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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.
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.
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)
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.
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,
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
Dengue in Vietnamese infants--results of infection-enhancement assays correlate with age-related disease epidemiology, and cellular immune responses correlate with disease severity.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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,
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.
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.
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.
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.
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.
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.
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. 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).
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.
Hematological abnormalities that are generally observed in severe dengue, such as thrombocytopenia, coagulopathy, bleeding and vasculopathy are related to platelet and endothelial dysfunction.
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.
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).
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.
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.
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.
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.
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.
Multiple controls in inflammation: extracellular and intracellular phospholipase A2, inducible and constitutive cyclooxygenase, and inducible nitric oxide synthase.
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.
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.
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.
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.
Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein.
Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein.
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,
Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein.
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.
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.
Dengue virus inoculation to human skin explants: an effective approach to assess in situ the early infection and the effects on cutaneous dendritic cells.
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.
Dengue in Vietnamese infants--results of infection-enhancement assays correlate with age-related disease epidemiology, and cellular immune responses correlate with disease severity.
Corticosteroids shift the Toll-like receptor response pattern of primary-isolated murine liver cells from an inflammatory to an anti-inflammatory state.
Dexamethasone inhibits high glucose-, TNF-alpha-, and IL-1beta-induced secretion of inflammatory and angiogenic mediators from retinal microvascular pericytes.
Multiple controls in inflammation: extracellular and intracellular phospholipase A2, inducible and constitutive cyclooxygenase, and inducible nitric oxide synthase.
Decreased mRNA stability as a mechanism of glucocorticoid-mediated inhibition of vascular endothelial growth factor gene expression by cultured keratinocytes.
Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein.
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