FEVER DENGUE VIRUS: NO ONE IS SAFE Prepared by: Mohamed Abdul Gader

Alternative Names West Nile Fever Break Bone Fever Dengue like Disease Onyong- Nyang Fever

WHAT IS DENGUE ? Dengue is an arthropod-borne disease caused by any one of four closely related viruses. Infection with one serotype of dengue virus provides immunity to that serotype for life. A person can be infected as many as four times, once with each serotype. Holly R. Hughes 2009

DENGUE (cont’d) Dengue virus (DEN) is a member of the Flavivirus genus in the Flaviviridae family of single-stranded, positive-polarity, enveloped RNA viruses. Dengue viruses are transmitted from person to person by Aedes mosquitoes (most often Aedes aegypti) in the domestic environment. Burke, D. S., and T. P. Monath

Dengue Virus Electron Micrograms

About 50–100 million cases of dengue fever and 500,000 cases of Dengue Hemorrhagic Fever (DHF), resulting in around 24,000 deaths, are reported annually. dengue is often found in urban areas of tropical nations, including Puerto Rico, Singapore, Malaysia, Taiwan, Thailand, Indonesia, Philippines, Pakistan, India, Brazil, Vietnam, Guyana, Venezuela, Bangladesh

Dengue’s vectors are two types of Aedes mosquitoes; Aedes aegypti and Aedes albopictus. However, it is the Aedes aegypti species that is most notorious for transmitting dengue.

1.Mosquitoes transmit dengue to human dendritic cells 2. Dengue targets areas with high WBC counts (liver, spleen, lymph nodes, bone marrow, and glands) 3. Dengue enters WBCs & lymphatic tissue 4. Dengue enters blood circulation HOW DENGUE SPREADS

Transmission of Dengue Virus by Aedes aegypti

DENGUE (cont’d)  Three Manifestations: 1. Dengue Fever 2. Dengue Hemorrhagic Fever 3. Dengue Shock Syndrome  Leads to death in 5% of cases  More dangerous if infected second time by different serotype

Dengue Fever Dengue Fever is an acute febrile illness of 2-7 days duration (sometimes with two peaks) with two or more of the following manifestations: Headache retro -orbital pain myalgia/arthralgia rash haemorrhagic manifestation (petechiae and positive tourniquet test). leukopenia

Dengue Hemorrhagic Fever (DHF) A severe form of Dengue resulting from a second infection of a different serotype of the virus First serotype … Dengue fever … Recovery Second serotype … Risk of DHF

P E T E C H I A E

P U R P U R A

E C C H Y M O S I S

NASAL HEMORRHAGING

Dengue Shock Syndrome Dengue Shock Syndrome (DSS) All the above criteria of DHF plus signs of circulatory failure manifested by rapid and weak pulse, narrow pulse pressure, hypotension for age, cold and clammy skin and restlessness

IMMUNE RESPONSE Stephenson, 2005

FIRST INFECTION  Humoral and cellular immune response - Ab serum neutralizing levels increase - T-lymphocytes activated by dendritic cells - Memory cells develop antibodies to fight off future infection of same serotype Stephenson, 2005

SECOND INFECTION  Antibody dependent enhancement - Enhancing immunoglobulin G (IgG) antibodies - Fc Receptors Stephenson, 2005

IMMUNO PATHOGENECITY Dengue viruses replicate within the cytoplasm of infected cells after receptor-mediated entry The known sites of viral replication in vivo are leukocytes, especially circulating B cells, Kupffer cells, and tissue macrophages outside of the neuroaxis Infection of dendritic cells by dengue viruses may play an important role in disease pathogenesis Magill, 2005

Continue ….. Infection with one dengue virus type appears to confer lifelong homologous immunity but little to no heterologous immunity Complement is activated, generating vasoactive cleavage products C3a and C5a. Immune activation and the resulting cytokine and complement cascade appear to account for the plasma leakage and hemostatic defects that occur in DHF Magill, 2005

Hypothesis on Pathogenesis of DHF -DSS Persons who have experienced a dengue infection develop serum antibodies that can neutralize the dengue virus of that same (homologous) serotype

Homologous Antibodies Form Non-Infectious Complexes

In a subsequent infection, the pre-existing heterologous antibodies form complexes with the new infecting virus serotype, but do not neutralize the new virus. Hypothesis on Pathogenesis of DHF-DSS

Heterologous Antibodies Form Infectious Complexes

Antibody-dependent enhancement is the process in which certain strains of dengue virus, complexed with non- neutralizing antibodies, can enter a greater proportion of cells of the mononuclear lineage, thus increasing virus production. Hypothesis on Pathogenesis of DHF-DSS

Heterologous Complexes Enter More Monocytes, Where Virus Replicates

Infected monocytes release vasoactive mediators, resulting in increased vascular permeability and hemorrhagic manifestations that characterize DHF and DSS. Hypothesis on Pathogenesis of DHF-DSS

Immunopathogenic Cascade of DHF/DSS Macrophage – monocyte infection Previous infection with heterologous Dengue serotype results in production of non protective antiviral antibodies These Ab bind to the virion’s surface Fc receptor and focus the Dengue virus on to the target cells – macro/monocytes T cell - cytokines, interferon, TNF alpha

(Libraty, D.H., et al. 2004) Elevations of circulating levels of activation markers including soluble TNF receptors, soluble IL-2 receptors, and soluble CD8 have been shown to correlate with disease severity

(Jamuna vadivelue 2007) Cytotoxic T lymphocytes (CTL) play an important role in the elimination of dengue virus-infected cells. Identification of antigenic peptides recognized by dengue virus-specific CTL may suggest new ways to suppress viral replication and prevent persistent infection Jamuna vadivelue 2007

( Chen ST, Lin YL 2008) Dr. Yi-Ling Lin in the Institute of Biomedical Sciences found that dengue virus binds to a human macrophage surface lectin receptor called CLEC5A and stimulates proinflammatory cytokines release. Lin YL 2008

Diagnosis Isolation of dengue virus Increased IgM or IgG antibody titer Dengue antigen detection by immunohistochemistry, immunofluroscence, ELISA PCR leucopenia,thrompocytopenia

Treatment of DF No antiviral agents are of proven value Supportive measures - Vector barrier Avoid Aspirin and Steroids should not be used Fluid replacement to avoid hemoconc. Children below 12 require careful watch for DHF / DSS

DHF / DSS Intensive Care Oxygen Rehydration Barrier Nursing Mosquito Screen Blood or platelet Transfusions

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