High levels of heat shock protein gp96 in patients with COVID-19 are predictive of severe disease and unfavorable prognosis, suggests a new study reported in the journal Microbiology Spectrum.¹

The study evaluated the plasma levels of gp96 in hospitalized patients with mild, severe and critical Covid-19 to assess its usefulness as a marker for disease severity. The participants included 12 patients with severe Covid-19, 18 with nonsevere Covid-19, 13 non-COVID-19 patients, 13 patients with hepatitis B as non-SARS-CoV-2 virus infection controls and 15 healthy persons as control group.

Levels of gp96 were increased in all patients with Covid-19 compared to healthy controls; 912.7 ng/mL vs 467.5 ng/mL, respectively. Higher plasma gp96 levels were seen in patients with nonsevere and severe Covid-19 compared to non-COVID-19 patients; 822.2 vvs 1,048.0 ng/mL vs 553.4 ng/mL, respectively.

Comparison of gp96 levels among Covid patients revealed significant elevation in patients with severe Covid-19 compared to patients with nonsevere disease. The levels were comparable between noncovid patients and health controls and also among the age subgroups of COVID-19 patients studied. No gender-related differences were observed.

Plasma gp96 levels were able to distinguish between severe and nonsevere patients with sensitivity of 83.3% and specificity of 66.7%. The best cut-off value was found to be 871.21 ng/mL. The predictive ability was further enhanced when gp96 and IL-6 were combined with sensitivity of 83.3% and specificity of 72.2%.

Patients in whom plasma gp96 levels declined from the time of hospitalization to treatment endpoint showed better chances of recovery indicating good prognosis (696.9 ng/mL to 127.3 ng/mL for nonsevere patients; 934.8 ng/mL to 303.6 ng/mL for patients with severe disease). Patients with nonsevere Covid-19 with increased plasma gp96 levels were more likely to develop severe illness.

“Heat shock proteins (Hsps) are released during oxidative stress, cytotoxic injury, and viral infection and behave as danger-associated molecular patterns (DAMPs)” Acting as a DAMP molecule, exogenous gp96 stimulated secretion of proinflammatory cytokines in peripheral blood mononuclear cells such as interleukin (IL)-6, IL-1β, IL-2, IL-9, interferon gamma (IFN-γ) and TNF-α and enhanced the inflammatory response.

This first-of-its-kind study has demonstrated significantly high levels of gp96 in nonsevere and severe hospitalized COVID-19 patients. 

Based on these observations, the study authors suggest that plasma gp96 may have a role as a potential predictive and prognostic biomarker for disease severity in Covid-19 patients. It may be used complementary to the other biomarkers such as C‐reactive protein (CRP), d‐dimer, fibrinogen currently in practice.

Early identification of patients likely to progress to severe disease may allow timely intervention to improve outcomes.

Reference

1. Wei R, et al. Plasma gp96 is a novel predictive biomarker for severe COVID-19. Microbiol Spectr. 2021 Nov 24;e0059721. doi: 10.1128/Spectrum.00597-21.