Clinical Relevance of Elevated Soluble ST2, HSP27 and 20S Proteasome at Hospital Admission in Patients with COVID-19

Abstract

Although, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents one of the biggest challenges in the world today, the exact immunopathogenic mechanism that leads to severe or critical Coronavirus Disease 2019 (COVID-19) has remained incompletely understood. Several studies have indicated that high systemic plasma levels of inflammatory cytokines result in the so-called "cytokine storm", with subsequent development of microthrombosis, disseminated intravascular coagulation, and multiorgan-failure. Therefore, we reasoned those elevated inflammatory molecules might act as prognostic factors. Here, we analyzed 245 serum samples of patients with COVID-19, collected at hospital admission. We assessed the levels of heat shock protein 27 (HSP27), soluble suppressor of tumorigenicity-2 (sST2) and 20S proteasome at hospital admission and explored their associations with overall-, 30-, 60-, 90-day- and in-hospital mortality. Moreover, we investigated their association with the risk of ventilation. We demonstrated that increased serum sST2 was uni- and multivariably associated with all endpoints. Furthermore, we also identified 20S proteasome as independent prognostic factor for in-hospital mortality (sST2, AUC = 0.73; HSP27, AUC = 0.59; 20S proteasome = 0.67). Elevated sST2, HSP27, and 20S proteasome levels at hospital admission were univariably associated with higher risk of invasive ventilation (OR = 1.8; p < 0.001; OR = 1.1; p = 0.04; OR = 1.03, p = 0.03, respectively). These findings could help to identify high-risk patients early in the course of COVID-19.

Keywords: 20S proteasome; ARDS; COVID-19; HSP27; biomarker; sST2.

Figure 1

Comparison of serum contents of (A) sST2, (B) HSP27 and (C) 20S proteasome showed significant elevations of investigated parameters in the event group. (sST2: p < 0.001, HSP27: p = 0.04, 20S proteasome: p = 0.017).

Figure 2

Serum levels of (A) sST2, (B) HSP27 and (C) 20S proteasome of patients not surviving 60 days differed significantly from patients surviving the first 60 days. (sST2: p < 0.001, HSP27: p = 0.036, 20S proteasome: p = 0.021).

Figure 3

Comparison of serum contents of (A) sST2, (B) HSP27 showed significant elevations of sST2 (p < 0.001) and HSP27 (p = 0.023). In (C) no significant alteration of 20S proteasome levels in the event group was detected (p = ns).

Figure 4

Comparison of serum contents of (A) sST2 and (C) 20S proteasome showed significant elevations in patients who died in the hospital when compared to surviving hospital patients. (sST2: p < 0.001, 20S proteasome: p = 0.001). Comparison of HSP27 serum content (B) showed no significant difference between these two groups (p = ns).

Figure 5

Serum levels of (A) sST2, (B) HSP27 and (C) 20S proteasome showed significant elevations of investigated parameters in the event group. (sST2: p < 0.001, HSP27: p < 0.001, 20S proteasome: p < 0.001).

Figure 6

Serum levels of (A) sST2, (B) HSP27 and (C) 20S proteasome showed significant elevations of investigated parameters in the event group. (sST2: p < 0.001, HSP27: p = 0.034, 20S proteasome: p = 0.016).

Figure 7

Serum levels of (A) sST2 and HSP27, (B) sST2 and 20S proteasome, (C) sST2 and TNFR1 and (D) HSP27 and 20S proteasome showed significant correlations using Spearman’s rank correlation.

Figure 8

ROCs for binary endpoints were computed and AUC with 95% CI were analyzed to determine diagnostic accuracy. This figure shows ROCs for (A) 30-day mortality, (B) 60-day mortality, (C) 90-day mortality and (D) in-hospital mortality.