Immunological and Neurological Manifestations of COVID-19: An Intimate Relationship


Background: COVID-19 has superseded all medical scientific challenges in 2020. It presented with a range of respiratory involvement from the mild upper respiratory tract to severe pneumonia with ARDS. A percentage of these patients manifested variable neurological presentations expanding the challenges of patients’ assessment, care, and management.

Objective: To discuss the neurological manifestations and the possible immunopathology of COVID-19.

Methods: A literature search was performed in the PubMed database for the relevant articles published in English language between April 9th , 2020 and June 1, 2020. Few papers were extracted from Google Scholar and pre-print material as well. The keywords used to perform search included “COVID-19,” “SARS Cov2,” “neurological manifestations,” and “immunology and pathology of COVID-19”. However, animal studies were excluded in the neurological manifestations, and the final number of literature search outcome was 27 articles.

Results: The immunopathology involves angiotensin-converting enzyme (ACE) receptor 2 and spike protein S1. COVID-19 has a tremendous affinity to the ACE2 receptor. The status of secondary hemophagocytic lymphohistiocytosis (sHLH) and the cytokine storm lead to different organ damage and the corresponding clinical manifestations. The documented neurological manifestations mainly include acute ischemic stroke, hemorrhagic stroke, temporal lobe, thalamic encephalitis, and one case of Guillain-Barre Syndrome, in addition to agitation, headache, and seizures.

Conclusion: Although the intimate relationship between the neurons and the immune activation is the basic concept of COVID-19 immunopathology, the definite routes of entry to the neuronal cells are yet to be disclosed. Acute stroke, myositis, headache, and meningoencephalitis are the most common types of complications of COVID-19 so far.

1. Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS chemical neuroscience. 2020;11(7):995-8.
2. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020.
3. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450-4.
4. Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503-16.
5. Karakike E, Giamarellos-Bourboulis EJ. Macrophage Activation-Like Syndrome: A Distinct Entity Leading to Early Death in Sepsis. Frontiers in immunology. 2019;10:55.
6. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
7. Li Y, Li H, Fan R, Wen B, Zhang J, Cao X, et al. Coronavirus Infections in the Central Nervous System and Respiratory Tract Show Distinct Features in Hospitalized Children. Intervirology. 2016;59(3):163-9.
8. Oddo M, Carrera E, Claassen J, Mayer SA, Hirsch LJ. Continuous electroencephalography in the medical intensive care unit. Crit Care Med. 2009;37(6):2051-6.
9. al YLe. Acute Cerebrovascular Disease Following COVID-19: A Single Center, Retrospective, Observational Study. lancet 2020.
10. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet Respiratory medicine. 2020;8(4):420-2.
11. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2020.
12. Cao X. COVID-19: immunopathology and its implications for therapy. Nature reviews Immunology. 2020;20(5):269-70.
13. Zhao J, Yuan Q, Wang H, Liu W, Liao X, Su Y, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2020.
14. Zhang G, Zhang J, Wang B, Zhu X, Wang Q, Qiu S. Analysis of clinical characteristics and laboratory findings of 95 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a retrospective analysis. Respiratory research. 2020;21(1):74.
15. M Ling MW, et al. Neurological manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study. 2020.
16. Ding Y, Wang H, Shen H, Li Z, Geng J, Han H, et al. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. The Journal of pathology. 2003;200(3):282-9.
17. AAO-HNS AAoOHaNS. Anosmia, Hyposmia, and Dysgeusia Symptoms of Coronavirus Disease 2020 [cited 2020 23/03/2020]. first [Available from: ;
18. ENT UK at The Royal College of Surgeons of England 35-43 Lincoln’s Inn Fields London WC2A 3PE Tel: 020 7404 8373 | Email:|Web: www.entuk.org1Loss of sense of smell as marker of COVID-19 infection 2020 [cited 2020 March 30]. Available from: |Web: www.entuk.org1Loss of sense of smell as marker of COVID-19 infection.
19. system Hfh. 2020.
20. Romero-Sanchez CM, Diaz-Maroto I, Fernandez-Diaz E, Sanchez-Larsen A, Layos-Romero A, Garcia-Garcia J, et al. Neurologic manifestations in hospitalized patients with COVID-19: The ALBACOVID registry. Neurology. 2020.
21. Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, et al. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. N Engl J Med. 2020;382(20):e60.
22. A Cervantes DG, T Ford,, J Shulman, A Daneshmand, T Nguyen, K Suchdev, C Takahashi, M Abdennadher, A Saxena, P Anand, K. H. Vincent Lau, A Macone, M Perloff, S Zhu. COVID-19 Neurology Protocols [cited 2020 08/04/2020]. Focused Guidelines ].
23. Josephson SA, Hills NK, Johnston SC. NIH Stroke Scale reliability in ratings from a large sample of clinicians. Cerebrovascular diseases. 2006;22(5-6):389-95.
24. Shah VA, Martin CO, Hawkins AM, Holloway WE, Junna S, Akhtar N. Groin complications in endovascular mechanical thrombectomy for acute ischemic stroke: a 10-year single center experience. Journal of neurointerventional surgery. 2016;8(6):568-70.
25. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344-e418.
26. Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, et al. Neurologic Features in Severe SARS-CoV-2 Infection. N Engl J Med. 2020;382(23):2268-70.
27. Wada R, Aviv RI, Fox AJ, Sahlas DJ, Gladstone DJ, Tomlinson G, et al. CT angiography "spot sign" predicts hematoma expansion in acute intracerebral hemorrhage. Stroke. 2007;38(4):1257-62.
28. Arabi YM, Harthi A, Hussein J, Bouchama A, Johani S, Hajeer AH, et al. Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV). Infection. 2015;43(4):495-501.
29. Chalouhi N, Ali MS, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, et al. Biology of intracranial aneurysms: role of inflammation. J Cereb Blood Flow Metab. 2012;32(9):1659-76.
30. Seguin A, Galicier L, Boutboul D, Lemiale V, Azoulay E. Pulmonary Involvement in Patients With Hemophagocytic Lymphohistiocytosis. Chest. 2016;149(5):1294-301.
31. Takeshi M ea. A first Case of Meningitis/Encephalitis associated with SARS-Coronavirus-2. IJID. 2020.
32. Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020;368:m606.
33. Tian S, Hu N, Lou J, Chen K, Kang X, Xiang Z, et al. Characteristics of COVID-19 infection in Beijing. The Journal of infection. 2020;80(4):401-6.
34. Liu M, He P, Liu HG, Wang XJ, Li FJ, Chen S, et al. [Clinical characteristics of 30 medical workers infected with new coronavirus pneumonia]. Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases. 2020;43(3):209-14.
35. WHO. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with COVID-19 2020.
36. Ling MH, J. Mengdie, W. et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurology 2020; Published online April 10, 2020. doi:10.1001/jamaneurol.2020.1127.
37. Zhao H, Shen D, Zhou H, Liu J, Chen S. Guillain-Barre syndrome associated with SARS-CoV-2 infection: causality or coincidence? Lancet Neurol. 2020.
38. Manji H CA, Brownlee WJ, et al. Neurology in the time of covid-19. J Neurol Neurosurg Psychiatry. 2020.
39. Visser LH. Critical illness polyneuropathy and myopathy: clinical features, risk factors and prognosis. European journal of neurology. 2006;13(11):1203-12.
40. Giovannoni G, Hawkes C, Lechner-Scott J, Levy M, Waubant E, Gold J. The COVID-19 pandemic and the use of MS disease-modifying therapies. Multiple sclerosis and related disorders. 2020;39:102073.
41. Barzegar M, Mirmosayyeb O, Nehzat N, Sarrafi R, Khorvash F, Maghzi AH, et al. COVID-19 infection in a patient with multiple sclerosis treated with fingolimod. Neurology(R) neuroimmunology & neuroinflammation. 2020;7(4).