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  • 1. Peran Antigen NS1 Dengue Untuk Diagnosis Infeksi Virus Dengue
    Oleh: T.Elfin W.
    Pembimbing : Aryati
    1
    Tinjauan Pustaka Penyakit Infeksi
    1
  • 2. Pendahuluan
    2
    ANGKA KEJADIAN DAN INSIDEN
    DemamBerdarah Dengue (DBD)
    TH. 2008
    DinkesTk.IJatim
    2.145 orang
    10 org meninggal
    75,50/100.000 penduduk
    CFR 0,47 %
    16.589 orang
    165 org meninggal
    44,68 /100.000 penduduk
    CFR 0,99 %
    Jatim
    Surabaya
    2
  • 3. Sulit
    diagnosis
    Tidakkhas
    Manifestasi
    klinis
    Pendahuluan …
    Infeksi virus dengue
    penyakit flu, demam tifoid, demam
    chikungunya, leptospirosis, malaria
    Peran NS1 dengue
    Terutamapadamasaawaldemam (3-4 hari)
    Beragam : asimtomatik, undifferentiated febrile illness, demam dengue, demam berdarah dengue (DBD) ,perembesan plasmasyok hipovolemik (SSD),kematian
    Manifestasi
    laboratoris
    Trombositopenia ringan sampai dengan berat,
    berbagai kombinasi kehadiran IgG dan IgM dan variasi kadar sitokin.
    3
    3
  • 4. 4
    DEN 3
    Virus dengue
    DEN 2
    DEN 1
    DEN 4
    Struktur virus dengue
    4
  • 5. Struktur Virus dengue…
    5
    Gambar . Sketsa Genom RNA Virus Dengue.
    Gambar. Sketsa Virion Virus Dengue
    5
  • 6. Struktur Virus dengue…
    glikoprotein 46-50 kDa
    terdapat di intraselular, permukaan sel (membrane-associated /mNS1 ) & secreted form (sNS1)
    bentuk homodimer, partially hydrophobic nature
    bukan bagian dari struktur virus
    diekspresikan pada permukaan sel yang terinfeksi
    1 dari 7 protein NS yang dihasilkan selama replikasi virus
    protein yang disekresikan melalui cellular secretory pathway ke permukaan sel
    6
    antigen NS1 dengue
    6
  • 7. 7
    Gambar: Siklus hidup virus dengue dalam sel.
    Role of T cells, cytokines and antibody in dengue fever and dengue haemorrhagic fever. Rev. Med. Virol. 2006; 16: 263–275.
  • 8. 8
    Struktur Virus dengue…
    tidak menunjukkan perbedaan pada infeksi primer maupun sekunder, dan beberapa kasus masih (+) pada fase konvalesen
    marker deteksi dini infeksi dengue primer-sekunder
    Antigen NS1
    ditemukan dalam sirkulasi darah selama fase akut infeksi virus dengue
    protein non-struktural yang disekresikan di permukaan sel terinfeksi
    8
  • 9. Keuntungan pemeriksaan antigen NS1  deteksi infeksi dengue pada fase awal demam (hari ke-1 sampai ke-9 sakit), tanpa menunggu terbentuknya antibodi.
    Sensitivitas pemeriksaan NS1 (88,7%) lebih tinggi dibandingkan kultur virus (68,1%) dan RT-PCR (66,7%).
    Pemeriksaan IgG dan IgM antidengue tetap diperlukan untuk membedakan infeksi primer atau infeksi sekunder
    9
    9
  • 10. Patogenesis
    Virus dengue masuk ke dalam tubuh manusia lewat gigitan nyamuk Aedes aegypti atau Aedes albopictus. Organ sasaran dari virus adalah organ RES meliputi sel kupffer hepar, endotel pembuluh darah, nodus limfaticus, sumsum tulang, serta paru-paru. Dalam peredaran darah, virus tersebut akan difagosit oleh sel monosit perifer.
    10
    10
  • 11. 11
    Gambar: Imunopatogenesis dari DHF.
    Immunopathological mechanisms in dengue and dengue hemorrhagic fever
    Current Opinion in Infectious Diseases 2006, 19:429–436
  • 12. 12
    ManifestasiKlinisInfeksi Virus Dengue
    Infeksi Virus Dengue
    Asimtomatik
    Simtomatik
    Demam Dengue
    Demamtidakspesifik
    Perdarahan (-)
    Perdarahan (+)
    Syok (+)
    Syok (-)
    DD
    DBD
    12
  • 13. Gambar : Kurva saddle back fever
    13
    13
  • 14. Diagnosis
    14
    14
  • 15. Diagnosis
    15
    15
  • 16. Diagnosis…
    16
    Derajatberatringannyamanifestasiklinis
    16
  • 17. Pemeriksaan Antigen NS1
    Pemeriksaan yang cepat, sensitif dan spesifik diperlukan untuk mendiagnosis demam dengue selama fase demam
    Sensitivitas 93,4% dan spesifisitas 100 % (Kurasamy, 2006)
    Sensitivitas 63 % dan spesifisitas 100% (Blacksell, 2008)
    17
    17
  • 18. Kit Pemeriksaan NS1
    1
    3
    2
    Panbio
    SD Diagnostik
    Biorad
    18
    18
  • 19. Pemeriksaan Antigen NS1 Metode ELISA
    NS1 antigen-capture ELISA
    Prinsip pemeriksaan: one-step sandwich ELISA dengan serum atau plasma penderita.
    Menggunakan Monoclonal antibody (Mab) murine sebagai capture.
    Jika terdapat antigen NS1 pada sampel, akan terbentuk komplek imun Mab-NS1-Mab/ peroksidase.
    19
    19
  • 20. 20
    Prosedur pemeriksaan antigen NS1 dengue (contoh: Platelia TM dari BIO-Rad).
    20
  • 21. 21
    Pemeriksaan NS1 denganImmuno Chromatography Test
    A B C D
    Serum 50µL Buffer 1 tetes masukkan strip tunggu 15 menit
    Gambar . Prosedur pemeriksaan Dengue NS1 Ag STRIP
    21
  • 22. Kesimpulan
    22
    22
  • 23. 23
    Marketing Diagram
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    Terima kasih
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    23
  • 24. 24
    Structural proteomics of dengue virus.
    Current Opinion in Microbiology 2008, 11:369–377
    24
  • 25. 25
    Figure: Colour-enhanced transmission electron micrograph of dengue virus.
    Severe dengue: the need for new case definitions. Lancet Infect Dis 2006; 6: 297–302
  • 26. Gambar 5. Struktur Virion Virus dengue dan konfirmasi protein prM , E
    26
    26
  • 27. 1
    1
    1
    1
    1
    Homologous Antibodies Form
    Non-infectious Complexes
    Dengue 1 virus
    Neutralizing antibody to Dengue 1 virus
    Non-neutralizing antibody
    Complex formed by neutralizing antibody and virus
    27
    27
  • 28. 2
    2
    2
    2
    2
    2
    Heterologous Antibodies Form Infectious Complexes
    Dengue 2 virus
    Non-neutralizing antibody to Dengue 1 virus
    Complex formed by non-neutralizing antibody and virus
    28
    28
  • 29. 2
    2
    2
    2
    2
    2
    2
    2
    2
    2
    2
    2
    Heterologous Complexes Enter More Monocytes, Where Virus Replicates
    Dengue 2 virus
    29
    Non-neutralizing antibody
    Complex formed by non-neutralizing antibody and Dengue 2 virus
    29
  • 30. 30
    Dengue
    Derajatkeparahan (WHO)
    Demam
    Perdarahan
    Permeabilitas pembuluh darah meningkat
    Kerusakan hemostasis
    I
    Trombositopenia
    Coagulopathy
    Plasma Leakage
    Hemokonsentrasi
    II
    Hipovolemik
    perdarahan
    Circulatory colapase
    III
    Syok
    IV
    meninggal
    Gambar . Derajat keparahan infeksi dengue
    30
  • 31. 31
    31
  • 32. 32
    Dengue haemorrhagic fever. Diagnosis, treatment, prevention and control. SECOND EDITION. World Health Organization. Geneva 1997
    32
  • 33. 33
    33
  • 34. 34
  • 35. 35
  • 36. 36
  • 37. 37
    Schema for the differential diagnosis of dengue-like diseases based on clinical dengue illness day
    Military Preventive Medicine: Mobilization and Deployment, Volume 2
    37
  • 38. 38
    VIRUSES AND HUMAN DISEASE 2002. JAMES H. STRAUSS. ELLEN G. STRAUSS. Division of Biology california Institute of Technology Pasadena, California
  • 39. 39
    Dengue viral infections. Postgrad Med J 2004;80:588–601.
  • 40. 40
    Dengue viral infections. Postgrad Med J 2004;80:588–601.
  • 41. 41
  • 42. 42
    Macrophage & dengue virus: Friend or foe? Indian J Med Res 124, July 2006, pp 23-40
  • 43. 43
  • 44. 44
    Macrophage & dengue virus: Friend or foe? Indian J Med Res 124, July 2006, pp 23-40
  • 45. 45
  • 46. 46
  • 47. 47
    Rev. Med. Virol. 2006; 16: 263–275.
  • 48. 48
    Pathogenesis of dengue virus infection. DENV initially infects a cell of the dendritic cell/macrophage/monocyteline (reviewed in reference 5) via receptor-mediated endocytosis and/or enhanced uptake via antibody-virus complexes attached to Fcγreceptors (reviewed in references 5 and 73). TNF-α(22, 52) and NO (24, 141) are produced primarily by infected monocytes/macrophages and activate endothelial cells, which can contribute to increased vascular permeability (reviewed in reference 17). Changes in vascular permeability in DENV infections have classically been measured by monitoring levels of albumin in the plasma (195). IFN-γis produced primarily by NK and CD8+ T cells and activates macrophages as well as CD4+ T cells (17). High levels of DENV and sNS1 circulate in the bloodstream (9, 114), and both have been shown to circulate as immune complexes as well. FcγR, Fc gamma receptor
    Recent Advances in Deciphering Viral and Host Determinants of Dengue Virus Replication and Pathogenesis. JOURNAL OF VIROLOGY, Dec. 2006, p. 11418–11431
  • 49. 49
    The early contact of DV with the host. DV enters through skin during the mosquito feeding, and DCs are the prime immune cells at the early times of dengue infection. Infected DCs into the dermis migrate to regional lymph nodes along with their maturation process. Innate Immune Responses to Dengue Virus. Navarro-Sa ´nchez et al. /Archives of Medical Research 36 (2005) 425–435
  • 50. 50
    Figure . Innate immune encounter upon virus injection in the capillary vessel. There are several immune-related components circulated in the capillary, which is surrounded by multiple cell layers. The enlarged circle indicates the mosquito’s probing site. Prior to the feeding process,mosquito saliva-containing factors (e.g., apyrases) and virus are released into the blood stream. A color figure is available in the online version.
    Alternate Hypothesis on the Pathogenesis of Dengue Hemorrhagic Fever (DHF)/ Dengue Shock Syndrome (DSS) in Dengue Virus Infection. MINIREVIEW. Accepted October 14, 2007.
  • 51. 51
    MINIREVIEW.
    Accepted October 14, 2007.
  • 52. 52
    A hypothetical model of autoimmunity in dengue pathogenesis. Severe thrombocytopenia, plasma leakage, bleeding tendency, and hepatomegaly are the hallmarks of DHF/DSS. Viral pathogenesis and immunopathogenesis of DV infection are the causes of DHF/DSS in DV infection. Increased virus load by ADE and virus variation may directly cause an effect. In addition, immunopathogenesis by DV-induced inflammatory activation and autoimmunity may be involved in dengue pathogenesis. Our findings suggest that a mechanism of molecular mimicry is responsible for the induction of autoimmunity in DV infection. Autoimmune Pathogenesis in Dengue Virus Infection. VIRAL IMMUNOLOGY. Volume 19, Number 2, 2006
  • 53. 53
    Dengue viral infections. G N Malavige, S Fernando, D J Fernando, S L Seneviratne Postgrad Med J 2004;80:588–601.
  • 54. 54
    Dengue: an escalating problem. BMJ 2002;324:1563–6
  • 55. 55
    VIRUSES AND HUMAN DISEASE. JAMES H. STRAUSS. ELLEN G. STRAUSS. Division of Biology california Institute of Technology Pasadena, California
  • 56. 56
  • 57. 57
    Report of the Scientific Working Group on Dengue, 2006
  • 58. 58
    www.thelancet.com Vol 370 November 10, 2007
  • 59. 59
    Dengue: an arthropod-borne disease of global importance. Eur J Clin Microbiol Infect Dis (2004) 23: 425–433
  • 60. 60
    Immune mediated and inherited defences against flaviviruse. Clinical and Diagnostic Virology 10 (1998) 129–139
  • 61. 61
    Dengue viral infections. Postgrad Med J 2004;80:588–601.
  • 62. 62
    Atypical manifestations of dengue.
    Tropical Medicine and International Health. volume 12 no 9 pp 1087–1095 september 2007
  • 63. 63
    Dengue hemorrhagic fever with special emphasis on immunopathogenesis.
    Comparative Immunology, Microbiology & Infectious Diseases 30 (2007) 329–340
  • 64. 64
  • 65. 65
    Endothelial cells in infection. Normal endothelium produces inhibitors of blood coagulation such as thrombomodulin, heparan sulphate, and plasminogen activators. Non-thrombogenic properties are lost when endothelial cells are stimulated by microorganisms (dengue virus?) and/or mediators (ie, cytokines). Plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor (vWF), and tissue factor (TF), the critical inducer of in vivo coagulation, are expressed. F1 and F2=prothrombin fragments 1 and 2; VIIa/TF=activated factor VII/tissue factor complex; Xa/Va=activated factor X/activated factor V complex; IXa/VIIIa=activated factor IX/activated VIII complex.
  • 66. Thank You !
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    66