Dengue Virus (DENV) infection can result in significant morbidity and mortality in the world. Treatment approach is believed to be supportive to regulate the provision of fluids and there is no specific therapy for DENV. (1-11) Corticosteroids are not recommended by the WHO in the management of dengue but empirically been used by clinicians based on immunological mechanisms in the pathogenesis of Dengue infection. (12) Evidence of the benefits and safety of corticosteroids for DENV infection is still limited in number and methodologies with varying results. (2, 5, 12-22)
Cytokine play an important role in the pathogenesis and severity DENV infection, especially TNF alpha, IL-1B, and IL-8. (23-28) Cytokines are associated with bleeding manifestations, activation of coagulation and fibrinolysis, (29-30) involved in the increased vascular permeability and disease morbidity. (31) Changes in cytokine levels have occurred in DENV infections changed significantly in mild and severe clinical conditions. (32-33)
Mononuclear phagocyte, such as dendritic cells and monocyte are a good cell to study dengue infection in vitro and in vivo. (34-37) Monocyte is DENV-infected leukocytes, although often in patients with DHF is often atypical lymphocytes and PMN obtained. (34) Monocytes from patients in the acute phase showed DENV-Ag during natural infection DF. (38)
TNF alfa and IL-1B produced by monocytes is an early cytokine that appears on DENV infection. (39-40) Macrophages in vitro will release TNF-α, IFN-α, IL-1β, IL-8, IL-12, MIP-1, and RANTES after infection but not IL-6, IL-15, or nitric oxide. (41) The study by Reis et al. (2007) showed that human monocytes from 15 healthy donors in the Brazilian monocyte infected with DENV can induce cytokines TNF-α, IFN-α, IL-6, and IL-10 which occur also in patients with DF. (42) Cytokine IL-1β, IL-8, IL-12, and IL-15 were not detected in cultured monocytes in which cytokines are produced at least in patients with DF. (31, 42) Interferon alpha has increased dramatically during defervescence DHF. (43)
Research at the cellular level swowed that the corticosteroids effects on cytokine production. Corticosteroids enter the cell that will bind to the receptors and will be interacting with buclear factor - kB (NF-kB) caused negative regulation of IL-8 and RANTES. Intitute of corticosteroids on the GRE in the nucleus of cells would inhibit the transcription of several cytokines including IL-1B, TNF alpha, GM-CSF, IL-2 to IL-6, IL-8, RANTES and MIP-1 alpha. (44) Kurane et al. (1993) measured the levels of IFN-α in the serum of patients with DHF and DF. The highest levels of IFN-α in patients with DHF and DF occured on the first day of devervescence phase and gradually decreases during deververcence. The research results indicate that IFN-α produced in high amounts in acute phase of DHF and DF. IFN-α level remained high in patients with DHF after phase of fever but not for the DF. (43)
Inhibitory effect of dexamethasone occurred on cytokine production by DENV infected monocytes and viral load reduction. (42) Dexamethasone working on the production of cytokines TNF-α, IFN-α and IL-10 by monocytes after infection with DENV-2. Dexamethasone effects on the production of TNF-α and translocation of NF-kβ, which is an important step for the induction of TNF-α by monocytes. (42)
Interleukin 1β, IL-6, and IL-10 is inhibited by dexamethasone after monocytes induced by lipopolysaccharide (LPS) bacteria in shock septik. (42) Dexamethasone does not alter significantly the production of IL-6 during DENV infection in vitro. Other cytokines related to severity DENV infection, such as IL-18 and TGF-β, (29) and dexamethasone effects need to be studied. (42)
Pathogenesis of dengue was believed due to the dysregulation of immune response. Monocytes / macrophages infected with DENV will secrete monokin that play a role in the manifestations of DHF / DSS. During the acute phase, mononuclear cells proliferate poorly in response to mitogen and dengue antigens as detected by the radiolabel of timidine. During the convalescent phase, limfoploriferatif response returned to normal. (29)
Dexamethasone, inhibits expression of inflammatory mediators such as cytokines proinflamatory. (45) Corticosteroids inhibit monocyte function including the release of TNF alpha stimulated by endotoxin. Monocytes also release TNF receptor (cTNF-R) that modulates the bioactivity of TNF-α. Effect increased with increasing concentration of dexamethasone. Dexamethasone concentraton of 1 umol/L can inhibit the released of sTNF-RT75 by monocyte as much as 86% and 40% in culture. Dexamethasone also reduced TNF bioactivity in peripheral monocyte cultures, especially TNF-α. Dexamethasone also inhibits the release of IL-1β and IL-1ra by monocytes culture. (45)
Dexamethasone, inhibits expression of inflammatory mediators such as cytokines proinflamatory. (45) Corticosteroids inhibit monocyte function including the release of TNF alpha stimulated by endotoxin. Monocytes also release TNF receptor (cTNF-R) that modulates the bioactivity of TNF-α. Effect increased with increasing concentration of dexamethasone. Dexamethasone concentraton of 1 umol/L can inhibit the released of sTNF-RT75 by monocyte as much as 86% and 40% in culture. Dexamethasone also reduced TNF bioactivity in peripheral monocyte cultures, especially TNF-α. Dexamethasone also inhibits the release of IL-1β and IL-1ra by monocytes culture. (45)
The study by Reis et al (2007) have tested the effect of dexamethasone on cytokine production by monocytes infected by DENV in vitro. (42) TNF-α, IL-6, IL-10, and IFN-α was measured in cell supernatant PBML 10-15 different donors with immunoassay. Inhibition occurred significantly in monocyte cultures were added dexamethasone especially TNF-α, and IL-10. Interleukin 6 is not statistically different although 8 of the 15 donors PBML showed resistance> 35% (Figure 1). (42)
Downregulation of IFN-α initiate immunomodulatory effects of dexamethasone. This effect is not related to different viral clearance with antiviral effects caused by other molecules such as nitric oxide, which is known for controlling DENV replication in monocytes. Interleukin 10 38 46 block in STAT-1 and IRF-1, activation factor for nosocomial infection, whose expression can lead to inhibition of nitric oxide effect on DENV replication. (47, 48) After the downregulation of IL-10 by dexamethasone, activation of nosocomial infection can occur, resulting in a more efficient nitric oxide to the antiviral effects on monocytes. (42)
Dexamethasone acts as immunomodulator DENV infection that can reduce viral load and reduces the inflammatory reaction caused by a virus. (49) Dexamethasone significantly inhibited expression of DENV antigens and reduce the number of infected cells in 11 of the 15 culture monocytes. DENV particles decreased significantly after administration of dexamethasone for 2 days (Figure 1). (42) Although dexamethasone has a very interesting effect on in vitro models of dengue infection, clinical evidence is insufficient to recommend the use of corticosteroids in managing DHF / DSS.
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