Advertisement

Corticosteroid actions on dengue immune pathology; A review article

Published:November 12, 2019DOI:https://doi.org/10.1016/j.cegh.2019.11.001

      Abstract

      Introduction

      Dengue infection causes significant morbidity and mortality in over 125 countries worldwide, and its incidence is on the rise. Currently, no therapy is available beyond supportive care. In fact, corticosteroids are used therapeutically for a broad spectrum of diseases including autoimmune, allergic, inflammatory diseases and organ transplant rejection. However, only a few studies were done to evaluate the effectiveness of corticosteroids in dengue infection, although the immune pathology of dengue is similar to other diseases treated effectively by corticosteroids for several decades.

      Objectives

      This review is aimed at identifying biological actions of steroids at molecular and receptor level in dengue immune pathology after reviewing pharmacological and immunological research findings of corticosteroids and dengue.

      Methods

      We searched medline/pubmed and Google scholar for publications with the search terms ‘dengue’ and ‘steroid’, ‘corticosteroid’, ‘prednisolone’, ‘methylprednisolone’ or ‘dexamethasone’ in the title and abstract. Then the publications were analyzed according the action of steroids in dengue pathology under different subheadings.

      Results

      The results are presented under four categories and it shows that corticosteroids can suppress cells involved in innate immunity, T cells, B cells and antibodies,complements and heamatological manifestations in dengue pathology.

      Conclusion

      This article explains strong supportive evidence for actions of corticosteroids in dengue pathology at receptors and molecular levels. Therefore it is suggested that a gold standard steroid protocol for each phase of dengue pathology that can be tested further with a double blind control trial study.

      Keywords

      1. Introduction

      Dengue fever (DF) often presents with fever, rash, headache and myalgia, which are caused by a flavi virus with four distinct stereotypes; DENV-1, DENV-2, DENV-3, and DENV-4.
      • Bäck A.T.
      • Lundkvist Å
      Dengue viruses – an overview.
      An infection with one stereotype does not protect against the others and sequential infections put patients at a greater risk for dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS)
      • Soo K.-M.
      • Khalid B.
      • Ching S.-M.
      • Chee H.-Y.
      Meta-analysis of dengue severity during infection by different dengue virus serotypes in primary and secondary infections.
      that are mainly caused by immunological dysfunction.
      • Green S.
      • Rothman A.
      Immunopathological mechanisms in dengue and dengue hemorrhagic fever.
      The World Health Organization (WHO) estimates that 50 to 100 million-dengue infections occur annually and it affects more than 125 countries that are known to be dengue endemic. Moreover, it includes 500,000 cases of DHF and 22,000 deaths annually. Most of them are children. The incidence has increased by 30 folds during the past 50 years.
      • Hadinegoro S.R.S.
      The revised WHO dengue case classification: does the system need to be modified?.
      In Sri Lanka, 110,372 cases and 301 deaths were reported within the first seven months of the 2017 epidemic.
      • Jayarajah U.
      • Faizer S.
      • de zoysa I.
      • Seneviratne P.S.
      A large dengue epidemic affects Sri Lanka.
      Currently, no specific therapy is available beyond supportive care while untreated complicated dengue fever can have a 50% mortality rate.
      • Ebi K.L.
      • Nealon J.
      Dengue in a changing climate.
      Therefore, unless exact or partial treatment is introduced to suppress this life threatening immune dysfunction pathology of dengue, 5 million cases of DHF and 0.22 million deaths will occur within the next decade (2018–2028).
      Corticosteroids (CSs) are used therapeutically for a broad spectrum of diseases including autoimmune diseases, allergic and inflammatory diseases and in organ transplant. However, only a limited number of studies were done to evaluate the effectiveness of CSs in dengue infection,
      • Zhang F.
      • Kramer C.V.
      Corticosteroids for dengue infection. Cochrane infectious diseases group.
      although the immune pathology of dengue has been within the range of immune pathology of other diseases, which have been treated effectively by CSs for several decades.
      In fact, fear of administration of corticosteroid to dengue patients still exists because it is an infective illness. Very recently a review article stated favorable effect of steroid in dengue.
      • Bandara S.M.R.
      • Herath H.M.M.T.B.
      Effectiveness of corticosteroid in the treatment of dengue – a systemic review.
      In clinical trials there were no evidence of viremia with use of steroids and there were no significant side effects after the administration of low and high oral doses of corticosteroids and high doses of IV corticosteroids.
      • Tam D.T.H.
      • Ngoc T.V.
      • Tien N.T.H.
      • et al.
      Effects of short-course oral corticosteroid therapy in early dengue infection in Vietnamese patients: a randomized, placebo-controlled trial.
      • Nguyen T.H.T.
      • Nguyen T.H.Q.
      • Vu T.T.
      • et al.
      Corticosteroids for dengue – why don't they work? Halstead SB.
      Moreover, no evidence of harmful effects of corticosteroids was found
      • Tassniyom S.
      • Vasanawathana S.
      • Chirawatkul A.
      • Rojanasuphot S.
      Failure of high-dose methylprednisolone in established dengue shock syndrome: a placebo-controlled, double-blind study.
      and beneficial effects were found.
      • Premaratna R.
      • Jayasinghe K.G.N.U.
      • Liyanaarachchi E.W.
      • Weerasinghe O.M.S.
      • Pathmeswaran A.
      • de Silva H.J.
      Effect of a single dose of methyl prednisolone as rescue medication for patients who develop hypotensive dengue shock syndrome during the febrile phase: a retrospective observational study.
      In this recent review of dengue and steroids, it was concluded that the effectiveness of corticosteroid for immune suppression in dengue is depended on sustained maintained therapeutic blood levels of corticosteroids using a higher receptor affinity steroids for required time duration.
      With the conclusion of clinical trial studies data, a hypothesis was formulated. It is suggested that different doses, roots of administration, and particular groups of steroids contribute to suppress immune pathology of dengue at different stages of dengue infection due to different pharmacological actions of CSs at molecular and receptor levels. This could open a new direction to assess molecular and receptor level evidence of CSs to prove this hypothesis.

      2. Objectives

      This review is aimed at identifying biological actions of steroids at molecular and receptor level in dengue immune pathology after reviewing pharmacological and immunological research findings of CSs and dengue under different subheadings.

      3. Methods

      We searched medline/pubmed and Google scholar for publications with the search terms ‘dengue’ and ‘steroid’, ‘corticosteroid’, ‘prednisolone’, ‘methylprednisolone’ or ‘dexamethasone’ in the title and abstract. Then the publications were analyzed according the action of steroids in dengue pathology under different subheadings.

      4. Results

      The results are presented under four categories depending on steroids action on innate immunity, T cells, B cells and antibodies, complement system and hematological manifestations.

      4.1 CSs suppress cells involved in innate immunity in dengue pathology (Fig. 1)

      Dengue virus (DENV) is presumably injected into the bloodstream during the feeding of mosquitoes on humans and attacks the immune system cells. Firstly, it results in the infection of immature epidermal dendritic cells (DCs) in the epidermis and dermis.
      • Flores A.Y.L.
      • Tapia M.P.
      • Garcia I.E.
      • et al.
      Dengue virus inoculation to human skin explants: an effective approach to assess in situ the early infection and the effects on cutaneous dendritic cells.
      Infected DCs then migrate from the site of infection to lymph nodes where monocytes and macrophages are recruited. Thereafter the infection is amplified and the virus is disseminated through the lymphatic system.
      • Durbin A.P.
      • Vargas M.J.
      • Wanionek K.
      • et al.
      Phenotyping of peripheral blood mononuclear cells during acute dengue illness demonstrates infection and increased activation of monocytes in severe cases compared to classic dengue fever.
      As a result of this primary viremia, several cells of the mononuclear lineage, including blood-derived monocytes, myeloid DCs and splenic and liver macrophages are infected.
      • Blackley S.
      • Kou Z.
      • Chen H.
      • et al.
      Primary human splenic macrophages, but not T or B cells, are the principal target cells for dengue virus infection in vitro.
      The time gap between the bite of an infected mosquito and the onset of clinical symptoms is believed to be 3–15 days.
      • Lozach P.-Y.
      • Burleigh L.
      • Staropoli I.
      • et al.
      Dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN)-mediated enhancement of dengue virus infection is independent of DC-SIGN internalization signals.
      Fig. 1
      Fig. 1Steps from dengue virus induce deactivation of dendritic cells and leucocytes to dengue pathogenesis and corticosteroid action in the steps
      DENVs (1) infect im DCs (2) is facilitated by CD209(3) which has high affinity to the ICAM-3(4)on T cells. MMPs(4) are released by infected DCs and contributes to vascular leakage. DENVs infected immune cells (6) secret cytokines e.g. TNFα, IFNγ, IL-6(7) and activated T cells(8) promote the maturation and sensitivity(9) of imDCs. TNFα, IFNγ and IL-1B induce COX-2 gene expression through NF kB (10). The anti-inflammatory activity of steroids in leukocytes (6) is partly due to inhibition of signaling by NF- kB (11). mDCs(12) facilitate ADE(13) via FcγIIa and FcγIIb receptors(14) that contribute to increase of viral RNA production (15) over 100-fold. Macrophages(MQ), monocytes(Mo) and natural killer (NK) cells (6) are also involved in viral replication and cytokines production and killing of infected cells. In addition, mDCs can also activate T and B-cells(16). MP(17) usually enhances their (DCs) antigen uptake (18) and prevents DC differentiation and maturation(19). It also reduces the production of MMPs (20), TNF-α, TNF γ, IL-6 (21) and IL-12. MP also reduces the elevated expression of COX-2/PGE2 (22) associated with dengue infection and its replication (23). CSs causes up-regulation of the anti-inflammatory cytokine IL-10(24) that suppress production of macrophage inflammatory proteins such as IL-1, IL-6, IL-8, IL- 12, TNF, the granulocyte-macrophage colony stimulating factor (GM CSF), MHC class II molecules, B7 and ICAM-1(25). IL-10 also inhibits TNF-induced NF-κB activity (26) and acts to diminish Th1 cell activity by suppression of IL-2 and interferon-γ(27). CSs alter the trafficking and function of neutrophils, eosinophils, mastcells and endothelial cells(28). (29)Maternal IgG cause to increase severity of Dengue immune dysfunction in infants.
      (DENVs = dengue virus
      im DCs = Immature dendritic cells
      ICAM = intercellular adhesion molecule
      MMPs = producing matrix metalloproteinase
      DCs = Dendritic Cells
      TNFα = Tumor necrosis factor alpha
      IFNγ = Interferon gamma
      IL = Interleukin
      COX-2 = cyclooxygenase-2
      NF kB = nuclear factor kappaB
      mDCs = Mature Dendritic Cells
      ADE = Antibody-Dependent Enhancement
      MP = Methyl prednisolone
      PGE2 =cyclooxygenase-2
      Th1 = Type1 T helper).
      Immature dendritic cells (imDCs) express high levels of DC-SIGN (Dendritic Cell Specific Intercellular adhesion molecule-3 (ICAM-3) Grabbing Non-integrin)/CD209 which facilitates initial viral binding and entry. CD209 is a known target of dengue virus, having a high affinity for ICAM3 molecules expressed on T-cells.
      • Boonnak K.
      • Slike B.M.
      • Burgess T.H.
      • et al.
      Role of dendritic cells in antibody-dependent enhancement of dengue virus infection.
      ,
      • Pokidysheva E.
      • Zhang Y.
      • Battisti A.J.
      • et al.
      Cryo-EM reconstruction of dengue virus in complex with the carbohydrate recognition domain of DC-SIGN.
      Thus DCs are the most effective antigen presenting cells (APC) able to acquire and display viral antigens and finally activate T-cells. In dengue pathology, infected imDCs also contribute to vascular leak by producing matrix metalloproteinase (MMPs).
      • Tirado S.M.C.
      • Yoon K.-J.
      Antibody-dependent enhancement of virus infection and disease.
      The maturation and sensitivity of DCs are promoted by dengue virus induced cytokines e.g. TNFα, IFNγ, IL-6, and activated T cells.
      • Green S.
      • Rothman A.
      Immunopathological mechanisms in dengue and dengue hemorrhagic fever.
      ,
      • Palmer D.R.
      • Sun P.
      • Celluzzi C.
      • et al.
      Differential effects of dengue virus on infected and bystander dendritic cells.
      Mature Dendritic Cells (mDCs) lose their ability to capture and process antigens, up-regulate their production of cytokines, increase their expression of MHC class which has been suggested as a mechanism by which the immune system may enhance viral pathogenesis.
      • Tirado S.M.C.
      • Yoon K.-J.
      Antibody-dependent enhancement of virus infection and disease.
      ,
      • Henrickson S.E.
      • Mempel T.R.
      • Mazo I.B.
      • et al.
      T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation.
      The mDCs do not possess high levels of DC-SIGN but they do facilitate Antibody-Dependent Enhancement (ADE) via FcγIIa and FcγIIb receptors.
      • Pokidysheva E.
      • Zhang Y.
      • Battisti A.J.
      • et al.
      Cryo-EM reconstruction of dengue virus in complex with the carbohydrate recognition domain of DC-SIGN.
      ,
      • Nielsen D.G.
      The relationship of interacting immunological components in dengue pathogenesis.
      ADE in mDCs can increase viral RNA production over 100-folds making dendritic cells potent components in dengue pathogenesis.
      • Green S.
      • Rothman A.
      Immunopathological mechanisms in dengue and dengue hemorrhagic fever.
      ,
      • Nielsen D.G.
      The relationship of interacting immunological components in dengue pathogenesis.
      When DCs fail to mature properly, they will fail to stimulate T-cells and may induce tolerance.
      • Nielsen D.G.
      The relationship of interacting immunological components in dengue pathogenesis.
      Moreover, mDCs can also activate B-cells through co-stimulation of CD40, IL-6 and IL-14. In addition to DCs, macrophage, monocyte and natural killer (NK) cells also mediate for viral replication, cytokines production and killing of infected cells.
      • Nielsen D.G.
      The relationship of interacting immunological components in dengue pathogenesis.
      In fact, IL-15 produced by DCs has comparable activity with IL-2 for the induction of B and NK cell proliferation and differentiation.
      • Henrickson S.E.
      • Mempel T.R.
      • Mazo I.B.
      • et al.
      T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation.
      • Armitage R.J.
      • Macduff B.M.
      • Eisenman J.
      • Paxton R.
      • Grabstein K.H.
      IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation.
      Among CSs, methylprednisolone (MP) usually enhance antigen uptake and prevent DC differentiation and maturation and production of TNF-a, IL-6, and IL-12. But MP does not affect the viability of DC.

      Vanderheyde N, Verhasselt V, Goldman M, Willems F. Inhibition of human dendritic cell functions by methylprednisolone. Transplantation. 67(10):1342.

      • Piemonti L.
      • Monti P.
      • Allavena P.
      • et al.
      Glucocorticoids affect human dendritic cell differentiation and maturation.
      • Wong P.
      • Cuello C.
      • Bertouch J.V.
      • et al.
      The effects of pulse methylprednisolone on matrix metalloproteinase and tissue inhibitor of metalloproteinase‐1 expression in rheumatoid arthritis.
      By these ways, the maturity function of DCs is retarded. This may in turn indirectly suggests, reduce dengue viral replication that was 100 times in mDCs. In addition, MP treated DCs were deficient in their ability to elicit proliferative responses and production of MMPs.

      Vanderheyde N, Verhasselt V, Goldman M, Willems F. Inhibition of human dendritic cell functions by methylprednisolone. Transplantation. 67(10):1342.

      This may contribute to prevent vascular leak in dengue. Furthermore, CSs exert potent suppressive effects on human DCs and thereby inhibit the induction of primary T and B cell responses preventing immune dysfunction induced by dengue virus. MP also cause up-regulation of the anti-inflammatory cytokine IL-10, which gets its anti-inflammatory effect by suppressing the production of macrophage inflammatory proteins such as IL-1, IL-6, IL-8, IL-12, TNF, the granulocyte-macrophage colony stimulating factor (GM CSF), MHC class II molecules, B7 and intercellular adhesion molecule-1 (ICAM-1).
      • Moore K.W.
      • de Waal Malefyt R.
      • Coffman R.L.
      • O'Garra A.
      Interleukin-10 and the interleukin-10 receptor.
      • Hodge Flower
      Han. Methyl-prednisolone up-regulates monocyte interleukin-10 production in stimulated whole blood.
      More interestingly, IL-10 inhibits TNF-induced NF-κB activity and acts to diminish Th1 cell activity by suppressing IL-2 and interferon-γ.
      • Coutinho A.E.
      • Chapman K.E.
      The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights.
      The anti-inflammatory effects of CSs on leucocytes is partly by inhibition of signaling of NF-κB. Moreover, glucocorticoids (GCs) alter the trafficking and functioning of leucocytes such as neutrophils, eosinophils, mast cells and endothelial cells.
      • Santini G.
      The human pharmacology of monocyte cyclooxygenase 2 inhibition by cortisol and synthetic glucocorticoids.
      Elevated cyclooxygenase-2 (COX-2) and Prostaglandin E2 (PGE2) expression caused by viral infection have been reported to be associated with viral replication and viral pathogenesis.
      • Steer S.A.
      • Corbett J.A.
      The role and regulation of COX-2 during viral infection.
      ,
      • Lin C.-K.
      • Tseng C.-K.
      • Wu Y.-H.
      • et al.
      Cyclooxygenase‐2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents.
      Administration of a single oral dose (4, 8, or 16 mg) of MP was found to cause a dose and time-dependent inhibition of whole-blood COX-2 activity and significantly lower the levels of PGE232. Thus it could be suggested that CSs contribute indirectly to reduce both replication and viral pathogenesis either through DCs or COX-2/PGE2.

      4.2 CSs suppress T cells, B cells and antibody in dengue pathology (Fig. 2)

      Another important molecule in dengue pathology is the antibody. The normal interaction of dengue virus with anti-dengue antibody generally leads to neutralization. However, in heterotypic dengue viral infections, the antibodies are non-neutralizing and lead to enhancement. Thus pre-existing antibodies (Ig G and Ig M) are associated with antibody-dependent enhancement and complement activation.
      • Tirado S.M.C.
      • Yoon K.-J.
      Antibody-dependent enhancement of virus infection and disease.
      In infants also dengue hemorrhagic fever can occur in primary dengue viral infection that could be due to maternally derived nonneutralizing IgG facilitated antibody-dependent enhancement.
      • Chau T.N.B.
      • Hieu N.T.
      • Anders K.L.
      • et al.
      Dengue virus infections and maternal antibody decay in a prospective birth cohort study of Vietnamese infants.
      The non-neutralizing levels of dengue virus-reactive IgG were postulated to be a critical risk factor for severe dengue during infancy. Therefore live actuated dengue vaccine is a cause for risk of severe dengue in such infants, even in their primary infection. In addition the disease severity due to a robust immune response in infants with primary infections would be associated with a consequence of higher viral burdens in vivo and an activation phenotype of peripheral-blood NK cells and CD8+ and CD4+ T cells.
      • Chau T.N.B.
      • Quyen N.T.H.
      • Thuy T.T.
      • et al.
      Dengue in Vietnamese infants--results of infection-enhancement assays correlate with age-related disease epidemiology, and cellular immune responses correlate with disease severity.
      Fig. 2
      Fig. 2Steps from activation of T and B cells to dengue pathogenesis and corticosteroid action in the steps
      DENVs(1) infected DCs or antigen presenting cells(2) activate CD8(3) and CD4 T cells.(4). CD8+cells mature into NK cells that help in controlling early viral infection (3-1) but the intense proliferation of CD8+ cells(5) can also contribute to dengue pathogenesis. Activated Type1 T helper (Th1) cells(6) produce interferon-gamma
      (IFN γ)(7), interleukin (IL)-2, and tumour necrosis factor (TNF)-β (8), which activates macrophages (9) to release immune mediators in dengue pathology(10). IFNγ up regulates number of Fcγ receptors(11) resulting in increased ADE(12). Activated type 2 Th (Th2) cells (13) produce IL-4, IL-5, IL-10 and IL-13,(14) which are mainly responsible for antibody production, eosinophils activation, and inhibition of several macrophage functions. CSs (15) further involve in the inhibition of the release of pro-inflammatory cytokines IL-1 α and beta, IL-2, IFN γ and TNF- α, and up-regulation of the anti-inflammatory cytokine IL-10(16). DENVs infected cells secrets NS-1 antigen (17). Antibodies against DENVs and anti-NS1 are produced by B cells which are suppressed by lowering of amounts of IL-2 and IL-2 receptors(18). The former antibodies(19) contribute to ADE(12) and the latter stimulates immune cells to release of IL-6, IL-8, and MCP-1 and involves in activation of a complement (21). In addition CSs inhibits cytokine-induced apoptosis by up regulating anti-apoptotic genes(22). The autoimmune part of dengue illness is brought about by anti-NS1antibodies mediated via IL-17 and IFN-γ (23) which leads to multi organ failure and death (24). All these effect of CSs contribute to the reduction or suppression of the pathogenesis (10) of dengue.
      (DENVs = Dengue virus
      NK = Natural killer
      Th1 = Type1 T helper
      IFN γ = interferon-gamma
      TNF = tumour necrosis factor
      IL = Interleukin
      CSs = Corticosteroids
      ADE = Antibody-Dependent Enhancement
      MCP = Monocyte chemoattractant protein).
      Type1 T helper (Th1) cells produce IFNγ, IL-2 and the tumour necrosis factor (TNF)-beta, which activate macrophages.
      • Swain S.L.
      • McKinstry K.K.
      • Strutt T.M.
      Expanding roles for CD4+ T cells in immunity to viruses.
      ,
      • Weiskopf D.
      • Sette A.
      T-cell immunity to infection with dengue virus in humans.
      By contrast, type 2 T helper (Th2) cells produce IL-4, IL-5, IL-10 and IL-13, which are mainly responsible for antibody production, eosinophil activation and inhibition of several macrophage functions.
      • Weiskopf D.
      • Sette A.
      T-cell immunity to infection with dengue virus in humans.
      IFNγ and TNFα were also strongly associated with dengue disease severity and correlate well with T-cell activation.
      • Green S.
      • Rothman A.
      Immunopathological mechanisms in dengue and dengue hemorrhagic fever.
      IFNγ secretion by dengue specific T-cells has been shown to up regulate the number of Fcγ receptors, which play a noted role in ADE.
      • Kontny U.
      • Kurane I.
      • Ennis F.A.
      Gamma interferon augments Fc gamma receptor-mediated dengue virus infection of human monocytic cells.
      This effect in turn leads to increased replication of dengue virus as well. Interestingly, CD8+ cells help in controlling early viral infection but the intense proliferation of CD8+ cells can also contribute to dengue pathogenesis.
      • de Matos A.M.
      • Carvalho K.I.
      • Rosa D.S.
      • et al.
      CD8+ T lymphocyte expansion, proliferation and activation in dengue fever.
      CSs inhibit the synthesis of several T cell-derived cytokines at the transcriptional level and perform their action through inhibition of the release of pro-inflammatory cytokines IL-1α, beta, IL-2, IFNγ, TNF-α and up-regulation of the anti-inflammatory cytokine IL-10 40. Another corticosteroid, hydrocortisone had significantly decreased endotoxin induced expression of TNF–α, IL-6, IL-8 and IL-1 and could ameliorate the inflammatory cytokines expression without impairing innate immune responses needed to combat bacterial infections.
      • Hart K.A.
      • Barton M.H.
      • Vandenplas M.L.
      • Hurley D.J.
      Effects of low-dose hydrocortisone therapy on immune function in neonatal horses.
      More interestingly dengue virus infected cells secrete nonstructural protein 1 (NS1) glycoprotein which can be found bound to platelets, endothelial cells and cells in the lung and liver.
      • Avirutnan P.
      • Zhang L.
      • Punyadee N.
      • et al.
      Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E.
      In an in-vitro model of vascular leak, treatment with NS1 alone resulted in the disruption of endothelial cell monolayer integrity
      • Modhiran N.
      • Watterson D.
      • Muller D.A.
      • et al.
      Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity.
      and the vascular leak that plays a major role in the pathology of dengue hemorrhagic fever and shock. Therefore availability of circulating NS1 can be reduced by inhibiting the replication of virus. It could be achieved by early administration of CSs which inhibit whole-blood COX-2 activity and significantly lower the levels of PGE232 reducing both replication of virus and viral pathogenesis either through DCs or COX-2/PGE2.It was also found that no increase of viremia in the early administration of CSs in clinical research.
      • Nguyen T.H.T.
      • Nguyen T.H.Q.
      • Vu T.T.
      • et al.
      Corticosteroids for dengue – why don't they work? Halstead SB.
      On the other hand circulating NS1 level also activates toll-like receptor 4 (TLR4) and the TLR2/6 heterodimer in immune cell contributing to the vascular leak that leads to the induction and release of proinflammatory cytokines and chemokines.
      • Modhiran N.
      • Watterson D.
      • Blumenthal A.
      • Baxter A.G.
      • Young P.R.
      • Stacey K.J.
      Dengue virus NS1 protein activates immune cells via TLR4 but not TLR2 or TLR6.
      On this background it was proposed that NS1 plays a major role in the pathology of dengue hemorrhagic fever and shock via activation of immune cells and NS1-induced vascular leak in vitro. Those actions were inhibited by a TLR4 antagonist and by anti-TLR4 antibody treatment44 45.Moreover, it has also been said that TLR signaling is modulated by even CSs in a cell type-specific fashion resulting in down-regulation of TLR expression, suppression of pro-inflammatory and up-regulation of anti-inflammatory cytokines
      • Broering R.
      • Montag M.
      • Jiang M.
      • et al.
      Corticosteroids shift the Toll-like receptor response pattern of primary-isolated murine liver cells from an inflammatory to an anti-inflammatory state.
      On the other hand anti-NS1 antibodies (auto antibody formation) are produced against NS1antigen, leading to the development of an autoimmune pathology in dengue patients.
      • Lin C.-F.
      • Wan S.-W.
      • Cheng H.-J.
      • Lei H.-Y.
      • Lin Y.-S.
      Autoimmune pathogenesis in dengue virus infection.
      Moreover, anti-NS1 antibodies show affinity to human fibrinogen, thrombocytes and endothelial cells.
      • Avirutnan P.
      • Zhang L.
      • Punyadee N.
      • et al.
      Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E.
      When vulnerable human tissue cells or molecules are exposed to NS1 antibodies, they undergo intrinsic apoptosis, which can be blocked with an inducible nitric oxide synthetase (iNOS) inhibitor.
      • Lin C.F.
      • Lei H.Y.
      • Shiau A.L.
      • et al.
      Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide.
      In addition, anti-NS1 antibodies stimulate the release of IL-6, IL-8 and MCP-1, that involves the activation of complements
      • Avirutnan P.
      • Punyadee N.
      • Noisakran S.
      • et al.
      Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement.
      in dengue pathology. MP was found to suppress IL-17and IFN-γ, which are important immune molecules for the autoimmune role in dengue illness induced by anti NS-1 anti bodies.
      • Elsabahy M.
      • Wooley K.L.
      Cytokines as biomarkers of nanoparticle immunotoxicity.
      Moreover, MP indirectly decreases the cytotoxic effects of nitric oxide (NO) and TNF-α.
      • Lin C.F.
      • Lei H.Y.
      • Shiau A.L.
      • et al.
      Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide.
      This effect could help to prevent anti NS1 antibody induced intrinsic apoptosis and vital tissue damage, which may contribute to organ failure and death in dengue.
      • Coutinho A.E.
      • Chapman K.E.
      The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights.
      ,
      • Meßmer U.K.
      • Winkel G.
      • Briner V.A.
      • Pfeilschifter J.
      Suppression of apoptosis by glucocorticoids in glomerular endothelial cells: effects on proapoptotic pathways.
      More interestingly, CSs inhibit cytokine-induced apoptosis by up-regulating anti-apoptotic genes and by suppressing humoral immunity through B cells to express lower amounts of IL-2 and IL-2 receptors,
      • Coutinho A.E.
      • Chapman K.E.
      The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights.
      leading to reduce antibody induced immune pathology in dengue patients.

      4.3 Corticosteroids suppress DENVs induced complement activation (Fig. 3)

      The complement system is an important component of the innate immune system against various pathogens. The C3 amplification loop lies at the core of all the complement pathways.
      • Harboe M.
      • Mollnes T.E.
      The alternative complement pathway revisited.
      The system controls viral infections through multiple mechanisms, including lysis of virions or infected cells, production of anaphylatoxins and priming of T and B cell responses.
      • Shresta S.
      Role of complement in dengue virus infection: protection or pathogenesis?.
      However, in dengue infection a deficiency in Mannose-binding lectin (MBL) level or activity due to host polymorphisms in the MBL2 gene correlates with reduced levels of DENV neutralization, which may modulate DHF/DSS manifestations. Therefore, the MBL pathway contributes to protection against DENV infection in humans.
      • Madsen H.O.
      • Garred P.
      • Kurtzhals J.A.L.
      • et al.
      A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein.
      • Basta M.
      Ambivalent effect of immunoglobulins on the complement system: activation versus inhibition.
      Moreover, the complement peptides C3a, C4a and C5a are referred to as anaphylatoxins, which have a wide variety of biological functions.
      • Harboe M.
      • Mollnes T.E.
      The alternative complement pathway revisited.
      Following dengue viral infections, both DCs and T-cells up-regulate C3a and C5a receptors and produce C3 peptide.
      • Nielsen D.G.
      The relationship of interacting immunological components in dengue pathogenesis.
      Furthermore, the complement peptides are activated by DC antigen uptake and presentation. Some of the primary sources of C3 are APCs such as DC and macrophages. In patients with severe dengue, large amounts of C3a have been detected to serve to recruit monocytes, macrophages and dendritic cells that regulate vasodilatation, increase permeability of small blood vessels, disrupt vasculature and smooth muscle contraction.
      • Yamanaka A.
      • Hendrianto E.
      • Mulyatno K.C.
      • et al.
      Correlation between complement component levels and disease severity in dengue patients in Indonesia.
      These complementary molecules and enzymes can induce oxidative burst and generation of cytotoxic oxygen radicals, mediate chemotaxis, inflammation and basophils, neutrophils, eosinophils and mast cells to release histamine.
      • Harboe M.
      • Mollnes T.E.
      The alternative complement pathway revisited.
      C3a, C5a, and C5b-9 cause circulatory collapse similar to an IgE mediated allergic response e.g. anaphylaxis when their concentrations are high enough to invoke a general systemic response.
      • He S.-H.
      • Zhang H.-Y.
      • Zeng X.-N.
      • Chen D.
      • Yang P.-C.
      Mast cells and basophils are essential for allergies: mechanisms of allergic inflammation and a proposed procedure for diagnosis.
      Thus higher complement levels correlate to increasing disease severity of dengue illness.
      • Yamanaka A.
      • Hendrianto E.
      • Mulyatno K.C.
      • et al.
      Correlation between complement component levels and disease severity in dengue patients in Indonesia.
      Cross reactive antibodies activate complements further. Finally increased alternative complement proteins, complement receptors and C proteins facilitate a positive feedback loop that can lead to dangerous consequences in a dengue-infected patient.
      Fig. 3
      Fig. 3Steps from complement activation to dengue pathogenesis and action of corticosteroid
      DENVs(1) infect both DCs and T-cells (2)and up-regulate C3a and C5a receptors (3) and produce C3 peptide (4).Viral infected macrophage also involve in C3 peptide production (5). The complements are activated through antigen antibody complexes(6) named the classical pathway(7); recognition of carbohydrate structures on pathogens(8) by mannose binding lectin/MBL pathway (9) and hydrolysis of C3(H2O) (10) named as alternative pathway(11). DENVs can be directly neutralized via the MBL pathway(12). The increase in alternative complement proteins, complement receptors(3) and C protein(4), all facilitate (13) a positive feedback loop (amplification pathway)(14). They mediate basophiles, neutrophils, eosinophils and mast cells to release histamine (15). Dengue pathology is increased by complement molecules and enzymes (C3a and C5a) that can induce oxidative bursts, generation of cytotoxic oxygen radicals, chemotaxis, inflammation, circulatory collapse as well (e.g.anaphylaxis)(16). MP(17) directly inhibits the alternative(18) and amplification pathway (19) of the complement but not the MBL path way. CSs in higher doses (20) may function by regulating multiple events in the immunological apparatus including inhibition of compliments, stabilization of membranes and modulation of vivo components levels (21).
      (DENV = Dengue virus
      DC = Dengue virus
      MBL = Mannose-binding lectin
      MP = Mannose-binding lectin
      CSs = Corticosteroids).
      In this life threatening steps of dengue pathology, it is observed that MP directly inhibits the alternative and amplification pathway of complements.
      • Weiler J.M.
      • Packard B.D.
      Methylprednisolone inhibits the alternative and amplification pathways of complement.
      Moreover, steroids in higher doses may regulate multiple steps in the immunological apparatus, including stabilization of membranes, modulation of in vivo component levels and inhibition of complements, which help to stop or prevent histamine release, vascular permeability and circulatory collapse.
      • Hammerschmidt D.E.
      • White J.G.
      • Craddock P.R.
      • Jacob H.S.
      Corticosteroids inhibit complement-induced granulocyte aggregation. A possible mechanism for their efficacy in shock states.

      4.4 Corticosteroids suppress DENV induced hematological manifestation (Fig. 4)

      Hematological abnormalities that are generally observed in severe dengue, such as thrombocytopenia, coagulopathy, bleeding and vasculopathy are related to platelet and endothelial dysfunction.
      • Azeredo EL de
      • Monteiro R.Q.
      • de-Oliveira Pinto L.M.
      Thrombocytopenia in dengue: interrelationship between virus and the imbalance between coagulation and fibrinolysis and inflammatory mediators.
      Disseminated intravascular coagulation and major hemorrhages in a minority of patients with severe or prolonged shock may be due to severe thrombocytopenia and the secondary effects of hypoxia and acidosis.
      • Azeredo EL de
      • Monteiro R.Q.
      • de-Oliveira Pinto L.M.
      Thrombocytopenia in dengue: interrelationship between virus and the imbalance between coagulation and fibrinolysis and inflammatory mediators.
      Thrombocytopenia may be due to bone marrow suppression, immune mediated platelet destruction, augmented platelet adhesiveness to vascular endothelial cells and high levels of platelet activating factor (PAF).
      • Wang S.
      • He R.
      • Patarapotikul J.
      • Innis B.L.
      • Anderson R.
      Antibody-enhanced binding of dengue-2 virus to human platelets.
      Moreover marked thrombocytopenia is evident in patients with elevated IL-1β, IL-8, TNF-α and Monocyte chemo-attractant protein-1 (MIP-1).
      • Bozza F.A.
      • Cruz O.G.
      • Zagne S.M.O.
      • et al.
      Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity.
      Spontaneous bleeding is strongly associated with platelet count below 100,000 cells/c.mm or a rapid drop in the platelet count.
      • Bozza F.A.
      • Cruz O.G.
      • Zagne S.M.O.
      • et al.
      Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity.
      In addition, the cause for increased spontaneous bleeding may be brought about by low plasma fibrinogen levels, release of Heparansulphate and secretion of Von Willebrand factor (VWF) in DHF. Low plasma fibrinogen may be due to permeation of fibrinogen through the endothelial cells, development of antibodies potentially cross-reactive to plasminogen and impaired synthesis of fibrinogen.
      • Azeredo EL de
      • Monteiro R.Q.
      • de-Oliveira Pinto L.M.
      Thrombocytopenia in dengue: interrelationship between virus and the imbalance between coagulation and fibrinolysis and inflammatory mediators.
      • Wills B.A.
      • Oragui E.E.
      • Minh Dung N.
      • et al.
      Size and charge characteristics of the protein leak in dengue shock syndrome.
      Heparansulphate in blood vessels acts like an anti-coagulant and is damaged by the initial cytokine response in DHF and liberated to the circulation. This may be the reason for the prolonged Activated partial thromboplastin time (APTT) in DHF.
      • Palmer R.N.
      • Rick M.E.
      • Rick P.D.
      • Zeller J.A.
      • Gralnick H.R.
      Circulating heparan sulfate anticoagulant in a patient with a fatal bleeding disorder.
      Severe dengue is associated with increased circulating levels of VWF, which is associated with thrombocytopenia, clinical bleeding and plasma leakage.
      • Nehmé A.
      • Edelman J.
      Dexamethasone inhibits high glucose-, TNF-alpha-, and IL-1beta-induced secretion of inflammatory and angiogenic mediators from retinal microvascular pericytes.
      However, the tendency to bleed after a high dose of CSs could not be observed because non-genomic effects of GSs enhance the rapid activation of endothelial nitric oxide synthase (eNOS), which is a possible inhibitor of VWF secretion.
      • Chopra A.
      • Kumar R.
      • Kishore K.
      • et al.
      Effect of glucocorticoids on von Willebrand factor levels and its correlation with von Willebrand factor gene promoter polymorphism.
      Fig. 4
      Fig. 4Steps from hematological manifestation to dengue pathogenesis and corticosteroid action in the steps.
      DENVs(1) infect and suppress megakaryocyte cells (MCs) (2) in bone marrow leading to thrombocytopenia(3) that is aggravated by endothelial cells adhesion molecule (4),antiplatelet antibodies(5) and platelet adhesion molecule (15). Infected immune cells(7) secrete platelet activating factor (PAF) (8) and cytokines(9) and chemokines. These effects are suppressed or reduced by CSs (6) PAF is implicated in platelet aggregation and activation (10) resulting thrombocytopenia (3), increased release of VWF (11) and Heparan sulphate(12), low levels of fibrinogen (13) contribute to aggravated bleeding(14) tendency in dengue. The dengue induced pathological effect such as production of cytokines (9), platelet adhesive molecules (15) NS-1 antibody (16) formation are suppressed by CSs/MP. The ability of increased endothelial NO (e NO)(17) production by MP leads to reduced secretion of (18). All contribute to reduce the tendency to bleed(13) and its cause in dengue. Activation of platelets(10),complements(19) and release of inflammatory mediators such as PAF(8), MCP-1(20), VEGF(21), TNF(22) leading to plasma leakage and contribute to the development of vasculopathy (23). It is brought about by PAF through altered expressions of the pattern of the tight junction protein ZO-1 (24). Dexamethasone (DEX) (25) increases the expression of ZO-1 and decreases levels of PAF via suppression of immune molecules. CSs suppress immune cells(26) and reduce production of prostanoids (PTs), NO(27) and COX-2 (28) which are the permeability facilitators of VEGF and TNF respectively. (29) CSs also suppress the action of NS-1directly and indirectly.
      (DENV = Dengue virus
      MCs = megakaryocyte cells
      PAF = platelet activating factor
      VWF = Von Willebrand factor
      CSs = Corticosteroids
      MP = Methylprednisolone
      MCP = Monocyte chemoattractant protein
      VEGF = Vascular endothelial growth factor
      TNF = Tumor necrosis factor alpha
      DEX = Dexamethasone
      PTs = prostanoids
      NO = Nitric oxide
      COX-2 = Cyclooxygenase-2).
      Activation of both platelets and complements and release of inflammatory mediators such as vascular endothelial growth factor (VEGF), TNFα, PAF and Monocyte chemoattractant protein-1 (MCP-1) is proposed as the mechanism that causes vasculopathy leading to the plasma leakage.
      • Mukerjee R.
      • Chaturvedi U.C.
      • Dhawan R.
      Dengue virus-induced human cytotoxic factor: production by peripheral blood leucocytes in vitro.
      VEGF may induce permeability via prostanoids and NO or via PAF.
      • Murohara T.
      • Horowitz J.R.
      • Silver M.
      • et al.
      Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin.
      TNFα may lead to permeability via cyclooxygenase induction and the release of prostanoids.
      • Cirino G.
      Multiple controls in inflammation: extracellular and intracellular phospholipase A2, inducible and constitutive cyclooxygenase, and inducible nitric oxide synthase.
      In fact, it was observed that CSs inhibit the pro angiogenic gene VEGF
      • Gille J.
      • Reisinger K.
      • Westphal-Varghese B.
      • Kaufmann R.
      Decreased mRNA stability as a mechanism of glucocorticoid-mediated inhibition of vascular endothelial growth factor gene expression by cultured keratinocytes.
      resulting in reduced plasma leakage. PAF is produced and secreted by several types of cells, including mast cells, monocytes, tissue macrophages, platelets, eosinophils, endothelial cells and neutrophil which has also been shown to be involved in the production of many inflammatory cytokines such as TNFα and IL-1β.
      • Valone F.H.
      • Epstein L.B.
      Biphasic platelet-activating factor synthesis by human monocytes stimulated with IL-1-beta, tumor necrosis factor, or IFN-gamma.
      PAF levels were significantly higher in more severe forms of dengue and were associated with a reduced expression of tight junction proteins and reduced cell layer integrity resulting in increased para cellular leak.
      • Yang K.D.
      • Lee C.S.
      • Shaio M.F.
      A higher production of platelet activating factor in ex vivo heterologously secondary dengue-2 virus infections.
      Moreover, PAF acts as a potent activator and a mediator of both immune-mediated and non-immune mediated anaphylaxis. It is implicated in platelet aggregation and activation through oxidative bursts, chemotaxis of leukocytes, augmentation of arachidonic acid, metabolism and release of vasoactive amines in the inflammatory response, resulting in increased vascular permeability, circulatory collapse, decreased cardiac output and various other biological effects.
      • Valone F.H.
      • Epstein L.B.
      Biphasic platelet-activating factor synthesis by human monocytes stimulated with IL-1-beta, tumor necrosis factor, or IFN-gamma.
      ,
      • Yang K.D.
      • Lee C.S.
      • Shaio M.F.
      A higher production of platelet activating factor in ex vivo heterologously secondary dengue-2 virus infections.
      In dengue patients, PAF was found to alter the expression pattern of the tight junction protein ZO-1 and had decreased the integrity of human endothelial cell monolayer, as measured by trans-endothelial resistance.
      • Yang K.D.
      • Lee C.S.
      • Shaio M.F.
      A higher production of platelet activating factor in ex vivo heterologously secondary dengue-2 virus infections.
      Among the CSs, dexamethasone was investigated earlier and proved that it can increase transendothelial electrical resistance and ZO-1 expression.
      • Hue C.D.
      • Cho F.S.
      • Cao S.
      • Dale Bass C.R.
      • Meaney D.F.
      • Morrison B.
      Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein.
      In addition, dexamethasone has also been found to influence tight junction expression leading to a reduction of permeability.
      • Hue C.D.
      • Cho F.S.
      • Cao S.
      • Dale Bass C.R.
      • Meaney D.F.
      • Morrison B.
      Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein.
      Furthermore, it was observed that the amount of plasma extravasations produced by PAF was decreased by dexamethasone in adrenalectomized rats.
      • Boschetto P.
      • Musajo F.G.
      • Tognetto L.
      • et al.
      Increase in vascular permeability produced in rat airways by PAF: potentiation by adrenalectomy.
      On the other hand, TNF and IL-1were found to stimulate the synthesis and release of the platelet-activating factor (PAF) by neutrophils and vascular endothelial cells,
      • Aikawa T.
      • Hirose T.
      • Matsumoto I.
      • et al.
      Effect of platelet-activating factor on cortisol and corticosterone secretion by perfused dog adrenal.
      which could be effectively suppressed by CSs as mentioned above.
      • Hue C.D.
      • Cho F.S.
      • Cao S.
      • Dale Bass C.R.
      • Meaney D.F.
      • Morrison B.
      Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein.

      5. Conclusion

      Lack of knowledge and clinical practice on the use of corticosteroids in relation to immune pathology exists and causes clinical manifestations of DSS/DHF and their complications. Therefore all clinicians must be provided with adequate scientific evidence in these regards. Apart from the existing fluid management for dengue disease, this immune pharmacological approach is suggested as a treatment option to suppress the immune dysfunction that leads to DHF and other complication of dengue. Therefore the value of steroid on dengue immune pathology cannot be underestimated and this could open a completely new scientific approach and will be suggested for management of more than 250,000–500,000 patients in the world who suffer from sever dengue disease annually. This can be tested further with a double blind control trial study using a standard steroid protocol considering the stages of immunopathology of dengue. This review article (a) provides an immunological link between dengue and steroid treatment (b) offers scope for corticosteroid based treatment as an approach for DF and DHF,DSS (c) provides a better understanding of actions of corticosteroid in dengue immune pathology (d) provides and opens well known arguments, completely new to dengue, but with strong scientific evidence to reconsider use of steroid to manage dengue and its complications (e) offers scope to consider steroids for primary and secondary prevention of dengue and complication and treatment. (f) provides information on the main cause for aggravation of existing dengue pathology under non-steroid therapy (g) provides a plausible explanation as to why not all patients with dengue develop DHF/DSS and differently associated complications. (h) can be used to explain other treatment methods that are used to explain such as herbal and other approaches to control dengue disorders and its complications (i) offers a novel coherent picture of the immune pathology of dengue related to the pharmacological approach of corticosteroid treatment at different severity of dengue immune pathology.

      Declaration of Competing interest

      None to declare.

      Acknowledgements

      I thank all the researchers and their medical and non-medical staff for their dedication to do research on dengue related topics and publishing them for past few decades. I am most grateful to Dr Rohitha Muthugala (Consultant Virologist) Dr. Indunil Wijeweera (Consultant Neurologist Neurology Unit), Dr. R.M.S.K Rathnayake (The Director) and Dr. Nishshanka Wijewardane, (Deputy Director) at General Hospital Kandy. I also thank Mr. P.G.A.C.Siriwardana, Mr.Y.C.Senanayake (fourth year Medical students,university of Peradeniya) Ms.T.N.Senanyake (First year medical student,university of Karapitiya) for their contribution to draw diagrams. I would also like to acknowledge Dr.W.A.W.M.R.M.P.Wijesingha, Dr.Mrs.W.M.J.K.K.Buddadasa, Dr.Mrs.J.Abbas Dr Mrs. Deepa Gunawardana and Dr. Mrs Awanthi (Teaching Hospital Kandy) and the administrative staff at the Teaching Hospital, Kandy. In addition, I extend my gratitude to the Editorial Board of the Journal for taking early steps to publish this.

      Abbreviations

      DF
      Dengue fever
      DHF
      Dengue hemorrhagic fever
      DSS
      Dengue shock syndrome
      WHO
      World Health Organization
      CSs
      Corticosteroids
      DENV
      Dengue virus
      DCs
      Dendritic cells
      imDCs
      Immature dendritic cells
      DC-SIGN
      Dendritic Cell Specific Intercellular adhesion molecule-3 (ICAM-3) Grabbing Non-integrin
      MMPs
      Matrix metalloproteinase
      TNFα
      Tumor necrosis factor alpha
      IFNγ
      Interferon gamma
      IL
      Interleukin
      mDCs
      Mature Dendritic Cells
      MHC
      Major histocompatibility complex
      ADE
      Antibody-Dependent Enhancement
      NK
      Natural killer
      MP
      Methylprednisolone
      GM CSF
      Granulocyte-macrophage colony stimulating factor
      ICAM-1
      Intercellular adhesion molecule-1
      GCs
      Glucocorticoids
      COX-2
      Cyclooxygenase-2
      PGE2
      Prostaglandin E2
      Th1
      Type1 T helper
      Th2
      Type 2 Th
      NS1
      Nonstructural protein 1
      iNOS
      Inducible nitric oxide synthatase
      NO
      Nitric oxide
      MBL
      Mannose-binding lectin
      PAF
      Platelet activating factor
      VWF
      Von Willebrand factor
      APTT
      Activated partial thromboplastin time
      eNOS
      Endothelial nitric oxide synthase
      VEGF
      Vascular endothelial growth factor
      MCP-1
      Monocyte chemoattractant protein-1

      Ethical approval

      Not required.

      Availability of data and material

      The data set for this publication is available upon request from the authors.

      Funding

      None.

      Authors contribution

      SMRB Formulated hypotheses on following topics such Corticosteroid actions on dengue immune pathology effectiveness of corticosteroid in dengue treatment and management of dengue and post dengue Syndrome hypothesis for dengue, devised the project and review articles, the main conceptual ideas and proof outline, wrote the manuscript. HMMTBH corrected, edited the manuscript and supervised the review.

      References

        • Bäck A.T.
        • Lundkvist Å
        Dengue viruses – an overview.
        Infect Ecol Epidemiol. 2013; 3: 19839https://doi.org/10.3402/iee.v3i0.19839
        • Soo K.-M.
        • Khalid B.
        • Ching S.-M.
        • Chee H.-Y.
        Meta-analysis of dengue severity during infection by different dengue virus serotypes in primary and secondary infections.
        PLoS One. 2016; 11e0154760https://doi.org/10.1371/journal.pone.0154760
        • Green S.
        • Rothman A.
        Immunopathological mechanisms in dengue and dengue hemorrhagic fever.
        Curr Opin Infect Dis. 2006; 19: 429-436https://doi.org/10.1097/01.qco.0000244047.31135.fa
        • Hadinegoro S.R.S.
        The revised WHO dengue case classification: does the system need to be modified?.
        Paediatr Int Child Health. 2013; 32: 33-38https://doi.org/10.1179/2046904712Z.00000000052
        • Jayarajah U.
        • Faizer S.
        • de zoysa I.
        • Seneviratne P.S.
        A large dengue epidemic affects Sri Lanka.
        . 2017; 6 (2017): 84-86
        • Ebi K.L.
        • Nealon J.
        Dengue in a changing climate.
        Environ Res. 2016; 151: 115-123https://doi.org/10.1016/j.envres.2016.07.026
        • Zhang F.
        • Kramer C.V.
        Corticosteroids for dengue infection. Cochrane infectious diseases group.
        Cochrane Database Syst Rev. 2014; 85: 525https://doi.org/10.1002/14651858.CD003488.pub3
        • Bandara S.M.R.
        • Herath H.M.M.T.B.
        Effectiveness of corticosteroid in the treatment of dengue – a systemic review.
        Heliyon. 2018; 4e00816https://doi.org/10.1016/j.heliyon.2018.e00816
        • Tam D.T.H.
        • Ngoc T.V.
        • Tien N.T.H.
        • et al.
        Effects of short-course oral corticosteroid therapy in early dengue infection in Vietnamese patients: a randomized, placebo-controlled trial.
        Clin Infect Dis. 2012; 55: 1216-1224https://doi.org/10.1093/cid/cis655
        • Nguyen T.H.T.
        • Nguyen T.H.Q.
        • Vu T.T.
        • et al.
        Corticosteroids for dengue – why don't they work? Halstead SB.
        PLoS Neglected Trop Dis. 2013; 7e2592https://doi.org/10.1371/journal.pntd.0002592
        • Tassniyom S.
        • Vasanawathana S.
        • Chirawatkul A.
        • Rojanasuphot S.
        Failure of high-dose methylprednisolone in established dengue shock syndrome: a placebo-controlled, double-blind study.
        Pediatrics. 1993; 92: 111-115
        • Premaratna R.
        • Jayasinghe K.G.N.U.
        • Liyanaarachchi E.W.
        • Weerasinghe O.M.S.
        • Pathmeswaran A.
        • de Silva H.J.
        Effect of a single dose of methyl prednisolone as rescue medication for patients who develop hypotensive dengue shock syndrome during the febrile phase: a retrospective observational study.
        Int J Infect Dis. 2011; 15: e433-e434https://doi.org/10.1016/j.ijid.2011.03.006
        • Flores A.Y.L.
        • Tapia M.P.
        • Garcia I.E.
        • et al.
        Dengue virus inoculation to human skin explants: an effective approach to assess in situ the early infection and the effects on cutaneous dendritic cells.
        Int J Exp Pathol. 2005; 86: 323-334https://doi.org/10.1111/j.0959-9673.2005.00445.x
        • Durbin A.P.
        • Vargas M.J.
        • Wanionek K.
        • et al.
        Phenotyping of peripheral blood mononuclear cells during acute dengue illness demonstrates infection and increased activation of monocytes in severe cases compared to classic dengue fever.
        Virology. 2008; 376: 429-435https://doi.org/10.1016/j.virol.2008.03.028
        • Blackley S.
        • Kou Z.
        • Chen H.
        • et al.
        Primary human splenic macrophages, but not T or B cells, are the principal target cells for dengue virus infection in vitro.
        J Virol. 2007; 81: 13325-13334https://doi.org/10.1128/JVI.01568-07
        • Lozach P.-Y.
        • Burleigh L.
        • Staropoli I.
        • et al.
        Dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN)-mediated enhancement of dengue virus infection is independent of DC-SIGN internalization signals.
        J Biol Chem. 2005; 280: 23698-23708https://doi.org/10.1074/jbc.M504337200
        • Boonnak K.
        • Slike B.M.
        • Burgess T.H.
        • et al.
        Role of dendritic cells in antibody-dependent enhancement of dengue virus infection.
        J Virol. 2008; 82: 3939-3951https://doi.org/10.1128/JVI.02484-07
        • Pokidysheva E.
        • Zhang Y.
        • Battisti A.J.
        • et al.
        Cryo-EM reconstruction of dengue virus in complex with the carbohydrate recognition domain of DC-SIGN.
        Cell. 2006; 124: 485-493https://doi.org/10.1016/j.cell.2005.11.042
        • Tirado S.M.C.
        • Yoon K.-J.
        Antibody-dependent enhancement of virus infection and disease.
        Viral Immunol. 2003; 16: 69-86https://doi.org/10.1089/088282403763635465
        • Palmer D.R.
        • Sun P.
        • Celluzzi C.
        • et al.
        Differential effects of dengue virus on infected and bystander dendritic cells.
        J Virol. 2005; 79: 2432-2439https://doi.org/10.1128/JVI.79.4.2432-2439.2005
        • Henrickson S.E.
        • Mempel T.R.
        • Mazo I.B.
        • et al.
        T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation.
        Nat Immunol. 2008; 9: 282-291https://doi.org/10.1038/ni1559
        • Nielsen D.G.
        The relationship of interacting immunological components in dengue pathogenesis.
        Virol J. 2009; 6: 211https://doi.org/10.1186/1743-422X-6-211
        • Armitage R.J.
        • Macduff B.M.
        • Eisenman J.
        • Paxton R.
        • Grabstein K.H.
        IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation.
        J Immunol. 1995; 154: 483-490
      1. Vanderheyde N, Verhasselt V, Goldman M, Willems F. Inhibition of human dendritic cell functions by methylprednisolone. Transplantation. 67(10):1342.

        • Piemonti L.
        • Monti P.
        • Allavena P.
        • et al.
        Glucocorticoids affect human dendritic cell differentiation and maturation.
        J Immunol. 1999; 162: 6473-6481
        • Wong P.
        • Cuello C.
        • Bertouch J.V.
        • et al.
        The effects of pulse methylprednisolone on matrix metalloproteinase and tissue inhibitor of metalloproteinase‐1 expression in rheumatoid arthritis.
        Rheumatology. 2000; 39: 1067-1073https://doi.org/10.1093/rheumatology/39.10.1067
        • Moore K.W.
        • de Waal Malefyt R.
        • Coffman R.L.
        • O'Garra A.
        Interleukin-10 and the interleukin-10 receptor.
        Ann. Rev. 2003; 19: 683-765https://doi.org/10.1146/annurev.immunol.19.1.683
        • Hodge Flower
        Han. Methyl-prednisolone up-regulates monocyte interleukin-10 production in stimulated whole blood.
        Scand J Immunol. 1999; 49: 548-553https://doi.org/10.1046/j.1365-3083.1999.00538.x
        • Coutinho A.E.
        • Chapman K.E.
        The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights.
        Mol Cell Endocrinol. 2011; 335: 2-13https://doi.org/10.1016/j.mce.2010.04.005
        • Santini G.
        The human pharmacology of monocyte cyclooxygenase 2 inhibition by cortisol and synthetic glucocorticoids.
        Clin Pharmacol Ther. 2001; 70: 475-483https://doi.org/10.1067/mcp.2001.119213
        • Steer S.A.
        • Corbett J.A.
        The role and regulation of COX-2 during viral infection.
        Viral Immunol. 2003; 16: 447-460https://doi.org/10.1089/088282403771926283
        • Lin C.-K.
        • Tseng C.-K.
        • Wu Y.-H.
        • et al.
        Cyclooxygenase‐2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents.
        Sci Rep. 2017; 7: 299https://doi.org/10.1038/srep44701
        • Tirado S.M.C.
        • Yoon K.-J.
        Antibody-dependent enhancement of virus infection and disease.
        Viral Immunol. 2004; 16: 69-86https://doi.org/10.1089/088282403763635465
        • Chau T.N.B.
        • Hieu N.T.
        • Anders K.L.
        • et al.
        Dengue virus infections and maternal antibody decay in a prospective birth cohort study of Vietnamese infants.
        J Infect Dis. 2009; 200: 1893-1900https://doi.org/10.1086/648407
        • Chau T.N.B.
        • Quyen N.T.H.
        • Thuy T.T.
        • et al.
        Dengue in Vietnamese infants--results of infection-enhancement assays correlate with age-related disease epidemiology, and cellular immune responses correlate with disease severity.
        J Infect Dis. 2008; 198: 516-524https://doi.org/10.1086/590117
        • Swain S.L.
        • McKinstry K.K.
        • Strutt T.M.
        Expanding roles for CD4+ T cells in immunity to viruses.
        Nat Rev Immunol. 2012; 12: 136-148https://doi.org/10.1038/nri3152
        • Weiskopf D.
        • Sette A.
        T-cell immunity to infection with dengue virus in humans.
        Front Immunol. 2014; 5: 571https://doi.org/10.3389/fimmu.2014.00093
        • Kontny U.
        • Kurane I.
        • Ennis F.A.
        Gamma interferon augments Fc gamma receptor-mediated dengue virus infection of human monocytic cells.
        J Virol. 1988; 62: 3928-3933
        • de Matos A.M.
        • Carvalho K.I.
        • Rosa D.S.
        • et al.
        CD8+ T lymphocyte expansion, proliferation and activation in dengue fever.
        in: PLOS Neglected Tropical Diseases. vol. 9. 2015e0003520https://doi.org/10.1371/journal.pntd.0003520 (2)
        • Coutinho A.E.
        • Chapman K.E.
        The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights.
        Mol Cell Endocrinol. 2011; 335: 2-13https://doi.org/10.1016/j.mce.2010.04.005
        • Hart K.A.
        • Barton M.H.
        • Vandenplas M.L.
        • Hurley D.J.
        Effects of low-dose hydrocortisone therapy on immune function in neonatal horses.
        Pediatr Res. 2011; 70 (1971 5:7): 72-77https://doi.org/10.1203/PDR.0b013e31821b502b
        • Avirutnan P.
        • Zhang L.
        • Punyadee N.
        • et al.
        Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E.
        PLoS Pathog. 2007; 3: e183https://doi.org/10.1371/journal.ppat.0030183
        • Modhiran N.
        • Watterson D.
        • Muller D.A.
        • et al.
        Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity.
        Sci Transl Med. 2015; 7 (304ra142-304ra142)https://doi.org/10.1126/scitranslmed.aaa3863
        • Modhiran N.
        • Watterson D.
        • Blumenthal A.
        • Baxter A.G.
        • Young P.R.
        • Stacey K.J.
        Dengue virus NS1 protein activates immune cells via TLR4 but not TLR2 or TLR6.
        Immunol Cell Biol. 2017; 95: 491-495https://doi.org/10.1038/icb.2017.5
        • Avirutnan P.
        • Punyadee N.
        • Noisakran S.
        • et al.
        Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement.
        J Infect Dis. 2006; 193: 1078-1088https://doi.org/10.1086/500949
        • Broering R.
        • Montag M.
        • Jiang M.
        • et al.
        Corticosteroids shift the Toll-like receptor response pattern of primary-isolated murine liver cells from an inflammatory to an anti-inflammatory state.
        Int Immunol. 2011; 23: 537-544https://doi.org/10.1093/intimm/dxr048
        • Lin C.-F.
        • Wan S.-W.
        • Cheng H.-J.
        • Lei H.-Y.
        • Lin Y.-S.
        Autoimmune pathogenesis in dengue virus infection.
        Viral Immunol. 2006; 19: 127-132https://doi.org/10.1089/vim.2006.19.127
        • Lin C.F.
        • Lei H.Y.
        • Shiau A.L.
        • et al.
        Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide.
        J Immunol. 2002; 169 (2215-2215)https://doi.org/10.4049/jimmunol.169.4.2215
        • Elsabahy M.
        • Wooley K.L.
        Cytokines as biomarkers of nanoparticle immunotoxicity.
        Chem Soc Rev. 2013; 42: 5552https://doi.org/10.1039/c3cs60064e
        • Meßmer U.K.
        • Winkel G.
        • Briner V.A.
        • Pfeilschifter J.
        Suppression of apoptosis by glucocorticoids in glomerular endothelial cells: effects on proapoptotic pathways.
        Br J Pharmacol. 2000; 129: 1673-1683https://doi.org/10.1038/sj.bjp.0703255
        • Harboe M.
        • Mollnes T.E.
        The alternative complement pathway revisited.
        J Cell Mol Med. 2008; 12: 1074-1084https://doi.org/10.1111/j.1582-4934.2008.00350.x
        • Shresta S.
        Role of complement in dengue virus infection: protection or pathogenesis?.
        mBio. 2012; 3: 476https://doi.org/10.1128/mBio.00003-12
        • Madsen H.O.
        • Garred P.
        • Kurtzhals J.A.L.
        • et al.
        A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein.
        Immunogenetics. 1994; 40: 37-44https://doi.org/10.1007/BF00163962
        • Basta M.
        Ambivalent effect of immunoglobulins on the complement system: activation versus inhibition.
        Mol Immunol. 2008; 45: 4073-4079https://doi.org/10.1016/j.molimm.2008.07.012
        • Yamanaka A.
        • Hendrianto E.
        • Mulyatno K.C.
        • et al.
        Correlation between complement component levels and disease severity in dengue patients in Indonesia.
        Jpn J Infect Dis. 2013; 66: 366-374https://doi.org/10.7883/yoken.66.366
        • He S.-H.
        • Zhang H.-Y.
        • Zeng X.-N.
        • Chen D.
        • Yang P.-C.
        Mast cells and basophils are essential for allergies: mechanisms of allergic inflammation and a proposed procedure for diagnosis.
        Acta Pharmacol Sin. 2013; 34: 1270-1283https://doi.org/10.1038/aps.2013.88
        • Weiler J.M.
        • Packard B.D.
        Methylprednisolone inhibits the alternative and amplification pathways of complement.
        Infect Immun. 1982; 38: 122-126
        • Hammerschmidt D.E.
        • White J.G.
        • Craddock P.R.
        • Jacob H.S.
        Corticosteroids inhibit complement-induced granulocyte aggregation. A possible mechanism for their efficacy in shock states.
        J Clin Investig. 1979; 63: 798-803https://doi.org/10.1172/JCI109365
        • Azeredo EL de
        • Monteiro R.Q.
        • de-Oliveira Pinto L.M.
        Thrombocytopenia in dengue: interrelationship between virus and the imbalance between coagulation and fibrinolysis and inflammatory mediators.
        Mediat Inflamm. 2015; 2015: 1-16https://doi.org/10.1155/2015/313842
        • Wang S.
        • He R.
        • Patarapotikul J.
        • Innis B.L.
        • Anderson R.
        Antibody-enhanced binding of dengue-2 virus to human platelets.
        Virology. 1995; 213: 254-257https://doi.org/10.1006/viro.1995.1567
        • Bozza F.A.
        • Cruz O.G.
        • Zagne S.M.O.
        • et al.
        Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity.
        BMC Infect Dis. 2008; 8: 86https://doi.org/10.1186/1471-2334-8-86
        • Wills B.A.
        • Oragui E.E.
        • Minh Dung N.
        • et al.
        Size and charge characteristics of the protein leak in dengue shock syndrome.
        J Infect Dis. 2004; 190: 810-818https://doi.org/10.1086/422754
        • Palmer R.N.
        • Rick M.E.
        • Rick P.D.
        • Zeller J.A.
        • Gralnick H.R.
        Circulating heparan sulfate anticoagulant in a patient with a fatal bleeding disorder.
        N Engl J Med. 1984; 310: 1696-1699https://doi.org/10.1056/NEJM198406283102603
        • Nehmé A.
        • Edelman J.
        Dexamethasone inhibits high glucose-, TNF-alpha-, and IL-1beta-induced secretion of inflammatory and angiogenic mediators from retinal microvascular pericytes.
        Investig Ophthalmol Vis Sci. 2008; 49: 2030-2038https://doi.org/10.1167/iovs.07-0273
        • Chopra A.
        • Kumar R.
        • Kishore K.
        • et al.
        Effect of glucocorticoids on von Willebrand factor levels and its correlation with von Willebrand factor gene promoter polymorphism.
        Blood Coagul Fibrinolysis. 2012; 23: 514-519https://doi.org/10.1097/MBC.0b013e3283548dfc
        • Mukerjee R.
        • Chaturvedi U.C.
        • Dhawan R.
        Dengue virus-induced human cytotoxic factor: production by peripheral blood leucocytes in vitro.
        Clin Exp Immunol. 1995; 102: 262-267
        • Murohara T.
        • Horowitz J.R.
        • Silver M.
        • et al.
        Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin.
        Circulation. 1998; 97: 99-107https://doi.org/10.1161/01.CIR.97.1.99
        • Cirino G.
        Multiple controls in inflammation: extracellular and intracellular phospholipase A2, inducible and constitutive cyclooxygenase, and inducible nitric oxide synthase.
        Biochem Pharmacol. 1998; 55: 105-111https://doi.org/10.1016/S0006-2952(97)00215-3
        • Gille J.
        • Reisinger K.
        • Westphal-Varghese B.
        • Kaufmann R.
        Decreased mRNA stability as a mechanism of glucocorticoid-mediated inhibition of vascular endothelial growth factor gene expression by cultured keratinocytes.
        J Investig Dermatol. 2001; 117: 1581-1587https://doi.org/10.1046/j.0022-202x.2001.01573.x
        • Valone F.H.
        • Epstein L.B.
        Biphasic platelet-activating factor synthesis by human monocytes stimulated with IL-1-beta, tumor necrosis factor, or IFN-gamma.
        J Immunol. 1988; 141: 3945-3950
        • Yang K.D.
        • Lee C.S.
        • Shaio M.F.
        A higher production of platelet activating factor in ex vivo heterologously secondary dengue-2 virus infections.
        Acta Microbiol Immunol Hung. 1995; 42: 403-407
        • Hue C.D.
        • Cho F.S.
        • Cao S.
        • Dale Bass C.R.
        • Meaney D.F.
        • Morrison B.
        Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein.
        J Cereb Blood Flow Metab. 2015; 35: 1191-1198https://doi.org/10.1038/jcbfm.2015.38
        • Boschetto P.
        • Musajo F.G.
        • Tognetto L.
        • et al.
        Increase in vascular permeability produced in rat airways by PAF: potentiation by adrenalectomy.
        Br J Pharmacol. 1992; 105: 388-392https://doi.org/10.1111/(ISSN)1476-5381
        • Aikawa T.
        • Hirose T.
        • Matsumoto I.
        • et al.
        Effect of platelet-activating factor on cortisol and corticosterone secretion by perfused dog adrenal.
        in: Platelet-Activating Factor and Structurally Related Alkyl Ehter Lipids. vol. 101. AOCS Publishing, 2009: 1108-1111https://doi.org/10.1201/9781439832042.ch27