High mortality of SFTS may be associated with cytokine storm and immune dysfunction. Therefore, we compared cytokines and lymphocyte subsets between severe and non-severe SFTS patients to identify predictors for severe patients.
Interleukin-6 (IL-6) is a pleiotropic cytokine [8], known for its role in inducing the acute immune response to combat infectious agents and facilitate tissue repair [9]. However, while IL-6 expression is tightly regulated, excessive release can contribute to the development of inflammatory cytokine storms and severe inflammatory diseases [10]. A previous study has identified IL-6 as a promising biomarker for assessing severity and as a prognostic indicator during cytokine storms [11]. In our study, we observed that the levels of IL-6 were higher in the severe group compared to the non-severe group. Furthermore, the results of multivariable logistic regression analysis suggested that IL-6 might serve as an independent predictor for severity in SFTS.
Interleukin-8 (IL-8), produced by various cell types, serves as a potent neutrophil chemotactic agent and activator [12]. In the context of local inflammation, IL-8 facilitates neutrophil migration, enhances vascular permeability, and promotes angiogenesis [13]. Previous studies have highlighted elevated IL-8 secretion levels in deceased SFTS patients [6, 14]. In our research, we similarly observed higher levels of IL-8 in severe SFTS patients, with a statistically significant difference between the two groups. However, despite this association, our analysis did not identify an elevated level of IL-8 as an independent risk factor for the severity of SFTS.
Interleukin-10 (IL-10) is a cytokine known for its anti-inflammatory properties, crucial for immunoregulation during infection. It plays a vital role in limiting excessive host damage caused by the immune reactions and in controlling the immune response to pathogens [15]. However, in certain infections, such as viral, fungal, helminth, or bacterial infections, excessive secretion of IL-10 may hinder pathogen clearance and contribute to the development of chronic disease [16, 17]. Although IL-10 was not identified as an independent predictor for the severity of SFTS in our analysis, we observed a statistically significant difference in IL-10 levels between the severe and non-severe groups, consistent with previous reports [6]. We speculate that the significantly elevated levels of IL-10 might contribute to immune dysregulation, potentially leading to the progression of SFTS [18, 19].
Interferons (IFNs), including type I (IFN-α and IFN-β), type II (IFN-γ), and type III (IFN-λ), play a crucial role in initiating effective antiviral immune response by disrupting virus replication within host cells, thereby promoting antiviral immunity [20]. Previous research on cytokines in SFTS has indicated elevated levels of IFN-α among deceased patients [4, 21]. In our study, we similarly observed higher levels of IFN-α in the severe group, with a statistically significant difference between the severe and non-severe groups. While some studies have reported significantly increased levels of IFN-γ in deceased SFTS patients [4, 21, 22], others have found lower levels of IFN-γ in SFTS patients compared to healthy individuals [5]. However, our study did not reveal a significant difference in IFN-γ levels between the severe and non-severe groups. These discrepancies in findings may be attributed to differences in the populations being studied.
Most SFTS patients are usually elderly, and our study confirms previous findings that age is an independent risk factor for the severity of the disease [14]. Immune function generally decreases with age, and impaired immune function can accelerate disease progression [23]. In our previous study, we observed decreased counts of CD4 + and CD8 + T cells in SFTS patients with invasive pulmonary aspergillosis [24]. Similarly, in the present study, we found decreased counts of CD4 + and CD8 + T cells in the severe group. Notably, CD4 + T cell count emerged as an independent predictor for the severity of SFTS. According to the ROC curve analysis, the sensitivity and specificity for predicting the severity of SFTS were higher when the count of CD4 + T cells was below 255/µl. In severe SFTS cases, the reduction in CD4 + and CD8 + T cell counts results in an insufficient number of active T cells to engage in cellular immune responses, thereby compromising cellular immune function and increasing the risk of infection from other pathogens. Therefore, the severity of SFTS may indeed be associated with the decreased counts of CD4 + and CD8 + T cells.