A recent study reveals changes in the immune complement system and platelet-associated blood markers may be responsible for sustained symptoms following acute Covid-19 infection, representing hope for understanding the mechanisms behind Long Covid.
In 2020, the SARS-CoV-2 virus wreaked havoc on the world, contributing to over seven million cumulative deaths and afflicting many more with symptoms ranging from sinus inflammation to cardiopulmonary failure (“COVID-19 Epidemiological Update” 2024). The majority of Covid-19 survivors recover completely and carry on with their lives, while a fraction continue to suffer from symptoms. Long Covid is a poorly understood and debilitating condition that can be associated with fatigue, brain fog, blood clots, heart disease, and much more (Cervia-Hasler et al. 2024). The main hypothesis on the development of Long Covid involves sustained changes to the body’s immune system, leading to long-term inflammation. A new study by Cervia-Hasler et al.uses a combination of immunological and proteomic techniques to pinpoint what exactly is going on that causes patients to remain sick after acute Covid-19 has passed through.
For up to a year, researchers followed 113 patients with a confirmed diagnosis of Covid-19 and 39 healthy individuals. Patients were classified as having mild or severe disease and were further divided upon follow-up depending on the presence of residual symptoms. This included no Long Covid, 1-month (1M) Long Covid, 6-month (6M) Long Covid, and 12-month (12M) Long Covid. At each appointment, participants were screened for immunological dysregulation using immunosorbent assay and had serum SomaScan analysis, which characterizes protein expression, performed to assess for tissue injury. Single-cell transcriptomic techniques were also used to analyze how genes are differentially expressed in Long Covid patients.
The complement system is an immunological pathway that allows your body to effectively target and fight off infectious agents (Charles A Janeway et al. 2001). A series of proteins activate and interact with each other, named C1, C4, C2, C3, C5, C6, C7, C8, and C9 in order of progression. At various points in the process, components can be cleaved into multiple products, such as C5 becoming C5a and C5b. C5b then forms a complex with C6 called C5bC6. This is important because the binding of C5bC6 to C7 facilitates the formation of larger complexes that ultimately make way for water to enter and burst a viral particle. Two of the inflammatory markers that Cervia-Hasler et al. analyzed were the levels of C5bC6 and C7 complexes (Cervia-Hasler et al. 2024). Patients with 6M Long Covid had decreased levels of C7 complexes. Increased levels of C5bC6 were reported in patients with severe acute Covid-19 infection and in those with 6M Long Covid. Overall, this suggests an increase in complement pathway activity and a sustained inflammatory response in Long Covid.
The proteomic analysis revealed several components associated with 6M Long Covid, several of which pertain to blood clot formation and the breakdown of red blood cells, or hemolysis. Firstly, the researchers noted an increase in hemopexin and heme levels for Long Covid patients. The two molecules often come together following hemolysis, suggesting that Long Covid may be associated with red blood cell death. Von Willebrand Factor was increased in patients with both severe acute Covid-19 and in 6M Long Covid. Antithrombin III is a clotting regulator examined with immunosorbent assay that was seen to have the opposite effect. Both von Willebrand Factor and antithrombin III are involved in coagulation pathways. The coupling of these two differences may help to explain why Covid-19 survivors are at an increased risk of deep vein thrombosis and serious blood clots. This was further supported when the scientists looked at the messenger RNA expression of CD41, a platelet marker, in immune cells. Patients whose Long Covid persisted for the full twelve months of the study had the highest levels of CD41-tagged cells. This suggests that platelet-immune cell aggregates are associated with Long Covid and may indicate a link between immune pathway dysregulation and abnormal platelet activity.
I am very glad to see more research being done to understand the mechanisms of Long Covid. There is currently no treatment specific to the condition aside from treating symptoms. I have watched friends struggle with the side effects of Long Covid, including one who faints frequently as a result of a neurocardiovascular disconnect. We also do not know how the damage associated with Long Covid can progress over time since the condition is only a few years old, which is part of what makes it so scary. Following severe Covid-19 infection, patients are at an elevated risk for blood clots and ischemic stroke (Roberts et al. 2020). This is supported by Cervia-Hasler et al.’s findings of decreased antithrombin in Long Covid patients. There are reports from neuroscientists and assisted living staff of new onset dementia or rapid worsening of existing dementia cases following acute Covid-19 in older adults (Numbers and Brodaty 2021). Questions remain as to whether Long Covid patients will eventually deal with the same consequences as disease activity continues. I truly hope that case studies like Cervia-Hasler et al.’s will provide insights towards treating Long Covid and even preventing the immunological dysfunction associated with it from developing in the first place.
References:
1) Cervia-Hasler C., S. C. Brüningk, T. Hoch, B. Fan, G. Muzio, et al., 2024 Persistent complement dysregulation with signs of thromboinflammation in active Long Covid. Science 383: eadg7942. https://doi.org/10.1126/science.adg7942
2) Charles A Janeway J., P. Travers, M. Walport, and M. J. Shlomchik, 2001 The complement system and innate immunity, in Immunobiology: The Immune System in Health and Disease. 5th edition, Garland Science.
3) COVID-19 Epidemiological Update, 2024
4) Numbers K., and H. Brodaty, 2021 The effects of the COVID-19 pandemic on people with dementia. Nat Rev Neurol 17: 69–70. https://doi.org/10.1038/s41582-020-00450-z
5) Roberts K. A., L. Colley, T. A. Agbaedeng, G. M. Ellison-Hughes, and M. D. Ross, 2020 Vascular Manifestations of COVID-19 – Thromboembolism and Microvascular Dysfunction. Front. Cardiovasc. Med. 7: 598400. https://doi.org/10.3389/fcvm.2020.598400
6) Unsplash, 2020 Photo by Fusion Medical Animation on Unsplash
I appreciate you picking this article and providing an analysis of long covid as it is poorly understood but is actively impacting people in the contemporary moment. I wonder if the researchers who are doing this study/other researchers are looking into more mechanistic pathways concerning prolonged immune responses in long covid cases. The CD4 immune cell could perhaps act as a target for future immune therapies which could be extremely beneficial for people struggling with long covid symptoms.