Serological biomarkers for COVID-19

Establishing clinical biomarkers for COVID-19 could help clinicians identify the onset of severe disease earlier, improve prognosis and stratify patients to support treatments.

Updated May 19, 2022.

Serological biomarkers offer a measure of an individual's biochemistry, from a simple patient blood sample, that can help quantify health and disease. The majority of biomarker research and diagnostics have used ELISAs for rapid and quantifiable bioassays from small volumes of patient samples, with the ability to easily adapt this technology to automation and high throughput screening. 

While COVID-19 typically manifests as a respiratory tract infection, some patients experience more severe pathologies, including acute respiratory distress syndrome, lung injury, shock and multiple organ failure. In addition to the involvement of the respiratory system, increasing research indicates that coagulation abnormalities and hyper-inflammatory responses are features of severe cases of COVID-19, with a range of serological indicators that could act as viable biomarkers for disease outcomes.

Coagulopathy biomarkers

COVID-19 is associated with frequent thrombotic events at both the micro- and macro-vascular levels due to hypercoagulability. So-called ‘COVID-19 associated coagulopathy’ (CAC) represents a key factor in organ damage resulting from COVID-19.^1-4 Both retrospective and prospective studies have highlighted elevated levels of coagulatory proteins in patients with severe COVID-19 compared to non-severe cases. The most commonly identified coagulopathy biomarkers are elevated D-dimer levels, thrombocytopenia, elevated fibrinogen levels, platelet count reduction and a mildly prolonged prothrombin time.¹

In an early 2020 study, for example, patients with D-dimer levels over 1 µg/mL (standard range <250 ng/mL) showed an 18-fold increased risk of death.² Thrombocytopenia has been negatively correlated with COVID-19 severity in some studies.² However, other analyses have suggested that true thrombocytopenia, low platelet count, is only present within 5% of patients, while mild thrombocytopenia was observed in 70-95% of severe COVID-19 cases.¹

Together these factors of thrombocytopenia, elevated D-dimer and increased prothrombin time have implicated disseminated intravascular coagulation (DIC). Still, the biomarker levels observed in COVID-19 are not reflective of those seen in other conditions, such as sepsis, which also cause DIC. In comparison to sepsis-induced DIC, COVID-19-induced DIC shows much higher levels of D-dimer and reduced levels of thrombocytopenia.¹ With CAC, in fact, high levels of D-dimer are found, but also high levels of fibrinogen and only minimal variations in platelet count and PT compared to SIC and DIC, thus missing the typical characteristic of ‘consumption coagulopathy’.⁴

Kawasaki disease (KD) has also been associated with SARS-CoV-2 infection in children.^5-6 KD symptoms include multisystem inflammation,^7,8 and various studies have indicated that D-dimer, troponin and BNP levels may be elevated in COVID-19-related Kawasaki disease. As it stands, the association and triggers of KD-associated COVID-19 are poorly understood, necessitating further research.​

Other markers of coagulopathy in COVID-19 include elevated lactate dehydrogenase and ferritin levels. These have been observed across several patient cohorts and indicate thrombotic microangiopathy, which has been seen in some severe cases of COVID-19 post-mortem.¹

Inflammatory biomarkers

Hyperactivation of the inflammatory cascade, leading to cytokine storm, has been extensively cited as a critical response in patients with severe COVID-19. The most significantly elevated inflammatory cytokines of severe COVID-19 are thought to be TNF-α, IL-1, IL-6 compared to non-severe disease cases.^{1, 10-12}

Studies also show an increase in C-reactive protein (CRP) levels associated with more severe forms of COVID-19 and hospitalization.^3,4 Elevated CRP was also identified by researchers investigating COVID-19 related Kawasaki disease, with patients exhibiting both elevated CRP and ferritin levels.⁷

Blood-type biomarkers

ABO blood types have been linked to various conditions, such as blood group O being protective for cardiovascular disease and thrombosis risk. In COVID-19 analysis of ABO blood types has shown a further protective role for blood type O.^{13, 14} ABO antigens are expressed on epithelial cells, platelets, erythrocytes and the blood glycoproteins, von Willebrand factor (VWF) and Factor VIII. Cases of severe pneumonia in COVID-19 patients have been associated with higher levels of both VWF and Factor VIII, and individuals with blood type O have previously been shown to exhibit 20-30% lower levels of VWF compared to non-O type individuals.¹³

​​SimpleStep ELISA^® for serological biomarkers

Validation of serological biomarkers for COVID-19 could improve patient care and disease outcomes for severe cases. As many of the biomarkers under investigation are commonly elevated in other conditions, assays that target these factors are often already in existence and could be adapted for COVID-19 research. Our range of SimpleStep ELISA^® kits target many of these potential biomarkers and deliver results in just 90 minutes with a simple single-wash protocol for minimal hands-on lab time. Developed with our own in-house recombinant matched antibody pairs, these rapid ELISA kits offer continuity of results across platforms and in transitioning research to the clinic.

A more extensive list of COVID-19 associated serological biomarkers can be found below:^{15, 16}

IL-6 | D-Dimer | LDH | CRP | BNP | Troponin | CK | Ferritin | Fibrinogen | AST | PCT | Myoglobin | 
​ AP | Albumin

Abcam’s products are intended for research use only, not for use in diagnostic, therapeutic, or any other purposes.

References

1. Levi, M. et al. (2020) Lancet Haematol. 7(6): e438–e440.
2. Sardu, C. et al. (2020) J Clin Med 9(5), 1417
3. Kermali, M. et al. (2020) Life Sci 117788.
4. Lorini, FL. et al. (2021) European Heart Journal 23(E), E95-98
5. Verdoni, L. et al. (2020) Lancet [Epub ahead of publication]
6. Loomba, R.S. et al. (2020) Cardiol Young 1-5
7. Sample, I. (2020) The Guardian 17 May [https://www.theguardian.com/science/2020/may/17/possible-breakthrough-in-coronavirus-related-syndrome-in-children]
8. Jakob, A. et al. (2020) Eur J Paediatr. 179(3):377-384
9. Kong, W.X. et al. (2019) World J Paediatr 15(2):168-175
10. Chen, L. et al. (2020) Chinese J Tuberculosis Respir Dis 43(0):E005
11. Wang, W. et al. (2020) medRxiv [https://doi.org/10.1101/2020.02.26.20026989]
12. Ruan, Q. et al. (2020) Intensive Care Med. 46(5):846-848
13. O’Sullivan, J.M. (2020) British J Haematol [https://doi.org/10.1111/bjh.16845]
14. Ellinghaus, D. et al. (2020) medRxiv [doi:https://doi.org/10.1101/2020.05.31.20114991]
15. Sheth, A. et al. (2021). Nat Sci Rep 11(4930)
16. Wang, F. et al. (2020). JCI Insight 5(10)​