Elevated hyaluronic acid levels in severe SARS-CoV-2 infection in the post-COVID-19 era

Abstract

Objective: Human identical sequences of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) promoted the coronavirus disease 2019 (COVID-19) progression by upregulating hyaluronic acid (HA) via NamiRNA-enhancer network, based on previous experimental research. This study aimed to investigate the predictive value of HA for the severity of SARS-CoV-2 infection in the post-COVID-19 era.

Methods: A total of 217 consecutive patients with COVID-19 were enrolled at Beijing Ditan Hospital between July 2023 and October 2023. HA levels were analyzed using biochemical detector. Logistic regression analysis was used to screen independent factors for severe COVID-19. The predictive performance of HA for severe infection was assessed by ROC curve. Furthermore, the relationship between HA levels and COVID-19 severity was investigated using multivariate logistic regression models after adjustment for potential confounders.

Results: According to the cut-off value of HA, COVID-19 patients were divided into HA < 90 ng/mL group (80 cases) and HA ≥ 90 ng/mL group (137 cases). High HA levels were positively associated with the severe SARS-CoV-2 infection, including elevated inflammatory indicators, severe lung involvement, prolonged clinical course, and higher incidence of respiratory failure and death (P < 0.05). Logistic regression analysis suggested that HA was an independent predictor of severe COVID-19 (OR = 4.540, 95% CI = 2.105-9.790, P < 0.001). ROC curve analysis showed that the AUC of HA for severe infection was 0.724. HA levels were significantly higher in COVID-19 cases compared to the healthy population (123.9 (82.6, 174.1) vs. 50.5 (37.8, 66.8), P < 0.001), but similar to those with non-SARS-CoV-2 lung infection (121.6 (78.5, 175.6) vs. 106.0 (66.5, 149.7), P = 0.244). We also found that the first COVID-19 infections had higher HA levels (118.8 (79.5, 174.3) vs. 85.0 (61.1, 128.8), P < 0.001) and a higher proportion of severe infection (37.1% vs. 21.3%, P = 0.043) than re-infections. However, HA expression failed to fully return to normal levels with infection recovery (204.7 (152.9, 242.2) vs. 97.0 (69.3, 137.3), P < 0.001).

Conclusion: HA was associated with severe SARS-CoV-2 infection and could be used as a novel serum biomarker to predict the risk of COVID-19 progression in the post-COVID-19 era.

Keywords: coronavirus disease 2019; hyaluronic acid; lung involvement; progression; severe acute respiratory syndrome coronavirus-2; severe infection.

Figure 1

ROC curve analysis of HA compared to other risk factors in predicting COVID-19 progression. Areas under the ROC curve indicate model predictive power. ROC, receiver operating characteristic; AUC, areas under the curve; HA, hyaluronic acid; COVID-19, coronavirus disease 2019.

Figure 2

HA levels according to frequency of infection (A), severity of infection (B), and course of infection (C). HA, hyaluronic acid. Differences between groups were analyzed by Mann-Whitney U test.

Figure 3

Serum HA levels between different status of infection (A) and different etiology of lung infection (B). HA, hyaluronic acid; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2. Differences between groups were analyzed by Mann-Whitney U test. "ns" means "not significant".

Figure 4

Matrix heatmap showing the expression of HA in COVID-19 patients and healthy controls. Heatmap mainly indicates the numerical size by different colors or shades. The abscissa represents different groups (A-E reflects the HA levels of severe COVID-19 group, F-O represents the HA levels of mild COVID-19 group, P-Q represents the HA levels of healthy control group), while the ordinate only represents the number of rows. HA, hyaluronic acid; COVID-19, coronavirus disease 2019.