Elevated levels of TNF receptors may predict COVID-19 mortality and disease severity

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

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

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


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

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

Tumor necrosis factor (TNF)-related inflammatory markers, including TNF receptors (TNFR1 and TNFR2) and progranulin (PGRN), may also play a role in the disease processes of obesity, diabetes, and obesity. ‘IRC. Additionally, these markers often predict a greater likelihood of rapid disease progression and death in patients with these conditions.

The present study examines possible associations between these markers and severe or fatal COVID-19. This retrospective study was conducted between April and September 2021, where 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?

The two groups of patients had comparable characteristics of age, mean blood pressure levels and history of cardiovascular disease.

Patients in intensive care were more often male, with diabetes, hypertension and CKD, compared to non-hospitalized patients. This group of patients also had increased levels of white blood cells (WBC), D-dimer, and lactate dehydrogenase (LDH); however, their body mass index (BMI) was lower. These patients also presented with relative lymphopenia and reduced renal function.

Inflammatory markers, including TNFR1 and TNFR2, were significantly higher in intensive care patients compared to all other severity levels. In contrast, CRP and interleukin-6 (IL-6) levels showed a gradual increase with disease severity.

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

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


Older men, especially those with low diastolic blood pressure, reduced lymphocyte counts, and higher WBC, LDH, and D-dimer levels, were at higher risk of death from COVID-19. Moreover, the increase in inflammatory markers was also associated with a higher risk of mortality.

TNFR levels were similar in mild and moderate COVID-19 cases, with only severe disease marked by a large increase in TNFR1 and TNFR2. However, an increase in TNFR2 was associated with a higher mortality risk, independent of other clinical parameters.

The enzyme disintegrin and metalloprotease 17 (ADAM17) is essential for clearing the ectodomain of the angiotensin-converting enzyme 2 (ACE2) receptor from the host cell after binding to the SARS-CoV spike protein- 2. However, this enzyme also causes the loss of TNF, TNFR and IL-6 receptors. Thus, increased TNFR levels are likely due to excessive loss rather than overproduction.

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

[This] increased IL-6 and CRP may be helpful in distinguishing early stage of COVID-19.”

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

Journal reference:

  • Gohda, T., Murakoshi, M., Suzuki, Y., et al. (2022). Circulating tumor necrosis factor receptors are associated with mortality and disease severity in patients with COVID-19. PLOS ONE 17(10): e0275745. doi:10.1371/journal.pone.0275745.

Leave a Reply