Charlotte Small

Background: Long COVID (LC) is a chronic condition characterized by symptoms progressing, relapsing, or persisting for three or more months after likely COVID-19 infection that affect at least one organ system.^1-2 It is also called post-COVID syndrome or post-acute sequelae of SARS-CoV-2 infection (PASC), and globally affects approximately 65 million people.^1-4 The clinical presentation is extremely varied in both complexity and severity, closely resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with fatigue, shortness of breath, and chest or joint pain being the most common symptoms.^3-4,6-7 Iatrogenic or organ damage from acute COVID treatment may present as LC and respond to traditional intervention, but idiopathic LC has no current consensus of mechanism or treatment.^3-4,6-9

Objective: The purpose of this review is to examine potential mechanisms contributing to LC symptomology.

Methods: Publications were found using online searches in PubMed, Google Scholar, and Web of Science with the exception of one recommendation by a mentor, using the following keywords: “Long COVID”, “SARS-CoV-2”, “Post COVID syndrome”, “endothelial dysfunction”, “nitric oxide”, “Inflammation”, “Neuroinflammation”, “Neuroimaging”, “T Cells”, “Immune”, and “Coagulation”. Results published prior to 2018 were excluded.

Results: Endothelial and immune dysregulation are hallmarks of LC.^3,4,6-12 In both acute and LC, endothelial inflammation is demonstrated by biomarkers including  inflammatory cytokines, fibrinogen, increased nitrate and decreased nitrite levels, and monocyte-platelet aggregations.^7,8,11 The ratio of serum biomarkers vWF/ADAMTS13 is predictive of LC development.⁷ In these patients, the classic and alternate complement pathways are upregulated with suggested increased membrane attack complexes, while B cell recruitment via CXCL13 is downregulated.⁷  Cardiac sino-atrial node-like pacemaker cells infected with COVID-19 in vitro significantly upregulate ferroptosis and reactive oxygen species (ROS).¹⁰ Prophylactic administration of either deforaxamine or imatinib prevents ferroptosis, as does post-infection imatinib¹⁰, indicating a potential avenue for treatment.  Neurologic symptoms in LC patients correlate with neuroinflammation, decreased brain volume, increased blood-brain barrier (BBB) permeability measured via S100-b, and upregulation of T cell differentiation pathways. ⁹ LC patient serum addition to uninfected brain cells causes upregulation of immune trafficking markers, but TGF-b  upregulates only when COVID spike protein is added, indicating potential reservoirs or spike production involved in long-term disease. ⁹ T and B cell responses appear independently coordinated in ongoing LC, with surprising differences in the ratio of IL-4 to IL-5 expression.¹²  Altered fibrin bound to the COVID-19 spike protein significantly increases inflammatory responses in mice by downregulating NK1.1+ natural killer cells. When these cells are removed from infected fibrinogen-knockdown and -knockout mice, inflammation returns to infected wild-type levels (high).⁸ Both spike protein and fibrin are necessary to cause inflammation, with the amount of spike linearly correlating with ROS production. ⁸ A mouse antibody blocking the fibrin-spike binding site, 5B8, negated the ROS effect when administered in mice. ⁸

Conclusions: Long COVID is characterized by persistent inflammatory changes across multiple systems accompanied by improperly regulated immune cell responses. Symptom severity correlates with neuro- and endothelial inflammation and indicates a multimodal etiology resultant of this systemic dysregulation. Mechanisms of acute COVID infection like fibrin modulation and ferroptosis may provide insight into initial causes of the continued inflammatory response, as well as treatment options potentially including 5B8, imatinib, and immune modulation. Future directions include testing treatments developed for similar diseases such as ME/CFS, elucidating the long-term role of spike protein, and clarifying the role of nitric oxide, nitrates, and nitrites in ongoing endothelial dysfunction.

Works Cited:

1. Ely EW, Brown LM, Fineberg HV; National Academies of Sciences, Engineering, and Medicine Committee on Examining the Working Definition for Long Covid. Long Covid Defined. N Engl J Med. 2024;391(18):1746-1753. doi:10.1056/NEJMsb2408466
2. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV; WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22(4):e102-e107. doi:10.1016/S1473-3099(21)00703-9
3. Komaroff AL, Lipkin WI. ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature. Front Med (Lausanne). 2023;10:1187163. Published 2023 Jun 2. doi:10.3389/fmed.2023.1187163
4. Turner S, Khan MA, Putrino D, Woodcock A, Kell DB, Pretorius E. Long COVID: pathophysiological factors and abnormalities of coagulation. Trends Endocrinol Metab. 2023;34(6):321-344. doi:10.1016/j.tem.2023.03.002
5. Bach K. Is “long covid” worsening the labor shortage? Brookings. January 11, 2022. Accessed February 15, 2025. https://www.brookings.edu/articles/is-long-covid-worsening-the-labor-shortage/
6. Georgieva E, Ananiev J, Yovchev Y, et al. COVID-19 Complications: Oxidative Stress, Inflammation, and Mitochondrial and Endothelial Dysfunction. Int J Mol Sci. 2023;24(19):14876. Published 2023 Oct 4. doi:10.3390/ijms241914876
7. Cervia-Hasler C, Brüningk SC, Hoch T, et al. Persistent complement dysregulation with signs of thromboinflammation in active Long Covid. Science. 2024;383(6680):eadg7942. doi:10.1126/science.adg7942
8. Ryu JK, Yan Z, Montano M, et al. Fibrin drives thromboinflammation and neuropathology in COVID-19. Nature. 2024;633(8031):905-913. doi:10.1038/s41586-024-07873-4
9. Greene C, Connolly R, Brennan D, et al. Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment [published correction appears in Nat Neurosci. 2024 May;27(5):1019. doi: 10.1038/s41593-024-01644-0.]. Nat Neurosci. 2024;27(3):421-432. doi:10.1038/s41593-024-01576-9
10. Han Y, Zhu J, Yang L, et al. SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells. Circ Res. 2022;130(7):963-977. doi:10.1161/CIRCRESAHA.121.320518
11. Wang J, Bai L, Cai K. Nitric Oxide May Serve as a Hallmark of Long COVID. Chest. 2022;161(6):A137. doi:10.1016/j.chest.2021.12.169
12. Yin K, Peluso MJ, Luo X, et al. Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2. Nat Immunol. 2024;25(2):218-225. doi:10.1038/s41590-023-017246 .
13. Tosato M, Calvani R, Picca A, Ciciarello F, Galluzzo V, Coelho-Júnior HJ, Di Giorgio A, Di Mario C, Gervasoni J, Gremese E, et al. Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial. Nutrients. 2022; 14(23):4984. https://doi.org/10.3390/nu14234984
14. Wu E, Mahdi A, Nickander J, et al. Enhanced External Counterpulsation for Management of Postacute Sequelae of SARS-CoV-2 Associated Microvascular Angina and Fatigue: An Interventional Pilot Study. Cardiol Res Pract. 2023;2023:6687803. Published 2023 Dec 27. doi:10.1155/2023/6687803
15. Nikolaidis A, Kramer R, Ostojic S. Nitric Oxide: The Missing Factor in COVID-19 Severity? Medical Sciences. 2022; 10(1):3. https://doi.org/10.3390/medsci10010003
16. Mikuteit, M., Baskal, S., Klawitter, S. et al. Amino acids, post-translational modifications, nitric oxide, and oxidative stress in serum and urine of long COVID and ex COVID human subjects. Amino Acids 55, 1173–1188 (2023). https://doi.org/10.1007/s00726-023-03305-1