Re-Framing Long COVID as Central Nervous System Dysfunction
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Published
Jun 29, 2024
Abstract
Four years after the emergence of long COVID, science is little closer to understanding its cause, pathogenesis, prevention or treatment than it was at its outset. This is due in part to the lack of an explanatory hypothesis that fits the scattergram of data emerging from basic, clinical and epidemiological research. We propose a unifying hypothesis that connects a triggering viral infection to the pathogenesis and the plethora of 200 symptoms: that long COVID is a central nervous system disorder of biologic origin, provisionally named “Post-COVID CNS dysfunction (PCCD)”. As neuroscience develops, it has become increasingly evident that much of mental illness and cognitive impairment has its basis in brain structure, chemistry and function. Applying this to long COVID, we propose that its symptoms are mediated through virus-induced biological mechanisms acting on or within the CNS. Both past and future research should be combined to test the PCCD hypothesis. This can open the pathway to significant progress in prevention, care and therapeutics. A multi-sector collaborative platform—with the leadership of the federal government’s Office of Long COVID Research and Practice—could, for example, assist in testing, improving, and implementing this hypothesis.
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Keywords
Long Covid, Central Nervous System, Post-COVID CNS Dysfunction
References
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31. Kim EJ, Kim JJ. Neurocognitive effects of stress: A metaparadigm perspective. Mol Psychiatry 2023; 28(7):2750-2763. DOI: https://doi.org/10.1038/s41380-023-01986-4
32. Hilliard AA, Weinberger SE, Tierney LaMJr, Midthun DE, Saint S. Clinical problems-solving. Occam’s razor versus Saint’s triad. N Engl J Med. 2004; 350:599-603. DOI: https://doi.org/10.1056/NEJMcps031794
33. Pescador Ruschel MA, De Jesus O. Migraine Headache. [Updated 2023 Aug 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan. Available at: https://www.ncbi.nlm.nih.gov/books/NBK560787/
34. Roth PH, Gadebusch-Bondio M. The contested meaning of “long COVID” - Patients, doctors, and the politics of subjective evidence. Soc Sci Med 2022; 292:114619. DOI: https://doi.org/10.1016/j.socscimed.2021.114619
35. Ely EW. Don’t give COVID-19 long-haulers the silent treatment. STAT News. October 22, 2021. Available at: https://www.statnews.com/2021/10/22/dont-give-covid-19-long-haulers-the-silent-treatment/
36. Patient-led Research Collaborative. An analysis of the prolonged COVID-19 symptoms survey by patient-led research team. May 11, 2020. Available at: https://patientresearchcovid19.com/research/report-1/
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40. Jammoul M, Naddour J, Madi A, Reslan MA, Hatoum F, Zeineddine J, Abou-Kheir W, Lawand N. Investigating the possible mechanisms of autonomic dysfunction post-COVID-19. Auton Neurosci 2023; 245:103071. DOI: https://doi.org/10.1016/j.autneu.2022.103071
41. Telles-Correia D. The mind-brain gap and the neuroscience-psychiatry gap. J Eval Clin Pract 2018; 24(4):797-802. DOI: https://doi.org/10.1111/jep.12891
42. Leng A, Shah M, Ahmad SA, Premraj L, Wildi K, Li Bassi G, Pardo CA, Choi A, Cho SM. Pathogenesis underlying neurological manifestations of Long COVID syndrome and potential therapeutics. Cells 2023; 12(5):816. DOI: https://doi.org/10.3390/cells12050816
43. US Department of Health and Human Services, HHS establishes secretary’s advisory committee on long COVID. November 16, 2023. Available at: https://www.hhs.gov/about/news/2023/11/16/hhs-establishes-secretarys-advisory-committee-long-covid.html
44. US Department of Health and Human Services, The office of long COVID research and practice. March 11, 2024. Available at: https://www.hhs.gov/longcovid/index.html
2. Phillips S, Williams MA. Confronting our next national health disaster - Long-Haul Covid. N Engl J Med 2021; 385(7):577-579. DOI: https://doi.org/10.1056/NEJMp2109285
3. Centers for Disease Control and Prevention. Post-COVID conditions. June 14, 2024. Available at: https://data.cdc.gov/NCHS/Post-COVID-Conditions/gsea-w83j
4. Cutler DM. The Costs of Long COVID. JAMA Health Forum 2022; 3(5):e221809. DOI: https://doi.org/10.1001/jamahealthforum.2022.1809
5. Al-Aly Z, Topol E. Solving the puzzle of Long Covid. Science 2024; 383(6685):830-832. DOI: https://doi.org/10.1126/science.adl0867
6. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: Major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023; 21(3):133-146. DOI: https://doi.org/10.1038/s41579-022-00846-2. Erratum in: Nat Rev Microbiol 2023; 21(6):408. DOI: https://doi.org/10.1038/s41579-023-00896-0
7. Topol E, Al-Aly Z, Ground Truths: Toward solving the Long Covid puzzle. February 22, 2024. Available at: https://erictopol.substack.com/p/towards-solving-the-long-covid-puzzle?utm_medium=ios
8. Lubell J. Long COVID: Over 200 symptoms, and a search for guidance. AMA Connect. April 29, 2022. Available at: https://www.ama-assn.org/delivering-care/public-health/long-covid-over-200-symptoms-and-search-guidance
9. Payne D. “Left to rot”: The lonely plight of Long Covid sufferers. Politico. August 14, 2022. Available at: https://www.politico.com/news/2022/08/14/left-to-rot-long-covid-patients-around-the-world-call-for-more-government-action-00051161
10. Zhang RC. Long Covid research funding at NIH gets a nearly 50% boost, STAT News. February 15, 2024. Available at: https://www.statnews.com/2024/02/15/long-covid-nih-funding-boost/
11. Long Covid Moonshot, We are demanding $1B+ in annual research funding for Long Covid. 2024. Available at: https://longcovidmoonshot.com/
12. Zhang RC, Ladyzhets B. STAT News, The NIH has poured $1billion into long Covid research—with little to show for it. April 20, 2023. Available at: https://www.statnews.com/2023/04/20/long-covid-nih-billion/
13. Phillips S. Williams MA. STAT News, Long Covid is a new name for an old syndrome. September 14, 2023. Available at: https://www.statnews.com/2023/09/14/long-covid-me-cfs-myalgic-encephalomyelitis-chronic-fatigue/
14. Bannister BA. Post-infectious disease syndrome. Postgrad Med J 1988; 64(753):559-567. DOI: https://doi.org/10.1136/pgmj.64.753.559
15. Behan PO, Behan WM. Postviral fatigue syndrome. Crit Rev Neurobiol 1988; 4(2):157-178.
16. Swoboda DA. The social construction of contested illness legitimacy: A grounded theory analysis. Qual Res Psychol 2006; 3(3):233-251. DOI: https://doi.org/10.1191/1478088706qrp061oa
17. Swoboda, D., Embodiment and the Search for Illness Legitimacy among Women with Contested Illness, University of Michigan MPublishing, Ann Arbor, MI. 2005.
18. Gorman S, Gorman JW. How should we treat “contested” illnesses? – The relationship between contested illnesses and psychiatric illnesses, Psychology Today. January 8, 2009. Available at: https://www.psychologytoday.com/us/blog/denying-the-grave/201906/how-should-we-treat-contested-illnesses
19. Callard F, Perego E. How and why patients made Long Covid. Soc Sci Med 2021; 268:113426. DOI: https://doi.org/10.1016/j.socscimed.2020.113426
20. National Institutes of Health (US); Biological Sciences Curriculum Study. NIH Curriculum Supplement Series [Internet]. Bethesda (MD): National Institutes of Health (US); 2007. Information about Mental Illness and the Brain. Available at: https://www.ncbi.nlm.nih.gov/books/NBK20369/
21. Al-Aly Z, Rosen CJ. Long Covid and impaired cognition - More evidence and more work to do. N Engl J Med 2024; 390(9):858-860. DOI: https://doi.org/10.1056/NEJMe2400189
22. Reiss AB, Greene C, Dayaramani C, Rauchman SH, Stecker MM, De Leon J, Pinkhasov A. Long COVID, the brain, nerves, and cognitive function. Neurol Int 2023; 15(3):821-841. DOI: https://doi.org/10.3390/neurolint15030052
23. Monje M, Iwasaki A. The neurobiology of long COVID. Neuron 2022; 110(21):3484-3496. DOI: https://doi.org/10.1016/j.neuron.2022.10.006
24. Phetsouphanh C, Jacka B, Ballouz S, Jackson KJL, Wilson DB, Manandhar B, Klemm V, Tan HX, Wheatley A, Aggarwal A, Akerman A, Milogiannakis V, Starr M, Cunningham P, Turville SG, Kent SJ, Byrne A, Brew BJ, Darley DR, Dore GJ, Kelleher AD, Matthews GV. Improvement of immune dysregulation in individuals with long COVID at 24-months following SARS-CoV-2 infection. Nat Commun 2024;
15(1):3315. DOI: https://doi.org/10.1038/s41467-024-47720-8
25. Albrecht DS, Forsberg A, Sandström A, Bergan C, Kadetoff D, Protsenko E, Lampa J, Lee YC, Höglund CO, Catana C, Cervenka S, Akeju O, Lekander M, Cohen G, Halldin C, Taylor N, Kim M, Hooker JM, Edwards RR, Napadow V, Kosek E, Loggia ML. Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation. Brain Behav Immun 2019; 75:72-83. DOI: https://doi.org/10.1016/j.bbi.2018.09.018
26. Walitt B, Singh K, LaMunion SR, Hallett M, Jacobson S, Chen K, Enose-Akahata Y, Apps R, Barb JJ, Bedard P, Brychta RJ, Buckley AW, Burbelo PD, Calco B, Cathay B, Chen L, Chigurupati S, Chen J, Cheung F, Chin LMK, Coleman BW, Courville AB, Deming MS, Drinkard B, Feng LR, Ferrucci L, Gabel SA, Gavin A, Goldstein DS, Hassanzadeh S, Horan SC, Horovitz SG, Johnson KR, Govan AJ, Knutson KM, Kreskow JD, Levin M, Lyons JJ, Madian N, Malik N, Mammen AL, McCulloch JA, McGurrin PM, Milner JD, Moaddel R, Mueller GA, Mukherjee A, Muñoz-Braceras S, Norato G, Pak K, Pinal-Fernandez I, Popa T, Reoma LB, Sack MN, Safavi F, Saligan LN, Sellers BA, Sinclair S, Smith B, Snow J, Solin S, Stussman BJ, Trinchieri G, Turner SA, Vetter CS, Vial F, Vizioli C, Williams A, Yang SB; Center for Human Immunology, Autoimmunity, and Inflammation (CHI) Consortium; Nath A. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nat Commun 2024; 15(1):907. DOI: https://doi.org/10.1038/s41467-024-45107-3
27. Liu Y, Gu X, Li H, Zhang H, Xu J. Mechanisms of long COVID: An updated review. Chin Med J Pulm Crit Care Med 2023; 1(4):231-240. DOI: HTTPS://DOI.ORG/https://doi.org/10.1016/j.pccm.2023.10.003
28. Peron JPS. Direct and indirect impact of SARS-CoV-2 on the brain. Hum Genet 2023; 142(8):1317-1326. DOI: https://doi.org/10.1007/s00439-023-02549-x
29. Gallegos M, Portillo N, Martino P, Cervigni M. Long COVID-19: Rethinking mental health. Clinics (Sao Paulo) 2022; 77:100067. DOI: https://doi.org/10.1016/j.clinsp.2022.100067
30. Wang S, Quan L, Chavarro JE, Slopen N, Kubzansky LD, Koenen KC, Kang JH, Weisskopf MG, Branch-Elliman W, Roberts AL. Associations of depression, anxiety, worry, perceived stress, and loneliness prior to infection with risk of post-COVID-19 conditions. JAMA Psychiatry 2022; 79(11):1081-1091. DOI: https://doi.org/10.1001/jamapsychiatry.2022.2640. Erratum in: JAMA Psychiatry 2022; 79(11):1141. DOI: https://doi.org/10.1001/jamapsychiatry.2022.3336
31. Kim EJ, Kim JJ. Neurocognitive effects of stress: A metaparadigm perspective. Mol Psychiatry 2023; 28(7):2750-2763. DOI: https://doi.org/10.1038/s41380-023-01986-4
32. Hilliard AA, Weinberger SE, Tierney LaMJr, Midthun DE, Saint S. Clinical problems-solving. Occam’s razor versus Saint’s triad. N Engl J Med. 2004; 350:599-603. DOI: https://doi.org/10.1056/NEJMcps031794
33. Pescador Ruschel MA, De Jesus O. Migraine Headache. [Updated 2023 Aug 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan. Available at: https://www.ncbi.nlm.nih.gov/books/NBK560787/
34. Roth PH, Gadebusch-Bondio M. The contested meaning of “long COVID” - Patients, doctors, and the politics of subjective evidence. Soc Sci Med 2022; 292:114619. DOI: https://doi.org/10.1016/j.socscimed.2021.114619
35. Ely EW. Don’t give COVID-19 long-haulers the silent treatment. STAT News. October 22, 2021. Available at: https://www.statnews.com/2021/10/22/dont-give-covid-19-long-haulers-the-silent-treatment/
36. Patient-led Research Collaborative. An analysis of the prolonged COVID-19 symptoms survey by patient-led research team. May 11, 2020. Available at: https://patientresearchcovid19.com/research/report-1/
37. World Health Organization. Post COVID-19 condition (Long COVID). December 7, 2022. Available at: https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition
38. Centers for Disease Control, Long COVID basics. June 11, 2024. Available at: https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html
39. Matta J, Wiernik E, Robineau O, Carrat F, Touvier M, Severi G, de Lamballerie X, Blanché H, Deleuze JF, Gouraud C, Hoertel N, Ranque B, Goldberg M, Zins M, Lemogne C; Santé, Pratiques, Relations et Inégalités Sociales en Population Générale Pendant la Crise COVID-19–Sérologie (SAPRIS-SERO) Study Group. Association of self-reported COVID-19 infection and SARS-CoV-2 serology test results with persistent physical symptoms among French adults during the COVID-19 pandemic. JAMA Intern Med 2022; 182(1):19-25. DOI: https://doi.org/10.1001/jamainternmed.2021.6454. Erratum in: JAMA Intern Med 2022; 182(5):1. DOI: https://doi.org/10.1001/jamainternmed.2022.0451. Erratum in: JAMA Intern Med 2022; 182(5):579. DOI: https://doi.org/10.1001/jamainternmed.2022.0450
40. Jammoul M, Naddour J, Madi A, Reslan MA, Hatoum F, Zeineddine J, Abou-Kheir W, Lawand N. Investigating the possible mechanisms of autonomic dysfunction post-COVID-19. Auton Neurosci 2023; 245:103071. DOI: https://doi.org/10.1016/j.autneu.2022.103071
41. Telles-Correia D. The mind-brain gap and the neuroscience-psychiatry gap. J Eval Clin Pract 2018; 24(4):797-802. DOI: https://doi.org/10.1111/jep.12891
42. Leng A, Shah M, Ahmad SA, Premraj L, Wildi K, Li Bassi G, Pardo CA, Choi A, Cho SM. Pathogenesis underlying neurological manifestations of Long COVID syndrome and potential therapeutics. Cells 2023; 12(5):816. DOI: https://doi.org/10.3390/cells12050816
43. US Department of Health and Human Services, HHS establishes secretary’s advisory committee on long COVID. November 16, 2023. Available at: https://www.hhs.gov/about/news/2023/11/16/hhs-establishes-secretarys-advisory-committee-long-covid.html
44. US Department of Health and Human Services, The office of long COVID research and practice. March 11, 2024. Available at: https://www.hhs.gov/longcovid/index.html
How to Cite
Phillips, S., & Williams, M. A. (2024). Re-Framing Long COVID as Central Nervous System Dysfunction. Science Insights, 44(6), 1397–1402. https://doi.org/10.15354/si.24.vp055
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