Pathophysiology of Long COVID 4: Biomarkers

Pathophysiology of Long COVID 4: Biomarkers

Patients with Long COVID can experience more than 200 different symptoms across various systems of the body. As a result, Long COVID often remains undiagnosed. Biomarkers for Long COVID can play a key role in improving the diagnosis, prognosis, and treatment.

A biomarker, or biological marker, is a measurable characteristic that provides information about a disease or biological process in a person's body. Biomarkers can include a wide range of substances, such as molecules, proteins, cells, and genes and can be found in locations like the blood, urine, and tissues. In a scoping review (see Infobox) published earlier this year, researchers analyzed 23 studies and found 239 biomarkers in the blood that can be used for the diagnosis or prediction of Long COVID. These biomarkers include various immune cells and molecules like cytokines, chemokines, antibodies as well as other proteins or substances.

Blood levels of these biomarkers differ significantly between Long COVID patients and a control group comprising healthy people who were not exposed to SARS-CoV-2, who recovered or who suffered from only mild Long COVID.


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Study design: A group of 2163 Long COVID patients was compared to a control group.


The acute phase

First, the authors investigated which immune cells and molecules differ from the control group in the early phase of SARS-CoV-2 infection. They found that the immune response to viral infection causes changes in certain parts of the immune system which can be used to predict who might develop Long COVID. For example, there were differences in specific immune cells called CD8+ T-cells, which are important for protection against viruses (see Part 1 of this series). Researchers also noted that changes in immune cells were different in patients who develop respiratory symptoms from those who develop gastrointestinal symptoms as we showed in Part 3: Subphenotypes.

Compared with the control group, different cytokines are increased during the acute COVID-19 phase in patients who later developed Long COVID. These included inflammatory molecules called interleukins and tumor necrosis factor-alpha (TNF-α), as well as the antiviral molecule interferon-gamma (IFN-γ). Studies have also shown that alterations in antibodies and autoantibodies (antibodies that mistakenly attack and destroy healthy cells) are associated with the onset of Long COVID. Patients who developed Long COVID also presented with a higher amount of the vascular endothelial growth factor (VEGF), which is important for the growth of blood vessels.


Early recovery

During the recovery phase after the initial infection, researchers have also identified biomarkers that can be used to predict the onset of Long COVID. Studies have demonstrated that higher numbers of specific immune cells, including CD8+ T-cells, monocytes, and dendritic cells in this period are associated with Long COVID. Similar to the early phase of infection, several immune molecules, such as cytokines and certain autoantibodies were increased as well. Studies have also found various other substances that might be used as biomarkers for Long COVID. These include different coagulation proteins (related to blood clotting), acute phase proteins, specific hormones, and markers of fungal and bacterial infections.

Various biomarkers are present at different time points.

Biomarkers for specific Long COVID symptoms

The scoping review also aimed to identify specific biomarkers for various symptoms of Long COVID, including respiratory, neurologic, and gastrointestinal.

In patients with respiratory symptoms, higher levels of specific inflammatory immune cells were reported, as well as molecules like the cytokine Il-6 and the C-reactive protein CRP. Interestingly, these patients also showed increased hemoglobin levels, which indicate a mechanism to improve the transfer of gases like oxygen between lungs and blood. Moreover, a molecule called S-sulfocysteine that is associated with cough symptoms was elevated, while levels of cortisol, a hormone related to stress, were decreased.

The review further demonstrates that patients with neurologic symptoms had higher amounts of proteins associated with SARS-CoV-2 itself, mitochondria, and nerve cells (neurons) in specific transport systems called vesicles. Increased levels of specific inflammatory cytokines were also observed in this group of patients. The authors emphasized that it is critical to discover biomarkers for neurologic Long COVID because this subtype can be present for up to two years and might increase the risk for neurodegenerative diseases.

Moreover, research has shown that fatigue in patients with Long COVID might be associated with damage to blood vessels due to the virus. More specifically, these patients have a different abundance of molecules known as endothelin-1 and angiopoietin-2, which are both important for the functioning of blood vessels. Fatigue symptoms might also be connected to the presence of the Epstein-Barr virus (EBV) in the early infection phase, as Altea reported here.

Finally, data shows that biomarkers for digestive symptoms include the presence of active CD8+ T-cells and specific autoantibodies. Also, higher levels of β-glucan were reported, which suggest fungal infection in the body.


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Summary of biomarkers by symptoms. For detailed image see original publication.

What is a scoping review?