Growing evidence exists that immune mechanisms rather than direct viral cytopathology are responsible for the changes in vascular permeability, the principal abnormality, in both HFRS and HCPS [6
]. Activation of hantavirus specific CD8+ T cells and cytokine production seem to be of special importance, since high levels of these cells have been found in blood, lung, and kidney tissues of HCPS and HFRS patients [16
This study is the first to describe serum cytokine levels in patients infected with DOBV and also to compare the detected levels in patients infected with DOBV and PUUV. In our study, increased levels of IL-10, INF-γ, and TNF-α were found in serum samples of most HFRS patients. On average, higher concentrations were detected in patients infected with DOBV than PUUV. Furthermore, in patients infected with DOBV, higher levels of these cytokines were found in patients with a more severe clinical course of disease. No differences in cytokine concentrations according to disease severity were observed in patients infected with PUUV. It has previously been established, that severe cases of HFRS in Slovenia are mainly caused by DOBV, while infection with PUUV usually results in a milder form of disease [12
]. This has once again been confirmed with patients included in this study, since the occurrence and intensity of clinical and laboratory findings were higher in patients infected with DOBV than PUUV. Therefore, it is expectable, that the differences in disease severity in patients infected with PUUV are smaller.
Increased levels of TNF-α have also been demonstrated in studies of patients with Korean hemorrhagic fever and patients with HCPS. However, no association with disease severity could be established in either of these studies [8
]. Increased levels of TNF-α, IL-6 and IL-10 have previously been detected in patients with NE, where TNF-α levels were found to correlate with hypotension and serum NO levels and plasma IL-6 levels were associated with a more severe form of NE [9
]. In addition, increased IL-10 and TNF-α production was demonstrated in cynomolgous monkeys infected with wild-type PUUV, where highest concentrations of TNF-α were detected in the most affected monkey [21
]. High IL-10 and TNF-α serum values were also found in patients with severe course of dengue hemorrhagic fever and Argentine hemorrhagic fever, which have similar clinical presentations to HFRS [22
On the basis of the results of our and previous studies, we believe that imbalance in production of proinflammatory and regulatory cytokines might be associated with disease severity in HFRS. Similar has been proposed for HCPS, where a mixed Th1/Th2 immune response was observed in serum samples of HCPS patients and the levels of Th1 cytokines correlated with disease severity [19
In our opinion, a strong inflammatory response to virus particles and immune complexes, mainly represented by TNF-α and INF-γ, causing changes in vascular permeability, could contribute to a more severe clinical course of HFRS. Also, high production of inflammatory cytokines in turn leads to increased production of regulatory cytokines, such as IL-10, and possibly to immunosuppression. IL-10 also promotes further antibody production, likely resulting in even higher number of immune complexes, which deposit on capillary walls and in tissues. At the same time, IL-10 inhibits cell-mediated immunity by down regulating IL-12 expression, thus interfering with phagocytosis and clearance of immune complexes. This can cause formation of new inflammation sites or even a systemic inflammatory response. Our hypothesis is further supported with low IL-12 levels found in patients infected with DOBV. We believe that higher levels of IL-12 in patients infected with PUUV help to enable the development of cell-mediated immunity, resulting in a more successful clearance of immune complexes and consequently in a milder form of disease.
Similar has been hypothesized for patients with sepsis caused by gramnegative bacteria, where a strong inflammatory response to lipopolisaharid in bacterial wall, characterized by cytokines such as TNF-α, IL-1, IL-6 and IL-12, is thought to trigger a strong regulatory response, with high levels of IL-10. This could lead into immunosuppression and consequently in the worst cases cause a multi-organ failure [25