSF, blood-brain barrier dysfunction, and neurological outcome: Studies in 8 stuporous and comatose patients. Neurol Neuroimmunol Neuroinflamm. 2020; 7: e893.

[12]

Virhammar J, Kumlien E, Fällmar D, Frithiof R, Jackmann S, Sköld MK, et al. Acute necrotizing encephalopathy with SARS-CoV-2 RNA confirmed in cerebrospinal fluid. Neurology. 2020; 95: 445-9.

[13]

Ramani A, Müller L, Ostermann PN, Gabriel E, Abida-Islam P, Müller-Schiffmann A, et al. SARS-CoV-2 targets neurons of 3D human brain organoids. EMBO J. 2020; 39: e106230.

[14]

Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. J Exp Med. 2021; 218: e20202135.

[15]

Ortiz OHH, Ramírez AFN, Ramírez AS, Arias MR, Rodriguez NB, Saldarriaga FJM, et al. Post-COVID-19 syndrome: When an acute infection causes a chronic illness. Acta Colombiana de Cuidado Intensivo. 2024; 24: 387-97.

[16]

Grant RA, Poor TA, Sichizya L, Diaz E, Bailey JI, Soni S, et al. ; Northwestern University Successful Clinical Response In Pneumonia Therapy (NU SCRIPT) Investigators. Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19. JCI Insight. 2024; 9: e178859.

[17]

Bauer ME, Teixeira AL. Inflammation in psychiatric disorders: what comes first? Ann N Y Acad Sci. 2019; 1437: 57-67.

[18]

Li Y, Fu L, Gonzales DM, Lavi E. Coronavirus neurovirulence correlates with the ability of the virus to induce proinflammatory cytokine signals from astrocytes and microglia. J Virol. 2004; 78: 3398-406.

[19]

Zozulya SA, Sizov SV, Oleichik IV, Klyushnik TP. Clinical and immunological correlates in endogenous psychoses developed after COVID-19. Zh Nevrol Psikhiatr Im S S Korsakova. 2022; 122: 71-7.

[20]

Mangalmurti N, Hunter CA. Cytokine Storms: Understanding COVID-19. Immunity. 2020; 53: 19-25.

[21]

Sun X, Wang T, Cai D, Hu Z, Chen J, Liao H, et al. Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev. 2020; 53: 38-42.

[22]

Hussman JP. Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention. Front Pharmacol. 2020; 11: 1169.

[23]

Hu B, Huang S, Yin L. The cytokine storm and COVID-19. J Med Virol. 2021; 93: 250-6.

[24]

Pillinger T, Osimo EF, Brugger S, Mondelli V, McCutcheon RA, Howes OD. A Meta-analysis of Immune Parameters, Variability, and Assessment of Modal Distribution in Psychosis and Test of the Immune Subgroup Hypothesis. Schizophr Bull. 2019; 45: 1120-33.

[25]

Sugimoto MA, Sousa LP, Pinho V, Perretti M, Teixeira MM. Resolution of Inflammation: What Controls Its Onset? Front Immunol. 2016; 7: 160.

[26]

Panigrahy D, Gilligan MM, Serhan CN, Kashfi K. Resolution of inflammation: An organizing principle in biology and medicine. Pharmacol Ther. 2021; 227: 107879.

[27]

Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013; 13: 862-74.

[28]

Oronsky B, Larson C, Hammond TC, Oronsky A, Kesari S, Lybeck M, et al. A Review of Persistent Post-COVID Syndrome (PPCS). Clin Rev Allergy Immunol. 2023; 64: 66-74.

[29]

Vaz de Paula CB, Nagashima S, Liberalesso V, Collete M, da Silva FPG, Oricil AGG, et al. COVID-19: Immunohistochemical Analysis of TGF-β Signaling Pathways in Pulmonary Fibrosis. Int J Mol Sci. 2021; 23: 168.

[30]

Cañas CA. The triggering of post-COVID-19 autoimmunity phenomena could be associated with both transient immunosuppression and an inappropriate form of immune reconstitution in susceptible individuals. Med Hypotheses. 2020; 145: 110345.

[31]

Galán M, Vigón L, Fuertes D, Murciano-Antón MA, Casado-Fernández G, Domínguez-Mateos S, et al. Persistent overactive cytotoxic immune response in a Spanish cohort of individuals with long-COVID: identification of diagnostic biomarkers. Frontiers in immunology. 2022; 13: 848886.

[32]

Opsteen S, Files JK, Fram T, Erdmann N. The role of immune activation and antigen persistence in acute and long COVID. J Investig Med. 2023; 71: 545-62.

[33]

Craddock V, Mahajan A, Spikes L, Krishnamachary B, Ram AK, Kumar A, et al. Persistent circulation of soluble and extracellular vesicle-linked Spike protein in individuals with postacute sequelae of COVID-19. J Med Virol. 2023; 95: e28568.

[34]

Peluso MJ, Deitchman AN, Torres L, Iyer NS, Munter SE, Nixon CC, et al. Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symeeeptoms. Cell Rep. 2021; 36: 109518.

[35]

Finsterer J, Mehri S. Post-COVID ‘brain fog’ will clear up only through neuropsychological examination. Neurol Neurochir Pol. 2023; 57: 322-3.

[36]

Suvorov A, Gupalova T, Desheva Y, Kramskaya T, Bormotova E, Koroleva I, et al. Construction of the Enterococcal Strain Expressing Immunogenic Fragment of SARS-Cov-2 Virus. Front Pharmacol. 2022; 12: 807256.

[37]

Pilotto A, Cristillo V, Piccinelli SC, Zoppi N, Bonzi G, Sattin D, et al. Long-term neurological manifestations of COVID-19: prevalence and predictive factors. Neurol Sci. 2021; 42: 4903-7.

[38]

Petersen M, Nägele FL, Mayer C, Schell M, Petersen E, Kühn S, et al. Brain imaging and neuropsychological assessment of individuals recovered from a mild to moderate SARS-CoV-2 infection. Proc Natl Acad Sci U S A. 2023; 120: e2217232120.

[39]

Al-Ramadan A, Rabab’h O, Shah J, Gharaibeh A. Acute and Post-Acute Neurological Complications of COVID-19. Neurol Int. 2021; 13: 102-19.

[40]

Almeria M, Cejudo JC, Deus J, Krupinski J. Neurocognitive and Neuropsychiatric Sequelae in Long COVID-19 Infection. Brain Sci. 2024; 14: 604.

[41]

Carvalho-Schneider C, Laurent E, Lemaignen A, Beaufils E, Bourbao-Tournois C, Laribi S, et al. Follow-up of adults with noncritical COVID-19 two months after symptom onset. Clin Microbiol Infect. 2021; 27: 258-63.

[42]

Abdelhak A, Foschi M, Abu-Rumeileh S, Yue JK, D’Anna L, Huss A, et al. Blood GFAP as an emerging biomarker in brain and spinal cord disorders. Nat Rev Neurol. 2022; 18: 158-72.

[43]

Zingaropoli MA, Pasculli P, Barbato C, Petrella C, Fiore M, Dominelli F, et al. Biomarkers of Neurological Damage: From Acute Stage to Post-Acute Sequelae of COVID-19. Cells. 2023; 12: 2270.

[44]

Schultze JL, Aschenbrenner AC. COVID-19 and the human innate immune system. Cell. 2021; 184: 1671-92.

[45]

Lai Y, Liu S, Manachevakul S, Lee T, Kuo C, Bello D. Biomarkers in long COVID-19: A systematic review. Front Med (Lausanne). 2023; 10: 1085988.

[46]

Litmanovich A, Khazim K, Cohen I. The Role of Interleukin-1 in the Pathogenesis of Cancer and its Potential as a Therapeutic Target in Clinical Practice. Oncol Ther. 2018; 6: 109-27.

[47]

Yang L, Liu S, Liu J, Zhang Z, Wan X, Huang B, et al. COVID-19: immunopathogenesis and Immunotherapeutics. Signal Transduct Target Ther. 2020; 5: 128.

[48]

Bortolato B, Carvalho AF, Soczynska JK, Perini GI, McIntyre RS. The Involvement of TNF-α in Cognitive Dysfunction Associated with Major Depressive Disorder: An Opportunity for Domain Specific Treatments. Curr Neuropharmacol. 2015; 13: 558-76.

[49]

Wong AC, Devason AS, Umana IC, Cox TO, Dohnalová L, Litichevskiy L, et al. Serotonin reduction in post-acute sequelae of viral infection. Cell. 2023; 186: 4851-67.e20.

[50]

Ma A, Zhang L, Ye X, Chen J, Yu J, Zhuang L, et al. High Levels of Circulating IL-8 and Soluble IL-2R Are Associated With Prolonged Illness in Patients With Severe COVID-19. Front Immunol. 2021; 12: 626235.

[51]

Breville G, Lascano AM, Roux-Lombard P, Lalive PH. IL-8 as a potential biomarker in Guillain-Barre Syndrome. Eur Cytokine Netw. 2019; 30: 130-4.

[52]

Queiroz MAF, das Neves PFM, Lima SS, da Costa Lopes J, da Silva Torres MK, Vallinoto IMVC, et al. Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome. Front Cell Infect Microbiol. 2022; 12: 922422.

[53]

Vilela MC, Campos RDdL, Mansur DS, Rodrigues DH, Lacerda-Queiroz N, Lima GK, et al. Role of IL-4 in an experimental model of encephalitis induced by intracranial inoculation of herpes simplex virus-1 (HSV-1). Arq Neuropsiquiatr. 2011; 69: 237-41.

[54]

Eisen HN. Affinity enhancement of antibodies: how low-affinity antibodies produced early in immune responses are followed by high-affinity antibodies later and in memory B-cell responses. Cancer Immunol Res. 2014; 2: 381-92.

[55]

Albarbar B. The Importance of IgM and IgG Antibodies Testing in Infectious Diseases. Libyan Medical Journal. 2024; 16: 84-9.

[56]

Garcia-Beltran WF, Lam EC, Astudillo MG, Yang D, Miller TE, Feldman J, et al. COVID-19-neutralizing antibodies predict disease severity and survival. Cell. 2021; 184: 476-88.e11.

[57]

Xu Y, Zheng Y, Qiu Y. A rare case of IgG4-associated disease caused by COVID-19: Case report and literature review. Int J Rheum Dis. 2024; 27: e14863.

PDF (16259KB)

5

Accesses

0

Citation

Detail

Sections
Recommended

/