High TNF receptors levels could predict COVID-19 mortality and disease severity

By Dr. Liji Thomas, MDReviewed by Benedette Cuffari, M.Sc.Oct 16 2022

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19), can cause a wide range of symptoms. While most people remain asymptomatic or are mildly affected, a significant minority develop severe or fatal disease.

Considerable research has been directed toward identifying risk factors for severe COVID-19. To this end, a recent PLoS One journal study finds that high levels of a specific inflammatory molecule might successfully predict the increased severity of COVID-19.

Study: Circulating tumor necrosis factor receptors are associated with mortality and disease severity in COVID-19 patients. Image Credit: joshimerbin / Shutterstock.com

Introduction

COVID-19 may trigger a hyperinflammatory response, or cytokine storm, in some patients. This leads to systemic injury, mediated by damage to the vascular endothelium, with thrombosis within multiple organs. The outcomes include lung damage, acute respiratory distress syndrome (ARDS), and multi-organ breakdown.

Some of the biomarkers that are indicative of progressive COVID-19 include C-reactive protein (CRP), ferritin, and D-dimer. Prior research has also shown that diabetes and chronic kidney disease (CKD), which affect one in ten people worldwide, significantly increases the patient’s risk of severe illness and death when infected with SARS-CoV-2.

Inflammatory markers related to tumor necrosis factor (TNF), including TNF receptors (TNFR1 and TNFR2) and progranulin (PGRN), may also play a role in the disease processes of obesity, diabetes, and CKD. In addition, these markers often predict a greater likelihood of rapidly progressive disease and death in patients with these conditions.

The current study examines possible associations between these markers and severe or fatal COVID-19. This retrospective study was conducted between April and September 2021, wherein the researchers compared biomarker levels among COVID-19 patients who required intensive care unit (ICU) admission to non-severe COVID-19 patients.

What did the study show?

Both sets of patients had comparable age characteristics, mean blood pressure levels, and prior cardiovascular disease histories.

ICU patients were more often male, with diabetes, hypertension, and CKD, compared to non-ICU patients. This patient group also had increased levels of white blood cells (WBCs), D-dimer, and lactate dehydrogenase (LDH); however, their body mass index (BMI) was lower. These patients also showed relative lymphopenia and lower kidney function.

Inflammatory markers, including TNFR1 and TNFR2, were markedly higher among ICU patients as compared to all other levels of severity. In contrast, CRP and interleukin-6 (IL-6) levels showed a graduated increase with the severity of the illness.

TNFR1 and TNFR2 concentrations were well-correlated with each other and CRP. These levels were also linked to other inflammatory parameters, including WBCs, lymphocytes, D-dimer, and LDH, all of which showed varying degrees of correlation with each other.

Both TNFR1 and TNFR2 were also associated with higher mortality risk, with the latter associated with higher sensitivity and the former with higher specificity. When only clinical parameters were included, a higher WBC count almost doubled the likelihood of mortality, with age and lower lymphocyte counts associated with a slightly increased risk of mortality.  

Conclusions

Older males, especially those with lower diastolic pressure, reduced lymphocyte counts, and higher WBC, LDH, and D-dimer levels were at a higher risk of mortality due to COVID-19. In addition, increased inflammatory markers were also associated with a higher risk of mortality.

TNFR levels were similar in mild and moderate COVID-19, with only severe illness marked by a sharp rise in TNFR1 and TNFR2. However, increased TNFR2 was associated with greater mortality risk, independent of other clinical parameters.

The disintegrin and metalloprotease 17 (ADAM17) enzyme is essential for shedding the host cell angiotensin-converting enzyme 2 (ACE2) receptor’s ectodomain following its binding to the SARS-CoV-2 spike protein. However, this enzyme also causes the shedding of TNF, TNFR, and IL-6 receptors. Thus, the rise in TNFR levels is likely due to excessive shedding rather than overproduction.  

These findings suggest that TNFR1 and TNFR2 are linked to severe COVID-19, while other inflammatory markers reflect mild to moderate illness.

[This] increase in IL-6 and CRP might be helpful to distinguish the early stage of COVID-19.”

Conversely, TNFR levels may help identify those who may require ICU care. Finally, high TNFR2 levels could predict mortality in these patients.