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

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

  3. 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

  4. DENGUE (cont’d) • Dengue virus (DEN) is a member of the Flavivirus genus inthe Flaviviridae family of single-stranded, positive-polarity, envelopedRNA 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. 2001.

  5. Dengue Virus Electron Micrograms

  6. 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. 2008

  7. 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.

  8. 1 2 3 4 3 HOW DENGUE SPREADS • 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

  9. Transmission of Dengue Virus by Aedes aegypti

  10. 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

  11. 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

  12. 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

  13. P E T E C H I A E

  14. P U R P U R A

  15. E C C H Y M O S I S


  17. 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

  18. IMMUNE RESPONSE Stephenson, 2005

  19. 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

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

  21. IMMUNO PATHOGENECITY • Dengue viruses replicate within thecytoplasmof infected cells after receptor-mediated entry • The known sites of viral replicationin vivo are leukocytes, especially circulating Bcells, Kupffer cells, and tissue macrophages outsideof the neuroaxis • Infection of dendritic cells by dengueviruses may play an important role in diseasepathogenesis Magill, 2005

  22. 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 hemostaticdefects that occur in DHF Magill, 2005

  23. 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

  24. Homologous Antibodies Form Non-Infectious Complexes

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

  26. Heterologous Antibodies Form Infectious Complexes

  27. Hypothesis on Pathogenesis of DHF-DSS 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.

  28. Heterologous Complexes Enter More Monocytes, Where Virus Replicates

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

  30. 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

  31. (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. 2004

  32. (Jamuna vadivelue 2007) Cytotoxic T lymphocytes (CTL) play an important role in theelimination of dengue virus-infected cells. Identificationof antigenic peptides recognized by dengue virus-specific CTLmay suggest new ways to suppress viral replication and preventpersistent infection Jamuna vadivelue 2007

  33. (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

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

  35. 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

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

  37. Thank Youfor Your Attention