Potential molecular and clinical biomarkers of COVID-19 severity

By Sam HancockMar 4 2022Reviewed by Danielle Ellis, B.Sc.

Coronavirus disease 2019 (COVID-19) first emerged in Wuhan, China, and has since spread to nearly every country in the world. Initially, the lack of available treatments and tests for the disease forced many countries to enact costly and restrictive measures to prevent the rapid transmission of the disease. These included mandatory face masks, social distancing laws, and even the introduction of full lockdowns/stay-at-home orders.

While mass vaccination programs in developed nations have helped curb the severity of the disease, threats remain from emerging variants, and developing nations have struggled to achieve the necessary nationwide vaccination levels to pass the herd immunity threshold. However, scientists continue to study the disease to help healthcare workers and patients. In an article published in Pathogens, researchers have reviewed the currently published data examining the potential molecular and clinical biomarkers of COVID-19 severity.

The review

Changes in cell populations have been often linked to disease severity, including changes such as lymphopenia, increases in neutrophil count/neutrophil to lymphocyte ratio (NLR), higher levels of white blood cells (WBCs), and thrombocytopenia. Inflammatory markers found in the blood have also repeatedly been found to rise in cases that end with a worse outcome. In those that do not survive, it is typical to see high levels of D-dimer, PT, alanine transaminase (ALT), and quick reductions in the levels of fibrinogen, while elevated levels of IL-6, IL-10, ESR, and PCT indicate that the patient is likely to progress to more severe disease.

The proportion of neutrophils in COVID-19 patients is another factor that can provide insight into the severity of COVID-19. Patients hospitalized with severe disease have higher levels of CD16low and CD16int than mild and moderate cases. Classical and immature monocytes such as CD14+ or CD14++CD16- are often seen in more severe cases, and higher proportions of CD1aCD14+ and other monocytes that express ALCAM are associated with patients that will suffer from an adverse reaction within 30 days.

Severe patients also tend to show decreased natural killer cell populations upon hospital admission - but there is a significant increase in natural killer cells activated. As expected with an inflammatory disease, elevated proportions of B cells are often seen in severe or critical disease patients.

Viral titers are normally higher in severe viral disease, and COVID-19 infection follows this pattern. Higher RNA loads are significantly higher in the plasma of patients that do not survive compared to other patients, with non-survivors averaging around 1,587copies/mL of the N1 region and 2,798 copies/mL of the N2 region, while survivors showed viral loads of 574 copies/mL and 523 copies/mL, respectively. Other studies found that genes encoding the regions of IgA1, IgA2, IgG1, and IgG2 were upregulated in plasma B cells in severe patients.

COVID-19 patients who need admission to the ICU show different gene expression levels compared to milder cases, specifically showing upregulation of ELANE, OLFM4, MPO, RETN, ARG1, CD177, S100A12. Many of these are associated with granulocytes or granulocyte activation. Further investigation of the granulocyte transcriptome in the day following hospitalization revealed upregulation of genes encoding matrix metallopeptidase 9/25 in neutrophils and macrophages - associated in severe patients with leukocyte migration to inflamed sites. CD15, S100A8/9, PADI4, NLRC4, MMP8, and MMP9 were also upregulated.

Gene ontology analysis further revealed differentially expressed genes in the regulation of the inflammatory responses, as well as the cellular response to IL-1 and tumor necrosis factor. Both IL1Beta and IL-6 show overexpression in severe cases of COVID-19 compared to milder disease, while the anti-inflammatory IL-10 is downregulated. Other patients reporting severe disease show high levels of TNF-alpha and CXCL10 that can remain high for weeks following infection - the original researchers suggested that this could be at least partially responsible for the difficulty in concentration seen in many 'long-COVID' patients.

Conclusion

The authors highlight that while the standard biomarkers found in blood tests can continue to act as effective biomarkers for the severity of infection with COVID-19, many alternate candidates exist, including cell population subsets and transcriptomic signatures. The dynamic changes in biomarker levels could be very useful for healthcare workers and COVID-19 researchers and could help both identify possible drug targets as well as potentially help to triage cases if another serious epidemic breaks out.