Long COVID pathophysiology

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A number of research studies have investigated long COVID or Post-Acute Sequelae of COVID-19 (PASC), the long term health problems that occur in a significant minority of people who remained ill for an extended time after developing COVID-19.


“ Research has found ongoing endothelial dysfunction, hypometabolism in the brains of long Covid patients, microclots in long Covid blood samples, reduced aerobic capacity and impaired systemic oxygen extraction in non-hospitalized patients without cardiopulmonary disease, disrupted gut microbiota that persists over time, damage to corneal nerves, immunologic dysfunction persisting for at least eight months, numerous findings of dysautonomia (a common post-viral disorder of the autonomic nervous system), and countless other conditions.[1] ”

—Hannah Davis,  The Guardian


Overview[edit | edit source]

Main article: Long COVID

Diagnosis[edit | edit source]

A blood test to identify Long COVID patients by (IFN-gamma + IL-2)/CCL4 > 0.4) could identify Long COVID patients with 100% sensitivity and 88% specificity in a cohort of 144 individuals among them 64 individuals with Long COVID.[2]

Pathophysiology[edit | edit source]

Infection and immunity[edit | edit source]

A range of antibodies have been found in patients with persistent post-acute COVID symptoms. Elevated G-protein coupled receptor autoantibodies have been found.[3] One study founded elevated antinuclear antibody (ANA) titles in 43.6% of long COVID patients twelve months after symptom onset.[4]

Long COVID may be associated herpesvirus reactivation such as Epstein-Barr Virus,[5] which has been shown to cause elevations of certain G-protein coupled receptor autoantibody types.[6][7][8][9]

Non-classical monocytes (CD14low, CD16+) have been found in the blood of Long COVID patients up to 15 months after infection.[10] It has been determined that these particular non-classical monocytes express the fractalkine receptor and the CCR5 receptor.[10] Since TNF-alpha and IFN-gamma, which is elevated in Long COVID patients[2], cause endothelial cells to produce fractalkine (CX3CL1) ligands[11], said monocytes bind to endothelial cells and cause inflammation. The presence of fractalkine (CX3CL1) and TNF-alpha inhibits apoptosis[12] and thereby allows these non-classical monocytes to survive for a long time.

Neurological and neuropsychiatric[edit | edit source]

Cardiovascular[edit | edit source]

Pulmonary[edit | edit source]

In a single cardiopulmonary exercise test, Post-COVID-19 patients exhibited markedly reduced peak exercise aerobic capacity (VO2) compared to controls and impaired oxygen extraction, even in those without cardiopulmonary disease.[13]

Prevention[edit | edit source]

The only way to prevent Long COVID is by preventing an infection with SARS-CoV-2. Antibodies from vaccination can protect against an infection in case of exposure to the virus.[14]

Comparison to other conditions[edit | edit source]

Findings Long COVID Post-acute SARS ME/CFS POTS MCAS Chronic Lyme disease
G-protein coupled receptor autoantibodies β2- and α1-adrenoceptors, angiotensin II AT1-, muscarinic M2-, MAS-, nociceptin- and ETA-receptors M3 and M4 muscarinic acetylcholine receptors, as well as ß2 adrenergic receptors α1, β1 and β2 adrenergic receptor autoantibodies

Post-SARS syndrome[edit | edit source]

Main article: Post-SARS syndrome

ME/CFS[edit | edit source]

Main article: Myalgic encephalomyelitis

Postviral fatigue syndrome[edit | edit source]

Main article: Postviral fatigue syndrome

Chronic fatigue and Idiopathic chronic fatigue[edit | edit source]

Main article: Idiopathic chronic fatigue

POTS[edit | edit source]

Main article: Postural orthostatic tachycardia syndrome

MCAS[edit | edit source]

Main article: Mast cell activation syndrome

Post-Ebola syndrome[edit | edit source]

Main article: Post-Ebola syndrome

Chronic Epstein-Barr virus[edit | edit source]

Main article: Chronic Epstein-Barr virus

Post-Treatment Lyme disease syndrome[edit | edit source]

Post-treatment Lyme disease syndrome (PTLDS) is hypothesized to be caused by the presence of residual bacterial debris (possibly bacterial cell envelope fragments) stimulating the immune system. The relapsing character and the symptoms of this syndrome are very similar to the symptom presentation of Long COVID. The discovery of antigen-presenting non-classical monocytes in Long COVID[10] supports the theory that both syndromes are similarly caused by residual debris of pathogens after the infection is cleared. 

Alzheimer's disease[edit | edit source]

Traumatic Brain Injury[edit | edit source]

Notable studies[edit | edit source]

  • 2021, 18F-FDG brain PET hypometabolism in patients with long COVID[15] (Full text)
  • 2021, Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients[16] (Full text)
  • 2021, Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID[17] (Full text)
  • 2021, Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19[18] (Full text) - Pre-print
  • 2021, Persistent clotting protein pathology in Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin[19] (Full text) - Pre-print
  • 2021, Immunological dysfunction persists for 8 months following initial mild-moderate SARS-CoV-2 infection[20] (Full text) - Pre-print
  • 2021, Clinical characterization of dysautonomia in long COVID-19 patients[21] (Full text)
  • 2021, Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing[13] (Full text)
  • 2021, Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome[22] (Full text)
  • 2021, Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms[23] (Full text)
  • 2020, Long COVID-19: Challenges in the diagnosis and proposed diagnostic criteria[24] (Full text)
  • 2020, Multi-organ impairment in low-risk individuals with long COVID[25] (Full text) - Pre-print
  • 2020, Living with covid-19. A dynamic review of the evidence around ongoing covid-19 symptoms (often called long covid)[26] (Full text)

News and articles[edit | edit source]

Learn more[edit | edit source]

See also[edit | edit source]

References[edit | edit source]

  1. ↑ Davis, Hannah (August 12, 2021). "When it comes to breakthrough cases, are we ignoring long Covid once again?". The Guardian.
  2. ↑ 2.0 2.1 Patterson, Bruce K.; Guevara-Coto, Jose; Yogendra, Ram; Francisco, Edgar; Long, Emily; Pise, Amruta; Rodrigues, Hallison; Parikh, Purvi; Mora, Javier (December 22, 2020). "Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning". bioRxiv: 2020.12.16.423122. doi:10.1101/2020.12.16.423122.
  3. ↑ "Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms". Journal of Translational Autoimmunity. 4: 100100. January 1, 2021. doi:10.1016/j.jtauto.2021.100100. ISSN 2589-9090.
  4. ↑ Seeßle, Jessica; Waterboer, Tim; Hippchen, Theresa; Simon, Julia; Kirchner, Marietta; Lim, Adeline; Müller, Barbara; Merle, Uta (July 5, 2021). "Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study". Clinical Infectious Diseases (ciab611). doi:10.1093/cid/ciab611. ISSN 1058-4838.
  5. ↑ Gold, Jeffrey E.; Okyay, Ramazan A.; Licht, Warren E.; Hurley, David J. (June 2021). "Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation". Pathogens. 10 (6): 763. doi:10.3390/pathogens10060763.
  6. ↑ Giannoni, Francesca; Albani, Salvatore (2002). "Molecular mimicry and autoimmunity". In Angelini, Lucia; Bardare, Maria; Martini, Alberto; Pierfranco, Fondazione; Mariani, Luisa (eds.). Immune-mediated Disorders of the Central Nervous System in Children. Mariani Foundation paediatric neurology. 10. John Libbey Eurotext. p. 7. ISBN 0861966317.
  7. ↑ Gebhardt, B.M. (June 26, 2000). "Evidence for antigenic cross-reactivity between herpesvirus and the acetylcholine receptor". Journal of Neuroimmunology. 105 (2): 145–153. ISSN 0165-5728. PMID 10742556.
  8. ↑ Brenner, T.; Timore, Y.; Wirguin, I.; Abramsky, O.; Steinitz, M. (October 1989). "In vitro synthesis of antibodies to acetylcholine receptor by Epstein-Barr virus-stimulated B-lymphocytes derived from patients with myasthenia gravis". Journal of Neuroimmunology. 24 (3): 217–222. ISSN 0165-5728. PMID 2553772.
  9. ↑ Kaminski, Henry J.; Janos, Minarovits (June 2010). "Epstein-barr virus: Trigger for autoimmunity?". Annals of Neurology. 67 (6): 697–8. doi:10.1002/ana.22031. ISSN 0364-5134. PMID 20517931.
  10. ↑ 10.0 10.1 10.2 Patterson, Bruce K.; Francisco, Edgar B.; Yogendra, Ram; Long, Emily; Pise, Amruta; Rodrigues, Hallison; Hall, Eric; Herrara, Monica; Parikh, Purvi (July 26, 2021). "Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) Up to 15 Months Post-Infection". bioRxiv: 2021.06.25.449905. doi:10.1101/2021.06.25.449905.
  11. ↑ Matsumiya, Tomoh; Ota, Ken; Imaizumi, Tadaatsu; Yoshida, Hidemi; Kimura, Hiroto; Satoh, Kei (April 15, 2010). "Characterization of Synergistic Induction of CX3CL1/Fractalkine by TNF-α and IFN-γ in Vascular Endothelial Cells: An Essential Role for TNF-α in Post-Transcriptional Regulation of CX3CL1". The Journal of Immunology. 184 (8): 4205–4214. doi:10.4049/jimmunol.0903212. ISSN 0022-1767. PMID 20231691.
  12. ↑ Narasimhan, Prakash Babu; Marcovecchio, Paola; Hamers, Anouk A.J.; Hedrick, Catherine C. (April 26, 2019). "Nonclassical Monocytes in Health and Disease". Annual Review of Immunology. 37: 439–456. doi:10.1146/annurev-immunol-042617-053119. ISSN 1545-3278. PMID 31026415.
  13. ↑ 13.0 13.1 Singh, Inderjit; Joseph, Phillip; Heerdt, Paul M.; Cullinan, Marjorie; Lutchmansingh, Denyse D.; Gulati, Mridu; Possick, Jennifer D.; Systrom, David M.; Waxman, Aaron B. (August 10, 2021). "Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing". CHEST. doi:10.1016/j.chest.2021.08.010. ISSN 0012-3692.
  14. ↑ Antonelli, Michela; Penfold, Rose S.; Merino, Jordi; Sudre, Carole H.; Molteni, Erika; Berry, Sarah; Canas, Liane S.; Graham, Mark S.; Klaser, Kerstin (May 27, 2021). "Post-vaccination SARS-CoV-2 infection: risk factors and illness profile in a prospective, observational community-based case-control study". medRxiv: 2021.05.24.21257738. doi:10.1101/2021.05.24.21257738.
  15. ↑ Guedj, E.; Campion, J.Y.; Dudouet, P.; Kaphan, E.; Bregeon, F.; Tissot-Dupont, H.; Guis, S.; Barthelemy, F.; Habert, P. (August 1, 2021). "18F-FDG brain PET hypometabolism in patients with long COVID". European Journal of Nuclear Medicine and Molecular Imaging. 48 (9): 2823–2833. doi:10.1007/s00259-021-05215-4. ISSN 1619-7089. PMC 7837643. PMID 33501506.
  16. ↑ Blitshteyn, Svetlana; Whitelaw, Sera (April 1, 2021). "Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients". Immunologic Research. 69 (2): 205–211. doi:10.1007/s12026-021-09185-5. ISSN 1559-0755. PMC 8009458. PMID 33786700.
  17. ↑ Bitirgen, Gulfidan; Korkmaz, Celalettin; Zamani, Adil; Ozkagnici, Ahmet; Zengin, Nazmi; Ponirakis, Georgios; Malik, Rayaz A. (July 8, 2021). "Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID". British Journal of Ophthalmology. doi:10.1136/bjophthalmol-2021-319450. ISSN 0007-1161. PMID 34312122.
  18. ↑ Yeoh, Yun Kit; Zuo, Tao; Lui, Grace Chung-Yan; Zhang, Fen; Liu, Qin; Li, Amy YL; Chung, Arthur CK; Cheung, Chun Pan; Tso, Eugene YK (April 1, 2021). "Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19". Gut. 70 (4): 698–706. doi:10.1136/gutjnl-2020-323020. ISSN 0017-5749. PMID 33431578.
  19. ↑ Pretorius, Etheresia; Vlok, Mare; Venter, Chantelle; Bezuidenhout, Johannes A.; Laubscher, Gert Jacobus; Steenkamp, Janami; Kell, Douglas B. (May 24, 2021). "Persistent clotting protein pathology in Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin". medRxiv: 2021.05.21.21257578. doi:10.1101/2021.05.21.21257578.
  20. ↑ Phetsouphanh, Chansavath; Darley, David; Howe, Anette; Munier, C. Mee Ling; Patel, Sheila K.; Juno, Jenifer A.; Burrell, Louise M.; Kent, Stephen J.; Dore, Gregory J. (June 3, 2021). "Immunological dysfunction persists for 8 months following initial mild-moderate SARS-CoV-2 infection". medRxiv: 2021.06.01.21257759. doi:10.1101/2021.06.01.21257759.
  21. ↑ Barizien, Nicolas; Le Guen, Morgan; Russel, Stéphanie; Touche, Pauline; Huang, Florent; Vallée, Alexandre (July 7, 2021). "Clinical characterization of dysautonomia in long COVID-19 patients". Scientific Reports. 11 (1): 14042. doi:10.1038/s41598-021-93546-5. ISSN 2045-2322.
  22. ↑ Fogarty, Helen; Townsend, Liam; Morrin, Hannah; Ahmad, Azaz; Comerford, Claire; Karampini, Ellie; Englert, Hanna; Byrne, Mary; Bergin, Colm. "Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome". Journal of Thrombosis and Haemostasis. doi:10.1111/jth.15490. ISSN 1538-7836.
  23. ↑ Proal, Amy D.; VanElzakker, Michael B. (2021). "Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms". Frontiers in Microbiology. 12: 698169. doi:10.3389/fmicb.2021.698169. ISSN 1664-302X. PMC 8260991. PMID 34248921.
  24. ↑ Raveendran, A.V. (2021). "Long COVID-19: Challenges in the diagnosis and proposed diagnostic criteria". Diabetes & Metabolic Syndrome. 15 (1): 145–146. doi:10.1016/j.dsx.2020.12.025. ISSN 1871-4021. PMC 7737559. PMID 33341598.
  25. ↑ Dennis, Andrea; Wamil, Malgorzata; Kapur, Sandeep; Alberts, Johann; Badley, Andrew D.; Decker, Gustav Anton; Rizza, Stacey A.; Banerjee, Rajarshi; Banerjee, Amitava (October 16, 2020). "Multi-organ impairment in low-risk individuals with long COVID". medRxiv: 2020.10.14.20212555. doi:10.1101/2020.10.14.20212555.
  26. ↑ National Institute for Health Research (October 2020). "Living with covid-19. A dynamic review of the evidence around ongoing covid-19 symptoms (often called long covid)". National Institute for Health Research. doi:10.3310/themedreview_41169. Retrieved October 15, 2020.
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