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Neurological disorders in patients with long COVID syndrome and cell therapy methods for their correction a literature review


The review presents the current understanding of the incidence and nature of neurological disorders in patients with the so-called long COVID syndrome. Symptoms, putative pathophysiological mechanisms, risk factors, search for methods of treatment and rehabilitation of patients using the patient's own hematopoietic cells are discussed. A search was carried out for scientific articles, including those published in peer-reviewed journals indexed in PubMed, Web of Science, Scopus and RSCI. The inclusion of stem cells (SC) in rehabilitation programs for patients with various injuries and diseases of the central nervous system (CNS) is a promising area of research. The mechanisms of CNS damage therapy based on the use of adult-type pluripotent stem cells, including CD34+, consist of many aspects. On the background of SC transplantation, damaged nerve cells and surrounding tissues, including neurons and glial cells, can be restored, which helps to ensure the integrity of the nerve conduction pathway and, thus, restore nerve function. SC therapy can suppress genes involved in inflammation and apoptosis, as well as activate genes with neuroprotective action, thereby protecting spinal neurons from secondary damage. This line of cell therapy can be used to treat long COVID syndrome.

About the Authors

I. S. Dolgopolov
Tver State Medical University
Russian Federation

Igor S. Dolgopolov - Dr. of Sci. (Medicine), Head of the Department of Pediatrics, Faculty of Pediatrics, Vice-Rector for Regional Development of Healthcare.

4, Sovietskaya str., Tver, 170100

G. L. Mentkevich
Tver State Medical University; Clinic Neurovita
Russian Federation

Georgii L. Mentkevich - Dr. of Sci. (Medicine), Chief Physician of the Neurovita Clinic; Professor, Department of Oncology, Faculty of Additional Professional Education.

4, Sovietskaya str., Tver, 170100; 23, Kashirskoe highway, Moscow, 115478

M. Yu. Rykov
Tver State Medical University
Russian Federation

Maksim Y. Rykov - Dr. of Sci. (Medicine), Head of the Department of Oncology, Faculty of Additional Professional Education, ViceRector for Research and Innovation.

4, Sovietskaya str., Tver, 170100, Tel.: +7 (4822) 34-34-60

L. V. Chichanovskaya
Tver State Medical University
Russian Federation

Lesya V. Chichanovskaya - Dr. of Sci. (Medicine), Professor, Head of the Department of Neurology, Faculty of Medicine, Rector.

4, Sovietskaya str., Tver, 170100


1. Wang F., Kream R.M., Stefano G.B. Long-term respiratory and neurological sequelae of COVID-19. Med Sci Monit. 2020 Nov 1; 26: e928996. PMID: 33177481

2. Bourgonje A.R., Abdulle A.E., Timens W., et al. Angiotensinconverting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol. 2020 Jul; 251(3): 228-248. Epub 2020 Jun 10. PMID: 32418199

3. Wang D., Hu B., Hu C., et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020 Mar 17; 323(11): 1061-1069. Erratum in: JAMA. 2021 Mar 16; 325(11): 1113. PMID: 32031570; PMCID: PMC7042881

4. Garrigues E., Janvier P., Kherabi Y., et al. Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19. J Infect. 2020 Dec; 81(6): e4-e6. Epub 2020 Aug 25. PMID: 32853602

5. Nalbandian A., Sehgal K., Gupta A., et al. Post-acute COVID-19 syndrome. Nat Med. 2021 Apr; 27(4): 601-615. Epub 2021 Mar 22. PMID: 33753937

6. Singal C.M.S., Jaiswal P., Seth P. SARS-CoV-2, more than a respiratory virus: its potential role in neuropathogenesis. ACS Chem Neurosci. 2020 Jul; 11(13): 1887-1899. Epub 2020 Jun 18. PMID: 32491829

7. Tian S., Xiong Y., Liu H., et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol. 2020 Jun; 33(6): 1007-1014. Epub 2020 Apr 14. PMID: 32291399

8. Stonesifer C., Corey S., Ghanekar S., et al. Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms. Prog Neurobiol. 2017 Nov; 158: 94-131. Epub 2017 Jul 23. PMID: 28743464; PMCID: PMC5671910

9. Stenudd M., Sabelstrom H., Frisen J. Role of endogenous neural stem cells in spinal cord injury and repair. JAMA Neurol. 2015 Feb; 72(2): 235-237. PMID: 25531583

10. Gao L., Xu W., Li T., et al. Stem Cell Therapy: A Promising Therapeutic Method for Intracerebral Hemorrhage. Cell Transplant. 2018 Dec; 27(12): 1809-1824. Epub 2018 Jun 5. PMID: 29871521

11. Pezzini A., Padovani A. Lifting the mask on neurological manifestations of COVID-19. Nat Rev Neurol. 2020 Nov; 16(11): 636-644. Epub 2020 Aug 24. PMID: 32839585

12. Barrantes F.J. Central nervous system targets and routes for SARS-CoV-2: current views and new hypotheses. ACS Chem Neurosci. 2020 Sep; 11(18): 2793-2803. Epub 2020 Aug 26. PMID: 32845609

13. Brann D.H., Tsukahara T., Weinreb C., et al. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Sci Adv. 2020 Jul; 6(31): eabc5801. Epub 2020 Jul 24. PMID: 32937591

14. Tsai L.K., Hsieh S.T., Chang Y.C. Neurological manifestations in severe acute respiratory syndrome. Acta Neurol Taiwan. 2005 Sep; 14(3): 113-119. PMID: 16252612

15. Abassi Z., Knaney Y., Karram T., Heyman S.N. The lung macrophage in SARS-CoV-2 infection: a friend or a foe? Front Immunol. 2020 Jun; 5(11): 1312. PMID: 32582222

16. Jose R.J., Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med. 2020 Jun; 8(6): e46-e47. Epub 2020 Apr 27. PMID: 32353251

17. Kremer S., Lersy F., de Seze J., et al. Brain MRI findings in severe COVID-19: A retrospective Observational study. Radiology. 2020 Nov; 297(2): E242-E251. Epub 2020 Jun 16. PMID: 32544034

18. Aghagoli G., Gallo Marin B., Katchur N.J., et al. Neurological involvement in COVID-19 and potential mechanisms: A Review. Neurocrit Care. 2021 Jun; 34(3): 1062-1071. PMID: 32661794

19. Xu Z., Shi L., Wang Y., et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020 Apr; 8(4): 420-422. S2213-2600(20)30085-0. Epub 2020 Feb 25. PMID: 32109426

20. Mao L., Jin H., WangM., et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020 Jun; 77(6): 683-690. PMID: 32275288

21. Guan W.J., Ni Z.Y., Hu Y., et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020 Apr; 382(18): 1708-1720. Epub 2020 Feb 28. PMID: 32109013

22. Giacomelli A., Pezzati L., Conti F., et al. Self-reported olfactory and taste disorders in patients with severe acute respiratory coro-navirus 2 infection: A cross-sectional study. Clin Infect Dis. 2020 Jul; 71(15): 889-890. PMID: 32215618

23. Muhamad S.A., Ugusman A., Kumar J., et al. COVID-19 and Hypertension: The what, the why, and the how. Frontiers in Physiology 2021; 12: 589.

24. Yong S.J. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (Lond). 2021 Oct; 53(10): 737-754. Epub 2021 May 22. PMID: 34024217; PMCID: PMC8146298

25. Long COVID: let patients help define long-lasting COVID symptoms. Nature. 2020 Oct; 586(7828): 170. PMID: 33029005

26. The Lancet. Facing up to long COVID. Lancet. 2020 Dec 12; 396(10266): 1861. PMID: 33308453

27. Goёrtz Y.M.J., Van Herck M., Delbressine J.M., et al. Persistent symptoms 3 months after a SARS-CoV-2 infection: the post-CO-VID-19 syndrome? ERJ Open Res. 2020 Oct 26; 6(4): 005422020. PMID: 33257910

28. Sudre C.H., Murray B., Varsavsky T., et al. Attributes and predictors of long COVID. Nat Med 2021 Apr; 27(4): 626-631. Epub 2021 Mar 10. Erratum in: Nat Med. 2021 Jun; 27(6): 1116. PMID: 33692530

29. Havervall S., Rosell A., Phillipson M., et al. Symptoms and functional impairment assessed 8 months after mild COVID-19 among health care workers. JAMA. 2021 May 18; 325(19): 2015-2016. PMID: 33825846

30. Salmon-Ceron D., Slama D., De Broucker T., et al. Clinical, vi-rological and imaging profile in patients with prolonged forms of COVID-19: a cross-sectional study. J Infect 2021; 82(2): e1-4. Epub 2020 Dec 4. PMID: 33285216

31. Burton C., FinkP., Henningsen P., et al. Functional somatic disorders: discussion paper for a new common classification for research and clinical use. BMC Med. 2020 Mar 3; 18(1): 34. PMID: 32122350

32. MazzaM.G., De Lorenzo R., Conte C., et al. Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors. Brain Behav Immun. 2020 Oct; 89: 594-600. Epub 2020 Jul 30. PMID: 32738287

33. Huang C., Huang L., Wang Y., et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021 Jan 16; 397(10270): 220-232. Epub 2021 Jan 8. PMID: 33428867

34. Taquet M., Luciano S., Geddes J.R., Harrison P.J. Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA. Lancet Psychiatry. 2021 Feb; 8(2): 130-140. Epub 2020 Nov 9. Erratum in: Lancet Psychiatry. 2021 Jan; 8(1): e1. PMID: 33181098

35. WeissmanI.L., AndersonD.J., GageF Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu Rev Cell Dev Biol. 2001; 17: 387-403. PMID: 11687494

36. Lakhan S.E., Kirchgessner A., Hofer M. Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med. 2009 Nov 17; 7: 97. PMID: 19919699

37. Muheremu A., Peng J., Ao Q. Stem cell based therapies for spinal cord injury. Tissue Cell. 2016 Aug; 48(4): 328-333. Epub 2016 Jun 1. PMID: 27318871

38. De Feo D., Merlini A., Laterza C., Martino G. Neural stem cell transplantation in central nervous system disorders: from cell replacement to neuroprotection. Curr Opin Neurol. 2012 Jun; 25(3): 322-333. PMID: 22547103

39. Cusimano M., Biziato D., Brambilla E., et al. Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. Brain. 2012 Feb; 135(Pt 2): 447-460. Epub 2012 Jan 23. PMID: 22271661

40. Bryukhovetskiy A.S., Bryukhovetskiy I.S. Effectiveness of repeated transplantations of hematopoietic stem cells in spinal cord injury. World J Transplant. 2015 Sep 24; 5(3): 110-128. PMID: 26421264

41. Divani A.A., Hussain M.S., MagalE., et al. The use of stem cells’ hematopoietic stimulating factors therapy following spinal cord injury. Ann Biomed Eng. 2007 Oct; 35(10): 1647-1656. Epub 2007 Jul 20. PMID: 17641973

42. Koshizuka S., Okada S., OkawaA., et al. Transplanted hematopoietic stem cells from bone marrow differentiate into neural lineage cells and promote functional recovery after spinal cord injury in mice. J Neuropathol Exp Neurol. 2004 Jan; 63(1): 64-72. PMID: 14748562

43. Xiong L.L., Liu F., Deng S.K., et al. Transplantation of hematopoietic stem cells promotes functional improvement associated with NT-3-MEK-1 activation in spinal cord-transected rats. Front Cell Neurosci. 2017 Jul; 19(11): 213. PMID: 28769769

44. Yoshihara H., Arai F., Hosokawa K., et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2007 Dec 13; 1(6): 685-697. Epub 2007 Nov 20. PMID: 18371409

45. Suarez-Monteagudo C., Hernandez-RamirezP., Alvarez-Gonzalez L., et al. Autologous bone marrow stem cell neurotransplantation in stroke patients. An open study. Restor Neurol Neurosci. 2009; 27(3): 151-161. PMID: 19531871

46. Barbosa da Fonseca L. M., Gutfilen B., Rosado de Castro P. H., et al. Migration and homing of bone-marrow mononuclear cells in chronic ischemic stroke after intra-arterial injection. Exp Neurol. 2010 Jan; 221(1): 122-128. Epub 2009 Oct 22. PMID: 19853605

47. Savitz S. I., Misra V., Kasam M., et al. Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann Neurol. 2011 Jul; 70(1): 59-69. PMID: 21786299

48. He J.Q., Sussman E.S., Steinberg G.K. Revisiting stem cell-based clinical trials for ischemic stroke. Front Aging Neurosci. 2020 Dec 14; 12: 575990. PMID: 33381020

49. Prasad K., Sharma A., Garg A., et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke. 2014 Dec; 45(12): 36183624. Epub 2014 Nov 6. PMID: 25378424

50. Sharma A., Sane H., Gokulchandran N., et al. Autologous bone marrow mononuclear cells intrathecal transplantation in chronic stroke. Stroke Res Treat. 2014; 2014: 234095. Epub 2014 Jul 8. PMID: 25126443

51. Taguchi A., Sakai C., Soma T., et al. Intravenous autologous bone marrow mononuclear cell transplantation for stroke: phase1/2a clinical trial in a homogeneous group of stroke patients. Stem Cells Dev. 2015 Oct 1; 24(19): 2207-2218. Epub 2015 Aug 17. PMID: 26176265

52. Barish M., Herrmann K., Tang Y., et al. Human neural stem cell biodistribution and predicted tumor coverage by a diffusible therapeutic in a mouse glioma model. Stem Cells Transl Med. 2017 Jun; 6(6): 1522-1532. Epub 2017 May 8. PMID: 28481046

53. TakahashiH., KodaM., HashimotoM., et al. Transplanted peripheral blood stem cells mobilized by granulocyte colony-stimulating factor promoted hindlimb functional recovery after spinal cord injury in mice. Cell Transplant. 2016; 25(2): 283-292. Epub 2015 May 13. PMID: 25975570

54. FehlingsM.G., Tetreault L.A., Wilson J.R., et al. A Clinical Practice Guideline for the Management of Acute Spinal Cord Injury: Introduction, Rationale, and Scope. Global Spine J. 2017 Sep; 7(3 Suppl): 84S-94S. Epub 2017 Sep 5. PMID: 29164036

55. Zakerinia M., Kamgarpour A., Nemati H., et al. Intrathecal autologous bone marrow-derived hematopoietic stem cell therapy in neurological diseases. Int J Organ Transplant Med. 2018; 9(4): 157-167. Epub 2018 Nov 1. PMID: 30863518

56. Shyu W.C., Lin S.Z., Chiang M.F, et al. Intracerebral peripheral blood stem cell (CD34+) implantation induces neuroplasticity by enhancing beta1 integrin-mediated angiogenesis in chronic stroke rats. J Neurosci. 2006 Mar 29; 26(13): 3444-3453. PMID: 16571751

57. Chen D.C., Lin S.Z., Fan J.R., et al. Intracerebral implantation of autologous peripheral blood stem cells in stroke patients: a randomized phase II study. Cell Transplant. 2014; 23(12): 15991612. Epub 2014 Jan 29. PMID: 24480430

58. Gao L., Peng Y., Xu W., et al. Progress in stem cell therapy for spinal cord injury. Stem Cells Int. 2020 Nov 5; 2020: 2853650. PMID: 33204276

59. Chen C., Shi J., Stanley RM., et al. Trends of ED visits for pediatric traumatic brain injuries: implications for clinical trials. Int J Environ Res Public Health. 2017 Apr 13; 14(4): 414. PMID: 28406438

60. Lee J.A., Kim B.I., Jo C.H., et al. Mesenchymal stem-cell transplantation for hypoxic-ischemic brain injury in neonatal rat model. Pediatr Res. 2010 Jan; 67(1): 42-46. PMID: 19745781

61. Bonilla C., ZuritaM., Otero L., et al. Delayed intralesional transplantation of bone marrow stromal cells increases endogenous neurogenesis and promotes functional recovery after severe traumatic brain injury. Brain Inj. 2009 Aug; 23(9): 760-769. PMID: 19637001

62. Pigott J.H., Ishihara A., Wellman M.L., et al. Investigation of the immune response to autologous, allogeneic, and xenogeneic mesenchymal stem cells after intra-articular injection in horses. Vet Immunol Immunopathol. 2013 Nov 15; 156(1-2): 99-106. Epub 2013 Sep 18. PMID: 24094688

63. Rodrigues M.C., Glover L.E., Weinbren N., et al. Toward personalized cell therapies: autologous menstrual blood cells for stroke. J Biomed Biotechnol. 2011; 2011: 194720. Epub 2011 Nov 20. PMID: 22162629


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